WELCOME EVERYONE TO THE 2024
WORKSHOP ON RESEARCH IN THE
TREATMENT OF MITRAL VALVE
PROLAPSE.
THE WORKSHOP IS SPONSORED BY THE
NATIONAL NATIONAL HEART, LUNG
AND BLOOD INSTITUTE OF THE
U.S. NATIONAL INSTITUTES OF
HEALTH.
THE GOAL OF THE WORKSHOP IS TO
REVIEW THE STATE OF THE SCIENCE
AND IDENTIFY RESEARCH NEEDS AND
OPPORTUNITIES FOR THE TREATMENT
OF INDIVIDUALS WITH MITRAL VALVE
PROLAPSE INCLUDING THOSE AT RISK
FOR SUDDEN CARDIAC ARREST OR
SUDDEN CARDIAC DEATH.
IT'S NOT NECESSARY THE
PARTICIPANTS ACHIEVE CONSENSUS.
INDIVIDUAL PARTICIPANTS COULD
IDENTIFY DIFFERENT RESEARCH
NEEDS AND OPPORTUNITIES AND
THAT'S FINE.
THIS 2024 WORKSHOP IS AN UPDATE
OF OUR 2021 WORKSHOP AND PART OF
THE NHLBI'S IMPLEMENTATION OF
THE CARDIOVASCULAR ADVANCES IN
RESEARCH AND OPPORTUNITIES
LEGACY OR CAROL ACT.
THE WORKSHOP IS BEING CARRIED ON
TWO PLATFORMS.
ZOOM AND NIH VIDEOCAST.
ON ZOOM WE HAVE TWO OVERLAPPING
GROUPS OF PARTICIPANTS.
WE HAVE THOSE WHO PARTICIPATED
IN THE 2021 WORKSHOP, THANK YOU
FOR RETURNING.
AND WE HAVE PARTICIPANTS WHOSE
RESEARCH IS FUNDED IN PART BY
THE CAROL ACT AND TWO ADDITIONAL
PARTICIPANTS.
THE ZOOM PLATFORM ALSO HAS NHLBI
STAFF AND THE SUPPORT STAFF.
EVERYONE ELSE IS ON NIH
VIDEOCAST.
EACH PRESENTATION IS SCHEDULED
FOR 20 MINUTES.
THERE MAY BE TIME FOR DISCUSSION
AND QUESTIONS WITHIN THAT 20
MINUTES.
BUT THERE ARE ALSO DISCUSSION
PERIODS AT THE END OF EACH
SESSION.
THOSE ON ZOOM CAN ASK QUESTIONS
THROUGH THE Q&A FEATURE OF ZOOM.
THOSE ON VIDEOCAST AS YOU HEARD
A MOMENT AGO CAN SUBMIT
QUESTIONS THROUGH THE LIVE
FEEDBACK LINK.
THE LIVE FEEDBACK PRODUCES AN
E-MAIL IN A WORKSHOP SPECIFIC
MAILBOX.
WE'LL TRY TO MONITOR THAT
MAILBOX DURING THE WORKSHOP.
OKAY.
WE HAVE HAD A COUPLE LATE DROP
OUTS IN THE AGENDA.
WE HAD HOPED TO HAVE CONGRESSMAN
ANDY BARR, WHO IS THE ORIGINAL
SPONSOR OF THE CAROL ACT WHICH
IS IN FACT NAMED AFTER HIS WIFE
CAROL WHOSE DEATH WAS ATTRIBUTED
TO MITRAL VALVE PROLAPSE.
UNFORTUNATELY CONGRESSMAN BARR
CAN'T BE WITH US TODAY SO I
BELIEVE WE HAVE ALL OF THE
SPEAKERS FOR THE FIRST SESSION.
MY SUGGESTION IS WE'LL PROCEED
AND ADJUST THE AGENDA THROUGH
THE DAY AS NECESSARY.
DOES ANYONE HAVE THOUGHTS ON
THAT OR COMMENTS?
HEARING NONE -- YES.
>> SOUNDS GOOD.
>> LET'S DO THAT THEN.
I SEE NO REASON TO WAIT ANY
LONGER LET'S BEGIN WITH THE
FIRST SESSION ON IMAGING AND THE
FIRST SPEAKER IS JUDY HUNG FROM
MASSACHUSETTS GENERAL HOSPITAL.
JUDY.
TO FIND THE TREATMENT GAPS FOR
MITRAL VALVE PROLAPSE --
>> JUDY, WE HAVE A PROBLEM WITH
YOUR SOUND.
I DON'T KNOW IF YOU CAN DO
SOMETHING WITH YOUR MICROPHONE
BECAUSE OTHERWISE WE CAN'T HEAR
YOU OR I CAN'T HEAR YOU.
>> WE DID THE SOUND CHECK
EVERYTHING LOOKED FINE SO LET ME
SEE --
>> SOUNDS BETTER NOW.
IT'S CLEARER NOW.
>> OKAY.
WELL, THAT WAS GREAT WHOEVER
DISCLOSED THAT.
ANYWAY, LET ME KNOW IF I SOUND
METALLIC.
GOD FORBID I WANT TO SOUND MORE
LIKE AN A.I. AVATAR.
I HAVE NO FINANCIAL DISCLOSURES
BUT DIRECT THE PRIMARY CLINICAL
TRIAL.
EC
ECHOCARDIO GRAPHY IS AN IMAGE OF
THE HEART AND COMPARES TO OTHER
MODALITIES.
IT'S ALSO NONINVASIVE, SAFE
IMAGING MODALITY AND AVAILABLE
AND ACCESSIBLE AND RELATIVELY
COST EFFECTIVE.
ECHOCARDIOGRAPHY IS THE PRIMARY
INITIAL IMAGING MODALITY TO
DIAGNOSE MITRAL VALVE MITRAL
VALVE AND HAS A HIGH ACCURACY
RATE WITH A LARGE NUMBER OF
STUDIES CONFIRMING ACCURACY OF
DIAGNOSIS COMPARED TO SURGICAL
INSPECTION.
AND ECHO HAS HAD AN IMPORTANT
ROLE IN THE ACCURATE DIAGNOSIS
OF MITRAL VALVE PROLAPSE BASED
ON INSIGHTS FROM 3-D CARD YOKING
GRAPHY WHICH HELPED US REFINE
THE DIAGNOSIS OF MVP MAKING IT
MORE ACCURATE.
THE PREVALENCE OF MVP WAS FOUND
TO BE LOWER ON THAT PREVIOUSLY
THOUGHT IN AN NIH/NHLBI
FRAMINGHAM HEART STUDY.
PRIOR TO THE STUDY PUBLISHED IN
1999, THE PREVALENCE OF MVP WAS
THOUGHT TO BE ANYWHERE FROM 5%
TO 15%.
WHEN THEY APPLIED THE MORE
ACCURATE DIAGNOSIS OF MVP IT WAS
FOUND MORE A 2.4% PREVALENCE
WHICH IS A SIGNIFICANT CHANGE IN
OUR AWARENESS OF MVP.
SO MITRAL VALVE PROLAPSE IS
ESSENTIALLY DEFINED BY
ECHOCARDIOGRAPHIC CRITERIA.
ON THE LEFT IS NORMAL MITRAL
VALVE WITH THE IMAGE AND THE
NORMAL MITRAL VALVE CLOSURE IS
AT THE PLANE RIGHT HERE AND
SHOULDN'T HAVE LEAFLETS INTO THE
LEFT ATRIUM.
THAT'S THE ISSUE WITH MITRAL
VALVE PROLAPSE AS YOU SEE ON THE
SCREEN ON THE RIGHT IT'S WHEN
THE LEAFLET EXTENDS TWO MILL
MITERS INTO THE LEFT ATRIUM AND
SEE A NICE EXAMPLE HERE.
THE POSTERIOR LEAFLET BUCKLING
BELOW THE PLANE WITH THE
DIAGNOSIS OF MITRAL VALVE
PROLAPSE.
ALSO IMPORTANT TO DISTINGUISH
BETWEEN PROLAPSE AND MITRAL
VALVE FLARE AND THIS IS WHEN YOU
HAVE THE TIP OF THE LEAFLET INTO
THE ATRIUM AND TYPICALLY DUE TO
THE FACT OF A RUPTURED CORD AND
THE TIP IS FULLY INTO THE LEFT
ATRIAL CHAMBER.
AND THE IMPORTANT ISSUE WITH
RECOGNIZING FLAIL IS ONCE YOU
HAVE FLAIL, IT'S OFTEN ALMOST
ALWAYS ASSOCIATED WITH
SIGNIFICANT OR SEVERE MITRAL
REGURGITATION.
AND UNDERSTANDING THE MITRAL
CORDAL ANATOMY IS KEY CAN TO
UNDERSTANDING WHY PROLAPSE
DEVELOPS TO FLAIL LEAFLET AND
THE CORDS OF THE MITRAL VALVE
ONE ARE THE BASAL CORD FOUR TO
EIGHT IN EACH LEAFLET PROVIDING
THE BASIC STRUCTURAL SUPPORT.
HOWEVER, THE WORKHORSE CORDS ARE
THE PRIMARY CORDI AND ATTACH
ALONG THE TIPS OF THE LEAFLETS
AND RESPONSIBLE FOR COLLAPSING
OF THE LEAFLETS.
AND IN THE SCHEMATIC YOU SEE THE
PROGRESSION OF WHAT HAPPENS IN
THE NORMAL VALVE SITUATION TO
DEVELOP INTO PROLAPSE AND THEN
DEVELOP INTO FLAIL AND YOU HAVE
PNEUM OF NIGHT CORDS INTACT AND
HOLDING THE LEAFLETS TOGETHER.
IN THE PROLAPSE YOU HAVE THE
LEAFLET BODY EXTENDS INTO THE
LEFT ATRIAL BODY BUT STILL HAVE
SOME ELEMENT OF IS CHORDAL
RUPTURE AND AT THAT POINT WHAT
HAPPENS IS LEAFLETS YOU HAVE A
FLAIL PORTION OF LEAFLET.
SO THERE'S AN ANATOMIC SPECTRUM
FIBRAL ELASTICITY AND INCREASING
THE MORE ADVANCED FORMS OF
PROLAPSE WITH THE MOST SEVERE
FORM CALLED BARLOW'S DISEASE
NAMED AF THE CARDIOLOGIST WHO
FIRST DESCRIBED CLINICALLY AND
BY PHYSICAL DIAGNOSIS THE SIGNS
OF MITRAL VALVE PROLAPSE AND
LEAFLET.
SO FIBROELASTIC DEFICIENCY FIRST
DESCRIBED BY ALAIN CARPENTIER
AND YOU'LL HAVE RUPTURED CORDS
AND LEAFLET REDUNDANCY AND
THICKENING ON HIS TOLL -- HIS
HISTOLOGY ASSOCIATED WITH MITRAL
VALVE PROLAPSE.
THESE ARE THE CLINICAL FEATURES
YOU SEE IN FIBROELASTIC
DEFICIENCY.
THE PATIENTS ARE OLDER THAN 60
AND SHORT HISTORY OF VALVE
DISEASE AND ASSOCIATED WITH
FIBRAL INEFFICIENCY AND HAVE
THICKENING ASSOCIATED AND OFTEN
ISOLATED TO A SINGLE SEGMENT AND
OFTEN THE P2 SEGMENT.
CHORDALE ARE OFTEN THIN WITH
RUPTURE AND HAVE A SMALL SIZE
AND THERE ARE ABSENT CAL
FICTIONS.
LET'S TALK ABOUT OPPOSITE END
TERMED BARLOW'S DISEASE.
IT AFFECTS PATIENTS AT A YOUNGER
AGE.
THEY PRESENT LESS THAN 60 YEARS.
THERE'S OFTEN A LONG HISTORY OF
CARDIAC MURMURS AND CARDIAC
VALVE DISEASE PRESENT EARLY IN
AGE AND IT'S A VERY DIFFUSE
COMPLEX LESIONS WITH
MULTI-SEGMENT OR EVEN ENTIRE
VALVE INVOLVEMENT, LOSS OF
EXCESS TISSUE WITH THICK
REDUNDANT LEAFLETS AND
DEGENERATION OF THE LEAFLETS.
YOU HAVE OFTEN ELONGATED
THICKENED AND THEY EVENTUALLY
RUPTURE AND LARGE SIZES AND AND
CALCIFICATION IS OFTEN PRESENT.
AND I WANT TO POINT OUT THERE
ARE A LOT OF TERMS USED FOR
PROLAPSE MOMENT PEOPLE REFER TO
B
BARLOW'S AND THERE'S BILLOWING
LEAFLETS AND FLOPPY VALVE
SYNDROME BECAUSE IT LOOKS LIKE
AUTO FLOPPY EARS AND JOHN BARLOW
WHO CONTINUED TO THE TERM OF
SEVERE PROLAPSE.
THERE'S IN BETWEEN VARIANTS.
YOU CAN HAVE ADVANCE NOT JUST
ONE SEGMENT INVOLVEMENT BUT
MULTIPLE SEGMENTS INVOLVED AS
SHOWN HERE.
THERE'S THE P2 SEGMENT EXTENDS
TO THE P2 SEGMENT AND YOU CAN
SEE IT CAN HAVE FURTHER
ADVANCEMENT.
HERE YOU HAVE A FORM OF BARLOW'S
WHERE PRACTICALLY EVERY LEAFLET
IS ABNORMAL AND YOU CAN SEE THE
WHOLE POSTERIOR LEAFLET IS
PROLAPSED WITH A1 AND A3 ONE --
WITH ONE SEGMENT LOOKING NORMAL
BEFORE YOU CALL OUT A BARLOW'S
SITE.
FROM FIBROELASTIC DEFICIENCY YOU
SEE THE SPECTRUM OF MITRAL VALVE
PROLAPSE WE SEE BUT THERE ARE
ALSO PRODROMAL FORMS DESCRIBED
AS WELL.
THIS IS FROM WORK FROM THE MORPH
OLO
MORPHOLOGIES ARE NON-DIAGNOSTIC
BUT HAVE FEATURES CONSISTENT
WITH THE PROLAPSE AND OFTEN
CALLED THE PROTOMAL OR MINIMAL
SYSTOLIC DISPLACEMENT AND YOU'LL
HAVE EXCESS LEAFLET MOTION, AND
NOT QUITE MEETING THE CRITERIA
FOR PROLAPSE.
AND OFTEN YOU'LL GET THE ASEM TI
OF COAPTATION BETWEEN THE
POSTERIOR AND ANTERIOR LEAFLET
IN THE PRODOMAL FORM AS WELL.
IT'S NON DIAGNOSTIC BUT SHARES
FEATURES CHARACTERISTIC OF MVP.
ANOTHER IMPORTANT IMAGING
FEATURE OF MITRAL VALVE PROLAPSE
THAT ECHOCARDIOGRAPHY SHOW
ESSENTIALLY INDENTATIONS THAT
OCCUR IN THE INDENTATION BETWEEN
P2 AND P1 AND P3 AND THEY GET
EXAGGERATED AND IT'S A MECHANISM
FOR MIGHT RAL 3 -- MITRAL
REGURGITATION.
YOU CAN SEE WHAT HAPPENS HERE.
THESE ARE BEEN DEFINED AS
INDENTATIONS WHICH ARE GREATER
OR EQUAL TO 50% OF THE LEAFLET.
DEATH HAS TO BE AT LEAST 50% AND
ERROR SHOWS IN INDENTATION AND
IT'S IMPORTANT TO RECOGNIZE
BECAUSE THE CAUSE OF MR THAT IS
NOT DIRECTLY RELATED TO THE
FLAIL MECHANISM AND HAS
IMPLICATIONS FOR PLANNING FOR
TYPE OF REPAIR, SURGICAL VERSUS
TIER, FOR IF THERE'S SIGNIFICANT
PORTION OF THE MR THAT GOES
THROUGH A CLEFT THEN TIER IS
LESS LIKELY TO BE SUCCESSFULLY
DONE.
ANOTHER IMPORTANT ANATOMIC
FEATURE IS MITRAL ANULAR
DYSFUNCTION DISPLACEMENT OF THE
HINGE POINT BETWEEN THE ANULUS
AND LOOKS AT THE LEAVE LET
PROLAPSE AND THE CLINICAL
ASSOCIATION WE'RE INCREASINGLY
RECOGNIZING IS ASSOCIATED WITH
SUDDEN TEJ.
THIS IS A SPECIMEN OF MITRAL
ANNULAR DISJUNCTION.
THIS IS VERY DISCREET AND
ATTACHES THE ATRIAL PORTION TO
THE VENTRICULAR PORTION.
THIS IS ON THE RIGHT WHAT YOU
SEE WITH MITRAL ANNULAR
DISJUNCTION AND SEE WHERE THE
ATRIAL ANNULUS STARTS.
YOU HAVE THIS LONG FIBROUS
TISSUE THAT SEPARATES THE TWO
SPACES.
AND WHAT'S IMPORTANT ABOUT THE
MITRAL ANNULUS SYNDROME IT'S
FELT BECAUSE THE ABNORMAL SPACE
BETWEEN ANNULUS AND VENTRICLE
CAN RESULT IN ABNORMAL
MECHANICAL FORCES ON THE VALVE
AND MUSCLE WHICH CAN LEAD TO AN
ARRHYTHMIC SYNDROME.
THIS IS THE PAPER BY A GROUP
WHICH DEMONSTRATED AN
ASSOCIATION OF MITRAL ANNULAR
DISJUNCTION WITH VENTRICULAR A
RARIDGE -- ARRHYTHMIA AND SUDDN
DEATH.
AND LOOKING AT ECHO FEATURES OF
ARRHYTHMIC MITRAL VALVE
PROLAPSE, THIS GROUP DEFINED THE
PRESENCE OF MITRAL ANNULAR
DYSFUNCTION AND LEAFLETS AS
INDEPENDENT RISK FACTORS FOR
ARRHYTHMIAS IN THIS POPULATION.
AND THIS PATTERN BY ECHO
DESCRIBED AS A DOUBLE PEAK
STRAIN PATTERN IS POTENTIALLY A
MECHANISTIC MARKER THAT FOR
THESE ABNORMAL MECHANICS AND
FIBROSIS THAT OCCURS IN THE
SETTING OF MITRAL ANNULAR
DYSFUNCTION AND THIS DESCRIBES
THE MECHANICS THAT RELATE TO
MITO CARDIAL FIBROSIS IN
PATIENTS WITH MITRAL VALVE
PROLAPSE.
AND THIS IS FROM THE PAPER AND
WHAT YOU SEE ON THE TOP IS SORT
OF THE PRODOMAL FORM OF THE
SYSTOLIC PROLAPSE AND YOU HAVE
TIS PLACEMENT BUT NOT PROLAPSE
YET AND GET A SINGLE PEAK.
IN PATIENTS WITH MITRAL ANNULAR
DYSFUNCTION AND THE VENTRICULAR
MECHANICS BECAUSE OF THE EXTRA
TUG THAT HAPPENS YOU GET A
DOUBLE PEAK FORMED AS SHOWN HERE
THE SPECTRAL PATTERN BY ECHO.
AND IT'S THOUGHT THESE ABNORMAL
MECHANICS ARE ACTUALLY MARKERS
FOR FIBROSIS AND THIS SHOWS THE
DOUBLE PEAK PATTERN IS
ASSOCIATED AS BY MRI IS
ASSOCIATED WITH INCREASING OF
VENTRICULAR ARRHYTHMIA EVENTS.
THERE'S A NICE MECHANISTIC BASIS
FOR WHY THAT HAPPENS WITH A
DOUBLE PEAK IN THE ABNORMAL
MECHANICAL STRESS ON THE PATHWAY
MUSCLE.
AND OF COURSE ECHOCARDIOGRAPHY
IS THE MAINSTAY FOR HOW WE
ASSESS HOW MUCH MITRAL
REGIRTHTARE GUGIR GUGIR
REGURGITATION IS ASSOCIATED IN
THE MITRAL VALVE PROLAPSE SHOWN
HERE.
AND THE AMERICAN SOCIETY OF
ECHOCA
ECHOCARDIOGRAPHY HAS A BASE
INCLUDING ANATOMIC FEATURES OF
PRESENCE OF A FLAIL LEAFLET FOR
INSTANCE AND ENLARGED LV AND
COLOR DOPPLER CRITERIA BY ECHO
IN GOING ABOUT GRADING MITRAL
REGURGITATION AND WHETHER MILD,
MODERATE OR SEVERE AND MR
QUANTIFICATION.
TO SUMMARIZE, ECHO HE'S A ROLE
IN MITRAL VALVE PROLAPSE.
IT'S THE BASIS FOR DIAGNOSIS OF
MVP AND THE SUB A TOPIC SUB
TYPES.
THE FUNCTIONAL FEATURES ARE FELT
TO BE AT HIGH RISK FOR ADVERSE
EVENTS AN PERFORMED BY
ECHOCARDIOGRAPHY AND PROVIDES
THE ANATOMIC AND FUNCTION DATA
TO TAILOR THERAPY FOR PATIENTS.
THANK YOU VERY MUCH.
>> THANK YOU VERY MUCH, JUDY.
THAT WAS A VERY COMPREHENSIVE
DISCUSSION.
DOES ANYONE HAVE ANY BRIEF
QUESTIONS OR COMMENTS?
>> JUDY, IT'S DAVID ADAMS, HOW
ARE YOU?
>> GREAT, HOW ARE YOU?
>> I WANTED TO PLANT THE SEED
AND ONE TOPIC I LOOKED FORWARD
TO SPEAKING TO YOU ABOUT THE
FRONT END WHICH YOU TALK ABOUT
THE ANATOMY AND HOW THAT MIGHT
HELP US CHOOSE A POTENTIAL
OPTION INCLUDING MEDICAL
MANAGEMENT AND TIER IN TERMS OF
DEGREE BUT WHAT I HOPE WE CAN
TALK ABOUT A LITTLE WHILE LONGER
IS ABOUT THE POST REPAIR
ASSESSMENT.
I THINK THIS IS SOMETHING THAT
ALL OF US WANT TO GET MORE
EDUCATED ABOUT AS WE MOVE INTO
THIS AREA BOTH WITH SURGERY AND
WITH PARTICULARLY WITH TIER
BECAUSE I DON'T THINK IT'S
REALLY WELL DEFINED OUTSIDE
EXACTLY HOW ALL THE OUTCOMES GET
GRADED AND HOPING WE CAN LEAVE
THIS AS AN ACTION ITEM FROM THE
MEETING HOW WILL WE ASSESS
POST-REPAIR OUTCOMES IN
PATIENTS.
>> WE'RE LEARNING HOW TO
QUANTITATE AND AS WE
INCREASINGLY RECOGNIZE THE
IMAGING MARKERS FOR HIGH RISK
SUCH AS SUDDEN DEATH I THINK
THEY CAN BE LOOKED AT POST
SURGERY OR POST INTERVENTION TO
SEE IF THEY IMPROVE.
I KNOW PART OF ONE OF THE
RESEARCH GRANTS FUNDED BY THE
CAROL ACT IS ONE OF THE
FEATURES.
>> WE'VE BEEN INVOLVED IN THE
TRANS-CATHETER TRIALS AND DEPEND
ON THE CRISP AN CLEAR DATA AND
THEN MOVE TO CLINICS AND IT'S
NOT SO CLEAR WHAT IS SUCCESS
ANYMORE.
I THINK WE HAVE AN OPPORTUNITY
OR I CERTAINLY THINK IT'S AN
ACTIVE AREA FOR RESEARCH IS HOW
ARE WE GOING TO ASSESS OUTCOMES
NOT JUST IDENTIFY PATIENTS AND
TREATMENT BUT ALSO ASSESS
OUTCOMES INCLUDING HOW DO WE
CREATE SOME WAY TO DO MORE THAN
JUST IMMEDIATE POST PROCEDURE TD
ASSESSMENT.
WE HAVE TO THINK ABOUT THAT AS A
GROUP.
YOU NEED TO LOOK AT POST REPAIR
INTERVENTION AND MAY BE AN AREA
WHERE ARTIFICIAL INTELLIGENCE
CAN HELP US BY DEVELOPING
ALGORITHMS THAT ARE POTENTIALLY
MORE PRODUCIBLE AND NOT JUST
WITHIN CORE LAPSE AND I KNOW
AGAIN ONE OF THE RESEARCH GRANTS
IS LOOKING INTO RADIOMICS TO
ASSESS THAT.
>> I'LL LET THE FLOOR KEEP
MOVING.
THANK YOU.
IS
>> THE NEXT SPEAKER IS DIPAN
SHAH FROM HOUSTON METHODIST.
>> THANK YOU, FRANK AND THANKS
TO THE NIH AND I THINK JUDY DID
AN OUTSTANDING JOB OF SETTING UP
THE BACKGROUND BEHIND MIGHT RAL
VALVE PROLAPSE AND TALKING ABOUT
THE VALUE OF ECHOCARDIOGRAPHY
AND THE INITIAL ASSESSMENT WILL
START WITH THAT AND SOMEWHERE
THERE'S QUESTIONS STILL
REMAINING AFTER ECHOCARDIOGRAPHY
WHERE IT CAN BE USEFUL.
ONE AREA IS IN ASSESSING THE
SEVERITY OF REGURGITATION.
I THINK MOST OF US IN OUR
PRACTICE HAVE ADOPTED THAT IN
CASES WHERE DISCREPANCY OF
REGURGITATION CARDIAC MRI CAN BE
USEFUL TO LOOK AT THE
REMODELLING OF THE VENTRICLE AND
REFLECTED IN THE ASE GUIDELINES
IN 2017 WHICH HIGHLIGHTED THE
ROLE FOR CARDIAC MRI.
WITH THAT BACKDROP I'LL FOCUS IS
HOW CARDIAC MRI IN THE
ASSESSMENT OF THE ARRHYTHMIC
PHENOTYPE.
AND MITRAL VALVE PROLAPSE NOT
UNCOMMON BY ANY MEANS.
EITHER BY THE CURRENT DEFINITION
WHICH ARE MORE IMPROVED COMPARED
TO WHAT PEOPLE WERE USING IN THE
'70s AND '80s AND PRESENT IN 2%
TO 3% OF THE POPULATION AND
THOUGHT TO BE BENIGN SOME CAN
EXPERIENCE ARRHYTHMIAS AND
CARDIAC DEATH.
IF YOU LOOK AMOUNT THE LEFT SIDE
THIS IS ONE ESTIMATE OF THE
ANNUAL INCIDENTS OF SUDDEN
CARDIAC DEATH IT IN THE GENERAL
POPULATION HIGHER IN THE
PATIENTS WITH MITRAL VALVE
PROLAPSE BUT NOT AS HIGH AS
REPORTED COHORTS OF OTHERS AND
THE PARADOX OF NUMBERS IS THE
PROLAPSE IS PRESENT OR
PREVALENCE IS HIGHER THAN
HYPERTROPIC CARDIOMYOPATHY AND
THE EVENTS PLAY BE HIGHER THAN
WHAT OCCURS FROM HYPERTROPIC
CARDIOMYOPATHY AND THE ABSOLUTE
NUMBER OF EVENTS.
THOUGH THE OVER ALL INDENTS ARE
LOW IN MITRAL VALVE PROLAPSE
BECAUSE OF THE LARGE PREVALENCE
OF PATIENTS IT'S AN IMPORTANT
THING TO STUDY.
THIS HIGHLIGHTS THE RISK AND WE
NEED TO IDENTIFY THE SUB GROUP
THAT INCREASED ARRHYTHMIC RISK.
SO, THERE'S A NUMBER OF PROPOSED
MARKERS OUT THERE.
MANY OF THE PANELISTS REALLY
RESPONSIBLE FOR CONTRIBUTING
THIS LITERATURE.
WE TALK ABOUT MONITORING AND
PREMATURE VENTRICULAR ACTION AS
A RISK FACTOR IN MITRAL VALVE
PROLAPSE AND DYSFUNCTION OF
STRAIN PATTERN AND THIS PATTERN
STRIKED AS WELL.
