Environmental. Vascular / Tissue. Metabolics

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2 Global Risk Reduction--WINS Picking Mom and Dad-2016 Environmental Vascular / Tissue Metabolics Stop smoking-1b Physical activity-1b Weight control-1b Chelation therapy-3c Influenza vaccination-1b Blood pressure-1b RAAS blockade-1a Aldosterone blockade-1a/b Lipids-1B Triglycerides-1B Diabetes-1B Antiplatelets-1A/B AHA 2007 Guidelines for C SA.pdf Circulation. 2007;116:

3 Nothing to disclose for this lecture

4

5 BP 145/90 LDL cholesterol 140 mg/dl HDL cholesterol 35 Triglycerides 280 Patient from San Antonio 2 over weight dogs

6

7 This patient Percent mortality per year Adapted from al Patel et al 1 vessel dx 2 vessel dx 3 vessel dx 3VDx + prox 95% LAD) J Am Coll Cardiol. 1996;27:

8 Years Years of life remaining Healthy CAD MI CHF Stroke 4 Framingham 40 year follow up N= Eur Heart J 2002; 23:

9 MEDICAL STUDENTS NEJM 1993;328:313

10 NOTE: IT STARTS MAINLY AFTER 15-20YRS NEJM 1993;328:313

11 N Engl J Med 1998;338:1650-6

12 CHD rates- percentage Non HDL >160 Control 1-10 yrs yrs Circulation 2015;131:

13 Journal of Clinical Lipidology (2007) 1, Within each triglyceride subgroup, the lower the LDL level, the lower the amount of cholesterol per particle Median values were 131 mg/dl for LDL-C and 1414 nmol/l for LDL-P

14 Copenhagen General Population Study recruited in 2003 through 2014 Am J Cardiol 1997;79: ) European Heart Journal (2016) 37,

15 Approval Canada Europe Brazil 2016 ACCE ACE USA 2017 Endocr Pract 2017;23:1-87

16 DM/ ACS/Very high risk LDL <70 Clinical ASHDx LDL 70 very high risk LDL 100 high risk LDL 115 low to moderate hscrp>2 >7.5% risk at 10 years 40% stenosis Drugs Lifestyle first Statin (50% reduction) Ezetimibe if <25 mg/dl required PCSK9 if >25% mg/dl required Metabolic syndrome JACC 2017;70:1785 guidelines

17 The guidelines

18 Circulation. 2007;116:

19 STABLE CHRONIC ASPIRIN BETA-BLOCKERS ACE INHIBITOR LDL-LOWERING THERAPY SUBLINGUAL NITROGLYCERIN CALCIUM ANTAGONISTS OR LONG-ACTING NITRATES

20 CLASS IIA CLOPIDOGREL LONG-ACTING NON-DIHYDROPYRIDINE LIFESTYLE AND/OR DRUG THERAPIES WEIGHT REDUCTION NICOTINIC ACID OR FIBRIC ACID ACE INHIBITOR

21 III (NOT INDICATED) 1. DIPYRIDAMOLE B 2. CHELATION THERAPY B

22 Ranolazine- new first line indication for the treatment of chronic angina Development of ischemia Consequences of ischemia O 2 demand Heart rate Blood pressure Preload Contractility O 2 supply Conventional anti-ischemic medications Ischemia (Ca 2+ overload) ß blockers Nitrates Ca ++ blockers Ranolazine Electrical instability Myocardial dysfunction ( systolic function/ diastolic stiffness) MERLIN-TIMI 36 trial ACS Compression of nutritive blood vessels

23 Modifiable Factors Account for 90% of First MI INTERHEART Trial % PAR 18 Lipids Smoking Abd Obesity HT Diabetes 10 PAR = population attributable risk, adjusted for all risk factors Yusuf S et al. Lancet. 2004;364:937-52

24 Tight blocks have usually more healed plaque ruptures Circ 2001;103:9364

25 Environmental Vascular / Tissue Metabolics Stop smoking-1b Physical activity-1b Weight control-1b Chelation therapy-3c Influenza vaccination-1b Blood pressure-1b RAAS blockade-1a Aldosterone blockade-1a/b Lipids-1B Triglycerides-1B Diabetes-1B Antiplatelets-1A/B

