Cardiovascular remodelling in coronary artery disease and heart failure

Abstract

Remodelling is a response of the myocardium and vasculature to a range of potentially noxious haemodynamic, metabolic, and inflammatory stimuli. Remodelling is initially functional, compensatory, and adaptive but, when sustained, progresses to structural changes that become self-perpetuating and pathogenic. Remodelling involves responses not only of the cardiomyocytes, endothelium, and vascular smooth muscle cells, but also of interstitial cells and matrix. In this Review we characterise the remodelling processes in atherosclerosis, vascular and myocardial ischaemia-reperfusion injury, and heart failure, and we draw attention to potential avenues for innovative therapeutic approaches, including conditioning and metabolic strategies.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Positive and negative arterial remodelling influences the clinical consequences of atherosclerosis

Normal laminar shear stress (upper left) elicits atheroprotective and homeostatic functions of endothelial cells (ECs). These functions maintain normal arterial caliber and properties (A). Disturbed blood flow in endocardial disease is shown by the reversed arrows in the upper right. In (B) the red circle portrays the tunica media, and the orange circle indicates the intima of the artery. Disturbed flow promotes the recruitment of monocytes, as depicted in the nascent plaque (B), where monocyte diapedesis (in blue) penetrates between ECs to form a thin-capped, lipid-rich inflamed plaque (C), which can rupture and cause a thrombus (D), leading to myocardial infarction, indicated by cyanosis in the heart diagram. Alternatively the plaque in E can undergo constrictive remodelling to promote flow-limiting stenosis (E) that can cause demand ischaemia and angina pectoris

Figure 2. Role of microembolisation in coronary vascular remodelling

Plaque rupture or fissure without complete epicardial coronary occlusion releases particulate debris from the atherosclerotic culprit lesion which, together with superimposed thrombotic material and soluble substances such as serotonin and thromboxane A 2, is washed into the coronary microcirculation by the residual blood flow. Coronary microembolisation causes microinfarcts with an inflammatory reaction. Inflammatory mediators such as nitric oxide (NO), TNFα and sphingosine induce contractile dysfunction through increased reactive oxygen species (ROS) formation and oxidative modification of the contractile machinery. TNFα in lower concentrations is, however, cardioprotective (upward arrow). Arrhythmias, contractile dysfunction and impaired coronary reserve are the functional consequences of coronary microembolisation. Modified from reference.

Figure 3. Reduction of infarct size

In acute myocardial ischaemia rapid reperfusion decreases infarct size variably, roughly by about 40%, leaving 30% still damaged by lethal reperfusion injury. With molecular cardioprotection or pharmacologic agents that inhibit reperfusion injury, the final myocardial infarct size may be rescued by a further 25% thereby achieving a much smaller final infarct. Remote Ischaemic conditioning is a simple non-invasive method of reducing final infarct size.

Figure 4. Myocardial remodelling in response to pressure load

Proposed transition from pressure (Pr) load to concentric hypertrophy to dilated failing left ventricle (LV). Note the role of signals that that break down collagen compared with the opposing role of tissue inhibitors of matrix metalloproteinases (TIMPs). The primary stimulus to the increased collagen are stretch-induced growth factors such as angiotensin II. Concentric remodelled myocardium underoges splitting of the collagen cross-links in response to modifying molecular signals such as metalloproteinases and other signals that disrupt collagen crosslinks to promote LV dilation and systolic heart failure. Adapted from reference.

Figure 5. The metabolic vicious circle in heart failure

Dilation of the myocardium in heart failure (1) leads to adrenergic activation (2) that in turn hyperphosphorylates the sarcoplasmic reticulum (3) and increases levels of circulating free fatty acids (4). The latter inhibit mitochondrial function at the level of acyl carnitine transferase (ACT) (5), thus inhibiting fatty acid oxidation and synthesis of ATP (6). Plasma FFAs also inhibit pyruvate dehydrogenase (PDH, 7) to promote anaerobic glycolysis (8) rather than oxidative metabolism. Adapted from reference.