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OUR SPEAKERS TODAY, THREE
PEOPLE.
DR. SEAN AGBOR, THAT'S ME,
DR. ASHLEY PARK, AND DR. CONNOR
O'BRIEN.
I WILL START WITH AN
INTRODUCTION OF DR. CONNOR
O'BRIEN, JUST WITH KIND
PERMISSION, ONE MINUTE, PLEASE.
DR. CONNOR O'BRIEN IS A
COLLABORATOR OF OURS, WE'VE
COLLABORATED FOR A FEW YEARS
NOW.
BRILLIANT SCIENTIST.
HE'S A CRITICAL CARE TRAINED
CARDIOLOGIST, TRAINED CURRENTLY
AT THE UNIVERSITY OF CALIFORNIA
SAN FRANCISCO, WHERE HE HOLDS
THE POSITION OF ASSOCIATE
DIRECTOR OF THE CARDIAC ICU.
DR. O'BRIEN COMPLETED MEDICAL
SCHOOL IN COLOMBIA, FELLOWSHIP
STANFORD, AND NOW TOOK UP A JOB
AS ASSOCIATE DIRECTOR OF THE
CICU AT THE UNIVERSITY OF
SAN FRANCISCO, WHERE HE
CO-DIRECTS THE UNIT WITH CHRIS
BARNETT, WHO DID HIS TRAINING
HERE WITH US AS WELL.
RESEARCH-WISE, DR. O'BRIEN IS
ONE OF REALLY OUR NATION'S
LEADER IN CARDIOGENIC SHOCK.
HE WORKS ON BIOMARKERS IN
DESCRIBING PHYSIOLOGICAL CHANGES
THAT ARE CAUSED IN THESE
UNFORTUNATE PATIENTS WHO DEVELOP
CARDIOGENIC SHOCK.
OUTSIDE OF WORK, HE'S A
WONDERFUL HUSBAND, WONDERFUL
FRIEND, FATHER OF TWO GIRLS, AND
HE PLAYS RUGBY.
YOU DON'T WANT TO MEET HIM
THERE, I TELL YOU THAT.
SO HOPEFULLY WE'LL HEAR HIS TALK
AFTER THIS.
AFTER DR. O'BRIEN, I HAVE ALSO
THE REAL DISTINCT PRIVILEGE OF
INTRODUCING DR. ASHLEY PARK.
A FELLOW HERE WITH US IN THE
CRITICAL MEDICINE DEPARTMENT
HERE AT NHLBI.
I'VE KNOWN DR. PARK FOR ABOUT
TWO YEARS NOW, SHE DOES HER
RESEARCH IN THE LAB.
UNDERGRADUATE DEGREE AT
DARTMOUTH MEDICAL SCHOOL
PITTSBURGH, MED PEDS RESIDENCY
THE A GEORGETOWN, SHE ALSO
SERVED AS CHIEF RESIDENT AND
THEN JOINED OUR CRITICAL CARE
MEDICINE DEPARTMENT HERE AS A
FELLOW AND CURRENTLY DOES
RESEARCH IN THE LAB.
I WILL LET DR. PARK'S WORK IN
THE LAB SPEAK FOR ITSELF, AND
MAYBE IT THEN WILL BECOME QUITE
CLEAR WHY SHE'S SUCH A
REMARKABLE FELLOW, AND I'VE
JUST -- HAD MAJOR FELLOWSHIP
APPOINTMENTS AND MAJOR
UNIVERSITIES ACROSS THE NATION.
I'VE BEEN EXTREMELY FORTUNATE TO
BE HER MENTOR, RESEARCH MENTOR
DURING THIS TIME.
WITHOUT MUCH ADO, I WILL STOP
HERE AND I WILL PASS IT OVER TO
DR. O'BRIEN TO START -- TO GIVE
THE FIRST SET OF THE LECTURES.
THANK YOU.
[APPLAUSE]
>> IT'S A PLEASURE TO BE HERE.
THANK YOU VERY, VERY MUCH FOR
HAVING ME AND COLLABORATING WITH
THESE TWO HAS BEEN ABSOLUTELY A
PLEASURE.
LOOKING FORWARD TO MANY MORE
YEARS TO COME.
SO WITHOUT FURTHER ADO, WE'RE
GOING TO TALK ABOUT CARDIOGENIC
SHOCK AND WE'VE ENTITLED THIS
FIRE BEFORE THERE IS SMOKE, AND
IDEA BEING IT'S OUR CURRENT WAY
OF IDENTIFYING CARDIOGENIC SHOCK
IS TOO LATE.
AND WE'LL GO THROUGH THAT HERE
IN THE NEXT FEW SLIDES.
I HAVE A SINGLE DISCLOSURE,
WORKING FOR JOHNSON, JOHNSON MED
TECH AS A CONSULTANT.
SO WE'RE GOING TO START TALKING
ABOUT A CONTEMPORARY VIEW OF
CARD CARDIOGENIC SHOCK, WHAT ISH
RISK PHYSIOLOGY, AND THEN LOOK
AT THE LOGISTICAL CHALLENGES FOR
DELIVERING CARE THAT REALLY SET
THESE PATIENTS BACK, AND THEN
NOVEL TECHNIQUES FOR IDENTIFYING
THEM EARLIER TO GIVE US BETTER
OPPORTUNITIES TO RESPOND TO THIS
REALLY HIGH RISK DISEASE STATE.
SO BEFORE WE GO FORWARD TO
MODERN SCIENCE, IT'S HELP TOWEL
TO KNOW WHERE WE CAME FROM AND
UNDERSTAND THE PITFALLS THAT
HELD THE STUDY BACK OF
CARDIOGENIC SHOCK.
IN CARDIOLOGY WE HAVE TONS OF
DATA WHICH GIVES US LOTS OF
HISTORICAL CONTEXT AND WE CAN GO
ALL THE WAY BACK TO DESMOND
JULIAN IN THE 1960s WHEN THE
FIRST CCU WAS DEVELOPED.
THIS WAS DEVELOPED BY COHORTING
PATIENTS WHO ARE SUSPECTED TO
HAVE AN M.I. TOGETHER TO LOOK
FOR EARLY SIGNS OF V TV F AND
OFFERING EARLY DEFIBRILLATION.
THIS WAS OFFERED BY THOMAS
KILLUP, HIS CONTRIBUTION WAS TO
GET TRAINED NURSES TO
DEFIBRILLATE.
SO HE EXPANDED THE CARE TEAM,
THE IDEA THAT SORT OF TAKING
DOWR BARRIERS, IT DOESN'T NEED
TO BE A PHYSICIAN TO PUSH THIS
BUTTON.
WE NEED EARLY RECOGNITION.
IT'S BETDER BETTER TO DO THINGS,
LET'S MAKE THIS TEAM BIGGER AND
MORE COLLABORATIVE.
WE THEN MOVE FORWARD IN THE
PIPELINE WHERE WE START SEEING
COAGULATIONS COME OUT, LYTICS,
STENTS, AND THEN STENTS COME
WITH SOME STRUCTURAL CHANGES IN
RESPONSE NETWORKS AND EMS
NETWORKS THAT WERE DEVELOPED AND
WE GET TO THE MORTALITY IN ACS
WE ENJOY TODAY WHICH IS ABOUT
2 TO 4%.
OVERLYING THAT MORTALITY IS THE
MORTALITY OF CARDIOGENIC SHOCK.
AND AGAIN, THIS IS ALL FOR AMI,
SO WE'LL TALK A LITTLE MORE
ABOUT OTHER STATE IN A LITTLE
BIT.
BUT YOU CAN SEE THE MORTALITY IS
MUCH, MUCH HIGHER.
AND WHEN THERAPIES COME OUT
LIKELY TICKS, PCI, THERE IS SOME
MODEST IMPROVEMENT IN MORTALITY,
BUT AGAIN, VERY, VERY MODEST.
FOLLOWING THE LATE '90S, YOU SEE
A QUICK DROP AFTER THE SHOCK
TRIAL COMES OUT, A LOT HAD TO DO
CAN EMS CENTERS, WE'LL TALK
ABOUT THAT IN A LITTLE BIT.
NOVEL MCS DEVICES COME OUT IN
THE MID 2000s AND THERE'S
STILL A STAGNANT PERIOD.
TRIALS COME OUT AND WE'LL TALK
ABOUT THOSE IN A MINUTE.
LOOKING AT THIS WITH A LITTLE
MORE FIDELITY, LOOKING AT THE
DIFFERENT TYPES OF CARDIOGENIC
SHOCK, AGAIN YOU SEE THAT DROP
IN MORTALITY IN THE EARLY
2000s, FOLLOWED BY A PLATEAU,
WITH A LITTLE BIT OF A POSSIBLE
TREND TOWARDS IMPROVEMENT 2015
TO 2018, WHICH WE'LL TALK ABOUT
IN A FEW SLIDES.
BUT THERE'S REALLY BEEN A REALLY
STAGNANT PERIOD OVER THE LAST 20
YEARS IN WHICH SCIENCE HAS
EXPANDED, WE HAVE LOTS OF NEW
TOOLS, MEDICAL CARE IN GENERAL
HAS DRAMATICALLY IMPROVED ACROSS
A NUMBER OF CONDITIONS.
AND IN CARDIOLOGY, WE HAVE A
MILLION NEW TECHNOLOGIES, BUT
CARDIOGENIC SHOCK REALLY HAS NOT
BENEFITED EVEN THOUGH WE
THEORETICALLY CAN TREAT THE
UNDERLYING CONDITIONS THAT DRIVE
THIS STATE BETTER.
SO THINKING ABOUT UNDERSTANDING
WHY WE'RE NOT SEEING
IMPROVEMENTS, IT'S BETTER TO GO
BACK AND LOOK AT THE FAILURES OF
EACH TRIAL.
WE USE TO SUPPORT PATIENTS
THROUGH THE BUMPS IN THE ROAD
BUT WHEN YOU LOOK AT LONG TERM
USE, PATIENTS DO NOT LIVE LONGER
ON EYE ONOTROPES RELATIVE TO
PLACEBO.
IN YIF YOU LOOK AT THE DARK LINN
ISCHEMIC PATIENTS, IT MAY
ACCELERATE THEIR DEATH, SORT OF
INTUITIVELY LIMITED.
USING ROUTINE LINES IS SHOWN TO
NOT IMPROVE MORTALITY AS WELL,
ROUTINE USE, REALLY WANT TO
HIGHLIGHT THAT WORD, ROUTINE USE
OF BALLOON AND IMPELLA, NOT ABLE
TO IMPROVE MORTALITY, EMPRESS IN
2015.
MOVING FORWARD, ECLS SHOCK MADE
A SLASH BECAUSE EVERYBODY HAD
BEEN ASSUMING ECMO WOULD BE THE
HOLY GRAIL.
ECMO ROUTINE USE, AGAIN, DID NOT
IMPROVE MORTALITY IN AMI
CARDIOGENIC SHOCK.
I WOULD LIKE TO HIGHLIGHT THERE
IS THIS LITTLE GAP YOU CAN SEE
OUT TO DAY 14, WHERE THERE SEEMS
TO BE A LITTLE BIT OF
IMPROVEMENT IN SURVIVAL.
IN THIS COHORT, THE PATIENTS
DIED FROM REFRACTORY CARDIOGENIC
SHOCK.
SO IT'S REALLY IMPORTANT TO LOOK
AT THIS DATA AND SAY WE DEPLOYED
ECMO ON SOMEBODY WHO HAD A HEART
ATTACK WHO HAD TERRIBLE HEART
FAILURE, THEIR HEART NEVER GOT
BETTER.
