>> OKAY, GOOD AFTERNOON . DUE TO AN OVERSIGHT, WHICH WAS PROBABLY UNDOUBTEDLY MY FAULT, I'M RESPONSIBLE FOR IT, THERE WAS NOTHING ON THE PRINTED PROGRAMS THAT WERE DISTRIBUTED FOR NEXT TUESDAY. WELL, IT TURNS OUT THAT WAS MY MISTAKE. THE PROGRAM FOR NEXT TUESDAY IS ON DEMENTIA. PARTICULARLY DEMENTIA IN THE GENOMIC E RSM A, AND THE PEOPLE WHO ARE -- ERA, AND THE PEOPLE WHO ARE SPEAKING ARE REALLY AT THE FOREFRONT OF TRYING TO DETECT GENETIC RISK FACTORS AND ALSO PREDICT THE INTERACTION OF JE NE TIB AND ENVIRONMENTAL FACTORS. IT'S AN EXTRAORDINARILY EXCITING STORY AND THERE ARE SOME INHERITABLE DISORDERS THAT ARE AFFECTED BY THE ENVIRONMENTAL ACTIVATORS. AND THEN THE FINAL SESSION ON THE -- MICHAEL GOTTESMAN AND SHARON MILGRAM AND I ARE GOING TO HAVE A SESSION ON THE FUTURE FOR PH.D. SCIENTISTS. THIS IS REALLY AN OPEN DISCUSSION. THERE ACTUALLY IS SOME YOU NEW DATA THAT CAN BE PRESENTED, AND OF COURSE YOU'RE ALL WELCOME TO ATTEND. THE FINAL EXAM IS A NOT SO DIFFICULT MULTIPLE CHOICE THING WHICH WILL BE PUT UP ON THE WEB LATER -- NO, LATER THIS WEEK OR EARLY NEXT WEEK, AND IF YOU'VE BEEN TO AT LEAST 50% OF THE SESSIONS AND YOU GET A PASSING GRADE AND IF YOU DON'T, YOU CAN TAKE IT AGAIN, YOU'LL GET A CERTIFICATE IF YOU WISH THAT YOU'LL PARTICIPATE IN THE COURSE. SO THE LAST TWO QUESTIONS ON THE EXAM, I WILL TELL NEW ADVANCE. ONE OF THEM IS TO IDENTIFY THIS STRUCTURE. WHICH I WON'T BELABOR THE POINT BECAUSE IT'S BEEN THE INTRODUCTION FOR 19 YEARS OF THIS COURSE NOW, SO THOSE OF YOU WHO HAVE BEEN TO MANY OF THESE SESSIONS HAVE ALREADY HEARD WHY, BUT FOR THOSE THAT HAVEN'T, GIVE ME 30 SECONDS TO POINT OUT THAT THE WHOLE PURPOSE OF DEMYSTIFYING MEDICINE IS TO BRING PEOPLE WHO SPEAK A DIFFERENT SCIENTIFIC LANGUAGE TOGETHER TO LEARN AND TO BRIDGE THE ENORMOUS GAPS BETWEEN ADVANCES IN BASIC BIOLOGICAL AND ENGINEERING SCIENCES ON ONE HAND AND PATIENTS, ILLNESS, DISEASE, TREATMENT, PREVENTION ON THE OTHER. SO WE'RE ALL BRIDGE BUILDERS IN A WAY. SO THAT'S ONE QUESTION. THE SECOND QUESTION REQUIRES YOU TO WRITE A YOU FEW SENTENCES WHICH WE REAL SERIOUSLY HOPE THAT THOSE WHO TAKE THIS EXAM WILL DO, TO PARTICULARLY POINT OUT DEFICIENCIES IN WHAT WE'RE DOING, WE CAN ALL LIVE WITHOUT THE LAUDATORY THINGS, BUT WHAT WE REALLY WANT TO KNOW IS WHAT COULD WE DO BETTER AND IF YOU HAVE SPECIFIC SUGGESTIONS AS TO TOPICS AND PEOPLE WHOM YOU WOULD LIKE TO HAVE PRESENT NEXT YEAR. SO TODAY WE'RE GOING TO DISCUSS ESSENTIALLY THE NUMBER ONE KILLER OF OUR SOCIETY, AND I SUSPECT IN ALMOST ALL OF WESTERN CULTURE, AND THAT'S CORONARY HEART DISEASE. A HUGE BREAKTHROUGH TOOK PLACE GOING WAY BACK IN 1984, AND I PUT THE REFERENCE ON THE WEBSITE BECAUSE IT'S WELL WORTH LOOKING AT. DO ANY OF YOU KNOW WHERE FRAMINGHAM IS? WHERE IS FRAMINGHAM? FRAMINGHAM IS A SMALL BURR BAN TOWN, IT'S MUCH BIGGER NOW THAN IT WAS IN 1984. IT'S ABOUT 10 MILES AWAY FROM DOWNTOWN BOSTON. AND THE PUBLIC HEALTH SERVICE DECIDED AT THAT POINT TO DO AN EPIDEMIOLOGIC STUDY ON THE ENTIRE POPULATION AND FOLLOW THEM FOR YEARS AND YEARS AND YEARS, AND EVEN GENERATIONS. LOOKING NOT ONLY AT HEART DISEASE, BUT THAT WAS THE MAIN THING. AND AT THAT TIME, VERY LITTLE WAS KNOWN AS TO THINGS LIKE RISK FACTORS, THERE WAS A LOT OF CLINICAL EXPERIENCE WITH IT BUT ACTUAL FACTUAL DATA WAS HARD TO COME BY. THE RESULTS OF THE FRAMINGHAM STUDY FORMED THE BASIS OF A LOT OF MODERN CLINICAL CARDIOLOGY UNTIL THE IMPACT OF BASIC SCIENCES, AND PARTICULARLY GENOMICS NOW ARE DRAMATICALLY CHANGING THE PICTURE. AND WHAT THAT STUDY CAME UP WITH WERE SOME FACTS THAT ROUGHLY ABOUT 20% OVER THE AGE OF 60 ABOUT, SOMETHING LIKE 20% OF MEN WOULD DEVELOP CORONARY HEART DISEASE, A FEW PERCENTAGE LESS OF WOMEN, ABOUT 10% OF THEM DEVELOP STROKES, EITHER MALE OR MEE FEMALE, AND FROM THE EPIDEMIOLOGY, A WHOLE SERIES OF RISK FACTORS CAME ABOUT INCLUDING IN THE CONCENTRATION OF CHOLESTEROL AND CHOLESTEROL BINDING PROTEINS, PARTICULARLY HDL AND LDL, THE ASSOCIATION WITH TOBACCO, OBESITY, EXERCISE AND A VARIETY OF OTHER THINGS, AND THESE FORMED THE BASIS OF THERAPY, WHICH HAS PERMEATED THE FIELD AND STILL IS SORT OF ARGUE MEANTED MORE IMPORTANT THAN ANOTHER BUT NONETHELESS, IT'S ALL THERE, AND THE THERAPY IS ALSO PHARMACOLOGIC, AFFECTING LIPIDS, WHO ISN'T ON STATINS AT THIS TIME. WELL, THE FACT OF THE MA IS TER MATTER IS, AS DRAMATIC AS THAT WHOLE EPIDEMIOLOGIC STUDY WAS, AND IT PROFOUNDLY CHANGED DEATH RATES, PROLONGED SURVIVAL AND SO FORTH, IT STILL IS NOT THE ANSWER, AND IN FACT, WE'LL HEAR FROM OUR SPEAKERS THE FACT THAT A LARGE PROPORTION OF PEOPLE LIKE THESE RISK FACTORS FOR DEVELOPING CORONARY -- LACK THESE RISK FACTORS FOR DEVELOPING CORONARY HEART DISEASE, SO WHAT ELSE IS GOING ON. AND IN A WAY, TODAY'S SIGH TELL, DEMYSTIFYING MEDICINE IS WHAT ELSE IN CORONARY HEART DISEASE. SO OUR TWO SPEAKERS ARE HIGHLY EXPERIENCED WITH THIS. OUR FIRST SPEAKER, DOUGLAS ROSING, AFTER GRADUATING MEDICAL SCHOOL AND TRAINING IN MEDICINE AND IN CARDIOLOGY HERE AT THE NIH, ALSO IN BOSTON, HE CAME TO BETHESDA AND FOR A PERIOD OF ABOUT 17 YEARS, WAS A PRACTICING CARDIOLOGIST, THE CHIEF OF CARDIOLOGY AT THE SUBURBAN HOSPITAL ACROSS THE WAY. THEN REJOINED NIH, WHERE HE'S A SENIOR RESEARCH PHYSICIAN, AND HE HEADS THE CARDIAC CONSULTATION SERVICE. HIS EXPERIENCE, PUBLICATIONS, HIS INTEREST ARE REALLY PROFOUND FROM A CLINICAL PERSPECTIVE THIS IS A GREAT PLACE TO BE BECAUSE A CLINICAL PERSPECTIVE IS BALANCED OFTEN BY VERY EXCITING SORT OF BASIC RESEARCH, IF YOU WILL, AS IT'S GOING ON, AND OUR SECOND SPEAKER, MAN MANFRED BOEHM, TOOK HIS TRAINING IN GERMANY, AND WHEN HE CAME HERE, HE'S NOW THE BRANCH CHIEF OF THEIR TRANSLATIONAL VASCULAR MEDICINE BRANCH. HIS BIG INTEREST HAS BEEN IN MATCHING UP THE PRINCIPLES OF PRECISION MEDICINE, HI THROUGHPUT SEQUENCING DATA, MATCHED UP WITH PEOPLE HAVING CARDIOVASCULAR DISEASE, SEEKING SOME ANSWERS AS TO THAT LARGE POPULATION THAT IS NOT PRIMARILY ASSOCIATED WITH THE PREVIOUSLY DESCRIBED RISK FACTORS. AND IN THAT COURSE, HE STUDIED MANY MONOGENIC INHERITABLE RARE DISEASES WHICH HAVE PROVIDED IMPORTANT INSIGHTS INTO HOW THE ATHEROSCLEROTIC PROCESS OCCURS. SO WE'RE VERY GRATEFUL TO BOTH OF YOU, AND I GUESS, DOUG, YOU ARE GOING TO SPEAK FIRST? >> THANK YOU, DR. ARIAS, FOR THOSE KIND WORDS. BEFORE I BEGIN, I WOULD LIKE TO EXTEND SOME KUDOS TO YOU FOR HAVE ING PROVIDED THIS COURSE FOR 19 YEARS NOW, AS YOU JUST SAID. OF COURSE AS SOON AS I GET START, I GET PAGED. AND IN THOSE 19 YEARS, YOU'VE BEEN VERY CREATIVE, TAKING SUBJECTS AND TWISTING AND TURNING THEM IN VARIOUS WAYS AND PROVIDING VERY ENLIGHTENING ASPECTS OF MEDICINE WHICH HAS KEPT EVERYBODY INTERESTED IN ATTENDING. ALWAYS SOMETHING NEW THEY CAN EXPECT. SO TODAY, AS DR. ARIAS INDICATED, DR. BOEHM AND I ARE GOING TO TRY TO BRIDGE THE GAP BETWEEN THE CLINICAL ASPECT OF THE NUMBER ONE KILLER IN THE WESTERN WORLD, CORONARY HEART DISEASE, AND THE RESEARCH SIDE OF IT, AND THE GAPS THAT EXIST AND OUR KNOWLEDGE, TREATMENT AND DIAGNOSIS AND HOW WE TRY TO BRIDGE THOSE GAPS. SO I HAVE NO DISCLOSURES, NO FINANCIAL INTERESTS, OR NON-FDA USES FOR ANYTHING WE'RE GOING TO TALK ABOUT. OUR OBJECTIVES, US A MAY HAVE GOTTEN IN SOME HANDOUTS PRIOR TO THIS, ARE TO DISCUSS THE PATHOPHYSIOLOGY OF MYOCARD YAL IS ISCHEMIA OR ANGINA, DISCUSS THE TREATMENT OF MYOCARDIAL ISCHEMIA AND TO DESCRIBE THE GENETIC APPROACHES AND CHARACTERIZATION OF MOLECULAR MECHANISMS INVOLVED IN PREMATURE CORONARY ARTERY DISEASE BUT I'M GOING TO LEAVE THAT TO DR. BOEHM TO DESCRIBE. SO THIS IS DATA THAT WASN'T TAKEN SPECIFICALLY FROM FRAMINGHAM BUT WAS SIMILARLY OBTAINED DATA, AND IT SHOWS THE PREVALENCE OF CORONARY HEART DISEASE BY AGE AND BY SEX ACCORDING TO 20-YEAR PERIODS. SO WE START WITH THE YOUNG, 20 TO 39, AND END WITH THE OLD, 80 AND ABOVE. AND AS YOU CAN SEE, THERE'S AN ALMOST LOGARITHMIC BUT CERTAINLY EXTENSIVE PROGRESSION OF THE PREVALENCE OF THIS DISEASE STARTING WITH MALES BEING ABOUT TWICE AS FREQUENT AS FEMALES IN THE YOUNGEST GROUP, BUT THE TOTAL BEING LESS THAN 1% AND WHEN WE GET TO 80 AND ABOVE, ABOUT A THIRD OF MALES AND A QUARTER OF FEMALES HAVE CORONARY HEART DISEASE. OH SO STILL A SO STILL A VERY BIG PROBLEM IN THE YEARS THIS WAS LOOKED AT IN 2013 TO 2016. SO JUST TO GIVE YOU SOME SPECIFIC NUMBERS IN THOSE YEARS, A LITTLE OVER 18 MILLION AMERICANS HAVE CORONARY ARTERY DISEASE, WHITE MALES HAVE THEM IN GREATER FREQUECY THAN BLACK MALES, BLACK FEMALES GREATER THAN WHITE FEMALES AND THEREFORE, IF YOU ADD THE TWO TOGETHER, BLACKS AND WHITES ACTUALLY HAVE ABOUT A SIMILAR INCIDENCE OF CORONARY ARTERY DISEASE. HISPANICS SLIGHTLY LESS, ASIANS SLIGHTLY LOWER THAN THAT, AND THERE ARE ABOUT A LITTLE OVER 800,000 AMERICANS HAVE A MYOCARDIAL INFARCTION EVERY YEAR, AND ABOUT HALF A MILLION AMERICANS DIANE YOU'LLLY FROM DIE ANNUALL Y FROM CORONARY ARTERY DISEASE AND OF THOSE HALF A MILLION, .35 MILLION DIE SUDDENLY, SO SUDDEN DEATH IS THEIR MODE OF EXODUS. 350,000 INDIVIDUALS. THE ANNUAL COST FOR PROVIDING HEALTHCARE, IN THIS DISEASE AS WELL AS TIMES LOST AND LIVES LOST IS ABOUT 19 IT TI BILLION DOLLARS A YEAR, AND THIS WAS IN 1915. 