Prognostic Utility of Secretory Phospholipase A 2 in Patients with Stable Coronary Artery Disease M. O'Donoghue, Z. Mallat, D.A. Morrow, J. Benessiano,

Prognostic Utility of Secretory Phospholipase A2 in Patients with Stable Coronary Artery Disease

M. O'Donoghue, Z. Mallat, D.A. Morrow, J. Benessiano, S. Sloan, T. Omland, S.D. Solomon, E. Braunwald, A. Tedgui, and M.S. Sabatine

http://www.clinchem.org/cgi/content/full/57/9/1311

October 2011

© Copyright 2011 by the American Association for Clinical Chemistry


IntroductionIntroduction

The secretory phospholipase A2 (sPLA2) family consists of 10 isoenzymes involved in a variety of biological processes

Growing evidence suggests sPLA2 may play a causal role in atherogenesis

sPLA2-X promotes macrophage foam cell formation in murine models

Up-regulated sPLA2-IIA or –V expression has been shown to increase atherosclerotic lesion size in transgenic mice

Genetic deletion of sPLA2–V or direct inhibition of sPLA2 activity reduces atherosclerotic lesion size in animals


IntroductionIntroduction

To date, a small number of studies have evaluated the utility of sPLA2 mass or activity for risk stratification in primary prevention and after an acute coronary syndrome

The prognostic utility of sPLA2 is not well established in a large population of patients with stable coronary artery disease (CAD)

We therefore evaluated the prognostic utility of sPLA2 in the PEACE trial, a large trial population of patients with stable CAD


QuestionsQuestions

Is sPLA2 useful for risk stratification in patients with stable CAD?

If yes, does it add any incremental value to established markers including high sensitivity troponin T, C-reative protein (hsCRP), lipoprotein-associated phospholipase A2 (Lp-PLA2), and NT- pro B-type natriuretic peptide (NT-proBNP)?


MethodsMethods

sPLA2 activity (Aterovax) was measured at baseline in 3708 subjects

Median follow-up was 4.8 years

Cox regression models were used to adjust for baseline differences, apoB, apoA1, and medications

The incremental value of sPLA2 was evaluated compared to established markers, including high sensitivity troponin T (Roche), Lp-PLA2 mass (diaDexus), NT-proBNP (Roche), and hsCRP (Denka Seiken)


Baseline characteristics by quartile of Baseline characteristics by quartile of sPLAsPLA22 activity activity

Table 1. Baseline characteristics by quartile of sPLA activity (U/mL).a 2

Quartile 1, Quartile 2, Quartile 3, Quartile 4,

Characteristic <18.4 U/mL 18.5–30.9 U/mL 31.0–45.7 U/mL >45.7 U/mL P value

n 928 926 927 927

Age, years 64 (8.3) 64 (8.4) 64 (8.2) 64 (7.9) 0.18

Female sex 13.3 13.5 19.7 29.3 < 0.001

M edical history

Hypertension 40.2 44.8 44.9 48.4 0.005

Diabetes mellitus 14.8 13.3 16.0 21.0 < 0.001

Current tobacco use 12.8 14.2 15.8 17.6 0.02

Prior MI 53.3 56.5 57.7 57.6 0.18

Prior PCI or coronary artery bypass graft surgery 80.0 75.5 70.33 64.36 < 0.001

M edications before randomization

Aspirin or antiplatelet drug 91.0 92.0 90.5 91.5 0.68

Beta-blocker 61.2 60.0 61.7 65.3 0.11

Lipid-lowering medication 75.3 72.0 71.6 67.8 0.002

Data at randomization

Systolic blood pressure, mmHg 132 (16) 133 (16) 134 (17) 135 (18) < 0.001

eGFR 80 (20) 77 (18) 79 (20) 76 (20) < 0.001

Body mass index, kg/m2 28 (4.3) 28 (4.5) 29 (4.8) 29 (5.2) 0.001

ApoB, mg/dL 102 (22) 105 (22) 110 (23) 112 (23) < 0.001

ApoA1, mg/dL 136 (22) 137 (23) 140 (25) 140 (27) 0.002

Cardiac troponin T, f.Lg/L 7.1 (5.7) 7.8 (7.2) 7.4 (5.9) 8.0 (6.5) 0.005

C-reactive protein, mg/L 2.2 (3.3) 2.4 (3.6) 3.3 (5.6) 5.5 (8.8) < 0.001

Lp-PLA2 mass, ng/mL 226 (68) 230 (74) 228 (73) 237 (74) 0.002

NT-proBNP, pg/mL 225 (294) 221 (274) 255 (373) 278 (384) 0.001

a Data are mean (SD) or % .

© Copyright 2009 by the American Association for Clinical Chemistry© Copyright 2009 by the American Association for Clinical Chemistry

Kaplan-Meier event rates & hazard ratios by Kaplan-Meier event rates & hazard ratios by quartile of sPLAquartile of sPLA22 activity activity

Table 2. Multivariable model: age, sex, tobacco use (current, former, never), eGFR, body mass index, systolic blood pressure, apoB, apoA1, history of hypertension, diabetes mellitus, lipid-lowering therapy, history of coronary revascularization, randomized treatment arm.

