WELCOME TO THE NATIONAL HEART,
LUNG AND BLOOD INSTITUTE VIRTUAL
WORKSHOP, SLEEP HEALTH AND
DYSFUNCTION ACROSS THE SPECTRUM
OF PULMONARY VASCULAR DISEASE.
I'M DR. LEI XIAO, PROGRAM
DIRECTOR, DIVISION OF LUNG
DISEASE, OVERSEEING THE
PORTFOLIO, WITH THE ORGANIZING
COMMITTEE FOR THIS WORKSHOP.
ON BEHALF OF THE COMMITTEE AND
NHLBI LUNG DIVISION I WOULD LIKE
TO WELCOME EVERYONE TO THIS
IMPORTANT NHLBI WORKSHOP.
SORRY, CAN SOMEBODY MUTE THEIR
MICROPHONE?
I HEAR SOME NOISE.
ESPECIALLY I WANT TO THANK THOSE
SPEAKERS AND CO-CHAIRS WHO SPENT
MANY HOURS OF PERSONAL TIME
WORKING ON THEIR PRESENTATION.
WE APPRECIATE YOUR EFFORTS AND
CONTRIBUTION.
BEFORE STARTING THE
PRESENTATIONS I WOULD LIKE TO
QUICKLY INTRODUCE SOME OF MY NIH
LUNG DIVISION COLLEAGUES WHO
HAVE BEEN WORKING ON ORGANIZING
THIS WORKSHOP IN THE PAST YEAR.
IF YOU COULD, PLEASE TURN ON
YOUR CAMERA AND LET EVERYONE SEE
YOU WHEN I CALL YOUR NAME.
I'LL START WITH MY COLLEAGUE DR.
ALFONSO ALFINI, AND DR. ROY
SUTLFF AND THE BRANCH CHIEF, NOT
SURE WHETHER HE'S HERE, HE'S
PART OF THE COMMITTEE, ALSO DR.
MARISHKA BROWN, SLEEP CENTER
DIRECTOR, ALONG WITH OUR LUNG
DIVISION DIRECTOR DR. JIM KILEY
WHO WILL GIVE OPENING REMARKS IN
A FEW MINUTES.
I WOULD LIKE TO GIVE A SPECIAL
THANKS TO THE WORKSHOP
COORDINATOR, BRITTANY, AND HER
SUPPORT TEAM WHO HAVE BEEN DOING
ALL THE HEAVY LIFTING, LOGISTIC
WORK FOR SETTING UP THIS
WORKSHOP.
THANK YOU, BRITTANY AND TEAM,
FOR A WONDERFUL JOB WELL DONE.
ANOTHER TWO WORKSHOP COMMITTEE
MEMBERS ARE THE CO-CHAIRS, THE
MAIN DRIVING FORCE FOR THIS
WORKSHOP, YOU MAY KNOW THEM, DR.
SUSAN REDLINE FROM HARVARD
MEDICAL SCHOOL AND DR. ANNA
HEMNES FROM VANDERBILT, WHO WILL
YOU INTRODUCED IN A FEW MINUTES.
NOW I'M GOING TO MOVE TO THE
NEXT SESSION OF THIS WORKSHOP,
FOR THE SPEAKERS
SELF-INTRODUCTION.
I BELIEVE BRITTANY IS GOING TO
SHOW SOME ROSTER SLIDES WITH ALL
THE SPEAKERS AND THE
DISCUSSANTS' NAMES.
WE'LL RUN DOWN THE ROSTER FOR A
QUICK ROLL CALL SO THAT EVERYONE
COULD HAVE A CHANCE TO BRIEFLY
INTRODUCE YOURSELF FOR THE
WORKSHOP AUDIENCE.
IN ORDER TO MAKE SURE WE CAN
STAY ON TIME, EACH PERSON
PROBABLY WILL HAVE LESS THAN 30
SECONDS TO INTRODUCE YOURSELF IN
A FEW SENTENCES, INCLUDING YOUR
NAME, TITLE, INSTITUTION, AND
YOUR RESEARCH INTERESTS AND/OR
CLINICAL SPECIALTY IF
APPLICABLE.
AGAIN, ONCE YOUR NAME IS CALLED
PLEASE TURN DOWN YOUR CAMERA AND
MICROPHONE AND START TO
INTRODUCE YOURSELF.
LET'S START WITH DR. BRYANT.
IS HE HERE?
OKAY.
>>HEY GUYS.
SORRY ABOUT THAT.
FORGIVE THE INFORMAL NATURE.
WE'RE IN THE MIDST OF A
HURRICANE HERE BUT I HAVEN'T
LOST POWER YET.
ANDREW BRYANT, UNIVERSITY OF
FLORIDA, AND MY CLINICAL
EXPERTISE IS IN PULMONARY
HYPERTENSION, AND WE HAVE
ONGOING STUDIES LOOKING AT
SEVERAL SLEEP MODELS.
>>OKAY.
THANKS, ANDREW.
DR. MESAWRI?
>>HI THERE.
OMAR SEMAWRI, UNIVERSITY OF
CALIFORNIA SAN DIEGO, NOT IN THE
MIDST OF A HURRICANE ANY LONGER.
MY CLINICAL EXPERTISE IS MORE
LIKE SLEEP MEDICINE, GENERAL
SLEEP MEDICINE, AND ICU, BUT I'M
INTERESTED IN PULMONARY
HYPERTENSION FROM A RESEARCH
PERSPECTIVE AND INTERSECTION OF
HYPOXIA AND HYPERTENSION.
>>EVAN BRITAIN, CARDIOLOGIST,
VANDERBILT, RESEARCH ON
MECHANISMS OF PULMONARY VASCULAR
DISEASE, THAT WORK GENERALLY
INVOLVES CLINICAL TRIALS AND
EPIDEMIOLOGY.
>>NEXT, DR. GILELES-HILLEL.
>>PULMONOLOGIST AND SLEEP
PHYSICIAN FROM THE
HADASSAH-HEBREW MEDICAL CENTER,
PULMONOLOGY, DYSPLASIA,
HYPERTENSION, MY LAB STUDIES
INTERMITTENT HYPOXIA AND HOW IT
RELATES TO CARDIOMETABOLIC
OUTCOMES.
>>ALL RIGHT.
THANK YOU.
NEXT, DR. MOKHLESI.
>>YES, FROM CHICAGO, RUSH
UNIVERSITY MEDICAL CENTER, AND
I'M DIVISION CHIEF OF THE PULL
PULMONARY CRITICAL CARE AND
SLEEP.
MY INTEREST IN HYPERTENSION WAS
PERIPHERAL AS WE NOTICE MANY
PATIENTS WITH OBESITY SYNDROME
HAVE PULL KNOW MARRY
HYPERTENSION, MY RESEARCH IS NOW
FOCUSED ON ANIMAL MODELS OF
OBESITY AND HYPOXIA AS WELL AS
CLINICAL STUDIES LOOKING AT
INTERSECTION OF MOUSE MODEL
DISEASE OF OF PULMONARY DISEASE
AND SLEEP DISORDER BREATHING.
>>NEXT DR. PARTHASARATHY, IF I
PRONOUNCE IT RIGHT.
I HOPE SO.
IS HE HERE?
ALL RIGHT.
MAYBE HE'S NOT HERE AT THIS
TIME.
LET'S MOVE TO NEXT SPEAKER, DR.
LIAO.
>>RHEUMATOLOGIST AT BRIGHAM AND
WOMEN'S HOSPITAL, ALSO HARVARD
MEDICAL SCHOOL, DEPARTMENT OF
MEDICINE AND DEPARTMENT OF
BIOMEDICAL INFORMATICS.
I WILL BE TALKING MORE ABOUT THE
APPLICATIONS OF BIOINFORMATICS
AND MACHINE LEARNING, MY
RESEARCH ON RUMOR OF ARTHRITIS
AND CARDIOVASCULAR DISEASE.
>>THANK YOU.
NEXT DR. CADE.
>>GOOD MORNING, BRIAN CADE,
BRIGHAM AND WOMEN'S HOSPITAL,
FOLLOWING DR. LIAO TALKING ABOUT
EHRs, SLEEP DISORDER
BREATHING, PULMONARY
HYPERTENSION AND INTEREST IN
GENETICS.
>>DR. LEWIS?
>>HI, ELDRIN LEWIS, STANFORD,
HEART FAILURE AND TRANSPLANT,
RESEARCH INTEREST IS IN CLINICAL
TRIALS, LARGE CLINICAL TRIALS,
IMPLEMENTING QUALITY OF LIFE
INTO MEDICAL DECISION MAKING,
BUT ALSO STUDIED INTERFACE
BETWEEN SLEEP APNEA AND HEART
FAILURE, LOOK FORWARD TO TALKING
WITH YOU TOMORROW.
>>THANK YOU.
NEXT DR. LEOPOLD.
>>YES, HI, JANE LEOPOLD,
CARDIOLOGIST AT BRIG BRIGHAM
AND WOMEN'S HOSPITAL, RESEARCH
INTEREST IN PRECISION MEDICINE
APPROACHES TO OMICS AND
PULMONARY VASCULAR DISEASE.
>>THANK YOU, JANE.
NEXT WILL BE DR. BERTISCH.
>>HI, SUZIE BERTISCH,
APPLICATION OF PATIENT SCIENCE
TO TREATING SLEEP DISORDERS
ACROSS CLINICAL AND COMMUNITY
SETTINGS, HOPEFULLY TO SET A
FRAMEWORK FOR MOVING FORWARD IN
OVERLAP BETWEEN SLEEP DISORDERS
AND PULMONARY HYPERTENSION TO
BROADEN REACH OF IMPACT OF THE
RESEARCH THAT YOU ARE ALL DOING.
THANK YOU.
>>CAN WE MOVE TO DAY 1
SPEAKERS?
I THINK WE SKIPPED THE DAY 1
SPEAKERS.
THIS IS DAY 1 SPEAKER.
NEXT ONE WILL BE DR. BUYSSE.
>>UNIVERSITY OF PITTSBURGH,
POSSIBLY THE ONLY PSYCHIATRIST
ON THE PANEL AT THIS TIME.
MY INTERESTS ARE IN MEASURING
AND DEFINING SLEEP HEALTH AND
LOOKING AT IT IN RELATION TO A
VARIETY OF HEALTH OUTCOMES, ALSO
VERY INTERESTED IN BEHAVIORAL
INTERVENTIONS FOR IMPROVING
SLEEP.
>>THANK YOU.
DR. SHAH?
>>GOOD MORNING, ICAHN SCHOOL OF
MEDICINE, VICE CHAIR OF MEDICINE
HERE, MY RESEARCH LOOKS AT
OBSTRUCTIVE SLEEP APNEA AND
CARDIOVASCULAR SHE'S FOR AS --
DISEASE, FOCUSED ON
HETEROGENEITY OF TREATMENT
EFFECTS WITH CPAP.
>>THANK YOU.
NEXT ONE, DR. CHAN.
>>GOOD TO BE WITH YOU ALL,
STEVE CHAN, DIRECTOR OF VASCULAR
RESEARCH MEDICINE INSTITUTE,
PITTSBURGH SCHOOL OF MEDICINE,
MOLECULAR MECHANISMS, SYSTEMS
BIOLOGY OF PULMONARY VASCULAR
DISEASE.
>>THANK YOU.
NEXT DR. DEJESUS PEREZ.
>>GOOD MORNING, ASSOCIATE
PROFESSOR OF PULMONARY CRITICAL
CARE MEDICINE AT STANFORD.
RESEARCH INTEREST IS PULMONARY
VASCULAR DISEASE WITH FOCUS ON
GENETIC AND MOLECULAR MECHANISMS
AND TODAY I WILL BE TALKING TO
YOU ABOUT THE GENERAL PURVIEW OF
PULMONARY HYPERTENSION,
RELEVANCE TO SLEEP HEALTH.
>>THANK YOU.
DR. HILL.
NICK, ARE YOU THERE?
>>I AM THERE, EXCEPT I FORGOT
TO PRESS MY BUTTONS.
>>THAT'S WHAT I FIGURED.
>>BUT NICK HILL, PULMONARY
CRITICAL CARE, TUFTS MEDICAL
CENTER IN BOSTON, I'VE HAD
LONGSTANDING RESEARCH AND
CLINICAL INTERESTS IN PULMONARY
HYPERTENSION AND NON-INVASIVE
RESPIRATORY SUPPORT, ALSO CHAIR
OF THE STEERING COMMITTEE OF THE
OMICS NETWORK.
>>NEXT ONE DR. MEHRA.
>>HI, GOOD MORNING.
LOOKS LIKE I'M WEARING THE SAME
JACKET AS IN MY PICTURE.
I DO HAVE MORE THAN ONE.
SO, GREAT TO BE WITH YOU HERE
THIS MORNING.
I'M DIRECTOR OF SLEEP DISORDERS
RESEARCH, CLEVELAND CLINIC,
PROFESSOR OF MEDICINE, AND HAVE
APPOINTMENTS ALIGNED WITH
INTERESTS IN HEART AND VASCULAR
INSTITUTE LERNER RESEARCH
INSTITUTE, AND TRAINED PULMONARY
AND CRITICAL CARE PHYSICIAN, MY
RESEARCH HAS BEEN FOCUSED OVER
THE LAST SEVERAL DECADES ON THE
INTERSECTION OF SLEEP DISRUPTION
AND SLEEP DISORDERS ON
CARDIOPULMONARY DISEASE VIA
CLINICAL RESEARCH, ALSO
TRANSLATIONAL SCIENCE.
I'M LEAD FOR THE PVD OMICS SLEEP
CORE, SO WILL BE SHARING SOME OF
OUR FINDINGS IN OUR TALK TODAY
DISCUSSING GROUPS 1 AND 2 WITH
PULMONARY HYPERTENSION WITH
SLEEP DISORDERS.
THANK YOU.
>>THANK YOU.
NEXT, DR. PUNJABI.
>>GOOD MORNING, MY CAMERA IS
NOT WORKING, CHIEF OF PULMONARY
CRITICAL CARE AND SLEEP
MEDICINE, UNIVERSITY OF MIAMI,
INTERESTED IN SLEEP APNEA
EFFECTS, EPIDEMIOLOGICALLY, ALSO
IN THE CONTEXT OF CLINICAL
TRIALS.
>>DR. GOSS?
>>GOOD MORNING, U.T.
SOUTHWESTERN, TREATING HEART
FAILURE IN CLINIC BUT HAVE A
RESEARCH FOCUS ON LONG-TERM
OUTCOMES AFTER PRE-TERM BIRTH OR
EXTREME PRE-TERM BIRTH AROUND
RVPV ACCESS AND CARDIOPULMONARY
OUTCOMES, EXCITED TO LEARN MORE
TODAY.
>>NEXT, DR. KATZ.
>>DAN KATZ, CARDIOLOGIST,
STANFORD UNIVERSITY, AND
ADVANCED HEART FAILURE AND
CARDIOLOGY GROUP.
MY RESEARCH IS FOCUSED ON
LEVERAGING MULTIOMIC DATA TO
BETTER UNDERSTAND HEART FAILURE,
HETEROGENEITY AND MECHANISMS,
AND MY TALK TODAY WILL FOCUS ON
GIVING OVERVIEW OF MULTIOMICS
STRATEGIES.
>>THANK YOU.
NEXT SPEAKER, DR. SOFER.
>>HI, ASSISTANT PROFESSOR AT
BETH ISRAEL DEAN ONES, WORKING
ON SLEEP FOR SIX YEARS, MOSTLY
TRYING TO DO OMICS, UNDERSTAND
SLEEP, HOW IT RELATES TO OTHER
HEALTH OUTCOMES.
>>ALL RIGHT.
BRITTANY, CAN WE MOVE TO THE
NEXT SLIDE FOR THE DISCUSSANTS.
GOOD.
SO THE NEXT ONE WILL BE DR.
ABMAN.
>>GOOD MORNING, EVERYBODY.
PLEASURE TO BE HERE, PROFESSOR
OF PEDIATRICS IN COLORADO, AND
MY BACKGROUND IS IN PULMONARY
AND CRITICAL CARE MEDICINE,
LONGSTANDING INTEREST IN TERMS
OF CLINICAL RESEARCH AND
LABORATORY SCIENCE IN THE
DEVELOPING LUNG AND PULMONARY
MORE BROADLY IN CHILDREN,
ESPECIALLY INTERESTED IN THE
ROLE OF SLEEP DISORDERED
BREATHING AND INTERMITTENT
HYPOXIA AND DISEASE PROGRESSION,
ALSO PREMATURE INFANT,
PATHOGENESIS OF DISEASE WITH
INTERMITTENT HYPOXIA AND FEEL
GRATEFUL TO JOIN YOU TODAY,
LOOKING FORWARD TO THE
PRESENTATIONS.
THANK YOU.
>>THANK YOU.
DR. HASSAN?
>>GOOD MORNING, A PLEASURE TO
BE HERE.
I JUST JOINED BRIGHAM AND
WOMEN'S HOSPITAL AFTER FINISHING
PRIMARY CRITICAL CARE,
INTERESTED IN PHENOTYPING SLEEP
APNEA IN PRIMARY HYPERTENSION
PATIENTS USING OTHER MARKERS IN
ADDITION LIKE HYPOXIA BURDEN IN
THESE PATIENTS.
>>THANK YOU.
DR. MATHAI?
>>>PULMONOLOGIST AT JOHNS
HOPKINS, PATIENTS WITH
CONNECTIVE TISSUE DISEASES AND
EXCITED TO BE HERE TODAY AND
TOMORROW.
>>THANK YOU.
DR. MINHAS?
>>PART OF THE PULMONARY AND
CRITICAL CARE DIVISION
UNIVERSITY OF PENNSYLVANIA,
RESEARCH FOCUSED ON PULMONARY
HYPERTENSION PRIMARILY REMOTE
MONITORING OF PATIENTS WITH
PULMONARY HYPERTENSION USING
ACCELEROMETRY TO IDENTIFY
BIOMARKERS THAT CAN BE
INTERVENED ON.
>>THANK YOU.
DR. PAREKH?
>>THANK YOU FOR THE INVITE.
ASSISTANT PROFESSOR OF SLEEP
MEDICINE, MOUNT SINAI SCHOOL OF
MEDICINE, APPLIED MATHEMATICIAN
TRAINED IN SLEEP PHYSIOLOGY,
RESEARCH INTERESTS MAINLY
LOOKING AT CRITICAL MARKERS OF
IMMEDIATE AND LONG-TERM
CONSEQUENCES OF SLEEP APNEA.
>>THANK YOU.
DR. RISCHARD?
>>HI, THANKS FOR HAVING ME.
PULMONARY CRITICAL CARE,
UNIVERSITY OF ARIZONA.
AND MY RESEARCH IS IN --
INTERESTS IN RV FUNCTION AND RV
ADAPTATION TO STRESS, EXERCISE
PHYSIOLOGY, AND AN INTEREST IN
TODAY'S TOPIC PARTICULARLY AS
RELATES TO THAT.
THANKS AGAIN.
>>ALL RIGHT.
THANK YOU.
DR. SCHMICKL?
>>HI, ASSISTANT PROFESSOR AT
UCSD, I HAVE A FEW CAREER
DEVELOPMENT AWARDS INCLUDING ONE
FROM THE NIH, FOCUS ON USING
BETTER UNDERSTANDING OF
PHYSIOLOGY TO TRANSLATE THAT
INTO NEW TREATMENT OPTIONS FOR
PATIENTS WITH OBSTRUCTIVE SLEEP
APNEA, I'M EXCITED TO BE HERE
TODAY.
THANK YOU.
>>DR. SWEATT?
>>HI, EVERYBODY, I'M A
PHYSICIAN-SCIENTIST AT STANFORD
UNIVERSITY, DIVISION OF
PULMONARY AND CRITICAL CARE
MEDICINE, RESEARCH FOCUSES ON
USE OF MACHINE LEARNING TO
IDENTIFY NOVEL BIOMARKERS AND
SUBPHENOTYPES OF PULMONARY
HYPERTENSION.
>>I WANT TO DOUBLECHECK THAT IF
DOCTOR (INDISCERNIBLE) IS HERE.
IF YOU'RE HERE, TURN ON YOUR
CAMERA AND INTRODUCE YOURSELF.
PROBABLY HE'S NOT HERE AT THIS
TIME.
OKAY.
THANK YOU, EVERYONE, FOR STAYING
ON TIME.
NOW I WOULD LIKE TO WELCOME OUR
LUNG DIVISIONAL DIRECTOR TO GIVE
OPENING REMARKS FROM THE NHLBI
LEADERSHIP PERSPECTIVE.
JIM, ARE YOU HERE?
>>YEAH, GOOD MORNING.
>>A WARM WELCOME, AND WE'RE
GRATEFUL TO ALL OF YOU GIVING UP
SOME PRECIOUS TIME TO HELP WITH
CRITICALLY IMPORTANT TOPIC WE'RE
ALL QUITE EXCITED ABOUT IN THE
LUNG DIVISION AND ACROSS THE
INSTITUTE.
I DO WANT TO EXPRESS THANKS TO
LEI AND ALFONSO WHO DROVE THIS
FORWARD FROM THE NHLBI SIDE AND
SUSAN REDLINE.
IT IMPRESSES ME WHAT A SUPER
GROUP WE HAVE, NOT ONLY DO WE
HAVE A MIX OF BASIC AND CLINICAL
BUT WE ALSO CAN REALLY CROSS
BRIDGE VARIOUS DISCIPLINES THAT
MIGHT NOT NECESSARILY TALK TEACH
OTHER ON A REGULAR BASIS.
IF THERE'S A MESSAGE TO LEAVE
WITH YOU TODAY, THAT IS THE
GOAL, TO BRING COMMUNITIES
TOGETHER THAT DON'T SPEAK TO
EACH OTHER OR HAVE INTERACTIONS
TO SEE WHERE OPPORTUNITIES ARE
TO MAKE PROGRESS IN THE RESEARCH
DOMAIN.
I THINK THE TOPIC WE'RE GOING TO
ADDRESS IS JUST A SUPER EXAMPLE
OF WHERE WE HAVE DIVERSE
COMMUNITIES, WHEN YOU PUT THAT
COLLECTIVE BRAINPOWER TOGETHER
YOU GET REMARKABLE RESULTS.
SO, I DON'T HAVE TO TELL ALL OF
YOU OVER THE NEXT COUPLE DAYS
THIS WORKSHOP IS GOING TO ASK
THE BIDIRECTIONAL RELATIONSHIP
WITH SLEEP DISORDER BREATHING
AND CIRCADIAN DISORDERS WITH
PULMONARY VASCULAR DISEASES, NOT
JUST PULMONARY HYPERTENSION BUT
TO LEANING SOME OF THE
PATHOBIOLOGICAL UNDERSTANDING
AND UNDERPINNINGS TO THE
RELEVANCE TO CARDIOVASCULAR
HEALTH.
AND I THINK THERE'S THE SECOND
MESSAGE FOR YOU TO HEAR, THIS IS
CONSISTENT WITH OUR GOAL IN THE
INSTITUTE, TO TAKE THAT BASIC
SCIENCE AND TRY TO TRANSLATE
THAT TO BETTER UNDERSTANDING OF
HOW WE CAN HELP PATIENTS WITH
DISEASES THAT WE ARE MOST
CONCERNED ABOUT.
AND I THINK THIS IS, AGAIN, A
WONDERFUL OPPORTUNITY TO BRING
TOGETHER PATIENT COMMUNITIES AS
WELL AS CLINICIANS AND
INVESTIGATORS AND SCIENTISTS WHO
ARE NOT ONLY TAKING CARE OF
PATIENTS BUT TRYING TO
UNDERSTAND THEIR BASIC
PATHOBIOLOGY TO FIND BETTER WAYS
TO INTERVENE.
IT'S INTERESTING BECAUSE MANY,
MANY YEARS AGO, IN FACT, WE
RECOGNIZED THAT THE RELATIONSHIP
BETWEEN PULMONARY HYPERTENSION,
THE INVOLVEMENT OF HYPOXIA, AND
THEN WHERE THAT MAY INTERFACE
WITH THINGS THAT ARE GOING ON AT
NIGHT WITH SLEEP DISORDERED
BREATHING.
ONE OF THE THINGS I THINK THAT
IS EXCITING ABOUT THIS WORKSHOP
TO GET AN UPDATE ON WHERE WE ARE
WITH THE DATA THAT REALLY TELLS
US SOMETHING ABOUT NOT ONLY THE
MEDIATORS OF PULMONARY
HYPERTENSION BUT ALSO HOW SLEEP
DISORDERED BREATHING IMPACTS
PULMONARY HYPERTENSION
DEVELOPMENT, PROGRESSES IS, AND
WHAT CAN BE DONE TO HELP TREAT
SOME OF THOSE CONDITIONS.
SO THE ROLE OF SLEEP AND
CIRCADIAN HEALTH MORE GENERALLY,
THAT EXTENDS TO MORE THAN JUST
HYPOXIA, IT'S INSOMNIA,
INSUFFICIENT SLEEP DURATION,
MISALIGNMENT OF SLEEP, A LOT OF
THINGS GOING ON THAT WE'VE
LEARNED ABOUT IN TERMS OF THE
SLEEP PHYSIOLOGY PATHOBIOLOGY
AND MECHANISMS WITH WHAT WE'VE
LEARNED ABOUT PULMONARY
HYPERTENSION AND NEW ADVANCES
THERE WITH RESPECT TO
INTERVENTIONS, IT'S GOING TO
BRING US TO A BETTER
UNDERSTANDING OF LANDSCAPE, AND
WHAT IS MISSING, WHAT WE NEED TO
DO TO ADDRESS OVERLAPPING
CONDITIONS.
UNDERSTANDING THAT RELATIONSHIP
IS GOING TO BE IMPORTANT, NOT
ONLY TO REFINE THERAPEUTIC
APPROACHES, AND MANY THINGS
YOU'RE GOING TO ADDRESS WHETHER
IT'S OXYGEN, CPAP, BEHAVIOR,
OTHER THINGS THAT WILL HOPEFULLY
INFORM BOTH CONDITIONS.
THE OTHER PART OF THIS THAT I
THINK IS ALSO EXCITING IS THE
ABILITY TO NOW INTEGRATE
MULTIOMICS DATA, AND I THINK
THAT IS A GOAL THAT I KNOW THAT
THE AGENDA IS GOING TO ADDRESS
BECAUSE IT'S QUITE A NICE
PROGRAM, AND I THINK YOU'RE
GOING TO LOOK AT IT FROM NOT
JUST THE BASIC SCIENCE BUT ALSO
THE IMPLEMENTATION, HOW DO WE
THEN TAKE WHAT WE KNOW ABOUT
VARIOUS TECHNOLOGIES, MOBILE
HEALTH, YOU KNOW, HOW DO WE USE
ELECTRONIC HEALTH RECORDS AND
TAKE THAT INFORMATION INTEGRATE
IT AND USE IT IN A WAY THAT
MIGHT BE IMPACTFUL TO THE
PATIENTS THAT YOU'RE ALL SEEING
ON A REGULAR BASIS.
SO, THE OVERARCHING GOAL IS TO
DISCUSS THE STATE OF KNOWLEDGE
OF SLEEP HEALTH AND DYSFUNCTION
AND ITS IMPACT ON PULMONARY
VASCULAR DISEASE AND IDENTIFY
AREAS WHERE FUTURE RESEARCH IS
NEEDED AND EXPLORE WHERE
THOSE -- WHERE THE MOST PRESSING
NEEDS ARE THAT WILL HELP MOVE
THE FIELD FORWARD.
SO, ALL OF THIS ALIGNS VERY
NICELY, I DON'T HAVE TO SAY THIS
TO THIS GROUP, WITH THE SLEEP
RESEARCH PLAN, NIH SLEEP
RESEARCH PLAN, ALSO WITH THE
STRATEGIC VISION OF THE NHLBI,
VERY DEDICATED CRITICAL
QUESTIONS AND SUCH THAT ALIGN
WITH THE GOALS OF THIS WORKSHOP.
WE'RE REALLY EXCITED ABOUT NOT
ONLY FITTING NICELY WITH WHAT
THE INSTITUTE SAYS ARE
PRIORITIES BUT ALSO TO BRIDGE
THESE TWO DISCIPLINES AND REALLY
SEE WHERE WE CAN GO.
I'LL LEAVE YOU WITH ONE FINAL
THOUGHT, AND THIS IS FOR --
MOSTLY I THINK TO OUR CHAIRS TO
PAY ATTENTION TO, BUT IT'S VERY
TEMPTING FOR ALL OF YOU TO
REALLY PRODUCE A LAUNDRY LIST, A
VERY LONG LIST OF NEEDS AND
OPPORTUNITIES.
AND THAT'S WONDERFUL.
YOU CAN DO THAT.
IT'S ALSO VERY TEMPTING TO START
TO TELL US WE NEED A MECHANISM
AND FUNDING AND, YES, THAT'S
ALSO IN BOUND, YOU CAN DO THOSE
THINGS.
BUT REALLY WHAT WE WANT TO HEAR
AT THE END IS WHAT ARE THE BIG
ISSUES, IF YOU WERE ONLY ABLE TO
DO ONE THING, WHAT WOULD IT BE
THAT WOULD BE MORE THAN AN
INCREMENTAL ADVANCE BUT BOLD
MOVE FORWARD THAT WOULD HELP
CHANGE THE LANDSCAPE AND REALLY
IMPACT ON PATIENT OUTCOMES.
I THINK THE IMPORTANT POINT HERE
IS NOT TO BE ALL THINGS TO ALL
PEOPLE, TRY TO REALLY PUT YOUR
FOCUS ON WHAT ARE THE MAIN
THINGS AND IF NIH WERE TO HELP
PUSH THAT FORWARD, FACILITATE
THAT, WHAT WOULD IT BE?
BECAUSE OBVIOUSLY WE'RE IN A
CLIMATE OF DIFFICULT COMPETITIVE
RESOURCES AND SO FORTH, SO WE
REALLY WANT TO KNOW WHAT IS
GOING TO HAVE THE BIGGEST
IMPACT.
WE HOPE THERE WILL BE A
PUBLICATION OF THIS MEETING
BECAUSE NOT EVERYBODY CAN ATTEND
IT.
IF WE WERE IN BETHESDA HOLDING
THIS IN THE OLD DAYS, PRE-COVID,
IT WOULD BE ABOUT HALF THIS
GROUP IN THE ROOM, MAYBE LESS,
AND THE BENEFIT OF DOING THIS
VIRTUALLY IS THAT I THINK THE
LAST LOOK THERE WAS ALMOST 70
PEOPLE ONLINE, IT WILL PROBABLY
GROW OVER THE NEXT COUPLE DAYS
BECAUSE THE AGENDA AND FULL AND
RICH.
I HOPE ALL OF YOU ARE ABLE TO
SHARE THE WEALTH OF KNOWLEDGE
YOU BRING TO THIS WORKSHOP,
SHARE THOUGHTS WHERE WE NEED TO
GO AS A COMMUNITY AND GIVE GOOD
RECOMMENDATIONS AND
OPPORTUNITIES TO PUSH THE
ENVELOPE.
I LOOK FORWARD TO THE MEETING.
YOU'RE IN WONDERFUL HANDS WITH
OUR STAFF AND FACILITATORS AND
CONTRACTORS WHO HELPED US PUT
THIS TOGETHER.
MANY THANKS FROM US AT THE
INSTITUTE AND WE WISH YOU A VERY
PRODUCTIVE MEETING, AND I HOPE I
GET TO MEET YOU OVER THE NEXT
PERIOD OF TIME.
THANK YOU FOR THE INTRO AND
OPPORTUNITY TO INTRODUCE THE
WORKSHOP AND WELCOME YOU AND
LOOK FORWARD TO THE MEETING
TODAY AND TOMORROW.
I'LL TURN IT BACK OVER TO YOU,
LEI, OR ALFONSO, CAN'T REMEMBER
WHO IS NEXT.
>>ALFONSO, ALL YOURS.
>>THANK YOU, DR. KYLIE.
>>GOOD MORNING.
I'M A PROGRAM DIRECTOR IN THE
NATIONAL CENTER ON SLEEP
DISORDERS RESEARCH WHERE I
OVERSEE PORTFOLIO ON SLEEP
DISORDERS MEDICINE.
I'M A PART OF THE ORGANIZING
COMMITTEE, IT'S WITH GREAT
PLEASURE I INTRODUCE YOU TO OUR
TWO OUTSTANDING CO-CHAIRS, BOTH
PLAY CRITICAL ROLES IN PLANNING,
DEVELOPMENT, ORGANIZATION OF
THIS WORKSHOP.
FIRST DR. SUSAN REDLINE,
PROFESSOR OF SLEEP MEDICINE AT
HARVARD MEDICAL SCHOOL,
PROFESSOR OF EPIDEMIOLOGY AT
HARVARD pH CHAN SCHOOL OF
PUBLIC HEALTH, DIRECTOR OF
PROGRAMS IN SLEEP AND
CARDIOVASCULAR MEDICINE AND
SLEEP MEDICINE EPIDEMIOLOGY AT
BRIGHAM AND WOMEN'S HOSPITAL,
HAS LED TRIALS INCLUDING ROLE OF
GENETIC AND EARLY LIFE
DEVELOPMENTAL FACTORS, AND
SECOND TO UNDERSTAND
CARDIOVASCULAR AND OTHER HEALTH
OUTCOMES OF SLEEP DISORDERS AND
ROLE OF SLEEP INTERVENTIONS IN
IMPROVING HEALTH AND WELL-BEING.
SHE LEADS THE SLEEP READING
CENTER FOR A NUMBER OF MAJOR
MULTI-CENTER STUDIES, AND
FOUNDED AND CO-DIRECTS NATIONAL
SLEEP RESEARCH RESOURCE, AN
INTERNATIONAL SLEEP DATA SHARING
REPOSITORY THAT HAS MADE SLEEP
DATA SEARCHABLE AND ACCESSIBLE
SUPPORTING COMMUNITY ACCESS TO
DATA AND A SUITE OF OPEN SOURCE
TOOLS.
SHE SUPPORTS A SLEEP APNEA
PATIENT-FOCUSED VIRTUAL
COMMUNITY.
AND NEXT DR. ANNA HEMNES,
ENDOWED CHAIR IN PULMONARY
MEDICINE VANDERBILT UNIVERSITY
MEDICAL CENTER, TRANSLATIONAL
PHYSICIAN-SCIENTIST WITH
RESEARCH FOCUS ON ROLE OF
ALTERED METABOLISM, RESEARCH IS
ON EFFECT OF MUTATION ON
SIGNALING, INCLUDING ROLE OF
INSULIN RESISTANCE AND METABOLIC
SYNDROME IN HUMAN PVD, GENETIC
SUSCEPTIBLABILITY AND
PHENOTYPING, LEADING TO WORK IN
OMICS SIGNATURE OF VASODILATORY
HYPERTENSION.
HER LAB IS INVESTIGATING NOVEL
BLOOD-BASED OMIC PREDICTIVE
STRATEGIES FOR FDA APPROVED
THERAPIES FOR PULMONARY
HYPERTENSION.
HER LAB HAS UNIQUE AND POWERFUL
CAPACITY TO STUDY MOLECULAR
MECHANISMS OF PVD AND RIGHT
HEART DYSFUNCTION THROUGH
CLINICAL TRIALS.
WITH THAT I'M GOING TO TURN
THINGS OVER TO OUR CHAIRS,
STARTING WITH DR. REDLINE.
>>THANK YOU VERY MUCH.
I'M GOING TO SHARE MY SLIDES
RIGHT NOW.
OKAY.
CAN YOU SEE THIS?
OKAY, GREAT.
FIRST OF ALL, THANK YOU VERY
MUCH.
I FIRST WANT TO EXPRESS REALLY
MY DEEP GRATITUDE TO NHLBI FOR
REALLY IDENTIFYING AND REALLY
ADVANCING THIS VERY, VERY UNIQUE
WORKSHOP THAT BRINGS TOGETHER
TWO COMMUNITIES, THE SLEEP
COMMUNITY AND PULMONARY
HYPERTENSION COMMUNITY, IN A WAY
THAT I THINK IS GOING TO TRULY
BRING TOGETHER OVER THE COURSE
OF THE NEXT TWO DAYS A VERY
VIBRANT DISCUSSION, AND
HOPEFULLY ADDRESS MANY OF THE
GAPS THAT DR. KILEY SUMMARIZED.
I WANT TO EMPHASIZE THE INTEREST
IN NOT ONLY THE NEXT TWO DAYS OF
WORK BUT REALLY THE WEEKS,
MONTHS, AND YEARS AHEAD OF
WORKING ALTOGETHER TO TRY TO
BETTER UNDERSTAND THIS
INTERSECTION OF SLEEP AND
PULMONARY VASCULAR DISEASE.
TO BEGIN WITH, I WANTED TO
MENTION A FEW MAYBE HIGH LEVEL
THOUGHTS THAT UNDERSCORE THE
MOTIVATIONS FOR THE WORKSHOP,
SEVERAL OF THOSE THAT DR. KILEY
MENTIONED.
I WANTED TO FIRST GIVE A SHOUT
OUT TO THE AMERICAN HEART
ASSOCIATION, WHICH JUST IN THIS
YEAR WENT BEYOND THE HEALTHY
SEVEN TO UNDERSTAND THE
IMPORTANCE OF SLEEP NOW
EMBRACING THE TERM "LIFE'S
ESSENTIAL 8" AS A COMPONENT TO
HEART DISEASE AND GENERAL
WELL-BEING.
AS A MEMBER OF THE SLEEP
COMMUNITY, YOU KNOW, MYSELF AND
MY PEERS RECOGNIZE THAT 40 TO 60
MILLION PEOPLE IN THE U.S. ALONE
SUFFER FROM SLEEP DISORDER.
AND FURTHERMORE, WE UNDERSTAND
THAT SLEEP DISORDERS INCLUDE
SLEEP APNEA WITH ALL ITS MYRIAD
CO-MORBIDITIES BUT ALSO INCLUDE
OBESITY HYPOVENTILATION
SYNDROME, BEHAVIORS THAT IMPACT
SHORT SLEEP DURATION.
AND WHAT'S UNIQUE TODAY IS THIS
COMMUNITY OF SOME OF THE I THINK
LEADING EXPERTS IN SLEEP
MEDICINE ARE GOING TO BE
SPEAKING WITH LEADING EXPERTS IN
PULMONARY HYPERTENSION AWARE OF
THE MANY NUANCES AND SUBGROUPS
OF PULMONARY HYPERTENSION AND
THEIR MOLECULAR CLINICAL
BEHAVIORS, AND ONE OF THE GOALS
IS TO IN FACT UNDERSTAND THESE
LINKAGES, AND MANY OF THE
LINKAGES MAY IN FACT BE FROM
MECHANISMS FROM SLEEP DISORDERS,
INCLUDING INTERMITTENT
HYPOXEMIA, CIRCADIAN DISRUPTION
AND BIDIRECTIONAL ASSOCIATION OF
DIFFERENCE IN LUNG STRUCTURE MAY
PREDISPOSE AND EXACERBATE SLEEP
DISORDERS.
AND FINALLY, WE WILL BE
ADDRESSING SORT OF THE
UNDERLYING SORT OF SOIL OR
COMMON MECHANISMS OR PLEIOTROPY
THAT UNDERLIE DISORDERS
INCLUDING GENETIC AND
ENVIRONMENTAL EXPOSURES BUT ALSO
MAY INVOLVE CENTRAL DISRUPTION
OF REGULATORY NETWORKS AND
CIRCADIAN DYSFUNCTION.
WE'RE NOT ONLY GOING TO ADDRESS
THESE RELATIONSHIPS BUT WE'RE
GOING TO PUT OUR LENS IN FOR
LONG-TERM NEEDS IN TERMS OF THE
IMPLICATIONS OF THE EMERGING
SCIENCE ON PATIENT CARE.
WE'RE GOING TO BE BEGINNING TO
THINK OF WHICH PATIENTS, WHICH
DISORDERS, WHICH SUBDISORDERS OF
THESE DISORDERS MAY BEST BENEFIT
FROM IMPROVING THE TREATMENT OF
THEIR SLEEP OR PULMONARY
HYPERTENSION.
AND WHICH ARE THE TREATMENTS,
THERE ARE MANY TREATMENTS THAT
WE COULD THINK ABOUT, JUST FROM
A SLEEP PERSPECTIVE IT COULD
INCLUDE POSITIVE AIRWAY
PRESSURE, OXYGEN, BEHAVIORAL
INTERVENTIONS, AND MEDICATIONS.
AND, AGAIN, THE GOAL WILL BE
THAT EVENTUALLY WE'LL BE ABLE TO
CONNECT HEALTHY SLEEP WITH
HEALTHY HEARTS BY REALLY
IMPACTING SOME OF THESE
MECHANISTIC PATHWAYS THAT CAUSE
EXACERBATIONS AND EVEN
POTENTIALLY AMPLIFYING EFFECTS
OF DYSFUNCTION OF EITHER SLEEP
OR HEART FUNCTION.
AND I WANT TO CONCLUDE BEFORE
PASSING THIS OVER TO MY CO-CHAIR
THAT WHAT IS REALLY SPECIAL
AGAIN IS THAT WE'RE BRINGING
TOGETHER TWO GROUPS OF
INVESTIGATORS THAT BY AND LARGE
HAVE BEEN WORKING IN SILOS TO BE
IN THE VIRTUAL WORKSHOP, AND AS
DR. KILEY STATED, IT'S MORE --
ONE OF THE THINGS PARTICULARLY
EXCITING IS THAT WHAT WE HAVE AS
PARTICIPANTS IN THIS WORKSHOP
ARE ALSO REPRESENTATIVES FOR
MULTIPLE DISCIPLINES FROM BASIC
SCIENCE AND VASCULAR BIOLOGY,
GENETICS, EPIDEMIOLOGY,
TRANSLATIONAL RESEARCH, AND
CLINICAL TRIALS, AND AS I
MENTIONED MY REAL HOPE IS THAT
THIS WORKSHOP IN ADDITION TO
IDENTIFYING THOSE BOLD NEW IDEAS
DR. KILEY SPOKE ABOUT REALLY
HELPS COALESCE OUR TWO
COMMUNITIES TO CONTINUE TO WORK
TOGETHER AND ADVANCE THE FIELD.
SO I'M GOING TO -- I WANT TO
ALSO EMPHASIZE MY DEEP GRATITUDE
FOR EVERY PARTICIPANTS AND
DISCUSSANT ON THIS WORKSHOP,
EVERYONE'S GOING TO BRING
TOGETHER SOMETHING VERY SPECIAL
AND, AGAIN, I RECOGNIZE HOW
PRECIOUS YOUR TIME IS SO THANK
YOU.
NOW I'D LIKE TO TURN THIS OVER
TO OUR CO-CHAIR, ANNA HEMNES,
WHO I FEEL PRIVILEGED TO WORK
WITH.
ANNA?
>>THANK YOU SO MUCH, SUSAN.
I FEEL THE SAME WAY ABOUT YOU.
IT'S REALLY AN HONOR TO CO-CHAIR
THIS WORKSHOP.
I THINK FOR ME I WANTED TO START
WITH A PERSONAL STORY, AND SAY
WHY ARE WE HERE NOW.
THERE'S A LOT OF DATA THAT HAS
TALKED ABOUT SLEEP AND PULMONARY
HYPERTENSION FOR YEARS, BUT I
PERSONALLY HAD AN AHA MOMENT
WORKING WITH PVD-OMICS AND OUR
DATA.
IT IS WITH A MULTI-CENTER U.S.
COHORT STUDY THAT ENROLLED
PATIENTS ACROSS THE SPECTRUM OF
PULMONARY VASCULAR DISEASE
INCLUDING DISEASE COMPARATORS, I
THINK YOU'LL HEAR MORE ABOUT IT
IN THE TALKS LATER ON TODAY AND
TOMORROW.
BUT IT HAD PATIENTS WITH ALL
KINDS OF PULMONARY HYPERTENSION
AND DISEASE COMPARATORS AND
HEALTHY CONTROLS AND HAD
COMPREHENSIVE PHENOTYPING THAT
INCLUDED STUDIES LOOKING FOR
POSSIBLE SLEEP DISORDERS IN
PATIENTS WHO HAD PULMONARY
HYPERTENSION.
AND WHEN WE GOT THE DATA BACK,
WE CREATED THIS FIGURE THAT YOU
SEE THAT WAS ONE OF THE ONLY FEW
FIGURES THAT WE PUT IN OUR
MANUSCRIPT OF CLINICAL DATA
BECAUSE IT WAS SO IMPRESSIVE.
AND IF YOU LOOK AT PATIENTS,
THIS IS A SPIDER PLOT OF
NOCTURNAL RECORDING TIME, A HOME
SLEEP STUDY.
FOR PATIENTS WHO HAD GROUP 1
PULMONARY HYPERTENSION WE FOUND
THAT THE FOLKS THAT HAD
PULMONARY HYPERTENSION ABOUT 40%
OF THEIR NIGHT WAS SPENT WITH
OXYGEN SATURATION LESS THAN 90%.
I'M SORRY, 40% OF PATIENTS HAD
SOME TIMELESS THAN 90%, AND THEN
THAT WAS STRONGLY SIGNIFICANT
COMPARED TO DISEASE COMPARATORS,
ALSO PRESENT IN OTHER FORMS OF
HOW MANY HYPERTENSION GROUP 3
AND GROUP 4, AND GROUP 2 HAD
MORE TREATED SLEEP APNEA, SO I
THINK THAT IS WHY THAT
PERCENTAGE IS LOWER IN THERE.
BUT I REALIZED I'VE NOT BEEN
LOOKING FOR DEEP SLEEP DISORDERS
IN MY PATIENTS, AND I NEEDED TO
DO A BETTER JOB BASED ON THESE
DATA.
IT WAS REALLY EYE OPENING TO
PREVALENCE OF SLEEP DISTURBANCES
IN THE PATIENTS WHO HAVE
PULMONARY HYPERTENSION, AND IT'S
HARD TO IGNORE THIS AND SAY THIS
IS JUST UNRELATED, THERE ANYWAY
BE INTERPLAY BETWEEN THE TWO
THINGS IMPACTING BOTH DISEASES.
FOR ME THAT WAS A TIME WHERE WE
THOUGHT WE NEED TO LOOK INTO
THIS.
OBJECTIVES TO DISCUSS CURRENT
UNDERSTANDINGP SLEEVE HEALTH AND
DYSFUNCTION IN FIVE ESTABLISHED
GROUPS, TO IDENTIFY GAPS IN
KNOWLEDGE AND CRITICAL NEEDS
REGARDING IMPACT OF SLEEP
DISORDER BREATHING, AND OTHER
DISTURBANCES ON PULMONARY
VASCULAR DISEASE INCLUDING MILD
PULMONARY HYPERTENSION, EXPLORE
INTERVENTIONS, TRIALS DESIGNS TO
EVALUATE EFFECTIVENESS IN
TREATING PULMONARY VASCULAR
DISEASE, AND ADDRESS
DISPARITIES.
AND YOU CAN SEE THAT IN THE
AGENDA WE ALIGNED OUR TALKS AND
SESSIONS TO ADDRESS THESE
SOMETIMES THROUGHOUT AN ENTIRE
SMALL SESSION OR SOMETIMES
PROGRAMMATICALLY THROUGHOUT THE
TWO DAYS OF DISCUSSING.
SO OUR HOPES AND EXPECTATIONS WE
HOPE YOU DISCUSS AND CLARIFY KEY
UNANSWERED QUESTIONS OR UNMET
NEEDS, TO THINK AS A COMMUNITY
WHERE ARE THE MOST IMPORTANT AND
IMPACTFUL WAYS WE WOULD ANSWER
QUESTIONS THAT HAVE ARISEN FROM
THIS.
HOPE TO HAVE ACTIVE DISCUSSION
FROM PARTICIPANTS.
THIS IS A TIME TO RAISE YOUR
HAND AND PARTICIPATE ACTIVELY.
WE WANT TO HEAR FROM EACH OF YOU
WHO HAS COME HERE.
EACH OF YOU IS HIGHLY VALUED
ACCOMPLISHED PERSON IN THESE
FIELDS AND YOUR INPUT IS
CRITICAL TO MAKING THIS A
PRODUCTIVE WORKSHOP.
WE HOPE TO IDENTIFY FUTURE
DIRECTIONS FOR NHLBI AND
SCIENTIFIC COMMUNITY.
SO DELIVERABLES, AT THE END OF
THE WORKSHOP WE'RE GOING TO
IDENTIFY KEY FUTURE DIRECTIONS
FOR SCIENTIFIC COMMUNITY AND
NHLBI INCLUDING AREAS OF
MULTI-DISCIPLINARY SYNERGY WHICH
I THINK IS A TREMENDOUS STRENGTH
OF THE WORKSHOP.
WE WILL MAKE AN EXECUTIVE
SUMMARY, THE GOAL IN THE BALL
PARK OF FOUR TO SIX WEEKS FROM
THE WORKSHOP, AND IN SIX MONTHS
WE WILL WRITE A MANUSCRIPT AND
SUBMIT IT TO A JOURNAL THAT IS
TO BE DETERMINED FROM THIS
WORKSHOP.
I'D LIKE TO SAY THANK YOU,
ECHOING WHAT OTHERS HAVE SAID.
EVERYBODY HERE, YOUR TIME IS
PRECIOUS AND WE'RE THANKFUL
YOU'RE TAKING THE TIME TO
DISCUSS, LEARN, PRESENT AND
PARTICIPATE IN THE AUDIENCE AND
THESE ACTIVITIES OVER THE NEXT
TWO DAYS.
I'M THANKFUL FOR THE NIH
LEADERSHIP INCLUDING DR. KILEY
FOR SUPPORTING THIS WORKSHOP.
ALSO THE HELP IN PUTTING
TOGETHER THIS SESSION AND FOR
SUPPORT OF THIS REALLY EXCITING
WORKSHOP.
WE HAVE WRITING SUPPORT FROM DR.
TARABOLETTI, I'M THANKFUL FOR
THE WORK SHE'S GOING TO DO IN
THE FUTURE, THAT WILL HELP TO
KEEP US ON TRACK AND GET OUR
DELIVERABLES ACCOMPLISHED.
AND A SPECIAL THANK YOU TO THE
SUPPORT FROM NIH AND NHLBI,
ESPECIALLY BRITTANY VILLAFANA
WHO RECEIVED COUNTLESS E-MAILS
AND WORKED HARD TO MAKE SURE WE
DELIVER A TECHNICALLY GREAT
WORKSHOP OVER THE NEXT TWO DAYS.
ALSO THANKS TO SUSAN WHO HAS
TAUGHT ME ABOUT THE BREADTH AND
VARIOUS KINDS OF SLEEP
DISORDERED BREATHING AND EXCITED
TO LEARN FROM EVERYBODY HERE
TODAY.
WITH THAT WE'LL GO INTO OUR
FIRST SESSION I THINK.
>>OKAY, GREAT.
THANK YOU SO MUCH, ANNA.
THAT WAS SUCH A NICE OVERVIEW OF
WHAT WE'RE GOING TO BE STEPPING
INTO.
JUST TO MAYBE REMIND YOU, WE'RE
GOING TO BE ORGANIZING, WE'LL
HAVE SESSIONS BY TEAM TOPICS,
AFTER EACH SPEAKER FIVE MINUTES
FOR SOME QUESTIONS AND
CLARIFICATIONS, AND AT THE END
OF EACH SESSION THERE WILL BE A
WRAP-UP OPPORTUNITY,
PARTICULARLY FOR DISCUSSANTS AND
PARTICIPANTS TO REALLY SHARE
THEIR THOUGHTS AND ENGAGE IN
SOME DISCUSSION.
SO, FIRST SESSION WILL SET THE
STAGE FOR EMPHASIZING THE
SPECTRUM OF SLEEP HEALTH, SLEEP
DISORDERS, APPROACHES TO
ASSESSMENT AND OVERALL
APPROACHES TO CARDIOVASCULAR
DISEASE.
I KNOW NO BETTER SPEAKER TO KICK
OFF THIS SESSION THAN DAN
BUYSSE, OUR TOKEN PSYCHIATRIST
BUT THE MOST AMAZING SLEEP
RESEARCHER AND I WOULD SAY ONE
OF THE BEST METHODOLOGISTS I'M
AWARE OF WHO IS GOING TO BE
TALKING ABOUT SLEEP HEALTH, A
CONCEPT HE HAS REALLY HELPED
GALVANIZE ATTENTION TO IN TERMS
OF ITS MULTI-DIMENSIONALITY AND
HE WILL BE DISCUSSING
DEFINITIONS, MEASUREMENTS, AND
RELEVANCE TO DISEASE.
SO THANK YOU, DAN.
>>ALL RIGHT.
THANK YOU, SUSAN.
CAN YOU SEE MY SLIDES?
>>YES.
>>OKAY.
EXCELLENT.
LET ME DO ONE MORE THING HERE.
ALL RIGHT.
SO I APPRECIATE THE INVITATION
TO SPEAK WITH EVERYONE TODAY.
AS SUSAN SAID MY JOB IS TO
PRESENT A WIDE ANGLE OVERVIEW OF
SLEEP IN RELATION TO PULMONARY
VASCULAR DISEASE.
I DO NOT REALLY KNOW ANYTHING
ABOUT PULMONARY VASCULAR DISEASE
BUT I HOPE THAT IN THIS
DISCUSSION OF SLEEP AND
CIRCADIAN RHYTHM WE MAY GENERATE
NEW IDEAS ON HOW TO INCORPORATE
SLEEP INTO INTERROGATION OF THIS
IMPORTANT CONDITION.
SO, FOR STARTERS, WE KNOW SLEEP
IS RELATED TO HEALTH IN MANY
WAYS.
SLEEP IS RELATED TO OBESITY,
DIABETES, CANCER, HEART DISEASE,
DEPRESSION, SUBSTANCE USE, AND
EVEN MORTALITY.
AND THIS RECOGNITION THAT SLEEP
IS CRITICAL TO HEALTH HAS REALLY
BEEN TAKEN UP AS SUSAN MENTIONED
BY THE AHA THAT HAS NOW
INDICATED THAT SLEEP IS ONE OF
THE ESSENTIAL BEHAVIORAL FACTORS
THAT WE NEED TO CONSIDER IN
EVALUATING PERSONS' HEALTH AND
MORTALITY.
SO, THE QUESTION IS WHY IS THAT
SLEEP SHOULD BE RELATED TO ALL
OF THESE IMPORTANT OUTCOMES?
TO INVESTIGATE THAT QUESTION, WE
NEED TO GO BACK QUITE A WAYS AND
REMIND OURSELVES THAT WE LIVE ON
A PLANET THAT ROTATES ON ITS
AXIS EVERY 24 HOURS, EXPOSING TO
US REGULAR ENVIRONMENTAL SIGNALS
OF LIGHT AND DARKNESS.
WHAT THAT MEANS IS DURING THE
COURSE OF EVOLUTION VARIOUS
RESOURCES AVAILABLE TO ANY
ANIMAL AND SPECIES WILL VARY
ACCORDING TO THIS TEMPORAL
ENVIRONMENT JUST AS THEY VARY
WITH PHYSICAL ENVIRONMENT.
SO, EVOLUTION HAS ENDOWED US
WITH A MECHANISM TO MATCH OUR
BIOLOGY TO THIS GEO PHYSICAL
REALITY, AND THE MECHANISM BY
WHICH IT DOES THAT IS WITH A SET
OF CANONICAL CLOCK GENES THAT
REGULATE THEIR OWN TRANSCRIPTION
AND TRANSLATION ON A 24-HOUR
BASIS.
NOW, BECAUSE THE CIRCADIAN
24-HOUR MECHANISM IS EMBEDDED IN
OUR GENES, THAT MEANS THAT IT'S
PRESENT IN EVERY CELL AND TISSUE
IN OUR BODY, INDEED IF YOU TAKE
LUNG CELL CULTURES AND PLACE
THEM OUT, YOU CAN DETERMINE THAT
THEY CYCLE ON A 24-HOUR BASIS
JUST AS THE PRODUCTS OF OTHER
TISSUES THROUGHOUT THE BODY
CYCLE ON A 24-HOUR BASIS.
WE HAVE CLOCKS EVERYWHERE IN OUR
BODY, AND THOSE CLOCKS ARE
REGULATED BY A MASTER CLOCK IN
THE SUPER CHIASMATIC NUCLEI OF
THE HYPOTHALAMUS WHICH THROUGH
ENDOCRINE OUTPUTS SYNCHRONIZES
RHYTHMS OF OUR BODY CLOCKS.