2015. THE PROBLEMS, THE PATHOPHYSIOLOGY IS WHAT'S CALLED MYOCARDIAL ISCHEMIA, THE LACK OF OXYGEN SUPPLIED TO CELLS. THE CELLS SPECIFICALLY BEING THE MYOCYTES OF THE MYOCARDIUM, AND IN THE SITUATION OF ANGINA OR THE PROBLEMS OF THIS DISEASE, THE MY MYOCARDIAL OXYGEN DEMAND IS GREATER THAN THE MAY OWE CARD YAL OXYGEN SUPPLY. DEMAND IS CREATED BY THE PUMP, THE HEARTBEATING, REQUIRING ENERGY TO BEAT, AND THAT ENERGY IS SUPPLIED BY OXYGEN CARRIED BY RED CELLS AND IF THE SUPPLY CAN'T MEET THE DEMAND, WE HAVE ISCHEMIA AND WE HAVE THE CLINICAL SITUATION OF CORONARY ARTERY DISEASE. IN OTHER WORDS, MYOCARDIAL OXYGEN SUPPLY DOES NOT MEET MYOCARDIAL OXYGEN DEMAND AND WE'LL COME BACK TO THAT IN TERMS OF THE EVENTS THAT OCCUR BECAUSE OF THAT PHENOMENON AND HOW DO WE TREAT AND HOW DO WE BALANCE SUPPLY AND DEMAND. SO THIS IS JUST AN ARTIST'S RENDITION OF THIS PROBLEM. THIS IS THE HEART, THIS IS THE AORTA, THE MAIN BLOOD VESSEL COMING OUT OF THE HEART, THE BLUE VESSELS ARE THE SUPERIOR AND INFERIOR VENA CAVA, AND THE FUEL LINES THAT CARRY THE RED CELLS WITH THE OXYGEN THAT PROVIDE THE ENERGY FOR THE MYOCYTES, THE MUSCLES WHICH FORM, THEN THE ACTUAL CHAMBERS OF THE HEART AND PUMP BLOOD TO THE BODY, SUPPLYING THE NEEDS OF THE BO BODY. THE PRIMARY DISEASE THAT CAUSES A SUPPLY/DEMAND MISMATCH IS ATHEROSCLEROSIS OR BLOCKAGES IN THE CORONARY ARTERIES. IN THIS RENDITION GOING FROM LEFT TO RIGHT, YOU CAN SEE MILD STENOSIS, MODERATE STENOSIS AND SEVERE OBSTRUCTION AND THEN AT THE TOP, YOU ACTUALLY HAVE AN UNSTABLE SITUATION OF PLAQUE RUPTURE, AN UNSTABLE SITUATION IN THE MIDDLE WHERE THERE ISN'T COMPLETE RUPTURE BUT IT'S CALLED THE THIN CAPPED FIBRO ATHEROMAS, AND FINALLY YOU HAVE STABLE DISEASE. THE DIFFERENCE BETWEEN THE THREE IS THE MAKEUP OF THE NECROTIC CORE VERSUS CALCIFIED FIBROTIC AREAS AND THROMBOSIS, AND IN THE PROGRESSION FROM MILD OR MODERATE THROMBOTIC PLAQUE SITUATION TO RUPTURE, YOU HAVE A THROM WITH THROMBUS, THE FINAL EVENT THAT OCCLUDES THE ARTERY DISEASED WITH A NECROTIC CORE AS WELL AS FIBROUS TISSUE. THEN IN AN UNSTABLE PLAQUE, YOU HAVE LOTS OF NECROTIC CORE WHICH INCREASES IN SIZE AND THEN EVENTUALLY WILL BECOME PLAQUE RUPTURE AND IN YOUR STABLE PLAQUE U HAVE RELATIVELY LITTLE NECROTIC CORE, YOU HAVE MORE FIBROUS TISSUE IN CALCIUM DEPOSITS, ALTHOUGH THAT STILL CAN BE QUITE SEVERE. SO TODAY TO TRY TO ILLUSTRATE THE OCCURRENCE AND THE PROGRESSION AND THE PROBLEMS ASSOCIATED WITH THE DEVELOPMENT OF CORONARY ARTERY DISEASE, WE ACTUALLY HAVE ONE OF THE SUBJECTS PARTICIPATED IN A RESEARCH PROJECT AT THE NIH LOOKING AT THE OCCURRENCE OF THIS DISEASE IN THE 1%, IN THE RELATIVELY YOUNG PEOPLE, AND HE HAS AGREED TO PARTICIPATE TODAY IN THE DISCUSSION AND I WANT TO INTRODUCE TO YOU JUSTIN DAVIS, THE DAPPER JUSTIN DAVIS. WHY DON'T YOU STAND UP, JUSTIN. AND I'M GOING TO INTERACT WITH HIM AS WE GO THROUGH THIS DISCUSSION. SO RIGHT NOW JUSTIN IS 29, AND HE FIRST -- WHY DON'T WE LET HIM FACE THE AUDIENCE ACTUALLY. THANK YOU. SO JUSTIN IS 29 AT THE PRESENT TIME BUT IT WAS 10 YEARS AGO WHEN HE WAS IN THE U.S. ARMY THAT HE FIRST BEGAN TO EXPERIENCE CHEST DISCOMFORT AND EXERTIONAL CHEST DISCOMFORT THAT WAS PRETTY TYPICAL OF ANGINA. JUSTIN, WHY ARE DON'T YOU -- IF YOU RECALL THAT TIME, WHAT WERE THE SYMPTOMS THAT YOU EXPERIENCED AND WHAT CAME TO YOUR AIT TENSION THAT YOU AATTENTION THAT YOU SOUGHT MEDICAL HELP AND KNEW SOMETHING WAS WRONG? >> SO AS I WAS IN THE MILITARY AND I WAS GOING THROUGH MY P.T., I STARTED NOTICE ING ANGINA WITH EXERTION. SO I WOUND UP GOING TO THE MEDICAL FACILITY ON BASE. THEY DIAGNOSED ME WITH ANXIETY. STARTED GIVING ME ANXIETY MEDICATIONS. WELL, THROUGH MY DEPLOYMENT IN IRAQ, I WAS HAVING FURTHER COMPLICATIONS, AND KEPT GOING BACK TO THE MEDICA FACILITY, THEY KEPT TELLING ME IT'S OKAY, YOU'RE DOING ALL RIGHT, IT'S JUST ANXIETY. UPON RETURNING TO MY HOME STATION AND GOING BACK TO MEDICAL FACILITY AGAIN, NOT ONLY DID THEY GIVE ME ANXIETY MEDICATIONS BUT THEY GAVE ME SLEEPING MEDICATIONS AS WELL, AND FINALLY, AFTER A LONG PERIOD OF TIME OF NOT HAVING ANY SUCCESS THEY GAVE ME A MEDICAL SEPARATION AND IT WASN'T UNTIL I WAS IN COLLEGE YEARS LATER -- >> WE'RE GOING TO -- WE'LL PICK THAT UP. >> OKAY. >> SO BESIDES TELLING YOU THAT THIS WAS JUST ANXIETY, DID THEY DO ANY CARDIAC TESTING OTHER THAN ELECTROCARDIOGRAMS? >> NO. NO, THEY DIDN'T SUSPECT ANYTHING FURTHER WAS WRONG, SO THEY CEASED DOING ANY FURTHER TESTS. >> OKAY. SO WHEN HE WAS 19, HE DID HAVE A COUPLE OF CORONARY ARTERY DISEASE RISK FACTORS WHICH YOU HEARD DR. ARIAS TALK ABOUT THAT WERE DEVELOPED THROUGH THE EPIDEMIOLOGIC WORK AT FRAMINGHAM. HE WAS A SEVEN PACK A YEAR SMOKER AT THAT TIME WHICH HE DID DISCONTINUED EVENTUALLY AND WE'LL TELL YOU WHY IN 2014 AND HE ALSO TRIED A LITTLE BIT THE WHEN HE WAS OVERSEAS, FIGHTING, IN WAR SITUATIONS, I GUESS, SOME SMOKELESS TOBACCO BUT THAT WAS VERY MINIMAL. AND HIS OTHER RISK FACTOR IS SOMETHING HE HAS NO CONTROL OVER, IS THAT HE DOES HAVE A POSITIVE FAMILY HISTORY FOR PREMATURE CORONARY ARTERY DISEASE, IN THAT HIS FATHER HAD AN ANGIOPLASTY AT THE AGE OF 36 AND HAD A CORONARY ARTERY BYPASS OPERATION AT THE AGE OF 49. NOW HE'S STILL ALIVE 20 YEARS AGO AND DOING WELL, BUT HE HAD THE ONSET OF CORONARY ARTERY DISEASE AT THE AGE OF 36. AS WELL, HIS FATHER'S MOTHER HAD A BYPASS OPERATION IT AT THE AGE OF 46, AND SHE LIVED ANOTHER 20 YEARS AND THEN DIED. SO FOR A WOMAN TO HAVE CLINICALLY SIGNIFICANT CORONARY ARTERY DISEASE AT 46 IS A PREMATURE CONDITION AND SITUATION AND IS A RISK FACTOR, A MAJOR RISK FACTOR. HE HAS A BROTHER WHO'S A LITTLE OLDER THAN YOU? >> CORRECT. >> AND HE WAS 27 AT THE TIME JUSTIN STARTED HAVING SYMPTOMS AND SHORTLY THEREAFTER WHEN HE WAS 27, HE UNDERWENT CORONARY ANGIOGRAPHY TO BE SURE HE WITH HIS FAMILY HISTORY DIDN'T HAVE DISEASE AND HE'S FREE OF DISEASE. HE'S LUCKY, ALIVE AND FREE OF DISEASE. SO TALKING IN GENERAL ABOUT CORONARY ARTERY DISEASE RISK FACTORS, AND AGAIN GOING BACK TO THE FACTORS THAT HAVE BEEN DEVELOPED THROUGH THE WORK AT FRAMINGHAM, WE HAVE OUR ENVIRONMENTAL RISK FACTORS, WHICH INCLUDE SMOKING, WHICH JUSTIN WAS GUILTY OF AT THAT TIME, HIGH FAT DIET DYE ETS S AND EXERCISE, WHICH HE WAS NOT GUILTY. WE HAVE HERITABLE GENETIC RISK FACTORS, LDL CHOLESTEROL, HYPERTENSION, DIABETES TYPE II, FAMILY HISTORY PREMATURE ATHEROSCLEROSIS, UNFLOIRNT WE CAN'T PICK OUR PARENTS, SO HE DID EXHIBIT THAT RISK FACTOR, LOW HDL, HIGH TRIGLYCERIDES, HOMOCYSTEINE, AND PROGERIA SYNDROMES, WHEN YOU SEE SOMEONE THAT LOOKS LIKE DR. ARIAS' AGE BUT HE'S REALLY 10, THAT'S CALLED A PROGERIA SIN SIN SYNDROMES. BEING A MALE OVER 45 AND BEING A WOMAN OVER 55 IS A MAJOR RISK FACTOR, AS WELL AS INFLAMMATION, WHICH IS AN AREA THAT'S RECEIVED A LOT OF EXCITEMENT AND INTEREST INCLUDING OUR LABORATORY RECENTLY AND CLEARLY IS A FACTOR CONTRIBUTING TO THIS PROBLEM. SO THE SIX RISK FACTORS CONSIDERED MAJOR RISK FACTORS COME FROM ALL THREE GROUPS: SMOIKING, AGE, GENERAL IT DER, LDL CHOLESTEROL, HYPERTENSION, DIABETES, AND FAMILY HISTORY OF PREMATURE ATHEROSCLEROSIS. THIS IS A QUOTE FROM EUGENE BRONWELL, FORMERLY HEAD OF THE CARDIOLOGY SECTION HERE AT NIH QUITE A NUMBER OF YEARS AGO, AND LEFT HERE WHEN I ARRIVED IN 1968 ACTUALLY, AND IN 20 YEARS AGO, HE MADE THE STATEMENT, ALTHOUGH DR. ARIAS ACTUALLY PARROTED TO SOME DEGREE JUST BEFORE: ALTHOUGH MUCH HAS BEEN LEARNED ABOUT THE CAUSES OF CORONARY HEART DISEASE, THE GAPS IN KNOWLEDGE ARE NOTEWORTHY. FOR EXAMPLE, FULLY HALF OF ALL PATIENTS WITH THIS CONDITION DO NOT HAVE ANY OF THE ESTABLISHED CORONARY ARTERY RISK FACTORS, WHICH WE JUST DESCRIBED. AND THEN A COLLEAGUE AT HARVARD, CHARLES HENNE KE. NS, ALSO AN EPIDEMIOLOGIST A YEAR LATER MADE A VERY SIMILAR STATEMENT. HE SAID IT WAS ALSO IMPORTANT TO CONSIDER THAT DATA FROM THE EU.D& KINGDOM HEART DISEASE PREVENTION PROJECT AND OTHER COHORTS, APPROXIMATELY HALF OF ALL PATIENTS SUFFERING A CORONARY HEART DISEASE EVENT HAVE NO ESTABLISHED RISK FACTORS. WE'RE GOING TO GO INTO A LITTLE BIT OF THAT THROUGH THE REST OF OUR DISCUSSIONS TODAY AND BY DR. BOEHM. SO WHAT ARE AND WERE THE UNANSWERED QUESTIONS, WHAT IS THE RISK FACTOR OR MECHANISM FOR THE DEVELOPMENT OF ATHEROTHROMBOTIC DISEASE IN PATIENTS WITHOUT NIT OF THE IDENTIFIABLE RISK FACTOR OR JUST AGE AS A RISK FACTOR? WHY TO PEOPLE WITH RISK FACTORS HAVE NO APPARENT ATHEROTHROMBOTIC DISEASE, WHY HAVE THEY ESCAPED, LIKE THE PERSON WHO SMOKED CIGARETTES FOR 60 YEARS AND DOESN'T HAVE LUNG DISEASE AND DOESN'T HAVE VASCULAR DISEASE, AND WHY DID JUSTIN, WHEN HE WAS 19 YEARS OLD, WITH ONLY REALLY TWO SOMEWHAT MILD RISK FACTORS POSSIBLY HAVE CORONARY ARTERY DISEASE, AND I SAY POSSIBLY BECAUSE THE ARMY WASN'T CONVINCED HE HAD CORONARY ARTERY DISEASE WHEN HE WAS DISCHARGED FOR MEDICAL REASONS IN 2011. SO THE HYPOTHESES ARE THAT WE REALLY DIDN'T TAKE INTO CONSIDERATION MUCH THE GENETIC BASIS OTHER THAN TO SAY FAMILY HISTORY BUT THERE'S CERTAINLY SUSCEPTIBILITY CHANGES INCLUDING THOSE SUCH AS THE MARKER ON CHROMOSOME 9P21 AMONGST MANY AND THIS WHOLE AREA OF INFLAMMATION, WHICH HAS ONLY RECENTLY STARTED TO BE DEVELOPED AND TO DETERMINE ITS ETIOLOGIC BASIS AND HOW TO TREAT DISEASE BY USING THAT AS A GOAL OF REDUCING INFLAMMATION. SO RETURNING TO JUST YOU TIN'S STORE EE JUSTIN'S STORY -- I GUESS HE DID HAVE ONE STUDY BACK IN JUNE OF 2009. HE REACHED STAVE 5, 17 METs, 5 MILES AN HO UR AT AN 18% INCLINE AND HE WAS STOPPED BECAUSE HE REACHED 85% OF HIS TARGET HEART RATE, AND I DARE SAY THAT THAT'S PROBABLY A GREATER DEGREE OF EXERCISE THAN ANYBODY IN THIS ROOM IS CAPABLE OF PRODUCING EXCEPT THOSE THAT ARE MAYBE COMPETITIVE RUNNERS, BUT THAT'S REALLY -- SO DESPITE HAVING THE CHEST PAIN IN 2009, AND