IT'S A PLEASURE TO WELCOME
YOU TO ANOTHER SESSION IN THE
22ND YEAR OF A COURSE AT THE
NATIONAL INSTITUTES OF HEALTH IN
BETHESDA, MARYLAND.
THE COURSE IS CALLED
DEMYSTIFYING MEDICINE.
I AM WIN ARIAS, SENIOR SCIENTIST
EMERITUS HERE, AND WITH MY
COLLEAGUE, DAN KASTNER, WE HAVE
PREPARED THIS SERIES OF SESSIONS
FOR 2025, AND WE ARE COMING TO
THE END OF THIS WITHIN THE NEXT
THREE WEEKS.
SO DEMYSTIFYING MEDICINE IS
DIFFERENT FROM MEDICAL GRAND
ROUNDS, IT'S DIFFERENT FROM A
RESEARCH SEMINAR.
ITS INTENT IS TO BE A COURSE IN
BRIDGE-BUILDING.
ESSENTIALLY, BRIDGING EXCITING
DEVELOPMENTS IN BIOLOGY,
ENGINEERING AND COMPUTER
SCIENCES WITH MEDICINE AND
PUBLIC HEALTH.
THE COURSE IS HELD FROM 3:00 TO
5:00 P.M. EASTERN STANDARD TIME,
FROM JANUARY THROUGH MAY.
IT CAN BE WATCHED ON THE WEBSITE
INDICATED HERE,
VIDEOCAST.NIH.GOV.
FOR THOSE SEEKING CME CREDIT,
THE CODE FOR TODAY IS 58793.
NOW MOST IMPORTANTLY DURING THE
COURSE OF THESE PRESENTATIONS
TODAY, WE ENCOURAGE ALL OF YOU
TO SUBMIT QUESTIONS, AND YOU CAN
DO THIS USING THE "SEND LIVE
FEEDBACK" ON YOUR VIDEOCAST
DISPLAY.
THESE QUESTIONS WILL THEN FORM
THE BASIS OF WHAT IS INVARIABLY
A VERY ACTIVE INTERCHANGE
BETWEEN THE SPEAKERS, THE
WORLDWIDE ATTENDEES, AND AMONGST
THE SPEAKERS THEMSELVES AT THE
CONCLUSION OF THE TWO
PRESENTATIONS.
NOW I CALL YOUR ATTENTION TO THE
FACT THAT ALL PREVIOUS SESSIONS
FOR THE PAST 23 YEARS ARE
AVAILABLE ON THE LINKS I'VE
SHOWN ON THIS SLIDE, AND YOU CAN
ACCESS THEM AT ANY TIME.
IF YOU HAVE ANY ADDITIONAL
INFORMATION OR REQUEST FOR
INFORMING, COMMUNICATE WITH US
AT DEMYSTIFYINGMED@NIH.GOV.
NOW THE PICTURES ON THE RIGHT
SIDE OF THIS SLIDE ARE TWO.
ONE IS A SILO, WHICH REPRESENTS
THE IDEA THAT MUCH OF THE
EXCITING DEVELOPMENTAL
DEVELOPING INFORMATION IS SORT
OF LOCKED AWAY FROM ONE ANOTHER.
IT'S SORT OF LIKE SEPARATE
PIECES OF A PIZZA PIE.
WHAT WE SEEK TO DO IS IN THE
UPPER RIGHT.
AND THAT IS TO BRIDGE THESE GAPS
AND, FOR EXAMPLE, IN THIS
EXCELLENT PHOTOGRAPH OF THE
CONSTRUCTION OF THE BROOKLYN
BRIDGE, TWO INDIVIDUALS,
PRESUMABLY ONE FROM BROOKLYN AND
ONE FROM MANHATTAN, ARE MEETING
ON THE CATWALK TO EXCHANGE THEIR
OWN BEDS OF ADVANCED
INFORMATION.
IN EFFECT, THAT'S WHAT
DEMYSTIFYING MEDICINE IS.
YOU WILL SEE THAT THROUGH THE
YEARS, WE HAVE TOUCHED ON WIDE
AREAS OF BIOLOGY FROM THE ORIGIN
OF LIFE TO PROBLEMS OF BIOLOGY
IN SPACE TO THE IMPACT OF THE
GENETIC AND MOLECULAR
REVOLUTION, AND WITH
PRESENTATION OF PATIENTS
FREQUENTLY WHEN POSSIBLE TO
ILLUSTRATE THE GOAL OF ALL OF
THIS RESEARCH.
NOW, TODAY'S TOPIC DEALS WITH
SOMETHING WE HAVE NOT DISCUSSED
BEFORE.
AND THAT IS CONGENITAL HEART
DISEASE.
THE NIH HAS PLAYED A SIGNIFICANT
ROLE IN UNDERSTANDING CONGENITAL
HEART DISEASE THROUGHOUT THE
YEARS, IN LARGE PART BY
SUPPORTING WORK NOT ON THE
INTRAMURAL CAMPUS BUT SOME.
SO IN A VERY SIMPLISTIC WAY FOR
THE ULTIMATE MOLECULAR
BIOLOGIST, LET US REMEMBER THAT
THE HEART IS A FOUR CHAMBERED
PUMP.
VENOUS BLOOD FLOWS INTO RIGHT
CHAMBER EN ROUTE TO THE LUNG FOR
OXYGENATION, AND THEN THEY PASS
THROUGH THE LEFT HEART INTO THE
PERIPHERY VIA THE ARTERIAL
CIRCULATION.
NOW THERE WERE MANY CONGENITAL
DEFECTS THAT OCCUR INVOLVING
ABNORMAL CONNECTIONS OF VESSELS,
ABNORMAL CONNECTIONS BETWEEN
INDIVIDUAL CHAMBERS, STENOSIS OF
VARIOUS VESSELS, AND OTHERS.
AND ALL OF THOSE ONE WAY OR
ANOTHER IMPAIR OXYGENATION, AND
FREQUENTLY THE VICTIMS ARE
CYANOTIC, THAT IS, THEY LOOK
BLUE BECAUSE THEIR BLOOD IS NOT
OXYGENATED, AND THEY HAVE
LIFE-THREATENING DISEASES.
AND FOR MANY IN THE PAST, PRIOR
TO THE 1950s, MANY FACED EARLY
DEATH.
SO THESE ARE ALL YOUNG CHILDREN.
IT IS SAID THAT THE FIRST
ANATOMIC DESCRIPTION OF THE
VARIOUS CONGENITAL HEART
DISEASES OR AT LEAST SOME OF
THEM GOES BACK TO D DEVINCI IN E
15TH CENTURY.
AT ANY RATE, IT WASN'T UNTIL THE
1930s THAT A REMARKABLE WOMAN,
HELEN TAUSIG, SET UP THE FIRST
PEDIATRIC CARDIOLOGY CENTER, AND
THIS WELCOMED PATIENTS, ALTHOUGH
THERE WASN'T MUCH THAT COULD BE
DONE FOR THEM THAT WAS
DEFINITIVE.
THE FIRST ADVANCE IN THAT TOOK
PLACE IN 1938, WHEN THE SURGERY
WAS PERFORMED FOR ONE OF THE
CONGENITAL HEART DISORDERS WE'LL
HEAR ABOUT, BUT THE SURGERY, OF
COURSE, WAS EXTREMELY
CHALLENGING BECAUSE WHAT DO YOU
DO WITH THE ONGOING CIRCULATION
IF YOU'RE ACTUALLY OPERATING ON
A HEART?
AND OF COURSE THE CHEST HAD TO
BE OPENED.
IT WAS A VERY DANGEROUS AND
ALMOST HEROIC CHALLENGE.
BUT THE BIG BREAKTHROUGH TOOK
PLACE IN AROUND 1950, WITH THE
DEVELOPMENT OF MACHINES, THE
HEART LUNG MACHINE OR ALSO KNOWN
AS THE CARDIOPULMONARY BYPASS,
IN WHICH BLOOD COULD BYPASS THE
HEART AND HENCE THE SURGEON
PRETTY MUCH HAD A DRY FIELD IN
WHICH TO CONDUCT MORE EXPANSIVE
SURGERY.
AND HERE THE SUCCESSES WERE
SUBSTANTIAL.
AND SURVIVAL WAS GREATLY
INCREASED.
SOMETIMES COMPLETELY NORMAL
LIVES RESULTED.
AND THE SPECIALTY OF CONGENITAL
HEART DISEASE BECAME A REALITY.
THIS OF COURSE WAS ENHANCED BY
THE DEVELOPMENT OF IMAGING
TECHNIQUES, AND IN MORE RECENT
TIMES, THE AMAZING DEVELOPMENT
OF SURGERY DONE IN AND ON THE
HEART USING CATHETERS, WHICH ARE
PASSED THROUGH THE CIRCULATION,
AND AVOIDING THE NECESSITY FOR
MAJOR OPENING UP OF THE CHEST TO
OPERATE DIRECTLY.
NOW WITH THESE GREAT ADVANCES,
PROBLEMS HAVE OCCURRED.
AND THE FOCUS IN SOME OF THESE
INSTANCES HAS BEEN ON LONG-TERM
PROBLEMS, PROBLEMS THAT DEVELOP
SOMETIMES PROGRESSIVELY OVER
YEARS AFTER SUCCESSFUL SURGERY.
AND THAT'S THE SUBJECT OF
TODAY'S TOPIC, BRIDGING SUCCESS
WITH CHALLENGE.
AND I LIKE THE QUOTE FROM A
DANISH CARTOONIST WHO WROTE
YEARS AGO, "PROBLEMS WORTHY OF
ATTACK PROVE THEIR WORTH BY
STRIKING BACK."
NOW OUR FIRST SPEAKER TODAY IS
TOM BURKLOW, WHO GOT HIS
MEDICAL DEGREE FROM WASHINGTON
UNIVERSITY IN ST. LOUIS.
HE DID A PEDIATRIC RESIDENCY AT
WALTER REED ARMY MEDICAL CENTER,
AND THEN A PEDIATRIC CARDIAC --
CARDIOLOGY FELLOWSHIP AT THE
CHILDREN'S NATIONAL HOSPITAL IN
WASHINGTON.
TOM SERVED FOR 30 YEARS IN ARMY
MEDICINE, INCLUDING BEING CHIEF
OF PEDIATRICS FROM 2003 TO 2011
AT THE WALTER REED NATIONAL
MILITARY MEDICAL CENTER, WHERE
HE BECAME INCREASINGLY ENGAGED
IN UNDERGRADUATE AND GRADUATE
MEDICAL EDUCATION.
HE WAS THE DIRECTOR FOR
HEALTHCARE OPERATIONS AND
POPULATION HEALTH PROGRAMS, AND
DURING HIS CAREER WAS DEPLOYED
TO SAUDI ARABIA, KUWAIT, AND
IRAQ.
IN 2017, HE JOINED THE NIH,
WHERE HE IS CURRENTLY THE
DIRECTOR FOR EDUCATION AND
TRAINING AT THE NIH CLINICAL
CENTER.
THIS IS A REMARKABLE
INSTITUTION, AND THE PROGRAM HE
DIRECTS OVERSEES A PORTFOLIO OF
TRAINING AND EDUCATION PROGRAMS,
WHICH INCLUDE CONTINUING MEDICAL
EDUCATION ACTIVITIES, GRADUATE
MEDICAL EDUCATION, AND THE
HEALTHCARE SIMULATION TRAINING
PROGRAM, AND A REMARKABLE
UNDERGRADUATE MEDICAL STUDENT
RESEARCH TRAINING PROGRAM, WHICH
IS A MODEL FOR THE WORLD.
IT'S CALLED THE MEDICAL RESEARCH
SCHOLARS PROGRAM, WHERE ABOUT 50
MEDICAL STUDENTS ARE SELECTED ON
A COMPETITIVE BASIS TO SPEND A
YEAR ON THE BETHESDA CAMPUS
DOING BASIC TRANSLATIONAL OR
LINKED RESEARCH.
TOM IS A BOARD CERTIFIED
PEDIATRIC CARDIOLOGIST, AND HE
HAS A JOINT NATIONAL HEART, LUNG
AND BLOOD INSTITUTE APPOINTMENT
AS CHIEF OF PEDIATRIC
CARDIOLOGY.
AS PART OF THE CONSULT SERVICE
OF THE NIH CARDIOLOGY CENTER.
SO TOM IS GOING TO BE THE FIRST
SPEAKER AND WILL EDUCATE US ALL
ABOUT THE ISSUES AND THE NATURE
OF THE PROBLEMS OF CONGENITAL
HEART DISEASE.
THE SECOND SPEAKER IS THEO
HELLER.
SO THEO GOT HIS MEDICAL DEGREE
IN SOUTH AFRICA FROM THE
UNIVERSITY OF WITWATERSRAND, A
RESIDENCY IN GEORGETOWN, A
FELLOWSHIP IN HEPATITIS VIRUSES
HERE AT NIAID, AND THEN A
GASTROENTEROLOGY HEPATOLOGY
FELLOWSHIP AT THE UNIVERSITY OF
MARYLAND MEDICAL CENTER.
AND A HEPATOLOGY FELLOWSHIP THEN
HERE ON THE NIH CAMPUS.
THEO IS A SECTION CHIEF OF THE
TRANSLATIONAL HEPATOLOGY SECTION
OF THE LIVER DISEASE BRANCH OF
THE NATIONAL INSTITUTE OF
DIABETES AND DIGESTIVE KIDNEY
DISEASE.
HE'S A SENIOR INVESTIGATOR, AND
THE CLINICAL RESEARCH -- IN THE
CLINICAL RESEARCH SECTION.
NOW HIS INTERESTS ARE BROAD AND
THEY INCLUDE MANY APPROACHES, A
LOT OF COLLABORATIVE WORK, BUT
HIS UNDERLYING THESIS, I THINK
IS SOMEWHAT UNIQUE.
AND HIS RESEARCH HAS BEEN
BRILLIANT IN APPROACHING THIS.
OF HIS THESIS IS THAT ONE CAN
TESS HYPOTHESTEST HYPOTHESES INL
SITUATIONS WITH PATIENTS AND
THEN RESULTS CAN BE ADAPTED INTO
LABORATORY PROJECTS THAT CAN
LEAD TO FUNDAMENTAL BIOLOGIC
INSIGHTS AND BETTER DIAGNOSIS
AND MANAGEMENT.
THIS IS A CHALLENGE FOR CLINICAL
INVESTIGATION AND ONE IN WHICH
HE HAS CARRIED OUT BRILLIANTLY,
FOCUSING IN AREAS OF CLINICAL
RESEARCH, INFECTIOUS DISEASES,
SYSTEMS ANALYSIS, MOLECULAR
BIOLOGY, AND BIOCHEMISTRY.
THEO IS GOING TO DISCUSS THE
EFFECTS OF AT LEAST ONE MAJOR
FORM OF SURGERY FOR CONGENITAL
HEART DISEASE, THE EFFECTS ON
THE LIVER, WHICH CAN CREATE A
VERY SERIOUS PROBLEM AND WAS NOT
FULLY ANTICIPATED.
SO PLEASE SEND IN YOUR QUESTIONS
DURING THE PRESENTATIONS, AND
NOW OUR FIRST SPEAKER.
TOM, IT'S ALL YOURS.
>> THANK YOU, DR. AIR JUST.
T ARIAS.THANK YOU FOR YOUR GENES
INTRODUCTION AND BOTH THEO AND I
REALLY APPRECIATE THE
OPPORTUNITY TO SHARE THIS
INFORMATION.
I WANT TO THANK DR. KASTNER,
CO-DIRECTOR, THANK YOU FOR
SUPPORTING US THROUGH THIS AND
ESPECIALLY I WANT TO GIVE AN
EARLY SHOUT OUT TO A PATIENT AND
HER MOTHER WHO WILL BE JOINING
US AS WELL.
AND THIS IS A PATIENT OF BOTH
DR. -- I'M GOING TO DO THE MOST
DIFFICULT THING HERE IN THE 20TH
CENTURY AND SEE IF I CAN SHARE.
MY PRESENTATION WITHOUT LOGGING
OFF.
ALL RIGHT.
IS IT COMING UP?
SO AGAIN THANK YOU.
WE'RE GOING TO ACTUALLY DELVE
INTO A LITTLE MORE COMPLEX
ASPECT OF GENERAL HEART DISEASE
AND PUT THIS UNDER THE UMBRELLA
OF WHAT WE CALL THE SINGLE
VENTRICLE.
IN ADDITION, WE'RE GOING TO
DELVE INTO HOW THIS IS ADDRESSED
FROM A SURGICAL PERSPECTIVE.
WITH THAT, I'M GOING TO -- SO
THE OBJECTIVES FOR MY PART OF
THE PRESENTATION, THIS IS TO LAY
A FOUNDATION AND BACKGROUND FOR
DR. HELLER'S PRESENTATION.
