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Sinoatrial node (SAN) pacemaker cells originate from T‐box transcription factor 18 (Tbx18)‐expressing progenitor cells. The present study aimed to investigate whether overexpression of human transcription factor Tbx18 could reprogram human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) into SAN‐like pacemaker cells (SANLPCs) in vitro. In the study, hiPSCs were first differentiated into hiPSC‐CMs through regulating the Wnt/β‐catenin pathway, then purified hiPSC‐CMs were transfected by Tbx18 adenovirus (Tbx18‐CMs group) or green fluorescent protein (GFP) adenovirus (GFP‐CMs group). The beating frequency of the Tbx18‐CMs group was significantly higher than that of the hiPSC‐CMs group and GFP‐CMs group. Compared with the other two groups, the expression levels of hyperpolarization‐activated cyclic nucleotide‐gated potassium channel isoform 4, connexin‐45 in the Tbx18‐CMs group were markedly upregulated, while the expressions of transcription factor NKX2.5, CX43 were significantly downregulated. Whole‐cell patch‐clamp results illustrated that action potential and "funny" current (If) similar to SAN pacemaker cells could be recorded in the Tbx18‐CMs group. In conclusion, this present study demonstrated that overexpression of Tbx18 promoted the conversion of hiPSC‐CMs into SANLPCs. [ABSTRACT FROM AUTHOR]

Intracardiac injection of the growth-promoting transcription factor of the sinoatrial node T-box18 (TBX18) has been shown to reprogram cardiomyocytes into induced sinoatrial nodes that produce high-frequency and neuroregulated ectopic beats. Fibroblasts, the most important non-cardiomyocyte cell type in the heart, can affect the electrophysiological properties of cardiomyocytes by electrically coupling with them. The aim of the present study was to explore the reprogramming of cardiac fibroblasts (CFs) transfected with TBX18 in vitro and observe its effect on the pacing frequency of neonatal rat ventricular cardiomyocytes (NRVMs) in a co-culture system. CFs transfected with TBX18 could be transformed into cardiac myofibroblasts that expressed high levels of hyperpolarization-activated cyclic nucleotide-gated cation channel 4 protein and low levels of connexin 43 (COX43) and COX45 protein. In addition, TBX18-CFs could increase the beating rates of NRVMs and TBX18-NRVMs in a co-culture system. The results of the present study indicated that the TBX18 gene could induce CFs to undergo a transformation that promotes an increase of the beating rates of NRVMs and TBX18-NRVMs. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study was to evaluate the cardiac electrophysiologic effects of targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic myocardial infarction (MI)., Methods and Results: Thirty-eight anaesthetized dogs were randomly assigned into the sham-operated, MI, and MI-TACSN groups, respectively. Myocardial infarction-targeted ablation of cardiac sympathetic neuron was induced by injecting cholera toxin B subunit-saporin compound in the left stellate ganglion (LSG). Five weeks after surgery, the cardiac function, heart rate variability (HRV), ventricular electrophysiological parameters, LSG function and neural activity, serum norepinephrine (NE), nerve growth factor (NGF), and brain natriuretic peptide (BNP) levels were measured. Cardiac sympathetic innervation was determined with immunofluorescence staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Compared with MI group, TACSN significantly improved HRV, attenuated LSG function and activity, prolonged corrected QT interval, decreased Tpeak-Tend interval, prolonged ventricular effective refractory period (ERP), and action potential duration (APD), decreased the slopes of APD restitution curves, suppressed the APD alternans, increased ventricular fibrillation threshold, and reduced serum NE, NGF, and BNP levels. Moreover, the densities of GAP43 and TH-positive nerve fibres in the infarcted border zone in the MI-TACSN group were lower than those in the MI group., Conclusion: Targeted ablation of cardiac sympathetic neuron attenuates sympathetic remodelling and improves ventricular electrical remodelling in the chronic phase of MI. These data suggest that TACSN may be a novel approach to treating ventricular arrhythmias.