Cardiometabolic Risk Reduction: Mechanistic Rationale and the Burden of Proof

Section overview: Cardiometabolic risk reduction

Contributing factors in cardiometabolic risk Obesity, dysglycemia, dyslipidemia, and hypertension frequently cluster and are major risk factors for both diabetes and cardiovascular (CV) disease. The impact of these risk factors is amplified by lifestyle (physical inactivity, smoking, and diet) as well as by genetics, gender, and age. Abbreviations: ACC = American College of Cardiology ADA = American Diabetes Association Apo = apolipoprotein BP = blood pressure HDL-C = high-density lipoprotein cholesterol LDL-C = low-density lipoprotein cholesterol TG = triglyceride(s)

Risk of T2DM increases as cardiometabolic risk factors increase The association of cardiometabolic risk factors and diabetes is illustrated by data from the Framingham Heart Study. Using a diabetes risk assessment model developed from 3224 men and women who participated in the study in the 1990s, Wilson et al calculated the 8-year risk of developing diabetes for various combinations of risk factors. As expected, as the number of coexisting risk factors rises, the risk of diabetes also rises, with dysglycemia having the greatest impact.

The evolving view of adipose tissue as an endocrine organ Once thought to be merely a passive storage depot for TG, the adipocyte is now understood to be the source of a number of bioactive molecules (adipokines). As an active endocrine organ, adipose tissue can have effects on the structure and function of other organ systems.

Visceral adiposity associated with increased levels of IL-6 Fat depots appear to differ in their pathogenic potential. Venous return from visceral adipose tissue drains directly into the liver, while venous return from the subcutaneous abdominal fat depot does not. In addition, visceral adipose tissue may be more metabolically active than peripheral adipose tissue.(1) A recent study by Cartier et al matched subjects with similar BMIs and demonstrated that increased visceral fat mass was associated with significantly increased levels of circulating IL-6. In contrast, overweight or obese subjects with predominantly peripheral fat had levels of IL-6 similar to lean controls. However, it should be stressed that even excessive subcutaneous adipose tissue may become pathogenic.(1) 1. Bays HE et al. Expert Rev Cardiovasc Ther. 2008;6:343-68.

Pathologic effects of nutritional overload Chronic energy imbalance caused by an excess of calories consumed vs expended leads to increased storage of TG within adipocytes, which in turn causes both increased adipocyte size (hypertrophy) and adipocyte number (hyperplasia). Manifestations of this process include increased levels of proatherogenic and pro-inflammatory cytokines, free fatty acids, and inflammatory mediators. Monocyte recruitment by adipose tissue further exacerbates inflammation.

Consequences of ectopic fat deposition Normally, the amount of TG stored in nonadipocyte tissue is minimal. However, a number of lines of evidence suggest that obesity may also be associated with excessive TG accumulation within the liver, pancreatic beta-cell, and myocardium. Adverse consequences of such ectopic fat accumulation include nonalcoholic steatohepatitis, pancreatic beta-cell failure, and dilated cardiomyopathy.

Epicardial fat is associated with myocardial dysfunction in humans Until recently, most of the data linking ectopic fat accumulation with cardiomyopathy came from animal studies. However, advances in magnetic resonance spectroscopy have permitted studies in humans. McGavock et al used proton magnetic resonance spectroscopy to quantify TG accumulation in 134 subjects, who were recruited from the Dallas Heart Study database. The investigators demonstrated that compared with lean, normoglycemic study subjects, those with IGT or T2DM had more than twice the amount of myocardial TG accumulation, a significant difference. Myocardial TG was also elevated (but nonsignificantly) in obese but normoglycemic subjects. Using cardiac magnetic resonance imaging, the investigators further showed that diastolic function (as measured by early diastolic peak filling rate) was abnormal in dysglycemic and obese, normoglycemic subjects vs lean, normoglycemic subjects.

Evolving view of cardiometabolic risk: Summary The slides in this section have summarized evidence that targeting visceral adiposity is a potentially important strategy for reducing multiple cardiometabolic risk factors. Visceral adiposity may be conveniently assessed via waist circumference.