Sacubitril/valsartan attenuates atrial conduction disturbance and electrophysiological heterogeneity with ameliorating fibrosis in mice

BackgroundSacubitril/valsartan (SacVal) has been shown to improve the prognosis of heart failure; however, whether SacVal reduces the occurrence of atrial fibrillation (AF) in heart failure has not yet been elucidated. In this study, we aimed to determine whether SacVal is effective in reducing the occurrence of AF in heart failure and identify the underlying mechanism of its electrophysiological effect in mice.MethodsAdult male mice underwent transverse aortic constriction, followed by SacVal, valsartan, or vehicle treatment for two weeks. Electrophysiological study (EPS) and optical mapping were performed to assess the susceptibility to AF and the atrial conduction properties, and fibrosis was investigated using heart tissue and isolated cardiac fibroblasts (CFs).ResultsEPS analysis revealed that AF was significantly less inducible in SacVal-treated mice than in vehicle-treated mice. Optical mapping of the atrium showed that SacVal-treated and valsartan-treated mice restored the prolonged action potential duration (APD); however, only SacVal-treated mice showed the restoration of decreased conduction velocity (CV) compared to vehicle-treated mice. In addition, the electrophysiological distribution analysis demonstrated that heterogeneous electrophysiological properties were rate-dependent and increased heterogeneity was closely related to the susceptibility to AF. SacVal attenuated the increased heterogeneity of CV at short pacing cycle length in atria, whereas Val could not. Histological and molecular evaluation showed that SacVal exerted the anti-fibrotic effect on the atria. An in vitro study of CFs treated with natriuretic peptides and LBQ657, the metabolite and active form of sacubitril, revealed that C-type natriuretic peptide (CNP) combined with LBQ657 had an additional anti-fibrotic effect on CFs.ConclusionsOur results demonstrated that SacVal can improve the conduction disturbance and heterogeneity through the attenuation of fibrosis in murine atria and reduce the susceptibility of AF in heart failure with pressure overload, which might be attributed to the enhanced function of CNP

Image-based evaluation of contraction–relaxation kinetics of human-induced pluripotent stem cell-derived cardiomyocytes: Correlation and complementarity with extracellular electrophysiology

AbstractIn this study, we used high-speed video microscopy with motion vector analysis to investigate the contractile characteristics of hiPS-CM monolayer, in addition to further characterizing the motion with extracellular field potential (FP), traction force and the Ca2+ transient. Results of our traction force microscopy demonstrated that the force development of hiPS-CMs correlated well with the cellular deformation detected by the video microscopy with motion vector analysis. In the presence of verapamil and isoproterenol, contractile motion of hiPS-CMs showed alteration in accordance with the changes in fluorescence peak of the Ca2+ transient, i.e., upstroke, decay, amplitude and full-width at half-maximum. Simultaneously recorded hiPS-CM motion and FP showed that there was a linear correlation between changes in the motion and field potential duration in response to verapamil (30–150nM), isoproterenol (0.1–10μM) and E-4031 (10–50nM). In addition, tetrodotoxin (3–30μM)-induced delay of sodium current was corresponded with the delay of the contraction onset of hiPS-CMs. These results indicate that the electrophysiological and functional behaviors of hiPS-CMs are quantitatively reflected in the contractile motion detected by this image-based technique. In the presence of 100nM E-4031, the occurrence of early after-depolarization-like negative deflection in FP was also detected in the hiPS-CM motion as a characteristic two-step relaxation pattern. These findings offer insights into the interpretation of the motion kinetics of the hiPS-CMs, and are relevant for understanding electrical and mechanical relationship in hiPS-CMs

Important cardiac transcription factor genes are accompanied by bidirectional long non-coding RNAs

BackgroundHeart development is a relatively fragile process in which many transcription factor genes show dose-sensitive characteristics such as haploinsufficiency and lower penetrance. Despite efforts to unravel the genetic mechanism for overcoming the fragility under normal conditions, our understanding still remains in its infancy. Recent studies on the regulatory mechanisms governing gene expression in mammals have revealed that long non-coding RNAs (lncRNAs) are important modulators at the transcriptional and translational levels. Based on the hypothesis that lncRNAs also play important roles in mouse heart development, we attempted to comprehensively identify lncRNAs by comparing the embryonic and adult mouse heart and brain.ResultsWe have identified spliced lncRNAs that are expressed during development and found that lncRNAs that are expressed in the heart but not in the brain are located close to genes that are important for heart development. Furthermore, we found that many important cardiac transcription factor genes are located in close proximity to lncRNAs. Importantly, many of the lncRNAs are divergently transcribed from the promoter of these genes. Since the lncRNA divergently transcribed from Tbx5 is highly evolutionarily conserved, we focused on and analyzed the transcript. We found that this lncRNA exhibits a different expression pattern than that of Tbx5, and knockdown of this lncRNA leads to embryonic lethality.ConclusionThese results suggest that spliced lncRNAs, particularly bidirectional lncRNAs, are essential regulators of mouse heart development, potentially through the regulation of neighboring transcription factor genes

