Christopher E. Woods

APJ acts as a dual receptor in cardiac hypertrophy.

Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.

Sequential Percutaneous LAA Ligation and Pulmonary Vein Isolation in Patients with Persistent AF: Initial Results of a Feasibility Study

Left atrial appendage (LAA) ligation results in LAA electrical isolation and a decrease in atrial fibrillation (AF) burden. This study assessed the feasibility of combined percutaneous LAA ligation and pulmonary vein isolation (PVI) in patients with persistent AF.

In situ optical mapping of voltage and calcium in the heart.

Electroanatomic mapping the interrelation of intracardiac electrical activation with anatomic locations has become an important tool for clinical assessment of complex arrhythmias. Optical mapping of cardiac electrophysiology combines high spatiotemporal resolution of anatomy and physiological function with fast and simultaneous data acquisition. If applied to the clinical setting, this could improve both diagnostic potential and therapeutic efficacy of clinical arrhythmia interventions. The aim of this study was to explore this utility in vivo using a rat model. To this aim, we present a single-camera imaging and multiple light-emitting-diode illumination system that reduces economic and technical implementation hurdles to cardiac optical mapping. Combined with a red-shifted calcium dye and a new near-infrared voltage-sensitive dye, both suitable for use in blood-perfused tissue, we demonstrate the feasibility of in vivo multi-parametric imaging of the mammalian heart. Our approach combines recording of electrophysiologically-relevant parameters with observation of structural substrates and is adaptable, in principle, to trans-catheter percutaneous approaches.

Load-dependent effects of apelin on murine cardiomyocytes

The apelin peptide is described as one of the most potent inotropic agents, produced endogenously in a wide range of cells, including cardiomyocytes. Despite positive effects on cardiac contractility in multicellular preparations, as well as indications of cardio-protective actions in several diseases, its effects and mechanisms of action at the cellular level are incompletely understood. Here, we report apelin effects on dynamic mechanical characteristics of single ventricular cardiomyocytes, isolated from mouse models (control, apelin-deficient [Apelin-KO], apelin-receptor KO mouse [APJ-KO]), and rat. Dynamic changes in maximal velocity of cell shortening and relaxation were monitored. In addition, more traditional indicators of inotropic effects, such as maximum shortening (in mechanically unloaded cells) or peak force development (in auxotonic contracting cells, preloaded using the carbon fibre technique) were studied. The key finding is that, using Apelin-KO cardiomyocytes exposed to different preloads with the 2-carbon fibre technique, we observe a lowering of the slope of the end-diastolic stress-length relation in response to 10 nM apelin, an effect that is preload-dependent. This suggests a positive lusitropic effect of apelin, which could explain earlier counter-intuitive findings on an apelin-induced increase in contractility occurring without matching rise in oxygen consumption.

In Vivo Post-Cardiac Arrest Myocardial Dysfunction Is Supported by Ca2+/Calmodulin-Dependent Protein Kinase II-Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2.

Background: Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies. Methods: We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca2+-induced Ca2+ release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo. Results: We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca2+ potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo. Conclusions: Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.

Cardiac electrophysiological imaging systems scalable for high-throughput drug testing.

Multi-parametric electrophysiological measurements using optical methods have become a highly valued standard in cardiac research. Most published optical mapping systems are expensive and complex. Although some applications demand high-cost components and complex designs, many can be tackled with simpler solutions. Here, we describe (1) a camera-based voltage and calcium imaging system using a single ‘economy’ electron-multiplying charge-coupled device camera and demonstrate the possibility of using a consumer camera for imaging calcium transients of the heart, and (2) a photodiode-based voltage and calcium high temporal resolution measurement system using single-element photodiodes and an optical fibre. High-throughput drug testing represents an application where system scalability is particularly attractive. Therefore, we tested our systems on tissue exposed to a well-characterized and clinically relevant calcium channel blocker, nifedipine, which has been used to treat angina and hypertension. As experimental models, we used the Langendorff-perfused whole-heart and thin ventricular tissue slices, a preparation gaining renewed interest by the cardiac research community. Using our simplified systems, we were able to monitor simultaneously the marked changes in the voltage and calcium transients that are responsible for the negative inotropic effect of the compound.

