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a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
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TODAY I'M HONORED TO INTRODUCE
OUR SPEAKER DR. VERONIQUE ROGER,
A SENIOR INVESTIGATOR AND BRANCH
CHIEF AT THE DIVISION OF
INTRAMURAL RESEARCH FOR NHLBI,
PROFESSOR OF MEDICINE AND
EPIDEMIOLOGY AT THE MAYO CLINIC
COLLEGE OF MEDICINE.
DR. ROGER EARNEDDED A MEDICAL
DEGREE FROM UNIVERSITY OF PARIS
SORBONNE SCHOOL OF MEDICINE,
MASTER'S AT THE UNIVERSITY OF
MINNESOTA, IN PUBLIC HEALTH.
AFTER TRAINING IN CARD RADIOLOGY
AT THE MAYO -- CARDIOLOGY AT
MAYO BECOME PROFESSOR OF
MEDICINE IN 2002 AND
EPIDEMIOLOGY IN 2006.
AT THE MAYO, DR. ROGER SERVED IN
VARIOUS LEADERSHIP POSITIONS
INCLUDING AS CHAIR OF THE
DEPARTMENT OF HEALTH SCIENCES
RESEARCH, AS A MEMBER OF THE
MAYO CLINIC'S BOARD OF
GOVERNORS, AND BOARD OF
TRUSTEES.
SHE JOINED NHLBI AS A SENIOR
INVESTIGATOR BRANCH CHIEF IN
2021, RESEARCH FOCUSING ON
EPIDEMIOLOGY OUTCOMES OF
CARDIOVASCULAR DISEASES, AND HAS
BEEN FUNDED BY THE NATIONAL
INSTITUTES OF HEALTH FOR MORE
THAN 20 YEARS.
HER LABORATORY OF HEART DISEASE
INVESTIGATES HEART FAILURE
PHENOTYPES, CRITICAL TO
CONTEMPORARY EPIDEMIOLOGY.
THE GROUP'S GOAL TO DETECT
MECHANISMS OF SYNDROME WITH
AGING AND DIVERSE POPULATIONS.
SHE'S AN INTERNATIONAL LEADER IN
CARDIOLOGY, CHAIR OF THE
EXECUTIVE COMMITTEE OF THE NHLBI
CORONARY ARTERY DISEASE IN YOUNG
ADULTS STUDY, AMERICAN HEART
ASSOCIATION SCIENTIFIC
PUBLISHING COMMITTEE STATISTICS
TASKS FOR, BOARD OF SCIENTIFIC
COUNSELOR COMMITTEE, REVIEWER
FORE20 JOURNALS INCLUDING NEW
ENGLAND JOURNAL OF MEDICINE,
LANCET, CIRCULATION, JAMA,
ABRIDGED MEDICAL JOURNAL.
DR. ROGER HAS RECEIVED NUMEROUS
SCIENTIFIC AND ACADEMIC AWARDS
IN HONOR INCLUDING RECOGNITION
AS DISTINGUISHED SCIENTIST OF
AMERICAN HEART ASSOCIATION MAYO
CLINIC INVESTIGATOR, ELECTED
MEMBER OF THE ASSOCIATION OF
AMERICAN PHYSICIANS.
INTERNATIONALLY RECOGNIZED
SUBJECT MATTER EXPERT IN CARDIAC
DISEASE EPIDEMIOLOGY, AUTHORED
OVER 400 ARTICLES AND BOOK
CHAPTERS, AND WORK CITED OVER
130,000 TIMES, H-INDEX OF 127.
NOW, PLEASE WELCOME OUR SPEAKER
DR. ROGER, FOR HER PRESENTATION,
HEART FAILURE IN POPULATIONS
FROM DESCRIPTIVE EPIDEMIOLOGY TO
MOLECULAR TAXONOMY.
>> THANK YOU, DR. BURKLOW, FOR
THIS REALLY OVERLY KIND
INTRODUCTION.
I'M THE ONE WHO IS HONORED TO
GIVE CLINICAL CENTER GRAND
ROUNDS AND LOOK FORWARD TO OUR
TIME TOGETHER FOCUSING ON
EPIDEMIOLOGY AND CLINICAL
CLASSIFICATION OF HEART FAILURE.
SO FIRST NO
FINANCIAL DISCLOSURE, NO
UNAPPROVED OR OFF-LABEL DRUG
STATEMENT.
OBJECTIVES FOR OUR TIME TOGETHER
TODAY IS TO DESCRIBE
EPIDEMIOLOGY OF HEART FAILURE
ACROSS POPULATIONS, RECOGNIZE
LIMITATIONS OF THE CURRENT
CLASSIFICATION, AND AT THE SAME
TIME RECOGNIZE OPPORTUNITIES OF
MOLECULAR METHODS TO PHENOTYPE
HEART FAILURE.
SO IT'S CUSTOMARY TO START WITH
A DEFINITION AND THE ONE THAT IS
MOST COMMONLY USED IS THE ONE
PUT FORTH BY THE AMERICAN
COLLEGE OF CARDIOLOGY, AMERICAN
HEART ASSOCIATION, IN THEIR
GUIDELINE FOR THE EVALUATION AND
MANAGEMENT OF CHRONIC HEART
FAILURE.
THOSE GUIDELINES, HEART FAILURE
IS A COMPLEX CLINICAL SYNDROME
THAT CAN RESULT FROM ANY STRUCK
THY OR FUNCTIONAL CARDIAC
DISORDER THAT IMPAIRS THE
ABILITY OF VENTRICLE TO FILL
WITH OR EJECT BLOOD.
THERE'S A COUPLE POINTS TO
EXTRACT OUT OF THIS DEFINITION
THAT SERVES AS THE FOUNDATION OF
THE CONVERSATION THIS AFTERNOON.
THE ACKNOWLEDGMENT BY THE TWO
LEADING PROFESSIONAL SOCIETY AND
CARDIOLOGY WORLD OF THE
SYNDROMIC NATURE OF HEART
FAILURE, IT'S NOT A DISEASE,
IT'S A COLLECTION OF DISEASES OR
A SYNDROME AND IT'S IMPORTANT TO
KEEP THIS IN MIND AS WE TALK
THROUGH THIS.
THE SECOND PIECE IS THAT IT
ACKNOWLEDGES THE COMPLEXITY OF
THE HEART FAILURE SYNDROME WHICH
AGAIN WE'LL DIVE DEEPER INTO
THROUGHOUT THE TALK.
FINALLY THIS DEFINITION HAS BEEN
INSERTED VERBATIM OVER THE PAST
20 YEARS OF THE LIFESPAN OF THE
GUIDELINES SINCE 2005, SO THIS
IS A BIT OF AN INDIRECT SIGN, IF
YOU WILL, THAT OUR APPREHENSION,
IF YOU WILL, HASN'T EVOLVED MUCH
OVER THE PAST TWO SEC DECADES.
THE INTENSE INTEREST ON HEART
FAILURE AT LEAST IN THE
EPIDEMIOLOGY COMMUNITY STEMS
FROM A PIECE WRITTEN IN 1997, AT
THE TIME DR. BRAUNWALD ANNOUNCED
THESE TWO, HEART FATURE AND
ATRIAL FIBRILLATION.
HE WAS GROUNDING THIS
OBSERVATION GOOD HEART FAILURE,
ADMISSIONS CLIMBING STEADILY,
STILL IS THE MOST SINGLE
FREQUENT CAUSE OF
HOSPITALIZATION IN PERSONS 65
YEARS AND OLDER.
KEEPINGHOSPITAL ADMISSION AS THE
METRIC BY WHICH THE STATEMENT
WAS MADE WHAT DO HOSPITAL
ADMISSIONS LOOK LIKE IN THAT
TIME PERIOD?
AND THIS SLIDE IS PURPOSEFULLY
DATED REPRESENTING HOSPITAL
ADMISSIONS, DISCHARGE IN THIS
CASE, FOR HEART FAILURE BETWEEN
1979 AND 2005.
AND WHAT YOU CAN SEE IN THE
STATISTIC IS THAT INDEED THERE
HAS BEEN A STEADY CLIMB,
QUASI-EXPONENTIALAL, FOR WOMEN
IN BLUE, MEN IN RED.
WHEN YOU LOOK AT THIS CERTAINLY
IT RAISES THE QUESTION OF AN
EPIDEMIC.
HOWEVER, WE NEED TO REMEMBER
THAT THESE HOSPITAL DISCHARGES
ARE AT THE EPISODE LEVEL, NOT
THE PERSON LEVEL.
SO THAT A PATIENT WHO IS
HOSPITALIZED THREE TIMES IN TWO
YEARS, WHICH IS FREQUENTLY THE
CASE WITH HEART FAILURE, IS
COUNTED THREE TIMES, NOT ONE
TIME.