THEN YOU START TO INTERPRET
ECMO, ECMO DID NOT MAKE THE
HEART BETTER.
YOU HOPE THAT REVASCULARIZATION
FOLLOWED BY GDMT OR TRANSPLANT
OR LVAD WOULD BE YOUR ULTIMATE
DESTINATION.
AND THOSE WEREN'T DEPLOYED WITH
FREQUENCY IN THIS TRIAL.
TRYING TO UNDERSTAND SOME OF THE
GAPS THAT THESE TRIALS ARE
LEAVING OUT THERE FOR TREATMENT
OPPORTUNITIES AND THINKING ABOUT
HOW OTHER DATA INFORMS OUR CARE.
DANGER SHOCK GAVE US A LITTLE
BIT OF LIGHT AT THE END OF
TRIAL, SHOWING MORTALITY BENEFIT
AT AMI SHOCK, THE CURVES
CONTINUE TO SEPARATE AT 180
DAYS, SUGGESTING THAT EARLY
INTERVENTIONS THAT OFFLOAD THE
HEART MAY PROMOTE SURVIVAL AND
MITIGATE END ORGAN INJURY THAT
CONTRIBUTES TO BAD OUTCOMES
LATER.
THERE ARE ALSO -- OR IN THIS
TRIAL, THE SUBTEXT IS IT TOOK 10
YEARS TO ENROLL.
AND THIS TRIAL FOCUSED ON A
VERY, VERY, VERY SMALL FRACTION
OF EVEN AMI SHOCK.
SO WHEN WE LOOKED AT -- LOOK IN
THE COHORT OF PATIENTS ABOUT
40,000 PATIENTS, I APOLOGIZE FOR
THE SMALL TEXT BUT WE STARTED
WITH 20,000 SHOCK ADMISSIONS.
AND WE ENDED UP SHOWING THAT
ONLY ABOUT 30% OF ALL STEMI
SHOCK AND ONLY 5% OF ALL
CARDIOGENIC SHOCK IN OUR COHORT
WOULD HAVE QUALIFIED FOR DANGER
SHOCK.
WHILE WE HAVE SOME DATA, THE
VAST MAJORITY OF OUR PATIENTS DO
NOT FALL UNDER THIS TRIAL.
THERE'S LOTS OF PITFALLS WHERE
IF WE START DEPLOYING INDIVIDUAL
TECHNOLOGY AND TESTING THEM,
WE'RE UNLIKELY TO DEMONSTRATE
BENEFIT.
SO IF WE REALLY WANT TO FIGURE
OUT HOW TO CHANGE OUTCOMES IN
CARDIOGENIC SHOCK I THINK YOU
HAVE TO GO BACK TO THE DRAWING
BOARD, REDIE FINE UNDERSTAND WHO
THESE PATIENTS ARE, WHO ARE WE
TREATING, HOW ARE WE TREATING
THEM AND WHAT ARE THE THINGS
THAT ARE SETTING THEM BACK.
SO SHOCK IS VERY MUCH AN
EVOLVING LANDSCAPE.
WE CAN SEE INCIDENCE OF SHOCK IS
GOING UP AND A LOT OF THAT HAS
TO DO WITH THE FACT THAT PEOPLE
ARE SURVIVING LONGER WITH HEART
DISEASE.
THIS POOL OF PATIENTS IS GETTING
LARGER.
THEY'RE GETTING OLDER.
AND WE'RE ALSO SEEING -- AND IT
HIGHLIGHTED BY THE FACT THAT
NON-AMI CARDIOGENIC SHOCK IS THE
FASTEST GROWING POPULATION HERE,
AS WE TREAT CORONARY DISEASE,
WE'RE MITIGATING HEART ATTACKS
AND WE'RE SEEING MORE CHRONIC
HEART DISEASE CONTRIBUTING TO
THE SHOCK POPULATION.
HERE IT'S DEMONSTRATING THAT AS
WELL.
YOU CAN XENON ISCHEMIC DISEASE
AND ALSO CHRONIC ISCHEMIA, NOT
ACUTE PLAQUE RUPTURE BUT CHRONIC
ISCHEMIA, VERY DIFFERENT BEAST,
IS A PRIMARY DRIVER OF
CARDIOGENIC SHOCK IN MODERN
COHORTS.
IN ADDITION TO THAT, LOOKING AT
MODERN CICU DATA, YOU CAN SEE
THAT IT'S NOT JUST PURE
CARDIOGENIC SHOCK THAT'S SHOWING
UP IN ICU.
SAY THESE PEOPLE ARE SHOWING UP
AND IT THEIR HEART THAT'S THE
PROBLEM FI THE HEART, THEY GO
OUT THE DOOR, IS MISREPRESENTING
THE ISSUE.
FIRST, THE HEART DISEASE IS VERY
DIVERSE.
YOU CAN SEE THERE ON THE
STATISTICS ON THE LEFT, ISOLATED
LV FAILURE IS LESS THAN 50% OF
THE COHORT.
PULMONARY HYPERTENSION LEADING
TO RV VAI YOU'RE IS TESTIMONY
ALMOST 10% IN MODERN COHORTS.
HEHEPPEF, TO SAY IS LV WORKING ,
ARE WE GOING TO TRIAGE THE
PERSON TO CARDIOLOGY OR AWAY,
YOU'RE GOING TO MISS 10 TO 20%
OF THESE PATIENT WHO HAVE LOW
STROKE VOLUME WHERE THEIR
PRIMARY PROBLEM IS ACTUALLY
STEMMING FROM THEIR HEART MOST
LIKELY.
IN ADDITION I'D LIKE TO DRAW
YOUR EYES HERE TO FIGURE A, AND
YOU CAN SEE PURE CARDIOGENIC
SHOCK IS ONLY TWO THIRDS OF THIS
POPULATION.
WITHIN THIS GROUP, MIXED SHOCK
AND DISTRIBUTIVE SHOCK WHICH IS
BOTH INFECTIOUS AND
NON-INFECTIOUS DISTRIBUTIVE
SHOCK IS A LARGE POOL AND THE
HIGHEST RISK PORTION OF THIS
COHORT.
IT'S A DIFFERENT PHYSIOLOGY.
SO MOVING FORWARD, WE CAN TALK
ABOUT HOW THESE PATIENTS ARE
GETTING OLDER, THEY'RE COMING IN
WITH CHRONIC DISEASE.
ONE THE OTHER THINGS THAT'S
UNIQUE IN CARDIOGENIC SHOCK
THAT'S VERY DIFFERENT FROM
SEPTIC SHOCK, MOST OF THE TIMES
WHEN PATIENTS HAVE SEPTIC SHOCK,
ONCE THEY GET SEPTIC, THEIR PEAK
DISEASE ASUPERVISING YOU HAVE
THE RIGHT DRUG AND RIGHT BUG IS
WITHIN 24 TO 48 HOURS.
PATIENTS WHO ARE ADMITTED WITH
CARDIOGENIC SHOCK, IF YOU LOOK
AT THE TOP LEFT HERE, THE
EARLIEST PHASES OF SHOCK BEING
B, LATEST BEING E, IF YOU LOOK
IN EACH OF THOSE CATEGORIES,
THAT IS THE PERCENTAGE OF
PATIENTS WHO ARE ADMITTED IN
THAT THAT SCAI STAGE WHO GOT SIR
DURING THEIR ADMISSION.
IF YOU GO TO THE TOP RIGHT, THAT
IS THE NUMBER OF HOURS IT TOOK
THEM TO GO FROM THAT BASELINE
STAGE TO A HIGHER SCAI SHOCK
STAGE.
YOU CAN SEE THE MAJORITY OF OUR
PATIENTS ARE GETTING SICKER
DESPITE MEDICAL ATTENTION, AND
IT'S HAPPENING VERY LATE IN
THEIR HOSPITAL PROCESS, WHICH IS
SUGGESTING WE HAVE PATIENTS WITH
CHRONIC DISEASE WHO ARE STARTING
TO FAIL TRADITIONAL TREATMENT
OPTIONS.
SO YOU'RE STARTING TO MOVE INTO
A REALLY COMPLICATED PHASE OF
DISEASE WHERE ALL OF THINGS YOU
WOULD REACH FOR THAT ARE
STANDARD AREN'T WORKING.
CARDIAC SURGERY, INTERVENTIONAL
DEVICES AND THINGS OF THAT
NATURE, WHEN YOU SEE PATIENTS
PROGRESS, THEY DIE WITH A VERY
HIGH FREQUENCY.
SO ON THE LEFT THERE YOU'LL SEE
THE BASELINE SCAI SHOCK STAGE.
PROGRESSING TO THE RIGHT YOU'LL
SEE THE PEAK.
THE PERCENTAGE IN THE BOTTOM THE
IN SINGLE COHORT IS MORTALITY
ASSOCIATED WITH ACHIEVING THAT
PEAK SKAI SHOCK STAGE.
SO PROGRESSION IS INPATIENT.
THESE ARE THE PATIENTS WE'RE
LOSING.
THE PATIENT PATIENTS THAT GOT R
WITH US AND THEN WE LOSE OUR
OPPORTUNITY TO TREAT THEM.
FURTHER HIGHLIGHTING THIS, THE
CONTEMPORARY DRIVERS OF
MORTALITY, YOU CAN SEE THE
MAJORITY OF OUR PATIENTS EVEN
THOUGH THEY'RE COMING IN WITH
MIXED SHOCK AND ALL THIS
COMPLICATED PHYSIOLOGY I SPOKE
ABOUT, THE MAJORITY OF THEM DIE
FROM REFRACTORY CARDIOGENIC
SHOCK.
SO WHEN YOU TALK IN A HOSPITAL
POPULATION WHERE CAN YOU TAKE
THEM TO SURGERY, YOU CAN
TRANSPLANT THEM, TOTAL
ARTIFICIAL HEART, LVAD, WE ARE
LOSING PEOPLE BECAUSE THAT
PRIMARY ORGAN WHERE WE HAVE ALL
THESE THINGS TO OFFER CANNOT BE
MODIFIED.
SO WE REALLY GOT TO THINK WHY
ARE WE LOSING THEMG, WHAT ARE
THE THINGS THAT ARE MAKING THEM
UNABLE TO TREAT THEM?
ARE THEY TOO OLD, TOO SICK, ARE
WE TOO LATE?
WHAT ARE THOSE FEATURES?
SO MOVING INTO -- IT'S A VERY
COMPLEX PATIENT POPULATION.
SO FIRST THINGS FIRST, WE'VE GOT
TO GET EVERYBODY ON THE SAME
PAGE.
CRITICAL CARE DID THIS A LONG
TIME AGO.
SO WHEN YOU START TALKING ABOUT
SOFA SCORE, SOME OF THE OTHER
ACUTE CALCULATORS, PEOPLE
FIGURED THIS OUT IN THE 2000s,
WE HAVE TO HAVE SOMEBODY WHEN
THEY HIT THE DOOR, WE KNOW HOW
LIKELY YOU ARE TO NEED
ESCALATION OF SERVICES AND WHAT
YOU MAY NEED WHEN YOU GET TO OUR
HOSPITAL.
THAT HAS NOT BEEN TRUE IN
CARDIOLOGY UNTIL 2019, WHEN SCAI
SHOCK STAGES WAG DEVELOPED.
IT USED TO BE YOU HAD TO GET TO
THE CATH LAB, GET A LINE, OR GET
AN ECHO TO QUANTIFY THE
COMPROMISE OF YOUR CIRCULATORY
SYSTEM.
