Rad protein: An essential player in L-type Ca2+ channel localization and modulation in cardiomyocytes.

Rad is an emerging key Ca modulator. In the present issue of , Elmore, Ahern et al. examine how the Rad C-terminus affects its subcellular distribution and Ca regulation.

The ryanodine receptor microdomain in cardiomyocytes.

The ryanodine receptor type 2 (RyR) is a key player in Ca handling during excitation-contraction coupling. During each heartbeat, RyR channels are responsible for linking the action potential with the contractile machinery of the cardiomyocyte by releasing Ca from the sarcoplasmic reticulum. RyR function is fine-tuned by associated signalling molecules, arrangement in clusters and subcellular localization.

InsPR-RyR Ca channel crosstalk facilitates arrhythmias in the failing human ventricle.

Dysregulated intracellular Ca handling involving altered Ca release from intracellular stores via RyR channels underlies both arrhythmias and reduced function in heart failure (HF). Mechanisms linking RyR dysregulation and disease are not fully established. Studies in animals support a role for InsP receptor Ca channels (InsPR) in pathological alterations in cardiomyocyte Ca handling but whether these findings translate to the divergent physiology of human cardiomyocytes during heart failure is not determined.

Inducing I and phase 1 repolarization of the cardiac action potential with a Kv4.3/KChIP2.1 bicistronic transgene.

The fast transient outward potassium current (I) plays a key role in phase 1 repolarization of the human cardiac action potential (AP) and its reduction in heart failure (HF) contributes to the loss of contractility. Therefore, restoring I might be beneficial for treating HF. The coding sequence of a P2A peptide was cloned, in frame, between Kv4.

Ventricular Arrhythmias in Ischemic Cardiomyopathy-New Avenues for Mechanism-Guided Treatment.

Ischemic heart disease is the most common cause of lethal ventricular arrhythmias and sudden cardiac death (SCD). In patients who are at high risk after myocardial infarction, implantable cardioverter defibrillators are the most effective treatment to reduce incidence of SCD and ablation therapy can be effective for ventricular arrhythmias with identifiable culprit lesions. Yet, these approaches are not always successful and come with a considerable cost, while pharmacological management is often poor and ineffective, and occasionally proarrhythmic.

Discrete sites of frequent premature ventricular complexes cluster within the infarct border zone and coincide with high frequency of delayed afterdepolarizations under adrenergic stimulation.

Background: Sympathetic activation in ischemic heart disease can cause lethal arrhythmias. These often are preceded by premature ventricular complexes (PVCs), which at the cellular level could result from delayed afterdepolarizations.

Objective: The purpose of this study was to identify and map vulnerable areas for arrhythmia initiation after myocardial infarction (MI) and to explore the link between PVCs and cellular events.

Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure.

Aims: Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS.

CaMKII inhibition reduces arrhythmogenic Ca2+ events in subendocardial cryoinjured rat living myocardial slices.

Spontaneous Ca2+ release (SCR) can cause triggered activity and initiate arrhythmias. Intrinsic transmural heterogeneities in Ca2+ handling and their propensity to disease remodeling may differentially modulate SCR throughout the left ventricular (LV) wall and cause transmural differences in arrhythmia susceptibility. Here, we aimed to dissect the effect of cardiac injury on SCR in different regions in the intact LV myocardium using cryoinjury on rat living myocardial slices (LMS).

Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability.

Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects.

Nanoscale Study of Calcium Handling Remodeling in Right Ventricular Cardiomyocytes Following Pulmonary Hypertension.

Pulmonary hypertension is a complex disorder characterized by pulmonary vascular remodeling and right ventricular hypertrophy, leading to right heart failure. The mechanisms underlying this process are not well understood. We hypothesize that the structural remodeling occurring in the cardiomyocytes of the right ventricle affects the cytosolic Ca handling leading to arrhythmias.

Altered adrenergic response in myocytes bordering a chronic myocardial infarction underlies in vivo triggered activity and repolarization instability.