THIS IS MAYBE WHAT REASSURED HIS ARMY DOCTORS, HE REALLY PERFORMED EXTREMELY WELL ON THE TREADILL. HIS BASELINE EK GWAS ABNORMAL, BUT IT DIDN'T CHANGE WITH EXERCISE. HIS LEFT VENTRICULAR CAVITY DILATED SLIGHTLY WITH EXERCISE BECAUSE THIS WAS BY NUCLEAR MEANS, THEY WERE IMAGING THE HEART, AND THAT'S A SIGN OF -- THAT'S AN ABNORMAL RESPONSE AND SHOULD HAVE SUGGESTED THAT SOMETHING WAS WRONG, BUT THAT WAS AN ISOLATED FINDING, AND WITHOUT ST SEGMENT CHANGES AND BEING ABLE TO REACH THE FIFTH STAGE, THEY MINIMIZED THE DILATATION OF THE LV CAVITY. HIS EJECTION, FRACTION, HOWEVER, WAS 48%, THAT'S 48% OF THE BLOOD NE LEFT VENTRICLE WAS BEING PUMPED WITH EACH BEAT, NORMAL IS 55 TO 65. YOU'D THINK THAT MAYBE 100% OF BLOOD SHOULD BE PUMPED OUT WITH EACH BEAT OF THE HEART BUT ONLY ABOUT 55 TO 65 IS NORMALLY PUMPED WITH EACH BEAT AND JUSTIN WAS A LITTLE LESS THAN THAT AT 48%. HE ALSO, HOWEVER, HAD A FIXED DEFECT IN THE INFERIOR OR UNDERSURFACE OF THE HEART WHICH SUGGESTED THAT DAMAGE HAD BEEN DONE. AND 19-YEAR-OLD SHOULD NOT HAVE THAT KIND OF A FINDING. HE DIDN'T HAVE ACTIVE ISCHEMIA, IN OTHER WORDS, IT DIDN'T GET WORSE WITH EXERCISE, THE DEFECT, BUT IT WAS THERE, SO SOMETHING HAD HAPPENED TO HIS HEART, WHICH WAS NOT FOUND OUT UNTIL A NUMBER OF YEARS LATER WHAT THAT WAS. SO WE TALKED ABOUT RISK FACTORS. HIS LIPID PANEL IN DECEMBER OF 2009, HIS TOTAL CHOLESTEROL LOOKED GOOD, 177, HIS LDL WAS NOT ELEVATED, 130 IS THE UPPER LIMENTSZ OF NORMAL, HE WAS 111. HIS HDL WAS A LITTLE BIT LOW. WE'D LIKE TO SEE A MAN HAVE AN HDL LEVEL ABOVE 40, HIS WAS 5 AND HIS 35, AND NOT VERY DRAMATIC LIPIDS, CERTAINLY NOT SOMETHING ANYBODY WOULD THINK OF DOING ANYTHING ABOUT AT THAT TIME. AS HE SAID, HE WAS DIAGNOSED WITH ANXIETY OR PANIC DISORDER BUT HE CONTINUED TO HAVE THE CHEST PAIN AND AS HE INDICATED HE WAS SEPARATED FROM THE ARMY AND HE SMARTLY ENROLLED IN COLLEGE AT THAT TIME. HOWEVER, IN 2014, DURING THE SUMMER, HE AWOKE WITH TERRIBLE CHEST PAIN ONE DAY, DYSPNEA AND DIE PHORESIS, PERSPIRATION. HE ATTEMPTED TO WALK TWO BLOCKS TO MORNING CLASS AND HE COLLAPSED. YOU WANT TO DESCRIBE THAT SITUATION TO US? YOU MIGHT NOT WANT TO REMEMBER IT, BUT -- >> YEAH, I WOKE UP THAT MORNING, I WAS ALREADY IN A SWEAT AND VERY SHORT OF BREATH WITH TERRIBLE CHEST PAIN. BUT AS PREVIOUSLY DIAGNOSED WITH ANXIETY, I DIDN'T THINK IT WAS ANYTHING OUT OF THE NORMAL. I'D GONE THROUGH EPISODES LIKE THIS BEFORE. SO I PROCEEDED ON TO THE SUBWAY OVER TO MY COLLEGE AND AS DOCTOR SAID, I GOT THE METRO AND WALKED THE TWO BLOCKS OVER TO MY COLLEGE AND THE ENTIRE TIME, I GOT TO SAY, THAT WAS THE LONGEST WALK I'VE EVER TAKEN IN MY ENTIRE LIFE. GET TO THE COLLEGE WHERE I SIT DOWN AND ON THIS TABLE IN FRONT OF ME, JUST FORMS A PUDDLE OF SWEAT. SO TRYING TO GET HELP, I WAS ON MY WAY TO THE FRONT DESK, AND COLLAPSED OUTSIDE THE ELEVATORS WHERE ONE OF MY INSTRUCTORS FOUND ME. >> SO HE WAS IMMEDIATELY TAKEN TO THE CARD CATHETERIZATION LABORATORY AT THE UNIVERSITY OF MINNESOTA MEDICAL CENTER AND IT WAS FOUND THE REASON HE'S BEEN HAVING CHEST PAIN FOR THE LAST FIVE YEARS IS THAT HE HAD OBSTRUCTIONS IN ALL THREE OF HIS CORONARY ARTERIES. AND WE ACTUALLY HAVE THAT ANGIOGRAM, AND I'M GOING TO GO THROUGH IT WITH YOU SLOWLY AND SHOW YOU WHAT WE'RE DESCRIBING. THIS IS A CATHETER THAT HAS COME UP FROM HIS GROIN, BENDS AROUND THE AORTA AND IS SITTING IN THE OPENING OF THE LEFT CORONARY ARTERY, WHERE THE POINTER IS. AND THIS IS CONTRAST GOING DOWN THE LEFT CORONARY ARTERY, THIS IS THE MAIN LEFT CORONARY ARTERY AND THEN THIS IS WHAT'S CALLED THE CIRCUMFLEX ON THE LEFT SIDE OF YOUR PICTURE, AND THEN THIS IS A BRANCH CALLED THE OBTUSE MARGINAL CIRCUMFLEX. THERE SHOULD BE TWO OTHER VESSELS OVER HERE NEAR WHERE THE NUMBERS ARE, AND THAT WOULD BE THE LEFT ANTERIOR DESCENDING, THE MOST IMPORTANT VESSEL THAT SUPPLIES THE ANTERIOR PART OF THE LEFT VENTRICLE, AS WELL AS IN JUSTIN, A THIRD BRANCH THAT'S CALLED THE RAMUS BRANCH, WHICH RUNS BETWEEN THE CIRCUMFLEX AND THE LEFT ANTERIOR DESCENDING. SO THE RAMUS BRANCH WAS TOTALLY OCCLUDED, YOU CAN'T EVEN SEE IT FROM THIS VIEW, AND THE LEFT ANTERIOR DESCENDING IS TOTALLY OCCLUDED JUST AFTER ITS ORIGIN AND THE CIRCUMFLEX HAS A HIGH GRADE BLOCKAGE, YOU CAN SEE IT NARROWS JUST BEFORE IT BIFURCATES INTO THE DISTAL CIRCLE PLEX AND ITS OBTUSE MARGINAL BRAN. NOW HERE'S A PICTURE OF THE RIGHT CORONARY ARTERY. AND HERE WE HAVE THE CATHETER WHICH IS ACTUALLY A LITTLE DEEP THROATED, MEANING IT'S NOT ONLY AT THE OSTIUM, IT'S ACTUALLY RIGHT INTO THE RIGHT CORONARY ARTERY, AND YOU SEE THE CONTRAST GOING DOWN THE RIGHT CORONARY ARTERY AND ALSO THERE'S DISEASE NOT QUITE AS SEVERE AS IN THE PREVIOUS ARTERY, BUT HERE IN THE MID PORTION OF THE ARTERY, AND THEN IN THE BRANCHES HERE. THE OTHER THING YOU CAN SEE HERE IS THAT THERE'S WHAT'S CALLED COLLATERAL FLOW. YOU SEE SOME LATE HAZY LACY TYPE OF LIGHT LITING UP OF THE CONTRAST, WHICH MEANS THAT'S CONTRAST GOING FROM THE RIGHT CORONARY SUPPLYING COLLATERALS TO THE LEFT ANTERIOR DESCENDING, AND IF WE BACK UP, AND SHOW YOU THE SAME PICTURES ON THE LEFT, YOU CAN SEE THIS PART OF THE RIGHT OVER HERE FILLING, SO THERE'S COLLATERALS GOING BOTH WAYS. COLLATERALS FROM THE LEFT TO THE RIGHT AND COLLATERALS FROM THE RIGHT TO THE LEFT. SO AT THIS POINT, THEY THOUGHT THE FIRST THING THEY SHOULD DO, THEY OPEN OHED UP THAT RAMUS WHICH THEY THOUGHT WATT THE ACUTE EVENT WHICH CAUSED HIM TO COLLAPSE, AND THEY THOUGHT IF THEY RESTORED FLOW TO THAT, THEY WOULD STABILIZE THE SITUATION, WHICH THEY DID SUCCESSFULLY. THEY PUT HIM ON AN INTRAAORTIC BALLOON PUMP WHICH SUPPORTS THE HEART BY UNLOADING THE HEART, IT'S A BIG BALLOON THAT'S PUT INTO THE DESCENDING AORTA INTO THE CHEST, AND IT INFLAITS DURING DIASTOLE AND DEFLATES DURING CYSTOLY AND UNLOADS THE HEART AND MAINTAINS THE BLOOD PRESSURE, AND THEN THEY TOOK HIM TO THE OPERATING ROOM AND THEY BYPASSED ALL OF THE ARTERIES WHICH WERE DISEASED. SO HE RECEIVED FOUR GRAFTS. THE LEFT INTERNAL MAMMARY ARTERY, AN ARTERY THAT RUNS DOWN THE FRONT OF THE HEART OFF THE LEFT SUBCLAVIAN ARTERY WAS AMASS TOE MOSTED TO THE LEFT ANTERIOR DESCENDING DOWN THE FRONT OF THE HEART. HE HAD A VEIN GRAFT, VEIN TAKEN FROM THE LEG, ATTACHED ON ONE END TO THE ACOR IT TA AND THE OTHER END TO THAT RAMUS BRANCH I SAID WAS OCCLUDED AND WHICH THEY HAD ACTUALLY OPENED UP, WHICH IS GOING TO CREATE A PROBLEM BECAUSE NOW YOU HAVE COMPETING FLOW. YOU YOU HAVE FLOW DOWN THE NATIVE VESSEL WHICH HAS BEEN RE-OPENED AND YOU HAVE FLOW DOWN A GRAFT. USUALLY THAT MEANS BOTH AREN'T GOING TO STAY OPEN. THEN THEY TOOK THE OTHER SIDE AND REMOVED THAT FROM ITS ORIGIN AND HOPE HOOKED ONE END UP TO THE SAPHENOUS VEIN UP TO THE FIRST DIAGONAL WHICH IS A BRANCH OF THE LEFT ANTERIO DESCEND SOG THEY'VE GOT TWO GRAFTS GOING TO THE LEFT ANTERIOR DESCENDING, ONE TO THE MAJOR VESSEL AND ONE TO THE BRANCH, THEN THEY DID A SAPHENOUS VEIN GRAFT FROM THE POST TIER YOUR DESCENDING, WHICH IS THE DISTAL PART OF THE CORONARY ARTERY. SO ALL OF HIS AREAS OBSTRUCTED SHOULD HAVE BEEN BUY BI-PASSED. HE WAS DISCHARGED ON ASPIRIN, ATORVAST ATTACHMENT IN, LISINOPRIL. DESPITE ALL OF THE ARTERIES WERE IMPROVED, HE LEFT AFTER HOSPITAL AND HOW SOON AFTER SURGERY DID YOU NOTICE YOU WERE STILL HAVING CHEST PAIN? >> IT WAS ALMOST IMMEDIATELY. AS SOON AS I WAS DISCHARGED. >> SO HE GOT NO RELIEF FROM THE OPERATION, WHICH WAS UNUSUAL. SO THIS, REMEMBER, WAS IN JULY OF 2014. SO TWO MONTHS LATER IN -- EARLY THIS SEPTEMBER, THE PAIN GOT SO BAD, HE WENT TO THE MNL DEPARTMENT THE EMERGENCY DEPARTMENT AND ANOTHER CATHETERIZATION WAS DONE THE NEXT DAY WHICH SHOWED A BLOCKAGE IN THAT GRAFT GOING TO THE RAMUS. REMEMBER WHEN I SAID THERE'S COMPETING FLOW YOU USUALLY END UP IN TROUBLE, THEY CALLED IT A SIGNIFICANT BLOCKAGE AT THE ORIGIN OF THE GRAFT TO THE RAMUS. THE GRAFT TO THE RIGHT CORONARY DIDN'T STAY OPEN, IT WAS TOTALLY OCCLUDED. THE INTERNAL MAMMARY ARTERIES STAYED PATENT. ONE, REMEMBER, IS HOOKED UP TO THE SAPHENOUS VEIN GRAFT GOING TO THE RAMUS AND THE OTHER IS HOOKED DIRECTLY TO THE LEFT ANTERIOR DESCENDING ARTERY. SO HE'S GOT PARTIAL REVASCULARIZATION BUT HE'S ALSO NOT GOT COMPLETE REVASCULARIZATION WHICH WAS UNDOUBTEDLY THE CAUSE OF HIS CONTINUING CHEST PAIN, AND IT MUST HAVE BEEN PROBLEMS THAT OCCURRED EITHER AT THE TIME OF OPERATION OR SHORTLY THEREAFTER, BECAUSE AS HE DESCRIBED HIS PAIN RECURRED AS SOON AS HE LEFT THE HOSPITAL. HIS NATIVE VESSELS NOW HAD TOTAL OCCLUSIONS IN THE MID RIGHT WHICH DIDN'T PREVIOUSLY, THE LAD WAS ALREADY TOTALLY OCCLUDED SO THAT STAYED OCCLUDED AND THE RAMUS, MILD ABNORMALITIES BUT NO SIGNIFICANT OBSTRUCTION. THEY TRIED TO DO AN ANGIOPLASTY WHICH IS A PERCUTANEOUS CORONARY INTERVENTION, PCI, TO THE NATIVE RIGHT CORONARY ARTERY BUT THEY WERE UNSUCCESSFUL. SO HERE IS THE PICTURES AFTER THE SURGERY, SO REMEMBER THIS AGAIN, HERE IS YOUR CATHETER COMING UP FROM THE GROIN INTO THE ORIGIN OF THE LEFT CORONARY ARTERY, AND THIS WAS THAT VESSEL THAT WE DIDN'T SEE BEFORE, THE RAMUS, BUT YOU CAN SEE THAT THERE'S ONLY -- YOU CAN ONLY SEE A LITTLE FLOW COMING -- WHICH WOULD BE UNOWE PACIFIED WHICH WOULD BE COMING DOWN FROM THE AORTA AND SHOULD BE FILLING THIS VESSEL BUT MOST OF THE FLOW IS NATIVE ANTIGRATED FLOW FROM THE ARTERY CAN SELF. BUT YOU CAN SEE WHERE THAT VEIN GRAFT IS LOOKED IN HERE. YOU'VE STILL GOT THE DISEASE IN THE CIRCUMFLEX AND THE OBTUSE MARGINAL, AND THEN