AND SO WHAT I'M GOING TO DO IS
SEE HOW CARDIAC MR CAN HELP
BUILD THE MARKERS AVAILABLE OR
PROPOSED FROM ECHOCARDIOGRAPHY
AND YOU LOOK AT THE MOTION IN
PATIENTS WITH THOSE WITH THE
ADVANTAGE OF MRI WE HAVE THIS
HYPER DYNAMIC MOTION OF THE
LATERAL AND BASAL WALL OFTEN
FITTING OF THE MID LATERAL WALL
WHERE THE MUSCLE INSERTS AND IF
THE MOVIE WOULD CONTINUE IT
WOULD SHOW YOU IN THE PATIENTS
WITH MITRAL VALVE PROLAPSE OFTEN
YOU CAN HAVE A PARADOXICAL
MOTION OF THE MUSCLE WHERE ON
THE LEFT SIDE IT SHOULD DESCEND
TOWARD THE APEX TOWARDS THE
PROLAPSE AND IN BARLOW'S
PATIENTS YOU SEE THE MUSCLE
MOVING PARADOXICALLY UPWARD
THROUGH THE ANNULAR PLANE
OPPOSED TO DOWN TOWARDS THE
APEX.
S
I THINK THE ABILITY TO SEE THE
MORPHOLOGY OF THE VENTRICLE AND
VALVES AND THE DYNAMIC OF THE
MOTION BY MRI CAN BE HELPFUL.
ONE WAY IT'S ADDED INSIGHTS IS
IN TRYING TO BETTER CHARACTERIZE
MITRAL ANNULAR DYSFUNCTION AND
TO SEPARATE WHAT'S TRUE
DYSFUNCTION FROM PSEUDO MAB.
THIS WAS BROUGHT UP IN THE
JOURNAL OF THE AMERICAN SOCIETY
OF ECHO YEARS AGO LOOK BEING AT
A TRUE SEPARATION FOR
DYSFUNCTION FROM THE BOTTOM
RIGHT WHERE YOU SIMPLY ARE
HAVING THE MITRAL LEAFLET WHICH
IS HUGGING UP AGAINST THE LEFT
WALL AND CAN BE HARD TO SEPARATE
THE ATRIAL WALL FROM THE LEAFLET
HUGGING NEXT IT THE WALL AND
MAKE SURE YOU'RE LOOKING AT
IDENTIFYING TRUE ANNULAR
DYSFUNCTION VERSUS THIS ENTITY.
AND THEN A RECENT PUBLICATION
FROM THE U.K. BIO BANK LOOKING
AT A SERIES OF PATIENTS AND
FOUND THAT SOME LEVEL OF
DISPLACEMENT OR DISJUNCTION CAN
BE PRESENT IN A LARGE NUMBER OF
PATIENTS FROM THE U.K. BIO BANK.
IN FACT FROM NEARLY 2600
PATIENTS INCLUDED THEY FOUND
THAT DYSFUNCTION COULD BE
PRESENT IN AS MANY AS
THREE-QUARTERS OF THE CASES AND
MOST COMMONLY IN THE INTERIOR
AND ANTERIOR WALLS AND OUR
UNDERSTANDING MAY HAVE
PROGRESSED OVER THE LAST FEW
YEARS IN SOME PART WITH THE AID
OF CARDIAC MRI AND DYSFUNCTION
IN THE LATERAL WALL WHICH MAY BE
MORE IMPORTANT THAN THIS
JUNCTION WHICH MAY BE EVIDENT OR
APPEAR TO BE IN OTHER AREAS AND
MAY NOT HAVE AS MUCH
SIGNIFICANCE.
SO I THINK A FEW QUESTIONS I
THINK WILL BE USEFUL FOR US OVER
THE COURSE OF THE NEXT FEW YEARS
THE RESEARCH IS DONE TO TRY TO
BETTER UNDERSTAND ANNULAR
DYSFUNCTION AND UNDERSTAND THE
TRUE DEFINITION AND IS THIS A
MEASURE YOU DO IN DIASTOLIC AND
WHICH WHERE NORMAL ANATOMIC
VARIANTS AND CAN IT OCCUR
WITHOUT MITRAL VALVE PROLAPSE OR
IS AN ENTITY ASSOCIATED WITH
MITRAL VALVE PROLAPSE AND THE
QUESTION IS IS IT AN INDEPENDENT
SUBSTRATE FOR ARRHYTHMIC RISK
AND DOES IT RESOLVE AFTER MITRAL
VALVE REPAIR AND DOES ARRHYTHMIC
RISK CORRECT AFTER REPAIR?
THAT'S IMPORTANT TO ASK.
I'LL SHIFT THE FOCUS TO TALK
ABOUT THIS PUBLICATION IN 2015.
AN AUTOPSY SERIES OF PATIENTS
FROM THE BENITO REGION OF ITALY
OF PATIENT WHO'S SUFFERED SUDDEN
DEATH AND LOOKED AT THE
AUTOPSIES OF THE PATIENTS.
MITRAL VALVE PROLAPSE WAS THE
ONLY THING IDENTIFIED IN 70% OF
THE CASES AND 13% OF THE WOMEN
THAT SUFFERED SUDDEN CARDIAC
DEATH IN THE REGISTRY.
MOST CASES WERE MITRAL VALVE
PROLAPSE.
AND 90% OF THE PATIENTS
CLASSIFIED AS SOME DEATH WITH NO
ABNORMALITY OTHER THAN MITRAL
VALVE PROLAPSE, WHICH AGAIN WAS
NEARLY 50 PATIENTS, THEY HAD
HISTOLOGIC EVIDENCE OF FIBROSIS
ON THE MUSCLES AT AUTOPSY.
BRINGING UP THIS HYPOTHESIS THAT
FIBROSIS MAY REPRESENT THE
ANATOMIC SUBSTRATE IN
ARRHYTHMIAS.
THE STUDY A GROUP DID WAS
LOOKING AT THE PART BY AUTOPSY.
AND THE WAY TO IDENTIFY FIBROSIS
IN THE CARDIUM IS ENHANCEMENT
MRI AND WE'VE SEEN IT EVOLVE
SINCE ITS FIRST DEVELOPMENT.
AND THIS IS AN EX VIVO IMAGING
MODEL.
AND LOOKING AT THE HISTOLOGIC ON
THE LEFT AND ENHANCED MRI ON THE
RIGHT YOU CAN SEE HOW CLOSELY
THEY MIRROR AND TRACK EACH
OTHER.
IF WE EMPLOY THIS TECHNIQUE TO
LOOK AT THIS FIBROSIS SUBSTRATE,
WHAT DO WE SEE?
THIS IS A PUBLICATION FROM A FEW
YEARS AGO FROM OUR GROUP WHERE
WE LOOKED AT PATIENTS WHO
PRESENTED WITH MITRAL VALVE
PROLAPSE AND COMPARED THEM TO A
GROUP OF PATIENTS WITH PRIMARY
MR WITHOUT MITRAL VALVE
PROLAPSE.
HERE'S A CASE WHERE YOU NOTICE
IN THE LATERAL WALL
CORRESPONDING TO WHAT WAS SEEN
ON THE AUTOPSY STUDY, THERE'S
EVIDENCE OF HYPER ENHANCEMENT WE
SEE IN THE BASAL AND THEN
INTRALATERAL WALL AND THE MID
MITOCARDIAL PATTERN OF
ENHANCEMENT.
IN THIS SERIES WHEN WE COMPARED
THE LEFT HAND GROUP THE ONES IN
BLUE WITH THE PATIENTS WITH
MITRAL VALVE PROLAPSE AND THOSE
WITHOUT MITRAL VALVE PROLAPSE
AND THERE WERE AREAS WHERE IT
WAS EVIDENCE IN THE DELAYED
ENHANCEMENT MRI AND IN THE BASAL
INTRALATERAL WALL AGAIN
CORRESPONDING WHAT WAS SEEN ON
THE HISTOLOGIC STUDIES AND ALSO
NOTICE COMPARED TO A GROUP OF
PATIENTS THAT HAVE A SIMILAR
DEGREE OF MITRAL REGURGITATION
THE PREVALENCE IS HIGHER IN THE
SEGMENT.
THIS STUDY PROVIDES ONE LEVEL OF
EVIDENCE OF FIBROSIS THAT OCCURS
UNIQUE TO MITRAL VALVE PROLAPSE
AND LOCALIZED PRIMARILY TO THESE
ENTINTERIOR AND INTRALATERAL WA
SEGMENTS.
THIS SHOWED THE RELATIONSHIP
BETWEEN THE PREVALENCE OF
FIBROSIS IN THE COHORT AND THE
SEVERITY OF MIGTRAL REGIRTHTATIN
-- REGURGITATION AND SEE
PATIENTS WITH SEVERE MR AND
MITRAL VALVE PROLAPSE ALMOST
HALF HAD EVIDENCE WITH DELAYED
ENHANCEMENT MRI AND IN THE
CONTROL GROUP WITHOUT MITRAL
VALVE PROLAPSE THE OVER ALL
PREVALENCE WAS LOWER AND NOT
RELATED TO SEVERITY OF MITRAL
REGURGITATION.
WE LOOKED AT ARRHYTHMIC EVENTS
AND WHAT WE NOTICED WAS THE
RIGHT HAND BAR WERE THOSE
PATIENTS WITH MITRAL VALVE
PROLAPSE AND SCAR AND THE
INCIDENTS OF ARRHYTHMIC EVENTS
WAS HIGHER IN THAT GROUP OF
PATIENTS THAN THOSE WITH MITRAL
VALVE PROLAPSE WITH NO EVIDENCE
OF FIBROSIS ON DELAYED
ENHANCEMENT MRI OR THE CONTROL
GROUP WITHOUT MITRAL VALVE
PROLAPSE.
SINCE THE OVER ALL NUMBER OF
EVENTS WAS SMALL, MULTI-VARIATE
ANALYSIS COULD NOT BE DONE BUT
THERE WAS PRESENCE OF FIBROSIS
AND THE ETIOLOGY OF THE MITRAL
REGURGITATION WERE THE FACTORS
ASSOCIATED WITH THE INCREASED
ODDS RATIO OF THE ARRHYTHMIC
EVENT.
AFTER THAT PUBLICATION FROM A
FRENCH GROUP WHERE THEY LOOKED
AT DATA FROM TWO COHORT OR TWO
CENTERS AND BEEN LOOKED TO
IDENTIFY FIBROSIS SUBSTRATE IN
PATIENTS WITH MITRAL VALVE
PROLAPSE AND INCREASING
REGURGITATION WAS ASSOCIATED
WITH THE INCREASED PREVALENCE OF
HAVING FIBROSIS BY DELAYED
ENHANCEMENT MRI IN THE COHORT
AND LOCALIZED IT TO A SIMILAR
REGION AROUND THE BASAL
INFRALATERAL WALL AND THEN ON
LONGITUDINAL FOLLOW-UP THEY
LOOKED AT EMBOLISM AND
ARRHYTHMIAS AND THOSE WITH
EVIDENCE OF FIBROSIS BY MRI HAD
A WORSE EVENT PRESURVIVAL THAN
THOSE WITH PROLAPSE BUT NO
EVIDENCE OF FIBROSIS BY MRI.
THIS WAS ANOTHER PUBLICATION
THAT CAME OUT A YEAR AFTER THE
PRIOR ONE AND THIS WAS A
MULTICENTER RETROSPECTIVE
EUROPEAN COHORT LOOKING AT CLOSE
TO 500 PATIENTS FROM DIFFERENT
SITES.
THE COMPOSITE END POINT WAS
SUDDEN DEATH OR SUSTAINED VP OR
UNEXPLAINED SYNCOPE AND
STRATIFYING BY ABSENCE OR
PRESENCE OF MRI AND NOTICED THE
PATIENTS WITH MITRAL VALVE
PROLAPSE OR FIBROSIS HAD LOWER
SURVIVAL COMPARED TO PATIENTS
WITH MITRAL VALVE PROLAPSE
WITHOUT EVIDENCE OF FIBROSIS AND
DIDN'T SEE MUCH IN THE WAY OF
SEPARATION OF THE DISRUPTION.
THEN I'LL SHARE RECENT DATA FROM
OUR SITE PUBLISHED OR PRESENTED
AT AHA RECENTLY.
THIS IS NOW LONGITUDINAL
FOLLOW-UP ON 550 PATIENTS AND A
LITTLE OVER FOUR YEARS AND
EQUALLY DIVIDED BETWEEN MEN AND
WOMEN.
HERE NOW WE HAD A TOTAL OF 58
COMPOSITE EVENTS AND THE
COMPOSITE HERE WAS SUDDEN DEATH,
AVOIDED SUDDEN DEATH OR
SUSTAINED VENTRICULAR CARDIAC
WITH REPLACEMENT OR PROCEDURE.
AND THE PRESENCE OR ABSENCE OF
LGE IN THE COHORT OF PATIENTS
WITH MITRAL VALVE PROLAPSE
SEEMED TO SEPARATE THOSE LIKELY
TO HAVE AN EVENT VERSUS THOSE
UNLIKELY TO HAVE AN EVENT WITH A
HAZARD OF EVENTS IN MITRAL VALVE
PROLAPSE WITH EVIDENCE OF
FIBROSIS BY DELAYED ENHANCEMENT
MRI.
INTERESTINGLY IN THE COHORT
DESPITE THE PREVALENCE OR SEX
PREVALENCE WITH THE GROUP WAS
EQUAL, 50% MEN AND 50% WOMEN,
MOST EVENTS IN FACT 75% OF
EVENTS OCCUR IN WOMEN.
THIS SHOWS STRATIFICATION OF
LIKELIHOOD OF A COMPOSITE EVENT
STRATIFIED BOTH BY SEX AND
PREVALENCE OF LGE.
WHAT YOU'LL NOTICE IF YOU LOOK
THET GREEN DASH LINE WITH MEN
WITH NO FIBROSIS WITH MRI HAD
LOWEST COMPOSITE EVENTS OR
MIDDLE IS WOMEN WITHOUT FIBROSIS
WHERE THERE WAS AN IMMEDIATE
COMPOSITE EVENT AND THE NUMBER
OF EVENTS OCCURRED IN WOMEN WITH
EVIDENCE OF FIBROSIS EVIDENT ON
MRI.
AND AGAIN WITH THE LARGER NUMBER
OF EVENTS ALLOWED FOR COVARIATES
AND WE ADJUSTED FOR SEVERITY AND
PROLAPSE AND ADJUST FOR MITRAL
ANNULAR DYSFUNCTION SEVERITY AND
THE TWO FACTORS THAT REMAIN
INDEPENDENTLY SIGNIFICANT WERE
PRESENCE OF LGE OR FIBROSIS
DETECTED BY MRI WITH OVER
THREE-FOLD HIGHER HAZARD AND
FEMALE SEX WITH A THREEFOLD
HIGHER HAZARD OF COMPOSITE
EVENTS.
THE OTHER QUESTION THAT COMES UP
IS MOST THE DATA SO AS FAR WITH
REGARD TO DELAYED ENHANCEMENT
MRI WITH FIBROSIS USED A
TECHNIQUE EXCELLENT FOR
IDENTIFYING FIBROSIS WITHIN THE
SEGMENTS.
I'LL SHOW YOU NOW THERE'S A
NEWER TECHNIQUE WE'RE ABLE TO
EMPLOY A DARK BLOOD TECHNIQUE
WE'VE BEEN USING SEVERAL YEARS
WHICH IS VERY GOOD FOR
IDENTIFYING PAPULAR MUSCLE
FIBROSIS AND MAY BE NOT CLEARLY
EVIDENT BUT THE DARK TECHNIQUE
WHERE IT SUPPRESSES IT IT'S ABLE
TO ALLOW YOU TO ASSESS FOR
FIBROSIS WITHIN THE PAPULARRY
MUSCLES AND THE QUESTION IS WE
NEED TO PROBABLY LOOK AT A
COMBINATION OF THE FIBROSIS
WITHIN THE WALL AND WITHIN THE
PAPULARMUSCLES.
AND WHAT ABOUT INTERSTITIAL
FIBROSIS WHICH MAY BE A MORE
DYNAMIC PROCESS.
WE DO MAPPING TO ALLOW THE
ESTIMATION OF THE VOLUME
REFRACTION WHICH HAS ASSOCIATION
WITH INTERSTITIAL BURDEN BASED
ON HISTOLOGY SAMPLING.
AND THIS IS A PUBLICATION FROM
OUR GROUP YEARS AGO WHERE WE
LOOKED AT PATIENTS WITH MITRAL
VALVE PROLAPSE AND THE CONTROL
GROUP AND NOTICED ACROSS THE
SPECTRUM OF SEVERITY THERE'S AN
INCREASING IN VOLUME REFRACTION
THAT SEEMS TO BE RELATED OR
SEEMS TO BE INDEPENDENT OF
SEVERITY OF ETIOLOGY WHETHER
MITRAL VALVE PROLAPSE OR
NON-PROLAPSE.
AND I'LL WRAP UP IN A COUPLE
SECONDS.
THERE'S MORE RECENT WORK FROM A
GROUP AND UCSF WHERE THEY
PUBLISHED RECENTLY THE THOSE
WITH THE ARRHYTHMIC PHENOTYPE
VERSUS THOSE THAT DO NOT AND AT
LEAST WITH REGARD TO THE ARE
AREEGE -- AREEGE DEF
AAND THINKING HOW TO APPROACH
THE ISSUE OF ARRHYTHMIC MVP
FIBROSIS REPRESENTS ONE
SUBSTRATE BUT IS PROBABLY ITSELF
NOT THE ONLY FACTOR.
SO WE NEED TO TAKE A
MULTI-FACTORIAL APPROACH AND I'M
EXCITED ABOUT THIS
MULTI-MODALITY APPROACH BEING
EMBARKED UPON HERE.
AND ULTIMATELY BECAUSE I'LL
SHARE WITH YOU QUICKLY A PROJECT
ONGOING AT HOUSTON METHODIST
WITH A TEAM PHENOTYPING COHORT
ENROLLING PATIENTS WITH MITRAL
VALVE PROLAPSE AND INTERSTITIAL
FIBROSIS AND MONITORING TO
QUANTIFY ARRHYTHMIC BURDEN AND
BLOOD SAMPLIING SAMPLE UTILIZED
PROTEOMIC PLATFORMS AS WELL.
AND LASTLY THE FINAL AIM WITH
THIS PROJECT IS TO COMBINE A
COHORT OF NEARLY 2,000 CARDIAC
MRI STUDIES DONE ACROSS SEVERAL
SITES AND TRY TO IDENTIFY A RISK
PREDICTION MODEL FOR MITRAL
VALVE PROLAPSE USING CARDIAC MRI
AS POTENTIALLY A SEN IS --
CENTRAL MARKER.
THANK YOU FOR YOUR ATTENTION.
>> THANK YOU, DIPAN, THAT WAS
EXCELLENT.
WE RECEIVED A QUESTION FROM THE
VIDEOCAST JUST AFTER JUDY'S TALK
BUT IT'S KIND OF A GENERAL
QUESTION SO I'D LIKE TO DEFER
THAT UNTIL THE DISCUSSION AT
THEN OF THE SESSION.
IN THE MEANTIME DOES ANYONE HAVE
QUESTIONS OR COMMENTS ABOUT
DIPAN'S ?
-- PRESENTATION.
>> THIS IS MAURICIO.
CAN YOU COMMENT ON THE SPECIAL
AND TEMPORAL RESOLUTION OF MRI
BECAUSE IN THE DESCRIPTION OF
THE ANATOMIC FEATURE OF THE
MITRAL VALVE I'M A BIG BELIEVER
IN THE FIBROSIS AND METRICS.
I'M A LITTLE CONCERNED ABOUT THE
ABILITY TO SEE IN TIME ALL THE
STRUCTURE AND IN PARTICULAR THE
ANNULUS AND I'M CONCERNED A LOT
OF THINGS ON THE MAD IN THE MRI
LITERATURE MAY BE RELATED TO
DIFFICULT ASSESSMENT OF THE
MITRAL ANNULAR STRUCTURE.
>> THAT'S A GET QUESTION.
IF YOU LOOK AT WHAT THE SCMR
GUIDELINES FOR SPATIAL AND
TEMPORAL RESOLUTION FOR IMAGES
AN IN MANY LABS DO HIGHER
SPATIAL RESOLUTION THAN THAT BUT
WANT TO TARGET BETWEEN IT 25 TO
30 MILLISECOND RESOLUTION AND
SPATIAL RESOLUTION IS IN THE
ORDER OF ONE AND A HALF TO TWO
MILLIM
MILLIMETERS.
I AGREE ONE THING IS WHEN WE
LOOK AT THE CASES FOR MAD IT'S
TO GO FRAME BY FRAME THROUGH
THIS AND TRY TO SEPARATE OUT
ESPECIALLY WHERE THE LEAFLET
SEEMS TO BE HUGGING UP AGAINST
THE WALL WHICH ON A FRAME BY
FRAME ANALYSIS YOU CAN GET SOME
ASSESSMENT OF THAT.
BUT I AGREE WITH YOU IF WE HAVE
ULTRA HIGH IMAGING WHICH NO ONE
HAS AT THIS POINT WOULD HELP
FURTHER SORT THIS OUT.
>> I JUST WANT TO COMMENT ON
BUILDING A COMMUNITY OF INTEREST
IN THIS AREA AS THIS WORKSHOP IS
DOING.
I WANTED TO SAY YOUR PAPER IN
2018 ABOUT THE FIBROSIS.
OF COURSE THE IDEA HAD BEEN
INTRODUCED WITH DATA FROM THE
GROUP AND PATHOLOGY BEFORE BUT
THE FIRST LARGE GROUP SHOWING
THE PREVALENCE OF THIS MITRAL
CARDIO FIBROSIS STIMULATED THE
THINKING OF OUR GROUP TO MOVE
AHEAD AND EXPLORE MECHANISTIC
POSSIBILITIES AND PROGNOSTIC
IMPLICATIONS.
I WANTED TO COMPLIMENT YOU ON
STARTING THE BALL MOVEMENT IN
GOOD DIRECTIONS.
>> THANK YOU VERY MUCH, BOB.
I NEED IT SAY NOTHING FURTHER.
THE ENTIRE DEFINITION ABOUT
PROLAPSE IS CREDITED TO YOU IN
THE FIELD COULD NOT HAVE MOVED
FORWARD WITHOUT YOUR
CONTRIBUTIONS MANY YEARS AGO.
>> THANK YOU.
THIERRY, YOU'RE MUTED.
>> IN THE MEANTIME, JONATHAN, DO
YOU HAVE A QUESTION?
>> GREAT TALK AND INTERESTING
DATA IN TERMS OF THINKING ABOUT
THIS AND THANKS TO JUDY HUNG AS
WELL.
TWO QUESTIONS RELATED TO THE
DATA THAT YOU PRESENTED.
FIRST, YOU PRESENTED CERTAINLY
MUCH OF THE LITERATURE THOUGH
THE LITERATURE IS EVOLVING AS
RELATED TO BOTH MITRAL ANNULAR
DYSFUNCTION AS WELL ENHANCEMENT
AS A MARKER OF ARRHYTHMIC RISK
IN PATIENTS WITH MITRAL VALVE
PROLAPSE.
CERTAINLY MANY STUDIES BUT NOT
ALL INCLUDING THE RECENT DATA
WHICH IS AN EXCEPTION USE
TELEMETRY OR MONITORING EVIDENCE
VENTRICULAR ATROPY AS AMYTH RICK
RISK AND WE LEARNED FROM OTHER
TRIALS THAT MONITORING EVIDENCE
ARRHYTHMIAS ARE NOT A SURROGATE
FOR ACTUAL EVENTS.
WHAT IS YOUR THOUGHT ON THAT
WITH THE MITRAL VALVE PROLAPSE
LITERATURE AND I HAVE A
FOLLOW-UP.
>> EXCELLENT POINT.
BECAUSE OF SAMPLE SIZE
LIMITATIONS IN A LOT OF THE
EARLY WORK MARKERS ARE USED FOR
MONITORING OF ARRHYTHMIA IF WE
TELL THEM WE REDUCED YOUR RISK
OF THIS AND THEY SAY WHAT'S MY
CHANCE OF DEATH AND IT'S
FOSTERING THE ABILITY TO DO
LARGER COHORTS WHICH HOPEFULLY
WILL BE DESIGN TO LOOK
SPECIFICALLY AT CLINICAL END
POINTS OPPOSED TO SURROGATE
MARKERS AND THAT MAY EXPLAIN THE
DIFFERENCES WE SEE ALSO BETWEEN
SMALL COHORTS VERSUS LARGER
GROUPS WHERE THERE'S MORE
CLINICAL OUTCOMES.
>> SECOND.
FOLLOW-UP QUESTION I'LL ASK WITH
REGARD TO THE DATA YOU AND
OTHERS PRESENTED, RELATES TO
DIFFERENTIAL CONCEPT BETWEEN
INDEPENDENT ASSOCIATIONS AND
LEVEL OF PRECISION TO GUIDE
CARE.
CERTAINLY WE HAVE MANY RISK
MARKERS FOR MANY INDEPENDENT
MARKERS INCLUDING ENHANCEMENT IN
MYOPATHY AND OTHERWISE YET
THERE'S A MARKED DISORDERANCE OF
A FINDING AND RATES.
ONE WOULD LOOK AT THE
LITERATURE.
HOW TO YOU COMMENT ON PREVALENCE
OF LGE AND EVENTS AND IN YOUR
OUTCOMES DATA, 6% OF PATIENTS
WITH EVENTS HAD NO ENHANCEMENT.
>> I THINK IT'S A VERY GOOD
POINT.
SO ONE IS WITH REGARD TO THE
OVER ALL PREVALENCE OF LGE AMONG
PATIENTS WITH MITRAL VALVE
PROLAPSE IS HIGH ENOUGH YOU SORT
OF CAN'T USE THIS ALONE AS A
MARKER TO SAY I'M GOING TO DO
TREATMENT ON ALL THESE PATIENTS.
THAT'S TOO LARGE A GROUP OF
PATIENTS.
THE WAY I THINK ABOUT THIS IS
THIS REPRESENTS A CENTRAL
SUBSTRATE BUT THERE'S OTHER
FEATURES THAT GO WITH THAT TO
INCREASE THE LIKELIHOOD THESE
PATIENTS MAY GO ON TO HAVE AN
ARRHYTHMIC EVENT AND LGE MAY NOT
FULLY CAPTURE ALL RISK HERE.
I TRIED TO HIGHLIGHT THE ONE
AREA WHICH IS THE DIFFERENCE
BETWEEN THE DEF TEF
PAPILLARY TISSUE AND SMALLER
BURDENS MAY GO UNIDENTIFIED ON
THE INITIAL SET OF IMAGING.
THANK YOU, JONATHAN, THOSE ARE
GREAT QUESTIONS.
>> CAN YOU HEAR ME NOW?
>> YES.
>> CONGRATULATIONS FOR YOUR
PRESENTATION.
I WAS VERY INTERESTED BY THE
STUDY AT THE AHA.
I DISCOVERED YOUR DATA.
I HAVE TWO QUESTIONS RELATED.
ONE TO THE OTHER.
AND DID YOU SELECT A SUBGROUP OF
PATIENTS ESPECIALLY PATIENTS
WITH FREE COUNT PVC AND DID YOU
INCLUDE PATIENTS WITH MITRAL
VALVE PROLAPSE DISEASE DID YOU
TEST BY GENETICS ETCETERA?
>> GREAT QUESTIONS.
>> THE COHORT IS PATIENTS
UNDERGOING A CLINICALLY
INDICATED SCAN.
THE REASON FOR THE CARDIAC MRI
SCAN VARIED.
ABOUT A THIRD WERE BECAUSE OF
SOME ARRHYTHMIA SYMPTOMS, P
PALPITATIONS AND SOME WERE FOR
ASSESSMENT OF REGIRTHTATION --
REGURGITATION.
THAT HOPEFULLY ANSWERS YOUR
FIRST QUESTION.
THE SECOND QUESTION WAS WITH
REGARD TO SYSTEMIC ASSESSMENT
FOR INHERITED ARRHYTHMIAS.
THIS IS MORE OF A LONGITUDINAL
OBSERVATIONAL COHORT AND THE
ASSESSMENT WOULD HAVE BEEN AT
THE TREATING PHYSICIAN.
THERE'S NOT A SPECIFIC PROTOCOL
WHERE THEY UNDERWENT AN
ASSESSMENT FOR OTHER INHERITED
ARRHYTHMIC CONDITIONS.
>> THE FEMALE RELATIONSHIP WITH
HIGHER EVENTS, WOMEN.
REMIND ME HOW DID YOU CONTROL
FOR MITRAL VALVE ANATOMY NOT
JUST FOR SINGLE LEAFLET PROLAPSE
BUT VOLUME AND WIDTH NOT HEIGHT
BUT VOLUME, WIDTH AND HEIGHT OF
LEAFLET.
>> THAT'S A VERY GOOD QUESTION.
