Rate-dependent force, intracellular calcium, and action potential voltage alternans are modulated by sarcomere length and heart failure induced-remodeling of thin filament regulation in human heart failure: A myocyte modeling study
By Zile, Melanie A. ; Trayanova, Natalia A. ;
Source: Prog Biophys Mol Biol. 120(1-3):270-280.	
Title : Rate-dependent force, intracellular calcium, and action potential voltage alternans are modulated by sarcomere length and heart failure induced-remodeling of thin filament regulation in human heart failure: A myocyte modeling study Personal Author(s) : Zile, Melanie A.;Trayanova, Natalia A.; Published Date : Dec 25 2015 Source : Prog Biophys Mol Biol. 120(1-3):270-280. URL : https://stacks.cdc.gov/view/cdc/40539
Zile, Melanie A. ; Trayanova, Natalia A. ;
Zile, Melanie A. ; Trayanova, Natalia A. ; Less -
Microvolt T-wave alternans (MTWA) testing identifies heart failure patients at risk for lethal ventricular arrhythmias at near-resting heart rates (<110 beats per minute). Since pressure alternans occurs simultaneously with MTWA and has a higher signal to noise ratio, it may be a better predictor of arrhythmia, although the mechanism remains unknown. Therefore, we investigated the relationship between force alternans (FORCE-ALT), the cellular manifestation of pressure alternans, and action potential voltage alternans (APV-ALT), the cellular driver of MTWA. Our goal was to uncover the mechanisms linking APV-ALT and FORCE-ALT in failing human myocytes and to investigate how the link between those alternans was affected by pacing rate and by physiological conditions such as sarcomere length and heart failure induced-remodeling of mechanical parameters. To achieve this, a mechanically-based, strongly coupled human electromechanical myocyte model was constructed. Reducing the sarcoplasmic reticulum calcium uptake current (Iup) to 27% was incorporated to simulate abnormal calcium handling in human heart failure. Mechanical remodeling was incorporated to simulate altered thin filament activation and crossbridge (XB) cycling rates. A dynamical pacing protocol was used to investigate the development of intracellular calcium concentration ([Ca]i), voltage, and active force alternans at different pacing rates. FORCE-ALT only occurred in simulations incorporating reduced Iup, demonstrating that alternans in the intracellular calcium concentration (CA-ALT) induced FORCE-ALT. The magnitude of FORCE-ALT was found to be largest at clinically relevant pacing rates (<110 bpm), where APV-ALT was smallest. We found that the magnitudes of FORCE-ALT, CA-ALT and APV-ALT were altered by heart failure induced-remodeling of mechanical parameters and sarcomere length due to the presence of myofilament feedback. These findings provide important insight into the relationship between heart-failure-induced electrical and mechanical alternans and how they are altered by physiological conditions at near-resting heart rates.	
Action Potential Alternans
Force Alternans
Pressure Alternans
Prog Biophys Mol Biol. 120(1-3):270-280.	
DP1 HL123271/DP/NCCDPHP CDC HHS/United States ; DP1 HL123271/HL/NHLBI NIH HHS/United States ; R01 HL103428/HL/NHLBI NIH HHS/United States ;
DP1 HL123271/DP/NCCDPHP CDC HHS/United States ; DP1 HL123271/HL/NHLBI NIH HHS/United States ; R01 HL103428/HL/NHLBI NIH HHS/United States ; Less -
urn:sha256:843571d73b28a33c933ae700f5baa9b15b4c2e12d1f4ba2d913fab7b9257d4fa	
Grandi, Eleonora ; Ripplinger, Crystal M. ;
Pharmacol Res. 146:104274	
Sympathetic activity plays an important role in modulation of cardiac rhythm. Indeed, while exerting positive tropic effects in response to physiologi...	