BECAUSE WE HAVE CLOCKS
EVERYWHERE, IT STANDS TO REASON
THAT OUR PHYSIOLOGY THEN VARIES
AS A FUNCTION OF THE TIME OF DAY
AS WELL.
TO TAKE ONE OBVIOUS EXAMPLE,
BLOOD PRESSURE, OUR BLOOD
PRESSURE VARIES ROUTINELY WITH
TIME OF DAY SO THAT IT'S LOWEST
AT NIGHT, AND HIGHEST IN THE
EARLY EVENING HOURS.
AS YOU'RE AWARE THE DEGREE OF
NIGHTTIME DIPPING AND BLOOD
PRESSURE ASSOCIATED WITH
CARDIOVASCULAR OUTCOMES, THAT
24-HOUR CYCLING IS SEEN IN
PEOPLE WHO ARE NORMO TENSIVE AND
HYPERTENSION, IN THIS CASE
DURING PREGNANCY, AND IF YOU
THINK THAT MAYBE OUR BLOOD
PRESSURE DIPS ONLY BECAUSE WE'RE
ASLEEP, THERE ARE EXPERIMENTAL
PARADIGMS THAT CAN SEPARATE THE
EFFECTS OF SLEEP FROM CIRCADIAN
RHYTHM, DEMONSTRATING RHYTHM OF
BLOOD PRESSURE VARIES
INDEPENDENT OF OUR SLEEP.
CLOCK TIME, EVERYTHING IN
PHYSIOLOGY INCLUDING KEY ASPECTS
OF CARDIOVASCULAR FUNCTION.
IN SOME CASE THE MOST OBVIOUS
MANIFESTATION OF THE CIRCADIAN
CLOCK IS SLEEP AND WAKE RHYTHM
WHICH VARIES WITH TIME OF DAY.
WE ALL KNOW WHAT SLEEP IS, BUT
WHAT IS SLEEP GOOD FOR?
WE KNOW SLEEP MUST BE PRETTY
IMPORTANT BECAUSE IT'S PRESENT
THROUGHOUT THE PHYLOGENETIC
SPECTRUM FROM JELLYFISH WITHOUT
A PROPER BRAIN TO C. ELEGANS TO
DROSOPHILA, ALL SERVED AS
EXCELLENT MODELS FOR SLEEP/WAKE
FUNCTION IN SPECIES.
AND WHILE WE COULD HAVE A LONG
ARGUMENT ABOUT WHAT SLEEP IS FOR
I THINK THAT IT PRETTY MUCH GOES
WITHOUT SAYING THERE'S NO
FUNCTION AT ANY LEVEL OF
BIOLOGICAL ORGANIZATION, NO
FUNCTION THAT DOESN'T WORK
BETTER IN THE PRESENCE OF SLEEP
AND REGULAR REST ACTIVITY
RHYTHMS.
INDEED, WE KNOW THAT SLEEP IS
RELATED TO A NUMBER OF KEY
SYSTEMIC PHYSIOLOGICAL
MECHANISMS RELEVANT TO PULMONARY
VASCULAR DISEASE AS WELL AS
CARDIOVASCULAR DISEASE, A HOST
OF OTHER AILMENTS AS WELL.
NOW, WHEN IT COMES TO MEASURING
SLEEP IN HUMANS WE HAVE SEVERAL
OPTIONS AVAILABLE TO US.
SIMPLEST WAY IS TO USE
SELF-REPORTS OF SLEEP THAT STILL
CONTINUE TO BE A USEFUL
METHODOLOGY.
WE CAN MEASURE SLEEP
BEHAVIORALLY, WE CAN MEASURE
REST ACTIVITY RHYTHMS WITH
SOMETHING LIKE RISK ACTIGRAPHY,
MOVEMENT IS CORRELATED WITH
SLEEP BUT KNOWS A PHYSIOLOGIC OR
ELECTROPHYSIOLOGIC MEASURE OF
SLEEP.
THAT'S FROM POLYS OMNOGRAHPY AND
BREATHING AND RESPIRATORY
FUNCTION AND OXYGEN SATURATION
DURING SLEEP THAT YOU'LL BE
HEARING MORE ABOUT.
WE CAN MEASURE FUNCTIONAL NEURAL
IMAGING THAT WE AND OTHERS HAVE
DONE.
I WANT TO PROVIDE THAT BROAD
OVERVIEW TO GET US ALL THINKING
AND KIND OF LEVEL SETTING WITH
REGARD TO WHAT SLEEP IS, HOW WE
MIGHT MEASURE IT AND WHY,
BROADLY SPEAKING, IT'S IMPORTANT
TO OUR HEALTH.
NEXT I'D LIKE TO TALK ABOUT THIS
CONCEPT OF MULTI-DIMENSIONAL
SLEEP HEALTH.
AGAIN, WE'VE ALREADY ESTABLISHED
THAT SLEEP IS RELATED TO HEALTH
IN SEVERAL WAYS.
AND IF WE TRY TO INVESTIGATE
THOSE RELATIONSHIPS, THERE ARE
SEVERAL -- THERE ARE BROAD WAYS
WE MIGHT TRY TO LOOK FOR MORE
INFORMATION ON HOW AND WHY THIS
HAPPENS.
SO, THE FIRST WAY THAT WE CAN DO
THAT IS BY CONSIDERING SLEEP
DISORDERS.
THERE ARE SIX MAJOR CATEGORIES
OF SLEEP DISORDERS, AS DEFINED
BY THE SLEEP COMMUNITY, AND YOU
SEE THEM HERE.
WE'LL BE TALKING MAINLY ABOUT
SLEEP-RELATED BREATHING
DISORDERS DURING THIS CONFERENCE
BUT THIS IS JUST A REMINDER THAT
SLEEP DISORDERED BREATHING IS
NOT THE ONLY DISORDER.
THEY CAN BE COMORBID AND THERE'S
EVIDENCE EACH TYPE OF DISORDER
IS ASSOCIATED WITH POOR HEALTH
OUTCOMES.
NOT TO BELABOR THE POINT, OTHERS
WILL BE PRESENTING MUCH MORE
DETAIL ON THIS, WE KNOW FOR
INSTANCE THAT OBSTRUCTIVE SLEEP
APNEA SYNDROME AS A PARTICULAR
SLEEP DISORDER IS RELATED TO ALL
SORTS OF HEALTH OUTCOMES,
INCLUDING RISK OF FATAL
CARDIOVASCULAR EVENTS FROM THIS
CLASSIC STUDY FROM SPAIN THAT
EXAMINED PEOPLE WITH AND WITHOUT
OBSTRUCTIVE SLEEP APNEA AND WITH
AND WITHOUT TREATMENT SHOWING
SEVERE OBSTRUCTIVE SLEEP APNEA
SYNDROME IS ASSOCIATED WITH AN
INCREASE IN FATAL CARDIOVASCULAR
EVENTS, AND SUGGESTING IF NOT
DEMONSTRATING THAT TREATED SLEEP
APNEA REDUCES ONE'S RISK.
BUT CARDIOVASCULAR AND HEALTH
OUTCOMES ARE NOT THE EXCLUSIVE
DOMAIN OF OBSTRUCTIVE SLEEP
APNEA SYNDROME.
INSOMNIA IS ALSO ASSOCIATED AND
DOSE-RESPONSE WAY WITH ADVERSE
HEALTH OUTCOMES INCLUDING
ALL-CAUSE MORTALITY.
THESE ARE DATA FROM THE HEALTH
AND RETIREMENT STUDY SHOWING
THAT AS THE NUMBER OF INSOMNIA
SYMPTOMS INCREASE, ADJUSTED
HAZARD FOR MORTALITY ON 14-YEAR
FOLLOW-UP GOES UP IN MORE OR
LESS LINEAR FASHION.
HOWEVER, SLEEP DISORDERS ARE
CLEARLY IMPORTANT IN OUR
CONSIDERATION OF HEALTH
OUTCOMES, BUT NOT EVERYBODY HAS
A SLEEP DISORDER.
THIS RAISES THE QUESTION OF ARE
THERE OTHER ASPECTS OF SLEEP
THAT MIGHT BE RELATED TO HEALTH
WHICH HINGES ON THE QUESTION OF
WHAT IS GOOD SLEEP.
AGAIN, A SIMPLE QUESTION,
DECEPTIVELY.
IN A 24-HOUR DAY, GOOD SLEEP
TYPICALLY OCCUPIES ABOUT A THIRD
OF THAT.
SLEEP HERE IS INDICATED IN BLUE.
WAKEFULNESS IN YELLOW.
BUT NOT EVERYBODY HAS GOOD
SLEEP.
AND SLEEP CAN BE POOR IN MANY
WAYS.
FOR INSTANCE, ONE MIGHT HAVE
SATISFACTION WITH THEIR SLEEP OR
GOOD QUALITY OF SLEEP, OR POOR
QUALITY SLEEP.
YOU MIGHT HAVE SLEEP THAT
RELATES -- RESULTS IN GOOD DAY
TIME ALERTNESS OR POOR DAYTIME
ALERTNESS.
SLEEP TIMING THAT'S NORMAL,
EXPECTED CIRCADIAN TIME OR TOO
LATE OR TOO EARLY RELATIVE TO
EXPECTED TIMING.
YOU MIGHT HAVE HIGHLY EFFICIENT
SLEEP WITH LITTLE WAKEFULNESS OR
POORLY EFFICIENT SLEEP WITH LOTS
OF AWAKENINGS.
YOU MIGHT HAVE SLEEP DURATION
THAT IS NORMAL, SHORT, OR LONG.
AND YOU MAY HAVE SLEEP THAT
OCCURS AT REGULAR TIMES IN
AMOUNTS THROUGHOUT THE WEEK OR
IRREGULAR IN ANY OF THESE WAYS.
NOW, IT MAY SEEM THAT, AGAIN,
CHARACTERIZING THESE BASIC
FEATURES OF SLEEP IS UNLIKELY TO
BE RELATED TO HEALTH OUTCOMES
BUT THAT'S NOT THE CASE.
IN FACT, EACH OF THESE DIFFERENT
DIMENSIONS HAS INDIVIDUALLY BEEN
ASSOCIATED WITH A RANGE OF
ADVERSE HEALTH OUTCOMES,
INCLUDING ASPECTS OF
CARDIOVASCULAR DISEASE.
AND OF COURSE WHEN WE THINK
ABOUT THESE DIFFERENT DIMENSIONS
OF SLEEP, THEY DON'T EXIST IN
ISOLATION.
AN INDIVIDUAL CAN HAVE MULTIPLE
WAYS IN WHICH SLEEP IS DISTURBED
AT ONCE.
YOU MIGHT HAVE LATE SLEEP
TIMING, POOR SLEEP EFFICIENCY,
SHORT SLEEP DURATION, POOR
SATISFACTION WITH SLEEP.
THE QUESTION IS WHETHER THAT
NUMBER OF ABNORMAL SLEEP
CHARACTERISTICS HAS A CUMULATIVE
EFFECT ON HEALTH.
IN ORDER TO INVESTIGATE THAT WE
DEVELOPED THIS DEFINITION
PROPOSAL FOR SLEEP HEALTH AS A
MULTI-DIMENSIONAL PATTERN OF
SLEEP AND WAKEFULNESS.
AND WHAT IT REALLY SAYS IS THAT
AN INDIVIDUAL, EVERY INDIVIDUAL,
CAN BE CHARACTERIZED AT SOME
POINT ON THESE DIFFERENT
DIMENSIONS AT ALL TIMES, IN
AGGREGATE OUR MULTI-DIMENSIONAL
SLEEP HEALTH RELATES TO OTHER
IMPORTANT HEALTH OUTCOMES.
THESE DIFFERENT DIMENSIONS, YOU
CAN REMEMBER BY THE ACRONYM
RU-SATED FOR THE SIX DIMENSIONS
HERE.
AS AN ILLUSTRATION OF WHY IT'S
IMPORTANT TO THINK ABOUT
MULTIPLE SLEEP DURATIONS LET'S
CONSIDER THREE INDIVIDUALS.
EACH OF WHOM HAS A SLEEP
DURATION OF FIVE HOURS.
BUT THE FIRST PERSON IS A NIGHT
SHIFT WORKER WHO HAS MODERATE
QUALITY AND EFFICIENCY OF SLEEP
BUT SLEEPING AT THE WRONG TIME
OF DAY.
THAT'S ONE WAY THAT A PERSON
MIGHT SLEEP FIVE HOURS.
ANOTHER WAY IS A PERSON MAY HAVE
ADEQUATE OPPORTUNITY FOR SLEEP
BUT SLEEP WITH LOW QUALITY, LOW
SATISFACTION, HAVE POOR SLEEP
EFFICIENCY, THAT INDIVIDUAL
MIGHT HAVE INSOMNIA.
YET ANOTHER WAY A PERSON MIGHT
GET TO FIVE HOURS IS BY JUST NOT
HAVING ENOUGH TIME.
SOMEONE WHO IS WORKING MULTIPLE
JOBS, RAISING A FAMILY, AND WHEN
THEY SLEEP THEY MAY ACTUALLY
HAVE GOOD SLEEP QUALITY AND
EFFICIENCY BUT THEY JUST HAVE
LIMITED TIME TO SLEEP.
SO IF WE WERE ONLY CONSIDERING
SLEEP DURATION, WE WOULD NOT BE
ABLE TO DISTINGUISH BETWEEN
THESE THREE CONDITIONS AND YET
THE CONSEQUENCES FOR HEALTH AND
FUNCTION MAY BE VERY DIFFERENT.
IT'S ALSO IMPORTANT TO MENTION
THAT THESE DIFFERENT ASPECTS OF
SLEEP HEALTH HAVE BEEN SHOWN TO
VARY WITH RACE AND SOCIOECONOMIC
STATUS AND REALLY ULTIMATELY IF
YOU DIG BENEATH THAT WHAT WE'RE
TALKING ABOUT ARE SOCIAL
DETERMINANTS OF HEALTH.
SO, IT'S BEEN SHOWN THAT THINGS
LIKE NEIGHBORHOOD SOCIAL
COHESION, NAKED AND HOUSEHOLD
CHARACTERISTICS, SOCIOECONOMIC
SOCIAL DETERMINANTS OF HEALTH
RELATE.
AS WE THINK ABOUT ANY SLEEP
DISORDER, ANY OTHER HEALTH
OUTCOMES RELATED TO SLEEP, WE
SHOULD KEEP IN MIND AS WELL THAT
ALL OF THESE THINGS ARE GOING TO
BE AFFECTED BY THESE IMPORTANT
SOCIAL DETERMINANTS OF HEALTH.
I'D LIKE TO TALK ABOUT IDEAS HOW
WE MEASURE AND ANALYZE
MULTI-DIMENSIONAL SLEEP HEALTH.
I'M NOT GOING TO BELABOR THIS
BUT WHEN YOU'RE TRYING TO
MEASURE SIX OR MORE THINGS
SIMULTANEOUSLY AND MAKE SENSE OF
THEM AS A COMPOSITE THERE ARE
DIFFERENT WAYS YOU CAN DO THAT.
ONE WAY IS THAT YOU CAN
CHARACTERIZE THE DIFFERENT
DIMENSIONS OF SLEEP AND SIMPLY
ADD THEM UP.
COME UP WITH A COMPOSITE SCORE.
ANOTHER WAY THAT YOU CAN ANALYZE
THIS IS TO SEE AND ENSURE THAT
YOU HAVE CORRECT DIMENSIONS BY
DOING FACTOR ANALYSIS, PRINCIPAL
COMPONENT ANALYSIS.
CLUSTER ANALYSIS TO IDENTIFY
WERE CHARACTERISTICS HANG
TOGETHER IN SPECIFIC GROUPS OF
PEOPLE WHO HAVE DIFFERENT
PHENOTYPES OR PROFILES OF SLEEP
HEALTH.
AND FINALLY YOU CAN USE VARIETY
OF MACHINE LEARNING APPROACHES
TO IDENTIFY PATTERNS IN THE
SLEEP DATA AND HEALTH OUTCOMES
THAT MAY NOT BE IMMEDIATELY
APPARENT.
I'M NOT GOING TO GO THROUGH
THESE IN DETAIL.
I'D LIKE TO GIVE YOU A COUPLE
EXAMPLES OF HOW PEOPLE HAVE
CONSIDERED MULTI-DIMENSIONAL
SLEEP HEALTH IN RELATION TO
IMPORTANT HEALTH OUTCOMES.
SO, FIRST IF WE LOOK AT A
COMPOSITE MEASURE OF SLEEP
HEALTH, THESE ARE DATA FROM THE
MIDUS STUDY, SELF-REPORT AND
ACTIGRAPHY MEASURES, I WON'T GO
INTO DETAILS BUT IF WE LOOK AT
HEART DISEASE RISK, AND THIS WAS
CROSS-SECTIONAL, NONETHELESS THE
SLEEP HEALTH COMPOSITE SCORE WAS
SIGNIFICANTLY RELATED TO
CARDIOVASCULAR -- TO HEART
DISEASE RISK WHETHER USING
SELF-REPORT COMPOSITES OR
COMBINATION OF ACTIGRAPHY AND
SELF-REPORT SLEEP HEALTH
MEASURES.
NOW, CONSIDER AS WELL THAT THE
RISK ASSOCIATED WITH THE SLEEP
HEALTH MEASURES IS ON PAR WITH
OR EXCEEDS THAT OF MANY COMMON
RISK FACTORS FOR HEART DISEASE,
SUGGESTING, AGAIN, THAT THIS
COMPOSITE MEASURE OF SLEEP
HEALTH IS SOMETHING THAT WE
SHOULD REALLY BE CONSIDERING AS
WE INVESTIGATE ALL SORTS OF
HEART DISEASE AND CARDIOVASCULAR
OUTCOMES.
ONE OTHER EXAMPLE OF HOW WE CAN
MEASURE SLEEP HEALTH AND HOW
THAT MIGHT BE IMPORTANT IS TO
CONSIDER LATENT CLASS ANALYSES,
THESE ARE DATA FROM MY COLLEAGUE
MEREDITH WALLACE, WHO DID LATENT
CLASS ANALYSES IN THE MROS AND
SOF STUDIES, IN EACH GROUP
IDENTIFIED THREE LATENT CLASSES,
THREE PROFILES OF
MULTI-DIMENSIONAL SLEEP HEALTH.
THOSE PROFILES WERE A HIGH SLEEP
PROPENSITY GROUP, AVERAGE GROUP,
INSOMNIA WITH SHORT SLEEP GROUP.
NOT ONLY CAN YOU MEASURE
DIMENSIONS BUT THEY CLUSTER IN
INDIVIDUALS IN DIFFERENT WAYS
AND INDEED THIS PHENOTYPES WERE
ASSOCIATED WITH MORTALITY
OUTCOMES IN EACH OF THESE
COHORTS AND IN THE AGGREGATE
COHORT.
IN THIS CASE TURNED OUT THE HIGH
SLEEP PROPENSITY GROUP IN
PARTICULAR WAS THE ONE THAT
CARRIED INCREASED RISK.
WE'VE BEEN PROPONENTS OF THIS
MODEL BUT THERE ARE OTHER WAYS
OF MEASURING SLEEP HEALTH AS
WELL.
NATIONAL SLEEP FOUNDATION HAS A
SLEEP HEALTH INDEX WITH THREE
SUBSCALES YOU SEE HERE.
AND OTHER INVESTIGATORS USING
DATA FROM THE U.K. BIOBANK
INCLUDED A MULTI-DIMENSIONAL
SLEEP HEALTH MEASURE THAT
INCLUDED TIMING, DURATION,
INSOMNIA, WHICH IS ESSENTIALLY
LIKE EFFICIENCY, BUT ALSO
INCLUDED SNORING, SO A SLEEP
DISORDER SYMPTOM WITHIN THEIR
CLASSIFICATION OF
MULTI-DIMENSIONAL SLEEP HEALTH.
WHEN PEOPLE HAVE USED VARIOUS
DEFINITIONS OF SLEEP HEALTH,
WE'VE BEEN FINDING INCREASINGLY
THAT THERE ARE A NUMBER OF
HEALTH OUTCOMES THAT ARE
ASSOCIATED WITH THESE SLEEP
HEALTH PROFILES, BOTH
CROSS-SECTIONALLY AND
LONGITUDINALLY.
A COUPLE OTHER EXAMPLES RELATING
TO CARDIOVASCULAR AND PULMONARY
DISEASES, ONE IS LOOKING AT
MULTI-DIMENSIONAL SLEEP HEALTH
IN CARDIOVASCULAR DISEASE AND
CARDIOMETABOLIC HEALTH OUTCOMES.
THIS IS FROM THE NHANES STUDY.
HERE WE HAD CROSS-SECTIONAL DATA
AGAIN, BUT SHOWING THAT
MULTI-DIMENSIONAL SLEEP HEALTH
IS RELATED TO A NUMBER OF
CARDIOMETABOLIC OUTCOMES AND
SIGNIFICANTLY SO.
A LONGITUDINAL STUDY LOOKING AT
DIFFERENT OUTCOMES HERE LOOKING
ACTUALLY AT RISK OF DEVELOPING A
POST COVID-19 19, A PROSPECTIVE
STUDY FROM THE NURSES HEALTH
STUDY, LOOKING AT BASELINE SLEEP
HEALTH AND HOW IT WAS RELATED TO
THE RISK OF DEVELOPING A
POST-COVID CONDITION A NUMBER OF
YEARS LATER.
AND AS YOU CAN SEE, A
MULTI-DIMENSIONAL SLEEP HEALTH
SCORE IN THE BETTER RANGE WAS
ASSOCIATED WITH LOWER RISK OF
DEVELOPING THIS IMPORTANT
OUTCOME.
FINAL EXAMPLE THEORETICAL BASIS,
IF WE LOOK AT PULMONARY ARTERIAL
PRESSURE RELATED TO OBSTRUCTIVE
SLEEP APNEA, IT MAY BE THAT
SLEEP HEALTH IS RELATED TO SOME
OF THE KEY MECHANISMS BECAUSE
INDEED WE KNOW INDIVIDUAL
DIMENSIONS ARE RELATED TO THESE
DIFFERENT ASPECTS OF THE
PATHOPHYSIOLOGY OF PULMONARY
ARTERIAL HYPERTENSION.
VERY LAST FEW SLIDES, I WANT TO
POINT OUT THAT WE CAN USE THIS
CONCEPTUALIZATION TO DEVELOP
BEHAVIORAL INTERVENTIONS THAT
CAN IMPROVE HEALTH, ONE EXAMPLE
IS SOMETHING CALLED
TRANSDIAGNOSTIC INTERVENTION
THAT ALLISON AND I DEVELOPED,
AND BASICALLY THIS IS A
BEHAVIORAL INTERVENTION THAT CAN
TARGET NUMEROUS ASPECTS OF SLEEP
HEALTH.
THIS HASN'T BEEN USED WIDELY TO
LOOK AT CARDIOVASCULAR HEALTH
OUTCOMES, THERE'S A TANTALIZING
CLUE FROM A SMALL PILOT STUDY
THAT LOOKED AT JUST ONE
DIMENSION OF SLEEP, THAT IS
SLEEP DURATION, AND LOOKED AT
WHETHER INCREASING SOMEONE'S
SLEEP DURATION MIGHT HAVE AN
EFFECT ON 24-HOUR BLOOD
PRESSURE, THESE ARE DATA FROM
MONICA HAAK AND JANET
MULLINGTON.
BASELINE, GROUPS DIDN'T DIFFER
IN TERMS OF 24-HOUR BLOOD
PRESSURE BUT AFTER TWO WEEKS OF
SLEEP EXTENSION THE GROUP THAT
HAD SLEEP EXTENSION SHOWED LOWER
24-HOUR BLOOD PRESSURE COMPARED
TO SLEEP MAINTENANCE GROUP, THAT
IS THE ONE THAT DID NOT CHANGE
THEIR SLEEP DURATION.
AND FINAL CONSIDERATION I WANT
TO GO BACK TO THE FACT THAT WE
DO HAVE CIRCADIAN RHYTHMS
EXISTING IN MORE THAN JUST
SLEEP.
AND THOSE RHYTHMS RESULT FROM
CLOCKS EVERYWHERE IN OUR BODY
THAT DETERMINE VARIOUS BRAIN AND
BODY FUNCTIONS, TRANSLATING TO
PHYSIOLOGY, BEHAVIOR,
PERFORMANCE, INCLUDING ALL OF
THESE KEY HEALTH BEHAVIORS, ALL
OF WHICH IN TURN FEED BACK TO
THE CIRCADIAN CLOCK.
SO, IT MAY BE THAT WHEN WE TAKE
INTO ACCOUNT THE FACT THAT
EVERYTHING IN OUR PHYSIOLOGY
VARIES AS A FUNCTION OF TIME OF
DAY, THAT WE CAN USE SOME
PRINCIPAL CIRCADIAN PRINCIPLES
TO ADDRESS A NUMBER OF KEY
HEALTH BEHAVIORS, USING
CIRCADIAN PRINCIPLES, AGAIN,
PAYING ATTENTION TO THE AMOUNT
OF EACH BEHAVIOR, REGULARITY AND
TIMING BOTH OF WHICH REALLY TEND
TO LOCK IN OUR CIRCADIAN
RHYTHMS.
I HOPE I'VE GIVEN AN OVERVIEW
THAT SUPPORTS THE NOTION THAT
SLEEP AND CIRCADIAN RHYTHMS
AFFECT A WIDE RANGE OF HEALTH
OUTCOMES, SLEEP DISORDERS IN
PARTICULAR RELATED TO
CARDIOVASCULAR OUTCOMES, WE CAN
DEFINE MULTI-DIMENSIONAL SLEEP
HEALTH AND ITS RELATED TO
CARDIOVASCULAR AND MORTALITY
HEALTH OUTCOMES AND HAVE INKLING
THAT INTERVENTIONS TARGETING
MULTI-DIMENSIONAL SLEEP HEALTH
MAY PLAUSIBLY IMPROVE
CARDIOVASCULAR OUTCOMES.
THESE ARE THE THREE KNOWLEDGE
GAPS THAT I'VE IDENTIFIED FOR
FURTHER CONSIDERATION, FOCUSING
ON MEASURES OF SLEEP HEALTH,
MECHANISMS, INTERVENTIONS, AND
THANK ALL SORTS OF COLLEAGUES,
ESPECIALLY MEREDITH WALLACE WHO
HAS BEEN PUSHING FORWARD THIS
NOTION OF MULTI-DIMENSIONAL
SLEEP HEALTH MEASUREMENT AND
RELATION TO CONSEQUENCES.
THANK YOU.
>>THANK YOU FOR AN OUTSTANDING
PRESENTATION AND I THINK
CHALLENGING ALL OF US AS WE
THINK ABOUT PULMONARY
HYPERTENSION TO BROADEN OUR
LENS, WHICH IS ABSOLUTELY
PERFECT FOR THE THEME OF THE
WORKSHOP AND NOT ONLY TO THINK
ABOUT SLEEP APNEA, OTHER DEEP
SLEEP DISORDERS, EVEN AGGREGATE
OR WAYS TO THINK ABOUT THE
COMBINATION.
THANK YOU FOR THAT.
WE HAVE TIME FOR ONE QUESTION,
IF ANYONE HAS IT.
IF NOT MAYBE WE COULD PICK UP
ANY STRANDS IN THE WRAP-UP
DISCUSSION.
IS THERE ANY BURNING QUESTIONS
FROM ANYONE?
OKAY.
WE'LL TAKE THIS UP AGAIN.
THANKS, DAN.
WE'RE GOING TO THE NEXT SPEAKER,
NOW WE'RE GOING TO TAKE A LITTLE
DIFFERENT APPROACH AND DIVE INTO
SLEEP APNEA AND ITS COMPLEXITY
AND HETEROGENEITY AND GIVING
THIS TALK IS DR. NEOMI SHAH,
DOING INNOVATIVE WORK IN THIS
SPATES, SHE'S GOING TO BE
SPEAKING ON UNRAVELING THE
HETEROGENEITY OF SLEEP APNEA AND
ITS RELEVANCE TO PULMONARY
HYPERTENSION.
THANK YOU.
>>YOU CAN SEE MY SLIDES AND THE
--
>>YES.
>>OKAY, GREAT.
THE RIGHT SCREEN?
>>YEAH.
>>OKAY.
WONDERFUL.
THANK YOU.
THANK YOU FOR THE INVITATION TO
SPEAK HERE TODAY.
IT'S AN HONOR AND I'M LOOKING
FORWARD TO THE TALKS.
DAN'S TALK WAS INFORMATIVE SO I
CAN ONLY IMAGINE HOW MUCH I'M
GOING TO LEARN IN THE NEXT TWO
DAYS.
TODAY DISCUSSING HETEROGENEITY
OF SLEEP APNEA, WHAT I TRIED TO
DO IS TIE THAT AS BEST I CAN TO
PULMONARY HYPERTENSION EVEN
THOUGH MOST OF THE WORK IS ON
CARDIOVASCULAR DISEASE END
POINTS LIKE STROKE AND
CARDIOVASCULAR DISEASE-RELATED
DEATH, TO HELP ADDRESS WHAT DR.
KILEY SAID, TO THINK BROADLY AND
MAYBE COME UP WITH SOME SPECIFIC
DIRECTIONS.
SO WITH THAT I'LL GET STARTED.
SO, THERE'S A LOT OF EMERGING
EVIDENCE SUGGESTING A NEED FOR
DEFINING SPECIFIC SUBGROUPS,
WE'VE SEEN THIS WORK IN THE LAST
FIVE YEARS FOR SURE, MAYBE MORE.
AND WHAT IT'S DOING IS REALLY
PUSHING US TOWARDS PRECISION AND
PERSONALIZED MEDICINE
PARTICULARLY FOR OSA.
SUBGROUPS REPRESENT A
SIGNIFICANT STEP TO MORE
TAILORED EFFECTIVE TREATMENTS
FOR OSA PATIENTS.
I KNOW AT THE LAST SLEEP MEETING
WHERE I SPOKE ABOUT THIS TOPIC,
THERE WAS A LITTLE BIT OF
CONCERN ABOUT WHERE WE ARE IN
THE FIELD IN TERMS OF NOT HAVING
THE OSA FOR ALL AND WE SHOULD
TREAT ALL.
THIS IS A REALLY GOOD TIME FOR
THE FIELD, AND WE SHOULD BE
CAUTIOUSLY OPTIMISTIC.
THIS SLIDE SHOWS YOU THAT
PULMONARY HYPERTENSION IS COMMON
IN OBSTRUCTIVE SLEEP APNEA, A
SLIDE FROM MY MENTEE WHO IS
WORKING IN THIS, BOTTOM LINE
THAT DEPENDING ON HOW YOU
DIAGNOSE OBSTRUCTIVE SLEEP APNEA
AND DIAGNOSIS OF PULMONARY
HYPERTENSION, PREVALENCE OF 70%,
AN IMPORTANT ASSOCIATION,
HOPEFULLY WE'LL BE ABLE TO
IDENTIFY HOW HETEROGENEITY OF
OBSTRUCTIVE SLEEP APNEA AND
FINDINGS MAY HELP US WITH THIS
ASSOCIATION.
SO IN STANDARD MEDICINE WE HAVE
CLINICAL PRESENTATION,
ENDOTYPING, RANDOMIZED CLINICAL
TRIALS, NON-OSA ACROSS THE BOARD
FOR ALL DISEASES WE SEE,
PHYSICIAN EXPERIENCE PLAYS IN,
BUT THERE'S STANDARDIZED
TREATMENT EVENTUALLY.
EFFECTIVE INSIDE VARIES.
SOME PATIENTS HAVE 100%
EFFECTIVENESS, SOME GROUPS OR
SUBGROUPS HAVE PARTIAL RESPONSE,
SOME NO RESPONSE.
I THINK IF YOU APPLY THIS TO
OPA, THERE ARE ENDOTYPES AND
CLINICAL MANIFESTATION OR
PHENOTYPES BECOMING INCREASINGLY
IMPORTANT TO BETTER PREDICT
RESPONSE TO TREATMENT BECAUSE WE
ARE SORT OF IN THIS NEUTRAL OR
NULL FINDING TERRITORY
ESPECIALLY FOR CARDIOVASCULAR
DISEASE OUTCOMES.
HETEROGENEITY RESEMBLES MANY
CONDITIONS, FAR AHEAD IN TERMS
OF THIS PERSONALIZED APPROACH,
HOPEFULLY SLEEP MEDICINE WILL BE
THERE SOON ENOUGH.
AGAIN, PRECISION MEDICINE
APPROACH DRIVEN THROUGH THESE
ENDOTYPING AND PHENOTYPING AND
SUBGROUP ANALYSIS WILL ALLOW US
TO GET TO MORE OF THE PRECISION
AND PERSONALIZED TREATMENT
APPROACH.
A LOT IS GOING TO BE DEPENDENT
ON INDIVIDUAL PATIENT
CHARACTERISTICS, INCLUDING
PHYSIOLOGIC CHARACTERISTICS THAT
ARE DEPENDENT ON DATA THAT WE
WOULD SEE FROM SONNOGRAMS, AND
THE FOCUS IN THE FIELD TO
IMPROVE OUR ABILITY TO PREDICT
TREATMENT RESPONSE TO
CARDIOVASCULAR DISEASE OUTCOMES
BUT EVEN THINGS LIKE NEURO
COGNITIVE DYSFUNCTION,
ALZHEIMER'S DISEASE, SLEEPINESS,
AND THE LIKE.
OSA DIAGNOSIS COMPRISES OF
MECHANISTIC AND CLINICAL
PHENOTYPES AND ENDOTYPES
PRIMARILY THROUGH
POLYSOMNOGRAPHIC FEATURES.
AND OVERLOOKING HETEROGENEITY
THAT OSA PRESENTS.
WE'RE TRYING, THE FIELD IS
PERHAPS MOVING AWAY FROM USING
THE SOLE PREDICTOR AND THAT'S A
REALLY IMPORTANT TIME TO FURTHER
AGAIN GET TO THE PERSONALIZED
TREATMENT AND PRECISION MEDICINE
APPROACHES.
SO IN TERMS OF ENDOTYPING, AS A
REVIEW FOR THOSE NOT IN THE
FIELD RESPIRATORY ENDOTYPING
IDENTIFIES PATHOPHYSIOLOGIC
TRAITS, AND THESE CORRELATE
DIRECTLY WITH PATHOPHYSIOLOGIC
MECHANISMS WHICH IS HOPEFULLY
PAVING THE WAY FOR PERSONALIZED
TREATMENT STRATEGIES.
SO HERE ARE THE FOUR COMMONLY
KNOWN ENDOTYPES WE'RE TALKING
ABOUT IN THE FIELD.
THERE WOULD BE ANATOMICAL COME
COMPROMISE, ON THE LEFT LOWER
THRESHOLD PREDISPOSED TO WAKING
UP WITH DISTURBANCE MORE OFTEN
THAN OTHERS.
THERE'S THE IMPAIRED PHARYNGEAL
DILATOR MUSCLE AND UNSTABLE
VENTILATORY CONTROL.
THE ALOWER AROUSAL THRESHOLD
PREVENTS AROUSALS, POTENTIALLY
SYMPATHETIC ACTIVATION,
SIMILARLY RESPONDING TO DRUGS,
AS OPPOSED TO CPAP.
THIS HAS HELPED US BRING THIS TO
THE CLINICAL PRACTICE BY
PROVIDING US A TOOL CALLED
PHENOTYPING USING
POLYSOMNOGRAPHY, TO INCORPORATE
THESE ENDOTYPES INTO DISCUSSIONS
ABOUT PULMONARY VASCULAR
DISEASE, AND SO ON, THIS IS
ANOTHER SLIDE THAT I LIKE FROM A
PAPER THAT DEMONSTRATES HOW THE
POSSIBLE ENDOTYPE AND POSSIBLE
PHENOTYPE MAY THEN INFORM
THERAPEUTIC OPTIONS IN DIFFERENT
PATIENT SCENARIOS.
SO THE OSA PHENOTYPES ARE BASED
ON RISK FACTORS, THERE'S OBESITY
WHICH IS A MAJOR RISK FACTOR,
THERE'S CRANIOFACIAL
RESTRICTION, AS WE SAW NEURAL
AND VENTILATORY CONTROL.
THERE ARE ALSO CLINICAL
PHENOTYPES, SPECIFICALLY GAINING
MOMENTUM AS SLEEPINESS AND
INSOMNIA PHENOTYPE IS WELCOMING
INCREASINGLY IMPORTANT IN TERMS
OF RISK FACTOR AND PHENOTYPE FOR
OUTCOMES PERTAINING TO
CARDIOVASCULAR DISEASE.
PHYSIOLOGIC FEATURES ARE ALSO
HYPOXIC HEART, SLEEP STAGE
DEPENDENCY, AND OF COURSE
COMORBIDITY, MEDICATIONS FOR
HYPERTENSION, FOR DIABETES, FOR
CARDIOVASCULAR HEALTH, HOW ARE
THEY POTENTIALLY IMPACTING
PHENOTYPES WE SEE BUT MORE
IMPORTANTLY SOME WORK WE'RE
DOING HOW DO THEY IMPACT
TREATMENT RESPONSE.
FOR EXAMPLE IN INDIVIDUALS ON
STATINS DO THEY BENEFIT FROM
CPAP THERAPY AS MUCH AS OTHERS,
AND THERE ARE COMBINATION DRUGS.
I'M GOING TO LOOK AT SLEEPINESS,
HEART RATE RESPONSE AS
PHENOTYPES, AND I CAN'T COVER
ALL OF IT BUT WE'LL JUST
HOPEFULLY TRY TO DEMONSTRATE BY
EXAMPLES WITH THESE THREE
ENDOPHENOTYPES.
SO THIS IS WORK BY MAZZOTTI IN
2019, FOCUSING ON CHARACTERIZING
OSA SYMPTOM SUBTYPES AND IMPACT
ON CARDIOVASCULAR HEALTH.
THEY USED DATA FROM HEART STUDY
IDENTIFYING FOUR SYMPTOM
SUBTYPES.
AND THEN THE SUBTYPE THAT WAS
PRIMARILY THE ONE THAT HAS LED
TO A LOT OF ATTENTION IS THE
SLEEPY SUBTYPE, WHICH WAS LINKED
TO A THREE-FOLD RISK OF HEART
FAILURE AND EVENTS ON THE RIGHT
AND PRIMARY TAKEAWAY IS THAT OSA
SYMPTOM SUBTYPES DO INDEED HOLD
UNIQUE ASSOCIATIONS OF
CARDIOVASCULAR OUTCOMES WITH
SUBTYPE SHOWING SIGNIFICANT
RISK.
THIS IS ANOTHER AREA THAT
POTENTIALLY WE COULD FOCUS ON AS
WE TALK ABOUT PULMONARY VASCULAR
DISEASE HOW DOES SLEEPINESS AS A
PHENOTYPE GET INTO NOT JUST THE
EVALUATION AND TREATMENT BUT
ALSO RESPONSIVENESS TO TREATMENT
FOR SPECIFIC PATIENTS AND WHAT
ARE THE UNDERLYING MECHANISMS
LINKING SLEEPINESS TO
CARDIOVASCULAR OUTCOMES AND
POTENTIALLY PULMONARY
HYPERTENSION-RELATED OUTCOMES.
THIS WORK DEMONSTRATES SYMPTOM
BASED SUBTYPES SUCH AS DISTURBED
SLEEP FROM DIFFERING IMPACT ON
CPAP.
ALL OF THESE MAY VARY IN RISK
AND RESPONSE TO THERAPY.
AND THIS IS AGAIN WORK FROM
YALE, LIMB MOVEMENTS, RISK FOR
CARDIOVASCULAR DISEASE EVENTS IN
THE CLUSTER WITH PERIODIC LIMB
MOVEMENTS, IN HOME SLEEP TESTING
WE'RE NOT GETTING THIS DATA, NOT
SEEING LIMB MOVEMENTS, A LOT OF
CLINICAL DIAGNOSTICS HAVE MOVED
TO HOME SLEEP TESTING,
EXCLUSIVELY IN SOME PLACES, AND
AS WE KNOW CONVENTIONALLY ARE
REALLY NOT TURNING OUT TO BE
PRIMARILY ASSOCIATED WITH
CARDIOVASCULAR DISEASE ENDPOINTS
SO THESE PHENOTYPES THAT MAY BE
HIDDEN IN Ph.D. DATA WE'RE
MISSING SO, AGAIN, IMPORTANT TO
HAVE COMPREHENSIVE INFORMATION
INCLUDING MOVEMENTS.
HYPOXIC BURDEN IS GAINING
INTEREST, WORK HAS HIGHLIGHTED
AS SHOWN HERE REALLY DOES
PREDICT CARDIOVASCULAR DISEASE
MORTALITY.
AND THIS IS PRIMARILY BASED ON
DURATION OF SLEEP RELATED
OBSTRUCTION.
THIS IS DATA FROM THE HEART
HEALTH STUDY, AGAIN POINTING
HYPOXIC BURDEN OUTPERFORMS
TRADITIONAL METRIC FOR
DIAGNOSING SLEEP APNEA, IN BOTH
COHORTS.
INDIVIDUALS WITH HIGHEST HYPOXIC
BURDEN HAD HIGHEST CVD MORTALITY
RISK SO THIS IS IMPORTANT IN
UNDERSTANDING OUR NEED AND
BRIDGE THE POLYSOMNOGRAPHIC
DATA.
THEY LOOKED AT AUTONOMIC
RESPONSE, ELEVATED DELTA HEART
RATE, ASSOCIATED WITH INCREASED
RISK FOR CARDIOVASCULAR
MORBIDITY AND MORTALITY,
DEMONSTRATING HOW THE PULSE RATE
RESPONSE POST EVENT, SO HAVING
TOO HIGH DELTA HEART RATE OR TOO
LOW WAS ASSOCIATED WITH
INCREASED RISK FOR
CARDIOVASCULAR DISEASE EVENTS.
WHAT WAS MOST INTRIGUING TO ME
IN THEIR SUBSEQUENT WORK WHERE
THEY LOOKED AT HOW THESE
SUBGROUPS OF HEART RATE RESPONSE
RESPOND TO CPAP THERAPY, WHAT
THEY FOUND IS THAT, YOU KNOW,
THERE WAS A PREFERENTIAL BENEFIT
OF CPAP IN HIGH PULSE RATE
RESPONSE BUT REALLY THERE WAS
SUGGESTION OF POTENTIAL HARM
FROM CPAP IN THOSE WITH LOW
DELTA HEART RATE.
THIS IS, AGAIN, IMPORTANT FOR US
TO NOT ONLY SUBGROUP AND
PHENOTYPE AND ENDOTYPE
INDIVIDUALS FOR PROGNOSTICATION
FOR CARDIOVASCULAR DISEASE
ENDPOINTS AND SIMILARLY
HYPERTENSION BUT CAN'T ASSUME
RESPONSE TO CPAP IN HIGH RISK
SUBGROUPS IS GOING TO BE THE
SAME, THAT WE CAN PREDICT IT'S
GOING TO BE BENEFICIAL.
THIS IS WHERE HETEROGENEITY OF
TREATMENT RESPONSE FOR CPAP OR
OTHER THERAPIES AND ITS
RELEVANCE TO PULMONARY
HYPERTENSION IS IMPORTANT.
SO WE TALKED ABOUT THE ENDOTYPES
AND PHENOTYPES, OF COURSE THE
GENOTYPE IS IMPORTANT AND
THERE'S WORK THAT'S BEEN DONE.
HOWEVER I THINK THERE'S MORE
THAT NEEDS TO BE DONE TO BETTER
UNDERSTAND THE GENETIC
ASSOCIATIONS BUT HOW -- AND HOW
THEY SORT OF INFORM RATES FOR
CARDIOVASCULAR DISEASE AND MAYBE
SIMILARLY PULMONARY HYPERTENSION
RISK AND SO OVERALL A DEEPER
UNDERSTANDING OF HOW OSA
ENDOTYPES DRIVE CLINICAL
PHENOTYPE OF OSA TO BETTER
DECIDE INTERPRETATION AND USE
DIAGNOSTIC AND PROGNOSTIC
MARKERS, AND THIS IS REALLY JUST
A BEAUTIFUL PICTURE FROM BRAD
EDWARDS' PAPER.
SO IN THE LAST FEW MINUTES I
BELIEVE I GO TILL 11:35, RIGHT?
YES.
JUST CHECKING ON TIME.
PROPOSED MECHANISMS ARE SHOWN IN
THIS FIGURE HERE.
PRIMARILY THERE'S HYPOXIC
VASOCONSTRUCTION, NEGATIVE
PRESSURE IS LINKED TO THE
INCREASED LOAD AND CAPILLARY
DECREASED VENTRICULAR
COMPONENTS, AND THEN ENDOTHELIAL
DYSFUNCTION, HEIGHTENED
INFLAMMATORY STATE, SYMPATHETIC,
IMPLICATED AS PROPOSED
MECHANISMS AND AS DAN POINTED
OUT OBSTRUCTIVE SLEEP APNEA IS
IMPORTANT BUT OF COURSE OTHER
SLEEP DIMENSIONS INCLUDING
INSOMNIA PHENOTYPE, FREQUENT
AROUSAL, MAY DRIVE THE
SYMPATHETIC ACTIVATION, SYSTEMIC
HYPERTENSION AND PULMONARY
OUTCOME WE'RE ALL HERE TO
DISCUSS.
HYPOXIC BURDEN AND PULMONARY
HYPERTENSION, MOST OF THE DATA
IS LOOKING AT CARDIOVASCULAR
DISEASE ENDPOINTS LIKE
MYOCARDIAL INFUNCTION, STROKE,
HOWEVER WHAT DO WE KNOW ABOUT
THIS, AND THERE ARE STUDIES THAT
LOOKED AT THIS, THIS IS ONE THAT
IS MOST RECENT WORK PUBLISHED IN
THE JOURNAL OF CLINICAL SLEEP
MEDICINE WHERE WE LOOK AT
CORRELATION BETWEEN PULMONARY
HEMODYNAMICS AND PARAMETERS.
WHAT WAS INTERESTING HERE IS
THAT T90 WAS THE FACTOR
ASSOCIATED WITH MEAN ARTERIAL
PRESSURE AND EVERY FIVE UNIT
INCREASE 36% GREATER RISK OF
MEAN ARTERIAL PRESSURE GREATER
THAN 25 MILLIMETERS OF MERCURY,
NOT AN INDEPENDENT RISK FACTOR,
CONFIRMED IN OTHER STUDIES AT
THE BOTTOM WHERE WHEN USED ALONE
IT WAS NOT STRONGLY LINKED WITH
PULMONARY HYPERTENSION, AND THAT
T90 IN ANOTHER STUDY WAS A
BETTER -- STRONGLY CORRELATED
WITH PULMONARY HEMODYNAMICS, H I
WAS NOT.
THERE IS INTEREST HERE,
INTERESTING DATA HERE,
SUGGESTING THAT THE HYPOXIC
BURDEN MAY HELP US IDENTIFY HIGH
RISK PHENOTYPES.
T 90 ONLY MEASURES DESATURATION
BELOW 90%, IN SOME INDIVIDUALS
IF YOU ARE STARTING AT 96% T90
WILL MISS ALL OF THESE
INDIVIDUALS.
ON THE OTHER HAND IF YOUR
BASELINE OXYGEN IS SLIGHTLY
BELOW T90 THE WHOLE TIME, IT
WILL BE 100%.
IT IS NOT HIGHLY CORRELATED WITH
HYPOXIC BURDEN BUT JUST, AGAIN,
FOOD FOR THOUGHT, DIRECTIONS WE
MAY WANT TO MOVE TOWARDS.
PULSE RATE RESPONSE AND
PULMONARY HYPERTENSION, WHAT
EVIDENCE DO WE HAVE ON
DYSREGULATION, AND THE CHANGE
FROM MINIMUM HEART RATE TO
MAXIMUM HEART RATE, DELTA HEART
RATE, AFTER A RESPIRATORY EVENT
MAY REFLECT THE FACT THAT BOTH
PARASYMPATHETIC AND SYMPATHETIC
SYSTEM AND MORE PRONOUNCED
SYMPATHETIC RESPONSE, A LARGER
INCREASE IN HEART RATE, MAY BE
SYMPATHETIC RESPONSE, OR
COMBINATION.
BOTTOM LINE IN THE FIGURE ON THE
LEFT HERE, YOU CAN SEE THERE'S A
VERY HEAVY AUTONOMIC NERVOUS
SYSTEM INVOLVEMENT IN THE
TRACHEOBRONCHIAL TREE IN THE
LUNG, IN THE HEART, AND THE BLUE
FIBERS ARE THE PARASYMPATHETIC
NERVOUS SYSTEM, I THINK THIS MAY
POTENTIALLY HELP US FURTHER
PHENOTYPE PATIENTS WITH
PULMONARY HYPERTENSION IF WE
FURTHER UNDERSTAND RULES OF THE
SYMPATHETIC AND PARASYMPATHETIC
IN PATIENTS BASED ON WORK IN THE
NON-PULMONARY HYPERTENSION
SETTING.
AND THIS SLIDE SHOWS SAME THING,
MAGNIFIED.
WHAT I WANT TO POINT OUT THERE
IS WORK, I'M MORE FAMILIAR IN
THE LAST FEW MONTHS, PREPARING
FOR THIS TALK.
BETA BLOCKERS REALLY APPARENTLY
DID NOT PAN OUT AS A MAJOR
TARGET AND EXPERTS ON THIS PANEL
CAN SPEAK TO THAT MORE BUT MAYBE
PULMONARY ARTERY INNERVATION MAY
BE AN OPTION, HAS SHOWN PROMISE
IN EARLY CLINICAL TRIALS, BUT
HOW DOES THIS FIT INTO
OBSTRUCTIVE SLEEP APNEA, WHAT
DOES CPAP DO TO THE RESPONSE,
POST EVENTS IN INDIVIDUALS WITH
SLEEP APNEA AND PULMONARY
HYPERTENSION ARE THE QUESTIONS
TO HELP US UNDERSTAND THE ROLE
OF THE AUTONOMIC NERVOUS SYSTEM
BECAUSE THERE'S INCREASED
SYMPATHETIC ACTIVITY.
LET'S TALK ABOUT THE EFFECTS
CPAP THERAPY.
THERE'S A TALK SPECIFICALLY
DEDICATED TO THIS.
I WANT TO SHOW A RANGE OF DELTA
IMPROVEMENT IN THE PRESSURE WITH
CPAP.
SO THERE MAY BE A POTENTIAL, YOU
KNOW, HETEROGENEITY OF TREATMENT
RESPONSE SIGNAL THAT WE MAY BE
SEEING IN PULMONARY HYPERTENSION
PATIENTS.
AND WE'RE SORT OF GETTING CLOSER
TO THE END OF MY TALK BUT I WANT
TO DEMONSTRATE THAT BY SHOWING
THAT THE AVERAGE TREATMENT
RESPONSE, AND WE'VE SEEN
CARDIOVASCULAR DISEASE TRIALS
THAT HAVE NOT SHOWN IMPACT OF
CPAP THERAPY BUT MAYBE BY
SEGREGATING PATIENT POPULATION
BASED ON TREATMENT RESPONSE WE
CAN GO AFTER THE INDIVIDUALS
THAT WE SEE A GREATER SIGNAL FOR
BENEFIT, FOR CPAP OR ANY OTHER
TREATMENT RESPONSE, SIMILAR
APPROACH CAN HELP WITH PULMONARY
HYPERTENSION.
WE'VE DONE THIS WORK IN OUR
COLLABORATION WITH A STUDY THAT
LOOKED AT IMPACT OF CPAP ON
CARDIOVASCULAR DISEASE EVENTS IN
INDIVIDUALS WITH ACUTE CORONARY
SYNDROME.
WE APPLIED MACHINE LEARNING AND
WHAT WE FOUND IS THAT BASICALLY
THERE'S THIS SORT OF -- THERE
ARE SUBGROUPS WITH DIFFERENTIAL
TREATMENT RESPONSE, THERE ARE
TREATMENTS THAT THERE ARE
SUBGROUPS THAT MAY EXPERIENCE
HARM, THIS WORK IS CURRENTLY
UNDER REVIEW AND WE PRESENTED
THIS AT THE ATF, AND THERE ARE
SPECIFIC VARIABLES IN OUR MODEL
THAT SEEM TO RISE TO THE TOP AS
A DECISION POINT FOR TREATMENT
RESPONSE IN INDIVIDUALS WITH
SHORTER EVENT DURATION SEEMED TO
BENEFIT MORE FROM CPAP THERAPY.
AND THIS HAS BEEN SHOWN BY WORK
FROM BUTLER AND REDLINE WHERE
EVENT DURATION DID PREDICT
MORTALITY IN A THREE-PART
HEALTHY STUDY.
THERE ARE MORE TO SLEEP DATA AND
HI THAT WE'RE MISSING AND
HOPEFULLY SOME OF THESE
PHYSIOLOGIC ENDOTYPES AND
PHENOTYPES WE TALKED ABOUT WILL
HELP INFORM THE RELATIONSHIP
BETWEEN OBSTRUCTIVE SLEEP APNEA
AND PULMONARY HYPERTENSION AND
MORE IMPORTANTLY HOW CPAP OR
OTHER TREATMENT OPTIONS MAY
INFLUENCE THAT.
FINALLY WE HAVEN'T TALKED ABOUT
OMICS OR BIOMARKERS AND I THINK
THAT'S ANOTHER AREA THAT REALLY
NEEDS TO BE EXAMINED BECAUSE OUR
WORK WHERE WE'VE USED
INFLAMMATION IN BASELINE
BIOMARKERS TO THEN DETERMINE HOW
THESE INDIVIDUAL SUBGROUPS
RESPOND TO CPAP THERAPY WE DO
SEE THAT CPAP THERAPY HAS
DIFFERENTIAL TREATMENT RESPONSE
IN INDIVIDUALS WITH HIGH
INFLAMMATION AT BASELINE VERSES
LOW.
I WON'T GO INTO THIS BUT JUST
AGAIN TO PROVIDE A LITTLE BIT OF
FLAVOR AND YOU CAN LOOK AT THE
MANUSCRIPT IF YOU'RE INTERESTED.
AGAIN, TO DRAW ATTENTION TO THIS
FIGURE ON THE LEFT, 3A,
INDIVIDUALS IN THE HIGH
INFLAMMATORY SUBGROUP USING
BASELINE BIOMARKERS BENEFITED
FROM CPAP, SCORE FOR
INFLAMMATION REDUCED.
HOWEVER INDIVIDUALS WHO HAD LOW
INFLAMMATION AT BASELINE, THEIR
INFLAMMATION APPEARED TO WORSE
WITHIN CPAP.
AGAIN, JUST USING THIS APPROACH
IN PULMONARY HYPERTENSION I
THINK WILL MOVE THE NEEDLE.
SPECIFICALLY ON INFLAMMATION, I
WANT TO SHARE MY COLLEAGUE
DEMONSTRATE BY PET MRI
ASSOCIATED WITH PULMONARY
HYPERTENSION AND THAT INTENSITY
CORRELATED WITH PULMONARY ARTERY
PRESSURE, WORK IN SARCOIDOSIS.
WHAT WE'RE DOING AT THE MOMENT,
A FELLOW HERE AT SINAI IS
MEASURING UPTAKE IN ABOUT 200
PATIENTS BEFORE AND AFTER CPAP
THERAPY, SHE'S PRETTY MUCH DONE
SO WE'RE HOPING TO SUBMIT THE
WORK TO OF SO PLEASE KEEP AN EYE
OUT.
WE'RE TRYING TO AGAIN UNDERSTAND
HOW OBSTRUCT IVE SLEEP APNEA MAY
BE POTENTIALLY, YOU KNOW, I USE
THE WORD CAUSING IN QUOTATIONS,
PULMONARY HYPERTENSION OR HOW
TREATMENT RESPONSE MAY VARY
BASED ON PULMONARY ARTERY
INFLAMMATION FOR EXAMPLE.
I HOPE I'VE SHED SOME LIGHT ON
PHENOTYPES, SPECIFICALLY
POLYSOMNOGRAPHIC DATA.
