2018 Demystifying Medicine: Does inflammation cause cardiovascular disease? If so, how?

2018 Demystifying Medicine: Does inflammation cause cardiovascular disease? If so, how?


I ONCE HAD A PROFESSOR WHO TOLD ME IF YOU HAVE WHAT YOU THINK IS A SILLY QUESTION AND DON’T ASK THEN YOU ARE BEING SILLY. YOU SHOULD ASK WHAT ARE IS ON YOUR MIND BECAUSE THAT’S THE WAY WE LEARN. IS THERE ANYBODY WHO DOESN’T KNOW WHAT THIS PICTURE IS? EVERYBODY KNOWS. WHAT IS IT? THAT’S RIGHT THE BROOKLYN BRIDGE. HAVING GIVEN THIS LITTLE SPEECH FOR EACH SESSION NOW FOR 17 YEARS I’M BEGINNING TO THINK PEOPLE HAVE HAD ENOUGH OF IT BUT IT’S VERY IMPORTANT BECAUSE WE ARE LIKE THE TWO MEN ON THE CATWALK AND IF YOU VISUALIZE BROOKLYN OVER THERE WITH ALL THE ADVANCES AND MODERN MOLECULAR, CELLULAR, MATHEMATICAL AND ANALYTICAL BIOLOGY AND NEW YORK ON THIS SIDE IS WHERE THERE ARE PATIENTS AND PHYSICIANS TRYING TO FIGURE OUT WHAT TO DO WITH THEM. SO THE WHOLE POINT IS TO LINK UP AND COMMUNICATE AND NOT TO TURN Ph.D.s TO MDs BUT TO EXCITE THROUGH CHALLENGES. YOU HAVE SEEN EVERYTHING HAS CHALLENGES AND MANY ANSWERS WHY AND WITH A REDUCTIONIST TECHNOLOGY AND IDEAS, NOBODY KNOWS THE ANSWERS TO THESE PROBLEMS. HOPEFULLY YOUNGER CREATIVE MINDS, NOT NECESSARILY A LOT OF YOUNGER BUT CREATIVE, FREE-THINKING COME UP WITH IDEAS. SO WHAT IS THE MAJOR CAUSE OF DEATH IN THE WESTERN WORLD?>>WE STALK ABOUT HIV AND MAL MALARIA BEING A MAJOR KILLER AND WE’RE TALKING ABOUT THE WESTERN WORLD, UNITED STATES, CANADA AND SO ON. IT’S NOT ARTERIOSCLEROTIC CARDIOVASCULAR DISEASE. SO PEOPLE ARE LIVING LONGER AND THERE’S BEEN TREMENDOUS ADVANCES IN AMELIORATING THE DEATH RATE FROM PARTICULARLY MYOCARDIAL IN INFARCTION AND YET IT REMAINS AND BECAUSE WHAT HAS GIVEN RISE TO THIS HASN’T CHANGED AND THE POPULATION GETS BIGGER. SO IT’S STILL THE MAJOR CAUSE OF DEATH EVEN THOUGH THESE GREAT ADVANCES HAVE BEEN MADE. SO THE ADVANCES HAVE BEEN MADE BECAUSE OF THE IDENTIFICATION OF RISK FACTORS. THINGS LIKE OBESITY, HYPERTENSION, CHOLESTEROL, DIABETES, A SEDENTARY LIFESTYLE, SMOKING, PROBABLY A FEW OTHER THINGS. AND ALL OF THOSE HAVE BEEN SUBJECT TO I WOULDN’T BE SURPRISED IF HALF THE MEN IN THE UNITED STATES OVER THE AGE OF 50 ARE TAKING A STATIN AND THESE THINGS ARE MADE A TREMENDOUS EFFECT CONTRIBUTING TO HYPERTENSION. YET DESPITE THE RISK FACTORS pIT’S STILL A MAJOR CAUSE OF DEATH IN THE WESTERN WORLD. WHY? WHAT ARE WE MISS THAT’S THE CHALLENGE. IN RECENT YEARS THERE’S BEEN A GREAT DEAL OF INTEREST AND ENTHUSIASM AND RESEARCH ALONG THE IDEA THAT THE MISSING FACTOR IS INFLAMMATION. NOW, IF SO, AND WE HAVE SPOKEN OF PEOPLE ACCEPTING IT IN GENERAL. PHYSICIANS TEND TO ACCEPT IT BUT WHAT ARE THE MECHANISMS WHEREBY INFLAMMATION PARTICIPATES IN ARTER ARTERIOSCLEROTIC ARTERIAL DISEASE SO IT’S A COMPLEX SUBJECT. WE’RE PLEASED TO HAVE TWO EXPERTS WHO DEVOTE — ONE CLINICAL AND ONE WITH RESEARCH ACTIVITIES TOWARDS THE STUDIES OF MECHANISMS OF ARTERIOSCLEROTIC CARDIOVASCULAR DISEASE. THE FIRST SPEAKER RECEIVED HIS Ph.D. AND MD FROM THE UNIVERSITY OF PITTSBURGH. TRAINED IN CLINICAL PATHOLOGY AND CAME AS A MEDICAL STAFF FELLOW IN 1990 AND GOT INTERESTED IN THE PROTEUM MECHANISM AT THE DISEASE INSTITUTE. IN 2007 HE BECAME THE CHIEF OF THIS PROTEIN METABOLISM LABORATORY WHICH IS WIDELY LONE KNOWN. HE’S THE DIRECTOR OF THE SPECIAL CHEMISTRY SECTION OF THE DEPARTMENT OF LABORATORY MEDICINE AT THE NIH. HE IS WIDELY PUBLISHED AND HAS MADE MANY CONTRIBUTION AND WILL DISCUSS HIS VIEW ON THE SUBJECT. NOW, OUR SECOND SPEAKER CAME TO THE NIH IN 2012 IN A RATHER UNIQUE POSITION. HE WAS THE INAUGURAL CLINICAL RESEARCH SCHOLAR — THAT’S A NEW PROGRAM STARTED AT NIH AND HE CAME WITH A HEART, CARDIOVASCULAR AND PULMONARY BRANCH IN 2012 AND GRADUATED IN MEDICINE WITH DISTINCTION FROM GEORGE WASHINGTON AND PURSUED AN INTERESTING AND UNIQUE PATH. I DWELL ON THIS A LITTLE BIT BECAUSE IT DEALS WITH THE QUESTION OF THERE IS NO STRAIGHT HIGHWAY. THOSE WHO TAKE THE ROAD LESS TRAVELED BY — TO COIN A PHRASE, OFTEN COME UP WITH UNIQUE IDEAS AND I THINK IT’S A GOOD EXAMPLE BECAUSE AFTER HIS MEDICAL RESIDENCY AT THE UNIVERSITY OF PENNSYLVANIA HE TOOK A FELLOWSHIP ANDCARDIOVASCULAR DISEASE AND DID A POST-DOCTORAL FOCUSSING ON INFLAMMATION AND LIPID PROTEINS. HE’S HAD A WIDE EXPERIENCE IN MANY FIELDS INCLUDING EPIDEMIOLOGY AND BASIC INFLAMMATORY RESEARCH, RESOLUTION IMAGING TECHNOLOGY AND IT’S ALL RELATED TO TRYING TO UNDERSTAND THIS RELATIONSHIP BETWEEN INFLAMMATORY DISEASES AND CARDIOVASCULAR DISEASE AND ASSOCIATE IT WITH THAT METABOLIC CONSEQUENCES THAT TAKE PLACE. YOU ALL KNOW PSORIASIS IS A SKIN DISEASE. IT’S REALLY AN INFLAMMATORY DISEASE AND INVOLVES MORE THAN THE SKIN. IT’S A SYSTEMIC DISEASE AND PART OF THE SYSTEMIC MANIFESTATIONS OF THIS SKIN DISEASE IS AN INCREASED RISK FOR CARDIOVASCULAR DISEASE AND GOT HIM GOING INTO CARDIOVASCULAR RESEARCH AND WHAT BROUGHT HIM HERE TO THE NIH. SO WHAT BROUGHT HIM HERE TO THE NIH.