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Action potential dynamics explain arrhythmic vulnerability in human heart failure: a clinical and modeling study
Sanjiv M Narayan1, Jason D Bayer, Gautam Lalani
1Department of Medicine and Whitaker Institute for Biomedical Engineering, University of California, San Diego, California 92161, USA. snarayan@ucsd.edu
Journal of the American College of Cardiology
|November 22, 2008
Summary
In heart failure patients, abnormal calcium cycling causes ventricular action potential alternans, leading to T-wave alternans and predicting dangerous arrhythmias like ventricular tachycardia/fibrillation.
Area of Science:
- Cardiology
- Electrophysiology
- Computational Biology
Background:
- Heart failure patients face increased risk of malignant ventricular arrhythmias (ventricular tachycardia/fibrillation).
- The underlying mechanisms linking heart failure to these arrhythmias remain unclear.
- This study investigates action potential alternans and T-wave alternans as potential indicators.
Purpose of the Study:
- To determine if calcium cycling abnormalities explain ventricular action potential (AP) oscillations.
- To ascertain if these oscillations cause electrocardiogram T-wave alternans (TWA).
- To explore the predictive value of AP alternans for ventricular tachycardia/fibrillation.
Main Methods:
- Recorded monophasic action potentials in 53 heart failure patients and 18 controls.
- Analyzed action potential alternans magnitude, particularly in phases II and III.
- Utilized computer simulations to model cellular mechanisms and employed prospective follow-up for arrhythmia events.
Main Results:
- Patients with systolic dysfunction exhibited significantly higher AP amplitude alternans compared to controls.
- Reduced sarcoplasmic reticulum calcium uptake in simulations directly led to calcium oscillations, AP alternans, and TWA.
- AP amplitude alternans prospectively predicted ventricular tachycardia/fibrillation and showed high concordance with TWA.
Conclusions:
- Ventricular AP amplitude alternans, observed in systolic dysfunction, prospectively predict ventricular tachycardia/fibrillation.
- Alternans in AP amplitude, not duration or conduction, explain TWA at heart rates <=109 beats/min.
- Reduced sarcoplasmic reticulum calcium uptake is implicated as the cellular mechanism, linking calcium abnormalities to arrhythmias in heart failure.
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