SO THIS PARTICULAR METRIC CANNOT
MEASURE THE INCIDENCE OF THE
DISEASE.
FURTHERMORE IT'S NOT VALIDATED.
IT'S DERIVED FROM HOSPITAL
CODING OF ADMISSIONS WHICH AS WE
KNOW HAS BEEN AMPLY
DEMONSTRATED, SHIFTED AS
REIMBURSEMENT PRACTICES EVOLVED.
THIS KIND OF DATA IS IN FACT AN
INTERESTING QUESTION, IT POSES A
QUESTION, HYPOTHESIS GENERATING,
NOT HYPOTHESIS TESTING, BUT IT
CHALLENGES EPIDEMIOLOGIST TO
INVESTIGATE THE EPIDEMIC OF
HEART FAILURE.
HOW WE'RE GOING TO GO ABOUT THAT
TO INVESTIGATE THE EPIDEMIC,
THAT'S EPIDEMIOLOGY 101, WE NEED
TO UNDERSTAND SOME KEY METRICS
THAT PERTAIN TO HEART FAILURE.
WE NEED TO BE ABLE TO MEASURE
INCIDENCE AND MORTALITY RATE.
THOSE RATES ARE MADE, INCLUDING
NUMERATOR AND DENOMINATOR, THE
PATIENT ADMITTED THREE TIMES
WILL BE COUNTED ONCE DURING THE
FIRST UP SIDE.
EPISODE.
WE NEED TO FIND CASES VALIDATE
BY RIGOROUS DIAGNOSIS, WE NEED
TO HAVE A DENOMINATOR, STUDY
DEFINED POPULATION THAT ENABLES
US TO CALCULATE THOSE RATES.
WHEN WE START THINKING ABOUT
CRITERIA, WHICH AGAIN ARE SIMPLE
CONCEPTUALLY, IT TURNS OUT THEY
ARE SELDOM MET.
THERE IS NO NATIONAL
CARDIOVASCULAR DISEASE
SURVEILLANCE AS OPPOSED TO
CANCER, FEW PROGRAMS CONDUCTED
SURVEILLANCE, RISK IN COMMUNITY
STUDIES, WORCESTER HEART ATTACK,
FRAMINGHAM AND ROCHESTER, ALL
FUNDED BY NHLBI EXTRAMURAL
GRANTS OR CONTRACTS.
WE KNOW WHAT TO DO, HOW DO WE GO
ABOUT IT?
WE NEED AGAIN TO GROUND OUR
INVESTIGATION INTO RIGOROUS
DIAGNOSTIC CRITERIA.
FOR THAT WE AND OTHERS HAVE USED
THE FRAMINGHAM CRITERIA
SUMMARIZED ON THIS SLIDE, WE
FIND POTENTIAL CASES AND WE
APPLY THESE CRITERIA TO
ASCERTAIN THE VALIDATED
DIAGNOSIS OF HEART FAILURE TO
THAT PARTICULAR CASE.
IF YOU LOOK AT THESE CRITERIA,
YOU CAN SEE THERE'S QUITE A FEW
OF THEM.
THEY ARE CATEGORIZED AS MAJOR OR
MINOR.
YOU CAN STILL IN MOST CASES
CLASSIFY THE CASES OF HEART
FAILURE.
THE OTHER IMPORTANT THING TO
UNDERSTAND BY LOOKING AT THE
CRITERIA, THEY ONLY INCLUDE ONE
IMAGE AING MODALITY, THE CHEST
X-RAY, PRESENT IN THE ENTIRE
TIME PERIOD FOR THIS WORK.
IT'S NOT DEPENDENT ON ANY OTHER
IMAGING TECHNIQUE, IN PARTICULAR
NO CARDIAC IMAGING OTHER THAN
THE SILHOUETTE IS PART OF THIS
ASSESSMENT.
LET'S START WORKING WITH THE
FRAMINGHAM CRITERIA.
WE'RE GOING TO START WITH THE
STUDY ITSELF.
THIS IS DAN LEVY'S PAPER,
LOOKING AT FOUR TIME PERIODS
1950 IN BLUE TO TURN OF THE
CENTURY IN PURPLE.
DIVIDING THE INCIDENCE RATES
MEASURED IN MORE RECENT TIME
PERIODS IN REFERENCE TO THE
EARLIER TIME PERIOD IN BLUE.
SO WHAT IS PLOTTED HERE IS THE
RATIO OF THE MORE RECENT
INCIDENCE RATES IN THESE TIME
PERIODS, COMPARED TO THE MOST --
THE OLDEST ONE.
WHAT YOU CAN SEE HERE SPEAKS FOR
ITSELF GRAPHICALLY, YOU CAN SEE
THAT IN MEN ON THE LEFT THE AGE
ADJUSTED INCIDENCE OF HEART
FAILURE HAS NOT CHANGED COMPARED
TO EARLIER TIME PERIOD.
AND IN WOMEN, THERE'S EVEN AN
INDICATION OF A DECLINE.
NOW, WHAT ABOUT ELSEWHERE?
THIS IS FRAMINGHAM.
WE DID THE EXACT SAME STUDY IN
OLMSTED COUNTY, APPLIED
FRAMINGHAM CRITERIA, STUDIED
ANALOGOUS TIME PERIODS.
IN THE SAME FORMAT YOU CAN SEE
AGAIN IN MEN ON THE LEFT AND IN
WOMEN ON THE RIGHT THERE HAS
BEEN NO CHANGE IN THE INCIDENCE
OF HEART FAILURE OVER TIME.
WHEN YOU JUXTAPOSE THESE TWO
STUDIES, YOU CAN CLEARLY SEE BY
LOOKING AT THIS WITH
EPIDEMIOLOGY METHODS, WE'RE
GETTING A VERY DIFFERENT PICTURE
THAN THE STEADY RAISE IN
ADMISSIONS FOR HEART FAILURE
THAT I SHOWED AT THE BEGINNING
IN THE VITAL STATISTICS.
WE'RE INTERESTED IN SEEING
WHETHER THIS TREND CONTINUES,
THE DATA I'VE SHOWN ARE OLD,
TURN OF THE CENTURY.
WE LOOKED AT THIS IN AN UPDATED
STUDY THROUGH 2010.
AND THIS WAS PUBLISHED BY MY
COLLEAGUE DR. GERBER IN JAMA OF
INTERNAL MEDICINE IN 2015.
YOU CAN SEE ON THIS SLIDE WE'RE
REPRESENTING INCIDENCE RATES
OVER TIME, MEN ON THE LEFT,
WOMEN ON THE LEFT, MEN ON THE
RIGHT, AND IF I COULD DRAW YOUR
ATTENTION TO THE TOP CURVE, IN
BLACK, YOU CAN SEE THE INCIDENCE
OF HEART FAILURE IN WOMEN IS
GOING DOWN, UP TO A NADIR OF
2007 WHERE IT FLATTENS, IN MEN
NADIR DELAYED TO 2008.
NO PICTURE OF A STEADY RISE IN
INCIDENCE OF HEART FAILURE IN
MOST RECENT YEARS.
IN THIS PARTICULAR STUDY WE HAD
INFORMATION ON THE EJECTION
FRACTION MARKED BY ECHO
CARDIOGRAPHY, I'LL GET BACK TO
THAT LATER.
WE'RE ALSO ABLE TO LOOK AT THE
INCIDENCE OF HEART FAILURE
ACCORDING TO THE EJECTION
FRACTION.
WHAT YOU CAN SEE IN THOSE
COLORED CURVES, TURQUOISE ONE,
AND ORANGE ONE, IS THAT THERE'S
ROUGHLY THE SAME NUMBER OF
PATIENTS GIVE OR TAKE A FEW WITH
PRESERVED AND REDUCED EJECTION
FRACTION, TRENDS ARE REASONABLY
PARALLEL TO ONE ANOTHER.
WHAT ABOUT IN DIFFERENT SETTINGS
AND COUNTRIES?
THIS IS A PAPER PUBLISHED IN
"LANCET" IN 2018 PERTAINING TO
U.K.
VERY LARGE COHORT, MUCH LARGER
THAN THAT WHAT DR. LEVY WORKED
WITH AT FRAMINGHAM AND US IN
OLMSTEAD COUNTY.
LET'S WALK THROUGH THIS AND
FOCUS ON PANEL A ON THE LEFT
PART OF THE SLIDE.
WHAT YOU CAN SEE HERE IS A
SERIES OF HORIZONTAL
REPRESENTING REPRESENTING
STANDARDIZED INCIDENCE OF HEART
FAILURE BY AGE SO THE VERTICAL
COLUMN IN THE MIDDLE REPRESENTS
AGE OF THE POPULATION FROM 15 TO
19 ALL THE WAY TO 90, HORIZONTAL
BARS REPRESENT INCIDENCE OF
HEART FAILURE IN TWO TIME
PERIODS, 2002 IN GRAY, AND 2014
IN BLUE.