>>CAN EVERYONE HEAR ME? I’D LIKE TO THANK EVERYONE NOR NOR — FOR COMING AND I’D LIKE TO THANK DR. ARIAS. I’VE KNOWN HIM SENSE HE CAME TO THE NIH AND I FEEL CONFIDENT WHEN I HAVE DATA I DON’T UNDERSTAND BECAUSE HE HAS A UNIQUE PERSPECTIVE. I DON’T REALLY STUDY INFLAMMATION PER SE BUT WHAT I’M GOING TO DO TODAY IS GIVE YOU A CRASH COURSE OF CARDIOVASCULAR DISEASE AND PROTEIN METABOLISM AND I STUDY INTENSE FIBER PROTEINS THEY’RE CALLED GOOD CHOLESTEROL. ONE WAY THAT MAY DAMPEN INFLAMMATION AND HOPEFULLY AFTER MY TALK YOU’LL BE WELL PREPARED TO HEAR ABOUT INFLAMMATION ARTHROSCLEROSIS. AND I TOOK OUT A SLIDE. NOT ONLY IS CARDIOVASCULAR DISEASE THE NUMBER ONE KILLER BUT IF YOU HAD BREAST CANCER YOU’LL LIKELY DIE OF HEART DISEASE THAN BREAST CANCER ITSELF TO SHOW YOU HOW IMPORTANT THIS IS. I’D LIKE YOU TO CONSIDER CARDIOVASCULAR SCIENCE BECAUSE IT’S AN IMPORTANT PROBLEM. I’M GOING TO IT’S HARD TO BELIEVE BUT THE FIRST RECOGNITION OF THIS PROCESS OF ARTHROCLEROSIS WASN’T ACTUALLY UNTIL AFTER THE FIRST ANATOMIC DESCRIPTION OF THE PROCESS WE CONNECTED THE CLINICAL PICTURE OF THE PLAQUE. AND THE CONNECTION WITH CHOLESTEROL GOES BACK NOW OVER 100 YEARS AND HE WAS AN OFFICER IN THE ARMY AND WOULD RAISE RABBITS FOR FOOD AND FED THEM TABLE SCRAPS AND WE ONLY KNEW THREE MOLECULES, GLUCOSE, CHOLESTEROL AND ACID. AND WE KNEW THE CHEMICAL STRUCTURES OF THOSE ENTITIES. IT WAS KNOWN WHAT FOODS WERE RICH IN CHOLESTEROL AND FED THEM EGG YOKES. SO WE’VE KNOWN ABOUT CHOLESTEROL FOR OVER 100 YEARS. AND THE NEXT WAS DISCOVERED HERE AT NIH. GOFMAN WAS A PHYSICISTS WHO WORKED ON A LARGE PROJECT AND THEY COINED THE TERM OF HIGH DENSITY AND LOW DENSITY AND REALIZED CHOLESTEROL WAS CARRIED ON PARTICLES AND REALIZED THAT CHOLESTEROL AND LDL WAS PARTICULARLY BAD. WE FIND CHOLESTEROL IS AN INDICATION OF DECREASED RISK. THEN I’M NOT GOING TO TALK A LOT ABOUT IT BUT THERE WAS A MAJOR CONCEPTUAL BREAKTHROUGH BY DAN STEINBERG IN THE ’80s THAT LDL CAN GO OXIDATION OR MODIFICATION AND THAT’S NOT LDL WHERE YOU HAVE DIFFERENT FRACTIONS OF LDL AND HDL AND THEY HAVE A DIFFERENT EFFECT ON ARTERIOSCLEROSIS. AND THIS IS A SLIDE OF THE FIRST HOWARD HUGHS DIRECTOR AND DISCOVERED DISEASES WE STUDY TODAY. HIS BEST LEGACY WERE THE NUMBER OF PEOPLE HE TRAINED. MOST OF WHOM HAVE PASSED OR RETIRED BUT TONY GAUDO IS STILL ACTIVE AND VIRGIL BROWN WHO IS ONE OF MY MENTORS IS STILL AROUND. SO A LOT OF THEM I’LL TALK ABOUT AND THE PATHWAYS WERE DISCOVERED HERE. IN REGARD TO THE PATHWAYS. THESE THE PARTICLES. THERE’S DIFFERENT TYPES OF LIPO PROTEIN PARTICLES. THE LARGEST ARE AS LARGE AS A MICRON IN DIAMETER AND THE PIE CHART INDICATE THE RED IS TRIGLYCERIDES. THEY CARRY MOSTLY TRIGLYCERIDES AND CARRY THEM FROM THE DYE TO THE REST OF THE BODY. THE NEXT LARGEST PARTICLES OF THE LDL IS ABOUT 100 NANOMETERS PRODUCED IN THE LIVER AND IT’S A TRIGLYCERIDE RICH PARTICLE AND WHAT I’LL TALK ABOUT HERE IS WHAT I CIRCLED IN YELLOW. THAT IS HDL. IT’S ABOUT 10 NANOMETERS AND IT’S A PROTEIN BALL THOUGH IT HAS SOME LIPIDS. SO THIS IS PROBABLY GOING TO SCARE YOU. IN MEDICAL SCHOOL WHEN I SAW A COAGULATION PATHWAY AND I DECIDED I LOOK AT THE THREE PATH WAYS AND I THINK IT’S SIMPLE. YOU HAVE TWO OVERLAPPING PATHWAYS AND I WON’T GO INTO GREAT DETAIL BUT I MENTIONED THE MICRON. YOU HAVE THEANENDOGENOUS WAYS AND THEY HAVE TRIGLYCERIDES AND THE FATTY ACIDS GO TO THE LIVER AND IT UNDER GOES GLYCOLOSIS AND A LITTLE BIT LEAKS IN YOUR VESSELS AND CAUSE THEAGE — SCLEROSIS. THIS HAS TISSUES THAT CAN SYNTHESIZE THE CHOLESTEROL AND IT’S WATER SOLUBLE AND 8 GRAMS EACH DAY CAN RETURN TO THE LIVER FOR SECRETION. AND HDL COMES IN TWO BASIC FLARES. A MAYOR COMPONENT I’LL TALK ABOUT LATER. IT STABILIZES THE STRUCTURE AND IT’S PARTICULARLY GOOD IN REMOVING EXCESS CHOLESTEROL FROM CELLS AND EXPLAIN HOW THAT WORKS IN A SECOND BEEN AND MOST LIPO PROTEINS ARE SPHERICAL AND A SINGLE LAYER OF PHOSPHO LIPIDS AND THIS IS WHERE THE TRIGLYCERIDES ARE STORED. IN THE CASE OF THE LDL THEY’RE DELIVERED TO THE THE LIVER. IT’S A CONVENIENT WAY TO MEASURE THE NUMBER OF THE PARTICLES. AND THESE ARE COMPLEX PARTICLES. AND THEY CARRY OVER 80 DIFFERENT PROTEINS IN THE CASE OF HDL AND OVER 200 SPECIES OF LIMB IDS. I — LIPIDS. GIVEN THE COMPOSITIONAL COMPLEXITIES IT’S NOT SURPRISING THERE’S DIFFERENT FUNCTIONS OF HDL AND WE DON’T UNDERSTAND THE TRUE CLINICAL SIGNIFICANT CELLS AND I’LL EXPLAIN HOW IT’S LINKED. THIS PATHWAY BEGINS MAIN THE MAIN PROTEIN COMPONENT INTERACTS WITH A PROTEIN DISCOVERED IN PART BY AND WAS THE ABC1 TRANSPORTER AND THIS ACQUIRED LIPID AND FORMS STRUCTURES AND THEY GO OUT TO THE PERIPHERY TO TAKE ADDITION CHOLESTEROL BY MACRO-PHAGES AND IT’S AN ANTHROPATHIC LIPID AND IT GOES TO THE CORE AND TRAPPED OR SOME IS TRANSFERRED IN EXCHANGE FOR LDL. THIS IS THE FULL PATHWAY. AND SOME IS FREE AND IT’S ALSO D DISASSOCIATES AND IT’S CARRIED BY THE TRANSPORTER WE’RE STILL NOT SURE WHAT IT’S FLIPPING AND THE MIC DOMAIN CAUSES IT TO DISASSOCIATE AND THROUGH A DETERGENT-LIKE PROCESS YOU GET THE PARTICLES AND CAN GET MOVEMENT BY DIFFUSION OR OTHER MEANS. THIS CHOLESTEROL IS NOW TRAPPED IN THE CORE AND THEN RETURNED. HOW DOES THIS RELATE TO THE PATHOGEN OF SCLEROSIS? SOME IS A SEMANTIC ARGUMENT. WHAT IS INFLAMMATION. I WON’T TRY TO ANSWER THAT BUT I THINK MY INFORMATION IS THE RESPONSE OF BODY TO INJURY. IT’S A BROAD VIEW. SO THERE’S DEFINITELY INJURY TO THE VESSEL WALL. LDL IS NOT THE WHOLE STORY