scholarly journals Nucleoside Diphosphate Kinase B Contributes to Arrhythmogenesis in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with Arrhythmogenic Right Ventricular Cardiomyopathy

2020 ◽  
Vol 9 (2) ◽  
pp. 486 ◽  
Author(s):  
Fanis Buljubasic ◽  
Ibrahim El-Battrawy ◽  
Huan Lan ◽  
Santosh K. Lomada ◽  
Anupriya Chatterjee ◽  
...  

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare, inheritable cardiac disorder characterized by ventricular tachyarrhythmias, progressive loss of cardiomyocytes with fibrofatty replacement and sudden cardiac death. The exact underlying mechanisms are unclear. Methods: This study investigated the possible roles of nucleoside diphosphate kinase B (NDPK-B) and SK4 channels in the arrhythmogenesis of ARVC by using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Results: In hiPSC-CMs from a patient with ARVC, the expression levels of NDPK-B and SK4 channels were upregulated, the cell automaticity was increased and the occurrence rate of arrhythmic events was enhanced. Recombinant NDPK-B applied into hiPSC-CMs from either healthy donors or the patient enhanced SK4 channel current (ISK4), cell automaticity and the occurrence of arrhythmic events, whereas protein histidine phosphatase 1 (PHP-1), a counter actor of NDPK-B, prevented the NDPK-B effect. Application of PHP-1 alone or a SK4 channel blocker also reduced cell automaticity and arrhythmic events. Conclusion: This study demonstrated that the elevated NDPK-B expression, via activating SK4 channels, contributes to arrhythmogenesis in ARVC, and hence, NDPK-B may be a potential therapeutic target for treating arrhythmias in patients with ARVC.

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Takuji Watanabe ◽  
Shigeru Miyagawa ◽  
Akima Harada ◽  
Ai Kawamura ◽  
Takuji Kawamura ◽  
...  

Introduction: Right ventricular (RV) failure following definitive repair of congenital heart diseases (CHD) have great impact on survival after surgical intervention. Recently, human induced pluripotent stem cell-derived cardiomyocyte (hiPS-CM) sheet transplantation ameliorated left ventricular dysfunction in preclinical study, associating possible efficacy in RV failure of CHD. Hypothesis: We hypothesized whether hiPS-CM patch could improve distressed RV function in rat pressure overload model. Methods: F344/NJcl- rnu/rnu rat (7-9 weeks old, male, 180-210g) underwent pulmonary artery banding (PAB) via left thoracotomy under general anesthesia. Four weeks after PAB, hiPS-CM patch transplantation to the RV was performed in the hiPS-CM patch transplantation group (n = 10), whereas a sham operation was performed in the sham group (n =10). We evaluated for cardiac catheterization (CATH) data and pathological findings 8 weeks after PAB. Results: In CATH, RV end diastolic pressure (sham; 10.0 ± 4.1 vs hiPS-CM; 5.5 ± 2.7 mmHg, P < 0.01), time constant of isovolumic relaxation (sham; 24.9 ± 8.6 vs hiPS-CM; 16.5 ± 6.4 ms, P < 0.01) and end-diastolic pressure volume-relation (sham; 365.6 ± 246.3 vs hiPS-CM; 214.0 ± 147.4 mmHg/mL, P <0.05) were significantly ameliorated in hiPS-CM group compared with sham group. Sirius-red staining showed a significant anti-fibrotic effects in the hiPS-CM group compared with the sham group (13.4 ± 5.3 vs 20.7 ± 4.8 %, P <0.05). Factor VIII stain showed that myocardial capillary vascular density in the hiPS-CM group was significantly higher than in the sham group (640 ± 131 vs 362 ± 31 units/mm 2 , P <0.001). hiPS-CMs were detectable on epicardium 2 weeks after hiPS-CM patch transplantation. The expression levels of vascular endothelial growth factor and hepatocyte growth factor in the hiPS-CM group was significantly higher than in the sham group (P <0.05). Conclusions: In a rat model of a pressure-overload RV, hiPS-CM patch transplantation improved the diastolic function with suppressed ventricular fibrosis and increased capillary density, suggesting a promising treatment for RV failure in CHD patients after surgical repair.


2018 ◽  
Author(s):  
Fantuzzi Federica ◽  
Toivonen Sanna ◽  
Schiavo Andrea Alex ◽  
Pachera Nathalie ◽  
Rajaei Bahareh ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document