Remodeling and Fibrosis of the Cardiac Muscle in the Course of Obesity-Pathogenesis and Involvement of the Extracellular Matrix

Abstract

Obesity is a growing epidemiological problem, as two-thirds of the adult population are carrying excess weight. It is a risk factor for the development of cardiovascular diseases (hypertension, ischemic heart disease, myocardial infarct, and atrial fibrillation). It has also been shown that chronic obesity in people may be a cause for the development of heart failure with preserved ejection fraction (HFpEF), whose components include cellular hypertrophy, left ventricular diastolic dysfunction, and increased extracellular collagen deposition. Several animal models with induced obesity, via the administration of a high-fat diet, also developed increased heart fibrosis as a result of extracellular collagen accumulation. Excessive collagen deposition in the extracellular matrix (ECM) in the course of obesity may increase the stiffness of the myocardium and thereby deteriorate the heart diastolic function and facilitate the occurrence of HFpEF. In this review, we include a rationale for that process, including a discussion about possible putative factors (such as increased renin-angiotensin-aldosterone activity, sympathetic overdrive, hemodynamic alterations, hypoadiponectinemia, hyperleptinemia, and concomitant heart diseases). To address the topic clearly, we include a description of the fundamentals of ECM turnover, as well as a summary of studies assessing collagen deposition in obese individuals.

Keywords: cardiac fibrosis; cardiac remodeling; collagen; extracellular matrix (ECM); metalloproteinase (MMPs); obesity; tissue inhibitor of metalloproteinases (TIMPs).

Figure 1

Pathogenesis of hemodynamic alterations in the course of obesity. RAAs—renin–angiotensin–aldosterone system; SVR—systemic vascular resistance; SV—stroke volume; HR—heart rate; CO—cardiac output; LV—left ventricle.

Figure 2

Two distinctive patterns of cardiac remodeling in the course of obesity and a proposition for their pathogenesis based on adipose tissue distribution. SVR—systemic vascular resistance; CO—cardiac output.

Figure 3

Rationale for cardiac fibrosis in the course of obesity and its clinical sequel. Ang II—angiotensin II; ACE—angiotensin-converting enzyme; SNS—sympathetic nervous system; ANP—atrial natriuretic peptide; BNP—brain natriuretic peptide; ERK1/2—extracellular-signal-regulated kinase; JAK—Janus-activatedkinase; TGF-β—transforming growth factor beta; cGMP—cyclic guanosine monophosphate; p38MAPK—p38 mitogen-activated protein kinase; JAK/STAT—Janus kinase/signal transducer and activator of transcription; AMPK—AMP-activated protein kinase; Pi3k/Akt—phosphatidylinositol 3-kinase/protein kinase B; MI—myocardial infarction; HTN—hypertension; LAE—left atrial enlargement; HFrEF—heart failure with reduced ejection fraction; HFpEF—heart failure with preserved ejection fraction.