AND SOME PEOPLE HAVE WILDLY DIFFERENT LDLs AND RESPOND DIFFERENTLY TO THE PROCESS BUT WITHOUT LDL YOU PROBABLY DON’T DEVELOP ATHEROSCLEROSIS AND I MENTIONED DAN STEINBERG AND HE TALKED ABOUT OXIDIZATION AND I’M NOT SURE ABOUT THAT AND WE STILL DON’T UNDERSTAND HOW LDL GETS IN BUT ONCE IT GETS IN IT PRIME THE MACROPHAGES AND THAT MAY BE BECAUSE WHEN MACROPHAGES GOBBLE UP MEMBRANE THAT’S A SIGNAL THAT’S DAMAGES AND ONCE THEY TAKE UP THE LDL THEY SECRETE ENZYMES THAT CAUSE PROLIFERATION OF CELLS AND THEY SECRETE CITE CITE — CYTOKINES AND CAUSE CHANGES IN THE EPITHELIUM. HAVE YOU INFILTRATION OF LDL WHICH TRIGGERS GREATER MACROPHAGES. THIS HAPPENS TO EVERYONE TO A SMALL DEGREE. NOW, AFTER MANY YEARS THERE’S COMPLEX PLAQUE. YOU DEVELOP WHAT IS ESSENTIALLY A NECTROTIC COUR AND YOU HAVE A FIBROUS CAP THAT’S THIN AND COVERS THAT AND THIS ALL HAPPENS IN THE CELLS. WE ALL VIT TO SOME DEGREE. THIS IS WHAT CAUSES A HEART ATTACK HE IS YOU CAN HAVE IT IN YOUR FEMORALS. AND THIS IS THE LUMEN AND YOU CAN SEE YOU HAVE THE FINAL PART IS YOU HAVE SOME IMPEDING OF THE BLOOD FLOW BUT THE FINAL ONE IS USUALLY A THROMBIS. AND ONE DISCOVERY WAS RISK FACTORS. IT’S A CORRELATED WITH CARDIOVASCULAR DISEASE BUT FROM THE WORK IN THE ’50s WHAT IS CLARIFIED IS THAT HDL IS VIRTUALLY RELATED. THEY HAD HIGH LDL CHOLESTEROL. THIS START THE THIS INAND YANG OF THE BAD CHOLESTEROL AND GOOD CHOLESTEROL. YOU NEED LDL TO HAVE ATHEROSCLEROSIS AND IN TERMS OF A RISK FACTOR, LDL IS NOT GREAT AND MANY ARE ON STATINS AND YOU GET THIS PERVERSE THING AND HAVE YOU LOWER LDL BUT EVEN IT’S NOT GOOD AS HDL AND EVEN THOUGH LDL CHOLESTEROL IS A TARGET FOR THERAPY. WHY IS HDL SO GOOD. LDL INFILTRATES THE WALL AND IF YOU HAVE GREATER UPTAKE AND HAVE YOU CELLS WHICH BECOME SENSE — S SENSITIZED CELLS AND THEY BECOME LAZY AND DON’T MOVE. WHEN YOU REMOVE CHOLESTEROL THEY BECOME MORE MOBILE. HDL IS ALSO ANTI-INFLAMMATORY AND SEEMS TO EXPRESS CD11 MONOCYTES AND HDL HYDROLIZE LIPIDS. AND STATINS HELP REDUCE CARDIOVASCULAR DISEASE AND HEARD DISEASE IS STILL COMMON AND THE MOST COMMON CAUSE HAS DECREASED THANKS TO THE RECENT DISCOVERIES BUT WE STILL HAVE A WAY TO GO. WHAT MOST DON’T REALIZE IS STATINS UNDER THE BEST CIRCUMSTANCES REDUCE CHANCES BY 30%. PATIENTS ARE COMPLYING AND SOMETIMES AREN’T COMPLYING AND GO OFF MEDS. IN PRACTICE, THEY CHIEF THIS. THERE ARE NEW DRUGS THAT ARE INHIBITORS BUT BECAUSE OF THE FACT WE’RE WE HAVEN’T SOLVED IT COMBINATION DRUGS.LS THAT USE – THEY DO MANY THINGS. ONE COMBINATION OFTEN TIMES RAISE HDL SO THIS RAISED ENTHUSIASM 10, 15 YEARS AGO THAT SUGGESTS WE CAN STOP ATHEROSCLEROSIS AND I’M NOT GOING TO TALK TOO MUCH ABOUT THAT DURING THIS TALK BUT UNFORTUNATELY, IT’S BEEN DISAPPOINTING SO FAR. THERE’S BEEN A LOT OF EFFORT TO TRY TO RAISE HDL AND THE FOCUS IS MOSTLY ON HDL CHOLESTEROL AND I’LL TALK MORE ABOUT THAT AND SO FAR WE DON’T REALLY HAVE GOOD DRUGS THAT RAISE HDL THAT SEEM TO DO MORE THAN WHAT WE CAN DO WITH STATINS BUT I’M STILL CONVINCED WE STILL NEED TO DO RESEARCH TO UNDERSTAND HOW HDL IS WORKING. SO A LITTLE ABOUT HDL INFORMATION. SO I THOUGHT ABOUT HOW COULD HDL INTERFERE WITH THE INFLAMMATORY PROCESS IN TERMS OF WHAT WE THINK HDL DOES. ONE THING WE THINK HDL DOES IS PROMOTE CHOLESTEROL REMOVAL. IT MOSTLY REMOVES IT FROM CELLS BUT IT MAY HAVE AN IMPACT ON EXTRA CELLULAR CHOLESTEROL AS WELL. AND IT CAN SEQUESTER OXIDIZED LIPID AND SEQUESTER ENDOTOXIN AND THERE’S RECENT DATA NOT PUBLISHED YET AND HDL BINDS START WITH CYTOKINES ARE BOUND TO HDL AND THERE’S A POSSIBLE CONNECTION BETWEEN CYTOKINES AND HDL ITSELF. AND FINALLY, I SAID HDL HAS HAS SOME CARGO THAT’S ANTI-INFLAMMATORY AND THAT MAY BE HOW IT’S BENEFICIAL. SO IN REGARD TO CHOLESTEROL SO THIS IS A PEPTIDE THAT PEOPLE IN MY LAB WOERE WORKING ON AND IT’S A PEPTIDE THAT HAS AMINO ACIDS ON ONE SIDE ARE HYDROPHOBIC. THAT ALLOWS IT TO BIND TO A LIPID AND WHAT THEY HAVE FOUND THERE’SATHERO-SCOTIC EFFECTS. AND THERE’S STILL ONGOING TESTS. AND YOU CAN GET A SIMILAR RESULT WITH THE HDL WITH THE PEP SIDE. IF YOU TAKE THAT PEPTIDE OR HDL AND INCUBATE IT ONE THING YOU’D NOTICE IT SUPPRESSES THE RELEASE OR IF YOU TAKE BLOOD AND STIMULATE WITH ELECTIN AND IT NORMALLY CAUSES CYTOKINES AND YOU CAN SUPPRESS THEM AND THERE’S A POLYMER OF GLUCOSE THAT REMOVES CHOLESTEROL. SO WHY ARE YOU TURNING ON THE IN FLAMATION AND THE ENGULFMENT OF LIPID MAY BE A DANGEROUS SIGNAL. THE OTHER POSSIBILITY I FAVOR IS THAT CHOLESTEROL IS VERY IMPORTANT IN MANY BIOLOGIC PROCESSES AND YOU NEED THE RIGHT AMOUNT OF CHOLESTEROL. SO IF YOU MODULATE THE CHOLESTEROL THE SIGNALLING IS DIFFERENT AND YOU NEED LIVE CELLS AND IF YOU MODULATE THAT IT DAMAGES. AND THIS IS A COMMON INFORMATION THAT INFLAMMATION IS DAMAGES AND MAY RELATE TO THE REMOVAL OF CHOLESTEROL. THERE’S ANOTHER DISEASE DISCOVERED IS L-PATH EFFICIENCY. THEY GET FISH EYE DISEASE. IF YOU HAVE COMPLETE DEFICIENCY YOU ALSO HAVE RENAL DISEASE AND GET DEPOSITS OF LIPIDS IN THE KIDNEY AND NORMALLY LIPO PROTEINS ARE SINGLE LAYER PHOSLIPIDS BUT THEY REORGANIZE AND HAVE STRUCTURES THAT ARE ABOUT 50, 30, 40 PERCENT THAT GET TRAPPED IN THE TISSUES. AND THEY TRIGGER INFORMATION AND RENAL DAMAGE. SO THIS SIS