HDL Function, Independent of Levels, Impaired in STEMI Patients

HDL Function and STEMI

June 29, 2011

June 29, 2011 (Gothenburg, Sweden) — HDL function is significantly impaired in patients with acute MI, and this impairment is independent of HDL-cholesterol levels, according to the results of a new study. Investigators report that STEMI patients had reduced cholesterol-efflux capacity and an impaired inflammatory response, two markers indicative of impaired HDL function.

"With HDL-cholesterol levels, it is already well established that levels of HDL cholesterol are inversely correlated with the risk of cardiovascular disease, but now it's emerging that in certain clinical situations HDL cholesterol can be dysfunctional," lead investigator Dr Wijtske Annema (University Medical Center, Groningen, the Netherlands) told heartwire .

Presenting the results of the study here at the European Atherosclerosis Society 2011 Congress, the researchers assessed whether three antiatherogenic properties of functional HDL cholesterol were altered independent of HDL-cholesterol levels in patients presenting with acute MI. In addition to cholesterol-efflux capacity, the group measured 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH)–induced oxidation of native LDL cholesterol, a measure of how well HDL cholesterol inhibits oxidation, and the inhibition of tissue necrosis factor-{:alpha:}–induced vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells, a measure of the anti-inflammatory function of HDL cholesterol.

Three patient groups compared

In total, 111 patients were studied, including 33 noncardiac patients, 41 non-STEMI patients, and 37 STEMI patients. The three groups were well-matched in terms of age and cardiovascular risk factors. Importantly, baseline HDL-cholesterol levels were similar in all three groups. Compared with the noncardiac and non-STEMI patients, HDL functionality, as assessed by two of the three measures, was significantly impaired in patients with STEMI.

"We found that in STEMI patients with a really severe MI, there was a reduced capacity for cholesterol efflux, but we didn't see any change in the antioxidative effects of HDL cholesterol," said Annema. "We did find that the HDL cholesterol in STEMI patients was less able to inhibit VCAM expression."

To heartwire , Annema said the study highlights the importance of HDL functionality and that simply measuring quantity is not good enough, in some settings, when assessing cardiovascular risk. Annema added that the group focused on STEMI patients as they wanted to focus on a clinically relevant setting of cardiovascular care.

Trials designed to show a clinical benefit with drugs that increase HDL cholesterol have hit some rocky patches of late, hence some of the focus on HDL functionality. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study of high-dose extended-release niacin (Niaspan, Abbott) given in addition to statin therapy in patients with a history of cardiovascular disease, high triglycerides (TG), and low levels of HDL cholesterol was halted prematurely because niacin offered no additional benefits in this patient population. The Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study, however, another large trial with niacin, is still ongoing.

A cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib (Merck, Whitehouse Station, NJ), was recently shown to increase HDL-cholesterol levels a whopping 138% when compared with placebo, but outcome studies with the CETP inhibitor have not yet been concluded. One CETP inhibitor, torcetrapib, made by Pfizer, met a disastrous end when it was pulled from development after researchers found it increased the risk of death and cardiovascular events, an outcome experts attributed to the drug's off-target increase in blood pressure.

Need for hard data with HDL-raising drugs

Speaking during a plenary session earlier in the week, Dr M John Chapman (Pitié-Salpetriere University Hospital, Paris, France) also turned his attention to the quality, rather than the quantity, of HDL cholesterol. Chapman focused on the particle structure of HDL cholesterol and its functionality, noting that there are multiple HDL-particle subpopulations. The current hypothesis, he said, is that the biological activities of HDL cholesterol are the result of the lipid and protein components of these subparticles.

In addition, Chapman cited data published this year showing that cholesterol-efflux capacity from macrophages has a strong inverse association with carotid intima-media thickness and angiographic coronary artery disease, independent of HDL-cholesterol levels.

Regarding future research, Chapman said experts need to define the quality of HDL cholesterol by identifying the optimal HDL particle subpopulation profile, as well as its optimal functional properties, in patients at low cardiometabolic risk who have normal lipid levels. This profile could then be used as the "gold standard" for future pharmacotherapeutic research and development. In addition, there is a need to define the key abnormalities of the HDL-particle profile in patients with metabolic disease and various stages of the disease process.