WHAT YOU CAN SEE IF YOU JUST
LOOK AT THE SITE OF THESE BLUE
AND GRAY BARS, ON THE LEFT PART
OF THE SLIDE YOU CAN SEE THEY
ARE THE SAME.
WHICH WOULD TELL YOU THAT THE
INCIDENCE OF HEART FAILURE
HASN'T CHANGED DURING THOSE TWO
TIME PERIODS.
AND THAT'S WHAT THE AUTHORS
CONCLUDED.
NOW, WHAT WHAT DO WE MEAN BY
STANDARDIZED INCIDENCE?
CALCULATING TO ELIMINATE IMPACT
OF A CHANGING IN AGE OF
POPULATION TO LOOK AT WHAT'S
HAPPENING AS IF THE POPULATION
HAD NOT AGED.
BUT OF COURSE THE POPULATION OF
THE U.K. HAS AGED DURING THIS
TIME PERIOD.
SO THE INVESTIGATORS ALSO LOOKED
AT THE INCIDENCE WHICH THEY
CALLED THE CRUDE INCIDENCE
WITHOUT ELIMINATING EFFECT OF
AGE.
AND THAT'S ON THE RIGHT PART OF
THE SLIDE.
SO IF YOU LOOK ON THE RIGHT
PANEL, PANEL B, YOU CAN LOOK
AGAIN AT THE HEIGHT OR THE
LENGTH I SHOULD SAY OF THE
HORIZONTAL BARS AND YOU CAN SEE
THIS TIME THE BLUE BARS
REPRESENTING THE MOST RECENT
NUMBERS OF INCIDENT CASES OF
HEART FAILURE ARE QUITE A BIT
HIGHER, PARTICULARLY IN THE
VALLEY OF THAT SHAPE, IF YOU
WILL, THAN THEY WERE IN 2014
THAN IN 2010.
MEANING THAT WHEN YOU DO NOT
ELIMINATE THE EFFECT OF AGE, THE
INCIDENCE OF HEART FAILURE IS
INCREASING QUITE SIGNIFICANTLY
IN THE UNITED KINGDOM OVER THAT
TIME PERIOD.
WHAT ABOUT OUTCOMES?
WHAT HAPPENS ONCE THEY HAVE THE
DIAGNOSIS?
I'M JUST THAT POSING RESULTS IN
MINNESOTA AND THE PAPER.
LOOKING AT TWO KEY DETERMINANTS,
MORTALITY AND HOSPITALIZATION,
DIFFERENT DRIVERS BUT STILL THE
TWO KEY OUTCOMES WE LOOK AT.
STARTING WITH MORTALITY, YOU CAN
SEE IN OUR EXPERIENCE ON THE
LEFT PART OF THE SLIDE 54% OF
THE DEATHS DUE TO
NON-CARDIOVASCULAR CASES,
NON-CARDIOVASCULAR CAUSES.
WE HAVE A HEART DISEASE RELATED
SYNDROME, BUT YET MORE THAN HALF
OF THE PEOPLE DIE OF DEATHS NOT
ATTRIBUTED TO CARDIOVASCULAR
DISEASE.
AND THEY DIE A LOT.
AT THE END OF THE FIRST YEAR 20%
ARE DEAD, AT THE END OF FIVE
YEARS MORE THAN HALF ARE
DECEASED, WORSE THAN STICKS
STATISTICS FOR A LOT OF CANCERS,
IN THE LAST DECADE THERE'S BEEN
NO IMPROVEMENT.
IF YOU NOW LOOK AT MORTALITY IN
THE U.K. GOING TO THE RIGHT PART
OF THE SLIDE YOU CAN SEE THE
SAME MESSAGE, HALF OF THE DEATHS
ARE NON-CARDIOVASCULAR RELATED.
IMPROVEMENT HAS BEEN QUITE
MARGINAL, FROM 32 TO 29%, AND
RESULTS, ACTUAL NUMBERS FOR
MORTALITY IN THE TIME PERIODS
ARE COMMENSURATE IN THE U.K. TO
SOUTHEASTERN MINNESOTA.
AS FAR AS HOSPITALIZATIONS IT'S
VERY MUCH THE SAME MESSAGE, MOST
HOSPITALIZATIONS ARE RELATED TO
NON-CARDIOVASCULAR CAUSES, AMONG
PEOPLE LIVING WITH HEART
FAILURE, PARTICULARLY STRIKING
IN THE U.K., 73% ARE
NON-CARDIOVASCULAR RELATED.
HOSPITALIZATIONS HAVE NOT
CHANGED OVER TIME IN
SOUTHEASTERN MINNESOTA.
THEY HAVE INCREASED OVER TIME IN
THE UNITED KINGDOM.
THESE PEOPLE DIE.
WHILE THEY WERE ALIVE THEY ARE
IN THE HOSPITAL A LOT, QUALITY
OF LIFE IS SEVERELY IMPAIRED BY
HEART FAILURE.
THESE OUTCOMES HAVE NOT IMPROVED
OVER TIME AND THEY REMAIN GRIM
DESPITE MAJOR EFFORTS IN
IMPROVING THEM OVER THE TIME
PERIOD OF INTEREST IN THE TWO
STUDIES.
THINGS ARE NOT GOING WELL.
AND THEY ARE NOT FORECASTED TO
IMPROVE.
THE AMERICAN HEART ASSOCIATION
PUTS TOGETHER EVERY YEAR A
MASSIVE COMPENDIUM OF
STATISTICS, THIS IS THE MOST
RECENT VERSION THAT JUST CAME
OUT.
AND THEY APPLY SOPHISTICATED
MODELING, BASED ON CURRENT STATE
TO IDENTIFY FUTURE STATE, FOR
HEART FAILURE FORECASTING THAT
WE WILL GO FROM 6.7 MILLION
AMERICANS TO 8 MILLION IN 2030
LIVING WITH HEART FAILURE AND
POPULATION OF THE UNITED STATES
AS A WHOLE PERCENTAGE OF THOSE
LIVING WITH HEART FAILURE WILL
INCREASE FROM 2.4% OF POPULATION
TO 3%.
SO THESE ARE STAGGERING NUMBERS,
FORECASTING IS AS GRIM AS THE
CURRENT OUTCOME.
WHAT IS THE PICTURE OF THE HEART
FAILURE EPIDEMIC?
IT REFLECTS AS WE'VE SEEN AN
INCREASING PREVALENCE OF A
DISEASE IN AN AGING POPULATION.
WE COULD OFFER TO YOU THIS
GRAPHIC CARTOON OF THE PICTURE
OF HEART FAILURE EPIDEMIC,
REVOLVING DOOR OF RECURRENT
HOSPITALIZATIONS IN AN AGING
POPULATION.
THAT'S A COMPELLING PICTURE.
IT'S AN INCOMPLETE PICTURE.
LET'S TRY TO DRAW DOWN INTO
OTHER ASPECTS.
IN THIS COHORT OF 4 MILLION
INDIVIDUALS THEY HAD DATA,
ECONOMIC STATUS, ANALYZED BY
QUINTILES, REPRESENTED IN THIS
PLOT.
SO WHAT THEY WERE ABLE TO
DEMONSTRATE VERY ELOQUENTLY WHEN
YOU GO FROM THE LEAST DEPRIVED
PEOPLE AT THE BOTTOM OF THE SET
OF CURVES TO THE MOST DEPRIVED
PEOPLE AT THE TOP OF THE FAMILY
OF CURVES, YOU CAN SEE A GRADED
INCREASE IN THE INCIDENCE OF
HEART FAILURE IN THE POPULATION
OF THE U.K. WHICH TELLS YOU THAT
THE MORE SOCIOECONOMICKICALLY
DEPRIVED YOU ARE, THE MORE
LIKELY YOU ARE TO EXPERIENCE
HEART FAILURE, TO GET HEART
FAILURE AND HAVE TO LIVE WITH
HEART FAILURE.
THE SECOND POINT ON THIS PLOT,
YOU CAN SEE OVERALL THE CURVES
ARE PARALLEL, AND DESCRIBE
NICELY THE EXACT SAME PATTERN OF
THE INCIDENCE OF HEART FAILURE
WE OBSERVED IN OLMSTEAD COUNTY
WITH DECLINED FOLLOWED BY NADIR
IN 2006-2007 AND PLATEAU OR EVEN
ARGUABLY AN INCREASE.
THAT'S ONE ADDITIONAL FACET
WHICH IS CRITICALLY IMPORTANT,
THE ASSOCIATION WITH SOCIAL
DEPRIVATION AND HEART FAILURE.