UNPUBLISHED DATA BUT WE FOUND IT ACTIVATES YOU GET SECRETION. IT’S NOT JUST PHOS LIPIDS WON’T DO THAT AND IT DESTABILIZES THE LI LIPO SOMES. THIS CAN PRIME CELLS TO ACTIVATE THE INFLAMMATORY PROCESS. AND WE FOUND THERE’S A FIXATION IN THE KIDNEY BY THE ALTERNATIVE PATHWAY. THERE’S A FIX WITH THE GLOBULIN AND IT ATTACH HERE. WE MADE ARTICLES THAT WERE MISSING THE GROUP WE THINK AS THE ACCUMULATION IN THE HYDROXYL GROUP. AND EARLY ON YOU SEE CELLULAR DEPOSITS AND THEY’RE VERY INFLAMMATORY. THE WAY URIC CRYSTALS ARE INFLAMMATORY. THEY’RE REACTIVE BECAUSE THE MACROPHAGES RESPOND TO THAT. IT SHOWS AS DESCRIBED BY OTHERS, PHOSPHO CRYSTALS WILL IN FLAME THEM BUT WE THOUGHT IT WAS DUE TO HDL AFFECTING THE CRYSTALS. WE SAW THE SIGNAL — YOU NEED TO HAVE THE MACROPHAGIA PRIMED AND YOU GET THE CELLS DECREASING THE DATA WITH THE TRUE HDL AND THINK IT HAS TO DO WITH THE COUPLING BETWEEN THE MEMBRANE AND SIGNALS.>>SO ENDOTOXIN SAY LIPID AND HAS BASAL CHAINS. THERE’S STILL GREAT INTEREST IN-DL FOR SEPSIS. THE REASON IS HDL WILL SEQUESTER AND NEUTRALIZE ENDOTOXIN. TIS WILL THE REMOVES THE LIPID MOLECULE AND THE HIGHEST PATIENTS HAD 60 VERSUS 30 AND THE PATIENTS WITH HIGH HDL DON’T DEVELOP CYTOKINES. THERE’S A NEW THEORY HAVE YOU LOW AMOUNTS OF ENDOTOXIN SXESHG — EXPOSURE FROM WHAT THEY CALL LEAKY GUT AND THE SEQUESTER IS BENEFICIAL. THE LAST THING I’D LIKE TO TALK ABOUT IS IT THE REST THE BENEFICIAL EFFECTS OF HDL. OF WASHINGTON HAS A MAJOR DISCOVERY IN 2007 SHOWING BESIDES 70% OF THE THE PROTEIN MASS, THERE’S OTHER PROTEINS THAT ARE LOOSELY ATTACHED. AND IF HAVE YOU EVEN A SMALL HYDROPHOBIC LOOP IT WILL INSERT IT INTO THE HDL. THE WAY AND HDL SEEMS TO HAVE THE CORONA THAT ARE LOOSELY ATTACHED RIGHT TO THE INSERTION INTO THE HDL.>>AND ONE EXAMPLE IS ACUTE REACTANT AND IT NEUTRALIZES THE ABILITY TO THE E-FLUX. THAT’S ONE EXAMPLE. IS THIS FROM OUR LABORATORY BY SCOTT GORDON. THE OTHER THING SCOTT DID WAS A STUDY WAS A FAMOUS STUDY DONE BY THE JUPITER STUDY WHERE THEY HAD PATIENTS WITH LOW LDL AND THEY BENEFIT. PEOPLE THINK IT DOESN’T MAKE SENSE. THIS WAS ACTUALLY NOW ALMOST TEN YEARS AGO AND SUGGESTED THAT STATINS THEMSELVES MAY BE ANTI-INFLAMMATORY. WE ASKED WHAT ELSE DO STATINS DO BESIDES LOWERING LDL. WE SAID LET’S LOOK AT THE PROTEOME OF LDL AND WE DID THAT BY MODELLING.>>THERE’S BINDINGS AND ONCE THEY’RE OXIDIZED IT DOESN’T WORK. SO WHY’S THAT IMPORTANT? THE ENZYME IS SECRETED FOR DIGESTION AND ONE IS RELEASED AND THEY NIBBLE ON THE SO-CALLED RECEPTORS. AND IF THEY’RE EXPOSED THEY CAN GET QUICKLY INACTIVATED BY OXYGEN RADICALS PRODUCED BY WHITE CELLS. THE IDEA IS IT’S PROTECTED AND CAN DO ITS JOB. AND THEY FOUND IT WORKS. AND THIS MAY BE MODULATING INFLAMMATION. AND THERE’S RECEPTORS IN THE ENDOTHELIAL CELLS AND THIS IS SCOTT IN MY LAB AND A PROJECT HE’S WORKING ON. MOST PEOPLE TALK ABOUT CHOLESTEROL BUT IT CARRIES DIFFERENT LIPIDS. SO THERE’S WORK DONE AT THE NIH AND THEY FOUND MOST BOND TO HDL AND DELIVERED TO THE RECEPTORS AND MEANS THE WONDERFUL IMPACTS. PEOPLE ARE INTERESTED IN DEVELOPING STABLE ANALOGS AS A TREATMENT FOR ATHEROSCLEROSIS AND WE LOOKED AT PATIENTS FROM THE HEART STUDY AND HAD A HIGH OR LOW HDL, WITH OR WITHOUT HEART DISEASE AND PATIENT WITH HIGHER S1P CONTENT HAD A LOWER INSTANCE OF HEART DISEASE. THIS IS DONE IN COLLABORATION WITH SCOTT HARGRAVES. HE DESERVES ALL THE CREDIT. HE WORKS IN THE CELLS AND FOUND DELIVERING IT IMPROVES BARRIER FUNCTION. FINALLY, IS IT A PATHOGENIC TO HEART DISEASE AND I THINK WE HAVE TO DO MORE THAN JUST LOOK AT CHOLESTEROL. SHOULD WE MEASURE IT? IT’S NOT A GOOD MARKER FOR MEASURING IT AND THERE MAY BE OHER WAYS TO MEASURE IT ONE HAS TO BE CAREFUL GOING FORWARD IN THE FUTURE USING AS A TARGET THERAPY. WE MAY HAVE TO MEASURE OTHER FUNCTIONS OF HDL IN TERMS OF DEVELOPING DRUGS THAT MODULATE HDL THE BOTTOM LINE IS WE NEED TO LEARN MORE ABOUT HDL AND DO MORE CAREFUL COMPOSITION AND DESPITE RECENT DISAPPOINTS I RESEARCH AND MORE NOT LESS IS NEED TO HARNESS THE POWER OF HDL FOR REDUCING HEART DISEASE. THESE ARE PEOPLE, SOME OF WHICH HAVE LEFT MY LAB, I’M ANSWER QUESTIONS AFTER.>>THANK YOU VERY MUCH. >>I THINK IT RELATES TO THE BIOPHYSICS OF THE CURVATURE. THERE’S PROBABLY SOME PROTEIN-PROTEN INTERACTION. I HAVEN’T FOUND IT YET.>>WHAT ABOUT A HYDROPROBIC DRUG?>>SOME BIND TO THE PROTEINS AS WELL. THERE ARE PHYSICAL DIFFERENCES BETWEEN THE LIPIDS ON THE SURFACE OF LDL AND HDL AND THE CORE. THERE’S PROBABLY SOME DIFFERENCES BUT NOT A LOT OF DIFFERENCE. IN MANY DIFFERENCE IT’S THE SIZE OF THE PARTICLES AND RELATE TO THE CURVATURE OR PEPTIDES THEY PREFER TO BOND TO HDL.>>ANOTHER PART OF THAT, BRIEFLY IN SCIENCE, THERE WAS A CLAIM THAT LIPIDS PRODUCED MATERIALS WIND UP IN PLAQUES. IS THAT TRUE?>>THERE’S A NEW HYPOTHESIS WE’RE AUD EXPOSED TO ENDOTOXIN SO WE ALL HAVE LOW DOSE NETOXIN AND ONE HAS PURE LIPID. SO LOTS OF THINGS END UP THERE. IT’S TRUE THE TOXIN IS PRESENT. THR [QUESTION INDISCERNIBLE]>>I THINK AGAIN IT GOES TO WHAT I SAID EARLIER AS YOU KNOW, WE MEASURE LDL AND HDL BY THE CONTENT. IF YOU DO ANOTHER BASE THERE’S 30 TO 40 TIMES MORE LDL THAN HDL. MOST THE DATA SHOWS HIGHER HDL IS BENEFICIAL FROM AN EPIDEMIOLOGIC STANDPOINT AND LIKE MANY THINGS IN LIFE, MANY TOO MUCH HDL IS BAD AND NOT ALL IS GOOD. PEOPLE WITH EXTREME LEVEL OF HDL MAY NOT HAVE THE PROTECTION YOU THINK BUT IN GENERAL LOW HDL IS BAD AND OFTEN ASSOCIATED WITH HIGH TG AND LDL CHOLESTEROL AND SORT OUT THE CAUSE AND WHICH IS A MARKER. WE STILL DON’T KNOW YET.