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LE Magazine November 2008

Atherosclerotic plaque

Identifying the vulnerable patient with rupture-prone plaque.

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States, and the obesity epidemic combined with aging of the population seems destined to increase the burden of this disease. Traditional cardiovascular risk assessment accounts for <50% of the variability in risk in the United States. Therefore, better and more effective identification of persons at high cardiovascular risk is needed. Our understanding of atherosclerosis has shifted from a focal disease whose hallmark is symptoms caused by a severe stenosis to a systemic disease characterized by endothelial dysfunction (ED) and plaque inflammation, with the potential for rupture and thrombosis mainly in those with subcritical stenosis. Under the new paradigm, clinicians require updated strategies to better assess the quality of arterial plaque. Effective tools for primary and secondary prevention of heart attack and stroke include intensive lifestyle modification, blood pressure reduction, and lipid-modifying therapies. These interventions are now understood to decrease plaque inflammation and thereby promote plaque stability. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be a specific marker of plaque inflammation that may play a direct role in the formation of rupture-prone plaque. In contrast, traditional risk factors, lipid measurement, and most vascular imaging modalities do not directly assess the acute ischemic potential in the arterial wall. Measuring Lp-PLA(2) levels in human serum or plasma is noninvasive and relatively inexpensive. Lp-PLA(2) may provide additional clinically relevant information that shows which patients have a high level of atherosclerotic disease activity as manifested by vascular inflammation, ED, and increased risk for progression toward rupture-prone plaque.

Am J Cardiol. 2008 Jun 16;101(12A):3F-10F

The molecular basis of vulnerable plaque: potential therapeutic role for immunomodulation.

PURPOSE OF REVIEW: Athero-sclerosis is a chronic inflammatory/immune disease involving multiple cell types including monocytes-macrophages, T-lymphocytes, mast cells, and endothelial cells. Through recent studies the role of the immune system on development of atherosclerosis and approaches to modulate this response are being elucidated. RECENT FINDINGS: The use of statins, PPARgamma agonists or lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors may play a role in reducing progression of atherosclerosis through immunomodulatory pathways. Oxidized LDL biases development toward the pro-inflammatory T-cell Th1 subset and recruits macrophages into the vascular wall. IFNgamma, produced by Th1 cells, inhibits PPARgamma effects. Lp-PLA2 levels correlate with an increased risk of recurrent ischemic events in patients presenting with acute coronary syndromes or myocardial infarction. SUMMARY: Recent research has shown that immune pathways play a major role in the development and progression of atherosclerosis. Commonly used medications, specifically statins and some PPARgamma agonists, have demonstrated anti-inflammatory/immune effects unrelated to their primary mode of action. Treatment of infectious agents has proven elusive in the clinical arena. Novel agents targeting immune and inflammatory pathways may prove beneficial in reducing progression and instability of the atherosclerotic plaque.

Curr Opin Cardiol. 2007 Nov;22(6):545-51

Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques.

BACKGROUND AND PURPOSE: Circulating lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has emerged as a novel biomarker for cardiovascular diseases. However, the correlation between the plaque expression of Lp-PLA(2) and plaque oxidative stress, inflammation, and stability as well as the clinical presentation remains poorly defined, especially for cerebrovascular disease. Therefore, this study was performed to test the hypothesis that Lp-PLA(2) expression is higher in symptomatic than in asymptomatic carotid plaques of patients undergoing carotid endarterectomy. METHODS: The expression of Lp-PLA(2) in 167 carotid artery plaques was determined by immunoblotting and immunostaining. Plaque oxidative stress, inflammation, and stability were quantified by NAD(P)H oxidase p67phox and MMP-2 immunoblotting, oxidized LDL (oxLDL) immunoreactivity, macrophage and Sirius red collagen staining. Lysophosphatidylcholine 16:0 (lysoPC) concentration was measured in 55 plaques using liquid chromatography tandem mass spectrometry. RESULTS: Lp-PLA(2) expression was significantly higher in plaques of symptomatic patients than asymptomatic patients (1.66+/-0.19 versus 1.14+/-0.10, P<0.05) and localized mainly to shoulder and necrotic lipid core areas in colocalization with oxLDL and macrophage content. Similarly, Lp-PLA(2) expression was related to collagen content, which was lower in plaques from symptomatic patients than in plaques from asymptomatic patients (9.1+/-2.2 versus 18.5+/-1.7% of staining/field, P<0.001). LysoPC plaque concentration was significantly higher in plaques of symptomatic than asymptomatic patients (437.0+/-57.91 versus 228.84+/-37.00 mmol/L, P<0.05). CONCLUSIONS: Symptomatic carotid artery plaques are characterized by increased levels of Lp-PLA(2) and its product lysoPC in correlation with markers of tissue oxidative stress, inflammation, and instability. These findings strongly support a role for Lp-PLA2 in the pathophysiology and clinical presentation of cerebrovascular disease.