WE GET TO THE SEVERITY OF THE
PATIENTS.
>> IT'S THE AMOUNT OF VOLUME
BECAUSE VOLUME CREATES TENSION.
CERTAINLY MECHANISTICALLY IT'S A
POSSIBILITY.
I'M THINKING MORE ABOUT LEAFLET
VOLUME OPPOSED TO PROLAPSE
NECESSARY.
>> THE VOLUME OF THE LEAFLETS
NOT THE VOLUME OF PROLAPSES.
THE ANNULAR SIZE IS 26, 28 IN
THE ABSENCE OF SYSTOLIC MOTION
YOU NEED LESS LEAFLET VOLUME TO
FIT INSIDE THE ANNULUS WHERE IF
YOU'RE IN THE 34, 36, 38 AND 32
YOU HAVE MORE EVEN IN VALVES
THAT DON'T LEAK VERY MUCH.
>> WE HAVEN'T DONE THAT ANALYSIS
YET.
WE TRY TO QUANTIFY WHAT IS THE
TOTAL VOLUME OF THE LEAFLETS.
I HAVE OTHER PROGRAMS ONGOING
LOOKING AT STRAIN ON THE
LEAFLETS THEMSELVES WITH
MATHEMATICIAN COLLEGIATE THE
UNIVERSITY OF HOUSTON.
THOSE ARE EARLY PHASES RIGHT
NOW.
THOSE ARE GOOD COMMENTS AND GOOD
POINT.
>> IT'S INTERESTING.
IT MAY WELL BE THE LINKAGE IS
NOT FOR INSTANCE WHETHER THAT
COULD BE HORMONAL OR LATER
PRESENTATION OR SOME OF THE
THINGS WE'RE USED TO DESCRIBING
TO SOME DIFFERENCES, SEX
DIFFERENCES IN OUTCOMES IN
CARDIOVASCULAR DISEASE BUT THIS
MAY BE ANATOMIC AND MAY JUST BE
WOMEN HAVE A TENDENCY FOR MORE
DIFFUSED VOLUME ARE MORE
EXCESSIVE TISSUE.
>> CAN I MAKE A POINT ABOUT
THIS?
SO, DIPAN PRESENTED SOME DATA
ABOUT T1 MAPPING IN SEX
DIFFERENCES.
WHEN WE SEE CASES OF SUDDEN
CARDIAC ARREST IN FEMALES THAT
DON'T HAVE IT THE KEY POINT IS
REALLY THE DIFFUSED FIBROSIS,
THE INTERSTITIAL FIBROSIS FOR
NON DETECTION AND POSTMORTEM WE
HAVE SHOWN 30% OF CASES HAVE
REPLACEMENT FIBROSIS AND CASES
OF SUDDEN CARDIAC DEATH BUT ALL
HAVE INTERSTITIAL FIBROSIS.
THE KEY THING IS WE CAN'T
EXPLAIN CARDIAC ARREST BECAUSE
OF REPLACEMENT FIBROSIS.
WE HAVE TO THINK OF FIBROSIS AND
IT'S A PROBLEM WITH ANATOMY BUT
A MYOCARDIAL DIFFERENCE THAT MAY
BE HORMONAL OR GENETIC WE DON'T
KNOW BUT IN CASES WITHOUT SEVERE
CASES HAVE FIBROSIS UNRELATED TO
VOLUME AND MYOPATHIC PROCESS IN
FEMALES ESPECIALLY.
>> ONE POINT I'D LIKE TO MAKE IS
WE DIDN'T FIND IN OUR
ASSOCIATION BETWEEN THE PROLAPSE
AND ARRHYTHMIA WE DIDN'T FIND
RELATIONSHIP TO SEX.
THERE MAY BE A BIAS IN SAYING
WOMEN HAVE MORE ARRHYTHMIC RISK
AND IN THE NATURAL STUDIES THE
COHORT DON'T SHOW IT.
YOU SEE THE RISK WITH MR BUT NOT
WITH MORTALITY SO THE QUESTION
OF ARRHYTHMIA AND SEX REMAINS
QUITE NOT DEFINED AND I'M QUITE
RESISTANT TO SAY, OH, WOMEN HAVE
ARIDRHYTHMIA AND THERE'S THEIR
PROBLEM.
>> IT'S A QUESTION OF SETTING
AND LOOK AT THE POPULATION BUT
NOT WITH MORE PENETRANT VARIANCE
IS WHERE YOU SEE THE FEMALE
PRODOMINANCE AND DESCRIBED IN
THE PAST LITERATURE.
FROM ALL THAT IS IN MINUTE
VOLUME OF DATA AND SO WHEN YOU
GET LARGE NUMBERS YOU DON'T SEE
THE ASSOCIATION IN WOMEN AND SO
MAYBE WE NEED TO HAVE WORK ON
MITRAL VALVE PROLAPSE UP WOMEN
TO SEE IF THERE'S SOMETHING
SPECIAL IN TERMS OF RISK OF
SUDDEN DEATH BEYOND THE UNDER
ESTIMATION OF MR WE HAVE SEEN.
>> WOMEN WERE LESS LIKELY TO TWO
ON TO GET MITRAL VALVE SURGERY
COMPARED TO MEN.
THERE'S STILL A LOT OF STUFF TO
SORT OUT AND LARGER SAMPLE SIZES
WILL HELP BUT I THINK IT'S ALSO
IMPORTANT TO HAVE A LARGE GROUP
OF INVESTIGATORS TO ADDRESS THE
QUESTIONS.
>> I TO THINK FRANCESSCA'S POINT
IN MITRAL CARDIAL RESPONSE AND
LOOKING AT STEN OVERSOSIS AND T
WERE DIFFERENCES AND THE REASON
FRANK GOT US TOGETHER.
>> WE HAVE A QUESTION FROM THE
VIDEOCAST FROM DR. VASSAN.
THANK YOU, DR. SHAH THERE'S AN
ASSOCIATION BUT COMPENSATORY
MECHANISMS PROTECT THE VALVE
RATHER THAN THE CAUSE OF
MORBIDITY?
>> I'M NOT SURE I UNDERSTAND THE
QUESTION PAUSE WE'RE TALKING
ABOUT ARRHYTHMIAS AND THEY COULD
BE COMPENSATORY?
>> COULD THE FIBROSIS BEING
COMPENSATORY.
IT WOULD BE INTERESTING TO SEE
IF FIBROSIS CAN BE AN CAUSE AND
EFFECT RELATIONSHIP BUT I DON'T
THINK IT'S COMPENSATORY.
>> THANK YOU.
AGAIN WE HAVE TIME AT THE END
FOR DISCUSSION.
THE NEXT SPEAKER IS DR. MARIA
TRIVIERI FROM MOUNT SINAI.
SFWR IT'S A PLEASURE TO BE HERE
TODAY AND WANTED TO THANK DR
DR. EVANS FOR COMPOSING THE
SYMPOSIUM AND THE MEMBERS OF
NIH.
THE OBJECT OF MY TALK IS TO GO
OVER THE USE OF IMAGING IN
MITRAL VALVE PROLAPSE.
I'M ASSOCIATE PROFESSOR OF
CARDIOLOGY AT RADIOLOGY AT THE
ICAHN SCHOOL OF MEDICINE.
AND MY ONLY RELEVANT DISCLOSURE
ABOUT THE TALK IS I'M THE
CONTACT P.I. FOR A LARGE NIH
GRANT LOOKING AT THE USE OF
PET/MR IMAGING AND DR. MILLER
WILL BE SPEAKING AS WELL.
SO BRIEFLY MY OBJECTIVE WILL BE
TO REVIEW THE RATIONALE FOR THE
STUDY.
PROVIDE YOU WITH SOME EARLY
EVIDENCE OVER THE LAST FEW YEARS
ON THE USE OF THIS TECHNOLOGY IN
MITRAL VALVE PROLAPSE DISEASE
AND TOUCH UPON ONE OF THE NEW
TRACER INTRODUCED TO LOOK AT
MITRAL VALVE PROLAPSE.
IT SEEMS LIKE SOMEBODY'S NOT
ABLE TO SEE THE SLIDES.
IS THAT TRUE?
WHY HAVE WE BEEN THINKING OF
USING THE TECHNOLOGY AND PET
STANDS FOR POSITRON ELECTRIC
TOMOGRAPHY AND IT'S A HYBRID
TECHNIQUE OF THIS DATA AND MRI
DATA.
SO, AS WE HAVE HEARD OVER THE
PAST HOUR OR SO THE PATHOLOGY IS
IN MITRAL VALVE PROLAPSE DISEASE
THE SYSTOLIC MOTION OF THE
PERICPE
PERICARDIA IS THOUGHT TO EXERT
STRESS AND THERE BE CAUSE
MYOCARDIAL INJURY AND FIBROSIS.
DESPITE THIS HYPOTHESIS HAS BEEN
WIDELY ACCEPTED WE DON'T HAVE
MONITOR OR ACTIVE PATIENT
CHARACTERIZATION AND AS ALLUDED
TO BEFORE LG IS ASSOCIATED TO
WORSE PROGNOSIS BUT DON'T KNOW
IF A PERSON WITH IT WILL HAVE AN
EVENT.
AND THERE'S THE FEATURE THAT
PATIENTS ALLOW US TO ACCURATELY
CHARACTERIZE AND DECIDE ON
TREATMENT.
WE ALSO DON'T HAVE ACCEPTED
STRATEGY TO MANAGE AND REDUCE
THIS RISK AND THE IMPACT OF
MITRAL VALVE SURGERY ON
VENTRICULAR ARRHYTHMIAS IS
UNKNOWN.
WE CAN IDENTIFY WHAT CORRELATES
WITH THE RISK BUT LACK THE
ABILITY TO IDENTIFY SPECIFIC LEC
LAR PATHWAY AND HAVE THE ISSUE
WITH THE TEF MISSION AND THIS IS
CAR BUT WE CANNOT DISTINGUISH
ONE PATIENT FROM SCAR FROM
ANOTHER.
WITH AND WITHOUT ECHO WE CAN
GAIN MORPHOLOGY AND FUNCTION AND
DO LACK MOLECULAR DEFINITION.
ANOTHER IMAGING FEATURE TALKED
ABOUT THAT CAN BE SEEN WITH THIS
IS IS THE DYSFUNCTION AND SOME
THINK OF IT AS A NORMAL VARIANT.
WE STILL HAVE UNCERTAINTY
BETWEEN THE ARRHYTHMIA AND THE
REMODELLING AND DISJUNCTION.
SO WHAT DO WE THINK ABOUT USING
PET MRI IN MITRAL VALVE
PROLAPSE?
ONE REASON WE DECIDED TO USE THE
TECHNOLOGY WE'RE A REFERENCE
CENTER FOR CARDIAC SARCOIDOSIS
AND DID WORK IN PATIENTS AND
ABLE TO IDENTIFY SOME IMAGING
FEATURE THAT IN CARDIAC
SARCOIDOSIS PARTICIPANTS AND IN
THE SLIDES I WANTED TO PRESENT
IMAGES OF A PATIENT WITH CARDIAC
SARCOIDOSIS AND SEE ON THE FAR
LEFT AN IMAGE AND SEE THE
INSERTION POINT OF THE LEFT
VENTRICLE AND LOOKING AT THE EMR
YOU'RE NOT ABLE TO KNOW WHEN THE
PATIENTS ARE ACTIVE.
YOU CAN ONLY SEE SCAR.
IF YOU SUPER IMPOSE THE PET OVER
EMR YOU'LL SEE THE PATIENTS NOT
ONLY WITH SR BUT ACTIVE AND THAT
IS VERY IMPORTANT IN TERMS
DECIDING TREATMENT.
INTERESTINGLY THE DEFINITION WE
GET ON PET MR CORRELATES WELL
WITH THE HISTOLOGY AND JUST AS
AN EXAMPLE OF THE ACCURACY AND
WANTED TO SHOW THE PHASE OF THE
WITH THIS CARDIAC SARCOIDOSIS
AND SAW EVIDENCE OF SCAR WITH
ASSOCIATED UPTAKE OF FDG IN THE
SAME LOCATION.
WE'RE LOOKING AT THE MODALITY IN
CARDIAC SARCOIDOSIS WE FELT IT
LED TO INFORMATION FOR THE
MODALITY OF THE PRODUCTS.
AND IN THE LITERATURE IN CARDIAC
SARCOIDOSIS IS RELEVANT TO
MITRAL VALVE PROLAPSE BECAUSE
IT'S ASSOCIATED WITH ARRHYTHMIA
AND THERE'S EVIDENCE FROM THE
CLINICAL LITERATURE THAT
INFLAMMATION COULD BE IMPORTANT
IN MITRAL VALVE DISEASE.
THERE'S PRECLINICAL MODEL OF
MITRAL VALVE DISEASE IN THE
SYNDROME AND THE MODEL OF MITRAL
VALVE DISEASE WHAT INVESTIGATORS
FOUND WAS MIGHT INCREASE
MACROPHAGES WITH INCREASED CH
CHEMOKINE AND THE EXTRA CELLULAR
MATRIX IN AN INFLAMMATORY WAY
AND WHEN THEY INDUCED DEFICIENCY
OF MONOCYTE THEY ARE FOUND THAT
WAS PROTECTIVE AGAINST THE
DEVELOPMENT OF MITRAL VALVE
DISEASE AND REDUCTION IN LEAFLET
THICKENING PRESERVING THE
INTEGRITY AND DESPITE THE FACT
OF MITRAL VALVE DISEASE THERE
WAS NO FORMATION.
AND THERE'S AN EVIDENCE FROM THE
CLINICAL LITERATURE MUCH
INFLAMMATION BEING ASSOCIATED
WITH ROW LAPSE AND THEY CREATED
A GENETICALLY MODIFIED MOUSE
WHERE THEY SAW IN THE
INTRALATERAL WALL THERE WAS
INCREASED FIBROSIS AND
MACROPHAGE INCREASE AND SHOWING
A MARKER OF DISEASE PROGRESSION.
AND THE MODEL COULD BE PART OF
THE DISEASE PROCESS OF MITRAL
VALVE PROLAPSE AND MITRAL VALVE
DISEASE AND EXPLAIN THE
PROGRESSION OF FIBROSIS ARE IN
PATIENTS THAT LATER DEVELOPED
ENHANCEMENT.
ALL THE PRESENCE OF THE
VENTRICULAR ATROPHY FROM THE
BURDEN OF FIBROSIS AND EXPLAIN
WHY MAYBE PATIENTS WITH NO
FIBROSIS OR MINIMAL FIBROSIS CAN
EXPERIENCE THIS AND IN THE PRIOR
DISCUSSION.
WE ARE LEADING HYPOTHESIS THAT
INFLAMMATION IS A PART OF THE
PROLAPSE DISEASE EITHER IN THE
DEVELOPMENT OF FIBROSIS AS A
SUBSTRATE OR INCREASED
PHENOMENA.
SO WHEN WE STARTED LOOKING AT
THE USE OF THIS MODALITY WE WERE
THE FIRST TO USE PET/MR IN
MITRAL VALVE DISEASE AND THE
DATA WASN'T PUBLISHED SO WE
CONDUCTED THE PILOT STUDY WHICH
WAS FUNDAMENTAL IN GETTING OUR
WORK MOVING FAST AND THEN GET
THE SUBSEQUENT NIH AWARD WHERE
WE LOOKED AT THE PATIENT WITH
SEVERE MITRAL VALVE PROLAPSE AND
WE SAW IN 85% THERE WAS EVIDENCE
OF INCREASED UPTAKE IN THE BASAL
INTRALATERAL WALL AND 70% OF
PATIENTS SIMULTANEOUSLY HAD
POSITIVITY SHOWING INCREASE.
AND WHEN WE GROUP PATIENTS BASED
ON WHETHER OR NOT THEY HAVE
COMPLEX ARRHYTHMIA WE SAW
PATIENTS WITH COMPLEX
VENTRICULAR ARRHYTHMIA THEY ARE
HAD LATE ANNOUNCEMENT COMPARED
AND THE OPPOSITE FOR VENTRICULAR
AND THOSE WHO HAD MORE UPTAKE.
WHAT WE DID FEEL WAS WE ONLY HAD
20 PATIENTS AND COULDN'T
CONCLUDE ANYTHING DEFINITIVE BUT
OUR SPECULATION WAS LG AND FDG
PROPERTIED DIFFERENT STAGES.
THE FIRST PILOT STUDY LOOKED AT
PATIENTS WITH SEVERE
REGURGITATION.
WE WENT AHEAD AND STARTED
LOOKING AT PATIENTS WITH LESS
THAN SEVERE MR TO TRY TO
UNDERSTAND WHERE THERE COULD BE
PRESENCE OF UPTAKE IN PRESENCE
WITH LEAVE SEVERE MR.
THIS WAS APILOT STUDY OF LOOKING
AT APPROXIMATELY 12 PATIENTS AND
IN PATIENT WITH MILD TO MODERATE
MR WITH A HISTORY OF ATROPHY
THERE WAS A HIGH DEGREE OF FDG
POSITIVELY AND LGE POSITIVITY
WITH CONCORDANCE BETWEEN
INFLAMMATION AND SCAR UP TO 83%
WERE POSITIVE AND 75% OF THEM
POSITIVE ON FDG AND MR.
SO SOME OF YOU THAT MAY BE
FAMILIAR IF YOU CAN SCROLL
THROUGH MIGHT KNOWING TO A SCAN
WITH FDG COULD BE SOMETIMES
PROBLEMATIC.
WE HAVE TO ESSENTIALLY SWITCH
THE METABOLISM OF THE MYOCYTE
AND SOMETIMES CANNOT BE
ACHIEVED.
WE HAVE A SITUATION OF
SUPPRESSION AND A PATIENT NEEDS
TO FOLLOW A SPECIFIC TIGHT.
AS A RESULT OF THAT CAN LEAD TO
THIS RESULT.
TO COUNTER ACT THAT WE LOOKED AT
THE POSSIBILITY OF USING OTHER
TRACER IN MITRAL VALVE STEEZ.
AND THIS STAT IN RECEPTOR BIND
TO THE INFLAMMATORY CELL.
BASED ON THE LITERATURE IN HUMAN
MOSTLY USED TO IDENTIFY A NEURAL
ENDOCRINE TUMOR AND CAN
VISUALIZE THE LYMPHOSITE THE --
LYMPHOCYTE AND CAN BE USED AS A
SURROGATE MARKER FOR
INFLAMMATION.
THEY LOOKED AT THE GA INFORM
DOTATATE IN THE RAT MODEL.
AND LOOKED AT THE USE OF GA
DOTATATE IN PATIENT.
THIS IS AN EXAMPLE OF HOW
POWERFUL THE TECHNIQUE CAN BE IN
IDENTIFIED DYNAMIC CHANGES
OCCURRING WITHIN THE MYOCARDIUM.
AND I THINK IT'S RELEVANT TO
SHOW HOW PET MRI TAKES PLACE AND
THIS IS 13 YEARS POST TRANSPLANT
ADMITTED FOR FAILURE AND TREATED
FOR REJECTION AND COMPLETED THE
TREATMENT FOR REJECTION AND
UNDERWENT A BIOPSY NEGATIVE AND
AT BASELINE GA DOTATATE SCAN AND
SEE IN THE SCAN THERE WAS NO
UPTAKE OF THE TRACER IN THE
PERICARDIUM AND SIX WEEKS LATER
THE PATIENT PRESENTED WITH
RECURRENT HEART FAILURE AND
UNDER GOES A SUBSEQUENT PET/MR
AND WERE ABLE TO SEE INCREASED
UPTAKE IN THE LATERAL WALL.
WHAT WAS INTERESTING IS WITH THE
TRACER WE WITH WERE ABLE TO
FOLLOW OVER TIME THE DYNAMIC
CHANGES TAKING PLACE IN THE
MYOCARDIUM AND LOOK AT THE AREA
AFFECTED AND THERE WAS GOOD
CORRELATION AND IN FACT THE
PATIENT CONSISTENT ONE WILL THE
FACT OF UPTAKE DEVELOPED THE AV
BLOCK.
A VERY POWERFUL TECHNIQUE TO
LOOK AT INFLAMMATION OF THE
MYOCARDIUM.
AND RELEVANT TO MITRAL VALVE
PROLAPSE AND THE POSSIBILITY OF
SEEING EVOLUTION OF DISEASE OVER
TIME.
ON THE BASIS OF THE OBSERVATION
I MENTIONED WE THEN DESIGN THE
CLINICAL STUDY POSUPPORTED BY T
GRANT TO LOOK AT MITRAL VALVE
PROLAPSE WITH PET MRI.
WE HAVE A TWO COHORT AN ONE OF
THE SURGICAL CORD INCLUDES
PATIENTS WITH PLANNED REPAIR
SURGERY AS PART OF THE CLINICAL
INDICATION FOR MITRAL VALVE
PROLAPSE.
THE PATIENT WILL UNDER GO TWO
SCANS ONE WITH FDG AND ONE WITH
GA DOTATATE AND IDENTIFIED AS
MORE ACTIVE ON IMAGING.
AND THE ALL OF THIS PROPOSAL IS
ESSENTIALLY TO LOOK AT CHANGES
IN INFLAMMATION AS WELL AS
ARRHYTHMIA IN RESPONSE TO
SURGERY AND UNDER TWO A PET MR
IMAGING AT BASELINE AND AGAIN AT
24 MONTHS AFTER INITIAL SCAN.
THIS IS SHOWING THE WORK FLOW WE
FOLLOW AND THE SCAN AND PLANNED
THE BIOPSY ON THE BASIS OF THE
AREA WE SEE AND THEN ANALYZE THE
TISSUE WITH HISTOLOGY.
WHAT I WANTED TO ESSENTIALLY
PRESENT WAS THE USEFULNESS OF
THE TECHNIQUE IN THE CAMPUS OF
MITRAL VALVE DISEASE BECAUSE OF
THE LACK OF UNDERSTANDING OF THE
STRATIFICATION THAT CAN
CONTRIBUTE TO THE PHENOTYPE AND
WE HEARD ABOUT IMAGING MODALITY
AND PROVIDED INTO THE
PATHOPHYSIOLOGY OF DISEASE AND
LACK THE PROCESSES THAT OCCUR
WITH THE MYOCARDIUM AND BELIEVE
PET/MR CAN PROVIDE THAT AND IF
COUPLED WITH FDG AND GA DOTATATE
I THINK IT'S A PROMISING NEW
TOOL WHICH CAN BE USED TO
PREDICT IN PATIENTS WITH MITRAL
VALVE DISEASE AND STRATEGY FOR
MR AND ARRHYTHMIA PRESENTATION
AND THANK YOU FOR LISTENING AND
THAT WAS MY PRESENTATION.
>> THANK YOU VERY MUCH.
DOES ANYONE HAVE QUESTIONS OR
COMMENTS ABOUT THIS PARTICULAR
PRESENTATION?
>> WHAT I'VE BEEN STRUCK BY IS
SOME PATIENTS HAVE THEIR
ECHOCARDIOGRAM LOOKS GARDEN
VARIETY WITH PRESERVED LV
FUNCTION AND YET THEIR HEARTS
ARE BRIGHT RED WHEN YOU STUDY
THEM.
IT ALLOWS US TO SEE THINGS
EARLIER THAN OTHER ABNORMALITIES
AND WITH GA DOTATATE WE MAY HAVE
THE CONCENTRATION BY
INFLAMMATORY CELLS.
>> I WAS IN WASHINGTON AT A
MEETING PRESENTING THE OTHER DAY
AND WHEN I CAME OFF THE STAGE A
CARDIOLOGIST CAME TO ME WITH HIS
CD AND HIS SYSTOLIC DIMENSION IS
ABOUT 32 AND RUNNING MANY MILES
A WEEK WITHOUT ANY PROBLEMS AND
WANTED TO KNOW WHETHER TO HAVE
SURGERY OR NOT AND I TOLD HIM HE
SHOULD ENROLL IN THE TRIAL TO TO
THE PROPER ANALYSIS AT THE
MOLECULAR LEVEL BECAUSE IF HIS
HEART DOESN'T LIGHT UP IT'S OKAY
TO KEEP WAITING AND DO STRESS
ECHO IF IT LIT UP I ALWAYS SAID
THAT'S ANOTHER WAY TO ADD A NEW
LENS TO ACTIVE SURVEILLANCE FOR
PATIENTS AND I HAVE A HUNCH
THEY'LL BE PERSUADED BASED ON
THE IMAGING YOU'VE BEEN
PRESENTING.
>> THANK YOU.
IN THE 2021 MEETING WE USED A
SPEAKER AND DISCUSSANT FOR MAT.
WE HAVE BEEN TO AWAY FROM THAT
IN THE 2024 MEETING BUT IN THIS
MEETING WE HAVE A DISCUSSANT,
IT'S DR. JONATHAN WEINSAFT.
WOULD YOU LIKE TO LEAD THE
DISCUSSION?
>> THANK YOU, FRANK AND THANKS
WILL TO EVERYONE FOR PHENOMENAL
TALKS.
I'LL ASK A FEW BROAD QUESTIONS
AND THEN CERTAINLY OPEN THE
FLOOR FOR MANY IN THE AUDIENCE
WHO HAVE DONE WORK IN THIS AREA.
YOU'VE GIVEN DATA ON PET/MR
IMAGING AND WANT TO START WITH
YOU WHAT WE'RE FUNDAMENTALLY
MEASURING IN TERMS OF THE PET
DATA?
THE MEASURE IS A FUNDAMENTAL
MEASURE OF GLUCOSE UTILIZATION
AND COULD REPRESENT AN AND LOOK
AT CONTRACTILE DYNAMICS.
OR IS THE PREMISE THERE'S A
PRIMARY MOLECULAR INFLAMMATORY
PROCESS WHICH WOULD INFORM A
DIFFERENT AREA OF THERAPY?
>> THANK YOU FOR THE QUESTION.
WE HAVE MYOCYTES RAND ONE OF THE
REASONS WE DECIDED TO
INCORPORATE IN OUR STUDY A
TRACER MORE SPECIFIC FOR
INFLAMMATORY CELL AND I THINK BY
LOOKING AT THE COMPARISON OF THE
SCAN AND THE PATHOLOGY WE'LL BE
IN A POSITION TO UNDERSTAND WHAT
IS STRESS AND INFLAMMATION.
REGARDLESS OF WHETHER OR NOT IT
SHOWS INFLAMMATORY TRAITS
REGARDLESS OF THE NATURE OF THE
SIGNAL, THERE'S A SIGNAL WE CAN
STILL USE TO IDENTIFY AND
PROGNOSTICATE WITH THAT IS AN
ADDITIVE OR ADDITIONAL TO LG.
WHAT I'M TRYING TO SAY IS YOU
CAN LOOK AT THE SIGNAL AS A
STAND ALONE AND POSITIVE AND
NEGATIVE WHAT DOES THAT MEAN AND
LOOK AT THE SPECIFIC OF THE FDG
SIGNAL.
AND I THINK FOR THAT, WHAT I
FEEL WILL BE FUNDAMENTAL IS THE
SCAN.
AND WE CAN ALSO USE PRESENCE OF
FDG OR LGE AND REPRESENTATIVE
ISCHEMIA AS A MARKER OF RISK.
THERE'S A BROADER WAY OF LOOKING
AND MORE REFINED OR HISTOLOGICAL
WAY.
PRIOR TO OUR WORK THERE WAS NO
LITERATURE IN THE USE OF THIS
MODALITY SO I THINK WHAT OUR
LONGITUDINAL STUDY, PROSPECTIVE
STUDY IS GOING TO SHOW AND
PROVIDE US INFORMATION ON WHAT
EXACTLY THAT MEANS.
I THINK THE COMBINATION WITH THE
HISTOLOGY AS WELL AS THE SCAN
WE'LL BE DOING IN THE
NON-SURGICAL CAUSE CAN SHOW SOME
INFLAMMATION AND LOOK AT THIS AS
A MARKER REGARDLESS OF THE
UNDERLYING MATRIX.
I DON'T KNOW WHETHER THAT
ANSWERED YOUR QUESTION.
>> THAT'S IMPORTANT.
>> DR. HUNG AND TRIVIERI HAVE
OPPORTUNITY WORK AND IN TERMS OF
MITRAL VALVE PROLAPSE WITH
REGARD TO VENTRICULAR SUBSTRATE,
HOW DOES THAT IMPACT OUR
THINKING IN SURGICAL
INTERVENTIONS AND SHOULD THE
FINDING OF FIBROSIS OR SHOWING
THE ENHANCEMENTS ALTERED
MYOCARDIAL STRAIN BE USED TO
TIME THE CUTANEOUS INTERVENTIONS
AND IRRESPECTIVE OF THE TIMING
OF THE INTERVENTIONS, HOW TO WE
APPROACH THE PATIENT WHO'S BEEN
INTERVENED AND HAD THE MITRAL
REGURGITATION AFFECTED AND
REMAINS ALTERED.