IT MADE IT VERY HARD TO ENTER A
TREATMENT PATHWAY.
SO SCAI STAGING BECAME A WAY TO
START SAYING HOW SICK IS THIS
PERSON?
THIS HAS EVOLVED AND WE'RE NOT
GOING TO GO THROUGH THE METRICS
RIGHT NOW, BUT IT'S BEEN VERY
WELL VALIDATED GOING FROM LEFT
TO RIGHT, YOU SEE THE LOWER SKY
STAGES AT B OR A, DEPENDING ON
THE COHORT AND DARKER BLUE
COLORS MOVING TO RIGHT BEING B.
THE THINK ABOUT SCAI STAGING IS
THIS IS CLINICIAN HA-DRIVEN,
SOMEBODY WHO'S AN EXPERT LOOKING
AT THE PATIENT SAYING YOU ARE
THIS SICK.
YOU WERE SAYING THIS VENTRICLE
IS 9 CENTIMETERS SEVERELY
DILATED, YOUR LACTATE COULD BE F
DEATH.
SO THAT STARTS TO CAPTURE THESE
PATIENTS WHO ARE REALLY, REALLY
SICK AND NEED AN ESCALATION OF
CARE THAT MIGHT NOT BE OBVIOUS
BY THE NUMBERS THAT YOU'RE
PRESENTED IN EMR.
SO HOW DOES THIS GET DEPLOYED IN
EXPERT CENTERS?
SO PEOPLE DEVELOPED SHOCK TEAMS
BECAUSE WHAT BECAME REALLY CLEAR
IS IT'S VERY HARD TO GET
PEOPLE'S ATTENTION.
IT'S HARD TO GET ENOUGH DATA IN
A TIMELY FASHION TO GET A
CARDIOLOGIST TO BEDSIDE OR AN
APPROPRIATE PERSON TO RESPOND TO
THESE PATIENTS TO ESCALATE CARE.
SO WE CREATED SHOCK TEAMS.
WHAT THEY DID IS YOU NOTICE HERE
RATHER THAN IN THE INITIAL
TRIALS WHICH WE DIDN'T SHARE,
BUT THEY DIDN'T CREATE COMPLEX
CRITERIA TO GET THEIR ATTENTION.
YOU DIDN'T HAVE TO HAVE A
CARDIAC INDEX ESTIMATED.
YOU DON'T HAVE TO HAVE A WEDGE
MEASURED.
BUT THEY SAID IF YOU THINK THE
HEART IS INVOLVED AND YOU'RE
HYPOTENSIVE AND THE PESH IS
MAKING LACTATE, CALL US.
THEY MADE 24/7 RESPONSE SYSTEMS,
AND THEN THEY CREATED CARE TEAMS
WITH PROTOCOLIZED ASSESSMENTS.
SO THEY SAID WE ARE ALL GOING TO
COME IN, WE'RE GOING TO DO X, Y
AND Z AND AT THE END OF THIS
WE'RE GOING TO HAVE AN AGREED
UPON ESCALATION STRATEGY OF HOW
WE'RE GOING TO THINK THROUGH
DEVICES, WHAT WE NEED TO DO FOR
THIS PATIENT AND WE'RE GOING TO
MOVE EXPEDITIOUSLY.
WE'RE NOT GOING TO SECOND-GUESS
EACH OTHER, WE'RING GO TO HAVE A
GROUP DISCUSSION, COLLABORATIVE
CARE MODEL AND MOVE THIS PATIENT
FORWARD.
REALLY IMPORTANTLY THERE'S
CONTINUED ASSESSMENT.
SO THIS TEAM STAYED INVOLVED AND
THEY'RE IN CHARGE OF THE
PATIENT.
BECAUSE EVERYTHING YOU DO IN AN
ICU HAS CONSEQUENCES.
SO IT'S REALLY IMPORTANT WHILE
YOU'RE ADDING THINGS, YOU HAVE
TO TAKE THAT THERAPY AWAY AS
QUICKLY AS YOU CAN, AND IF YOU
CAN'T TAKE IT AWAY, YOU HAVE TO
MOVE THAT PERSON DOWN TO A
DEFINITIVE CARE PATHWAY SO
THEY'RE NOT EXPOSED TO SIDE
EFFECT OF THAT DEVICE, BREATHING
TUBE, WHAT HAVE YOU THAT
PRECLUDE YOU FROM MOVING
FORWARD.
THESE ARE SOME OF MY FAVORITE
PIECES OF DATA.
THERE'S VALIDITY ISSUES THAT
PEOPLE ARGUE WITH, BUT THREE
TRIALS CAME OUT NP A TWO-YEAR
PERIOD.
FROM THREE DIFFERENT CENTERS.
ALL OF THEM COMPARED THEIR
OUTCOMES FROM THE SHOCK TEAM TO
TWO TO THREE YEARS PRECEDING.
NONE HAD NEW ATTENDINGS, NONE
HAD NEW DEVICES.
THERE WERE NO MAJOR MEDICAL
ADVANCES IN THE TIME PERIOD IN
WHICH THESE STUDIES WERE DONE.
AND ALL THREE OUTCOMES IMPROVED
MORTALITY BY ALMOST IDENTICAL
AMOUNTS.
AND WHAT THEY SHOWED IS THAT BY
OPTIMIZING YOUR CARE PATHWAY,
DEPLOYING MEDICAL KNOWLEDGE THAT
MOST OF US KNOW, WE ALL READ THE
SAME TEXTBOOKS, AND WE WORK AS A
TEAM, WE'RE ABLE TO DROP MORTAL
PRETTY SIGNIFICANTLY AND
REPRODUCIBLY.
WHEN YOU LOOK AT THIS IN A
LARGER COHORT, CHRIS WAS ONE OF
THE -- WAS THE LEAD -- OR WAS
THE SENIOR AUTHOR IN THE STUDY,
THIS IS FROM OUR CRITICAL CARE
CARDIOLOGY NETWORK, AGAIN,
20,000 SHOCK ADMISSIONS, AND
ACTUALLY THIS WAS BEFORE, THIS
WAS A FEW YEARS AGO, A LITTLE
BIT SMALLER COHORT.
THEY LOOKED AT CENTERS WITH AND
WITHOUT SHOCK TEAMS.
AND THEY WERE ABLE TO SHOW THAT
THERE WAS REDUCED MORTALITY, AND
REALLY IMPORTANTLY, THERE WAS
EARLY PAUs, PA CATHETER USE,
BUT DIRECTED PA CATHETER USE, SO
IT WAS USED MORE FREQUENTLY AND
EARLIER.
THEY ENDED UP USING LESS OVERALL
MCS BUT MORE ADVANCED MCS.
WHAT THAT MEANS, -- BALLOON PUMP
GENERALLY LESS EFFECTIVE IN
PEOPLE IN SIGNIFICANT SHOCK.
HAS A ROLE BUT NOT A UBIQUITOUS
TREATMENT.
AND THEY FAVOR MORE IMPELLA,
TANDEM AND ECHO TO FULLY TAKE
OVER SOMEBODY'S CIRCULATORY
SUPPORT AND THOSE THINGS SEEM TO
BE ASSOCIATED WITH IMPROVED
SURVIVAL.
BUT AGAIN, COMPLEX CARE TEAMS
AND THERE'S REQUIREMENTS THAT
THIS IS NOT JUST ONE PERSON
COMING IN, THIS IS A TEAM-BASED
APPROACH.
IN THIS SAME PERIOD OF TIME
YOU'VE SEEN EXPANSION IN THE
UNITED STATES IN USE OF
TEMPORARY MCS.
SO MORE ECHO AND IMPE LA AND
TANDEM HEART, LESS BALLOON PUMP.
YOU LOOK AT TWO COUNTRIES, WE
HAVE CANADIAN PARTNERS, SO THESE
ARE PEER INSTITUTIONS LOOKING IN
THE SAME PERIOD OF TIME.
PER SCAI SHOCK STAGE, IN RED THE
CANADIAN MORTALITY, IN BLUE THE
U.S.
IT SEEMS THAT THE U.S. OUTCOMES
IN MATCHED CASES SEEM TO BE
BETTER.
QUESTION, WHAT IS DRIVING THIS?
AGAIN THESE ARE ALL ASSOCIATIONS
SO WE HAVE TO BE REALLY CAREFUL,
BUT AGAIN, THIS THEME OF MORTEME
TEMPORARY MCS, MORE PRECISE
DIAGNOSES THAT GUIDE YOUR
THERAPIES SEEM TO BE A THEME
HERE AS WELL.
HERE YOU CAN LOOK AT A
DISTRIBUTION OF THE DEVICES YOU
USE.
IN CANADA, AGAIN, MUCH MORE
BALLOON PUMP, MUCH LESS ADVANCED
MCS.
SO WE STARTED SAYING HOW CAN
WE -- CAN WE EXPERIENCE THESE
OUTCOMES BEYOND THESE CENTERS?
IN THE U.S., THERE'S -- WE DON'T
HAVE UBIQUITOUS ACCESS TO
SPECIALISTS.
PEOPLE CROSS TRAINED,
ENVIRONMENTS THAT CAN SUPPORT
ALL OF OUR CAREERS SO WE HAVE
TIME TO ALL SHARE OUR EXPERTISE.
A LOT OF PEOPLE ARE WORKING OUT
IN THE COMMUNITY.
AND INOVA WAS ABLE TO
DEMONSTRATE THAT BY CREATING A
SHOCK PROTOCOL, THEY WERE ABLE
TO EXPERIENCE SIMILAR OUTCOMES
REGARDLESS OF WHERE THEIR
PATIENTS PRESENTED.
SO NOW ALL OF A SUDDEN YOU START
TO SAY OH HE KAY, WE HAVE THIS
COMPLEX PATIENT, IF WE ESCALATE
THEM QUICKLY, WE CAN GET THE
SAME OUTCOMES.
BUT INOVA WORKS IN A 10,000
SQUARE MILE AREA.
THIS IS WHERE I WORK.
FREUCIAL RATHER THAN HAVING A
SMALL NUMBER OF INSURANCE
SYSTEMS, WE HAVE 58 COUNTY, A
BUNCH OF DIFFERENT INSURANCE
SYSTEMS, A TON OF AMBULANCE
SYSTEMS TO WORK WITH AND FOR
ADVANCED THERAPIES, WE HAVE ONE
COMPANY TO TRANSPORT IN
CALIFORNIA.
NOW IT'S UP TO TWO.
BUT STILL, NOT VERY MUCH.
AND IF YOU LOOK AT THIS MAP, WE
JUST DEVELOPED -- THIS IS STILL
A ROUGH ESTIMATE, BUT FROM A
SURVEY STUDY, RED IS LEVEL
1CICUs, BLUE IS LEVEL 2.
THIS IS THE HOSPITALS IN
CALIFORNIA FROM OUR SURVEY STUDY
THAT ARE -- OR THE POPULATION OF
CALIFORNIA WITHIN 30 MINUTES OF
A HOSPITAL DESCRIBED AT ONE OF
THOSE CICU LEVELS.
SO ENORMOUS, ENORMOUS GAPS IN
CARE AND ABILITY TO GET PATIENTS
TO PLACES IN THE RIGHT AMOUNT OF
TIME.
AND STAFFING REALLY MATTERS.
WHEN YOU LOOK AT STUDIES, YOU
LOOK AT CICUs, HIGH INTENSITY
AND SPECIALTY TRAINED CICUs
HAVE LOWER MORTALITY, BOTH
HOSPITAL AND CICU MORTALITY, AND
IT'S IMPORTANT -- IT'S NOT THAT
THE CARDIAC DIAGNOSES BENEFIT.