Stroke. 2008 May;39(5):1448-55

Lipoprotein-associated phospholipase A2: a risk marker or a risk factor?

Multiple cardiovascular biomarkers are associated with increased cardiovascular disease (CVD) risk. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be relatively unique in its high specificity for and the causal pathway of plaque inflammation. In both primary and secondary prevention study populations, Lp-PLA(2) was consistently associated with higher cardiovascular risk, and the risk estimate appears to be relatively unaffected by adjustment for conventional CVD risk factors. Risk ratios were similar, whether the mass concentration or activity of the enzyme was measured. The purpose of this article is to review the evidence for the clinical utility of Lp-PLA(2), both as a risk marker and as a risk factor involved in the causal pathway of plaque inflammation and the formation of rupture-prone plaque.

Am J Cardiol. 2008 Jun 16;101(12A):11F-22F

Lipoprotein-associated phospholipase A2: an independent predictor of coronary artery disease events in primary and secondary prevention.

In recent years, atherosclerosis has become recognized as an inflammatory disease whose activity can be assessed by circulating biomarkers. Along with C-reactive protein (CRP), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) may now be considered as a biomarker with sufficient accumulated evidence to support its application in clinical practice. Lp-PLA(2) is especially appealing because of its vascular specificity, which directly derives from its role in plaque pathophysiology. This article reviews the highlights of the >25 prospective epidemiologic studies now published on Lp-PLA(2) as a risk marker in primary or secondary prevention. These trials demonstrate generally consistent correlations between elevated Lp-PLA(2) levels and the increased risk for cardiovascular events, even after multivariable adjustment for traditional risk factors, with roughly a doubling of risk associated with upper quantile levels. Furthermore, Lp-PLA(2) as a risk predictor has been shown to be independent of and complementary to high-sensitivity CRP. These study results combined with recommendations from the American Heart Association/Centers for Disease Control (AHA/CDC) and the National Cholesterol Education Program III (NCEP III) suggest that Lp-PLA(2) might best be used in current clinical practice to refine risk prediction in those at intermediate cardiovascular risk. An increasingly prevalent group at intermediate risk shown to benefit from Lp-PLA(2) risk modification is the population with the cardiovascular metabolic syndrome, clinically identified as overweight patients with features of mixed dyslipidemia, dysglycemia, and hypertension. An additional application supported by these studies is further risk stratification of high- (often secondary-) risk patients into a group at very high risk, for whom a more aggressive target for low-density lipoprotein of <70 mg/dL (1 mg/dL = 0.02586 mmol/L) is now recommended as a reasonable therapeutic goal.

Am J Cardiol. 2008 Jun 16;101(12A):23F-33F

Lipoprotein-associated phospholipase A2 is an independent predictor of incident coronary heart disease in an apparently healthy older population: the Rancho Bernardo Study.

