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Marc Penn,  MD, PhD, FACC - Trials and Tribulations of Assessing CVD Risk in 2013
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Marc Penn, MD, PhD, FACC - Trials and Tribulations of Assessing CVD Risk in 2013

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Cleveland HeartLab 2013 Symposium

Cleveland HeartLab 2013 Symposium

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  • 17, 802 patients (1.9 years)LDL < 130Tgs < 500hsCRP>/= 2

Marc Penn,  MD, PhD, FACC - Trials and Tribulations of Assessing CVD Risk in 2013 Marc Penn, MD, PhD, FACC - Trials and Tribulations of Assessing CVD Risk in 2013 Presentation Transcript

  • Trials and Tribulations of Assessing CVD Risk in 2013 Marc S. Penn, MD, PhD, FACC Co-Founder & Chief Medical Officer Cleveland HeartLab, Inc. Director of Research Summa Cardiovascular Institute Professor of Medicine and Integrative Medical Sciences Director, Skirball Laboratory for Cardiovascular Cellular Therapeutics Northeast Ohio Medical University
  • Biomarkers to define risk Long-Term Risk Mid-Term Risk Near-Term Risk Life Long Decade(s) Years Classic Lipid Panel Advanced Lipid Testing Inflammatory Markers Also offered through CHL CHL’s Unique Focus
  • Why monitor inflammation? Atherosclerosis is a chronic inflammatory disease1 Markers of inflammation help refine cardiovascular risk estimation 1Ross R et al. Atherosclerosis-An inflammatory disease. N Engl J Med. 1999; 340: 115-126.
  • Russell Ross’s response to injury hypothesis 1976 Injury Response Cholesterol • Developed statins which reduce events • Advanced testing to help identify risk (ApoB, ApoA1, LDL-P) Inflammation Approximately 50% of individuals who experience heart attack or stroke have normal lipids • Landmark JUPITER Trial • Advanced testing to help identify risk (MPO, hsCRP, LpPLA2, F2IsoPs, MicroAlb)
  • Why monitor inflammation? Treatment benefits occur when you reduce both LDL and hsCRP2 1Ridker 2Libby et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359: 2195-2207 et al. Inflammation in atherosclerosis: From pathophysiology to practice. J Am Coll Cardiol. 2009; 54: 2129-2138.
  • hsCRP in Statin Treated Patients Predicts Event Risk Puri et al. Circulation, In Press, 2013
  • hsCRP in Statin Treated Patients Predicts Event Risk Puri et al. Circulation, In Press, 2013
  • hsCRP in Statin Treated Patients Predicts Event Risk Puri et al. Circulation, In Press, 2013
  • The CVD Risk Panel 9
  • What are F2-IsoPs? • Lifestyle markers (inversely related to conditioning) Exercise daily & eat healthy Sedentary lifestyle, eat poorly & smoke Low F2-IsoPs High F2-IsoPs
  • The CVD Risk Panel 11
  • OxLDL association with future metabolic syndrome From: 1889 participants in The CARDIA Study Holvoet, P. et al. Future Lipidol. 2008 December; 3: 637–649
  • OxLDL association with future metabolic syndrome Indian Atherosclerosis Study 2316 patients without CAD Rao et al. Cardiology Research and Practice. 2011
  • The CVD Risk Panel 14
  • Baseline hsCRP levels in apparently healthy men can predict the risk of first myocardial infarction or ischemic stroke1 Physicians’ Health Study • 1,086 men (>8 yrs) • hsCRP measured at baseline 1Ridker PM et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973-979.
  • hsCRP is a stronger predictor of cardiovascular events in women than LDL-C and adds prognostic information to Framingham risk scores1 Women’s Health Study • 28,345 women (8 yrs.; 15,745 were not on HRT) • hsCRP and LDL-C measured at baseline 1Ridker PM et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557-1565.
  • Elevated levels of microalbuminuria are a robust independent continuous risk factor for cardiovascular events and death1 The HOPE study • 5,545 (w/o DM ; history of CVD) • 3,498 (w/ DM + at lease 1 risk factor) 1Gerstein HC et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and non-diabetic individuals. JAMA. 2001; 286: 421-426.
  • The CVD Risk Panel 18
  • Lipoprotein-Associated Phospholipase-A2 (Lp-PLA2; The PLAC® Test) What does Lp-PLA2 measure? • The amount of plaque within the artery wall due to accumulation of oxidized LDL
  • Clinical implications of The PLAC® Test • Elevated Lp-PLA2 levels are independently associated with high stroke risk in individuals who have low LDL-C levels The ARIC study • 960 middle-aged men and women • Follow-up ~6-8 yrs. 1Ballantyne CM et al. Lp-PLA2, hsCRP, and risk for incident coronary artery disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004; 109: 837-842.
  • Elevated MPO levels predict cardiovascular mortality at 13 yrs in patients with angiographic evidence of CAD1 First tertile (lowest) Second tertile Third tertile (highest) Log-rank test: p=0.007 1Modified HR: 2.38 (95% CI: 1.47-2.98) for top vs bottom MPO tertile from Heslop CL et al. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol . 2010; 55:1102-1109.