IT'S THE EXTRA CARDIAC
COMPLICATIONS OF CARDIOVASCULAR
DISEASE THAT SEEM TO BENEFIT
PRIMARILY FROM THIS EXTRA
TRAINING AND FOR A LOT OF
INTENSIVISTS IN THE ROOM, IT'S
MAKING SURE UR DOING THE EVENT
RIGHT, NOT INJURING LUNG,
REPLACEMENT THERAPY DONE
PROPERLY.
I MEAN, REALLY CAUTIOUS WITH
YOUR MULTI-DISCIPLINARY CARE.
AND AGAIN, IF YOU LOOK AT HIGH
AND LOW INTENSITY STAFFING AT
CICUs, YOU SEE NOT ONLY THAT
SPECIALTY TRAINING BUT ALSO THE
INTENSIVITY OF STAFFING, HAVING
YOUR OWN PHARMACISTS, SPECIALLY
TRAINED NURSES, RTs, PHYSICAL
THERAPISTS, THOSE ALL CONTRIBUTE
TO PEN F BENEFIT AND THEY SEEM O
BENEFIT MOSTLY THE -- DAYS ON
THE VENTILATOR.
PROBLEM IN THE U.S. IS THIS IS
NOT A COMMON PRACTICE PARADIGM.
THE MAJORITY OF OU ICUs IN THE
UNITED STATES ARE OPEN ICU
MODEL, MEANING SOMEBODY WHO IS
NOT GEOGRAPHICALLY LOCATED IN
ICU FOR THEIR PRACTICE IS
ADMITTING PATIENTS IN AND MAYBE
COMANAGING WITH AN INTENSIVIST.
IN ADDITION GOING ALL THE WAY TO
THE RIGHT, YOU CAN SEE THE
NUMBER OF CICUs THAT ARE
STAFFED WITH PEOPLE WHO ARE DUAL
TRAINED IN CARDIOLOGY AND
INTENSIVE CARE.
THIS IS A RARE RESOURCE, AND WE
ARE NOT SET UP IDEALLY TO
DELIVER CARE AND FOLLOW THE DATA
THAT SEEMS TO BE ASSOCIATED WITH
IMPROVED OUTCOMES IN CARDIOGENIC
SHOCK.
SO BIOMARKERS BECOME A VERY
INTUITIVE TOOL HERE WHERE YOU
WANT TO START SAYING WE NEED TO
IDENTIFY THESE PATIENTS EARLIER,
MOVE THEM TO THE RIGHT PLACE SO
THEY CAN STILL BENEFIT FROM
THERAPY.
HOW DO BIOMARKERS FIT INTO THIS
PARADIGM?
FIRST BEFORE WE GET INTO THESE
BIOMARKER SPECIALTY
DESCRIPTIONS, WE REALLY WANT TO
UNDERSTAND WHAT ARE THE
BIOCHEMICAL PROFILES WE WANT TO
TARGET?
TAKING ALL OF OUR LESSONS FROM
THE TRIALS WE TALKED ABOUT IN
THE BEGINNING, IT'S A MISTAKE TO
GO INTO CARDIOGENIC SHOCK AND
SAY WE ARE GOING TO TAKE THIS
AND JUST GO BOOM.
YOU WILL FAIL.
THESE PATIENTS ARE ALL VERY
COMPLICATED AND THE MOST
SUCCESSFUL SHOCK TRIAL WE HAD
WAS DANGER SHOCK WHICH TOOK 10
YEARS TO ENROLL.
SO HOW DO WE GET TARGETED, HOW
DO WE BENEFIT THESE PATIENTS WHO
MAY BENEFIT?
FIRST YOU WANT TO UNDERSTAND
PARTICIPATING PROGRESSION TO
UNDERSTAND WHO HAS THE
OPPORTUNITY TO BENEFIT.
SOME OF THE EARLY WORK, YOU CAN
SEE HERE THREE PROPOSED PROFILES
FOR CARDIOGENIC SHOCK.
ON THE LEFT, WE DON'T HAVE TO GO
THROUGH ALL THE DATA THERE, BUT
IT'S ESSENTIALLY LOW OUTPUT, NO
SYSTEMIC ACIDOSIS AND LIMITED
SYSTEMIC CONGESTION.
MOVING TO THE MIDDLE, YOU SEE
THE CARD YAL RENAL SYSTEM WHERE
YOU'VE MOVED INTO LOW OUTPUT BUT
ALSO YOU HAVE CONGESTION AND
PRIMARILY CONGESTIVE MARKERS,
BILIRUBIN.
THE THIRD IS CARDIOMETABOLIC
CACARDIOGENIC SHOCK.
YOU ALSO HAVE CELLULAR ACIDOSIS
SETTING IN.
WHEN YOU LOOK AT THE OUTCOMES
ASSOCIATED WITH THESE THREE
PHENOTYPES, BY THE TIME YOU MOVE
INTO THIS ACIDOSIS STATE, YOU
HAVE VERY, VERY, VERY POOR
OUTCOMES.
AND IF YOU LOOK AT HOW MCS WORKS
IN THESE PATIENTS, YOU SEE
EXTREMELY HIGH MORTALITIES WHEN
YOU'RE STARTING TO DEPLOY
DEVICES, AND AGAIN, SMALL
NUMBERS, NOT WELL SELECTED, BUT
IT'S HARD TO ARGUE THAT YOU'RE
MODIFYING OUT COME VERY MUCH
WITH 60% MORTALITY OF SOMEBODY
ON ECMO WHO'S ALREADY HIT
CARDIOMETABOLIC SHOCK.
SO WE OUGHT TO GET IN THERE
EARLIER, WE HAVE TO FIGURE THIS
OUT BEFORE THEY HIT THAT.
LOOKING AT EVOLVING PREDICTORS,
PREVIOUSLY PEOPLE LOOKED AT A
LOT OF COMPLEX HEMODYNAMIC
METRICS, SOME OF YOU MAY HAVE
HEARD OF THINGS LIKE -- AS WE
MOVE MORE GRANULAR AND WE LOOK
IN LARGE COHORTS OF PATIENTS,
ONE OF THE THINGS THAT STAND OUT
IS DRIVING MORTALITY.
AND THE THINGS THAT REALLY STAND
OUT, LOW SVR, SYSTEMIC
CONGESTION.
AND THAT'S PHYSIOLOGY WE ALL
LEARNED.
YOU LOSE YOUR PERFUSION GRADIENT
ACROSS YOUR ORGANS.
AS YOUR MAP DROPS AND VENOUS
OUTFLOW PRESSURE GETS HIGHER,
YOU CAN'T DELIVER OX JEP TO YOUR
ORGANS.
THAT'S PHYSIOLOGY 101.
THAT OVERWHELMINGLY OUTPOWERS OR
PREDICTS MORTALITY THAN ALL
THESE OTHER FANCY METRICS.
SO WE'VE GOT TO GET AHEAD OF
THAT, START IDENTIFYING PATIENTS
BEFORE THEY'RE CONGESTED.
IN ADDITION TO THAT, PATIENTS
WHO ARE ON VASOP VASOPRESSORS, N
ESCALATING, THAT IS A
SIGNIFICANT PREDICTOR OF
MORTALITY.
PEOPLE ARE THINKING THIS IS
SOMETHING WHO GOES FROM 1 TO 4.
THAT'S NOT TRUE.
YOU'RE LOOKING AT SWINGS AT .02
TO .06.
THAT TRIPLES YOUR MORTALITY.
AND YOU CAN SEE, IT'S A
PROGRESSIVE -- IT DEMONSTRATES
HOW THAT'S A CONTINUUM.
SO THESE CARDIOGENIC SHOCK --
YOU'RE KIND OF WATCHING THEM,
THAT CAN AFFECT THE CANARY IN
THE COAL MINE.
A LOT OF PEOPLE START LOOKING
SAYING, WELL, LACTATE IS STILL
FLAT.
THIS IS A STUDY OF LOOKING AT
ADVANCED HEART FAILURE PATIENTS
AND LOOKING AT THEIR LACTATE
PRODUCTION.
FOCUS ON THE BOTTOM PANEL, THEY
ESSENTIALLY SHOW THE SAME THING.
IF YOU LOOK AT CARDIAC INDEX,
THAT IS A LEVEL OF LACTATE
PRODUCTION ASSOCIATED WITH EACH
CARDIAC INDEX MEASURED BY RIGHT
HEART CATH IN AN ADVANCED HEART
FAILURE POPULATION.
SO YOU SEE PEOPLE WITH INDICES
IN THE 1s, VERY, VERY
CRITICALLY LOW WHO ARE NOT
MAKING LACTATE.
IN MANY OF THE PATIENTS ACTUALLY
MAKING LACTATE ARE ACTUALLY
CIRCULATING NORMAL AMOUNTS OF
BLOOD.
YOU LOOK AT THEIR INNER MACK
SCORING, IT GOES 1 TO 7 BUT 1ING
TO 4 WHAT YOU SEE IN THE
HOSPITAL.
1 BEING THE SICKEST WE HAVE,
ONLY ABOUT 40% OF THEM MAKE
LACTATE ON PRESENTATION.
SO YOU'RE THINKING THESE
PATIENTS, THE EXPERT HAS ALL THE
DATA IN FRONT OF THEM WALKING
INTO THE ER, YOU DON'T HAVE ALL
YOUR ECHO, YOUR SCAN, ALL THE
PIECES OF THIS PERSON'S
PHYSIOLOGY, THAT BASIC SCREEN OF
CHECKING LACTATE, YOU'RE GOING
TO MISS 60% OF YOUR INTERMAX
1 PATIENTS DURING YOUR
EVALUATION.
SO THIS REALLY STARTS TO
DESCRIBE WHY WE'RE MISSING THESE
PATIENTS ON ADMISSION.
IT BECOMES REALLY TRICKY.
SO HOW DO WE IDENTIFY THESE
PATIENTS?
THERE ARE SOME NO MEL TOOLS,
START GOOGLING BIOMARKERS AND
CARDIOGENIC SHOCK.
THERE'S SOME ROUTINE LABS THAT
PEOPLE CAN SEND IF YOU SEE THAT
BNP DOESN'T CLEAR DURING
ADMISSION, THERE'S INCREASED
MORTALITY BUT YOU'RE LOOKING AT
TIMELINES OF 30 TO 60 DAYS.
THIS DOESN'T HELP YOU IN THAT
MINUTE TO MINUTE, DOESN'T HELP
YOU UNDERSTAND, I HAVE SOMEBODY
WHO'S UP IN FAR NORTHERN
CALIFORNIA, HOW FAST DO I HAVE
TO GET THEM TO US CF.
BUT AGAIN, VALUABLE TOOL, AND IF
YOU START SEEING THESE THINGS
PERCOLATING, YOU CAN START
PUTTING THEM INTO YOUR PRACTICE.
ADDITIONALLY, THERE'S
HIGH-THROUGHPUT PROAD YOE MIBG
SCREENING.
PEOPLE ARE USING -- THIS STUDY
WAS DONE SPECIFICALLY TO
DIFFERENTIATE CARDIOGENIC SHOCK
FROM HEART FA FAILURE.
AGAIN, THIS IS DIFFERENTIATING
PEOPLE WHO ARE IN SHOCK FROM
THOSE WHO AREN'T.
SO WHILE IT'S HELPFUL TO START
TO UNDERSTAND THE BIOLOGY,
YOU'RE TRYING TO PICK OUT THESE
PATIENTS BEFORE THEY MOVE INTO
METABOLIC ACIDOSIS, BEFORE THEY
GO INTO SHOCK.