>> I'LL START OFF.
YOU'RE VERY GOOD AT ASKING VERY
TOUGH QUESTIONS.
I AGREE 100%.
I DON'T KNOW WE HAVE ANY DATA
RIGHT NOW TO SAY OKAY BASED ON
THE PRESENCE OR EXTENT OF
FIBROSIS COULD THAT INFORM
DECISION FOR EARLIER
INTERVENTION IN A PATIENT WHO
OTHERWISE DOESN'T MEET THE
INTERVENTIONAL CRITERIA AND
APPROACH?
I DON'T THINK WE HAVE DATA ON
THAT RIGHT NOW SO IT'S A VERY
GOOD QUESTION.
THIS CONCEPT OF SAYING FIBROSIS
AS A MARKER AND THE HEALTH OF
THE VENTRICLE COULD THAT INFORM
EARLIER SURGERY AS BEING TESTED
IN OTHER -- BESIDES THE MITRAL
VALVE PROLAPSE.
I THINK THE QUESTION STILL
REMAINS TO BE ANSWERED.
I DON'T THINK WE KNOW THE ANSWER
TO THAT YET.
>> IF THEY FEEL THE VENTRICLE'S
SMALL AND ASKING ME I DOES THE
STRESS STUDY AND WENT 12 MINUTES
AND FEEL GREAT, DO I NEED
SURGERY OR CAN I WAIT SIX MONTHS
AND YOU DO THE MRI AND SHOW THEY
HAVE VENTRICLE WITH A LOT OF
SCAR IN IT ARE YOU GOING TO SAY
WE DON'T KNOW BECAUSE WE DON'T
HAVE THE RANDOMIZED TRIAL OR
LONGITUDINAL FOLLOW-UP AND A LOT
OF THE VALVE DECISIONS ARE STILL
MADE EVIDENCE OF C AND WHAT
WOULD YOU RECOMMEND TO THE
PATIENT?
>> YOU LIKE TO PIN PEOPLE DON'T,
DON'T CHA?
YOU BRING UP A GOOD POINT WHICH
IS IN CLINICAL PRACTICE YOU MAKE
DECISIONS IN THE ABSENCE OF
RANDOMIZED OR LONGITUDINAL
FOLLOW-UP DATA.
YES, I TAKE THAT AS ONE MARKER
TO SAY, HEY, THIS VENTRICLE FROM
THE STANDPOINT OF HOW IT'S
TOLERATING WHATEVER LOAD IT HAS
WHETHER MVP OR REGIRTHTATION --
REGIRTHTATION AND
S AND ONE THING WE KNOW IS WITH
THE FIBROSIS WE SEE BY LGE IS
IRREVERSIBLE SUBSTRATE AND IT'S
A QUESTION TO TRY TO SORT OUT
FURTHER.
>> AND DAVID, LET ME COMMENT ON
THAT IN TERMS OF THINKING ABOUT
WITH RESPECT TO ENHANCEMENT AND
YOU CERTAINLY CAN COMMENT ON
THIS AS WELL.
THE OVERWHELMING BODY OF DATA WE
HAVE WITH RESPECT TO THE
ENHANCEMENT AND THE UTILITY AS A
PREDICTOR OF VENTRICULAR
REMODELLING IN SURGERY RELATES
TO PATIENTS ONE ISCHEMIC
MYOPATHY WHICH IS A HIGHLY
POWERFUL PREDICTOR OF MARKER OF
IMPROVED REMODELLING IN SURGICAL
OR CUTANEOUS INTERVENTIONS.
IN PATIENTS WITH PROLAPSE WE'RE
TYPICALLY TALKING ABOUT
MYOCARDIAL FIBROSIS AND 2% TO 5%
OF LEFT VENTRICULAR MYOCARDIUM.
I ASK THE QUESTION BACK TO DIPAN
OR TO YOU, DAVID OR OTHERS, DO
WE HAVE DATA DEMONSTRATING THE
ENHANCEMENT IS A PREDICTOR OF
ADVERSE REMODELLING AFTER
SURGICAL OR CUTANEOUS VALVE
REPAIR?
ARE THESE THE PATIENT FALL OFF
THE CLIFF?
>> WE DON'T KNOW THAT YET BUT I
THINK THIS IS INTERESTING BEEN
BECAUSE WE HAVE THE VOLUME I'LL
TALK ABOUT TOMORROW ABOUT
SURGERY.
THE VOLUME LOAD FROM
REGURGITATION AND ALSO HAVE THE
POTENTIAL FOR TENSION WHETHER
THAT'S CREATING ISCHEMIA OR WHAT
THE TENSION OF THESE LARGE
LEAFLETS IS DOING ASYSTOLE
TUGGING ON THE MUSCLE AND
DIFFERENT FROM ISCHEMIC DISEASE.
ON THE OTHER HAND I'M SURE MARK
WILL HAVE A COMMENT AND WHAT I
DON'T WANT TO HAVE IS SCAR THAT
THEN RELATES TO ARRHYTHMIAS
BECAUSE THE WAY WE LOSE THE GAME
THESE DAYS IS TO HAVE MALIGNANT
ARRHYTHMIA.
I THINK THAT'S THE SUDDEN DEATH
RISK WE'VE SEEN THE LAST 45
YEARS AND I NEVER REALLY
UNDERSTOOD IT UNTIL A FEW YEARS
AGO, THANK YOU, CONGRESSMAN BARR
AND OTHERS FOR GETTING US
PLUGGED INTO THIS AND THE WORK
AROUND IT BUT THAT SEEMS TO BE
THE MOST LIKELY REASON WE'VE
ALWAYS HAD THIS NAGGING IN THE
RISK IN ASYMPTOMATIC PATIENTS.
I DON'T WANT ANY SCAR.
>> THE VENTRICULAR ATROPY I
DON'T THINK SHOULD BE UNDER
PLAYED AFTER THE MAYO CLINIC
DATA ABOUT THE PREDICTOR OF
MORTALITY.
I HAVE PATIENTS THAT ARE 85
YEARS OLD AND HAVE LGE AND HAVE
LIVED A LONG TIME.
IT'S RAY COMBINATION OF THINGS
IN RESPONSE TO THE VENTRICLE AND
NOT JUST FIBROSIS WE AND THE
MECHANICS AND THE TRACTION THAT
COULD NOT ALL MANIFEST WITH
FIBROSIS BUT AT THE MEC
MOLECULAR AND CHANNEL LEVEL.
WE SHOULD NOT ONLY FOCUS ON
FIBROSIS BUT SO MANY OTHER
ELEMENTS IN THE PICTURE WE
SHOULD PAY ATTENTION TO AND THE
VENTRICULAROPATHY IS VERY
IMPORTANT.
>> AND JONATHAN YOU ASKED AY
QUESTION.
THE KEY QUESTION AND WHAT I'M
HEARING IS WE DON'T KNOW BUT WE
NEED TO ANSWER IT SO I WOULD
PROPOSE WE NEED TO TO A CLINICAL
TRIAL TO ADDRESS THAT ISSUE.
FOR FOLKS WHO HAVE ASYMPTOMATIC
SEVERE MRR SHOULD WE RANDOMIZE
SOME PATIENTS BASED ON LGE OR
OTHER FEATURES AND LOOK AT
MECHANISTIC IMPROVEMENTS
FOLLOWING.
I THINK THAT WOULD BE A TRIAL.
>> WHAT ARE WE RANDOMIZING THEM
TO?
>> YOU COULD TIKE A SELECTION OF
PATIENTS WITH SEVERE
ASYMPTOMATIC MR.
THAT IS ALL CRITERIA ONE BUT
THERE ARE PEOPLE WHO STILL DO IT
AS 2A.
LOOKING AT MS. AND LGE TRIAL.
>> THAT WOULD BE BETTER.
>> I PROPOSE SEVERE MR.
>> THE LEFT ATRIAL FUNCTION AND
SO MANY MARKERS.
WE HAVE A SLEW OF MARKERS OF
OUTCOME HOW WILL YOU SAY WE HAVE
MARKERS AND THE PEOPLE ARE NOT
DOING SO WELL NATURALLY WHEN
THEY HAVE THOSE MARKERS AND I'M
SURE THAT THERE IS POTENTIAL TO
DO THE TRIAL BUT CAN'T JUST BE
FOR ONE FIBROSIS AND THE ATRIAL
FUNCTION.
YOU HAVE PLENTY OF MEASURES WE
CAN DO THAT MARKERS OF OUTCOME.
AND IS SOMEBODY WITH BNP
INCLUDED OR NOT?
THE CONSTRUCTION OF A TRIAL
COULD BE ANY MUCH THESE MARKERS
PRESENT TO TWO OR MORE PRESENT
TO DECIDE WHAT TO DO AND WHAT TO
RANDOMIZE.
>>
>> I THINK THERE'S A LOT OF
UNCERTAINTY AND DISCOMFORT WE
DON'T KNOW WHICH PATIENTS WE
SHOULD BE POTENTIALLY OPERATING
ON EARLIER, RIGHT?
AND TO MY POINT WE SHOULD BEING
TO CLINICAL TRIAL TO FIGURE OUT
WHO THOSE PEOPLE ARE.
>> JUDY, THAT'S IN MODERATE MR,
I AGREE.
THAT'S NOT AN ENROLLABLE TRIAL.
YOU HAVE TO GET PATIENTS WITH
SEVERE MR AND THE ONES WE REALLY
WANT TO STUDY ARE 50 AND 60 AND
70 NOT 80 YEAR OLDS THAT DON'T
WANT SURGERY.
I THINK I SAW 14 NEW PATIENTS
YESTERDAY AND 13 SIGN YOU HAD ON
THE TO THE -- DOT I DON'T KNOW
ANY NOT ASYMPTOMATIC OR IN CLASS
1 INTERESTED IN ACTIVE
SURVEILLANCE THAT'S A SMALL
NUMBER AND THEN YOU HAVE TO
RANDOMIZE THEM.
THE MR IS MORE INTERESTING.
YOU
>> I DISAGREE.
>> I SECOND DAVID AS A HUMBLE
CARDIOLOGIST FROM THE STANDPOINT
AS SOMEONE WHO LOOKED AT AN
ARRAY OF VIABILITY STUDIES AND
LOOKING AT ANGIOPROSTY AND WE'LL
HAVE TO LOOK AT PATIENTS WITH
SEVERE ENHANCEMENT AND YOU HAVE
TWO OTHERS OFFERING SURGERY BUT
MAYBE BY THE WAY WE WANT TO
FOLLOW YOU BUT YOU MAY BE AT
RISK OF SUDDEN DEATH.
>> THIS IS NEW YORK CITY SPEAK.
YOU DON'T NOT HAVE A DAVID ADAMS
NEXT TO THEM SO THEY HAVE TO BE
VERY CAREFUL THEY'LL SEND AN
ASYMPTOMATIC PERSON WITH NORMAL
FUNCTION FOR SURGERY.
I THINK THIS IS ENROLLABLE
TRIAL.
>> I THINK IT'S RAY SMALL NUMBER
OF PATIENTS.
PEOPLE WITH SEVERE MR THERE'S A
SMALLER NUMBER NORMAL AND HAVE
SEVERE MR AND THEY'RE INTERESTED
IN BEING FOLLOWED IF SOMETHING
WILL HAPPEN AND DON'T THINK IT'S
THAT LARGE A NUMBER ANYMORE.
>> JOE, HELP ME OUT HERE.
>> A LARGE NUMBER ARE
ASYMPTOMATIC.
>> IN L.A. THERE'S MORE CLIPS
THAN SURGERY.
>> NOW, NOW.
>> JUST SAYING.
IN ALL SERIOUS THE REAL QUESTION
IS THE MODERATE MR -- I GET BACK
TO CAN I SIT WITH A PATIENT AND
SAY YOU HAVE SEVERE MR AND SCAR
IN YOUR VENTRICLE AND SOLID
CLASS 2 INDICATION I'D LIKE TO
CONTINUE TO FOLLOW YOU AND TO A
NATURAL HISTORY STUDY AND HAVE
LONG ARRHYTHMIA AND MAY HAVE
DEATH.
IN MODERATE MR YOU DON'T HAVE A
GUIDELINE INDICATION BUT IF MY
HEART IS BRIGHT RED I'M LOOKING
FOR A SURGEON TO GET MY ANATOMY
BACK TO NORMAL.
I THINK YOU'D ENROLL IT QUICKLY
BUT YOU ALL HAVE TO DEFINE THE
IMAGING CRITERIA TO LEAD US TO
FEEL COMFORTABLE DOING SURGERY.
WE HAD THE PATIENTS BEFORE, THE
THREE OF US HAD THE PATIENTS
WITH MODERATE MR BUT THE REASON
WE OPERATED WAS ARRHYTHMIA
BURDEN BUT DON'T HAVE SEVERE MR.
>> WITHOUT THE SCAR AND NO
SURGICAL FIGURES BUT TRUE
COMP
COMPLEX ECTOPY.
>> THIS IS STILL IN THE EUROPEAN
GUIDELINES BUT ATRIAL
FIBRILLATION IS NOT INDICATED
FOR SURGERY FOR MR THE
FACILITATION OF EARLY SURGERY IN
U.S.-LED TO THE DISAPPEARANCE OF
OTHER MARKERS.
>> IF YOU HAVE SEVERE MR AND NON
SUSTAINED V.P. WHICH IS A
TRIGGER FOR THE DOCTOR, DOES
ANYONE NOT SEND THAT PATIENT FOR
SURGERY?
ATRIAL ENLARGEMENT IS HIGHER AND
HAVE A SLEW OF CRITERIA THAT CAN
BE USED.
I AGREE WITH DAVID NOW SURGEONS
TEND TO DO THE SURGERY COMPETENT
IN REPAIR.
THE PEOPLE NOT TREATED ARE THE
MODERATELY SEVERE MR THAT WOULD
BE A PERFECT CANDIDATE AND
ALREADY AT RISK AND I WILL SAY
THE TRIAL I WOULD LIKE TO DO.
>> BUT THE QUESTION STILL
STANDS, THERE'S LOTS OF PEOPLE
OUT THERE SITTING ON PATIENTS
WITH SEVERE MR.
I SEE IT IN THE COMMUNITY ALL
THE TIME.
WHAT I'VE NOTICED IS -- THANK
YOU.
AND I'VE NOTICED MORE
CARDIOLOGISTS ARE DOING MORE
MONITOR AND SHOWING MORE TEF TEF
DEF
WI
WITH ECTOPY AND NOT DOING
ANYTHING?
>> AND NOT FOR REPAIR OF
REGURGITATION, I DON'T THINK
ACROSS THE COUNTRY
EVERYBODY'SIEVERYBODY'S
ING TO -- EVERYBODY'S DOING
THAT.
YOU'RE A UNIQUE CENTER BUT I BET
IF WE POLLED THE U.S. ARE THEY
SENDING SOMEBODY TO SURGERY
>> IT'S A WHEN THEY HAVE
MALIGNANT OR SEMI MALIGNANT
ARRHYTHMIAS AND KEEPS GET
THERAPIES FOR THE MONITOR.
PEOPLE MAY SAY LET ME PUSH THEM
FOR SURGERY AND LESSER THAN
SEVERE I DON'T THINK IS
HAPPENING.
MORE ARE BEING REFERRED BECAUSE
OF THE MONITOR AND MR.
>> MY HYPOTHESIS IS THE EFFECT
OF SURGERY IS TO REDUCE THE
ABNORMAL DYNAMIC ON THE
PAPILLARY MUSCLE TO REDUCE
ARRHYTHMIA BURDEN.
IT NEEDS TO BE PROVEN STILL BUT
NEED TO BE IN THE HYPOTHESIS.
>> SHOULD
>> I WISH WE COULD TO THIS
ANOTHER HOUR I'M LEARNING A LOT
AND LEARNING ABOUT THE GOALS OF
MITRAL VALVE REPAIR AND SURGERY.
I ALWAYS SAY TO PATIENTS, NATURE
DOESN'T MAKE MISTAKES.
IF WANTED US TO HAVE A DOUBLE
BARREL SEPTUM IT WOULD DO THAT
AND I THINK THESE PERTURBATIONS
INCLUDING THE STEEZ BUT
PROLAPSES BY ASKING ABOUT VOLUME
VERSUS SIZE OF LEAFLETS THEY ARE
ALL CREATE TENSION AND THE
NORMAL VALVE APPARATUS IS TO TRY
TO MINIMIZE TENSION WHICH IS WHY
IS RECURRENT PROLAPSE SO
UNUSUAL?
WHY DON'T MORE CHORDS ELONGATE
AND RUPTURE?
WE THINK TENSION ON THE LEAVE
-- LEAFLETS ON THE APPARATUS
AND SAME IS TRUE FOR FLOW AND
FLOW AND DIASTOLIC PERFORMS OF
VALVES PROBABLY INFLUENCES THE
VENTRICLE AS WELL.
NONE OF THIS IS PROVABLE YET BUT
I BELIEVE NATURE IS RIGHT AND I
HAVE A HUNCH MITRAL VALVE AFLNAT
ANATOMY IS THAT WAY FOR A REASON
AND IT CREATES ABNORMAL TENSION.
>> THIS HAS BEEN A FASCINATING
DISCUSSION, THANK YOU, FOLKS.
YOU MAY RECALL A QUESTION I HAD
DEFERRED ON THE VIDEOCAST AND
THE QUESTION CAME IN SHORTLY
AFTER JUDY'S PRESENTATION.
IS THE ETIOLOGY OF PROLAPSE
GENETIC OR CAUSED BY OTHER
DISEASES SUCH AS MI.
DOES ANYONE CARE TO TAKE THAT?
>> NO.
>> WE DON'T KNOW FOR SURE.
THERE'S SOME GENETIC
PREDISPOSITION TOMORROW OR THIS
AFTERNOON.
WE KNOW THERE IS SOME FAMILIAL
STORY.
WE'LL LEARN MORE TODAY OR
TOMORROW.
I DON'T THINK -- I WILL SAY THAT
ONE OF THE THEORIES INCREASINGLY
AM INTERESTED IN AND FRANK WELSH
USED TO TALK ABOUT WHICH IS THE
ABNORMAL ANATOMY THAT CREATES
TENSION THAT ULTIMATELY LEAD TO
PROLAPSE AND JUDY HAD A
BEAUTIFUL CASE WITH A DEEP
INDENTATION A RESEGMENT VALVE
BUZ THE INDENTATION GOES TO THE
ANNULUS AND IT CREATES
COMMISEWER AND THE MORE I DO THE
MORE I REALIZE MANY TIMES YOU'RE
DOING REPAIRS WITH A MULTI-
MULTI-SEGMENTED LEAFLET AND
ANATOMY MAY DICTATE THAT TOO
SOMETIMES AND VARIANCE OF MITRAL
VALVE ANATOMY ARE MORE PRONE TO
DISEASE BECAUSE OF THE LEAFLETS.
IT'S PROBABLY WHY WE'RE SUPPOSED
TO HAVE TWO SEGMENTS AND TWO
COMMISURES.
>> THAT WAS THE CHIME.
DOES ANYONE HAVE FINAL QUESTIONS
OR COMMENTS?
>> I WANT TO THANK EVERYONE FOR
A PHENOMENAL SESSION AND
DISCUSSION IT WILL INFORM
RESEARCH AND TRIELGZ AND MUCH OF
THE IMAGING WORK WILL BE
ENHANCED AND FOCUSSED BASED ON
ADDITIONAL RESEARCH ADVANCEMENTS
IN TERMS OF CARDIOVASCULAR
GENETICS IN OTHER ANCILLARY
MARKERS TO INFORM ADDITIONAL
PRECISION AND THAT'S CRITICAL
AND LOOKING FORWARD TO FUTURE
SESSION TO FOLLOW UP AND
TOMORROW.
THANKS VERY MUCH.
>> THANK YOU, EVERYONE.
I PROPOSE THAT WE GO AHEAD AND
TAKE OUR BREAK NOW UNTIL 40
MINUTES AFTER THE HOUR PUTTING
US BACK ON SCHEDULE.
OUR FIRST SPEAKER IS
FRANCESSCA DELLING.
>> THANK YOU FOR THE OPPORTUNITY
TO SPEAK ABOUT OUR WORK ON
PHENOTYPIC PEDIGREES.
THIS WORK IS FUNDED BY THE CAROL
ACT AND PRIOR R03 GRANT.
I WON'T SPEND TIME ON THE
DEFINITION.
IT VARIES A LOT WITH STUDIES AND
I UTILIZED THE DEFINITION OF A
CONSENSUS STATEMENT PUBLISHED IN
2022 WHICH IT CAN DEFINES IT
FREQUENT OR COMPLEX VENTRICULAR
ECTOPY AND THE HIGHEST IN SEVERE
REGURGITATION AND CARDIAC
IMAGING ESSENTIAL TO IDENTIFY
THOSE AT RISK.
SOME AT RISK MENTIONED BY
DR. HUNG, I'LL BRIEF GO OVER
THEM AGAIN BECAUSE WE DID
UTILIZE THEM FOR THE PHENOTYPING
IN THE PED FWIGPEDIGREES.
THE LEAFLET PHENOTYPE IS
IMPORTANT AND YOU SEE THE
CURLING WITH THE MOTION AT THE
INTRAL LATERAL BASE OF THE LEFT
VENTRICLE WHICH CAN BE CAPTURED
NICELY BY THE INCREASED VELOCITY
AT THE LATERAL ANNULUS.
THIS IS A SCHEMATIC AT THE BASE
WITH THE TRACTION OF THE
PROLAPSING LEAFLETS IN THE
MUSCLE AND MYOCARDIUM.
MECHANICS CAN BE MEASURED BY
PARAMETERS PUBLISHED IN A NUMBER
OF PAPERS INCLUDING THE DOUBLE
PEAK PATTERN AND POST SYSTEMIC
SHORTENING INDEX CALCULATED WITH
THE FORMULA SHOWN HERE AND
MECHANICAL DISPERSION WE
PUBLISHED YEARS AGO BASICALLY
DEMONSTRATING HETEROGENEOUS
CONTRACTION AND COULD BE
ELECTRICAL DISPERSION AND IS
SEEN AND CARDIO MYOPATHY WITHOUT
PROLAPSE AND THIS WILL COME UP
IN THE DISCUSSION OF THE
PEDIGREE PHENOTYPING.
AS A RESULT OF THE BASE SHOWN BY
THIS BOSTON GROUP.
IN TERMS OF GENETICS THERE'S NOT
A LARGE DATA SET SO FAR.
GENETICS ARE LIMIT TO CASE
STUDIES.
THE GENETICS FOR WHAT I'LL BE
DESCRIBING IS UNDERGOING AND
FOCUSSING ON THE PHENOTYPING
WHICH HAS LED TO INTERESTING
DISCOVERIES.
THE INTEREST IN DETAILED
PHENOTYPING HAS COME FROM THE
FACT THAT FIRST OF ALL FAMILY
HISTORY OF PROLAPSE HAS ONLY
BEEN REPORTED IN SMALL
PATHOLOGICAL AND THE ARRHYTHMIC
CAUSE OF DEATH OF THE CASES WITH
SUDDEN DEATH NOT BEEN
CORROBORATED SO THE RISK OF
AFAMILIAR RISK IN MVP IS UNCLEAR
AND THE INHERITANCE OF THE
PHENOTYPIC IMAGING FEATURES OF
ARRHYTHMIC MVP REMAINS POORLY
DEFINED SO FAR AT THIS LEVEL.
THIS IS ONE OF THE CASE SERIES
ABOUT GENETICS AND ARRHYTHMIC
MVP AND THIS SHOWS A GENE WHICH
PLAY SERVE AS A SUBSTRATE FOR
LEAFLET MVP.
THIS IS FOUR INDIVIDUAL
SEQUENCING STUDY BUT IT
INTRODUCES THE INTERESTING POINT
THERE MAY BE A GENETIC SUBSTRATE
UNDERLYING THE MOST SEVERE CASES
OF ARRHYTHMIC COMPLICATIONS AND
WEAK MYOCYTE COUPLING AND HAVE A
TRIG
TRIGGER AND THIS IS IMPORTANT
FOR THE DATA I'LL PRESENT NEXT.
THERE'S A CASE REPORT ALLOWING A
CARDIO MYOPATHY GENE AND A
CHANNELOPATHY GENE WITH SEVERE
PERTURBATION.
THIS LOOKED AT STUDYING SUDDEN
DEATH OF THE YOUNG WITH WHOLE
EXOME SEQUENCING AND SIX
INDIVIDUALS WITH MITRAL VALVE
PROLAPSE AND THREE WERE
HIGHLIGHTED LIKELY PATHOGENIC
VARIANTS RELATED TO CARDIO MY
ON -- CARDIO MYOPATHY OR
CHANNELOPATHY GENE.
THANKS TO A SUPPLEMENT FROM MY
R1 I WAS ABLE TOE STUDY THE
SUDDEN DEATH OR ARREST IN A
NUMBER OF MVP PEDIGREES AT UCSF
AND LEVERAGING THE LARGE
COLLECTION AND THIS POSTMORTEM
INVESTIGATION OF POST CARDIAC
SUDDEN DEATH FOR TRUE ARRHYTHMIC
CAUSE OF DEATH AND IDENTIFY
PARAMETERS USING CARDIO GRAPHY
IN PEDIGREES WITH SUDDEN DEATH
OR ATROPHY AND WANTED TO COMPARE
FAMILY MEMBERS WITH NON-PROLAPSE
TO NON-PEDIGREE HEALTHY CONTROLS
TO IDENTIFY INDEPENDENT OF MVP
EXPRESSION.
SO WE LEVERAGED OUR UCSF
REGISTRY TO IDENTIFY PEDIGREES.
THIS INCLUDES OVER 700 CASES
FROM THE ECHO DATABASE AND HAVE
TRACKING AND STANDARD ECHO
VARIABLES AS WELL AS CLINICAL
VARIABLES.
ALL HAVE SAMPLES FOR GENOMICS
AND IDENTIFIED 23 WITH MVP AND
THE TOTAL OF 121 FAMILY MEMBERS
COLLECTED.
SO THIS IS THE STUDY WHICH IS
STRENGTHENED WITH AUTOPSY ON 100
WHO TEE FIND SCD ABLED 18 TO 90.
THERE'S NO SELECTION BIAS.
THIS IS ALL COMERS.
IT WAS A HIGH AUTOPSY RATE IN
POSTMORTEM PHENOTYPES IN CAUSE
WAS BASED ON EXCLUSION OF OTHER
ETIOLOGIES OF SUDDEN DEATH WHICH
MIMIC ARRHYTHMIC DEATH AND
EPILEPSY OR DRUG OVERDOSES.
AND THE PREVALENCE OF MVP WAS 4%
SUDDEN ARRHYTHMIC DEATHS.
WE LEVERAGED THE HEALTHY START
STUDY ALSO A UCSF STUDY LARGE
COHORT OF ADULTS A SET WITHOUT
KNOWN CARDIOVASCULAR DISEASE AND
PARAMETERS AT UCSF.
AND TWO DEATHS WERE FROM THE
STUDY.
FOUR HAD 121 PARTICIPANTS AND
THE SPECTRUM IDENTIFIED.
WE HAVE NORMAL INDIVIDUALS WHICH
HAVE A LOW POINT AND AND
MEASURED THE DYSFUNCTION AND
ALSO AND A TOTAL OF FOUR CASES
IN THE GROUP AND THE CARDIAC
CASES WERE FOUND IN 14%.
SO PARTICIPANTS ALSO WERE
RECONTACTED SIX YEARS AFTER THE
INITIAL RECRUITMENT AND IN CA
CASE -- NO CASE OF DEATH WERE
IDENTIFIED AND NONE HAD A
HISTORY OF CORONARY DISEASE OR
VALVE DISEASE.
AND THEY AND WE HAD ARRHYTHMIC
AND NON ARRHYTHMIC AND WHEN LG
WAS PRESENT WAS IN THE TYPICAL
LOCATIONS OF THE PATHWAY MUSCLES
OR BASAL INTRALATERAL WALL.
THESE ARE THE RESULTS OF THE
ANALYSIS.
