ROLE OF EPICARDIAL AND INTRATHORACIC FAT

In the setting of obesity, epicardial adiposity and VAT mass increase in concert, and an increase in either has a significant independent association with established cardiovascular (CV) risk factors, according to work reviewed by Amalia Gastaldelli, PhD, Institute of Clinical Physiology, CNR, Pisa, Italy, and University of Texas Health Science Center, San Antonio, Texas, USA.

On imaging, epicardial adiposity can be visualized as perivascular adipose tissue, surrounding coronary vessels, and, as with adipose tissue in other depots, it releases fatty acids and cytokines. Fat deposition also occurs in the intrathoracic region and inside cardiomyocytes. All of the cardiac fat depots have been shown to be markers of cardiac lipotoxicity, mitochondrial dysfunction, inflammation, local and systemic insulin resistance, atherosclerosis, and cardiac dysfunction, she stated.

Although cardiac fat is associated with impairment in heart metabolism and cardiac dysfunction, Prof. Gastaldelli stated that the interplay between cardiac fat accumulation, insulin resistance, and cardiac dysfunction remains to be fully established. Men accumulated more fat around their heart, with more intrathoracic and epicardial fat deposition, than women in a CT study [Rosito GA et al. Circulation 2008]. A study of men with untreated hypertension showed that increased levels of epicardial and visceral adipose tissue were independent from subcutaneous fat accumulation [Sironi AM et al. Hypertension 2004].

In the Framingham Heart Study women with higher levels of both epicardial adiposity and visceral fat had a higher prevalence of impaired fasting glucose and hypertension while in men the association was with metabolic syndrome [Rosito GA et al. Circulation 2008]. In general visceral fat was a stronger predictor than epicardial adiposity of cardiometabolic risk factors, probably because of its size.

An association was shown between cardiac fat accumulation and fatty liver, and between increased epicardial adiposity and reduced myocardial energy [Perseghin G. Hepatology 2008]. Epicardial adiposity thickness was correlated with endothelial dysfunction, as measured by reduced flow mediated vasodilation in patients with metabolic syndrome [Aydin H et al. Metab Syndr Relat Disord 2010]. Pericardial fat was an independent risk factor for coronary artery stenosis in the Korean Atherosclerosis Study 2 although the odd ratio was small when adjusted for age, gender, and body mass index (BMI; OR, 1.01; p<0.03) [Kim TH et al. Obesity (Silver Spring) 2011]. Table 1 details the relation between fat depots and CV disease burden in the Framingham Heart Study [Mahabadi AA et al. Eur Heart J 2009].

Epicardial adiposity increases in parallel to intrathoracic fat and BMI [Rosito G et al. Circulation 2008; Sironi et al. Diabet Med 2011; Yerramasu A et al. Atherosclerosis 2012]. Both epicardial adiposity and intrathoracic fat were shown to be associated with glucose metabolism and type 2 diabetes, decreased left ventricular diastolic function [Sironi AM et al. Hypertension 2008], and increased blood pressure in men with newly detected, untreated essential hypertension [Sironi AM et al. Hypertension 2004] and in the Framingham Heart Study [Rosito G et al. Circulation 2008].

RAISING HDL-C TO REDUCE CV RISK

Epidemiologic data have shown a robust association between low levels of high-density lipoprotein cholesterol (HDL-C; <60 mg/dL) and increased hazard of coronary heart disease, stroke, and CV events, according to Philip Barter, MD, PhD, University of New South Wales, Sydney, Australia. Low HDL-C (<42 mg/dL) remains associated with CV events even in patients with low-density lipoprotein cholesterol (LDL-C) levels, as shown by the TNT study [Barter P et al. N Engl J Med 2007]. Furthermore, HDL-C has several properties with the potential to inhibit development of atherosclerosis.

However, to date, interventions that raise HDL-C have not shown CV benefits in statin-treated patients. The AIM-HIGH and HPS2-THRIVE trials tested the benefit of raising HDL-C with niacin and failed to show a benefit. Prof. Barter stated AIM-HIGH was not powered to detect the 8% between-group difference in CV event rate expected from population-studies [Boden WE et al. N Engl J Med 2011], and the negative result in HPS2-THRIVE, presented at ACC. 13 in March 2013, was consistent with what would be predicted from modest changes in the lipid profile observed in the trial. Further, he stated the absence of a positive result in HPS2-THRIVE does not refute the hypothesis of significant beneficial effects with greater reductions in LDL-C or greater increases in HDL-C.

Trials with cholesteryl ester transfer protein (CETP) inhibitors that have been reported to date have also not shown a benefit. Torcetrapib was associated with adverse off-target pharmacology unrelated to CETP that likely was responsible for the negative result of ILLUMINATE, said Prof. Barter [Barter PJ et al. N Engl J Med 2007]. The dal-OUTCOMES trial with dalcetrapib, which increases HDL-C by about 30% with minimal effects on LDL-C levels, was terminated early for futility [Schwartz GG et al. N Engl J Med 2012]. Prof. Barter stated CETP inhibition may not be effective in patients treated soon after an acute coronary syndrome (ACS), which is supported by the observation that HDL-C isolated from patients after an ACS has impaired function, and by the unexpected observation in dal-OUTCOMES that the level of HDL-C in the placebo group did not predict CV risk.

The future of CETP inhibitors depends on the results of ongoing, clinical outcome trials with more potent agents without off-target effects. REVEAL HPS-3 TIMI 55 trial is testing anacetrapib in 30,000 patients with stable coronary artery disease and the ACCELERATE trial is testing evacetrapib in 11,000 patients with high-risk vascular disease.