SECOND FACET I WANT TO SHOW YOU
COMES FROM HERE, IN THE UNITED
STATES.
THESE ARE DATA FROM CDC WONDER,
FROM THE CENTERS FOR DISEASE
CONTROL, THAT REPRESENTS DEATH
RATE RELATED TO HEART FAIL, YOU
--
FAILURE IN THE UNITED STATES
STRATIFIED BY AGE, BY SEX, AND
BY RACE.
LET'S WALK THROUGH THIS DATA.
FIRST OF ALL LET'S TURN OUR
ATTENTION TO THE LEFT PANEL,
YOUNGER ADULTS BETWEEN AGE 35
AND 64, YOU CAN SEE HERE THAT
THE PLOT REALLY SPEAKS FOR
ITSELF, BY ILLUSTRATING PROFOUND
DISPARITIES IN DEATHS RELATED TO
HEART FAILURE BY RACE, BLACK MEN
IN BLUE AT THE TOP OF THE CURVE,
BY SEX -- BLACK WOMEN IN ORANGE,
RIGHT BELOW BLACK MEN, BUT ALSO
BY SEX WITH GREATER BURDEN OF
HEART FAILURE AMONG MEN, WITHIN
RACE.
AND WHAT IS IN ADDITION TO THESE
FINDINGS WHICH ARE QUITE
STRIKING, ADDITIONAL MAJOR
CONCERN IS THE FACT THESE
DISPARITIES ARE GETTING WORSE.
IF YOU FOCUS YOUR ATTENTION ON
THE BLACK MEN IN BLUE, AND WHITE
MEN IN GRAY, YOU LOOK AT THE
SEPARATION OF THE CURVES, YOU
CAN SEE IN MOST RECENT YEARS THE
SEPARATION IS INCREASING.
SO WE'RE ACTUALLY LOSING GROUND
IN A DISEASE THAT'S ALREADY
AFFECTED BY PROFOUND DISPARITIES
AND HAS VERY POOR OUTCOMES AS WE
KNOW.
WHEN WE GET TO THE OLDER ADULTS
ON THE RIGHT PART OF THE SLIDE,
65 TO 84, YOU CAN SEE
DIFFERENCES GET BLUNTED, BUT
MAJOR DISPARITIES STILL HAPPEN.
SO HEART FAILURE IS A DISEASE
CHARACTERIZED BY PROFOUND
DISPARITIES, RACE, ALSO TO SOME
EXTENT BY SEX, PARTICULARLY
PROMINENT AMONG YOUNGER ADULTS
AT THE PRIME OF THEIR LIVES.
SO WHEN WE THINK ABOUT STUDYING
HEART FAILURE EPIDEMIOLOGY AND
THINK ABOUT MOVING IN MOLECULR
FIELD IT'S IMPERATIVE TO INCLUDE
STUDY OF DIVERSE RACIAL AND
ETHNIC POPULATIONS.
WE CANNOT AIN ORDER NOT --
CANNOT AFFORD NOT TO DO IT OR
ELIMINATE THE POPULATION MOST
AFFECTED BY THE DISEASE UNDER
CONSIDERATION.
I WOULD ENCOURAGE YOU TO TURN TO
THIS BEAUTIFUL PIECE WRITTEN BY
OUR COLLEAGUES FROM NHLBI AND
COLLABORATORS, PUBLISHED IN
CIRCULATION RESEARCH IN 2019,
PROVIDES US WITH A CONCEPTUAL
FRAMEWORK TO STUDY
CARDIOVASCULAR DISEASE IN
CONTEMPORARY TIMES, CALLING FOR
STRATEGIES THAT DIRECTLY ADDRESS
DIVERSITY AND INCLUSION GOING
BEYOND RACE AND ETHNICITY TO
EXPLORE CONSTRUCTS INCLUDING
ANCESTRY MATCH ROLES, CULTURAL
AND ENVIRONMENTAL DETERMINANTS
OF HEALTH.
YOU MIGHT SAY, YEAH, THAT'S
GREAT BUT SOUNDS LIKE IT'S A
LOT.
I CANNOT BOIL THE OCEAN.
I WOULD SUBMIT TO YOU THAT WE DO
NOT HAVE A CHOICE BUT TO
INTERNALIZE THIS ROAD MAP
OPERATIONALIZING IT LITTLE BY
LITTLE BUT BY BEING COGNIZANT F
THE ENTIRE IMPACT.
THE NATIONAL INSTITUTE OF
MINORITY HEALTH HAS CREATED THAT
ROAD MAP, PUBLISHED ON THEIR
WEBSITE.
DR. PEREZ-STABLE AND TEAM HAVE
PROVIDED US WITH A GRID, WITH A
PARTITIONING OF LEVELS OF
INFLUENCE ON THE HORIZONTAL
AXIS, AND IN EACH OF THE BOXES
YOU CAN BEGIN TO ORGANIZE YOUR
THINKING ABOUT THE INTERSECTION
WITH LEVEL OF INFLUENCE AND
DOMAIN OF INFLUENCE.
FOR EXAMPLE, IF YOU'RE
INTERESTED IN LOOKING AT THE
INDIVIDUAL FOR A STUDY YOU'RE
DOING AND WANT TO LOOK AT THE
BIOLOGICAL COMPONENT YOU'LL
START THINKING ABOUT BIOLOGICAL
VULNERABILITY AND MOLECULAR
MECHANISMS.
SO YOU WILL BE COGNIZANT OF THE
FACT THERE ARE OTHER DIMENSIONS
THAT NEED TO BE CONSIDERED
PERHAPS NOT IN YOUR RESEARCH IF
YOU DON'T HAVE ALL THESE
DIMENSIONS THOUGH WE NEED TO
STRIVE TO COLLECT THEM, BUT
APPLIED TO HEART 235EU8URE THIS
IS THE WORK THAT SARAH, A
MEDICAL RESEARCH SCHOLAR
PROGRAM, SHE DID WHEN SHE WORKED
WITH US DURING HER FIRST YEAR,
CAME AND SAID I'M INTERESTED IN
HEALTH DISPARITIES AND
UNDERSTAND WHAT IT DOES WHEN
IT'S COUPLED WITH RURALITY AND
I'D LIKE TO APPLY NIMHD
FRAMEWORK.
LET'S BEGIN TO WORK, SARAH.
WHEN WE APPLIED THIS TO HEART
FAILURE WE STARTED TO THINK
ABOUT DOMAINS THAT ARE GOING TO
COME TO PLAY AND HOW CAN WE
BUCKET CONSTRUCTS IN EACH
CONCEPT SO WE CAN BEGIN TO
SYSTEMATIZE ANALYTICAL APPROACH,
YOU APPLY THE SAME REASONING TO
OUTCOME.
WE NEEDED TO FIND A COHORT IN
WHICH WE COULD CAPTURE MAYBE NOT
EVERYTHING HERE BUT A GOOD PART
OF IT.
SO FOR THAT WE TURNED TO THE
SOUTHERN COMMUNITY COHORT STUDY,
FUNDED BY NCI, ENROLLED VERY
LARGE NUMBER OF PARTICIPANTS,
MORE THAN 84,000, BETWEEN 2002
AND 2009, AND INCLUDED 12 STATES
IN THE SOUTHEASTERN UNITED
STATES, AND IN THIS COHORT WHICH
WAS AGAIN FUNDED BY NCI, THE
FOCUS WAS ON CANCER AND CHRONIC
DISEASES, AND THE COHORT WAS
TRULY UNIQUE, ITS AIMED BY
DESIGN AT PREFERENTIALLY
RECRUITING LOW INCOME
INDIVIDUALS WHO ARE RESOURCE
LIMITED, BLACK POPULATIONS AS
WELL.
IT'S QUITE DISTINCT POPULATION
COMPARED TO MAJORITY OF OTHER
COHORTS WHICH LACK ENROLLMENT OF
THESE PARTICULAR POPULATIONS OR
GROUPS OR SOCIAL GROUPS, THERE
BY PRECLUDING TO UNDERSTAND THE
OUTCOMES IN RELATIONSHIP TO
THESE EXPOSURES.
IN ORDER TO ASCERTAIN HEART
FAILURE WE NEEDED TO RELY ON CMS
MEDICARE LINKAGE, LANDING WITH
27,000 PEOPLE, A LITTLE OVER
20,000 INDIVIDUALS FREE OF HEART
FAILURE AT BASELINE WITH CMS
LINKED HEART FAILURE EVENTS IN
FOLLOW-UP WE COULD ANALYZE.
SO WHAT SARAH REPORTED IN THIS
PAPER IN JAMA CARDIOLOGY IN
JANUARY WHAT SHE REPORTED IS
COMPELLING POWERFUL RESULTS
DEMONSTRATING THE
INTERSECTIONALITY BETWEEN RACE,
BETWEEN SEX, AND BETWEEN
RURALITY.