WHAT I WANT DO IS GO THROUGH
QUICKLY TO DESCRIBE THE ANATOMY
AND PHYSIOLOGY OF THE NORMAL
HEART AND CARDIOVASCULAR SYSTEM.
WE'RE GOING TO TALK ABOUT HOW
SURGICAL PALLIATION OF
CONGENITAL HEART DISEASE WITH
ONE DOMINANT VENTRICLE, THAT IS
WHAT'S CALLED A FONTAN
PALLIATION MAY IMPART NORMAL
CIRCULATION.
THEN WE'RE GOING TO SEGUE AT THE
END TO ILLUSTRATE HOW FONTAN
PALLIATION PROGRESSIVELY RESULTS
IN LONG TERM DISEASE.
AS FAR AS DISCLOSURES, SADLY, I
HAVE NONE.
SO ARISTOTLE IDENTIFIED THE
HEART AS THE MOST IMPORTANT
ORGAN OF THE BODY.
DR. HILL WOULD PROBABLY OBJECT
BUT THE MOST IMPORTANT ORGAN OF
THE BODY, BEING THE FIRST THAT
HE OBSERVED TO -- CHICKEN
EMBRYOS, HE FELT IT WAS THE SEED
OF INTELLIGENCE, EMOTION, AND
SENSATION, AS HE DESCRIBED IT AS
A HOT DRY ORGAN, AND ALL THE
OTHER ORGANS SURROUNDING IT,
BRAIN, LUNG, SIMPLY EXISTED TO
COOL THE LIVER.
CONGENITAL HEART DISEASE AFFECTS
1% OF ALL LIVE BIRTHS, SO IN THE
UNITED STATES, ABOUT 40,000
BABIES PER YEAR ARE BORN WITH
SOME TYPE OF HEART DISEASE.
OF THOSE WHO ARE BORN, ABOUT 25%
OF THEM REQUIRED SOME SORT OF
INTERVENTION OR CATH PROCEDURE
IN THE FIRST YEAR OF LIFE.
CONSEQUENTLY, HEART DISEASE IS
RESPONSIBLE FOR THE LARGEST
PORTION OF MORTALITY RESULTING
FROM BIRTH DEFECTS TODAY AND
IT'S THE MOST COMMON
NON-INFECTIOUS CAUSE OF DEATH IN
INFANTS, AND OVERALL, IF YOU
LOOK AT THE OVERALL MORTALITY,
IT ACCOUNTS FOR -- THIS IS BOTH
ADULTS AND PEDIATRICS, PROBABLY
ABOUT .21% OF ALL MORTALITY IN
THE UNITED STATES TODAY.
BEGINNING WITH LANDMARK WORK
INTO 1930 THAT DR. ARIAS HAD
REFERRED TO, WITH ADVANCES IN
DIAGNOSTICS AND THERAPEUTIC
INTERVENTIONS, ESPECIALLY
THROUGH SURGERY AND EVENTUAL
CARDIAC CATHETERIZATION,
CONGENITAL HEART DISEASE RELATED
MORTALITY WITH SUCCESS OF THE
FIRST COHORT IMPROVING AND
DECLINE IN CHILD MORTALITY OF
FUTURE GENERATIONS.
NOW AT THE BEGINNING, MOST
MORTALITY SEEN WITH HEART
DISEASE IS SHOWN IN BLUE HERE
OCCURRED IN CHILDREN WHO ARE
LESS THAN ONE YEARS OF AGE BUT
IF YOU LOOK AT THE MOST RECENT
COHORT, YOU CAN SEE NOW THAT
INFANT DEATHS ACTUALLY ARE
MARKEDLY LESS COMMON AND WE SEE
THAT MOST PEOPLE WHO SUCCUMB TO
CONGENITAL HEART DISEASE ARE 15
YEARS AND OLDER.
AS A CONSEQUENCE OF THIS, THE
MOST COMMON COHORT OF FOLKS WITH
HEART DISEASE, THEY ARE ACTUALLY
ADULTS AND NOT CHILDREN.
SO DESPITE BEING LABELED HEART
DISEASE, SO ABOUT 2.4 MILLION
FOLKS ARE LIVING WITH CONGENITAL
HEART DISEASE IN THE UNITED
STATES TODAY, A MAJORITY ARE
ADULTS, BECAUSE OF THE -- THERE
HAS BEEN AN 85% INCREASED NUMBER
OF ADULTS LIVING WITH SEVERE
HEART DISEASE.
BUT CONGENITAL HEART DISEASE HAS
A HUGE IMPACT OP OUR MEDICAL
ECONOMICS AND ACCOUNTS FOR -- AS
WELL AS OVER $1.4 BILLION IN
HOSPITAL COSTS.
AS A REMINDER, THE HEART IS AN
INTERTHORACIC ORGAN FOUND
BETWEEN THE LUNGS AND SUPERIOR
TO DIAPHRAGM AND MID THORAX.
ALTHOUGH THE STRUCTURES OF THE
HEART ARE PREDOMINANTLY IN THE
LEFT HEMOTHORAX AS SHOWN IN THIS
CT IMAGE.
THE HEART WAYS ABOUT 250,
350 GRAMS.
ONE THING I LIKE TO POINT OUT TO
MY CLINICAL TRAINEES IS THAT
WHILE WE SORT OF IMAGINED THE
HEART IS A VERTICAL ORGAN LIKE
THE HALLMARK -- IT IN FACT A
HORIZONTAL ORGAN BECAUSE ALL
FOUR CHAMBERS OF THE HEART WILL
GO TO -- ARE, IN FACT, ADJACENT
TO THE INFERIORLY LOCATED
DIAPHRAGM.
THE THORACIC RELATIONSHIP IS
IMPORTANT WITH REGARD TO
PHYSICAL FINDINGS AND ARE OPEN
FOR INTERPRETATION OF THE IMAGE
ITSELF.
IF ONE WERE TO GO AFTER YOU WITH
AN ICE PICK, MOST ANTERIOR
CHAMBER IS GOING TO BE THE RIGHT
VENTRICLE, WHICH IS LOCATED HERE
ON CT SCAN AS YOU CAN SEE THE
LEFT ATRIUM AND WILL GO THROUGH
THE SECOND IS THE MOST POSTERIOR
ORGAN.
THE APEX OF THE HEART IS IF WE
ENTER -- THE -- BETWEEN THE
BREAST BONE AND THE SHOULDER,
THAT'S THE FIFTH INTERCOSTAL
SPACE, WHERE YOU SEE YOUR POINT
OF MAX MULL IMPULSE.
THE HEART IS THE PUMP FOR THE
CARDIOVASCULAR SYSTEM WHOSE
PURPOSE IS TO TAKE NUTRIENTS TO
THE BODY'S CELLS, WHILE REMOVING
CARBON DIOXIDE GENERATED BY
THE -- THE SYSTEM CONSISTS OF
TWO SERIAL CIRCUITS AND THIS
BECOMES IMPORTANT TO REMEMBER.
SO RECEIVING OXYGEN-RICH BLOOD
FROM THE LURNTION WITH AVERAGE
HEMOGLOBIN SATURATION ABOUT 98%
AND PEACIAL PRE PARTIAL PRESSURN
THIS IS ARTERIAL BLOOD.
THE BLOOD WILL ENTER THE LEFT
VENTRICLE AND THEN IT'S
DISTRIBUTED AT THE AORTA TO THE
REST OF THE BODY THROUGH THE
HEAD, ARMS AND DOWN TO THE
INTESTINAL SYSTEM, KIDNEYS, AS
WELL AS THE OTHER TISSUE.
AFTER PASSING TO CAPILLARY BEDS,
THE OXYGENATED OR BLUE BLOOD IS
NOW RETURNED TO THE VENULES AND
VEINS AND THE VENA CAVA, WHICH
GOES TO THE RIGHT OF THE HEART,
PUMPED -- TO BEGIN TO CYCLE
AGAIN.
THIS ENTIRE CYCLE TO TAKE A RED
BLOOD CELL THROUGH THE ENTIRE
CIRCUIT TAKES ABOUT 20 SECONDS.
SO SI SIMPLE PHYSICS -- DRIVING
FORWARD BLOOD THROUGH THE
SYSTEM.
SO IF WE START IN THE VENA CAVA
HERE, WE SEE THAT OXYGEN
SATURATION IS NOW DESATURATED
BECAUSE OF THE OXYGEN EXCHANGE
THAT'S OCCURRED, SATURATIONS ARE
ABOUT 70% IN THE VENA CAVA, BOTH
SUPERIOR AND INFERIOR, AND THE
MEAN PRESSURES OF THIS PART OF
THE SYSTEM, LESS THAN
6 MILLIMETERS OF MERCURY.
I'D LIKE YOU TO REMEMBER THAT
NUMBER BECAUSE THIS IS GOING TO
BECOME IMPORTANT AS WE TALK
ABOUT OUR PROBLEM.
THE RIGHT ATRIUM SATURATION 70%,
MEAN PRESSURE IS LESS THAN 4.
IT GOES FROM THE RIGHT ATRIUM TO
THE TRICUSPID VALVE INTO THE
RIGHT VENTRICLE, AND NOW BECAUSE
OF THE PRESSURE THAT'S GENERATED
BY THE CHAMBER FOR PEAK
PRESSURE, SYSTOLIC PRESSURE IS
ABOUT 25-MILLIMETERS OF MERCURY.
ONCE IT GOES INTO THE PULMONARY
ARTERY, IT'S ABOUT -- FROM THERE
IT GOING TO ENTER THE -- SYSTEM,
BECOME OXYGENATED, COME BACK
AGAIN, LESS THAN 6 MILLIMETERS
OF MERCURY.
LEFT VENTRICLE GENERATES A
PRESSURE AHEAD BETWEEN 120,
130 MILLIMETERS OF MERCURY, INTO
THE AORTA, WHERE IT'S THEN
DISTRIBUTED TO THE REST OF THE
BODY.
THE ATRIA IS SHOWN IN YELLOW AND
THE VENTRICLE IS SHOWN HERE IN
THE BLUE.
ONE CARDIAC CONTRACTION REFERRED
TO AS THE SYSTOLE, THEN THE
BLOOD IS PUMPED INTO THE AORTA,
GENERATING A PRESSURE HEAD, THE
AORTIC PRESSURE.
THIS IS THE PRESSURE THAT WE SEE
WHEN WE CHECK BLOOD PRESSURE BY
A MANUAL CUFF.
DURING DIASTOLE, THEY'LL FILL
WITH BLOOD AND PUMP AGAIN.
AS MENTIONED, OUR RED LINE HERE
IS OUR AORTIC PRESSURE.
IT'S BL 120 MILLIMETERS OF
MERCURY.
AND IS THE VENTRICLE PREPARED TO
FILL BLOOD FROM THE ATRIUM, THE
MEAN ATRIAL PRESSURES ARE LOW
BUT NOT ZERO AND THIS IS
REFERRED TO AS PRELOAD.
NO WAY IN THE LEFT VENTRICLE,
ATRIAL PRESSURE IS BELOW THE
RANGE OF 55 LITERS OF MERCURY,
HOWEVER -- ESPECIALLY WITH
REGARDS TO RELAXATION, THESE
HIGHER FILLING PRESSURES ARE
REQUIRED.
AS I MENTIONED A COUPLE TIMES,
THIS IS GOING TO BE AN IMPORTANT
CONCEPT THAT I'M GOING TO REFER
TO LATER.
SO THAT'S CARDIAC ANATOMY,
NORMAL CARDIAC PHYSIOLOGY.
NOW THAT WE'RE FAMILIAR WITH
THIS, THIS IS THE AREA OF HEART
DISEASE THAT ARE A CHALLENGING
PROBLEM AND THAT'S THE ISSUE OF
A SINGLE VENTRICLE.
THERE'S A CLASSIC -- VENTRICLES
ARE UNDERDEVELOPED, UNDERSIZED
AND INADEQUATE CIRCULATION, IN
FACT, IN SOME CASES, RATHER
INVOKING A WHOLE LAUNDRY LIST,
I'M GOING TO SIMPLY REFER TO ALL
OF THESE AS SINGLE VENTRICLE.
HERE IN THIS CASE, COMPARED TO
OUR NORMAL DIAGRAM, THIS IS THE
LEFT VENTRICLE, BECAUSE OF
ATRESIA, THE NITRILE VALVE,
THERE ARE SCORES OF VARIATION,
EACH HAVE UNIQUE ETIOLOGY, AND
EACH OF THEM HAVE ASSOCIATED
CARDIAC DEFECT.
BECAUSE BLOOD BEING A MIXTURE OF
BOTH FULLY SATURATED AND
DESATURATED BLOOD, THESE
PATIENTS ARE OFTEN BLUE OR
CYANOTIC.
HOWEVER, FOR MANY OF THESE
DEFECTS, THE MANAGEMENT GOAL IS
A SYSTEM FOR FULLY RESTORED
CIRCULATION TO IMPROVE
OXYGENATION.
I'M GOING TO GO BACK TO THIS AS
A MODEL.
SO THIS DEFECT IS CALLED
HYPOPLASTIC LEFT HEART.
WE'RE GOING TO USE THIS AS OUR
ARCHETYPE BECAUSE THIS IS
PROBABLY THE MOST COMMON SINGLE
VENTRICLE ANATOMY THAT WE
ENCOUNTER.
IT OCCURS IN 1 IN 5,000 BIRTHS
WITH ABOUT A THOUSAND BABIES
BORN ANNUALLY WITH THIS
CONDITION.
PRIOR TO THIS, INFANTS WITH THIS
DEFECT EXPERIENCED MORTALITY IN
THE FIRST FEW WEEKS OR MONTHS OF
LIFE.
HYPOPLASTIC LEFT HEART, AORTIC
VALVE, IS EITHER SEVERELY -- OR
CYANOTIC.
THE MITRAL VALVE TOO IS -- OR
STENOTIC.
THIS PREVIOUS CIRCLE -- THE LEFT
VENTRICLE -- AND THE ONLY WAY
THESE INFANTS REMAIN ALIVE IS
BECAUSE OF THE PRESENCE OF THIS
VESSEL HERE, AND THIS VESSEL IS
REFERRED TO AS A PATENT DUCTUS
DUCTUSARTERIOSUS OR PDA.
THE PHYSIOLOGY AT BIRTH FOR
THESE BABIES, BLUE BLOOD IS
COMING BACK FROM THE HEAD AND
THE LOWER BODY, SATURATION IS
NORMALLY ABOUT 70% AND THESE
CHILDREN, THE SATURATION SYSTEM
IS MORE IN THE 60% RANGE.
THE BLOOD FLOW BACK TO THE LUNGS
IS FULLY SATURATED SO THIS IS
98%, SO THE BLOOD IN THE RIGHT
ATRIUM -- OR LEFT ATRIUM WOULD
BE ABOUT 90%.
BUT ALL THE BLOOD SINCE IT CAN'T
EXIT THE LEFT ATRIUM THROUGH THE
MICRO VALVES, IT HAS TO GO
THROUGH A HOLE, LEFT OR RIGHT
THROUGH THAT HOLE AND WE CREATE
AN ADMIXTURE OF FLOW BETWEEN THE
DESATURATED AND FULLY SATURATED
BLOOD.
SO THIS BLOOD TENDS TO RANGE IN
A SATURATION OF 70%, SO IN OUR
SUBSEQUENT DIAGRAMS, IF YOU SEE
PPURPLE, THAT MEANS SATURATION
ABOUT 70%.
AND THESE PATIENTS WOULD BE
VISIBLY CYANOTIC, IN AN INFANT
OR AN ADULT NORPLY YO NORMALLY E
SATURATIONS IN THE MID TO UPPER
80s IF YOU'RE CYANOTIC.
YOU CAN SEE ALL THE CARDIAC
OUTPUT SINCE THE BLOOD CAN'T GO
OUT THE AORTA, THIS IS NORMAL,
THE BLOOD GOING TO THE HEAD, TO
THE ARMS AND TO THE LOWER BODY
IS GOING THROUGH THIS PATENT
DUCTUS ARTERIOSUS.
THE ISSUE, THOUGH, IS THAT PDA
CLOSES.
IN NORMAL PHYSIOLOGY, VARIOUS
TRIGGERS, BIOCHEMICAL CHANGES,
YOUR ACID BASE STATUS, IT
PROMPTS PDA CLOSURE.
SO THE PDA WILL ESSENTIALLY
CLOSE EVEN THOUGH IT'S NEEDED TO
MAINTAIN CIRCULATION.
SO YOU CAN SEE ONCE THE PDA
CLOSES THERE'S LESS CARDIAC
OUTPUT, CARDIOVASCULAR CLEFT
BECAUSE OF KNOW CARDIAC OUTPUT.
