A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice.

Chronic heavy alcohol use is associated with lethal arrhythmias. Whether common East Asian-specific aldehyde dehydrogenase deficiency (ALDH2*2) contributes to arrhythmogenesis caused by low level alcohol use remains unclear. Here we show 59 habitual alcohol users carrying ALDH2 rs671 have longer QT interval (corrected) and higher ventricular tachyarrhythmia events compared with 137 ALDH2 wild-type (Wt) habitual alcohol users and 57 alcohol non-users. Notably, we observe QT prolongation and a higher risk of premature ventricular contractions among human ALDH2 variants showing habitual light-to-moderate alcohol consumption. We recapitulate a human electrophysiological QT prolongation phenotype using a mouse ALDH2*2 knock-in (KI) model treated with 4% ethanol, which shows markedly reduced total amount of connexin43 albeit increased lateralization accompanied by markedly downregulated sarcolemmal Nav1.5, Kv1.4 and Kv4.2 expressions compared to EtOH-treated Wt mice. Whole-cell patch-clamps reveal a more pronounced action potential prolongation in EtOH-treated ALDH2*2 KI mice. By programmed electrical stimulation, rotors are only provokable in EtOH-treated ALDH2*2 KI mice along with higher number and duration of ventricular arrhythmia episodes. The present research helps formulate safe alcohol drinking guideline for ALDH2 deficient population and develop novel protective agents for these subjects.

Testosterone does not shorten action potential duration in Langendorff-perfused rabbit ventricles.

BACKGROUND: Women have longer baseline QT intervals than men. Because previous studies showed that testosterone and 5α-dihydrotestosterone shorten the ventricular action potential duration (APD) in animal models, differential testosterone concentrations may account for the sex differences in QT interval. OBJECTIVE: The purpose of this study was to test the hypothesis that testosterone shortens the APD in Langendorff-perfused rabbit ventricles. METHODS: We performed optical mapping studies in hearts with or without testosterone administration. Acute studies included 26 hearts using 2 different protocols, including 17 without and 9 with atrioventricular (AV) block. For chronic studies, we implanted testosterone pellets subcutaneously in 7 female rabbits for 2-3 weeks before optical mapping studies during complete AV block. Six rabbits without pellet implantation served as controls. RESULTS: The hearts in the acute studies were paced with a pacing cycle length (PCL) of 200-300 ms and mapped at baseline and after administration of 1 nM, 10 nM, 100 nM, and 3 µM of testosterone. There was no shortening of APD80 at any PCL. Instead, a lengthening of APD80 was noted at higher concentrations. There were no sex differences in testosterone responses. In chronic studies, heart rates were 136 ± 5 bpm before and 148 ± 9 bpm after (P = .10) while QTc intervals were 314 ± 9 ms before and 317 ± 99 ms after (P = .69) testosterone pellet implantation, respectively. Overall, ventricular APD80 in the pellet group was longer than in the control group at 300- to 700-ms PCL. CONCLUSION: Testosterone does not shorten ventricular repolarization in rabbit hearts.

Intelligent Bio-Impedance System for Personalized Continuous Blood Pressure Measurement.

Continuous blood pressure (BP) measurement is crucial for long-term cardiovascular monitoring, especially for prompt hypertension detection. However, most of the continuous BP measurements rely on the pulse transit time (PTT) from multiple-channel physiological acquisition systems that impede wearable applications. Recently, wearable and smart health electronics have become significant for next-generation personalized healthcare progress. This study proposes an intelligent single-channel bio-impedance system for personalized BP monitoring. Compared to the PTT-based methods, the proposed sensing configuration greatly reduces the hardware complexity, which is beneficial for wearable applications. Most of all, the proposed system can extract the significant BP features hidden from the measured bio-impedance signals by an ultra-lightweight AI algorithm, implemented to further establish a tailored BP model for personalized healthcare. In the human trial, the proposed system demonstrates the BP accuracy in terms of the mean error (ME) and the mean absolute error (MAE) within 1.7 ± 3.4 mmHg and 2.7 ± 2.6 mmHg, respectively, which agrees with the criteria of the Association for the Advancement of Medical Instrumentation (AAMI). In conclusion, this work presents a proof-of-concept for an AI-based single-channel bio-impedance BP system. The new wearable smart system is expected to accelerate the artificial intelligence of things (AIoT) technology for personalized BP healthcare in the future.

Biomaterial-induced conversion of quiescent cardiomyocytes into pacemaker cells in rats.