WE ASSESSED THE LONGITUDINAL
STRAIN AND MECHANICAL DISPERSION
AND DOUBLE PEAK.
SAME PATTERN.
THERE WAS NO DIFFERENCE AND THE
PEAK STRAIN PATTERN WAS NOT IN
THE NORMAL VALVES.
INTERESTINGLY THE ARRHYTHMIC
PEAK HAD MORE STRAIN IN THE
BASAL WALL AND OF INTEREST THE
ARRHYTHMIC MVPs HAD INTRALATERAL
PSI TYPICAL AREAS OF TRACTION
BUT ALSO HAD ABNORMAL PSI NOT
SUBJECT TO TRACTION.
THE APEX AND SEPTUM OR
INTRALATERAL WALL AND ARRHYTHMIC
MVP HAD SINGLE PSI VALUES
COMPARED TO THOSE WITHOUT SUDDEN
CARDIAC ARREST.
AND THE MAIN POINT OF ARREST WAS
IN 14% OF PEDIGREE SO THEY'RE
ALL LOW AND THE STRAIN IN
ARRHYTHMIC MVP IN THE FAMILIAR
SETTING IS PRESENT NOT JUST IN
THE TYPICAL AREAS OF TRACTION
BUT DIFFUSED SUGGESTING A
MYOPATHIC PROCESS AND LOOKING AT
INDIVIDUALS OUTSIDE THE SETTING
AND CONTROLS FROM THE HEALTHY
HEART STUDY WITH NORMAL VALVES
AND COMPARED THEM WITH THE
FAMILY MEMBERS WITH NORMAL
VALVES THE INDIVIDUALS WITHIN
PEDIGREES BUT HAD HIGH
MECHANICAL DISPERSION AND LOWER
STRAIN.
AND AGAIN INDICATE IING THE PROS
EVEN INDEPENDENT OF PROLAPSED
EXPRESSION.
STUDYING CARI AC ARREST WE FOUND
IN 33% OF CASES INSTEAD CARDIAC
ARREST MAY REQUIRE A COMBINATION
OF MYOCARDIAL MECHANICS AS
EXPRESSED BY HIGHER ELECTRICAL
MECHANICAL DISPERSION AND FAMILY
MEMBERS WITH NORMAL MITRAL
VALVES HAVE EXHIBIT PARAMETERS
SUGGESTING AN UNDERLYING
MYOPATHY IN INDEPENDENT OF
EXPRESSION AND SUDDEN DEATH
REQUIRES THE CONCEPT FIRST
INTRODUCED BY THE MAYO CLINIC
PAPER SO TWO-HIT MODEL OF THE
PRESENCE OF A NORMAL MECHANICS
IN A PRIMARY GENETIC MYOPATHY.
I'D LIKE TO THANK MY TEAM AND MY
COLLABORATORS DR. SCHILLER AT
UCSF WHO PROVIDED THE HEALTHY
HEART CONTROLS AND CHIP AND
COURTNEY WORKING ON THE GENETICS
AND BOB WHO HAS LAID A SECOND
PAIR OF EYES ON MY MOST
DIFFICULT CONUNDRUMS IN THE
PEDIGREES.
>> THANK YOU.
DOES ANYONE HAVE ANY QUESTION OR
COMMENT ABOUT THIS PARTICULAR
PRESENTATION?
>> WE HAD THE SAME OBSERVATION
SO I LIKED IT VERY MUCH.
>> AGREED.
>> WE HAVE TWO PEDIGREES AND
THERE'S NO REOCCURRENCE OR RARE
REOCCURRENCE IN FAMILIES OF
MITRAL VALVE COLLAPSE.
AND LOOK AT THE DISEASE IN
SIGNIFICANT PART OF OUR
POPULATION AND LOOKS AT CAUTIONS
AND ALSO IN SOME CASES WE DON'T
FIND ANYTHING BUT DON'T KNOW IF
IT FINDS THE CAUSES OF SUDDEN
DEATH AND HAVE A PAPER AND IN
THE SPECIFIC MUTATION WITH SEVEN
FAMILIES I THINK WE FOUND TE
LARGEST DELETION IN THE GEEM AND
VARIANT IN THE GENE THAT LEAD TO
THIS AND TO MITRAL VALVE
COLLAPSE AND DEATHS RELATES TO
THE MITRAL VALVE COLLAPSE.
MAYBE A TRIPLE.
>> WHAT IS HEARD TO UNDERSTAND
IF THE SPECIFIC GENE CAUSES
PROLAPSE IN CARDIOMYOPATHY OR
WE'RE JUST PICKING UP THE
CARDIOMYOPATHY GENES.
IN THE CLINICAL WORLD THE
CLINICAL PANELS CONTAIN THE
GENES AND DON'T HAVE OF A
PROLAPSED GENE AND AT THE
MECHANISTIC LEVEL.
HOW CAN ONE PARTICULAR GENE AND
WHAT IS INVOLVED IN CELL TO CELL
COMMUNICATION AND HOW CAN IT
CAUSE THIS MAYBE CHIP CAN TELL
IN MORE DETAIL.
>> SOME ARE ASSOCIATED WITH
CARDIOMYOPATHY.
DID YOU FIND ANY LINK TO THOSE
GENES MENTIONED IN THE PAPER?
>> IN THE CARDIOMYOPATHY YOU'RE
MAKING UP SEVERE CASES NOT
REALLY FOCUSSING ON ARRHYTHMIC
CASES.
WE'RE MISSING A LARGE SCALE
ARRHYTHMIC FOCUS INVESTIGATION
TO KIND OF SORT OUT THE TWO AND
COMPARING MVP THAT'S NOT
ARRHYTHMIC AND WHICH ARE AND
SORT OUT WHICH ARE CAUSING THE
CARDIOMYOPATHY AND PROLAPSE.
THE TWO-PHASE APPROACH WILL MAKE
IT TO SORT OUT THE TRIGGER OR
INFLUENCE PLAY VARY FOR
NON-GENETIC FACTORS UNLESS ON
CHANNEL MYOPATHIES OR CHANNEL
GENES.
IT MAY BE INTERESTING TO
STRATIFY THE STRESS ON THE
MYOCARDIUM AND IF IT CAN BE
DONE, WE'LL DO IT.
>> ABOUT WHAT IF THEY ONLY HAVE
ONE HIT?
DOES IT PUT IT INTO A LOWER RISK
CATEGORY?
THAT WOULD BE INTERESTING TO SEE
IN THE FUTURE.
>> OR ONE GENE VERSUS MULTIPLE
GENES.
>> TO HAVE AN IDEA WHAT IS RISK
AND NOT RISK AND WHAT COMES OUT
OF WHAT YOU'RE SAYING.
>> FOR SURE.
>> FRANCESSCA MENTIONED THE
PROSPECT OF CHUCK NORRIS GIVING
US INFORMATION BUT -- CHIP NOR
IS GIVING US ENFORCEMENT.
NEXT IS NABILA BOUATIA-NAJI.
>> THANK YOU FOR ALLOWING ME TO
SHARE WITH YOU OF THE THE
WORKSHOP ON THE DATA ON WORKSHOP
AND THERE'LL BE AN OVERLAP WITH
THE WORK I SHARED WITH SOME OF
YOU.
JD WORKING ON CASES AND WHY THE
GENETIC RESULTS WERE ENRICHED IN
SURGERY CASES BUT AND YOU HAVE
LIMITATIONS IN GENETIC STUDIES
YOU HAVE BIG NUMBERS AND LARGE
PANELISTS TO HAVE THE SITUATION
OF GETTING CONTROLS AND SUPER
CLOSE PHENOTYPES AND HARD TO GET
FAMILIES FOR SPECIFIC PHENOTYPES
AND THE SPORADIC SITUATION DOES
NOT FIT INTO WHAT STUDY UP LARGE
PANELS.
AND THIS WAS A SUCCESS STORY BUT
MANY MANY ATTEMPTS WERE NOT
SUCCESSFUL AS MOST THE PEOPLE OF
THE CALL WERE AND RECENTLY THE
WORK WE CONDUCTED ALL TOGETHER
INVOLVING MANY GENETICS OF MVP
PRESENT TODAY AND THE PROBLEM
WHERE GENETICS AND PROLAPSE AND
THIS IS SOMETHING I'M HAPPY I
WAS INVOLVED IN THE
DEMONSTRATION THAT THERE IS
ACTUALLY A COMPLEX GENETIC
FEATURE OF THIS DISEASE.
IT'S HIGHLY POLY GENIC AND
THERE'S AN INFLUENCE COULD BE
LIFESTYLE OR MECHANICAL BEATING
OF THE HEART OR LIFESTYLE.
THEY'RE ALL TRIGGERS THAT
INTERACT WITH THE GENETIC
SUSCEPTIBILITY AND NOT TALKING
ABOUT CAUSALITY AND
SUSCEPTIBILITY WITH TINY
INDIVIDUAL AFFECTS.
AND WE DON'T HAVE A FULL PICTURE
YET.
WE HAVE ATTEMPTS TO IMPROVE OUR
IMAGE OF THE PUZZLE AND IT'S BIG
FOR MOST CARDIOVASCULAR
DISEASES.
I WAS INVOLVED IN APPLYING
GENETIC ASSOCIATION STUDIES TO
UNDERSTAND THE GENETIC BASES AND
THERE'S PROOF THERE'S A POLY
GENIC NATURE OF THE DISEASE.
WE TAKE A NORMAL SAMPLE OF
POPULATION BASE AND A DISEASE
SAMPLE AND WE COMPARE THE
GENETIC INFORMATION THAT WE
EXTRACT SOMETIMES BY GENOTYPING
MORE AND MORE BY SEQUENCING OF
THE DATA OF THE INDIVIDUALS AND
THEN WE AND DISTINGUISH BETWEEN
WHAT ARE THE GENETIC POSITIONS
WHERE WE SEE A DIFFERENCE IN
FREQUENCY AND BETWEEN THE CASES
AND THE CONTROLS.
THIS APPROACH WAS APPLIED IN THE
RECENT YEARS.
WE'RE GOING TO CELEBRATE THE 10
YEARS OF OUR PAPERS IN 2015 WITH
OTHERS AND THIS WAS PUBLISHED 10
YEARS AGO WHERE WE DESCRIBE THE
LOCI AND THIS WAS A SMALL COHORT
BUT WE HAD ACTUALLY TWO
DISCOVERY COHORTS WHERE WE GOT
THESE SURGERY ENRICHMENT IN THE
SAMPLES AND THAT'S DEFINITELY IN
MY OPINION THE REASON WHY WE
WERE SUCCESSFUL DESPITE THE VERY
SMALL NUMBERS FOR THE DISCOVERY
OF 1500 INDIVIDUALS.
RECENTLY WE AND HERE WE GO THIS
IS WHAT MAY BE PRESENTED YEARS
AGO.
THE WORKSHOP AND THE UPDATE FROM
A MORE RECENT EFFORTS.
THIS IS AN INITIATIVE LED BY THE
BROAD AND THEY ARE WERE ABLE TO
COLLECT A MUCH LARGER SAMPLE OF
CASES OF MITRAL VALVE PROLAPSE
AND THE GENETICS CONSORTIUM OF
MVP AND MADE RAY HUGE EFFORT TO
USE ACD TO COLLECT MORE IN
INDIVIDUALS AFFECTED AND
INCREASE FROM 5,000 TO 19,000
CASES RIGHT NOW.
SO THE IDEA WAS WAS TO LEVERAGE
CONTINENTAL GENETIC DATA AND
U.S.-BASED COHORT TO PERFORM THE
LARGEST U.S. MVP AND THE
MOTIVATION IS WE SEE LOCI WE
KNOW IS NOT COVERED AND WE ALSO
WANTED TO PRIORITIZE CAUSE OF
GENES AND USING MORE
SOPHISTICATED ROTATION TO
UNDERSTAND WHAT ARE THE PATHWAYS
THAT ARE COVERED BY THOSE
GENETIC RISK GENES OF LVP.
THIS IS A DESCRIPTION OF THE
COMPOSITION.
ALL THESE LARGE STUDIES ARE
BASED ON THE PROGRAM AND THE
STUDIES HAVE MORE CONTROLS THAN
CASES.
WE MAKE SURE IT'S NOT
INTRODUCING VIRUS USING
STATISTICAL TRICKS.
THE ANCESTRY IS PREDOMINANTLY
EUROPEAN AND ONE OF THE
LIMITATIONS OF THE STUDY AND HOW
COMPLICATED IT IS TO GET LARGE
AND WELL POWERED NON-EUROPEAN
POPULATIONS THAT STILL HAVE A
SMALL FRACTION OF AFRICAN
AMERICAN AND HISPANIC BUT IT'S
ONLY THE ANCESTRY BASE IN THE
U.S. WHICH IS DIFFERENT FROM
WHAT WOULD BE HAPPENING IN
CONTINENTS AND THE PROGRAM WHERE
IT IS PREDOMINANTLY MALE
POPULATION.
THIS IS THE IMAGE WE HAVE.
AND THERE'S A NEW COHORT AND WE
ARE 74 LOCI AND THESE ARE MOSTLY
NOVEL.
AGAIN IT THIS JUST SHOWS THE
OBSESSION TO GET LARGER AND
LARGER COHORTS IT'S VERY
EFFICIENT TO RECOVER THE
VARIANTS WHICH IDENTIFY THE GWAS
AND HERE YOU COVER MORE
MECHANISMS AND GENETIC RISK BY
INCREASING THE SAMPLES YOU
OVERCOME THE HETEROGENEITY OF
THE DISEASE THOUGH YOU NEVER
COMPLETELY COVER THAT ISSUE
THROUGH THIS KIND OF DESIGN BUT
STILL IT GIVES YOU A LITTLE BIT
MORE STATISTICAL POWER TO DETECT
MORE LOCI THIS IS THE CASE HERE.
IT'S IMPRESSIVE EVERY TIME I RUN
A GWAS I'M SURPRISED HOW MUCH
RISK AND SIGNALS WE CAN SEE FROM
THOSE THAT SUPPORT THE POLY
GENETIC NATURE OF THE DISEASE.
SO, NOW ONE OF THE VERY
IMPORTANT QUESTIONS WE WANT TO
ADDRESS ESPECIALLY IN MY LAB IS
WE WANT TO REALLY KNOW WHAT IS
GETTING BEHIND THE STATISTICAL
ASSOCIATION AGAIN FROM GENETICS
TO THE BIOLOGICAL IMPACT OF THE
VARIANTS.
SO THIS IS SOMETHING WE CAN DO
AT A SMALL SCALE.
AND IN ONE OF OUR RECENT WORK
WE'RE ABLE TO USE THE GENETIC
INFORMATION TO REFINE THE SIGNAL
IN ONE AND IMPORTANT LOCUS
IDENTIFIED IN THE INITIAL STUDY
AS CAUSING THIS IN ZEBRAFISH AND
MORPHOLOGY MITRAL VALVE IN MOUSE
AND APPLY A CHROMATIN
INTERACTION EXPERIMENT.
THAT MEANS BECAUSE THE VARIANT
FOR REGULATION WAS FAR AWAY WE
WERE ABLE TO PROVE THERE WAS AN
INTERACTION BETWEEN THE REGION
AN PROMOTER AND ALSO IN VITRO
ANALYSIS TO DEMONSTRATE THE ROLE
OF THIS VARIANT IN THE ACTIVITY
OF INDIVIDUAL ACTIVITY USING
REPORTER ASSAYS.
AND MOST INTERESTING IS PROVIDE
AN OPEN CHROMATIN MATCH AND AND
THIS WAS INTERESTING TO GENERATE
AND WE GET INTEREST IN LESSONS
LEARNED FROM THIS EXPERIMENT.
FIRST WE USED IT TO ANNOTATE OUR
GWAS RESULTS THAT WAS MORE
DESCRIBING MORE LOCI.
>> THIS IS USING DATA THE
UPDATED GWAS WE CONFIRMED THERE
IS AN IMPORTANT ROLE OF
ENRICHMENT IN TERMS OF FOLD IN
THE NORMAL AND YOU'LL NOTICE THE
NORMAL HAS A HUNDREDFOLD
ENRICHMENT PROBABLY BECAUSE YOU
HAVE MORE CELLS AND METRICS AND
FIBROSIS THAT DIMINISH THE
CHANCES TO DETECT ENRICHMENT THE
BUT ALSO THERE IS THE ENRICHMENT
FOR THE VENTRICLE.
WE SEE CONSISTENTLY AROUND OUR
ANALYSIS EACH TIME WE DO
ENRICHMENT.
SO THE EXPERIMENTS JUST GIVE YOU
A COMPARISON BETWEEN THE
POSITION ASSOCIATED WITH MVP AND
WHERE THEY ARE COMPARED TO OPEN
CHROMATIN AND THE TISSUE BECAUSE
OPEN CHROMATIN IS SPECIFIC TO
TISSUES.
IT MAKES SENSE TO WHAT IS
HAPPENING.
SOMETIMES IT'S IMPORTANT FOR ALL
TISSUES BECAUSE IT'S UBIQUITOUS
GENE BUT SOMETIMES YOU CAN SEE
WHAT IS HAPPENING IN THE HEART
AND ALSO IN THE MITRAL VALVE
TISSUE.
SHE PERFORMED AN INTEGRATION OF
THE GWAS INTO SINGLE CELL DATA
AND MOST THE VARIANTS ASSOCIATED
WITH MVP HAVE EXPRESSION IN
CELLS AND MYOFIBROBLASTS BUT
NOTHING IS HAPPENING FOR THE
ENDOTHELIAL CELLS WHICH IS
INTERESTING TO KNOW AND WE NEED
TO CONFIRM IT DOESN'T MEAN THE
CELL TYPE IS NOT IMPORTANT BUT
THE MODIFICATION WE SEE ARE
PREDOMINANTLY DRIVEN BY WHAT IS
HAPPENING WITH THE PEAKS.
AND YOU MAY HAVE CANDIDATE GENES
AROUND THE SIGNAL AND ONE OF THE
MOST IMPORTANT QUESTIONS YOU
WANT TO ANSWER IS THE LIKELY
GENE TO BE DRAWN DRAWING THE
BIOLOGICAL IMPACT MUCH THE
ASSOCIATION.
AND SOMETIMES THE ASSOCIATED
VARIANT IS A COMBINANT STILL
CODED SO WHEN THE GENE HAS
VARIATION WE PRIORITIZE THAT
GENE AND SOMETIMES IT'S THE
PROMOTER WHERE IT'S LOCATED.
SOMETIMES A CORALS WITH
EXPRESSION IN A CARDIAC TISSUE
OR RELEVANT TO THE CARDIAC
FUNCTION.
WE PRIORITIZE THE GENES BASED ON
ASSOCIATION AND CONFIRMATION
INFORMING FROM THE DATABASES IN
CARDIAC TISSUE AS WELL AND AT
THE END WE PRIORITIZE 60 ALMOST
70 GENES.
WE DID HALFWAY GENES TO SEE HOW
THEIR FITTING IN THE PATHWAYS WE
HAVE TWO MAIN GROUPS.
ONE RELATED TO EXTRA CELLULAR
MATRIX AND THE ONE YOU SEE IN
THE LEFT OF THE PATHWAY.
UNFORTUNATELY WE DON'T SEE
CLEARLY THE CONNECTED DIFFERENT
GENES BUT THAT'S PROBABLY DUE TO
THE CONVERSION INTO PDF AND YOU
HAVE ON THE OTHER HAND MANY
GENES RELATED TO INVOLVEMENT OR
CARDIOMYOPATHY GENES.
THIS HAS BEEN DONE AS SAYS BY
FRANCESSCA BUT WE HAVE GOOD
MORNING WORK BETWEEN MVP AND
MANY OTHER CARDIAC PHENOTYPES
ESPECIALLY CARDIOMYOPATHY.
SEE WHAT THE FIBROSIS ONSET AND
HERE IN THE GENES THIS IS ONE OF
THE IDEAS WITH FOLLOW-UP AND
SOME ARE LINKED OR ASSOCIATED
WITH ARRHYTHMIA GENES.
WHEN WE TAKE OFF A LARGE NUMBER
OF HETEROGENEOUS CASES BUT
INCREASING THE SAMPLES YOU START
TO DETECT DIFFERENT GENETIC RISK
FACTORS RELATED TO THE ASPECTS
OF MVP THOUGH WE COULD NOT HAVE
A MECHANISM HOW THIS WORKS IS
ALWAYS VERY DIFFICULT WHEN YOU
COME TO AN AGING OR PHENOTYPE
THAT DEVELOPS WITH AGE.
YOU CAN KNOW WHICH ONE COMES
FIRST AND THIS SOMETHING THAT
MAYBE NEEDS TO BE DISCOVERED
WITH OTHER METHODOLOGY.
AND THE FACT IT'S BEING
GENETICALLY ASSOCIATED THAT
MEANS YOU CAN ALSO HAVE THE
PHENOTYPING HAVE DIFFERENT
ORI
ORIGINS.
WHEN WE SEE DIFFERENT GENETIC
MECHANISMS THIS IS WHAT IT MEANS
BECAUSE IT'S MULTI-FACTORIAL AND
MAY HAVE REASONS DIFFERENT FROM
EACH OTHER.
THERE'S DIFFERENT RESOURCES FOR
STUDIES AND ALSO THE CASE
CONTROLS THAT HAS EFFORTS TO
COLLECT AND ANALYZE LARGER AND
BIGGER SAMPLES AND HELPS TO
COVER THE HETEROGENEITY OF THE
DISEASE AND THIS IS NOT ONLY FOR
MOST CARDIOVASCULAR DISEASES
WITH THIS PATTERN OF INHERITANCE
AND A HARD TIME TO TRANSLATE TO
BIOLOGY AND WE TRY TO ACQUIRE
MULTI-OMIC COMBINATIONS AND
USING COLLABORATION WITH CHIP
MOUSE TISSUE SOMETIMES AND
DIFFERENT RESOURCES TO TRY TO
INTEGRATE TOGETHER INTO A WAY TO
UNDERSTAND HOW THESE DIFFERENT
LITTLE DYSFUNCTION IN THE
GENETIC REGULATION IN PARTICULAR
CONTRIBUTING TO MVP ONSETS.
AND THE LAST SLIDE IS THE TAKE
HOME MESSAGES.
I'LL SUMMARIZE THAT MVP GENETICS
IS CHALLENGING DUE TO THE
COMPLEX PHENOTYPE AND GENETIC
MODEL AND THE INTEGRATION OF
MULTI-OMIC RESOURCES MAINLY GWAS
INFORMED THE BIOLOGY AND WE HAVE
MECHANISMS AND DATA FROM FAMILY
STUDIES AND FROM GWAS AND
LOOKING AT FIBROTIC PHENOTYPES
BUT NEED FUTURE EFFORTS TO
TRANSLATE THEM TO PREVENTIVE AND
THERAPEUTICS.
THAT WAS MY LAST SLIDE.
I'D LIKE TO THANK MY
COLLABORATORS FOR SHARING SLIDES
AND AND MANY OF THE CONSORTIUM
AND THANK YOU FOR YOUR
ATTENTION.
6:
>> DOES ANYONE HAVE COMMENTS OR
QUESTIONS ABOUT THIS PARTICULAR
TALK?
>> INFLUENCING THE QUALITY OF
THE GENOTYPING, DO YOU SCREEN
ALL THESE GENES THAT YOU HAVE
DISCOVERED BY IN A SENSE
MEDIOCRE PHENOTYPING TO SEE IF
THEY PRODUCE AN MVP OR DO YOU
PREFER TO HAVE BETTER DEFINED
PHENOTYPES LESS VARIATIONS AND
MORE TARGETED GENES TO ANALYZE
THEIR ROLE?
WHAT'S YOUR VIEW ON HOW TO
PROCEED?
DO WE NEED TO HAVE A CONSORTIUM
WHERE THE MVP IS WELL DEFINED BY
GOOD IMAGES OR WE DON'T CARE?
>> ALL THE APPROACHES HAVE AN
INPUT.
THIS HAS THE POWER TO DETECT
MORE LOCI AND COVERS MORE OF THE
DIFFERENT ASPECTS OF MVP.
I CAN DEFINITELY ENVISION A
SPECIFIC SPEENT WE WANT TO
INVESTIGATE IN THE CONTEXT OF
MVP AND AGAIN IF YOU HAVE A
LARGE SERIES OF PATIENTS WITH
FOR EXAMPLE MVP AND ARRHYTHMIA
AND CONDUCT THE GWAS YOU MAY
SPECIFICALLY FIND WHAT IS FOR
THIS PHENOTYPE IF YOU HAVE
LARGER SAMPLE.
THIS IS THE LIMITATION WHEN
YOU'RE DEALING WITH THIS COMPLEX
AND POLY GENIC DEFICIT YOU NEED
THE BIG NUMBERS BECAUSE THE
STATISTICAL POWER DOES NOT
FORGIVE YOU IF YOU PUT SMALLER
SAMPLES YOU WILL NOT HAVE
RESULTS.
EVEN IF THE PHENOTYPE IS VERY
PRECISE.
IF YOU GO FOR A BALANCE AND BOTH
APPROACHES GIVE AN INTEREST IN
AND A STEP AHEAD.
.
THE CHALLENGE OF THIS KIND OF
APPROACH IS WE HAVE GOT WE HAVE
TO GO BACK TO EACH OF THOSE
CONTRIBUTING COHORTS LEFT TO
DEVELOP ALMOST 30 CENTERS AND
STRATIFIED BEFORE DOING THE
ANALYSIS WHICH IS CHALLENGING.
THIS COULD AN EFFORT TO THE WORK
AND WE NEED TO PUSH INTO HAVING
A LARGE AND ANALYSIS DEFINITELY.
>> AND A QUICK QUESTION,
EXCELLENT TALK.
WHEN YOU WERE SHOWING THE DATA
ON THE RNA SEQUENCING WAS THIS
FROM THE TISSUE YOU WERE
PROCESSING OR SAMPLE.
>> YOU CAN HAVE INFORMING FROM
THAT AND THE PUBLICATION IS IN
CIRCULATION.
THERE WAS A HEALTHY MITRAL VALVE
AND THE SEQ THE ONE WE PERFORMED
IN THE LAB THAT WAS ALSO MITRAL
VALVE AND WE DID THIS IN NORMAL
AND --
>> THANK YOU.
>> FANTASTIC SCIENCE, NABILA
YOU'VE BEEN SHEPHERD.
NOW THAT THERE'S A MULTIPLICITY
OF VARIANTS WITH MVP AT
DIFFERENT LEVELS HOW DO WE
TRANSLATE THIS TO POTENTIAL
MECHANISMS AND TREATMENTS FOR
PATIENTS?
>> THAT'S THE BIG QUESTION WE'D
LIKE TO MOVE FORWARD.
I JUST WANT TO EMPHASIZE THE
FACT THAT IT'S NOT BECAUSE YOU
FIND THE MECHANISM RECENTLY OR
GENE IT'S LESS IMPORTANT THAN
THE FIRST ONE IDENTIFIED.
THIS IS THE LIMITATION OF GWAS
IS JUST WE DIDN'T HAVE THE GOOD
CONFIGURATION STATISTICALLY TO
OBSERVE THE EFFECT OF THE NEW
SERIES OF GENES.
THE GOOD NEWS IS WE HAVE
CONSISTENTLY THE SAME MECHANISMS
WHICH IS ASSURING AND IN TERMS
OF HOW THIS COULD BE TRANSLATED
TO BIOLOGY.
WE HAVE TOO MANY GENES AND FOR
THE INDIVIDUAL ANALYSIS TO MAKE
SURE YOU HAVE THE RIGHT TARGET
GENE AND CAN DO CRISPR
INHIBITION METHODS.
WE CAN DO THAT AND END UP WITH
MORE PRECISE DESIGN DESIGNATION
OF WHAT IS THE CANDIDATE GENE.
FROM THERE TO TRY TO AND THEY
ARE RECOMMEND TO DO NETWORK
ANALYSIS OF THE GENES AND TAKE
MAYBE THE GENES THAT ARE MOSTLY
ESSENTIAL IN THE NETWORK.
THEY'LL MORE LIKELY TO BE
IMPORTANT AND YOU'LL BE ABLE TO
MAY BE TO CREATE A CONSEQUENCE
OF THIS MECHANISM SOMEHOW AND
FROM AN OVERVIEW I DID WHAT IS
THE BEST DRUG TARGET FROM GWAS
DATA IS PROBABLY A GENE
ESSENTIAL IN THE NETWORK BUT NOT
SO MUCH WE DON'T MAKE IT
DISAPPEAR AND AT THE SAME TIME
WE HAVE A MOLECULE TO AFFECT ITS
CRITERION AND GIVE THE MOST
LIKELY GENE.
