Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

Abstract

Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias and sudden cardiac death in obese subjects. Our review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiologic alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiologic alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the Renin-Angiotensin-Aldosterone System, induction of Transforming Growth Factor-β, oxidative stress, advanced glycation end-products (AGEs), endothelin-1, Rho-kinase signaling, leptin-mediated actions and upregulation of matricellular proteins (such as thrombospondin-1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response following cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to development of novel therapies to prevent heart failure and to attenuate post-infarction cardiac remodeling in obese patients.

The high-fat diet induces myocardial fibrosis in the metabolically healthy obese minipigs—The role of ER stress and oxidative stress

“…Clinical 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 studies demonstrate considerable association between obesity and cardiac fibrosis; potential mechanisms contributing to cardiac fibrosis include hemodynamic factors, neuro-humoral substances, metabolic dysregulation, inflammation and oxidative stress [18,19]. Nevertheless, we previously found that neither metabolic dysfunction (hyperglycemia, insulin resistance and dyslipidemia) nor hypertension was induced in O-MHO pigs [11].…”

Smad3 Signaling Promotes Fibrosis While Preserving Cardiac and Aortic Geometry in Obese Diabetic Mice

“…Diastolic dysfunction is the hallmark of diabetic cardiomyopathy 19,20 and may be due to cardiac hypertrophy, or to the development of interstitial fibrosis 21,22 . Our findings demonstrate that in the db/db mouse model of fibrotic diabetic cardiomyopathy, partial loss of Smad3 improves ventricular compliance (Figure 4).…”

HDAC6 Promotes Cardiac Fibrosis Progression through Suppressing RASSF1A Expression

“…Cardiac fibroblasts play a key role in the pathogenesis of cardiac fibrosis [18]. The epigenetic control of gene expression by the HDAC family has been demonstrated to play critical roles in fibrosis progression and development [19,20].…”