SO THIS IS OUR ARCHETYPE MODEL,
BUT I WANT TO GO BACK ONE STEP
BECAUSE SURGEONS HAD TO FIGURE
OUT THIS HAS TO BE TREATABLE BY
MEDICATION OBVIOUSLY AND SOME
TYPE OF INTERVENTION WOULD BE
REQUIRED.
AND THE PROBLEM OF THE SINGLE
VENTRICLE AN ACTUALLY REALLY BEN
IN THE LATE 60s.
AT THE UNIVERSITY OF BORDEAUX,
THE SURGEON WAS APPROACHED BY A
COLLEAGUE ABOUT AN ADOLESCENT
PATIENT WHO HAD A HEART DISEASE.
WONDERING IF IT MIGHT BE
POSSIBLE TO IMPROVE ON EXISTING
SURGERY FOR CARDIAC
MALFORMATION, FONTAN HAD DONE A
SERIES OF EXPERIMENTS IN DOGS
THROUGH THE PULMONARY ARTERY,
WHICH IS HERE, ALLOWING BLOOD TO
ENTER THE LUNGS.
IT WAS INTERESTING, ALL THESE
DOG SURGERIES WERE UNIFORMLY
UNSUCCESSFUL.
SO IT DOES SEEM A BIT SURPRISING
THAT HIS COLLEAGUE WOULD HAVE
APPROACHED DR. FONTAN ABOUT IT,
BUT DR. FONTAN DID TAKE THIS
WOMAN TO THE OPERATING ROOM AND
DESPITE A ROCKY POSTOPERATIVE
COURSE, THE WOMAN SURVIVED HIS
SURGERY.
SO IN TRICUSPID ATRESIA, THE TRY
TRICUSPID VALVE, WHICH IS HERE,
FAILS TO DEVELOP.
AND WHEN IT FAILS TO DEVELOP,
YOUR RIGHT VENTRICLE BECOMES
HYPOPLASTIC.
YOU CAN SEE OVERWEIGHT BLOOD IS
ABLE TO GET OUT INTO THE LUNGS,
ACTUALLY WOULD HAVE BEEN THROUGH
RIGHT TO LEFT THROUGH THIS
ATRIAL SEPTAL DEFECT, MIRING
MIXING WITHTHE PULMONARY VENOUSG
TOGETHER IN THE AORTA.
WHAT FONTAN PROPOSED THAT WE'RE
GOING TO CALL THE FONTAN --
WE'LL TALK ABOUT THAT IN ONE
SECOND, HE PROPOSED CONNECTING A
PORTION OF THE RIGHT ATRIUM
CALLED THE APPENDAGE TO THE
PULMONARY ARTERY ITSELF.
AND BY DOING THAT, IT ALLOWS A
CONNECTION FROM THE SYSTEMIC --
SIDE TO THE RIGHT ATRIUM TO THE
APPENDAGE, THEREFORE PROVIDING A
STABLE SUPPLY OF BLOOD FLOW.
THE BLOOD COMING FROM THE
PULMONARY VEIN WAS NOW FULLY
SATURATE AND THERE WAS NO
ADMIXTURE BETWEEN THE TWO.
THIS SURGERY SUCCESSFULLY
SEPARATES -- CARDIAC OUTPUT
RECOVERED AND THIS PATIENT'S
CYANOSIS WAS RESOLVED.
AND AS I MENTIONED, DESPITE A
RATHER ROCKY -- HE DID SURVIVE
AND RECOVERED.
SO DR. FONTAN -- 32 PATIENTS IN
1971, ARGENTINA -- SURGICAL
APPROACH -- THEY'RE BOTH HONORED
TODAY BY NAMING THIS PROCEDURE
THE FONTAN KREUTZER PROCEDURE
BUT FOR SIMPLICITY TO AVOID ME
CONSTANTLY TRIPPING OVER THIS,
I'M SIMPLY GOING TO REMEMBER TO
THIS AS THE FONTAN PROCEDURE.
SO THE SINGLE VENTRICLE
HYPOPLASTIC LEFT HEART.
UNLIKE THE -- IT IS THE SYSTEMIC
LEFT VENTRICLE THAT IS
UNDERDEVELOPED AND THE OTHER
CRITICAL ISSUES WE TALK ABOUT
THE FACT THAT ALL THE CARDIAC
OUTPUT WAS GOING TO THE PDA
WHICH WAS DESTINED TO CLOSE.
SEE MY ARROW HERE, REMEMBER TH
THE -- AND OUR PATENT DUCTUS
ARTERIOSUS.
SO THE NEXT SERIES OF DIAGRAMS
SHOWS SOME OF THE COMPLEXITY
OF -- AND SERIOUS SURGERY THAT
IT TAKES -- I DON'T WANT TO GET
TOO MUCH INTO THE WEEDS BUT
WE'RE GOING TO BE TALKING ABOUT
A THREE-STAGE PROCEDURE TO
PALLIATE THIS COMPLEX HEART
DISEASE.
SO AS WE TALKED ABOUT AT BIRTH,
THIS IS WHAT OUR CHILD LOOKS
LIKE.
SO THE FIRST THING WE HAD TO DO
WAS TO CREATE A -- AORTA, WHICH
IS RIGHT HERE, SO AGAIN, IF YOU
LOOK HERE, WE HAD TO GET RID OF
THIS PDA, WE HAD TO GET BLOOD
INTO THE AORTA ITSELF AND SO YOU
DO THIS BY CREATING A CONNECTION
FROM THE ASCENDING AORTA
BASICALLY USING THE PULMONARY
ARTERY TO CREATE A NEW PULMONARY
ARTERY.
THIS PROVIDES RELIABLE SOURCE OF
BLOOD FLOW.
WE ADDED A SHUNT SHOWING HERE,
WHICH NOW PROVIDES RELIABLE
PULMONARY BLOOD FLOW.
WE CREATE THIS BECAUSE WE DON'T
WANT ANYTHING TO OBSTRUCT FLOW
AND RETURN OF THE VENOUS BLOOD,
SO NOW WHAT WE SEE IS OUR VENA
CAVAL FLOW GOING INTO THE RIGHT
ATRIUM, VENOUS RETURN TO RIGHT
ATRIUM, MIXING GOING INTO THE
AORTA WHO IS NOW BLUE, WE HAVE
STABLE CARDIAC OUTPUT AS WELL AS
VENOUS FLOW THROUGH OUR SHUNT.
THIS WAS DONE WITHIN A COUPLE
DAYS OF BIRTH.
THE NEXT, THIS IS A PROCEDURE TO
BASICALLY ALLOW VOLUME UNLOADING
OF THE HEART.
SO WE NOW CREATE ANASTOMOSIS
BETWEEN THE SUPERIOR VENA CAVA
AND PULMONARY ARTERY THAT WE
CALL A MODIFIED GLENN OR
HEMI-FONTAN.
THAT SHUNT W WE HAD HERE, WE TOK
THAT DOWN SO NOW YOU CAN SEE WE
HAVE A STABLE BLOOD FLOW, IVC IS
MIXING STILL WITH THE PULMONARY
VENOUS RETURN, AND IT'S STILL
BLUE, BUT NOW WE STILL HAVE A
STABLE BLOOD FLOW.
AGAIN, AS I MENTIONED, THIS
ALLOWS UNLOADING AT A DISTANT
VENTRICLE SO THE PATIENT REMAINS
CYANOTIC.
FINALLY THE FONTAN, WHICH IS A
STAGE III, WHICH IS OUR TOTAL
ANASTOMOSIS, WHAT WE'RE DOING
HERE IS WE'RE ADDING IN A
TUNNEL, A PATCH OR WE CAN PUT A
TUBE GRAFT IN THAT'S GOING TO
DIRECT FLOAM TO THE PULMONARY
ARTERY AND SEV HAS ALREADY BEEN
CONNECTED.
SO YOU CAN SEE NOW OUR BLOOD HAS
M COME BACK THROUGH THE LEFT
ATRIUM IS COMPLETELY SEPARATED
FROM THE SYSTEMIC VENOUS RETURN
SO THE PATIENT IS FULLY
SATURATED.
AS WE FIND -- THE SCOPE OF THIS
DISCUSSION RIGHT NOW.
CURRENTLY THERE'S THREE
VARIATIONS OF FONTAN.
THERE'S ORIGINAL AORTIC
PULMONARY SECTION AND DR. FONTAN
HAD DESCRIBED.
YOU CAN PUT A PATCH IN HERE TO
DIRECT FLOW FROM THE IVC UP INTO
THE S DC PULMONARY ARTERY,
CALLED THE LATERAL - -- WHEN YOU
LOOK AT -- AS WE'RE TRYING TO
DEFINE EXACTLY WHAT IS AN
OPTIMAL APPROACH, I'LL SHARE
SOME DATA HERE IN JUST A LITTLE
BIT, COMPUTATIONAL FLUID
DYNAMICS CONDUCTED BY CARDIAC
MI, THIS IS PROBABLY THE MOST
OPTIMAL APPROACH BECAUSE ARE IT
MINIMIZES POWER LOSS OF FLOW,
AND ONE OF THE CHALLENGES WITH
THIS TYPE OF CIRCUIT IS -- SO
BECAUSE THERE'S LESS COMPETITION
BETWEEN THE SCV AND IVC FLOW
COMING IN TO THE PULMONARY
ARTERY, [INAUDIBLE] OTHER
ADVANTAGES AS WELL.
AS FAR AS INDICATIONS FOR THE
FONTAN, AGAIN, THE HYPOPLAS
HYPOPLASTIC -- TRICUSPID
ATRESIA.
WE TALKED BRIEFLY ABOUT THE
ETIOLOGY FOR THE SINGLE
VENTRICLE.
IN A NORMAL SITUATION, WE HAVE A
LEFT VENTRICLE, WE HAVE A RIGHT
VENTRICLE, AND -- CONNECTS TO
THE PULMONARY CIRCULATION IN
THEORY.
THE MOST IMPORTANT TAKEAWAY FROM
THIS, AGAIN, THIS IS OUR CHANGE
IN PRESSURE OVER TIME CURVE,
LEFT VENTRICLE, AS IT GOES
THROUGH THE MAJOR ARTERIES,
ARTERIOLES AND CAPILLARY BED
REPRESENTED HERE, SYSTEMIC
VENOUS RETURN THROUGH HERE, INTO
THE RIGHT ATRIUM, RIGHT
VENTRICLE, RIGHT VENTRICLE THEN
INCREASES PRESSURE AND GETS IN
THE PULMONARY CIRCUIT AND THEN
WE START THE CYCLE OVER AGAIN.
THE MOST IMPORTANT THING I WANT
TO POINT OUT IS THE DRIVING
FORCE TO OVERCOME -- NOW IN A
FONTAN, WE HAVE BLOOD THAT'S
GOING THROUGH THE SYSTEM.
THIS VENTRICLE HAS TO -- LIKE
THIS NORMAL CIRCULATION WHERE WE
HAVE TWO VENTRICLES ABLE TO
PROVIDE THE TOTAL ENERGY IN
ORDER TO GET BLOOD TO THE LUNGS
AND OUR FONTAN, WE HAVE ONLY A
SINGLE VENTRICLE THAT COULD --
THAT INITIAL PRESSURE GRADIENT,
AND ONCE WE GET TO THE -- IT A
CENTRAL BETA PRESSURE, NOT A
VENTRICLE THAT'S PROVIDING --
WHAT HAPPEN PS OVER TIME,
PULMONARY VASCULAR DISTANCE HERE
INCREASES, AND AS THAT
INCREASES, THE CENTRAL VENOUS
PRESSURE MUST INCREASE TO
MAINTAIN CARDIAC OUTPUT, AND TO
THINK WHEN YOU INCREASE -- THAT
INCLUDES THE SYSTEM -- AND THERE
ARE CLINICAL SIGNS AND SYMPTOMS.
AND AS TIME GOES ON, AND WE'LL
TALK A LITTLE BIT AGAIN, WE SEE
THAT THE CARDIAC OUTPUT
DECREASES RELATED TO RISK
FACTORS.
MORBIDITY AND COMPLICATION ARE
DIRECTLY ASSOCIATED TO BOTH
INCREASE IN CDC AND CARDIAC
OUTPUT.
ONE MEASURE OF CARDIAC OUTPUT IS
EJECTION FRACTION, OR EF HERE.
WHICH IS PERCENTAGE OF VOLUME
INJECTED INTO THE --
CONTRACTIONS.
THE NORMAL EF, WHICH IS HERE,
NORMAL EF, NORMAL HEART,
EJECTION FRACTION IS BETWEEN 55
AND 70%.
IN A WELL FUNCTIONING FONTAN,
EVEN THE PRESENCE OF THAT, WE
FIND OUR CARDIAC OUTPUT IS GOING
TO BE MUCH LOWER, EVEN THOUGH
ESSENTIAL FACTOR IS -- AS YOUR
EF DIMINISHES IN A FONTAN, YOU
CAN SEE OUR CARDIAC DECREASES,
AND YOU CAN SEE HOW HIGHLY
DEPENDENT IT IS ON -- SO THEIR
PVR INCREASES, EF -- INCREASED
NUMBER OF ADULT PATIENTS NOW
LIVEING WITH THE FONTAN IS NOW
ESTIMATED AT ABOUT 40% OF
PATIENTS THAT HAVE A FONTAN ARE
OVER 18 YEARS OF AGE.
THIS GRAPH SHOWS THE LONG-TERM
SURVIVAL, AND OVERALL ESTIMATED
SURVIVAL -- SO ESTIMATED
SURVIVAL, 30-YEAR SURVIVAL FOR
THE PATIENT WITH A FONTAN IS
ABOUT 85%.
WE TALK ABOUT THREE DIFFERENT
TYPES OF FONTANS.
WE TALK ABOUT THE EXTRA CARDIAC
CONTENT, THAT TUBE GRAFT,
REPRESENTED BY THIS SOLID BAR
HERE, THE LATERAL TUNNEL, WHICH
IS THAT PATCH WE PUT IN, AND THE
PULMONARY CONNECTION, THE ONE
THAT DR. FAN ORIGINALLY
CONCEIVED.
NOW, IF YOU LOOK AT PATIENTS WHO
HAVE INTACT FONTAN CIRCULATION,
THAT PREVIOUS WAS ABOUT OVERALL
SURVIVAL BUT PATIENTS CAN
REQUIRE CONTINUED INTERVENTION.
SO AT 20 YEARS OF AGE, 74% ARE
INTERVENTION-FREE, 8% OF THEM
WILL HAVE HAD A TRANSPLANT AT --
OR 20 YEARS -- AND SOME HAD IT
TAKEN DOWN.
WHEN WE TALK ABOUT -- PRESERVE
EJECTION FRACTION OR REDUCE THE
EJECTION FRACTION.
YOU SEE BOTH HYPERTROPHY AND
DILATION.
ALSO WE SEE AN INCREASE IN THE
INABILITY TO RELAX.
CORONARY INSUFFICIENCY IS
COMMON, AND NOW WE HAVE INSTEAD
OF -- WE HAVE TWO AV VALVES.
IN OUR SINGLE VENTRICLE
PATIENTS, WE HAVE ONE, -- BOTH
CONGENITAL ANATOMY, BECAUSE OF
SURGICAL SCARRING, THESE ARE
COMMON IN FONTAN CASES.
EACH ANATOMIC SUBSTRATE IS
SINGLE VENTRICLE, EACH POSES ITS
OWN CHALLENGE.
NOW THE SUTURE LINES THAT GO
THROUGH THE SURGERY INTERFERE
WITH ATRIAL CONDUCTION.
IT MAY ACTUALLY HAVE A LOWER --
THAT'S ANOTHER REASON IT'S
BECOME THE MORE FAVORED
TECHNIQUE.
10 YEARS AFTER A FONTAN, 15% OF
PATIENTS WILL HAVE SOME TYPE O
OF -- EITHER BRAY EE RIT -- YOU0
YEARS -- 15 YEARS.
COMORBIDITIES ARE COMMON.
ONE OF THE THINGS THAT WE'RE
RECOGNIZING IS LIKE THE LONGER
PATIENTS ARE SURVIVING, ONCE
THEY HAVE INCURRED -- SURVIVED
THE INITIAL SURGERY, 10, 15, 20,
25 YEARS AFTER THE SURGERY,
WE'RE STARTING TO IDENTIFY OTHER
PROBLEMS.
LYMPHATIC DYSFUNCTION IS NOT
UNCOMMON AND PROBABLY LED TO
PRESSURE ELEVATION AS WELL AS --
PRPRO-INFLAMMATORY STATE ALTERIG
MEMBRANE PERMEABILITY, AS WELL
AS VARIABILITY IN LYMPHATIC
SYSTEM WHICH MAY DISPOSE TO
COMORBIDITIES.
IN MORE DETAIL THAT HAS BEEN
BEEN -- -- WHICH AFFECTS 5 TO
12% OF PATIENTS WITH FONTAN
CIRCULATION, AND ALSO CLASSIC
BRONCHITIS, THICK TENACIOUS
CASTS WITHIN THE AIRWAY LUMEN.
