Lp-PLA2: Eliciting the risk of CVD events

Marking World Heart Day (September 29), Arnab Roy, Kshama Pimpalgaonkar, Abhik Banerjee, and Faisal Khan, Division of R&D and Department of Biochemistry; (SRL Mumbai) elaborate on the Indian phenotype-genotype and their propensity towards heart disease as well as highlight an emerging bio-marker for assessing the risk of CVD events

Speaking of coronary artery disease in specific and cardiovascular disorders in general, as native Indians, let us confess that we are certainly a disadvantaged lot. Not that we prefer to begin this article on such a sombre note, but that’s what medical evidence tells us and that’s where the truth lies. Our peculiar genotypes and phenotypes as native Indians, amplify our predilection towards truncal obesity, diabetes, aberrant lipid profile characteristics and consequently an increased propensity towards early atherosclerosis.

Now add to these; the facts that India is urbanising at a frenetic pace, stress levels are skyrocketing, lifestyles have become sedentary, dietary patterns have gotten unhealthy, junk and processed food has become the mainstay of meals, alcoholism is on the rise. A recipe for disaster? Sure it is. The crux of it all – As Indians, we were born with an increased susceptibility towards heart diseases as compared to our other racial and ethnic counterparts across the world. To make matters worse, an aggravation of the other modifiable risk factors, caused by our changing surroundings and lives, makes us doubly vulnerable to heart disease.

The estimates of heart disease in India can make you skip a heart beat!!

Just to give you a peek into how humongous is the scale of this medical concern, let us quote stats presented in a recent study published in the British Medical Journal. CAD is the leading cause of death in India and since 1985 until 2015, the number of CAD related deaths in India has doubled. It is alarming to learn that by the end of 2015, a whopping 62 million Indians are estimated to have fallen prey to CAD. What makes us more apprehensive is the projection that an estimated 23 million of these total CAD patients, would be from India’s most productive workforce, the youth below the age of 40 years.

Early diagnosis and treatment: A wake up call for risk mitigation

This is certainly time for a concerted action by India’s medical fraternity, government bodies and the general masses to spread awareness regarding the risk of CVD looming large on our human and healthcare resources and to propose and execute remedial measures to curb this rise. One of the key mitigation strategies that could offer a major panacea to this problem is timely and accurate identification of individuals at risk of suffering a cardiovascular adverse event like an infarction. Hence, we are faced with a dire need of methods and tools that could be employed by a clinician to stratify patients based on their risk of having a CVD event in future.

Risk assessment in heart disease: Looking beyond ECGs and lipid profiles

How could the clinician possibly predict the risk of a CVD event among patients or healthy individuals? At a superficial level, one could cite several methods which could be used for this purpose – ECG, TMT, Doppler scans, CT/MRI scans, Echo studies, lipid profile studies and other lab tests like CRP, apolipoproteins etc; and all of these needs to be correlated with the individual’s clinical history. However, these are either radiological assessments or biochemical assays, which evidence tells us, might not show the accurate degree of risk of having a CVD event. Just a case in point, are those several clinical studies which stand testimony to the fact that patients with a normal or near normal LDL cholesterol levels are at an equal risk of CVD as compared to those with abnormal LDL cholesterol values!

Biomarkers of vascular inflammation: New and pragmatic tools for assessing the risk of CVD events

From a medical standpoint, such risk prediction can be better accomplished when the clinician gets a clear hint of the actual pathophysiological changes occurring at the level of the vascular lumen and vascular walls. Atherosclerosis is an inflammatory process occurring within the walls of the arteries. Hence, measuring the risk of developing atherosclerotic plaques and assessing the character, extent and activity of existing plaques could be a nodal point of interest while predicting the risk of CVD events. This approach has garnered recent acceptance in the risk prediction and risk stratification of CVD patients. Stemming from this approach, the medical fraternity has been deliberating with great interest upon cardiovascular biomarkers which play an important role in pathological development and activity of atherosclerotic plaques. Such biomarkers can serve as the best possible surrogates of the inflammatory process brewing along the vascular wall. Lp-PLA2 (lipoprotein associated phospholipase A2) which closely mirrors the plaque activity and the inflammatory changes is a frontrunner among the various vascular inflammatory biomarkers.

Lp-PLA2: What is it and why is it important?

As we shared previously, LDL-cholesterol concentrations are insufficient to identify individuals with incident CVD events because ~50 per cent of all CVD events occur in persons with normal or even low LDL-cholesterol concentrations. This has led to the hypothesis that other factors may be involved in the pathogenesis of CVD. Recent clinical studies showed that Lp-PLA2 is an independent risk factor for CVD. Data from numerous large population studies and systematic reviews consistently indicated a positive association between plasma Lp-PLA2 mass or activity and the risk for incident atherosclerotic events.

The enzyme, originally named platelet-activating factor acetylhydrolase (PAF-AH), multiple inflammatory cells involved in atherogenesis secrete Lp-PLA2, including monocytes, macrophages, neutrophils, activated bone marrow-derived mast cells, and activated platelets. It has two prominent biological activities. First, it inactivates proinflammatory mediator PAF. Second, Lp-PLA2 hydrolyzes oxidatively modified polyunsaturated fatty acids producing lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (OxNEFA). OxNEFA have potent monocyte chemotactic activity and LysoPC upregulates inflammatory mediators, including cytokines, adhesion molecules and the chemotactic mediator MCP-1.

Stable atherosclerotic plaques contain few inflammatory cells and a small amount of Lp-PLA2. In contrast, unstable plaques most often do not have significant impact on arterial lumen but may be detected by their thin connective tissue cap, low collagen and high lipid content. A distinguishing factor between stable and unstable atherosclerotic plaque are the presence of activated inflammatory cells and increased Lp-PLA2 concentration in unstable plaque.

Lp-PLA2 is strongly expressed within the necrotic core of the plaque and surrounding macrophages of vulnerable and ruptured plaques in humans and is thought to promote apoptotic cell death. Excess production of Lyso-PC in response to PLA2 activation, prevents the apoptotic cell debris from being cleared up from the vascular lumen. Resultantly, the cell debris pile up in the lumen around the lesion; thereby perpetuating vascular inflammation and promoting necrotic core formation.

Lp-PLA2 has low biological variability and is directly involved in the pathogenesis of atherosclerotic plaque progression.

Past clinical evidence has shown that high Lp-PLA2 was a potential risk factor, which was important not only for the formation of atherosclerotic plaque but also for its rupture. The purpose of applying markers of inflammation is to improve stratification of patients at risk, so that treatment intensity may be adjusted to the imminent risk level as well.