26 IMPORTANCE OF GENETIC FACTORS WHEN PICKING YOUR PARENTS Bogalusa Heart Study Circ1995; 91: Selected risk factor variables in offspring ages 18 to 31 years by parental history of disease, race, and sex

27 IHD Mortality (Floating absolute risk and 95% CI) Systolic Blood Pressure Age at risk years years years years years Usual Systolic BP (mm Hg) Normal BP is defined as <120/<80 mm Hg Use of BP-lowering medications is recommended for secondary prevention of recurrent CVD events in patients with clinical CVD and an average SBP 130 mm Hg or a DBP 80 mm Hg, or for primary prevention in adults with no history of CVD but with an estimated 10- year ASCVD risk of 10% and SBP 130 mm Hg or DBP 80 mm Hg

28 MYOCARDIAL OXYGEN CONSUMPTION FACTORS MVO 2 HEART RATE Pressure MOST IMPORTANT =Wall Tension P=Pressure R=Radius h=wall thickness σ R h Wall Thickness = P x R/2h LaPlace s Law

29 Environmental Vascular / Tissue Metabolics Stop smoking-1b Physical activity-1b Weight control-1b Chelation therapy-3c Influenza vaccination-1b Blood pressure-1b RAAS blockade-1a Aldosterone blockade-1a/b Lipids-1B Triglycerides-1B Diabetes-1B Antiplatelets-1A/B

30 44% ADP (P2Y1, P2X1) Platelet GP2b/3a Platelet Activation PAR1-4 Thrombin TxA 2 Factor Xa % Glycoprotein 2b/3a blockade ASA Blocks platelet activation-(8 to 10 days) Prevents conversion of arachidonic acid to prostaglandin H 2 Thromboxane A 2 Platelets are unable to generate (no nucleus) new cycloxygenase enzyme Endothelial cells also blocked but recovery quickly cycloxygenase Chilton et al Clinical diabetology March 2011 Mehta et al JACC 2003;41:79s N Engl J Med Jul 20;321(3):183-5

31 UKPDS 75: ELEVATED GLUCOSE AND BP INCREASE MI RISK 50 N = 4320 with newly diagnosed diabetes Observational data Rate (per 1000 personyears) *Updated mean. HbA1C (%)* SBP (mm Hg)* Stratton IM et al. Diabetologia. 2006;49:

32 ADDITIVE EFFECT OF CHOLESTEROL AND SYSTOLIC BP ON RISK OF CHD DEATH N=316, CRP amplifies both CV Risk Deaths /10,000 Patient-years < <118 Neaton et al. Arch Intern Med. 1992;152:56-64

33 Lowering LDL with statins reduces CV events PROVE-IT-40 PROVE-IT-80 MIRACL A to Z P/20 4S MIRACL LIPID A to Z 40/80 LIPID CARE CARE HPS CARDS CARDS HPS ASCOT WOS TNT-10 TNT-80 ASCOT AFCAPS ACS AFCAPS 4S Secondary Prevention WOS (20 yr follow up beneficial) Primary Prevention (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2) LDL, mg/dl (mmol/l) Patients with CHD events (%).Statins work

34 Trial Drug N Events,* n Control Group Statin Group Risk Reduction, % Events not Avoided, % 4S WOSCOPS CARE AFCAPS LIPID TNT Simvastatin Pravastatin Pravastatin Lovastatin Pravastatin Atorvastatin >30,817 2,042 1, HPS Simvastatin 20,586 1, PROSPER Pravastatin 5, ASCOT-LLA Atorvastatin 10, Total 67,462 3,764 2, * Nonfatal MI and CHD death; AFCAPS also included unstable angina Weighted average Adapted from Bays H. Expert Rev Cardiovasc Ther 2004;2:

35 Percent Survival (%) Rest Stress Baseline 35 lb Wt Loss LDL-70 BP 122/70 1 yr Stress 33% CROSSED OVER Overall Survival Years PCI Medical Therapy Hazard ratio 0.87 (95% CI ) p=0.38 N Engl J Med March 27, 2007;356:000

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