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Molecular aspects of arrhythmias associated with cardiomyopathies
1Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. gtomasel@jhmi.edu
Insights
Myocardial hypertrophy and heart failure increase sudden cardiac death risk due to cellular remodeling. Altered ion channel function, particularly potassium currents, and calcium handling in heart muscle cells contribute to dangerous heart rhythms.
Area of Science:
- Cardiology
- Molecular Cardiology
- Cardiac Electrophysiology
Background:
- Sudden cardiac death risk is elevated in myocardial hypertrophy and heart failure.
- Cellular remodeling in myocytes and the interstitium underlies this increased risk.
- Action potential prolongation is a key electrophysiological change in these conditions.
Purpose of the Study:
- To investigate the changes in membrane currents and intracellular calcium handling in hypertrophied and failing myocardium.
- To understand how these alterations contribute to the substrate for potentially lethal ventricular arrhythmias.
Main Methods:
- Analysis of differential expression and function of membrane currents and transporters.
- Assessment of potassium currents (I(to), I(K1), I(K)) and their density.
- Evaluation of intracellular calcium handling and the Na+-Ca2+ exchanger activity.
Main Results:
- Consistent downregulation of the transient outward potassium current (I(to)) was observed.
- Data on inward (I(K1)) and delayed rectifier (I(K)) currents were contradictory.
- Altered intracellular calcium handling prolongs L-type Ca current decay and favors Na+-Ca2+ exchanger activity.
Conclusions:
- Functional downregulation of K+ currents and altered Ca2+ handling create a substrate for ventricular arrhythmias.
- The interplay between altered membrane currents and neurohumoral changes increases the risk of sudden cardiac death.
Abstract:
The increased risk of sudden cardiac death in patients with myocardial hypertrophy and heart failure is the result of remodeling that occurs in both the myocyte and interstitial compartments of the heart. Action potential prolongation is a hallmark of hypertrophied and failing myocardium and is a consequence of differential expression and function of membrane currents and transporters. Functional downregulation of K currents in the ventricle is a recurring theme in hypertrophy and failure; the reduction in the density of the transient outward current (I(to)) is the most consistent observation, whereas data on the density of the inward (I(K1)) and the delayed rectifier (I(K)) currents are more contradictory. The altered intracellular Ca handling of the myopathic hearts prolongs the decay of the L-type Ca current and favors extrusion of cytosolic Ca2+ via the Na+-Ca2+ exchanger. The interaction between such altered membrane currents and a changed neurohumoral milieu creates a substrate that is highly susceptible to potentially lethal ventricular arrhythmias.