THIS OCCURS IN A SMALL NUMBER OF
PATIENTS WITH FONTAN.
-- A QUICK SHOUT OUT TO
DR. HELLER.
BEFORE WE DO, I'D LIKE TO
INTRODUCE A PATIENT, BUT BEFO
BEFORE -- SO WE'VE KNOWN EACH
OTHER BEFORE SHE WAS BORN, AND
AS IT TURNS OUT, I FOLLOWED HER
FOR CLOSE TO 20 YEARS, AND AS I
TRANSITIONED OUT OF MILITARY,
SHE TRANSITIONED AS WELL AND
BEING FOLLOWED BY DR. HELLER --
FONTAN PROTOCOL.
SO THIS IS ANGELICA'S HEART.
SHE WAS BORN WITH TRICUSPID
ATRESIA.
SHE HAD -- THE AORTA -- HAVE
ACTUALLY SWITCHED IN PLACE.
SO NORMALLY THE RIGHT VENTRICLE,
YOU PUMP BLOOD INTO THE
PULMONARY ARTERY.
HERE IN HER ANATOMY, HERS WAS
PUMPING INTO THE AORTA.
SHE HAD A VENTRICULAR SEPTAL
DEFECT, AS WELL AS -- NARROWING
OF THE BLOOD VESSEL THAT COMES
OFF THE HEART.
SO WE HAVE TO BURN -- HER
PHYSIOLOGY, YOU CAN SEE VENA
CAVAL FLOW, IT WAS ALL CROSSING
INTO HER LEFT ATRIUM.
ALL THE BLUE BLOOD IS GOING TO
HER LEFT ATRIAL SIDE.
IT WAS MIXING WITH HER FULLY
SATURATED BLOOD AND
CONSEQUENCELY WITH THIS
ADMIXTURE, SOME OF THAT FLOW WAS
GOING INTO -- ARTERIES, SOME WAS
GOING TO THE AORTA.
-- 75%.
SORTLY AFTER BIRTH SHE UNDERWENT
A PROCEDURE BASICALLY CONNECT
BEING THE PULMONARY ARTERY,
WHICH IS HERE, INTO THE AORTA.
SHE HAD A BTT SHUNT RIGHT HERE
TO ENSURE -- BECAUSE ONCE WE DID
THAT, IT CUT OFF HER ARTERY --
THAT WAS DONE THROUGH THE SHUNT.
THEY ALSO DID A PARTIAL
CORRECTION OF HER -- BUT SHE
STILL HAD ACUTE -- AFTER HER
SURGERY.
HER NEXT PROCEDURE, THEY WENT
BACK AND THEY DID A REVISION.
HER LAST PROCEDURE -- OR NEXT
PROCEDURE WAS THE FONTAN
PROCEDURE.
BECAUSE WHEN THEY DID HER
INITIAL -- CASE CANCELED THIS,
IS NOT UNCOMMON BECAUSE THERE
WAS SCAR TISSUE HERE, THE
PULMONARY ARTERY WAS STENOTIC
OR -- THIS PRESSURE HAS TO BE
REMAIN UNDER AS LITTLE PRESSURE
AS POSSIBLE, SO WHENEVER WE
IDENTIFY ANY STENOSIS, WE HAVE
TO BE VERY -- ABOUT SEVEN YEARS
OF AGE.
FINALLY SHE HAD -- NOW AS A
RESULT OF ALL THE SURGERIES, HER
LEFT AND RIGHT ARE SEPARATED.
SO IF YOU LOOK AT HER INITIAL
ANATOMY, VERSUS WHAT HER FINAL
ANATOMY WAS, SHE'S NO LONGER
MIXING AND SHE WAS FULLY
SATURATED.
ONE OF THE THINGS, WE MAY TOUCH
ON THIS, ONE OF THE THINGS THAT
ADULTS WILL STILL HAVE IS SHE
HAS VENOUS CONNECTION WHICH
CONNECT FROM HER VENOUS SIDE
INTO AREAS OF HER ATRIUM, SO
BECAUSE OF THAT, THERE REMAINS
SOME RIGHT TO LEFT SHUNTING --
FOR THAT REASON, SATURATION IS
STILL NOT 100% -- BUT COMPARING
TO WHERE SHE WAS BEFORE,
OBVIOUSLY THE FACT THAT SHE HAD
A CARDIAC MALFORMATION, THAT WAS
WHY -- ABOUT WHERE SHE HAS GONE,
AND SO NEXT I WANT TO INTRODUCE
HER MOTHER AND ANGELICA, WHO IS
OUR PATIENT FOR TODAY AND ONE OF
MY FAVORITE PATIENTS.
I'M GOING TO STOP SHARING.
HOW ARE YOU?
>> FINE, THANKS.
>> HI.
>> ANGELICA, HOW ARE YOU?
>> I'M GOOD.
HOW ARE YOU?
>> FIRST I WANT TO THANK YOU FOR
ACCEPTING OUR INVITATION TO
SPEAK WITH ME AND THEO ABOUT
YOUR HEART AND STUFF LIKE THAT.
SO JUST HAVE A -- WE'LL JUST GO
THROUGH A FEW THINGS AND THEN AT
THE END, WE'LL OPEN UP FOR --
PROBABLY AFTER DR. HELLER'S
TALK, WE'LL OPEN UP FOR
QUESTIONS.
ANYWAY, ANGELICA, IF YOU DON'T
MIND INTRODUCING YOURSELF?
>> HI, I'M ANGELICA.
I'M 23.
DR. MER CLOA HAS BURKLOW HAS BER
SINCE I WAS 2.
I AM A TEACHER'S ASSISTANCE AT A
MONTESSORI SCHOOL, I'VE BEEN
WORKING THERE FOR ALMOST TWO
YEARS.
I LOVE WORKING WITH CHILDREN.
I WORK WITH 1 TO 3-YEAR-OLDS SO
I'M ALWAYS ON MY FEET 24/7, BUT
AGAIN, IT'S MY PASSION, IT MY
GREAT THING TO DO AND I GET TO
CHANGE THE WORLD AND HELP
CHILDREN.
>> THANK YOU, ANGELICA.
WE'LL COME BACK TO YOU IN A
SECOND.
YOU DON'T HAVE TO STATE YOUR AGE
BUT IF YOU WANT TO INTRODUCE
YOURSELF?
>> SURE, I'M ANGELICA'S MOM AND
YES, I WILL NOT SHARE MY AGE,
YOU GUYS CAN GUESS.
I HAVE ACTUALLY BEEN A
STAY-AT-HOME MOM SINCE THE DAY
SHE WAS BORN.
I'M A MILITARY NOW RETIRED AFTER
35 YEARS, A WIFE, I HAVE TWO
OTHER CHILDREN WHO ARE NOW 19
AND ALMOST 16.
I'VE JUST STARTED GOING BACK TO
WORKING THE LAST SEVERAL YEARS
AS A SOUTH ASIAN WEDDING
PLANNER.
>> THANK YOU.
SO CAN YOU SHARE YOUR THOUGHTS
WHEN YOU WERE FIRST INFORMED
ABOUT ANGELICA'S HEART
ABNORMALITY?
>> SURE.
GOSH, I FOUND OUT ACTUALLY WITH
HER HEART CONDITION WHEN I WAS
8 1/2 MONTHS PREGNANT.
SO AT THIS POINT -- AT THAT
POINT WE DIDN'T HAVE MUCH TIME
TO REALLY PREPARE OR EVEN
COMPREHEND WHAT WAS GOING ON AS
WE WERE SO CLOSE TO HER DUE
DATE.
WHEN WOULD WE FOUND OUT, THEY Y
MUCH TOLD US SHE WOULD NOT BE
VIABLE BASED ON WHAT THEY WERE
SEEING IN THE SONOGRAM, SO ON
AND SO FORTH.
SO WHEN WE HEARD THAT BETWEEN,
YOU KNOW, SHE BEING OUR FIRST
CHILD, I HAVE -- WHAT I RECALL
IS I DON'T EVEN -- I CAN'T EVEN
FULLY REMEMBER EXACTLY WHAT I
WAS DEALING WITH BECAUSE IT WAS
JUST LIKE OUR -- YOU KNOW, JUST
LIKE -- WHAT'S THE WORD I'M
LOOKING FOR, BUT IT JUST FELT
LIKE THE WORLD HAD DROPPED ON
OUR SHOULDER, BEING OUR FIRST
CHILD, BEING PARENTS FOR THE
FIRST TIME, AND THINGS LIKE
THAT, IT WAS JUST -- IT WAS
HARD.
>> YEAH.
AT THE TIME OF FETAL DIAGNOSIS
OR SHORTLY AFTER BIRTH, WE HAD
PEDIATRIC CARDIOLOGISTS WITH
OVERWHELMED PATIENTS, ESPECIALLY
WHEN YOU HAVE -- PEOPLE ARE
TALKING ABOUT SURGERY OVER THE
COURSE OF YEARS, THAT IS
OVERWHELMING.
TRICUSPID ATRESIA, EVEN FOR
MEDICAL FOLKS, IS NOT
NECESSARILY INTUITIVE, FOR
NON-MEDICAL FOLKS, PERHAPS EVEN
MORE SO.
HOW DID YOU SORT OF COME TO
UNDERSTAND HER ANATOMY AND
PHYSIOLOGY, AT LEAST IN A WAY
THAT IT ALLOWED YOU TO
UNDERSTAND WHAT SHE NEEDED?
>> WELL, I WAS VERY BLESSED, I
COULD SAY THAT WE HAD AMAZING
DOCTORS, INCLUDING DR. BURKLOW,
WE HAD OTHER DOCTORS OUT THERE
THAT ACTUALLY REASSURED US WHICH
WAS -- WE HADN'T HEARD I THINK
FOR THE FIRST TWO WEEKS OF THE
TIME OF OUR DIAGNOSIS, PRETTY
MUCH SAID SHE WILL NOT SURVIVE
AND THEN IN THE PROCESS OF
SEEING DIFFERENT DOCTORS AND
TALKING TO -- FINALLY WE HEARD
ONE OF THE DOCTORS SITTING THERE
TELLING US, WE CAN WORK WITH
THIS.
WE CAN WORK WITH THIS.
THIS CAN WORK.
THAT WAS THE FIRST TIME I THINK
I EVER HEARD, MIND YOU DURING
THIS WHOLE TIME I WAS GOING
THROUGH CONTRACTIONS, I THOUGHT
I WAS GOING TO GIVE BURT WITHOUH
WITHOUT HAPPENING AND WHEN I
HEARD HE COULD DO SOME SURGICAL
PROCEDURE AT THAT POINT, I THINK
MY CONTRACTIONS STOPPED AND I
JUST LOOKED AT MY HUSBAND SAYING
ALL RIGHT, WHERE DO WE SIGN THE
DOTTED LINE, WHERE DO WE -- SO
BECAUSE WE HAVE SUCH GOOD
DOCTORS EXPLAIN WHAT WAS THE
SITUATION, HOW TO GO ABOUT DOING
WHAT WE NEEDED TO DO TO SURVIVE
WAS A BLESSING, BECAUSE
OBVIOUSLY BEING FIRST-TIME
PARENTS AND NOT KNOWING WHAT
CONGENITAL HEART DISEASE OR ANY
TYPE OF HEART SITUATION WAS
KNOWN TO US, WE WERE VERY
BLESSED TO HAVING GREAT DOCTORS
TO EX-PLAINL TO US THROUGH A TO
Z, I WAS ABLE TO EXPLAIN THAT TO
MY FAMILY AND WHOEVER CAME
ACROSS THE PATH BUT WAY ABLE TO
TALK -- HAVE THE CONVERSATION,
SO YES, THANKS TO THE DOCTORS
AND EXPLAINING IN LAYMAN'S TERNL
MAN'S TERMSAND TREATING ME LIKEA
5-YEAR-OLD TO EXPLAIN WHAT HAS
COME ABOUT, HOW IT CAME ABOUT,
EVERYBODY DOESN'T UNDERSTAND
THAT BECAUSE IT'S A FLUKE HOW
THEY USE -- IN LEHMANN'S TERMS
AND HAVING DOCTORS EXPLAINING TO
US WAS -- WHAT WE NEEDED WAS
GREAT AND MAKE US UNDERSTAND.
>> ALTHOUGH ONE THING THAT'S
ALWAYS IMPRESSED ME WITH
FAMILIES LIKE YOU IS HOW
SOPHISTICATED YOU DO BECOME IN
UNDERSTANDING NOT JUST THE
ANATOMY BUT THE NEEDS, AND SO
GETTING PHONE CALLS FROM UM,
ESPECIALLY WHEN YOU WERE VERY
YOUNG, I KNEW THAT YOU WERE ABLE
TO RECOGNIZE CHANGES IN HER
ACTIVITIES OR EVALUATION.
SO I APPRECIATE THE -- I
DEEPLY -- I MEAN THIS SINCERELY,
I THINK YOU AND MATTHEW,
ANGELICA'S FATHER, HAVE MADE THE
DIFFERENCE IN HER LIFE TO MAKE
SURE SHE GOT THE CARE SHE
NEEDED.
>> THANK YOU.
>> IN THE YEARS, HOW -- CAN YOU
SHARE KIND OF GENERAL THOUGHTS
ABOUT --
>> THE ONE THING I REMEMBER, DRD
I WAS STRUCK BY WAS TAKE HER
HOME, LOVE ON HER AS MUCH AS YOU
CAN, WE DON'T KNOW HOW MUCH TIME
SHE HAS, BUT MAKE SURE YOU DON'T
SPOIL HER SO SHE DOESN'T BECOME
A BRAT.
>> DID I SAY THAT?
OKAY.
>> I DON'T KNOW IF IT WAS THOSE
EXACT WORDS BUT I GOT THE GIST
OF IT AT THAT POINT.
AND THEY SAID WHAT YOU -- THEY
SAID JUST WATCHING HER, I MEAN,
ONE THING AFTER YOU TOLD US,
DON'T TREAT HER LIKE A PATIENT,
TREAT HER LIKE A NORMAL CHILD.
BECAUSE WHEN YOU TREAT A CHILD
OR ANY PERSON, IF YOU TREAT THEM
LIKE THEY'RE SICK, THAT'S WHAT
HAPPENS.
THEY BECOME SICK.
IF YOU TREAT THEM NORMALLY,
GIVEN THE ENVIRONMENT, THAT
HAPPY GO LUCKY BE AS NORMAL AS
POSSIBLEMENT LIFE WOULD BE
NORMAL.
SO OBVIOUSLY I DON'T -- A BLACK
CLOUD OVER OUR HEAD, I REMEMBER
ONE TIME WE WERE IN -- SITTING
THERE WATCHING WHEN SHE WAS
MAYBE LESS THAN A YEAR OLD, AND
WE WERE JUST TALKING AND I --
NEAR THE COUCH WATCHING TV AND
SHE KIND OF BUCKLED OVER, I
THINK THAT WAS WHEN MY HEART --
LIKE WHAT JUST HAPPENED, DID SHE
HAVE A HEART ATTACK, WAS IT
HEART FAILURE.
I REMEMBER BOTH MY HUSBAND AND I
ARE LIKE WHAT DO WE DO, WE
RUSHED OVER, SHE LITERALLY WENT
TO SLEEP AND HAD NO CARE, BUT
THOSE ARE THOSE KIND OF THINGS
THAT WE WERE VERY -- NOT REGARD
TO BEING -- WE WATCHED EVERY
GUIDANCE THAT WE GOT FROM ANY
DOCTOR, WE REALLY TOOK THAT AND
WAMPED IT.
WATCHED IT.
BUT AGAIN WE DEFINITELY TOOK
YOUR ADVICE AND MADE SURE SHE
DIDN'T TURN OUT TO BE A BRAT.
>> I STILL TURNED OUT TO BE A
BRAT.
>> I KNOW, BUT THAT'S THE
DIFFERENCE --
>> THAT'S A TOPIC FOR ANOTHER
DAY.
>> SO ANGELICA, GROWING UP, WHAT
WAS YOUR FIRST SORT OF INKLING
THAT YOUR HEART WAS DIFFERENT
FROM OTHER KIDS?
>> LIKE MOM SAID, I WAS
FORTUNATE ENOUGH TO LIVE A
NORMAL LIFE AS I WORK IN -- I
WORK IN LIKE -- I WAS TOLD THAT
I WASN'T ABLE TO PLAY SPORTS,
SO -- AGAIN, THAT DIDN'T REALLY
STOP ME FROM DOING ANYTHING, SO
I FEEL -- I SING, I DANCE, I DO
EVERYTHING ELSE.
BUT I THINK IT WAS TOWARDS
MIDDLE SCHOOL TIME WHERE I WAS
TOLD, LIKE, HEY, SOMETHING IS
DIFFERENT WITH YOU BUT WE'RE NOT
GOING TO TREAT YOU ANY
DIFFERENT.