SEAS IMAGINE TO WORK ON AND IT'S
IMPORTANT TO GET UPDATED GENETIC
EFFORTS BECAUSE IT GIVES YOU
MORE QUANED DA CANDIDATES AND T
TO FIGURE OUT WHAT IT MOST
INTERESTING TO BE TARGETED
THERAPY.
>> THAT'S A WONDERFUL VISION OF
THE FUTURE.
>> THE FINAL PRESENTATION IN
THIS PORTION IS CHIP NOR IS --
NORRIS.
>> I'M A MERE SCIENTIST AND
INTERESTED TO SEE HOW YOU'RE
MAKING LIVES BETTER FOR THESE
PATIENTS.
INTEGRATION IS KEY TO
UNDERSTANDING MVP AND THE PI
FIBROSIS ASSOCIATED WITH THIS
AND WITHOUT THE INTEGRATION THE
POTENTIAL COULD BE LIMITED AND
HOW CAN WE DEVELOP THESE
PREDICTIVE TOOL TO TELL US
WHETHER PATIENTS IS READY FOR
SURGERY?
SO YOU HAVE TO INTEGRATE THE
MOLECULAR TOOLS, MOLECULAR
IMAGING AND THE CURRENT ECHO
BASE AND OTHER PHYSIOLOGICAL
MACHINES TO BE ABLE TO CAPTURE
HOW TO DEFINE THESE PATIENTS AND
KNOW WHICH ONES WILL BENEFIT
FROM EARLIER SURGERY.
SO I'M GOING TO TELL YOU A
LITTLE BIT ABOUT HOW WE SORT
OF -- WE WANT TOO UNDERSTAND THE
QUESTION OF WHY.
WHY DO PATIENTS DEVELOP THESE
FIBROTIC LESIONS.
WHAT'S THE MECHANISM BEHIND THEM
AND CAN THAT LEAD TO NOT ONLY
THERAPIES BUT MOLECULAR TOOLS
THAT CAN THEN BE APPLIED TO
FOLLOW THESE PATIENTS -- YOU
GUYS CAN FOLLOW THESE PATIENTS
AND ASSESS WHETHER THE CHANGES
IN THE FIBROTIC REGIONS ARE
PROGRESSING TO A REAL PATHOGENIC
REPLACEMENT FIBROTIC STATE.
WE'VE BELABORED THIS ALL MORNING
FROM PEOPLE MORE EXPERT THAN I
AM AND THIS IS A COLLABORATION
AND YOU CAN CLEARLY SEE
SIGNIFICANT REPLACEMENT FIBROSIS
IN BASAL MYOCARDIUM IN SOME
PATIENTS AND SOME ARE PROFOUND.
THIS IS A PRETTY SEVERE CASE BUT
THERE'S DIFFERENT LEVELS OF
FIBROSIS NOT JUST REPLACEMENT
BUT INTERSTITIAL FIBROSIS AS
WELL.
WITH THE WORK MUCH THE PREVIOUS
NETWORK LED BY DR. LAVIGNE, WE
ESTABLISHED THIS LARGE CORNER
SUM AND ONE OF THE POWERS OF THE
GENETICS IS NOT ONLY HAVING THE
DEVELOP TO DEVELOP THE POLY
GENETIC RISK SCORE OR A GENETIC
MAP OR ARCHITECTURE OF THE
DISEASE BUT ONE OF THE TRUE
POWERS IS TO ESTABLISH MODEL
SYSTEMS TO AND THIS IS A COMMON
STRATEGY PHYSICIANS INTEGRATE TO
MAKE POSITIVE BENEFIT FOR
PATIENTS.
ONE OF THE VERY FIRST THINGS WE
DID WHEN WE IDENTIFIED THE
MUTATION I BELIEVE THIS WAS
FRANCESCA'S FAMILY --
>> IT WAS.
>> I THOUGHT SO.
WE MADE THE EXACT SAME MUTATIONS
AND PUT IT IN THE MOUSE AND
PUBLISHED THIS YEARS AGO AND
WITH A SINGLE MUTATION DEVELOPED
MITRAL VALVE PROLAPSE SEEN AND
QUANTIFIED BY ECHO CARDIOGRAPHY
AND SAW CHANGES IN PATIENT LTZ
WITH MVP.
THE YELLOW STAIN IS COLLAGEN A
PAN MARKER FOR FIBROSIS.
EARLY ON THERE'S LITTLE FIBROSIS
IN THE MICE AND PROGRESSIVELY
DEVELOPED AND THERE'S A TIME AND
TEMPORAL COMPONENT TO THE LV
MOLECULAR CHANGES.
AND THIS INDICATED THE POTENTIAL
ROLE FOR MECHANICAL FORCES FOR
REDUCTION IN MVP.
THIS IS A NON-ISCHEMIC EVENT.
AND HOW DO CELLS SENSE THIS AND
KNOW TO RESPOND.
6:
HOW DOES THIS EFFECT STRESS AND
DEVELOPED TOOLS AND METHODS TO
TRY TO STUDY THIS.
LINKING MECHANICAL STRESS TO
FIBROSIS WOULD BE IDENTIFIED AND
WE CAN IDENTIFY THE PATHWAYS BY
UNBIASSED PROFILING AND THE RISK
COULD LEAD TO LEAD TO NEW
OPPORTUNITIES AND TOOLS THAT
COULD POTENTIALLY HAVE USE IN
CLINIC.
AND THERE'S AN OPPORTUNITY FOR
NEW MECHANISTIC INSIGHT AND THE
CRUX OF THE EXPERIMENTS IN AN
UNBIASSED WAY IS TO LOOK AT
EVERYTHING THE CELLS ARE MAKING
BY RNA AND THE STATUS OF THE
CHROMATIN AND IDENTIFY
TRANSCRIPTION FACTORS THAT ARE
DIFFERENTIAL BETWEEN THE DISEASE
REGIONS AND THE FIBROTIC
REGIONS.
THIS COULD BE DONE WITHIN THE
SAME HEART OR HUMAN AS THE CASE
FOR SOME STUDIES WE HAVE GOING
ON NOW.
WE CAN GET PERSONALIZED MEDICINE
LEVEL DATA ON THE STUDIES.
AND A HUMOR -- HUMAN OR MOUSE
HEART AND WE LOOKED AT THE
SIGNAL AND IT'S LIKELY STRETCH
OR MECHANICAL CHANGE.
SO LET'S PUT THESE CELLS UNDER A
STRINGENT CRITERIA AND STRESS
AMOUNT AND SEE HOW THEY CHANGE
IN AN ACUTE MODEL.
THESE WERE ALL DONE IN CELL
CULTURE.
WE DID A MULTI-OMIC APPROACH AND
COLLECTED RNA SEQ DATA AND ATAC
SEQ DATA AND WE'LL TALK ABOUT
THAT MORE.
WE CAN INTEGRATE.
WE'RE ABLE TO PRIORITIZE AND WE
HAVE SITES PRIORITIZED WHERE
THEY ARE WERE OPEN OR CLOSED
CHANGED CHROMATIN STATUS AND
INTEGRATE THAT WITH THE RNA SEQ
PROFILES FOR SPECIFIC GENES.
THAT'S LIST IN THE CIRCLE PLOT
ON THE TOP.
MOST ARE IN TRONIC REGIONS
ANYONE TO BE REGULATORY REGIONS
AROUND FOLD CHANGES REPRESENTED
WITH LOG VALUES DOWN BELOW.
SO FROM THIS WHAT DOES THIS TELL
US?
THE CELLS ARE DYNAMIC.
AND THESE ARE GENERALLY
QUIESCENT CELLS AND ABLE TO
RESPOND PROFOUNDLY AND RAPIDLY
TO CHANGES IN THEIR ENVIRONMENT.
WE WENT AHEAD AND LOOKED AT
MYH10 BETTER.
THE RATIONALE WAS IT CON
FUNCTION AS A COLLAGEN CHAPERONE
AND HAS BEEN IMPLICATED IN
CARDIOMYOPATHY AND VALVE DISEASE
SO A LOGICAL CANDIDATE TO GO
AFTER.
ON THE LEFT IS OUR FLOW CHART OF
WHAT WE'RE DOING.
BUT ON THE RIGHT IS YOU CAN SEE
UNDER HIGH STRESS ENVIRONMENT
WHICH IS HIGH 1, 2 AND 3 THE RED
PEAKS, THEY LOSE -- THEY CLOSE
THEIR CHROMATIN.
THE BLUE PEAKS REPRESENT THE
OPEN CHROMATIN AND IN THE LOWER
YOU CAN SEE THE PROFOUND
DIFFERENCE FROM THE ONE REGION.
THAT ONE REGION IS VERY
INTERESTED IN THAT BECAUSE
THAT'S ONE OF THE MAJOR CHANGES
IN THE CELLS AND WE'RE
INTERESTED IN WHAT IS BINDING
AND REGULATING TO THAT SPECIFIC
REGION.
AND WE WASN'T BACK TO PATIENT
BIOPSIES FROM MICHAEL BERGER'S
GROUP AND IN THE FIBROTIC REGION
NYH10 HAS A FIBROBLAST AND
ENDOTHELIAL MARKER AND IN
PATIENT BIOPSIES THERE'S
SIGNIFICANT ELEVATION IN NCH10
AND SPECIFIC FOR THE FIBROTIC
REGIONS AND NOT ATHLETE
NON-STRESSED PARTS OF THE HEART.
COLLECTIVELY THIS IS CONSISTENT
WITH IN VITRO.
WE'VE TAKEN BASICALLY
REDUCTIONIST APPROACH AND TAKING
CELLS IN A DISH.
ASKED THE QUESTION OF WHAT IS
BEING CHANGED.
BOTH AT A MOLECULAR AND GENOMIC
LEVEL AND THEN TAKING THAT BACK
TO VALIDATE IT IN THE HUMAN
BIOPSIES.
WE'RE TRYING TO UNDERSTAND WHAT
IT HOLDS AS INFORMATION.
AND WE WANT TO WORK UP STREAM TO
IDENTIFY WHAT IS SIMULATING THE
REGULATION AND CAUSING THE
INCREASE.
AND FROM VARIOUS TATE SETS AND
NETWORK IDENTIFICATION WE WERE
ABLE TO IDENTIFY THREE MAIN
TRANSCRIPTION FACTORS AS
MECHANICALLY SENSITIVE TARGETS.
THEY'RE RELGULATED IN THE AREAS
OF HIGH STRESS.
WHY IS THIS IMPORTANT?
IF YOU IDENTIFY THE SEGMENTS AND
FACTORS AND TRANSCRIPTION OR
OTHER ELEMENTS IN THE CELL AND
THERAPEUTIC INTERVENTION AS WELL
AS DEVELOPING MOLECULAR PROBES
THAT CAN RECOGNIZE THESE
TARGETS.
SO THAT CAN GO BACK AND ASIDE
FROM UNDERSTANDING THE
MECHANISTIC BASIS OF THE
PROGRESSION OF THIS DISEASE WE
CAN ARM PHYSICIANS WITH TOOLS TO
SAY YES, THE PATIENT IS
PROGRESSING.
THE FIBROTIC REGION OF THE
PATIENT IS PROGRESSION IN A
DIFFERENT WAY THAN THE VALVE AND
MAYBE WE NEED A DIFFERENT
INTERVENTION.
WE'VE DEMONSTRATED THE
FIBROBLASTS HAVE THE ABILITY TO
SENSE AND RESPOND TO MECHANICAL
CHANGES BY GLOBAL EXPRESSION RNA
AND CHROMATIN ACCESSIBILITY.
THERE ARE REGULATORS THAT DON'T
JUST REGULATE ONE GENE BUT MAY
REGULATE A HOST OF FWEENZ TO
AMPLIFY A FIBROTIC RESPONSE.
AND INTERFWRITING SINGLE CELL
RNA SEQ HAS BEEN REVIEWING OF A
NEW MECHANISM AND NOW
APPLICATIONS IN HUMAN AND MOUSE
BIOPSIES AS A VALIDATION CORE IS
IMPORTANT AS WELL AS IN BOB
LAVIGNE'S LARGE ANIMAL MODEL
WILL BE INCREDIBLY TELLING
BECAUSE IT'S A SURGICAL MODEL
MAYBE YOU'LL TALK ABOUT LATER
THAT GETS AROUND ANY GENETIC
QUESTION.
SO MAYBE IN THE END AND MAYBE
IT'S SO COMPLICATED IT'S GIVING
US A TOOL TO STUDY THE DISEASE.
THE SECONDARY TERTIARY
CONSEQUENCES OF WHATEVER
MUTATION YOU HAVE IS REALLY WHAT
NEEDS TO BE ALSO FOCUSSED ON.
AND NATURAL HISTORY OF DISEASE
NEEDS TO BE INTEGRATED.
AND HOW DOES THIS TRANSLATING.
REPLACEMENT FIBROSIS IS THE
POINT OF NO RETURN.
SO WE NEED TO LEARN MORE ABOUT
EPIGENETIC VARIANTS AND WHAT ARE
THE ROLE OF CHANNEL ON THE GENE
AND CARDIOMYOPATHY FWEENZ WE
KNOW THEY'RE PLAYERS.
AND YOU CAN TWO THROUGH THESE
THINGS AND SEE IF WE SHOULD BE
DOING BIOMARKERS FROM PATIENTS
AT DIFFERENT TIMES IN STUDIES.
AND CAN MOLECULAR DRIVERS OF
FIBROSIS BE REVERSED AND THAT
ATTRIBUTE TO ARRHYTHMIAS.
THE QUESTIONS ARE MANY.
I'LL LEAVE IT AT THAT.
THANK YOU FOR THE OPPORTUNITY TO
SPEAK.
AND BOB LAVIGNE IN PARTICULAR
HAS BEEN A CONTRIBUTOR TO THIS
AND LARGELY CONTRIBUTED TO MY
THINKING ON THIS MATTER.
THANK YOU.
>> PHENOMENAL.
ALWAYS YOU NEVER CEASE TO
INSPIRE OUR THINKING IN VERY
VERY EXCITING WAYS.
I THINK ONE OF THE INTERESTING
QUESTIONS YOU ALLUDED TO AT THE
END IS THERE REVERSIBILITY.
THAT'S ALWAYS BEEN THE QUESTION
IN TERMS OF PARTICULARLY DOES
SURGERY HELP REDUCE THE RISK OF
ARRHYTHMIAS AND IF THE FIBROSIS
IS THERE AND REPLACEMENT
FIBROSIS DOES IT GO AWAY?
I THINK ONLY THE KIND OF
ANALYSIS YOU'RE DOING ONLY
THROUGH THAT CAN WE POSSIBLY
CONSIDER WAYS TO REDUCE THE
FIBROSIS.
I WAS A SYMPOSIUM FOR TWO DAYS
IN BOSTON CALLED THE
ANTI-FIBROTIC DRUG THERAPY
DEVELOPMENT AND PEOPLE FROM
ACADEMIA AND INDUSTRY AND IT'S
INTERESTING INDUSTRY IS
INTERESTED IN LOOKING AT THE
SAME SINGLE CELL SEQUENCING TATE
AND TRYING TO FIND AND THEY ARE
DON'T HAVE A GOOD MODEL YET FOR
FIBROSIS BUT ACHIEVING THE
REVERSAL OF FIBROSIS WOULD BE AN
AMAZING COUP.
THANK YOU FOR THE INSPIRATION.
>> I'M EXCITED TO WORK WORTH YOU
ON THE BASIC -- THE SAME
QUESTIONS IN A MODEL WHERE YOU
CAN DISSECT --
>> WE HAVE BEEN WORKING ON
BUILDING THE GENOME.
>> AND IN GOATS IT'S
CHALLENGING.
WE HAVE GAPS SO I DON'T KNOW
ABOUT SHEEP.
>> SHEEP ARE WORSE.
>> OKAY.
>> IS THE LIST OF IDENTIFIED
GENES PUBLICALLY AVAILABLE IN
ADDITION TO GENETIC VARIATION IS
THERE ANY INFORMATION AVAILABLE
REGARDING TRANSCRIPTOMIC AND
PROTEOMIC CHANGES.
>> SO WE DON'T HAVE PROTEOMIC
DATA AVAILABLE.
IT'S AGAIN THE SAME CHALLENGES
WHEN YOU ARE DEALING WITH THE
MITRAL VALVE TISSUE.
ANYBODY WHO WORKED WITH THAT
IT'S DIFFICULT TO HANDLE.
WE WERE HAPPY TO GET THE ATAC
MAP ONE DAY AND MOTIVATED TO DO
IT AGAIN.
IT WAS A NIGHTMARE TO GET IT OUT
OF THE TISSUE.
THE WEEKS OR MONTHS TO GET THIS
IN THE PREPRINT AND MAYBE
AVAILABLE AND PEOPLE CAN LOOK IN
DETAIL INTO THOSE MECHANISMS.
YEAH.
>> THANK YOU.
>> ANY OTHER QUESTIONS OR
COMMENTS?
>> I HAVE A QUESTION FOR CHIP IN
TERMS OF REVERSAL.
I ASSUME IT'S DIFFERENT THAN
FIBROSIS AND IS THERE A WAY YOU
CAN STUDY THIS AT THE ANIMAL
MODEL LEVEL?
>> YEAH, SO THE MOUSE DOESN'T --
ONLY IN RARE SITUATIONS DOES THE
MVP MOUSE MODEL DEVELOP TRUE
REPLACEMENT FIBROSIS OR VERY
SPECIFIC REGIONS.
MOST IS INTERSTITIAL FIBROSIS.
SO THAT WOULD BE A GOOD MODEL TO
SEE IF WE COULD REVERSE THE
INTERSTITIAL FIBROSIS.
REPLACEMENT OF FIBROSIS IS
PRETTY MUCH DONE.
IT'S HARD TO IMAGINE HOW YOU CAN
BLAST THROUGH THE CONCRETE
THERE'S OTHER MODEL SYSTEMS YOU
CAN USE TO ASK THAT QUESTION.
ORGANOIDS AND 3-D CULTURE
SYSTEMS.
BUT AS FAR AS THE MOUSE GOES,
MOST OF THE FIBROSIS IS MORE
INTERSTITIAL.
>> AND REDUCE PROGRESSION FOR
THE SIZE.
>> WE SEE A CLEAR INCREASE IN
THE AMOUNT OF COLLAGEN
DEPOSITION AND SO WE'RE JUST NOT
KILLING MYOCYTES HUMANS HAVE.
OUR TIME PERIOD IS SIX MONTHS
VERSUS 60 YEARS.
IT'S A LITTLE BIT HARD TO
COMPARE THOSE.
IF WE CAN FIND A WAY TO SUPPRESS
OR RESTRICT THE FIBROTIC
PROCESS, THEN I THINK THAT'S
GOING TO BE GOOD.
AND CERTAINLY GOING THROUGH
HIGHER ORDER MALES, BOB'S MODEL
OF THE SHEEP HAS PROFOUND
REPLACEMENTS FIBROSIS.
YOU'D GO UP THE CHAIN TO SEE IF
THE MECHANISM YOU'VE IDENTIFIED
IN THE LOWER MANTLE IS WORKING
IN A LARGER ANIMAL.
>> YOU CAN ALSO SORT OUT THE
INFLUENCE OF REGURGITATION THE
MOUSE BECAUSE IT'S HARD TO
IMAGINE THE NATURAL
REGURGITATION.
>> AND IT'S HARD TO HAVE A MODEL
WHERE YOU JUST HAVE MR ONLY SO
IT'S VERY DIFFICULT IN THE
MOU
MOUSE.
IT'S A FAST RHYTHM.
UTILITIES CAN BE SIGNIFICANT AS
FAR AS THE SURGICAL APPROACH.
>> GREAT TALKS.
I WANTED TO GO BACK TO THE
CLINICAL WORLD FOR A SECOND AND
MAYBE YOU COULD THIS AND JUST
CURIOUS IN PATIENTS GETTING
CLINICAL TARGETED EXOME, WHICH
ARE TESTED IN FRANCE FOR EXAMPLE
AND CURIOUS ABOUT THE DIFFERENCE
IN TESTING BETWEEN HERE AND
FRANCE.
>> IN THE CLINICAL PRACTICE?
>> YES.
>> IN CLINICAL PRACTICE WE DON'T
HAVE THE GENETICS OF THE
PROLAPSE BECAUSE THERE ARE A FEW
MEMBERS OF GENES IDENTIFIED SO
FAR AND HAVE THE GENETICS
OUTSIDE THE RESEARCH BUT WE
DIDN'T FIND MANY WITH PATHOGENIC
MUTATION IN OUR SEGMENTS AROUND
300 PATIENTS WITH FULL GENOME
AND WE DIDN'T FIND A NEW FAMILY
OR WITH A SPECIFIC MUTATION
INVOLVING THE PROLAPSE AND A
DIFFERENT STATE THAN OTHER
CASES.
>> MAYBE YOU CAN CONFIRM MAYBE
THE CONTEXT OF SYNDROMES OR
ARRHYTHMIA IS RECOMMENDED IF WE
HAVE AN AARRHYTHMIC GENE AND
THERE'S GENETIC TESTING.
FOR EXAMPLE WE HAVE CENTERS
WHERE THE PATIENTS ARE BUT IT'S
IN THE PRESENTATION AND OFTEN
DISCOVERED LATER.
>> IT COULD BE THE FIRST STEP IN
MITRAL VALVE PROLAPSE AND
DIALYSIS AND WE HAVE FAMILIES
WITH THE SYNDROME.
WHEN I WE HAVE PROLAPSE AND THE
SYNDROME AFTER EXAMINATION
SOMETIMES I SEND THE PATIENT FOR
GENETIC TESTING OF THE SIN --
SYNDROME AND WITH PATIENTS WITH
SUDDEN DEATH WE PERFORM TESTS
AND IT'S A FAMILY WITH THE
MOTHER AND DAUGHTER WITH THE
SAME PHENOTYPES IN THE GENE
SEQUENCING AND THERE WERE NO
KNOCK FOR THE MODEL.
>> WE HAVE A QUESTION FROM CHIP
FROM THE VIDEOCAST.
WHAT KIND OF STRESS ARE THE
FIBROBLASTS EXPERIENCING AND
WHAT ARE THE SENSORS?
>> WE DON'T KNOW WHAT THE SENSES
ARE ON THE CELLS.
WE THINK -- SENSORS ARE ON THE
CELLS.
WE THINK THEY'RE MEMBRANE BOUND.
WE THOUGHT FOR A WHILE THEY MAY
BE CONNEX OMS BUT DIFFERENT
RESPONSES ON FIBE REBLASTS.
-- FIBROBLASTS.
WE HAVE STRETCHED THE CELLS AT
DIFFERENT AMPLITUDES AND UNDER
PATH LOGIC STRAIN VERSUS LOW
STRESS.
AND A SECOND APPROACH WAS--THAT
WOULD MODEL THE EARLY STAGES OF
PROLAPSING VALVE OR PRODOMAL
FORM AND ALSO DID STUDIES WHERE
WE PUT IT THE FIBROBLAST VERSUS
STIFF VERSUS VERY SOFT.
AND SUBSTRATES AND DID THE SAME
STUDIES TO ASK THE QUESTION OF
WHETHER OR NOT THE SUBSTRATES
ARE SUFFICIENT AND NECESSARY FOR
AMPLIFYING A RESPONSE OF THE
FIBROBLASTS OR THE FIBROBLAST
JUST SHUT OFF.
IS A CONTINUAL PROCESS AND
AMPLIFIES THE COLLAGEN AND
FIBROTIC RESPONSE IN THE CELLS.
>> THANK YOU.
WE'RE GOING TO TAKE ANOTHER
BRIEF BREAK AND RETURN 10
MINUTES AFTER THE HOUR AND
RETURN FOR THE FINAL SESSION OF
THE DAY.
THE FIRST PRESENTATION OF THIS
SESSION WILL BE FROM THIERRY LE
TURNEAU.
>> THANK YOU FOR LETTING ME
DISCUSS THE INTERVENTION AND
RESEARCH.
WE MAY NEED TO HAVE THE MEETINGS
DURING THE NET WORK SO IT'S
FRIENDLY MEETING TODAY AND I
APPRECIATE THAT.
I DON'T HAVE DISCLOSURE
REGARDING THE PRESENTATION.
SO AS YOU PROBABLY NOW THE FIRST
STEPS WERE ELABORATED DURING THE
SECOND WORLD WAR.
AND THE MACHINE WAS ABLE TO
DECODE AND PROVIDE THE ADVANTAGE
DURING THE SECOND WORLD WAR.
SO THE DEFINITION OF ARTIFICIAL
INTELLIGENCE IS THE ABILITY OF
MACHINES, COMPUTERS TO PERFORM
TASK THAT REQUIRE HUMAN
INTELLIGENCE AND MACHINE
LEARNING IS WHERE COMPUTERS ARE
ABLE TO IMPROVE AND LEARN
AUTOMATICALLY.
MACHINE LEARNING ALGORITHM USES
DATA TO BUILD MODELS AND MAKE
PREDICTIONS OR DECISION AND DEEP
LEARNING IS RAY NEW SUB-CATEGORY
BASED ON MULTI-LAYERED
ARTIFICIAL NEURAL NETWORKS WHICH
IS DESIGN TO MIMIC THE AND
FUNCTION OF THE HUMAN BRAIN IN
THE COMPUTER.
IT'S AN IMPROVEMENT COMPARED TO
BASIC MACHINE LEARNING.
FINALLY, TOPOLOGICAL OR
GEOMETRIC DATA ANALYSIS CAN
PROVIDE A SHAPE AND APPLIED TO
MACHINE LEARNING AND MACHINE
LEARNING METHODS.
ARTIFICIAL INTELLIGENCE IS
EVERYWHERE IN OUR LIFE AND CAR
AND HOUSE AND COMPUTER FOR SURE.
THE APPLICATION ARE MULTIPLE BUT
CANNOT REPLACE HUMAN KNOWLEDGE
AND HERE YOU HAVE A LIST OF
POTENTIAL APPLICATIONS
STANDARDIZATION OF IMAGE
ACQUISITION AND AUTOMATIC
MEASUREMENTS AND SIMPLE OR MORE
COMPLEX AND CAN HELP DIAGNOSIS
AORTIC STENOSIS AND HELP PERFORM
CLUSTERING OF PATIENTS REGARDING
TO PHENOTYPE AND CAN DEVELOP
ALGORITHM WITH MACHINE LEARNING
FOR THE RISK ASSESSMENT OR
CLINICAL DECISION MAKING
PROCESS.
HERE YOU HAVE DIFFERENT STEPS
AND PROVIDE DATA OR VALUES TO
THE COMPUTERS.
YOU CAN PROVIDE THIS DATA IN
SUPERVISED APPROACH.
YOU CHOOSE THE DATA YOU'RE
PROVIDING FOR THE COMPUTER.
AND ASK THE COMPUTER TO MAKE A
DIAGNOSIS YOU WILL VALIDATE
AFTER THE WORK OF THE MACHINE.
SO YOU HAVE TO CHECK THE MODEL
AND HAVE TO ADVOCATE THE MODEL
IN THE COHORT OF PATIENTS FOR
EXAMPLE.
IT'S NOT THE END OF THE MODEL.
BECAUSE WE CHANGE OVER TIME AND
YOU HAVE TO RETRAIN THE MODEL
AND YOU WILL HAVE CHANGE IN THE
KNOWLEDGE AND TECHNOLOGICAL
CHANGES.
YOU CAN CHANGE YOUR POPULATION,
ETCETERA.
HERE YOU HAVE THE STENOSIS WHICH
IS INTERESTING AND USED THE LONG
AXIS VIEW.
ONLY ONE VIEW TO DIAGNOSIS THE
AORTIC STENOSIS AND TRAIN THE
MODEL AND SIMILAR TO REPLICATE
THE MODEL AND EXTERNAL COHORT
WHICH IS VERY GOOD BECAUSE
THEY'RE ABLE TO OBTAIN ALL THE
DATA FROM IMAGES TO CONFIRM THE
VALIDITY OF THE MODEL AND IT'S
VERY GOOD WHICH MEANS THE MODEL
WORKS VERY WELL.
SO A MACHINE LEARNING MODEL
BASED ON YOU CAN DIAGNOSIS THE
STENO
STENOSIS.
