Protecting the Heart in Obesity: Role of ACE2 and Its Partners

Heart failure, which is among the most common and disabling forms of cardiovascular disease, is closely associated with obesity (1). This is not a new observation, and as highlighted in a historical treatise on the heart and obesity by Alexander (2), in the 1700s the relationship of excess fat deposition involving the heart in obese individuals was reported. In the early 1800s, the fatty heart as an entity was described, and in 1847, William Harvey reported in a postmortem examination of a morbidly obese man that the heart was “large, thick and fibrous, with a considerable quantity of adhering fat” (2). Although the association between obesity and heart disease is well accepted, underlying pathophysiological processes remain elusive, and it is unclear whether obesity cardiomyopathy is due to increased adiposity itself or due to the effects of obesity-associated comorbidities, including hypertension, metabolic syndrome, and diabetes.In obesity, the heart undergoes structural remodeling due to interstitial fibrosis, cardiomyocyte hypertrophy, and cardiac steatosis, leading to functional alterations (3). Molecular mechanisms associated with these processes include oxidative stress, natriuretic peptides, endothelin-1, advanced glycation end products, and activation of the renin-angiotensin-aldosterone system (RAAS) (4,5). In addition, inflammation is now considered to be important in obesity-related heart disease, especially in the context of diabetes and insulin resistance (6). In support of this are studies demonstrating that adipocyte-derived factors (adipokines) directly influence proinflammatory signaling in the heart (7).Common in many of the above processes is activation of the RAAS, which is upregulated in obesity (5). Angiotensin (Ang) II, through the angiotensin type 1 receptor (AT1R), promotes cardiovascular fibrosis, inflammation, and insulin resistance and plays a role in the cardiovascular complications of diabetes and obesity. Recent evidence indicates that cardiac steatosis amplifies the injurious actions of Ang II through reactive oxygen species (8), thereby …