OBJECTIVES: Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels predict incident coronary heart disease (CHD) in adults without known CHD, independent of heart disease risk factors. We examined whether the independent association was apparent in older adults. BACKGROUND: Serum levels of Lp-PLA2, an enzyme that hydrolyzes oxidized phospholipids to yield potentially proatherogenic particles, have been associated with CHD and may help predict cardiovascular risk. METHODS: Participants were 1,077 community-dwelling men and women, median age 72 years, who had no known CHD at baseline (1984 to 1987) when blood samples and risk factor data were collected. Participants were followed for CHD events for a mean of 16 years, through 2002. Cox proportional hazards regression models were used to examine the association of serum Lp-PLA2 with incident CHD (myocardial infarction, angina, or coronary revascularization). RESULTS: The Lp-PLA2 levels positively correlated with age (r = 0.09), body mass index (r = 0.11), low-density lipoprotein (r = 0.37), triglycerides (r = 0.25), and C-reactive protein (r = 0.10), and negatively correlated with high-density lipoprotein (r = -0.27) (all p < 0.05). During follow-up, 228 participants had incident CHD events. Lipoprotein-associated phospholipase A2 levels in the second, third, and fourth quartiles predicted an increased risk of CHD compared with the lowest quartile (hazard ratios 1.66, 1.80, and 1.89, respectively; p < 0.05 for each). This association persisted after adjusting for C-reactive protein and other CHD risk factors. CONCLUSIONS: Elevated Lp-PLA2 levels predict CHD events in apparently healthy older adults, independent of CHD risk factors.

J Am Coll Cardiol. 2008 Mar 4;51(9):913-9

Lipoprotein-associated phospholipase A2 and risk of stroke.

Stroke is the second-leading cause of death worldwide and is a disabling disease of both older and younger adults. Stroke is also among the most highly preventable disorders because there are well-defined risk factors and preventatives. The establishment of new risk markers or factors for stroke risk assessment provides a new avenue for stroke prevention. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that hydrolyzes oxidized phospholipids, releasing lysophosphatidylcholine, which has proinflammatory properties thought to be involved in the development of atherosclerosis and plaque rupture. In 2005, the Lp-PLA(2) blood test was approved by the US Food and Drug Administration (FDA) for assessing the risk of ischemic stroke and coronary artery disease. In epidemiologic studies, low-density lipoprotein cholesterol and other lipid factors have not been shown to be consistent predictors of stroke risk. Lp-PLA(2) measures, on the other hand, have shown a consistent association with stroke risk, conferring about a 2-fold increase in stroke occurrence. This relation has been studied in both first and recurrent stroke and is reviewed in this article. Importantly, a recent study has now shown that Lp-PLA(2) may increase the area under the curve beyond that of traditional cardiovascular risk factors and C-reactive protein. Therefore, Lp-PLA(2) determination may provide a pivotal opportunity to appropriately classify previously misclassified persons who are actually at high risk of stroke and in need of aggressive stroke intervention.

Am J Cardiol. 2008 Jun 16;101(12A):34F-40F

Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Measurement of inflammatory markers has been reported to identify individuals at increased risk for ischemic stroke. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a proinflammatory enzyme secreted by macrophages. We assessed Lp-PLA2 and C-reactive protein (CRP) levels along with traditional risk factors to examine their relation to ischemic stroke. METHODS: A proportional hazards model was used in a prospective case-cohort study of 12,762 apparently healthy middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study who were observed for about 6 years. RESULTS: Mean Lp-PLA2 and CRP levels adjusted for sex, race, and age were higher in the 194 stroke cases than the 766 noncases, whereas low-density lipoprotein cholesterol (LDL-C) level was not significantly different. Both Lp-PLA2 and CRP levels were associated with ischemic stroke after adjustment for age, sex, and race: hazard ratios were 2.23 for the highest vs the lowest tertile of Lp-PLA2 and 2.70 for CRP level higher than 3 vs lower than 1 mg/L. In a model that included smoking, systolic hypertension, lipid levels, and diabetes, Lp-PLA2 and CRP levels in the highest category were associated with hazard ratios of 1.91 (95% confidence interval, 1.15-3.18; P = .01) and 1.87 (95% confidence interval, 1.13-3.10; P = .02), respectively. Individuals with high levels of both CRP and Lp-PLA2 were at the highest risk after adjusting for traditional risk factors compared with individuals with low levels of both, whereas others were at intermediate risk. CONCLUSION: Levels of Lp-PLA2 and CRP may be complementary beyond traditional risk factors in identifying middle-aged individuals at increased risk for ischemic stroke.