THERE ARE SEVERAL CAN RECENT
PUBLICATION AND USED MACHINE
LEARNING TO DIAGNOSE MODERATE
BASED ON THE REVIEW AND YOU CAN
SEE THE MODEL PERFORMED VERY
GOOD, VERY WELL WITH DIAGNOSIS
OF AT LEAST THIS MODIFICATION.
I DON'T KNOW WHAT IS EXACTLY THE
MODEL IN THE TWO INSTITUTION.
HERE YOU CAN SEE THE AREA IS
VERY GOOD WITH VALUE OF 0.9.
AND IN ADDITION, THE SECOND
STUDY THEY THE MODEL WAS ABLE TO
TRACK THE CHANGE OF THE TIME
BECAUSE SOME PATIENTS AND
SEVERAL ECHOCARDIOGRAPHY AND
SIMILAR TO THE CHANGES
DIAGNOSED.
SO IT MEANS THE MODEL WORKS VERY
WE
WELL.
AND WE HAVE NINE PARAMETERS AN
VIEWS.
SO IT'S A BIT MORE COMPLEX BUT
NEVERTHELESS IT'S FEASIBLE AND
FAST AND ACCURATE AND CAN MODEL
IN PATIENTS WITH SEVERE CASES
EXPECTED.
OUR FRENCH AND CANADIAN
PUBLICATION WAS PERFORMED
RECENTLY AND THE METHODOLOGY IS
A BIT MORE COMPLEX USING CARDIO
GRAPHY AND PARAMETERS AND PUT
EVERYTHING IN THE MODEL.
AND TRIED TO STRATIFY PATIENTS
IN LOW RISK AND PATIENTS WITH
HIGH RISK AND THEY REPLICATED
THE MODEL AND FOUND GOOD MODEL
BUT YOU KNOW IT'S MORE COMPLEX.
AND IT'S LESS WELL DONE WHEN YOU
TRY TO DIAGNOSIS BASED ONLY ON
THE IMAGING.
HERE YOU USE THE PARAMETERS BY
ECHOCARDIOGRAPH AND WHAT IS
INTERESTING IN THE MODEL IS THE
DIASTOLIC FUNCTION IS IMPORTANT
FOR THE STRATIFICATION OF THE
PATIENTS IN THE MODEL.
THE MACHINE LEARNING CAN DICTATE
SOME PARAMETERS OR ASPECTS OF
PHYSIO PATHOLOGY WE DON'T USE
R
REGULARLY TO STRATIFY PATIENTS.
PATIENTS WITH HIGH RISK OR
SEVERE ARE OFTEN REFERRED TO
SURGERY AND ABOUT WHAT IS
INTERESTING IS ONLY PATIENTS
WITH HIGH RISK BENEFITTED AND
THOSE WITH LOW RISK DIDN'T
BENEFIT BUT IT'S EXPECTED.
HERE YOU HAVE THE DATA
REPRESENTATION AND YOU CAN SEE
THE THREE GROUPS AND A GROUP B
WITH A PATIENT WITH DYSFUNCTION
AND GROUP C WITH DIASTOLIC AND
SYSTOLIC VENTRICULAR DYSFUNCTION
AND PATIENTS WITH BOTH
DYSFUNCTIONS COMPARED TO OTHER
GROUPS OF PATIENTS.
THE DIASTOLIC FUNCTION IS
IMPORTANT TO CLASSIFICATION.
MAYBE THANKS TO THE MACHINE
LEARNING MODEL WE'LL CONSIDER IN
A DIFFERENT WAY DIASTOLIC
FUNCTION FOR OUR PATIENTS WITH
THIS.
I WON'T TWO THROUGH THE SLIDE
BUT I WANT TO STRESS MYOCARDIAL
FIBERS IS A MARKER OF ADVANCED
ING IS A MARKER OF
MALDEPARTMENTIVE MODELS AND WE
CANNOT REPLACE THE FIBERS
INSTEAD OF INTERSTITIAL FIBROSIS
WE CAN REVERSE INTERSTITIAL
FIBERS AND THE FIRST MEANS IS
SURGERY.
WE WENT FOR OUR DATA AND APPLIED
MACHINE LEARNING TO CLASSIFY THE
PATIENTS IN FOUR PHENOGROUPS AND
THE MODEL USED ONLY THREE
PARAMETERS AND THE DEGREE OF
MODELLING AND THE VALUE OF
STRAIN WHICH IS A MARKER OF
DIASTOLIC FUNCTION.
THE PHENOGROUP 4 HAD AN
INCREASED PREVALENCE OF THE F
FIBERS IN THE PATIENTS AND RISK
OF CARDIOVASCULAR EVENTS DURING
FOLLOW-UP.
YOU CAN SEE ON THE GRAPH
PATIENTS AND 50% RATE OF FOLLOW
UP WHICH MEANS THE MODEL IS
WORKING VERY WELL.
AND THEY CAN PREDICT
CARDIOVASCULAR OUTCOME WHICH IS
IMPRESSIVE AND SO IN MACHINE
LEARNING CAN IMPROVE OR SIMPLIFY
OUR APPROACH OF PATIENTS.
I DON'T MEAN WE HAVE TO APPLY
DIRECTLY THE MODEL TO CLINICAL
PRACTICE BUT VERY INTERESTING TO
RAISE THIS AND BY A PREVIOUS
SPEAKER THEY ARE SPOKE ABOUT THE
WITH 500 PATIENTS WITH PROLAPSE
AND DYSFUNCTION.
AND THEY ARE USED DIFFERENT
PARAMETERS OR WEARABLES TO
CLASSIFY THE PATIENTS RAND THE
SEVERITY OF THE PROLAPSE AND THE
DEGREE OF RIGHT VENTRICULAR
REMODELLING AND THE DEGREE OF
MODELLING AND THE PRESENCE OF
FIBERS AND PRESENCE OF THIS AND
WE HAD TACHYCARDIA AND STRATIFY
PATIENT TO TWO SUB GROUPS.
THE MORE SEVERE PHENOTYPE AND
LOW RISK PHENOTYPE.
THE PAPER IS INTERESTING BECAUSE
THIS POPULATION IS VERY LOW RISK
POPULATION, NO PARTICULAR
DYSFUNCTION ONLY MITRAL VALVE
MITRAL VALVE EXPLORED WITH
RESONANCE IMAGING TO AND
FIBRO
FIBROSIS.
PATIENTS OF ARE FOURFOLD
INCREASE AND RISK AT DEVELOPING
SEVERE OR LIFE-THREATENING STEEZ
AND THE NUMBER OF EVENTS IS VERY
LOW ONLY 18 EVENTS DURING FIVE
YEAR FOLLOW UP AND HAVE TO ADD
MORE PATIENTS AND LONGER
FOLLOW-UP TO DECIDE IF THE
DIFFERENT PARAMETERS FOUND BY
THE MACHINE LEARNING METHOD OR
MODEL IS ACCURATE TO BE APPLIED
IN THE CLINICAL PRACTICE.
TO FINISH I WANT TO HIGHLIGHT
THE NICE PAPER FROM THE TEAM OF
FRANCESCA DELLING AND I USED A
SIMPLE ECG AND THE COMPUTER
ANALYZED A DIFFERENT PART IN
BLUE HERE AND SO WE CANNOT SEE
THIS BUT THE MACHINE LEARNING
MODEL WAS ABLE TO SEE SOMETHING
AND IDENTIFY THIS IN THE PATIENT
AND THE PRESENCE OF FIBROSIS AND
PREDICT THE OUTCOME OF THE
PATIENT.
YOU CAN SEE THE METHOD CAN GO
OVER OUR LIMITATION AND IT'S
DIFFICULT TO BE VERY COMPETENT
WHERE WE CAN'T SEE WHAT THE
MACHINE LEARNING MODEL IS
ANALYZING.
MAYBE IN THE FUTURE WE'LL USE
ECG TO TREAT OUR PATIENTS
WITHOUT THIS AND I'LL TWO TO THE
PAGE.
TO CONCLUDE THE INTELLIGENCE
APPLIED TO THE CMR CAN IMPROVE
THE DIAGNOSIS OF SEVERITY AND
THOSE MOST AT RISK.
ARTIFICIAL INTELLIGENCE IS A
VALUABLE TOOL TO CLUSTER
PATIENTS WITH MVP AND
INTERVENTIONS NOT KNOWN IN THE
CLINICAL SETTING.
ARTIFICIAL INTELLIGENCE MAY
SIMPLIFY THE ALGORITHM USED IN
CLINICAL PRACTICE FOR IMPROVING
OUR CLINICAL DECISION MAKING
PROCESS BASED ON PATIENTS
CLUSTERING FOR EXAMPLE.
HOWEVER, MACHINE LEARNING NEEDS
TO TRAIN THE MODEL AND TO
VALIDATE THE FINAL MODEL AND TO
MONITOR THE MODEL.
SO IT IS NOT ONLY THE MACHINES
THAT WILL WORK WITHOUT.
AND TO CONCLUDE THE VALUE NEEDS
TO BE EXPLORED AND LOOKING AT
THE MITRAL VALVE PROLAPSE.
>> THANK YOU.
VERY INTRIGUING.
IT LOOKS LIKE THE BEACH BEHIND
YOU.
DOES ANYONE HAVE QUESTIONS OR
COMMENTS ON THE PARTICULAR
PRESENTATIONS?
>> IF THERE'S NO QUESTIONS,
THANK YOU SO MUCH.
>> JUST ONE.
EXCELLENT TALK.
THE ISSUE IS PEOPLE PUT
ARTIFICIAL INTELLIGENCE IN THE
PAPER TO GET IT PUBLISHED.
BUT WHEN YOU SEE PEOPLE
PUBLISHING ARTIFICIAL
INTELLIGENCE ON 18 EVENTS YOU
SAY I MAY NOT HAVE TO SEE THIS
PAPER.
IT MAY -- WE MAY WANT TO MAKE IT
DISAPPEAR.
SO IT'S -- WHAT IS THE
UTILIZATION THAT WILL ALLOW TO
EXTEND OUR VIEW TO DETECT THE
PATIENTS WITH MITRAL VALVE
PROLAPSE EVEN JUST MITRAL VALVE
PROLAPSE IN THE POPULATION?
AND FACILITATE OUR WORK ON THESE
PATIENTS?
>> THANK YOU SO MUCH.
I DIDN'T SEE A MODEL BUT I THINK
MODELS OF MODELLING WILL BE TO
LEARN HOW TO DIAGNOSIS THE
MITRAL VALVE PROLAPSE AND WE
NEED TO DO THAT.
WE NEED TO PUT A LOT IMAGES IN
THE MODEL WITH DIFFERENT TYPES
OF MITRAL VALVE PROLAPSE TO
EXPLAIN TO THE MACHINE IT'S
MITRAL VALVE PROLAPSE AND
WITHOUT MITRAL VALVE PROLAPSE
AND AT THE END THE DEEP LEARNING
METHOD WILL BE ABLE TO LEARN AND
DIAGNOSE THE MACHINE LEARNING.
IT'S A VERY DIFFICULT FIELD OF
DEVELOPMENT BECAUSE AS YOU KNOW
MAYBE MACHINE LEARNING MODELS
ARE ABLE TO DIAGNOSIS WITH ALL
THE PICTURE YOU HAVE IN THE
IMAGE AND CAN MAKE MISTAKES WITH
THE DIFFERENT PIXELS ASSOCIATED
WITH THE DISEASE AND FOR EXAMPLE
IN THE PAST YOU PUT SOME ANIMALS
IN THE SNOW AND MACHINE LEARNING
MODEL WAS ABLE TO DIAGNOSIS OR
IDENTIFY THE ANIMAL IN THE SNOW.
BUT WITHOUT SNOW IT WAS NOT ABLE
TO IDENTIFY THE SAME ANIMAL.
THE DNA IS ALSO IMPORTANT.
IT'S WHY IT IS VERY IMPORTANT TO
HAVE A COHORT FROM ANOTHER
INSTITUTION WITH DIFFERENT
SETTINGS OF IMAGES TO TEST THE
MODEL OF MACHINE LEARNING.
>> THE REPRESENTATION STILL
VALID.
IT DEPENDS ON THE INTERPRETATION
OF THE DIAGNOSIS ON THE CONTEXT.
>> YES.
AND DIAGNOSIS WITH THE
CARDIOLOGIST BUT IT WILL HELP
PHYSICIAN IN ONCOLOGY FOR SURE
AND IN HEMATOLOGY AND PROBABLY
IN CARDIOLOGY.
>>
>> I HAVE A QUICK COMMENT ON OUR
WORK AND WE HAVE PATIENTS WHO
ARE ASYMPTOMATIC AND THEN WE
FIND OUT A PATIENT HAD A CARDIAC
ARREST THAT WAS COMPLETELY
ASYMPTOMATIC SO MAYBE WE SHOULD
MONITOR THE PATIENTS AND AN EKG
IS ROUTINE DONE CHEAP CAN MAYBE
TELL US THE PATIENT NEEDS AT
LEAST AMBULATORY MONITORING.
WE DON'T KNOW THE INTEGRAL WE
SHOULD USE FOR THE MONITORS.
IF WE GET ONE THERE'S NO
ACTIVITY ON ONE MONITOR AND WHAT
ABOUT PROGRESSION OF ECTOPY.
THE CLASSIFICATION IS TO FIT THE
ASYMPTOMATIC PATIENTS WHO MAY
NEED MORE AMBULATORY MONITORING.
>> IMPRESSIVE WORK.
THANK YOU FOR THE PUBLICATION.
I'M INTERESTED TO GET THE MODEL,
PLEASE.
I WILL SPEND MORE TIME ON THE
ECHOCARDIOGRAPHY OR SEND THEM TO
EMR.
>> WE DIDN'T HAVE A VALIDATION
CORE FOR THE PAPER SO THAT WOULD
BE GREAT.
>> PALPITATIONS IS A SYMPTOM
PATIENTS ARE AWARE OF.
I COULDN'T AGREE IF YOU HAVE
DOCUMENTED MITRAL VALVE DISEASE
AND EXPERIENCED PALPITATIONS
LIKE WE BUY OUR WRIST BLOOD
PRESSURE CUFF CAN FOR $99 NOW
YOU CAN BUY SOPHISTICATED
DEVICES TO DO AN EKG AND EASILY
AND TRANSLATE IT TO THE CLOUD
FOR THE SAME AMOUNT OF MONEY AND
UNDERSTANDING PAL PPITATIONS AN
WHAT THEY MEAN AND ARRHYTHMIA IS
QUITE INTERESTING.
GREAT TOPIC IN TERMS OF FUTURE
RESEARCH TO THINK ABOUT.
>> THANK YOU.
THERE WAS A PRIOR PAPER USING
EKG TRYING TO DETECT PROLAPSE
AND THE PERFORMANCE OF THE MODEL
WAS NOT AS GOOD AS OPPOSED TO
ARRHYTHMIC PROLAPSE.
WE'RE PICKING UP AN ELECTRICAL
PHENOMENON WHERE WE PICK UP
ARRHYTHMIC PROLAPSE SO IT WAS
DIFFERENT IN DETECTION OF MVP
ALONE.
>> THANK YOU VERY MUCH.
WE'LL HAVE A FEW MORE MINUTES
FOR DISCUSSION AT THE END OF THE
SESSION.
I'D LIKE TO MOVE ALONG NOW TO
THE NEXT SPEAKER, FARAH SHEIKH
FROM THE UNIVERSITY OF
CALIFORNIA SAN DIEGO.
>> I'M COMING FROM AN OUT OF BOX
FIELD.
I WORK ON ARRHYTHMIC GENIC
CARDIOMYOPATHY WHICH MAY HAVE
POTENTIAL TO TRANSLATE TO MVP AS
WELL.
ARRHYTHMOGENIC RISK AND SOME
HAVE MORE SERIOUS RISK.
ONE SUB TYPE IS THE BARLOW'S
DISEASE AND PATIENTS ARE YOUNGER
AND THEY'RE THE ONES WITH THE
MOST OR HIGHEST ARRHYTHMIC RISK
AND THERE'S STILL A RISK BUT NOT
ADDS HIGH AS BARLOW'S.
IT GOES TO IMPROVE THE PATIENT
OUTCOME AND GUIDE THERAPEUTIC
DESIGNS AND ARRHYTHMIC RISK IN
THE POPULATION AND MY TAKE ON
IT.
THERE'S CLEARLY A RISK OF SUDDEN
DEATH AND THREEFOLD HIGHER THAN
THE GENERAL POPULATION AND 4% OF
DEATHS ARE AMONG YOUNG ATHLETES.
WE TALKED ABOUT THE RISK
ARRHYTHMOGENIC RISK FACTORS AND
LEAFLET THICKNESS AND BEAUTIFUL
TALKS ABOUT FIBROSIS AND
VENTRICULAR MYOPATHY AND
CLINICAL MARKERS EXPLAIN ONLY
PARTIALLY WHO IS AT RISK.
UNFORTUNATELY MVPs ARE BENIGN OR
AS I'LL REFER TO THEM AS
CONCEALED AND IT ONLY LIES
WITHIN A SUBSET OF PATIENTS WITH
UNIQUE FEATURES LIKE MAD WHICH
IS DIFFICULT TO DETECT USING
STANDARD CLINICAL IMAGING AND
REQUIRES ADVANCED TECHNIQUES.
SO WHEN I LOOK AT THE GENETIC
BASIS OF THIS STEEZ -- DISEASE
AND COMING FROM A RARE DISEASE
PERSPECTIVE AND WE DON'T HAVE A
LOT OF TO WORK WITH AND
SOMETIMES HAVE TO BE CREATIVE IN
WHAT YOU'RE LOOKING AT AND
PATTERN AND WHAT DRIVES
COMMONALITIES AND WITH FAMILIAL
STUDIES THERE'S SOME SORT OF
AUTO SOMAL DOMINANT PATTERN AND
AGE-DEPENDENT PENETRANTS BUT
MANY ARE LINKED TO THE CELL-CELL
AND CYTOSKELETAL COMPONENTS FROM
THE CARDY MYOPATHY SPACE I'M IN.
DCH AS ONE IS PART OF THE SAME
FAMILY.
WHEN WE TALK ABOUT CELL-CELL
FUNCTION IN CARDIAC MUSCLE
THERE'S THREE TYPES AND ONE ARE
FASCIA LINKED TO ACTIN AND I SEE
A LOT RELATED TO FILAMENT C AND
DZIB PART OF THE MICRO TUBULE
FUNCTION AND ALPK3 AND A LOT OF
THE PROTEIN-PROTEIN INTERACTS
THAT FORMULATE AND FORM A LOT OF
THE DISEASES THAT I'M STUDYING
IN TERMS OF THE CARDIOMYOPATHY
SPACE.
THEY ARE CONVERGE TO ME AT THIS
JUNCTURE OF THE CELL-CELL
ADHESION.
AND SPTBN1 PART OF THE BETA 2
SPECTRIN CONNECTS SO AND WHAT
JUMPED OUT TO ME WHEN I LOOKED
AT THE SMALL SET OF GENES.
I FEEL THERE'S A LOT OF PRAYER
-- PARALLELS.
ARRHYTHMOGENIC CARDIOMYOPATHY IS
COMPLEX AND DEFINED BY A RIGHT
HEART DISEASE BUT MORE AND MORE
STUDIES SUGGEST THE LEFT HEART
OR BIVENTRICULAR INVOLVEMENT AND
IN THE EARLY STAGE OF THE
DISEASE WHERE ELECTRICAL ISSUES
THERE'S NO STRUCTURAL PROBLEM
WITH THE HEART BUT CAN HAVE
SUDDEN DEATH AND CAN BE MADE
WORSE WITH EXERCISE.
WHEN YOU LOOK AT PATIENTS WHO
DIE OF HEART FAILURE THREES
CLEARLY A STRUCTURAL COMPONENT
AND CARDIAC MUSCLE CELL DEATH
AND LESS RED MUSCLE IN THE
AUTOPSIED HEART AND SCARRING,
WHICH IS BLUE AND THE CIRCULAR
CELLS WHICH ARE ACTUALLY FAT.
SIMILAR TO MVP IT CAN OCCUR
PRIOR TO THE TRANSITION TO SOME
OVERT STRUCTURAL ANOMALY AND THE
LATE ONSET IS ASSOCIATED WITH
SERIOUS CARDIAC ARREST SUCH AS
HEART FAILURE.
SO WHEN WE LOOK AT
ARRHYTHMOGENIC CARDIOMYOPATHY
IT'S PART OF THE CELL-CELL
FUNCTION AND LOOK AT THE HEART
AND ZOOM INTO A REGION OF THE
HEART THERE'S TWO MUSCLE CELLS
THAT LINK AND THREE COMPONENTS
AND THEY ESSENTIALLY ARE THE
MECHANICAL ANCHORS AND PREVENT
YOUR CELLS FROM RIPPING A PART
AND THERE'S THE GAP JUNCTIONS
THE ELECTRICAL CHANNELS AND
THOSE THAT CONNECT TO ACTIN.
WHEN YOU ZOOM INTO THE COMPLEX
THERE'S FIVE GENES AND THESE ARE
RIGHT IN THE MIDDLE, DESMOSOMES
AND IT'S LINKED TO THE
INTERMEDIATE FILAMENTS AND 40%
TO 50% ARE CONNECTED TO
AUTOSOMAL DEFICIENCIDEFICIENCIE.
IT DESTROYS THE WHOLE FUNCTION.
MOST THINK THERE'S NO THERAPY
BECAUSE YOU HAVE TO BRING THEM
ALL BACK AND A PARALLEL BETWEEN
MVP AND ACM IS THE MRAERJ GENES
ARE CONGREGATED OR ASSOCIATED
WITH THE CELL-CELL FUNCTION.
SO I FOCUSSED ONE OF THE MOST
PREVALENT MUTATIONS IN THE
DESMOSOMAL GENES FOR ACN.
THEY ACCOUNT FOR MORE THAN 70%
OF PATIENTS.
THESE MUTATIONS WHETHER
INSERTION, DELETIONS ARE THOUGHT
TO LEAD TO LOSS OF THE PROTEIN
AT THE CELL-CELL FUNCTION.
BUT WHEN I STARTED DIGGING INTO
IT, I THOUGHT THERE'S A LOT OF
EFFECTS WHERE AT THE RNA LEX
LEVEL BECAUSE THE TRANSCRIPT
LEVELS WERE DOWN REGULATED WITH
THE PATIENTS WITH THESE
MUTATIONS AND THE MUTATION FOR
P52 IS A RNA SPLICE SITE
MUTATION.
HIGHLIGHTING IT MAY BE A
CRITICAL MECHANISM TO GO AFTER
AND AT THE TIME THERE WERE NO
MECHANISTIC INSIGHTS IT'S HARD
TO UNDERSTAND HOW TO
THERAPEUTICALLY INTERVENE
BECAUSE YOU MAY GET A LARGER OR
SMALLER PRODUCT WHEN DEALING
WITH SPLICING TARGETS.
WE HYPOTHESIZED THE MUTATIONS
WERE SUFFICIENT TO TRIGGER
ARRHYTHMO
ARRHYTHMOGENIC CARDIOMYOPATHY
AND CIRCUMVENT THE DEFICITS.
THE NUMBER ONE MUTATION WAS A
SPLICE SITE MUTATION AND WE
GENERATED A CRISPR CAS KNOCK-IN
MOUSE WITH THE MUTATION.
AND I HEARD TWO HITS IN MVP AND
THAT'S ALSO THE CASE FOR ACM.
PATIENTS THE MOST SEVERE HAVE
TWO MUTATIONS OR ONE HIT AND
EXERCISE AND THAT DRIVES
SEVERITY.
WE SAW IN PATIENTS THAT THE
HOMOZYGOUS WITH TWO HITS AT THE
MORE SEVERE PREMATURE DEATH.
HETEROZYGOUS SHOWED LATER
EFFECT.
AND THROUGH SURFACE ANALYSIS WE
WERE ABLE TO SHOW TONS OF
ARRHYTHMIAS NOT FOUND IN THE
COUNTERPARTS OF THE MICE.
WE WERE ABLE TO SHOW THE
HISTOLOGICAL DEFICIT.
YOU CAN SEE FROM THE GROSS
MORPHOLOGY THE LEVEL OF FIBROSIS
THAT GOES ON IN THE HEARTS AND
THROUGH GENE EXPRESSION ANALYSIS
WERE ABLE TO SHOW UP REGULATED
COLLAGENS AND THE DEPOSITION IN
THE SUBCARDIUM OF THE RIGHT VENT
VENTRICLE AND SEE THE LIPID
DEPOSITION HIGHLIGHTING THE
MOUSE MODEL REALLY RECAPITULATES
THE HALLMARK OF THE DISEASE AS
SEEN IN THE PATIENTS.
WE WANTED TO LOOK AT THE
MECHANISM OF WHERE THE DRIVERS
LIE.
WHEN WE DID RNA ANALYSIS WE
FOUND IT RESULTED IN A HIGHER
PRODUCT WHICH WAS VERY LOW IN
LEVELS.
WHEN WE SEQUENCED IT WE FOUND IT
CAUSED PARTIAL INTRON RETENTION
BECAUSE IT SKIPPED OVER THE
SPLICE SITE MUTATED AND WENT
INTO THE INTRON AND RETAINED
PART OF IT.
AND AS A RESULT I'M SHOWING YOU
THE TWO HIGHER PRODUCTS AT VERY
LOW LEVELS AND YOU CAN SEE THE
DEFICITS AND THE YOU DESMOSOMAL
QUALITIES.
IS IT QUALITY OR QUANTITY.
WE DID AN EXPERIMENT AND CELLS
IN A DISH AND TOOK THE MYOCYTES
AND PUT THEM IN A DISH AND JUST
UP REGULATED THE WILD TYPE AND
MUTANT FORM AND WHAT WE SAW WAS
COMPARED NO THE UNINFECTED YOU
SEE THE BLANK SPACE BECAUSE ALL
THE GENES ARE DOWN REGULATED
WHETHER WE PUT THE WILD TYPE OR
THE MUTANT WE'RE ABLE TO
RESURRECT THE WHOLE COMPLEX.
IT JUST DIDN'T INCREASE THE
LEVEL OF PK 2 BUT ALL THE
PROTEINS ASSOCIATED WITH PK2
BECOME UP REGULATED HIGHLIGHTING
THERE'S A ONE FITS ALL THERE
COULD BE A SCAFFOLDING PROTEINS
IN TERMS OF PROTEINS, PROTEINS
INTERACTIONS.
THIS IS THE GENESIS FOR USING
GENE THERAPY AS A STRATEGY TO
CIRCUMVENT ACN IN OUR MOUSE
MODEL.
WE FIRST TRIED TO PREVENT THE
DISEASE AND LOOKED FOUR WEEKS
LATER.
YOU CAN SEE THE UNTREATED MICE
AT FOUR WEEKS WHERE ALL THESE
PROTEINS ARE DISASSOCIATED.
ON THE RIGHT SIDE YOU CAN SEE
WHEN WE RESURRECT OR INCREASE
ALL THE PROTEINS GET UP
REGULATED AGAIN AND THIS HAD A
HUGE EFFECT ON THE MORPHOLOGY OF
THE HEART IN C WHERE YOU CAN SEE
A VERY NORMAL LOOKING MUSCLE OR
HEART WHEN YOU COMPARE IT TO THE
CONTROLS.
ALSO COMPLETE PREVENTION OF
FIBROSIS.
IN H IF YOU LOOK AT THE SECOND
PANEL IN GREEN BARS WHERE THE
FUNCTION IS COMPARABLE TO THE
BLACK BARS AND GET COMPARABLE
FUNCTION AND ABSOLUTELY NO
ARRHYTHMIAS IN THE MICE AND YOU
CAN SEE THE MICE HAVE ABSOLUTELY
NO ARRHYTHMIAS AT THE TIME
POINT.
WE WANTED TO KNOW THE LONG-TERM
EFFECTS BECAUSE IT'S ONLY AT
FOUR WEEKS.
WE LET THEM GO FOR SIX MONTHS
AND THEY ARE SURVIVED AND NONE
OF THE UNTREATED MICE SURVIVED.
THE LEVEL OF THE CELL-CELL
FUNCTION ARE COMPARABLE TO
CONTROLS.
YOU COULD NEVER GET UNTREATED
MICE AT THIS POINT.
FUNCTION THROUGH MRI IS
COMPARABLE FOR THE LEFT AND
RIGHT SIDE.
ABSOLUTELY NO ARRHYTHMIAS IN THE
MICE BUT LOOKING AT PATIENTS
THEY'LL COME IN WITH EXISTING
STEEZ.