Kaplan-Meier event rate by quartiles of sPLA2

activity at 5 years

Outcome

n

<18.4 U/mL

18.5–30.9

U/mL

31.0–45.6

U/mL >45.7 U/mL

Unadjusted HR (95% CI), Q4:Q1

Adjusted HR

(95% CI), Q4:Q1a

928 926 927 927 Cardiovascular death, MI, or stroke 7.84 9.20 10.2 13.2 1.78 (1.32–2.40) 1.55 (1.13–2.14)

Cardiovascular death or HF 3.26 5.05 5.52 7.93 2.25 (1.47–3.46) 1.91 (1.20–3.03)

Cardiovascular death 2.51 2.71 3.19 4.88 2.00 (1.18–3.37) 1.66 (0.95–2.88)

MI 4.54 4.70 6.59 7.00 1.63 (1.09–2.44) 1.49 (0.96–2.32)

Stroke 1.26 1.92 1.20 2.55 2.10 (1.01–4.38) 1.59 (0.74–3.41)

HF 1.22 2.43 2.84 3.98 2.73 (1.38–5.38) 2.63 (1.19–5.80)

Coronary revascularization 20.7 16.7 20.3 23.1 1.09 (0.89–1.33) 1.03 (0.83–1.27)


Cumulative incidence of CV death, MI or Cumulative incidence of CV death, MI or stroke by quartile of sPLAstroke by quartile of sPLA22 activity activity


Cumulative incidence of CV death or heart Cumulative incidence of CV death or heart failure by quartile of sPLAfailure by quartile of sPLA22 activity activity


Multimarker analysis for sPLAMultimarker analysis for sPLA22, Lp-PLA, Lp-PLA22

mass, hsCRP and risk of CV death, MI or mass, hsCRP and risk of CV death, MI or strokestroke

CV death, MI or stroke

sPLA2 activity

Lp-PLA2 mass

hsCRP

1.47 (1.06-2.04)

1.35 (0.97-1.88)

1.25 (0.91-1.73)

Adj HR Q4:Q1 (95% CI)

2.0 5.0 10.01.00.50.20.1

Figure 3. The independent association between sPLA2 activity, Lp-PLA2 mass, hsCRP, and the risk of cardiovascular death, MI or stroke. MV model includes the 3 biomarkers by quartile, age, sex, hypertension, diabetes mellitus, tobacco use, history of coronary revascularization, history of lipid-lowering therapy, body mass index, systolic blood pressure, eGFR, apoB, apoA1, and randomized treatment arm.


Figure 4. The independent association between sPLA2 activity, NT-proBNP, and cardiac troponin T and the risk of cardiovascular death or HF. MV model includes the 3 biomarkers by quartile, age, sex, hypertension, diabetes mellitus, tobacco use, history of coronary revascularization, history of lipid-lowering therapy, body mass index, systolic blood pressure, eGFR, apoB, apoA1, and randomized treatment arm.

Multimarker analysis for sPLAMultimarker analysis for sPLA22, NT-proBNP , NT-proBNP

and troponin T and risk of CV death or HFand troponin T and risk of CV death or HF

CV death or HF

sPLA2 activity

NT-proBNP

hsTroponin T

1.79 (1.12-2.86)

5.39 (2.88-10.1)

3.39 (1.81-6.32)

Adj HR Q4:Q1 (95% CI)

2.0 5.0 10.00.50.20.1 1.0


Multimarker Results (cont’d)Multimarker Results (cont’d)

In ROC analysis, sPLA2 activity significantly improved the AUC for identifying patients at risk of CV death, MI or stroke compared with clinical risk factors alone (P=0.01). Lp-PLA2 and hsCRP did not improve the AUC

sPLA2, NT-proBNP and troponin T all significantly improved the AUC as compared with clinical risk factors alone for identifying patients at risk of CV death or heart failure (P=0.02, P<0.001, P<0.001, respectively)


ConclusionsConclusions

sPLA2 activity provides independent prognostic information beyond established clinical risk factors in patients with stable CAD

sPLA2 activity also provides incremental information for risk stratification independent of established markers including hsCRP, troponin T, Lp-PLA2 mass and NT-proBNP


QuestionsQuestions

Would routine measurement of sPLA2 activity help to improve outcomes in patients with stable CAD? Would it help to guide treatment decisions?

If sPLA2 is causal in the pathway for atherogenesis, will direct inhibition of the sPLA2 enzyme with the

novel drug varespladib reduce the risk of CV events?


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Prognostic Utility of Secretory Phospholipase A 2 in Patients with Stable Coronary Artery Disease M. O'Donoghue, Z. Mallat, D.A. Morrow, J. Benessiano,