By the time the heart reaches the pathological state clinically recognized as heart failure (HF), it has undergone profound and often irreversible alterations in structure and function at the molecular, cellular, and organ level. Although the etiologies of HF are diverse (hypertension, myocardial infarction, atherosclerosis, valvular insufficiency, mutations in genes encoding sarcomeric proteins, etc), some alterations are commonly found in most forms of HF, and they may account for the maladaptive structural remodeling and systolic dysfunction that characterize this syndrome. At the cellular level, there are well-documented changes in ionic channel density and function (electric remodeling), increased ROS production, mitochondrial dysfunction, imbalanced energy intake and consumption, genetic reprogramming, altered excitation-contraction coupling, and, in general, dysregulation of a multitude of other processes and pathways that are essential for proper cardiac function.1 Combined, this myriad of alterations leads to loss in contractility and ejection fraction, ventricular wall remodeling, increased vascular resistance, and dysregulated fluid homeostasis. In this issue of Circulation Research , Respress et al2 report that preventing phosphorylation of cardiac ryanodine receptors (RyR2) at a single residue, S2814, is sufficient to avert many of these alterations and improve cardiac function in HF. The results presented follow a string of papers that touch on the delicate and controversial subject of ryanodine receptor phosphorylation and HF. They offer a new twist to a contentious story and attempt to reconcile many apparently contradicting results, but key issues remain.
Article, see p 1474
### Calcium Leak in HF
Although, as mentioned above, the etiologies of HF are diverse, it appears that suppressing the dysfunction of a select group of biological and molecular signaling pathways may substantially improve or even reverse the cardiac deterioration observed in HF. For example, correcting the characteristically depressed sarcoplasmic reticulum (SR) calcium content of failing cardiomyocytes is a target of HF gene therapy.3 …