CLINICAL RESEARCH: RHYTHM DISORDERS IN HEART FAILURE
Action Potential Dynamics Explain Arrhythmic Vulnerability in Human Heart FailureA Clinical and Modeling Study Implicating Abnormal Calcium Handling
Sanjiv M. Narayan, MD, FRCP, FACC*,*,
Jason D. Bayer, MS ,
Gautam Lalani, MD* and
Natalia A. Trayanova, PhD
* Department of Medicine and Whitaker Institute for Biomedical Engineering, University of California, San Diego, California
Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland
Manuscript received June 16, 2008;
revised manuscript received August 7, 2008,
accepted August 14, 2008.
* Reprint requests and correspondence: Dr. Sanjiv M. Narayan, University of California, San Diego, Cardiology/111A, 3350 La Jolla Village Drive, San Diego, California 92161 (Email: snarayan{at}ucsd.edu).
Objectives: The purpose of this study was to determine whether abnormalities of calcium cycling explain ventricular action potential (AP) oscillations and cause electrocardiogram T-wave alternans (TWA).
Background: Mechanisms explaining why heart failure patients are at risk for malignant ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]) are unclear. We studied whether oscillations in human ventricular AP explain TWA and predict VT/VF, and used computer modeling to suggest potential cellular mechanisms.
Methods: We studied 53 patients with left ventricular ejection fraction 28 ± 8% and 18 control subjects. Monophasic APs were recorded in the right ventricle (n = 62) and/or left ventricle (n = 9) at 109 beats/min.
Results: Alternans of AP amplitude, computed spectrally, had higher magnitude in study patients than in controls (p = 0.03), particularly in AP phase II (p = 0.02) rather than phase III (p = 0.10). The AP duration and activation restitution (n = 11 patients) were flat at 109 beats/min and did not explain TWA. In computer simulations, only reduced sarcoplasmic reticulum calcium uptake explained our results, causing calcium oscillations, AP amplitude alternans, and TWA that were all abolished by calcium clamping. On prospective follow-up for 949 ± 553 days, 17 patients had VT/VF. The AP amplitude alternans predicted VT/VF (p = 0.04), and was 78% concordant with simultaneous TWA (p = 0.003).
Conclusions: Patients with systolic dysfunction show ventricular AP amplitude alternans that prospectively predicted VT/VF. Alternans in AP amplitude, but not variations in AP duration or conduction, explained TWA at  109 beats/min. In computer models, these findings were best explained by reduced sarcoplasmic reticulum calcium uptake. Thus, in heart failure patients, in vivo AP alternans may reflect cellular calcium abnormalities and provide a mechanistic link with VT/VF.
Key Words: calcium cycling • electrical restitution • ventricular action potentials • computer modeling • conduction velocity • T-wave alternans • sudden cardiac arrest
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Abbreviations and Acronyms
| | AP = action potential | | APD = action potential duration | | APD90
= action potential duration at 90% repolarization | | AT = activation time | | [Ca]i
= intracellular calcium | | CaSR = sarcoplasmic reticulum calcium | | DI = diastolic interval | | ECG = electrocardiogram | | ICaL
= L-type calcium current | | Irel
= sarcoplasmic reticulum calcium release current | | Ito
= transient outward current | | Iup
= sarcoplasmic reticulum calcium uptake current | | LV = left ventricle/ventricular | | LVEF = left ventricular ejection fraction | | MAP = monophasic action potential | | ROC = receiver-operator characteristic | | RV = right ventricle/ventricular | | SCA = sudden cardiac arrest |  h,j
= time constants of fast and slow sodium channel gating | | TTP = Ten Tusscher-Panfilov | | TWA = T-wave alternans | | Valt = absolute voltage of alternation | | VF = ventricular fibrillation | | VT = ventricular tachycardia |
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Inside This Issue of JACC
J. Am. Coll. Cardiol. 2008 52: A36.
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