Abstract 17043: Enhanced Na + Influx Alters Myocyte Mechanics and Diastolic Function
| Autor: | Marcello Rota, Dong Sun, Thomas H. Hintze, Heather A. O'Malley, Saketh Anand, Chaoyu Sun, Lori L. Isom, Daniel O Cervantes, Alejandro Andrade-Vicenty |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Circulation. 138 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circ.138.suppl_1.17043 |
| Popis: | The late Na + current has emerged as a therapeutic target for conditions characterized by depressed diastolic function, but whether enhanced Na + fluxes in cardiomyocytes interfere with cellular and myocardial relaxation remain to be clarified. For this purpose, we employed mice with inducible, cardiac restricted deletion of the non-pore forming beta1 subunit of the Na + channel ( Scn1b -KO), a rodent model associated with enhanced Na + influx in cardiomyocytes. Two-dimensional and Doppler echocardiography and ECGs were employed to evaluate cardiac function in Scn1b -KO and control (Ctrl) animals. Properties of Ca 2+ transient and contractility were established in isolated left ventricular (LV) myocytes obtained by enzymatic digestion. Deletion of the Scn1b gene had no consequences on ejection fraction, whereas LV filling pattern was altered, isovolumic relaxation time prolonged (+30%), and electrical recovery, measured by the QT interval, was protracted (+14%). In a subgroup of animals, acute administration of GS967 (0.5 mg/kg body weight), a specific inhibitor of the late Na + current, partly ameliorated diastolic indices and shortened the QT interval. At the cellular level, kinetics of cell shortening and Ca 2+ transients were delayed in Scn1b -KO myocytes (n=609-693), with respect to Ctrl cells (369-298). Specifically, time to peak Ca 2+ and time to 50% decay of the Ca 2+ transient were increased in Scn1b -KO cells by 5% and 17%, respectively. Similarly, time to peak contraction and time to 50% relaxation were enhanced by 6% and 7% in Scn1b -KO. Interestingly, GS967 (300 nM) accelerated temporal parameters of contraction in Scn1b -KO myocytes by ~8% and led to an attenuation of fractional shortening. These effects were not observed in Ctrl cells. Thus, enhanced Na + influx modulates electromechanical coupling in cardiomyocytes and delays kinetics of contraction and relaxation with consequences on diastolic properties of the heart. |
| Databáze: | OpenAIRE |
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