SERCA in heterogeneity of diastolic dysfunction in post-infarction heart failure with reduced ejection fraction

This editorial refers to ‘Regional diastolic dysfunction in post-infarction heart failure: role of local mechanical load and SERCA expression’, by Å.T. Røe et al., pp. 752–764. Congestive heart failure (CHF) is classically defined to be associated with cardiac contractile dysfunction, which plays a central role in pathogenesis and development of the disease leading preferentially to cardiac systolic dysfunction. However, it has recently been recognized more often that a high percentage of heart failure patients are associated with ejection fraction preserved within normal range, but with disturbance of diastolic cardiac function.1 Based on these observations, the CHF is classified into two subclasses by the presence or absence of the decrease in ejection fraction, i.e. HFrEF (heart failure with reduced ejection fraction) and HFpEF (heart failure with preserved ejection fraction), which has facilitated the current understanding of aetiology and development of heart failure to provide the therapeutic strategy for CHF.1 HFrEF accounts for approximately 50% of all cases of heart failure in the United States and is associated with substantial morbidity and reduced quality of life.2 Local differences and global decreases in systolic function due to loss of cardiomyocytes induced by myocardial infarction play a primary role in initiation and development of HFrEF. However, global diastolic dysfunction resulting from regional changes in cardiac relaxation in HFrEF patients has drawn relatively less attention and the details remain still unclear. In the study, Røe et al.3 focused on the diastolic function across the heart of post-infarction HFrEF rats and patients. They found that the relaxation is particularly impaired in cardiomyocytes adjacent to the scar tissue compared with the remote region. The regulation of cardiac contractility by Ca2+ is achieved by upstream mechanism, including SR Ca2+ pump regulated by SERCA, ryanodine receptors, sarcolemmal Na+-Ca2+ exchanger and mitochondria, and central and downstream mechanism regulating the myofilament Ca2+ sensitivity.4 Among them, SR Ca2+ pump is specifically impaired in HFrEF leaving other components relatively intact.3 Important paradigm of the novel mechanistic insight proposed is the contribution of the inhomogeneity of ischaemia and reperfusion (I/R)-induced deficient relaxation depending on the cardiac region, leading to the cardiac global diastolic dysfunction in post-infarction HFrEF. There are molecular and functional differences in the myocardium adjacent to scar tissue compared with the region remote from the infarction in which the SERCA expression level and function are maintained well even after the I/R insult. The authors conclude that the heightened wall stress is responsible for the down-regulated SERCA, thereby the excessive regional mechanical load plays a central role in disrupting myocardial structure and function leading to global diastolic dysregulation in HFrEF. They argue that the heightened stress has chronic effects on myocardial relaxation through remodelling of diastolic Ca2+ homeostasis. This notion is supported by the strong pieces of experimental evidence. The decrease in SERCA activity does not occur in HFpEF with concentric hypertrophy, in which an increased wall stress or inhomogeneity of diastolic phase is absent, and the diastolic dysfunction in these hearts are resulting from the enhanced passive stiffness.1 Furthermore, diastolic dysfunctions in dyssynchronous failing heart5 and recovery by unloading of the heart by cardiac resynchronization therapy6 are strongly related to down-regulation and up-regulation of SERCA expression, respectively; left ventricular assist device reversed remodelling in some cases with up-regulation of SERCA.7 These pieces of experimental evidence altogether imply that inhomogeneity of diastolic function subsequent to I/R resulting in an increased wall-stress may lead to structural damages and molecular dysfunction, namely the decreased SERCA expression. While SERCA gene transfer by adenovirus has been shown to reverse not only mechanical but also excitatory disorders,8 its region-dependent effectiveness is not known. The scar region may have got the most serious damage resulting in myocyte necrosis and subsequent fibrosis, and there might be a gradient from the scar tissue in the extent of severity of ischaemia to the remote region, which may have caused graded damages suffering from the ischaemia even in the adjacent region that might have likewise contributed to the inhomogeneity of diastolic function. How the different extent of