  • Value of Multimarker Approach
  • MPO and CRP have combined utility in predicting cardiovascular mortality risk in patients with angiographic evidence of CAD1 MPO CRP Low and Low High or High High and High Patients with either a high MPO or high CRP elevated had 5.3-fold higher mortality risk Patients with high levels of both MPO and CRP had a 4.3-fold risk vs. patients with only one elevated marker Log-rank test: p<0.001 for trend 1Modified from Heslop CL et al. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol . 2010; 55:1102-1109.
  • Lp-PLA2 and MPO identify unique patients Vessel Wall Risk 5.2% PLA2 Highest Risk WBC Risk 6.2% MPO
  • Anatomical and biological assessment of cardiovascular risk • Anatomy is important but hard to follow • Biology is important and can be measured routinely • Additive risk stratification
  • In apparently healthy individuals, mean MPO levels were greater according to increasing CAC categories, and the risk for CVD increased by quartiles of MPO1 1Wong ND et al. Myeloperoxidase, subclinical atherosclerosis, and cardiovascular disease events. J Am Coll Cardiol Img. 2009; 2: 1093-1099.
  • Clinical implications of MPO testing • In apparently healthy individuals, moderate and significant CAC ( 100) and MPO levels ( 257 pm) demonstrated increased risk for CVD1 MPO levels 257 pm remained an independent predictor of CVD events even after adjusting for various risk factors (HR: 1.9, p=0.04) 1Wong ND et al. Myeloperoxidase, subclinical atherosclerosis, and cardiovascular disease events. J Am Coll Cardiol Img. 2009; 2: 1093-1099.
  • Elevated MPO levels predict a significantly higher incidence of cardiovascular events in patients with PAD1 MPOx >183.7 pM had higher hsCRP levels versus MPOx ≤183.7 pM 1Modified from Brevetti G et al. Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease. Eur Heart J. 2008; 29: 224-230.
  • Measurement of MPO, in addition to ABI, improved the ability to identify PAD patients at risk for MI and stroke1 1Modified from Brevetti G et al. Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease. Eur Heart J. 2008; 29: 224-230.
  • Case of JM • 33 yo male well developed, thin, smoker • 3 days of intermittent non-specific muscle ache to left arm • 1 day of constant chest pain and diaphoresis • 8 pm EMS to house -> Outside hospital diagnosed with acute heart attack • Failed clot busting therapy • Transferred to CCF for rescue stenting at Midnight (7/20/01)
  • Case of JM (cont.) • Left heart catheterization – Proximal LAD occlusion - Stent • Transferred to CICU in cardiogenic shock • 9 days later mechanical support weaned on oral medicines and transferred out of CICU
  • Case of JM (cont.) Good News: •33 yo male with great lipids – LDL – 98 mg/dL – HDL - 48 mg/dL – TG - 86 mg/dL Bad News: •33 yo male with severe LV dysfunction – Risk of severe CHF high – Class II-III CHF on telemetry – Heart function ~20%, normal 55-60%
  • 531 Patients at Symposium in Nashville Percent Participating Attendees (%) All these patients have normal LDL cholesterol 30 135 121 20 +MPO or +Lp-PLA2 10 13 0 Abnormal Cholesterol LDL > 130 Hardened Arteries +hsCRP Increasing Risk Increased Risk Active Plaque +MPO or +Lp-PLA2 and +hsCRP +MPO and +Lp-PLA2 24 1 Active Hardened Active Vessel Wall Arteries and White Cell Response
  • Where is the disconnect?
  • HMG-CoA Reductase Inhibition Blocks Multiple Pathways
  • HMG-CoA Reductase Inhibition Blocks Multiple Pathways RAC / RHO Signaling NADPH Oxidase
  • Statins Inhibit Leukocyte Derived Oxidants
  • WBC Inflammation was blocked only in NADPH Oxidase KO mice PAI-1 KO tx with PAI-1 KO total BM cells Vs PAI-1 KO tx with WT total BM cells 100 PAI-1 KO marrow tx into PAI-1 KO(n=7) 90% PAI-1 KO tx with PAI-1 KO total BM cells Vs PAI-1 KO tx with CP KO total BM cells 80 WT marrow tx into PAI-1 KO(n=12) 80 Survival% 41.66 40 100 Survival% 60 60 60 40 20 20 0 66.66% 20 0 41.66 40 5 Days Post MI 10 P<0.05 0 Days Post MI 5 PAI-1 KO tx with PAI-1 KO total BM cells Vs PAI-1 KO tx with MPO KO total BM cells 0 10 0 Days Post MI 120 120 100 100 80 60 54.5% 80 60 40 40 20 20 0 0 33.33% 0 5 Days Post MI 10 5 PAI-1 KO tx with PAI-1 KO total BM cells Vs PAI-1 KO tx with iNOS KO total BM cells Survival% 0 Survival% Survival% 80 120 100 120 PAI-1 KO tx with PAI-1 KO total BM cells Vs PAI-1 KO tx with NADPH Oxidase KO total BM cells 120 0 5 Days Post MI 10 10
  • Where is the disconnect?
  • Where is the disconnect? THERE ISN’T ONE !
  • Summary • It is clear that inflammation is the operative mechanism of adverse events in patients with atherosclerosis • Growing evidence that monitoring inflammatory markers identifies patients at risk • Understanding the physiology represented by a marker not only identifies patients at risk, but define where they exist on the spectrum of risk • Multimarker inflammation approach allows identification of graded risk within a population