THIS IS AN OBJECTION INTO THAT RAMUS GRAFT IN THE AREA THAT -- THEY CALLED IT 70%, I THINK IT LOOKS MORE LIKE MAYBE 50%, AND THAT'S A NICE BIG GRAFT WHICH IS FILLING THAT OBTUSE MARGIN NICELY, AND HERE'S THE BRANCH COMING OFF, IF YOU FOLLOW THIS, THIS IS THE FREE RIMA THAT HOOKED UP TO THE RAMUS AND NOW HAVE ATTACHED TO A DIAGONAL WHICH IS STILL FILLING. HERE'S AN INJECTION INTO THE LIMA GRAFT, THE LEFT INTERNAL MAMMARY ARTERY GRAFT. THE CATHETER IS NOW SITTING IN THE ORIGIN OF THE LEFT INTERNAL MAMMARY ARTERY AND WE'RE FILLING HIS LEFT ANTERIOR DESCENDING WHICH UNFORTUNATELY ISN'T A VERY BIG VESSEL AS IT USUALLY IS. THE GRAFT IS HOOKED INTO THE MIDDLE OF THE VESSEL AND WE'RE SEEING THE DISTAL VESSEL WHICH IS SMALL AND AGAIN WE'RE SEEING THE RIGHT CORONARY FILLING VIA OBJECTION NOOSE THE LEFT, WHICH TELLS US THERE'S TROUBLE IN THE RIGHT. THAT SHOULDN'T BE FILLING. IF IT THE GRAFT TO THAT HAD STAYED PATENT, YOU WOULDN'T SEE COLLATERALS GOING TO THE RIGHT. SO HERE IS THE INJECTION INTO THE ROOT OF THE AORTA TO SHOW WHERE THE RIGHT GRAFT HAD BEEN, AND YOU CAN SEE IT'S BLOCKED RIGHT AT ITS ORIGIN. SO IT HE WAS DISCHARGED ON AN ANTI-PLATELET DRUG TO TRY AND KEEP THE REMAINING GRAFTS OPEN, DISMISSED ON LONG ACTING NITRATE, DISCHARGED ON A STATIN, ON ANOTHER ANTI-PLATELET DRUG, ASPIRIN, METOPROLOL, TO TRY AND MATCH SUPPLY TO DEMAND. HE CAME BACK SHORTLY THEREAFTER SO THEY COULD TRY AGAIN TO DO A SUCCESSFUL ANGIOPLASTY TO PUT TWO DRUG ELUTING STENTS, AND THEY PUT TWO STENTS INTO THE ORIGIN AND MIDDLE OF THE RIGHT CORONARY ARTERY, BUT THEY COULDN'T GET THE THIRD STENT INTO THE DISTAL PART OF THE RIGHT. SO THEY WERE ABLE TO IMPLANT FOUR STENTS TO IMPROVE HIS BLOOD FLOW AND IMPROVE THE REVASCULARIZATION OF HIS DISEASED ARTERIES. BUT CHEST PAIN CONTINUED. SO IT WASN'T SUCCESSFUL. STILL CONTINUED TO HAVE CHEST PAIN. SO AT THAT POINT HE WAS EVALUATED BY THE CLEVELAND CLINIC, THIS WAS ONLY ABOUT FIVE MONTHS NOW AFTER HIS COLLAPSE AND HE UNDERWENT THE FOUR-VEST EL BUY BI-PASS. HE -VESSEL BYPASS. NOW HE HAS ANOTHER NUCLEAR STRESS TEST, HE DEVELOPED MILD CHEST PAIN. THERE WAS THE OLD SCAR WE HAD SEEN BEFORE RIGHT FROM THE BEGINNING IN THE DISTRIBUTION OF THE RIGHT CORONARY ARTERY BUT THEY COULDN'T SEE ANY ACTIVE ISCHEMIA, MEANT THAT ALL AREAS THAT WERE VIABLE IN THE HEART MUSCLE SHOULD HAVE BEEN RECEIVING BLOOD FLOW AND THEY WERE AT A LOSS AS TO WHY HE WAS SO LIMITED BY HIS CHEST DISCOME AT THAT POINT. AN ULTRASOUND STUDY OF HIS HEART SHOWED THAT HIS LEFT VENTRICULAR FUNCTION WAS EVEN BETTER THAN WE THOUGHT, IT DIDN'T SHOW ANY OLD SCAR, AND IT SHOWS YOU WHY THE ECHOCARDIOGRAM IS NOT QUITE AS SENSITIVE AS SOME OF OUR OTHER IMAGING DEVICES TODAY. HE HAD A FULL WORKUP INCLUDING COAGULATION STUDIES, INFLAMMATORY VASCULITIS TYPE OF STUDIES, AND ALL OF THESE STUDIES WERE NEGATIVE. THEY COULDN'T IDENTIFY A COEXISTING PROBLEM WHICH WAS CAUSING THIS NOW 24-YEAR-OLD TO HAVE SUCH SEVERE DISEASE THAT WE USUALLY SEE IN 60 AND 80-YEAR-OLDS, WITHOUT VERY MANY RISK FACTORS. THE OTHER THING THAT WAS UNUSUAL, ALTHOUGH I DIDN'T POINT IT OUT AS WE WERE GOING THROUGH THE PICTURES, IS YOU DIDN'T SEE MUCH CALCIUM IN HIS CORONARY ARTERIES. USUALLY IF YOU HAVE SUCH SEVERE DISEASE, TRIPLE VESSEL DISEASE SUCH AS THIS, YOU SEE CALCIUM IN THE WALS OF CORONARY ARTERIES. VIRTUALLY NO CALCIUM IN THE WALLS OF THE CORONARY ARTERIES WHICH MAKES US THINK MAYBE THIS ISN'T JUST GARDEN VARIETY ATHEROSCLEROSIS AND THERE'S ANOTHER PROCESS GOING ON IN HIS ARTERIES THAT ARE CAUSING OBSTRUCTION IN WHICH DR. BOEHM IS GOING TO TALK TO US MORE ABOUT IN THE NEXT DISCUSSION. NEVERTHELESS, HIS CHEST PAIN IS CONTINUED, AND THE GOAL IS TO MAKE SOMEONE FREE OF CHEST PAIN, TO GET OXYGEN SUPPLY EQUAL TO OXYGEN DEMAND, SO THERE'S NO ISCHEMIA. SO HE MOVED BACK TO LIMA, OHIO TO LIVE WITH HIS PARENTS. HE WAS HOSPITALIZED IN FEBRUARY OF 2015 FOR UNSTABLE ANGINA, HE AGAIN HAD REPEAT CATHETERIZATION, HE HAD THE SAME OBSTRUCTION OF THE MARGINAL BRANCH, STILL THE STENTS IN THE CIRCUMFLEX HADN'T FIXED THAT. HE HAD A SUBTOTAL STENOSIS OF A SEPTAL PERFORATOR BRANCH, AND HE RETURNED TO THE LABORATORY FIVE DAYS LATER FOR FURTHER UNDER VENGSES FURTHER INTERVENTIONS. HE HAD ANOTHER STENT PUT IN THE MARGINAL BRANCH WHERE THERE WAS THAT 95% OCCLUSION. AND WHAT'S THE NEXT LINE GOING TO SAY? YOU GUESSED IT. YOU WERE PAYING ATTENTION. VERY GOOD. SO HIS CHEST PAIN STILL CONTINUED UNFORTUNATELY. HE AGAIN WAS HOSPITALIZED IN APRIL AND MAY FOR CHEST PAIN, AND THEY FOUND THAT I.V. NIGH CROW GLIS RIN DID HELP NITROGLYCERIN HELPED AND HE WAS ABLE TO BE DISCHARGED WITHOUT FURTHER INTERVENTIONS. IN JUNE OF 2015, WE SAW HIM FOR THE FIRST TIME AT THE NIH. AND ONE OF THE FIRST THINGS WE DID WAS A STRESS CARDIAC MRI, AND THIS IS ANOTHER WAY OF LOOKING AT BOTH FUNCTION AND PERFUSION IMAGING USING MRI TECHNIQUES, AND THIS REPORT DIVIDES THE HEART INTO THE THREE MAJOR VESSELS. THE CIRCLE PLEX INCLUDES THAT RAMUS WHICH HE HAS, SO IT DIVIDES IT INTO THOSE THREE TERRITORIES. WE'RE GOING TO LOOK AT REST FUNCTION, STRESS FUNCTION, REST PERFUSION AND STRESS PERFUSION. YOU CAN SEE AT REST, HE HAS VERY LITTLE ABNORMALITY, JUST THAT OLD INFERIOR DAMAGE THAT HE HAD. AND THEN IF WE LOOK AT STRESS FUNCTION, IT REALLY EXTENDS A LITTLE BIT THAT INFEAR BUT MOST OF THE HEART IS FUNCTIONING NORMALLY WHEN WE LOOK AT STRESS. HOWEVER, IF YOU LOOK AT REST, WE HAVE THE ABNORMAL REST PERFUSION AGAIN IN THAT LIMITED AREA IN THE INFERIOR SURFACE, BUT YOU IF WE LOOK AT STRESS PERFUSION, YOU CAN SEE THAT MOST OF THE HEART IS STILL NOT GETTING ENOUGH BLOOD FLOW. SO THERE'S STILL A MISMATCH BETWEEN THE AREAS UNDER DEMAND, WHEN THE DEMAND INCREASES, VERSUS -- AND REST. AT REST, THE PERFUSION IS PRETTY GOOD, BUT AS SOON AS HE UNDERTAKES STRESS, WHICH IN AN MRI IS GIVING A VASODILATOR, IT SHOWS YOU THAT THERE'S AN IMBALANCEBALL ANS AGAIN THIS IS WHY HE WAS STILL HAVING CHEST PAIN, BECAUSE HE STILL WASN'T ADEQUATELY RIVAS COLLARRIZED, EVEN THOUGH THERE WERE MANY ATTEMPTS FROM GOOD OPERATORS. SO, THEN AGAIN IN AUGUST OF 2017, HE THREE MORE STENTS SINCE THE MAJOR AREA THAT WASN'T GETTING ENOUGH BLOOD FLOW WAS THE LEFT ANTERIOR DESCENDING, HE HAD THREE STENTS PLACED IN HIS LAD IN AUGUST OF 2017. SO THAT'S A YEAR AND A HALF, ALMOST TWO YEARS AGO. DID YOU GET ANY RELIEVE AFTER THAT? >> NO, SIR. >> OKAY. SO THEN HE CAME BACK TO THE NIH TWO YEARS LATER AND WE REPEATED THE SAME MRI STUDY AND YOU CAN SEE THERE'S BASICALLY REST FUNCTION IS PRETTY GOOD. WE DIDN'T DO STRESS BUT WE DIDN'T ANALYZE STRESS FUNCTION BUT REST PERFUSION AGAIN WAS PRETTY MUCH LIMITED BUT A LITTLE BIT LARGER AREA IN THE INFERIOR SURFACE WAS NOW NOT GETTING THE BLOOD FLOW AT REST AND WITH EXERCISE, IT LOOKS AS THOUGH HE REALLY IS PERFUSING MOST OF THE HEART EXCEPT THAT ONE AREA WHERE WE KNOW THERE'S PERMANENT DAMAGE. SO THIS IS MUCH IMPROVED OVER HIS 2015 STUDY AND WE WOULD HAVE EXPECTED HIS SYMPTOMS TO HAVE BEEN IMPROVED ALSO BUT THEY WEREN'T, SO WE WERE SOMEWHAT BEFUDDLED AND BEGAN LOOKING FOR OTHER CAUSES OF CHEST PAIN, WHICH WE DIDN'T FIND. OTHER CAUSES OF CHEST PAIN COULD BE CHEST WALL -- COURT CORONARY ARTERY SPASMS, AGAIN THESE ARE GI G.I. PROBLEMS AND NONE WERE PRESENT. MEDICAL MANAGEMENT OF CORONARY DISEASE IN GENERAL SHOULD INCLUDE NITRATES WHICH IMPROVE SUPPLY, BETA-BLOCKERS WHICH DECREASES DEMAND, CALCIUM CHANNEL BLOCKERS WHICH DILATE ARTERIES AND INCREASE SUPPLY, AND DECREASE DEMAND, PARTIAL P FOX INHIBITORS LIKE RANOLAZINE AFFECTING GLUCOSE METABOLISM, USING LESS OXYGEN, REDUCING DEMAND, AS WELL AS ACES AND ARBS WHICH INCREASE DEMANDS AND HAVE OTHER BENEFITS, STATINS WHICH WE KNOW HAVE MULTIPLE BENEFICIAL EFFECTS IN CORONARY ARTERY DISEASE, ANTI-PLATELET WHICH INHIBITS -- CREATES MORE OBSTRUCTION BLOCKAGES. THEN WE HAVE REVASCULARIZATION, EITHER PCI WHICH HE UNDERWENT OR CABG WHICH HE ALSO UNDERWENT. WE HAVE EXTERNAL COUNTERPULSATION WHICH MOST YOU HAVE HAVE PROBABLY NOT HEARD OF AND REFERS TO A TECHNIQUE OH WHICH INCREASES ARTERIAL BLOOD PRESSURE BECAUSE THEY HAVE CUFFS, ACTUAL BLOOD PRESSURE CUFFS AND THESE ARE PUMPED UP TO 300 300 MILLIMETERS OF MERCURY, IN A SEQUENTIAL FASHION, AND THEY UNDER50 SESSION GO SESSIONS FOR A HALF AN HOUR. JUSTIN UNDERWENT THIS THERAPY ANY BENEFIT? >> NO, NOT MUCH BENEFIT. >> WAS IT TOLERABLE? A LOT OF PEOPLE CAN'T TOLERATE THE PRESSURES OF 300 MILLIMETERS OF MERCURY ON THEIR LEGS AND PELVIS. >> IT WAS -- IT WASN'T THE MOST COMFORTABLE THERAPY IN THE WORLD. HOWEVER, IT WAS TOLERABLE, YES. >> OKAY. BENEFITS OCCUR, AND IT DOES OCCUR IN SOME PEOPLE IN SOME STUDIES; NOT TOTALLY CLEAR. IT'S PROBABLY RELATED, HOWEVER, TO IMPROVEMENTS IN STRESS INDUCED MYOCARDIAL PERFUSION, IMPROVEMENT IN LEFT VENTRICULAR DIASTOLIC FILLING, PERIPHERAL ARTERIAL FLOW MEDIATED DILATATION, IN OTHER WORDS, AFTER REDUCTION IN IMPROVEMENT AND ENDOTHELIAL FUNCTION. SO WHEN YOU'VE USED EVERYTHING UP, WHAT'S LEFT? WELL, SOME PEOPLE HAVE TRIED SPINAL CORD STIMULATION, WHICH REALLY IS NOT ADDRESSING THE PATHOPHYSIOLOGY OF THE DISEASE, BUT IS TRYING TO REDUCE THE OCCURRENCE OF PAIN, WHICH IS REALLY PALLIATION. THERE'S TRANSMYOCARDIAL REVASCULARIZATION, WHICH THE JURY IS STILL OUT AFTER MANY YEARS OF MAKING CHANNELS WITH A LASER IN THE MYOCARDIUM AND HOPING TO INITIATE AND STIMULATE REVASCULARIZATION, THE GROWTH OF NEW BLOOD VESSELS. THERE IS A CORONARY SINUS REDUCING DEVICE USED VERY UNCOMMONLY