Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction

Cho, Jae Hyung; Zhang, Rui; Kilfoil, Peter J.; Gallet, Romain; Couto, Geoffrey de; Bresee, Catherine; Goldhaber, Joshua I.; Marbán, Eduardo; Cingolani, Eugenio

doi:10.1161/circulationaha.117.028202

Cited by 60 publications

(79 citation statements)

References 52 publications

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“…The increase in the incidence and duration of AF may be correlated with the extent of myocardial fibrosis in the TAC model. 26,27 At the same time, there was likely a tendency to develop atrial fibrosis in the TAC animal models. Moreover, a greater degree of fibrosis was observed in HH mice than in the NH mice ( Figure 3I).…”

Section: Discussionmentioning

confidence: 99%

Protective mechanism of SIRT1 on Hcy‐induced atrial fibrosis mediated by TRPC3

Han

Tang

et al. 2019

J Cellular Molecular Medi

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High plasma levels of homocysteine (Hcy) are regarded as a risk factor for atrial fibrillation (AF), which is closely associated with the pathological consequence of atrial fibrosis and can lead to heart failure with a high mortality rate; here, we show that atrial fibrosis is mediated by the relationship between canonical transient receptor potential 3 (TRPC3) channels and sirtuin type 1 (SIRT1) under the stimulation of Hcy. The left atrial appendage was obtained from patients with either sinus rhythm (SR) or AF and used to evaluate the relationship between the concentration of Hcy and a potential mechanism of cardiac fibrosis mediated by TRPC3 and SIRT1. We next performed transverse aortic constriction (TAC) in mouse to investigate the relationship. The mechanisms underlying atrial fibrosis involving TRPC3 and SIRT1 proteins were explored by co‐IP, BLI and lentivirus transfection experiments. qPCR and WB were performed to analyse gene and protein expression, respectively. The higher level of atrial fibrosis was observed in the HH mouse group with a high Hcy diet. Such results suggest that AF patients may be more susceptible to atrial fibrosis and possess a high probability of progressing to hyperhomocysteinemia. Moreover, our findings are consistent with the hypothesis that TRPC3 channel up‐regulation leads to abnormal accumulation of collagen, with the down‐regulation of SIRT1 as an aetiological factor of high Hcy, which in turn predisposes to atrial fibrosis and strongly enhances the possibility of AF.

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Section: Discussionmentioning

confidence: 99%

Protective mechanism of SIRT1 on Hcy‐induced atrial fibrosis mediated by TRPC3

Han

Tang

et al. 2019

J Cellular Molecular Medi

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“…To address this question and lay the foundation for future therapeutic approaches, Cho et al 7 recently showed reduction in the potassium currents (I to , I Kr , and I K1 ) in a high-salt diet-induced heart failure with preserved EF rat model led to increased susceptibility to ventricular arrhythmias via QT prolongation and delayed repolarization.…”

Section: Mechanisms Of Altered Repolarizationmentioning

confidence: 99%

“…Among 138 patients hospitalized for dofetilide reinitiation, Cho et al 7 demonstrated that roughly one third of these patients required dofetilide dose modification or discontinuation, among both groups that were restarting a previously tolerated dose or receiving an increased dose.…”

Section: Antiarrhythmic Therapymentioning

confidence: 99%

Year in Review in Cardiac Electrophysiology

Tzou

Hussein

Madhavan

et al. 2018

Circ: Arrhythmia and Electrophysiology

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1 In the past year, there have been key advances in our understanding of arrhythmia mechanisms and diagnosis and important new therapies. We have seen advances in basic cardiac electrophysiology with demonstration of optogenetic targeting of atrial fibrillation (AF) rotors, induced pluripotent stem cell-based biological pacemakers, small-conductance Ca 2+ -activated K + (SK) channels as targets for AF treatment, and reductions in inward rectifier potassium current in promoting ventricular fibrillation. Hand-held ECG devices and implantable loop recorders have been shown to detect subclinical AF. Catheter ablation of AF in patients with left ventricular dysfunction improves outcomes compared with medical therapy. Both hybrid thoracoscopic surgical and catheter ablation procedures and off-pump surgery for AF have demonstrated efficacy. Anticoagulation with uninterrupted dabigatran had a lower major bleeding rate compared with uninterrupted warfarin after AF ablation. Studies have examined optimizing access to automatic external defibrillators by identifying optimal locations for placement and possibility of using a drone delivery network. In long-QT syndrome, there are advances in understanding of ECG predictors of arrhythmic events, the role of the role of gene variants in conferring arrhythmic risk, and effect of age and sex on QTc interval. There are numerous advances in the treatment of ventricular tachycardia, including noninvasive cardiac radiation. Catheter ablation and implantable devices continue to demonstrate effectiveness in patients with congenital heart disease.In the past year, there have been numerous ground-breaking discoveries and observations that illustrate the vibrancy and promise of our field. In this review, we have tried to capture articles published in the year 2017 of particular interest to cardiac electrophysiologists. Although we have focused on articles from our journal, we have captured many of the most impactful articles in numerous other journals. We apologize for omitting a large number of other important articles that cannot be included in this review because of space limitations. We have placed some of these in our Data Supplement. BASIC ELECTROPHYSIOLOGY BradyarrhythmiasThe search for new biological therapies for bradycardia met with recent progress as human keratinocytes genetically reprogrammed into electrically unstable cardiomyocytes were shown to persist and provide continued catecholaminergic-responsive pacing for 13 weeks after subepicardial injection into immunosuppressed dogs at the time of atrioventricular (AV) node ablation.1 Although only 40% to 80% of the beats matched the site of cell injection, this is first study to test a human induced pluripotent stem cell-based biological pacemaker in a large animal model of heart block and represents an important step forward in biological pacing.