Arch Intern Med. 2005 Nov 28;165(21):2479-84

Lipoprotein-associated phospholipase A2 predicts progression of cardiac allograft vasculopathy and increased risk of cardiovascular events in heart transplant patients.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk factor for coronary artery disease (CAD) in nontransplant patients. We evaluated the association between Lp-PLA2, cardiac allograft vasculopathy (CAV) assessed by 3D intravascular ultrasound, and incidence of cardiac adverse events in heart transplant recipients. MATERIALS AND METHODS: Fasting blood samples were obtained and stored from a cross-section of 112 cardiac transplant recipients attending the Mayo cardiac transplant clinic in 2000 to 2001, mean of 4.7 years after transplant. Lp-PLA2 was measured in plasma aliquots using an enzyme-linked immunoassay. Fifty-six of these patients subsequently underwent two 3D intravascular ultrasound studies in 2004 to 2006 12 months apart. Cardiovascular (CV) events included percutaneous coronary intervention, coronary artery bypass grafting (CABG), reduction in left ventricular ejection fraction (LVEF) < or =45% secondary to CAV and CV death. RESULTS: High Lp-PLA2 level was associated with increase in plaque volume (r=0.43, P=0.0026) and percent plaque volume (r=0.45, P=0.0004). The association remained significant after adjusting for clinical and lipid variables. During follow-up of 5.1+/-1.6 years, 24 CV adverse events occurred in 15 of 112 (13%) heart transplant patients. Lp-PLA2 level>236 ng/mL (higher tertile) identified a subgroup of patients having a 2.4-fold increase of relative risk for combined endpoint of CV events (percutaneous coronary intervention, CABG, LVEF<45%, and CV death; 95% CI 1.16-5.19, P=0.012) compared with patients with Lp-PLA2< or =236 ng/mL. CONCLUSIONS: Lp-PLA2 is independently associated with progression of CAV and predicts a higher incidence of CV events and CV death in transplant patients. This finding supports the concept that systemic inflammation is an important mediator of CAV. Lp-PLA2 may be a useful marker for risk of CAV and a therapeutic target in posttransplant patients.

Transplantation. 2008 Apr 15;85(7):963-8

Association of lipoprotein-associated phospholipase A2 with coronary calcification among American and Japanese men.

BACKGROUND: We have previously reported that the prevalence of coronary artery calcification (CAC) was substantially lower among Japanese than American men despite a less favorable profile of many traditional risk factors in Japanese men. To determine whether lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are related to the difference in the prevalence of CAC between the two populations. METHODS: A total of 200 men aged 40-49 years were examined: 100 residents in Allegheny County, Pennsylvania, United States, and 100 residents in Kusatsu City, Shiga, Japan. Coronary calcium score (CCS) was evaluated by electron-beam tomography, Lp-PLA2 levels, nuclear magnetic resonance (NMR) lipoprotein subclasses, and other factors were assessed in 2001-2002. RESULTS: Lp-PLA2 levels were higher among American than Japanese men (Mean +/- standard deviation 301.7 +/- 82.6 versus 275.9 +/- 104.7 ng/mL, respectively, p=0.06). Among all Japanese men and those with low density lipoprotein (LDL) cholesterol > or =130 mg/dL, there was an inverse association of the prevalence of CCS>0 with the tertile groups of Lp-PLA2 levels (p=0.08 and p=0.03, respectively). American men did not have any association between CCS>0 with the tertile groups of Lp-PLA2 (p=0.62). Although Lp-PLA2 among both populations correlated positively with LDL and total cholesterol, American and Japanese men had different correlations with NMR lipoprotein subclasses. Reported high odds ratio for CCS>0 among American compared to Japanese men was not reduced after adjusting for Lp-PLA2 levels. CONCLUSION: Lp-PLA2 may have different mechanisms of action among American and Japanese men. Lp-PLA2 levels can not explain the observed CAC differences between the two populations.

J Epidemiol. 2007 Nov;17(6):179-85

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