>>LET ME ASK YOU A QUESTION. ARE INTERNISTS AND CARD YOL — CARDIOLOGISTS MEASURE A PROTEIN AND THEY GIVE ADVICE ON WHAT YOU SHOULD DO FOR YOUR HEART. I FIND IT PUZZLING. I CAN SEE IF HAVE YOU OTHER PROBLEMS WITH YOUR HEART. WHAT’S IT MEAN? THE SECOND THING IS WHAT WE NOW CALL AUTOIMMUNE DISEASE WE BLAMED ON CHRONIC INFLAMMATION AND PEOPLE HAD THEIR GALLBLADDERS REMOVED AND APPENDIX APPENDIXES REMOVE AND SO FORTH. A AND WHAT’S IT MEAN IF SOMEBODY HAS CHRONIC INFLAMMATION BUT DOESN’T HAVE HEART DISEASE. IS THEY RISK FACTOR?>>I’LL LET DOCTOR ANSWER THAT BECAUSE THAT’S UP HIS ALLEY. SO ON THE FIRST ONE, THE SKEPTICISM ABOUT THE UTILITY OF CRP AS A MARKER PARTICULARLY IN EUROPE. LESS SO HERE. AND THIS IS MY VIEW AND I’M NOT AN EXPERT BUT MY VIEW IS WE UNDER TREAT HEART DISEASE AND MANY PEOPLE ON STATINS GO OFF THEM. WE’RE NOT TREATING EVERYONE WHO CAN BENEFIT FROM STATINS AND THERE’S A LARGE NUMBER OF PEOPLE AT AN INCREDIBLE RISK THAT CAN GO BOTH WAYS AND I THINK CRPs VALUABLE FOR PEOPLE AT RISK AND THERE’S MORE ADVANCED TESTING. I THINK IF YOU HAVE CLEAR HEART DISEASE YOU WANT TO DO STATINS. IF YOU’RE A TRIATHELETE AND HAVE NO RISK FACTORS.>>SOME DROP DEFEND A HEART ATTACK.>>IF YOU’RE LIKE MOST OF US YOU HAVE AN INTERMEDIATE RISK. MY THOUGHT SIT HELPS.>>THANK YOU VERY MUCH AND WE CAN ASK MORE QUESTIONS AFTER. >>I’M TAKING NOTES WHICH MEANS I’M LEARNING AND I ALWAYS LEARN SOMETHING FROM ALLEN. I’M GOING TO TAKE THE INFLAMMATORY ROUTE IN HUMANS AND I’M A CARDIOLOGIST BY TRAINING AS SAID. THIS IS A LITTLE BIT OF A I DO BELIEVE IT’S CAUSAL DEBATE. I’M GOING PRESENT A FEW LINES OF EVIDENCE. BURY BEGIN THE TALK FORMALLY I WANT TO MAKE SURE EVERYBODY KNOWS IT’S CALLED CARDIOMETABOLIC DISEASE NOT METABOLIC SYNDROME. WHEN I BRING IT UP IT’S A COMBINATION OF VASCULAR DISEASES AND METABOLIC DISEASES. I LEAD THE SECTION OF INFLAMMATION AND CARDIOMETABOLIC DISEASES. WHAT THOSE ARE ANYTHING ON THE SLIDE WHETHER IT’S INSULIN RESISTANCE OR OBESITY OR HIGH CHOLESTEROL. THE REASON THIS WAS DONE IS IT ENCOMPASSES AN EASIER WAY FOR A PROVIDER TO TELL A PATIENT HAVE YOU CARDIOMETABOLIC DISEASE RATHER THAN METABOLIC DISEASE. CARDIOMETABOLIC DISEASE COMES UP OFTEN. I WON’T GO THROUGH A LOT OF THE SLIDES WHICH I HAVE WHICH HAVE GREAT BECAUSE I CAN GET TO THE STUFF I WANT TO TALK ABOUT. ATHEROSCLEROSIS SAY DISEASE OF INFLAMMATION. IT STARTS WITH A VESSEL WALL NOT IN FLAMED AND IN THE RIGHT SETTING WHETHE IT’S SKIN DISEASE OR OBESITY OR SMOKING, THEY START ATTRACTING MESSENGERS THAT BEGIN THE PROFS THAT ENDS IN AN UNFORTUNATE AMOUNT OF PEOPLE, ONE IN FIVE, WILL GET PLAQUE RUPTURE AND THROMBUS AND HEART ATTACK. I BELIEVE YOU NEED INFLAMMATION TO START THIS. WE KNOW WHEN HAVE YOU HIGH LEVELS OF LDL IN 10,000 WOMEN HAVE YOU A TWO-FOLD INCREASE OF HEART DISEASE AND WHEN HAVE YOU HIGH SENSITIVITY C-REACTIVE PROTEIN HAVE YOU A FOUR-FOLD EVENTS OF FUTURE EVENTS. SOMETHING IN 2002, 15 YEARS AGO SHOWED IT LED TO THESE EVENTS IN WOMEN. IT BECAME SO IMPORTANT. IN 2012, THE TWO TRIALS STARTED. THE ONE ON YOUR RIGHT IS NOW DONE THE INHIBITOR TRIAL. LET ME WALK YOU THROUGH THIS. THIS IS NOW WHY IT’S EASY FOR ME TO END THE TALK HALF HOUR EARLIER AND SAY I BELIEVE INFLAMMATION IS CAUSAL BECAUSE THE TRY TO ON YOUR RIGHT REALLY GAVE ARGUMENT OR WEIGHT TO THE ARGUMENT. SO WHAT’S THE TRIAL? BASICALLY IF YOU HAD AN M.I. AND WERE RANDOMIZED TO SOMETHING WHO STOP THE INFLAMANT CELL. AND THIS IS AN INHIBITOR AND BROUGHT IT OUT TO THOSE WHO HAD AN M.I. AND 15,000 PEOPLE WERE IN THE STUDY AND UP AUGUST THEY RELEASED THE GROUPS HAD A 15% REDUCTION IN THEIR SECOND HEART ATTACK. THEY’RE MAIMALLY GETTING TREATED AND ON MAXIMUM TREATED AND THEY’RE OUR HIGHEST RISK POPULATION, 45% WILL HAVE ANOTHER EVENT. WE ASK, WAS IT INFLAMMATION. I RAISE MY HAND AND SAY IT WORKED AND I DON’T KNOW HOW BUT KEEPS US IN BUSINESS FOR ANOTHER DECADE BECAUSE NOBODY KNOWS WHY IT WORKS. THE TRIAL ON YOUR LEFT IS 5500 PEOPLE, WAVE YOUR HAND MORE, ME METHOTREXATE AS HAN INHIBITOR pPLACEBO AND IT’S NOW 5500 H THE STRONG. SO THESE TRIALS ARE $1 BILLION PEOPLE BELIEVE INFLAMMATION IS CAUSAL. THE TRIAL ON THE RIGHT IS $880 BILLION CHEAP. THE TRIAL ON THE RIGHT IS EXTRA MURAL. NOT BAD, RIGHT? THERE’S A DIFFERENT WAY OF LOOKING AT THE DEVELOPMENT OF HEART DISEASE. I LEARNED FROM THE FIRST FACTS WHEN I ARRIVED TRYING TO DERIVE MY PRECLINICAL PROGRAM IS A MOUSE IS NOT GOING TO GET ATHERO UNTIL YOU DO SOMETHING AND IF YOU’RE TRYING TO MAKE AN ARGUMENT TO LOOK AT THE TWO PAPERS THE SECOND PAPER WENT THROUGH HOW MANY RESPONSES DOWN TO SEXES, DOWN TO DIFFERENT PLACES THE HUMAN EQUIVALENT AT THE IMMUNE RESPONSE WAS DIE DIAMETRICALLY DIFFERENT OF THE MOUSE RESPONSE. SO WE NEED AT TIMES A HUMAN MODEL. HAVE YOU AN ASSOCIATION STUDIED WHEN IT’S MODULATED TO THE IN FLAMED STATE AND THEY CAN BE TESTED FOR MODULATION. MY NEXT 10 MINUTES, MAYBE