Modest association between Lp-PLA2 and coronary heart disease

April 29, 2010

Cambridge, UK - An analysis of more than 30 studies involving lipoprotein-associated phospholipase A2 (Lp-PLA2) has shown that increased activity and amount of the inflammatory enzyme are associated with an increased risk of coronary heart disease, as well as other, nonvascular outcomes[1].

Despite the positive results, the researchers, including more than 70 scientists participating in the Lp-PLA 2 Studies Collaboration (LSC), are cautious in their interpretation of the findings.

"We've demonstrated that there is this positive association between Lp-PLA2 levels and vascular and nonvascular outcomes," lead researcher Dr Alex Thompson (University of Cambridge, UK) told heart wire , "but what an observational study can't do is establish causality. Given all the complexities about disentangling the effects of a measured level of an enzyme in the blood, given that it is carried around and is physically bound to apolipoprotein B on LDL, it is extremely difficult to do. To get that level of evidence, we are going to need randomized, clinical trials."

Those studies are still some years away, however. The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial (STABILITY), a 15 000-patient outcomes study involving the Lp-PLA2 inhibitor darapladib (GlaxoSmithKline) is expected in 2012, while the Stabilization of Plaques Using Darapladib—Thrombolysis In Myocardial Infarction 52 Trial (SOLID-TIMI 52) will be completed in 2014. One recently presented intravascular ultrasound (IVUS) study with darapladib showed mixed results, with the drug failing to improve indirect, novel measures of plaque stability, while other secondary-end-point IVUS readings suggested the drug may stem expansion of the necrotic core of plaques.

Meta-analysis including 32 studies

Speaking with heart wire , Thompson said that Lp-PLA2 is an enzyme that is expressed by inflammatory cells in the atherosclerotic plaques. It has the attention of researchers because it potentially links arterial accumulation and oxidation of LDL cholesterol in the coronary arteries with a subsequent inflammatory response, that being a rise in the activity and amount of Lp-PLA2.

There is still uncertainty, however, about where Lp-PLA2 fits into the development of coronary atherosclerosis. Previous epidemiological and observational evidence has shown "generally positive associations" of Lp-PLA2 with subsequent risk of vascular diseases, said Thompson, but these studies were often small, used different clinical outcomes, studied different populations, and even had different ways of measuring Lp-PLA2.

In this newest study, the researchers used individuals records of 79 036 patients included in 32 prospective studies and calculated the relative risks per one standard deviation (SD) of Lp-PLA2 activity, which measured the amount of hydrolysis of the phospholipid substrate, and Lp-PLA2 mass, which is the amount of the protein.

The results showed a continuous, log-linear association with Lp-PLA2 mass and activity and a variety of chronic diseases, including coronary heart disease, ischemic stroke, death from vascular causes, and death from nonvascular causes. There was an approximate 10% higher risk of disease/death per 1-SD-higher Lp-PLA2 activity and mass.

Risk ratios for outcomes per 1-SD-higher Lp-PLA2 activity or mass from baseline

Outcome Relative risk (95% CI)
Lp-PLA 2 activity  
Coronary heart disease 1.10 (1.05-1.16)
Ischemic stroke 1.08 (0.97-1.20)
Vascular death 1.16 (1.09-1.24)
Nonvascular death 1.10 (1.04-1.17)
Lp-PLA 2 mass  
Coronary heart disease 1.11 (1.07-1.16)
Ischemic stroke 1.14 (1.02-1.27)
Vascular death 1.13 (1.05-1.22)
Nonvascular death 1.10 (1.03-1.18)

To heart wire , Thompson said these modest positive associations were at least partly explained by conventional risk factors. He noted there were moderate to strong correlations with conventional lipids, meaning that disentangling the association between Lp-PLA2 and heart disease from other risk factors, including LDL cholesterol, remains a challenge and that it is unclear how much of the association would remain if researchers were able to fully adjust for those risk factors.

In an editorial accompanying the published study[2], Dr Robert Rosenson (Mount Sinai School of Medicine, New York) writes that future studies that evaluate cardiovascular risks associated with Lp-PLA2 activity and/or mass should adjust for apolipoprotein B and small LDL-particle concentrations. Like Thompson, Rosenson said clinicians need to wait for the large outcomes studies with darapladib to determine the relationship between baseline and on-treatment Lp-PLA2 mass and activity with cardiovascular events. He notes that these data will also be relevant for future studies with varespladib (Anthera Pharmaceuticals), a new secretory PLA2 inhibitor.

Value of Lp-PLA
2
measurement unknown at this point

In the present study, the association between Lp-PLA2 activity and mass with coronary heart disease was similar in magnitude to non-HDL cholesterol and systolic blood pressure, although the association between blood pressure and non-HDL cholesterol and heart disease was only one-third as strong as observed in previous studies. Thompson noted the patients included in this study tended to be older and had a high prevalence of comorbidities, as well as cardiovascular disease, and this might have blunted the effect of systolic blood pressure and non-HDL cholesterol on coronary heart disease risk.

In the US, there are Food and Drug Administration-approved tests for measuring Lp-PLA2, but Thompson remains cautious about the clinical utility of measuring it until further studies prove its benefit.

"The value of the measurement of Lp-PLA2 in risk prediction, such as the 10-year risk stratification for primary prevention or perhaps to guide therapy in an acute or chronic disease setting, is still an open question," he said. "Unfortunately, this is one of the areas we weren't able to address. There were a relatively limited number of primary-prevention participants, those without a history of disease, which is where the majority of risk prediction has its value. Moreover, the average duration of follow-up was pretty short, around six years, and this prevented us from doing predicted 10-year absolute risk of disease in any sort of risk-stratification analysis."

Alex Thompson's institution has received research funding from the British Heart Foundation , GlaxoSmithKline, and the UK Medical Research Council . He has received honoraria and reimbursement for speaking at scientific meetings from GlaxoSmithKline. Rosenson reports research funding and consultant fees from Anthera Pharmaceutics. He has received consultant fees from and owns stock in LipoScience.

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