Rate-dependent action potential alternans in human heart failure implicates abnormal intracellular calcium handling

Bayer, Jason D.; Narayan, Sanjiv M.; Lalani, Gautam; Trayanova, Natalia A.

doi:10.1016/j.hrthm.2010.04.008

Cited by 51 publications

(64 citation statements)

References 38 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Computational models of the LV wall in combination with clinical data revealed that abnormal handing of intracellular calcium underlies alternans in action potential voltage (APV-ALT), defined as the oscillation of the plateau voltage of the action potential, which results in MTWA at moderate heart rates, i.e. < 110 bpm (Bayer et al, 2010; Narayan et al, 2008). Thus APV-ALT is the cell-level driver of MTWA at these rates under the conditions of heart failure.…”

Section: Introductionmentioning

confidence: 99%

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

Zile

Trayanova

2016

Progress in Biophysics and Molecular Biology

Self Cite

View full text Add to dashboard Cite

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 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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Zile

Trayanova

2016

Progress in Biophysics and Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The slope of the APD restitution curve is determined by the recovery of ion channels from inactivation and their dependence on V m . Computational [21,25,26,28,29] as well as several experimental studies [30,31] have suggested that self-sustaining oscillations of APD can occur if this relationship is steep enough, and that the role of V m as a causative factor of alternans becomes more prominent with increasing pacing rates [28,32]. However, simulation results still differ and remain dependent on the computational models applied, even if they are designed to recreate processes of the same tissue [33].…”

Section: Putative Mechanisms Of Alternansmentioning

confidence: 99%

“…As discussed above disturbances in intracellular Ca 2+ handling have been proposed as an underlying mechanism of alternans at the cellular level [17,32,50,51,53,54,75]. Spatial heterogeneities in electrical as well as Ca 2+ cycling properties of cardiac tissue between the endocardium and epicardium or between the base and apex of the heart are essential for maintaining normal function of the heart [105,106], including excitation spread and coordinated contractility.…”

Section: Mechanisms Of Spatially Discordant Alternansmentioning

confidence: 99%

Alternans in atria: Mechanisms and clinical relevance

Kanaporis

Blatter

2017

Medicina

View full text Add to dashboard Cite

Atrial fibrillation is the most common sustained arrhythmia and its prevalence is rapidly rising with the aging of the population. Cardiac alternans, defined as cyclic beat-to-beat alternations in contraction force, action potential (AP) duration and intracellular Ca2+ release at constant stimulation rate, has been associated with the development of ventricular arrhythmias. Recent clinical data also provide strong evidence that alternans plays a central role in arrhythmogenesis in atria. The aim of this article is to review the mechanisms that are responsible for repolarization alternans and contribute to the transition from spatially concordant alternans to the more arrhythmogenic spatially discordant alternans in atria.

show abstract

“…However, the mechanisms underlying these ECG indices, and their relationship to lethal arrhythmias, are not fully understood. Computational models of the heart have made inroads in this clinical cardiology arena [17,18,38,47,66,85,90,137]. Specifically, research has reported a strong correlation between increased arrhythmia risk and the presence of microvolt T-wave alternans (MTWA) [26,58].…”

Section: Modeling To Identify Individuals With a High Risk Of Developmentioning

confidence: 99%

“…However, the mechanistic basis of MTWA preceding lethal ventricular arrhythmias has been under debate since MTWA is most successful in stratifying risk in patients at heart rates < 110 bpm, where APD restitution is flat [86]. Computational models of the left ventricular (LV) wall in combination with clinical data revealed that abnormal intracellular calcium handling underlies alternans in action potential voltage, which result in MTWA at heart rates < 110 bpm [17,85]; abnormalities in intracellular calcium have long been linked to ventricular fibrillation [80,129]. Computational modeling studies have also shown that under conditions of abnormal calcium dynamics, the T-wave alternans magnitude is enhanced by structural heterogeneities in the myocardium [47].…”

Section: Modeling To Identify Individuals With a High Risk Of Developmentioning

confidence: 99%

Cardiac Arrhythmias: Mechanistic Knowledge and Innovation from Computer Models

Trayanova

Boyle

2015

MS&A

Self Cite

View full text Add to dashboard Cite

Computational simulation is increasingly recognized as an integral aspect of modern cardiovascular research. Realistic and biophysically detailed models of the cardio-circulatory system can help interpret complex experimental observations, dissect underlying mechanisms, and explain emerging organ-scale phenomena resulting from subtle changes at the tissue, cellular, and/or sub-cellular scales. This chapter provides an overview of recent advances in the simulation of cardiac electrical behavior, focusing specifically on detailed models of the initiation, perpetuation, and termination of ventricular arrhythmias, including fibrillation. The development and validation of such models has opened several noteworthy avenues of research, including close scrutiny of arrhythmia dynamics in healthy and diseased hearts, dissection of arrhythmogenic and cardioprotective properties of specialized cardiac tissue regions such as the Purkinje system, and exploration of emerging paradigms for anti-arrhythmia treatment, such as optogenetics. Excitingly, the clinical community is currently taking the first steps towards using patient-specific ventricular models to stratify arrhythmia risk, personalize treatment planning, and optimize device placement for difficult or unusual procedures.

show abstract

Rate-dependent action potential alternans in human heart failure implicates abnormal intracellular calcium handling

Cited by 51 publications

References 38 publications

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

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

Alternans in atria: Mechanisms and clinical relevance

Cardiac Arrhythmias: Mechanistic Knowledge and Innovation from Computer Models

Contact Info

Product

Resources

About