I DIDN'T HAVE TIME TO GO INTO
EFFECT DIFFERENCES BUT THAT'S AN
IMPORTANT AREA, PERTAINING TO
SLEEP APNEA, ANOTHER PHENOTYPE,
OBESITY, VISCERAL FAT IS ANOTHER
AREA OF INTEREST FOR OUR GROUP.
WHAT IS THE IMPACT OF PULMONARY
HYPERTENSION OF THESE
SUBPHENOTYPES, WHAT IS RESPONSE
TO CPAP IN TERMS OF VARIABLE
RESPONSE TO CPAP AND
HETEROGENEITY OF CPAP RESPONSE,
UNEXPLORED GENETIC INFLUENCES
AND OTHER OMICS LEVERAGING
ADVANCED TECHNIQUES LIKE WE HAVE
TO APPLY MACHINE LEARNING TO
EXISTING DATASETS TO THEN GET A
BETTER SORT OF MORE HYPOTHESIS
GENERATING AND REALLY USE
DATASETS AND CLINICAL TRIALS AND
EPIDEMIOLOGICAL COHORTS TO
ENRICH THE FUTURE OF RANDOMIZED
CONTROLLED TRIALS TO IDENTIFY
THROUGH ADVANCED ANALYSES, WE
CAN APPLY TO PULMONARY
HYPERTENSION.
I WANT TO END WITH THIS
ESSENTIALLY IMPORTANT REMINDER
AS A PHYSICIAN AND AS OUR
CO-CHAIR POINTS OUT, IN OUR
HASTE TO DEVELOP NEW TREATMENTS
FOR THIS DEADLY SYNDROME WE NEED
TO REMEMBER OUR PLEDGE AS
PHYSICIANS, FIRST DO NO HARM.
AND GIVEN THE SIGNALS WE'RE
SEEING OUR WORK AGAIN IT'S NOT
ENOUGH JUST TO SUBPHENOTYPE.
IT'S REALLY IMPORTANT TO FURTHER
UNDERSTAND THE RESPONSE TO CPAP
THERAPY IN ALL OF THESE
INDIVIDUALS.
SO I'LL STOP SHARING AND I THANK
YOU FOR YOUR ATTENTION AND TIME.
>>FANTASTIC.
AGAIN, SO EXPANSIVE AND DEEP AND
STIMULATING, AND PERFECT FOR
THIS SESSION.
AGAIN, I THINK YOU'VE HEARD A
LOT ABOUT THE INTRODUCTION ABOUT
HYPOXIA AND I THINK YOU'RE NOW
CHALLENGING US TO EVEN RECOGNIZE
THAT SLEEP APNEA, WHETHER
MEASURED BY SIMPLE HYPOXIC
MEASURE OR AHI MAY BE
INSUFFICIENT AS WE THINK ABOUT
THE SUBGROUPS AND THE TARGETS OF
INTERVENTION, I'M SURE WE'LL
PICK MORE UP LATER.
AGAIN, IS THERE ANYONE WITH ONE
OR TWO QUESTIONS BEFORE WE END
THIS PARTICULAR TALK?
>>GO AHEAD.
>>THANK YOU.
I HAVE A QUESTION ABOUT THE
DIRECTION WE'RE GOING WITH SLEEP
STUDIES, EMPHASIS ON DOING A LOT
OF HOME SLEEP STUDIES USING
SIMPLE DEVICES, HOW WILL THAT
AFFECT YOUR PLEA FOR MORE
PRECISION MEDICINE AND DOING
THESE FAIRLY SOPHISTICATED
TECHNIQUES TO BETTER PHENOTYPE
PATIENTS?
>>YEAH, A GREAT QUESTION.
MY COLLEAGUE ON THIS CALL, WE'RE
WORKING TO HELP ANSWER THAT IS
WHAT I WILL SAY.
WE'RE PUTTING TOGETHER GRANT
PROPOSAL TO ADDRESS THAT.
WITHOUT REALLY GOING INTO THE
DETAILS I HAVE SORT OF
POTENTIALLY THOUGHT ABOUT MAYBE
WHETHER IT'S TIME TO BRING BACK
FULL (INDISCERNIBLE) BECAUSE
THERE'S ALL OF THIS INFORMATION
THAT'S LEFT ON THE TABLE IN OUR,
YOU KNOW, SEARCH FOR EASY
DIAGNOSTIC TOOL.
YOU COULD DO THIS FULL AT HOME,
SUSAN CAN SPEAK TO THAT, BUT I
AGREE, I THINK THERE'S -- WE'RE
GOING TO HAVE TO TAKE A PAUSE TO
FIGURE OUT HOW WE APPLY WHAT
WE'RE DOING IN THE RESEARCH
SETTING, CLINICAL SETTING,
BECAUSE IT IS MOVING TOWARDS A
VERY NARROW FEW CHANNELS OF
QUICK H I AND AS I SHARED NONE
OF THE STUFF I PROVIDED TODAY
REALLY TALKED ABOUT THE H I
EXCLUSIVELY.
WE MAY BRING THG BACK OR HAVE A
TOTALLY NEW DIAGNOSTIC DEVICE
THAT WILL BE, YOU KNOW, DRIVEN
BY SOME FINDINGS AND WILL
BASICALLY HAVE A NEW CATEGORY OF
HOME SLEEP TEST.
>>THANK YOU.
THAT'S A GREAT QUESTION.
I SUGGEST THAT THAT MAY BE ONE
OF THE ITEMS WE PICK UP IN THE
WRAP-UP DISCUSSION AREA.
JUST FOR THE PURPOSES OF TIME, I
APOLOGIZE TO DR. CHAN BUT IF YOU
COULD KEEP YOUR QUESTIONS FOR
THE WRAP-UP, I WILL MAKE SURE
THAT YOU ARE THE TWO THAT ARE
FIRST CALLED ON.
I'LL GIVE DR. CHAN OPPORTUNITY
TO NOW REALLY WRAP UP THIS
SESSION AND I THINK MOST PEOPLE
REALIZE HE'S A KEY LEADER IN
REALLY THE FIELD IN TERMS OF
UNDERSTANDING MECHANISMS FOR
PULMONARY HYPERTENSION SO OUR
FIRST CARDIOLOGIST JOINING US
TODAY, DR. CHAN WILL CONTINUE
THE THEME OF PRECISION MEDICINE
BUT NOW FOCUSING SPECIFICALLY ON
THE LINK BETWEEN VASCULAR
DISEASE AND SLEEP APNEA.
THANK YOU, DR. CHAN.
>>WELL, THANK YOU FOR THE
INVITATION, HAPPY TO BE HERE.
I'M GOING TO TRY TO SHARE MY
SLIDES.
DO YOU SEE PRESENTATION MODE?
HOPEFULLY THAT'S A YES.
>>YES.
>>SO AS SUSAN MENTIONED I'M
GOING TO TRY TO ADDRESS AND GIVE
OVERVIEW FROM A MOLECULAR
BIOLOGIST PERSPECTIVE, AS A
CARDIOLOGIST, VASCULAR
BIOLOGIST, THE LINK BETWEEN
VASCULAR DISEASE IN GENERAL AND
SLEEP APNEA, SPINNING WITH A
PRECISION MEDICINE LENS, THAT'S
A LOT OF WHERE THE THEMES ARE
GOING WITH THIS WORKSHOP.
THESE ARE MY DISCLOSURES.
TO START, WE HAVE HEARD THE
CONNECTION HAS BEEN KNOWN FOR
TWO DECADES, AN EXCERPT FROM A
SEMINAL NEW ENGLAND JOURNAL
PAPER FROM 2000 WHERE THEY
REPORTED ON SLEEP DISORDERED
BREATHING AND HYPERTENSION AND
IT WAS REPORTED THAT THERE WAS
PERSONS WITH INCREASING SEVERITY
OF SLEEP DISORDERED BREATHING
MEASURED BY AHI AND I KNOW THERE
ARE A LOT OF QUESTIONS ABOUT
THAT GOING FORWARD IN TERMS OF
ENDOTYPING BUT IN THIS CASE IT
WAS SEEN ACROSS THE BOARD IN
TERMS OF ASSOCIATION WITH
ADJUSTMENTS OF NON-MODIFIABLE
RISK FACTORS SUCH AS AGE AND SEX
AS WELL AS MODIFIABLE SUCH AS
HABITS, ALCOHOL AND SMOKING, THE
CONNECTION IS COMPELLING.
OVER THE PAST TWO DECADES DATA
HAVE BEEN GENERATED FOR MORE
ACUTE VASCULAR DISEASE LIKE
ACUTE CORONARY SYNDROME SHOWN
FROM A PUBLICATION IN 2015 WHERE
DISEASE SEVERITY OF ACS AS
REFLECTED BY NUMBER OF DISEASE
VESSELS, CARDIAC EJECTION
FRACTION AND TROPONIN ASSOCIATED
WITH SLEEP APNEA.
THIS WAS TAKEN FROM A WHITE
PAPER FROM 2017, BEYOND
HYPERTENSION AND ACS RISK AND
SEVERITY OF OTHER VASCULAR
DISEASES HAVE SHOWN ASSOCIATIONS
WITH SLEEP APNEA INCLUDING
STROKE, PULMONARY HYPERTENSION,
THE FOCUS OF THIS WORK SHOPPE
AND DIABETES AND DYSLIPIDEMIA.
PEOPLE ARE AT RISK FOR
CARDIOMYOPATHY, HEART FAILURE,
AND PORTENDS HIGHER
CARDIOVASCULAR MORTALITY RATE IN
GENERAL AS DR. BUYSSE SHOWED.
THERE'S ALSO AN INCREASING
APPRECIATION THAT THESE
CARDIOVASCULAR AND METABOLIC
CONSEQUENCES MAY IN TURN WORSEN
PATHOGENIC CAUSES TURNING THIS
INTO A BIDIRECTIONAL AND VICIOUS
DISEASE CYCLE.
THERE ARE A NUMBER OF KEY
KNOWLEDGE GAP QUESTIONS THAT WE
CAN GO INTO THIS TALK.
THE FIRST QUESTION IS THE ONE
WE'RE GOING TO SPEND THE MOST
TIME ON.
ESSENTIALLY EMPHASIZING WHAT IS
KNOWN IN THE FIELD AT THIS POINT
AND EMPHASIZING WHAT THE FUTURE
DIRECTIONS COULD BE PARTICULARLY
IF PRECISION MEDICINE MAY BE
ABLE TO FILL IN THE GAPS OF
KNOWLEDGE AND TRANSLATIONAL
IMPLEMENTATION.
THE FIRST QUESTION IS WHAT ARE
THE MOLECULAR MECHANISMS THAT WE
KNOW ABOUT THAT CONTROL THE
BIDIRECTIONAL RELATIONSHIP
BETWEEN SLEEP APNEA AND MULTIPLE
VASCULAR DISEASES?
CERTAINLY PULMONARY VASCULAR
DISEASE IS ONE OF THOSE BUT
THERE'S A LOT OF OVERLAP IN
TERMS OF VASCULAR PATHOBIOLOGY
IN GENERAL.
THINKING FIRST AT THE MOLECULAR
LEVEL WE KNOW SLEEP APNEA HAS
BEEN LINKED TO INTERMITTENT
HYPOXIA AND HYPOXEMIA, WE HAVE
EXPERTS WORKING ON THAT IN THIS
WORKSHOP.
THIS IS THE BASIS OF MOLECULAR
AND CELLULAR STUDIES RELATING TO
CONTROL OF BREATHING AND CONTROL
OF SEQUENCES ON PULMONARY
VASCULATURE.
CENTRAL IS THE MAJOR
TRANSCRIPTION FACTOR OR FACTORS
OF HYPOXIA, INDUCIBLE FACTORS,
HIF.
HIF ABILITIES TO REPROGRAM
RESPONSE IN TERMS OF OXYGEN
UTILIZATION, METABOLISM, ROS
FORMATION AND ANGIOGENESIS, IN
ADDITION TO HYPOXIA, THIS CAN
DRIVE INFLAMMATORY PROGRAMMING,
PRIMARILY THROUGH A NUMBER OF
CENTRAL TRANSCRIPTION FACTORS
SHOWN HERE, NF-kappaB, THERE
BE A NUMBER OF OTHERS KNOWN AT
THE LEVEL OF TRANSCRIPTOMICS
THAT ARE IN PLAY HERE.
NOTABLY IN CASES OF SLEEP APNEA,
FRAGMENTATION CAN DRIVE.
TOGETHER, THEY CAN DRIVE
DYSFUNCTION OF ENDOTHELIAL
BARRIER, IMMUNE RECRUITMENT OF
LEUKOCYTES AND MACROPHAGES,
INCREASED COLLAGENATION BY FOAM
CELLS AS WELL AS VASCULAR AND
SMOOTH MUSCLE REMODELING IN
GENERAL.
NOW, ALL OF THESE POINTS CAN
HAVE EVEN GREATER EFFECTS ON
MOLECULAR PROGRAMS IN THE
VASCULATURE.
THIS IS A CARTOON OF ENDOTHELIUM
WHERE THOSE PATHWAYS WHEN
INITIATED CAN FURTHER CONTROL
VASOMOTOR TONE, PLATELET
AGGREGATION, INCREASE APOPTOSIS
AND AFFECT SURVIVAL, AGAIN REDOX
STATE IS IMPORTANT IN THIS
REGARD AND DOWNSTREAM SMOOTH
MUSCLE REMODELING IN GENERAL.
IN RECENT YEARS NEW LANDSCAPES
OF REGULATORY MOLECULES
EMERGED.
IN THIS EXAMPLE FROM A BLUE
JOURNAL ARTICLE IN 2023 HYPOXIA
DEPENDENT microRNA 210 FOUND
TO BE CIRCULATING IN PLASMA,
IDENTIFIED AS A BIOMARKER AND A
MAJOR REGULATOR OF INFLAMMATION,
METABOLIC SYNDROME AND
METABOLISM AND PULMONARY
VASCULAR FUNCTION IN SLEEP
RELATED DISORDERS.
THESE FINDINGS OFFER US A WINDOW
AND IMPETUS TO LOOK PRECISELY AT
THESE NEW PERHAPS EMERGING
SYSTEMS OR MULTIOMICS LEVEL OF
DATA TO DEFINE FULL MOLECULAR
PROFILE THAT'S ALTERED IN SLEEP
APNEA AND VASCULAR DISEASE.
BEYOND MOLECULES, IN ADDITION
AND BEYOND THAT, SLEEP APNEA
ALSO IS KNOWN TO HAVE MANY
EFFECTS ON COMPLEX
INTERRELATIONSHIPS BETWEEN THE
SYMPATHETIC NERVOUS SYSTEM AND
CARDIOVASCULAR TISSUE.
DR. SHAH'S TALK ALSO TOUCHED
UPON THIS AS WELL.
THIS CARTOON FROM 2014 DESCRIBED
THIS, UNDER BASELINE CONDITIONS
AND PANEL A ON THE LEFT NORMAL
VENTILATION AND NORMOXIA CAN
REGULATE INHIBITOR AND
EXCITATORY NEURAL INPUT TO THE
BRAINSTEM, AND WITH MODULATORS
CAN LEAD TO A BASELINE
HOMEOSTASIS OF SYMPATHETIC
NEURAL ACTIVITY THAT LEADS TO
REGULATION OF BLOOD PRESSURE AND
CARDIAC FUNCTION.
HOWEVER, UNDER CONDITIONS OF
APNEA WHICH INHIBIT THIS
INHIBITORY INPUT, HYPOXIA WHICH
EXCITES NEURAL ACTIVITY ACROSS
THE BRAINSTEM CAN LEAD TO
EXCESSIVE SUSTAINED SYMPATHETIC
ACTIVITY, ULTIMATELY END ORGAN
DAMAGE.
INTERESTINGLY THERE IS EMERGING
WORK NOW SUGGESTING THAT THESE
CARDIOVASCULAR DISEASE STATES
CAN FEED BACK AND REINFORCE SUCH
DYSFUNCTION ACROSS SPINAL CORD
GANGLIA AND COGNITIVE FUNCTION
DRIVING THE CYCLE OF DISEASE.
THIS IS COMING FROM A RECENT
REVIEW, KNOWS SAME PRINCIPLES
CAN PROMOTE PATHOGENIC VASCULAR
AND THROMBOTIC COMPLICATIONS.
THIS FOCUSES ON VASCULAR
COMPLICATIONS, IT IS IMPORTANT
TO NOTE THAT THERE ARE KNOWN
THORACIC AND CARDIAC HEMODYNAMIC
COUPLING AVENUES THAT LEAD TO AN
INCREASE THE REALM OF
INTRATHORACIC PRESSURE SWINGS IN
SLEEP APNEA, THAT COUPLING
ALTERS PRE-LOAD AND AFTER-LOAD
SPECIFICALLY SEEN BY THE LEFT
VENTRICLE, LEADING TO FIBROSIS
AND REMODELING OF CARDIAC
TISSUE, LEADING TO HEART
FAILURE.
I WANT TO NOTE THERE ARE MORE
ADVANCES EMERGING IN
UNDERSTANDING HOW OTHER ORGAN
SYSTEMS RELATE TO BOTH SLEEP
APNEA AND VASCULAR DISEASE.
THIS IS AN EXAMPLE OF THE GUT
MICROBIOME, HOW THOSE CHANGES IN
THE GUT MICROBIOME MAY ACTUALLY
BE ALTERED WITH SLEEP APNEA AND
CARDIOVASCULAR DYSFUNCTION AND
WHETHER OR NOT IT REMAINS TO BE
SEEN IF SELECTIVE OR PRECISE
PROBIOTIC MODULATION OF THE GUT
MICROBIOME CAN BE USED AS A
NOVEL THEY HAVE -- THERAPEUTIC.
IN ADDITION, WHAT IS THE
RELATIONSHIP BETWEEN THOSE AND
SPECIFIC VASCULAR DISEASES THAT
WE'RE SEEING, PULMONARY AND
PERIPHERAL.
SO IN THAT CONTEXT, I FOUND AT
LEAST IN TERMS OF A LOT OF
REVIEWS OUT THERE THAT THERE'S
QUITE A BIT OF OVERLAP BETWEEN
THOSE PATHOGENIC PROGRAMS ACROSS
THESE VASCULAR STATES.
EXAMPLE HERE IS ATHEROSCLEROSIS,
OBVIOUSLY CORONARY ARTERY
DISEASE, ACUTE CORONARY SYNDROME
AND STROKE ASSOCIATED WITH
OBSTRUCTIVE SLEEP APNEA THOUGHT
TO BE REGULATED BY SAME
PATHOGENIC PATHWAYS REPRESENTED
WITHIN THESE GIVEN STATES.
I WANT TO EMPHASIZE THAT IN
ADDITION TO THE DIRECT HYPOXIC
AND INFLAMMATORY MECHANISMS THAT
AFFECT CARDIAC AND VASCULAR
TISSUE SHOULD NOT FORGET
CONVERGES OF PATHOGENIC EFFECTS
THAT'S APPRECIATED THROUGH SLEEP
APNEA ALTERATIONS OF INSULIN
RESISTANCE AND DIABETES,
PANCREATIC AND ADIPOCYTE
FUNCTION BY SLEEP DISORDERED
BREATHING.
I WON'T GO INTO DETAIL HOW THEY
DRIVE PULMONARY HYPERTENSION,
WE'RE GOING TO SEE MULTIPLE
DETAILED TALKS, AND DR. SHAH
ALREADY MENTIONED THIS, I THINK
I WOULD EMPHASIZE THAT WE KNOW
THERE ARE MECHANISMS THAT ARE
SURROUNDING THE DEVELOPMENT OF
BOTH PRE-CAPILLARY AS WELL AS
POST-CAPILLARY PULMONARY
HYPERTENSION CENTRALIZED IN
TERMS OF APNEIC EVENTS AS WELL
AS NEGATIVE INTERTHORACIC
PRESSURE LEADING TO RV
DYSFUNCTION, FROM THE
POST-CAPILLARY STANDPOINT AGAIN
THE IDEA OF RV STRAIN DUE TO
INCREASED VENOUS RETURN FROM THE
NEGATIVE PRESSURE CAN LEAD TO A
CASCADING EFFECT ULTIMATELY
REDUCING LV FILLING, INCREASING
SYMPATHETIC TONE, COMPROMISING
LV FUNCTION IN THE
POST-CAPILLARY STATE, SOMETHING
STILL ONGOING IN TERMS OF
INVESTIGATION, WE STILL DON'T
UNDERSTAND PRECISELY WHAT THE
MOLECULAR MECHANISMS ARE THAT
DIFFERENTIATE THOSE TWO.
AS MENTIONED PREVIOUSLY THERE IS
ADVANCING APPRECIATION OF
BIDIRECTIONAL RELATIONSHIPS
COLLECTING SLEEP APNEA AND
CARDIOVASCULAR DISEASE, NAMELY
THROUGH THE SAME THORACIC
CARDIOVASCULAR COUPLING THAT
WORSENS CARDIAC FUNCTION AND
THAT CAN FEED BACK AND AUGMENT
INTERTHORACIC SWINGS, CHRONIC
INFLAMMATION IS PATHOGENIC FOR
VASCULAR DISEASE AND SLEEP
REDUCTION AND NEURAL ACTIVITY
WORSENS SLEEP EFFICIENCY, AT THE
MOLECULAR AND PATHWAY LEVEL
INFLAMMATION, HYPOXIA AND HEART
FAILURE ARE DRIVEN AND DRIVE
SYMPATHETIC ACTIVATION.
SO, FINAL WORD ABOUT SOME
MOLECULAR MECHANISMS, WE'RE
STILL IN THE MIDST OF TRYING TO
UNDERSTAND MORE PRECISELY THE
LANDSCAPE OF MOLECULES AND
PATHWAYS THAT ARE IMPORTANT,
THERE ARE SOME UNMET NEEDS TO DO
THAT.
FUTURE DIRECTIONS FOR
FUNDAMENTAL INSIGHT IN THIS
REGARD SHOULD INCLUDE NEED FOR
MORE SPECIFIC SLEEP RELEVANT
ANIMAL MODELS THAT GO BEYOND
INTERMITTENT HYPOXIA.
I BELIEVE THAT WE'RE NOW IN AN
AGE WHERE EX VIVO SYNTHETIC
BIOLOGY MODELS, SO FOR INSTANCE
ENGINEERED 3D BIOPRINTED
TISSUES, EXAMPLE HERE IS
BIOPRINTED HEART FROM OUR
INSTITUTE, MAY BE VERY USEFUL IN
TERMS OF IDENTIFYING MECHANISMS
AND SCREENING FOR THERAPEUTIC
APPLICATIONS.
OF COURSE, THE NEED FOR
A.I.-DRIVEN MACHINE LEARNING AND
MULTIOMIC PROFILING OF
OBSTRUCTIVE SLEEP APNEA AND
LINKED CARDIOVASCULAR DISEASE
ARE ONGOING, WE'LL HEAR MORE BUT
THE NEED IS PROMINENT IN THAT
REGARD TO MAKE PROGRESS.
IN TERMS OF SECOND QUESTION,
WHAT ROLE DOES GENETICS PLAY IN
CONTROLLING LINK BETWEEN SLEEP
APNEA AND VASCULAR DISEASE,
TOUCHED UPON IN PRIOR TALKS BUT
A NUMBER OF GENOME I'D
ASSOCIATION STUDIES IDENTIFIED
POLYMORPHISMS.
HOWEVER, THERE'S SPARSE DATA
LINKING THESE PARTICULAR SNPs
TO A DYNAMIC RISK OF VASCULAR
DISEASE AND FURTHERMORE THE
GENOMIC OR GENE REGULATORY
MECHANISMS HAVE NOT BEEN
EXPLORED.
IF SLEEP ENDOTYPES AS DISCUSSED
ELEGANTLY BY DR. SHAH COULD BE
ADJUDICATED PRECISELY WE AS A
COMMUNITY ARE IN A POSITION TO
LEVERAGE SOME EXISTING AT LARGE
POPULATION COHORTS, EXAMPLES
INCLUDING U.K. BIOBANK, I WAS
INTRIGUED BY A RECENT
PRESENTATION AT THE AAJ SESSION
WHERE IS MGH GROUP UTILIZED THE
U.K. BIOBANK MRI DATA, THOSE
HITS COULD BE ANALYZED THROUGH
SLEEP DISORDERED BREATHING TO
GAIN INSIGHTS OF GENETIC FACTORS
DRIVING AGAIN THOSE CONNECTIONS
OF SLEEP APNEA AND PULMONARY
VASCULAR AND EVEN PERIPHERAL
VASCULAR DISEASE.
FINALLY, CAN MULTI-MODALITY
THERAPIES REDUCE CARDIOVASCULAR
DISEASE OR SEVERITY?
THIS IS A BURNING QUESTION.
THERE'S A LONG HISTORY OF DATA
SHOWING CPAP OR CONTINUOUS
POSITIVE AIR WAY PRESSURE IS
IMPROVE MULTIPLE MOLECULAR
INDICES OF HYPOXIA,
INFLAMMATION, VASCULAR
DYSFUNCTION, SHOWN HERE, AND IN
THIS SUMMARY TABLE THERE HAVE
BEEN A NUMBER OF CLINICAL
STUDIES DEMONSTRATING BENEFIT OF
CPAP, PARTICULARLY IN PRIMARY
PREVENTION OF HYPERTENSION AND
OTHER CARDIOVASCULAR EVENTS,
THERE'S DATA ALSO REGARDING
BENEFIT OF USING CPAP BUT NOT
ALL DATA ARE CLEAN AND POSITIVE.
EXAMPLE IS THIS ISAAC STUDY,
MANY INVESTIGATORS ARE VERY
FAMILIAR WITH THIS, WERE PART OF
THAT TRIAL, SHOWING NO
SIGNIFICANT BENEFIT IN REDUCING
PREVALENCE OF ACUTE CORONARY
SYNDROME WHEN NOT FULLY
ENDOTYPING THAT POPULATION.
SO THE QUESTION REMAINS WHETHER
OR NOT THERE ARE ENDOTYPES WHERE
CPAP COULD BE HELPFUL OR PERHAPS
WE SHOULD BE THINKING MORE AT
THE PRECISION LEVEL.
THAT'S TO SAY THE SIMPLE
MODULATION OF CPAP FOR AIRWAY
ANATOMY MAY BE THE TIP OF THE
ICEBERG IN ORDER TO INTERVENE
ACROSS ASSOCIATED DETERMINANTS
AS WELL AS MOLECULAR
DETERMINANTS IN THIS REGARD
GENETICALLY AND OTHERWISE.
I'D LIKE TO END, I SHOULD BE
RIGHT ON TIME, CONCLUDE WE
CONTINUE TO BUILD OUR
UNDERSTANDING OF THE MOLECULAR
PHYSIOLOGIC AND GENETIC
MECHANISMS THAT CONTROL WHAT ARE
BIDIRECTIONAL RELATIONSHIPS
BETWEEN SLEEP APNEA AND A NUMBER
OF VASCULAR DISEASES.
I THINK THAT FUTURE WORK, AND
I'D LOVE TO DISCUSS THIS MORE
WITH YOU ALL, SHOULD SEEK TO
PROMOTE MULTIOMIC PROFILING AND
ADVANCE DISEASE MODELING SO
COMPUTATIONAL METHODOLOGIES IN
THIS SPACE TO BROADEN
FUNDAMENTAL UNDERSTANDING OF
THIS CONNECTION.
I THINK IT'S IMPORTANT TO
ACTUALLY HAVE MORE THAN JUST
SIMPLY IN VITRO AND TO
UNDERSTAND ENGINEERED SYNTHETIC
BIOLOGY MODELS TO ADVANCE
FURTHER AND THAT WOULD HOPEFULLY
MOVE US BEYOND AND/OR IN
ADDITION TO IDENTIFYING HOUSE
CPAP AND OTHER MULTI-MODAL
THERAPEUTICS MAY REDUCE
CARDIOVASCULAR DISEASE IN SLEEP
APNEA.
WITH THAT, I'D LIKE TO END.
THANK YOU FOR YOUR ATTENTION.
HAPPY TO TAKE QUESTIONS.
AND ENGAGE IN DISCUSSION WITH
YOU ALL.
THANK YOU VERY MUCH.
>>DR. CHAN, I FEEL LIKE I KEEP
REPEATING MYSELF, BUT EVERY TALK
HAS BEEN SO FANTASTIC, AS YOURS
WAS.
AND AGAIN, I SO APPRECIATE YOU
NOT ONLY ELUCIDATING SOME OF THE
MULTIPLE PATHWAYS BUT THESE
MOLECULAR MECHANISMS.
SO WHAT WE'LL DO NOW IS ANNA AND
I WILL CO-FACILITATE THIS
DISCUSSION.
WHAT WE WILL BE DOING AGAIN, IF
YOU CAN USE THE CHAT BOX, IF YOU
PREFER, BUT JUST AS EASY TO
RAISE YOUR HAND.
WE HAVE NOT ONLY THE
PARTICIPANTS BUT DISCUSSANTS
INCLUDING EARLIER STAGE
INVESTIGATORS AND WE WANT TO
HEAR YOUR VOICES AND QUESTIONS
TOO.
BUT BEFORE I OPEN THIS UP TO
EVERYONE LET ME GO BACK TO MY
PROMISE TO GIVE AN OPPORTUNITY
ASK HER QUESTION FROM ONE
BEFORE.
>>THANK YOU.
MY QUESTION FOR DR. SHAH.
SPECIFICALLY, AROUND THE
FINDINGS OF HARM WITH CPAP IN
PATIENTS WITH REDUCE THE HEART
RATE RESPONSE AFTER CERTAIN
EPISODES.
THE QUESTION COMES DOWN AROUND
WE KNOW PATIENTS HAVE AUTONOMIC
DYSFUNCTION THAT LIMITS THEIR
ABILITY TO MOUNT A HEART RATE
RESPONSE, THIS HAS BEEN WELL
DOCUMENTED.
HEART RATE VARIABILITY IN FREE
LIVING ENVIRONMENTS OR SLEEP,
BUT IN MY MIND I WOULD THINK
PATIENTS WITH MORE SEVERE
PULMONARY HYPERTENSION WOULD
FALL INTO THE SECOND CATEGORY OF
PATIENTS THAT CAN'T MOUNT A
HEART RATE RESPONSE AFTER
EPISODES WITH SLEEP, YOU KNOW,
AND THAT GROUP ALSO HAD WORSE
OUTCOMES.
I WAS WONDERING, NUMBER ONE, IF
YOU KNEW, HYPOTHESES AND
LOOKING AT HEART RATE RESPONSE
IN PRIMARY HYPERTENSION WITH
THESE EVENTS.
>>THANK YOU FOR THAT QUESTION.
I WAS LOOKING FOR THAT EVIDENCE
AS WELL.
THERE'S NOT A LOT FOR THE LAST
PART OF THE QUESTION.
WE WROTE AN EDITORIAL ON THIS
PULSE RATE RESPONSE AND I DIG
INTO EXACTLY YOUR QUESTION ABOUT
THE LOW HEART RATE RESPONSE AND
I THINK IT MAY BE CARDIOLOGISTS
HERE, FEEL FREE CHIME IN, MAY BE
A DEGREE OF INCOMPETENCE AND
THAT IS SORT OF WHAT I WAS
THINKING.
THERE'S ALSO THIS IDEA OF CPAP
POTENTIALLY HAVING A
PARASYMPATHETIC INFLUENCE, MAYBE
THAT'S ANOTHER WAY TO LOOK AT
THE RESPONSE AND HARM SIGNAL
WHICH MAY HAVE FURTHER DAMPENED
THAT RESPONSE, HEART RATE
RESPONSE, AND THEN
COMORBIDITIES, RIGHT?
SO INDIVIDUALS MAY HAVE OTHER
CO-MORBIDITIES THAT MAY BE
REFLECTIVE OF THAT DELTA HEART
RATE RESPONSE THAT'S LOWER,
MAYBE PHYSICAL ACTIVITY LEVELS
AND SEDENTARY LIFESTYLE AND
THINGS LIKE THAT.
THAT COMES TO MIND.
BUT I REMEMBER WE DEDICATED A
FEW SENTENCES OR A PARAGRAPH, WE
URGE YOU TO LOOK AT THAT, IN THE
INTEREST OF TIME.
>>THANKS FOR THE GREAT QUESTION
AND FOR THE RESPONSE.
THIS HAS BEEN AN AREA OUR GROUP
HAS BEEN PARTICULARLY INTERESTED
IN, AGAIN DELTA HEART RATE, THAT
PAPER, THOSE WITH LOWEST HEART
RATE TEND TO HAVE DIABETES,
EXISTING CARDIOVASCULAR DISEASE,
THEY WERE OLDER.
BUT VERY INTERESTINGLY, THIS IS
LARGELY UNPUBLISHED DATA, THE
INDIVIDUALS WITH THE HIGHEST
HEART RATE RESPONSES WERE THOSE
WITH THE SHORTER APNEAS.
THE GREATEST AND AS WELL AS
BLACK WOMEN IN PARTICULAR, AND
IN FACT HIGHEST DELTA HEART
RATES OCCURRED IN BLACK WOMEN
WHOSE APNEAS RESULTED IN A BRISK
HEART RATE RESPONSE BUT LITTLE
DESATURATION.
AND WHAT THOSE FINDINGS WHICH
WE'RE EXPLORING NOW EMPHASIZE TO
ME, WHICH MAY BE RELEVANT FOR
SOME DISCUSSIONS, REALLY IS THAT
IF WE THINK OF HYPOXIA AS ONE
DRIVER FOR PULMONARY VASCULAR
DISEASE AND COMORBIDITY, THEN
MAYBE AN ORTHOGONAL DRIVER
RELATED TO CARDIAC RESPONSE OR
AUTONOMIC NERVOUS SYSTEM
DYSFUNCTION THAT IS ACTUALLY
ORTHOGONAL, AND IN FACT THESE
EXPOSURES MAY BE DIFFERENTIALLY
DISTRIBUTED, DEEP DESATURATIONS
MAY TEND TO OCCUR WITH PEOPLE
ARE LONG APNEAS, DIFFERENCE IN
RECEPTOR, THE INDIVIDUALS WITH
MORE INHIBITION WITH THOSE
LONG -- WHICH HAVE INHIBITION
AND GREATER BASELINE STRESS,
WOMEN, MAYBE AFRICAN AMERICANS
IN PARTICULAR, MAY HAVE LESS
HYPOXIA BUT MORE OF THIS
AUTONOMIC RESPONSE.
I THINK THE REAL CHALLENGE IS
HOW WE TREAT EACH GROUP AND
WHETHER WE NEED TO THINK ABOUT
EACH GROUP AS HAVING DIFFERENCES
IN RISK OUTCOMES AS WELL AS
DIFFERENCES IN MANAGEMENT.
SO I DON'T KNOW IF THAT CONFUSED
THINGS OR ADDED INCREASED
COMPLEXITY.
HASSAN, YOUR HAND IS UP.
>>I HAD A QUESTION.
IT'S BEEN HARD TO ASSESS RHYTHM
BUT WITH NEW TOOLS LIKE SALIVARY
MELATONIN ASSAYS, PPG TO ASSESS
RHYTHM, TWO QUESTIONS.
DO YOU FEEL LIKE IT'S MORE THAN
IN MULTIOMIC TRIALS TO INCLUDE
IN MULTIOMICS IN LARGE TRIALS
AND IF SO DO YOU THINK THESE
MEASURES ARE THERE IN TERMS OF
ACCURACY TO BE INCLUDED IN THESE
LARGE PROSPECTIVE TRIALS?
>>YEAH, THANKS.
GREAT QUESTION.
I DO THINK IT'S IMPORTANT TO
MEASURE CIRCADIAN RHYTHM.
HOWEVER, I DON'T AT THIS POINT
KNOW THE BEST WAY TO DO THAT.
I THINK UNFORTUNATELY, YOU KNOW,
AS I WAS SAYING, WE HAVE CLOCKS
EVERYWHERE IN OUR BODIES, BUT
ACCESSING THE TIMING OF THOSE
DIFFERENT CLOCKS IS EXTREMELY
CHALLENGING.
AND EVEN OUR SO-CALLED GOLD
STANDARD KIND OF WHOLE BODY
MEASURES ARE, IN MY OPINION,
PRETTY SIGNIFICANTLY FLAWED.
IF YOU CONSIDER MELATONIN AS ONE
EXAMPLE, ASSAYING -- OR
EVALUATING MELATONIN AS A PHASED
MARKER OF CIRCADIAN CLOCK
DEPENDS CRITICALLY ON ALL SORTS
OF ENVIRONMENTAL AND BEHAVIORAL
FACTORS, RIGHT?
SO, THE MINUTE SOMEONE IS
EXPOSED TO LIGHT DURING TIME
THEIR MELATONIN IS RISING IT
SUPPRESSES MELATONIN.
SO I THINK THAT IN VIVO WHOLE
BODY PHYSIOLOGIC ASSAY IS THE
BEST WE CAN DO FOR NOW BUT IT'S
NOT NEARLY GOOD ENOUGH FOR WHAT
WE NEED, AND IT COULD BE THAT,
YOU KNOW, I THINK THERE'S
INITIALLY SOME GREAT PROMISE OF
TRANSCRIPTOMIC APPROACHES BUT I
THINK THAT IS MORE LIKELY TO BE
THE WAY THAT LEADS US FORWARD
THAN FRANKLY SOME OF THESE WHOLE
BODY PHYSIOLOGIC MEASURES.
>>THANKS FOR THE QUESTION AND
RESPONSE.
I BELIEVE NHLBI IS SPONSORING AN
UPCOMING WORKSHOP ON MEASURES OF
CIRCADIAN DYSFUNCTION THAT MAY
BE USING SOME OF THESE --
DISCUSSING TRANSCRIPTOME
APPROACHES, SO THANK YOU.
DR. MATHAI?
>>I WANTED TO FOLLOW ON
COMMENTS REGARDING DURATION OF
HIGH -- HYPOXIA, WITH LONGER
PERIODS TO LEAD TO RESPONSE, SO
I APPRECIATE YOUR SUGGESTION,
THERE'S ORTHOGONAL RELATIONSHIP,
I'M CURIOUS WHETHER THERE'S
SOMETHING THAT WE'LL BE
DISCUSSING OR ANYONE HAS INSIGHT
INTO WHY THAT MECHANISM MIGHT
EXIST WITH SHORTER PERIODS OF
HYPOXIA, IT ASSOCIATES WITH
CARDIOVASCULAR RISK DOES THAT
PERTAIN TO PULMONARY VASCULATURE
AS WELL.
>>REALLY GREAT QUESTIONS.
AND I HOPE WE CAN GET INTO SOME
OF THOSE.
YOU KNOW, I THINK OTHERS MAY
HAVE SOME THOUGHTS, MY OWN
THOUGHT IS IN FACT THAT PERHAPS
MEASURING DELTA HEART RATE MAY
BE DOWNSTREAM TYPES OF
RESPONSES, AND MY COLLEAGUES
HAVE BEEN FOCUSING ON
QUANTIFYING WHAT THEY CALL THE
BURDEN OF EVENTS WHICH RELATES
TO -- THINK OF HYPOXIC BURDEN,
THIS IS THE CHANGE OR REDUCTION
IN VENTILATION AND EFFORT
ASSOCIATED SO BOTH THE DURATION
OF THE REDUCTION AND VENTILATION
AND DEPTH OF REDUCTION, IT MAY
BE AS WE PIVOT TO THAT MAYBE
UPSTREAM PHYSIOLOGIC PROCESS AND
LINK TO THE DIFFERENCES IN THESE
DOWNSTREAM EFFECTS WITH HYPOXIA
AND DELTA HEART RATE, WE MAY
HAVE MORE INSIGHT INTO THESE
MULTIPLE PHENOTYPES.
>>I WAS GOING ASK A QUESTION OF
DR. SHAH.
I FELT THE DISCUSSION OF SLEEP
PHENOTYPE WAS FASCINATING AND
NEW TO ME, THAT GETS INTO THE
NEXT POINT, WHAT IS THE BEST WAY
TO MEASURE A SLEEP PHENOTYPE AND
YOU BROUGHT UP SOME CHALLENGES
WITH HOME SLEEP TESTING VERSUS
FULL POLYSOMNOGRAPHY, MAYBE YOU
MIGHT COMPARE AND CONTRAST DATA
AND WHAT THE BENEFITS VERSUS
DOWN SIDES ARE TO A MORE LIMITED
SLEEP STUDY VERSUS MORE
COMPREHENSIVE ONE.
>>YEAH, THANKS FOR THE
QUESTION.
FEEL FREE TO CHIME IN, SUSAN, IF
YOU HAVE THOUGHTS.
I WANT TO RESPOND TO THE LAST
DISCUSSION IF I CAN BRIEFLY.
I THINK VENTILATORY BURDEN IS
REALLY IMPORTANT, FASCINATING,
I'D LIKE TO MAYBE HERE YOUR
THOUGHTS, SUSAN, AFTER I
RESPOND, HOW DO YOU TIE IN OTHER
SLEEP DIMENSIONS AND FEATURES WE
TALKED ABOUT, PARTICULARLY
AROUSALS, YOU KNOW, CARDIAC
MANIFESTATIONS, RESPONSES,
PHYSIOLOGIC RESPONSES THAT WE
MAY NOT BE FULLY CAPTURING IN
VENTILATORY BURDEN.
I THINK BASED ON MY
UNDERSTANDING OF THE LITERATURE,
AUTONOMIC RESPONSE IS
FASCINATING.
I THINK, YOU KNOW, THE --
ESPECIALLY CPAP, IT HAS A
TREMENDOUS IMPACT ON THE HEART
THAT I THINK WE'RE JUST STARTING
TO APPRECIATE, OR I AM, WE
THOUGHT IT WAS BENIGN AND IT
STILL MAY BE BUT THERE ARE
INFLUENCES ON THE AUTONOMIC
NERVOUS SYSTEM, ON THE HEART
THAT MAY PLAY OUT WHEN YOU START
TO SUBPHENOTYPE.
I WANTED TO PLANT THAT IN THERE
AND TO RESPOND TO YOUR QUESTION,
I CAN CALL YOU BY YOUR FIRST
NAME, ANNA?
OKAY.
THIS IS EXACTLY WHERE THE
PROBLEM IS, RIGHT?
JUST TO SET THE STAGE, WE DO
CLINICALLY NOW IS THAT MAJORITY
OF THE PATIENTS WHO COME IN FOR
SLEEP DISORDER BREATHING
ESPECIALLY APNEA RELATED
REFERRALS HAVE EVALUATED BY
SLEEP PHYSICIAN AND THEN OFTEN
DIAGNOSED USING HOME SLEEP TEST,
THAT CAN VARY FROM USING A
COUPLE CHANNELS WHERE YOU HAVE
AN OXYGEN DESATURATION INDEX OR
MEASURE, HEART RATE MEASURE, AND
POTENTIALLY MAYBE THORACIC OR
THORACO ABDOMINAL SENSORS, I
WOULD SAY THREE TO FOUR
CHANNELINGS TO DIAGNOSE
OBSTRUCTIVE SLEEP APNEA USING
THE NUMBER OF TIMES SOMEONE
STOPS BREATHING PARTIALLY OR
COMPLETELY OVER THE RECORDED
TIME OR IN SOME CASES SURROGATE
SLEEP TIME.
WE WOULD HAVE PATIENTS SPEND AN
ENTIRE NIGHT IN THE SLEEP LAB,
WOULD DO A MULTI-CHANNEL UP TO
20 CHANNELS OF DATA, EMG, EOG,
I-CHANNELS, LEG MOVEMENT
INDICATORS, OXYGEN, PRESSURE
EKG, A LOT OF OTHER DATA WE JUST
DON'T SEE IN THE HOME SLEEP.
WHAT WE'RE LEARNING IS THAT
THERE ARE HIDDEN FEATURES THE
HOME SLEEP TEST IS SIMPLY NOT
CAPTURING.
PULSE RATE RESPONSE IS ONE THAT
POTENTIALLY YOU COULD GET FROM
HOME SLEEP TEST BUT THERE ARE
OTHERS LIKE PERIODIC LIMB
MOVEMENT, FOR EXAMPLE, OR SLEEP
STAGE DEPENDENCY, AND HOW EACH
OF THESE RELATE.
YOU HAVE AN EVENT.
AND THEN WORK SHOWS THE PULSE
RATE RESPONSE BUT MAYBE THERE'S
ANOTHER RESPONSE THAT WE'RE NOT
CAPTURING.
AND SO ALL OF THOSE THINGS, HOW
THEY FIT IN TOGETHER A HOME
SLEEP TEST IS NOT ABLE TO DO.
WHAT DOES THE FUTURE HOLD?
WE CONTINUE TO USE THESE
BEAUTIFUL EPIDEMIOLOGIC COHORTS
THAT SUSAN AND OTHERS ON THE
CALL HAVE HELPED US GET THIS
COMPREHENSIVE DATA, FIND SOME
HIDDEN FEATURES, MAYBE TAKE THEM
THE NEXT STEP, IN A TRIAL
SETTING, AND MAYBE VALIDATING
EHR INTERESTED IN BRIAN CADE'S
TALK TODAY, EHR IS GETTING
THERE, WE HAVE SO MUCH DATA, SO
I'LL STOP THERE.
BUT I HOPE I ADDRESSED YOUR
QUESTION.
>>THANKS, NEOMI.
FROM YOUR FIRST COMMENTS, I
COMPLETELY AGREE.
I THINK THERE'S SO MUCH
OPPORTUNITY TO BETTER
CHARACTERIZE THE OVERALL
CARDIOVASCULAR AND AUTONOMIC
CHANGES THAT MAY CORRELATE.
THERE WAS JUST THIS PAST YEAR AN
ARTICLE IN "NATURE" FROM A GROUP
OF BIOMEDICAL ENGINEERS FROM SAN
DIEGO THAT REPORTED THE USE --
THE WEARABLE ECHO CARDIOGRAM,
AND I HAPPENED TO CONTACT THE
AUTHOR JUST THIS WEEK WHO SAID
SLEEP WOULD BE THE PERFECT
SETTING TO COLLECT DYNAMIC ECHO
MEASUREMENTS.
UNFORTUNATELY IT'S NOT AT THE
COST POINT MOST OF US CAN AFFORD
TO INTEGRATE INTO RESEARCH BUT
IF HE COMMERCIALIZES THAT THESE
ARE REALLY, REALLY EXCITING
OPPORTUNITIES TO GO BEYOND WHAT
WE ACTUALLY DO AND THINK GETTING
DYNAMIC MEASURES OF CARDIAC
DIMENSION AND VOLUME CHANGES
WITH EVEN OF THESE APNEAS.
I WANT TO BE PROVOCATIVE.
GETTING BACK TO DR. HILL AND DR.
HEMNES' QUESTION ABOUT HOME
VERSUS LABORATORY-BASED STUDIES
I THINK ONE OF THE REAL
OPPORTUNITIES AND CHALLENGES IS
TO START THINKING MORE DEEPLY
ABOUT WHAT WE CAN DO OVER
MULTIPLE NIGHTS, NOT SINGLE
NIGHTS, AND WITH RELATIVELY LESS
INVASIVE TECHNOLOGY.
I ACTUALLY THINK ONE OF THE
THINGS, BEING PROVOCATIVE, ONE
OF THE THINGS THAT'S KEPT US
BACK AS A FIELD IS THIS MOTION
WE HAVE TO MEASURE EEG-BASED
AROUSALS.
AND THAT THAT IS AN ESSENTIAL
FEATURE OF THE SLEEP
FRAGMENTATION, ET CETERA.
WE'RE BEGINNING FROM SOME WORK
JUST THIS PAST YEAR IN SLEEP
HEALTH AND COHORTS FINDING THAT
ACTUALLY AROUSAL INDEX WHICH IS
ONE REASON WE MEASURE EEG, WHICH
IS EASIER TO DO IN THE LAB THAN
AT HOME, IS ACTUALLY A TERRIBLE
PROGNOSTIC INDICATOR AND
POSSIBLY A MEASURE OF ADAPTATION
OVER TIME AND PATIENTS
DEVELOPING WHAT I CALL SLEEPY
BRAIN RATHER THAN SHOWING
PRACTICING MENTATION.
WITH THIS DEVELOPMENT OF
WEARABLES AND USE OF EVEN
SIGNALS THAT WE ROUTINELY
CAPTURE THAT WE JUST ARE NOT
CURATING BUT NOW WITH A.I.,
MACHINE LEARNING, ET CETERA, WE
ARE.
ONE SIGNAL WE COULD FAIRLY
EASILY GET IN HOME STUDIES, FOR
EXAMPLE, IS THE PPG SIGNAL,
PHOTOGRAM SIGNAL, BEAUTIFUL WORK
ABOUT HOW THAT MAY --
SYMPATHETIC ACTIVATION, VASCULAR
CHANGES AND STIFFNESS, SOMETHING
THAT'S BEEN IN FRONT OF OUR FACE
FOR YEARS.
UNTIL RECENTLY USED AS Q.C.
SIGNAL TO SEE IF OUR OXYGENATION
SATURATION SIGNAL WAS
REASONABLE.
AS WE THINK ABOUT CHANGES, WHAT
WE CAN MEASURE IN TERMS OF HEART
RATE, PPG, MOVEMENT-BASED
MEASURES OF SLEEP, WAKE, MAYBE
EVENTUALLY USING DYNAMIC
ECHOCARDIOGRAMS I THINK WE MAY
HAVE A DIFFERENT APPROACH THAN
POLYSOMNOGRAMS.
WE STILL NEED TO KNOW WHETHER
PEOPLE ARE IN REM OR SLEEP-WAKE
BUT NOT SUCH TERRIBLE WORK USING
HEART RATE VARIABILITY AND
MOVEMENT AND BREATHING TO EVEN
SLEEP STAGE.
>>THIS SEEMS LIKE AN IMPORTANT
QUESTION AND ISSUE.
I THINK ONCE AGAIN THERE ARE
MULTIPLE WAYS OF APPROACHING
WHAT YOU'VE MENTIONED, SUSAN,
THAT IF WE INTERPRET A
LABORATORY PSG AS REPRESENTATIVE
OF AN INDIVIDUAL'S USUAL SLEEP,
THEN THINK WE MAY BE MISTAKEN.
IF WE LOOK AT IT RATHER AS A
PARTICULAR CHALLENGE RESPONSE TO
THAT ENVIRONMENT, IT MAY HAVE
VALUABLE INFORMATION.
SO ULTIMATELY I THINK, YOU KNOW,
IT MAY BE IMPRACTICAL BUT WE
NEED BOTH.
WE NEED TO KNOW WHAT'S HAPPENING
IN A PERSON'S USUAL ENVIRONMENT
OVER YEARS OF EXPOSURE, AND
PERHAPS WE NEED TO KNOW HOW AN
INDIVIDUAL'S PHYSIOLOGY RESPONSE
TO A PARTICULAR TESTING OR
CHALLENGE SITUATION.
>>THANK YOU FOR THOSE REMARKS.
AND DAN IS TALKING ALSO AS A
PSYCHIATRIST WHO IS AWARE THAT
SOME OF THE FOLKS, WHEN YOU
BRING IN PATIENTS WITH INSOMNIA
AND HAVE SLEEP STUDIES, YOU MAY
GET ACTUALLY INFORMATION THAT
MAY IN FACT RELATE TO EITHER
FEELING REALLY SECURE AND
MONITORED IN THE LAB OR ACTUALLY
BEING FACED WITH A BIG
PSYCHOLOGIC STRESS THAT MAKES IT
MORE DIFFICULT TO SLEEP.
AND SO THANK YOU SO MUCH FOR
THAT.
>>I'M APPRECIATIVE OF THE
RESPONSES.
I ASKED IT BECAUSE I THINK AS WE
THINK ABOUT IDENTIFYING SLEEP
PHENOTYPES AND PULMONARY
HYPERTENSION, WHAT -- HOW BEST
TO DO THAT IS GOING TO BE REALLY
IMPORTANT.
SEEMS LIKE WE'RE RIGHT NOW WITH
TECHNOLOGY THAT WE HAVE, WE HAVE
HOME TESTS THAT HAVE LIMITATIONS
BUT ARE WIDELY AVAILABLE,
PERHAPS CHEAPER, YOU COULD GET
MORE DATA ON SLEEP DISORDERED
BREATHING, THEN THERE ARE
LAB-BASED TESTS LIKE
POLYSOMNOGRAMS IS, RICH DATA ON
FEWER PEOPLE, HARD TO OVERCOME,
WITH LIMITS OF STATISTICS FOR
INSTANCE IF YOU MEASURE HUNDREDS
OF THINGS AND LOOK AT
PHENOTYPES, YOU MAY HAVE A FALSE
DISCOVERY RATE.
YOU MAY ALSO GET RICHER
PHENOTYPING.
I THINK IT'S A REALLY
INTERESTING TENSION RIGHT THERE
AND ALSO CONCERN ABOUT HOME
VERSUS LAB.
WHAT IS TRULY REPRESENTATIVE OF
WHAT A PERSON IS LIVING AND
EXPERIENCING.
>>TOMORROW OR LATER TODAY WE'LL
TALK ABOUT HOW TO USE GENOMICS,
MAY BE NOT ONLY FOR MECHANISMS
BUT TO ACTUALLY CREATE
SURROGATES FOR PHENOTYPES AND I
KNOW DR. SOFIR HAS BEEN DOING
THAT.
THAT MAY BE A POSSIBILITY IF WE
COULD GET SUFFICIENT DATA TO
TRAIN GENETICS PANEL TO CREATE A
CORE FOR LIE OF HIGH LOOP GAIN
OR LOW AROUSAL INDEX TO LIMIT
NEED TO PHENOTYPE DATABASES,
ANOTHER THOUGHT.
>>THANK YOU FOR THE GREAT
PRESENTATIONS.
ONE COMMENT AND QUESTION.
I THINK GIVEN THERE'S MORE THAN
30 MILLION PEOPLE ESTIMATED TO
HAVE SLEEP APNEA IN THE U.S.,
IT'S UNLIKELY THAT EVERYBODY IS
GOING TO HAVE LIKE AN IN LAB PSG
AS FIRST LINE SO HOME SLEEP
TESTS ARE HERE TO STAY AS FIRST
LINE FOR BREAD AN BUTTER CASE.
IF WE DEMONSTRATE THERE'S A
VALUE IN CERTAIN PATIENTS TO GO
BEYOND AND GET ADDITIONAL
INFORMATION, I THINK EVENTUALLY
ALSO LIKE CLINICS, LABS,
INSURERS WILL COME AROUND AND
ALLOW FOR WHERE THERE'S
POTENTIAL BENEFIT.
I THINK TRYING TO TEASE OUT
BETTER WHAT SPECIFIC FEATURES
FROM THE SLEEP STUDIES MIGHT BE
USEFUL, SPECIFICALLY FOR THIS
PATIENT SUBGROUP OF PATIENTS
WITH PULMONARY HYPERTENSION, FOR
DR. REDLINE, BUILDING A RESOURCE
FOR SO MANY COHORTS, IS THERE
ANOTHER AVAILABLE COHORT THAT IS
RICH IN PULMONARY HYPERTENSION
PATIENTS WHERE ONE COULD TRY TO
FIND OR ASSESS LIKE SOME OF
THESE BIOMARKERS?
>>THANK YOU FOR THAT QUESTION.
AND THE SHORT ANSWER IS WE'RE
LOOKING TO ENHANCE THAT, DR.
HILL AND DR. MIRREN AND OTHERS
HAVE SHOWED A LOT OF INTEREST
AND HAVE BEEN WORKING WITH
NATIONAL SLEEP RESEARCH RESOURCE
TO DEPOSIT THE HOME SLEEP STUDY
DATA INTO SLEEP DATA.ORG, NOT
FULL POLYSOMNOGRAMS BUT A STEP
IN THAT DIRECTION.
I'LL USE THIS AS AN OPPORTUNITY
TO ENCOURAGE INDIVIDUALS
COLLECTING ANIMAL DATA, WE NOW
INGESTING ANIMAL DATA, CLINICAL
DATA, POPULATION DATA, WE WOULD
LOVE TO HELP MAKE THAT AVAILABLE
TO THE COMMUNITY.
>>THANK YOU.
>>LET ME ASK A QUESTION TO DR.
BUYSSE AS WELL.
ONE OF THE DOMAINS IN YOUR
MULTI-DIMENSION SLEEP PANEL IS
REGULARITY.
HOW DO YOU DEFINE REGULARITY,
HOW MANY DAYS AND WHAT IS
STANDARD REGULAR?