SIMILARLY OTHERS SHOW A LOT OF
THE INTERLEUKINS, AND THIS IS
SHOWING IL-6, PARTICULARLY
ASSOCIATED WITH THE VASODILATORY
STATE, BUT AGAIN YOU'RE
IDENTIFYING LATE.
ONCE THIS HIGH RISK PHYSIOLOGY
HAS ALREADY SET IN.
DPP3, VERY INTERESTING MOLECULE,
ELABORATED FROM ENDOTHELIUM,
VERY, VERY HIGH FROM
NON-SURVIVORS, THIS IS ALSO PART
OF VASODILATORY SHOCK.
HOW YOU CAN START THINKING ABOUT
SOME OF THESE, THOSE ACTUALLY
MIGHT BE TREATMENT TARGETS.
YOU CAN USE AN ANTIBODY FOR
DP3 IN ANIMAL MODELS AND IMPROVE
BLOOD PRESSURE IN SHOCK.
SO STARTING TO THINK ABOUT
THESE, LIKE WE TALKED ABOUT
BEFORE, BEING MORE PRECISE,
THERE ARE OPPORTUNITIES TO
IDENTIFY TREATMENT TARGETS TO
HELP YOU TREAT HIGH RISK STAGES
BUT THE GOLD STANDARD IS ALWAYS
TO STAY OUT OF THAT, HOW DO YOU
STAY AHEAD OF IT.
SO WHAT IS NEEDED IN CARDIOGENIC
SHOCK?
YOU WANT TO IDENTIFY THESE
PATIENTS BEFORE THEY'RE THIS
SICK.
IF THEY HAVE TO GO ON TO
CARDIOPULMONARY BY PASS FOR
CARDIAC SURGERY, TRANSPLANT, YOU
CAN'T TRANSPLANT SOMEBODY IN
MULTISYSTEM ORGAN FAILURE,
THERE'S NOT GOING TO BE A
CANDIDATE.
HOW DO YOU FIGURE THESE PATIENTS
OUT, HOW DO YOU IDENTIFY THEM
FOR APPROPRIATE ESCALATION OF
CARE BEFORE IT'S TOO LATE?
AND THEN FOR PATIENTS AT HIGH
RISK OF CARDIOGENIC SHOCK, OR
ZOE, THATHAT'S A DUPLICATE, I A.
BUT THEME BEING, EARLIER
IDENTIFICATION, YOU WANT TO STAY
OUT OF SYSTEMIC ACIDOSIS, AND
HOW CAN BIOMARKERS HELP YOU
IDENTIFY THESE PATIENTS AHEAD OF
TIME?
WITH THAT --
>> THANK YOU VERY MUCH.
YOU CAN SEE WHY I GOT VERY
INTERESTED WHEN CONNOR PRESENTED
THESE.
IT'S A VERY COMPLEX AND
HETEROGENEOUS DISEASE.
INDEED, NHLBI ON THE HEART SIDE
AND THE NATIONAL ACADEMY OF
SCIENCE A FEW YEARS AGO PUT OUT
THESE STATEMENTS.
I SUMMARIZED THEM HERE AND THE
REFERENCES, WE'LL PROVIDE THEM
FOR PEOPLE WHO WOULD LIKE TO
READ.
IT'S A GOOD READ.
I WOULD RECOMMEND IT.
THERE'S A NEED FOR CLINICAL
EXPERTS TO DEFINE THESE CLINICAL
SYNDROMES IN A VERY ELABORATE
WAY.
HOWEVER, THERE IS A NEED FOR
DATA INTEGRATION, INTEGRATION OF
CLINICAL DATA, BIOMARKERS PLUS
MULTIPLE OMICS DATASETS TO
REDEFINE THIS HETEROGENEOUS
DISEASE.
THAT IS YOU'RE GOING FROM BIG
DATA TO PRECISION.
NHLBI TOOK ON EVEN A STEP
FARTHER WITH THESE BY CREATING
THESE ENTITY TRANS OMIC FOR
PRECISION MEDICINE OR TOP NET,
WHERE IN THEY PROVIDE
MULTI-MODALITY OMIC ASSESSMENT
WITH DATASETS THAT COULD BE
INTEGRATED NOW INTO CLINICAL MES
TO REDEFINE DISEASES LIKE WHAT
DR. O'BRIEN JUST TOLD US HERE.
THERE IS A NEED TO DEVELOP
BIOMARKERS THAT COULD BE
DEPLOYED EARLY TO IDENTIFY THESE
COMPLEX PATIENTS EARLY, TO GUIDE
THEM TOWARDS THE RIGHT KIND OF
TREATMENT.
CELL-FREE DNA.
THESE ARE SHORT FRAGMENTS OF DNA
THAT ARE RELEASED WHEN CELLS DIE
INTO THE CIRCULATION.
THEY ARE EARLY MARKERS OF INJURY
AND THEY'RE QUITE ABUNDANT IN
PLASMA.
I'LL GIVE YOU AN EXPERIENCE IN
TRANSPLANTATION AND HOPEFULLY
GIVE YOU A FEW CONCEPTS AND PASS
IT ON TO ASHLEY TO PROVIDE
EXPERIENCES IN CARDIOGENIC
SHOCK.
IF YOUR MARGIN TIMES ZERO AS THE
TIME A TRANSPLANT PATIENT GETS
REJECTION, THIS IS A HEART
TRANSPLANT GROUP OF PATIENTS.
THIS IS WHEN THEIR BIOPSY ON THE
PATIENT SHOWS ANY CLINICAL
SYMPTOMS.
CELL-FREE DNA FROM THAT
TRANSPLANTED ORGAN IS HIGH.
HOWEVER, 2 TO 4, 5, 6 MONTHS
BEFORE THAT BIOPSY BECOMES
POSITIVE, THERE'S ELEVATION IN
THE CELL-FREE DNA DERIVED FROM
THAT ORGAN.
EARLY, EARLY DETECTION.
BUT AGAIN, TRANSPLANT IS EASY
BECAUSE THERE'S GENOMIC
ADMIXTURE.
WHAT IF IN CARDIAC SHOCK OR
OTHER CONDITIONS WHERE THERE ARE
NO GENOMIC ADMIXTURE?
HERE'S REALLY WHERE I HIGHLIGHT
THE UNIQUE OPPORTUNITIES THAT
NIH PROVIDES US.
IT'S A SAND BOX, BUT THIS SAND
BOX IS WHERE YOU HAVE TRULY
DEDICATED BRILLIANT SCIENCES.
ALLOW ME TO TELL YOU THE NIH
HERE, BUT I'VE BEEN EXTREMELY
FORTUNATE TO FIND THESE PEOPLE
HERE.
THE CHIEF SCIENTIST IN OUR LAB,
DR. MOON JANG, DEVELOPED SOME
MODELS WHERE YOU COULD NOW LOOK
AT CELL-FREE DNA IN CONDITIONS
WITHOUT GENOMIC ADMIXTURE,
LEVERAGING TISSUE-SPECIFIC
EPIGENETIC MARKERS.
AND YOU CAN THEN USE THOSE
TISSUE EPIGENETIC MARKERS TO
SCAN CELL-FREE DNA COMING FROM
ALL THESE DIFFERENT ORGANS,
VASCULAR ENDOTHELIUM, HEART AND
ALL THESE ORGANS, PROVIDING A
WHOLE BODY MOLECULAR INJURY
SCAN.
WE'VE TESTED THAT IN MULTIPLE
DISEASES, AND IT SEEMS TO WORK.
I WAS GOING TO SHOW SOME SLIDE
HERE ON COVID-19 PATIENTS WHO
DIED -- SURVIVE, BUT I'LL LET
DR. PARK COME IN AND TRY TO GIVE
OUR EXPERIENCE IN CARDIOGENIC
SHOCK.
BUT WITH THESE METHODS, THESE
ARE THE DIFFERENT ORGANS THAT
YOU CAN QUANTIFY WITH 1 ML OF
PLASMA, YOU CAN QUANTIFY
THE DEGREE OF INJURY COMING FROM
ALL THESE DIFFERENT ORGANS.
THE LIBRARY CURRENTLY THAT WE
HAVE IN THE LAB CAN QUANTITATE
INJURY FROM AT MOST 35 DIFFERENT
TISSUE TYPES.
SO THE QUESTION THEN, HOW COULD
YOU USE THIS IN CARDIOGENIC
SHOCK?
I WOULD STOP HERE AND PASS IT
OVER TO DR. PARK.
>> HELLO.
THANK YOU, DR. AGBOR AND
DR. O'BRIEN FOR THIS
OPPORTUNITY.
ONE OF THE THINGS THAT WE'VE
HEARD OVER AND OVER AGAIN IS
THAT CARDIOGENIC SHOCK OUTCOMES
HAVE REALLY PLATEAUED OVER THE
LAST TWO DECADES, AND ONE NEED
IS TO IDENTIFY HIGH RISK
PATIENTS EARLIER ON.
AND ONE SPECIFIC AREA OF
INTEREST IS TO FIND BIOMARKERS
THAT ARE ABLE TO IDENTIFY THESE
PATIENTS.
SO ONE ATTRACTIVE CANDIDATE IS
THE USE OF CELL-FREE DNA IN
IDENTIFYING THESE PATIENTS.
SO BUILDING ON THIS, I'LL BE
PRESENTING SOME OF OUR EARLY
DATA THAT TAKES A LOOK AT
WHETHER ADMISSION CELL-FREE DNA
CAN HELP US IDENTIFY THESE HIGH
RISK PATIENTS.
SO IN ORDER TO ANSWER THIS
QUESTION, WE TOOK A LOOK AT A
COHORT TAKEN FROM THE UCSF
CARDIAC ICU.
SPECIFICALLY WE LOOKED AT THEIR
CARDIOGENIC SHOCK BIOBANK, WHICH
TAKES SAMPLES FROM PATIENTS ADD
ADMITTED TO THEIR CICU WITH A
DIAGNOSIS OF CARDIOGENIC SHOCK.
THIS WAS PART OF A LARGER
MULTI-INSTITUTIONAL EFFORT TO
FIND BIOMARKERS IN THIS
POPULATION.
NOW LOOKING SPECIFICALLY AT THE
UCSF BIOBANK ALONE, THIS BIOBANK
STARTED IN JANUARY OF 2023 AND
HAS MASSIVELY EXPANDED, AND TO
DATE HAS OVER 300 PATIENT
SAMPLES AND CLINICAL DATA THAT
WERE COLLECTED.
LOOKING A LITTLE BIT MORE
DETAIL, THIS BIOBANK COLLECTED
DATA AND SAMPLES FROM DAY ZERO,
DAY TWO AND DAY EIGHT AS OF
ADMISSION, AND ALONGSIDE THIS
CLINICAL DETAILS WERE COLLECTED,
SPANNING OVER 600 VARIABLES UP
UNTIL PATIENT DISCHARGE.
WE INITIALLY TOOK A LOOK AT THE
FIRST 225 PATIENTS OF WHICH THE
MEDIAN AGE WAS 58 YEARS, THE
MAJORITY OF PATIENTS HAD
INTERMEDIATE DISEASE SEVERITY
SCAI SHOCK C AND ABOUT 50% OF
PATIENTS HAD UNDERGONE CARDIAC
ARREST PRIOR TO ADMISSION.
OUR PRIMARY OUT COME OF INTEREST
WAS IN-HOSPITAL MORTALITY.
AND ACROSS THE 225 PATIENTS, WE
OBSERVED A 23% MORTALITY RATE
SHOWN HERE IN ORANGE.