Circulating KCNH2 Current-Activating Factor in Patients with Heart Failure and Ventricular Tachyarrhythmia

It is estimated that approximately half of the deaths in patients with HF are sudden and that the most likely causes of sudden death are lethal ventricular tachyarrhythmias such as ventricular tachycardia (VT) or fibrillation (VF). However, the precise mechanism of ventricular tachyarrhythmias remains unknown. The KCNH2 channel conducting the delayed rectifier K(+) current (I(Kr)) is recognized as the most susceptible channel in acquired long QT syndrome. Recent findings have revealed that not only suppression but also enhancement of I(Kr) increase vulnerability to major arrhythmic events, as seen in short QT syndrome. Therefore, we investigated the existence of a circulating KCNH2 current-modifying factor in patients with HF.We examined the effects of serum of HF patients on recombinant I(Kr) recorded from HEK 293 cells stably expressing KCNH2 by using the whole-cell patch-clamp technique. Study subjects were 14 patients with non-ischemic HF and 6 normal controls. Seven patients had a history of documented ventricular tachyarrhythmias (VT: 7 and VF: 1). Overnight treatment with 2% serum obtained from HF patients with ventricular arrhythmia resulted in a significant enhancement in the peaks of I(Kr) tail currents compared to the serum from normal controls and HF patients without ventricular arrhythmia.Here we provide the first evidence for the presence of a circulating KCNH2 channel activator in patients with HF and ventricular tachyarrhythmias. This factor may be responsible for arhythmogenesis in patients with HF

Acute Effects of Sex Steroid Hormones on Susceptibility to Cardiac Arrhythmias: A Simulation Study

Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The “female” model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The “male” model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias

Networking analysis on superior vena cava arrhythmogenicity in atrial fibrillation

Atrial fibrillation (AF) can be initiated from arrhythmogenic foci within the muscular sleeves that extend not only into the pulmonary veins but also into both vena cavae. Patients with SVC-derived AF have the common clinical and genetic risk factors. Bayesian network analysis is a probabilistic model in which a qualitative dependency relationship among random variables is represented by a graph structure and a quantitative relationship between individual variables is expressed by a conditional probability.We used data of meta-analysis of 2170 AF patients with and without SVC arrhythmogenicity in the previous article. Bayesian Networking analysis was performed using the software “bnlearn”. Using the clinical and genetic factors associated with SVC arrhythmogenicity in the previous article, we investigated a Bayesian networking structure to determine the probabilitic causation of variants to clinical parameters and found that the rate of recurrence depended on SVC arrhythmogenicity and LA diameter, and that SVC arrhythmogenicity was conditionally dependent on gender, body mass index, and genetic risk score. We found the possibility of prediction model generated from three factors. Receiver-operation characteristic analysis showed the area under the curve was 0.84.Using the clinical/genetic factors associated with SVC arrhythmogenicity through the previous meta-analysis of over 2000 patients, Bayesian networking analysis indicated the probabilistic causation of SVC arrhythmogenicity and associated clinical/genetic factors. Keywords: Superior vena cava arrhythmogenicity, Atrial fibrillation, Bayesian networking structur

THE USE OF EVOKED ENDOCARDIAL RESPONSE FOR ASSESSMENT OF ANTIARRHYTHMIC DRUG EFFECTS ON MYOCARDIUM

The technique “asymmetric biphasic stimulation” which paces the heart and neutralizes the post-stimulus polarization at the electrode-tiessue interface allows for the recording of the entire evoked endocardial response via a single electrode for both pacing and recording. Using this system the effects of antiarrhythmic drugs, procainamide and N-acetylprocainamide, on the myocardium were studied in 20 dogs. Before and during the five step drug infusion, the evoked endocardial responses were recorded during bipolar and unipolar at the rates of 120, 150 and 200/min. The plasma concentration of the procainamede ranged from 1.7 to 32.5 mg/l and that of N-acetylprocainamide ranged from 8.1 to 116.l mg/l. Procainamied significantly prolonged both the depolarization duration and the repolarization duration at a low plasma concentration (Class I antiarrhythmic drug property). N-acetylprocainamide significantly prolonged the repolarization duration at a low plasma concentration, while the depolarization duration was not significantly changed at a low or therapeutic plasma concentration (Class III antiarrhythmic drug property). The prolongacion of the depolarization duration by procainamide and N-acetylprocainamide was rate-dependent; the faster the rate the greater the prolongation. This simple and accurate assessment of the antiarrhythmic drug effects on the myocardium may provie a future means for the pharmacologic antiarrhythmic therapy