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“…For this reason, we use TAC to establish the model of HFpEF, which means that not only could we observe the relationship between cardiac fibrosis and a high Hcy diet in our HF model, but we could also detect the susceptibility of AF to Hcy stimulation in HF model. The increase in the incidence and duration of AF may be correlated with the extent of myocardial fibrosis in the TAC model [27,28] . At the same time, there is likely a tendency to develop atrial fibrosis in the TAC animal models, moreover, a greater degree of fibrosis was observed in HH mice than in the NH group (Fig.…”

Section: Discussionmentioning

confidence: 99%

The signaling mechanism of Hcy-induced atrial fibrosis mediated by TRPC3

Han

Tang

Chen

et al. 2019

Preprint

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Background-High plasma levels of homocysteine (Hcy) are regarded as a risk factor for atrial fibrillation (AF), which is closely associated with the pathological consequence of atrial fibrosis and can lead to heart failure with a high mortality rate;Currently, there is no effective therapy for preventing atrial fibrosis, owing to a lack in fundamental understanding of the underlying mechanism. Here, we show that atrial fibrosis is mediated by the relationship between canonical transient receptor potential 3 (TRPC3) channels and sirtuin type 1 (SIRT1) under the stimulation of Hcy.Methods-The left atrial appendage was obtained from patients with either sinus rhythm (SR) or AF, who underwent cardiothoracic surgery, and used to evaluate the relationship between the concentration of Hcy and a potential mechanism of cardiac fibrosis mediated by TRPC3 and SIRT1. We next performed transverse aortic constriction (TAC) in mouse to investigate the relationship. The mechanisms underlying atrial fibrosis involving TRPC3 and SIRT1 proteins were explored by co-immunoprecipitation (co-IP), bio-layer interferometry (BLI) and lentivirus transfection experiments. Quantitative polymerase chain reaction (qPCR) and western blotting (WB) were performed to analyse gene and protein expression, respectively. Results-The majority of AF patients displayed atrial fibrosis, as demonstrated by Masson staining and immunohistochemistry. In the mouse model of TAC, more severe fibrosis was detected in the high-Hcy diet (HH) group, compared to NH mice; and the duration of induced AF was longer in the HH groups than in the normal diet (NH) group. Moreover, the HH group exhibited higher expression levels of TRPC3 and related fibrosis proteins, such as TGF-ß and Col-I, than the NH group, despite also showing a higher level of SIRT1 was observed. The activator of SIRT1 (Resveratrol, Res) attenuated the enhancement of TRPC3 and decrease in SIRT1 observed in the HH group. Further cell culture experiments confirmed that Hcy could promote the proliferation and differentiation of fibroblasts, the up-regulation of TRPC3, and the decrease in the protein level of SIRT1. Ultimately, the results of Co-IP and BLI indicated a direct interaction between TRPC3-C terminal domain (569-863) and SIRT1 proteins, in which the two proteins are antagonistic and in combination regulate the pathogenesis of atrial fibrosis.Conclusions-The higher level of atrial fibrosis were observed in the HH mouse group, compared with the NH mice group, Such results suggest that AF patients may be more susceptible to atrial fibrosis and possess a high probability of progressing to hyperhomocysteinemia. Moreover, our findings are consistent with the hypothesis that TRPC3 channel up-regulation leads to abnormal accumulation of collagen, with the down-regulation of SIRT1 as an aetiological factor of high Hcy, which in turn predisposes to atrial fibrosis and strongly enhances the possibility of AF.

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Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction

Cited by 60 publications

References 52 publications

Protective mechanism of SIRT1 on Hcy‐induced atrial fibrosis mediated by TRPC3

Protective mechanism of SIRT1 on Hcy‐induced atrial fibrosis mediated by TRPC3

Year in Review in Cardiac Electrophysiology

The signaling mechanism of Hcy-induced atrial fibrosis mediated by TRPC3

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