WHERE YOU NARROW THE CORONARY SINUS WHERE VENOUS BLOOD IS RETURNING, TRYING TO BUILD UP THE PRESSURE LOAFNT SIDE OF THE HEART AND IMPROVE OF THE PERFUSION PRESSURE IN THE CORONARY ARTERIES. IT ISN'T USED VERY WIDELY BECAUSE IT HASN'T SHOWN TO BE VERY SUCCESSFUL. APHERESIS HAS BEEN USED IN PEOPLE ESPECIALLY WITH CHOLESTEROL PROBLEMS WHERE THEY CAN TAKE OFF PEOPLE WITH FAMILIAL HYPERCHOLESTEROL I'M YA WHICH JUSTIN DID NOT HAVE AND THEN MULTIPLE NEW MEDICATIONS SUCH AS THOSE THAT INHIBIT FATTY ACID PRODUCTION, NIC RO. A NDIL WHICH DILATES BLOOD VESSELS, ALLOPURINOL WHICH IS SMOAS TODAY REDUCE OXYGEN USAGE, IVABRADINE, AND IF ALL THAT FAILS, HEART TRANSPLANTATION WOULD BE CONSIDERED. SO JUSTIN, RETURNING TO JUSTIN, WAS ON MOST OF THOSE MEDICATIONS. HE WAS ON AN ACE INHIBITOR, LICINOPRIL, CLO PIDOGREL, HE WAS ON A STATIN, A NITRATE, SPIRO NSM OLACTONE, A DIURETIC WHEN HIS LEGS WOULD SWELL, HE WAS ON THE ALLOPURINOL AND AN ACID SUPPRESSANT. AND STILL, HE STILL CONTINUED TO HAVE PAIN. PERHEXALINE WAS CONSIDERED. THAT HASN'T BEEN USED YET. AND HE HAS HAD AS HE DESCRIBED EXTERNAL COUNTERPULSATION. SO IMAGING STUDIES WE THEN LOOKED TO SEE IF HE HAD DISEASE IN OTHER VEST VEST ELS. WAS THIS LIMITED TO JUST THE CORONARY ARTERIES, THIS PROCESS, OR DID HE HAVE SYSTEMIC DISEASE OF HIS VESSELS? AND HE HAD A TOTAL BODY CT ANGIOGRAM UNREMARKABLE EXCEPT FOR ONE BIT OF KALS YUL IN THE WALL OF THE DESCENDING AORTA. SO PRETTY CLEAR OTHER VESSELS, RIGHT UP FROM THE CAROTIDS DOWN TO THE LOWER LEG VESSELS. HE HAD A PET CT TO SEE IF THERE WAS AN INFLAMMATORY PROCESS WE WERE MISSING BY OUR BIOMARKERS. THERE WAS NO EVIDENCE OF INCREASED PET AK ATIVITY, INCREASED RADIO KNEW CLEE RAID OWE KNEW R ADIO KNEW CLEE I'D ACTIVITY. AS OF TODAY, HE WAS RE-EVALUATED YESTERDAY AND TODAY, HIS CHEST PAIN AND TNG CONTINUES, HE DOESN'T USE TFG VERY OFTEN BECAUSE -- WHY DON'T YOU USE TNG MORE OFTEN? >> . NITROGLYCERIN UNDER YOUR TONGUE. >> IT'S NEVER REALLY DONE TOO MUCH FOR ME. SO I HAD DISCUSSIONS WITH MY CARDIOLOGIST ABOUT IT AND BASICALLY UNLESS I'M GOING INTO THE HOSPITAL ANYMORE, I DON'T -- I DON'T USE IT. >> THE ONLY THING HE SEEMS TO RESPOND TO IS I.V. NITROGLYCERIN WHEN HE GETS TO THE HOSPITAL, THEN THAT BREAKS THE CYCLE OF THE SEVERE PAIN AND HE'S ABLE TO RESUME HIS ACTIVITIES. HIS ACG IS UNCHANGED, IT'S STILL PRETTY NORMAL EXCEPT FOR THE OLD INFERIOR MY OR CARD YAL INFARCTION WHICH WAS THERE IN 2009. HIS LIPID PROFILE NOW ON THE HIGH DOSE OF ATORVASTATIN, HIS LDL IS DOWN TO 54, HIS HDL IS STILL A LITTLE LOW, BUT THOSE ARE PRETTY GOOD NUMBERS. HIS APOPROTEIN A1 WHICH IS THE 1HDL ISN'T ATTACHED TO IS IN THE NORMAL RANGE, LOW NORMAL RANGE, AND THE THE OTHER IS LOW. HIS PRO BMP, IS HE AT ANY EVIDENCE FOR CONGESTIVE HEART FAIL EU HE'S HAD NORMAL PRO BMPs AND IT REMAINS NORMAL. HIS ECHOCARDIOGRAM TODAY WAS UNCHANGED AND A STRESS CMR HE HAD YESTERDAY WAS UNCHANGED FROM THAT IN 2015. SO HE HAD A TREADMILL EXERCISE IT TEST TODAY AND HE WENT ABOUT THE SAME, HE STARTED THE TEST WITH CHEST PAIN, IT SLOWLY INCREASED, HE GOT TO THE THIRD STAGE WHICH IS 9.6 METS, REMEMBER I SAID AT THE CLEVELAND CLINIC IN 2014, HE WENT 10 METs, TERMINATED DUE TO 8 OUT OF 10 CHEST PAIN. NITROGLYCERIN WE GAVE HIM AFTER THE TEST, IT HAD VERY LITTLE BENEFIT, THE PAIN GOT BACK TO BASELINE AFTER 17 MINUTES AFTER THE END OF THE TEST, AGAIN SO NO ARRHYTHMIAS. SO 14 CATHETERIZATIONS AND 23 STENTS LATER, FROM WHICH HE OFTEN RECEIVED SOMETIMES VERY BRIEF RELIEF, HE STILL HAS CHRONIC CHEST PAIN EXACERBATE BID EXERTION AND HE STILL HAS ISCHEMIA ON HIS MRI, SAYING THAT THERE IS A REASON FOR THIS CHEST PAIN, IT ISN'T IN HIS HEAD, AND IT ISN'T BECAUSE HE'S GOT SOMETHING ELSE GOING ON. AS WE SAID, HE USES MINIMAL NITROGLYCERIN, ANATOMICAL AND FUNCTIONAL TESTING SUN CHANGED AND HE'S BEEN REFERRED FOR HEART TRANSPLANTATION. WELL, HE WAS REJECTED FOR HEART TRANSPLANTATION BECAUSE THEY FELT IN A YOUNG MAN HIS AGE, THE RISKS WERE GREATER THAN THE BENEFITS. THEY THOUGHT WOULD HE PROBABLY NOT ONLY HAVE TO HAVE ONE BUT SEVERAL HEART TRANSPLANTS WHICH WOULD BECOME MORE DIFFICULT AS IT TIME WENT ON, AND BECAUSE OF THE CONFLICTING EVIDENCE THAT WAS PRESENT, THEY WEREN'T TOTAL LEISURE THEY WERE GOING TO RELIEVE HIS PAIN. SO THEY THOUGHT CORRECTLY HE SHOULDN'T BE EXPOSED AT THIS POINT TO SUCH A DRASTIC PROCEDURE. SO WHAT ARE WE LEFT THE WITH? WE'RE LEFT WITH GOING BACK TO DR. BRONWELL AND DR. HENNEKINS DESPITE OUR DIAGNOSING AND A UNDERSTANDING OF THE PATHOPHYSIOLOGY, ESPECIALLY IN OUR TREATMENT OF ATHEROTHROMBOTIC CORONARY DISEASE, WE STILL HAVE SIGNIFICANT GAPS, AND WE'D BENEFIT BY BETTER UNDERSTANDING OF THE IMPORTANCE OF ALREADY IDENTIFIED RISK FACTORS SUCH AS INFLAMMATION, THE NITRIC OXIDE SYSTEM, GENES, HOMOCYSTEINE, HORMONES, ET CETERA, AS WELL AS UNIDENTIFIED RISK FACTORS WHICH WE'RE LOOKING FOR. DIFFERENTIATING BETWEEN A BIOMARKER AND AN ETIOLOGIC FACTOR IS IMPORTANT AND WE STILL HAVEN'T TOTALLY MADE THAT DIFFERENTIAL. NUMBER TWO, BETTER UNDERSTANDING SUBSEQUENT MORE AGGRESSIVE THERAPY FOR DIABETES, DYSLIPIDEMIA, HYPERTENSION AND SMOKING CESSATION WOULD CERTAINLY BENEFIT US SO WE'VE MADE GREAT STRIDES BUT THERE'S STILL A LOT OF PEOPLE OUT THA ARE SMOKING, STILL A LOT OF PEOPLE WITH UNTREATED HYPERTENSION AND LIPIDS THAT WE CAN'T TREAT AS WELL AS WE'VE BEEN ABLE TO TREAT JUSTIN'S. DIABETES, THERE'S LOTS OF NEW DIABETES MEDICATIONS AND WE'RE MAKING VAST ADVANCES THERE. IMPROVED VASCULAR DELIVERY SYSTEMS, DEVICES TO MAINTAIN PATENCY, WE CAN TAKE GOOD PICTURES OF JUSTIN BUT WE HAVEN'T BEEN ABLE TO DELIVER ENOUGH STENTS OR OTHER THINGS TO KEEP HIS ARTERIES OPEN. IMPROVE THE SURGICAL ACCESS, ANTICLOTTING AGENTS AND CONDUITS TO, AGAIN, IMPROVE REVASCULARIZATION. SO IN SUMMARY, WE'VE MADE PROGRESS BUT WE HAVE A LONG WAY TO GO. WE HAVEN'T DONE A GOOD JOB PROBABLY IN IDENTIFYING ALL THE ETIOLOGIES AND WE PICKED AN UNUSUAL SITUATION, THE OCCURRENCE OF PREMATURE DISEASE IN SOMEONE LIKE JUSTIN AND SOMEONE WHO PROBABLY DOESN'T HAVE GARDEN VARIETY ATHEROSCLEROSIS BUT WE DON'T HAVE TISSUE SO WE DON'T KNOW WHAT REALLY IS TAKE PLACE IN THE WALLS OF THOSE ARTERIES. AND I WOULD THEN TURN IT OVER TO DR. BOEHM AND LET HIM PICK UP AT THIS POINT AND TELL US WHAT WE'RE DOING TO TRY AND ANSWER SOME OF THOSE QUESTIONS AND ALSO TO COMPARE JUSTIN'S CASE TO ANOTHER CASE. [APPLAUSE] >> WE'LL HOLD QUESTIONS UNTIL AFTER DR. BOEHM'S TALK. >> SO JUSTIN IS A MEDICAL MYSTERY. IT WAS WHEN HE CAME, AND HE STILL HAVE. SO I DO NOT HAVE ANSWERS TO UNDERSTAND WHAT IS HAPPENING, BUT WHY DO WE STUDY CASES LIKE JUSTIN? FOR SURE, WHICH IS PART OF THE NIH MISSION TO LOOK AT CASES THAT DO NOT INTEREST PHARMA INDUSTRY AND LARGE MEDICAL CENTER, THESE WERE THE PATIENTS WITH VERY RARE DISEASE PRESENTATION. WITH YOU BUT WE ALSO DO SCIENCE HERE, AND WHY IS A CASE LIKE JUSTIN'S PARTICULARLY INTERESTING TO US? BECAUSE HE IS SO RARE THAT IT IS UNLIKELY THAT THIS IS JUST A COINCIDENCE OF A LOT OF ENVIRONMENTAL FACTORS. SO WE'RE LOOKING FOR THESE RARE PATIENTS BECAUSE WE THINK THERE IS AN UNDERLYING GENETIC CAUSE THAT BRINGS ALL THESE PATHOLOGY PATHOLOGY -- BUT HOW DO YOU WORK WITH PATIENTS WHO HAVE CORONARY ARTERY DISEASE, HOW DO YOU DECIDE WHICH IS COMMON VARIETY, LIKE CAD AS WE KNOW IT, OR THIS IS SOMETHING DIFFERENT THAT LOOKS LIKE CAD BUT IS NOT. AND KEY IS TO WORK WITH CLINICIANS LIKE DOUG ROSING WHO HAS SEEN IT ALL. AND I GO TO DOUG AND SAY, DOUG, DID YOU EVER SEE SOMETHING LIKE THAT? AND IF HE SAYS, NO, I DON'T THINK SO, THEN WE'RE GETTING ACTIVE. SO ARE WE REALLY WORKING ON PREMATURE CAD? SO OH THIS IS A REVIEW ARTICLE ON PREMATURE CAD. SO PREMATURE EARLY CORONARY ARTERY DISEASE. IF YOU LOOK AT MOST OF THESE STUDIES ARE DOING, THEY'RE LOOKING FOR PATIENTS WHO ARE LESS THAN 45, 40, 45, 60, 45, 45. SO I THINK THESE STU YOU STUDIES ARE LOOKING FOR REALLY PREMATURE COMMON CORONARY ARTERY DISEASE. BUT WHAT WE ARE LOOKING ARE PATIENTS WHO DEVELOP VERY SIMILAR SYMPTOMS NOT WHEN THEY ARE 40, NOT WHEN THEY ARE 30, WHEN THEY ARE BELOW 20. AND ACTUALLY JUSTIN HAD FIRST SYMPTOMS WHEN HE WAS 19. WE HAD TWO PATIENTS WHO HAVE SYMPTOMS -- I'LL SHOW ANOTHER A LITTLE LATER WHO WAS 18 AND WE HAVE A BOY ALSO 21 WHO HAD HIS FIRST M.I. WHEN HE WAS 8 YEARS OLD. SO THESE ARE THE IN DARK ALREADY WENT THROUGH, THESE ARE THE RISK FACTORS FOR PREMATURE CORONARY ARTERY DISEASE YOU AND SEE A WHOLE BATTERY OF GENES THAT ARE LINKED TO THAT. THERE ARE OTHER DISEASES WHERE WE KNOW THEY ARE PREDISPOSED TO CORONARY ARTERY DISEASE. SOME OF THEM, WE DO NOT KNOW THE GENES, SOME OF THEM, WE DO. BUT YOU WHAT WE ARE LOOKING FOR ARE PATIENTS THAT HAVE NO MUTATIONS IN THESE GENES AND HAVE NO DISEASE OVER THERE. IT WAS, I DON'T KNOW, SIX OR SEVEN YEARS AGO WHEN WE GOT A PHONE CALL FROM A DOCTOR FROM NEW YORK WHO SAID I HAVE A VERY INTERESTING PATIENT FOR YOU. AND -- JUSTIN, DID YOU SEE -- YES, AND THIS WAS THE VIDEO WHILE YOU CONTACTED US, ACTUALLY YOU CONTACTED THE DOCTOR AND THEN HE SAID, O I HAVE ANOTHER PATIENT JUST LIKE -- >> THIS MORNING A YOUNG WOMAN WHO CAME CLOSE TO DEATH SEVERAL TIMES BUT THROUGH LUCK AND PERSEVERANCE, SHE IS NOW GOING STRONG. KATE SNOW HAS THAT STORY. >> GOOD MORNING, GUYS. CHRISTINA BELL BELTRAN IS AN UPBEAT PERSON, HAPPY, SHE IS ALSO LITERALLY ONE AFTER KIND. THE MEDICAL COMMUNITY HAS NEVER DOCUMENTED ANOTHER CASE LIKE HERS. AT 24 YEARS OLD, CHRISTINA WAS LIVING HER DREAM