Cleveland HeartLab 2013 Symposium

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. 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. 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. 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. 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. hsCRP in Statin Treated
Patients Predicts Event Risk
Puri et al. Circulation, In Press, 2013

7. hsCRP in Statin Treated
Patients Predicts Event Risk
Puri et al. Circulation, In Press, 2013

8. hsCRP in Statin Treated
Patients Predicts Event Risk
Puri et al. Circulation, In Press, 2013

9. The CVD Risk Panel
9

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. The CVD Risk Panel
11

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. OxLDL association with future metabolic
syndrome
Indian Atherosclerosis Study
2316 patients without CAD
Rao et al. Cardiology Research and Practice. 2011

14. The CVD Risk Panel
14

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. 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. 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. The CVD Risk Panel
18

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. 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. 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. Value of Multimarker Approach

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. Lp-PLA2 and MPO identify
unique patients
Vessel Wall
Risk
5.2%
PLA2
Highest Risk
WBC Risk
6.2%
MPO

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. 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. 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. 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. 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. 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)

32. 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

33. 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%

34. 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

35. Where is the disconnect?

36. HMG-CoA Reductase Inhibition Blocks
Multiple Pathways

37. HMG-CoA Reductase Inhibition Blocks
Multiple Pathways
RAC / RHO Signaling
NADPH Oxidase

38. Statins Inhibit Leukocyte Derived Oxidants

39. 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

40. Where is the disconnect?

41. Where is the disconnect?
THERE ISN’T ONE !

42. 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