LESS, WILL BE ABOUT THE MODEL OF GIVING ENDOTOXIN TO A HUMAN BEING AND I DID THIS IN OVER 300 INDIVIDUALS BEFORE COMING TO THE NIH AND IT’S SAFE AND WE GAVE VARYING DOSES. HERE THE HYPOTHESIS WE’LL BE ABLE TO STUDY METABOLIC SERVICES IN THIS AND THE ENDOTOXEMIC STATE RESEMBLES CARDIOMETABOLIC DISEASES. SO THIS STUDIES I’LL GO OVER I THINK ARE TWO IN THE LPS MODEL AND THEN TURN TO A CHRONIC DISEASE SO YOU GET THE IDEA OF WHAT I’LL TALK ABOUT. THIS IS MY CONCEPTUAL DIAGRAM IN 2006. WE USED ENDOTOXIN TO LOOK AT THE ACCESSIBLE TISSUES AND USED THE PATHWAY DOWN WHICH WE KNOW LEADS TO CARDIOVASCULAR EVENTS AND ARE USING THE TWO CELLS AS A WAY TO UNDERSTAND HOW INFLAMMATION MODULATES THE PROCESSES. THERE WERE HEALTHY HUMANS SCREENED LOOKING FOR OBESITY AND HAVE THEM GO ON A STANDARD DIET AND MEASURE THEM FOR FAT AND ADMIT THEM AND GIVE THEM SALINE AND WE HAD INSULIN SENSITIVITY DONE HERE, HERE AND HERE. HERE’S DATA. IF YOU AND THERE’S LOW LEVELS OF THE PROTEINS. THIS IS ADD — AND WHAT WAS EYE OPENING WAS THE ADIPOSE CONTINUED TO EXPRESS. DEF AND THIS IS MY CONCEPT OF REVERSE CHOLESTEROL TRANSPORT. IT’S A MACROPHAGE LOADED WITH CHOLESTEROL MAKES IT WAY BACK FOR THE HDL TO DEPOSIT CHOLESTEROL INTO YOUR POOP SO IT GETS EXCRETED IN THE FECES. WE HAVE ABOUT 30% ON AVERAGE OF HDL FUNCTION. THIS TOOK TIME AND AFTER 36 HOURS WE STARTED SEEING RECOVERY. INFLAMMATION RETARDS THE FUNCTION IN HEALTHY HUMANS. THAT’S A GOOD OBSERVATION. WHAT ABOUT INSULIN RESISTANCE. I WON’T GO INTO THIS AT 5:00 ON A WEEKDAY AFTERNOON BECAUSE IF YOU’RE NOT ALREADY ASLEEP YOU’LL BE ASLEEP AND THIS MOVES UP ONCE THE INSULIN IS DOWN AND IN THE PRESENCE OF ANYTHING IN RED, THIS PROCESS SLOWS DOWN AND SO ENDOTOXIN VIA THE TNF RECEPTOR CAN HAVE A SEARING RELATION THAT RETARDS IT SO THE CELL AND CAN GO TO THE NUCLEUS AND TRANSCRIBE THE INFLAMMATORIO INFLAMMATORY CYTOKINES. WELL, WHAT HAPPENED TO THE HEALTHY HUMANS? AT SALINE NOTHING HAPPENED AND THEN THEY BECOME INSULIN RESISTA RESISTANT AS MUCH AS DIABETICS. AND THAT WAS A KEY QUESTION BY THE REVIEWER, DID HAVE YOU THE BETA CELL CHANGED? NO. MANY RECEPTORS WENT DOWN AND THE SUPPRESSER OF THE CYTOKINE SIGNALLER WENT UP. A NEAT FOLLOW. AT THAT MOMENT YOU SHOULD SAY, THAT’S CREATE. I HAVE PROVEN SOMETHING. IT’S NOT CAUSAL YET. WHAT I LEARNED IN 2007 IS WRITING GRANTS IS HARD AND WRITING PAPERS IS HARD BECAUSE EVERYBODY KEPT SAYING YOUR MODEL WORKS BUT IT DOESN’T REPRESENT TRUE IN VIVO INFLAMMATION. IT COULD A STRESS RESPONSE. AT THAT MOMENT, IT WAS 2007, I HAD MY — IT’S LIKE A DEFLATION AT THAT MOMENT BECAUSE WE HAD A PAPER PUT OUT BUT NO GRANTS WERE BEING FUNDED. I’M RIDING AN ELEVATOR WITH MY SMILE AND HEART ON MY CARDIOLOGY ON AT PENN AND SOMEONE ASKED ME DO YOU WANT TO STUDY INFLAMMATION AND HEART DISEASE AND I SAID I AM, WHY DO YOU ASK AND THEY SAID CARDIOLOGY LOOKS INTERESTING TO YOU. I’M GOING IT TELL YOU WHAT THE HUMAN STUDIES ARE. COULD THERE BE A CHRONIC INFLAMMATORY HUMAN STATE. I DON’T KNOW WHY MY PICTURE DIDN’T COME THROUGH BUT I USUALLY HAVE A BIG PICTURE AND THIS DERMATOLOGIST GAVE ME THE NICE INTRODUCTION BUT I DISCOVERED PSORIASIS ASSOCIATED WITH M.I. PSORIASIS IS AN INFLAMMATORY SKIN DISEASE, ITCHY, SCALY SKIN. THE LAST PART, THERE’S BIG IMMUNE CELLS WHERE THEY’RE ACTIVATED. THIS COMES BY WAY OF A CONCEPTUAL MODEL PUT TOGETHER WITH A STUDENT OF MIND AND WE LOOKED AS PSORIASIS AS A MODEL OF IMMUNE CELL SIGNATURE AND ACCELERATES ATHEROSCLEROSIS AND PSORIASIS MAY SIGNAL IMMUNE AND METABOLIC DYSFUNCTION. THE FIRST DISCOVERY WAS THAT WHEN HAVE YOU PSORIASIS HAVE YOU A HEART ATTACK RISK THAT’S 58% SELL — ELEVATED AND WHEN YOU ARE 40 OR 50, YOU HAVE A TWO-FOLD INCREASE. HAVING A HEART ATTACK WHEN HAVE YOU PSORIASIS. THAT’S ASTOUNDING. I WANTED TO MAKE SURE THERE WAS AN EPIDEMIOLOGICAL SIGNAL. IT SHOWED INTERNATIONAL ENERGY AGENCY IT SHOWED AN INCREASED RESPONSE. SO NOW’S WHERE IT GETS FUN. WE’VE CONVINCED YOU, HOPEFULLY, THAT INFLAMMATION IS IMPORTANT IN METABOLIC DISEASE. pWITH INFLAMMATION AND PRESIDES
A CAUSALITY. WEAVER ABLE TO USE APPROVED THERAPIES THAT ARE ANTI-AISLE 1223. SO IF THEY INTEREST YOU, RETREAT THEM WITH THE AGENTS AND CAN STUDY WHAT IS THE IN THE HUMAN BY PICKING OFF THE PATHWAY. THE FIRST LEVEL OF EVIDENCE IS SYSTEMIC INFLAMMATION RESEMBLES HAVING A REAL HEART ATTACK. WHEN HAVE YOU PSORIASIS YOU HAVE A NINEFOLD ELEVATION AND FIVEFOLD ELEVATION OF INFLAMMATORY BETA. VERY INTERESTING SYSTEMIC STATE. IT SHOWS WHEN HAVE YOU PSORIASIS YOU HAVE MORE SMALL LDL WHICH IS OXIDIZED AND HAVE YOU THIS SHIFT AND THERE’S ABOUT A 15% DIFFERENCE IN CHOLESTEROL REFLUX. SO I STUDY PSORIASIS. I HAVE A FLAGSHIP PROTOCOL, PSORIASIS. ANYBODY WINDSOR ISIS, 18 TO NO AGE LIMIT, THEY GET SCREENED FOR MAKING SURE THEY HAVE PSORIASIS AND GET IMAGED AND COME BACK IN FOUR YEARS AND WE’LL HAVE 100 NOW AND WE’LL GET 300 AT BASELINE AND 150 FOLLOWED AT ONE YEAR. WE DEEPLY PHENOTYPE ALL OF THEM AND GET CORONARY CTA AND GET BLOOD FOR ALL THE THINGS WE TALKED ABOUT AND GET TISSUE FROM 20% OF THE INDIVIDUAL AND COMPARE THEM TO HEALTHY INDIVIDUALS AND DIABETICS AND PATIENT WITH CORONARY DISEASE AND WE NOW HAVE A ONE-YEAR FOLLOW UP IN THESE PATIENTS TO