T-Wave Alternans, Restitution of Human Action Potential Duration, and Outcome

Narayan, Sanjiv M.; Franz, Michael R.; Lalani, Gautam; Kim, Jason; Sastry, Ashwani

doi:10.1016/j.jacc.2007.10.011

Cited by 73 publications

(86 citation statements)

References 29 publications

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“…Thus, APD restitution likely does not explain alternans at this rate. This result has also been confirmed in patients with steep maximum APD restitution at short diastolic intervals (14). …”

Section: Discussionsupporting

confidence: 53%

T-Wave Alternans Testing for Ventricular Arrhythmias

Narayan¹

2008

Progress in Cardiovascular Diseases

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Section: Discussionsupporting

confidence: 53%

T-Wave Alternans Testing for Ventricular Arrhythmias

Narayan¹

2008

Progress in Cardiovascular Diseases

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“…Until the last decade, it was believed that a steep action potential duration (APD) restitution (>1) at rapid heart rates (Weiss et al, 2006) produces alternans in APD that underlie T-wave alternans and the genesis of fibrillation (Pastore et al, 1999). However, MTWA is most successful in stratifying risk in patients at near-resting heart rates < 110 bpm, where APD restitution is flat (Narayan et al, 2007). 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.…”

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

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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.

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“…Specifically, research has reported a strong correlation between increased arrhythmia risk and the presence of microvolt T-wave alternans (MTWA) [26,58]. 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].…”

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

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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.

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T-Wave Alternans, Restitution of Human Action Potential Duration, and Outcome

Abstract: The mechanism by which TWA predicts arrhythmic mortality does not reflect the maximum slope of ventricular APD restitution. Better understanding of the mechanisms underlying TWA may enable improved prediction and prevention of ventricular arrhythmias.

Cited by 73 publications

References 29 publications

T-Wave Alternans Testing for Ventricular Arrhythmias

T-Wave Alternans Testing for Ventricular Arrhythmias

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

Cardiac Arrhythmias: Mechanistic Knowledge and Innovation from Computer Models

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