Pacemaker cells can be differentiated from stem cells or transdifferentiated from quiescent mature cardiac cells via genetic manipulation. Here we show that the exposure of rat quiescent ventricular cardiomyocytes to a silk-fibroin hydrogel activates the direct conversion of the quiescent cardiomyocytes to pacemaker cardiomyocytes by inducing the ectopic expression of the vascular endothelial cell-adhesion glycoprotein cadherin. The silk-fibroin-induced pacemaker cells exhibited functional and morphological features of genuine sinoatrial-node cardiomyocytes in vitro, and pacemaker cells generated via the injection of silk fibroin in the left ventricles of rats functioned as a surrogate in situ sinoatrial node. Biomaterials with suitable surface structure, mechanics and biochemistry could facilitate the scalable production of biological pacemakers for human use.

Bio-Impedance Measurement Optimization for High-Resolution Carotid Pulse Sensing.

Continuous hemodynamic monitoring is important for long-term cardiovascular healthcare, especially in hypertension. The impedance plethysmography (IPG) based carotid pulse sensing is a non-invasive diagnosis technique for measuring pulse signals and further evaluating the arterial conditions of the patient such as continuous blood pressure (BP) monitoring. To reach the high-resolution IPG-based carotid pulse detection for cardiovascular applications, this study provides an optimized measurement parameter in response to obvious pulsation from the carotid artery. The influence of the frequency of excitation current, electrode cross-sectional area, electrode arrangements, and physiological site of carotid arteries on IPG measurement resolution was thoroughly investigated for optimized parameters. In this study, the IPG system was implemented and installed on the subject's neck above the carotid artery to evaluate the measurement parameters. The measurement results within 6 subjects obtained the arterial impedance variation of 2137 mΩ using the optimized measurement conditions, including excitation frequency of 50 kHz, a smaller area of 2 cm2, electrode spacing of 4 cm and 1.7 cm for excitation and sensing functions, and location on the left side of the neck. The significance of this study demonstrates an optimized measurement methodology of IPG-based carotid pulse sensing that greatly improves the measurement quality in cardiovascular monitoring.

IPG-based field potential measurement of cultured cardiomyocytes for optogenetic applications.

BACKGROUND: Electrophysiological sensing of cardiomyocytes (CMs) in optogenetic preparations applies various techniques, such as patch-clamp, microelectrode array, and optical mapping. However, challenges remain in decreasing the cost, system dimensions, and operating skills required for these technologies. OBJECTIVE: This study developed a low-cost, portable impedance plethysmography (IPG)-based electrophysiological measurement of cultured CMs for optogenetic applications. METHODS: To validate the efficacy of the proposed sensor, optogenetic stimulation with different pacing cycle lengths (PCL) was performed to evaluate whether the channelrhodopsin-2 (ChR2)-expressing CM beating rhythm measured by the IPG sensor was consistent with biological responses. RESULTS: The experimental results show that the CM field potential was synchronized with external optical pacing with PCLs ranging from 250 ms to 1000 ms. Moreover, irregular fibrillating waveforms induced by CM arrhythmia were detected after overdrive optical pacing. Through the combined evidence of the theoretical model and experimental results, this study confirmed the feasibility of long-term electrophysiological sensing for optogenetic CMs. CONCLUSION: This study proposes an IPG-based sensor that is low-cost, portable, and requires low-operating skills to perform real-time CM field potential measurement in response to optogenetic stimulation. SIGNIFICANCE: This study demonstrates a new methodology for convenient electrophysiological sensing of CMs in optogenetic applications.

Anti-Inflammatory and Antiarrhythmic Effects of Beta Blocker in a Rat Model of Rheumatoid Arthritis.

Background Patients with rheumatoid arthritis are at twice the risk of ventricular arrhythmia and sudden cardiac death as the general population. We hypothesize that ß-blocker treatment of rheumatoid arthritis is antiarrhythmic by producing synergistic anticatecholaminergic and anti-inflammatory effects. Methods and Results Collagen-induced arthritis (CIA) was induced in Lewis rats by immunization with type II collagen in Freund's incomplete adjuvant. The treatment with propranolol (4 mg/kg) started on the first day of immunization. We evaluated the ventricular vulnerability to ventricular arrhythmia using in vivo programmed stimulation and performed ex vivo optical mapping to measure the electrical remodeling of the heart. The ventricular tissue was further processed for immunohistochemical staining and protein array analysis. The assessment of ventricular vulnerability showed that the number and duration of the induced ventricular arrhythmia episodes were increased in CIA rats, which were improved with propranolol treatment. The sympathovagal index and the plasma level of catecholamines significantly increased in CIA rats, whereas the use of propranolol attenuated sympathetic hyperactivity. In the optical mapping study, electrical remodeling, characterized by prolonged action potential duration, slow conduction velocity, and steepened action-potential duration restitution, were noted in CIA rats and reversed in the propranolol-treatment group. The propranolol treatment was associated with decreases in paw thickness, fewer inflammatory cell infiltrations in the heart, reduced levels of cardiac inflammatory cytokines, and less cardiac fibrosis as compared with the CIA group. Conclusions CIA increased ventricular arrhythmia vulnerability through sympathetic hyperinnervation and proarrhythmic ventricular electrophysiological remodeling. Treatment with propranolol in CIA rats was both anti-inflammatory and antiarrhythmic.