IN THE BIG CITY. THE CALIFORNIA TRANSPLANT MOVED IN WITH HIS BEST FRIEND FROM COLLEGE. >> WE WERE EXCITE TODAY LIVE IN NEW YORK AND GET GOING WITH OUR LIVES. >> BUT AFTER A WEEKEND AWAY WITH FRIENDS, THE UNTHINKABLE HAPPENED. >> MY ROOMMATE AND I WERE STARTING TO UNPACK, I REMEMBER SHE SAID WHAT DO YOU WANT FOR DINER? THREE DAYS LATER, I WOKE UP IN THE HOSPITAL. >> CHRISTINA HAD GONE INTO CARDIAC ARREST, SAVED BY HER FAST ACTING ROOMMATE. >> I RAN TO CHRISTINA'S ROOM AND SHE WAS ON THE GROUND AND FACE DOWN. IT WAS REALLY SCARY. >> LIZY HAD JUST RECENTLY BEEN CERTIFIED IN CPR. HOW LUCKY IS THAT? >> YEAH. >> CHRISTINA'S PARENTS RUSHED TO HER SIDE. WHAT DID THE DOCTOR TELL YOU? >> BEFORE WE EVEN SAW CHRISTINA, HE SAID SURVIVAL RATE FOR CARDIAC ARREST OUTSIDE THE HOSPITAL IS 7.9% AND SHE'S IN A VEGETATIVE STATE. WHEN SHE WAKES UP, WE WILL NOT KEEP HER ALIVE. >> CHRISTINA BEAT THE ODDS. >> I THINK IT WAS EIGHT OR NINE DAYS WHICH MY DOCTOR SAID WAS ONE OF THE QUICKEST REARE RECOVERY TIMES. >> JUST MONTHS LATER, SHE FELT CHEST PAINS AGAIN. DOCTORS DID AN ANGIOGRAM AND SAW BLOCKAGES IN HER ARTERIES THAT APPEARED TO BE PLAQUE, BUT IT DIDN'T ADD UP. >> I WORK OUT EVERY DAY, I RUN, I DO YOGA. >> THERE'S NO FAMILY HISTORY, SHE HAS NO EXPOSURES. THERE'S NO BAD HABITS, HER CHOLESTEROL LEVELS ARE PERFECT. >> THIS CARDIOLOGIST HAS TREATED CHRISTINA FROM THE START. HE WAS BAFFLED. DOCTORS USED STENTS TO HELP OPEN CHRISTINA'S ARTERIES, MULTIPLE TIMES, BUT THEY WERE ONLY A TEMPORARY FIX. >> THE DOCTOR SAID WE CAN'T PUT ANY MORE STENTS IN. IT'S CLEARLY NOT WORKING. >> DOES THAT PEEN YOU'RE BOUND TO HAVE A HEART ATTACK? >> YEAH, IT DID. >> AT 25 YEARS OLD, CHRISTINA NEEDED TRIPLE BYPASS SURGERY. >> I REMEMBER THE DOCTOR SAYING WE NEED TO DO SURGERY. AND I START TODAY CRY. >> BUT ONCE AGAIN, CHRISTINA BOUNCED BACK. >> SHE ALWAYS SEES THE POS ITTIVE OUT OF ALL OF IT. >> BUT THERE WAS NO GUARANTEE EVEN THIS FIX WOULD LAST. FINALLY, A BIOPSY OF CHRISTINA'S ARTERIES UNLOCKED A CLUE TO HER MYSTERIOUS ILLNESS. IT WASN'T PLAQUE CLOGGING HER ARTERIES, THEY WERE CLOSING. >> THE ARTERIES ARE GROWING FROM THE INSIDE. >> BUT WHY? THE ASTOUNDING ANSWER WAS THERE ALL ALONG. GENETIC TESTING FOUND EACH OF CHRISTINA'S PARENTS CARRY A RARE GENE MUTATION. CHRISTINA RECEIVED BOTH DEFECTIVE GENES, ONE FROM EACH PARENT. >> THE GENE THAT SHE'S GOTTEN FROM HER MOM AND HER DAD THAT IS A BLUEPRINT FOR THE MUSCLE CELLS IN THE ARTERIES OF HER HEART IS DEESKTDTIVE. >> THE SMOOTH MUSCLE CELLS IN CHRISTINA'S ARTERIES DUPLICATE, MULTIPLYING UNTIL THE ARTERIES CLOSE. >> THEY'RE SAYING I'M THE ONLY DOCUMENTED CASE OF IT. >> THE ONLY DOCUMENTED CASE. >> YEAH. EVER. >> THAT'S RIGHT. CHRISTINA'S CASE ISN'T JUST RARE. >> IT WAS SINGULAR. WHICH DOESN'T REALLY HAPPEN IN MEDICINE. AND WHEN IT DOES HAPPEN, IT'S SCARY. >> REFUSING TO GIVE UP, THE DOCTOR PUT CHRISTINA ON A YOU UNIQUE COMBINATION OF DRUGS. >> THE MEDICINE THAT WE CHOSE AS A BEST GUESS HUNCH, WE GOT VERY, VERY LUCKY AND IT TURNS OUT TO BE VERY EFFECTIVE FOR HER. >> WITH FREQUENT MONITORING, CHRISTINA LIVES A NORMAL LIFE. SHE WORKS IN FASHION AND CHRONICLES IT ALL ON A POPULAR BLOG, UNAFRAID OF WHAT THE FUTURE HOLDS. >> A LOT OF OF OPT OH MYSTIC THINKING, YOU THINK THAT'S WHAT WORKS AND I THINK THAT'S WHAT KIND OF GETS EVERYONE THROUGH THINGS. >> YOU GET THAT SHE'S REMARKABLY POSITIVE. THE TRUTH; BELIEVE IT OR NOT, EVEN AFTER ALL OF THIS, THEY STILL DON'T REALLY KNOW EXACTLY HOW HER GENETIC CONDITION AFFECTS HER HEART, AND PART OF WHY SHE WANTED TO TALK TO US IS BECAUSE SHE IS A CASE STUDY, THE NATIONAL INSTITUTES OF HEALTH ARE STUDYING HER AND HER FAMILY AND THEY'RE HOPING THAT MAYBE BY PUTTING THIS ON TV, THEY'LL FIND A SECOND CASE OUT THERE, SOMEONE ELSE WHO'S YOUNG AND HAS HAD THEIR ARTERIES BLOCKING OVER AND OVER AGAIN MAYBE HAS THIS SAME -- THERE'S GOT TO BE ANOTHER PERSON WHO HAS THIS SAME CONDITION. >> ONE MORE SHOUT OUT FOR LIZZY, HER ROOMMATE, FOR SAVING HER LIFE. >> INCREDIBLE. WE WON'T EVEN REALLY HAD THIS STORY IF LIZZY HADN'T JUMPED IN ABANDON CPR. >> FASCINATING. THERE'S MORE OF CHRISTINA'S STORY AT TODAY.COM. >> ALL RIGHT. SO DO YOU THINK WE FOUND A SECOND CASE? I AM NOT SURE. I DON'T KNOW. I THINK THERE ARE SUCH CASES THAT ARE SIMILAR BUT NOT NECESSARILY IDENTICAL. SO IN REGARDS TO THIS FAMILY, TO CHRISTINA, IS THIS CAD, YOUNG AGE, NO FAMILY HISTORY, NO RISK FACTOR, NO NON-ATHEROSCLEROTIC FMD, BUERGER'S DISEASE, KAWASAKI DISEASE, VASCULITIS, NONE OF THESE FIT INTO HER PATHOLOGY. SO IN 2010, SHE HAD SHARP CHEST PAIN WHICH WAS PROBABLY THE FIRST SIGN OF THESE CORONARY ARTERY DISEASE. IN 2011, SHE HAD AN M.I. WITH CARDIAC ARREST, AND WAS RESUSCITATED, AND SHE WAS RUSHED TO THE LAB WHERE THEY IDENTIFIED A SEVERE THREE VESSEL DISEASE, VERY SIMILAR TO WHAT JUSTIN JUST DESCRIBED. AND THEN IN 2012, DISEASE PROGRESSION WITH SEVERAL ATTEMPTS FOR REVASCULARIZATION AND CORONARY BYPASS GRAFT. SO WE MET HER BETWEEN 2011 AND 2012. WHEN THEY TOLD US THAT THEY WILL UNDERGO CORONARY BYPASS, WE SAT TOGETHER AND WE THOUGHT WHAT ARE THE DIFFERENT VESSELS, WHAT ARE THE TISSUES THAT WE CAN GET? BECAUSE THIS IS KEY. WE THOUGHT THIS CANNOT BE A NORMAL CORONARY ARTERY DISEASE. SO WHAT KIND OF -- AND DOUG ALREADY TOLD YOU WHAT THE PROCEDURE IS, WHAT KIND OF VESSELS CAN YOU GET? YOU CAN GET THE SUBVENOUS VEIN, MAMMALIAN ARTERY, REMEMBER THESE SHORT FORMS THAT YOU USE TO HOOK UP TO THE CORONARIES, YOU CAN ACTUALLY GET PART OF THE AORTA WHERE THEY PUT IN THE SAPHENOUS VEINS, WE THEY WHERE THEY PUNCH A HOLE IN TO HOOK IT UP AND MOVE IT OVER TO THE CORONARY. AND IF YOU HAVE A VERY BRAVE SURGEON, YOU CAN EVEN GET A SAMPLE FROM THE CORONARY ARTERY ITSELF. AND THESE THREE SAMPLES WERE KEY TO BETTER UNDERSTAND WHAT IS HAPPENING IN CHRISTINA'S CASE. SO WHAT YOU SEE HERE ARE THESE DIFFERENT SAMPLES. YOU SEE THE MAMMALIAN ARTERY HERE, THE SAPHENOUS VEIN, THIS IS A COMPLETELY NORMAL VEIN, YOU SEE THERE IS NOTHING WRONG WITH THAT, THAT'S THE MEDIA, . THIS IS THE CORONARY ARTERY THAT THEY -- WHERE WE GET A PATTERN AND YOU CAN SEE HERE ALREADY, THIS IS THE NORMAL VESSEL WALL, AND HERE YOU SEE A PIECE OF TISSUE THAT SHOULD NOT BE HERE. WE THIS THIS AS WE SAW IN THE VIDEO IS SMOOTH MUSCLE CELL PROLIFERATION. BUT THIS HAPPENS IN MANY COMMON CORONARY ARTERY DISEASES AS WELL. BUT WHAT WAS STRIKING AND WAS COMPLETELY SURPRISING WAS THAT THE TWO ARTERIES THAT ARE USED TO BYPASS WERE HEAVILY DISEASED ALREADY. SO THIS IS AN ALMOST OCCLUDED RIGHT INTERNAL MA MARIAN ARTERY AND YOU SEE A MASSIVE PROLIFERATIVE RESPONSE, YOU SEE INFLAMMATION, AND THESE ARTERIES ARE BELIEVED TO BE SPARED FROM CORONARY ARTERY DISEASE. SO HOW CAN IT BE THAT THESE ARTERIES ARE AFFECTED? THE SAME THING IS TRUE FOR THE LEFT INTERNAL MA MARIAN ARTERY. THIS IS ALL NEW, ALL PATHOLOGICAL CROSS. SO WHAT WE DID, WE LOOK ARE THERE ANY INFLAMMATORY MARKER, WE HERE AT THE NIH, DON'T LOOK AT CRP AND OTHER MODELS, WE WANT -- CYTOKINE ARRAY WITH WHAT'S CALLED A -- SO WE RUN CLOSE TO 100 DIFFERENT CYTOKINES AND YOU SEE THESE LINES, THE DIFFERENCE FROM THE CONCENTRATION FROM ONE LINE TO THE NEXT IS TENFOLD. AND WE FOUND A COUPLE OF INTERESTING CYTOKINES UPREGULATED, PGBF BETA, OART IS HUMAN CSF AND IP10. IP10, THESE ARE -- MUSCLE CELLS. IP10 WOULD POINT US TO INTERFERON MEDIATED PROCESS. BUT HOW CAN WE STUDY THAT IN MORE DETAIL? THIS IS WHAT WE ARE DOING IN OUR LAB. IT'S THE PATIENT-CENTERED TRANSLATIONAL PROGRAM TO UNDERSTAND AND TREAT VASCULAR DISEASES. SO THE CENTER IS THE PATIENTS, WE BRING THE PATIENTS HERE INTO CLINICAL. I HAVE A TEAM AND MANY OF OUR TEAM ARE HERE. EVALUATE AND CLINICALLY CHECK THE PATIENT HEAD TO TOE, AND THEN WE USE CELLS FROM THE PATIENT TO DEVELOP SPECIFIC IN VITRO DISEASE MODEL SYSTEMS WHERE WE LOOK IF ANY ALTERATIONS IN -- ARE CHANGED THAT CAN LEAD US TO BETTER UNDERSTAND THE DISEASE AND WE DO A GENETIC EVALUATION, SO WE TAKE THE PATIENTS, NOT ONLY TAKE THE PATIENTS, WE ALSO TAKE THE FATHER, THE MOTHER, THE SIBLINGS, AND SOMETIMES YOU GO EVEN FURTHER AND SEQUENCE ALL THE GENES, WE DO WHOLE GENOME SEQUENCING, AND LOOK IF WE CAN FIND THAT NEEDLE IN THE HAY STACK THAT MAY CAUSE THE DISEASE. SO WE HAVE BEEN WORKING ON A VARIETY OF DIFFERENT -- WE IDENTIFIED THE GENE IN THAT DISEASE, IN COLLABORATION WITH INVESTIGATORS, THEY IDENTIFIED -- ADA2 -- WHICH IS INTERFERON -- SO THESE ARE VASCULAR DISEASES OR -- ALL OF THESE DISEASES GENETIC EVALUATION WAS KEY AND JE NE IT TICK EVALUATION HELP US TO BETTER UNDERSTAND WHAT IS DOWN THE LINE DISEASE MECHANISM. SO HOW DO WE DO THAT? SO WE GET SAMPLES, BLOOD SAMPLES FROM THE PATIENTS. WE USE A SEQUENCER AND THEN THE SEQUENCER GIVES US READS AND THESE READS ARE VERY SMALL FRAGMENT, 100, 50, THAT YOU CAN SEE HERE AND YOU GET A LOT OF THESE AND WE ASSEMBLE THEM AND PUT THEM IN AS A PUZZLE TO GET ONE, ONE, ONE STRAIN, ONE READ. THAT WE THEN USE WITH CERTAIN PIPELINES TO SEE IF THIS FITS WITH HOW THE DISEASE RUNS IN THE FAMILY, HOW FREQUENT THIS DISEASE IS, TO COME UP WITH A LIST OF VARIANTS. SO JUST VERY QUICKLY, THE DNA COMES FROM THE PATIENTS, WE DO FRAGMENTS, SEQUENCE THEM, WE GO IMIK QIKLY THROUGH QUICKLY THROUGH THAT, BUT IT IN THESE FLOW CELLS. SO THIS PART IS DONE IN SEQUENCING FACILITY, THEN THERE'S A LOT OF EFFORT IN BIOINFORMATICS TO USE ALL OF THESE DATA TO COME UP WITH A VARIANT LIST. SO THIS IS JUST A PIPELINE THAT WE USE, SO