I/R-induced injury affects the therapeutic strategy including gene therapy remains for the future study. The mechanosensitive signalling pathways, which trigger SERCA down-regulation were investigated in the rat HFrEF model, but neither the ERK/MEK-pathway, mir25 nor TNFα signalling showed marked specific up-regulation in the adjacent region compared with the more remote myocardium,3 though locally distinct Ca2+ regulation adjacent to the infarction may have contributed to such signalling processes. Since a number of factors affect the alteration of cardiac contractile function during I/R, it is crucial to analyse the individual parameters under the conditions, in which the wall stress does not affect the diastolic function. In this context, it is worthy to analyse the classical data in blood-perfused canine right ventricular papillary muscle preparation that has been developed to investigate the impact of physiological and pharmacological interventions on cardiac contractility under the condition mimicking the heart in vivo.9 In this preparation, the right ventricular papillary muscle is perfused through the cannulated anterior septal artery with heparinized arterial blood conducted from the anaesthetized donor dog and stimulated at a rate of 120 b.p.m. at 38–39˚C. Isometric contractions of the papillary muscle were, thereby maintained in physiological condition with intact autonomic nerve regulation, which is evident from the response to electrical field stimulation9 and perivascular nerve stimulation.10 In this preparation, the influence of I/R by coronary occlusion on contractile function could be analysed in detail by investigating the alteration of tension developed, ±dT/dt, and relaxation time.11 Its advantage is that the changes in systolic and diastolic function induced by I/R could be investigated under the condition, in which they are free from the elevated wall stress. The most remarkable alteration during reperfusion is the prolongation of contraction due to that of relaxation time, which reached approximately 170% of the control and lasted for the duration five times that of coronary occlusion of 3 min. This implies that just after coronary occlusion, the function of SERCA is suppressed remarkably by the I/R insult in a reversible manner prior to the alteration of SERCA expression. It would be highly likely that the functional disorder of SERCA would not readily recover even for a longer duration in the presence of elevated wall-stress in vivo. This initial insult induced by acute coronary occlusion may trigger the inhomogeneity contributing to the diastolic dysfunction in the early phase of heart failure. This functional disability of SERCA, in combination with the elevation of wall stress in vivo, and other endogenous compensatory factors such as neurohumoral, renin–angiotensin–aldosterone system and paracrine activation, may have likewise significantly contributed in vivo to the remodelling of myocardium adjacent to scar region. The schematic representation of the role of functional inhomogeneity in the initiation and development of HFrEF is presented in Figure 1. The inhomogeneity of the systolic and diastolic function contributing to the global contractile dysfunction may play a key role in the pathogenesis of HFrEF. The role of functional inhomogeneity in the course of initiation and development of HFrEF. (A) Schematic relation of scar tissue, adjacent, and remote region affecting the functional inhomogeneity. (B) Alterations of SERCA function in adjacent region contributing to the global systolic and diastolic dysfunction in HFrEF. It appears to be extremely difficult to differentiate and analyse separately the extent of contribution of the diastolic from systolic heterogeneity in the development of HFrEF, for both of which the altered function and expression of SERCA play a predominant role. It is evident that the detailed investigation of the time course of development of diastolic dysfunction and SERCA expression after I/R, i.e., the factor contributing to the transition of acute functional disability to the remodelling-related SERCA down-regulation. This time-dependent process may lead to the diastolic inhomogeneity in HFrEF, which remains for clarification in the future study to provide the basis for understanding the pathophysiology, including the role and mechanism of diastolic inhomogeneity that contributes to the global cardiac dysfunction, of post-infarction HFrEF. I would like to express my sincere thanks to Dr Kuniaki Ishii, Professor, Department of Pharmacology, Yamagata University School of Medicine for reading and providing valuable comments in the course of preparation of this article. Conflict of interest: none declared.