>>YEAH, SO IT'S A FAIR
QUESTION.
I HAVE TO SAY THAT WHEN I WAS
ORIGINALLY THINKING ABOUT THIS I
DIDN'T INCLUDE REGULARITY AS ONE
OF THE THINGS TO THINK ABOUT
BECAUSE IT STANDS TO REASON THAT
ANYTHING YOU MEASURE ABOUT SLEEP
CAN BE CHARACTERIZED BY AN
AMOUNT OF VARIABILITY OR
REGULARITY ACROSS TIME, RIGHT?
IT'S TRUE OF SLEEP DURATION,
SLEEP TIMING, TRUE OF SLEEP
EFFICIENCY.
SO, TO SOME EXTENT REGULARITY IS
JUST A SECONDARY PROPERTY OF ALL
OF THOSE OTHER DIMENSIONS.
HOWEVER, THERE'S BEEN I THINK AN
INCREASING AMOUNT OF EVIDENCE
THAT VARIATION, SPECIFICALLY IN
THE TIMING AND DURATION OF SLEEP
ACROSS DAYS, IN ITSELF HAS SOME
HEALTH IMPLICATIONS.
THAT IS, YOU KNOW, THE DEGREE OF
VARIABILITY EVEN INDEPENDENT OF
THE MEAN TIMING IS REFERRED TO
AS SOCIAL JET LAG, I THINK YOU
CAN CERTAINLY --
>>WE JUST LOST YOU.
>>MAKE AN ARGUMENT FOR
MEASURING REGULARITY, DIFFERENT
DIMENSIONS BUT MOST COMMON ARE
REGULARITY OF SLEEP TIMING FROM
DAY TO DAY AND REGULARITY OF
SLEEP DURATION FROM DAY TO DAY.
>>AND WHAT IS YOUR ASSESSMENT
OF HOW AMENABLE THIS IS TO THE
WEARABLES WE HAVE, AGAIN
THINKING ABOUT SCALING.
>>I'M SORRY, HOW?
>>AMENABLE TO QUANTIFYING TO
USING WEARABLES OUT THERE.
>>I THINK IT'S VERY AMENABLE
ACTUALLY.
SOME WORK THAT YOU'RE DOING WITH
MODELING DATA OVER TIME AND
LOOKING AT DIFFERENT PARAMETERS
OF 24-HOUR RHYTHMS, I THINK THAT
IN PART IS GOING TO SHOW US WHAT
MAYBE THE OPTIMAL MEASURES WILL
BE.
>>THANK YOU.
DO WE HAVE TIME FOR ONE OR TWO
MORE QUESTIONS IF ANYONE -- I
WANT TO NOT MISS ANYONE.
>>I I THINK A HAND IS RAISED.
>>GREAT DISCUSSION.
I WANT TO PUT OUT A WORD OF
CAUTION HERE BECAUSE I THINK A
LOT OF GREAT WORK THAT SUSAN'S
GROUP IS DOING WITH ALI AND
OTHERS LOOKING AT DIFFERENT
METRICS OF SEVERITY, IT WILL BE
IMPORTANT WE DON'T FALL INTO THE
TRAP NOT TESTING THOSE IN, YOU
KNOW, CLINICAL TRIALS WITH
IMPORTANT PATIENT-CENTERED
OUTCOMES AND I THINK THAT'S ONE
OF MY MAIN CONCERNS, THAT WE
COME UP WITH THESE IMPORTANT
METRICS THAT ARE MORE ROBUST
THAN THE SIMPLE APNEA-HYPONNEA
INDEX BUT WHEN IT COMES TO
TESTING IN LARGE CLINICAL TRIALS
HISTORICALLY WE'VE HAD A
CHALLENGE IN THE FIELD OF SLEEP
AND I HOPE NOW THAT ALL THESE
GREAT MINDS ARE HERE GATHERED,
TOGETHER WITH NHLBI, WE CAN COME
UP WITH PLANS TO TEST THESE IN
THE FUTURE, AND COME UP WITH
ROBUST OUTCOMES IN PATIENTS.
>>THANK YOU FOR THAT.
VERY IMPORTANT POINT.
DR. GOSS?
>>MAYBE THIS IS TOO EARLY TO
ASK THIS QUESTION.
WE COULD COME BACK TO IT LATER,
BUT WITH THE IDEA HOW WE'RE
TESTING PATIENTS AND FOR WHICH
TESTING WE'RE USING FAIRLY
ROUTINELY WE DO OVERNIGHT
OXIMETRY, OUR LEAST DETAILED
AMOUNT OF DATA FOR OUR PATIENTS,
BUT WE TEST NEARLY EVERYONE
COMING THROUGH P-H CLINIC.
IS THERE A SPECIFIC PHENOTYPE TO
EXTRACT FOR ADDITIONAL TESTING
FOR CAPTURING HIGHEST RISK
PATIENTS?
>>THAT'S A FANTASTIC QUESTION.
I THINK THAT MAY BE AN ESSENCE
OF ONE OF THE -- MAYBE SUMMARY
AREAS THAT WE REALLY WANT TO GET
OUR HEADS AROUND.
DOES ANYONE WANT TO COMMENT MORE
OR HAVE A SIMPLE ANSWER, WHAT IS
THE MOST EFFECTIVE SCREENING,
WHO TO TARGET AND WHAT WOULD BE
THE MOST EFFECTIVE SCREENING AND
PROCEDURES IN PULMONARY
HYPERTENSION SETTINGS.
I THINK WE'RE GOING TO THAT AS
THE DAY AND A HALF PROGRESSES.
WE'RE ACTUALLY -- IT'S A GREAT
QUESTION AND A GREAT REMINDER OF
WHY WE'RE HERE TODAY AND
TOMORROW.
WE'RE READY FOR A BREAK.
AND WE WILL HAVE A 30-MINUTE
LUNCH BREAK, OR OTHER PEOPLE MAY
HAVE JUST EARLY MORNING BREAK,
AND COME BACK AT 1 P.M. EASTERN
TIME.
BUT THANK YOU FOR AN AMAZING
DISCUSSION AND THREE INCREDIBLE
TALKS.
AND GREAT QUESTIONS.
SO THANK YOU ALL.
>>I'D LIKE TO OPEN THE NEXT
SESSION WHICH PARALLELS THE
FIRST SESSION IN THAT FIRST
SESSION WAS HOPING TO INTRODUCE
CONCEPTS OF SLEEP HEALTH AND
DYSFUNCTION AS THEY PERTAIN TO
HYPERTENSION AND PULMONARY
VASCULAR DISEASE.
NEXT SESSION WILL FOCUS ON
PULMONARY HYPERTENSION AND
RELATIONSHIP TO SLEEP HEALTH.
IT'S A PLEASURE TO INTRODUCE THE
FIRST SPEAKER, DR. DE JESUS
PEREZ, TO GIVE AN OVERVIEW OF
PULMONARY HYPERTENSION WITH
RELEVANCE TO SLEEP HEALTH AND
GENERALLY INTRODUCE THIS TOPIC
SO WE'RE PRIMED FOR A GOOD
DISCUSSION.
WE'LL HAVE FIVE MINUTES FOR
QUESTIONS OR SO AFTER EACH TALK,
TIME PERMITTING, AND WE'LL HAVE
A 25-MINUTE DISCUSSION AT THE
END OF THE SESSION, SO FEEL FREE
TO ASK QUESTIONS AS APPROPRIATE
FOR THAT.
I'LL TURN IT OVER TO YOU.
>>THANK YOU.
CAN YOU SEE MY PRESENTATION?
>>YES.
>>WONDERFUL.
GOOD AFTERNOON, EVERYBODY.
MY JOB IS TO GIVE AN OVERVIEW OF
THE FIELD AS INTRODUCE KEY
CONCEPTS RELEVANT TO SLEEP
DISORDERS, SOME REMINISCENT OF
WHAT'S BEEN PRESENTED BUT IT
REMAINS AN ACTIVE TOPIC OF OUR
DISCUSSION.
TWO PARTS, AN INTRODUCTION TO PH
DIAGNOSIS, AND OPEN QUESTIONS
AND RESEARCH PRIORITIES.
SO LET ME INTRODUCE WHAT IS
CURRENT STANDARD.
PULMONARY HYPERTENSION AFFECTS
1% OF THE POPULATION WORLDWIDE.
THERE ARE FIVE GROUPS CURRENTLY
IN THE CLASSIFICATION.
GROUP 1 I WILL BE DISCUSSING IN
DETAIL SHORTLY.
GROUP 2 IS THOSE ASSOCIATED WITH
LESS HEART DISEASE.
GROUP 3, AGAIN, WHERE SLEEP
DISORDERS FALL INTO ARE THOSE
ASSOCIATED WITH LUNG DISEASE AND
HYPOVENTILATION.
GROUP 4 ASSOCIATED WITH
PULMONARY ARTERIAL OBSTRUCTION
SUCH AS CHRONIC HYPERTENSION,
GROUP 5 A MIXED BAG.
THE MOST COMMON FORM IS GROUP 2
DUE TO HIGH PREVALENCE OF
CARDIOVASCULAR DISORDERS IN THE
WORLD TODAY.
FOLLOWED CLOSELY BY THAT
PULMONARY HYPERTENSION
ASSOCIATED WITH LUNG DISEASE.
SO, THE BEST UNDERSTOOD I SHALL
SAY THE ONE FORM OF PULMONARY
HYPERTENSION FOR WHICH WE HAVE
THE MOST THERAPEUTICS BOTH
AVAILABLE NOW AND IN THE
PIPELINE IS GROUP 1, A DISEASE
AFFECTING WOMEN PREDOMINANTLY,
PRESENTATION BETWEEN 50-65
YEARS, 14 CURRENTLY APPROVED
DRUGS TO TREAT THIS.
HOWEVER, AS I WILL TOUCH UPON
FEWER THAN 66% OF PATIENTS STAY
ALIVE AT FIVE YEARS, SO THIS IS
A VERY PROGRESSIVE DISEASE
DESPITE OUR BEST EFFORTS TO
TREAT.
PATHOBIOLOGY INVOLVES SEVERAL
CHANGES IN THE PULMONARY
VASCULATURE.
I WILL BE REMISS TO -- IF I
DON'T POINT OUT THAT THE -- MOST
REGISTRIES THAT DEAL WITH
PULMONARY HYPERTENSION COME FROM
UNITED STATES AND EUROPE BUT IF
WE LOOK AT THE REST OF THE WORLD
WE CAN SEE WHEN IT COMES TO
GROUP 1, ETIOLOGIES CAN BE QUITE
DIFFERENT, WHETHER YOU ARE IN
NORTH AMERICA OR IF YOU ARE IN
SOUTH AMERICA, WHERE NOW YOU SEE
A GREATER PREVALENCE, IN AFRICA
NOW YOU SEE INCREASE IN THE
NUMBER OF CONGENITAL HEART
DISEASES AS WELL AS HIV.
SO WHATEVER PART OF THE WORLD
YOU'RE IN WILL LIKELY FACE
DIFFERENT ETIOLOGIES AND THEY DO
HAVE DIFFERENT OUTCOMES WHICH IS
IMPORTANT FOR THE PRACTICE TO
RECOGNIZE.
GENDER IS A KEY DETERMINANT OF
OUTCOMES.
AS I TOLD YOU BEFORE, IT IS A
FEMALE PREDOMINANT DISEASE, BUT
HERE IS THE INTERESTING FACT.
IT IS THAT WOMEN TEND TO HAVE A
BETTER OUTCOME, BETTER SURVIVAL
COMPARED TO MEN.
40% OF SURVIVAL DIFFERENCE CAN
BE EXPLAINED BY THE STATUS OF
RIGHT VENTRICULAR FUNCTION.
SO, THE ADAPTATION OF THE RIGHT
VENTRICLE IN FEMALES APPEARS TO
BE DIFFERENT AND MORE FAVORABLE
COMPARED TO THAT IN MEN, AND
THIS IS IMPORTANT BECAUSE AS WE
THINK ABOUT PULMONARY
HYPERTENSION ASSOCIATED WITH
SLEEP APNEA, THESE GENDER ISSUES
MAY HAVE TO BE CONSIDERED AS WE
PROCEED FURTHER INTO PHENOTYPING
OUR PATIENTS.
WHAT YOU CAN SEE HERE AGAIN IS
THAT, A, INDEPENDENT OF THE AGE,
YOU CAN SEE THAT IT SEEMS THAT
WITH AGE THE DIFFERENCE IN
SURVIVAL ASSOCIATED WITH PH
AMONG GENDERS IS PREVALENT, AGE
AND GENDER ARE KEY
DETERMINANTS, INDEPENDENT OF
THERAPEUTICS.
BEYOND GENDER, THERE ARE
MULTIPLE MECHANISMS OF DISEASE
ASSOCIATED WITH PULMONARY
HYPERTENSION, THE LAST YEARS
HAVE LED US TO GO TO FOCUS ON
ALTERED METABOLISM,
INFLAMMATION, GENETICS,
EPIGENETICS, AS MENTIONED, AND
ANGIOGENESIS, MECHANISMS THE
FOCUS OF THERAPEUTICS.
NOW, THE ISSUE HERE AND GREATEST
CHALLENGE IS DESPITE OUR BEST
EFFORTS TO TREAT WITH THE
APPROVED THERAPIES YOU CAN SEE
THERE'S AN EVOLUTION IN THE
SEVERITY OF THE LESIONS.
THESE ARE LESIONS THAT IN THIS
CASE, REDUCING CROSS-SECTIONAL
AREA FOR BLOOD FLOW.
IF WE WERE TO LOOK AT CT
RECONSTRUCTION OF PULMONARY
CIRCULATION AS LESIONS EVOLVE WE
SEE VESSEL DROPOUT, A
COMBINATION OF INAPPROPRIATE
VASCULAR REPAIR, PROGRESSIVE
VESSEL LOSS AS WELL AS
OBSTRUCTION LEADING TO HEART
FAILURE WHICH ULTIMATELY KILLS
THESE PATIENTS.
CURRENTLY THE WAY THAT WE SEE
DIAGNOSIS, WHEN PATIENTS GET
REFERRED, THERE HAS TO BE A
BATTERY OF DIAGNOSTIC TESTS
BECAUSE IT'S IMPORTANT TO KNOW
WHICH OF THE FIVE TYPES THE
PATIENT HAS.
WE USE THE ECHO, I'LL TALK MORE
ABOUT THAT, IMAGING LIKE HIGH
RESOLUTION CT SCAN TO SEE
EVIDENCE OF GROUP 4, CLOTS, OR
GROUP 3, LUNG DISORDERS.
SLEEP STUDIES, SOMETHING THAT IS
RECOMMENDED BUT AS WE HAVE
TALKED FOR, GIVEN THE
OPERATIONAL -- THE OPERATIONAL
CHALLENGES PARTICULARLY GETTING
THE PATIENT TO SLEEP CLINICS,
THIS DOESN'T TEND TO HAPPEN
EARLY IN THE EVALUATION.
WE NEED TO DO A RIGHT HEART
CATHETERIZATION BECAUSE CURRENT
DIAGNOSIS OF PULMONARY
HYPERTENSION DEPENDS ON
DEFINITION, AND THEN ULTIMATELY
WE TRY TO INITIATE MANAGEMENT AS
SOON AS POSSIBLE, ONCE WE HAVE
IDENTIFIED THE TYPE OF PULMONARY
HYPERTENSION THE PATIENT HAS AND
WE SEE THE PATIENT EVERY THREE
MONTHS, WHAT WE WANT TO DO IS
TRY TO ADJUST THERAPY SO WE CAN
IMPROVE SYMPTOMS AS WELL AS
REDUCE THE RISK OF MORTALITY.
THE ECHO REMAINS THE OPTIMAL
SCREENING TOOL.
NOT DIAGNOSTIC BUT IT IS VERY
USEFUL IN TERMS OF PROVIDING US
INFORMATION ABOUT RIGHT
VENTRICULAR STRUCTURE/FUNCTION,
USES AN ESTIMATOR OF SYSTOLIC
PRESSURE, GIVES EVIDENCE OF
PRESSURE, ALL OF WHICH CAN BE
PROGNOSTIC MARKERS IN PULMONARY
HYPERTENSION BUT THERE ARE SOME
LIMITATIONS.
FOR EXAMPLE, THIS IS OPERATOR
DEPENDENT, 25% OF CIRCUMSTANCES
WHERE WE CANNOT REALLY GET A
GOOD SIGNAL AND IF WE CANNOT GET
GOOD IMAGES PARTICULARLY IN
THESE PATIENTS, PATIENTS THAT
HAVE COPD, FOR EXAMPLE, MAY BE
DIFFICULT TO REALLY ASCERTAIN
THE PARAMETERS WHICH IS WHY
RIGHT HEART CATH IS THE GOLD
STANDARD.
WE USE OF INTRODUCE CATHETER
THROUGH A VEIN AND ADVANCE IT
INTO THE LUNGS, CAPTURING
PRESSURES IN THE DIFFERENT
CHAMBERS FROM THE VENA CAVA, TO
THE PULMONARY ARTERY, CATCHING
WHAT IS CALLED PULL MOWER IN
WEDGE, ESTIMATE OF PRESSURE ON
THE LEFT SIDE OF THE HEART.
AND HEMODYNAMICS, ALSO
IDENTIFYING PRESENCE OF SHUNTS,
IMPORTANT IF WE'RE CONCERNED
ABOUT CONGENITAL HEART DISEASE,
CAN ALSO DO ANGIOGRAPHY BY
LOOKING AT VESSELS, AS ALLUDED
BEFORE BY DR. HEMNES VASODILATOR
STUDY IS DONE, 10% OF PATIENTS
OR LESS MAY HAVE THIS RESPONSE.
HOWEVER, THOSE THAT HAVE A
BETTER OUTCOME.
THIS IS THE CURRENT HEMODYNAMIC
DEFINITION.
MEAN PRESSURE GREATER THAN 20,
DEFINITION OF PULMONARY ARTERIAL
NEEDS TO MET A WEDGE LESS THAN
15, PVR GREATER THAN 2, CURRENT
UPDATE, BEING DISCUSSED.
IN THE CASE OF ISOLATED
POST-CAPILLARY, GROUP 2, LEFT
HEART DISEASE, IN THIS CASE THE
BIGGEST DIFFERENCE, BIGGEST
DEFINITION BETWEEN THESE TWO IS
THAT THE WEDGE IS NOW GREATER
THAN 15, WHICH INDICATES LEFT
HEART DYSFUNCTION AND PULMONARY
VASCULAR RESISTANCE LESS THAN 2.
YOU HAVE THIS ENTITY COMBINED
PRE AND POST, A PHENOTYPE WHERE
WE FIND FEATURES OF LEFT HEART
DISEASE TOGETHER WITH FEATURES
OF PULMONARY ARTERIAL DISEASE.
AND THIS IS A CHALLENGE BECAUSE
IT'S ONE OF THE ENTITIES FOR
WHICH THE GROUP 1 THERAPIES IS
REALLY NOT OPTIMAL AND MAY
ACTUALLY EVEN DO HARM.
WE ALSO LOOK AT EXERCISE
PULMONARY HYPERTENSION, AS A WAY
TO ALSO SCREEN SOME PATIENTS,
WHO MAY BE AT EARLIER STAGE OF
THE DISEASE.
WHEN IT COMES TO THERAPY WE'RE
TRYING TO IMPROVE HEMODYNAMICS,
EXERCISE CAPACITY, FUNCTIONAL
CLASS, PREVENT CLINICAL
WORSENING AND WANT OUR PATIENTS
TO LIVE.
THE 14 DRUGS I TOLD YOU CAN BE
BROKEN DOWN INTO THREE PATHWAYS
TARGETING ENDOTHELIN.
TODAY WE CAN TARGET THESE
PATHWAYS THROUGH ORAL
MEDICATIONS, INHALED,
PARENTERAL, MEDICATIONS SUCH AS
PDE5 INHIBITORS, RECEPTOR
ANTAGONISTS.
PROSTANOIDS CAN BE GIVEN
INHALED, AS WELL AS PARENTERAL
ROUTE, OR THROUGH INTRAVENOUS
CATHETER.
THESE DAYS WE TRY TO IMPROVE
CONVENIENCE BY IMPROVING THE
DEVICE, SO INSTEAD OF THIS
PATIENTS CAN NOW USE THIS, WHICH
IS EASIER AND PORTABLE, AND OF
COURSE A SMALLER PUMP.
THE MAIN CHALLENGE REMAINS WE
REALLY DESPITE OUR BEST EFFORTS
CANNOT PREVENT PROGRESSION OF
DISEASE, EVEN THOUGH WE'VE
IMPROVED SURVIVAL, PATIENTS ARE
STILL NOT DOING WELL.
IT'S BECAUSE NONE OF THE
THERAPIES ARE ACTUALLY TACKLING
THE VASCULAR REMODELING OR
IMPROVING RIGHT VENTRICULAR
FUNCTION IN THESE PATIENTS.
SO, RIGHT NOW THERE'S A PLETHORA
OF MEDICATIONS BEING DEVELOPED
TARGETING NOVEL MECHANISMS, ONE
BEING CONSIDERED TARGETS GENETIC
MECHANISMS.
THAT DISCUSSION GOES BEYOND THE
CURRENT TOPIC.
FOR REMAINDER OF THE TIME I HAVE
I'M GOING TO TALK ABOUT
PULMONARY HYPERTENSION
ASSOCIATED WITH HYPOVENTILATION,
SOME DISCUSSED BY MY COLLEAGUES
BEFORE.
AS I MENTIONED PREVIOUSLY, GROUP
3, PH ASSOCIATED DISEASE, RIGHT
NOW SLEEP ASSOCIATED PULMONARY
HYPERTENSION IS CONSIDERED A
HYPOVENTILATION SYNDROME.
BASED ON THE PUBLISHED DATA, IT
IS CONSIDERED TO BE UNCOMMONLY
IN OBSTRUCTIVE SLEEP APNEA
UNLESS THERE'S OTHER CONDITIONS
SUCH AS COPD OR DAY TIME
HYPOVENTILATION.
SOLE KNOCK THURL BE ON STRUCK
TIP SLEEP APNEA IS NOT A CAUSE
OF PH BUT IT CAN CAUSE DAY TIME
HYPER CAPNIA, WHICH PHENOTYPES
MAY PROVIDE THE GREATEST GROUNDS
FOR SEVERITY.
I'M NOT GOING INTO THIS SINCE
DR. CHAN DID A BEAUTIFUL JOB IN
PRESENTING DATA BUT IN THE CASE
OF GROUP 3 WE'RE TALKING ABOUT
SYMPATHETIC HYPOXIC REACTIONS AS
WELL AS CHANGES IN THE CHEMISTRY
SUCH AS PH, CO2, AS WELL AS
EFFECTS ON THE LEFT SIDE OF THE
HEART SO VERY COMPLEX
PATHOBIOLOGY, WHICH MAKES IT
CHALLENGING TO TREAT THIS
DISORDER OR EVEN CONCEIVE IT IN
THE SAME WAY AS WE CONCEIVE
OTHER PULMONARY HYPERTENSION
ENTITIES.
THE APPROACH CURRENTLY IS THAT
IF THE ECHO CARDIOGRAM ON OSA
PATIENTS SHOWS EVIDENCE OF
PULMONARY HYPERTENSION OR
SUGGESTSIVE BECAUSE OF ELEVATED
RVSD CURRENT RECOMMENDATION IS
THE PATIENT SHALL BE TREATED
WITH CPAP OR NON-INVASIVE
VENTILATION FOR 3 TO 4 MONTHS
AND ECHO.
REDUCTION IN EPA WITH CPAP
RANGES BETWEEN 0 AND 6
MILLIMETERS, SOME WILL RESPOND,
OTHERS DO NOT.
THIS GOES IN HAND WITH WHAT DR.
SHAH TOLD US EARLIER ON, AT
WHICH POINT IN TIME YOU MAY WANT
TO CONSIDER WHETHER TO DO A
RIGHT HEART CATHETERIZATION
BECAUSE THERE COULD BE A
POSSIBILITY THAT THIS IS NOT
JUST ACCOUNTED FOR OSA, COULD BE
AN OVERLAP SYNDROME WHERE THERE
MAY BE A RISK FACTOR FOR GROUP
1, SAY, FOR EXAMPLE, THIS
PATIENT TAKES METHAMPHETAMINE,
THAT'S A FACTOR.
SO THIS IS THE PHENOTYPE THAT IS
PROBABLY ONE OF THE MOST
FREQUENTLY SEEN IN OUR CLINIC,
OBESITY HYPOVENTILATION
SYNDROME, ALSO KNOWN AS
PICKWICKIAN SYNDROME, VERY
COMPLEX, NOT ONLY DEALING WITH
OBSTRUCTION BUT DEALING WITH
HYPOVENTILATION, OBESITY, MYRIAD
OF FACTORS THAT ULTIMATELY
AFFECT DIFFERENT PARTS OF THE
CARDIOPULMONARY SYSTEM.
YOU CAN SEE THIS IS GOING BEYOND
OBESITY.
THE COMBINATION OF OBESITY
HYPOVENTILATION REALLY ALTERS
ESSENTIALLY THE RESPIRATORY
VOLUMES AS YOU CAN SEE, AS YOU
CAN SEE HERE.
IT ALSO ALTERS THE VENTILATORY
DRIVE, MUSCLE STRENGTH,
INCREASES WORK OF BREATHING, ALL
OF WHICH LEADS TO AN INCREASE IN
CARBON DIOXIDE, LOW DIURNAL
OXYGENATION AND ULTIMATELY
CHANGE IN PHYSIOLOGY AND
NEUROVASCULAR OUTPUT FOR THESE
PATIENTS.
MOREOVER, THESE PATIENTS CAN
EXHIBIT PRO FOUND PULMONARY
VASCULAR CHANGES REMINISCENT IN
GROUP 1, THESE ARE TISSUES OF
PATIENTS WITH PICKWICKIAN WHO
PASSED ON AND YOU CAN SEE HOW
VASCULATURE LOOKS PARTICULARLY
MOTTELED, TO FULLY OBSTRUCTED
LESIONS THAT ULTIMATELY MAY
DEVELOP RYE MOTTELING.
IN TERMS OF HOW THESE PATIENTS
DO, HOW MUCH -- WHAT'S
PREVALENCE OF PH, THE PICKWICK
PROJECT TRIED TO ANSWER THAT.
IT WAS A MULTI-CENTERED TRIAL
COMPARING EFFICACY OF
NONINVASIVE, CPAP AND LIFESTYLE
MODIFICATION.
55% HAD ELEVATED PULMONARY
SYSTOLIC PRESSURE BY ECHO, 51
WITH HYPERTROPHY, NOW DEALING
WITH A PHENOTYPE.
THEY ASSUME NON-INVASIVE
VENTILATION WILL BE SUPERIOR TO
CPAP, BY TREATING THE PRIMARY
TRIGGER, IN THIS CASE OBESITY
HYPOVENTILATION, WITH DIETARY
MODIFICATIONS, TREATING THE LEFT
HEART DISEASE IF THERE'S A
PRESENCE OF THAT, DIABETES, AT
THE SAME TIME PROVIDING THE
PATIENT WITH NOCTURNAL PAP
THERAPY WITH BIPAP OR CPAP CAN
IMPROVE OUTCOMES.
AT LEAST IN THIS PARTICULAR
STUDY IN THE CASE OF
NON-INVASIVE POSITIVE PRESSURE
VENTILATION OVER THREE MONTHS
YOU CAN SEE OVER THREE MONTHS'
TIME THE MEAN PA PRESSURE AND
PULMONARY VASCULAR RESISTANCE
SUBSTANTIALLY IMPROVED.
INTERESTINGLY NOT THE CARDIAC
INDEX, DID NOT, SUGGESTING THAT
THERE MAY BE OTHER FACTORS AT
PLAY IN DETERMINING CAPACITY OF
THE RIGHT VENTRICLE TO
COMPENSATE.
HERE YOU CAN SEE, AGAIN, THERE'S
REALLY NO SIGNIFICANT DIFFERENCE
BETWEEN THE GROUP.
WE SHOW EITHER OF THESE
MODALITIES MAY ACTUALLY HAVE A
BENEFIT WHEN APPLIED TO OUR
PATIENTS.
IN TERMS OF THE EXERCISE
CAPACITY IN THIS RECENT STUDY IT
WAS SHOWN TREATING PATIENTS WITH
PULMONARY HYPERTENSION
ASSOCIATED WITH OBSTRUCTIVE
SLEEP APNEA WITH CPAP CAN
INCREASE THE METS, LEVEL OF
ACTIVITY THE PATIENT CAN CARRY,
COMPARED TO UNTREATED PATIENTS.
SO TREATING PATIENTS WITH
TAILORED THERAPY FOR THEIR SLEEP
DISORDER DOES MAKE A DIFFERENCE.
BUT I THINK AT THIS POINT IN
TIME WE'RE AT A CRUX BECAUSE FOR
AS LONG AS I'VE BEEN IN THE
FIELD, THIS HAS BEEN KIND OF AN
ORPHAN FROM PULMONARY
HYPERTENSION WHEN WE SAY SEND
THEM TO THE SLEEP CLINIC, LET
THEM TREAT IT, WE'LL FOLLOW,
AND, YOU KNOW, WE'LL SEE WHAT
HAPPENS, WE REALLY DON'T HAVE A
GOOD HANDLE AND I THINK THIS IS
THE REASON WE'RE MEETING TODAY
BECAUSE IT'S TIMELY TO THINK
ABOUT WHERE WE NEED TO GO.
IT'S MUCH MORE COMPLEX PHENOTYPE
BUT WE JUST REALLY HAVEN'T BEEN
TRYING TO REALLY GET A GOOD
HANDLE.
SO WHAT DO WE NEED I BELIEVE
MOVING FORWARD TO REALLY BE ABLE
TO PROVIDE THE BEST SERVICE TO
THESE PATIENTS?
I THINK WE NEED TO START PUTTING
TOGETHER REGISTRIES TO
PROSPECTIVELY SEE WHAT PATIENTS
DO, WHAT THEIR EVOLUTION IS.
WE NEED BETTER RESTRATIFICATION,
SIMILAR TO THE ONES FOR THE
GROUP 1 PATIENTS, WHERE WE CAN
ACTUALLY PUT TOGETHER BIOMARKERS
AND PARAMETERS THAT ALLOWS TO
ENGAGE PATIENTS THAT MAY BE
HIGHER RISK OF HAVING MORBIDITY
AND MORTALITY ASSOCIATED WITH
THIS.
GENDER DIFFERENCES AFFECTING MEN
MORE OFTEN THAN WOMEN.
DOES THAT MEAN THESE PATIENTS
WILL HAVE WORSE SURVIVAL
COMPARED TO FEMALES?
WE DON'T KNOW.
I THINK THIS IS SOMETHING THAT
IS GOING TO BE IMPORTANT.
CLINICAL PHENOTYPES IS ONE OF
THE -- I REALLY LIKE DR. SHAH'S
PRESENTATION, EMPHASIZING THE
FACT NOT ALL ARE CREATED EQUAL.
GENETICS AND GENOMICS LIKE DR.
SHAN POINTED OUT, IT'S REALLY
IMPORTANT AND WE'RE JUST
SCRATCHING THE SURFACE HERE.
I THINK UNDERSTANDING HOW RIGHT
VENTRICULAR FUNCTION COMPENSATES
FOR -- ADAPTS TO SLEEP DISORDER
BREATHING PARTICULARLY IN
PRESENCE OR ABSENCE OF LEFT
HEART DISEASE IS CRITICAL.
THE ROLE OF PH THERAPY, SOME
PATIENTS MAY BENEFIT FROM
THERAPIES CONSIDERING LEVEL OF
REMODELING THAT I SHOWED YOU, WE
DON'T KNOW.
IT HADN'T BEEN PROPERLY STUDIED.
LAST BUT NOT LEAST AS PREVIOUSLY
MENTIONED HEALTH DISPARITIES, I
WOULD BE REMISS NOT TO POINT
THIS OUT BECAUSE IN THE SAME WAY
THAT WE SHOW HOW DISPARITIES
INFLUENCE OUTCOMES IN PATIENTS
WITH GROUP 1 PULMONARY
HYPERTENSION FOR EXAMPLE, PRETTY
CERTAIN THIS IS THE MAJOR FACTOR
THAT'S ALSO PLAYING A ROLE IN
THIS PATIENT POPULATION.
I HOPE I'VE GIVEN YOU SOME IDEAS
AND GOOD BACKGROUND SO THAT
MOVING FORWARD WE CAN HAVE A
GOOD CONVERSATION AND FIGURE OUT
HOW AS A GROUP WE CAN TACKLE
THIS CHALLENGE.
G
>>THANK YOU VERY MUCH.
IF ANYBODY HAS TIME FOR
QUESTIONS, FEEL FREE TO RAISE
YOUR HAND.
WE HAVE TIME FOR ONE OR TWO
QUESTIONS.
OR PUT IT IN THE CHAT.
DR. MATHAI?
>>IF YOU COULD COMMENT ON THE
ESTROGEN, ROLE OF ESTROGEN AND
PARADOX AND MAYBE CONTRAST WITH
WHAT WE SEE IN THE PREVALENCE OF
SLEEP APNEA IN WOMEN PRE-VERSUS
POST-MENOPAUSAL.
>>I THINK THAT IS A VERY
IMPORTANT QUESTION THAT SHOULD
BE FURTHER EXPLORED ON A
CLINICAL STUDIES.
I WOULD GO AND SAY THAT WITH
POST-MENOPAUSAL THE PREVALENCE
OF SLEEP DISORDERS ACTUALLY
INCREASES.
THE QUESTION THEN BECOMES
WHETHER GENDER-SPECIFIC
DIFFERENCE STILL PERSISTS IN
TERMS OF THE SEVERITY AND
OUTCOMES ASSOCIATED WITH THIS
PARTICULAR ENTITY.
YOU KNOW, I THINK THAT'S
IMPORTANT BECAUSE AS WE
DISCUSSED, GROUP 1 PATIENTS IT
MAKES A DIFFERENCE IF YOU'RE
FEMALE WITH PULMONARY
HYPERTENSION OR MALE, EVEN IF
YOUR HEMODYNAMICS ARE THE SAME,
THE THE WAY THE RIGHT EVENTUALLY
KEL-- HAVEN'TRY -- VENTRICLE
WILL ADAPT, ROLE OF ESTROGEN
NEEDS TO BE FURTHER ESTABLISHED,
SHOULD BE ADDRESSED WITH MORE
RESEARCH.
THANK YOU FOR THAT QUESTION.
>>THANKS.
REALLY INTERESTING DISCUSSION.
>>THANKS.
CAN YOU HEAR ME?
>>YES.
>>SO, MY QUESTION IS ON OHS.
THANKS FOR A GREAT TALK, FIRST.
BUT IN PARTICULAR, I FIND IT
VERY DIFFICULT IN REAL TIME TO
PHENOTYPE PATIENTS WITH OHS
VERSUS SOME OF THE OTHER
PARTICULARLY GROUP 1 DISEASE.
WHEN THEY COME IN AND
DECOMPENSATE, TYPICALLY WHEN WE
SEE THEM, ON IMAGING TO ME IT
LOOKS QUITE SIMILAR TO GROUP 1
DISEASE, OFTENTIMES, AND IN
REALITY THE DATA BEHIND THE
HEALTH TRIAL, WHICH I'M NOT SURE
IF THAT'S BEEN SUBSTANTIATED,
THAT TYPE OF A TRIAL, WHICH YOU
REFERENCED IN REGARDS TO PAP
THERAPY, OHS POPULATION,
PROFOUND IMPROVEMENT IN
HEMODYNAMIC IN PAP THERAPY BUT
WE TYPICALLY PLACE THEM ON
VASODILATORS AND PAP THERAPY AND
THEN SEE THINGS, BUT MY
QUESTION, ARE YOU FAMILIAR WITH
ANY PHENOTYPIC DIFFERENCES THAT
WE CAN USE EITHER IN THE
RESEARCH SETTING OR EVEN
ANECDOTES, MAYBE ON CARDIAC
IMAGING OR OTHERWISE, THAT CAN
HELP US MAYBE DIFFERENTIATE THE
TWO FOR FUTURE RESEARCH AND FOR
CURRENT PRACTICE.
>>I THINK THERE ARE -- THE
MAJOR CHALLENGE WITH THESE
PATIENTS IS THAT ALSO WILL
LIKELY HAVE A HIGH PREVALENCE OF
LEFT HEART DISEASE WHICH MAKES
IT CHALLENGING TO TRY TO, YOU
KNOW, GIVE THEM VASODILATORS.
AS YOU ALLUDE TO THE LEVEL OF
RIGHT VENTRICULAR FAVOR IN THESE
PATIENTS IS REALLY PROFOUND,
USUALLY COME RIGHT HEART
FAILURE, SEVERE EDEMA,
CONGESTIVE HEPATOTHY, YOU'LL
HAVE TO FOCUS ON WHAT YOU --
WHAT THE PRIORITY HERE IS WHICH
WILL BE OBVIOUSLY TRY TO DIURESE
THEM AND GET THEM TO RIGHT HEART
CATH SO YOU CAN POTENTIALLY RULE
OUT HOW MUCH LEFT HEART
DYSFUNCTION THERE IS OR NOT.
AND THEN, YES, YOU WANT TO PUT
THEM ON BIPAP OR WHATEVER IS
NECESSARY ACCORDING TO YOUR
SLEEP SPECIALIST COLLEAGUES, BUT
PERSONALLY I ALSO MAKE AN OFFER
TO PROVIDE PULMONARY
VASODILATORS, OF COURSE IT'S NOT
REALLY IN THE GUIDELINES.
IT'S SOMETHING THAT AS EXPERTS
BASED ON THE CLINICAL PHENOTYPE,
THE PHENOTYPE IS ONE THAT IS
MORE REMINISCENT TO GROUP 1 I
THINK THERE'S A ROLE FOR DOING
THAT.
IF A PATIENT HAS SIGNIFICANT
LEFT HEART DYSFUNCTION, BUT
SEVERE RIGHT VENTRICULAR FAILURE
AND THEY HAVE WHAT MAY BE
COMBINED PRE AND POST CAPILLARY,
THEN, YOU KNOW, IT IT IS
UNFORTUNATELY ONE OF THE AREAS
OF, YOU KNOW, PERSONALLY I
HAVEN'T SEEN ANY COMPELLING
STUDY THAT HAS ALLOWED TO US
PHENOTYPE JUST LIKE, FOR
EXAMPLE, WE TALK ABOUT COPD, WE
TALK ABOUT THOSE THAT HAVE MORE,
YOU KNOW, OUT OF PROPORTION
VERSUS NOT AND WE SORT OF LIKE
CAN DISTINGUISH WHICH ONE WE MAY
BE ABLE TO OFFER, YOU KNOW,
PULMONARY HYPERTENSION
MEDICATION OR NOT, ON THE BASIS
OF EXPERIMENTAL USE.
I HAVEN'T SEEN ANY STUDY WITH
SYNDROMES WHERE PHENOTYPES HAVE
BEEN CLEARLY IDENTIFIED WHERE WE
CAN SAY THERE MAY BE A ROLE FOR
THIS, LET'S TAKE THEM INTO A
STUDY AND SEE IF THAT WORKS OUT.
IT'S AN AREA, UNLESS I MISSED
ANYTHING IN THE LITERATURE, I
DON'T KNOW OTHER THAN MY
PROFESSIONAL OPINION, I'M SURE
OTHER PEOPLE HAVE THEIR OWN
EXPERIENCE, I DON'T KNOW THERE'S
ANYTHING IN THE LITERATURE THAT
WE CAN USE.
BUT, AGAIN, I WOULD LIKE TO HEAR
FROM OTHERS IF THERE'S ANY OTHER
VIEWPOINTS.
>>THAT'S A GREAT TOPIC THAT WE
CAN CONTINUE IN OUR EXTENDED
DISCUSSION AT THE END OF THIS
SESSION BECAUSE IT'S AN
IMPORTANT ONE.
THANKS.
THAT WAS A GREAT PRESENTATION,
AND GOOD DISCUSSION.
I'D LIKE TO MOVE TO THE NEXT
SPEAKER, DR. NICHOLAS HILL FROM
TUFTS UNIVERSITY.
AND DR. HILL IS AN EXPERT IN
BOTH PULMONARY HYPERTENSION AND
SLEEP DISORDER BREATHING AND SO
HE'S THE PERFECT PERSON TO GIVE
THE NEXT TALK, SLEEP DISORDERED
BREATHING IN GROUP 3 PULMONARY
HYPERTENSION.
I'LL TURN THE FLOOR OVER TO YOU,
DR. HILL.
>>THANK YOU, ANNA.
THANK YOU FOR THE OPPORTUNITY TO
SPEAK TO EVERYBODY.
I ASSUME YOU CAN HEAR ME OKAY.
>>I DON'T SEE YOUR SLIDES BUT I
CAN HEAR YOU.
>>THAT WAS MY NEXT QUESTION.
LET ME SEE WHAT HAPPENED HERE.
>>NOW WE SEE THEM.
>>OKAY.
AND YOU CAN -- OOPS.
YOU CAN SEE THEM ADVANCE?
>>YEP.
>>OH, EXCELLENT.
ALL RIGHT.
SO, WE WILL BE DISCUSSING SEEP
SLEEP DISORDERED BREATHING IN
GROUP 3 PULMONARY HYPERTENSION,
VINICIO PROVIDED A GOOD
FOUNDATION FOR MANY COMMENTS
I'LL MAKE, AND I WANTED TO PICK
UP WHERE HE LEFT OFF ON THE
CLASSIFICATION OF PULMONARY
HYPERTENSION, AND DATING BACK TO
1973, THE MEAN PULMONARY ARTERY
PRESSURE DEFINED BY WORLD
SYMPOSIUM EVERY FIVE YEARS WAS
DEFINED HERE, GREATER OR EQUAL
TO 25 MILLIMETERS OF MERCURY,
AND IF YOU WANTED TO DEFINE
PRE-CAPILLARY OF WHICH GROUP 3
IS ONE OF THE TYPES, THE WEDGE
PRESSURE WAS LESS THAN 15,
DEFINITION OF MODEST AS OPPOSED
TO SEVERE PRESSURE FOR THE MOST
PART LESS THAN OR GREATER THAN
35.
AND YOU WILL SEE THAT AT THE
SIXTH WORLD SYMPOSIUM, MEAN PA
PRESSURE WAS CHANGED TO
NEGATIVE -- RATHER GREATER THAN
20 MILLIMETERS OF MERCURY
BECAUSE THIS WAS CONSIDERED TO
BE MORE NORMATIVE AND THERE WAS
DATA TO SUGGEST PEOPLE WHOSE
MEAN PA PRESSURE WAS BETWEEN 21
AND 24 HAD WORSE OUTCOMES SO
THEY DIDN'T FLOOD THIS WITH TOO
MANY PATIENTS DEFINED PVR
GREATER OR EQUAL TO 3 WU, AS
VINICIO POINTED OUT SUBSEQUENTLY
QUESTIONED TO GREATER THAN 2
BECAUSE THEY SEEMED TO EXCLUDE
MORE PATIENTS THAN THEY
ANTICIPATED.
AND THEN THE DEFINITION OF
SEVERE HAS CHANGED TO -- AT THE
6th WORLD SYMPOSIUM GREATER
THAN 40 MILLIMETERS OF MERCURY.
MOST RECENTLY WITH THE
GUIDELINES IT WAS SUGGESTED THAT
A PVR GREATER THAN 5 SERVE AS
CUTOFF FOR SEVERE.
SO, PART OF THE POINT I'M GOING
INTO DETAIL HERE IS THAT THEY
HAVE BEEN CHANGING THE GUIDE
POSTS ON US SO THAT WHEN WE TALK
ABOUT THINGS LIKE PREVALENCE, A
LOT OF THE LITERATURE PREDATES
THE 2018 NICE SYMPOSIUM, SO THE
NUMBERS FLUCTUATE PARTLY BECAUSE
WE CHANGE THE GOAL POSTS.
ONE OTHER THING TO POINT OUT IS
THAT BETWEEN THE FIFTH AND SIXTH
WORLD SYMPOSIUM, THEY DROPPED A
COUPLE CATEGORIES INCLUDING
SLEEP DISORDERED BREATHING AND
CHRONIC EXPOSURE TO HIGH
ALTITUDE.
HERE YOU SEE IT WAS 3.4 AT THE
FIFTH, AND THEN DISAPPEARS FROM
THE SIXTH.
AND STEVE NATHAN, WHO WAS THE
FIRST AUTHOR OF THE CHAPTER ON
THE DOCUMENT FROM THE SIXTH
WORLD SYMPOSIUM HAD A STATEMENT
CHRONIC PH IS RARE AND MOST
COMMONLY MILD.
I ASKED STEVE ABOUT THIS, HE
SAID THEY DIDN'T REALLY MEAN TO
DROP SLEEP DISORDERED BREATHING
BUT THE TASK FORCE ON
CLASSIFICATION I GUESS IS
BECAUSE THERE WEREN'T MANY SLEEP
PEOPLE ON THE BOARD DROPPED IT
BUT EUROPEAN SOCIETY OF
CARDIOLOGY MEETING ADDED OBESITY
HYPOVENTILATION BUT
SLEEP-DISORDERED BREATHING IS A
MUCH BIGGER CATEGORY.
WE'RE STILL IN NEED OF A BETTER
CLASSIFICATION TO INCORPORATE
SLEEP-DISORDERED BREATHING, AND
I GUESS ONE OF THE ISSUES IS
THAT SLEEP-DISORDERED BREATHING
IS REALLY A VERY COMMON
COMORBIDITY IN ALL THE GROUPS OF
PULMONARY HYPERTENSION, AND
MAYBE DESERVES A SPECIAL
CATEGORY FOR THAT REASON.
SO TODAY I'M GOING TO SPEND TIME
TALKING ABOUT THE TWO MAIN
CATEGORIES OF LUNG DISEASE
RELATED GROUP 3 PH, COPD AND
ILD.
I'LL MAKE COMMENTS AT THE END
BECAUSE THESE HAVE LARGELY BEEN
COVERED IN PREVIOUS TALKS AND
SUBSEQUENT TALKS.
SO ONE POINT TO BE MADE IS THATS
IS A COMORBID DISEASE.
IT IS A SYSTEMIC DISEASE,
CHARACTERIZED BY INFLAMMATION
AND VASCULOPATHY, THIS DIAGRAM
SHOWS A NUMBER OF THESE
DIFFERENT COMORBIDITIES AND SIZE
OF THESE BALLOONS HAS TO DO WITH
PREVALENCE, SO SYSTEMIC
HYPERTENSION IS ONE OF THE MOST
COMMON COMORBIDITIES, DIABETES
IS VERY COMMON.
PULMONARY HYPERTENSION ISN'T
LISTED AS PARTICULARLY COMMON
HERE BUT AS YOU'LL SEE IT'S HARD
TO NAIL DOWN THE PREVALENCE.
AND THE CLOSER THE CENTER, THE
MORE LIKELY IT WAS TO BE
AFFILIATED WITH MORTALITY.
HERE IT'S A LITTLE BIT OUTSIDE
THE CIRCLE OF DEATH.
BUT IN FACT THERE ARE A NUMBER
OF STUDIES, I'M JUST GIVING AN
EXAMPLE OF ONE, THAT SHOW IN
PEOPLE WHO HAVE PULMONARY
HYPERTENSION ASSOCIATED WITH
COPD THE SURVIVAL IS
CONSIDERABLY WORSE THAN THOSE
WITHOUT.
AND PREVALENCE OF PH IN COPD
RANGES FROM 20 TO 91% IN
LITERATURE, AND A COUPLE OF THE
LARGER STUDIES OUT OF FRANCE DID
A LOT OF WORK ON THIS IN THE
'80s AND '90s, COMMONLY
CITED, BUT IN ONE OF THE STUDIES
OF 175 PATIENTS WITH SEVERE COPD
30% ARE GREATER THAN 35
MILLIMETERS OF MERCURY, AND 91%
WAS THE NETT TRIAL, TO GET IN
YOU WERE BEING CONSIDERED FOR
LUNG VOLUME REDUCTION TREATMENT
AND THEREFORE HAD VERY ADVANCED
COPD BUT STILL ONLY A MINORITY
HAD MEAN PRESSURE GREATER THAN
35%, IN OTHER STUDIES EVEN LESS.
THIS IS THE DISTRIBUTION OF
PRESSURES IN A SIZEABLE GROUP OF
COPD PATIENTS WHICH IS PART OF
WHITESSENBOUND'S FRENCH GROUP, A
BELL CURVE.
THE ARROW IS THE OLDER
DEFINITION, A MEAN PRESSURE OF
25.
IF WE INSERT ARROW FOR NEW
DEFINITION, SIZEABLE BARS, SO
PREVALENCE OF COPD IS GOING UP
CONSIDERABLY BASED ON NEW
DEFINITION, ESPECIALLY KNEW THAT
PVR RECOMMENDATION IS LOWERED TO
2.
AND THEN IF WE LOOK AT
DEFINITIONS FOR SEVERE, YOU CAN
SEE THERE'S JUST A TAIL HERE,
RELATIVELY SMALL GROUP OF
PATIENTS, AND VINICIO ALLUDED TO
OVERLAPS, CLASSIFICATION FOR PH,
AND ONE ASKS WHETHER SOME
PATIENTS MAY BE AN OVERLAP OF
GROUP 1 AND 3, GIVING RISE TO
THE CONCEPT THERE'S A PHENOTYPE
FIRST IDENTIFIED BY ONE OF THE
STUDIES, BUT WAS MENTIONED IN
THE WORLD SYMPOSIUM DOCUMENT
AUTHORED BY STEVE NACEM, LESS
AIR WAY OBSTRUCTION THAN THOSE
WITH LOWER P.A. PRESSURES, LOWER
DLCO, MORE HYPOXEMIC.
THIS MIGHT BE SUBPHENOTYPE THAT
WOULD RESPOND TO TREATMENT.
WE'VE SEEN THIS DIAGRAM BEFORE.
I WILL NOT BELABOR THIS, BUT THE
MECHANISMS THAT ARE ASCRIBED TO
THE DEVELOPMENT OF PULMONARY
HYPERTENSION FOR COPD INCLUDE
HYPOXIC VASOCONSTRUCTION, AND
NEGATIVE INTERTHORACIC PRESSURE
SWINGS, AND BOTH COPD AND SEVERE
ILD WILL INTENSIFY THE SWINGS OF
INTERTHORACIC PRESSURE, WHICH
HAVE ADVERSE EFFECTS ON LV
COMPLIANCE, AND THEN ALSO THE
ISSUES OF ENDOTHELIAL
DYSFUNCTION, HEIGHTENED
INFLAMMATORY STATE AND PRO
COAGULANT STATE WE'VE HEARD
ABOUT.
I'VE INSERTED SLEEP APNEA IN
HERE, AN IMPORTANT COMORBIDITY
LIKELY INTENSIFIES A LOT OF
THESE MECHANISMS BECAUSE IT WILL
LEAD TO INCREASED SWINGS IN
INTERTHORACIC PRESSURE AS WELL
AS THESE OTHER MECHANISMS AND
WHEN SUPERIMPOSED IT IS LIKELY
TO INTENSIFY MECHANISMS AND LEAD
TO WORSE OUTCOMES.
WE'VE KNOWN FOR A LONG TIME THAT
SLEEP DISORDERED BREATHING IS
COMMON IN COPD, AND SOME OF THE
EARLIER STUDIES, THIS IS ONE
FROM OVER 40 YEARS AGO, VERY
WIDELY CITED, BY JOHN FLEETHAM.
ON THE LEFT IS SLEEP STAGES, AND
THE CROSSHATCH BAR IS FOR A
SMALL GROUP OF NORMALS.
THE MORE WIDELY SPACED IN THE
MIDDLE CROSS-HATCH BAR FOR COPD
PATIENTS BREATHING AIR AND OPEN
BAR FOR THOSE BREATHING OXYGEN.
BASICALLY IT SHOWS THE SLEEP
QUALITY IS QUITE POOR, AND
THERE'S THIS SUBSTANTIAL
DECREASE IN REM SLEEP, TOTAL
SLEEP TIME REDUCED IN COPD
PATIENTS COMPARED TO NORMALS AND
SHIFTS, STAGE SHIFTS WHICH
CORRESPOND TO FRAGMENTATION ARE
MUCH MORE FREQUENT, AND OXYGEN
APPEARS TO HAVE NEW BENEFICIAL
EFFECT ON THESE ASPECTS OF
SLEEP-DISORDERED BREATHING.
A NUMBER OF STUDIES TRIED TO
LOOK AT THIS.
AGAIN, THERE'S A TREMENDOUS
RANGE OF THE ESTIMATED
PREVALENCE AND IT DEPENDS ON
MANY FACTORS INCLUDING THE
PATIENT DEMOGRAPHICS, SEVERITY
OF COPD, TOOLS, SHIFTING GOAL
POSTS.
IN A RECENT STUDY OF 100
PATIENTS, ONE OF THE THINGS THEY
FOUND IDENTIFYING PROBLEMS WITH
SLEEP USING GLOBAL SLEEP
ASSESSMENT QUESTIONNAIRE WAS
THAT INSOMNIA WAS THE MOST
COMMON MANIFESTATION OF A SLEEP
DISORDER, RESTLESS LEG SYNDROME
NEXT, OBSTRUCTIVE SLEEP SLEEP
APNEA IN 13%, WITH MORE SEVERE
AND SOMEWHAT LESS SEVERE COPD.
THE COME BIN OSA AND COPD,
OVERLAP SYNDROME, A TERM COINED
IN THIS ARTICLE IN 85, IS
IMPORTANT, ASSOCIATED WITH MORE
SYMPTOMS, WORSE OUTCOMES, CO2
RETENTION, MORE SEVERE
EXACERBATIONS.
HYPOXEMIA IS ANOTHER
MANIFESTATION, AND MOST IS NOT
ACTUALLY ASSOCIATED WITH
OBSTRUCTIONS BUT RATHER THERE
MAY BE HYPOVENTILATION, MAY BE
VENTILATION PERFUSION MISMATCH
AND DIAGRAM DYSFUNCTION MAY BE
AN ASPECT.
YOU CAN SEE AS FAR AS THE
NOCTURNAL HYPOXEMIA IS
CONCERNED, SUPPLEMENTING WITH
OXYGEN AS IN THESE CROSS-HATCH
BARS ACTUALLY IS USEFUL IN
CORRECTING HYPOXEMIA, THIS
FIGURE SHOWS THAT IN THIS RATHER
SEVERELY IMPAIRED COPD GROUP THE
INCREASE IN CO2 THAT WAS SEEN IS
CONSIDERABLY SMALLER THAN THE
DROP IN OXYGEN, AND HENCE
SUGGESTIVE OF SOME KIND OF
VENTILATION PERFUSION PROBLEM.
NOW, THE FACT THAT OXYGEN
THERAPY DOES IMPROVE OXYGENATION
RAISES THE QUESTION HOW
EFFECTIVE IT IS, AND I THINK
WE'RE PROBABLY ALL FAMILIAR WITH
THE TRIALS THAT ARE THE MOST
IMPORTANT DONE WITH REGARD TO
OXYGEN TREATMENT DATING BACK TO
THE EARLY 1980s, AND THIS IS
BASED ON THE HEMODYNAMIC DATA IN
THE NOTT TRIAL IN A SUBGROUP OF
PATIENTS WHO UNDERWENT PRE AND
POST RIGHT HEART
CATHETERIZATIONS AND DID
DOCUMENT IN THIS STUDY THERE WAS
A DROP IN PULMONARY VASCULAR
RESISTANCE AT REST AND EXERCISE,
AFTER SIX MONTHS OF TREATMENT,
THAT WAS STATISTICALLY
SIGNIFICANT, AND IT DID NOT
NORMALIZE THE ABNORMALITIES,
HOWEVER.
THIS WAS A PARTIAL CORRECTION.