-- DISEASE AND WE USED THE
AAVPKP2 AND LOOKED TWO WEEKS
LATER AND SEE VIA WESTERN BLOT
WE CAN RESURRECT THE WHOLE
COMPLEX EVEN IN A DISEASE STATE
AND NOW IN D IF YOU LOOK AT THE
QUANTIFICATION OF THE MRI DATA
YOU CAN ALSO SEE IT IN SOME OF
THE REPRESENTATIVE IMAGES THAT
DIMENSIONS OF THE HEART ARE
SIGNIFICANTLY REDUCED AND WITH
TREATMENT AND FUNCTION STARTS TO
PULL AWAY FROM THE UNTREATED
CONTROLS WHICH ARE ONLY AT TWO
WEEKS.
SO WE ESSENTIALLY LEFT THESE
MICE TWO UNTIL 20 WEEKS AND
AGAIN 100% OF THE MICE SURVIVED
COMPARED TO 80% AT THE UNTREATED
MICE AND HIGHLIGHTS LATE
POST-NATAL RESTORATION RESCUES
THE DYSFUNCTION AND PROMOTES
SURVIVAL.
SO IN SUMMARY, WHAT I'VE SHOWN
IS THE SPLICE-SITE MUTATION
CAUSES AN EFFECT ON PROTEIN
QUALITY AND QUANTITY AND THE
MUTANT FORM IS THERE FOR PATIENT
TO SURVIVE.
AND IT HAS FUNCTIONALITY.
BUT CLEARLY IT'S NOT ESSENTIAL
OR IT CAN'T ALLOW THE HEART TO
THRIVE.
SO AS A RESULT YOU GET
DESMOSOMAL PROTEIN RESOLUTION
AND ALL THE CELL-CELL FUNCTION
DEFICIT WHICH IS DRIVE ALL THE
FEATURES AT THE HISTOAND
PHYSIOLOGIC LEVEL AND THE
STRATEGIES WITH THESE AS THE
GENE THERAPY HIGHLIGHT THE
RESIDENT SCAFFOLDING FUNCTION AT
THE DESMOSOME OR CELL-CELL
FUNCTION TO PREVENT AND RESCUE
CARDIAC DISEASE.
AT THIS POINT WE'RE EXCITED WITH
THE RESULT BUT YOU WANTED TO SEE
HOW TO COMMERCIALIZE THIS AS A
RESULT I STARTED A SPIN OFF FROM
THE LAB CALLED ARCV THERAPEUTICS
IN AUGUST 2018 AND WERE ACQUIRED
BY A NEW YORK STAGE CLINICAL
GENETIC MEDICINE COMPANY.
WE THEN WORKED TOGETHER WITH
THEM THEY ARE HAVE A PRODUCT
CALLED LX2020 TO TREAT PATIENTS
WITH ACM AND WERE ABLE TO SHOW
WITH THE PRODUCT WE WERE ABLE TO
IN DISEASED MICE ALLEVIATE THE
ARRHYTHMIA DELETATION AND
DYSFUNCTION AND THE WILL FDA
CLEARED TO TAKE IT AS A GENE
THERAPY FOR ARRHYTHMOGENIC
CARDIOMYOPATHY AND YOU CAN SEE
IN THE VEHICLE AND UNTREATED
MICE HOW YOU GET SEVERE DEFICIT
AND DYSFUNCTION OF THE
VENTRICLES IN THE HOMOZYGOUS
MICE BUT AS YOU INCREASE THE
DOSE OF PKP2 THE HIGH DOSE MICE
LOOK LIKE WILD TYPE MICE.
SO WE IDENTIFIED SPECIFIC
MOLECULAR TARGETS AND LED TO THE
TRIAL AND HAPPY TO REPORT WE
FINISHED ENROLLING AND DOSING
THE FIRST COHORT OF PATIENTS AND
PHASE 1/2 CLINICAL TRIAL AND
HOPE TO HAVE EXCITING RESULTS IN
THE NEW YEAR ON SAFETY AND BIO
DISTRIBUTION.
SO SOME OF THE CONCLUSIONS MVP
CAN HAVE SIGNIFICANT
ARRHYTHMOGENIC CONSEQUENCES.
I FEEL THERE'S PARALLELS BETWEEN
AVP AND ACM THAT CAN PROVIDE
RISK PROJECTION AND TRACK A
ARRHYTHMOGENIC RISK AND STRATEGY
A POSSIBILITY AND BY LOOKING
THROUGH THE ACM LENS WE CAN
BRIDGE THE GAP BETWEEN MECHANISM
AND THERAPEUTIC INTERVENTIONS.
COULD THERAPEUTICS FOR ACM BE
RELEVANT FOR MVP?
THEY SEEM TO HINGE ONLY SOME OF
THE SAME PATHWAYS.
EMERGING TECHNOLOGIES WILL BE
IMPORTANT FOR GENE LEARNING AND
EDITING TOOLS AND THE WORKSHOP
IS TO ENHANCE LONG-TERM OUTCOMES
IN THE VULNERABLE POPULATIONS
AND REDUCE SUDDEN DEATH RISK.
WITH THAT I WANT TO ACKNOWLEDGE
THE GROUP.
IT INVOLVES ACADEMIA AND
INDUSTRY.
THANK YOU.
>> THANK YOU.
VERY INTRIGUING.
DOES ANYONE HAVE A QUICK
QUESTION OR COMMENT ON THIS
PARTICULAR PRESENTATION?
AGAIN, THANK YOU VERY MUCH AND
WE'LL MOVE ON TO OUR FINAL
PRESENTATION FOR THE DAY.
FROM BENJAMIN HORNE.
>> THANK YOU.
HAVE YOU FOR THE OPPORTUNITY TO
PRESENT AT THE WORKSHOP.
I MENTIONED THE MULTIPLE P.I.s
FOR RECENTLY FUNDED GRANT ARM
RISK ASSESSMENT IN MITRAL VALVE
PROLAPSE AND MY CO-P.I. IS A
CARDIOLO
CARDIOLOGIST.
HERE ARE MY DISCLOSURES.
SO OUR PROJECT THE PROJECT WE'RE
PROPOSING ENGAGED IN NOW IS
SOLIDLY FOCUSSED ON RESEARCH
PRIORITY 2.
YOU MAY RECOGNIZE THIS FROM THE
WORKSHOP THREE YEARS AGO AND
WE'LL BE FOCUSSED ON RISK
ASSESSMENT OF MITRAL VALVE
PROLAPSE IN A LARGE
RETROSPECTIVE COHORT.
I GOT INTO THIS IN TWO
DIRECTIONS.
MY TRAINING IS IN GENETIC
EPIDEMIOLOGY I DID A STUDY USING
THE UTAH POPULATION DATABASE
LOOKING AT MITRAL VALVE DISEASE
AND AORTIC VALVE DISEASE AND DID
A SERIOUS STUDY AND DID CLINICAL
RISK MARKERS ON THE ELECTRONIC
HEALTH RECORD AND RECOGNIZED AS
THE FIRST ELECTRONIC HEALTH
RECORD IN 1960.
IT'S TO PARTICIPATE IN THE GROUP
TODAY.
AND THEY'RE SUPPORTED BY THE
EASE OF ANALYSIS AND ALSO THE
RELATIVELY WIDESPREAD DATABASE
THAT NOT ONLY IS RESEARCH DRIVEN
DATABASES BUT MOST INSTITUTIONS
IN THE U.S. ELECTRONIC HEALTH
RECORD.
UNFORTUNATELY THOUGH MANY OF THE
RISK PREDICTION TOOLS OR RISK
MODELS CREATED OFTEN USED
EXPENSIVE OR DIFFICULT TO OBTAIN
ELEMENTS FOR RISK PREDICTION.
AND ESOTERIC SCORES.
AND SOME ARE EASILY AVAILABLE
AND USED IN PRACTICE AND
INTEGRATED INTO ETHIC FOR
INSTITUTIONS THAT HAVE
ELECTRONIC HEALTH RECORDS.
SO THEY'RE EASILY AVAILABLE BUT
NOT PARTICULARLY GOOD AT
PREDICTING PATIENT OUTCOMES.
A KEY ISSUE WITH RISK PREDICTION
IS ENVIRONMENT AND PREDICTIVE
ABILITY OF A RISK PREDICTION
TOOL AND THE USABILITY OF RISK
PREDICTION TOOL WHICH ARE OFTEN
COMPETING GOALS BECAUSE MAKING
IT USABLE OFTEN MEANS NOT HAVING
HIGH THROUGHPUT PREDICTABILITY.
AND FEASIBILITY OF USING RISK
SCORE FOR PRACTICE IS OFTEN
CHALLENGING BECAUSE MOST RISK
SCORES REQUIRE YOU AS A
CLINICIAN TO FIND THE DATA
ELEMENTS, PUT IT INTO A
CALCULATOR AND CALCULATE THE
SCORE AND THEN KNOW HOW TO USE
IT AND IT CAN ADD TO THE RISK.
WE HAVE RISK PREDICTION TOOLS
AND FOCUS ON THE PARADIGM OF
USING COMMON STANDARDIZED
ALBEITRIES AND
AND THE METABOLIC PROFILE AT THE
BASE OR COMPREHENSIVE FINAL.
AND DEPENDING ON THE PRACTICE
SETTING OF THE PATIENT
POPULATION WE'LL ADD OTHER
FACTORS IN FOR EXAMPLE SIMPLE
CASE OF HEART FAILURE IN
PATIENTS.
WE PREDICT AND CAN DERIVE SCORES
AS WE DO FOR A VARIETY OF END
POINTS OF MORTALITY AND MAJOR
ADVERSE HEALTH.
AND DIAGNOSE VARIOUS TYPE OF
HEALTH CARE UTILIZATION.
THE FOCUS OF THIS APPROACH IS
THEY ARE EASILY CODABLE.
FOR EXAMPLE WE CREATED AND
PUBLISHED IN 2009 THE MORTALITY
RISK SCORE AND THIS IS A STRANGE
ONE FROM OUR ELECTRONIC HEALTH
RECORD AND HEALTH RECORD AND YOU
CAN SEE ON THE SCREEN FOR THE
METABOLIC FILE THERE'S RAY RISK
SCORE BUT IT DOESN'T COST
ANYTHING TO ORDER THAT AND USE
LABS USED IN THE LAST 24 HOURS
OF THE CLINICAL LAB MACHINES AND
RATES THE SCORING SO IF THERE IS
NO SCORING IN THE LAST 24 HOURS
IT'S USED BY A SKILLED PHYSICIAN
AND ALLIED HEALTH PROVIDERS.
AT THIS POINT WE DON'T SURFACE
THOUGH THERE IS ONE PROGRAM TO
RECALCULATE FOR IN PATIENTS.
IN 2014 WE DID START AN
IMPLEMENTATION OF RISK
PREDICTION TOOLS IN IN-PATIENT
HEART FAILURE AND THIS A SCREEN
SHOT OF THE DASHBOARD WE CREATED
FOR THE SUBJECT.
THIS IS PRIOR TO IMPLEMENTATION
OF THE E.H.R.
YOU CAN SEE ON THE RIGHT SIDE WE
DON'T PROVIDE THE RISK VALUE
JUST RED, YELLOW OR GENE
INDICATING SOMETHING ACTIONABLE
OR NOT AND INDIVIDUALS HAD TO
HAVE A RED TO TWO INTO HIGHER
INTENSITY.
THE RISK SCORE ON THE LEFT IS
THE PROBABILITY AT THE END OF
THE CURRENT SESSION WAS THE
LIKELIHOOD THE PRIMARY
DIAGNOSIS, DISCHARGE DIAGNOSIS
WILL BE HEART FAILURE.
THE MIDDLE ONE IS WILL 30-DAY
RE
RE-ADMISSION RISK AND ON THE
RIGHT THE 30 DAY.
THIS SLIDE PROVIDES A REVIEW OF
THE PROCESS WE DERIVED FOR THE
IN PATIENT HEART FAILURE
POPULATION WHERE THE CRITICAL
DECISION POINT IN THE CARE
PROCESS IS REPRESENTED TO THE
CENTER RIGHT WHERE THE TWO RISK
SCORES THE 30 DAY MORTALITY AND
OTHER SCORES WERE CRITICAL IN
DECIDING IS THE PATIENT GO INTO
THE HIGHER INTENSITY CARE
PROCESS OR ALL HANDS ON DECK ALL
PARTICIPANTS IN
MULTIDISCIPLINARY TEAM HAVE
SPECIFIC WRITTEN THINGS THEY
HAVE TO DO FOR EVALUATING AND
TREATING HIGH RISK PATIENTS.
FOR THOSE WITH LOW OR MODERATE
RISK WENT TO STANDARD CARE ARM
WHERE THEY RECEIVED A STANDARD
PACKAGE OF CARE AND ENDED UP
RECEIVING LESS ATTENTION AND
LESS TIME.
IN THE END THE AND WOULD LIKE 30
DAY READMISSION AND MORTALITY IN
A STEP WEDGE IMPLEMENTATION
ACROSS 22 HOSPITALS.
MORTALITY AND PATIENTS WE SAW
REGRESSION IN RISK BEFORE
IMPLEMENTATION OF THE PROCESS
FOR INDIVIDUALS WITH LOWER RISK
OR MODERATE CHANGE THERE WAS NO
CHANGE OF RISK.
GOING FORWARD THERE MAY BE
SOMETHING ON THE SLIDE I FORGOT
TO TAKE OFF.
THANK YOU.
HOW DO WE TRANSLATE THIS
CLINICAL RISK PREDICTION PROCESS
WE'VE CREATED OVER THE LAST 20
YEARS INTO MITRAL VALVE
PROLAPSE?
WHAT WE ENVISION IS IT CAN
ADDRESS UNDER DIAGNOSIS AND LATE
REFERRAL AND TREATMENT BECAUSE
IT WILL STANDARDIZE THE
ASSESSMENT OF RISK AND RIGHT
CARE AT THE RIGHT TIME AT THE
RIGHT PLACE TO ALL INDIVIDUALS
REGARDLESS OF SOCIO DEMOGRAPHICS
AND THIS IS BASED ON POPULATION
EVALUATIONS AND INVOLVES
PERSONALIZED MEDICINE TO BE USED
IN CLINIC AND PRIMARY AND
SECONDARY CLINICS AND HOSPITAL
BASED AND HELP DRIVE EDUCATION
FOR PHYSICIAN AND PATIENTS AND
THE STANDARDIZED APPROACH.
TRANSFORMING THE EARLY BIOMARKER
BASED APPROACH WE HAVE TO MODIFY
THAT FOR MITRAL VALVE MITRAL
VALVE INCLUDES USING THE
LABORATORY ACTORS WHICH ARE
COMMON ACROSS MEDICINE MORE THAN
95% OF PATIENTS IN ALL CARE SEC
SETTINGS SO THEY'RE UBIQUITOUS
AND AVAILABLE AND ADDING ON SOME
OF THE COMPONENTS THAT ARE
SPECIFIC TO THE DIAGNOSIS OF
MITRAL VALVE PROLAPSE AND THAT
INVOLVES IMAGING AND ECB AND
OTHER PARAMETERS AVAILABLE A
CAVEAT IS WE DON'T NEED RISK
PREDICTORS BECAUSE SOME OF THE
FACTO
FACTORS AND AT LEAST NOT ON A
FULL BODY FRAMEWORK CAPTURES THE
RISK VARIANTS AND THE STUDIES WE
PUBLISHED IN 2020 THE RISK SCORE
ON TO THE PANELS AND THE
MORTALITY RISK SCORE CAPTURED
63% OF THE VARIANTS FOR
IN-HOSPITAL MORTALITY AND IT CAN
DO VERY WELL WITHOUT TO PREDICT
OUTCOMES AND STILL SUBSTANTIAL
AT ONE YEAR AND FIVE-YEARS.
SO USING A RISK MODEL BY
DECREASING THE COSTS BOTH IN
TERMS OF FINANCIAL COST AND TIME
TO COLLECT DATA AND THE DATA
ACCURACY FOR WHERE THEY MAY NOT
HAVE RISK PREDICTOR AVAILABLE
AND PROLAPSE AND THERE ARE
ADDITIONAL FACTORS THAT AT THE
DIFFERENT STAGES OF DIAGNOSIS
DATA ELEMENTS BECOME AVAILABLE
SO INTEGRATE THOSE INTO RISK
PREDICTION TOOLS THAT ARE
RELEVANT TO THE DIFFERENT FORM
OF MITRAL VALVE PROLAPSE.
THIS IS TO CREATE THE RISK
SCORES AND USE FOR
IMPLEMENTATIONS WHERE IT WILL BE
USABLE AND AVAILABLE TO
CLINICIANS FOR PEOPLE AT RISK OF
POORER OUTCOMES AND GET MORE
PRECISE CARE FOR THE INDIVIDUALS
AT AN EARLIER TIME TO PREVENT
FURTHER DAMAGE TO THE HEART THIL
LOOKS AT PROLAPSE IN OUR
POPULATION.
AIM TWO IS THE REGISTRY WE
TALKED ABOUT EARLIER AND FOLLOW
POPULATIONS.
AND LOOKING TOWARDS
IMPLEMENTATION.
SO OUR DATA THAT WE HAVE
AVAILABLE WE ACTUALLY HAVE THE
DATA GOING BACK 30 YEARS OR SO
AND INCREASED TO 250 CLINICS AND
THAT INCLUDES A RECENTLY BUILT
CHILDREN'S HOSPITAL AND IN 2022
WE INTEGRATED ANOTHER SYSTEM
WITH NINE HOSPITALS AND HOW HAVE
33 HOSPITALS AND ABOUT 385
CLINICS ACROSS UTAH AND IDAHO
AND MONTANA, COLORADO, MANY
PATIENTS.
I'VE TRAVELED TO UTAH.
WE HAVE ELECTRONIC DATA FROM ECG
GOING BACK MORE THAN 30 YEARS
INDICATING VARIOUS MOSTLY 20
YEARS WORTH.
AIM TWO IS LOOKING AT RISK IN A
VARIETY OF WAYS.
THE HERITABLE RISK AND
FAMILIARITY OF GENETIC RISK FOR
DISEASE AND ELECTRONIC HEALTH
RECORD FOR MORE THAN 24 MILLION
PEOPLE IN PEDIGREE STRUCTURE IN
UTAH OR SURROUNDING STATE THAT
SHARES A BORDER AND MORE THAN
700,000 PATIENTS IN THE
ELECTRONIC HEALTH RECORD LINKED
TO THOSE CATEGORIES AND ABLE TO
EVALUATE DESPITE THE CLUSTERING
OF PROLAPSE AND ALSO BASED ON
SUBPHENOTYPES SUCH AS SEVERITY
AND DISEASE AND ARRHYTHMIAS AND
OTHER CHARACTERISTICS.
AND LOOKING AT GENETIC RISK FOR
205,000 INDIVIDUALS INVOLVED
SINCE 2018 AND ABOUT 70,000 WE
HAVE FULL SEQUENCING.
COLLABORATION OTHER THAN THAT
FROM PHARMACEUTICAL COMPANIES
ARE AVAILABLE TO US NOW.
THERE'S INTEREST IN MITRAL VALVE
PROLAPSE.
THESE ARE A COUPLE PEDIGREES
FROM A SMALL GRANT FROM A LOCAL
FOUNDATION AND EVALUATED
FAMILIARITY OF THE MITRAL VALVE
PROLAPSE AND FOUND PEDIGREES
WHAT WE WERE DOING IN THE
PROJECT WAS ENROLLED AND
PARTICIPATING IN AN
INTERNATIONAL STUDY MENTIONED
EARLIER AND PUBLISHED I BELIEVE
IN 2021.
THE HEREDIGENE STUDY LOOKING AT
A POPULATION LINKED TO THE
ELECTRONIC HEALTH RECORD AND THE
DATA IS AVAILABLE.
WE'LL FOCUS ON THE GENETIC
VARIANTS AND ADDING THOSE
GENETIC VARIANTS MOSTLY WILL
FOCUS ON VARIANTS PUBLISHED IN
THE LITERATURE AND PUBLISHED AND
THEN ADDING IN OTHER CLINICAL
FACTORS TO PREDICT.
FINALLY LOOKING AT THE RISK
PREDICTION TOOLS TO IDENTIFY
PATIENTS AND STRATIFY THEM BASED
ON THEIR RISK FOR VARIOUS STATES
AND TO POWER PERSONALIZED
TREATMENT HELPING THEM LIVE
LONGER.
RISK MODELLING WILL USE
TRADITIONAL STATISTICS.
VALIDATE THE RISK SCORES AT
VARIOUS SITES PARTICIPATING.
THAT'S IT AND THANK YOU.
THANK YOU BEEN FOR YOUR TIME AND
ATTENTION.
>> THANK YOU VERY MUCH.
DOES ANYONE HAVE COMMENTS OR
QUESTIONS ON THIS PRESENTATION?
>> I HAD A HARD TIME HEARING
EVERYTHING SO ARE THERE -- ARE
YOU AWARE OF EXISTING SCORE
SYSTEM FOR MVP?
>> FROM WHAT I READ THERE'S NO
SCORE SYSTEMS USED FOR THE
MITRAL VALVE PROLAPSE.
CERTAINLY RISK MODELS AND
THERE'S GWAS AND THAT WOULD BE
SOMETHING THAT APPLIES DIRECTLY
TO THAT THAT EXIST AND ARE AWARE
OF THE SCORE THAT APPLIES TO MVP
AND A SCORE THAT ALLOWS
SURVIVAL --
>> NIDA.
>> ONE PUBLISHED IN EUROPEAN
HEART JOURNAL AND ONE IN
CIRCULATION.
I DON'T KNOW HOW YOU INTEGRATE
THAT IN YOUR.
-- AIMS.
>> THOSE ARE THINGS TO EVALUATE
AND LOOK AT THE COMPONENTS OF
THE SCORES.
>> ARE YOU LOOKING ALSO AT
ARRHYTHMOGENIC RISK OR MOST
HEART FALL FAILURE.
THE ARRHYTHMOGENIC RISK COULD
POTENTIALLY BE OF GREAT VALUE TO
PARTNER WITH PEOPLE LIKE
FRANCESCA DELLINGS AND OTHERS TO
GIVE A MORE DETAILED PHENOTYPE
AND BELIEVE THE PATIENTS LARGELY
HAVE ECHOCARDIOGRAMS AND CAN
IMMENSELY HELP YOUR PREDICTIVE
VALUE?
>> WE'LL LOOK AT HEART FAILURE
AND ARRHYTHMIC AND HAVE
ECHOCARDIOGRAMS WITH A LONG
HISTORY AND ELECTRONIC DATA.
>> VERY INTERESTING.
MAYBE YOU MENTIONED THIS, HOW DO
YOU CAPTURE THE ARRHYTHMIC
INFORMATION FROM THE MEDICAL
RECORDS?
A LOT OF THIS IS IN MONITOR
RECORD OR TELEMETRY ARE YOU
USING NATURAL LANGUAGE
PROCESSING OR REVERSE CODES OR
HOW ARE YOU TESTING THAT?
>> ULTRA MONITORING RESULTS AND
ECT DATA ARE AVAILABLE IN THE
ELECTRONIC FORMATS AND HAVE SOME
STRUCTURES THAT THEN WE HAVE
THOSE GOING BACK TO 1993.
I DON'T KNOW ABOUT INTENSIVE
CARE UNITS.
>> SO FOR THE AMBULATORY EKG ARE
YOU LOOKING AT REPORTS OR THE
SCRIPTS OF THE AMBULATORY
MONITORING?
>> WE LOOK TO THE STRUCTURED
DATA BUT THE OTHER DATA THE ECG
REPORTING IS AVAILABLE.
THAT'S ONE GOAL IN THE PROJECT.
WE'RE NOT EXPERTS AT USING
MACHINE LEARNING.
BUT WE HAVE PROCESSING.
I HAVEN'T DONE THAT PERSONALLY.
IT'S SOMETHING WE HAVE AVAILABLE
.
IF YOU HAVE SOME INSIGHTS I'D
LOVE TO TALK.
>> I DON'T KNOW ANY OTHER WAY
OTHER THAN NATURAL LANGUAGE
PROCESSING TO GET THROUGH THE
REPORTS.
THAT'S WHY I'M ASKING.
>> WE HAVEN'T JUMPED INTO THAT
YET.
WE DO HAVE EXPERTS IN THAT
PROCESS.
I'VE NOT YET USED ECG DATA IN
THAT WAY.
>> THANK YOU.
>> YEAH.
>> OKAY, THANK YOU VERY MUCH.
BEFORE WE GO, I'D LIKE TO TAKE
THE ORGANIZER'S PREROGATIVE AND
SHARE A COUPLE SLIDES WITH YOU.
SO AFTER WE ESTABLISHED THE
AGENDA AND THE ROSTER, I
HAPPENED TO HEAR A TALK FROM
JOHNS HOPKINS ON THE USE OF
DIGITAL TWINS.
AND JUST TO MENTION, WHAT SHE'S
DOING IS LOOKING AT MRI IMAGES
OF THE HEART TOGETHER WITH
ESTIMATES OF FIBROSIS AND THEN
INCORPORATING MEMBRANE MODELS
WHICH MAY INCORPORATE
CHANNELOPATHIES AND ESTIMATING
FROM VARIOUS STIMULUS PATTERNS
WHETHER OR NOT SHE CAN INDUCE
ARRHYTHMIAS WHICH SEEMED LIKE AN
INTERESTING APPROACH.
I WANTED TO BRING IT TO THE
ATTENTION OF THIS GROUP.
SHE'S REPORTED SOME IMPRESSIVE
RESULTS IN A VARIETY OF
CONDITIONS BUT NOT AS IT IS IN
MITRAL VALVE PROLAPSE.
THAT'S IT.
I JUST WANTED TO MENTION THAT.
THANK YOU.
>> THANK YOU.
I HAVE A COMMENT ABOUT THAT, IF
I MAY.
I THINK SHE'S DONE A LOT OF WORK
ON SARCOID MYOPATHY USING A
VARIETY OF TOOLS INCLUDING
METHODS AND DON'T KNOW IF IT'S
TRANSLATED INTO ANYTHING
CLINICALLY HELPFUL.
SOMEONE ON THE CALL CAN COMMENT.
I KNOW THERE WAS SOME
SARCOIDOSIS USING A SIMILAR
APPROACH BY THE SAME GROUP.
>> THE PATIENTS ARE VOID OF
CHANNELOPATHIES.
>> YES, YES.
YOU ARE CORRECT.
MY QUESTION WAS MORE ABOUT THE
TRANSLATABILITY OF THE MODEL
INTO MITRAL VALVE PROLAPSE AND
WHETHER THE STUDY DONE IN
SARCOIDOSIS HAD ANY APPLICATION
CLINICALLY BECAUSE IT WAS USING
THE SAME MACHINE LEARNING TOOL
AND PREDICTION AND CARDIAC
RECORDING.
I DON'T KNOW IF
ELECTROPHYSIOLOGISTS ARE USING
THAT TO PREDICT RISK.
>> ABOUT WHAT IS DIGITAL TWIN
MEAN?
>> CREATING A DIGITAL MODEL A
PART.
IT'S A VERY DETAILED SIMULATION.
>> OH, IT'S A SIMULATION.
OKAY.
>> I THINK WE FOUND SOMETHING WE
HAVEN'T SEEN BEFORE WITH THE
MODEL ON THE LEFT VENTRICLE AND
REGARDLESS OF SEVERITY.
IT'S A GREAT IDEA.
>> I'M ANOTHER ADVOCATING OR
OTHER WISE BUT SOUNDED
INTRIGUING AND WANTED TO BRING
IT TO THE ATTENTION OF THE
GROUP.
I WANT TO THANK EVERYBODY FOR
YOUR PARTICIPATION TODAY.
THIS HAS BEEN I THINK AN
EXCELLENT FIRST DAY.
GREAT DISCUSSION.
WE WERE KIND OF IN CLINICAL AND
BASIC AND CLINICAL AGAIN AND
WE'RE GOING TO TO THAT SAME
PATTERN TOMORROW.
DOES ANYONE HAVE ANY FINAL
COMMENTS OR QUESTIONS?
>> THANK YOU FOR PUTTING
TOGETHER EVERYTHING.
IT WAS AMAZING.
>> MY PLEASURE.
LOOK FORWARD TO SEEING EVERYONE
TOMORROW THEN.
THANK YOU.
>> THANK YOU.
GREAT WORK.
>> THANK YOU.