I HAD A PRETTY NORMAL CHILDHOOD
SO I DIDN'T REALLY FEEL ANY
DIFFERENT.
>> YOU DID KIND OF WHEN YOU HIT
SEVENTH GRADE.
I THINK YOU UNDERSTOOD -- WHEN
SHE WAS SEEING HER PEERS IN A
DIFFERENT WAY, THEY WERE
MATURING, THEY WERE --
DIFFERENTLY THAN HER, I THINK
THAT'S WHEN SHE REALIZED THERE'S
SOMETHING DIFFERENT IN MY
RECORD, I'M NOT ABLE TO DO NOT
EVEN THE SPORTS, JUST IN
GENERAL, HOW HER -- WERE
DEVELOPING DIFFERENTLY, I THINK
THAT'S WHAT SHE REALIZED HER
DEVELOPMENT WAS DIFFERENT AT
THAT POINT, WHEN SHE UNDERSTOOD
THE -- AND ALSO UNDERSTAND THE
LONGEVITY OF HER LIFE, IS SHE
GOING TO LIVE LONGER OR
WHATEVER, SO -- WE STARTED TO
TALK TO -- FOR HER SITUATION.
>> GO AHEAD, I'M SORRY.
>> SO THEN I GOT HELP, GOT
THERAPY, BUT -- AND NOW I'M
HERE.
SO ALL GOOD.
>> ADOLESCENCE IS -- AND EVEN
OLD ADULTHOOD, YOU KNOW, IT'S A
MOMENT -- PSYCHOLOGICAL, SOCIAL
PRESSURE IN TERMS OF GROWING UP
AND WANTING TO FIT IN, WANTING
TO BE NORMAL, THAT IS A COMMON
STRUGGLE.
I THINK YOU ALL -- HOW DO YOU
ADDRESS THAT AND HOW DO YOU --
SIMPLY TRYING TO FIX IT BY
YOURSELF, THERAPY -- DOING WELL.
SO WE'LL JUST KIND OF WRAP UP.
IS THERE -- HOW DO YOU -- LIKE
NOWADAYS, SO YOU'RE WORKING,
YOU'VE BEEN A TEACHER ASSISTANT
FOR A COUPLE YEARS AND I KNOW
THAT YOU LOVE KID, AND I THINK
THAT'S SUPER.
IS THERE -- HAVING YOUR HEART
DISEASE, IS THAT -- DO YOU FEEL
LIKE IT AFFECT YOU, DO YOU THINK
ABOUT IT ON A DAILY BASIS OR
NOT?
>> HONESTLY, THERE ARE TIMES
WHERE LIKE I FEEL SO NORMAL
THAT, LIKE, I FORGET I HAVE A
SCAR, OR I FORGET THAT I HAVE A
HALF A HEART, I FELT MYSELF
NORMAL.
SO NO, TO ANSWER YOUR QUESTION
I'VE NEVER REALLY -- IT'S
JUST -- I HAVE IT, IT'S
SOMETHING I LIVED WITH ALL MY
LIFE AND I WILL CONTINUE TO LIVE
WITH, BUT NO, IT DOESN'T REALLY
AFFECT ME.
I DON'T REALLY -- UNTIL
SOMETHING, LIKE, IF YOU HAVE AN
APPOINTMENT OR SURGERY OR
WHATEVER, BUT OTHER THAN THAT,
IT BARELY COMES TO MY MIND.
>> SHE WANTS TO SAY THIS IS A
PART OF ME, AND I THINK FOR HER,
I BELIEVE THAT THAT HAS BEEN HER
SAVING GRACE.
I BELIEVE THAT HER SAYING YOU
KNOW WHAT, I'M JUST GOING TO
KEEP ON GOING EVERY DAY AND NOT
LET THIS HOLD ME BACK IN ANY
WAY.
WHICH AS PARENTS WE'VE ALWAYS
PUSHED, DO NOT ALLOW THIS TO
HOLD YOU BACK BECAUSE FOR ALL
YOU KNOW, YOU'LL BE HERE UNTIL
YOU'RE 100 YEARS OLD, YOU KNOW?
YOU KNOW HOWL TO DISCONNECT.
>> IS THERE ANYTHING YOU FEEL
LIKE YOU CAN'T DO THAT YOU WANT
TO DO?
>> NO.
>> I GO --
>> I MEAN, I'VE GONE ON
HELICOPTERS, I GREW UP -- DURING
MY 12 YEARS OF SCHOOL, I WAS
ABLE TO BE WITH MY PEERS, PLAY
BASKETBALL, PLAY SOCCER, BEING
ABLE TO BE WITH THEM BUT AT THE
SAME TIME I KNEW MY LIMITS AND
WHEN I NEED TO SIT OUT, WHEN I
NEEDED TO TAKE A BREAK.
NOBODY JUDGED ME, I TOLD ALL MY
TEACHERS LIKE HEY, THIS IS MY --
I'M ALLOWED TO DO EVERYTHING,
I'LL LET YOU KNOW WHEN I NEED TO
SIT OUT.
I DID THAT AND I NEVER HAD A
PROBLEM WITH IT.
>> SO BEFORE WE TURN OVER TO DRG
YOU WANT TO ADD TO WHAT WE'VE
BEEN TALKING ABOUT?
>> EVERYTHING GO GREAT,
EVERYTHING WILL BE FINE.
>> AND BELIEVE IN YOUR
DOCTORS --
>> AND DOCTORS, YES.
>> WE'LL TURN YOUR CAMERAS OFF
AND LET DR. HELLER SPEAK.
>> THANK YOU.
>> OKAY, THANK YOU.
>> THANK YOU VERY MUCH.
THANK YOU TO ANGELICA AND HER
MOTHER FOR JUST SHOWING PEOPLE
THE IMMEDIATE RELEVANCE OF WHAT
WE DO.
AND WHAT IT MEANS TO PATIENTS
AND TO PEOPLE TO HAVE MEDICAL
PROFESSIONALS LIKE DR. BURKLOW
WHO ARE SO VESTED IN THEIR CARE.
IT'S NOT OFTEN THAT A DOCTOR CAN
SAY I'VE KNOWN YOU FROM BEFORE
YOU WERE BORN AND STILL BE
INVOLVED WITH YOUR CARE AND
STILL HAVE A RELATION SHIM.
RELATIONSHIP.
IT'S INSPIRING AND HUMBLING.
I ALSO WANT TO THANK DR. ARIAS
AND DR. KASTNER FOR THE
INVITATION AND FOR CHRIS, FOR
PUTTING UP WITH MY EMAIL FETISH.
THE TITLE OF MY TALK IS FONTAN
ASSOCIATED LIVER DISEASE OR
DON'T GET EXTINGUISHED.
THE FONTAN PALLIATION THAT
DR. BUT C BURKLOW EXPLAINED SO .
HERE ARE MY DISCLOSURES.
TODAY WE'RE GOING TO START BY
TALKING ABOUT THE LIVER.
AND WE'RE GOING TO THINK ABOUT
LIVER DISEASE, REVIEW THE
CURRENT UNDERSTANDING OF FONTAN
ASSOCIATED LIVER DISEASE, AND
ITS UNIQUENESS, AND TO
UNDERSTAND WHY IT IS WE'D BE
INTERESTED IN IT, AND THEN TALK
ABOUT WHAT LIMITS THE STUDY OF
FALD AND BE FRUSTRATED BY THE
LACK OF UNDERSTANDING.
I HOPE WE ALL END UP VERY
FRUSTRATED AND THEN BECOME
EXCITED ABOUT THE OPPORTUNITIES
TO EXPLORE FALD AND THINK ABOUT
WHAT WE CAN DO TO CHANGE THE
FIELD.
SO LET'S TALK ABOUT THE LIVER.
WHY SHOULD YOU LOVE YOUR LIVER?
WELL, I AGREE THE HEART IS
IMPORTANT BUT THE LIVER IS THE
MOST IMPORTANT ORGAN IN YOUR
BODY, AND IF WE THINK ABOUT WHAT
IT DOES, IF IT MAKES SO MANY
COMPOUNDS, CLOTTING FACTORS, YOU
WOULDN'T BE ABLE TO HAVE SURGERY
AND HEAL IF THE LIVER DIDN'T
MAKE CLOTTING FACTORS.
IT BREAKS DOWN PRODUCTS, THINK
ABOUT FEDEX, THEY HAVE HUBS, SO
LOTS OF DIFFERENT PACKAGES COME
INTO HUBS, SAY CINCINNATI AND
THEN THEY GET SORTED AND SENT
OFF, SO EVERYTHING WE EAT,
LIPIDS, PROTEINS, AMINO ACIDS,
GLUCOSE, COMES TO THE LIVER,
GETS SORTED OUT, BROKEN DOWN,
PACKAGED, REPACKAGED AND THEN
SENT OUT.
IT STORES THINGS LIKE VITAMIN A,
VITAMIN D, REPACKAGES THINGS.
WE SPOKE ABOUT THAT.
IT CLEANS AND DETOXIFIES.
IT PROTECTS.
IT'S THE LAST BARRIER.
WHEN YOU EAT SOMETHING REALLY
BAD, AN EVIL VIRUS, BACTERIA, IT
GETS INTO THE LAST OPPORTUNITY
YOUR BODY HAS TO PREVENT IT FROM
COMING INSIDE YOU.
SO WHEN I WAS IN MEDICAL SCHOOL,
THEY SPOKE ABOUT 19 MAJOR LIVER
FUNCTIONS, NOW IT'S OVER 500.
LIVER DOES LOTS AND LOTS.
WHAT CAN GO WRONG?
THE CLASSIC THING IS
INFLAMMATION AND THEN SCARRING.
THAT'S PRETTY MUCH WHAT HAPPENS
NO MATTER WHAT YOU DO TO THE
LIVER.
TOO MUCH IRON, TOO MUCH FAT,
VIRUSES, ALCOHOL, AND WHEN THAT
HAPPENS, WHEN THAT REACHES A
CERTAIN POINT, THE LIVER
FUNCTION BECOMES IMPAIRED AND
THE PRESSURE INCREASES.
LET'S START BY TALKING ABOUT THE
INFLAMMATION.
WE OFTEN TALK ABOUT LIVER
ENZYMES AS LIVER FUNCTION TESTS
BUT THEY'RE NOT.
LT AND ST REFLECT THE MOOD THE
LIVER IS IN.
I CAN BE AT HOME SITTING ON THE
COUCH, AND I HAVE TO TAKE OUT
THE TRASH.
I CAN BE IN A FANTASTIC MOOD AND
STAY ON THE COUCH.
MY LT COULD BE NORMAL AND THE
LIVER IS DOING ALL THOSE
FUNCTIONS WE JUST SPOKE ABOUT.
OR I COULD BE -- I STAND UP AND
I USE BAD LANGUAGE, LIKE NO, AND
I DON'T WANT TO DO THIS.
AND I TAKE OUT THE TRASH.
SO THE LT CAN BE ELEVATED AND
THE LIVER CAN STILL BE
PERFORMING ITS CHORES.
AND I CANNOT EMPHASIZE THIS
ENOUGH.
PEOPLE OFTEN TALK TO US ABOUT MY
LT WENT UP, MY LIVER IS DOING
WORSE.
THAT'S NOT TRUE.
THE LIVER IS IN A WORSE MOOD AND
THE LONGER THE LIVER IS IN A BAD
MOOD, THE MORE LIKELY IT IS IT
WON'T FUNCTION BUT THE TWO ARE
NOT IMMEDIATELY CORRELATED.
SO IN CIRRHOSIS, AND WHEN THE
LIVER REACHES A POINT OF ENOUGH
SCARRING, THE LIVER STOPS DOING
ITS CHORES.
ALL THOSE THINGS WE SPOKE ABOUT,
IT STOPS DOING ITS HOMEWORK,
MAKING ITS BED, TAKING OUT THE
TRASH.
AND THAT'S A FUNCTIONAL PROBLEM.
BUT I'M GOING TO TALK A LITTLE
BIT MORE ABOUT PRESSURE.
THE LIVER HAS ITS OWN BLOOD
PRESSURE AND IF IT'S HIGH, IT'S
CALLED PORTAL HYPERTENSION, AND
THERE ARE MANY REASONS FOR THE
PRESSURE TO BECOME ELEVATED BUT
THE COMMONEST IS CIRRHOSIS
INSIDE THE LIVER.
OR SCARRING IN THE LIVER THAT'S
REACHED THE POINT WHERE IT'S NOW
IMPAIRING FUNCTION AND PRESSURE.
YOU MIGHT HAVE HEARD OF SOMEONE
CALLED MEGAN TRAINOR, SHE HAD A
SON, IT WAS ALL ABOUT THE
PRESSURE BUT SHE COULDN'T SELL
IT SO SHE CHANGED TO IT'S ALL
ABOUT THE BASS BUT IT REALLY ALL
ABOUT THE PRESSURE.
WHAT HAPPENS IS THERE'S NO
SYMPTOMS DELAYED AND IT TAKES
TIME TO DEVELOP THIS.
IN ALL OF A DISEASE, IN MOST
LIVER DISEASE, THIS IS TRUE.
CLASSIC COMPLICATIONS, SPLE
KNOWMSPLENOMEGALY, WHEN WE THINK
ABOUT WHY PEOPLE DIE WITH LIVER
DISEASE, THESE ARE THE
REASONS -- LIVER CANCER.
MAJOR REASONS OF CAUSE OF DEATH
EVEN IN CIRRHOSIS IS THE
PRESSURE.
THIS IS WHAT VARICES LOOK LIKE.
THIS IS A PICTURE OF A PATIENT
WITH FULL COLUMNS OF VARICES AND
THE BOTTOM HALF, THE VARICES ARE
BIGGER AND YOU CAN SEE IT LOOKS
LIKE SNAKES GOING DOWN.
THE ESOPHAGUS, STOMACH, RECTUM,
OTHER PARTS OF THE
GASTROINTESTINAL TRACT OR BODY,
AND THE PROBLEM IN THE ESOPHAGUS
AND SOMETIMES THE RECTUM IS THAT
THE PRESSURE GETS VERY HIGH AND
THEY BEING BREAK OFF AND BLEED
AND IN CASE YOU'RE WONDERING,
THE BLEEDING IS BAD.
IT'S NOT GOOD.
SUBOPTIMAL.
AND THIS IS HOW IT HAPPENS.
IT'S ALL ABOUT THE LIVER AND
THIS IS HOW THE VARICES OCCUR.
YOU HAVE THE GUT, AND THE
SPLEEN, AND FOR THOSE WHO DON'T
KNOW THAT'S WHAT THE SPLEEN
LOOKS LIKE.
AND THE BLOOD GOES FROM THE GUT,
AND FROM THE SPLEEN INTO THE
MOST IMPORTANT ORGAN IN THE
BODY.
IN CASE I DIDN'T SAY IT, IT IS
THE MOST IMPORTANT ORGAN IN THE
BODY, THE LIVER.
FROM THE LIVER, IT GOES BACK TO
THE HEART AND FOR THOSE WHO
DIDN'T GO TO MEDICAL SCHOOL,
THAT'S WHAT THE HEART REALLY
LOOKS LIKE.
IF YOU THINK ABOUT IT NOW, IF
THERE'S A BLOCKAGE IN THE LIVER,
IT SIMPLE PLUMBING.
THERE WILL BE BACK PRESSURE TO
THE GUT, BACK PRESSURE TO THE
SPLEEN, THE SPLE SPLEEN WILL GET
BIGGER.
PART OF THE SPLEEN'S JOB IS TO
RECYCLE PLATELETS WHICH IS WHY
THE PLATELETS DROP AS THE SPLEEN
GETS BIG.
BUT THE BLOOD HAS THIS OBSESSION
WITH GETTING BACK TO THE HEART.
SO THAT IT CAN GET OXYGENATED,
WHICH DR. BUT CLOA EXPLAINED,
AND THAT'S WHEN VARICES FORM.
THEY ARE COLLATERALS, OR THEY
ARE VESSELS THAT BY IT IS BASS S
THE LIVER SO THE BLOOD CAN
RETURN TO THE HEART BECAUSE OF
THE BLOCKAGE IN THE LIVER.
SO I'VE SAID IT'S ALMOST ALWAYS
THE LIVER BUT WHAT IF IT'S THE
HEART?
SO HERE'S THE SAME THING I JUST
SHOWED YOU AND WENT THROUGH WITH
THE MOST IMPORTANT IN THE BODY,
BUT WHAT IF THE BLOCKAGE IS
HERE?
BACK PRESSURE, THE BLOOD FLUNG
TO THE HEART, THE LIVER WILL
BECOME DAMAGED AND LARGE, BACK
PRESSURE TO THE GUT, BACK
PRESSURE TO THE SPLEEN.
