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Transmural heterogeneity of calcium handling in canine
Kenneth R Laurita1, Rodolphe Katra, Barbara Wible
1Heart and Vascular Research Center, Case Western Reserve University, 2500 MetroHealth Dr, Rammelkamp, 6th Floor, Cleveland, Ohio 44109-1998, USA. klaurita@metrohealth.org
Insights
Endocardial cells show slower intracellular calcium handling, potentially due to reduced SERCA2a expression. This heterogeneity in calcium dynamics may increase arrhythmia vulnerability near the endocardium.
Area of Science:
- Cardiovascular Physiology
- Cardiac Electrophysiology
- Molecular Cardiology
Background:
- Spatial heterogeneity of cardiac action potentials influences arrhythmia vulnerability.
- The role of intracellular calcium handling heterogeneity in cardiac electrophysiology is less understood.
Purpose of the Study:
- To investigate the transmural heterogeneity of intracellular calcium handling in the canine left ventricle.
- To determine the impact of this heterogeneity on the electrophysiological substrate and arrhythmia vulnerability.
Main Methods:
- Simultaneous optical mapping of calcium transients and action potentials in a canine left ventricular wedge preparation.
- Analysis of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and Na+-Ca2+ exchanger expression across the ventricular wall.
Main Results:
- Endocardial cells exhibited slower intracellular calcium decay and longer calcium transient duration compared to epicardial cells during baseline pacing.
- Reduced SERCA2a expression was observed in subendocardial and midmyocardial layers.
- Calcium transient alternans and elevated diastolic intracellular calcium were significantly greater in endocardial regions during rapid pacing.
Conclusions:
- Endocardial cells display distinct intracellular calcium handling properties, characterized by slower calcium reuptake.
- Reduced SERCA2a expression likely contributes to this endocardial calcium handling heterogeneity.
- This transmural gradient in calcium dynamics may represent a pro-arrhythmic substrate, particularly in the subendocardium.
Abstract:
Spatial heterogeneity of the action potential and its influence on arrhythmia vulnerability is known. However, heterogeneity of intracellular calcium handling and, in particular, its effect on the electrophysiological substrate is less clear. Using optical mapping techniques, calcium transients and action potentials were recorded simultaneously from ventricular sites across the transmural wall of the arterially perfused canine left ventricular wedge preparation during steady-state baseline pacing and rapid pacing. During baseline pacing, the decay of intracellular calcium to diastolic levels and calcium transient duration were slower (70%, P<0.005) and longer (20%, P<0.005), respectively, closer to the endocardial surface compared with the epicardial surface. Tissue samples isolated from the left ventricular wall demonstrate that sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) expression was significantly less in the subendocardial and midmyocardial layers compared with the subepicardial layer. In contrast, no significant difference in the transmural expression of Na+-Ca2+ exchanger was observed. During rapid pacing, calcium transient alternans and increased levels of diastolic intracellular calcium were significantly greater (P<0.01) closer to the endocardium (101%+/-62% and 41%+/-15%, respectively) compared with the epicardium (12%+/-7% and 12%+/-14%, respectively). In conclusion, cells closer to the endocardium exhibit a slower decay of intracellular calcium compared with cells near the epicardium, which may be due in part to reduced expression of SERCA2a. As a possible consequence, calcium transient alternans and increased diastolic levels of intracellular calcium may occur preferentially closer to the endocardial surface.