AND SO WITH THIS AS OUR PRIMARY
OUT COME, WE REFRAMED OUR
QUESTION TO CAN ADMISSION
CELL-FREE DNA BE AN EARLY
INDICATOR OF MORTALITY IN THIS
POPULATION.
AND SO WHAT WE DID WAS WE TOOK
SAMPLES FROM DAY ZERO AND LOOKED
AT THEIR CELL-FREE DNA AND
CORRELATED THEM WITH OUR OUT OUE
OF IN-HOSPITAL MORTALITY.
WE FIRST ESTABLISH A BASELINE
UNDERSTANDING OF HOW HIGH
CELL-FREE DNA LEVELS WERE IN
THIS COHORT.
HERE WE COMPARE PATIENTS WITH
CARDIOGENIC SHOCK LABELED IN
RED, AND WE COMPARED THEM TO
HEALTHY INDIVIDUALS IN BLUE.
THEY'RE SEPARATED HERE ON THE X
AXIS BY THEIR SUBTYPE, SO
NUCLEAR OR MITOCHONDRIAL, AND WE
HAVE A SCALE OF LEVELS.
WHAT WAS STRIKING IS THAT
NUCLEAR AND MITOCHONDRIAL DNA
ARE 10 TIMES HIGHER IN
CARDIOGENIC SHOCK PATIENTS THAN
HEALTHY INDIVIDUALS.
WE THEN LOOKED AT HOW CELL-FREE
DNA LEVELS VARY BY CLINICAL
SEVERITY ON PRESENTATION, USING
THE SCAI SHOCK STAGING SYSTEM.
WHAT WE FOUND WAS THAT PATIENTS
WITH MORE SEVERE SHOCK ON
PRESENTATION HAD HIGHER
CELL-FREE DNA LEVELS.
SO THIS GAVE US A SNAPSHOT THAT
CELL-FREE DNA LEVELS CORRELATE
WITH HOW SICK SOMEONE IS ON
PRESENTATION.
BUT AS WE'VE SEEN CLINICALLY AND
AS WE'VE HEARD, SOMEONE'S
CLINICAL STATUS ISN'T
NECESSARILY STATIC, THAT MANY
PATIENTS WILL LATER ON GO ON TO
PROGRESS.
AND IN OUR COHORT, WE SAW THAT
35% OF PATIENTS EXPERIENCE
WORSENING IN DISEASE SEVERITY
DURING THEIR HOSPITAL STAY.
WE LABELED THESE PATIENTS AS
PROGRESSORS, SHOWN HERE IN
ORANGE.
SO THE NATURAL FOLLOW-UP
QUESTION WE HAD WAS, WELL, COULD
WE IDENTIFY EARLY ON WHO WOULD
GO ON TO PROGRESS LATER.
SPECIFICALLY WHERE THEIR
CELL-FREE DNA LEVELS ALREADY
ELEVATED AT TIME OF ADMISSION.
WHAT WE FOUND WAS SUGGESTED THAT
THOSE WHO LATER WENT ON TO
PROGRESS ACTUALLY DID TEND TO
HAVE HIGHER LEVELS OF CELL-FREE
DNA ON ADMISSION.
THIS IS A VERY ALLURING CONCEPT
THAT CELL-FREE DNA, EVEN WHEN
TAKEN ON ADMISSION, MAY BE
DETECTING SOMETHING EVEN BEFORE
IT MANIFESTS AS OVERT CLINICAL
DECOMPENSATION.
SO, SO FAR WHAT WE'VE SEEN IS
THAT CELL-FREE DNA CORRELATES
WITH HOW SICK YOU ARE, WHETHER
YOU ARE LIKELY TO PROGRESS.
OUR NEXT QUESTION WAS CAN IT
TELL YOU HOW SICK YOU'RE GOING
TO BECOME, HOW SEVERE YOUR
DISEASE WILL GET.
THIS FIGURE SHOWS CELL-FREE DNA
PLOTTED AGAINST SOMEONE'S WORST
OR PEAK SCAI SHOCK STAGE AND
AGAIN, WE FOUND A STRONG GRADED
RELATIONSHIP IN THAT PATIENTS
WHO WENT ON TO DEVELOP MORE
SEVERE STAGES DURING THEIR
HOSPITAL STAY HAD HIGHER
CELL-FREE DNA LEVELS AT
ADMISSION, SO AGAIN THIS, IS
REINFORCING THAT SAME CONCEPT
THAT CELL-FREE DNA CAN BE AN
EARLY RISK STRATIFICATION TOOL
AND HELP US TO ANTICIPATE
CLINICAL TRAJECTORIES EVEN
BEFORE IT'S APPARENT.
SO NOW WHAT DOES THIS MEAN IN
TERMS OF MORTALITY?
WHEN WE LOOK AT THE GROUP AS A
WHOLE, WE SEE THAT PATIENTS WHO
WENT ON TO DIE DURING THEIR
HOSPITAL STAY HAD HIGHER
CELL-FREE DNA LEVELS ON
ADMISSION.
WE THEN STRATIFIED THEM BY THEIR
INITIAL SCAI SHOCK STAGE OR
THEIR CLINICAL SCORE AND
COMPARED CELL-FREE DNA LEVELS BY
THEIR OUTCOME WHETHER THEY
SURVIVED OR N NOT.
WHAT'S STRIKING IS PATIENTS WHO
DIE TENDED TO HAVE HIGHER
CELL-FREE DNA LEVELS AT
ADMISSION.
SO THIS REINFORCES THAT IDEA
THAT CELL-FREE DNA MAY BE
PROVIDING ADDITIONAL INFORMATION
THAT'S NOT PRESENT WITH JUST THE
CLINICAL SCORE ALONE, AND THAT
PERHAPS THIS MAY BE ESPECIALLY
BENEFICIAL IN IDENTIFYING WHICH
PATIENTS MAY BE THE ONES TO
INTERVENE EARLIER ON AND
THEREFORE MAY BE THE BEST
CANDIDATES FOR ADVANCED
THERAPIES.
WE THEN LOOKED AT HOW WELL
CELL-FREE DNA PERFORMED AGAINST
THESE OTHER CLINICAL SCORES, AND
WE STARTED BY EVALUATING SOME
TRADITIONAL SCORES LIKE SCAI,
SOFA -- IN ICU PATIENTS.
INDIVIDUALLY, THEY PERFORMED
POORLY IN TREE PREE
DICTIONARYING INHOSPITAL
MORTALITY WITH AUCs RANGING
FROM .53 TO .63.
WHEN WE LOOKED AT NUCLEAR
CELL-FREE DNA ALONE, WE SAW THAT
THERE WAS A MARKED IMPROVEMENT
WITH THE AUC OF 7.765.
AND WHEN WE COMBINE CELL-FREE
DNA WITH A CLINICAL SCORE LIKE
SCAI, THE AUC IMPROVED FURTHER
TO .784.
WHILE THE DIFFERENCE BETWEEN
THIS COMBINED SCORE AND
CELL-FREE DNA ALONE IS MARGINAL,
WHEN YOU COMPARE TO THE
INDIVIDUAL CLINICAL SCORES, IT
PERFORMS SUBSTANTIALLY BETTER.
SO JUST TO SUMMARIZE, WE HAVE
SEEN THAT CELL-FREE DNA IS
SUBSTANTIALLY HIGHER IN THIS
POPULATION, THAT THE DEGREE OF
ELEVATION TRACKS WITH HOW SICK A
PATIENT IS AND HOW SICK THEY ARE
LIKELY TO BECOME.
AND IMPORTANTLY IT PERFORMS
BETTER THAN THESE CLINICAL
SCORES THAT WE'RE USING ALONE.
SO WHILE OUR CURRENT WORK HAS
FOCUSED A LOT ON TOTAL AMOUNTS
OF CELL-FREE DNA AS A MARKER OF
SEVERITY AND MORTALITY, OUR NEXT
QUESTION WAS TO ASK WHERE THE
CELL-FREE DNA IS COMING FROM AND
WHAT CAN IT TELL US ABOUT END
ORGAN INJURY.
AND SO DR. AGBOR HAD INTRODUCED
THIS IDEA OF METHYLATION, AND
WHILE WE HAVEN'T DONE
METHYLATION ANALYSIS ON OUR
CARDIOGENIC SHOCK PATIENTS, IN A
SEPARATE COHORT OF END STAGE
HEART FAILURE PATIENTS, WE'VE
SHOWN THAT CELL-FREE DNA CAN BE
TRACED BACK TO SPECIFIC TISSUES
AND THIS CAN -- AND THE TISSUE
INJURY PATTERNS CAN BE DYNAMIC
IN RESPONSE TO THERAPY.
HERE WE HAVE A HEAT MAP THAT
ILLUSTRATES HOW CELL-FREE DNA
SIGNATURES CHANGE OR EVOLVE
ACROSS ORGAN SYSTEMS AND IMMUNE
SYSTEMS, AND THIS REFLECTS
DYNAMIC SHIFTS IN RESPONSE TO
LVAD.
AND OUR GOAL NOW IS TO BRING
THIS LENS TO CARDIOGENIC SHOCK
TO SEE IF WE CAN USE CELL-FREE
DNA TO TRACK REALTIME CHANGES
AND MONITOR END ORGAN INJURY IN
THIS POPULATION.
SO FINALLY TO BRING US HOME,
TODAY WE PAINTED THE LAND SKIP
OF CARDIOGENIC SHOCK.
WE CURRENTLY USE A COMBINATION
OF CLINICAL ASSESSMENT TOOLS AND
BIOMARKERS THAT WE'VE SEEN OVER
AND OVER AGAIN THAT THESE TOOLS
ARE LIMITED.
SPECIFICALLY WHEN WE LOOK AT
BIOMARKERS, THE BIOMARKERS THAT
ARE CURRENTLY AVAILABLE OFTEN
REFLECT TISSUE DAMAGE THAT HAS
ALREADY OCCURRED AND IT'S
IRREVERSIBLE, AND OFTEN COMES
AFTER CLINICAL DECOMPENSATION.
IN CONTRAST, OUR PRELIMINARY
WORK FEATURES CELL-FREE DNA AS A
BIOMARKER THAT CAN PRECEDE
CLINICAL DEEXRENNIZATION AND MAY
BE AN EARLIER PREDICTOR OF
FURTHER PROGRESSION AND DEATH.
SO ACTUALLY WHAT WE HYPOTHESIZED
MOVING FORWARD IS THAT CELL-FREE
DNA MAY AUGMENT THESE EXISTING
SCORES, ESPECIALLY AS WE
UNDERSTAND MORE ABOUT END ORGAN
INJURY AND HOW THAT CHANGES
DURING THEIR HOSPITAL STAY.
THIS WILL ULTIMATELY HELP US TO
IDENTIFY THOSE WHO ARE AT
HIGHEST RISK AND, THEREFORE, MAY
BE THE BEST CANDIDATES FOR MPS.
BS.
THANK YOU FOR YOUR ATTENTION.
I WOULD BE REMISS WITHOUT
MENTIONING OUR MASSIVE, MASSIVE
TEAM ACROSS BOTH THE NIH AND
UCSF.
THIS IS OUR NIH TEAM, WHICH I
HAVE TO JUST MENTION A FEW
PEOPLE WHO HAVE BEEN SUPER
INSTRUMENTAL IN MOVING THE
SCIENCE FORWARD AND OF COURSE
DR. MOON JANG FOR DEVELOPING A
LOT OF THESE TECHNOLOGIES.