NOW BECAUSE THE LIVER IS DAMAGED
IN ADDITION TO THE HEART, IT'S A
DOUBLE WHAMMY, THE BLOOD STILL
HAS TO GET BACK AROUND THE LIVER
TO THE HEART AND VARICES STILL
FORM.
SO YOU STILL HAVE PORTAL
HYPERTENSION.
AND THAT BRINGS US TO FALD, OR
FONTAN ASSOCIATED LIVER DISEASE.
YOU HAVE TO ASK WHAT'S SO
SPECIAL ABOUT IT, WHY ARE WE AT
THE NIH SPENDING TAX DOLLARS
LOOKING AT A RARE DISEASE?
FIRST OF ALL I THINK IT COMES TO
EVERY PATIENT WHO HAS IT, THEY
DESERVE THE BEST POSSIBLE CARE,
BUT THERE ARE OTHER THINGS
BIOLOGICALLY THAT ARE ALSO
IMPORTANT.
THERE'S UNIVERSAL PROGRESSION TO
ADVANCE FIBROSIS AND I'M GOING
TO TALK ABOUT THAT IN A LITTLE
BIT.
THERE'S NO INFLAMMATION, AND
REMEMBER I TOLD YOU NO MATTER
WHAT YOU DO TO THE LIVER, IT
GOES FROM INFLAMMATION TO
FIBROSIS TO CIRRHOSIS.
HERE'S AN EXAMPLE, THE ONLY
EXAMPLE IN LIVER DISEASE WHERE
YOU GO FROM DAMAGE, WHATEVER
THAT IS, WHICH WE'LL TALK ABOUT
IN A MOMENT, BUT NO CELLULAR
INFLAMMATION, THERE MIGHT BE
INFLAMMATION ON THE MOLECULAR
LEVEL, BUT CELLULAR WISE,
THERE'S NO INFLAMMATION.
AND THEN TO CIRRHOSIS.
AND THIS IS A FIELD AND THESE
ARE PATIENTS WHERE THERE'S A
DESPERATE NEED FOR UNDERSTANDING
AND I THINK THAT MAKES IT
SPECIAL.
THIS IS FROM PERHAPS ONE OF THE
BEST OPINION PIECES WRITTEN
ABOUT IT AND A LOT OF IT IS
OPINION AND REVIEWS BECAUSE
THERE'S SO LITTLE PRIMARY DATA
AND IT'S SUCH A RARE DISEASE.
IT'S NOT AS COMPLICATED AS IT
LOOKS AND I'M GOING TO MAKE A
SIMPLE POINT.
THIS IS FOR PATIENTS WITHOUT
EVIDENCE OF LIVER DISEASE AND ON
THE RIGHT-HAND SIDE, YOUR
RIGHT-HAND SIDE, EVIDENCE OF
PATIENTS WITH LIVER DISEASE.
IN THE FIRST COLUMN, THOSE
WITHOUT FIBROSIS ON LIVER BIOPSY
WHICH IS STANDARD 10 YEARS AFTER
THE FONTAN, AND LOOK, THAT'S
RARE.
YOU ALMOST NEVER SEE FIBROSIS.
WHAT ABOUT PATIENTS WITH MILD TO
MODERATE FIBROSIS, THEY SHOULD
SEE A LIVER DOCTOR, HEPATOLOGY
REFERRAL.
WHAT ABOUT PATIENTS WITH
BRIDGING VIE BRO CYST OR
CIRRHOSIS OR MORE ADVANCED
FIBROSIS, THEY SHOULD SEE
HEMATOLOGY.
PATIENTS WITH ADVANCED LIVER
DISEASE, THEY SHOULD SEE
HEPATOLOGY.
SO IN ESSENCE EVERYBODY WHO'S
HAD A FON DAN WHO'S 10 YEARS OUT
SHOULD SEE A LIVER DOCTOR.
WE DISCUSSED THIS ALREADY.
YOU GO FROM HEALTHY TO FIBROSIS
TO CIRRHOSIS TO CARCINOMA, AND
IT NORMALLY TAKES 20 TO 40
YEARS, UNLIKE HEPATITIS B,
HEPATITIS C, A LOT OF
INFLAMMATION IN THE 20 TO 40
YEARS.
WHAT ABOUT FONTAN?
GOES FROM NORMAL TO CONGESTION
TO CIRRHOSIS.
AND WHENEVER YOU SEE LOTS OF
WAYS, THIS IS FROM A REVIEW FROM
2019 BUT HASN'T CHANGED, LOOK
HOW MANY WAY THERE IS ARE TO
MONITOR THE LIVER DISEASE.
YOU'VE GOT TO KNOW THAT NONE OF
THEM WORK.
THEY'RE SUGGESTING BLOOD,
ULTRASOUND, MRI, CAT SCAN AND
BIOPSY.
THAT'S LOTS OF DIFFERENT WAYS TO
THINK ABOUT IT.
AND AGAIN, NO INFLAMMATION, AND
ALL OF THESE WAYS THAT WE'RE
TALKING ABOUT WERE VALIDATED IN
THE SETTING OF LIVER DISEASE
WHERE THERE IS INFLAMMATION.
THAT SHOULD ALREADY BE RAISING
RED FLAGS AND RINGING BELLS.
LET'S LOOK AT TRADITIONAL
MARKERS OF LIVER DISEASE.
THE FIRST FOUR THINGS IN THE BOX
TO THE THE LEFT OF YOUR SCREEN,
THOSE ARE -- MARKERS.
BELOW THAT IS MORE FUNCTIONAL
TESTS AND MELD XI, MORE GLOBAL
ASSESSMENT OF PROGNOSIS, AND THE
REASON IT EXCRETES CLOTTING
FACTORS IS BECAUSE THESE
PATIENTS ARE OFTEN ON BLOOD
THINNERS.
IF YOU LOOK, THIS IS A LARGE
SERIES, A BIG STUDY, 16 PATIENTS
WITH MILD FIBROSIS AND 22 WITH
SEVERE FIBROSIS.
IF YOU WANT TO KNOW IF ANY OF
THESE DISTINGUISHED ANYTHING,
LOOK, NONE OF THEM APPROACH
SIGNIFICANCE, NONE OF THEM
APPROACH STATISTICAL
SIGNIFICANCE, IN OTHER WORDS,
NOT ONE OF THESE TESTS INCLUDING
THE FUNCTIONAL ASSAYS COULD
DISTINGUISH PATIENTS WITH MILD
AND SEVERE FIBROSIS.
OKAY, THAT'S NOT ENCOURAGING.
WHAT ABOUT NONINVASIVE MEASURES?
I'M GOING TO SUMMARIZE.
SCORES WERE ALL VALIDATED IN
INFLAMMATORY LIVER DISEASE AND
HAVE NOT BEEN USEFUL AT ALL IN
FONTAN.
IMAGING, THE IMAGING IS A LITTLE
BIT UNIVERSALLY SCARY AND I'M
GOING TO SHOW YOU THAT, NOT
USEFUL TO SEPARATE PATIENTS OR
PROGNOSTICATE.
A BIG ADVANCE OVER THE LAST 15
YEARS IN LIVER DISEASE IS
ELASTOGRAPHY, WHICH MEASURES HOW
STIFF THE LIVER IS AND ON THE
RIGHT-HAND SIDE, YOU CAN SEE AN
EXAMPLE OF A PATIENT WHO HAD A
NORMAL OF 5.5 AND THAT BLACK
LINE, THE WHITE DOTTED LINE
UNDERNEATH IT IS A WAVE THROUGH
THE LIVER AND BELOW IT IS A
PATIENT WITH CIRRHOSIS WITH A
MUCH DIFFERENT WAVE, 19.1.
IN HEPATITIS C, OR IN HEPATITIS
B, THE SIEVENESS OF THE LIVER IS
DIRECTLY PROPORTIONAL AND
MOTIONLY PROPORTIONAL TO THE
AMOUNT OF FIBROSUS BUT IN A
CONGESTED LIVER LIKE FONTAN, THE
CONGESTION IS SO MUCH MORE
IMPORTANT THAN THE FIBROSIS THAT
THIS IS A BETTER MARKER OF
CONGESTION THAN FIBROSIS.
THAT WAS FIRST SHOWN IN 2014 BY
WU.
SO NOT HELPFUL HERE EITHER.
WHAT BR INVAS ABOUT INVASIVE ME,
LIVER BIOPSY?
LIVER BIOPSY IS RELATIVELY
SIMPLE TO DO IN A REGULAR
SETTING, AND ON A PERSONAL
LEVEL, I THINK COMPLICATION
RATES HAVE BEEN OVERSTATED AND
RISK HAS BEEN OVERSTATED FOR
MOST PATIENTS BUT IN FONTAN, THE
RISK IS A LITTLE BIT DIFFERENT.
PATIENTS HAVE TO BE SEDATED,
IT'S COMPLEX, YOU'LL SEE IN A
MOMENT HOW WE GO THROUGH IT.
IT'S NOT TRIVIAL.
THE BIOPSY IS VERY REVEALING.
I DON'T WANT YOU TO THINK ABOUT
THE NUMBERS ON THE RIGHT OF YOUR
SCREEN BUT YOU CAN SEE
INCREASING REDNESS, AND THAT
GOES FROM NORMAL TO CIRRHOTIC.
AND YOU CAN SEE THAT YOU CAN
TELL THE DIFFERENCE.
CAN YOU REALLY SEE THE PATTERN
OF CIRRHOSIS IS DIFFERENT IN
PATIENTS WITH CONGESTION BUT THE
ESSENCE IS THE SAME.
I JUST WANT TO REINFORCE SOME OF
WHAT I'VE JUST SAID BY LOOKING
AT A PATIENT, NOT ANGELICA
MILLER, A DIFFERENT PATIENT.
THIS IS THE PATIENT'S BLOOD
TESTS OVER TIME AT THE NIH AND
YOU CAN SEE THAT THE MOOD
MARKERS ARE NORMAL, NOT JUST
NORMAL BUT LOW 20s.
LOOK AT 7/9/21, REALLY LOW.
BILIRUBIN IS ELEVATED BUT THAT'S
THE ONLY THING AND THE
PATIENT -- THE GGT WHICH IS
OFTEN THOUGHT OF AS THE BEST
MARKER OF CONGESTION, NORMAL IS
175 175 WHICH IS NORMAL, ALBUMI,
REMEMBER I SHOWED YOU HOW THE
SPLEEN GETS BIG, MO PLATELETS
ARE RECYCLED, NOT THE CASE HERE,
AND HIS ALBUMEN IS VERY NORMAL
AT 5.
THIS IS LIVER BIOPSY IN 2017.
AND HE CIRRHOSIS.
THANK DR. KLEINER FOR THIS
SLIDE.
AND IF YOU LOOK AT HIS UPPER
ENDOSCOPY, HE HAS VARICES.
HERE'S HIS IMAGING, MRI, AND YOU
CAN SEE THE LIVER LOOKS VEGGIE
GRAPHIC, IT'S BROKEN UP, THERE'S
LOTS OF THICK FIBROUS BANDS
RUNNING ALONG THE PORTAL TRACTS,
AND PARTICULARLY IN THE RIGHT
LOBE WHICH IS TO THE LEFT OF
YOUR SCREEN, IT LOOKS VERY
FRAGMENTED AND IF WE GIVE
CONTRAST, THIS IS AN ARTERIAL
PHASE, YOU CAN SEE THAT RIGHT
LOBE LOOKS EVEN WORSE.
AND THE LEFT LOBE IS SMALL AND
NOT QUITE NORMAL EITHER.
THIS PATIENT IS DOING WELL,
WORKS EVERY DAY, HAS CHILDREN,
IS MARRIED, GOES ABOUT HIS
REGULAR LIFE AND THE SAME WAY
THAT YOU HEARD FROM ANGELICA,
HE'S LIVING HIS LIFE, BUT WITH
CIRRHOSIS NOW FOR YEARS, I
SHOWED YOU THE BIOPSY FROM 2017.
HE'S DOING THE SAME TODAY.
THIS IS TAKEN FROM THAT PAPER I
REFERRED TO INITIALLY AND I WANT
TO READ A QUOTE NOT TO PUT THE
LIVER BIEBS IN CONTEXT.
SEVERE FIBROSIS ON A LIVER
BIOPSY MAY NOT IN AND OF ITSELF
INDICATE THE NEED OF LIVER
TRANSPLANT AND I CREASED RISK OF
LIVER RELATED MORTALITY.
SO WAIT.
WE'VE GOT TO BIOPSY THE PATIENT
AND IT DOESN'T REALLY TELL US
WHAT'S GOING TO HAPPEN?
SO IT'S NOT JUST THE BLOOD TESTS
AND THE NONINVASIVE IMAGING AND
THE SCORES.
THE LIVER BIOPSY ITSELF IS NOT
PREDICTIVE, AS I JUST SHOWED
YOU.
BUT THEN THEY STILL GO ON TO SAY
PATIENTS WITH CLINICAL SIGNS AND
SYMPTOMS WITH CHRONIC LIVER
DISEASE SHOULD UNDERGO BIOPSY AT
10 YEARS POST FONTAN AS
VIRTUALLY ALL PATIENTS HAVE BEEN
REPORT TODAY HAVE SOME EVIDENCE
OF FIBROSIS AND THESE DATA WILL
FURTHER DIRECT CLINICAL
MANAGEMENT.
SO DIFFICULT TO PUT IT TOGETHER
EVEN IN THE SAME PAPER.
FOR ME, IT MEANS HEPATOLOGY
REFERRAL FOR CLOSE FOLLOW-UP.
THAT'S HOW IT CHANGES CLINICAL
MANAGEMENT.
I WANT TO HIGHLIGHT ONE STUDY
BECAUSE THIS REALLY -- THERE ARE
OTHER STUDIES THAT SHOW THE SAME
THING BUT THIS REALLY PUTS IT
INTO CON TECH.
THIS ICONTEXT.THIS IS FROM THE L
AMERICAN HEART ASSOCIATION?
2023 AND THIS IS THE WHOLE DATA
SECTION LOOKING AT ALL PATIENTS.
512 FONTAN PATIENTS.
IN THE REGISTRY.
10,232 WITH VEN TRICK COLLAR
SEPTAL DEFECT WHICH IS A
DIFFERENT CONGENITAL HEART
CONDITION.
SEVERE FONTAN ASSOCIATED LIVER
DISEASE IN THE FONTAN PATIENTS.
WAS 12% AT 10 YEARS AND 52% AT
35 YEARS.
SEVERE LIVER COMPLICATIONS IN
THE VST WAS .5 AND .275
RESPECTIVELY AT 10 AND 35 YEARS.
SO FONTAN, VERY DIFFERENT, AND
THE RISK OF FONTAN ASSOCIATED
LIVER DISEASE SEVERE FONTAN
ASSOCIATED LIVER DISEASE AT 12%
AT 10 YEARS IS HIGH.
AND AT FIVE YEARS, THE
CUMULATIVE RISK OF DEATH WAS
12.6% IN SEVERE FONTAN
ASSOCIATED LIVER DISEASE VERSUS
3.7% IN FONTAN PATIENTS WITHOUT
FALD, A MORE THAN THREE FOLD
INCREASE IN MORTALITY JUST DUE
TO THE LIVER DISEASE.
SO THE LIVER DISEASE MATTERS,
THE LIVER DISEASE INCREASES THE
RISK OF DEATH FIVE YEARS OUT BY
THREE FOLD.
AND THE RISK OF FONTAN
ASSOCIATED LIVER DISEASE IS TIME
DEPENDENT AND CAN REACH 50% BY
35 YEARS.
JUST TO TALK A LITTLE ABOUT
MANAGEMENT, NOT BECAUSE I REALLY
WANT TO GO THROUGH IT BUT JUST
TO SHOW YOU THAT IT'S COMPLEX,
AND IN ITSELF SIGNIFICANT, TWO
OPTIONS WITH A FAILING FONTAN
AND FONTAN ASSOCIATED LIVER
DISEASE.
HEART TRANSPLANT ALONE IF YOU
LOOK IN THE UPPER RIGHT, AND
THEY CAN REGRESS FIBROSIS AND
THIS IS ONE OF THE MOST EXCITING
THINGS ABOUT LIVER DISEASE.
IS THAT FIBROSIS CAN REGRESS AND
EVEN CIRRHOSIS CAN REGRESS.
OR PATIENTS CAN STILL CONTINUE
TO CIRRHOSIS OR DECOMPENSATE
EVEN WITH A NEW HEART AND EVEN
WITHOUT PROGRESSION THEY CAN
DEVELOP H HEPATITIS CARCINOMA.
THIS IS SORT OF REALLY TAKING
OFF NOW WHERE THE LIVER PROTECTS
THE HEART, THERE'S FAR LESS
REJECTION AND THAT'S BECAUSE THE
LIVER -- ONE OF THE LIVER'S
MAJOR FUNCTIONS WHICH I DIDN'T
TALK ABOUT IS THAT IT'S IMMUNE
CENTRAL AND IT INDUCES
TOLERANCE.
