Coronary blood flow in heart failure: cause, consequence and bystander

Heart failure is a clinical syndrome where cardiac output is not sufficient to sustain adequate perfusion and normal bodily functions, initially during exercise and in more severe forms also at rest. The two most frequent forms are heart failure of ischemic origin and of non-ischemic origin. In heart failure of ischemic origin, reduced coronary blood flow is causal to cardiac contractile dysfunction, and this is true for stunned and hibernating myocardium, coronary microembolization, myocardial infarction and post-infarct remodeling, possibly also for the takotsubo syndrome. The most frequent form of non-ischemic heart failure is dilated cardiomyopathy, caused by genetic mutations, myocarditis, toxic agents or sustained tachyarrhythmias, where alterations in coronary blood flow result from and contribute to cardiac contractile dysfunction. Hypertrophic cardiomyopathy is caused by genetic mutations but can also result from increased pressure and volume overload (hypertension, valve disease). Heart failure with preserved ejection fraction is characterized by pronounced coronary microvascular dysfunction, the causal contribution of which is however not clear. The present review characterizes the alterations of coronary blood flow which are causes or consequences of heart failure in its different manifestations. Apart from any potentially accompanying coronary atherosclerosis, all heart failure entities share common features of impaired coronary blood flow, but to a different extent: enhanced extravascular compression, impaired nitric oxide-mediated, endothelium-dependent vasodilation and enhanced vasoconstriction to mediators of neurohumoral activation. Impaired coronary blood flow contributes to the progression of heart failure and is thus a valid target for established and novel treatment regimens.

A modern view of the pathophysiological aspects of the development of chronic heart failure on the background of ischemic heart disease

In the guidelines of the European Society of Cardiology for heart failure in 2016, the term “heart failure with mid-range ejection fraction” was introduced to refer to the patients with heart failure and a slightly reduced ejection fraction of 40–49 %. Today, it was found that about 20 % of people with heart failure fall into this category. It is proved that ischemic heart disease is one of the leading factors for the formation and progression of diastolic disorders of the left ventricle. More than 90 % of patients with ischemic heart disease have varying degrees of diastolic dysfunction, which may be based on disorders of active relaxation and fibrotic processes in the myocardium, which occur due to progressive atherosclerotic cardiosclerosis or acute myocardial infarction. In this regard, it is important to analyze recent data on the mechanisms involved in the formation of myocardial fibrosis of ischemic origin and its role in the pathogenesis of heart failure. It has been proved that chronic hypoxic ischemic myocardial damage is accompanied by necrosis of cardiomyocytes, in the place of which reparative fibrosis develops, and the collagen fibers that appeared fill the place of cardiomyocytes. Reactive fibrosis (perivascular and interstitial) develops in the border zone between the scar, which is formed due to reparative fibrosis, and the zone of hibernating myocardium, to a lesser extent in the intact myocardium. Its formation is indirectly caused by the pressure overload and overstretching of cardiomyocyte fibers. Myofibroblasts express contractile proteins, similar to smooth muscle actin that provide mechanical tension in the remodeled matrix, thereby reducing the scar area. In any case, the development of fibrosis in the extracellular matrix is an integral part of myocardial remodeling and requires continuing researches aimed at addressing the problem of participation of all mechanisms in the pathogenesis of chronic heart failure on the background of ischemic heart disease depending on its types.

Ischaemia, hibernation, and viability

It was dogma for many years that if myocardial ischaemia persists for more than 30 minutes, necrosis will develop, resulting in myocardial infarction. The unavoidable extrapolation of that dogma suggested that chronic ischaemia, in reality, cannot exist, as it will inevitably evolve into structural changes (i.e. irreversible damage). These tenets were overturned in the early 1980s when Rahimtoola reviewed the results of coronary bypass surgery trials and identified patients with coronary artery disease and chronic left ventricular dysfunction persisting for months and even years that improved after revascularization. The rapid amelioration of myocardial function obtained by revascularization ruled out the hypothesis that the reduced function was due to histological modification of the myocardium and left the entire scientific community with the dilemma to explain and recognize hibernating myocardium.

Macrophage Activities in Myocardial Infarction and Heart Failure

Heart diseases remain the major cause of death worldwide. Advances in pharmacological and biomedical management have resulted in an increasing proportion of patients surviving acute heart failure (HF). However, many survivors of HF in the early stages end up increasing the disease to chronic HF (CHF). HF is an established frequent complication of myocardial infarction (MI), and numerous influences including persistent myocardial ischemia, shocked myocardium, ventricular remodeling, infarct size, and mechanical impairments, as well as hibernating myocardium trigger the development of left ventricular systolic dysfunction following MI. Macrophage population is active in inflammatory process, yet the clear understanding of the causative roles for these macrophage cells in HF development and progression is actually incomplete. Long ago, it was thought that macrophages are of importance in the heart after MI. Also, though inflammation is as a result of adverse HF in patients, but despite the fact that broad immunosuppression therapeutic target has been used in various clinical trials, no positive results have showed up, but rather, the focus on proinflammatory cytokines has proved more benefits in patients with HF. Therefore, in this review, we discuss the recent findings and new development about macrophage activations in HF, its role in the healthy heart, and some therapeutic targets for myocardial repair. We have a strong believe that there is a need to give maximum attention to cardiac resident macrophages due to the fact that they perform various tasks in wound healing, self-renewal of the heart, and tissue remodeling. Currently, it has been discovered that the study of macrophages goes far beyond its phagocytotic roles. If researchers in future confirm that macrophages play a vital role in the heart, they can be therapeutically targeted for cardiac healing.