AND WEITDENBLUM HAD PATIENTS
TREATED WITH A DROP FROM 28 TO
24 AND RECENTLY THE LOTT STUDY
OF MODERATE OXYGEN SATURATION IN
THE NEW ENGLAND JOURNAL OF 2016
ON PATIENTS WHO EITHER HAD
NORMAL RESTING O2 OR MILDLY
REDUCED O2 SATS AT REST AND THEN
MORE WITH EXERTION SHOWED
OVER -- AVERAGE OF 6-YEAR PERIOD
WITH NO BENEFIT IN MEAN OUTCOME
VARIABLE TIME TO HOSPITALIZATION
OR DEATH, AND NOTHING WITH
QUALITY OF LIFE, NEGATIVE TRIAL
DIFFICULT TO DO, BUT MILDER
PATIENTS PERHAPS NOT
SURPRISINGLY DO NOT SEEM TO
RESPOND AND THEY DID NOT LOOK AT
PULMONARY HEMODYNAMICS BUT ONE
HAS TO SURMISE THERE PROBABLY
WASN'T A LOT.
A NUMBER OF STUDIES LOOKED AT
PHARMACOTHERAPY, IN BRIEF THEY
HAVE NOT SHOWN ANY CONSISTENT
IMPROVEMENT, THIS TAPIT-1 STUDY
OF INHALED TREPROSTINIL, THERE
WAS A DROP FROM 43 TO 37%, AND
THE PERFECT TRIAL THAT UNITED
THERAPEUTICS WAS DOING ON
INHALED WAS STOPPED BY DSMB,
WE'VE NOT BEEN TOLD UNITED
THERAPEUTICS SAYS IT WILL
PROVIDE FINDINGS TO THE
SCIENTIFIC COMMUNITY IN DUE
COURSE, ACCORDING TO PRESS
RELEASE.
ILD I'M SHOWING THIS BECAUSE
THAT ARE LOT OF DIFFERENT
ILDs, IT'S AN ENORMOUS
CATEGORY WITH A LOT OF DIFFERENT
PATHOPHYSIOLOGIES, SO LUMPING
THEM TOGETHER AND TRYING TO DO
STUDIES ON THEM NOT SURPRISINGLY
SHOWS A LOT OF VARIABILITY, THE
MECHANISMS ARE NOT WELL
UNDERSTOOD PARTLY BECAUSE THERE
ARE SO MANY SUBCATEGORIES, BUT
THEY DO OVERLAP WITH COPD WITH
THE MECHANISTIC PATHWAYS SHOWN
PREVIOUSLY.
THE INCIDENCE AND PREVALENCE OF
PH IS VERY VARIABLE, AND FOR
QUITE A NUMBER OF REASONS BUT
JUST IT'S SUCH A BROAD CATEGORY
AND REALLY HAS NOT BEEN WELL
STUDIED.
IN A DANISH COHORT OF 212
PATIENTS, 14% HAD PH ASSOCIATED
WITH LOWER FUNCTION PARAMETERS,
AND IT WAS A MARKER OF
MORTALITY.
THE PREVALENCE OF SLEEP
DISORDERED BREATHING IS ALSO
HIGHLY VARIABLE IN THIS
POPULATION, AND IT HAS THE SAME
PATTERNS OF SLEEP DISRUPTION AS
COPD DOES.
PARTICULARLY POOR QUALITY SLEEP
AND A LOT OF AROUSALS.
AND IN 31 CONSECUTIVE PATIENTS
WITH IPF, OBSTRUCTIVE SLEEP
APNEA WAS FOUND IN 90%, AND
SEVERE DROPS IN OXYGEN
SATURATION THAT CORRELATED WITH
MORTALITY, IN 50 PATIENTS, IN
IPF STUDY, ILD STUDY THAT
INCLUDED IPF, SARCOID,
SCLERODERMA AND OTHER ILDs,
IPF SEEMED TO HAVE A GREATER
PREVALENCE OF OSA.
THERE'S A THEORY MECHANICAL
SHRINKAGE OF THE IPF AND OTHER
ILD LUNGS PLACES MECHANICAL
STRESS ON THE UPPER AIRWAY THAT
MIGHT PREDISPOSE TO OBSTRUCTIVE
SLEEP APNEA.
HYPOXEMIA IS COMMON IN SLEEP AND
ILD.
WE SEE THESE PATIENTS WHO GET
SEVERE DESATURATIONS WITH
EXERTION OR FRAGMENTATION
MEANTED SLEEP, STUDIES IN A LUMP
ILDs TOGETHER.
IN ONE LARGER STUDY WITH ILD,
37% HAD SIGNIFICANT NOCTURNAL
DESATURATION, THE GREATER
HYPOXIC BURDEN, PH ON ECHO,
HIGHER PREDICTORS OF MORTALITY.
OXYGEN TREATMENT IN ILD HAS NOT
BEEN VERY WELL STUDIED.
THERE IS A SYSTEMIC REVIEW THAT
SHOWED THAT AMONGST ABOUT A
DOZEN STUDIES USING SHORT-TERM
APPLICATIONS THERE WAS RELIEF OF
BREATHNESSES IN --
BREATHLESSNESS, BUT OTHER
STUDIES DRAW NO CONCLUSIONS.
AND THEN AS FAR AS THE
PHARMACOTHERAPY IS CONCERNED,
THERE ARE MULTIPLE SMALL COHORTS
WITH SOME PROMISING RESULTS.
THE STEP IPF SHOWED SOME
IMPROVEMENT IN O2 SAT QUALITY OF
LIFE BUT NOT MEAN OUTCOME
VARIABILITY, 6-MINUTE WALK
DISTANCE, BUT SUBSEQUENT
STUDIES, A COUPLE HAD
DISAPPOINTING RESULTS.
RCTs SHOWED WORSE OUTCOMES AND
CONTRAINDICATED.
RECENTLY REBUILD STUDY OF
INHALED NITRIC OXIDE IN PH-ILD
REPORTED NO INCREASE IN MODERATE
TO VIGOROUS PHYSICAL ACTIVITY AS
PER ACTIGRAPHY, ITS MAIN OUTCOME
VARIABLE.
FINALLY THE INCREASE TRIAL DID
SHOW AN IMPROVEMENT AND HAS
BEEN GIVEN LABEL TO TREAT THE
ILDs, NOT COPD, AND SO IT IS
NOW AVAILABLE FOR THAT
APPLICATION.
WE'VE ALREADY HEARD A FAIR
AMOUNT ABOUT THE MECHANISMS.
THERE ARE A NUMBER OF STUDIES,
STEVE CHAN ALLUDED TO THEM ON
RODENTS AND INTERMITTENT
HYPOXEMIA SHOWING MOLECULAR
MECHANISMS BUT THE EXPOSURE TO
HYPOXIA INTERMITTENTLY MAY NOT
REPRESENT ACCURATELY ALL THE
ASPECTS OF HUMAN EXPOSURE AND SO
WE HAVE TO BE CAUTIOUS ABOUT
EXTRAPOLATING RESULTS BUT I
WOULD AGREE WITH HIM THAT THIS
IS AN IMPORTANT ADVANCE.
WE'VE HEARD QUITE A BIT ABOUT
THE MECHANISM BUT THE PREVALENCE
AGAIN IS VARIABLE.
YOU CAN SEE HOW WIDE THE RANGE
IS, 14 TO 89%, AND ONE OF THE
REASONS THE RANGE IS SO VARIABLE
IS BECAUSE THE PATIENTS WERE NOT
NECESSARILY VERY WELL
PHENOTYPED, AND THERE'S A STUDY,
17% IN 220 PATIENTS, BUT A LOT
OF THESE PATIENTS LOOK LIKE THEY
HAD COPD, WERE NOT CAREFULLY
PHENOTYPED SO THIS PROBABLY IS
REPRESENTATIVE OF PATIENTS WITH
OVERLAP SYNDROME.
THIS STUDY WITH 27% IN 44
PATIENTS HAD PATIENTS THAT WE
MIGHT CONSIDER AS HAVING
OBESITY, HYPOVENTILATION, AND
THIS STUDY BY MINAI FOUND 70%
PREVALENCE BUT EXCLUDING
PATIENTS WITH WEDGE PRESSURE
GREATER THAN 15 DROPPED TO 22%,
A LOT OF PATIENTS ARE MIX GROUP
2 AND 3, THIS ILLUSTRATES THE
IMPORTANCE OF UNDERSTANDING THE
COMORBIDITIES AND CAREFULLY
PHENOTYPING THESE PATIENTS.
NONETHELESS, PH ACCORDING TO THE
STUDY IS A RISK FACTOR FOR
SURVIVAL IN PATIENTS WITH SLEEP
APNEA.
AND VINICIO WENT OVER THE
OBESITY HYPOVENTILATION
SYNDROME, I WILL NOT BELABOR
THAT.
AND RATHER MOVE TO MY SUMMARY
WHICH IS THE DEFINITION AND
CLASSIFICATION HAVE BEEN
SHIFTING OF THESE VARIOUS GROUP
3 CATEGORIES, MAKING IT
DIFFICULT TO COME UP WITH
ACCURATE PREVALENCE DATA
MECHANISMS OF DISEASE, SIMILAR
ACROSS THE SPECTRUM AND THUS
WHEN THEY ARE LUMPED TOGETHER AS
CO-MORBIDITIES THEY INTENSIFY
THE MORBIDITY AND POTENTIAL
MORTALITY OF THE DISEASE.
THE PRESENCE WORSENS PROGNOSIS
AND OXYGEN SUPPLEMENTATION
IMPROVES OUTCOMES IN HYPOXEMIC
PATIENTS.
THERE ARE MANY KNOWLEDGE GAPS.
WE NEED TO LEARN ABOUT
MECHANISMS, STEVE CHAN RECOUNTED
A NUMBER OF THE OMIC PATHWAYS
THAT NEED TO BE EXPLORED.
BUT WE NEED TO UNDERSTAND HOW
BETTER TO PHENOTYPE THESE
PATIENTS SO WE CAN STUDY THEM
BETTER, AND WE NEED TO LOOK AT
THE POTENTIAL ROLE OF NEW
TREATMENTS, AND I THINK THE
SGLT2 AN TACK NIST AND GLP-1
CONSIDERING MANY HAVE
CO-MORBIDITIES AS WELL AS
METABOLIC DERANGEMENTS WITH
DIABETES AND OBESITY AND SO
FORTH, THESE PERHAPS DESERVE A
LOOK AT LEAST WELL-PHENOTYPED
SUBGROUPS IN THIS CATEGORY.
I'LL STOP THERE AND I DON'T KNOW
IF THERE'S QUESTIONS OR RATHER
TIME FOR QUESTIONS.
>>GREAT TALK.
WE HAVE TIME FOR ONE QUESTION IF
THERE IS ONE OUT THERE.
I DON'T SEE ANYBODY RAISING A
HAND SO I HAVE A QUESTION BUT
I'M GOING TO SAVE IT FOR THE
GENERAL DISCUSSION TO KEEP US ON
TIME.
THANKS VERY MUCH.
>>GOOD DEAL.
THANK YOU, ANNA.
>>SURE.
OUR NEXT SPEAKER IS DR. REENA
MEHRA, SHE DIRECTED OUR SLEEP
CORE, EXCITED SHE'S ABLE TO TALK
TO US TODAY ON HER TOPIC, GROUP
1 AND GROUP 2 PULMONARY
HYPERTENSION.
PLEASE TAKE OVER THE FLOOR.
>>CAN YOU HEAR ME OKAY?
>>YES AND SEE YOUR SLIDES TO.
>>OKAY, PERFECT.
WELL, THANK YOU FOR THIS
OPPORTUNITY.
IT'S A PLEASURE TO BE HERE FOR
THIS WORKSHOP AND THANKS TO THE
NIH FOR RECOGNIZING THIS
IMPORTANT TOPIC AND TO DR.
HEMNES AND DR. REDLINE FOR
SERVING AS CHAIRS AND THE
SUPPORT STAFF TO MAKE THIS A
GREAT SUCCESS.
AND SO MY CHARGE TODAY IS TO
FOCUS ON SLEEP HEALTH AND
DISORDERS IN GROUP 1 AND GROUP 2
PULMONARY HYPERTENSION.
WE'LL REVIEW SOME OF THE, YOU
KNOW, PRELIMINARY DATA FROM
PB-OMICS AS RELATES AND
HOPEFULLY DESCRIBE THE CO-HOFORT
-- COHORT AND HOW IT SERVES AS
A RESOURCE.
THE WAY THAT THE PRESENTATION IS
DISCUSSED, OVERVIEW OF
INTERSECTING PATHOPHYSIOLOGY.
WE'LL BRIEFLY DO THAT.
OTHERS HAVE NICELY ALREADY
DESCRIBED THIS.
WE'LL DELVE INTO GROUP 1 AND
GROUP 2 PULMONARY HYPERTENSION,
AS RELATES TO DISORDERS, AND
THEN END WITH KNOWLEDGE GAPS AND
SCIENTIFIC OPPORTUNITIES AND
CAVEATS TO BE AWARE OF, WE'LL BE
FOCUSING ON DISORDERED
BREATHING, ACTUALLY THERE'S VERY
LITTLE LITERATURE, AN
OPPORTUNITY ON THE AREA OF SLEEP
DISRUPTION AND SLEEP
DISTURBANCE, ASPECTS OF SLEEP
HEALTH, SLEEP QUALITY RELATED TO
GROUP 1 AND 2 PULMONARY
HYPERTENSION AND WE'LL ALSO
DESCRIBE AGAIN THE RESOURCE.
WE'LL FOCUS ON GROUP 1,
RECOGNIZING THERE ARE MANY
CONTRIBUTING FACTORS TO THIS
CATEGORIZATION OF PULMONARY
HYPERTENSION.
AND GROUP 2, LEFT HEART DISEASE,
POST-CAPILLARY PULMONARY
HYPERTENSION, THAT WILL BE THE
FOCUS.
IN TERMS OF OBSTRUCTIVE SLEEP
APNEA, WE'VE TALKED ABOUT THIS,
HIGHLY PREVALENT WITH 1 BILLION
PEOPLE WORLDWIDE AFFECTED, ALSO
QUITE UNDERRECOGNIZED, BASED
UPON EPIDEMIOLOGIC DATA THAT
UNCOVERED NEW DIAGNOSES AND A
LOT OF UNDERDIAGNOSIS FOCUSED ON
UNDERREPRESENTED MINORITIES,
CLAIMS DATA SHOW A DIFFERENT
LENS IN TERMS OF INCREASING
PREVALENCE OF SLEEP APNEA
DIAGNOSIS, PARALLELED BY THE
HOME SLEEP APNEA TESTING
INCREASES AS WELL, THAT WAS WORK
PUBLISHED IN 2020.
ALSO, GOING BACK TO THE 1970s
IT'S BEEN RECOGNIZED IN THIS
PARTICULAR STUDY, OBSTRUCTIVE
APNEA, OXYGEN DESATURATION, YOU
CAN SEE WITH THE BALLOON
MONITORING INCREASES IN
PRESSURE, THERE'S PROGRESSIVE
INCREASE IN SYSTOLIC PRESSURE
AND DIASTOLIC PRESSURE THAT'S
OCCURRING CONCORDANTLY.
THE PATHOPHYSIOLOGY, WHEN WE
INTERPRET SLEEP STUDIES WE CAN
SEE THERE'S JUST SO MUCH THAT IS
GOING ON FROM A PATHOPHYSIOLOGIC
STANDPOINT IN TERMS OF AUTONOMIC
NERVOUS SYSTEM DISTURBANCES WITH
A RELATIVE BRADYCARDIA,
TACHYCARDY SUBSEQUENT,
PUNCTUATED BY INCREASES IN BLOOD
PRESSURE, RISE IN CO2,
INTERMITTENT HYPOXIA ARE
RESATURATION WHICH MAY BE THE
PERIOD OF OXIDATIVE STRESS
LEADING TO GLOBAL LEVELS OF
INHANSED INFLAMMATION AND
OXIDATIVE STRESS.
UPPER AIRWAY OCCLUSION IT'S
IMPORTANT TO NOTE IN TERMS OF
ITS EFFECTS IN TERMS OF
INTERTHORACIC PRESSURES, AND
INTRAPLEURAL PRESSURES, SHIFTING
THE SEPTUM AND THEN REDUCTION,
EFFECTS ON CARDIAC OUTPUT,
INCREASES IN VENOUS RETURN,
HYPOXIC VASOCONSTRUCTION, AND
ANOTHER EXAMPLE SHOWING THAT
DURING AN OBSTRUCTIVE APNIC
EVENT, CESSATION OF BREATHING,
INCREASINGLY NEGATIVE
INTRATHORACIC PRESSURES AND
INCREASE IN ARTERIAL PRESSURE AS
WELL.
I THOUGHT IT WAS INTERESTING
BECAUSE THEY LOOKED CONCORDANTLY
AT EPISODES OF APNEA,
OBSTRUCTIVE APNEA, INTRAVASCULAR
PRESSURE IN TANDEM.
AND THEY LOOKED AT THE DISCRETE
EPISODES AND SO IN THIS PANEL C
HERE YOU CAN SEE THE OPEN DOT IS
THE BEGINNING OF THE APNIC
EVENT, CLOSED IS TERMINATION OF
EVENT.
WITH THE CHANGES IN OXYGEN
SATURATION, THERE ARE INCREASES
THAT ARE OCCURRING IN REAL TIME
IN THE PULMONARY PRESSURE WITH
DIPS AND YOU CAN SEE OVER TIME
THERE'S FAST CHANGE IMMEDIATELY
AND ALSO OVER TIME
PROGRESSESSIVE INCREASE IN
ARTERIAL PRESSURE WITH THESE
EVENTS.
IT'S INTERESTING TO THINK ABOUT
THE INTERMITTENT NATURE OF
HYPOXIA WITH SLEEP
APNEA-SPECIFIC HYPOXIC
MECHANISMS, AS WELL AS SUSTAINED
HYPOXIA WHICH CAN BE DUE TO
VARIETY OF REASONS, VENTILATION
PERFUSION MISMATCH, DESCRIBED IN
THE PLEXIFORM LESIONS IN THE
PATHOPHYSIOLOGY IN THE
VASCULATURE REMODELING AND
UPREGULATION AND MOLECULAR
MECHANISMS THAT HAVE IMPACT ON
THE CARDIAC FUNCTION, NAMELY
RIGHT VENTRICULAR FUNCTION IN
ADAPTIVE AND MALADAPTIVE
RESPONSES THAT LEAD TO RIGHT
VENTRICULAR FAILURE, INCREASED
MORTALITY.
AT THE LEVEL OF THE MOLECULAR
MECHANISMS, PATHWAYS HAVE BEEN
SHOWED TO LEAD TO REMODELING
INCLUDING SEROTONIN, AND VARIOUS
PATHWAYS CONSIDERED AS WE ARE
THINKING ABOUT HOW SLEEP
DISORDERED BREATHING AND
SLEEP-RELATED HYPOXIA CAN FIT IN
THE PARADIGMS.
FAIRLY RECENT DATA HAS SHOWN
ALVEOLAR HYPOXIA CAN LEAD TO
POOR HYPERTENSION THROUGH HIF-1
ALPHA DEPENDENT MECHANISMS,
SYSTEMIC HYPOXEMIA LEADS TO
ACTIVATION OF HIF-1 AND HIF 2
ALPHA IN THE RIGHT VENTRICLE,
AFFECTING REMODELING RESPONSE.
YOU CAN SEE CHRONIC HYPOXIA
ALTERS GENE RESPONSES IN RIGHT
EVENTUALLY -- VENTRICLE WITH
PATTERNING OF GENE EXPRESSION
THAT OCCURS.
CHRONIC HYPOXIA PATHOLOGICALLY
CAN LEAD TO PULMONARY VASCULAR
REMODELING AS SHOWN ON THE RIGHT
PART OF THE SLIDE.
AND THIS IS A POPULAR DIAGRAM
FROM DR. HILL AND HIS PAPER THAT
I THINK NICELY KIND OF GOES OVER
GROUP 1 VERSUS GROUP 2, GROUP 1
BEING PRE-CAPILLARY, AND GROUP 2
POST-CAPILLARY, MORE PRONE
PERHAPS TO INFLUENCES OF THE
INTRATHORACIC PRESSURES AND
EFFECTSS ON THE HEART AS WELL.
THIS IS A PROGRAM THAT WAS
ESTABLISHED BY THE NHLBI, AND
EXTENSIVELY WELL PHENOTYPED
COHORT FROM DR. HEMNES' PAPER.
HERE THAT DESCRIBES THE COHORT,
YOU CAN SEE AS SHE HAD MENTIONED
EARLIER THAT THERE ARE DISEASE
COMPARATORS AND CONTROLS FOR
EACH OF THE GROUPS, IT WAS VERY
RICHLY COLLECTED DATA IN TERMS
OF CHEST IMAGING, IN TERMS OF
CARDIAC IMAGING WITH ECHO AND,
VENTILATION PERFUSION SCANS,
PHYSIOLOGIC MEASURES THROUGH
SPIROMETRY, RIGHT HEART
CATHETERIZATION, INTEGRATED WITH
THAT WE'RE FORTUNATE TO HAVE
SLEEP DATA AS WELL SO OCCURRED
OVER SEVEN SITES, COMPREHENSIVE
PHENOTYPING, 1200 PARTICIPANTS.
THESE ARE EXAMPLES.
YOU CAN SEE REPETITIVE EPISODES
OF RESPIRATORY EVENTS AND BOUTS
OF HYPOXIA.
WE COLLECTED EKG DATA AS WELL
AND THIS ALLOWS TO REDUCE HEART
VARIABILITY AND HEART RATE
AROUSAL AS WELL.
IN SPIDER PLOTS, EXAMPLES OF
CLINICAL CHARACTERISTICS IN THE
COHORT, AND WITH PERCENTAGE OF
TIME SPENT BELOW 90% OXYGEN
SATURATION THERE'S -- YOU CAN
SEE THERE'S QUITE A LOT OF
VARIABILITY ACROSS THE GROUPS IN
TERMS OF THAT DEGREE OF HYPOXIA.
AND AS WE LOOK ACROSS THE
GROUPS, SO ALL GROUPS WERE,
AGAIN, REPRESENTED IN THE
COHORT, AND AS WE LOOK AT THE
FREQUENCY OF RESPIRATORY
DISTURBANCES AS THEY OCCUR PER
HOUR YOU CAN SEE THAT VARIES
ACROSS THE GROUPS AND AS WE'RE
TALKING ABOUT GROUPS 1 AND 2 YOU
CAN SEE HIGHER IN GROUP 2 THAN
SOME OTHER GROUPS, AND GROUP 1
YOU CAN SEE HYPOXIA APPEARS TO
BE HIGHEST IN GROUP 1 AND GROUP
5, IN PARTICULAR.
AND THEN AS ALSO WAS MENTIONED,
WE HAVE TO TAKE INTO
CONSIDERATION THOSE WHO ARE ON
CONTINUOUS POSITIVE AIRWAY
PRESSURE AN SUPPLEMENTAL OXYGEN,
VARIATION IN SLEEP APNEA AND
HYPOXIA ACROSS THE CATEGORIES.
WITH THAT PICTURE IN MIND, INTO
GROUP 1, AS DR. HILL MENTIONED
WITH GROUP 3 THE SAME IS THE
CASE WITH GROUP 1 IN TERMS OF
VARYING AMOUNTS OF PREVALENCE
THAT HAVE BEEN RECOGNIZED, IN
THIS STUDY 90% WITH MAJORITY
HAVING MILD BUT FAIR NUMBER
ABOUT 50% HAVING MODERATE TO
SEVERE DEGREE OF SLEEP APNEA
DEFINED BY THE INDEX.
PARTICULARLY FOUND AS HAVE MANY
STUDIES CONSISTENTLY FOUND THERE
ARE ASSOCIATIONS IN PARTICULAR
WITH NOCTURNAL HYPOXIA WITH MEAN
OXYGEN SATURATION IN THIS CASE
ASSOCIATED WITH SYSTOLIC VOLUME,
INVOLVING 71 INDIVIDUALS, ALONG
WITH 35 MATCHED CONTROLS.
AS WE KNOW THE SLEEP APNEA IS
OUR STANDARD INSTRUMENT TO
SCREEN, THEY DO NOT WORK WELL IN
THE CARDIOVASCULAR POPULATION.
THE SAME LIKE I HAD HOLDES
THROUGH FOR PULMONARY
HYPERTENSION.
THEY ELECTED TO IDENTIFY AN
APPROACH TO SCREENING FOR SLEEP
APNEA AND PULMONARY HYPERTENSION
AND FOUND VARIOUS
CHARACTERISTICS OF THE
INDIVIDUALS AS WELL AS
CIRCULATING BIOMARKERS THAT
APPEAR TO BE EFFECTIVE IN TERMS
OF ASCERTAINING OBSTRUCTIVE
SLEEP APNEA AND PULMONARY
HYPERTENSION AND PERFORMS WELL
AS THEY LOOKED AT IN THIS
PARTICULAR STUDY.
THIS HAS LOOKED AT HOW WE SCREEN
FOR SLEEP APNEA IN PULMONARY
HYPERTENSION.
IN THIS STATEMENT FROM THE
GERMAN GROUP, AS PERTAINS TO
PULMONARY HYPERTENSION, IN
PRE-CAPILLARY HYPERTENSION THEY
IDENTIFIED OVERALL INCREASED
RISK OF SLEEP APNEA AND HYPOXIA
AS WE'VE OBSERVED IN LITERATURE
BUT THEY HIGHLIGHT THERE'S NO
STUDIES AVAILABLE ON SLEEP
DURATION IN PATIENTS WITH
PRE-CAPILLARY PULMONARY
HYPERTENSION, THERE IS A STUDY
THAT LOOKED AT SLEEP QUALITY AND
FOUND IDIOPATHIC PULMONARY
HYPERTENSION, SELF-REPORTED
SLEEP QUALITY WAS ASSOCIATED
WITH MORE SEVERE EXERCISE
LIMITATION IN THIS COHORT OF 52
INDIVIDUALS.
THERE ARE LIMITED DATA ON SLEEP
QUALITY, INTERESTINGLY, RELATING
TO EXERCISE LIMITATION IN
PULMONARY HYPERTENSION.
AGAIN IN THIS SMALLER STUDY OF
39 INDIVIDUALS THEY LOOKED AT
DIFFERENCES IN OBSTRUCTIVE
VERSUS CENTRAL SLEEP APNEA,
FOUND MORE PRE-DOMMANCE, THAT'S
WHAT WE'VE IDENTIFIED IN THE
PVD-OMICS COHORT.
HALF HAD NOCTURNAL DESATURATION.
WE ALSO ELECTED TO LOOK AT
PULMONARY HYPERTENSION AND SLEEP
APNEA BASED UPON REGISTRY THAT'S
BEEN DEVELOPED AT THE CLEVELAND
CLINIC, STARLIT REGISTRY, BASIS
OF A RECENT IBM DISCOVERY
ACCELERATOR AWARD WHERE WE'RE,
AS MANY OTHERS, TRYING TO LOOK
FOR BETTER WAYS TO ASCERTAIN
SLEEP DISORDERED BREATHING AND
PREDICTION OF CLINICAL OUTCOMES
AND TREATMENT RESPONSIVENESS.
SO, AS WE MERGED SOME OF OUR
SLEEP REGISTRY DATA WITH
PULMONARY HYPERTENSION REGISTRY
THAT WE HAVE, WE WERE INTERESTED
IN LOOKING AT SOME OF THESE
RELATIONSHIPS WITH MEAN ARTERIAL
PRESSURE AND HEMO HEMODYNAMIC
MEASURES AND FOUND THESE ARE
ASSOCIATED WITH LONGER DURATION
OF NOCTURNAL HYPOXIA WITH NO
ASSOCIATION WITH HEMO
HEMODYNAMIC MEASURES.
THIS WAS IN A GROUP OF CLOSE TO
500 INDIVIDUALS.
SO SOME COMMON THEMES WE'RE
SEEING HERE IN STUDIES DONE, IN
PVDOMICS WE TRIED TO LOOK AT
RELATIONSHIPS WITH THESE
FREQUENCY OF APNEA PER HOUR, AS
RELATED TO RIGHT VENTRICULAR
FUNCTION, WITH THOSE WHO HAVE
CARDIAC MRI WE WERE ABLE TO LOOK
AT RIGHT EJECTION FRACTION AND
FOUND SOME SIGNIFICANT
ASSOCIATIONS IN PARTICULAR WITH
PERCENTAGE OF TIME SPENT BELOW
90% AS RELATED TO RIGHT
VENTRICULAR EJECTION FRACTION,
RIGHT SYSTOLIC -- RIGHT
VENTRICULAR PRESSURE AND MEAN
PULMONARY PRESSURE IN FINDINGS
NOT OBSERVED WITH APNEA
HIGHPOPNE INDEX.
IN GROUP 1 FOR ARTERIAL
HYPERTENSION HOW SLEEP APNEA
PREDICTS OUTCOMES, IN THIS
COHORT OF 150 SURROUNDS OF
INDIVIDUALS FOUND SLEEP APNEA IN
A THIRD OF INDIVIDUALS, AND
THERE WAS NO SIGNIFICANT
DIFFERENCE, IN THOSE VERSUS
THOSE WITHOUT OBSTRUCTIVE SLEEP
OF A KNEE A.
WHEN LOOKING AT OXYGEN
SATURATION WITH HIGHER DEGREE OF
HYPOXIA HAD WORSE SURVIVAL
COMPARED TO THOSE WITH LESSER
DEGREE OF HYPOXIA AND APPEARED
TO BE ASSOCIATED WITH POOR
PROGNOSIS.
THIS WAS OVER A 3-YEAR PERIOD OF
TIME.
WE LOOKED AT THESE RELATIONSHIPS
IN A MORE PROSPECTIVE FASHION,
APPROACHING WITH ENHANCED RIGOR
IN TERMS OF TAKING IT TO
CONSIDERATION, CONFOUNDING
FACTORS, SUCH AS AGE, SEX, BODY
MASS INDEX, DLCO IS A WAY TO GET
AT MASS MICHIGAN AND MEDICATIONS
AS WELL.
OVER FOUR-YEAR PERIOD OF TIME
WE'RE IDENTIFYING THAT DEGREE OF
HYPOXIA WAS ASSOCIATED WITH 17%
INCREASED RISK OF DEATH OR
TRANSPLANT, THIS WAS OVER ABOUT
APPROXIMATELY A 4-YEAR PERIOD OF
TIME, AND IT'S A GREAT PLATFORM
FOR OUR EARLY CAREER
INVESTIGATORS WITH DR. LOWRY
LEADING THIS WORK, CURRENTLY
UNDER REVIEW.
WE ALSO TRIED TO LOOK AT THINGS
RATHER THAN JUST DICHOTOMIZING
AT MEDIAN VALUE OF DEGREE OF
HYPOXIA LOOKING FOR LINEAR,
NON-LINEAR RELATIONSHIPS, AND
FOUND NO EVIDENCE OF NON-LINEAR
RELATIONSHIPS, LOOKED AT
RELATIONSHIPS ACROSS QUARTILES
AND FOUND THAT THIS WAS A
SIGNIFICANT LINEAR TREND, IN
TERMS OF INCREASING DEGREE OF
HYPOXIA, ASSOCIATED WITH WORSE
SURVIVAL IN GROUP 1 PULMONARY
HYPERTENSION.
WE CAN SURMISE SLEEP RELATED
HIGH -- HYPOXIA, POTENTIAL
LOCAL MOLECULAR INFLUENCES, AT
THE LEVEL OF PULMONARY ARTERY
LEADING TO PROGRESSION OF RIGHT
VENTRICULAR DYSFUNCTION, TO
SUMMARIZE IT WAS MORE -- THERE'S
MORBID ASSOCIATION WITH DEGREE
OF NOCTURNAL HYPOXIA WITH RIGHT
VENTRICULAR MEASURES, APNEA
INDEX WAS ASSOCIATED WITH RIGHT
VENTRICULAR EJECTION FRACTION,
MORE OF REDUCTION THERE, AND
OVERALL HYPOXIA WAS REALLY
DRIVING THE POORER SURVIVAL THAT
WAS SEEN IN THIS COHORT.
WE ELECTED TO GO DEEPER AND
LEVERAGE METABOLOMICS DATA.
METABOLIC ALTERATIONS ARE DRIVER
EVER PATHOGENESIS, AND WE KNOW
SLEEP DISORDERED BREATHING IS
ASSOCIATED WITH METABOLIC
DYSFUNCTION, AND IMPLICATED IN
HYPERTENSION, AND SINCE WE
IDENTIFIED HYPOXIA WAS
ASSOCIATED WITH RIGHT
VENTRICULAR DYSFUNCTION THE IDEA
TO SEE WHETHER BIOMARKERS CAN
SHED LIGHT ON WHAT CONNECTS
THEM, SLEEP APNEA, DEGREE OF
HYPOXIA AS RELATES TO POOR
SURVIVAL.
AS WE LOOKED AT THESE
METABOLITES WE FOUND SOME COMMON
THEMES WITH CERTAIN PATHWAYS
THAT WERE DYSREGULATED, AS IT
RELATES TO SLEEP-RELATED
HYPOXIA, SO SPECIFICALLY WE
FOUND DISRUPTION OF THE POLY
AMINE METABOLISM, FATTY ACID
AROUND PREGNANOLONE STEROIDS,
SEEMED LIKE MEN, THOSE WERE
YOUNGER, GREATER GRIEF
ALTERATIONS IN THE PREGNANOLONE
METABOLOME PATHWAYS.
WE THEN TRIED TO IDENTIFY THOSE
THAT WERE SIGNIFICANT IN TERMS
OF ASSOCIATION WITH HYPOXIA AND
SEE IF THE TOP CANDIDATE
BIOMARKERS WERE RELATED TO
ABNORMALITIES IN RIGHT
VENTRICULAR FUNCTION BASED
UPON -- THESE ARE MAINLY ECHO
MEASURES.
AND FOUND THAT IN PARTICULAR,
THE POLYAMINE METABOLITES WERE
ALTERED IN THE SETTING OF RIGHT
VENTRICULAR FUNCTION AND SIZE.
AND SO CAN POTENTIALLY ALLOW FOR
INSIGHT ON MECHANIC ISM AND
WE'RE DOING ANALYSES TO
INVESTIGATE THAT.
RECENTLY THIS YEAR IN TERMS OF
POLYAMINE METABOLISM IDENTIFIED
BY THE UNIVERSITY OF WASHINGTON
GROUP, IN TERMS OF IDENTIFYING
INDIVIDUALS AT HIGHER RISK FOR
POORER OUTCOMES IN PULMONARY
HYPERTENSION, AS POTENTIAL
IMPORTANT BIOMARKERS OF DISEASE
PROGRESSION, AND RIGHT
VENTRICULAR ADAPTATION.
SHIFTING TO TREATMENT THERE'S
DATA IN A SMALLER SAMPLE OF 23
INDIVIDUALS SHOWING SOME
IMPROVEMENT IN PULMONARY
ARTERIAL SYSTOLIC PRESSURE, IN
PARTICULAR THEY IDENTIFY THOSE
INTERESTINGLY WITH LEFT
VENTRICULAR DIASTOLIC FUNCTION
HAVE MORE IMPROVEMENT IN DEGREE
OF PULMONARY HYPERTENSION
PRESSURE REDUCTION.
IN THIS TRIAL THEY LOOKED AT
NOCTURNAL OXYGEN IN
PRE-CAPILLARY HYPERTENSION AND
FOUND BENEFITS WITH SUPPLEMENTAL
OXYGEN IN TERMS OF 6-MINUTE WALK
DISTANCE, RIGHT VENTRICULAR
FRACTION AREA CHANGE.
THAT PROVIDES A SUMMARY OF GROUP
1.
IN TERMS OF GROUP 2
UNFORTUNATELY THERE'S A LITTLE
BIT LESS LITERATURE IN THIS
AREA.
YOU KNOW THERE'S BIOLOGIC
PLAUSIBILITY FOR THERE TO BE
INTERRELATIONSHIPS WITH SLEEP
APNEA, PULMONARY HYPERTENSION,
AND HEART FAILURE.
WE KNOW IN SLEEP APNEA BECAUSE
OF THE MECHANISMS THAT HAVE BEEN
HIGHLIGHTED AS WELL AS ROSTRAL
FLUID SHIFT THAT CAN INCREASE
EDEMA, UPPER AIR WAY EDEMA,
PULMONARY CONGESTION, CAN LEAD
TO CENTRAL SLEEP APNEA.
DATA AT MOLECULAR LEVEL SHOW
INTERMITTENT HYPOXIA CAN INDUCE
CARDIOMYOCYTE DEATH, DIFFERENCE
IN TRANSCRIPTOME, EPIGENETIC
PROGRAMS, POST-TRANSLATIONAL
MODIFICATION IN TERMS OF
INTERMITTENT HYPOXIA AND DEFECT
ON CARDIOMYOCYTE DEATH WHICH HAS
DIRECT IMPLICATION TERMS OF
HEART FAILURE AND PULMONARY
HYPERTENSION.
ALSO RECENT DATA SHOWING THAT
INTERMITTENT HYPOXIA INDUCES
CARDIAC REMODELING, CONTRACTILE
DYSFUNCTION IN RODENTS, MIGHT
RIGGER -- TRIGGER OTHER
AGGRAVATE CHRONIC HEART FAILURE,
OPPORTUNITIES TO LOOK MORE
CLOSELY.
WITH SLEEP APNEA AND HEART
FAILURE, ACUTE DECOMPENSATED,
POOR SURVIVAL AND TREATMENT
POST-DISCHARGE IN THOSE WITH
SLEEP DISORDERED BREATHING
APPEARS TO IMPROVE SURVIVAL IN
THE POST-DISCHARGE PHASE.
AND THERE IS ONE TRIAL PUBLISHED
TO ACTUALLY LOOK AT TREATMENT OF
SLEEP APNEA, VIA AUTOPOSITIVE
AIR WAY PRESSURE, AND HOW THAT
IMPACTS PULMONARY ARTERIAL
PRESSURES IN THOSE ADMITTED WITH
HEART FAILURE, GROUP 2 PULMONARY
HYPERTENSION AND THEY IDENTIFY
IN THE INTERVENTION ARM WITH
POSITIVE AIRWAY PRESSURE THERE
WAS REDUCTION IN THE MEAN
PRESSURE AND IMPROVEMENT IN
EJECTION FRACTION THAT WAS
OBSERVED.
SO A SMALL CLINICAL TRIAL BUT
WITH SOME INTERESTING AND
PROMISING FINDINGS NONETHELESS.
TO SUMMARIZE, OVERALL THERE ARE
EXPERIMENT WRAL AND HUMAN
PHYSIOLOGIC DATA THAT ACTUALLY
IDENTIFY IMMEDIATE TEMPORALITY
IN THE PRESSURE, HYPOXIA EXPERTS
DETRIMENT AT LEVELS OF
VASCULATURE AND FUNCTION,
VARIOUS PATHWAYS DIDN'T HAVE
TIME TO REVIEW BUT VARIOUS
PATHWAYS IDENTIFIED FROM
MOLECULAR LEVEL, AND THAT GROUP
1 APPEARS TO HAVE HIGHER DEGREE
OF HYPOXIA, PERHAPS GREATER
DEGREE OF SLEEP APNEA.
AND WITH GROUP 1, THERE'S A WIDE
VARIETY AND WIDE RANGE I SHOULD
SAY OF PREVALENCE IN TERMS OF
OBSTRUCTIVE APNEA, AND
PREDOMINANCE VERSUS CENTRAL,
DATA SHOWING PERHAPS COMPOSITE
OF CLINICAL AND CIRCULATING
BIOMARKERS THAT MAY CHARACTERIZE
SLEEP APNEA IN A BETTER WAY IN
PULMONARY ARTERIAL HYPERTENSION,
POOR SLEEP QUALITY ASSOCIATED
WITH EXERCISE LIMITATION.
THERE'S DATA ON TO SHOW
SLEEP-RELATED HYPOXIA ASSOCIATED
WITH WORSE TRANSPLANT FREE
SURVIVAL EVEN AFTER
CONSIDERATION OF CONFOUNDING
FACTORS, THE POLYAMINE
METABOLITES AND THEIR ALTERATION
MAY PROVIDE SOME CLUES IN TERMS
OF THE MECHANISMS THAT ARE
INVOLVED AND THERE'S SOME SMALL
INTERVENTIONAL STUDIES THAT
SUGGEST THAT TREATMENT WITH
POSITIVE AIRWAY PRESSURE THERAPY
AND NOCTURNAL SUPPLEMENTAL
OXYGEN MAY BE FAVORABLE.
A SMALL TRIAL SEEMS TO SHOW SOME
IMPROVEMENT IN DEGREE OF
PULMONARY HEMODYNAMICS.
AS WAS MENTIONED, THERE ARE
OPPORTUNITIES TO DELVE FURTHER
TO LOOK AT SUBTYPE OF HYPOXIA
AND HOW THIS RELATES TO
OUTCOMES.
WE'VE BEEN DELVING IN FURTHER IN
THE PVDOMICS DATA TO IDENTIFY
DIFFERENT PATTERNINGS OF
HYPOXIA.
YOU CAN SEE IT'S MORE
PRECIPITOUS, SOMETIMES MORE
PROLONGED.
RELATED IN PART TO CIRCULATION
TIME BUT THIS AND INTEGRATED
MEASURES WITH THE HEART RATE
AROUSAL RESPONSE MAY PROVIDE
GREATER MEASURES.
PATHOPHYSIOLOGY OF SLEEP
DISTURBANCES INCLUDING ZIP
DISORDERED BREATHING IN GROUP 1,
WHAT IS DRIVING THAT IN TERMS OF
SLEEP DISORDERED BREATHING IS OF
INTEREST.
UNDERSTANDING HOW THESE
AUTONOMIC DYSFUNCTION IS
AFFECTING THE RIGHT VENTRICLE IS
INTERESTING.
AND CIRCULATING BIOMARKERS IS OF
INTEREST IN BOTH GROUPS.
OTHER IMPORTANT AREAS HAVE BEEN
MENTIONED, UNDERSTANDING
INFLUENCE OF INTERVENTIONS BUT
UNDERSTANDING THE SUBTYPES I
THINK IS THE FIRST STEP BEFORE
WE EMBARK ON UNDERSTANDING HOW
INTERVENTIONS TO UNDERSTAND WHO
IS GOING TO RESPOND BEST TO
TREATMENTS.
THANK YOU SO MUCH.
>>GREAT REVIEW OF THE STATE OF
KNOWLEDGE HERE AND RECENT
CONTRIBUTIONS.
WE HAVE TIME FOR ONE QUESTION
FOR DR. MEHRA AND OPEN UP TO
GENERAL DISCUSSION OF THE LAST
THREE TALKS.
I HAVE ONE FOR YOU.
WHEN I PRESENTED A LITTLE BIT OF
THE POLY AMINE DATA, PVD OMICS
AT APS, LAST, SOMEBODY IN THE
AUDIENCE CAME UP TO ME AND SAID
TO ME, YOU ARE AWARE THERE'S
LIKE A WHOLE LARGE BASIC SCIENCE
LITERATURE ABOUT POLYAMINES
DATING BACK TO THE EARLY
2000s, I WAS NOT.
SO I DID A DEEP DIVE.
YOU MAY BE AWARE, BUT THERE WAS
SOME PUBLICATIONS FROM THE FOLKS
NOW AT UNIVERSITY OF SOUTH
ALABAMA LOOKING AT POLYAMINE
DISTURBANCE IN RODENT MODELS,
PULMONARY HYPERTENSION, IT
DAWNED ON ME NOW THAT THE RODENT
MODELS OF PULMONARY HYPERTENSION
THEY WERE USING WERE HYPOXIA AT
THE TIME SO I JUST WENT BACK AND
DID SOME RESEARCH ON THAT AND I
THINK IT SPEAKS TO COMMENTS THAT
STEVE CHAN MADE EARLIER THAT WE
HAVE TO BE VERY CAREFUL ABOUT
WHAT RODENT MODELS WE'RE USING
BECAUSE WE MAY BE MAKING
IMPORTANT FINDINGS BUT NOT
NECESSARILY INTERPRETING THEM
100% FULLY, FOR INSTANCE HYPOXIA
MAY BE AFFECTING SPERMINE
METABOLISM, WE MAY INTERPRET BUT
PERHAPS IT'S A FUNCTION OF
HYPOXIA.
ANYWAY, JUST INTERESTING IN THE
CONTEXT OF YOUR FINDINGS.
>>THAT WAS MARK GILLESPIE'S
WORK, RIGHT?
>>YES.
AS I'M NOW MORE FAMILIAR WITH
IT.
>>THAT'S A GREAT COMMENT.
I THINK, YEAH, IT'S IMPORTANT TO
PUT THINGS INTO CONTEXT IN TERMS
OF WHAT PHYSIOLOGIC MODEL IS
BEING USED AND IMPACTING
SIGNATURES.
WE HAVE TO DO MORE VALIDATION
WORK AND ENSURE WHAT WE'RE
SEEING, AND WE'RE FORTUNATE TO
HAVE GENOMICS AND MULTIOMICS
CHARACTERIZATIONS.
YEAH, GREAT POINT.
>>WE CAN OPEN TO GENERAL
DISCUSSION.
DR. SWEATT HAS A HAND RAISED FOR
COMMENT OR QUESTION.
>>YES, MY QUESTION IS MORE
DIRECTLY RELEVANT TO PVD-OMICS
DATA, ONE OF THE MAIN FINDINGS
WAS THAT HYPOXIC BURDEN
ASSOCIATED WITH OVERALL OUTCOMES
MORE SO THAN AHI, WITHIN THAT
COHORT DID YOU FIND A
SIGNIFICANT SUBSET OF PATIENTS
WHO DOES NOT MEET DIAGNOSTIC
CRITERIA FOR SLEEP DISORDERED
BREATHING OR OSA YET
DEMONSTRATED SIGNIFICANT HYPOXIC
BURDEN?
IS THIS A SIZEABLE GROUP OF
PATIENTS WE'RE MISSING, MAYBE
WE'RE UNDERTREATING WITH
SUPPLEMENTAL OXYGEN?
>>YEAH, THAT'S A GREAT
QUESTION.
YOU KNOW, WE'RE IN THE PROCESS
OF KIND OF GOING THROUGH AND
FIGURING OUT HOW MUCH OF THIS IS
REALLY SLEEP APNEA SPECIFIC
INTERMITTENT HYPOXIA, THAT'S
WHAT THE SLEEP APNEA SPECIFIC
BURDEN ALLOWS US TO GET AT.
IT'S TRUE THERE'S THIS MAYBE
LEVEL OF HYPOXIA AND THEN
SUPER-IMPOSED BOUTS THAT MAY BE
EXPERTING EVEN GREATER
DETRIMENT.
ONE FINDING WHICH WAS OF
INTEREST WAS THAT THE DAY TIME
OXYGEN SATURATION, IT WASN'T
REALLY CORRELATED WITH OUTCOMES.
THERE'S SOMETHING UNIQUE AND
SPECIFIC TO THE NOCTURNAL OXYGEN
DESATURATION, BUT THAT'S A GREAT
POINT IN TERMS OF TRYING TO
DISENTANGLE THESE, YOU KNOW,
INFLUENCES OF SLEEP DISORDERED
BREATHING VERSUS THE BACKGROUND
HYPOXIA.
>>THANK YOU FOR A FANTASTIC
TALK AND STIMULATING DATA.
MAYBE ALSO POTENTIALLY TO FOLLOW
UP ON SOME OF THE LAST COMMENTS,
I THOUGHT ONE OF THE REALLY
UNIQUE THINGS THAT YOU AND YOUR
GROUP HAVE ARE MEASUREMENTS, YOU
KNOW, REALLY DETAILED DEEP
PHENOTYPING MEASUREMENTS, AND I
SAW THAT IN YOUR MODELS YOU
ADJUSTED FOR DLCL FOR EXAMPLE
AND OTHER RISK FACTORS.
AS WE GRAPPLE WITH THE CHICKEN
VERSUS THE EGG IS THIS, YOU
KNOW, AVERAGE HYPOXEMIA DRIVING
PULMONARY HYPERTENSION OR IS THE
PULMONARY HYPERTENSION OR IS
HYPOXEMIA A MANIFESTATION OF ONE
DISEASE.
AND I SAW, YOU KNOW, WHEN YOU
ADJUSTED THESE FACTORS YOU STILL
SAW RELATIONSHIPS BUT I WAS
WONDERING IF YOU TRIED TO MAYBE
SORT OF TEASE APART THE RELATIVE
CONTRIBUTIONS OF MAYBE WHAT
MIGHT BE RISK FACTORS, YOU NEED
TEMPORAL DATA TO DO THIS VERSUS
WHAT MIGHT BE SLEEP APNEA
SPECIFIC RESPONSES, LIKE FOR
EXAMPLE HOW IMPORTANT WAS THE
DLCO VERSUS MAYBE SOME OF THE
OTHER FACTORS IN PREDICTING
MORTALITY, WHAT PROPORTION, I
WAS JUST WONDERING IF THAT WOULD
BE HELPFUL, WHETHER YOU COULD DO
THAT.
>>SORRY, I'M MUTED.
THANK YOU, DR. REDLINE.
THAT'S A FANTASTIC IDEA,
SOMETHING WE REALLY ARE TRYING
TO BETTER UNDERSTAND, THE
DIRECTIONALITY AND I THINK
THAT'S A GOOD SEGUE INTO SOME OF
THE NEXT TALKS, BUT, YEAH, TO
THE EXTENT WE CAN LEVERAGE DATA
TO UNDERSTAND THE STRENGTH OF
THE ASSOCIATION, SAY, BETWEEN,
YOU KNOW, THE INTERMITTENT
HYPOXIA, VERSUS THE DLCO AS
REFLECTION OF MEASURES, AND
PERHAPS TRYING TO SEE IF THERE
ARE DIFFERENTIAL RELATIONSHIPS
THERE WITH CLINICAL OUTCOMES,
YOU KNOW, WE HAVEN'T DONE ANY
DIRECT COMPARISONS AS OF YET.
BUT THAT WAS OUR INITIAL ATTEMPT
TO TRY TO TAKE IT INTO ACCOUNT,
RECOGNIZING THERE'S PROBABLY
RESIDUAL CONFOUNDING BUT THERE'S
OPPORTUNITY TO DELVE INTO THAT
FURTHER.
>>DR. LEOPOLD HAS A HAND UP.
>>I HAD A QUESTION FOR NICK,
INTRIGUED BY YOUR FINAL COMMENT
TALKING ABOUT THE SGLT2
INHIBITORS AND HOW THEY COULD BE
BENEFICIAL, THERE'S BEEN SMALLER
REPORTS SHOWING THAT THEY REDUCE
SEVERE COPD EXACERBATIONS, AND
DAYS AGO THE EUROPEAN SOCIETY OF
CARDIOLOGY JUST RELEASED THEIR
UPDATED HEART FAILURE
GUIDELINES, UPGRADED THE USE OF
THESE DRUGS AMONG PATIENTS WITH
HEART FAILURE.
SO I GUESS THE QUESTION IS
BECAUSE ALL OF THESE DISEASES
AND CO-MORBIDITIES ALL SEEM TO
TRAVEL TOGETHER DO YOU THINK
WE'LL BE ABLE TO TEASE THIS OUT,
HOW WELL THE SGLT INHIBITORS
WORK AND WHETHER THEY ARE
AFFECTING SOMETHING ELSE THAT IN
TURN AFFECTS, YOU KNOW, THE
EXACERBATIONS OR SLEEP DISORDERS
ASSOCIATED WITH GROUP 3 PH?
>>I THINK IT'S GOING TO BE
PRETTY CHALLENGING TO DO THAT.
BUT BECAUSE AS YOU POINT OUT
THERE'S A LOT OF OVERLAP.
>>YEAH.
>>OVERLAP SYNDROME ITSELF, BUT,
YOU KNOW, THE MECHANISMS OF
THESE CONDITIONS CERTAINLY, YOU
KNOW, SHARE METABOLIC PATHWAYS,
AND SO FROM PRAGMATIC POINT OF
VIEW IF YOU HAVE SOMETHING THAT
CAN IMPROVE METABOLIC FUNCTION,
HELP PATIENTS LOSE WEIGHT
BECAUSE -- BMI BEING -- OBESITY
BEING, NO PUN INTENDED, A BIG
COMORBIDITY AS WELL.
DOES IT REALLY MAKE A DIFFERENCE
IF YOU CAN TEASE IT OUT?
BUT ON THE OTHER HAND, IT WOULD
BE HELPFUL IN TERMS OF TAILORING
THERAPY AND PRACTICING PRECISION
MEDICINE TO TRY TO DO THAT, BUT
WE'LL HAVE TO SEE HOW THAT GOES.
GREAT QUESTION.
THANK YOU.
>>I'M JUST CURIOUS, HAVE ANY OF
THE SLEEP MEDICINE PHYSICIANS
CELINE ANY CHANGES -- SEEN ANY
DIFFERENCE IN PATIENTS WHO HAVE
GONE ON THESE DRUGS?
>>I GUESS I CAN SAY TO REENA.
>>I CAN'T SAY THAT I HAVE BUT I
DON'T PERHAPS SEE AS MANY
PATIENTS WHO ARE ON THESE SCLT 2
INHIBITORS.
>>JANE, HAVE YOU BEEN USING
THEM?
>>THE PATIENTS WITH HEART
FAILURE, RIGHT NOW THE
INDICATION IS HEART FAILURE AND
DIABETICS, MAYBE ELDRIN WHEN
HE'S ON CAN TALK ABOUT THAT TOO.
SO WE'RE SEEING -- WE HAVE A LOT
OF PATIENTS GOING ON THEM.
WE'VE HAD A LOT OF PATIENTS, YOU
KNOW, DOING BETTER.
THEY ARE OBVIOUSLY LOSING WEIGHT
BUT THERE WAS JUST A VERY LARGE
CLINICAL TRIAL THAT WAS REPORTED
AGAIN AT ESC CALLED STEP-HF, ALL
THESE MORBIDLY OBESE PEOPLE
WITHOUT DIABETES WERE IN AN RCT
AND THOSE THAT GOT THE SGLT2
INHIBITOR LOST WEIGHT, HAD
MARKED IMPROVEMENTS IN 6-MINUTE
WALK DISTANCE, IMPROVED QUALITY
OF LIFE, AND, YOU KNOW, THE LIST
GOES ON AND ON.
AND IN THESE GROUPS OF PEOPLE
WE'RE STARTING TO SEE, YOU KNOW,
MORE EXERCISE, LESS ANGINA AMONG
THOSE WITH CAD, AND I THINK AS
YOU SAID, IT'S HARD TO KNOW HOW
MUCH OF THIS IS WEIGHT LOSS,
INCREASED PHYSICAL ACTIVITY, HOW
MUCH IS A DIRECT MECHANISM ON
THE VASCULATURE, THE HEART, ET
CETERA.
>>YEAH, I THINK THIS IS ANOTHER
TOPIC THAT I THOUGHT WAS WORTHY
OF DISCUSSION, FOR ME, THAT WHEN
YOU IDENTIFY A PROBLEM, LIKE I
THINK THERE IS AT LEAST SOME
DATA THAT PULMONARY HYPERTENSION
IS A PROBLEM, SORRY, THAT SLEEP
DISORDERS ARE A PROBLEM IN
INDIVIDUALS WITH PULMONARY
HYPERTENSION.
BUT HOW TO FIX IT BEST WITHOUT
HURTING THE PATIENT IS THE NEXT
QUESTION.
AND THE SGLT2 INHIBITORS SEEM
LIKE ONE WAY TO ADDRESS PEOPLE
WHO HAVE OBESITY-RELATED
PROBLEMS.
BUT I WAS WONDERING IF ANYBODY,
NICK, YOU MAY HAVE THOUGHT ABOUT
THIS, WHAT ARE THE SORT OF --
ARE THERE ACUTE HEMODYNAMIC
CONCERNS WITH PEOPLE WITH
POSITIVE AIRWAY PRESSURE WHEN WE
THINK ABOUT INTERVENTIONS?
I WANT TO MAKE SURE IF WE THINK
ABOUT MOVING THE FIELD FORWARD
WITH INTERVENTION TRIALS WE
DON'T HURT PEOPLE.
>>WELL, IF ANYTHING, THE DATA
ON SEVERE COPD AND USE OF
NON-INVASIVE VENTILATION IS
EITHER -- FOR A LONG TIME WE
WERE GETTING NO DEMONSTRABLE
BENEFIT BUT WE DISCOVERED THAT
WEREN'T USING ENOUGH PRESSURE,
AND HALF A DOZEN -- WELL, NINE
YEARS AGO NOW THERE WAS A STUDY
OUT OF GERMANY THAT SHOWED A
RATHER IMPRESSIVE SURVIVAL
BENEFIT IN PATIENTS WITH SEVERE
COPD TREATED WITH NON-INVASIVE
VENTILATION.