AND THEN HERE IS THE UCSF TEAM,
ALSO ANOTHER MASSIVE TEAM THAT
HAVE BEEN REALLY WORKHORSES IN
GETTING ALL OF THIS DATA TO US
AND ALL THE SAMPLES PROCESSED
FOR US.
SO WITH THAT, WE'LL TAKE
QUESTIONS AND THANK YOU FOR YOUR
TIME.
[APPLAUSE]
>> PLEASE COME UP TO THE
MICROPHONE.
FOR THOSE ONLINE, SEND YOUR
EMAIL.
WE'RE VERY FORTUNATE DR. MAZUR
WILL CHECK THE QUESTIONS.
>> I'LL KICK OFF THE QUESTIONS
BECAUSE THERE DOESN'T SEEM TO BE
SOMEBODY DUELING AT THE OTHER
MICROPHONE.
REALLY NICE COMPOSITE
PRESENTATION AMONG ALL OF YOU.
REALLY ENJOYED IT.
ONE THING THAT COMES TO MIND
KIND OF RIGHT AT THE END IS, HOW
DO YOU IMPLEMENT OR TEST TO
VALIDATE THAT THE ADDITION OF
CELL-FREE DNA WILL HELP TRIAGE
AND ULTIMATELY HELP IMPROVE
OUTCOMES FROM CARDIOGENIC SHOCK?
SO CAN YOU DO A PRE/POST, IS
THERE A POINT OF CARE THAT YOU
CAN, YOU KNOW, IMPLEMENT TO BE
ABLE TO GIVE YOU THE TRIAGE
INFORMATION THAT YOU WOULD THEN
PROPOSE A DIFFERENT TRIAGE
SYSTEM AND COMPARE MORTALITY
BEFORE THE IMPLEMENTATION VERSUS
AFTER, BUT WHAT'S THE NEXT STEP?
HOW DO YOU KIND OF ASSESS
WHETHER THIS IS A MEANINGFULLY
ADDITIONAL USEFUL TOOL AT THE
BEDSIDE AT THE TIME OF
ADMISSION?
>> SO I COULD GIVE YOU A SENSE
OF THE TECHNOLOGY AND THEN
DR. O'BRIEN IS AN EXPERT IN THE
SYSTEMS, COULD HELP DO THAT.
SO THE TECHNOLOGIES ARE GETTING
WAY SMALLER.
WHEN I CAME HERE FOR FELLOWSHIP
AT THE NIH, THE SEQUENCING
MACHINE WAS ABOUT THIS BIG.
NOW WE HAVE SYSTEMS ABOUT THE
SIZE OF A FLASH DRIVE THAT YOU
CAN TAKE INTO THE FIELD, AND
THEN THEY'VE BEEN DIGITAL
DROPLET PCR SYSTEMS THAT HAVE
BEEN DEVELOPED WHICH CAN GIVE
YOU ASSAY TURNAROUND TIME WITHIN
HOURS.
THEN ON THE BLOOD COLLECTION
SIDE, THERE HAVE BEEN PAPER
STRIPS THAT HAVE NOW BEEN
DEVELOPED WHERE WITH THE PRICK
OF A FINGER, JUST LIKE A
GLUCOMETER, AND YOU DROP A FEW
OUNCES OF -- DROPS OF BLOOD ON
THE PAPER, IT CAN SEPARATE OUT
CELLS FROM PLASMA, GIVING YOU AN
OPPORTUNITY TO THEN ASSESS JUST
PLASMA.
SO I THINK THAT THE TECHNOLOGIES
ARE HERE NOW.
AND YOU KNOW, THE NIH DIRECTOR
HAS THIS GRANT WHICH IS CALLED
THE NIH DIRECTOR'S GRANT, WHICH
ALLOWS FOR HIGH RISK, BUT HIGH
IMPACT, WHERE YOU CAN
MINIATURIZE THESE DEVICES, AND
COLLEAGUES IN THE INSTITUTE OF
LABORATORY MEDICINE ARE
BEGINNING TO THINK ABOUT THOSE
APPROACHES.
SO THE TECHNOLOGIES ARE THERE
AND CAN BE DEVELOPED.
NOW HOW THEY WOULD IMPROVE
OUTCOMES, I THINK DR. O'BRIEN
CAN -- AND ASHLEY COULD GIVE
SENSE INTO THAT.
I WILL STEP BACK.
>> SO IT'S A VERY COMPLICATED
QUESTION AND I THINK ONE OF THE
THINGS THAT WOULD BE WHERE THE
USE CASE DIFFERS FROM THE PLACE
WHERE YOU HAVE YOUR PROOF OF
CONCEPT IS IMPORTANT HERE.
SO YOU GO TO A TERTIARY MEDICAL
CENTER AND YOUR ABILITY TO TEASE
OUT ALL THE SAFETY LAYERS THAT
COULD INTERVENE ON A PATIENT TO
GET THEM TO THE SAME PLACE IS
VERY, VERY DIFFICULT.
NOBODY IS GOING TO LET A PATIENT
JUST DRIFT.
AND THERE'S A LOT OF WAYS,
ESPECIALLY WHEN YOU HAVE PEOPLE
WORK IN AN ICU AND HAVE HEART
FAIL DOCTORS AROUND, THE DEEDS
RECOGNITION IS GOING TO BE EARLY
SO PEOPLE ARE GOING TO SEE LOW
PULSE PRESSURE AND CALL THE ICU
OR GET AN AN ECHO AND LOOK AT E
NUANCES OF THE ECHO.
SO I WOULD IMAGINE WHERE YOU'D
WANT TO PROVE THIS AFTER YOU
HAVE SOME SENSE OF WHAT DO THE
RELATIVE OUTCOMES ACROSS THESE
GROUPS AND IMPORTANTLY I THINK
WE HAVE TO GET TRAJECTORY OF
CHANGE ON CELL-FREE DNA, BECAUSE
USING IT AS A POINT OF CARE
ASSAY AT ONE POINT IN TIME IS
GOING TO BE DIFFICULT TO DEPLOY
IN A TRIAL WHEREAS IF WHAT WE'RE
PLANNING ON DOING IS USING DAY
ZERO THROUGH EIGHT AND IDENTIFY
WHETHER OR NOT TRENDS ARE
ASSOCIATED WITH THAT PEAK SCAI
SHOCK STAGE THAT'S COMING, COULD
YOU GET SOMEBODY'S ATTENTION
SOMEWHERE ELSE EARLIER.
SO I WOULD IMAGINE, BECAUSE WE
HAVE A LOT OF LEVEL 2 CICUs,
WHICH WE SHOWED IN PARTNER
CICUs WHICH ARE SHOWN ON THAT
MAP ESPECIALLY THROUGHOUT
CALIFORNIA WHERE THE VOLUME OF
CARDIOGENIC SHOCK IS QUITE HIGH
AND WE'RE WORKING ON A STUDY TO
REALLY DEMONSTRATE THAT, THE
MAJORITY OF CARDIOGENIC SHOCK IS
NOT SEEN IN TERTIARY CENTERS.
IT'S SEEN IN COMMUNITY CENTERS
WHO HAVE TO SEND A LOT OF THESE
PATIENTS OUT.
SO IF YOU START TRYING TO FIND
PARTNER CENTERS WHERE YOU COULD
CREATE A CARE ALGORITHM AND
RANDOMIZE PEOPLE DIAGNOSED WITH
HEART FAIL INTO A -- PATHWAY AND
NOT AND THEN FOLLOW THEM, THAT
IS WHERE I THINK WE WOULD END UP
FINDING EFFICACY AND ALSO MOVING
FURTHER DOWN THE PATIENT
EXPERIENCE LADDER.
THE EARLIER
YOU IDENTIFY THESE PATIENTS, A
THAT'S BETTER FOR THE THE
PATIENT, BUT B YOU HAVE LESS
TOOLS TO REPLACE THE ASSAY.
WE SEE THE MOST EFFECT IN
PREDICTIVE VALUE IN B AND C, BUT
BY THE TIME YOU GET TO D,
EVERYBODY KNOWS YOU'RE SICK,
RIGHT?
YOU DON'T NEED A WEATHER VANE TO
SAY THE WIND IS BLOWING.
IT WINDY.
SO WHEN YOU'RE GETTING -- MOVING
THE TECHNOLOGY, THE MORE THE
FIDELITY DIFFERENTIATES AT THE
EARLY PHASES OF DISEASE, THE
MORE PROMISING IT IS IN MY MIND
AND THAT BECOMES EASIER TO START
DEPLOYING IN THE COMMUNITY OR
TESTING THE COMMUNITY BECAUSE
THAT PATIENT POPULATION IS HUGE.
ONE OTHER THING DR. AGBOR DID
NOT SAY OUTRIGHT IS THAT THE
CELL-FREE DNA IS ALSO A CLIA
APPROVED LAB.
IT'S SOMETHING THAT'S KIND OF
READY TO GO.
SO YOU'RE LOOKING AT A
TECHNOLOGY THAT COULD ACTUALLY
START BEING DISSEMINATED
POTENTIALLY.
SO THERE'S LOTS OF THINGS ABOUT
IT THAT I THINK IS RIPE FOR USE,
DEPLOYABLE IN MEDICAL CENTERS
AND THAT'S WHERE I THINK WE
WOULD START TARGETING PEOPLE TO
SHOW BENEFIT.
>> THANK YOU FOR THE TALK.
I WANT TO GET YOUR THOUGHTS LIKE
WE'VE BEEN -- IN THIS STUDY WE
USE IT AS A BIOMARKER RISK
STRATIFICATION, DO YOU SEE IT AS
A VENUE TO BE USED AS A MARKER
FOR RESPONSE TO TREATMENT, TO
THERAPIES AS DRUGS OR MECHANICAL
SUPPORT?
>> I'LL TAKE THAT ONE.
SO THE SHORT ANSWER IS YES,
ABSOLUTELY.
WE HAVEN'T YET DONE THIS IN THIS
COHORT WHERE WE'VE TAKEN THE
LONGITUDINAL SAMPLES
>> D
>>SAMPLE IS ANDANALYZED THEM YEE
TAKEN SAMPLES, LOOK AT THEM
BEFORE AND AFTER AND SEE THEIR
CELL-FREE DNA LEVELS TRACKS IN
COWARD YAITION WITH AT LEAST
THEIR PHYSIOLOGY NUMBERS, RIGHT
ATRIAL PRESSURES AND WHATNOT.
SO I THINK THERE IS SOME PROMISE
IN USING CELL-FREE DNA TO TRACK
THE EFFICACY OF CERTAIN
TREATMENTS LIKE MCS, AND I'M
HOPING THAT, YOU KNOW, ONCE WE
GET OUR NUMBERS HIGHER UP IN
THIS THAT WE'RE GOING TO BE ABLE
TO LOOK AT THAT A LITTLE BIT
MORE DEEPLY.
>> IF I MAY ALSO, YOU CAN USE TO
TRACK.
THE OTHER THING THAT WE COULD
ALSO USE THIS FOR IS IF YOU
THINK ABOUT THE CELL-FREE DNA,
THERE'S QUITE A BIT OF DATA NOW
THAT'S COMING OUT SHOWING THAT
THE CELL-FREE DNA IS NOT JUST
FLOATING AROUND IN THE
CIRCULATION.
IT COULD BE A POTENTIAL DAMAGE
ASSOCIATED MOLECULAR PATTERN.
WHICH ON THE RECEPTORS OR THE
PATHWAYS OF THESE DAM IF YOU MAY
CALL THOSE HAVE BEEN REALLY WELL
MAPPED OUT.