IN EPIDEMIOLOGY JARGON WE TALK
ABOUT A THREE-WAY INTERACTION,
RESULTS ARE PRESENTED HERE.
WHAT SARAH FOUND IS THAT BLACK
MEN WHO LIVE IN RURAL AREAS HAVE
A 34% INCREASE OF INCIDENCE OF
HEART FAILURE COMPARED TO THEIR
FEMALE COUNTERPART AND WHITE
COUNTERPART.
THIS DEMONSTRATES WHEN IT COMES
TO INCIDENCE OF HEART FAILURE,
MEN AND WOMEN ARE NOT CREATED
EQUAL.
BLACK AND WHITE PERSONS ARE NOT
CREATED EQUAL.
AND RURAL AND URBAN RESIDENTS
ARE NOT CREATED EQUAL OR DIDN'T
HAVE EQUAL EXPERIENCE, THAT
WOULD BE MORE CORRECT.
SO THIS WAS AN IMPORTANT
FINDING, NOT ONLY BECAUSE WE'RE
ABLE TO STUDY A UNIQUE COHORT
BUT ALSO BECAUSE THIS COHORT HAD
A VERY RICH NUMBER OF OTHER
CO-VARIANTS ASCERTAINED IN THIS
DATA COLLECTION ENABLING US TO
MAKE SURE THAT WHEN WE FOUND
THIS LARGE INCIDENCE OF HEART
FAILURE IT WAS NOT REFLECTING
ANY OTHER CONFOUNDERS, ANY OTHER
CHARACTERISTICS TRAVELING WITH
HEART FAILURE, IF YOU WILL.
BECAUSE OF THE RICHNESS OF DATA
IN THE SOUTHERN COMMUNITY COHORT
STUDY SHE WAS ABLE TO ADJUST
INCLUDING FOR INCOME VARIABLES
THAT MAP OUT TO SOCIAL
DETERMINANTS, MARITAL STATUS AND
RACE AND ETHNICITY, AS WELL AS
PHYSICAL ACTIVITY AND SEDENTARY,
SELDOM CAPTURED IN COHORTS,
RESULTS ARE COMPELLING, SPEAK
FOR INDEPENDENT IMPACT OF
RURALITY AMONG BLACK MEN, AND
WHAT IS THE USE OF THIS?
WELL, CERTAINLY HAVING THIS DAA
AVAILABLE CAN HELP US DESIGN
INTERVENTIONS TO REDUCE BURDEN
OF HEART FAILURE IN THIS
POPULATION, BY SPECIFICALLY
TAILORING INTERVENTIONS AIMING
AT REDUCING THE BURDEN IN THE
POPULATION THAT EXPERIENCES THE
MOST, WHICH IS BLACK MEN.
ANOTHER FACET, MULTI-MORBIDITY.
A LOT HAS BEEN WRITTEN, THIS HAS
BEEN THE SUBJECT OF INTENSE
INTEREST, I WOULD SAY OVER THE
PAST DECADE.
I WANT TO WALK YOU THROUGH SOME
RESULTS TO HELP US UNDERSTAND
WHY THIS WILL INFORM OUR
MOLECULAR STUDIES WHEN WE GET TO
THEM.
HERE MY COLLEAGUE ALANNA
CHAMBERLAIN ENUMERATED
STRATIFIED BY SEX WITH MEN ON
THE LEFT, WOMEN ON THE RIGHT,
PRESENTED BY EJECTION FRACTION
GREATER THAN 50% IN DARK BARS,
IN YELLOW BARS REDUCED.
YOU CAN IGNORE THE EJECTION
FRACTION PIECE FOR NOW AND
EYEBALL THE BARS AND FROM THAT
EXERCISE A FEW IMMEDIATE
OBSERVATIONS THAT COME TO MIND.
FIRST OF ALL COMORBIDITIES ARE
EXCEEDINGLY PRESENT IN PEOPLE
WITH HEART FAILURE, WHEN WE
TOTALED ALL OF THEM WHAT WE
FOUND IS THAT 79 OR 80% OF
PERSONS WITH HEART FAILURE LIVED
WITH TWO OR THREE COMORBID
CONDITIONS, HEART FAILURE AND
TWO OR THREE OTHER THINGS THAT
TRAVELED WITH HEART FAILURE FOR
THEM.
WHAT WERE THESE THINGS?
THERE'S A LOT OF CARDIOVASCULAR
COMORBID CONDITIONS,
HYPERLIPIDEMIA, ET CETERA, NO
SURPRISE THERE, HEART FAILURE IS
END RESULT OF MULTIPLE
CONDITIONS, THEY STILL EXIST
ONCE PATIENT DEVELOPS HEART
FAILURE, WE KNOW HOW TO TREAT
THEM, NOT INTERFERING WITH
TREATMENT OR MANAGEMENT BUT ARE
HIGHLY PREVALENT.
CONTRAST THIS WHEN WE LOOK AT
THE CONDITIONS ON THE FAR RIGHT
OF THE TWO PANELS, WHICH INCLUDE
DEMENTIA, SUBSTANCE ABUSE,
SCHIZOPHRENIA AND OTHERS.
IF PATIENTS ARE LIVING WITH
DEMENTIA OR SUBSTANCE USE OR
SCHIZOPHRENIA THIS WILL ENTIRE
FEAR -- INTERFERE WITH THE
MANAGEMENT.
WE HAVE OTHER PHYSICAL
CONDITIONS FROM ARTHRITIS TO
DEPRESSION, KIDNEY DISEASE, A
LOT WITH QUITE PRESENT AND WILL
INTERFERE WITH VARYING DEGREE
WITH MANAGEMENT OF THESE
PATIENTS.
NOW, WHEN YOU SEE DATA LIKE
THIS, WHAT ELSE IS NEW?
THESE PEOPLE ARE OLD, MEAN AGE
76, THEY HAVE COMORBIDITY,
WHAT'S SO SPECIFIC ABOUT HEART
FAILURE?
YOU NEED CONTROLS, PEOPLE
MATCHED FOR AGE AND MATCHED FOR
SEX, BUT THAT DON'T HAVE HEART
FAILURE AND YOU NEED TO LOOK AT
THE PREVALENCE OF COMORBIDITY IN
THESE TWO GROUPS, THE CASES AND
CONTROL.
ALANA CHAMBERLAIN DID THIS IN
THIS PAPER, AND WE HAD 3,000
MATCHED CASES AND CONTROLS AND
LOOKED AGAIN AT THIS SORT OF
LIST OF COMORBIDITIES.
WHAT YOU CAN SEE IS THAT CASES
ARE THE SAME AS CONTROL, IF
THOSE ODDS RATIOS REPRESENTED BY
THE HORIZONTAL BARS CROSSED THE
VERTICAL LINE OF ONE.
YOU CAN SEE A LOT CROSS VERTICAL
LINE OF ONE, ARTHRITIS, YES,
PREVALENT BUT NOT MORE SO IN
CASINGS -- CASES THAN CONTROLS.
ASTHMA, CANCER IS LESS FREQUENT
THAN HYPERLIPIDEMIA.
TURN YOUR ATTENTION TO OTHER
CONDITIONS, ON THE OTHER SIDE OF
THE VERTICAL LINE OF ONE,
MEANING THAT HAVING HEART
FAILURE IS ASSOCIATED WITH A
GREATER ODDS OF HAVING THESE
COMORBID CONDITIONS.
AT THE TOP WE SEE HYPERTENSION,
KNEW IT WAS GOING TO BE
PREVALENT, WE UNDERSTAND WHY
BECAUSE IT'S PART OF THE CAUSAL
PATHWAY.
LET'S LOOK CLOSELY AT THESE.
CHRONIC KIDNEY DISEASE, WE'LL
GET BACK TO THAT WITH OUR
MOLECULAR STUDIES, MUCH MORE --
GREATER ODDS RATIO.
FOR DIABETES IT'S HIGH,
SUBSTANCE ABUSE, THAT POPULATION
PLAYING A KEY ROLE.
THE OTHER THING THAT THIS SLIDE
SHOWS IS CONCEPT WE CALL
ATTRIBUTABLE RISK IN
EPIDEMIOLOGY, AN APPEALING
CONCEPT, BECAUSE IT TELLS YOU
WHAT WOULD HAPPEN TO THE DISEASE
UNDER CONSIDERATION, HERE HEART
FAILURE, IF THE CONDITION THAT
WE'RE LOOKING AT WAS ELIMINATED.