AND AS I SAID, IT ACTUALLY WAS
AN INCREASE IN PRESSURES THAT
SEEMED TO BE ASSOCIATED WITH THE
GREATER BENEFIT.
THEY SEEMED TO GET BETTER REST
OF MUSCLES AND THERE'S ALSO BEEN
A STUDY OUT OF THE U.K. USING
SLIGHTLY LOWER PRESSURES BUT
SHOWING THAT EXACERBATION RATE
AND THE HOSPITALIZATION RATE WAS
LESS AS WELL.
SO, IT LOOKS LIKE THIS APPROACH
IS GOING TO BE BENEFICIAL.
THESE PATIENTS WERE NOT
PHENOTYPED AS FAR AS THEIR P.A.
PRESSURES WERE CONCERNED, SO I
CAN'T SAY WHAT EFFECT THAT WOULD
HAVE, BUT IT LOOKS LIKE THEY ARE
PROBABLY SAFE AND EFFECTIVE IN
PEOPLE CHRONICALLY
HYPOVENTILATING WITH COPD.
>>CAN I COMMENT FROM A SLIGHTLY
DIFFERENT PER SPIC R. --
PERSPECTIVE TO YOUR QUESTION,
ALSO GETTING NEOMI TO CHIME IN.
IN SLEEP APNEA, YOU KNOW, I
THINK WE ALL ARE AWARE THAT CPAP
HAS NOT YIELDED IN LARGE
CLINICAL TRIALS THE BENEFITS
THAT WE EXPECTED AND IN FACT IN
HEART FAILURE, VENTILATION WAS
EVEN INCREASED MORTALITY, ONE
HYPOTHESIS MAYBE HIGHER
PRESSURES BY PAP MACHINES IN
CERTAIN PATIENTS MAY HAVE
DELETERIOUS EFFECTS, MANY
PATHWAYS THAT COULD HAPPEN, BUT
THERE IS NOW SOME PUBLISHED DATA
THAT, YOU KNOW, THAT
(INDISCERNIBLE) LEVELS GO UP IN
RELATION TO POSITIVE AIRWAY
PRESSURE AND CPAP VERSUS USUAL
CARE WILL BE ASSOCIATED IN
GENERAL WITH HIGHER ANGIOPOINTEN
2, AT COLUMBIA ALSO EVIDENCE
THAT THERE MAY BE SOME ADVERSE,
YOU KNOW, MARKERS OF ENDOTHELIA
FUNCTION ASSOCIATE WITH PAP
PRESSURE.
NEOMI HAS HER DATA TO SUGGEST
THERE MAY BE SUBGROUPS THAT HAVE
A NEGATIVE MAYBE, YOU KNOW,
PULMONARY OR INFLAMMATORY
RESPONSE TO POSITIVE PRESSURE.
THESE ARE ALL FAIRLY NEW DATA
THAT NEED CONFIRMATION, BUT
NEOMI, WOULD YOU LIKE TO SAY
ANYTHING?
NONE HAVE LOOKED AT THE OVERLAP.
>>YEAH, ABSOLUTELY.
I APPRECIATE YOU BRINGING THIS
POINT UP.
THERE'S A LOT MORE THAT WE NEED
TO LEARN ABOUT THIS SIGNAL BUT I
THINK IT MAKES ME PAUSE AND, YOU
KNOW, WHEN I'M SEEING PATIENTS
THAT ARE ASYMPTOMATIC, AND HAVE
BEEN PLACED ON CPAP BECAUSE OF A
HOME SLEEP TEST DONE YEARS AGO,
THOSE ARE THE PATIENTS THAT I'M
SORT OF AGAIN HAVING THESE
DISCUSSIONS AND MAKING DECISIONS
WITH THE EVIDENCE IN MIND WITH
THE PATIENT'S PRIORITY AND
PREFERENCE.
ABSOLUTELY, THE WORK PRESENTED
AT ATF, I BELIEVE CPAP PRESSURE
OF 7 IS WHERE SHE SAW THAT
DICHOTOMY PLAY OUT WITH HIGHER
CPAP PRESSURES, YOU KNOW,
IMPLICATED IN MORE LUNG STRETCH
AND THEN MARKER, BIOMARKERS OF
INFLAMMATION, MEASURED AND THEN
IF I RECALL CORRECTLY THE DATA
SHOWED INCREASED RISK FOR
CARDIOVASCULAR DISEASE OUTCOMES
IN THOSE WITH HIGHER CPAP
PRESSURE.
I THINK AGAIN WE'RE INTERESTING
A NEW AREA WHERE WE MAY NEED TO
BE MORE CAUTIOUS WITH CPAP AND
IDENTIFY PATIENTS WHERE THAT
SIGNAL IS CLEAN AND CLEAR AS IT
CAN BE THAT THERE'S NO HARM,
BECAUSE, AGAIN, THAT'S THE LAST
THING WE WOULD WANT TO DO AS
PROVIDERS AND CLINICIANS.
>>IF I COULD COMMENT ON THAT, I
DO THINK YOU HAVE TO BE VERY
CAREFUL ABOUT WHAT PATIENT
POPULATION YOU'RE TALKING ABOUT.
AND AS I SAID, IN COPD,
NON-INVASIVE VENTILATION HAS
BEEN STUDIED FOR YEARS, AND
THERE REALLY HAS NOT BEEN SIGNAL
FOR HARM.
AND, YOU KNOW, RECENTLY
THERE'S -- IN THE PAST DECADE
WE'VE BEEN SEEING SOME CLEARER
SIGNALS FOR BENEFIT.
BUT IF YOU LOOK AT HEART
FAILURE, IT'S KIND OF A
DIFFERENT STORY.
DOUG BRADLEY YEARS AGO DID A FEW
STUDIES SHOWING THAT USING CPAP
IN PEOPLE WITH HEART FAILURE
IMPROVED EJECTION FRACTION IN
SHORT-TERM STUDIES, AND THEN DID
THE CAM PAP TRIAL, WHICH WAS
GOING TO BE HIS LARGER TRIAL
NAILING THAT AND FOUND NEW
BENEFIT.
ADVENT-HF TRIAL, WHICH WAS USING
THE ASV WHICH WAS SUPPOSED TO BE
KIND OF DIRECTED TOWARD CHAIN
STOKES KIND OF BREATHING SHOWED
SURPRISING INCREASED MORTALITY
EVEN COMPARED TO CPAP IN THAT
STUDY, IN PATIENTS WITH
DIMINISHED EJECTION FRACTION.
ASV IS STILL USED IN COMPLEX
SLEEP APNEA, DOESN'T APPEAR
THERE'S HARM IDENTIFIABLE THERE.
IT DOES SEEM AS THOUGH IT'S --
I'M NOT FAMILIAR WITH THIS MOST
RECENT STUDY MENTIONED BUT IT
DOES APPEAR THIS IS SOMETHING
HAPPENING IN THE MORE HEART
FAILURE TYPE PATIENT, AND THERE
MAY BE SOMETHING A LITTLE
DIFFERENT ABOUT THESE POSITIVE
PRESSURES IN THOSE PATIENTS.
>>THANKS.
I FEEL LIKE THAT'S A REALLY
IMPORTANT DISCUSSION POINT TO
BRING OUT, NOT JUST BENEFITS
THAT POTENTIALLY EXIST BUT ALSO
THE DOWN SIDE.
I'M LOOKING IN THE CHAT.
THERE'S ONE FROM ANDREW BRYAN.
DO YOU WANT TO READ YOUR
QUESTION YOURSELF OR I CAN READ
IT.
HE'S STRUGGLING WITH THE
INTERNET AND THE HURRICANE.
>>I CAN BUT THERE'S A CHANCE
I'LL HAVE A HALF NAKED
9-YEAR-OLD RUNNING THROUGH, SO
FORGIVE ME AHEAD OF TIME.
YEAH, SO MY QUESTION PERTAINS TO
REALLY GETTING AT THIS TEASING
OUT SLEEP FRAGMENTATION, FIRST
GREAT TALK, REENA, THANK YOU SO
MUCH.
AND WHETHER OR NOT YOU WERE ABLE
TO LOOK AT ANY OF THE OTHER
SLEEP DISORDERS THAT DANIEL
DESCRIBED FROM BEFORE IN PH
POPULATION.
EXAMPLE I GAVE WAS, YOU KNOW, WE
WERE PROGRAMMED TO CHECK FOR
IRON DEFICIENCY IN OUR PATIENT
POPULATION, THAT BEING A RISK
FACTOR FOR RESTLESS LEG SYNDROME
AS WELL.
I DIDN'T KNOW IF THERE WAS ANY
WAY TO LOOK AT THOSE DIAGNOSES
AND OUTCOMES, AND THE CHRONOTYPE
SHIFT AS WELL, ESPECIALLY IN THE
AGING POPULATION.
I THINK IT'S SOMETHING THAT I AT
LEAST DON'T READ A LOT ABOUT OR
SEE.
>>THANK YOU SO MUCH, ANDREW.
HOPE EVERYTHING FARES WELL.
YOU'RE ABSOLUTELY RIGHT.
I THINK WITH THE TESTING THAT WE
DID, IT WAS ESSENTIALLY THE TYPE
3 APNEA TEST, RIGHT?
SO WE'RE KIND OF RELYING ON THAT
DATA.
AND WE ACTUALLY HAVE EKG DATA
THERE AS WELL THAT CAN BE
LEVERAGED.
WE DIDN'T SYSTEMATICALLY COLLECT
DATA, I DON'T THINK, ON RESTLESS
LEG SYNDROME BUT DR. HEMNES CAN
COLLECT ME IF I'M WRONG.
WE MAY BE ABLE TO PICK UP ON IT
A CO-MORBIDITIES THAT WERE
COLLECTED, SO THAT COULD PRESENT
AN OPPORTUNITY.
DID YOU DIRECT MEASURES OF
FRAGMENTATION WERE NOT
COLLECTED, OPPORTUNITY TO
UNDERSTAND CIRCADIAN RHYTHM
BIOLOGY AS WELL, IF FOLKS
HAVEN'T READ A WRINKLE IN TIME,
CIRCADIAN BIOLOGY, IT'S A GREAT
REVIEW BY DR. BRYANT,
PERSPECTIVE BY DR. BRYANT.
I HOPE THAT ADDRESSES YOUR
QUESTION.
THANKS.
>>SUBJECTS COULD HAVE AN
OPPORTUNITY, ONES THAT ENROLLED
IN THE OMICS, TO ROLE IN A TRIAL
THAT EVAN BRITAIN IS RUNNING,
USING FITBIT DATA NOT INTENDED
TO COLLECT CIRCADIAN DATA BUT BY
VIRTUE OF WEARING 24 HOURS A DAY
SOME DATA WILL ULTIMATELY BE
AVAILABLE.
IT'S ALSO ENROLLING THROUGH THE
FAR REGISTRY BUT THERE ALREADY
DATA, WHAT TIMES SLEEP IS
OCCURRING, FOR HOW LONG.
>>JUST SO YOU KNOW, THE
PATIENTS IN PVD-OMICS DID ANSWER
A SURVEY AFTER THEY DID DO THE
SLEEP STUDY THEY WERE SUPPOSED
TO COME AND COMMENT HOW MANY
TIMES THEY GOT UP DURING THE
NIGHT, WHEN THEY GO TO SLEEP,
GET UP, GET OUT OF BED, BUT IT'S
ALL PATIENT REPORTED AND IT'S,
YOU KNOW, QUITE LIKELY TO BE
LESS RELIABLE THAN WHAT EVAN
WILL BE COLLECTING.
>>YES, YES.
GREAT POINT.
WE LISTED THAT DATA
ARE DATA THAT COULD BE LOOKED
AT.
>>RIGHT.
>>I SEE A HAND RAISED FOR
QUESTION OR COMMENT.
>>YEAH, A QUESTION, MAYBE I
MISSED THIS, REENA.
GREAT TALK, BY THE WAY.
FOR THE PVD OMICS WAS THE
OXIMETER OR HOME SLEEP TESTING
DEVICE?
>>YEAH, SORRY FOR NOT OXIMETRA
COLLECTED, NOT TYPE 3 STUDY.
YEAH, THESE WERE USING NOTT T3
DEVICES.
>>ANY OTHER QUESTIONS OR
COMMENTS FROM AUDIENCE OR
DISCUSSANTS?
>>THERE IS THE ADAGE THAT THE
PULMONARY THERAPY DOES NOT WORK
AS WELL, UNTREATED SLEEP APNEA
PATIENTS, I DON'T KNOW IF THAT'S
BEEN EXAMINED IN ANY COHORTS TO
SEE IF THERE'S DIFFERENTIAL
EFFECT, RESPONSE TO THERAPY
PATIENTS WITH SLEEP APNEA
ADHERENT WITH PRESCRIBED
THERAPIES FOR SLEEP APNEA OR
NOT.
>>EXCELLENT POINT.
WE-- YEAH, THAT'S SOMETHING THAT
COULD BE LOOKED AT.
WE'RE SOME WHAT LIMITED IN
STRATIFICATION BUT DEPENDING HOW
MANY PARTICIPANTS ARE IN THOSE
CATEGORIES OF VASODILATOR USE WE
COULD LOOK INTO THAT MORE
CAREFULLY, SO THAT'S AN
OPPORTUNITY.
>>ONE QUICK QUESTION, I ALSO
HAVE FOR YOU, I DON'T KNOW IF
THE SAMPLE SIZE IS BIG ENOUGH
BUT ESPECIALLY IN YOUR
METABOLOMICS WORK ARE YOU ABLE
TO STRATIFY BY GENDER?
>>YES, WE ACTUALLY -- THE WAY
ANALYSES WERE CONDUCTED TRYING
TO LOOK AT SEX-SPECIFIC AND EVEN
ACROSS AGE DIFFERENCES, AND WITH
PREGNANOLONE METABOLITES IN
PARTICULAR SEEMED TO BE MORE OF
A PREDELICTION TO ALTERATIONS OF
METABOLITES TO MALES AND YOUNGER
INDIVIDUALS.
WE HAVEN'T DELVED VERY DEEPLY
INTO THAT BUT I DO THINK THAT'S
A REALLY IMPORTANT AREA GIVEN
THE SEX-SPECIFIC DIFFERENCES
THAT HAVE BEEN HIGHLIGHTED IN
PULMONARY HYPERTENSION.
>>THANK YOU.
>>THANKS.
>>WE HAVE TIME FOR ONE LAST
QUESTION IF YOU'D LIKE TO
UNMUTE.
>>SURE.
MORE ON THE SLEEP SIDE, I WONDER
WHETHER ONE OF THE IMPORTANT
TAKEAWAYS CONSIDERING COMPLEXITY
OF WONDERFUL TALKS AND THINGS,
REENA AND VINICA
MAYBE ONE OF THE TAKEAWAYS ARE
ACTIONABLE ITEM FOR THE WORKSHOP
SHOULD BE WAY OF PRIORITIZING
THE MOST PROMISING SUBPHENOTYPE
OF PULMONARY HYPERTENSION TIMES
SUBPHENOTYPES THE MOST PROMISING
AND MOST IMMEDIATELY ACTIONABLE
FOR SLEEP-BASED INTERVENTIONS, I
JUST WANTED TO PARK THAT ON THE
BACK OF PEOPLE'S MINDS, A VERY
NICE DELIVERABLE AS TO WHAT IS
PROBABLY THE MOST PROMISING,
ESPECIALLY I THINK THE NEWEST
KIDS ON THE BLOCK LIKE THE SGL 2
INNOVATORS SEEMS LIKE THEY MAY
ACTUALLY BE EVEN MORE PROMISING
BASED ON THE NEW TRIALS THAT ARE
BEING PUBLISHED, AND, YOU KNOW,
VIS-A-VIS GOING BACK TO 1950s
STUDIES, FOLKS SAYING THE
ADIPOSITY ON THE VASCULATURE
CANNOT BE IGNORED EITHER, SO
JUST THROWING THAT OUT THERE,
SUBPHENOTYPE OF OBESITY-RELATED
SYNDROME ASSOCIATED PULMONARY
HYPERTENSION, AND EFFECTS ON THE
RIGHT HEART AND DIASTOLIC
DYSFUNCTION WE SEE IN PEOPLE
WITH OBESITY, MAYBE WE'RE
LOOKING AT SUBPHENOTYPES MOST
AMENABLE.
I WANTED TO THROW THAT OUT THERE
TO BE SOMETHING ACTIONABLE TO
THINK ABOUT AT THE WORKSHOP.
>>THAT'S A GREAT COMMENT.
I THINK THAT SHOULD BE A TOPIC
OF DISCUSSION TOMORROW.
>>I AGREE.
>>SO, WITH THAT WE'VE COME TO
THE END OF THIS SESSION.
WE HAVE NOW A 15-MINUTE BRIEF
BREAK, SO WE'LL COME BACK AT
3:15 EASTERN TIME.
AND MOVE TO SESSION 3.
I'D LIKE TO THANK ALL THE
SPEAKERS IN THE LAST SESSION AND
DISCUSSANTS, AND EVERYBODY FOR A
ROBUST SESSION.
THANK VERY MUCH.
WELCOME BACK.
I HOPE EVERYONE HAD A LITTLE
REFRESHER.
IT'S REALLY MY PLEASURE TO
INTRODUCE THIS SESSION, AND NOW
WHAT WE'LL BE DOING IS EXAMINING
HOW SLEEP DISORDERS AND
PULMONARY HYPERTENSION
CO-AGGREGATE LOOKING ACROSS
PATIENT GROUPS, LOOKING AT
SPECIAL POPULATIONS, WE HAVE A
PEDIATRICIAN AS ONE OF OUR
SPEAKERS WHO WILL GIVE US THAT
VERY SPECIFIC LIFE COURSE
PERSPECTIVE.
WE WILL WRAP UP WITH A
MULTIOMICS APPROACH AS A WINDOW
INTO LOOKING AT SOME OF THE
MECHANISMS.
IT'S A PLEASURE TO INTRODUCE DR.
PUNJABI, LEADING STUDIES WHICH
INCLUDE SLEEP APNEA ASSOCIATIONS
ACROSS THE LIFESPAN AND SPECIAL
POPULATIONS INCLUDING PATIENTS
WITH HIV, HE'S ALSO NOT ONLY
DOES EPIDEMIOLOGIC WORK BUT HAS
DONE TRANSLATIONAL AND BASIC
WORK AND ACTUALLY HE'S ALSO DONE
EXPERIMENTS OF N-of-1s,
WHERE HE WAS THE 1.
DR. PUNJABI, TAKE IT AWAY.
>>THANKS FOR THE INTRODUCTION.
I'M SURPRISED YOU REMEMBER MY
EXPERIMENTS OF N-of-1.
THANK YOU FOR INCLUDING ME.
LET ME SHARE MY SCREEN AND MOVE
TO PRESENTATION AND PUT IT IN
PRESENTER MODE AT THIS POINT.
I THINK IT PROJECTS WELL.
I THANK YOU FOR ORGANIZING THIS
AND INCLUDING ME.
WHEN I GOT YOUR E-MAIL, SUSAN, I
SAW THE TITLE YOU PUT ON FOR ME
I THOUGHT IT WAS AN ENORMOUS
TEST, THE CONCEPT OF VARIATION
AND PULMONARY HYPERTENSION WHICH
I DO NOT THINK A THE LOW ABOUT,
TO THINK ABOUT AGE, SEX, RACE
AND ETHNICITY, WHAT HAVE I
GOTTEN MYSELF INTO IN I TOOK ON
THE CHALLENGE, THANKS FOR DOING
THAT, AND PUTTING ME IN THAT
SPOT.
IT MADE ME THINK ABOUT WHAT TO
TALK ABOUT, HOW TO REALLY PUSH
KNOWLEDGE GAP HERE, WHAT CAN WE
LEARN FROM ONE DISEASE AND WHAT
DOES IT OVERLAP WITH THE OTHER.
LET'S SEE IF I MET THE
CHALLENGE, SUSAN, WITH REGARDS
TO TALKING ABOUT SLEEP DISORDERS
AND I DON'T KNOW IF PEOPLE KNOW
THAT NOSOLOGY INCLUDES 100
DISORDERS IN THE ICSD THAT WE
HAVE.
HERE IS WHAT I DECIDED TO DO.
I'LL TALK ABOUT EPIDEMIOLOGY OF
SLEEP DISORDERS IN GENERAL.
WE'VE HEARD A LOT ALREADY, I'LL
FOCUS ON SLEEP APNEA, SLEEP
ONSET AND MAINTENANCE INSOMNIA.
DAN WILL DO A BETTER JOB BUT
I'LL GIVE IT A SHOT AND SHORT
SLEEP DURATION.
I THINK IT'S IMPORTANT TO THINK
ABOUT EFFECTS OF SHORT SLEEP
DURATION AND HOW THEY PERVASIVE
THINGS AFFECTS OUTCOMES OF pH.
I'LL FOCUS ON THINGS SUSAN
PUSHED ME TO THINK ABOUT, AGE,
SEX, ETHNICITY, I KNEW WHAT I
WAS GOING TO DO BUT DOVE IN AND
WAS SURPRISED TO LEARN THINGS I
BELIEVE IN, I WILL CAUTIOUSLY, I
USE THAT WORD CAUTIOUSLY, TO
TRAVERSE THE WATERS ON
EPIDEMIOLOGY OF PH, VERY BROAD,
AND THINK ABOUT THE OVERLAP
BETWEEN WHAT WE SEE IN SLEEP AND
WHAT YOU ALL IN THE PH WORLD
THINK ABOUT COMPONENTS OR TIMES
OF PH.
I WANT TO THINK ABOUT I KNOW ALL
OF US WANT TO THINK ABOUT OR
SOME WANT TO THINK ABOUT CAUSAL
EFFECTS, DOES SLEEP APNEA DO
THIS, DOES HYPOXEMIA DO THIS OR
THAT, BUT RATHER I PIVOTED AS I
STARTED WORKING ON THIS, MAYBE
IT'S A TWO-HIT PROBLEM.
WHAT HAVE YOU A HABITUAL SLEEP
DURATION AND GROUP 1 PH, WHAT
DOES THAT MEAN?
WE KNOW IF YOU'RE HABITUALLY
SHORT, WELL DEFINED, WHAT DOES
THAT DO WHEN YOU HAVE ONE PH OR
TWO, WHATEVER IT MAY BE, I
STARTED THINKING ABOUT
RELEVANCE.
IS IT A DIRECT CAUSAL EFFECT OF
SOMETHING, CLEARLY GROUP 3 CAN
TALK ABOUT CAUSALITY ISSUES BUT
I WANT TO THINK ABOUT AND PUSH
US TO THINK ABOUT MODIFICATION.
IT'S FINE TO HAVE TWO DISORDERS
BUT CUSS ONE MODIFY THE EFFECT
OF OTHERS?
WE'VE HEARD ABOUT THIS.
THE OBVIOUS FIGURE HERE IS
SHOWN, INCREASED ESOPHAGEAL
AIRWAYS, CLOSED AIRWAYS, BUT I
LOVE THE NICK HILL BROUGHT
THINGS IN, OTHERS BROUGHT THINGS
IN, LOOK, IT'S ONE THING TO
THINK ABOUT HYPOXEMIA BUT THAT'S
NOT ALL WE SEE.
HERE IS A PATIENT WITH COPD.
LOOK AT WHAT HAPPENS.
THIS DOES NOT HAVE THE VERY
TYPICAL THING WE SEE WITH SLEEP
APNEA.
HYPOXEMIA IS SLOW, PROGRESSIVE
AND SUSTAINED.
BOB AND NICK TALKED ABOUT
COMPONENTS.
SLEEP APNEA IS THERE.
IT'S IMPORTANT, EFFECTS OF
SOMETHING INTERMITTENTLY,
HYPOXEMIA, VERSUS MORE SUSTAINED
WAY WHETHER IT'S SUSTAINED OR
LONG PERIODS OF NIGHT,
THROUGHOUT THE 24-HOUR PERIOD
MAY HAVE DIFFERENT EFFECTS.
WE NEED TO BE CAREFUL ABOUT WHAT
IS IT PHYSIOLOGICALLY THAT
MOTIVATES US TO THINK ABOUT
CAUSALITY OR MODIFICATION?
SO, NO BRAINER HERE.
SLEEP APNEA COMMON, MEN AND
WOMEN HAVE IT.
THERE'S A GENDER DIFFERENCE
WHICH WE'LL GET INTO A LITTLE
BIT.
EFFECT ON AGE, OBESITY IS ONE OF
THE TOP MAJOR DETERMINANTS OF
DISEASE.
AND TWO DECADES WHERE MANY OF
YOU HAVE CONTRIBUTED ALL YOUR
LIFE, AND HYPERTENSION, THAT'S
ACCEPTED FACT THAT UNTREATED
SLEEP APNEA AND HYPERTENSION.
CORONARY ARTERY DISEASE,
POTENTIAL EFFECT OF CPAP STILL
UNKNOWN, TO BE WRITTEN IN FINE
FORM.
BUT AT LEAST HEALTH OUTSOME OF
HYPERTENSION AND
PATIENT-REPORTED OUTCOMES WELL
DEFINED.
GLOBAL BURDEN, THIS IS WORK FROM
BENJAFIELD, CONVEYS OBVIOUS
TOPIC.
IT'S COMMON.
EVEN IF THERE'S NO CAUSAL
EFFECTS, MEANING SLEEP APNEA,
ANY FORM OF PH EXTREMELY COMMON
PROBLEM, THE BURDEN NICK WAS
TALKING ABOUT, A LOT OF THE
VARIABILITY, PREVALENCE,
DETERMINED BY THINGS SUCH AS HOW
YOU DEFINE DISEASE, ONE DISEASE
THAT IS CLEARLY EVIDENT, YOU CAN
DEFINE IT ANY WAY YOU WANT, HERE
IT WAS DONE IN TWO WAYS, ANY
DEGREE OF APNEA, THE LAST -- YOU
SEE A HEAT MAP OF INDIVIDUALS,
YOU CAN LOOK AT REGIONS AND THE
PREVALENCE ESTIMATES ARE IN THE
VERY ORANGE ZONE, METRICS HERE,
ORANGE IS IN THE 70s.
THE U.S. IS IN THE MIDDLE,
RATCHET UP TO AHI OF 15 YOU
STILL HAVE A LOT OF COUNTRIES,
PARTICULARLY MIDDLE EAST AND
ASIAN CONTINENT.
THIS IS COMMON.
IT'S COMMON EVERYWHERE.
HERE ARE THE TOP TEN COUNTRIES.
U.S., INDIA, 54 MILLION WITH ANY
GRIEF APNEA, THIS IS OF COURSE
PREVALENT AND NOTHING NEW TO ANY
OF US.
HERE IS SOMETHING I FOUND
INTERESTING.
THIS IS A REANALYSIS OF THE SAME
DATA.
THEY TOOK THE SAME DATA IN THE
ARTICLE, AND PLOTTED THIS AS
FUNCTION OF TIME, WHAT THEY DID
TWO DEGREES OF DEFINITION, FIVE
AND TEN THRESHOLDS, WHAT'S GOING
ON TEMPORALLY, THERE'S NO DOUBT,
AGAIN MAYBE I'M MISINTERPRETING
THIS GRAPH, THERE IS A TREND.
THEY KIND OF MODEL LINEAR TREND,
IF THAT'S OKAY, SURE, YOU CAN
SEE THERE'S A GENDER DIFFERENCE,
RIGHT?
MEN AND WOMEN CLEARLY HAVE
DIFFERENCES.
WE'LL GET INTO THAT IN A MINUTE.
BUT ALSO THERE IS SEEMS TO BE
TEMPORAL TREND, WHETHER IT
PARALLELS OBESITY, OTHER FACTORS
UNKNOWN.
YES, IT'S COMMON BUT IT'S
BECOMING MORE COMMON, I FOUND
THIS FASCINATING.
THIS CAME OUT RECENTLY.
A FEW MONTHS AGO.
THIS IS A UNIQUE APPROACH.
I'M NOW GETTING INTO EFFECTS OF
AGE.
WHAT DO WE KNOW ABOUT AGE?
INTERESTING TO SHARE.
WELL, IT'S A GROUP OF
INDIVIDUALS CLUSTERED TOGETHER,
THREE COHORTS, HERE THEY ARE.
THERE'S A CHIME COHORT, THESE
ARE PEDIATRIC, YOUNGER
POPULATIONS, AND THEN MGH COHORT
FROM STANDPOINT OF POLY
SOMNOGRAPHIC DATABASE.
AHI DISTRIBUTION, WHAT IT SHOWS
IF YOU LOOK AT FUNCTION OF AGE
BEYOND LET'S SAY 18 THERE'S A
VERY NICE TREND THAT GOES UP.
AGAIN, I WANT TO HIGHLIGHT THIS.
GRAPHICALLY IT SHOWS A LOT OF
WHAT WE KNOW BUT DISPLAYED IN A
NEAT WAY.
YEAH, BMI IS HIGH BUT RELATIVELY
FLAT EVEN FOR CLINICAL COHORT.
THERE ARE ISSUES, BIAS, ET
CETERA.
THEY LOOKED AT STAGES OF SLEEP,
SPECTRAL DENSITY ANALYSES,
ARCHITECTURE.
BUT THE KEY THING TO POINT OUT
SOMETHING THAT WE'VE KNOWN,
APNEA AND AGE ARE RELATED.
THIS IS A COMMON DISORDER, AS WE
GET OLDER.
HERE'S ANOTHER INTERESTING
ARTICLE TO SHARE WITH YOU.
THIS IS A REVIEW OF ALL THE
PUBLISHED LITERATURE, COMPARING
MEN, WOMEN, AND DEGREES OF SLEEP
APNEA DEPENDING ON HOW YOU
DEFINE.
MY CHARGE WAS DESCRIBE AGE
EFFECT, GENDER EFFECT,
RACE/ETHNICITY.
THIS REALLY DOES A GREAT JOB.
IT DOES AT LEAST TWO OF THE
THREE FACTORS THAT I WAS
ASSIGNED.
WHAT DO YOU SEE HERE?
WELL, FIRST ON THE Y-AXIS THESE
HAVE PLOTTED DIFFERENT COHORTS
AND DIFFERENT PUBLICATIONS.
EACH COLOR IS A DIFFERENT
COHORT, AND THEREFORE DIFFERENT
PUBLICATION, WHAT THEY DID IS
THEY PLOTTED GENDER ISSUES, MALE
ON THE BOTTOM, FEMALE ON TOP,
WENT ACROSS THE BOARD, ACROSS
DISEASE SEVERITY.
AGAIN, YOU SEE THE SAME TREND.
AGE SEEMS TO PREDICT
IRRESPECTIVE OF GENDER OR HOW
YOU DEFINE IT, MILD, MODERATE,
SEVERE, ALL PROGRESSIVELY
INCREASING WITH AGE, A NICE
SUMMARY 20 TO 30 YEARS OF
LITERATURE OUT OF WISCONSIN,
PENN, VARIOUS COHORTS.
WHEN YOU LOOK AT POPULATIONS
COMMUNITY SAMPLES THERE'S A
DIRECTS RELATIONSHIP WITH AGE,
NOTHING NEW FOR MOST OF YOU,
IT'S FOR THE SLEEP FOLKS.
SO WHAT THE NUMBERS OF THIS
GROUP RECORDED A FEW YEARS BACK,
WE ARE SOMEWHERE IN THE 9 TO 30,
IF YOU LOOK AT THE METRIC.
MEN HAVING MORE, 10 TO 30%,
WOMEN 5 TO 20%.
MOVE IT UP, PREVALENCE IS LOWER,
HIGHER THRESHOLD.
IF YOU GO INTO HIGHER AGE
GROUPS, 50s AND 60s, YOU'LL
GOAT A HIGHER PREVALENCE.
SO, AGE AND GENDER, WELL KNOWN,
WELL DESCRIBED, THESE ARE THE
SUMMARIES OF WHAT I'VE BEEN ABLE
TO PULL FROM LITERATURE THAT
THAT BRING TOGETHER HISTORICAL
VARIATION.
THERE IS SEX-RELATED VARIATION,
SOME ISSUES WE NEED TO THINK
ABOUT BECAUSE THIS MATTERS FROM
THE STANDPOINT WHAT COULD
HAPPEN, THINK ABOUT EFFECT
MODIFICATION
WHAT COULD HAPPEN TO WHETHER YOU
LOOK AT GROUP 1, GROUP 3, IT
MATTERS THAT THERE'S GOING TO BE
DIFFERENCES OF AT LEAST PURE
GENDER-RELATED EXPOSITION OF
DISEASE.
THERE ARE ANATOMICAL
CONSIDERATIONS MANY SLEEP FOLKS
KNOW ABOUT.
THERE MAY BE ISSUES OF SHORTER
UPPER AIRWAY, COLLAPSABILITY,
ALLOWED FOR GENDER DIFFERENCES
BUT PRESENTATION IS EXTREMELY
DIFFERENT IN MANY CASE.
WOMEN TEND TO NOT PRESENT WITH
CLASSICAL SYMPTOMS AND WE'VE
KNOWN THIS FOR SOME TIME.
POLYSOMNOGRAPHY IS VARIED.
IT WAS MENTIONED THERE'S LOWER
DEGREE OF APNEA SEVERITY,
PERIODS MAY BE LOWER.
ALL OF THESE ARE RELEVANT, IF
ONE IS TO TEASE OUT, IF EFFECT
MODIFICATION OF A DISORDER OF
SLEEP, I'M PICKING ON SLEEP
APNEA HERE, IT'S GOING TO MATTER
HOW WE CHARACTERIZE THESE.
YOU CAN CALL THIS WHATEVER YOU
WANT, PHYSIOLOGICAL
CHARACTERIZATION OF HYPOXEMIC
BURDEN, MANY WAYS TO DO IT.
YOU CAN USE MEASURE OF AHI,
THINK ABOUT DURATION, LOOK AT
DEGREES, SLEEP STAGES.
THERE'S GOING TO BE A LOT OF
VARIABILITY BETWEEN MEN AND
WOMEN.
THAT'S VERY WELL DEFINED.
AS WE MOVE FORWARD I THINK
PEOPLE HAVE TO THINK ABOUT HOW
DO THESE THINGS TRANSLATE INTO
OUTCOMES-RELATED PH OR PH ITSELF
WORSENING.
SO THIS SUMMARIZES IT ALL, WHAT
DO WE KNOW ABOUT GENDER?
IF YOU LOOK AT THAT THRESHOLD OF
5, 10, 15, 20, 30, NO MATTER HOW
YOU LOOK AT IT MEN, THE DARK
BLUE BAR, ARE ALWAYS
CONSISTENTLY HIGHER.
LOOKING AT PREVALENCE OVERALL,
SOMETIMES ESTIMATES OF 85,
RIGHT?
WHAT'S INTERESTING ABOUT THIS
GROUP OF INDIVIDUALS, DESCRIBED
MENOPAUSAL STATE.
THIS WAS BROUGHT UP.
WHAT ACTUALLY HAPPENS WITH WOMEN
THAT HAVE ANY DISORDER, IN THIS
CASE SLEEP APNEA, ANY DISORDER
WHERE IT IS WITH REGARDS TO
MENOPAUSAL STATUS, AND YOU CAN
SEE CONSISTENTLY WHEN YOU LOOK
AT PRE-/POST, POSTMENOPAUSAL
WOMEN WILL HAVE A HIGHER
PREDISPOSITION.
SO, YES, AGE AND SEX ARE
RELEVANT.
WE'VE KNOWN THIS.
THIS IS AGAIN DEMONSTRATING IT
IN A MORE RECENT COHORT.
THEY ARE ALSO DESCRIBING
MENOPAUSAL EFFECTS.
THOSE HAVE DIRECT RELEVANCE FROM
PHYSIOLOGY, WHAT MAY BE
HAPPENING IN PH, WHAT'S
HAPPENING WITH REPRODUCTIVE
HORMONES AND THEIR EFFECTS ON
PULMONARY HYPERTENSION.
THIS IS AN OLD SLIDE FROM
WISCONSIN, 20 YEARS.
WHEN YOU LOOK AT WOMEN, BROKEN
INTO PRE, PERI, AND POST,
INCLINE WITH AGE, WOMEN AND MEN,
A RELATIONSHIP WITH BODY MASS
INDEX.
THERE IS CLEAR-CUT DIFFERENCES,
OVERLAPPING AGE RANGE.
IF YOU LOOK AT THIS OVERLAP,
POST MENOPAUSAL WOMEN ARE IN
FACT AT HIGHER RISK, FOR THIS
DISORDER.
NOW, MAYBE I'LL BET INTO -- GET
INTO THIS LATER.
I'M NOT DESCRIBING ANY NEW,
REMINDING OURSELVES WHAT WE'VE
LEARNED OVER THE LAST FEW
DECADES, DIFFERENCES WITH AGE,
BUT WITHIN A PARTICULAR SEX
THERE ARE ISSUES ABOUT MENOPAUSE
OF RELEVANCE.
YEAH, POLYSOMNOGRAPHIC
DIFFERENCES, SAID EARLIER TODAY.
THIS IS AN OLD STUDY THAT
CHARACTERIZED WHAT IS THE
DISTRIBUTION OF SEVERITY OF
SLEEP APNEA.
MY JOB WAS EPI, AGE, SEX, BMI,
BUT SEX DIFFERENCES, WOMEN,
BLACK BARS ON THIS SLIDE, HAVE
LOWER SORT OF INDEX FOR SEVERITY
NON-REM.
WHEN YOU LOOK AT REM HIGHER
PREDISPOSITION FOR WOMEN.
THERE IS REM PREDOMINANCE, OF
COURSE THAT'S GOING TO GET
MODIFIED BY AGE, OBESITY, ET
CETERA.
BUT AT LEAST GLOBALLY WE KNOW
THERE ARE DIFFERENCES BY SLEEP
STATE.
THIS GOES BACK TO THE QUESTION
OF, YOU KNOW, POLYSOMNOGRAPHY,
HOME SLEEP TESTING.
IF YOU DON'T HAVE NON-REM YOU
WON'T CHARACTERIZES COURSE AS
WELL.
WITHOUT THAT CHARACTERIZATION AS
WE MOVE FORWARD I THINK WE'LL
MISS OUT ON SOME OF THE
UNDERLYING PHYSIOLOGY OF WHAT A
DISORDER LIKE SLEEP APNEA MAY BE
DOING TO ANY OF THE GROUPS IN
REGARDS TO PH.
I THOUGHT I KNEW EVERYTHING WILL
RACE/ETHNICITY.
THIS CAME OUT RECENTLY.
I HAD TO RETHINK THIS ONE OUT.
SUSAN HAS DONE A TREMENDOUS
AMOUNT OF WORK OVER THREE
DECADES ON THE TOPIC OF RACE,
I'LL SHOW YOU SOME OF THIS.
IT GAVE ME TIME TO THINK ABOUT
AND SAY, WAIT A MINUTE, WILL ME
PRECONCEIVED NOTIONS BY RACE,
ETHNICITY, AND SLEEP APNEA BE
CORRECT?
WHAT DO WE KNOW ABOUT RACE.
IT'S MIXED, THAT'S THE BEST I
CAN TELL YOU.
WE DON'T I THINK UNDERSTAND.
I BET THERE ARE ARGUMENTS ON
BOTH SIDES, I'LL PRESENT SOME.
FEW STUDIES CLEARLY DEMONSTRATE
THAT IF YOU ARE ETHNIC MINORITY,
SUSAN HAS DONE THIS WORK, YOU'LL
BE AT HIGH RISK FOR SLEEP AP.
THIS HAS BEEN TALKED ABOUT,
WRITTEN ABOUT, SUBSTANTIALLY.
BUT ON THE OTHER HAND LITERATURE
SAYS WAIT A MINUTE, IT DOES NOT
SEEM TO ASSOCIATE WITH REGARDS
TO SLEEP APNEA.
I WANT TO REMIND THIS GROUP I
DON'T THINK, AGAIN, THIS IS MY
VIEWPOINT, I'M SURE PEOPLE HAVE
DIFFERENT VIEWS, I DON'T THINK
THE RACE/ETHNICITY IS COMPLETELY
SETTLED AT THIS POINT.
I HAD TO TAKE A SECOND LOOK.
I THOUGHT I KNEW ABOUT THIS.
I DID NOT.
SO, THE SWAN STUDY, THEY DIDN'T
FIND DIFFERENCES IN THE INDEX.
WHATEVER YOU THINK ABOUT THAT
METRIC THEY DIDN'T FIND
DIFFERENCES IN AHI BETWEEN
GROUPS IN THEIR COHORT BUT I
KNOW THERE ARE STUDIES THAT DO
SHOW DIFFERENCES.
I'LL SHOW YOU SOME.
WE SLEEP HEART HEALTH GROUP,
SOME ON THE CALL WERE ON THAT
COHORT STUDY SHOWED DIFFERENCES,
COMPARED CAUCASIANS, AFRICAN
AMERICAN, AFTER YOU CONTROL FOR
AGE AND SEX.
WHAT'S INTERESTING, MESA YEAH,
THERE ARE DIFFERENCES BUT HERE
IS SOMETHING INTERESTING.
THIS REVIEW POINTED THIS OUT.
I APPRECIATE IT.
BOTH STUDIES LACK CONTROL FOR
SOME IMPORTANT FACTORS THAT
COULD POTENTIALLY EXPLAIN RACIAL
DISPARITY THAT HAS BEEN
DOCUMENTED WITH REGARDS TO OSA
PROBLEMS.
I WANTED TO END THIS CONCEPT OF
RACE BY SAYING I DON'T THINK THE
ANSWER IS SO WELL DEFINED AS THE
AGE OR BMI OR SEX ISSUE.
I THINK THE RACE ISSUE, AT LEAST
IN SOME, COULD BE EXPLAINED.
GENETICS, THERE HAS TO BE AND IS
SOME EXPLANATION WHY WE SEE
HEAVY CLUSTERING CHARACTERIZED
IN SOME.
AGAIN, IT COULD BE BECAUSE OF
THE OBESITY DISTRIBUTION,
PARTICULARLY IF YOU THINK ABOUT
THE ASIAN CONTINENT, CONTROL
FACTORS MENTIONED, THAT MAYBE
HERITABLE, ET CETERA.
TO ME I WANT TO LEAVE THIS
CONCEPT OF RACE FOR THIS GROUP
SAYING I REALLY ONCE I LOOKED AT
EVIDENCE I WAS PRESENTED, THIS
GROUP DID A NICE JOB PUTTING IT
TOGETHER AT THE TIME, I'M
SURPRISED WHEN YOU LOOK AT THE
EVIDENCE IN TOTALITY, I DON'T
THINK WE'RE THERE YET AS FAR AS
DEFINITIVE ANSWER.
I APOLOGIZE TO THOSE WHO FEEL
THE ANSWER IS WELL KNOWN.
I HAD TO RETHINK MY VIEWS.
SWITCHING GEARS TO INSOMNIA,
SECOND DISORDER I WAS CHARGED
WITH, DAN WILL DO A BETTER JOB.
INSOMNIA, WHAT ABOUT OTHER SLEEP
DISORDERS?
ANDREW BRYAN TALKED ABOUT IT.
INSOMNIA IS COMMON.
NOT ONE PERSON ON THIS ZOOM,
WHETHER PARTICIPANT OR JUST
ATTENDING OR PRESENTING, NOT ONE
PERSON HAS NOT HAD DIFFICULTY
WITH INSOMNIA.
THIS IS A CLINICAL DIAGNOSIS,
COULD ENTAIL ONE OF THREE OR ALL
THREE, TROUBLE GOING TO SLEEP,
TROUBLE MAINTAINING SLEEP, OR
EARLY MORNING AWAKENINGS.
OR ALL THREE.
SO, THE ICSD REQUIRES AT LEAST
ONE, AND THERE BE AT LEAST ONE
CONSEQUENCE.
SOMETHING ABOUT FATIGUE,
COGNITIVE IMPAIRMENT, MOOD
ISSUES, ET CETERA.
THAT'S CLINICAL VIEW OF THIS
DISORDER.
AND DURATION OF AT LEAST THREE
MONTHS TO THINK ABOUT INSOMNIA
AS A DIAGNOSIS.
RISK FACTORS, THERE'S SO MUCH
WRITTEN ABOUT THIS.
THIS REALLY SUMS IT UP.
THERE'S EVERYTHING YOU CAN
IMAGINE LISTED ON THIS GRAPHIC.
HOST FACTORS, AGE, HERE WE GO
AGAIN, COMMON AGE.
COGNITIVE IMPAIRMENTS,
ENVIRONMENT PLAYS A ROLE,
MEDICATIONS.
SUBSTANCE ABUSE VERY CRITICAL.
OTHER SLEEP DISORDERS, THAT
COULD MANIFEST AS CHALLENGES
WITH MAINTAINING, EARLY MORNING
AWAKENING, BREATHING DISORDERS,
UNDERLYING CIRCADIAN ISSUES.
THINKING ABOUT A DISORDER LIKE
INSOMNIA WHAT IS IT GOING TO
SOMEONE WITH PH, NOT TO SAY IT
PAUSES PH BUT IF YOU HAVE
UNDERLYING SLEEP DIFFICULTY,
INSOMNIA FROM SOME ETIOLOGY,
WHATEVER IT MAY BE, WHAT DOES
THAT DO FROM THE STANDPOINT OF
YOU UNDERLYING PRIMARY DISORDER,
PULMONARY HYPERTENSION, WHICH
EVER GROUP YOU MAY FALL IN.
I LIKE THIS GRAPHIC BECAUSE THIS
GRAPHIC SAYS A LOT.
THE FOLKS THAT THINK ABOUT
INSOMNIA, THE WAY WE THINK ABOUT
NATURAL HISTORY, THERE'S GOT TO
BE A PREDISPOSING FACTOR, SOME
PREDISPOSITION.
SOMETHING TRIGGERS IT.
SOME PRECIPITATING FACTOR AND
SOMETHING TO PERPETUATE.
AGE IS CLEARLY AN IMPORTANT
DETERMINANT.
THERE'S HIGHER PREVALENCE OF
SLEEP-RELATED DIFFICULTY, I'LL
LEAVE IT AT THAT, IN OLDER
ADULTS.
SEX, HERE WE GO AGAIN WITH THE
MENOPAUSE ISSUE, FEMALE SEX IS
CLEAR-CUT UNDERLYING RISK
FACTOR.
MEDICAL CONDITIONS, PATIENTS
WITH HEART FAILURE, OF ANY SORT
, PSYCHIATRIC CONDITIONS,
PRESCRIPTION, SMOKING, ALCOHOL
OR DRUG USE, PSYCHOSOCIAL
STRESS, MANY IN COMBINATION OR
IN SOLITUDE CAN PREDISPOSE TO
INSOMNIA.
HOW COMMON?
TOO COMMON.
THE GRAPHIC IN THE MIDDLE FROM
NHLBI WEBSITE, YOU CAN BELIEVE
THESE DATA, ALMOST HALF OF US
HAVE SOME PROBLEM WITH
INSOMNIA.
PREGNANCY OF COURSE MAJOR ISSUE.
AGAIN PREVALENCE NEEDS TO EXCEED
THAT OF DISORDERED BREATHING
DISSLEEP.
HERE'S THE DEEP DOWN IN ALL
THIS.
THESE ARE DATA FROM THE NATIONAL
CENTER FOR HEALTH STATISTICS,
AVAILABLE ON THE WEB AND CDC
WEBSITE.
YOU CAN BREAK IT INTO SLEEP
ONSET INSOMNIA.
FALL ASLEEP MOST DAYS OR EVERY
DAY IN THE PAST 30 DAYS.
THERE'S CLEARLY AN AGE TREND, SO
SOME ISSUES ARE LESS COMMON,
WOMEN, HERE WE GO AGAIN WITH
GENDER DIFFERENCE, SEX
DIFFERENCE, CLEARLY RACE
DIFFERENCES.
NON-HISPANIC ASIANS DON'T HAVE
AS MUCH OF THIS PROBLEM AS SO
MANY OTHER RACIAL GROUPS.
NOW, THE STORY IS DIFFERENT WITH
MAINTENANCE INSOMNIA, OLDER AGE
GROUPS POP UP AND HOW COMMON
THIS IS.
THERE WE GO AGAIN WITH SEX,
WOMEN WITH HIGHER PREVALENCE OR
DIFFICULTY THAN OTHERS.
RACIAL DIFFERENCES EXIST.
NON-HISPANIC WHITES HIGHEST
PREVALENCE OF MAINTENANCE
PROBLEMS COMPARED TO OTHER
RACE/ETHNICITY GROUPS.
YOU CAN LOOK AT INSOMNIA BASED
ON SYMPTOMS AND PEOPLE HAVE DONE
THIS, USE OF SLEEP MEDICATIONS.
THIS IS, AGAIN, THE SAME
DATASETS WHERE YOU LOOK AT THE
USE OF MEDICATIONS EVERY DAY OR
MOST DAYS IN THE PAST 30 DAYS,
LOOKING AT AGE DISTRIBUTION.
VERY SIMPLE.
MEN VERSUS WOMEN, USE OF SLEEP
MEDICATIONS IS HIGHER, AS WE GET
OLDER.
WOMEN TEND TO BE HIGHER
UTILIZERS OF SLEEP MEDICATIONS
THAN MEN.
GLOBALLY IF YOU THINK ABOUT IT.
IT'S INTERESTING.
THERE ARE CORE COMPONENTS,
WHETHER AGE, SEX, AND THEY
PERMEATE THROUGH.
HERE THERE ARE CLEAR-CUT RACE
AND ETHNIC DIFFERENCE.
THERE'S A LOT OF SES FACTORS,
AND TAKE INTO ACCOUNT, BUT
CLEARLY THERE ARE VARIATIONS.
SAME DATA, SLEEP MEDICATIONS, IN
THE PAST 30 DAYS, NOW AS
FUNCTION OF RACE BUT IN MEN AND
WOMEN.
THERE ARE RACIAL DIFFERENCES IN
USE OF THESE.
AGAIN, SURROGATE MEASURE FOR
SLEEP-RELATED ISSUES.
THE POINT HERE IS EXACTLY WHAT
SUSAN AND ANNA WANTED ME TO DO,
WHAT IS THE DEMOGRAPHY OF
DISORDERS AND FACTORS WHEN YOU
THINK ABOUT THE PH WORLD MAYBE
MANY DON'T MATTER, MAYBE THEY
DO.
IT'S A DETERMINANT FROM
MODIFICATION.
HERE IS SOMETHING INTERESTING.
THESE ARE TRENDS, TREND AND
DISTURBANCES ON OLDER ADULTS, 60
OR MORE, WHAT'S FASCINATING, MEN
AND WOMEN, THERE SEEMS TO BE
AGAIN THAT TIME TREND.
THINGS ARE HAPPENING THAT ARE
MUCH MORE COMMONLY REPORTED OR
DIAGNOSED, IN ALL AGE GROUPS,
AND THERE'S A TREND WITH AGE AND
TREND WITH TIME.
THE BURDEN OF SLEEP DISORDER IS
IRRESPECTIVE OF MAN OR WOMEN,
THESE ARE DATA ALMOST A DECADE
OLD.
LET'S TRANSITION TO THE THIRD
DISORDER, SOMETHING THAT I
SUSPECT ALL OF US DO.
NOT SLEEP ENOUGH.
HERE IS WHAT'S THE RECOMMENDED
AMOUNT OF SLEEP ACROSS THE AGE
SPAN.
ADULTS, WHERE WE FALL, BETWEEN 7
OR 8, 8 1/2 KIND OF THING.
THERE'S A DOWNWARD TREND OVER
TIME.
THERE'S MAYBE APPROPRIATE, WHOLE
GRAY ZONE ABOUT NOT GETTING
ENOUGH OR GETTING TOO MUCH.
THIS IS A NICE PICTORIAL TO TALK
ABOUT WHERE WE NEED TO BE WITH
REGARDS TO EXPECTED OR HEALTHY
SLEEP DURATION.
YOU CAN SEE ABOUT 20 TO 30%, ON
THE LEFT SIDE, 30% OF US IN THE
U.S. POPULATION DO NOT HAVE
ENOUGH SLEEP, AND A PORTION OF
US GETTING TOO MUCH.
WE HAVE TO BE CAREFUL WHAT TOO
MUCH MEANS.
IS THAT JUST A MARKER OF
SOMETHING?
ON THE LEFT SIDE IS THE MORE
ACTION PLAY HERE, WHAT HAPPENS
WHEN A PATIENT FALLS IN THIS
GROUP, A PERSON WITH PH, WHERE
ARE EFFECTS OF CHRONICALLY SLEEP
DEPRIVED?
IT IS NOT WITHOUT ITS
CONSEQUENCES.
THERE'S SO MUCH KNOWN ABOUT
SYMPATHETIC ACTIVATION,
INFLAMMATORY RESPONSE, WEIGHT
GAIN, TONS, RISK FOR
HYPERTENSION, ET CETERA.
THE IDEA OF SHAPE DURATION IS
NOT A TRIVIAL THING THINKING
ABOUT OTHER COMORBID DISORDERS.
AGAIN, STAYING ON THE THEME OF
AGE, SEX, RACE, HOW DOES SLEEP
DURATION VARY AS A FUNCTION OF
AGE?
INSUFFICIENT SLEEP, AT LEAST 30%
OF US, UP TO 35% DEPENDING WHICH
AGE GROUP.
THERE'S AN AGE-RELATED
ASSOCIATION BETWEEN AMOUNT OF
SLEEP WE GET.
THIS MATTERS BECAUSE SOME PH
FALLS IN THIS CATEGORIZATION.
THIS IS A NICE GRAPHIC LOOKING
AT WHAT DOES THE WORLD DO?
MUCH OF EUROPE SEEMS TO BE
HANGING AROUND 7 OR SO HOURS.
YEAH, THERE ARE SOME AREAS
DIPPING DOWN TO LESS THAN 7, NOW
LET'S LOOK AT ASIAN CONTINENT.
INDIA 6 1/2.
6.4, JAPAN 6.3.
I'M SORRY, 6.2.
YOU CAN IMAGINE IF YOU START
GETTING DOWN TO AVERAGES BEING
THIS LOW THERE ARE GOING TO BE
SUBSETS MUCH LOWER THAN THAT.
WHAT ABOUT THE U.S.?
IT'S INTERESTING.
THIS IS IMPORTANT.
THERE ARE NOT JUST AGE-RELATED
TRENDS WITH SLEEP BUT ALSO
GEOGRAPHIC VARIATION.
WHAT YOU ALL MAY SEE IN THE
NORTH-NORTHEAST, WE MAY NOT
BECAUSE LOOK AT HOW -- PERCENT
OF ADULTS, FEWER THAN 7 HOURS ON
AVERAGE, LOOK AT THE HEAT MAP.
THERE'S A HUGE DENSE ACTIVE
INDIVIDUALS NOT SLEEPING ENOUGH
IN THIS AREA.
IF YOU LOOK AT MIDDLE AMERICA
YOU'RE LOOKING AT LOWER.
WHATEVER WE STUDY, WHEREVER WE
GO, THERE IS THIS REAL HARD CORE
ISSUE THAT'S GOING TO BE DOES IT
MATTER WHERE YOU ARE
GEOGRAPHICALLY?
DO TO PATIENTS WITH SIMILAR
DEGREE OF pH FOR EXAMPLE IN
MISSISSIPPI, IS THAT THE SAME
THING AS NEVADA WHERE THE
DENSITY OF SHORT SLEEP VERSUS
LESS?
SOMETHING TO THINK ABOUT.
HERE ARE THE MOST IMPORTANT, THE
HIGHEST AND LOWEST GETTING 7
HOURS OF SLEEP.
HIGHEST OVER WEST VIRGINIA,
KENTUCKY, HAWAII OF ALL PLACES.
PEOPLE IN COLORADO OR MINNESOTA
AND VERMONT SEEM TO BE NOT
AFFECTED.
AGAIN, THIS IS NOT JUST OLDER
INDIVIDUALS.
LOOK AT OUR TEENAGERS.
AGE 4 TO 17 BY STATE.
THIS IS HUGE DENSITY OF
TEENAGERS NOT SLEEPING ENOUGH,
AND THIS LOWER REGION OF THE
UNITED STATES.
