Myocardial fibrosis in congenital and pediatric heart disease

Abstract

Cardiac fibrosis is a common phenomenon in different types of heart diseases, such as ischemic heart disease, inherited cardiomyopathy mutations, diabetes, and ageing and is associated with morbidity and mortality. Increased accumulation of extracellular matrix (ECM) that impacts cardiac function, is the underlying cause of fibrotic heart disease. There are four different types of cardiac fibrosis, including, reactive interstitial fibrosis, replacement fibrosis, infiltrative interstitial fibrosis and endomyocardial fibrosis. They are involved in the activation and transformation of cardiac fibroblasts to myofibroblasts, which participate in ECM production and fibrotic process and several inflammatory pathways. Besides the ECM proteins, myofibroblasts also express smooth muscle α-actin, SM22 and caldesmon and other markers related to fibrotic process. Most commonly employed techniques to assess myocardial fibrosis include stress echocardiography, cardiac magnetic resonance imaging and positron emission tomography. Because of the involvement of renin-angiotensin-II-aldosterone system, transforming growth factor-β signaling and activin-linked kinase 5 in the mechanisms of cardiac fibrosis, these pathways and the involved proteins are useful as therapeutic targets. However, because of the importance of these pathways in many other physiological functions, their therapeutic targeting needs to be approached with caution.

Keywords: cardiac fibrosis; extracellular matrix; inherited cardiomyopathy.

Figure 1.

Insult and injury to heart lead to cardiac fibrosis. Several insults such as pressure and volume loading and even certain genetic abnormalities lead to the activation of different signaling pathways such as RAAS, catecholamines and natriuretic peptides. These pathways cause activation/transformation of cardiac fibroblasts to myofibroblasts, which participate in elevated ECM deposition and myocardial fibrosis. Fibrosis disturbance causes diastolic and systolic function and causes arrhythmia, all of which are clinical features of heart failure. RAAS, renin-angiotensin-aldosterone system; ECM, extracellular matrix.

Figure 2.

Signaling pathways involved in cardiac fibrosis and possible therapeutic targets. Angiotensin-II induces TGF-β, CCN2, and ET-1 directly; TGF-β, in turn can induce ET-1 and CCN2; ET-1 can also induce CCN2. There is positive feedback between TGF-β and angiotensin-II through the induction of angiotensin receptor. TGF-β signaling involves Smads3 or −4. All these signaling components promote fibroblast activation to myofibroblast, which plays a key role in fibrosis through the secretion of extracellular matrix proteins and α-SMA. These signaling components make potential therapeutic targets (indicated with red X) for preventing cardiac fibrosis. TGF-β, transforming growth factor-β; ET-1, endothelin-1.