AND SO FROM THIS WE CAN SEE THAT
IF CHRONIC KIDNEY DISEASE DID
NOT EXIST, BECAUSE THE RISK OF
HEART FAILURE FOR KIDNEY DISEASE
IS KEY PERCENT, IF CHRONIC
KIDNEY DISEASE WAS ELIMINATED WE
WOULD ELIMINATE 18% OF THE CASES
OF HEART FAILURE.
AND OF COURSE CORONARY DISEASE
IF WE ELIMINATED CORONARY
DISEASE ABOUT 30% OF CASES OF
HEART FAILURE WOULD BE LIMIT IN
AD.
THIS CONSTRUCT ALLOWS US TO IN
SOME CASES TARGET INTERVENTION
WHERE WE WOULD GET BIGGEST BANG
FOR THE BUCK IN TERMS OF
ATTRIBUTABLE RISK.
YOU CAN SEE EMERGE HEART FAILURE
AROUND SYSTEMIC ENTITY, THERE'S
ALSO IMPAIRMENT IN KIDNEY
FUNCTION, IMPAIRMENT IN LUNG
FUNCTION, COPD, CHRONIC KIDNEY
DISEASE, AND SO IN SOME CASES
IMPAIRMENT IN SKELETAL MUSCLE
FUNCTION, THAT MAPS OUT TO
CONCEPT OF FRAILTY WHICH I WON'T
HAVE TIME TO TALK ABOUT BUT
HIGHLY PREVALENT IN HEART
FAILURE.
KEEP IN MIND IT IS A SYSTEMIC
CONDITION AS WE GO IT THROUGH
THE REST OF THE TALK.
DOES IT MATTER?
DO COMORBID CONDITIONS PLAY A
ROLE IN OUTCOME OF HEART
FAILURE?
OF COURSE, A SIGNIFICANT ROLE.
IN THIS OTHER PEOPLE A COLLEAGUE
AT MAYO LOOKED AT, LOOKING AT
CONDITIONS CLASSIFIED AS I'VE
SEASON IN CARDIOVASCULAR OTHER
PHYSICAL AND MENTAL WHICH IS THE
NEUROCOGNITIVE ENTITIES
LOOKING AT TWO OUTCOMES,
CARDIOVASCULAR CONDITIONS DON'T
PLAY A ROLE OR HARDLY ANY LOCAL.
WHEREAS IT'S VERY DIFFERENT FOR
MENTAL CONDITIONS OR
NEUROCOGNITIVE CONDITIONS, 30%
INCREASE IN RISK OF DEATH, AND
FOR OTHER PHYSICAL CONDITIONS
WITH 26% INCREASE IN RISK OF
HOSPITALIZATIONS.
SO COMORBID CONDITIONS ARE
PREVALENT, NOT ONLY CAUSAL, AS
BEST WE CAN TELL FOR A LOT OF
PROPORTION OF HEART FAILURE
CASES, BUT ALSO ASSOCIATED WITH
VERY ADVERSE OUTCOMES.
NOW HEART FAILURE IN THE CLINIC,
LET'S LOOK AT HOW IT IS
CURRENTLY CLASSIFIED.
THIS IS EXCERPT OF 2020
GUIDELINES, AMERICAN HEART
ASSOCIATION GUIDELINES, ALSO
ENDORSED BY HEART FAILURE
SOCIETY OF AMERICA THAT PROPOSE
TO THE CLINICIANS, TO US,
CLASSIFICATION OF HEART FAILURE.
AND THESE ARE THE MOST RECENT
GUIDELINES, AUTHORITATIVE BODY
OF INDIVIDUALS, VERY AUGUST
PANEL OF EXPERTS.
WHEN WE SEE PATIENTS FIRST, THE
FIRST VISIT, WE NEED TO GET AN
IMAGING STUDY REPORTING ON THE
SQUEEZING FUNCTION OF THE HEART
MILLION, EJECTION FRACTION, OR
PERCENTAGE OF BLOOD EJECTED OUT
OF THE HEART AT EACH HEART BEAT,
NEVER 100%, NORMAL IS TYPICALLY
BETWEEN 50 AND SEVEN.
REDUCED, MID-RANGE, AND
PRESERVED GREATER OR EQUAL TO
50.
YOU SEE MRS. JONES TODAY, PUT
HER ON TREATMENT, ASK HER TO
COME BACK AND REEVALUATE HER,
AND REIMAGING DO A SECOND STUDY
AND ASSUMING THIS HAPPENS, THE
PATIENT COMES BACK AND GETS
SECOND IMAGING WE NEED TO GO
FROM THESE THREE CATEGORIES TO
NOW EIGHT CATEGORIES.
I WILL SPARE YOU FROM READING
ALL OF THESE CATEGORIES, BUT
SUFFICE TO SAY THAT THIS
RECLASSIFICATION EXERCISE IS
COMPLEX, AND CUMBERSOME,
REQUIRES THAT YOU WOULD GET THE
PATIENT TO COME BACK AND
OBVIOUSLY WOULD NEED A SECOND
IMAGING STUDY TO DO THAT.
SO BEFORE I MOVE ON TO THE NEXT
SLIDE I JUST WOULD LIKE TO ASK
ALL OF US HERE IN THIS
CONVERSATION TO HONESTLY ASK
OURSELVES TWO QUESTIONS.
FIRST, FOR THOSE WHO SEE
PATIENTS, WHICH IS MY CASE, I
ASK MYSELF HOW DO I USE THIS
EXACTLY IN MY PRACTICE?
HOW DO I MEMORIZE THIS?
AND HOW DO I APPLY IT?
AND FOR THOSE WHO DO CLINICAL
RESEARCH OR EPIDEMIOLOGY
STUDIES, LET'S ASK OURSELVES HOW
DO I USE THIS IN MY RESEARCH?
HOW DO I APPLY THESE VERY
DISTINCT AND DEFINITE THRESHOLDS
IN THE RESEARCH THAT I DO?
DOING SO WHILE BEING FAITHFUL TO
PROFESSIONAL GUIDELINES, IN THIS
PUBLICATION IN MARCH THE AUTHORS
PUBLISHED THE PROFESSIONAL
SOCIETY GUIDELINES ACROSS THE
CONTINENTS, IF YOU WILL, AND
ACROSS PROFESSIONAL SOCIETIES.
SO IF WE START AT THE BOTTOM WE
CAN SEE THE GUIDELINES I'VE
SHOWN YOU, AMERICAN COLLEGE OF
CARDIOLOGY, HEART ASSOCIATION,
CATEGORIES.
THIS DOES NOT INCLUDE
RECLASSIFICATION EXERCISE THAT
I'VE SHOWN BUT THIS IS ORIGINAL
ASSESSMENT WITH FOUR THRESHOLDS,
WITH GREEN, YELLOW, IN RED.
LET'S LOOK AT EUROPE, ACROSS THE
ATLANTIC OCEAN, EUROPEAN SOCIETY
GUIDELINES DON'T HAVE THE EXACT
SAME THRESHOLD.
IT'S NOT SO VERY DIFFERENT BUT
IT'S NOT THE SAME.
THAT'S THE NIGHTMARE OF THE
EPIDEMIOLOGIST, TWO CUT-POINTS
WE HAVE TO CONTEND WITH.
NOT TOO BAD ACROSS THOSE TWO.
BUT LET'S LOOK AT THE AMERICAN
SOCIETY OF ECHO CARDIOGRAPHY
WITH EUROPEAN SOCIETY OF IMAGING
AND YOU CAN SEE THE HEIGHT OF
THE RED BARS IS VERY DIFFERENT
THAN IN THESE TWO RED BARS, SAME
THING FOR THE YELLOW ONES, AND
GREEN ONES OF COURSE AS THE
REMAINDER, IF YOU WILL.
FINALLY THE BRITISH SOCIETY OF
ECHO CARDIOGRAPHY WITH OLD
GUIDELINES AND CAME UP WITH NEW
CUT-POINTS HAVE ALSO DIFFERENT
THRESHOLDS.
SO, THIS, IF YOU'RE THINKING
ABOUT EJECTION FRACTION AS A
RESEARCH TOOL, BECOMES
EPIDEMIOLOGIST NIGHTMARE BECAUSE
WE CAN REALLY AGREE THERE'S NO
AGREEMENT ACROSS PROFESSIONAL
SOCIETIES IN WHAT THRESHOLD TO
USE.
ANOTHER COMPONENT OF THE
EPIDEMIOLOGIST'S MIGHT NAIR --
NIGHTMARE IS THE VARIABILITY.
THE EARLY DAYS, DIDN'T GET
SPOKEN ABOUT BUT NOW SURFACING.
IF YOU LOOK AT LITERATURE ON
THIS TOPIC YOU'LL FIND A FAIR
AMOUNT OF DATA.