THIS IS CANCER RISK, DESCRIBED
IN TEENAGERS WITH FONTAN
ASSOCIATED LIVER DISEASE AND HOW
TO SCREEN IS COMPLETELY UNKNOWN.
MORE THAN THAT, THE GUIDELINES
IF I CAN COMMENT -- THE CRITERIA
WE USE TO ASSESS WHETHER OR NOT
SOMEONE HAS LIVER CANCER ON
IMAGING, CAT SCAN OR MRI, WAS
ALL DEVELOPED IN HEPATITIS C AND
HEPATITIS B IN INFLAMMATORY
LIVER DISEASE.
NOT RELEVANT HERE.
BUT IT'S BASED ON WHETHER
THERE'S ARTERIAL ENHANCEMENT OR
NOT AND WHETHER THERE'S WASHOUT
IN THE PORTAL VENOUS PHASE OF
THE IMAGING.
BUT REMEMBER THE LIVER GETS
NONPULSATILE FLOW, AND THE LIVER
IS CONGESTED.
SO THE WASHOUT AND ARTERIAL
PHASE DO NOT LOOK THE SAME AS IN
REGULAR CANCER.
SO THE CRITERIA DON'T APPLY
HERE, AND PATIENTS WITH FONTAN
HAVE A LOT OF BENIGN LESIONS,
LOT OF LIVER NODULES, INCREASING
COMPLEXITY, AND DIFFICULTY IN
SCREENING.
SO THIS IS FRUSTRATING, STANDARD
TESTS DON'T HELP, STANDARD TESTS
DON'T APPLY, STANDARD GUIDELINES
DON'T DIAGNOSE OR MANAGE.
NOT SO SIMPLE.
AND ANYWAY, WHY DID THIS GO ON,
WHY IS THERE PROGRESSION,
DECOMPOSITION AND CANCER, AND
WHY DOESN'T IT ALL PREDICT WHAT
IT SHOULD?
HOW SHOULD PATIENTS BE
MONITORED, WHAT SHOULD BE
MONITOR AND HOW DO WE PREDICT
WHO'S GOING TO NEED INTERVENTION
AND WHO DOESN'T?
WE CAN'T STUDY OR UNDERSTAND IF
WE CAN'T MEASURE OR EVEN KNOW
WHAT TO MEASURE.
IT'S VERY TRU FRUSTRATING.
I HOPE YOU FEEL MY FRUSTRATION.
SO MUCH CONFUSION.
SO IN TRUE NIH FASHION, WHEN
THERE'S CONFUSION AND WHEN
THERE'S CONSTERNATION, WE GO
BACK TO THE BASIC.
WE WRITE A PROTOCOL.
WE SAY WHAT IS IT THAT WE KNOW,
WHAT DO WE KNOW TO BE TRUE, AND
HOW CAN WE BUILD ON THAT?
SO THIS IS WHAT WE KNOW TO BE
TRUE.
IT'S A DIFFERENT WAY OF SHOWING
THE CIRCULATION.
HERE IS THE HEART, I HOPE YOU
CAN SEE THE MOUSE, THERE'S FLOW
FROM THE HEART TO THE LIVER AND
THE GUT, AND WHAT I WANT TO
EMPHASIZE IS THAT THERE'S A
CAPILLARY BED IN THE GUT WHICH
REMOVES MOST OF THE OXYGEN, THE
PORTAL BLOOD FLOWS TO THE HEART.
THERE'S ANOTHER CAPILLARY BED IN
THE SINUS -- WHICH I'M GOING TO
SHOW YOU AND THEN THE BLOOD
FLOWS PA PASSIVELY TO THE LUNGS
WHERE THE BLOOD GETS OXYGENATED
AND THEN GOES BACK TO THE HEART.
SO THREE CAPILLARY BEDS WITH
PASSIVE FLOW.
IF WE TAKE THE LIVER AND THE
SINUSOIDS AND BREAK THAT DOWN,
IF YOU FOCUS ON THE RIGHT, IN
THE BLUE HERE IS A VEIN, AND IN
THE RED IS THE ARTERY, AND THESE
MIX IN THE SINUSOIDS AND THE
PLATES ARE ILLUSTRATED HERE AND
FLOW BACK TO THE CENTRAL VEIN.
HERE'S A HISTOLOGICAL PICTURE OF
THAT.
ON THE RIGHT HERE, THERE'S A
SMALL BRANCH OF THE HEPATIC
ARTERY, A LARGE CENTRAL WHICH IS
TYPICAL PORTAL VEIN AND NEXT TO
THAT, A BILE DUCT.
ONE MORE LEVEL IF WE LOOK A
LITTLE BIT DEEPER IN A DIFFERENT
FORMAT, HERE'S THE PORTAL VEIN
ON THE LEFT WITH THE HEPATIC
ARTERIOLE AND THE BLOOD FLOWING
THROUGH THE SINUSOID TO THE
TERMINAL HEPATIC VEINS, AND THE
SPACE BETWEEN THE ENDOTHELIUM
AND THE -- IS THE SPACE OF THIS,
AND THIS IS FILLED WITH FLUID,
AND AS THIS PULSATILE FLOAL IN
THE -- IN THIS SINUSOID, THERE'S
COUNTERFLOW AND REVERSE FLOW IN
THE SPACE OF THIS HERE WHICH
BECOMES THE LYMPHATICS AND FLOWS
INTO THE SPACE OF -- WHICH
SURROUNDS THE PORTAL VEIN AND
THE ARTERY HERE.
SO AS THE PULSATILE FLOW COMES
IN, THE COUNTERFLOW IN THE SPACE
OF THIS OCCURS AND FORMS
LYMPHATIC FLOW OUTSIDE OF THE
LIVER WHICH GOES DOWN TO THE
PORTAL TRACTS TO THE PORTAL
HEPATIS, AND 70% OF THE
INTRAABDOMINAL LISM ACTUALLY
COMES FROM THE LIVER.
AS THE LIVER FIBROSES, THIS IS
ALL ALTERED AND MADE MORE
DIFFICULT.
BUT LET'S THINK ABOUT IT.
ARE SO WHAT WE DO KNOW IS THERE
ARE MULTIPLE PROCESSES.
THE PORTAL PRESSURE ITSELF IS
HIGH, BOTH BECAUSE THERE'S
OUTFLOW PROBLEMS AND BECAUSE
THERE'S DECREASED CARDIAC OUTPUT
OR INFLOW PROBLEMS.
WHEN THE PORTAL PRESSURE GOES
ABOVE 20 WHICH IS VERY
DIFFICULT, THERE'S LOSS OF
ARTERIAL BUFFERING.
THE ARTERY CAN BUFFER AND ADAPT
TO THAT BUT IT CAN'T ONCE THE
PRESSURE EXCEEDS A CERTAIN
AMOUNT.
THERE'S HYPOXIA, THE LYMPHATICS
ARE IMPAIRED, AS THERE'S LOSS OF
PULL TILE FLOW, THERE'S CHRONIC
CONGESTION AND THERE'S SHEAR
STRESS, ALL OF WHICH DAMAGE THE
LIVER.
AND WE KNOW FROM MULTIPLE
STUDIES THAT TIME IS MORE
IMPORTANT THAN FONTAN
CIRCULATION.
WE FOLLOW ABOUT 100 PATIENTS AT
THE NIH.
THERE'S AN EXTREMELY LARGE
COHORT AND IT'S THANKS TO THE
REFERRAL CENTER -- AND WE
DECIDED TO WRITE A PROTOCOL
WHERE WE WENT BACK TO THE BASICS
AND FOCUSED ON THE FUNDAMENTALS.
IT'S WRITTEN FOR UP TO 100
PATIENTS, LIVER BIOPSY, BLOOD,
STOOL, PRESSURES, CLINICAL
PRESSURE AND TO INTEGRATE ALL OF
THIS.
THERE'S NO BENEFIT TO THE
PATIENTS.
YOUR BENEFIT.
SO THINK ABOUT SOMEONE LIKE
ANGELICA, WHO'S BEEN THROUGH SO
MANY PROCEDURES AND SO MANY --
TALK ABOUT THE MEDICAL
INDUSTRIAL COMPLEX AND SHE
VOLUNTEERS TO COME IN, TAKE RISK
TO CONTRIBUTE TO A STUDY LIKE
THIS WITHOUT ANY BENEFIT TO HER,
SO WE CAN UNDERSTAND THE DISEASE
BETTER.
PRIMARY END POINTS ARE
IDENTIFICATION OF NOVEL
BIOMARKERS.
WE EXPLAINED HER DIFFICULTY TO
MEASURE THINGS SO WE WANT TO BE
ABLE TO MEASURE THE DISEASE AND
LOOK AT THINGS WITH DISEASE
PROGRESSION AND WE WANT TO
UNDERSTAND BITOLOGY.
BECAUSE IF WE CAN UNDERSTAND THE
BIOLOGY, WE CAN DEVELOP
THERAPEUTIC INTERVENTIONS.
SO AS A SIDE, WHY DO WE SCAR?
IT'S NOT AS SIMPLE AS
INFLAMMATION.
THE IMPLICATIONS BEYOND THE
LIVER.
THAT'S JUST TO SHOW YOU AN
EXAMPLE OF HOW LOOKING AT A VERY
RARE DISEASE, UNDERSTANDING RARE
BIOLOGY MIGHT HAVE IMPLICATIONS
BEYOND THAT.
AND I'LL POINT OUT THAT IT TAKES
LOVE.
YOU HAVE TO LOVE WHAT YOU DO.
IT TAKES CURIOSITY, FOCUS, AND
SO MANY PEOPLE AND PATIENTS,
PATIENTS ARE WILLING TO
VOLUNTEER AND DEDICATE THEIR
TIME.
ON THE LEFT-HAND SIDE, PREVIOUS
JUST FELLOWS HAVE BEEN INVOLVED
IN THE PROTOCOL, NURSES.
THE CHILDREN'S TEAM IN GREEN,
THE HOPKINS TEAM AND THE FAIRFAX
TEAM.
AT THE NIH, NOT POSSIBLE TO DO
ANY OF THIS WITHOUT DR. TOM
BURKLOW AND PREVIOUSLY DR. DOUG
ROSEN.
INCREDIBLE PARTNERS.
DR. ELLIOTT LEVY, A HIGHLY
SKILLED TALENTED INTERVENTIONAL
RADIOLOGIST WHO DOES THE
PROCEDURE.
DR. JULIE LEBOSKY WHO GIVES
SUPERB ANESTHESIA AND MAKES SURE
THE PATIENTS ARE SAFE, THE
ENTIRE TEAM.
AND BECAUSE IT'S COMPLEX, WE
HAVE REGULAR MEETINGS WITH THE
REFERRING TEAMS AND THIS IS WHEN
WE WERE ALLOWED TO DO ZOOM, THIS
WAS A ZOOM MEETING WITH THE
REFERRING TEAM.
DR. JOHN IS HERE SECOND FROM THE
BOTTOM.
AND THIS IS A STANDARD SLIDE
THAT WE MAKE WITH ALL THE DATA
FROM THE PATIENT, WHERE WE
PRESENT THAT DATA TO THE
REFERRING TEAM AND WE DISCUSS
MANAGEMENT AND MANAGEMENT
CHANGES, AND WE DO THIS
REGULARLY, WITH ALL OF THE
REFERRAL TEAMS TO KEEP THEM IN
THE LOOP AND MAKE SURE THAT
PATIENTS ARE GETTING THE BEST
MULTI-DISCIPLINARY CARE.
THIS IS THE CURRENT TEAM.
I WANT TO START WITH THE
RESEARCH NURSES.
IN THE CENTER IS CURRENTLY THE
RESEARCH NURSE RUNNING THE PRO
KOL.
BUT ALL OF THE NURSES.
THE GI FELLOWS WHO DO THE
ENDOSCOPY, THE LIVER FELLOWS AND
THE PEOPLE IN MY WORK GROUP, IN
THE LAB WHO ARE PERFORMING
INCREDIBLE THINGS, 3D ELECTRON
MICROSCOPY, LEK CON MICROSCOPY,
SAMPLES OBTAINED AND HERE IN
FRONT IS THE PERSON SPEARHEADING
THIS IN THE LAB.
AND HERE IN THE FRONT AS WELL IN
THE RED TOP.
WITH THAT, I'LL STOP AND THANK
YOU ALL FOR YOUR ATTENTION AND I
HOPE THIS WAS ENLIGHTENING, AND
AGAIN, THANK YOU TO ALL,
EVERYONE WHO'S BEEN PART OF THE
STUDY IN ANY WAY.
>> WELL, THANK YOU BOTH FOR
REALLY EXCITING INFORMATION,
EXCITEMENT, AND MOST
IMPORTANTLY, HOW THE GROUP'S
HIHYPOTHESIS IS ILLUSTRATED BY
TODAY'S BRIDGING EXPERIMENT.
PROBLEMS WORTHY OF ATTACK PROVE
THEIR WORTH BY STRIKING BACK,
BUT CREATING IMPORTANT ISSUES AS
THEO POINTS OUT, THAT EVEN WHERE
THE WEAR DISEASE BECOMES THE
STIMULUS FOR UNDERSTANDING
MECHANISMS THAT OCCUR IN OTHER
FORMS OF LIVER DISEASE THAT ARE
FAR MORE COMMON.
NOW WE HAVE A SERIES OF
QUESTIONS, AND, WELL, LET'S SEE,
HERE'S ONE THAT JUST CAME IN.
ARE CONGENITAL HEART DISEASE
PATIENTS SUITABLE AND ELIGIBLE
FOR LIVER TRANSPLANTS, AND IF
SO, WHAT PRIORITY LEVELS ARE
THEY GIVEN, AND ARE THERE KIND
OF SPECIFIC LIMITS AT WHICH A
TRANSPLANT IS DEEMED NECESSARY?
SO PERHAPS THEO YOU WANT TO
ANSWER THAT ONE.
>> I'LL FIRST REFER SPECIFICALLY
TO FONTAN ASSOCIATED LIVER
DISEASE.
PEOPLE HAVE DONE LIVER
TRANSPLANTS BUT UNLESS YOU FIX
THE HEART, THE SAME THING
HAPPENS AGAIN.
AND IN THE MORE IMMEDIATE SENSE,
IT'S VERY DIFFICULT TO GET
PATIENTS WITH A FAILING FONTAN
OR SUBOPTIMAL CARDIAC FUNCTION
THROUGH A LIVE TRANSPLANT.
SO PEOPLE HAVE NOT BEEN DOING
THAT.
THE TREND MORE RECENTLY -- I
SPOKE ABOUT THE MORE LOCAL
WORKING GROUP WE HAVE, HE BUT WE
FOMPLFORMED A NATIONAL WORKING P
AS WELL WHERE WE DISCUSS CASES
AND LOOK AT PATIENTS WITH AN EYE
TO DOING BOTH.
THE SAME CRITERIA WOULD BE
APPLIED WITH THE MELD CRITERIA.
>> SO HERE'S ANOTHER QUESTION.
IF THE CONVENTIONAL SO CALLED
LIVER FUNCTION TEST, WHICH YOU
ELEGANTLY CATEGORIZED AND SORT
OF PUT THEM IN THEIR PROPER
POSITION, IF THEY ARE INADEQUATE
FOR DIAGNOSING FONTAN RELATED
FIBROSIS, WHAT IN YOUR PROTOCOL
SEEKS TO FIND POTENTIAL OTHER
MARKERS?
I GUESS THIS GETS TO THE BASIC
NATURE OF HOW THE FIBROBLASTS
BECOME ACTIVATED, OR IS THAT
PART OF YOUR PROTOCOL?
>> YES.
WE'RE DOING A NUMBER OF -- WE'RE
LOOKING AT THE -- WE INTEND TO
LOOK AT THE TRANSCRIPTOME, WE
INTEND TO LOOK AT THE
TRANSCRIPTIONAL SIGNATURES
ACROSS THE LIVER.
WE INTEND TO LOOK AT A LOT OF
DIFFERENT MARKERS, BHOT BOTH IE
BLOOD AND THE LIVER AND WE'RE
ALSO COLLECTING THE STOOL
BECAUSE WE THINK THE CONGESTION.
GUT, PROTEIN ENTEROPATHY,
PERHAPS EXTREME DAMAGE TO THE
GUT, THAT THERE'S A SPECTRUM
BEFORE THAT.
SO WE WANT TO LOOK AND INTEGRATE
THAT AS WELL AND SEE IF WE CAN'T
FIND PREDICTORS OF DISEASE
PROGRESSION.
>> HERE'S ANOTHER QUESTION.