FIRST WE USE THE SMALL FRAGMENTS, REALIGNMENT, WE LOOK WHERE THEY FIT INTO THE GENOME, THEN WE LOOK INTO REFERENE GENOME IF THIS IS SOMETHING THAT IS A MUTATION OR IT'S NOT, AND THEN WE USE AN ALGORITHM TO FILL THESE HUNDREDS SOMETIMES MILLIONS OF VARIANTS DOWN TO A MANAGEABLE SIZE, GIVE US AN IDEA OF WHAT IS HAPPENING IN THE PATIENT. SO WE HAVE TWO FAMILIES HERE. AGAIN WE SEQUENCE THE WHOLE FAMILY, FATHER, MOTHER, SIBLINGS, FAMILY ONE AND FAMILY TWO. AND WHEN YOU LOOK AT FAMILY TWO, SO THESE ARE INHAIR TANTS WHERE WE LOOK FOR RECESSIVE DISEASE, MEANING THAT THE SAME MUTATION IS COMING, ONE MUTATION FROM THE MOTHER, ONE MUTATION FROM THE FATHER, AND YOU SEE THERE'S A LIST OF GENES, THREE OF THEM, AND WE ALSO LOOK FOR COMPOUND AND DE NOVO, IN THE SAME GENE BUT IN DIFFERENT LOCATION, THEN WE LOOK THROUGH THE GENE LIST AND RUN -- WHAT STRIKE US IMMEDIATELY, THIS WAS MI11, A CHAIN THAT IS SPECIFIC FOR -- THEY DESCRIBED THIS WAS A PROLIFERATION OF THE SMOOTH MUSCLE CELL. IT HAD A VERY HIGH CAT SCORE, IT WAS VERY -- WAS EVEN UNIQUE, WAS NEVER SEEN BEFORE, SO THERE WAS VERY GOOD CANDIDATE. SO WHAT DO WE KNOW ABOUT MY ?REFN ASSOCIATED WITH NON-SYNDROMIC THORACIC AORTIC ANEURYSMS AND DISSECTION, THAT THIS LEADS TO UPREGULATION OF GROWTH FACTORS, CHANGES IN THE VESSEL WALL, AND WHAT YOU CAN SEE HERE, NEW -- FORMATION. THE GENE IS ALSO PART OF THE SYNDROME WITH THORACIC ACOR IT TICK ANEURYSM AND PATENT DUCTUS ARTERIOSUS. IF YOU LOOK, OUR PATIENTS HAD THESE TWO MUTATIONS. THESE TWO MUTATIONS HAVE NEVER BEEN DESCRIBED IN THESE ANEURYSM ANEURYSMATIC -- SO OURS WAS A COMPOUND HEAD SO BOTH MUTATIONS, BOTH JEAN GENES, BOTH ALLELES WERE AFFECTED. BUT THE MUTATION THAT WE IDENTIFIED WAS NOT DESCRIBED BEFORE. WE HAVE THESE LOCATIONS, THESE GENES, ONE WAS ON THE THE THESE MYOSINES, THE FOURTH GENERATOR IN FORCE GENERATOR IN THE MUSCLE, THEY BIND TO THE ACTINS AND PULL TOGETHER TO MAKE THE HEART TO CONTRACT, SO ONE USING THE MACHINE, ONE IS IN THE TAIL TO WHERE THESE MACHINES ARE LOCALIZED. WHEN WE LOOKED IN TO THE SMOOTH MUSCLE CELLS IN OUR -- IN FAMILY TWO, WE SAW THAT THE PATIENT HAD AN INCREASE IN WHAT WE CALL MYOFIBROBLASTS, OH SO SO THESE ARE ACTIVATED FIBROBLASTS THAT WE IDENTIFIED IN THAT, AND WE ALSO SAW CHANGES WHEN WE GOT FURTHER HISTOLOGIC EVALUATION FOR DIFFERENT MARKERS, SMOOTH MUSCLE SELL MARKERS IN THE PATIENT. SO SM22, SMA, THERE ARE CHANGES IN HOW THESE MARKERS FOR SMOOTH MUSCLE CELL ARE EXPRESSED IN THESE VESSELS. WE ARE NOW COMING TO FAMILY ONE. THE OTHER FAMILY. WHERE WE HOPE WE CAN HIT THE SAME MUTATION, THE SAME GENE IN ORDER TO SAY, WHOA, THEY ARE GENETICALLY SIMILAR, SO THAT'S PROBABLY WHAT IT IS. WE GOT 7 MILLION DIFFERENT VARIANTS, AND THEN WE USE DIFFERENT RECESSIVE FILTER TO COME DOWN WITH A LIST, SO THIS SHOWS THE RECESSIVE DE NOVO. NONE OF THESE RECESSIVE -- MUTATIONS WERE DESCRIBED IN THE OTHER FAMILY. HOWEVER, WHEN WE LOOKED AT THE COMPOUND -- WE SAW SOMETHING WE DO NOT HOW YOU TO PRINT AT THIS POINT, THERE WAS ONE GENOME, ACTUALLY NOTHING TO DO WITH CORONARY ARTERY DISEASE, PK, KIDNEY DISEASE, ONE LIKE TWO PROTEIN. IT HAS A VERY HIGH CAT SCORE, VERY RARE MUTATION, AND WHEN WE LOOK IN FAMILY ONE AND TWO, WE SUDDENLY SEE THAT ALSO FAMILY TWO HAD MUTATIONS NOT IN THE PKD1L2, BUT IN THE PKD1. SO PKD1L2 IS -- CYSTINE DISEASE ONE-LIKE. GENE TWO AND -- PATIENT HAD THE MUTATION IN PKD1, POLYCYSTIC KIDNEY DISEASE ONE. SO ARE THESE DISEASE CAUSING GENES? WE HAVE ABSOLUTELY NO IDEA AT THIS POINT, WE NEED TO FURTHER EVALUATE THAT. BUT THERE ARE SOME STUDIES OUT TO SAY THAT MUTATION IN THIS IN THE GENE THAT CAUSES THIS DISEASE CAN CAUSE -- CHANGES EVEN IF IT DOES NOT AFFECT BLOOD PRESSURE. SO IT IS A HARD CANDIDATE. BUT WHAT WE DO TO STUDY THEM IS WE MOVE THE PATIENT INTO A DISH, DISEASE IN THE DISH. SO WE DO IPS TECHNOLOGY WHERE WE CAN DO GENETIC CORRECTION, WHERE WE TAKE CELLS FROM THE PATIENT AND MAKE THEM TO STEM CELLS AND THEN WE GENERATE CELLS FROM THEM AND STUDY HOW DO THESE CELLS WHO ARE HAR BORROWING THE GENETIC BLUEPRINT OF THESE PATIENTS, COMPARE TO -- TO OTHER PATIENTS WHO HAVE SIMILAR DISEASE PROGRESSION OR DISEASE PHENOTYPE. WE CAN MAKE ALL KINDS OF NEAT STEM CELLS, WE CAN MAKE ENDOTHELIAL CELLS, SMOOTH MUSCLE CELLS, INFLAMMATORY CELLS, SO WE HAVE ALL THE TOOLS TO PUT THAT TOGETHE. AND WE ALSO MOVE ONE LEVEL HIGHER WHERE WE GROW THESE HUMAN TISSUE IN THE MOUSE AND LOOK HOW THESE HUMAN TISSUE LOOKS DIFFERENT, AND ONE EXAMPLE IS HERE FROM FAMILY TWO, WHERE WE SEE -- SO OH THIS IS CALLED TEAR TERATOMA, YOU SEE THE NICE LINING OF SMOOTH MUSCLE CELL IN RED, AND ENDOTHELIAL CELL IN BLUE, AND IN FAMILY TWO, WE SEE THERE IS A CHANGE IN IT. IT DOES NOT LOOK LIKE A NICE COVERAGE FOR SMOOTH MUSCLE CELL IN THESE VESSELS. HOWEVER, THIS IS A MIXED VESSEL BETWEEN MOUSE AND HUMANS, AND EVEN IMPROVE THAT, WE COLLABORATEED WITH A GROUP IN AUSTRIA, WHERE WE WORKED ON GENERATING HUMAN BLOOD VESSEL ORGAN OIDS. THE SCHEMATIC OF THAT IS SHOWN HERE. IT'S BASICALLY YOU DO NOT TRANSPLANT STEM CELLS IN THE MOUSE FROM THE TERA IT TOMES BUT THAT YOU GENERATE VASCULAR ORGANOIDS IN A DISH AND THEN YOU TRANSPLANT THEM, AND HOW THESE VASCULAR OH ORGANIZE NIEDS LOOK OR BEGAN O IDS IS SHOWN HERE. SO IN GREEN YOU SEE CD31, WHICH IS AN ENDOTHELIAL CELL MARKER, THEN YOU SEE PDGF WHICH IS A PERICYTE MARKER. YOU CAN SEE HERE GENERATED IN THE DISH WITH ENDOTHELIAL CELL IN THE MIDDLE AND THE PERICYTES OUTSIDE AND WE ARE NOW TRANSPLANTING THESE CELLS AND SEE HOW IT GETS PERFUSED AND IF WE CAN SEE A DIFFERENCE BETWEEN THE PATIENTS AND THE CONTROL. WITH THAT, I WOULD LIKE TO THANK ALL THE PEOPLE IN THE LAB AS WELL AS OUR CLINICAL TEAM. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU VERY MUCH. THAT WAS VERY EXCITING. SO WE HAVE TIME FOR QUESTIONS. PLEASE COME TO THE MICROPHONE. >> QUESTION FOR JUSTIN. YOU HAVE BEEN WORKING AT ONE OF THE BEST RESEARCH CENTERS IN THE WORLD. DID YOU HAVE ANY IT TEST FOR GENETICS, ANY GENOME ANALYSIS? >> I'M SORRY? >> ANY ANALYSIS OF YOUR DNA? >> YES. >> PLEASE USE THE MICROPHONE. >> YES. AT OSU, THEY DID DO GENETIC STUDIES ON ME AS WELL AS I BELIEVE DR. BOEHM. >> SO ANY ABNORMAL FINDINGS? DID YOU LOOK AT THE GENETIC DATA OF JUSTIN? >> YES. >> IS THAT THE ONE YOU MENTIONED? OR A DIFFERENT PATIENT? >> [INAUDIBLE] AT THIS POINT, OUR ARE ONLY THERE TO GENERATE HYPOTHESIS. WE DID NOT VERIFY CAUSAL RELATIONSHIP BETWEEN SOME OF THE MUTATION THAT WE DESCRIBE AND THE DISEASE PROGRESSION. SO WE WOULD NEED TO -- IN ORDER TO DO THAT, WE WOULD NEED TO FIND MORE FAMILIES, MAYBE ONE OR TWO FAMILYS WHO HAVE MUTATION THE SAME GENE BUT IT MAKES IT A LITTLE COMPLICATED, WE DON'T KNOW IF YOU COMPARE APPLE AND ORANGES IF THE TWO CASES, FOR EXAMPLE, ARE REALLY SIMILAR DISEASE PROGRESS, YES OR NO. AND IT ALSO LOOKS LIKE WHEN WE COMPARE THESE TWO FAMILIES, WHAT I SHOW FAMILY ONE AND TWO, THAT MUTATIONS ARE IN DIFFERENT GENES, BUT BELONGING TO THE SAME PATHWAY. SO WE NEED TO SEE IF THE GENES REALLY CAUSES CHANGES IN THE PATHWAY AND IF THEY LEAD TO THE SAME CHANGES THAT COULD EXPLAIN THE CLINICAL PHENOTYPE. SO AT THIS POINT, WE DON'T KNOW. >> AND A QUESTION OF PAIN, SO WHAT CAUSES THE PAIN? WHAT PERCENTAGE OF THE PATIENTS WITH CHRONIC CHEST PAIN HAVE THIS ABNORMALITY, RAPID CORONARY OCCLUSION? >> SOME FIGURES THAT ARE THROWN AROUND IS THAT 20% OF PATIENTS HAVE SILENT DISEASE, SO 80% HAVE USUAL SYMPTOMS BUT 20% HAVE MYOCARDIAL INFARCTIONS WOWTD ANY PAIN AT WITHOUT ANY PAIN AT ALL. >> SO YOUR STATIN LEVEL INCREASED BUT IT LOOKS LIKE HIS CHOLESTEROL LDL AND HDL ARE MAINTAINED SO THAT SHOULD NOT CAUSE RAPID OCCLUSION, SO DID YOU HAVE ANALYSIS TO -- THE LESION -- ALONG WITH SOME OTHER MRI OF THE BLOOD VESSEL WALL TO SEE WHETHER IT IS PROLIFERATION OF HIGH MUSCLE? YOU MENTIONED THERE WAS NOT MUCH CALCIFICATION. >> YES, WELL, WE ATTEMPTED TO -- WHEN WE'VE DONE IN ALL OF THESE PATIENTS, A DEDICATED OR FOCUSED MRI OF THE VASCULAR WALL, BUT BUT WE CAN'T DO IT VERY WELL OF THE CORONARY SO WE HAVE TO USE LARGER VESSELS LIKE THE AORTA OR THE -- HE DOESN'T HAVE INVOLVEMENT IN MANY OF OUR PATIENTS DON'T HAVE INVOLVEMENT OF THE OTHER VESSELS, AND SO FAR WE VNTD BEEN ABLE HAVEN'T BEEN ABLE TO SA Y ENOUGH. THE ONE CASE THAT DR. BOEHM SHOWED, WHERE WE ACTUALLY HAD IT TISSUE, AND UNFORTUNATELY WE'VE SEEN MOST OF THESE PEOPLE AFTER THEY'VE HAD AN INTERVENTION WHERE THE OPPORTUNITY TO TAKE A SPECIMEN FROM A CORONARY ARTERY OR INTO A MAMMARY HAS ALREADY BEEN LOST AND THE ONLY PATIENT WE HAVE ACTUAL TISSUE -- >> SO -- [INAUDIBLE] >> SO I'M CURIOUS, HAVE YOU AND YOUR FAMILY HAD GENOMIC STUDIES PERFORMED? IS THAT SOMETHING IN PROCESS OR WHERE DOES THAT STAND? >> YES, THE ROSS HEART HOSPITAL AT OSU, MY FAMILY HAS GONE THROUGH GENETIC STUDIES AS WELL AS I BELIEVE THE LAB HAS TAKEN SAMPLES FROM MY FAMILY TO CONDUCT THE SAME STUDIES. >> SO YOUR FAMILY IS PART OF THE -- YOUR FAMILY IS PART OF THE STUDY THAT YOU ARE CREATING NOW, CORRECT? YEAH. AND WHAT IS -- WHAT WAS THE DEFECT IN THE PATIENT WHOSE VIDEO YOU SHOWED FROM THE NEW YORK HOSPITAL? >> [INAUDIBLE] >> ORIGINALLY WE THOUGHT IT WAS THE MUTATION OR IS THE MUTATION IN MY11 WHICH STILL CAN AB GOOD CANDIDATE. HOWEVER, SHE'S STILL UNIQUE. WE DID NOT FIND ANOTHER PATIENT WHO HAS THE SAME CLINICAL SIGNS AND HAS MUTATION IN THERE. THE ONLY MUTATIONS THAT WE SEE IN MORE THAN ONE FAMILY IS THE ONE IN THESE OTHER GENES. >> THANK