Reverse electromechanical modelling of diastolic dysfunction in spontaneous hypertensive rat after sacubitril/valsartan therapy.

AIMS: Hypertension is a significant risk for the development of left ventricular hypertrophy, diastolic dysfunction, followed by heart failure and sudden cardiac death. While therapy with sacubitril/valsartan (SV) reduces the risk of sudden cardiac death in patients with heart failure and systolic dysfunction, the effect on those with diastolic dysfunction remains unclear. We hypothesized that, in the animal model of hypertensive heart disease, treatment with SV reduces the susceptibility to ventricular arrhythmia. METHODS AND RESULTS: Young adult female spontaneous hypertensive rats (SHRs) were randomly separated into three groups, which were SHRs, SHRs treated with valsartan, and SHRs treated with SV. In addition, the age-matched and weight-matched Wistar Kyoto rats were considered as controls, and there were 12 rats in each group. In vivo ventricular tachyarrhythmia induction and in vitro optical mapping were used to measure the inducibility of ventricular arrhythmias and to characterize the dynamic properties of electrical propagation. The level of small-conductance Ca2+ -activated potassium channel type 2 (KCNN2) was analysed in cardiac tissue. Compared with SHR with left ventricular hypertrophy, treatment with SV significantly improved cardiac geometry (relative wall thickness, 0.68 ± 0.11 vs. 0.76 ± 0.13, P < 0.05) and diastolic dysfunction (isovolumetric relaxation time, 59.4 ± 3.2 vs. 70.5 ± 4.2 ms, P < 0.05; deceleration time of mitral E wave, 46 ± 4.8 vs. 42 ± 3.8, P < 0.05). The incidence of induced ventricular arrhythmia was significantly reduced in SHR treated with SV compared with SHR (ventricular tachycardia, 1.14 ± 0.32 vs. 2.91 ± 0.5 episodes per 10 stimuli, P < 0.001; ventricular fibrillation, 1.72 ± 0.31 vs. 5.81 ± 0.42 episodes per 10 stimuli, P < 0.001). The prolonged action potential duration (APD) and increase of the maximum slope of APD restitution were observed in SHR, while the treatment of SV improved the arrhythmogeneity (APD, 37.12 ± 6.18 vs. 92.41 ± 10.71 ms at 250 ms pacing cycle length, P < 0.001; max slope 0.29 ± 0.01 vs. 1.48 ± 0.04, P < 0.001). These effects were strongly associated with down-regulation of KCNN2 (0.38 ± 0.07 vs. 0.74 ± 0.12 ng/ml, P < 0.001). The treatment of SV also decreased the level of N-terminal pro-B-type natriuretic peptide, cardiac bridging integrator-1, and intramyocardial fibrosis of SHR. CONCLUSIONS: In conclusion, synergistic blockade of the neprilysin and the renin-angiotensin system by SV in SHRs results in KCNN2-associated electrical remodelling in ventricle, which stabilizes electrical dynamics and attenuates arrhythmogenesis.

Risk of ischemic stroke in patients with hypertrophic cardiomyopathy in the absence of atrial fibrillation - a nationwide cohort study.

Ischemic stroke (IS) is a catastrophic complication of hypertrophic cardiomyopathy (HCM) with aging. We investigated the incidence of IS in HCM patients without atrial fibrillation (AF) and compared the relative risk of IS with matched general population with AF. This study identified 17,371 HCM patients without AF and utilized propensity-score-matching to identify one-to-one matched control of general population with AF receiving oral anti-coagulants (OACs). During a median follow-up of 7.3 years, 847 (4.9%) subjects experienced IS with the incidence of 0.589/100 person-years. The corresponding matched controls experienced 788 (4.5%) events with the incidence of 0.494/100 person-years. Compared with control, HCM patients had similar risk of IS (Hazard ratios [HRs] 0.965, 95% confidence interval [CI] 0.854-1.091). HCM patients with age above 65 years had a significantly increased risk of IS (age 65-74 years, HR 1.278, 95% CI 1.070-1.335; age ≥75 years, HR 1.757, 95% CI 1.435-2.152). Stratified by CHA2DS2-VASc score, HCM subjects with score 0, 1 and 2 had significantly increased risk of IS than control while those with score ≥2 had similar risk as control. Compared with general population with AF, HCM patients without AF had similar risk of IS, suggesting OACs might be necessary in HCM patient without AF.

