BACKGROUND. Simultaneous noninvasively recorded skin sympathetic nerve activity (SKNA) and electrocardiogram (neuECG) can be used to estimate cardiac sympathetic tone. We tested the hypothesis that large and prolonged SKNA bursts are associated with temporal clustering arrhythmias. METHODS. We recorded neuECG in 10 patients (69 ± 10 years old) with atrial fibrillation (AF) episodes and in 6 patients (50 ± 13 years old) with ventricular tachycardia (VT) or fibrillation (VF) episodes. Clustering was defined by an arrhythmic episode followed within 1 minute by spontaneous recurrences of the same arrhythmia. The neuECG signals were bandpass filtered between 500–1000 Hz to display SKNA. RESULTS. There were 22 AF clusters, including 231 AF episodes from 6 patients, and 9 VT/VF clusters, including 99 VT/VF episodes from 3 patients. A total duration of SKNA bursts associated with AF was longer than that during sinus rhythm (78.9 min/hour [interquartile range (IQR) 17.5–201.3] vs. 16.3 min/hour [IQR 14.5–18.5], P = 0.022). The burst amplitude associated with AF in clustering patients was significantly higher than that in nonclustering patients (1.54 μ V [IQR 1.35–1.89], n = 114, vs. 1.20 μ V [IQR 1.05–1.42], n = 21, P < 0.001). The SKNA bursts associated with VT/VF clusters lasted 9.3 ± 3.1 minutes, with peaks that averaged 1.13 ± 0.38 μ V as compared with 0.79 ± 0.11 μ V at baseline ( P = 0.041). CONCLUSION. Large and sustained sympathetic nerve activities are associated with the temporal clustering of AF and VT/VF. FUNDING. This study was supported in part by NIH grants R42DA043391 (THE), R56 HL71140, TR002208-01, R01 HL139829 (PSC), a Charles Fisch Cardiovascular Research Award endowed by Suzanne B. Knoebel of the Krannert Institute of Cardiology (TK and THE), a Medtronic-Zipes Endowment, and the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative (PSC).

The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current ( I _KAS ) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. I _KAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current ( I _Na ) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent I _KAS blockade by apamin reduced J wave elevation and eliminated SVF. β-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0°C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that I _KAS activation contributes to the development of JWS in rabbit ventricles.

Background: Ischemic heart disease (IHD) is a leading cause of death and disability, particularly affecting the older adult population. Extreme temperatures, especially very low and very high temperatures, are known to exacerbate cardiovascular disease burden. With the ongoing global climate change, understanding the impact of non-optimal temperatures on IHD burden becomes increasingly important, especially in vulnerable populations such as the older adult.Methods: This study used data from the Global Burden of Disease Study 2021 (GBD 2021) to analyze the spatiotemporal trends of low and high temperatures on IHD burden in the older adult population (aged 60 and above) from 1990 to 2021. We used age-standardized rates (ASR), annual percentage change (EAPC), and the Bayesian age-period-cohort (BAPC) model to forecast 2050. Additionally, the geographic differences in IHD burden were analyzed using World Bank regions.Results: From 1990 to 2021, the IHD burden in the older adult population was mainly attributed to low temperatures. However, it has increased the burden of IHD due to high temperatures, especially in tropical and low-income regions. The analysis of gender difference revealed that men are usually more affected by high temperatures, though generally, women are more sensitive to low temperatures. Forecasts are that in the future, the burden of IHD due to high temperatures will continue to rise, especially in areas with limited adaptive capacity.Conclusion: Although low temperature remains the most important contributor to IHD burden among the older adult, the burden attributable to high temperature is on the rise, which increases the need to address the extreme temperature fluctuation. That is more so in poor-income and tropical regions where the most vulnerable populations bear a higher risk for health. Thus, there is an urgent need to develop adaptive public health measures against the dual health risks from extreme temperatures. The findings emphasize that targeted interventions are necessary, with adjustments in regional differences and gender-specific risks to effectively address the growing health threats from climate change.

Background: Existing methods for in vitro differentiation of human pluripotent stem cells (hPSCs) into sinoatrial node-like cells (SANLCs) require complex and undefined medium constituents. This might hinder the elucidation of the molecular mechanisms involved in cardiac subtype specification and prevent translational application. In our study, we aimed to establish a chemically defined differentiation methods to generate SANLCs effectively and stably. Methods: We induced human embryonic stem cells (hESCs)/induced PSCs (hiPSCs) to pan-cardiomyocytes by temporal modulation of the WNT/β-catenin (WNT) signaling pathway with GSK3 inhibitor and WNT inhibitor. During cardiac mesoderm stage of the differentiation process, signaling of WNT, retinoid acid (RA), and fibroblast growth factor (FGF) was manipulated by three specific molecules. Moreover, metabolic selection was designed to improve the enrichment of SANLCs. Finally, RT-PCR, immunofluorescence, flow cytometry, and whole cell patch clamp were used to identify the SANLCs. Results: WNT, RA, and FGF signaling promote the differentiation of hPSCs into SANLCs in a concentration- and time window-sensitive manner, respectively. Synergetic modulation of WNT, FGF, and RA signaling pathways enhance the pacemaker phenotype and improve the differentiation efficiency of SANLCs (up to 45%). Moreover, the purification based on lactate metabolism and glucose starvation further reached approximately 50% of SANLCs. Finally, the electrophysiological data demonstrate that cells differentiated with the proposed protocol produce a considerable number of SANLCs that display typical electrophysiological characteristics of pacemaker cells in vitro. Conclusion: We provide an optimized and chemically defined protocol to generate SANLCs by combined modulation of WNT, RA, and FGF signaling pathways and metabolic selection by lactate enrichment and glucose starvation. This chemically defined method for generating SANLCs might provide a platform for disease modeling, drug discovery, predictive toxicology, and biological pacemaker construction.