ISN'T THERE -- ARE THERE ANY
ANIMAL MODELS OF THE KIND OF
HEART DISEASE I GUESS MODELS
PRODUCE SURGICALLY RATHER THAN
CONGENITALLY OR MAYBE
CONGENITALLY.
ARE THERE ANY ANIMAL MODELS THAT
COULD PLAY A ROLE IN TRYING TO
ELUCIDATE ANSWERS TO SOME OF THE
QUESTIONS YOU ASK?
>> WELL, AS FAR AS AN MA MODELS
FOR HEART DISEASE, THERE ARE
VERY FEW.
AS YOU POINT OUT, IT WOULD BE --
THAT ARE CREATED TAKING NORMAL
HEARTS AND TRYING TO REPLICATE
HEART DISEASE TO LOOK AT THINGS
SUCH AS -- I DON'T KNOW, MAYBE
THEO, YOU'RE AWARE ABOUT THAT.
>> SO HERE'S A PROVOCATIVE
QUESTION.
ARE THE RESPONSES OF THE CARDIAC
MYOCARDIUM A CONSEQUENCE OF
HYPOXIA OR IS THIS STRICTLY AN
EMBRYOLOGICALLY DRIVEN DEFECTS
EMBRYOLOGICALLY DRIVEN, IS THERE
A SECONDARY ROLE FOR HYPOXIA?
>> THE SHORT ANSWER IS YES.
WE STILL DON'T HAVE A
FUNDAMENTAL UNDERSTANDING OF
WHAT CAUSES MANY CONGENITAL
HEART DISEASES.
OBVIOUSLY IT ALL RELATES TO
GENES.
THERE HAVE BEEN VERY FEW IF ANY
SINGLE GENE MUTATIONS THAT HAVE
BEEN ASSOCIATED WITH THE TYPE OF
HEART DISEASE.
IT OFTEN -- THERE ARE
MULTIPLE -- ISSUES AND OTHER
THINGS, THERE'S SOME --
TERATOGENS HAVE BEEN ASSOCIATED
WITH THAT AS WELL, AS WELL AS --
THERE ARE CERTAIN TYPES OF DOWN
SYNDROME -- ASSOCIATED SPECIFIC
TYPE OF HEART DISEASE.
SO AS FAR AS THE FUNDAMENTAL
ETIOLOGY FOR HEART DISEASE, IT'S
OBVIOUSLY MANY, MULTIFACTORIAL
AND THEN WITH MANY ETIOLOGIES.
NOW AS FAR AS THE ISSUE OF
HYPOXIA, AND TISSUE HYPOXIA
SPECIFICALLY, THE SHORT ANSWER
IS YES, AND SO THAT IS WHY
PATIENTS WHO HAVE, SAY, CHRONIC
HYPOXIA, WE SEE EVIDENCE OF --
TYPE INJURY, WE SEE THINGS SUCH
AS EFE -- OXIDATIVE STRESSES,
YET ONCE YOU HAVE A PATIENT WHO
HAS -- TISSUE AUTHORIZATION,
THEN WE DO SEE SOME CLINICAL
EFFECTS FROM THAT AS WELL.
IT'S NOTING NOT GOING TO HAVE
ALTERATIONS IN ANATOMY BUT IT'S
GOING TO HAVE DIRECT IMPACT ON
FUNCTION.
>> SO HERES A -- QUITE A PR
PROVOCATIVE QUESTION.
PRESUMABLY THE FIBROSIS PROCEEDS
FROM THE CENTRAL VENOUS AREA TO
THE PORTAL AREA.
SO THIS IS A THREE-PART
QUESTION.
DOES THIS CHANGE THE ZONAL
DISTRIBUTION OF HEPATIC
METABOLIC FUNCTION, WHICH IS
TURNING OUT TO BE, I THINK MORE
AND MORE OF M INTEREST AND
IMPORTANCE, ALL THESE LIVER
CELLS IN THE SINUSOID LOOK THE
SAME BUT THEY'RE DOING VERY
DIFFERENT THINGS UNDER DIFFERENT
STIMULI, HYPOXIA BEING ONE OF
THEM.
SO IS THERE A LINKAGE IN ANY WAY
OR RESEARCH TRYING TO DETERMINE
WHERE THE FIBROSIS OCCURS FIRST,
DOES IT HAVE EFFECTS ON THE
ZONAL DISTRIBUTION AND THEREBY
FUNCTION, AND THERE'S ALSO
SOMEONE IS ASKED WHILE YOU'RE AT
IT, IF THE EFFECT IS ESSENTIALLY
BLOCKADING THE LYMPHOID SYSTEM
AND PRODUCING ENTEROPATHY, IS
THAT A SENSITIVE INDEX FOR THE
DEVELOPMENT OF FIBROSIS OR IS
THAT REALLY JUST A LEITMAN 'FESS
TAITION?
DOLATEMANIFESTATION?
>> AS I MENTIONED THE FIBROSIS
IS DIFFERENT THAN VIRAL
HEPATITIS OR SOMETHING LIKE
THAT, IT DOES START SE CENTRALL,
THAT IS CORRECT.
I DON'T KNOW ANYBODY WHO'S
STUDIED DIFFERENCES IN FUNCTION,
IN CIRRHOSIS ITSELF, WE USE A --
TO LOOK AT DISTRIBUTION AND SO
THERE MAY BE SOME SIMPLE WAYS TO
LOOK AT A SIMPLISTIC APPROACH
TO -- IN THE FONTAN LIVER, BUT I
THINK -- IF WE THINK ABOUT THE
NORMAL OXYGEN TENSION IN THE
LIVER, IT'S 12%, 8% AND 3%, ZONE
THREE, HERE IT MUST BE EVEN
LOWER THAN THAT.
MUCH LOWER THAN THAT.
SO I WONDER HOW SEW ZONATION
WOULD WORK EVEN IN THE NON- -- I
THINK IT'S AN INCREDIBLY
INTERESTING QUESTION.
WE MAY BE ABLE TO LOOK AT IT IN
SOME WAYS.
LOOKING AT TRANSCRIPTION IN SITU
AND I THINK WE MAY GET SOME
ANSWERS FOR THAT.
WE'RE OBVIOUSLY INTERESTED IN
CONTINUED METABOLIC FUNCTION AND
HOW THAT'S AFFECT BID ALL THESE
DIFFERENT THINGS.
PROTEIN -- ENTEROPATHY IS I
THINK AN EXTREME, IT'S NOT JUST
AS SIMPLE AS LYMPHATICS, I THINK
IT'S ALSO CONGESTION IN THE GUT
AND BACK PRESSURE IN THE GUT.
IT'S NOT A SENSITIVE ENOUGH
MARKER TO IDENTIFY PATIENTS WITH
LIVER DISEASE, FOR SURE NOT.
>> HERE'S ANOTHER ONE.
DO WE KNOW ANYTHING ABOUT THE
SIZE OF THE HEPATIC SIGH EU SOY
DALSINUSOIDALFENESTRA, DOES IT S
FUNCTION?
>> WE DON'T KNOW, BUT WHEN WE DO
THE ELECTRON MICROSCOPY, WE
SHOULD HAVE A BETTER ANSWER TO
WHAT THEY ACTUALLY LOOK LIKE AND
IF THEY'VE CHANGED AT ALL IN
THIS SETTING.
>> TOM, WE HAVE THE INEVITABLE
PRACTICAL QUESTION THAT WHEN
SOME GREAT ADVANCE HAS TAKEN
PLACE, THAT BECOMES HIGHLY
SPECIALIZED, AND THE QUESTION
ALWAYS IS, WHO PAYS FOR IT, AND
IS THIS COVERED IN ANY FORM OF
AVAILABLE HEALTH INSURANCE, YOU
KNOW, TO THE LARGE MASS OF
PEOPLE, PARTICULARLY GIVEN THAT
SITS A RARE DISORDER?
>> SO THE QUESTION, IS IT NEW
INTERVENTIONS OR QUESTIONS ABOUT
SURGERY FOR HYPOPLASTIC --
>> THE WHOLE THING.
>> OKAY.
WELL, FOR THE MOST PART, THESE
HAVE BECOME STANDARD OF CARE, SO
GIVE A PATIENT A HYPOPLASTIC
LEFT HEART, ATRESIA,S IS
STANDARD CARE, SO PAYOR WILL
COVER FOR THE SURGERY.
IT DEPENDS ON YOUR OUT OF POCKET
EXPENSES, BUT IT'S NOT UNCOMMON
FOR FOLKS TO BE ON THE PHONE
ARGUING WITH THE INSURANCE
COMPANY, BUT IN GENERAL, IT IS A
COVERED BENEFIT.
SOMETIMES THE AREA BECOMES IF
THERE ARE NEW TECHNOLOGIES THAT
HAVE COME ON THE MARKET.
FOR EXAMPLE, I MENTIONED THE
CLOSURE DEVICE, WE KIND OF
BREEZED THROUGH THAT.
BUT THAT'S -- LIVER TO THE
CATHETER TO CLOSE UP A HOLE IN
THE HEART.
NOW THOSE THINGS, DEPENDING UPON
THE INSURANCE COMPANY, THEY MAY
OR MAY NOT BE WILLING TO COVER
THINGS THAT ARE IN PHASE THREE
TRIAL, POLICY BY POLICY, BUT
MEDICARE -- MEDICAID WILL COVER
FOR SURGERY, BUT -- AND IT'S A
GOOD QUESTION.
AND IT CAN BE VERY EXPENSIVE.
ONE OF THE COMPLICATIONS IS NOT
SIMPLY THE SURGERY ITSELF BUT
THE FOLLOW-ON CARE AS WELL.
NOW YOU ARE COVERED BY MILITARY
HEALTH, I DON'T KNOW IF YOU HAVE
ANY EXPERIENCE THAT YOU WANT TO
TALK ABOUT.
>> THE INSURANCE COMPANY --
WELL, SHE'S NOT IN THE MILITARY
ANYMORE BALLS SHE'S SHE'S OVER T
DOESN'T COVER AFTER THE AGE OF
23.
SHE FORTUNATELY -- SHE HAS --
THROUGH HER WORK, SHE HAS
INSURANCE, WHICH HAS BEEN
GRADE -- I MEAN, BEING IN THE
MILITARY OBVIOUSLY WE DON'T PAY
FOR NOTHING.
IT'S LIKE EVERYTHING IS DONE FOR
YOU, MEDICINE-WISE.
WITH HER INSURANCE, LUCKILY THEY
COVER 80% WHICH IS BETTER THAN
NOT HAVING INSURANCE, SO IN THAT
REGARDS, WE'RE BLESSED IN THAT
REGARD, YOU KNOW?
WE HAVEN'T COME ACROSS ANYTHING
THAT'S BEEN A PROBLEM OF GETTING
HELP OR CARE BASED ON -- THERE'S
A LITTLE MORE RED TAPE YOU HAVE
TO GO THROUGH, A LOT OF
REFERRALS TO GET TO WHERE YOU
NEED TO BE, BUT OVERALL, WE'VE
BEEN LUCKY, YEAH.
>> EXCUSE ME.
SORRY.
HERE YOU ARE.
THEO.
DO WE KNOW ABOUT THE
DISTRIBUTION OF STELLATE CELLS
IN THE FONTAN LIVER?
THIS PERSON SAYS THAT NORMALLY
THEY ARE MORE PROMINENT IN THE
PROXIMAL RATHER THAN THE DISTAL
SINUSOID, I DIDN'T REALIZE THAT,
BUT IS THERE A BIG SHIFT?
DO WE KNOW WHAT THE TYPE OF
COLLAGEN IS, PRESUMABLY IF IT'S
REVERSIBLE.
IT'S TYPE I COLLEGE AND IT'S NOT
CROSS LINKED.
SO WITH TIME, DOES IT BECOME
CROSS LINKED, IN WHICH CASE IT
PROBABLY WOULD NOT RESOLVE.
AFTER HEART SURGERY, FOR
EXAMPLE.
>> A LOT OF THE THINGS WE TAKE
FOR GRANTED IN LIVER DISEASE IS
NOT KNOWN IN FONTAN.
NO ONE KNOWS -- I DON'T THINK
THERE'S A SINGLE PUBLICATION
LOOKING AT STELLATE CELLS IN THE
FONTAN LIVER.
THERE IS NOT A SINGLE -- WHICH
REALLY LOOKS AT THE COLLAGEN,
TYPE OF COLLAGEN, COLLAGEN
DISTRIBUTION EXCEPT FOR THE
PATTERN OF CIRRHOSIS IN FONTAN.
SO THIS IS A FIELD THAT
DESPERATELY NEEDS STUDY AND THE
THINGS WE TAKE FOR GRANTED IN
MOST LIVER DISEASES HAVE NOT
BEEN EXPLORED AT ALL.
>> WELL, YOU'VE POINTED OUT THE
GREAT EXCITING CHALLENGE, AND I
THINK AGAIN, FOR THE PURPOSE OF
THE DEMYSTIFYING MEDICINE
HYPOTHESIS, THIS IS A BEAUTIFUL
EXAMPLE OF THE NEED FOR
EXTENSIVE BRIDGING AND
COMMUNICATION AMONGST PEOPLE WHO
VERY OFTEN LIVE IN SILOS.
WE HAVE ONE LAST QUESTION FOR
YOU, TOM, OR MAYBE THEO, AND
THAT IS, HOW DOES THE SINUSOID
HANDLE ARTERIAL BLOOD AT
120 MILLIMETERS OF MERCURY
INJECTED INTO THE SINUSOID,
WHERE MOST OF THE BLOOD FROM THE
PORTAL SYSTEM IS AT MUCH, MUCH
LOWER PRESSURE.
HOW DOES THE LIVER PREVENT THE
SINUSOID FROM EXPLODING?
>> WELL, BY THE TIME IT REACHES
THE CAPILLARY BED, IT'S GOING TO
BE A -- THE PRESSURES AT THAT
POINT WILL REACH MUCH LOWER
LEVELS.
I'M GUESSING IN THE PORTAL
SYSTEM 15 MILLIMETERS OF
MERCURY?
SO IF THAT ATTENUATION OF
PRESSURE AS IT GETS DOWNSTREAM.
>> SO THE TEXTBOOK DIAGRAMS, THE
CARTOONS ARE WRONG BECAUSE THEY
IMPLY A BRANCH OF THE HEPATIC
ARTERY, AND IN TRUTH, IT IS A
BRANCH, BUT IT'S THE CAPILLARY
BRANCH.
IS THAT THE POINT?
>> YES.
>> OKAY.
WELL, LISTEN, WE WANT TO THANK
BOTH OF YOU FOR -- YES, THEO.
>> CAN I SAY ONE THING?
THIS CAN ONLY BE DONE AT A PLACE
LIKE THE CLINICAL CENTER.
WHERE ELSE COULD I GO, COULD WE
ACCUMULATE THIS MANY PATIENTS,
FIND A WILLING PARTNER LIKE
DR. BURKLOW, AND TO LOOK AT A
DISEASE IN HUMANS, NOT IN
ANIMALS BUT IN HUMANS, AND I
THINK THIS ALSO SPEAKS TO NOT
ONLY THE HIGH BOTH HYPOTHESIS F
DEMYSTIFYING MEDICINE BUT ALSO
THE CLINICAL COMMUNITY, AND IT'S
IMPORTANT FOR ME TO SAY THANK
YOU FOR THE PEOPLE LIKE THAT
THAT HAVE REALLY MADE THIS
POSSIBLE.
>> TO GO BACK TO ANGELICA, WHAT
SHE SAID AT THE BEGINNING, IT
DOES TAKE A VILLAGE, NOT JUST
FRONT LINE PROVIDERS LIKE YOU
TRYING TO SOLVE A PLEX PROBLEM,
SO IT'S MY HONOR TO SUPPORT YOU
IN YOUR WORK AND TO BE HERE AT
THE CLINICAL CENTER.
>> ALL RIGHT.
LISTEN, I WANT TO THANK THE
PATIENT AND HER MOTHER AND BOTH
OF YOU FOR BRINGING THIS ISSUE
TO LIGHT TO A LARGE NUMBER OF
PEOPLE WHO KNEW LITTLE OR
NOTHING ABOUT IT AND I'M SURE
WILL BE HIGHLY MOTIVATED TO
THINK OF THEIR EXPERTISE AND HOW
IT MAY CONTRIBUTE TO
UNDERSTANDING SOME OF THE
IMPORTANT ISSUES RAISED FROM THE
STANDPOINT OF BASIC SCIENCE AND
OF COURSE IN RELATIONSHIP TO
IMPROVE MANAGEMENT OF THIS
DISORDER.
SO THANK YOU ALL FOR A VERY
EXCITING PRESENTATION, WHICH I'M
SURE I SPEAK ON BEHALF OF MANY
HUNDREDS OF PEOPLE WHO
APPRECIATE THIS VERY MUCH.
SO THANK YOU.
>> THANK YOU.