Trials and Tribulations of Assessing
CVD Risk in 2013
Marc S. Penn, MD, PhD, FACC
Co-Founder & Chief Medical Officer
Cleve...
Biomarkers to define risk

Long-Term
Risk

Mid-Term
Risk

Near-Term
Risk

Life Long

Decade(s)

Years

Classic
Lipid Panel...
Why monitor inflammation?

Atherosclerosis is a chronic inflammatory
disease1
Markers of inflammation help refine cardiova...
Russell Ross’s response
to injury hypothesis
1976
Injury

Response

Cholesterol
• Developed statins
which reduce events
• ...
Why monitor inflammation?

Treatment benefits occur when you reduce
both LDL and hsCRP2
1Ridker
2Libby

et al. Rosuvastati...
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 lifesty...
The CVD Risk Panel

11
OxLDL association with future metabolic
syndrome
From: 1889 participants in
The CARDIA Study

Holvoet, P. et al. Future Li...
OxLDL association with future metabolic
syndrome
Indian Atherosclerosis Study
2316 patients without CAD

Rao et al. Cardio...
The CVD Risk Panel

14
Baseline hsCRP levels in apparently healthy
men can predict the risk of first myocardial
infarction or ischemic stroke1

P...
hsCRP is a stronger predictor of cardiovascular
events in women than LDL-C and adds prognostic
information to Framingham r...
Elevated levels of microalbuminuria are a robust
independent continuous risk factor for
cardiovascular events and death1

...
The CVD Risk Panel

18
Lipoprotein-Associated Phospholipase-A2
(Lp-PLA2; The PLAC® Test)
What does Lp-PLA2 measure?
• The amount of plaque within...
Clinical implications of The PLAC® Test
• Elevated Lp-PLA2 levels are independently associated with
high stroke risk in in...
Elevated MPO levels predict cardiovascular
mortality at 13 yrs in patients with angiographic
evidence of CAD1

First terti...
Value of Multimarker Approach
MPO and CRP have combined utility in predicting
cardiovascular mortality risk in patients with
angiographic evidence of CA...
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 import...
In apparently healthy individuals, mean MPO levels
were greater according to increasing CAC categories,
and the risk for C...
Clinical implications of MPO testing
• In apparently healthy individuals, moderate and significant
CAC ( 100) and MPO leve...
Elevated MPO levels predict a significantly
higher incidence of cardiovascular events in
patients with PAD1

MPOx >183.7 p...
Measurement of MPO, in addition to ABI,
improved the ability to identify PAD patients at
risk for MI and stroke1

1Modifie...
Case of JM
• 33 yo male well developed, thin, smoker
• 3 days of intermittent non-specific muscle ache to
left arm
• 1 day...
Case of JM (cont.)
• Left heart catheterization
– Proximal LAD occlusion - Stent
• Transferred to CICU in cardiogenic shoc...
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:
•...
531 Patients at Symposium in Nashville
Percent Participating Attendees (%)

All these patients have normal LDL cholesterol...
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...
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
• Gr...
Marc Penn,  MD, PhD, FACC - Trials and Tribulations of Assessing CVD Risk in 2013
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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

    1. 1. 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
    2. 2. 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
    3. 3. 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.
    4. 4. 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)
    5. 5. 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.
    6. 6. hsCRP in Statin Treated Patients Predicts Event Risk Puri et al. Circulation, In Press, 2013
    7. 7. hsCRP in Statin Treated Patients Predicts Event Risk Puri et al. Circulation, In Press, 2013
    8. 8. hsCRP in Statin Treated Patients Predicts Event Risk Puri et al. Circulation, In Press, 2013
    9. 9. The CVD Risk Panel 9
    10. 10. 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
    11. 11. The CVD Risk Panel 11
    12. 12. OxLDL association with future metabolic syndrome From: 1889 participants in The CARDIA Study Holvoet, P. et al. Future Lipidol. 2008 December; 3: 637–649
    13. 13. OxLDL association with future metabolic syndrome Indian Atherosclerosis Study 2316 patients without CAD Rao et al. Cardiology Research and Practice. 2011
    14. 14. The CVD Risk Panel 14
    15. 15. 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.
    16. 16. 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.
    17. 17. 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.
    18. 18. The CVD Risk Panel 18
    19. 19. 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
    20. 20. 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.
    21. 21. 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.
    22. 22. Value of Multimarker Approach
    23. 23. 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.
    24. 24. Lp-PLA2 and MPO identify unique patients Vessel Wall Risk 5.2% PLA2 Highest Risk WBC Risk 6.2% MPO
    25. 25. 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
    26. 26. 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.
    27. 27. 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.
    28. 28. 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.
    29. 29. 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.
    30. 30. 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)
    31. 31. 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
    32. 32. 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%
    33. 33. 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
    34. 34. Where is the disconnect?
    35. 35. HMG-CoA Reductase Inhibition Blocks Multiple Pathways
    36. 36. HMG-CoA Reductase Inhibition Blocks Multiple Pathways RAC / RHO Signaling NADPH Oxidase
    37. 37. Statins Inhibit Leukocyte Derived Oxidants
    38. 38. 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
    39. 39. Where is the disconnect?
    40. 40. Where is the disconnect? THERE ISN’T ONE !
    41. 41. 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

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