SO REGIONAL DIFFERENCES IN WHAT
WE SEE, WHAT WE CHARACTERIZE, IF
YOU ARE GOING TO STUDY SLEEP AND
WHATEVER ELSE, IT'S GOING TO
MATTER.
I FOUND THIS TO BE FASCINATING,
TEMPORAL TRENDS OVER TIME BY ONE
OF MY OLD FELLOWS, AT WashU
NOW, DID WORK WITH THE ALAMEDA
COUNTY DATA LOOKING AT WHAT
HAPPENED FROM 1965 TO 1999.
AND WHAT SHE DID WAS REALLY
INTERESTING.
PLOTTED DATA AS FUNCTION OF
RACE, ETHNICITY, SOCIOECONOMIC
STATUS USING HIGH SCHOOL AS A
MARKER.
YOU SEE A PERFECT TEMPORAL
TREND.
LOOK AT THE GRAFT AND SEE.
SHORT SLEEPERS INCREASING,
WHETHER YOU'RE AN AFRICAN
AMERICAN, HISPANIC, THERE'S A
TEMPORAL TREND OVER TIME IN
SHORT SLEEP DURATION.
SLEEP FOLKS KNOW THIS WELL.
THERE ARE RACIAL DIFFERENCES AND
TEMPORAL TRENDS.
THERE'S A SHORT SLEEPER WITH A
COMPONENT OF SES STATUS AT LEAST
AS DETERMINED BY EDUCATION,
USING HIGH SCHOOL GRADUATION
VERSUS NOT, YOU CAN SEE HIGHER
SES STATUS USING HIGH SCHOOL
MEASUREMENT ASSOCIATED WITH
LOWER PREVALENCE OF SHORT SLEEP
DURATION.
>>WE'RE RUNNING LATE.
WOULD YOU ABLE TO QUICKLY WRAP
UP.
>>MY LAST ONE OR TWO SLIDES AND
I WILL WRAP UP.
SES, RACIAL DIFFERENCES, WE'RE
WATCHING TV AND STREAMING.
IT'S GOING TO GET WORSE.
JUST QUICKLY IN THE LAST MINUTE,
I HAVE NO EXPERTISE IN PH,
THERE'S RACIAL DIFFERENCES AT
GROUP 1, FEMALE PREDOMINANCE BUT
WE DON'T KNOW MUCH ELSE ABOUT
THE DEMOGRAPHY.
HERE IS RACIAL DATA.
IF YOU LOOK, THERE'S SOME
DISTRIBUTION BUT THERE'S NOT
CONSISTENCY AMONG WHAT'S
HAPPENING WITH MINORITY GROUPS.
MY LAST TWO SLIDES GROUP 3
DEMOGRAPHY OF THIS PH IS TOUGH,
HOW DO YOU DESCRIBE THE
DEMOGRAPHY OF COPD AND ALL THE
DIFFERENT THINGS THAT HAVE BEEN
DISCUSSED.
CLEARLY AGE, SEX, RACE, MATTER
FOR ALL THESE THINGS.
I THINK THE GROUP 3, AN EXAMPLE
OF PH RELATED TO PNEUMONIAS,
GROUP 3, DEMOGRAPHY WILL MATTER.
I'LL SAY, LOOK, WE KNOW
EPIDEMIOLOGY OF SLEEP DISORDERS,
THINGS THAT DETERMINE SOME OF
THESE THINGS, APNEA, INSOMNIA,
SHORT SLEEP DURATION.
WE DON'T HAVE AS MUCH
UNDERSTANDING WHAT'S HAPPENING
WITH GROUP 1.
WE HAVE SOME IDEAP GROUP 3
BECAUSE IT'S DIVERSE.
I WANT TO LEAVE YOU WITH I'M
CURIOUS WHEN YOU HAVE THESE
DISORDERS DOES IT MAKE THE
OUTCOMES WORSE?
THANK YOU, SORRY FOR RUNNING
OVER.
>>THANK YOU.
THAT WAS A VERY FORWARD AND
PROVOCATIVE TALK.
WE APPRECIATE IT.
PROBABLY I'M TO BLAME FOR THE
CHARGE WE GAVE YOU BUT HOPE WE
CAN BRING YOUR GREAT IDEAS INTO
THE DISCUSSION, ESPECIALLY HOW
WE THINK ABOUT RACE, ETHNICITY,
SES, SOCIAL DETERMINANTS OF
HEALTH, DEAL WITH THAT LATER.
BECAUSE WE'RE RUNNING OUT OF
TIME LET'S MOVE TO DR. KARA
GOSS, PEDIATRICIAN, LIFETIME
APPROACH.
>>THANK YOU.
I HAD A LITTLE BIT OF SIMILAR
FEELINGS ABOUT THE SCOPE OF THE
TOPIC, THINKING ABOUT TALKING
ABOUT DEVELOPMENTAL LUNG DISEASE
AND HOW THAT WAS GOING TO IMPACT
THE RISK FOR PULMONARY VASCULAR
DEVELOPMENT.
ADULT PULMONARY TRAINED, FOCUS
ON LIFESPAN IMPACT, PARTICULARLY
PRE-TERM BIRTH, HOW I ENDED UP
IN THESE TRANSITIONAL TOPICS.
WHEN I STARTED THINKING ABOUT
THE TOPIC AT HAND, INITIALLY I
TURNED TO THE PARADIGM PUT
TOGETHER SEVERAL YEARS AGO, THIS
IDEA THAT EARLY LIFE INSULT OR
INJURIES COULD IMPACT TOTAL
OVERALL PULMONARY VASCULAR
ENDOWMENT.
THIS IDEA NORMAL INDIVIDUAL
WOULD HAVE NORMAL GROWTH AND
AGING, BUT THOSE WITH EARLIER
VASCULAR DEVELOPMENT, PERINATAL
OR GENETIC OR EPIGENETIC RISK
FACTORS, EPIGENETIC GOT ME
THINKING ABOUT THE INTRACELLULAR
CLOCK AND SUSCEPTIBLE TO
SECONDARY INSULT, HYPOXIA BEING
ONE WE PROPOSED EVEN LED TO LEAD
ON DECREASE IN ADULT PULMONARY
VASCULAR ENDOWMENT AND RISK FOR
DISEASE.
THIS IS THE PARADIGM TO THINK
ABOUT.
BEFORE I CAN GO ON I WANT TO PUT
FORTH A COUPLE CAFFANTS.
FIRST THAT FIGURE IS A
HYPOTHETICAL FIGURE THAT I WOULD
SAY MIRRORS WHAT WE KNOW ABOUT
BUNKS FUNCTION DATA, SPIRO
METRIC DATA, BECAUSE WE'RE
FAIRLY LACKING IN NORMATIVE
PULMONARY GROWTH DATA, WE DON'T
CT SCAN CHILDREN ROUTINELY,
DON'T HAVE GREAT METRICS, TO
TRACK EVEN NORMAL PULMONARY
VASCULAR GROWTH OVER TIME.
BUT WE DO KNOW VERY WELL FROM
ANIMAL STUDIES IN PARTICULAR
THAT PULMONARY VASCULAR AND
ALVEOLAR GROWTH ARE INTEGRALLY
LINKED.
IF WE INHIBIT AIR SPACE, WE ALSO
INHIBIT VASCULAR DEVELOPMENT AND
VICE VERSA AND PRESUME THEY TACK
TOGETHER AND WOULD MIRROR OUR
SPIROMETRIC DATA WE HAVE MORE
READILY AVAILABLE.
WE CAN THINK ABOUT DISEASE
STATES IMPACTING US, FOCUS THE
SECOND TRIMESTER ONWARD BECAUSE
THAT'S WHERE WE END UP WITH
BABIES BORN PRE-TERM WITH
VIABILITY BEING AT 22 WEEKS, AT
THAT 22+ WEEK TIME POINT, WE'VE
GOT ALVEOLAR DUCTS AND AIR
SPACES, AIRWAYS FORMED, A
FAIRLY IMMATURE PULMONARY TREE,
VASCULAR TREE.
I ALSO ADDED IN HERE CONTROL OF
BREATHING, HOW IMPAIRED THAT IS
IN THE CONTEXT OF OUR EXTREMELY
PRE-TERM BABIES.
SO THEY DO HAVE DIAPHRAGMATIC
MOVEMENT STARTING EARLY ON BUT
AS THE SECOND TRIMESTER TIME
THEY ARE JUST DEVELOPING CHEMO
RECEPTOR SENSITIVITY TO CO2,
THAT CONTINUES TO PROGRESS
THROUGH THE END OF THE THIRD
TRIMESTER.
THEY WON'T DEVELOP NORMAL CHEMO
RECEPTOR SENSITIVITY TO OXYGEN
UNTIL BIRTH.
SO FOR A NORMAL TERM BORN BABY
THAT'S HAPPENING AT BIRTH.
FOR PRE-TERM THEY HAVE TO BEGIN
TO DEVELOP SENSITIVITY TO OXYGEN
WHICH I THINK IMPARTS SOME
BREATHING AND SLEEP DISORDERED
ISSUES THAT WE SEE LATER.
HOWEVER, AS THESE BABIES AGE WE
END UP WITH A SINGLE LAYER
CAPILLARY NETWORK, WITHIN THE
PULMONARY VASCULAR TREE MORE
EFFICIENT FOR GAS EXCHANGE
ESSENTIALLY SHORTENING DIFFUSION
SPACE THERE AND AS THESE BABIES
ARE AGING INTO EARLY CHILDHOOD
WE HAVE MORE SOMATIC GROWTH
WHICH IS VOLUMETRIC OF AIR
SPACES AND PRESUME SIMILARLY
WHAT'S HAPPENING IN THE BLOOD
VESSELS BUT REALLY DON'T HAVE A
LOT OF NORMATIVE DATA THERE SO
THAT REALLY IS A FAIRLY LARGE
KNOWLEDGE GAP TO BE ABLE TO
THINK ABOUT EARLY LIFE EVENTS
IMPACTING OVERALL DEVELOPMENT.
I WANT TO PROPOSE THAT TIMING OF
INJURY IS KEY HERE.
SO BREAK THIS DOWN IN TWO
POTENTIAL WINDOWS.
FIRST IS THAT FOR IMPAIRED
DEVELOPMENT, THIS IS DURING THAT
EARLY WINDOW IN UTERO WHERE WE
HAVE REALLY OUR ACTIVE AND
ONGOING PULMONARY ALVEOLAR AND
CONTROL OF BREATHING
DEVELOPMENT.
SO THE INJURY PATTERNS THAT WE
WOULD SEE DISEASE STATES IN THAT
CASE WOULD BE EXTREME
PREMATURITY, BRONCHOPULMONARY
DYSPLASIA, NOT OCCURRING WITH
ALL INFANTS, DOWN SYNDROME AN
CONGENITAL DIAPHRAGMATIC HERNIA
AND FROM AGE 2 TO 3 UP TO AGE 20
WHERE WE HAVE A REALLY RAPID
PERIOD OF LUNG GROWTH, PROPOSED
POTENTIAL DISEASE STATES THAT WE
COULD SEE IMPAIRED GROWTH BEING
INVOLVED WOULD BE SICKLE CELL
DISEASE, CHILD INTERSTITIAL LUNG
DISEASES.
WE'RE GOING TO FOCUS ON TWO
EXAMPLES OF DISEASES, STARTING
WITH BRONCHOPULMONARY DYSPLASIA.
SORT OF THIS IDEA, PARADIGM
SHIFTS TO DISRUPTED VASCULAR
DEVELOPMENT, DISRUPTED VASCULAR
GROWTH, AND POTENTIAL FOR SLEEP
DISORDERED BREATHING IN EITHER
ONE OF THE TIME PERIODS WHEN WE
SEE THAT OR TO OCCUR LATE.
FOLKS TO BE SYNERGISTIC IN
PATHOGENESIS FOR EITHER ONE OF
THE TWO DISEASES THAT WE'RE
DISCUSSING.
WE'LL TALK ABOUT BPD FIRST, NOT
TOO MANY PEDIATRICIANS ON THE
CALL AND SO VERY BRIEFLY TO
UNDERSTAND WHAT IT IS, AT THE
MOST BASIC LEVEL THIS IS A REST
IN ALVEOLAR AND VASCULAR
DEVELOPMENT, 22, 23, 24 WEEKS
BEING OUR MOST COMMON GROUP TO
DEVELOP THIS, AND DECREASING IN
FREQUENCY AS WE APPROACH SORT OF
EARLY TO MID-30s FOR
GESTATIONAL AGE.
IT'S DEFINED CLINICALLY BY THE
OXYGEN REQUIREMENTS, THE DISEASE
DIAGNOSTIC THRESHOLDS HAVE
VARIED OVER TIME BUT THESE ARE
BABIES REQUIRING OXYGEN AND THEY
SHOULD BE DEVELOPING NORMAL AIR
SPACES, AIR DUCTS, VASCULATURE
AND SO FORTH.
THESE BABIES ARE EXPOSED TO
VENTILATION OXIDATIVE STRESS,
GOING ON TO DEVELOP ABNORMAL
VASCULATURE AND AIR SPACES HERE
SHOWN LOOKS LIKE ADULT COPD,
ENLARGED AIR SPACES THAT THESE
BABIES CAN DEVELOP.
THAT'S BPD
WHAT ABOUT BPD AND PULMONARY
HYPERTENSION IN PRE-TERM BIRTH?
THERE IS THE COLORADO AND
INDIANA DATA COMBINED.
WITH BABIES WHO ARE BORN
GENERALLY LESS THAN 32 WEEKS,
LESS THAN 1500 GRAMS, IF YOU
LOOK OVERALL THERE ARE A
PERCENTAGE OF THEM WHO DO NOT
HAVE BPD AND DEVELOP PULMONARY
HYPERTENSION ANYWAYS BUT OVERALL
PBD AND PH CO-ASSOCIATE
FREQUENTLY.
IF YOU TAKE ALL COMERS HERE,
SOME IN THE MID-TEENS AS FAR AS
INCIDENCE RATE IN THESE BABIES.
WHAT ABOUT SLEEP DISORDER
BREATHING?
IT'S UBIQUITOUS.
I MENTIONED CONTROL OF BREATHING
IS PRE-DEVELOPMENTAL AND THERE'S
A LOT OF REASONS FOR THESE
BABIES TO HAVE ISSUES, PERIODIC
BREATHING CAN COMMON, ABNORMAL
BREATHING PATTERNS, APNEA
PREMATURITY, A 20-SECOND PAUSE,
MOST OF THESE ARE CENTRAL
APNEAS, AGAIN LARGELY RELATED TO
CHEMO RECEPTOR SENSITIVITY.
POTENTIAL OBSTRUCTIVE BE A KNEE
A, NASAL BREATHERS, THEY -- TWO
DISEASES.
WHAT HAPPENS WHEN THEY CONVERGE?
A NICE PAPER OUT FROM EARLIER
THIS YEAR STUDYING 40 PATIENTS
WITH BPD AND DIAGNOSIS OF
PULMONARY HYPERTENSION.
THEY ARE WATCHING DESATURATION
RATE ON THE MONITORS, RATES OF
INTERMITTENT HYPOXIA.
WHEN THEY LOOK AT FREQUENCY THEY
WERE SIMILAR BETWEEN THE TWO
GROUPS, BUT THOSE BABIES WHO HAD
BPD WITH PULMONARY HYPERTENSION
HAD SIGNIFICANTLY LONGER
DURATION OF HYPOXIA, AND
ACTUALLY THIS WAS A MORTALITY
PREDICTOR AS WELL, SO DEPENDING
HOW THEY SET THE THRESHOLD WITH
EVENT DURATION, SATURATIONS LESS
THAN 70% HERE, THEY HAVE A
PRETTY GOOD AREA UNDER THE CURVE
TO BE ABLE TO DETECT INFANTS WHO
WOULD NOT SURVIVE NEONATAL TIME
FRAME.
FORTUNATELY MANY OF THESE BABIES
DO SURVIVE NEONATAL TIME FRAME,
AND THIS IS A STUDY I WANTED TO
SHARE, ONE OF THE LARGER
STUDIES, CHILDREN WHO HAD ALSO
HAD AN ECHO RECENTLY, THEY
LOOKED AT INDIVIDUALSA PULMONARY
HYPERTENSION WAS PRESENT IN 4%,
ECHO-BASED METRICS SUGGESTIVE OF
4% OF CHILDREN, NOT COMMON
COMORBIDITY IN ALL CHILDREN AT
LARGE BUT WHEN THEY LOOKED
SPECIFICALLY AT PULMONARY
HYPERTENSION WAS A MAJOR RISK
FACTOR FOR PULMONARY
HYPERTENSION IN A GROUP WITH
SLEEP DISORDERED BREATHING AND
OSA.
WHAT HAPPENS TO THE KIDS FROM AN
OUTCOMES STANDPOINT?
I LIKE THIS NEAP WAS RECENT --
PAPER PUBLISHED FROM THE NETWORK
REGISTRY.
THEY HAD ALMOST 1500 PEDIATRIC
PULMONARY HYPERTENSION PATIENTS,
AND ABOUT HALF OF THE KIDS IN
THE REGISTRY WERE GROUP 3.
AMONG THE GROUP 3, HALF WERE
BPD.
NOW IN THIS GROUP 3 GROUP OVER
HERE, THIS IS HALF BPD PH KIDS
AND IF YOU LOOK AT TIME SINCE
DIAGNOSIS, THE LAST CURVE IS
INDIVIDUALS OFF PULMONARY
HYPERTENSION MEDICATION.
WHAT'S INTERESTING TO ME LOOKING
AT THESE -- MANY BABIES IF YOU
SUPPORT THEM LONG ENOUGH, IF
THEY DON'T DIE EARLY ON, THEY
HAVE AN OPPORTUNITY TO GROW AND
PULMONARY VASCULAR DISEASE AS
VASCULATURE DEVELOPS WITH TIME,
MANY TAKEN OFF PULMONARY
HYPERTENSION MEDICATION AND
FOLLOWED LONGER TERM.
I'M NOT SURE THAT MEANS
PULMONARY VASCULAR DISEASE IS
COMPLETELY GONE.
THESE ARE TWO STUDIES LOOKING AT
ADOLESCENTS AND ADULTS, STUDY ON
THE LEFT IS ECHO-BASED STUDY IN
ADOLESCENTS LOOKING AT RATES OF
PULMONARY HYPERTENSION, OVERALL
MEAN ARTERY PRESSURE OF 19, SO
JUST UNDER HALF OF THEM WOULD
MEET CURRENT CRITERIA FOR
PULMONARY HYPERTENSION, GREATER
THAN 20.
ECHO-BASED STUDY, IT'S ABOUT THE
SAME, JUST UNDER HALF WOULD MEET
THE 20 MILLIMETERS OF MERCURY
CUT OFF.
WE'RE ESTIMATING MILD PULMONARY
HYPERTENSION, LIKELY TO BE
SUBCLINICAL LESS LIKELY TO BE
DIAGNOSED.
AS THESE INDIVIDUALS AGE,
PRE-TERM BORN INDIVIDUALS ARE
ALSO AT INCREASED RISK FOR
DEVELOPMENT OF SLEEP DISORDERED
BREATHING, A LARGE POPULATION
BASED REGISTRY STUDY FROM SWEDEN
LOOKING AT POPULATION AND
DIAGNOSIS OF SLEEP DISORDERED
BREATHING OR SYMPTOMATIC SNORING
ESSENTIALLY.
AND THOSE EXTREMELY PRE-TERM HAD
2.6-FOLD HIGHER RISK, CLEARLY
DOSE-RESPONSE TO EXTREMELY
PRE-TERM BORN HERE.
THIS PLAYS IN THE MIDDLE, WE CAN
TALK ABOUT AGE AND DEVELOPMENT
AND PUBERTY EFFECTS, ANOTHER
DISCUSSION, BUT YOU CAN SEE
ACROSS THE LIFESPAN INDIVIDUALS
BORN EXTREMELY PRE-TERM AT
INCREASED WELCOME FOR SLEEP
DISORDERED BREATHING.
THERE'S NOT DATA ON HOW THEY
INTERACT, RISK FOR PULMONARY
VASCULAR DISEASE AND IMPACT OF
SLEEP DIS ORDERED BREATHING ON
THAT.
THIS IS EARLY DATA OUT OF OUR
LAB.
I'M HOPING WE'LL BE ABLE TO
ADDRESS THIS IN THE FUTURE
BECAUSE WE DO HAVE ECHO
PULMONARY FUNCTIONS, OVERNIGHT
OXIMETRY, 150 BORN PRE-TERM NOW,
HOPEFULLY CAN SEE HOW THESE
FINDINGS INTERACT IN FUTURE
STUDIES.
WE'RE GOING QUICK SHIFT GEARS TO
SICKLE CELL DISEASE.
YOU'RE MAGNIFY FACULTY WITH
SICKLE CELL, YOU SEE A HANDFUL
OF PATIENTS IN CLINICAL
PRACTICE.
WHAT I WANT TO POINT OUT THE
AVERAGE AGE OF FIRST DATES OF
OCCLUSIVE CRIES SIS AT 2 TO 5
YEARS OLD.
WE'RE GETTING INTO A LONG GROWTH
PHASE.
THEORETICALLY INSULT OR INJURY
IS OCCURRING IN THE EARLY GROWTH
PHASE.
SO CAN I TELL YOU THAT THE
PULMONARY VASCULATURE DOES NOT
GROW NORMALLY?
ACTUALLY NO BECAUSE THAT'S NOT
BEEN ASSESSED.
IF WE GO BACK TO OUR CAVEAT
NUMBER 1 EARLY ON, HOW THE
ALVEOLAR AND VASCULAR SPACES
WITH LINK, THERE'S IMPAIRED
GROWTH IN PULMONARY FUNCTION,
SPIRO METRIC MEASURES, SICKLE
CELL IS THE SOLID LINE, BOYS AND
GIRLS.
PERHAPS, STICK WITH ME,
PULMONARY HYPERTENSION IN SICKLE
CELL IS VERY MULTI-FACTORIAL,
CONSIDERED GROUP 5 PULMONARY
HYPERTENSION WHICH WE HAVEN'T
TALKED ABOUT YET TODAY.
BURDEN OF PULMONARY HYPERTENSION
INCREASES WITH AGE SO IT'S
PRIMARILY -- STUDIED USING ECHO.
OBVIOUSLY THE BEST DIAGNOSIS IS
CATH.
BUT ELEVATED VELOCITIES ARE
DOCUMENTED, CLOSE TO A THIRD OF
ADULTS, DEFINITELY ASSOCIATED
WITH INCREASED MORTALITY.
WHEN YOU LOOK AT AUTOPSY STUDIES
INCLUDING INDIVIDUALS WHO DIED
NOT JUST PULMONARY COMPLICATIONS
BUT EXTRA-PULMONARY
COMPLICATION, INVOLVEMENT OF
VASCULATURE IS ALMOST UNIFORM
WITH A MYRIAD OF PATHOLOGIES
SEEN, ARTERIAL THICKENING, ACUTE
AND CHRONIC THROMBOSIS, VEIN
THICKENING, EVEN THOUGH THEY MAY
DIE FROM SOMETHING NOT PULMONARY
SPECIFIC, MOST OF THEM HAVE SOME
DEGREE OF PULMONARY VASCULAR
DISEASE AT THE TIME OF DEATH.
ANYTHING WE CAN DO TO ALLEVIATE
THAT IN THIS PARTICULAR
POPULATION IS LIKELY TO BE
IMPACTFUL.
WHAT ABOUT SLEEP DISORDERED
BREATHING IN KIDS WITH SICKLE
CELL?
EXACT NUMBERS ARE DIFFICULT TO
PIN DOWN AND DEPENDS HOW YOU
DEFINE THIS.
ABOUT 20% WILL REPORT SLEEP
DISORDERED BREATHING.
OR SYMPTOMS OF IMPAIRED SLEEP.
WHEN IT'S BEEN STUDIED LOWER
THEY TEND TO HAVE LOWER MEAN AND
OXYGEN SATURATION, MORE
PROLONGRD NOCTURNAL
DESATURATION, THESE ARE THE
INDIVIDUALS WE'RE ALREADY
RECOGNIZING TODAY HIGHEST RISK,
WHO HAVE THE MORE PROLONGED
NOCTURNAL DESATURATION AND
HYPOXIA.
IF WE LOOK AT THOSE WHO HAVE
COMPLETED SLEEP STUDIES IN
RELATION TO ECHO METRICS, SICKLE
CELL WITH DIAGNOSIS OF SLEEP
APNEA MORE LIKELY TO HAVE
ELEVATED TRICUSPID REGURGITANT
DISEASE.
MOST WHO COMPLETED PSG AND ECHO
2/3 ARE ELEVATED AHI, GREATER
THAN 1 IS ABNORMAL FOR THIS AGE.
WE SEE AHI INCREASES OVER TIME.
I DON'T THINK THAT SIMPLY JUST
IS A REFLECTION OF AGING,
CERTAINLY THAT CAN BE
IMPLICATED.
LIKELY A REFLECTION OF DISEASE
PROGRESSION AS WELL.
AHI CORRELATED WITH TR
VELOCITIES.
THIS WAS THE SECOND STUDY
SIMILAR HOW IT WAS DONE BUT THIS
TIME FOCUSED ON NOCTURNAL
HYPOXIA AND THOSE INDIVIDUALS
WITH GREATER NOCTURNAL HYPOXIA
HAD HIGHER TR AND LESS
VENTRICULAR FUNCTION AND
DILATION, BIVENTRICULAR IMPACT
HERE.
TREATED LOTS OF WAYS,
TONSILLECTOMY IS ONE OF THE
INITIAL TREATMENTS FOR MOST KIDS
WHO HAVE SLEEP DISORDERED
BREATHING, SLEEP APNEA.
HYDROXYUREA IS IMPORTANT,
ADMINISTRATION OF OXYGEN
IMPROVES.
THERE'S NOT GREAT DATA THAT THIS
TRULY IMPACTS PAIN EVENTS,
VASO-OCCLUSIVE OR ACUTE CHEST
SYNDROME EVENTS.
DATA JUST ISN'T THERE AS OF
RIGHT NOW.
QUICK SUMMARY, I'VE GIVEN
EXAMPLE OF IMPAIRMENT IN
DEVELOPMENT, IMPAIRMENT IN
GROWTH, HOPEFULLY THIS IS
SOMETHING YOU CAN THINK ABOUT IN
OTHER DISEASE STATES AS WELL.
WE DIDN'T HAVE A LOT OF TIME TO
GO INTO DIRECT MECHANISMS BUT
YOU COULD SEE OVERLAP BETWEEN
MECHANISM FOR DEVELOPMENT OF
PULMONARY HYPERTENSION AND ALSO
FOR DEVELOPMENT OF SLEEP
DISORDERED BREATHING.
I WOULD ARGUE BOTH ARE
POTENTIATORS, POTENTIAL TO
WORSEN IN EACH OTHER, SO
UNDERSTANDING HOW WE SHOULD
INTERVENE IS IMPORTANT.
THESE ARE THE KNOWLEDGE GAPS I
SUBMITTED BUT I'LL STOP THERE IN
THE INTEREST OF TIME.
>>THANK YOU FOR THE FASCINATING
TALK, WONDERFUL PERSPECTIVE AND
I'M SURE WE'LL GET INTO THE
DISCUSSION.
FOR THE PURPOSES OF TIME, WE'LL
GO RIGHT TO THE NEXT TWO
SPEAKERS AND WE'LL BRING BACK
ANY OF THE SPECIFIC QUESTIONS AS
WELL AS MORE GENERAL SESSIONS
DURING THE DISCUSSION WRAP-UP.
LAST TWO SPEAKERS ARE GOING TO
DO A -- THEY COORDINATED.
FIRST DR. DANIEL KATZ WILL GIVE
AN OVERVIEW OF HOW TO APPROACH
METABOLOMICS DATA WITH EMERGING
DATABASES AND TOOLS AND DR.
SOFER WILL GIVE SPECIFIC
EXEMPLARS OF THE USE OF THOSE
TYPES OF DATA, SLEEP AND
CIRCADIAN HEALTH AND
RELATIONSHIPS TO OTHER HEALTH
OUTCOMES.
>>THANK YOU.
HOPEFULLY YOU'RE SEEING MY
SLIDES AND NOT NECESSARILY MY
PRESENTER MODE.
THANK YOU VERY MUCH FOR THE
OPPORTUNITY TO PRESENT HERE.
I'M DAN KATZ, HEART FAILURE
CARDIOLOGIST AT STANFORD,
RESEARCH LEVERAGES MULTIOMIC
DATA TO UNDERSTAND HEART
FAILURE.
NOT NECESSARILY SLEEP DISORDERED
BREATHING OR PVD.
I'M HERE TO PROVIDE AN
INTRODUCTION, MULTIOMIC DATA IN
COMPLEX DISEASE WITH EYE TOWARD
BETTER UNDERSTANDING INTERPLAY
OF SLEEP AND PULMONARY VASCULAR
DISEASE.
THIS IS SOMETHING I THOUGHT I
WAS GOING TO HAVE TO DO
CONVINCING BUT THERE'S BEEN SOME
PEOPLE THAT HAVE SPOKEN THAT
ALLUDED TO SOME DATA GENERATED.
I THINK WE HAVE A LOT OF
INTERESTED, WHICH IS GREAT.
MY HOPE IS TO PIQUE YOUR
INTEREST IN MULTIOMICS AND THINK
ABOUT HOW YOU MIGHT INCORPORATE
OMICS IN YOUR NEXT STUDY.
HERE ARE MY GOALS, SCRATCHING
THE SURFACE, SOME ADDRESSED IN
THE NEXT TALK BY DR. SOFER, AL.
FIRST WE'LL DESCRIBE AVAILABLE
OMICS PLAT FORMS AND COSTS,
BENEFITS, PITFALLS, EXPLORE
TECHNIQUES OR ANALYSIS AND
IDENTIFY EXISTING DATA SOURCES
USEFUL IN SLEEP AND PH WORK.
BEFORE WE BEGIN WE SHOULD TOUCH
WHAT MULTIOMICS IS.
TO ME MULTI-OMICS IS THE
COLLECTION OF BIOMOLECULAR
MEASURE.
S ACROSS TWO OMICS CATEGORIES.
WE NOW GENOMIC DATA IS
TRANSLATED TO PROTEIN PRODUCING
PHENOTYPES, MULTIOMICS SEEKS TO
UNDERSTAND IN A DATA DRIVEN
MATTER BY GATHERING INFORMATION
AND STUDYING HOW THEY BEHAVE.
WE HAVE ABILITY TO CAPTURE A
WIDE VARIETY OF MULTIOMIC DATA,
ALSO GENERATING DATA ON DIVERSE
POPULATIONS.
THE REAL DEFINITION IS
INTEGRATION OF MULTIPLE STREAMS
OF OMIC DATA FROM MULTIPLE
COHORTS IN AN EFFORT TO DO
THINGS LIKE BETTER UNDERSTAND
PATHOPHYSIOLOGY OF DISEASE SO WE
CAN IDENTIFY PATHWAYS THAT CAN
BE TARGETED BY DRUG THERAPY, OR
SEPARATELY, PERHAPS MORE
UNSUPERVISED WAY, TO LEVERAGE
THIS HIGH DIMENSIONAL DATA FOR
PATTERN INSIGHT INTO DISEASE SO
WE CAN MAKE BETTER DECISIONS AT
THE BEDSIDE BEFORE PERHAPS WE
UNDERSTAND UNDERLYING
PATHOPHYSIOLOGY.
SO THERE ARE VERY WIDE VARIETY
OF TOOLS FOR GATHERING MULTIOMIC
DATA, AND SPECIAL FEATURES OF
EACH IS MAYBE A LITTLE OUTSIDE
THE SCOPE OF THIS TALK BUT I DID
INCLUDE A SAMPLE TO GIVE YOU A
SENSE OF WHAT'S AVAILABLE, WHAT
IT MIGHT COST TO DO SORT OF A
COMPREHENSIVE MULTIOMIC STUDY.
ON THE GENOMIC SIDE, WHILE GOOD
DATA CAN BE GATHERED USING SNP
ARRAY DATA, THERE'S A SUBSET
DOING LONG READ FOR MORE
DETAILED INFORMATION.
EPIGENETIC PLATFORMS PROVIDE
INSIGHT ABOUT OPEN CHROMATIN,
AVAILABLE DNA FOR TRANSCRIPTION,
SOME OF THE MORE POPULAR ONES
ARE ATAC-SEQ, METHYL CAPTURE,
WHICH CAN PROVIDE INFORMATION ON
THE MODERATELY COSTLY SIDE.
RNAseq DATA MAY BE THE MOST
READILY AVAILABLE, ALSO PROBABLY
MOST COST EFFICIENT BECAUSE IT'S
BEEN SO WELL ESTABLISHED.
PROTEOMEICS I BREAK INTO TWO
COMPETING APPROACHES, THIS BEING
AFFINITY APPROACH, WHICH HAS
GAINED TRACTION AND MASS
SPECTROMETRY PLATFORMS ALLOWING
ADDED BENEFITS OF EVALUATING
POST-TRANSLATIONAL
MODIFICATIONS.
METABOLOMICS PROVIDES TARGETED
PLATFORMS FOR KNOWN METABOLITES
AND OPTION TO CAPTURE AND
ATTEMPT TO NAME THOUSANDS OF
UNKNOWN METABOLITES.
THAT'S PARTICULARLY AN EXCITING
AREA OF RESEARCH BECAUSE WHEN
YOU COMBINE OMIC DATA TOGETHER
YOU CAN TAKE SOME OF THESE
UNKNOWN METABOLITES, YET TO BE
DESCRIBED, AND USE SOME
MULTIOMIC DATA TO IDENTIFY,
WHICH MAY BE IMPORTANT.
TARGETED PLATFORMS ARE AVAILABLE
ON AND OFF THE SHELF.
PUT THIS TOGETHER, INCLUDING
ELEMENTS FROM ALL, COULD RUN UP
TO 12$0,000 TO 14 -- $1,200 TO
$1,400 A SAMPLE.
I DON'T THINK MULTI-OMICS WOULD
BE COMPLETE OUT IT, THIS DOESN'T
INCLUDE SPATIAL OR SINGLE CELL
OMICS ALLOWING FOR PROFILING
ACROSS VARIETY OF CELLS IN A
TISSUE SAMPLE SO RATHER THAN
DESCRIBING A TISSUE HOMOGENATE
WE'LL DO A MUSCLE BIOPSY, AFTER
A BOUT OF EXERCISE, BOY A LOT OF
INFLAMMATORY MARKERS GO UP, IT
MIGHT BE INFLUX INTO THE TISSUE,
AND THAT EXPLAINS THE CHANGE.
SPECIAL AND SINGLE CELLS COULD
GET A LARGE AMOUNT OF
INFORMATION BUT WILL ALSO SET
YOU BACK ANOTHER ONE TO SIX
THOUSAND ADDITIONAL DOLLARS PER
SAMPLE.
SO, I PUT IT TOGETHER THIS WAY,
MUCH LIKE HEALTH CARE ITSELF.
I THINK THAT MULTIOMIC DATA
BALANCE OUT ACROSS THE TRIANGLE.
YOU'RE CONSTANTLY TRYING TO
BALANCE SPECIFICITY AND
THROUGHPUT AND COST.
SO TAKE THE TWO ALTERNATIVE
APPROACHES FOR PROTEOMICS.
SHOWN ON THE SLIDE ARE TWO
POPULAR AFFINITY PLATFORMS.
COMPARED TO MORE TRADITIONAL
MASS SPECTROMETRY-BASED METHODS,
AFFINITY PLATFORMS ARE HIGHER
THROUGHPUT.
THEY CAN HAVE ISSUES WITH
ACCURACY WHICH WE'VE EXPLORED
EXTENSIVELY.
THEY DON'T COVER THE ENTIRE
PROTEOME AND ULTIMATELY HAVE
INTERFERENCE FROM
POST-TRANSLATIONAL INTERFERENCE
I CAN WITH INTERFERE WITH
BINDING.
WE SWAP ACCURACY FOR HIGHER
THROUGHPUT AND BETTER COST.
NOW WE CAN LEVERAGE TO ANSWER
KEY QUESTIONS, POSITING
QUESTIONS TO SHOW SCHEMATICALLY
AND PRACTICALLY HOW SUCH
QUESTIONS CAN BE TAKEN ON WITH
MULTIOMICS.
I'LL BORROW MORE FROM
CARDIOVASCULAR DISEASE.
WE'RE ALREADY SEEN SOME EXAMPLES
OF STRATEGIES BEING USED BUT DR.
SOFER WILL DEMONSTRATE HOW
APPROACHES ARE ALREADY BEING
USED IN THE SLEEP WORLD.
I'LL FOCUS MORE ON STRATEGIES
HERE THAN FINDINGS.
FIRST, WE'LL BEGIN WITH AN
IMPORTANT AND SIMPLY STATED
QUESTION, WHAT IS THE MOLECULAR
BASIS FOR PULMONARY VASCULAR
DISEASE.
CARDIOMETABOLIC DISEASE MIGHT
ASK THE SAME, HYPERTENSION, DATA
CAN COME FROM CASE CONTROL,
COHORT STUDIES, EVEN WITH JUST
ONE OMIC PLATFORM ATTACHED.
THE WAY THIS WORKS WE PLEASURE
ONE OR MORE OMICS SETS, LOOKING
TO SEE HOW THE FEATURES RELATE
TO PHENOTYPE OF INTEREST USING
STATISTICAL TESTING.
IF WE HAVE MANY FEATURES LINKED
TO THE SAME SITE OF INTEREST WE
CAN COMBINE INTO A SCORE AND SEE
IF MEASUREMENT ENHANCES
PREDICTIVE CAPABILITIES WITHIN
THE PHENOTYPE.
THIS IS A GREAT EXAMPLE,
PERFORMED PLASMA PROTEOMICS,
THEY FOUND DOWNREGULATION OF 19
PROTEINS AND UPREGULATION OF 8
ASSOCIATED WITH HIGHER
PROBABILITY OF HYPERTENSION,
AUTHORS COMBINED INTO A
MULTIOMICS SCORE AND SOW GOOD
PREDICTIVE POWER.
THE NICE THING, DE-IDENTIFIED
PROTEINS CAN PROVIDE INSIGHTS
INTO MOLECULAR PATHWAYS, SOME
PLAY ROLES IN CALCIUM
METABOLISM.
NEXT QUESTION, WHAT ARE THE
SHARED MOLECULAR SIGNATURES?
LOOKING AT DIABETES AND
HYPERLIPIDEMIA, IN MULTIPLE
STREAMS OF OMICS DATA ARE
ANALYZED TOGETHER, SO HERE
INSTEAD OF RELATINGOMES, WE
RELATIVELY TO TWO AND LOOK AT
SHARED FEATURES, FURTHER
SUMMARIZING TO SEE WHAT
BIOMOLECULAR PATHWAYS ARE
SHARED.
THIS IS A PORTION WHERE YOU LOOK
AT PATHWAYS AND THESE PROTEINS
AND METABOLITES WITH PART OF A
COMMON PATHWAY.
THIS IS A SEPARATE WAY RELATED
TO A AND B.
FOR THE RELATIONSHIP BETWEEN LP
AND I GLUCOSE CONTROL BY
CONSTRUCTING NETWORK MODELS WITH
SEQUENCING DATA FROM SEVEN
CARDIOMETABOLIC TISSUES OBTAINED
FROM CORONARY ARTERY DISEASE IN
BYPASS, BY INTEGRATING GENETIC,
THEY IDENTIFIED A REGULATORY NET
WORK WITH INVERSE RELATIONSHIP
TO EACH LIPID AND GLUCOSE.
NORMALLY THEY TRAVEL IN THE SAME
DIRECTION.
WHAT THEY FOUND ONE OF THE
MASTER REGULATORS, LSF,
CONFIRMED WHAT THEY FOUND IN THE
OMICS DATA.
THAT LEADS TO SOME NOVEL
MECHANISTIC INSIGHTS AROUND THE
TWO DISEASES.
A KEY INTEREST IN MULTIOMICS
STUDIES IS IDENTIFYING
ENDOTYPES, SUBGROUPS THAT MAY
BEHAVE DIFFERENTLY.
CAN MOLECULAR SIGNALS IDENTIFY
SUBGROUPS ANALOGOUS TO A
QUESTION WE WORKED ON TO
IDENTIFY PHENOTYPIC SIGNATURES.
THERE ARE MANY METHODS BUT ONE
OF THE MOST BASIC IS CLUSTERING,
BROUGHT UP IN ONE OF THE TALKS
ALREADY TODAY.
SO THIS APPROACH LEVERAGES LARGE
DATASETS BY TAKING THE FEATURES
AND LINKING THEM TO THE WAY WE
DID BEFORE, BUT NOW TO SOME
DIFFERENTIAL FEATURE, AS A
RESULT FEATURES CAN BE USED TO
PREDICT BEHAVIOR, PROGNOSIS,
TREATMENT RESPONSE.
YOU CAN DO THIS CLUSTERING IN A
SUPERVISED WAY, YOU KNOW
DIFFERENTIAL OUTCOME YOU'RE
INTERESTED IN, SAY PULL
PULMONARY VASCULAR DISEASE
PATIENTS THAT DEVELOP HEART
FAILURE AND THOSE THAT DON'T.
OR TYPES YOU MIGHT NOT HAVE
PREDICTED USING UNSUPERVISED
APPROACH TO IDENTIFY PATTERNS IN
THE DATA.
THIS WAS THE APPROACH THAT WE
ADVANCED FIRST USING PHENOTYPIC
DATA IN PATIENTS WITH HEART
FAILURE, UNSUPERVISED CLUSTERING
OF DENSE PHENOTYPIC DATA I WAS
THREE PHENOGROUPS WITHIN HEART
FAILURE WITH PRESERVED EJECTION
FRACTION WITH HIGHLY
DIFFERENTIAL OUTCOMES, THIS IS
AN UNSUPERVISED ANALYSIS.
TRULY MULTIOMIC WORK IS SPARSE
BUT I DID WANT TO HIGHLIGHT THIS
EFFORT FROM SOME OF MY
COLLEAGUES AT STANFORD.
THEY SHOWED 385 PERSON CENTER,
MARKERS WERE ABLE TO
DIFFERENTIATE PATIENTS INTO FOUR
CLUSTERS WITH DIFFERENTIAL
PROGNOSIS, FIVE YEAR TRANSPLANT
FREE SURVIVAL RATES UNFAVORABLE
FOR CLUSTER 1, FAVORABLE FOR
CLUSTER 3, SIMILAR WORK SHOWING
HETEROGENEITY OF RESPONSE TO
FEEDBACK.
THIS NEXT ONE IS OF PARTICULAR
INTEREST TO ME, ILLUSTRATED IN
THE CPAP STUDY I MENTIONED, TO
USE MULTIOMICS TO UNDERSTAND
INTERVENTIONAL EFFECTS.
HOW DOES INTERVENTION LIKE CPAP
AFFECT SYSTEMIC BIOLOGY?
THIS IS ANALOGOUS TO ANOTHER
TREATMENT WITH WIDE RANGING
SYSTEMIC EFFECTS, PHYSICAL
EXERCISE, FOR THESE QUESTIONS WE
CAN PAIR MULTIOMIC DATA
COLLECTION WITH CLINICAL TRIAL,
FOR ANIMAL EXPERIMENT.
THERE'S A HUGE NUMBER OF
ANALYSES THAT CAN COME OUT OF
DATA IN A TRIAL OR EXPECT,
SIMPLE TO SEE HOW LEVELS OF
MULTIOMIC MARKERS CHANGE WITH
INTERVENTION OF INTEREST BUT
MORE SOPHISTICATED APPROACH HOW
MULTIOMIC FEATURES CORRELATE
BEFORE AND AFTER INTERVENTION
SUCH AS CPAP OR EXERCISE, THIS
MULTIOMIC REWIRING WE CALL IT
CAN POINT US TO SOME OF THE KEY
PLAYERS IN THE MOLECULAR SPOTS
FOR THE INTERVENTION.
SHOWING HERE FROM A PRE-PRINT
FROM A MULTI-TISSUE MULTIOMIC
STUDY OF EXERCISE RESPONSE, DATA
FROM YOUNG RATS, 8 WEEKS OF
EXERCISE TRAINING, HOW TRAINING
INDUCED IMMUNE RESPONSES ACROSS
MULTIPLE TISSUES AND ENRICHMENT
ANALYSIS AT 8 WEEKS, IN KEG
IMMUNE SYSTEM PATHWAYS,
COMPREHENSIVE PICTURE OF
BIOMOLECULAR CHOREOGRAPHY OF
INTERVENTION GRADUALLY
UNTANGLED.
IT SUMMARIZES MOVEMENTS MULTIPLE
OMIC FEATURES ACCORDING TO KNOWN
PARTICIPATION AND BIOLOGIC
PATHWAYS.
A CLINICAL TRIAL IS USEFUL BUT
EXPENSIVE APPROACH TO ALLOWING
FOR CAUSAL INFERENCE AND AS WE
WORK OUR WAY IN COMPLEXITY AND
WANT TO DO MORE CAUSAL
INFREQUENCE WE CAN TAKE
ADVANTAGE TO HELP US INFER
CAUSALITY, USING TECHNIQUE OF
MENDELIAN RANDOMIZATION TO
ADDRESS CAN WE IDENTIFY CAUSAL
PATHWAYS FOR SLEEP DISORDERED
BREATHING OR PH AND
CARDIOVASCULAR DISEASE THIS
QUESTION IS SIMILARLY ASKED FOR.
SO MENDELIAN RANDOMIZATION DOES
NOT REQUIRE MULTIOMIC DATA, BUT
TO THE EXTENT VARIATION IS
LINKED TO OTHER FEATURES OR
PHENOTYPES MULTIOMIC CAN
ENHANCE, ALLOWING TO SHOW
CAUSALLY RELATED AND MIGHT GIVE
METABOLOMIC MEDIATOR AND
BIOMARKER IN THE SAME ANALYSIS.
THIS IS WHAT WAS DONE IN WORK
FROM OUR GROUP THAT PERFORMED MR
AND MULTIOMIC IN THE JACKSON
HEART STUDY, VALIDATING
DISCOVERED PATHWAYS IN MICE.
RESULTS IDENTIFIED NOVEL PROTEIN
PATHWAYS LINKED TO DISEASE WHICH
MIGHT RELIABLY BE THE TARGET OF
EFFECTIVE THERAPY WAS AVAILABLE
BIOMARKERS BUILT RIGHT IN TO
MONITOR TREATMENT EFFECT.
TAKEN TOGETHER, HAS POSSIBILITY
OF PRODUCING NOVEL PREDICTIVE
INSIGHTS ACROSS MULTIPLE COMPLEX
DISEASES.
THIS IS A MOMENT TO HIGHLIGHT
THERE ARE LOTS OF WAYS TO TIE
THESE METHODS TOGETHER SO, FOR
EXAMPLE, YOU MIGHT IDENTIFY
OMICS SIGNATURES IN COHORT STUDY
PREDICTIVE OF OUTCOME OF
INTEREST, MIGHT USE MARKERS AS
INCLUSION CRITERIA FOR PRECISION
TRIAL, ITSELF ENRICHED WITH
MULTIOMIC DATA TO TRACK
TREATMENT ADHERENCE, PREDICT
OUTCOMES.
HELPING US BE MORE EFFICIENT IN
TARGET PRECISION MEDICINE.
ALL THIS IS RAPID, PARTICULARLY
IN LARGE SCALE PRECISION HEALTH
EFFORTS, LARGE BIOBANKS, U.K.
BIOBANK, VETERANS PROGRAM AND
"ALL OF US," A COME AN APPROACH
TO BIOBANK UP FRONT AND OVER
TIME AS FUNDING AND ANALYTIC
TIME BECOMES AVAILABLE ADD OMICS
MEASUREMENTS TO DATASETS.
MV PARKS IS PARTNERS TO ADD
METABOLOMICS DATA, ALL OF US
ADDING DATA AS WELL IN THE
FUTURE.
IS IT FOR SLEEP AVAILABLE NOW?
I DID WANT TO HIGHLIGHT AN
EFFORT IN THE MoTrPAC STUDY,
GATHERING SLEEP DATA IN
PEDIATRIC PATIENTS WITH DENSE
SLEEP DATA, EEG, ECG, EMG, AS
WELL AS ACCELEROMETRY DATA, I R.
A RICH DATASET PAIRED WITH
MULTIOMIC EXERCISE RESPONSE DATA
AS WELL, EXCITING DOWN THE ROAD.
I'LL WRAP UP BY SAYING IF YOU'RE
THINKING ABOUT ADDING OMICS TO A
STUDY, PARTICULARLY A LARGE
STUDY OR DENSITY MULTIOMIC DATA,
IT'S IMPORTANT TO THINK UP FRONT
ABOUT THE RATHER LARGE AMOUNTS
OF BIOINFORMATIC MANAGEMENT AND
DATA WORK THAT GOES INTO THIS,
TRUE FOR RESEARCHERS AND FOR
FUNDING OFFICES, NIH, NHLBI TO
THINK ABOUT STUFF UP FRONT WHEN
DATA IS GENERATED WE NEED TO
INGEST, GENERATE DATA MANAGEMENT
PIPELINE, NORMALIZE, ANALYZE,
SHARE IT.
IN ADDITION TO ACCOUNTING FOR
DATA THERE NEEDS TO BE A
MECHANISM TO STORE RAW DATA BUT
ANALYSIS, THAT'S QUITE COSTLY
WITH CLOUD STORAGE AND
FORTUNATELY NIH HAS THE STRIDES
PROGRAM.
ALL THE EFFORTS THAT GO INTO
CREATING MOLECULAR MAPS OF WHAT
YOU'RE STUDYING NEED TO BE
DISSEMINATED THROUGH OUR
PACKAGES OR GITHUB SO DATA AND
ANALYSIS ARE SORT OF FOLLOWING
THE FAIR GUIDELINES.
DATA SHOULD BE DEPOSITED AND
CONNECTED IN OTHER DATABASES SO
YOU'VE GOT GEO, METABOLOMICS
WORKBENCH, WE KNOW ABOUT dbGAP
BUT WE'RE TRYING TO CREATE CLOUD
RESOURCES TO LINK DATASETS
TOGETHER AND ALLOW PEOPLE TO
EXPLORE THEM ON THE FLY AND
THROUGH THE WEB.
SO, WITH THAT I'LL WRAP UP AND
APPRECIATE EVERYONE AND TURN IT
OVER TO DR. SOFER TO GO INTO
MUCH MORE DETAIL.
>>THANKS, DAN, A WONDERFUL
TALK.
IT'S 4:34.
WE HAVE THE NEXT SESSION, THE
DISCUSSION, AND SO I WOULD --
WE'LL CUT INTO THE DISCUSSION A
LITTLE BIT.
WE WANT TO HEAR YOUR FULL TALK.
>>OKAY.
SO, MY TALK IS ABOUT USE OF
MULTIOMICS, AND I'LL START WITH
THIS SLIDE THAT I BORROWED FROM
DAN'S TALK, THIS IS THE
RELATIONSHIP BETWEEN DIFFERENT
OMICS.
AT THE END HERE WE SEE THE
PHENOTYPE.
IT CAN BE USED AS OUTCOME OF THE
PROCESSES BUT CAN BE USED AS THE
ENVIRONMENT RIGHT HERE.
IF WE THINK ABOUT THE
RELATIONSHIP BETWEEN TWO
PHENOTYPES WE CAN THINK ABOUT
THEM SIDE BY SIDE, EACH ONE OF
THEM IS THE OUTCOME OF THE
COMPLEX GENETIC AND OMICS AND
ENVIRONMENTAL PROCESSES OR WE
CAN THINK OF ONE BEING THE
ENVIRONMENT, MODIFYING THESE
EFFECTS IN THE WAY THEY LEAD TO
THE SECOND PHENOTYPE.
SO, I WILL GIVE EXAMPLES, RUN
THROUGH THE TWO TYPES OF
ASSOCIATION OMICS ASSOCIATION,
LEADING TO RELATIONSHIP BETWEEN
TWO PHENOTYPES.
SO, I WAS TRYING TO FIND
EXAMPLES RELATED TO SLEEP.
AND PULMONARY VASCULAR DISEASE
THAT RELATES THE TWO.
IT WAS VERY, VERY DIFFICULT
BECAUSE THIS FIELD IS STILL IN
THE INFANCY SO THESE EXAMPLES
ARE NOT AS NICE AS WE WOULD
HOPE.
SO FIRST EXAMPLE, USING GENETICS
TO LINK TWO CONDITIONS.
GENETICS IS VERY POWERFUL.
IT'S THE MOST ABUNDANT OF ALL
THE OMICS DATA BECAUSE WE'VE
BEEN STUDYING FOR IT FOR A WHILE
IN LARGE SAMPLE SIZES.
IT'S ALSO POWERFUL BECAUSE IT'S
FIXED AT BIRTH.
HERE WHEN WE LINK TO TWO
CONDITIONS WE OFTEN USE KNOWN
GENETIC ASSOCIATIONS, FOR
EXAMPLE WE MAY ALREADY KNOW WE
HAVE SOME GENETIC VARIANTS
ASSOCIATED WITH WHATEVER SLEEP
OUTCOME, AND WE WANT TO ASK,
UTILIZE GENETIC VARIANTS,
ASSOCIATED WITH THE FIRST
CONDITION, TO ASK QUESTIONS
ABOUT THE SECOND CONDITION AND
LEARN FROM THIS ABOUT
ASSOCIATION BETWEEN THE TWO
CONDITIONS.
EXAMPLES FOUND WITH THAT, 2020
ASSOCIATION OF CARDIOVASCULAR
RISK FACTORS AND LIFESTYLE
BEHAVIORS WITH HYPERTENSION,
MENDELIAN RANDOMIZATION STUDY,
HERE GWAS STATICS FROM THE U.K.
BIOBANK, OPEN ACCESS DATASETS OR
THERE ARE OPEN ACCESS COMPONENTS
TO THEM.
CONCLUDED GENETIC PREDICTED
INSOMNIA INCREASES RISK OF
HYPERTENSION.
FINDINGS RELATE TO THE CAUSAL
ASSOCIATION BETWEEN TWO
PHENOTYPES.
ANOTHER EXAMPLE WE'LL BE MORE
ELABORATE USING SIMILAR
TECHNIQUE, DIABETIC PHENOTYPES,
LATE LIFE DEMENTIA RISK,
SPECIFIC MENDELIAN STUDY, IT
MEANS THEY SELECTED VARIANTS
CORRESPONDING TO SPECIFIC
FUNCTIONS, BETA CELL FUNCTION,
INSULIN SENSITIVITY, ADIPOSITY.
HERE FOUND SUGGESTIVE EVIDENCE
THAT INSULIN-SENSITIVITY SCORE
IS ASSOCIATED WITH DEMENTIA.
FINDINGS RELATE TO CAUSAL
ASSOCIATION INFERENCE WITH
SPECIFIC WELL-DEFINED
GENETICALLY REGULATED MECHANISM
OF THE FIRST PHENOTYPE.
SUBTYPE OF DIABETES.
STANDARD WAY TO USE OMICS TO
PERFORM ASSOCIATION, FIRST THING
YOU WOULD DO.
ASSOCIATION ANALYSIS WITH SOME
OMICS, WITH FIRST CONDITION, AND
YOU CAN IDENTIFY FOR EXAMPLE
PATHWAY BASED ON RESULTS.
MAY BE KNOWN TO RELATE TO
CONDITION 2.
YOU MAY NOT EVEN HAVE DATA WITH
CONDITION 2 BUT THIS IS A VERY
STRAIGHTFORWARD WAY TO RELATE
THE TWO CONDITIONS.
HERE IN THIS STUDY THIS SHOWS
PROLONGED SLEEP RESTRICTION
INDUCES CHANGES IN PATHWAYS
INVOLVED IN CHOLESTEROL
METABOLISM AND INFLAMMATORY
RESPONSES.
AUTHORS DID EXPERIMENTAL SLEEP
RESTRICTION STUDY, COMBINED WITH
EPIDEMIOLOGICAL COHORTS, SLEEP
SUFFICIENCY QUESTIONS, AND THEY
ON AD BLOOD TRANSCRIPTOMICS TO
DO PATHWAY ANALYSIS AND FIND
HIGHLIGHTED LIPID PATHWAYS AND
FOUND ASSOCIATION WHEN THEY USED
METABOLITES.