Effects of long-term exercise on arrhythmogenesis in aged hypertensive rats.

Chronic hypertension is a multifactorial disease that is highly associated with cardiovascular disorders. Physical activity, such as long-term exercise, is advocated as a treatment for hypertension, but the responses of different age groups to long-term exercise are unknown. We used aged spontaneous hypertensive rats (SHRs, 80 weeks old) to test the hypothesis that long-term exercise compensated for deficient autonomic control and reduced susceptibility to ventricular tachycardia (VT) and ventricular fibrillation (VF) in this animal model. The aged SHRs were divided into control and voluntary exercise groups. Ambulatory electrocardiography was recorded for the heart rate variability (HRV) analysis. Programmed stimulation was applied to exposed hearts to induce ventricular arrhythmia in situ. Then, the hearts were isolated for an optical mapping study. The results showed that increased HRV indices were broadly related to vagal dominance in the high-intensity exercise group. Exercise altered the electrical propagation dynamic properties, such as the action potential duration restitution (APDR). Furthermore, the VF inducibility decreased with increased exercise intensity. Taken together, our results suggest that long-term exercise reduces the risk of arrhythmogenesis in aged SHRs through enhanced vagal control and stabilized electrical dynamics.

Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia.

Observational studies have established a strong association between matrix metalloproteinase-9 (MMP-9) and ventricular arrhythmia. However, whether MMP-9 has a causal link to ventricular arrhythmia, as well as the underlying mechanism, remains unclear. Here, we investigated the mechanistic involvement of myocardial MMP-9 in the pathophysiology of ventricular arrhythmia. Increased levels of myocardial MMP-9 are linked to ventricular arrhythmia attacks after angiotensin II (Ang II) treatment. MMP-9-deficient mice were protected from ventricular arrhythmia. Increased expressions of protein kinase A (PKA) and ryanodine receptor phosphorylation at serine 2808 (pS2808) were correlated with inducible ventricular arrhythmia. MMP-9 deficiency consistently prevented PKA and pS2808 increases after Ang II treatment and reduced ventricular arrhythmia. Calcium dynamics were examined via confocal imaging in isolated murine cardiomyocytes. MMP-9 inhibition prevents calcium leakage from the sarcoplasmic reticulum and reduces arrhythmia-like irregular calcium transients via protein kinase A and ryanodine receptor phosphorylation. Human induced pluripotent stem cell-derived cardiomyocytes similarly show that MMP-9 inhibition prevents abnormal calcium leakage. Myocardial MMP-9 inhibition prevents ventricular arrhythmia through pleiotropic effects, including the modulation of calcium homeostasis and reduced calcium leakage.

Proarrhythmic risk and determinants of cardiac autonomic dysfunction in collagen-induced arthritis rats.

BACKGROUNDS: Patients with rheumatoid arthritis (RA) have increased risk of sudden cardiac death (SCD), which is two-fold higher than general population. The driving cause of SCD was considered due to lift-threatening arrhythmia where systemic inflammation acts as the pathophysiological basis linking RA to autonomicdysfunction. METHODS: To assess the sympathetic over-activity of "inflammatory reflex", we measured heart rate variability (HRV) in a rat collagen-induced arthritis (CIA) model, whose arthritis is induced in Lewis rats by intradermal injection of emulsion of type II collagen. Single-lead electrocardiogram (ECG) was recorded for 30 min every two days. Time and frequency-domain parameters, detrended fluctuation analysis (DFA), deceleration (DC) and acceleration capacity (AC) were analyzed. RESULTS: Compared with 9 control rats, many of HRV parameters of 9 CIA rats revealed significant different. At the beginning of arthritis, LF/HF was significant higher than controls (1st week: 2.41 ± 0.7 vs. 1.76 ± 0.6, p < 0.05; 2nd week: 2.24 ± 0.5 vs. 1.58 ± 0.5, p < 0.05) indicating intensive inflammatory reflex at the initial phase of inflammation but no significant difference was observed in the following recover phase. The similar trend of DFA parameters was noted. However, the DC appeared progressive lower despite of no significant increase of the LF/HF compared with controls since 4th week. CONCLUSIONS: We observed sympathetic over-activation of inflammatory reflex during early stage of arthritis in CIA rats. The ongoing decline of DC indicated advanced cardiac autonomic dysfunction regardless of remission of acute arthritis.