THIS WAS PUBLISHED IN JAM A,
MEASURING EJECTION FRACTION IN
PEOPLE WITH HEART FAILURE,
DEEMED CANDIDATES FOR
INTERVENTIONS BY DIFFERENT
METHODS, ECHO CARDIOGRAPHY MOST
COMMONLY USED, NUCLEAR METHODS
AND MRI.
IT'S NOT EVEN REFLECTING ROUTINE
CLINICAL PRACTICES, IT'S
REFLECTING PRISTINE PRACTICE,
SUBSTANTIAL VARIATION IN THE
ORDER OF 10%, BETWEEN MODALITIES
IN EJECTION FRACTION
DETERMINATION.
SO I'M ASKING YOU THEREFORE ARE
THESE EIGHT CATEGORIES
EXCRUCIATING CLASSIFICATION
RECOMMENDED BY GUIDELINES REALLY
REALISTIC WHEN YOU'RE DEALING
WITH INSTRUMENT MUCH LESS
PRECISE THAN THE CUT-POINTS
PRE-DETERMINED, I'LL LET YOU
ANSWER THAT QUESTION ON YOUR OWN
IN YOUR OWN CONSCIENCE, I GUESS
WHAT CAN WE SUMMARIZE?
WE HAVE MULTIPLE AMPLE EVIDENCE
OF COMPLEXITY AND HETEROGENEITY
OF THE HEART FAILURE SYNDROME,
INCIDENCE IS NOT A MAJOR DRIVER,
IT'S STAGNATING OR ARGUABLY
GOING UP.
OUTCOMES ARE POOR AND
STAGNATING.
AND DISPARITIES ARE LARGE AND
INCREASING.
THERE'S A HIGH PREVALENCE OF
COMORBID CONDITION WITH A
SUGGESTION OF A MULTI-SYSTEM
COMPONENT TO HEART FAILURE AND
FINALLY CURRENT TAXONOMY IS
IMPRECISE AND NOT MECHANISTIC
AND WE NEED TO DO BETTER.
CLASSIFICATION BASED ON
MECHANISM RATHER THAN OUTDATED
IMPRECISE MEASUREMENTS WILL HAVE
PROFOUND IMPLICATIONS FOR THE
MANAGEMENT AND COST AND
WELL-BEING OF THE PATIENTS
LIVING WITH HEART FAILURE.
AND AS A MATTER OF FACT 2022
GUIDELINES, THE WITH UNDERSTOOD
THAT CAME UP WITH THE
CLASSIFICATION ACKNOWLEDGE THAT
WE NEED TO MOVE FORWARD WITH THE
APPLICATION OF ADVANCED
PRECISION MEDICINE TECHNIQUES TO
IMPROVE TAXONOMY OF HEART
FAILURE.
FIRST, LET'S NOT LOOK FOR ONE
UNIFYING DISEASES, THERE WILL BE
SEVERAL, EJECTION FRACTION BASED
CLASSIFICATION IS LIMITED.
WE NEED TO HAVE IN MIND, TO
COMPARE RESULTS TO WHAT WE SEE
WITH EJECTION FRACTION BUT
SHOULD NOT GUIDE THE WAY WE
APPROACH THE STUDY OF THESE
PATIENTS AS THE PRIMARY AXIS, IF
YOU WILL.
WE NEED TO THINK ABOUT
MULTI-SYSTEM INVOLVEMENT AND
MULTI-MORBIDITY, WE'LL USE SOME
IDENTIFIED GROUPS OF PATIENTS
WHO PRESENT WITH HEART FAILURE
SUCH AS CORONARY DISEASE,
DIABETES, RENAL DISEASE, OBESITY
TO GUIDE US AND IT IS IMPERATIVE
TO STUDY AND ENGAGE DIVERSE
POPULATIONS.
SO, WHAT ARE THE OMICS?
I WON'T TALK ABOUT GENOMICS OR
TRANSCRIPTOMICS, WE'VE ELECTED
TO FOCUS ON PROTEOMICS AND
METABOLOMICS.
THE QUESTIONS WE SET OUT TO
ANSWERS WERE IN THIS VERY EARLY
PHASE CAN MOLECULAR PHENOTYPING
IDENTIFY DIFFERENT PRESENTATIONS
OF HEART FAILURE?
ARE MOLECULAR PHENOTYPES
ASSOCIATED WITH MORTALITY?
AND IMPORTANTLY FOR THE
CLINICIAN, DO THEY GIVE US
INCREMENTAL INFORMATION OVER
WHAT WE ALREADY KNOW?
SO TO DO THAT WE'VE BEGUN
STUDIES, EARLY STUDIES, PILOT
STUDIES, IN WHAT WE REFER TO AS
LEGACY COHORT WHICH IS A COHORT
OF 1388 COMMUNITY RESIDENTS FROM
SOUTHEASTERN MINNESOTA, USING
COHORT ASSEMBLED YEARS AGO,
VALIDATED HEART FAILURE USING
FRAMINGHAM CRITERIA, COMMUNITY
COHORT AS EXPECTED 75 YEARS OLD,
GIVE OR TAKE A FEW YEARS, HALF
ARE WOMEN, REFLECTING
DEMOGRAPHICS OF THE STATE OF
MINNESOTA, 92% WHITE ANCESTRY,
EQUALLY DISTRIBUTED.
WE HAD DATA ALLOWING TO
ASCERTAIN COMORBIDITIES AND WE
CARRIED DEATH AS ENDPOINT.
DID TWO MULTIOMIC, ONE USING
SOMA LOGIC AND SPECTROSCOPY,
WITH MACHINE LEARNING AND
CONVENTIONAL STATISTICAL
TECHNIQUES.
PROTEOMEICS ARE NOT NEW.
THIS IS A COVER EVER A NATURE
ISSUE, 2003, DEDICATED TO
PROTEOMICS, IT'S BEEN 20 YEARS.
WE NOW HAVE HIGH-THROUGHPUT
ASSAYS TO ALLOW US TO MEASURE
PROTEOMICS SIGNATURES AND GET
PROTEOMIC SIGNATURES IN LARGE
COHORTS WITH ALMOST 1400
PATIENTS.
WE USED THE SOMALOGIC ASSAY,
MEASURING IN EXCESS OF 7,000
PROTEINS, AFFINITY ASSAY BASED
ON TECHNIQUES THAT BINDS TO THE
TARGET PROTEINS AND THEN SORT
OF -- THIS AFFINITY IS USED TOO
MEASURE RELATIVE CONCENTRATION
IN THE ASSAYS, USED IN
NEUROLOGICAL AND RELATIONSHIPS
AND CARDIOVASCULAR DISEASES.
A POSTDOC WORKING IN THE LAB HAS
CONCENTRATED A LOT OF HIS WORK,
MAYBE ALL HIS WORK, ON
PROTEOMICS IN THE COMMUNITY
COHORT, LEGACY COHORT I
DESCRIBED, HERE THIS VOLCANO
PLOT REPRESENTS ASSOCIATION
BETWEEN THE 7,000 PROTEINS WITH
MORTALITY IN THIS COHORT.
AND BELOW THE DOTTED LINE IN THE
GRAY ARE ALL THE PROTEINS NOT
ASSOCIATED WITH MORTALITY.
WE STOPPED CONSIDERING THEM.
WHAT WE DID CONSIDER IN THE
ANALYSIS ARE THE 447 PROTEINS
THAT ARE ABOVE THE LINE, IN
BLUE, WHICH IS PROTECTIVE
AGAINST MORTALITY, NEGATIVE
ASSOCIATION PROTECTIVE AGAINST
DEATH OR IN RED POSITIVE,
MEANING EXCESS RISK OF DEATH.
WE LANDED WITH 447 PROTEINS THAT
CARRY ASSOCIATION WITH DEATH,
AFTER CORRECTION FOR MULTIPLE
COMPARISONS BECAUSE WE'RE
TESTING VERY LARGE NUMBER OF
HIGH POTENTIAL APPROACHES THESE
WITH 7,000 PROTEINS SO WE'VE GOT
TO ACCOUNT FOR THAT ANALYTICS.
ONCE WE HAVE 47 PROTEINS APPLIED
MACHINE LEARNING AND CLUSTERING
ANALYSIS TO SEE IF WE COULD
IDENTIFY SOME SIGNATURES OF
CLUSTERS, GROUPS IF YOU WILL, OF
THESE PROTEINS AND ASSOCIATION
WITH DEATH AND FOUND TWO
CLUSTERS THAT CARRIED A VERY
DIFFERENT MEANING WHEN IT CAME
TO THE SURVIVAL OR PROBABILITY
OF SURVIVING LONGER TIME PERIOD,
IF YOU WERE IN THE RED CLUSTER
ABOVE ON THE TOP CURVE YOU WERE
GOING TO SURVIVE MUCH, MUCH
LONGER, STILL BAD OUTCOME, MUCH
LONGER THAN THE PEOPLE IN THE
BLUE CLUSTERS WHO DIED MUCH
SOONER.