OR TWO-STEP ANALYSIS FIRST
PERFORMED ASSOCIATION ANALYSIS
USING CONDITION 1, AND THEN YOU
USE YOUR FINDINGS, METABOLITES,
AND THEN TEST WITH SECOND
CONDITION OF INTEREST.
SO, WHAT ABOUT OMICS BEYOND
ASSOCIATION?
OMICS IS USED TO EXPLAIN
MECHANISM, IF YOU CAN EXPLAIN
BIOLOGY THEY ARE MORE LIKELY TO
BE TRUE.
IT CAN BE USED TO DETERMINE
RESPONSE TO THERAPY, AS A
BIOMARKER, HELPS ASSESS
RESPONSE, IDENTIFY SUBTYPES,
MORE LIKELY TO DEVELOP SECOND
CONDITION, THOSE LIKELY TO
RESPOND TO TREATMENT, AND OTHER
BRIEF EXAMPLES FROM 2021,
CHRONIC THROMBOEMBOLIC PULMONARY
HYPERTENSION, TO PERFORM
UNTARGETED ANALYSIS IN CTEPH
PATIENTS.
EVALUATED RESPONSE TO TREATMENT.
AND OF THE METABOLITES.
AND THEY FOUND MOST METABOLITE
LEVELS ARE SIMILAR BUT THEY
IDENTIFY SOME METABOLITES THAT
DIFFER BETWEEN THEM.
YOU CAN POTENTIALLY BE USED TO
IDENTIFY THE TWO, UNDERSTAND THE
BIOLOGY.
AND THEY CAN BE USED TO ASSESS
RESPONSE TO TREATMENT, THEY
OBSERVED RESPONSE TO TREATMENT
OF THESE METABOLITES THAT
DEFERRED BETWEEN THEM AND
SUGGEST THOSE ARE STILL NEED
WORK TO BE DONE.
THEY SUGGEST METABOLITES CAN BE
USED TO EVALUATE RESPONSIVE OF
OTHER NON-INVASIVE TREATMENT.
ANOTHER EXAMPLE, TO SHOW
MULTIOMICS MAY EXPLAIN BETTER
BIOLOGY, SO PROTEIN BIOMARKERS
AND RISK SCORES, ASSOCIATED WITH
VENTRICULAR SEPTAL DEFECT,
PERFORMED ANALYSIS, AND
INTEGRATED THEM BY MAPPING
ASSOCIATED PROTEINS INTO KNOWN
PATHWAYS.
REALLY THE MULTIOMICS SPACE IS
IN ITS INFANCY.
A LOT OF METHODS ARE BASICALLY
DOING EACH ONE SEPARATELY AND
THEN TRYING TO USES INFORMATION
FROM THE TWO, TOGETHER.
I STILL WANTED TO GIVE EXAMPLES
FROM OUR OWN RESEARCH.
SO I'LL DESCRIBE TWO STUDIES,
ONE IS OBSTRUCTIVE SLEEP APNEA,
CARDIOMETABOLIC PHENOTYPE, A
FORMER POSTDOC WHO WORKED ON
GENETIC DETERMINANTS,
OBSTRUCTIVE SLEEP APNEA IN THE
HISPANIC COMMUNITY HEALTH STUDY,
STUDYING ASSOCIATION BETWEEN OSA
AND PHENOTYPES.
TOOLS INCLUDE GENETIC
CORRELATION ESTIMATION,
POLYGENIC RISK SCORES, MENDELIAN
RANDOMIZATION ANALYSIS THAT WAS
MENTIONED BEFORE.
THIS IS THE DESIGN.
WE'LL WALK YOU THROUGH IT.
THE FIRST STEP ESTIMATED GENETIC
CORRELATION USING INDIVIDUAL
LEVEL DATA.
GENETIC CORRELATION BETWEEN TWO
TRAITS IS CORRELATION BETWEEN
EFFECTS OF GENETIC CARANTS
ON -- VARIANTS ON EACH OF THE
TRAITS, CORRELATION BETWEEN
GENETIC COMPONENTS OF THESE
TRAITS.
HERE WE USE RESPIRATORY EVENT
INDEX, 54 OTHER PHENOTYPES
RELATED TO ANTHROPO METRIC,
CARDIOMETABOLIC, ESTIMATED
GENETIC CORRELATION, GIVES US A
HINT, A GRIEF SHARED GENETICS
BETWEEN THEM.
WE NARROWED DOWN TO 22
PHENOTYPES, TRAITS INCLUDED
PULMONARY, CHOLESTEROL, BLOOD
COUNT.
WE MOVED TO THE NEXT STEPS,
USING POLYGENIC RISK SCORES
COMBINING ACROSS THE GENOME.
TO USE POLYGENIC RISK SCORES YOU
NEED SOME ESTIMATES OF RATE
ASSOCIATION.
THIS IS SOMETHING WE TAKE FROM
AN OUTSIDE STUDY.
AND THEN WE USE THIS INFORMATION
FROM AN OUTSIDE STUDY TO
CONSTRUCT.
HERE WE CONSTRUCTED POLYGENIC
RISK FOR FOR CORRELATED TRAITS
AND 22 YEARS AN OBSTRUCTIVE
SLEEP APNEA, STUDYING
ASSOCIATION.
THESE ARE THE RESULTS.
SO LET ME WALK YOU THROUGH THIS.
HERE WE SEE ALL THE PHENOTYPES
WITH EVIDENCE OF GENT
CORRELATION, SHARED GENETIC
BASIS.
BMI, RESPIRATION, SO ON.
WE SEE THEIR ASSOCIATION WITH
ONE OUTCOME.
HERE OUTCOME RESPIRATORY INDEX,
AND BMI ADJUSTED MODEL.
OSA DEFINED BASED ON RESPIRATORY
EVENT INDEX, SIMILAR BUT IF
THERE'S MEASUREMENT ERROR, WHICH
THERE IS, MAY BE SLIGHTLY MORE
POWERFUL.
AND THEN WE DID BMI ADJUSTED.
AND EACH POINT CORRESPONDS TO
ESTIMATED SIZE AND CONFIDENCE
INTERVAL.
WE COLOR CODED ACCORDING TO
THIS -- WHERE THE ASSOCIATION
WAS SIGNIFICANT.
HERE AFTER ADJUSTING FOR BMI
POLYGENIC RISK FOR INSOMNIA,
HBA1C, SHOW EVIDENCE OF
ASSOCIATION WITH RESPIRATORY
EVENT INDEX FOR OSA.
IT WAS ASSOCIATED WITH HBA1C AND
BMI-ADJUSTED ANALYSIS.
THE FOLLOWING STEP WAS TO LOOK
AT CAUSALITY OF ASSOCIATION
USING MENDELIAN RANDOMIZATION
ANALYSIS.
THE GOAL IS STUDY ASSOCIATION
BETWEEN EXPOSURE ANDOUT COME.
HERE COMPOSURE COULD BE
OBSTRUCTIVE SLEEP APNEA.
AND USUALLY THERE ARE CONFOUNDED
ASSOCIATIONS BETWEEN THE TWO,
FOR EXAMPLE BMI.
THE GOAL OF USING GENETIC
INSTRUMENT HERE INSTRUMENTAL
VARIABLES, GENOTYPES, IS TO
ASSESS THE EXPOSURE OUTCOME
ASSOCIATION IN A WAY THAT KIND
OF REMOVES THE BIAS FROM
CONFOUNDING.
WE NEED TO TAKE VARIANTS
ASSOCIATED WITH EXPOSURE,
HOPEFULLY NOT ASSOCIATED WITH
OUTCOME VIA OTHER PATHWAYS.
THERE ARE MANY METHODS USING
MANY GENETIC VARIANTS, SOMEHOW
CAN IDENTIFY PROCEDURES EVEN IF
THIS IS VIOLATED, SOMETIMES, YOU
CAN STILL OBTAIN UNBIASED
ESTIMATES OF EXPOSURE OUTSOME
ASSOCIATION.
IT HAS TO HAVE ESTIMATES OF
ASSOCIATION, YOU NEED HAVE
ESTIMATES OF GENETIC ASSOCIATION
WITH EXPOSURES AND OUTCOME.
IF YOU HAVE THAT, YOU CAN
PERFORM MENDELIAN ANALYSIS.
HERE WE FOCUSED ON THE 11
TRAITS, WITH SOME EVIDENCE OF
PEER ASSOCIATION WITH OSA OR
REI.
WE'RE NOT SHOWING RESULTS FORT
OSA HERE BECAUSE THERE WAS NO
EVIDENCE OF CAUSAL ASSOCIATION.
BUT WE HAVE EVIDENCE OF CAUSAL
ASSOCIATION, PHENOTYPES, TWO
FIGURES HERE ONE SHOWS RESULTS
FROM PRIMARY ANALYSIS, HERE WE
HAVE RESULTS FROM SENSITIVITY AM
SIS.
REMEMBER I MENTIONED WE HAVE
VARIOUS METHODS TO DEAL WITH
DEVIATIONS, STANDARD ANALYSIS
DOES SOMETHING PRELIMINARY AND
IF YOU SEE EVIDENCE THEN YOU GO,
TAKE ASSOCIATION AND RUN IT
THROUGH A BUNCH OF SENSITIVITY
ANALYSES.
WE FOUND EVIDENCE OF CAUSAL
EFFECTS.
LIMITATIONS IS MAINLY DATA.
GENETIC ANALYSIS METHODS RELY ON
INDIVIDUAL-LEVEL DATA, INCLUDING
COLLECTED TRAITS, SUMMARY
STATISTICS FROM ANALYSIS THAT
SOMEONE ELSE DID, USUALLY BOTH.
USUALLY YOU USE SOME INFORMATION
FROM PAST ANALYSES AND TRY TO
APPLY USING INDIVIDUAL LEVEL
DATA.
EITHER WAY, THE RIGHT PHENOTYPE
OR OTHER MEASURES ARE AVAILABLE.
AND YOU NEED LARGE SAMPLE SIZES.
IF THE OSA PHENOTYPE THAT WAS
USED IN THE GENOME WIDE
ASSOCIATION ANNUAL SILLS THAT
YOU TOOK FROM THE LITERATURE IS
NOT GOOD, IF YOU HAVE HIGH RISK
OR LOW SAMPLE SIZES, IT LIMITS
CONCLUSION FROM RESULTS.
THIS INCLUDES CONCLUSION, LIKELY
LIMITED BECAUSE OF THE SPECIFIC
RESULTS THAT WE USE THAT WE TOOK
FROM THE LITERATURE.
ANOTHER ANALYSIS WITH
METABOLOMICS, ASSESSED
ASSOCIATION WITH INCIDENT
DIABETES AND HYPERTENSION.
THIS PAPER IS IN REVIEW
CURRENTLY.
WE CREATED NEW MEASURE OF SLEEP
DISORDERED BREATHING USING
PRINCIPAL COMPONENTS ANALYSIS,
MAXIMIZING VARIANCE ACROSS 7 SDB
PHENOTYPES, INCLUDING MEASURES
OF SATURATION AND EVENT
DURATION.
THE GOAL WAS NOT TO BUILD THE
BEST AVAILABLE MEASURE OF SDB.
IT WAS TO MAXIMIZE VARIANCE
EXPLAINED.
AND TO REDUCE (INDISCERNIBLE).
SUMMARIZING THE TWO, SBD
PHENOTYPES, METABOLIC
ENVIRONMENT, ONE INDEX EACH.
WE STUDY ASSOCIATION OF THESE.
THIS FIGURE SHOWS ESTIMATED
CORRELATION BETWEEN THE TWO
SDB-PCS AND PHENOTYPE USED HERE.
WE HAD THESE PHENOTYPES,
RESPIRATORY EVENT INDEX WITH 3%
SATURATION, ZERO HYPOXIC BURDEN,
OXYGEN SATURATION DURING SLEEP
AND THEN WE HAVE SDB PC1, THE
FIRST PC IS HIGHLY ASSOCIATED
WITH STANDARD, YOU KNOW,
MEASURES OF OSA.
AND SECOND EXPLAINS LOWER
PROPORTION --
>>TWO-MINUTE WARNING.
>>WHAT HAPPENED?
>>TWO-MINUTE WARNING.
>>OKAY.
OH, THANK YOU.
YES, SO IT'S MAINLY EVENT LINES.
LINEAR COMBINATIONS OF
METABOLITE CONCENTRATIONS, BASED
ON 112 METABOLITES, IT'S OTHER
BASED ON 57, SOME OVERLAP.
WE LOOKED AT ASSOCIATION OF SDB
MRS WITH INCIDENT OUTCOMES.
THIS IS -- SO EACH POINT
PROVIDES ESTIMATED INCIDENT
RATIO OF MEASURE EITHER
METABOLITE RISK SCORES, SECOND,
FIRST, OR HYPOXIC BURDEN,
RESPIRATORY EVENT INDEX, 95
INTERVALS, ASSOCIATION WITH
INCIDENT DIABETES OR INCIDENT
HYPERTENSION, IN COMBINED
POPULATION MALE AND FEMALE.
BUT LET'S FOCUS ON EVIDENCE OF
SEX DIFFERENCES NOT BEING
STRONG.
WE SEE METABOLITE RISK SCORE HAS
STRONGER ASSOCIATION, FEELS
EXACTLY THE SAME DATASET, SAME
SET OF INDIVIDUALS.
ASSOCIATIONS WITH COMPARABLE TO
STRONGER ASSOCIATION COMPARED TO
PHYSIOLOGICAL MEASURES.
WHICH THIS IS WHAT I JUST SAID.
SOMETHING I HID HERE, SIMILAR
SCORE, RECONSTRUCTED BASED ON
OSA HAD STRONGER ASSOCIATION
WITH INCIDENT DIABETES AND
HYPERTENSION.
IT'S NOT CLEAR YET THAT USING
PC-BASED APPROACH IS GETTER THAN
USING STANDARD MEASURES OF OSA
OR SDB.
WE USED BIOMARKERS, I JUST
DIDN'T PRESENT IT HERE.
MRS IS GENERATED BASED ON A FEW
TRAITS.
THERE ARE MANY POTENTIAL FACTORS
FOR WHY ONE PERFORMS BETTER THAN
THE OTHER, EVEN THOUGH OSA
PERFORMS BETTER IT USED MUCH
SMALLER NUMBER OF METABOLITES.
IT WAS CONSTRUCTED BASED ON
DIFFERENT TOOL OF METABOLITES,
THAT MAY HAVE SOMETHING TO DO
WITH IT.
IT COULD BE THE PHENOTYPE, COULD
BE METABOLITES, SOME MAY BE MORE
RELIABLE.
SOMETHING WE STILL NEED TO
STUDY.
FINAL NOTE, BIG VERSUS SMALL
DATA.
WE HAVE TWO MAJOR APPROACHES FOR
LINKING TWO CONDITIONS.
ONE ONE IS LINK USING LARGE
OBSERVATIONAL DATASETS FOCUSING
ON PATHWAYS AND/OR OMICS-BASED
BIOMARKERS BASED ON FIRST STUDY
FOCUSING ON ONE CONDITION.
THIS IS WHAT I CALL HERE THE BIG
DATA APPROACH.
SECOND CAREFULLY DESIGNED STUDY
BASED ON SPECIFIC HYPOTHESES
RELATING TWO CONDITIONS.
THIS IS MUCH BETTER FOR
CAUSALITY INFERENCE, AND FOR
LIMITING REALIZED INTERVENTION.
IN PRACTICE THIS IS SMALL DATA
APPROACH.
SO HIGH FOCUS HERE ON BIG DATA
APPROACH BUT IDEALLY THE TWO
APPROACHES WILL BE COMBINED.
BIG DATA APPROACH IS VERY, VERY
POWERFUL NARROWING DOWN ON A FEW
OUT OF MANY CANDIDATE MARKERS.
AND THAT'S IT.
SO THANK YOU.
>>THANK YOU.
WE KNOW IT'S A CHALLENGE AT THIS
LATE HOUR, BEING A LITTLE BIT
BEHIND, BUT THOSE WERE SUPERB
PRESENTATIONS.
AT THIS POINT, ANNA AND I WILL
MAYBE FACILITATE MAYBE AN
OVERALL WRAP-UP SESSION, MAYBE
WE CAN BEFORE WE TRY TO THINK OF
OUR DISCUSSANT THEMES MAYBE I'LL
OPEN UP FOR ANY QUESTIONS OR
COMMENTS ANYONE HAS FOR ANY OF
THE THREE SPEAKERS TO BEGIN
WITH.
DR. SHAH?
>>THANK YOU FOR THOSE REALLY
GREAT TALKS.
I HAD QUESTIONS FOR TWO
SPEAKERS.
ONE WAS DR. KATZ, AND ONE FOR
DR. PUNJABI.
GREAT TALK.
I ENJOYED IT.
I WANTED TO FIND OUT SORT OF
WHAT YOU WOULD RECOMMEND FOR THE
FIELD IN TERMS OF INCORPORATING
MULTIOMICS AND THE PHENOTYPES
WE'VE BEEN DISCUSSING TO BETTER,
AGAIN, FIND A WAY FOR
SPECIALIZED AND PRECISION
MEDICINE APPROACHES.
>>I THINK I'LL PUT THIS INTO
SOMETHING I TOUCHED ON,
BIOBANKING.
BIOBANKING, BIOBANKING,
BIOBANKING.
THE FACT THAT THE BIOBANKING IS
RELATIVELY SPEAKING INEXPENSIVE
RELATIVE TO MULTIOMIC WORK
NECESSARY.
SO IF YOU CAN PLAN AHEAD, AND
COLLECT SAMPLES, AND THAT
INCLUDES TISSUES NOT JUST PLASMA
WHICH IS STRAIGHTFORWARD AND
EASY BUT ALSO TISSUES IF
POSSIBLE, AND SAVE THEM FOR THE
TIME THERE'S FUNDING AND BAND
WIDE THERE TO DO MULTIOMIC WORK
WILL BE HELPFUL.
EVEN ON STUDIES WHERE WE HAVE
ENOUGH MONEY TO DO THE TRIAL OR
ENOUGH MONEY TO DO THE STUDY BUT
NOT ENOUGH TO DO SPATIAL OMICS,
IT'S AN OPPORTUNITY TO STILL TRY
TO SEE IF YOU CAN GET JUST
ENOUGH TO BIOBANK AND LATER ON
FUNDING FOR MULTI OMICS.
STARTING WITH A FEW, GENETICS
AND TRANSCRIPTOMICS, PROTEOMICS
IS GREAT BUT TRANSCRIPTOMICS IS
MORE COST EFFECTIVE AS GETS
IMPORTANT BIOLOGY SO THAT'S
WHERE I WOULD START BUT I THINK
HAVING THE DENSITY OF DATA IS
REALLY VALUABLE.
IT MIGHT HAVE TO BE AVAILABLE
LATER.
HOPEFULLY THAT ANSWERS YOUR
QUESTION.
>>YES, THANK YOU.
AND I WANTED TO ASK THOUGHTS
WITH THE INSOMNIA, YOU KNOW, YOU
MENTIONED THAT BEAUTIFULLY
COVERED IT, WONDERING HOW YOU
SEE WEARABLES AND WEARABLES,
TECHNOLOGY USE BY PATIENTS,
DRIVING INSOMNIA, DRIVING
FURTHER, IF YOU HAD THOUGHTS ON
THAT.
>>I DIDN'T BUT WHAT A GREAT
QUESTION.
YOU KNOW, LOOK.
OUR GROUP, THE SLEEP GROUP ON
THIS PANEL, RECOGNIZES THAT ONE
TIME POINT MEASUREMENTS AS WE DO
IN THE LAB OR EVEN THE HOME SET
IS NOT ENOUGH TO THINK ABOUT
WHAT HAPPENS WITH EXPOSURE,
WHETHER IT'S SLEEP APNEA OR
SLEEP IN GENERAL.
CONCEPT OF HAVING SOMETHING THAT
CAN PROVIDE A REAL TRUE EXPOSURE
ASSESSMENT OVER TIME IS
BENEFICIAL.
AND AS YOU KNOW, MOST OF THE
FOLKS HERE KNOW TECHNOLOGY IS
GETTING CONVENIENT, EASY,
RELATIVELY CHEAP AND QUITE
EXPANSIVE, SURE, MONITORS ARE
SURROGATES, NOT NECESSARILY
MEASURING SLEEP PER SE, BUT WE
GET AN IDEA WHAT'S HAPPENING
OVER TIME IN A REPEATED FASHION,
MORE REFLECTIVE.
THE QUESTION ASKED EARLIER,
DAN'S CONVERSATION ABOUT WHAT IS
TRUE EXPOSURE ABOUT SLEEP,
DURATION, TIMING, IS IT
VARIATION, ALL OF THE ABOVE?
PROBABLY ALL OF THE ABOVE.
WEARABLES WILL HELP.
WE'RE LEARNING IN OUR OWN FIELD,
WE'RE LEARNING.
IF THE JUMP HAS TO OCCUR FROM US
TO THEM, WE HAVE TO HELP THEM
THINK ABOUT THESE THINGS AS
WE'VE LEARNED A LOT OURSELVES.
IT'S GOT A CRITICAL CENTRAL
FEATURE BUT HOW WE CHARACTERIZE
SLEEP.
EVEN HOME SLEEP APNEA, WE CAN DO
MORE
MULTIPLE NIGHTS, YEAH.
>>THANK YOU.
>>A QUESTION, STEVE?
>>I ENJOYED THE TALKS.
MY QUESTIONS ARE GEARED TOWARDS
OMICS AND DR. KATZ AND SOFIR, IF
YOU COULD COMMENT ON ADDITIONAL
COMPUTATIONAL METHODOLOGIES THAT
COULD BE UTILIZED AS THIS
INFORMATION EXPANDS, IN ADDITION
TO OMICS AND POLYGENIC RISK
SCORES AND ASSOCIATIONS THAT WE
TEND TO SEE IN THE LITERATURE
MORE, WE'VE BEEN INTERESTED ON
THE PULMONARY HYPERTENSION SIDE
OF STATES AT OMICS LEVEL, A.I.
AND MACHINE LEARNING TO PREDICT
STATES OF DISEASE AS A PERSON
GOES THROUGH DIFFERENT EXPOSURES
THROUGH TIME AND SO FORTH, SEEMS
LIKE A LITTLE BIT OF A PIE IN
THE SKY POSSIBILITY, IF YOU
COULD COMMENT ON HOW CLOSE OR
FAR AWAY ARE WE FROM THAT IN
THIS FIELD OF SLEEP DISORDERS
GIVEN THE FACT WE DON'T
TYPICALLY HAVE AS MUCH
INFORMATION AS WHAT WE WOULD SEE
IN CANCER, CARDIOVASCULAR
DISEASES?
>>I THINK THE LIMITATION IS THE
DATA.
THE ANALYTIC METHODS ARE THERE
IN THEORY BUT IT'S GOING
THROUGH -- IT'S OBTAINING THE
DATA, DYNAMIC DATA YOU NEED, THE
QUANTITY OF DATA THAT YOU WOULD
NEED.
>>YEAH, I COMPLETELY AGREE.
I THINK THAT WHAT I'VE SEEN IN
WORKING IN EVERY LARGER DATASETS
STARTING TO COME UP AGAINST
DENSITY OF DATA YOU WOULD NEED
TO DO THAT KIND OF STUFF YOU ARE
COMPOUNDED BY THE COMPLEXITY OF
HANDLING THAT DATA AS IT GROWS.
THAT'S THE COMPUTATIONAL COSTS,
CLOUD COSTS, BUT THAT'S ALSO THE
SORT OF ACCURACY COST BECAUSE
WHEN YOU ARE TRYING TO DO
STATISTICAL MODELING ON A ONCE
OF THOUSANDS OF INHERENTLY
INACCURATE MEASUREMENTS, YOU
START TO GET INTO A FACT WHERE
YOU'RE MODELING CHANGES OF ALL
OF THEM, USING ONE MODEL THAT
MAY NOT BE APPROPRIATE FOR ALL
OF THEM.
COMPLEXITY GROWS.
I'M EXCITED ABOUT THAT KIND OF
THING AND I THINK INTERVENTIONAL
OMICS WHERE YOU ACTUALLY APPLY
SOME STIMULUS, EXERCISE, WHETHER
IT'S CPAP, SOMETHING LIKE THAT,
CAN HELP BECAUSE IT KNOCKS OMICS
INTO ALIGNMENT AROUND THAT
PARTICULAR INTERVENTION AND
BECOMES EASIER TO STUDY WITH
SMALLER NUMBERS SO I THINK TO DO
THAT KIND OF THING WHICH I THINK
IS SUPER EXCITING REQUIRES SOME
OF THAT ASSISTANCE FROM THE
APPROACH.
>>THANK YOU.
>>I KNOW ONE OF THE I THINK
CHALLENGES IN DOING THOSE
INTERVENTIONS IS THAT TO BE MOST
RIGOROUS YOU WOULD HAVE MAYBE
CONTROL GROUP WITH NO
INTERVENTION.
AND YET THAT CAN BE PRETTY
CUMBERSOME.
HOW, YOU KNOW, WELL WHAT DO YOU
THINK THE BEST DESIGN IN TERMS
OF LOOKING AT OMICS RESPONSES TO
INTERVENTION DO WE NEED TO LOOK
AT TYPICAL RANDOMIZED CONTROL
LENS OR ALTERNATIVE AND MORE
EFFICIENT APPROACHES.
>>YEAH, I WAS HAVING A MEETING
ABOUT THAT YESTERDAY.
THIS IS A COMPLICATED ISSUE.
AND I THINK WE'VE SEEN REAL
BENEFITS IN HAVING THE CONTROL
GROUP.
IT IS -- AS MUCH AS IT ADDS
COMPLEXITY, YOU'RE MAYBE ADDING
IN A LAYER OF DSMB REQUIREMENTS
HOW YOU'RE ANALYZING DATA WHICH
CAN ADD DIFFICULTY BUT IT'S
VALUABLE.
A SIMPLE BIOPSY THAT LOOKS AT
MUSCLE, WE CAN SEE STRESS
RESPONSE IN THE CONTROLS, THAT
IF YOU DON'T HAVE THEM, YOU WILL
ATTRIBUTE TO YOUR INTERVENTION.
AND SO THAT I THINK HAVING
CONTROLS IS IMPORTANT, JUST AS
IT IS IN REALLY ANY TRIAL.
CAN YOU GEAT WITH USING PEOPLE
AS THEIR OWN CONTROL?
SURE.
BUT THERE COMES WITH THAT TYPE
OF RISK ABOUT (INDISCERNIBLE).
>>AND DR. SWEATT?
>>YES, I HAVE A FEW
QUESTIONS/COMMENTS FOR THE OMICS
FOLKS, MAYBE FOOD FOR THOUGHT
FOR THE GROUP IN GENERAL BECAUSE
I THINK I'M STILL VERY
EARLY-STAGE INVESTIGATOR, AND I
WAS -- I'M ALREADY GETTING AGED
IN MY EARLY RESEARCH CAREER, IN
DEALING WITH SINGLE OMIC
RESEARCH IN MAINLY PROTEOMICS
STUFF I'VE DONE IN GROUP 1 PH
NARROWING DOWN TO THAT POINT.
ALREADY, I SEE SUBSTANTIAL
COMPLEXITIES THAT MAY MAKE IT
DIFFICULT IN THE NEAR TERM TO
ACHIEVE SOME PIE IN THE SKY
VISIONS THAT WE HAVE.
I THINK SOME UNIQUE CHALLENGES
THAT WE FACE ARE, A, IT'S A RARE
DISEASE AND SO EVEN WHEN WE PUT
TOGETHER MULTI-CENTER
COLLABORATIVE EFFORTS WE
STILL -- SAMPLE SIZES ARE LOW.
B, THE SECOND ONE IS WE NEVER
HAVE DISEASE TISSUE AT OUR
DISPOSAL AND THAT CAN BE SAID
FOR THE SLEEP DISORDERED
BREATHING BIOBANKING TOO, WE'RE
STUCK DEALING WITH BLOOD AS A
WINDOW TO THE LUNG.
I CLEARLY UNDERSTAND THE PH
RESEARCHER IMMENSE HETEROGENEITY
OF PULMONARY HYPERTENSION IN
GROUP 1 AND I COME TO APPRECIATE
HETEROGENEITY OF OSA, AND SO
PART OF THE PATH FORWARD IS WE
REALLY NEED TO BE CAREFUL WITH
OUR CLINICAL DATA COLLECTION AND
CLINICAL PHENOTYPING OF THESE
PATIENTS BECAUSE THERE'S A LOT
OF POTENTIAL NOISE THAT WE'RE
PICKING UP IN THE BLOOD FROM
WHETHER IT BE CO-MORBIDITIES,
BACKGROUND MEDITATIONS, OTHER
THINGS THAT MIGHT NOT REFLECT
THE DISEASES WE'RE INTERESTED IN
THEMSELVES.
I WORRY IF WE HAVE THE VISION OF
UNDERSTANDING PATHOBIOLOGY,
DEVELOPING NEW DRUG TARGETS
BASED ON THE BLOOD, WE MAY BE UP
AGAINST IT.
IT MAY BE SIMPLER TO HAVE TOOLS
TO IDENTIFY CERTAIN CLINICAL
PHENOTYPES OR PREDICT RESPONSE
TO THERAPY OR RISK STRATIFIED,
MAYBE THAT'S MORE FORESEEABLE.
WE DON'T KNOW THAT REFLECTS
WHAT'S GOING ON IN THE LUNG
PATHOBIOLOGICALLY SPEAKING.
SO THERE'S THOSE COMMENTS.
MY FINAL ONE WITHIN THE SINGLE
OMIC DOMAIN, PROTEOMICS FOR
EXAMPLE IN OUR COHORT OF 400
SOME ODD PATIENTS AT STANFORD
WITH GOOD SAMPLES ON STARTED TO
HAVE SOME OVERLAPPING PROTEOMIC
DATASETS ACROSS LIKE MULTIPLEX
IMMUNOASSAY, MASS SPECTROMETRY,
SOMA SCANS, SOME DIFFERENT
PLATFORMS, CONCERNED ABOUT LACK
OF CORRELATION ACROSS PLATFORMS.
MY ULTIMATE QUESTIONS FOR YOU,
WHAT DO WE DO IN A RARE DISEASE
WHERE WE DON'T HAVE TISSUE AT
THE DISEASE SITE, AND THEN, B,
DO WE NEED TO GET IT RIGHT,
WHAT'S THE GROUND TRUTH WITHIN A
SINGLE OMIC DOMAIN WITH
DIFFERENT PLATFORMS, BEFORE WE
GET TO INTEGRATED OMICS.
>>SO, I MEAN, OMICS IS NOT THE
ONLY WAY.
I DON'T KNOW, I KNOW NOTHING
ABOUT THE FIELD, BUT THERE ARE
IMAGING AND OTHER THOUGHTS BUT
BLOOD GIVES YOU A LOT.
I THINK BLOOD CAN GIVE YOU A
LOT.
SO I DON'T, YOU KNOW -- DON'T
GIVE UP YET.
>>THANK YOU.
>>THERE'S STILL MULTIOMICS THAT
USES GENETICS, IF YOU HAVE A
REALLY STRONG INSTRUMENT FOR THE
PROTEINS AND METABOLITES, SOME
OF THEM, PEOPLE ARE STUDYING HOW
WELL THEY TRANSLATE BETWEEN
TISSUES OUTSIDE OF THE ONE.
I THINK THAT THE INFORMATION IS
SLOWLY ACCUMULATING BUT IT'S A
SLOW PROCESS, SO MUCH IS GOING
ON.
IT'S GOING TO GET THERE.
WE LEARN MORE ABOUT TRANSITION
BETWEEN TISSUES AT LEAST FOR
SOME OF THESE COMPONENTS, LIKE
CAN WE USE SOMETHING FOR PROTEIN
AND BLOOD, IN LUNGS, I BELIEVE
WE'LL KNOW MORE IN THE FUTURE,
IN THE NEAR FUTURE.
WHAT WAS ANOTHER QUESTION?
>>DIFFERENT CLASS ONES.
>>THIS IS ANOTHER ISSUE THAT IS
ADDRESSED, FOR EXAMPLE
RESEARCHERS COLLECT THE DATA, ON
THE SAME INDIVIDUAL, SOMA SCAN,
USING OLINK, AND WE WILL KNOW
MORE IN THE FUTURE WHICH
PROTEINS WE CAN HARMONIZE
BETWEEN PLATFORMS AND WHICH WE
CANNOT.
AND MAYBE THERE'S SOME PLACES
STATISTICAL METHODOLOGY CAN HELP
US CALIBRATE BETWEEN PLATFORMS
AND MAYBE SOME PROTEINS WE
CANNOT CALIBRATE BETWEEN
PLATFORMS.
>>TWO ADDITIONAL COMMENTS.
I SPENT TIME THINKING ABOUT THE
PROTEOMIC DISAGREEMENTS BETWEEN
SOMA SCAN AND OLINK, AND A
COMPARISON USED GENETICS, TO TRY
TO FIGURE OUT WHICH WAS RIGHT.
AND IT CAN BE USEFUL THAT WAY.
I THINK OUR TAKEAWAY FROM THE
WORK WAS YOU DON'T WANT TO THROW
THE BABY OUT WITH THE BATH WATER
BECAUSE, YES, THERE MAY BE SOME
DISAGREEMENTS AND ACCURACY
ISSUES BUT THOSE CAN BE SOLVED
ON THE BACK END, AFFINITY
PLATFORMS, YOU MENTIONED SOMA
SCAN, THEY ARE BINDING
SOMETHING.
IF THEY ARE ASSOCIATED WITH
SOMETHING, YOU'RE DOUBTING
ACCURACY, NUMBER ONE, CHECK IT.
NUMBER TWO, THERE ARE WAYS TO GO
IN SAND FIGURE OUT WHAT REALLY
IT'S BINDING TO, IF YOU HAVE A
STRONG ASSOCIATION YOU CAN
FIGURE OUT ON THE BACK END.
AND IN TERMS OF THE SMALL
STUDIES, WHAT WE COULD DO,
WE'RE GETTING PRE AND POST BLOOD
THAT WE COULD SAMPLE DURING
EXERCISE INTERVENTION AND THAT
CAN START TO UNTANGLE SOME OF
THE THINGS MORE ORGAN SPECIFIC
EVEN IF YOU ONLY HAVE BLOOD.
THAT'S ANOTHER AMOVIE THAT WE'VE
USED IN THE PAST USING -- IN THE
CASE OF KIDNEYS, PRE AND POST
KIDNEY BLOOD SAMPLES AND
COMPARED THEM.
THERE ARE WAYS OF GETTING AROUND
THE SPECIFICITY ISSUE.
>>THANK YOU FOR ADDRESSING
THOSE CHALLENGING ISSUES.
THERE'S A RELATED COMMENT AND
QUESTION.
WOULD YOU LIKE TO SPEAK UP RIGHT
NOW?
>>CAN YOU HEAR ME?
>>YES.
>>SO, THIS RELATES TO SOME
TOPICS RAISED ABOUT
PATHOPHYSIOLOGY AND FINDINGS
FROM HYPOXIC MODELS, SOME WAS
DONE IN CELL CULTURES, REALLY
DOESN'T RECAPITULATE THE HUMAN
DISEASE AT ALL, WONDERING IF
ANYONE HAS THOUGHTS ABOUT HOW WE
CAN MODEL PULMONARY HYPERTENSION
SPECIFICALLY WITH OSA AND
MODELING AND JUST A SHORT
TRIBUTE TO TOMORROW'S TALK, FROM
MY OWN EXPERIENCE, EVEN IF IT'S
SEVERE, DOES NOT RESULT IN
CLINICALLY RELEVANT OR AT LEAST
RIGHT HEART HYPERTROPHY AND
HYPERTENSION IN A MOUSE MODEL,
SOMETHING I WOULD LIKE TO HEAR
THE PANEL'S THOUGHTS ABOUT.
>>ANDREW BRYANT IS ON, IF YOU
WANT TO RESPOND, YOU MIGHT BE
EQUIPPED.
>>YEAH, YEAH.
HOPEFULLY I'LL ADDRESS THESE
ISSUES TOMORROW MORNING, WHEN I
TALK ABOUT THE ANIMAL MODELING
OF DISEASE.
YOU BRING UP GOOD POINTS.
A LOT OF WHAT, YOU KNOW, WE
TALKED ABOUT TODAY ADDRESSES THE
ISSUE OF HYPOXIA OR MAYBE EVEN
SLEEP FRAGMENTATION OR BOTH.
BUT I THINK A REALLY GOOD POINT
THAT ANNA BROUGHT UP WAS NONE OF
THESE REALLY ADDRESSED CHANGES
IN PRESSURE, INTRATHORACIC
PRESSURE, BASICS OF PHYSIOLOGY
THAT GO ALONG WITH NORMAL
BREATHING, NEGATIVE PRESSURE,
PULMONARY EDEMA, WHATEVER
CONTRIBUTES TO THIS OVERALL
PHENOTYPE, THAT'S SOME OF THE
POINTS THAT I WAS GOING TO TRY
TO BRING UP TOMORROW.
THERE ARE PRETTY GOOD ANIMAL
MODELS, I BROUGHT UP ONE OF THEM
TO -- AS AN EXPERIMENT OF
NATURE, SO TO SPEAK, AND MY
COLLEAGUE SAID THERE'S NOTHING
NATURAL ABOUT THAT.
YOU KNOW, WITH ANIMAL HUSBANDRY
IF YOU HAVE A COLLEGE OF
VETERINARY MEDICINE
>>FRENCH BULLDOG, YEAH.
>>OLD STUDIES FROM
GROUP-RANDOMIZED BLUE JOURNAL,
YOU HAVE A BUILT-IN PATIENT
POPULATION IF YOU HAVE A
VETERINARY MEDICINE COLLEGE, AT
LEAST FOR BIOBANKING, ALL
NATURAL DEATH, NO ONE IS GOING
TO DONATE THEIR PET, BUT THERE'S
A LOT OF THOSE THINGS TO
DISCUSS.
YEAH, IT'S COMPLICATED.
I AGREE.
PART OF THE PROBLEM IS WITH
INTERMITTENT HYPOXIA THAT CAN --
IF YOU GET TEN SCIENTISTS
TOGETHER THAT MEANS TEN
DIFFERENT THINGS.
BUT YEAH, TOMORROW, 10:45 I
THINK.
>>YES, THANK YOU.
WE'RE LOOKING FORWARD TO THAT.
DR. HILL HAD HIS HAND UP.
>>YES, I DID.
I HAD A QUESTION FOR NURESH.
I REALLY ENJOYED YOUR TALK.
BUT MY QUESTION HAS TO DO WITH
SLEEP WITH AGING, AS IT BECOMES
MORE PERTINENT TO ME.
>>ME TOO.
>>THE EVIDENCE IS VERY CLEAR
THAT THERE ARE INCREASING
PROBLEMS WITH SLEEP DURING
AGING.
AND AS PEOPLE AGE THEY GET LESS
SLEEP.
THE QUESTION I HAVE IS, IT'S
COMMONLY STATED THAT PEOPLE
DON'T NEED AS MUCH SLEEP AS THEY
AGE, I'M WONDERING WHETHER THEY
ARE GETTING CONFUSED WITH WHAT
OLDER PEOPLE ARE ACTUALLY
GETTING AS THEY AGE AS OPPOSED
TO WHAT THEY TRULY NEED, AND CAN
YOU COMMENT ON THAT?
>>YEAH, I'M SURE THE OTHERS ON
THE CALL CAN DO A BETTER JOB BUT
I'LL TAKE A STAB.
I THINK THE ISSUE OF NEED SLEEP
PERHAPS A MYTH, STANDPOINT OF
OLDER INDIVIDUALS NEEDING LESS.
I THINK SLEEP IS CLEARLY
DISRUPTED, YOU AND I ARE FEELING
IT, WE'VE GOT A LOT OF GRAY
HAIR, FEELING THE DISRUPTION IN
MY OWN SLEEP.
I THINK, YEAH, LOOK, I DON'T
KNOW HOW TO ANSWER THAT BUT
MAYBE SAY THE NEED FOR SLEEP IS
NOT GOING TO DECREASE.
I THINK THEY HAVE POOR QUALITY
SLEEP FOR A VARIETY OF REASONS,
FUNDAMENTALLY RELATED TO AGE
AFFECTED CELLS OR COMORBIDITY
THAT COMES ALONG WITH THE AGING
PROCESS.
SO, YEAH, VERY RELEVANT.
IF SLEEP QUALITY DETERIORATES,
IF DAN IS ON HE CAN CHIME IN
BETTER THAN I CAN, IF SLEEP
QUALITY DETERIORATES AND SLEEP
IS IMPORTANT FOR BIOLOGICAL
PROCESSES WHICH WE THINK IT IS,
COGNITION, WE'VE GOT AN ANIMAL
MODEL THAT WE LOOKED AT SLEEP
AND MUSCLE FUNCTION, AND IF WE
DISRUPT AS C57 SLEEP IT ACTUALLY
HAS IMPAIRED MUSCULAR ACTIVITY.
IT CAN'T DO MANY OF THE THINGS
IT USED TO DO.
SO, CLEARLY THERE ARE AFFECTS OF
QUALITY OF SLEEP.
WIFE BEEN INTERESTED IN ICU,
MODELED IN THE ANIMAL MODEL,
EFFECT OF SLEEP ON MUSCLE
FUNCTION, SO AGE EFFECTS OF
SLEEP CLEARLY IMPORTANT BUT I
DON'T THINK THE NEED FOR SLEEP
DECREASES.
I'D LOVE TO HEAR THOUGHTS ON
THAT COMMENT.
>>I MAY CHIME IN BRIEFLY.
I THINK SLEEP NEED IS ATTRACTIVE
CONCEPT THAT'S VERY HARD TO
ACTUALLY DEFINE AND DETERMINE.
IF YOU KIND OF FLIP IT ON ITS
HEAD, I THINK THAT IT'S SAFE TO
SAY THAT NO MATTER WHAT THE AGE
OF THE PERSON WHEN YOU -- IF
SLEEP IS DISRUPTED IN SOME WAY,
EXPERIMENTALLY, YOU'LL SEE WORSE
FUNCTION OF ALL SORTS EMANATING
FROM THAT.
CONVERSELY WHEN YOU IMPROVE OR
MAXIMIZE THE QUALITY OF SLEEP,
YOU'LL SEE IMPROVED FUNCTION BUT
IN TERMS OF LIKE DEFINING
ABSOLUTE LEVEL, THAT'S VERY,
VERY CHALLENGING.
I GUESS MAYBE THE BEST THING TO
THINK ABOUT IS IF YOU JUST GET
VERY REDUCTIONISTIC ABOUT IT AND
LOOK AT WHAT SLEEP DURATION
SEEMS TO BE ASSOCIATED WITH THE
LEAST AMOUNT OF MORBIDITY, IT
SEEMS TO BE A LITTLE BIT LOWER
IN OLDER PEOPLE BUT, AGAIN, IT'S
A VERY UNSATISFYING WAY OF
ANSWERING THE QUESTION BECAUSE
IF OLDER ADULTS ARE CAPABLE OF
GETTING LESS SLEEP THAT MAY
EXPLAIN WHY THE CURVE SHIFTS A
LITTLE BIT.
ANYWAY, VERY CHALLENGING BUT
GOOD QUESTION.
>>I WANT TO ADD MAYBE WIDENING
OUR LENS ACROSS THE LIFE COURSE,
AND I THINK WHAT WE CAN SAY FOR
SURE INFANTS AND YOUNG CHILDREN
NEED MORE SLEEP.
WE ALL KNOW INFANT SLEEPING 12
HOURS, 10 HOURS, 9 HOURS, 8
HOURS, ADOLESCENTS NEED MORE
SLEEP THAN YOUNG ADULTS BUT AS
WE GET INTO AGING IT BECOMES
MUCH MORE COMPLICATED.
AND THEN I WANTED TO MENTION, I
DON'T THINK WE WENT INTO THIS,
THERE IS THIS UNKNOWN ABOUT THE
SO-CALLED LONG SLEEPERS, DAN
TALKED ABOUT THE PHENOTYPE OF
HIGH SLEEP PROPENSITY PEOPLE WHO
SLEEP LONG AND YET MAY STILL BE
TIRED.
AND THAT MAY -- THAT APPEARS TO
HAVE GENETIC MARKERS TO IT.
AND ALSO MAY BE A MARKER OF
ACCELERATED AGING, BIOLOGICAL
AGING, THOSE ARE COMPLICATED
QUESTIONS.
>>I'M STILL GETTING OLDER BUT I
APPRECIATE THE DISCUSSION.
>>IF YOU NEED HELP WITH SLEEP,
THERE ARE SLEEP DOCTORS YOU KNOW
VERY WELL THAT WILL HELP YOU
WITH YOUR SLEEP.
>>THEY ALREADY HAVE.
I'M ON CPAP.
>>DR. GOSS?
>>THIS QUESTION GOES BACK TO
SOME OF THE OMICS INTEGRATION
AND SUPPORT.
FORGIVE MY IGNORANCE IF THIS IS
WELL ESTABLISHED BECAUSE IT'S
NOT WHERE I SPEND MY LIFE
THINKING ABOUT BUT TO WHAT
EXTENT DO WE HAVE MORE
STANDARDIZED TOOLS TO BE ABLE TO
INTEGRATE STUDIES?
YOU KNOW, SORT OF THE FAD THING
TO DO, EVERYBODY BIOBANKS, YOU
MAY RUN OMICS OR TWO, AND I
GUESS WHAT I WORRY ABOUT IS TO
THE EXTENT WHEN YOU COLLECT THE
BIOBANK IF YOU'RE NOT CAPTURING
KEY METRICS TO CHARACTERIZE YOUR
BIOBANK, THEN YOU RUN OF RISK OF
NOT HAVING A USEFUL LEADER OR
ASKING QUESTIONS THAT YOU'RE NOT
SET UP FULLY TO ANSWER SO ARE
THERE TOOLS AND IF NOT COULD THE
NIH HELP AND GUIDE THAT TO
CAPTURE PHENOTYPES OF PATIENTS
WE'RE ENROLLING, I WOULD ARGUE
FOR ANY GIVEN AGE POPULATION IF
THERE'S A DISEASE THAT AFFECTS A
CERTAIN PERCENTAGE OF THAT
POPULATION WE SHOULD KNOW YES OR
NO WHETHER THEY HAVE THAT
DISEASE OR THINGS LIKE THAT,
THAT I THINK COULD BE
STANDARDIZE
>>VERY COMPLEX ISSUE.
MY TWO CENTS REALLY THAT IT'S
VERY HARD AND THERE ARE STUDIES
LIKE THE U.K. BIOBANK WHERE IT'S
BASED ON A COMPILATION BUT IT IS
ALSO A STUDY AT THE SAME TIME,
SO COLLECT DATA FROM STANDARD
ELECTRONIC HEALTH RECORD BUT
ALSO DEPENDS UPON COMPREHENSIVE
STUDIES AND COHORT-LIKE MANNER.
I THINK "ALL OF US" MAY BE
TRYING TO DO THAT BUT NOT TO THE
SAME EXTENT.
I'M A PARTICIPANT IN "ALL OF
US."
I CAME FOR 30 MINUTES OR SO.
ANSWERED QUESTIONNAIRES IN A
COMPUTER.
MVP, VETERANS PROGRAM ALSO BASED
ON ELECTRONIC HEALTH RECORD, AND
DO YOU HAVE DIFFERENT SETS,
ELECTRONIC HEALTH RECORD
SYSTEMS, I DON'T KNOW WHAT IS
THE EXTENT TO POSSIBILITY OF
HARMONIZING ACROSS THEM, THAT'S
BEYOND MY LEVEL.
ALSO I HAVE SOME EXPERIENCE
WHERE WE HAVE MANY STUDIES THAT
CONTRIBUTED TO THIS DATA, AND
SOMETIMES WE STILL EVEN THOUGH
WE HAVE AGGREGATE GENETIC DATA,
WHEN WE DO OMICS ANALYSIS, WE
OFTEN DO IT SEPARATELY IN EACH
STUDY.
SO THERE'S LIMITATION TO HOW
MUCH WE COMBINE, IT'S KNOWSLY
-- NECESSARILY BAD, AND
AGGREGATE LATER, VIA
META-ANALYSIS OR OTHER WAYS.
I THINK THIS GIVES SOME ANSWER.
IT'S NOT PERFECT.
I THINK IT'S A CHALLENGE WE'LL
HAVE TO LIVE WITH.
>>I AGREE THAT THE DATA
INTEGRATION CAN BE LARD FROM --
HARD FROM A BATCH EFFECT ISSUE,
HAVING TO META ANALYZE IS THE
NAME OF THE GAME, YOU CAN'T
ACROSS RAW BATCHES BUT IT'S AN
INTERESTING POINT ABOUT
STANDARDIZING BIOBANKING
APPROACHES, I'M NOT AWARE OF
THOSE BUT THAT WOULD BE QUITE
USEFUL.
>>THE WHOLE NOTION OF DOING
MUCH MORE COORDINATED GLOBAL
WORK AND I DON'T KNOW IF MAYBE
WELLCOME TRUST AND OTHERS.
WE HAVE A FEW MINUTES.
I WANT TO GO BACK TO AN ISSUE
DR. PUNJABI BROUGHT UP, NOTING
CONTROVERSIES OF EVEN I THINK
THE BROADER CONTROVERSY, EVEN
USING THE TERM RACIST ETHNICITY,
AND REALLY THE -- YOU KNOW, I
GUESS THE BOTTOM LINE IS I THINK
WE'RE ALL EDUCATED NOW THAT IN
GENERAL IN OUR EPI WORK WHEN WE
USE RACE/ETHNICITY IT'S A PROXY
FOR SOCIAL DETERMINANTS OF
HEALTH AND EXPERIENCES OF
DISCRIMINATION, STRUCTURAL
RACISM.
SOMETIMES THERE'S ATTEMPT TO GET
AT ANCESTRY AND GENETIC VARIANTS
BUT I THINK I WOULD LIKE US
MAYBE TO THINK ABOUT MAYBE WE'LL
BRING IT UP MORE TOMORROW IS
SOMETHING WE DID NOT DISCUSS
EXPLICITLY ABOUT THE LIFESPAN
AND SLEEP DISORDERS AND
PULMONARY HYPERTENSION MIGHT
AGGREGATE, SOME MAY BE RELATED
TO SOCIAL DETERMINANTS OF HEALTH
LIKE AIR POLLUTION, PM2.5
LEVELS, TOBACCO SMOKING.
AND I HAVE TO SAY THAT I'M --
EVEN SLEEP APNEA WHICH WE'VE
THOUGHT OF AS A DISORDER
ASSOCIATED ANATOMIC FEATURES AND
OBESITY, ET CETERA, I'VE BECOME
INCREASINGLY INTERESTED IN HOW
PRO-INFLAMMATORY EXPOSURES TO
POLLUTION, INDOORS AND OUTDOORS,
MAY IN FACT BE A CONTRIBUTOR
ESPECIALLY IN CHILDREN.
SO I DON'T KNOW IF ANY -- WE
HAVE JUST A COUPLE MINUTES, IN
ANYONE WOULD LIKE TO EVEN SAY
THE POTENTIAL -- THE RELEVANCE
AM SOME EXPOSURES LINKING SLEEP
DISORDERS TO PULMONARY
HYPERTENSION AND THE ROLE OF
SUCH EXPOSURES IN THE VARIOUS
PULMONARY HYPERTENSION GROUPS.
>>I'LL TAKE A SHOT, I'M OPEN TO
COMMENTS FROM COLLEAGUES.
WE KNOW VERY LITTLE ABOUT
PULMONARY HYPERTENSION, AT THE
EXTREMES OF AGE.
I'M GOING TO RESTRICT COMMENTS
TO OLDER POPULATION BECAUSE OF
EXPOSURE QUESTION.
AND WE GENERALLY EXCLUDE FROM
STUDIES OF PHENOTYPING PATIENTS
OLDER THAN 70 OR 80.
PEOPLE DIDN'T BELIEVE YOU COULD
GET PULMONARY ARTERIAL
HYPERTENSION AT OLDER
TIMEFRAMES.
BUT I THINK WE'RE NOW BEGINNING
TO APPRECIATE THERE IS PULMONARY
HYPERTENSION, WHAT KIND OF GROUP
IT IS, WE DON'T REALLY KNOW,
PEOPLE WHO ARE OLDER THAN
TRADITIONAL MEAN AGE OF PH, LIKE
51.
SO I WOULD HYPOTHESIZE THAT MOST
OF THE PULMONARY HYPERTENSION IN
PEOPLE WHO ARE, SAY, 75 TO 85,
95, IS NOT GROUP 1, PROBABLY
GROUP 2 AND GROUP 3, MIX OF
BOTH.
WE HAVE SEEN SOMEBODY, SOME
FOLKS WHO HAVE CHRONIC
THROMBOEMBOLIC HYPERTENSION AT
THAT RANGE, INTERESTING TO THINK
HOW EXPOSURES MAY CREATE RISK
FOR PULMONARY HYPERTENSION AND
SLEEP DISORDER BREATHING AND MAY
ENERGY SIZE, I DON'T KNOW WHAT
OTHER PEOPLE THINK.
>>SO, I MEAN, IT IS AN
INTERESTING POINT AND I'M GOING
TO TALK ABOUT THIS TOMORROW.
BUT ONE OF THE THINGS WE DID DO
IS WE DID NOT PUT AN AGE LIMIT
ON WHO WE ENROLLED.
I THINK WE DO HAVE SOME PEOPLE
WHO PEOPLE WHO ARE PURE
CAPILLARY GROUP 1 PH THAT DID
NOT HAVE OTHER COMORBIDITIES TO
PUT THEM IN OTHER GROUPS BUT I
WONDER IF THEY ARE
PHENOTYPICALLY DIFFERENT THAN
SOME OF THE OTHER PEOPLE, LIKE
YOU SAID, ANNA, THAT THEY DO
HAVE SOME EXPOSURES THAT WE
HAVEN'T FIGURED OUT YET THAT
MAKE THEM LOOK SIMILAR TO THE
TYPICAL YOUNGER EITHER HERITABLE
OR IDIOPATHIC PH WE SEE.
>>THANK YOU.
MAYBE AS WE WERE TALKING A LOT
ABOUT THE MULTIOMICS OF THOSE
OMIC EXPOSOMES, WE HAVE TO THINK
ABOUT THE ENVIRONMENTAL
EXPOSOMES TOO.
AND THOSE ARE ALSO POTENTIALLY
MODIFIABLE.
WE'RE ACTUALLY OUT OF TIME FOR
TODAY.
WE DO HAVE UNFORTUNATELY ONE
ONE OF OUR MORNING SPEAKERS IS
ILL.
THE GOOD NEWS EVERYONE GETS TO
SLEEP IN A LITTLE BIT AND WE'LL
BEGIN AT 10:20 TOMORROW SHARPLY.
I JUST WANT TO THANK EVERYONE
FOR A FANTASTIC DAY, VERY
STIMULATING, LOTS OF THINGS TO
NOODLE OVERNIGHT, LET OUR SLOW
WAVES PROCESS AND CONSOLIDATE
THE IMPORTANT THINGS THAT COME
UP WITH CREATIVE TID-BITS FOR
TOMORROW.
ANNA, WOULD YOU LIKE TO SAY
ANYTHING?
AND LEI?
>>THANK YOU.
IT'S BEEN A GREAT STIMULATING
DAY.
WE APPRECIATE IT.
IT'S A LONG TIME TO STARE AT
YOUR COMPUTER BUT NICE TO SHARE
THOUGHTS.
THANK YOU FOR PARTICIPATING IN A
STIMULATING DISCUSSION, LOOK
FORWARD TO SEEING YOU TOMORROW
AT 10:20.
>>THANK YOU.
LEI OR NIH, DID YOU WANT TO SAY
ANYTHING BEFORE WE WRAP UP?
>>YOU COVERED EVERYTHING.
JUST ONE TO MENTION THAT WE WILL
PROBABLY START AT 10:20
TOMORROW, SO I THINK BRITTANY OR
SUPPORT TEAM WILL SEND OUT
UPDATED INVITE LATER TODAY, SO
EVERYBODY CAN SLEEP ANOTHER 20
MINUTES FOR THE WEST COAST
FOLKS.
THIS IS A GREAT MEETING.
I LEARNED A LOT.
THANK YOU, EVERYONE.
WE'LL TALK TOMORROW.
BYE-BYE.
>>BYE.