COMPARE SO THE LAST FIVE OR SEVEN MINUTES OF THE TALK ARE MOST FUN BECAUSE I’LL SHOW YOU DATA THE COHORTS. THE REASON I SPEND TIME ON THE SLIDES, IS IF YOU ARE INTERESTED — I FORGOT TO TELL YOU IN THE BACK OF THIS, THE MOST COMMON CAUSE OF DEATH OF WAS CVB. THE OTHER COMMON CAUSES OF DEATH THE POPULATION 25% CVB AND 15% CANCER AND 10% INFECTION. SO IF CANCER OR CBD INTEREST IT’S AN INTERESTING PROTOCOL AND I’LL GO THROUGH QUICKLY VASCULAR IMAGING AND WE’RE GOING TO FOCUS ON THE CORONARIES BUT THEY ALL GET CORONARY CTA. THE FIRST FINDING IS WHAT YOU SEE ON THE OUTSIDE AND HOW SEVERE THEIR PSORIASIS IS. WHAT YOU SEE ON THE INSIDE IS HOW IN — INFLAMED THEIR AN OWE OWE — AORTAS WORE. IF YOU WANT TO LOOK AT THE TRIAL, THE ENTRY CRITERIA WAS A TARGET TO BACKGROUND RATIO OF INFLAMMATION OF 1.6. ORE PSORIASIS PATIENTS ARE WALKING AROUND WITH THAT ALL THE TIME. HERE’S PSORIASIS AND A CONTROL. WHAT YOU SEE IS THIS TREMENDOUS AMOUNT OF ABNORMAL ACTIVITY. WE DON’T KNOW IF IT’S ATHEROSCLEROSIS. WE DON’T CARE, IT’S VASCULAR INJURY. WE HAVE A PROTOCOL WHERE I CAN RECRUIT SOMEBODY WITH A HEART ATTACK AND THEY’RE VASCULAR INFLAMMATION LOOKS JUST LIKE PSORIASIS AND YOU ARE STILL SEEING THIS ABNORMAL AMOUNT OF LINING IN THOSE WHO JUST HAD A HEART ATTACK. IF THESE ARE TRULY RELATED ENTITIES, PSORIASIS REPRESENTING INFLAMMATION AND CVD REPRESENTING ATHEROSCLEROSIS, MIGHT THEIR CORONARY BE AFFECTED. WE HAVE A CARDIAC CT TO GET CONTRAST AND GET PRETTY PICTURES. I’LL SHOW YOU HOW BECAUSE AT THIS HOUR IT’S NICE TO HAVE AUDIO/VISUAL. WE INJECT DYE AND GIVE A LITTLE BIT OF NITROGLYCERIN AND HAVE A 3-D DESCRIPTION AND MAKE THE MAKE CERTAIN STRUCTURES DISAPPEAR. AND THAT VESSEL IS THE LAD AND IT GOES TO THE APEX. I ASKED FELLOW TO FOLLOW THE MODEL OF THE REPORTING CORONARY SEGMENT. WE’RE LEFT WITH FOUR VIEWS OF THE ARTERY. I’LL PUT THAT IN A CARTOON FORMAT FOR YOU. IF THERE’S VESSELS WE CAN SEE HOW THICK THE ARTERY IS WITH ATHEROCL ATHEROCLOR ARTERIAL SCLEROSIS HAD NON CALCIFIED PLAQUE. SO WE HAVE TAKEN AN INFLAMMATORY SKIN DISEASE AND SHOW IT INCREASES HEART DISEASE. BETTER YET, THERE ARE THOSE READY TO RUPTURE AND WE HAD KNOWN THE RUPTURE PRONE PLAQUES CAUSE MYO CARDIAL INFARCTION. THESE WERE PUBLISHED LOOKING AT A SERIES OF PSORIASIS PATIENTS AND COMPARING THEM TO THOSE 15 YEARS OLDER AND THE PSORIASIS PATIENTS STILL HAD MORE HEART DISEASE NON-CALCIFIED AND HAD THE SAME AMOUNT OF PLAQUE AS SOMEONE 15 YEARS OLDER. ASTOUNDINGLY SCARY. THEY’RE DEVELOPING THE HIGH-RISK PLAQUES WHICH PROBABLY RUPTURE. THERE’S A SIXFOLD INCREASE OF JUSTED HIGH-RISK PLAQUE COMPARED TO THOSE THAT ARE HYPOLIPID PEOPLE. AT THAT POINT THEY PROBABLY OUTCOMPETED THEIR RISK. WHEN YOU TREAT THEM FOR THE FIRST 50 THAT CAME BACK IN ORDER, WE LOOKED AT WHETHER THE TREATMENT OF THE PSORIASIS IMPROVED THEIR HIGH-RISK PLAQUE AND CORONARY DISEASE AND IT DID. IT GIVES ME HOPE THAT TREATING A REMOTE ORGAN CAN AFFECT ANOTHER ORGAN. SO IN CONCLUSION, IT MAY BE CAUSAL IN ESTABLISHING THE DISEASE BUT WE KNOW OF OTHER MODELS WHERE THERE’S NO INFLAMMATION WHERE ATHEROCAN OCCUR BUT THAT’S SMOKING DAMAGE OR DIABETES. THOSE ARE SCENARIOS WHERE I CAN TELL YOU PROBABLY NOT RELATED TO INFLAMMATION. HUMAN DISEASES AUGMENT CDD BY GIVING YOU GOOD DATA AND THE LAST THING I WANT TO LEAVE YOU WITH BEFORE I CLOSE, WHICH IS TREATMENT REDUCES CORONARY DISEASES. HOWEVER, LARGER STUDIES ARE NEEDED. WE’RE NOT IN THE PROCESS OF THE RANDOMIZED TRIALS. IN THE MEANTIME I’LL LEAVE YOU WITH MY CELL PHONE NUMBER AND NIH E-MAIL BUZ BECAUSE I LIKE TO TALK AND HAVE COLLABORATIVE DISCUSSION AND I LEFT TIME FOR QUESTIONS.>>THANK YOU VERY MUCH. THAT WAS QUITE SPECTACULAR AND STIMULATING. ANY QUESTIONS?>>HI, THANKS FOR THE GREAT TALK. I WAS WONDERING WHAT YOU THOUGHT ABOUT THE INCREASED PREVALENCE OF AUTOIMMUNE DISEASE IN WOMEN AND HOW THAT MAY PLAY INTO DIFFERENCES IN GENDER RISK FOR CARDIOVASCULAR DISEASE.>>THAT’S A GREAT QUESTION. WE KNOW CERTAIN ONES ARE UP AND CERTAIN AREN’T. PSORIASIS IS ACROSS ALL MALES AND FEMALE. IBD, MORE WOMEN, LUPUS, MORE WOMEN. I’VE NEVER THOUGHT ABOUT THE HEART DISEASE FOR WOMEN. THERE’S PROBABLY AN INTERPLAY WITH HORMONAL AXIS WHERE MOST DISEASED WOMEN GET THEIR DISEASE PERIMENOPAUSALLY. SO YOU CAN KNOW ONE LEVEL OF EVIDENCES THAT WOMEN AND MEN GET PSORIASIS ABOUT THE SAME AND THE QUESTION YOU ASKED CAME UP IN THE REVIEW IN OUR PAPER WAS THERE GENDER IN THE ACTION ON CORONARY PLAQUE BUT WHEN DO YOU IT IN THE 250, WOMEN WITH PSORIASIS WITH LOW HDL ACTUALLY GET ACCELERATED HEART DISEASE AT AN EARLIER AGE BEFORE MEN PAUSE. — MENOPAUSE. THAT’S A GREAT QUESTION. I’D LOVE TO FOLLOW UP ON YOU WITH THAT. GREAT QUESTION.>>HOW EFFECTIVE DO YOU THINK DIET WOULD BE IN COMBINATION WITH THESE TYPES OF MEDICATIONS?>>ARE YOU ASKING ABOUT MAYBE LIKE A LOW-FAT DIED OR ANY DIET?>>LOW FAT, HIGH VEGETABLES.