Importance of Ventricular Tachycardia Induction and Mapping for Patients Referred for Epicardial Ablation

Many nonischemic cardiomyopathy (NICMP) patients referred for catheter ablation of ventricular tachycardia (VT) undergo an initial epicardial approach under general anesthesia (GA). However, GA may suppress inducibility and decrease tolerance of induced VT, leaving substrate modification as the sole ablation method.

Abrupt bradycardia and grouped beating during treadmill testing: A mimic of upper rate behavior

p t t Case summary A 67-year-old man with a biventricular implantable cardioverter-defibrillator (Medtronic Concerto C1540WK) presented for exercise treadmill testing. The patient had an ischemic cardiomyopathy and prior anterior infarction with a left ventricular ejection fraction of 25%. One year prior to this presentation, the patient presented with sustained monomorphic ventricular tachycardia and had catheter ablation for ventricular tachycardia, followed by implantation of the current device. An exercise treadmill test (ETT) was performed by using a ramp protocol. During the ETT, at peak exercise, his peak heart rate abruptly dropped and the ETT was stopped (data not shown). The device was again interrogated Programmed settings and measurements are shown in Table 1; the lower rate limit was 60 beats/min. No alerts or episodes were recorded during the ETT. To assess device function, the ETT was repeated with wireless device telemetry engaged. The preexercise 12-lead electrocardiogram and device rhythm strip at rest are shown in Figure 1A, demonstrating baseline atrial-paced and biventricular-paced rhythm. Figure 1B shows electrograms (EGMs) measured on the right ventricular channel of the device and the marker channel during early exercise. During the ETT, the abrupt bradycardia was again observed, this time with a drop from the peak heart rate of 107 to 56 beats/min (Figure 2). Stress testing was quickly terminated,

Apelin and APJ orchestrate complex tissue-specific control of cardiomyocyte hypertrophy and contractility in the hypertrophy-heart failure transition

The G protein-coupled receptor APJ is a promising therapeutic target for heart failure. Constitutive deletion of APJ in the mouse is protective against the hypertrophy-heart failure transition via elimination of ligand-independent, β-arrestin-dependent stretch transduction. However, the cellular origin of this stretch transduction and the details of its interaction with apelin signaling remain unknown. We generated mice with conditional elimination of APJ in the endothelium (APJendo-/-) and myocardium (APJmyo-/-). No baseline difference was observed in left ventricular function in APJendo-/-, APJmyo-/-, or control (APJendo+/+, APJmyo+/+) mice. After exposure to transaortic constriction, APJendo-/- mice displayed decreased left ventricular systolic function and increased wall thickness, whereas APJmyo-/- mice were protected. At the cellular level, carbon fiber stretch of freshly isolated single cardiomyocytes demonstrated decreased contractile responses to stretch in APJ-/- cardiomyocytes compared with APJ+/+ cardiomyocytes. Ca2+ transients did not change with stretch in either APJ-/- or APJ+/+ cardiomyocytes. Application of apelin to APJ+/+ cardiomyocytes resulted in decreased Ca2+ transients. Furthermore, hearts of mice treated with apelin exhibited decreased phosphorylation in cardiac troponin I NH2-terminal residues (Ser22 and Ser23) consistent with increased Ca2+ sensitivity. These data establish that APJ stretch transduction is mediated specifically by myocardial APJ, that APJ is necessary for stretch-induced increases in contractility, and that apelin opposes APJs stretch-mediated hypertrophy signaling by lowering Ca2+ transients while maintaining contractility through myofilament Ca2+ sensitization. These findings underscore apelins unique potential as a therapeutic agent that can simultaneously support cardiac function and protect against the hypertrophy-heart failure transition. NEW & NOTEWORTHY These data address fundamental gaps in our understanding of apelin-APJ signaling in heart failure by localizing APJs ligand-independent stretch sensing to the myocardium, identifying a novel mechanism of apelin-APJ inotropy via myofilament Ca2+ sensitization, and identifying potential mitigating effects of apelin in APJ stretch-induced hypertrophic signaling.