IN THE LAST FEW YEARS, THERE
HAVE BEEN SOME NICE MONOCLONAL
ANTIBODIES THAT HAVE BEEN
DEVELOPED TARGETING THESE
PATHWAYS.
ASHLEY HAS SOME DATA ON LVAD
PATIENTS WHICH SHOW THAT THOSE
PATIENTS WHO HAVE REALLY HIGH
CELL-FREE DNA DERIVED FROM
NEUTROPHILS, DERIVED FROM SOME
OF THESE OTHER PATHWAYS, SOME OF
THESE OTHER INNATE IMMUNE CELLS,
THOSE PATIENTS SEEM TO HAVE THE
WORST OUTCOMES.
THE QUESTION THEN BECOMES IS
CELL-FREE DNA ALSO CONTRIBUTING
TO THE PROGRESSION OF THIS
DISEASE, NOT JUST AS A BIOMARKER
TO TRACK THE DISEASE, BUT AS A
PATHOGEN, IF YOU MAY USE SUCH A
WORD, CONTRIBUTING TO THAT
DISEASE.
AND THEREFORE BY TARGETING THESE
PATHWAYS, COULD YOU THEN
ALLEVIATE THESE UNFORTUNATE
PATIENTS FROM THESE
COMPLICATIONS.
SO THAT'S HOPEFULLY THAT ALSO
OPENS UP THIS AREA OF RESEARCH.
WE'LL SEE.
THANK YOU.
>> HAVE YOU APPLIED MACHINE
LEARNING TO THE ANALYSIS OF THE
BIOMARKERS, OR HAS IT BEEN MOST
LEHIGH POTASSIUM CYST-DRIVEN SO
MOSTLY HYPOTHESIS-DRIVEN SO FAR?
>> YOU JUST STICK MY EXCITEMENT
THERE QUITE A BIT.
SO THE ANSWER IS NO.
WE'VE BEEN THINKING ABOUT THIS
IN A VERY LINEAR WAY.
BUT THERE COMES -- I BELIEVE
SOME OF THE ADVANTAGES OF REALLY
GETTING A BUNCH OF RESEARCHERS
IN THE SAME SAND BOX.
I RUN INTO -- JAI IN THE
HALLWAY, TRUE STORY, AND SHE IS
PUTTING TOGETHER A MULTI-OMIC
BASED APPROACH TO LOOK AT
ANOTHER HETEROGENEOUS DISEASE,
WHICH IS HEART FAILURE IN THE
COMMUNITY NOW.
THAT'S WHERE I LEARNED ABOUT THE
POWER OF HOW YOU CAN INTEGRATE
ALL THESE NICE DATASETS INTO A
SINKSINGLE PLATFORM AND USE MACE
LEARNING TO THEN GET BETTER BANG
FOR YOUR BUCK THAN SINGLE
MODALITY APPROACHES.
SO THROUGH HER, WE'RE BEGINNING
TO LEARN THAT.
THEN WE'VE ALSO BEEN VERY
FORTUNATE THAT WE FOUND A
WONDERFUL STATISTICIAN WITH THAT
EXPERIENCE, SHEN CHANG AT NHLBI.
SO IF YOU HOLD THAT QUESTION AND
ASK US THAT NEXT YEAR, MAYBE
WE'LL BE ABLE TO GIVE YOU A
BETTER ANSWER.
BUT WE BELIEVE THAT MAYBE WE
SHOULD BE ABLE TO -- THE SYSTEM
BY USING MACHINE LEARNING MODELS
TO IMPROVE THEM.
>> I'D ALSO LIKE TO PUT IN A
PLUG FOR THE AI WORKSHOP ON
FRIDAY.
>> OH.
EVERYBODY, AI WORKSHOP ON
FRIDAY.
>> ONE THING I WANTED TO THROW
IN THERE FOR MACHINE LEARNING,
ONE OF THE SIGNIFICANT
CHALLENGES THAT EXISTS FOR A LOT
OF MCS RESEARCH AND SHOCK
RESEARCH IS THE PHENOTYPING IS
NOT CONSISTENT.
SO IF YOU LOOK AT DIFFERENT
REGISTRIES, SCAI SHOCK HAS
SLIGHTLY DIFFERENT DE DEFINITIOS
ACROSS DIFFERENT REGISTRIES.
SO ONE CHALLENGE THAT THE FIELD
HAS WHEN YOU START POOLING THIS
TOGETHER, EVEN THOUGH THE SAME
LETTER VALUE IS ATTACHED TO
SPECIFIC PATIENTS, ALL OF A
SUDDEN YOU'RE GOING TO HAVE SOME
VARIATION.
AND THE OTHER THING THAT'S
REALLY TRICKY IS THAT SCAI SHOCK
STAGE, BECAUSE IT'S ALL DONE AT
THE REGISTRY LEVEL THUS FAR,
THERE ARE RULES FOR YOUR SCAI
SHOCK STAGING BUT I'M WILLING TO
BET AT SOME POINT IN THE FAR OFF
FUTURE, WE WILL FIND IT IS
IMPOSSIBLE TO DIVORCE WHAT WE
KNOW ABOUT THE PATIENTS FROM OUR
ASSESSMENTS OF THEIR ACUTITY AND
UNDERSTANDING WHAT THEIR
TRAJECTORY WAS.
THERE ARE A LOT OF THINGS ABOUT
AMYLOID PATIENTS WILL HAVE
NORMAL SIZED VENTRICLES AND IF
YOU GO THROUGH AN AI MODEL,
THEY'RE GOING TO BE VERY DIFFER
TO DIFFERENTIATE FROM PEOPLE
WITH HEALTHY VENTRICLES.
SO YOU HAVE TO BE REALLY CAREFUL
THAT YOU'RE GOING TO LOSE
SPECIFIC SIGNALS BY HIGH RISK
PHYSIOLOGY BY BURYING IT AGAINST
THINGS THAT LOOK SIMILAR BY SOME
METRICS, AND REALLY ENCOURAGE
PEOPLE WHO WANT TO LEARN ABOUT
THIS VERY MUCH LIKE WE HAVE, IS
BE ULTRA SPECIFIC AND HANDLE THE
DATA YOURSELF AND ASK YOUR
QUESTION IN A VERY, VERY, VERY
TARGETED WAY BEFORE WE START
GETTING TOO DIFFUSE.
BECAUSE I FEEL LIKE WE'RE GOING
TO GET OURSELVES LOST IN THE
WEEDS CHASING THE GOLD AT THE
END OF THE RAINBOW BEFORE WE'VE
EVEN STARTED IN A MEANINGFUL
WAY.
>> HI.
THANK YOU SO MUCH FOR
PRESENTATION.
I THOUGHT IT WAS MARVELOUS.
I HAVE TWO QUESTIONS, MAYBE
THREE.
THE FIRST QUESTION IS, ONE OF
THE SLIDES THAT DR. PARK SHOWED,
THERE WAS DEFINITELY A
DIFFERENCE BETWEEN SORT OF THE
PATIENTS WITH HIGHER NUCLEAR
CELL-FREE DNA AS WELL AS MIGHT
CON DREE A I BELIEVE SUBSEQUENT
SLIDES ALSO SHOW NUCLEAR
CELL-FREE DNA.
AND I WONDER THERE'S CORRELATION
SUBSEQUENTLY EVEN WITH THE
MITOCHONDRIAL CELL-FREE DNA.
THE SECOND QUESTION WAS, THE
LAST SLIDE, DR. PARK TALKED
ABOUT HOW IF YOU HAVE THIS
CELL-FREE DNA THEN, YOU CAN SORT
OF TRY TO TRACK THOSE PATIENTS
EARLY ON WHETHER THEY NEED M CS
OR OTHER INTERVENTIONS.
MY QUESTION IS, I WONDER IF YOU
CAN ALSO USE TO TRACK WHETHER
PATIENTS HAD REVERSIBLE OR
IRREVERSIBLE CARDIOGENIC SHOCK.
I DON'T KNOW IF DR. NATEESON IS
HERE, BUT HE TAUGHT ME THAT WHEN
PATIENTS UNDERGO SEPTIC SHOCK,
THERE IS A CARDIOGENIC INJURY
COMPONENT AND I WONDER IF THAT
HAS TO DO WITH WHAT DR. AGBOR
SAID ABOUT NEUTROPHILS AS A
CELL-FREE DNA PATHOGENIC PATHWAY
OR WHETHER IT HAS TO DO WITH
CERTAIN SORT OF THE CELLS WITHIN
THE HEART.
SO I WONDER IF CELL-FREE DNA
WOULD HAVE POTENTIAL TO SORT OF
DECIPHER THAT AS WELL.
AND THEN THE THIRD QUESTION I
GUESS IS, IF WE GET TO A WAY
WHERE IF IT'S JUST LIKE A BLOOD
DRAW, WHETHER WE CAN APPLY THIS
IN SORT OF RESOURCE LIMITED
SETTINGS NOT JUST IN CARDIOGENIC
SHOCK, BUT SEPTIC SHOCK, BECAUSE
YOU KNOW, MORTALITY AS WE KNOW
WITH SEPTIC SHOCK IS 50% OR
GREATER AND IN DEVELOPING
COUNTRIES IT'S HIGHER.
SO THOSE ARE MY THREE QUESTIONS.
>> I'LL START WITH THE FIRST
QUESTION WHICH IS MITOCHONDRIAL
CELL-FREE DNA AND WHY WE HAVEN'T
FEATURED THAT.
SO WE HAVE LOOKED AT
MITOCHONDRIAL DNA IN ASSOCIATION
WITH THESE SORT OF OUTCOMES.
IN GENERAL, RELATIONSHIP WITH
NUCLEAR CELL-FREE DNA AND THE
PROGRESSION IN DEATH IS OVERALL
STRONGER THAN MITOCHONDRIAL
CELL-FREE DNA.
I THINK ALSO FLAD OUR FOCUS HAS
BEEN ON NUCLEAR CELL-FREE DNA
BECAUSE A LOT OF OUR TISSUE
SPECIFIC RELIES ON NUCLEAR
DURAN, SO THAT IS MAINLY THE
REASON FOR WHY THAT WAS
FEATURED.
BUT YES, IT'S A FANTASTIC
QUESTION OF MIG MITOCHONDRIAL
CELL-FREE DNA AND WHETHER THAT
HAS ANY ROLE IN CARDIOGENIC
SHOCK AS WELL.
BUT THAT'S TO COME.
>> CAN I SAY, IF YOU DON'T MIND,
WE'LL TAKE THE REST OF YOUR
QUESTIONS IMMEDIATELY AFTER
THIS, BECAUSE FOR THE SAKE OF
TIME, IT'S A LITTLE -- 1 MINUTE
PAST THE HOUR, I WANT TO MAKE
SURE WE GIVE EVERYBODY THEIR
TIME BACK.
BUT REALLY THANK YOU FOR COMING
DOWN TO LISTEN TO ASHLEY AND TO
LISTEN TO DR. CONNOR, AND IF YOU
DO NOT MIND, YOU KNOW, AS A
MENTOR, SOMETIMES IT GREAT IF
YOU'RE CLAPPING FOR THE TRAINEE,
BUT IF YOU DO NOT MIND, VERY
KINDLY JOIN ME IN CLAPPING FOR
DR. CONNOR COMING ALL THE WAY
FROM UCSF TO VISIT US HERE.
HE'S GOING TO BE HERE FOR TWO
DAYS, AND ALSO REALLY WHAT COULD
GIVE A MENTOR SO MUCH JOY THAN
TO STAND AND CLAP FOR ASHLEY AS
WELL.
THANK YOU.
[APPLAUSE]
THANK YOU VERY MUCH.