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Cardiac hypertrophy, arrhythmogenicity and the new myocardial phenotype. II. The cellular adaptational process
B Swynghedauw1, B Chevalier, D Charlemagne
1U127-INSERM, Hôpital Lariboisière, Paris, France.
Insights
In left ventricular hypertrophy, cardiac hypertrophy and fibrosis independently contribute to ventricular arrhythmias. Phenotypic changes in myocytes, including altered ion currents and calcium handling, promote arrhythmogenesis.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Left ventricular hypertrophy (LVH) is associated with ventricular arrhythmias.
- Ventricular fibrosis is a known contributor to arrhythmias in LVH.
- Compensatory cardiac hypertrophy (CCH) presents a unique model to study arrhythmogenesis.
Purpose of the Study:
- To investigate the role of cardiac hypertrophy and associated myocardial phenotypic changes in ventricular arrhythmias.
- To explore the link between adaptational changes in CCH and arrhythmogenic potential.
- To identify specific ionic and cellular mechanisms contributing to arrhythmias in CCH.
Main Methods:
- Experimental model of compensatory cardiac hypertrophy (CCH) in rats.
- Analysis of action potential (AP) and QT duration.
- Assessment of calcium transient dynamics and sarcoplasmic reticulum function.
- Investigation of ionic currents (Ito, If) and membrane protein activity (Na+/Ca2+ exchanger, Na+, K+-ATPase).
- Evaluation of heart rate variability and myocardial receptor content.
Main Results:
- Cardiac hypertrophy degree is independently linked to ventricular arrhythmias in CCH.
- Increased AP and QT duration, prolonged calcium transient favor spontaneous calcium oscillations.
- Depressed Ito and induced If currents, altered sarcoplasmic reticulum Ca(2+)-ATPase and ryanodine receptors contribute to arrhythmogenesis.
- Reduced activity of Na+/Ca2+ exchanger and Na+, K+-ATPase may explain prolonged calcium transient.
- Myocardial adrenergic and muscarinic receptor content also influences arrhythmias.
Conclusions:
- Cardiac hypertrophy, beyond fibrosis, is a significant determinant of ventricular arrhythmias in CCH.
- Phenotypic modifications in myocytes, including altered ion channel function and calcium handling, have detrimental arrhythmogenic consequences.
- Adaptational changes during CCH possess a detrimental counterpart that, alongside fibrosis, promotes arrhythmias.
Abstract:
Ventricular fibrosis is not the only structural determinant of arrhythmias in left ventricular hypertrophy. In an experimental model of compensatory cardiac hypertrophy (CCH) the degree of cardiac hypertrophy is also independently linked to ventricular arrhythmias. Cardiac hypertrophy reflects the level of adaptation, and matches the adaptational modifications of the myocardial phenotype. We suggest that these modifications have detrimental aspects. The increased action potential (AP) and QT duration and the prolonged calcium transient both favour spontaneous calcium oscillations, and both are potentially arrhythmogenic and linked to phenotypic changes in membrane proteins. To date, only two ionic currents have been studied in detail: Ito is depressed (likely the main determinant in AP durations), and If, the pacemaker current, is induced in the overloaded ventricular myocytes. In rat CCH, the two components of the sarcoplasmic reticulum, namely Ca(2+)-ATPase and ryanodine receptors, are down-regulated in parallel. Nevertheless, while the inward calcium current is unchanged, the functionally linked duo composed of the Na+/Ca2+ exchanged and (Na+, K+)-ATPase, is less active. Such an imbalance may explain the prolonged calcium transient. The changes in heart rate variability provide information about the state of the autonomic nervous system and has prognostic value even in CCH. Transgenic studies have demonstrated that the myocardial adrenergic and muscarinic receptor content is also a determining factor. During CCH, several phenotypic membrane changes participate in the slowing of contraction velocity and are thus adaptational. They also have a detrimental counterpart and, together with fibrosis, favour arrhythmias.