TO QUANTIFY THE RISK OF DEATH
ASSOCIATE WITH BLUE WE USEDs
HAS HAZARD RATIO.
IF WE TAKE INTO ACCOUNT ALL OF
THE OTHER CLINICAL FACTORS THAT
WE ALREADY KNEW, REMEMBER THAT'S
THE INCREMENTAL QUESTION WE
WANTED TO ASK, IT'S STILL ALMOST
TWO-FOLD INCREASE IN RISK OF
DEATH.
SO IT'S VERY LARGE INCREASE,
ASSOCIATED WITH PROTEOMIC
SIGNATURES, INDEPENDENT OF THE
EJECTION FRACTION.
INTERESTED IN KIDNEY DISEASE,
KIDNEY IS CRITICALLY IMPORTANT,
COMORBIDITY CARRIES THE RISK OF
ADVERSE OUTCOME.
THERE'S A PROTEOMIC SCORE THAT
THE COMPANY SOMALOGIC
IDENTIFIED, IDENTIFYING BEFORE
THE CLINTON CAT CREATININE OR
ESTIMATE OF GFR SCORE, LINEAR
RELATIONSHIP WITH INCREASING
RISK OF DEATH ASSOCIATED WITH
WORSENING PROTEOMIC SCORE
REFLECTING KIDNEY FUNCTION.
WHAT ABOUT THE METABOLOMICS?
AS WE'VE CONCEPTUALIZED,
INTUITIVE TO THINK METABOLOMIC
ENTITIES WILL MAP OUT TO ADVERSE
OUTCOMES, WE'RE FORTUNATE TO BE
ABLE TO COLLABORATE AND DO NMR
SPECTROSCOPY, MEASURING 25
METABOLITES, I DON'T HAVE TIME
TO DETAIL THIS BUT GIVE CREDIT
WHERE CREDIT IS DUE, TO FOUR
STUDIES LED BY FOUR INDIVIDUALS,
ON THE TOP LEFT DR. JOO, WE'RE
SO EXCEPTIONAL FORTUNATE TO WORK
WITH, IDENTIFIED SPECIFIC
METABOLOMIC SIGNATURES OF HEART
FAILURE ON TOP LEFT, REBECCA
OYETORO, ADVERSE ASSOCIATION
WITH KETONE BODIES AND SURVIVAL.
REBECCA DID THAT AND SHOWED
KETONE BODIES AS OPPOSED TO
POPULAR BELIEF IS BAD FOR YOU,
NOT AN INNOCENT BYSTANDER IN THE
SETTING OF HEART FAILURE.
KATIE CONERS, UPPER RIGHT, NICE
ASSOCIATION, GRADED ASSOCIATION
WITH MALNUTRITION INFLAMMATION
SCORE, OUTCOME OF HEART FAILURE.
AND SARAH TURECAMO, THE PROJECT
WE'RE WORKING AT FINISHING,
ASSOCIATION OF ANOTHER COMPOSITE
SCORE, LIPOPROTEIN RESISTANCE
INDEX AND SURVIVAL IN HEART
FAILURE.
IMPORTANTLY ALL ASSOCIATIONS,
PRELIMINARY DATA, WERE
INDEPENDENT OF THE EJECTION
FRACTION AND OF KEY CLINICAL
INDICATORS KNOWN TO CLINICIANS
OR SHOULD BE KNOWN TO CLINICIANS
WHEN THEY CARE FOR HEART
FAILURE.
WHAT CAN WE CONCLUDE AT THE END
OF THE PILOT STUDIES?
MOLECULAR PHENOTYPING CAN
IDENTIFY SIGNATURES AND PROVIDE
INFORMATION OVER CLINICAL
FACTORS.
WE HAVE A LOT LEFT TO DO,
STUDIED CLINICAL PHENOTYPES,
WORK ON THE WAY, AND IT'S
IMPERATIVE THAT WE STUDY
DIFFERENT POPULATIONS FOR THE
EXTERNAL VALIDATION, ALSO FIRST
AND FOREMOST TO STUDY DIVERSE
POPULATIONS.
I'LL TRY TO BE BRIEF WILL -- DU
MUST ACKNOWLEDGE THE TEAM AT THE
MAYO CLINIC, THEY HAVE BEEN
INSTRUMENTAL, THE ONES WHO DID
THE WORK I'VE SHARED WITH YOU
DONE OVER THERE.
AND IT WAS JUST AN INCREDIBLE
RIDE WORKING WITH ALL OF THEM.
WHAT IS EQUALLY INCREDIBLE IS
SINCE JOINING NHLBI I'VE BEEN SO
FORTUNATE TO BE ABLE TO BE
WORKING WITH THE TEAM THAT'S AT
THE BOTTOM RIGHT OF THE SLIDE,
SHOWN HERE.
YOU'VE SEEN THEIR WORK.
THEY HAVE ROLLED UP THEIR
SLEEVES PROMPTLY AS WE STARTED
WORKING TOGETHER, AND THEY ARE
JUST AMAZING TO WORK WITH.
EQUALLY AMAZING ARE
COLLABORATORS DR. JOO, THE MOST
AMAZING PARTNER THAT WE DO DREAM
OF, TIFFANY POWELL WILEY IS
THERE TO GUIDE US IN OUR WORKING
IN THAT DIRECTION.
ALAN REMALEY FOR METABOLOMICS
WORKS, AND FINALLY VANDERBILT
COLLABORATORS FOR THE COHORT
STUDY NOTHING SHORT OF
EXCEPTIONAL.
FINALLY I THANK ALL THE THE
PATIENTS WHO HAVE GIVEN SAMPLES,
INFORMATION, HAVE BEEN SUCH
MAJOR CONTRIBUTORS TO THIS WORK,
AND FINALLY, VERY FINALLY, THANK
ALL OF YOU FOR YOUR PATIENCE.
WE'VE COVERED A LOT OF TERRAIN,
AND I'M HAPPY TO ANSWER ANY
QUESTIONS IF TIME PERMITS.
THANK YOU.
>> DR. ROGER, THANK YOU VERY
MUCH FOR THIS EXCEPTIONAL
PRESENTATION.
OPENING OUR EYES TO EPIDEMIC OF
HEART FAILURE, AND ESPECIALLY TO
DISPARITIES THAT EXIST IN THE
GROUPS LIKE UNDERREPRESENTED
MINORITIES.
THERE'S A LOT OF CONFOUNDERS AND
COMORBIDITIES, BUT YOUR
SOPHISTICATED RESEARCH AND
PRESENTATION OPENED OUR EYES WHO
SORTING OUT RISK FACTORS AND
NEED TO ENGAGE WITH DIVERSE
GROUPS.
WE HAVE TIME FOR AT LEAST ONE
QUESTION.
SO I'LL START WITH THIS.
HOW DO YOU ACCOUNT FOR THE
SEVERITY OF EACH COMORBID
CONDITION SUCH AS DIABETES AND
THE EPIDEMIOLOGY STUDY?
OFTEN THE DISEASE LABELS INCLUDE
PATIENTS ACROSS A WIDE SPECTRUM
OF DISEASE SEVERITY SUCH AS
HEMOGLOBIN A1c OF 7 WITH
PROGNOSTIC IMPLICATIONS.
>> WE STRIVE TO ACCOUNT FOR
DIABETES OR SEVERITY OF CHRONIC
OBSTRUCTIVE PULMONARY DISEASE.
SOMETIMES IT'S NOT AVAILABLE,
AND IF IT'S NOT AVAILABLE THEN
WE HAVE TO ACKNOWLEDGE IT'S A
LIMITATION, SHOULD NOT STOP US
STUDYING DIABETES BECAUSE IF WE
CAPTURE SIGNAL IT'S GOING TO
HELP OTHERS DO MORE PRECISE
STUDIES.
WE DID A STUDY OF COPD AND RISK
OF HEART FAILURE, MAYO CLINIC
POPULATION, 40% DIDN'T HAVE
PULMONARY FUNCTION TEST.
WE'RE INTERESTED IN QUANTIFYING
SEVERITY BUT WE DIDN'T HAVE THE
TEST, HOPING PEOPLE WERE
INTERESTED IN INTERSECTION OF
HEART FAILURE AND RESPIRATORY
DISEASE WILL DO THE NEXT STUDY
WHICH WILL BE A BETTER STUDY.
>> THAT TAKES US UP TO THE HOUR.
THANKS FOR SHARE YOUR EXPERTISE.
THANK YOU FOR JOINING US.
WE'LL SEE EVERYONE NEXT WEEK.
THANK YOU VERY MUCH.
>> THANK YOU SO MUCH.