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Calcium-dependent arrhythmias in transgenic mice with heart failure
Barry London1, Linda C Baker, Joon S Lee
1Cardiovascular Institute, University of Pittsburgh, Pennsylvania 15213, USA. londonb@msx.upmc.edu
Insights
Transgenic mice with tumor necrosis factor-alpha (TNF-alpha) overexpression in the heart exhibit heart failure and ventricular arrhythmias. Abnormal calcium handling and prolonged action potentials contribute to these arrhythmias, distinct from refractoriness dispersion.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Transgenic mice overexpressing tumor necrosis factor-alpha (TNF-alpha) in the heart develop heart failure.
- These mice exhibit ventricular arrhythmias and reduced survival compared to controls.
Purpose of the Study:
- To investigate the mechanisms underlying reentrant ventricular arrhythmias in TNF-alpha mice.
- To elucidate the roles of action potential duration and calcium handling in arrhythmogenesis.
Main Methods:
- Optical mapping of voltage and Ca(2+) in isolated perfused ventricles.
- Programmed electrical stimulation to induce arrhythmias.
- Measurement of action potential durations and Ca(2+) transients.
Main Results:
- TNF-alpha hearts showed prolonged action potentials and Ca(2+) transients.
- Diastolic [Ca(2+)] was elevated, and systolic [Ca(2+)] was depressed.
- Conduction velocity was slowed and heterogeneous, with diminished action potential amplitudes.
- Reducing extracellular [Ca(2+)] normalized conduction and prevented arrhythmias.
Conclusions:
- Action potential prolongation and abnormal Ca(2+) handling contribute to reentrant arrhythmias in this heart failure model.
- These mechanisms are distinct from enhanced refractoriness dispersion or triggered activity.
- Findings provide insights into the electrophysiological basis of heart failure-associated arrhythmias.
Abstract:
Transgenic mice overexpressing the inflammatory cytokine tumor necrosis factor (TNF)-alpha (TNF-alpha mice) in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias on ambulatory telemetry monitoring, and decreased survival compared with nontransgenic littermates. Programmed stimulation in vitro with single extra beats elicits reentrant ventricular arrhythmias in TNF-alpha (n = 12 of 13 hearts) but not in control hearts. We performed optical mapping of voltage and Ca(2+) in isolated perfused ventricles of TNF-alpha mice to study the mechanisms that lead to the initiation and maintenance of the arrhythmias. When compared with controls, hearts from TNF-alpha mice have prolonged of action potential durations (action potential duration at 90% repolarization: 23 +/- 2 ms, n = 7, vs. 18 +/- 1 ms, n = 5; P < 0.05), no increased dispersion of refractoriness between apex and base, elevated diastolic and depressed systolic [Ca(2+)], and prolonged Ca(2+) transients (72 +/- 6 ms, n = 10, vs. 54 +/- 5 ms, n = 8; P < 0.01). Premature beats have diminished action potential amplitudes and conduct in a slow, heterogeneous manner. Lowering extracellular [Ca(2+)] normalizes conduction and prevents inducible arrhythmias. Thus both action potential prolongation and abnormal Ca(2+) handling may contribute to the initiation of reentrant arrhythmias in this heart failure model by mechanisms distinct from enhanced dispersion of refractoriness or triggered activity.