Key Points: Ventricular arrhythmias are a major complication after myocardial infarction (MI), associated with sympathetic activation. The structurally heterogeneous peri-infarct zone is a known substrate, but the functional role of the myocytes is less well known. Recordings of monophasic action potentials in vivo reveal that the peri-infarct zone is a source of delayed afterdepolarizations (DADs) and has a high beat-to-beat variability of repolarization (BVR) during adrenergic stimulation (isoproterenol, ISO).

Calcium Signaling in Cardiomyocyte Function.

Rhythmic increases in intracellular Ca concentration underlie the contractile function of the heart. These heart muscle-wide changes in intracellular Ca are induced and coordinated by electrical depolarization of the cardiomyocyte sarcolemma by the action potential. Originating at the sinoatrial node, conduction of this electrical signal throughout the heart ensures synchronization of individual myocytes into an effective cardiac pump.

Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure.

Background: Interstitial fibrosis is an important component of diastolic, and systolic, dysfunction in heart failure (HF) and depends on activation and differentiation of fibroblasts into myofibroblasts (MyoFb). Recent clinical evidence suggests that in late-stage HF, fibrosis is not reversible.

Objectives: The study aims to examine the degree of differentiation of cardiac MyoFb in end-stage HF and the potential for their phenotypic reversibility.

Hyperactive ryanodine receptors in human heart failure and ischaemic cardiomyopathy reside outside of couplons.

Aims: In ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane system. TATS remodelling in heart failure (HF) and after myocardial infarction (MI) increases the fraction of non-coupled RyRs. Here we investigate whether this remodelling alters the activity of coupled and non-coupled RyR sub-populations through changes in local signalling.

Global fibroblast activation throughout the left ventricle but localized fibrosis after myocardial infarction.

Fibroblast (Fb) differentiation and interstitial fibrosis contribute to cardiac remodeling and loss of function after myocardial infarction (MI). We investigated regional presence and regulation of fibrosis in a pig MI model. In vivo analysis of regional function and perfusion defined three regions: the scar, the myocardium adjacent to the scar (MI, reduced function, reduced perfusion reserve), and the remote myocardium (MI, minimal functional deficit, maintained perfusion).

Reduced mitochondrial respiration in the ischemic as well as in the remote nonischemic region in postmyocardial infarction remodeling.

Scarring and remodeling of the left ventricle (LV) after myocardial infarction (MI) results in ischemic cardiomyopathy with reduced contractile function. Regional differences related to persisting ischemia may exist. We investigated the hypothesis that mitochondrial function and structure is altered in the myocardium adjacent to MI with reduced perfusion (MI) and less so in the remote, nonischemic myocardium (MI).

Calcium/calmodulin-dependent kinase II and nitric oxide synthase 1-dependent modulation of ryanodine receptors during β-adrenergic stimulation is restricted to the dyadic cleft.

Key Points: The dyadic cleft, where coupled ryanodine receptors (RyRs) reside, is thought to serve as a microdomain for local signalling, as supported by distinct modulation of coupled RyRs dependent on Ca /calmodulin-dependent kinase II (CaMKII) activation during high-frequency stimulation. Sympathetic stimulation through β-adrenergic receptors activates an integrated signalling cascade, enhancing Ca cycling and is at least partially mediated through CaMKII. Here we report that CaMKII activation during β-adrenergic signalling is restricted to the dyadic cleft, where it enhances activity of coupled RyRs thereby contributing to the increase in diastolic events.

Calcium release near L-type calcium channels promotes beat-to-beat variability in ventricular myocytes from the chronic AV block dog.

Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca(2+) handling.

Selective modulation of coupled ryanodine receptors during microdomain activation of calcium/calmodulin-dependent kinase II in the dyadic cleft.

Rationale: In ventricular myocytes of large mammals with low T-tubule density, a significant number of ryanodine receptors (RyRs) are not coupled to the sarcolemma; cardiac remodeling increases noncoupled RyRs.

Objective: Our aim was to test the hypothesis that coupled and noncoupled RyRs have distinct microdomain-dependent modulation.

Methods And Results: We studied single myocytes from pig left ventricle.