>>SO WE KNOW THEY’RE GOOD AND ANTI-INFLAMMATORY AND THE SOUTH BEACH DIET KIND OF RIPPED IT OFF. WE TALKED ABOUT THE KETO GENIC DIET IN THE LAB LAST WEEK. WE KNOW OUR MICE WERE IN THE PROCESS OF EATING ALL HIGH CARBOHYDRATE DIET. AND WE KNOW FAT CONTRIBUTES TO PSORIASIS IN HUMANS. WHEN HAVE YOU BYPASS SURGERY AND YOU LOSE WEIGHT YOUR PSORIASIS GOES AWAY IN ONE THIRD. THAT COULD BE THE MACROPHAGES OF THE FAT GOING AWAY. THE LAST IS THEY DID A — WHAT’S NICE ABOUT BEING IN CARDIOLOGY IS IN THE DETERMINE SPACE THEY’RE NOT DEFINITIVE, THE IS SMALL AND UNDER POWERED AND THERE’S A JOURNAL THAT SHOWED IF YOU PUT PEOPLE ON A SUPER RESTRICTIVE CALORIE DIET LIKE IMHUMAN 500, BY WEEK 12 THE PSORIASIS WENT AWAY ON ITS OWN WITH NOTHING ELSE. THERE’S CLEARLY A RELATIONSHIP AND THE LAST PIECE OF EVIDENCE I’LL THROW OUT BECAUSE THIS GOT ME WORKING A LOT RECENTLY, DID YOU KNOW WHAT YOU EAT CAN ILLICIT AN IMMUNE RESPONSE AND PERSON SEEM KNOW CERTAIN FOODS ILLICIT A PREDICTED IMMUNE RESPONSE. THE WAY PSORIASIS IS THAT CAN MAKE A LOT OF SENSE FOR OUR GROUP SO WE’RE LOOKING THAT AS WELL.>>I ALSO HEARD IT COULD BE RELATE TO GLUTEN INTOLERANCE?>>IT CAN. IT COULD BE ON THE SAME SPECTRUM WITH INFLAMMATION AND SETTING OFF DIFFERENT MACROPHAGES.>>NEXT WEEK THE SUBJECT IS THE MICROB MICROBIOME AND SOME OF THESE COMMENTS THAT HAVE BEEN MADE RAISE THE QUESTION OF A NEW FRONTIER MAY PLAY A PART IN ALL OF THESE PROCESSES.>> [QUESTION INDISCERNIBLE]>>GOOD QUESTION. I LOOKED AT THE VARIANTS AND IT STILL DOESN’T REACH SIGNIFICANCE AS AN OVERLAP AND THE ONE YOU HOPED WOULD HAVE WORKED THE GENE THAT CARRIES THE ONE GENE THEY AWAYS GET PSORIASIS BUT WE DON’T KNOW WHEN SO THERE’S CLEARLY AN ENVIRONMENT COMPONENT AND THERE’S CLONAL MUTATIONS ACQUIRED THROUGH PATHOGENETICS THERE MAY BE A GENETIC PREDISPOSITION IN PSORIASIS AND 35% GET AND THERE’S MUTATION ARE KNOWN TO CAUSE LEUKEMIAS BUT NOW IF YOU DON’T GET LEUKEMIA, YOU GET HEART DISEASE. SO PEOPLE ARE GETTING REALLY INTERESTED IN THE MUTANT CARRIERS. MAYBE THERE’S SOMETHING SIMILAR GOING ON AND THAT’S BEING ACCELERATED BY INFLAMMATION AND IN MY COHORT OF 300 NOW, I HAVE SEEN — I HAVE PSORIASIS BUT MY MOM AND DAD HAD M.I. THEIR PARENTS HAD PSORIASIS AND YOU GO TO THE UNCLE’S OR COUSIN’S SPACE AND THERE’S DEFINITELY AN UP REGULATION OR OVER REPRESENTATION OF INFLAMMATORY DISEASES WHETHER IT’S R.A., LUPUS, INFLAMMATORY BOWL DISEASE AND PSORIASIS AND CARDIOVASCULAR DISEASE AND THEY’RE EARLY EVENTS. MY GRANDFATHER HAD IT AT 38 AND YOU’RE LIKE, THIS IS — THEY’RE COMING IN AROUND THAT TIME BECAUSE IT’S ABOUT 10 YEARS BEFORE THEY’RE SCARED OF THEIR EVENT. GOOD QUESTION.>>DO YOU WANT TO ASK QUESTIONS OFF-LINE? ARE YOU OKAY STAYING LONG.>>THE SAYING GOES YOU CAN TALK AS LONG AS YOU WANT BUT WE’RE GOING HOME.>>I WANT TO BE RESPECTFUL.>>I THINK THERE’S A LOT OF MONEY FOR A LITTLE GAIN AND WE HAVE TO UNDERSTAND THE PURPOSE. IT’S $64,000 FOR THE 15% REDISCUSSION WHEREAS A STATIN IS 30% REDUCTION AND I DON’T EVEN KNOW WHAT IT COSTS, $300 OR SOMETHING LIKE THAT. IT’S A FRACTION. [QUESTION INDISCERNIBLE]>>IT’S NON-DETECTABLE IN OUR BLOOD. YOU CAN’T MEASURE LPS. YOU HAVE TO MEASURE WHAT IT’S REACTING TO AND USUALLY SOLUBLE CD-14 LEVELS AND CELL MARKERS. THE DOSE AT 3 NANOGRAMS IS HALF USED BY THE CRITICAL CARE DEPARTMENT. THEY USE 6. I USED THREE AND THE NEXT STUDY USED A FIFTH, .6.>>IS CALCIFICATION IN OTHER ISSUES?>>I THINK CALCIFICATION IS EFFECTIVE. I SAID YOUR LDL DID LOW AND THE CALCIFICATION MARKS YOU HAVE ARE UP FRONT BUT DOESN’T TELL YOU MORE. IN FACT, IF YOU KEEP CHECKING IT YOU’RE PROBABLY CHECKING FOR THE WRONG REASON. I THINK EARLY CALCIFICATION IS SHOWING THE BODY’S ABILITY TO PROTECTIVELY HEAL IT. IT’S A MARKER BUT I DISAGREE IT TELLS ABOUT THE ATHEROPROCESS.>>I SEEM TO RECALL A STUDY WHERE THEY’VE SHOWN THAT AND THANK YOU FOR EXCITING AND PROVOCATIVE PRESENTATIONS.

3 Comments

  • Tony Fatica says:

    Interesting presentation on Inflammation. Has the NIH investigated the use of Senolytics to remove Senescent cells that release cytokins and create the SASP to neighboring cells that promote inflammation? And how about new enzymes administered to the white blood cells so they can process oxidized cholesterol to prevent foam cells in the artery walls?

  • Just Call Me Bookworm says:

    Fascinating presentation on inflammation's relation to heart disease!

    I came here as a vegan, looking for answers to the question, "Does cholesterol actually cause heart disease?"

    I was pleasantly surprised to find that I did recognize at least a few of the studies (and finding that I probably interpreted studies correctly) mentioned and some of the biological mechanisms, chemicals, terms, etc. despite being a layman and having no college degree. All those hours reading through those complicated studies paid off!

    Was also surprised to find just how complicated this disease is. The number of biological chemicals and mechanisms involved is dizzying!

  • InfiniteUniverse88 says:

    Carbohydrates and sugars cause inflammation. Therefore, sugars and carbohydrates cause arteriosclerotic cardiovascular disease. Sugars and carbohydrates ought to be taxed in order to lower healthcare costs. Switching to the ketone diet is also a way to reduce the cost of food, and prevents all major diseases. On a side note, animals such as newts and salamanders, which have the ability to regenerate limbs, do not have an inflammatory response.

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