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.

PPAR Alpha Activation by Clofibrate Alleviates Ischemia/Reperfusion Injury in Metabolic Syndrome Rats by Decreasing Cardiac Inflammation and Remodeling and by Regulating the Atrial Natriuretic Peptide Compensatory Response

“…It is well known that neutrophils and/or macrophages show a strong affiliation to invade the damaged area due to the apoptotic cardiomyocytes and the need for their removal; however, in the present paper, we did not evaluate the cell subpopulations infiltrated [ 6 , 30 ]. Our data are in line with several studies that have demonstrated that MetS signs, such as obesity, insulin resistance, lipotoxicity, and inflammation, play an important role in myocardial fibrosis by activating several downstream signaling cascades [ 31 , 32 , 33 ]. In addition, scientific evidence has implicated angiotensin II in the inflammatory process as well as in the progression of myocardial fibrosis via binding to AT1 receptor [ 34 ].…”

“…In I/R injury, expression of MMP-2 is of particular interest because MMP-2 degrades extracellular matrix substrates including Type IV collagen, laminin, elastin, interstitial fibrillar collagen, and sarcomeric proteins [ 35 , 36 ]. The expression of this zinc-dependent protease is regulated by mechanical signals, inflammatory factors, hormones, and NPs, among other factors; some authors even suggest that MMP-2 can be used as a possible pharmacological target in the treatment of heart failure [ 31 , 36 , 37 , 38 ]. Therefore, we analyzed the expression of MMP-2 in all experimental groups and found that the expression of this enzyme was higher in hearts from MetS rats in sham-operated conditions and under I/R damage without there being changes in the Ct group.…”

Mitochondrial Oxidative Stress Induces Cardiac Fibrosis in Obese Rats through Modulation of Transthyretin

“…Cardiac fibrosis is a common feature observed in obesity, which ultimately leads to myocardial stiffness, arrhythmias and diastolic dysfunction [ 10 , 36 ]. Previous studies have confirmed the detrimental role of TTR in cardiac cells, showing toxic effects on cardiac myocytes [ 37 ]; however, there are no studies evaluating the effects of TTR on extracellular matrix synthesis.…”

“…Fibrosis is defined as excessive extracellular matrix accumulation, which could be due to an increase in extracellular matrix protein synthesis and/or a decrease in its degradation. It is a well-recognized cause of high morbidity and mortality, increasing myocardial stiffness and, therefore, promotion of diastolic dysfunction [ 9 , 10 ]. Furthermore, its evaluation has been suggested as a useful indicator of long-term mortality in heart failure patients [ 11 ].…”

Prevalence and clinical features of heart failure in Greenland

“…The 2018 population survey found that 27% of the Greenlandic population were obese [ 16 ] and 32% of the HF population in the UK [ 10 ]. Suggesting that obesity among Greenlandic Inuit induce HF through pathologic pathways such as insulin resistance, inflammation of adipokines and cardiac lipotoxicity as well as increased predisposition to established risk factors for HF [ 29 , 30 ].…”