YOU. SO WE HAVE -- YEAH. >> IS THE PATHOLOGY OF RESTENOSIS THE SAME AS THE ORIGINAL ONE, OR CAN YOU -- IT COMES ON MUCH MORE RAPIDLY, OF COURSE, AND CAN YOU LEARN FROM THAT? >> NO, ACTUALLY THE PATHOLOGY OF RESTENOSIS OR IN-STENT STE MOSES IS MORE SIMILAR TO THE PATHOLOGY THAT DR. BOEHM SHOWED US IN THAT WOMAN. IT'S ENDOTHELIAL AND NOT THE DEPOSITION SO MUCH OF THE CHOLESTEROL AND NECROTIC CENTERS. SO IT'S A PROLIFERATION OF MUSCLE AND FIBROUS TISSUE THAT'S FORMING AN OCCLUSION LIKE CHRISTINA BELTRAN HAD. AND NOT WHAT -- WELL, WE DON'T KNOW WHAT THE UNDERLYING PROCESS IS IN JUSTIN ANYWAY, SO IT MAY BE SIMILAR TO WHAT PROCESS HE HAS GOING ON. WE DON'T KNOW WHAT HIS PROCESS IS. WE DON'T THINK IT'S GENERAL ATHEROSCLEROSIS. >> ONE OTHER QUESTION. DOES ANY OH OTHER BLOOD VESSEL IN THE BODY GO THROUGH SO MUCH MECHANICAL ACTIVITY? IS THAT POSSIBLY RELATED TO WHAT'S CALLED INFLAMMATION? >> [INAUDIBLE] MECHANICAL -- IN THE HEART? >> THE HEART CONTRACTING AND BEATING. GLL THE BLOOD VESSEL ON THE VENTRICLE MOVES AN AWFUL LOT, MORE THAN MOST VESSELS IN THE BODY. >> QUESTION IS, THE HEART, THE MYOCARDIUM MORE ENERGETICALLY INVOLVED THAN OTHER MUSCLE TISSUES. MECHANICALLY AND -- >> COULD BE, BUT THE CORONARY USUALLY STAY OPEN FOR A VERY, VERY LONG TIME, AND WHEN YOU START TO OCCLUDE LATER IN LIFE, AND WHEN YOU LOOK AT CHRISTINA'S VESSELS, THE VESSEL THAT I USED TO BYPASS THESE CORONARIES, THEY WERE DISEASED. THEY WERE PROBABLY AS SEVERELY DISEASED AS THE CORONARY ARTERY IT SELF, AND THESE VESSELS DO NOT UNDERGO THE SAME MECHANICAL STRESS, THE MAIN SO I DON'T THINK THAT A MECHANICAL DIS -- IT IS SOMETHING ELSE. I THINK IT'S MAYBE A MISREGULATION OF SOME GENES. >> HI. I'M FROM NCI. I HAVE A QUESTION FOR THE GENETIC ANALYSIS YOU DID ON -- IN THE FAMILY. SO WHEN I SEE YOUR SLIDE, THE SYMPTOM -- BASED ON THE RARE -- SO WHEN YOU -- KIND OF FILTERING FILTERING, CANDIDATES AND REMAINING BUT HOW DO YOU PICK THE BEST CANDIDATES OR HOW DO YOU DO STATISTICAL ANALYSIS? >> SO THAT'S WHEN ONE FAMILY IS NOT ENOUGH, BECAUSE AS YOU SAID, EVEN WITH THE STRANGEST FILTER YOU END UP WITH 10, 20, 50 DIFFERENT VARIANTS, ALL POTENTIALLY DISEASE-CAUSING. WHAT YOU NEED IS INDEPENDENT SECOND FAMILY THAT YOU GET A HIT IN THE SAME GENE AND ONLY THEN, YOU GET AN IDEA IF THIS IS DISEASE CAUSING. SO THIS WAS BEFORE WE HAD IPS TECHNOLOGY AND GENETIC EDITING. NOW WE CAN ACTUALLY CHECK EACH VARIANT INDIVIDUALLY. WE CAN FIND IF THERE IS A VARIANT CAUSING A CELLULAR DEFECT OR SIGNALING DEFECT THAT COULD BE LINKED TO THE PATHOLOGY, AND THEN WE CAN REVERSE THAT. WE CAN GENERATE ISOGENIC CONTROLS FROM THE SAME PATIENTS FROM THE SAME CELL, AND IF YOU THEN LOSE THESE SIGNALING CHANGE, THEN THIS IS A GOOD INDICATION THAT IT'S ACTUALLY CAUSED, THE SIGNALING DEFECT. IF THE SIGNALING DEFECT IS LINK TODAY THE DISEASE, THERE'S THEN A FURTHER STEP BUT IT WOULD BE A FIRST IMPORTANT STEP TO IDENTIFY THE SIGNALING PATHWAY THAT ARE AFFECTED BY THE MUTATIONS. >> THE OTHER THING THAT -- QUESTION. DURING THE FILTERING PROCESS, THIS IS MY LIFETIME WONDER, IF DURING THE FILTERING PROCESS BASED ON THE 1% OF THE ALLELE FREQUENCY, SO WHAT IF THERE IS A -- CODING VARIANT MORE THAN 5% AND THEN EVEN THOUGH IT'S A RARE DISEASE, BUT SOMETHING INTERACTING ANOTHER VARIANT, YOU FIND OUT, SO THEN -- >> THEN THIS WILL BE VERY PROBLEMATIC TO IDENTIFY. SO YOU SAY BASICALLY -- THE MORE COMMON VARIANT, YOU WILL LOSE THE COMBINATION, YEAH, IT'S POSSIBLE, BUT WE NEED TO START SOMEWHERE. AND WE START WHEN WE HAVE TWO RARE VARIANT, TO COMBINE IT WITH ONE RARE, ONE COMMON IS SOMETHING WE HAVE IN MIND, BUT AT THE MOMENT, WE ARE NOT ACTIVELY PURSUING THESE KIND OF VARIANTS. IT COULD ALSO BE THAT YOU NEED AT LEAST TWO HITS, TWO GENES AFFECTED, RIGHT? >> YEAH M HMM. IN HSM. >> I HAVE A QUICK QUESTION ABOUT THE CASE THAT YOU PRESENTED. SO GIVEN THAT IT WAS CONGENITAL AND IT'S DUE TO SMOOTH MUSCLE PROLIFERATION, WHY WOULD YOU THINK THAT IT WOULDN'T PRESENT -- OR BECOME PROBLEMATIC UNTIL HER 20s? BECAUSE I MEAN, UNLESS THERE WAS SOME EPIGENETIC MODULATION A AT PLAY OR SOMETHING, WHY THEN, WHY NOW? BECAUSE ESPECIALLY SINCE SHE DIDN'T SEEM TO HAVE ANY OTHER RISK FACTORS, WHY WOULD IT TAKE UNTIL HER 20s OR MID 20s FOR TO BE -- UNLESS IT JUST -- UNLESS THE YOU LUMEN DIAMETER WAS CLOSING AT SUCH A SLOW RATE THAT MAYBE THAT WAS JUST THE FIRST INCIDENCE, BUT IT JUST SEEMS INTERESTING. >> SO IF THIS WOULD BE PRIMARY DEFECT LEADING TO SMOOTH MUSCLE CELL PROLIFERATION, YOU ARE RIGHT, YOU SHOULD SEE SOMETHING DURING DEVELOPMENT. OTHER THINGS LIKE INTESTINAL, UTERUS CHANGES AND THIS KIND OF THING. SO WE DON'T THINK THAT THIS IS A MUTATION THAT ALREADY CAUSED DEVELOPMENT OF THE -- BUT WE THINK THIS CAUSE IS A MUTATION THAT CHANGE THE THRESHOLD SENSITIVITY TO INJURY TO VASCULAR INDUSTRY, AND -- TO CAUSE TO PROGRESS TO A STATE WHERE IT'S CLINICALLY RELEVANT, THIS IS AN ACCELERATED DISEASE PROGRESSION, LINKED TO INJURY AND THE INJURY ARE CHANGES THAT ARE ACQUIRED BY THE PATIENT OVER 20 YEARS. I MEAN, WE HAVE PATIENTS WITH VASCULAR CALCIFICATION. WE KNOW THE GENE, CD73. IT'S A GENETIC INHERITED DISEASE. IT CAUSES CALCIFICATION WHEN THEY ARE 20 YEARS OLD. WHY DO THEY NOT HAVE IT IN -- EARLIER ON, LIKE OTHER PATIENTS WITH VASCULAR CALCIFICATION CALLED -- JUST DIRECTLY UPSTREAM. IT'S HOW THESE SIGNALING PATHWAY ARE LAYING, IT'S REGULATED AND THIS DISEASE PROGRESS CAN BECOME VERY EARLY OR CAN BECOME LATER IN LIFE. >> ANY COMMENT, DOCTOR? >> NO, I WAS GOING TO ASK, WHY IS IT LIMIT TODAY THE CORONARY ARTERIES? LIMITED TO THE CORONARY ARTERIES? >> ANYBODY HAVE ANY IDEA? THE CARDIOLOGISTS ASK ME THAT. [LAUGHTER] >> ONE OTHER QUESTION? >> GO AHEAD. >> THIS IS FOR DR. ROSING THIS IS ABOUT YOUR CHEST PAIN. I WAS JUST CURIOUS, YOU SAUD EXPLORED POTENTIAL OTHER CAUSES. I MEAN, IS IT POSSIBLE THAT THE HEART IS NOT AT ALL A FACTOR AND IT'S SOMETHING MUCH MORE OBSCURE LIKE INTERCOSTAL NEURALGIA OR SOME SORT OF REFERRED PAIN FROM JUST SOMEWHERE ELSE AND -- BECAUSE THERE ARE A NUMBER OF OTHER SOURCES OF PAIN THAT CAN BE SHARP, CAN BE LOCALIZED IN THAT AREA AND CAN SH BE INDUCED BY EXERTION THAT DON'T HAVE DO WITH THE HEART. >> WELL, JUSTIN HAS BEEN EVALUATED BY OUR GASTROENTEROLOGISTS O UR EUM REUM TOLL GIST, HEMATOLOGISTS, TEAM HOLG WOULDN'T NECESSARILY CAUSE ANOTHER SOURCE OF PAIN, IT MIGHT CAUSE A REASON FOR WHY BLOOD VESSELS WERE CLOGGING UP AND WITH CLINICAL STUDIES AND AS BEST WE CAN DO TO ELICIT PAIN SYNDROMES IN THOSE OTHER ORGAN SYSTEMS, WE'VE COME UP WITH NOTHING. OTHER INSTITUTIONS HAVE DONE THE SAME. AS LONG AS WE -- WE'RE STILL PURSUING THAT, BUT WE STILL HAVE THE FINDING THAT HE DOES HAVE A IF PHYSIOLOGIC OR A PATHOPHYSIOLOGIC BASIS FOR HIS PAIN AND THAT HE STILL HAS ABNORMAL MRI STRESS TESTING AND HE HAS PERFUSION ABNORMALITIES THAT STILL EXIST DESPITE ALL THE STENTS THAT HAVE BEEN PUT IN. I'M WAITING FOR SOMEONE ALSO TO ASK WHY HAVEN'T WE -- WHAT WAS THE BASIS FOR TRYING WHAT DR. YAKUBSA DID IN CHRISTINA, WHY HADN'T WE THOUGHT ABOUT USING THIS IN JUSTIN, WHICH WE HAVE. SO WHAT WAS THE -- DO YOU REMEMBER WHAT THE BASIS WAS, WHY THOSE THREE DRUGS WERE CHOSEN? >> YEAH, SO AGAIN, TO HAVE TISSUE IS KEY, SO WHEN WE LOOKED AT THESE VESSELS, MA MARIAN ARTERY, THAT'S USUALLY NOT AFFECTED BY CORONARY ARTERY DISEASE, IT LOOKED LIKE TO US SOMETHING THAT YOU GET WHEN YOU TRANSPLANT ORGANS, TRANSPLANT VAST QUEUE YOU LOP THEE. SO IT'S A PROCESS THAT'S LINKED TO AN ACTIVATION OF THE IMMUNE SYSTEM, VERY LOW ACTIVATION OF THE IMMUNE SYSTEM BECAUSE THE ORGANS ARE NOT 100% COMFORTABLE WITH THE HOST. THAT THEN LEADS TO THIS KIND OF PROLIFERATION OF SMOOTH MUSCLE CELLS. SO SHE WAS EXPERIMENTALLY PUT ON THAT KIND OF TREATMENT THAT WORKED IN HER CASE QUITE WELL. BUT THESE TREATMENTS ARE NOT WITHOUT RISK. THEY HAVE SIDE EFFECTS. AND TO INITIATE THAT OUT OF THE BLUE IS -- WITHOUT ANY MEDICALLY OR HISTOLOGIC EVALUATION IS VERY DIFFICULT FOR A PHYSICIAN ON THE OUTSIDE. SO NEST WHY WE THAT'S WHY WE ONLY HAD LIMITED INFORMATION FROM JUSTIN. >> LET ME ASK YOU A QUESTION. IN 1984, WERE THE PEOPLE IN FRAMINGHAM WHO WERE DOING THE STUDY, WERE THEY LOOKING WAY INTO THE FUTURE AND PUTTING MAYBE SOME FIBROBLASTS IN CULTURE OR A BIOPSY? I MEAN, WHEN YOU THINK OF IT, THERE'S A STUDY OF I DON'T KNOW HOW MANY THOUSANDS OF PEOPLE THROUGH SEVERAL GENERATIONS, IT'S THE WHOLE LIFE HISTORY OF WHAT WE'RE LOOKING FOR. IS THERE ANY LINKING OF THAT, EVEN IN TERMS OF HAVING THE TISSUE AVAILABLE FROM THEN OR SUBSEQUENTLY TO ACTUALLY EXAMINE SOME OF THE GENETIC AND EPIGENETIC CHANGES OCCURRING IN A POPULATION? DO YOU KNOW IT WAS -- WAS THAT DONE? >> I DON'T THINK IT WAS DONE AT THAT TIME. THAT STARTED OUT AS AN EPIDEMIOLOGICAL, OF COURSE, DESCRIBTIVE STUDY WHERE THEY WERE COLLECTING DATA AND SAVING SAMPLES. MOST OF THE SAMPLES WERE BLOOD SAMPLES. I DON'T KNOW ABOUT TISSUE SO MUCH BUT, I MEAN, WHAT YOU'RE ASKING IS BASICALLY TO SOME EXTENT WHAT WE'RE TRYING TO DO. >> RIGHT. >> TODAY. >> BUT NOW WE'RE STARTING FROM SCRATCH. WHEREAS YOU'RE ALL -- I REMEMBER WHEN ONE OF THE TALKS THAT DR. COLLINS GAVE, THIS HAD TO DO WITH PROJURIA. HE SAW PATIENTS IN THE 80s, AND TUCKED AWAY SOME TISSUE AND THEN LATER, YOU KNOW, FOUND IT AND WENT BACK. I'M JUST CURIOUS AS TO WHETHER THAT HAPPENED. IN ANY EVENT, I WANT TO THANK YOU BOTH FOR A VERY INFORMATIVE, VERY INTERESTING AFTERNOON. [APPLAUSE] >> THANK YOU.