Abstract
The role of IKCa in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of IKCa blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The IKCa blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by IKCa blockade in all of the groups studied. IKCa blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. IKCa blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, IKCa blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for IKCa in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.
Highlights
Heart failure (HF) is a chronic disease that develops over months to years, and is defined by insufficient cardiac output to meet the physiologic and metabolic needs of the body
One pacing lead was implanted in the right atria (RA) and the second lead was implanted in the right ventricular (RV), with HF induced as previously described
Electrocardiograms (ECGs) in all canines assigned to the HF+ Atrial fibrillation (AF) group demonstrated sustained atrial tachyarrhythmias, evident as the absence of P waves and the irregularly irregular ventricular rate characteristic of AF (Figure 1A)
Summary
Heart failure (HF) is a chronic disease that develops over months to years, and is defined by insufficient cardiac output to meet the physiologic and metabolic needs of the body. [1] in patients with HF, the development of AF significantly increases the risk of death. Small-conductance Ca2+- activated K+ (SK) channels are expressed in multiple tissues such as skeletal and smooth muscle, the central and peripheral nervous system and the heart.[3,4,5] Cardiac myocytes express SK1, SK2 and SK3 gene products. [6] SK- encoded current is voltage-independent and activated by intracellular calcium. IKCa, the potassium current conducted by SK channels, contributes to repolarization, [3,11] but the importance of IKCa in repolarization remains poorly elucidated. Ventricular IKCa shortens repolarization and promotes peri-infarct arrhythmias in rats. [12] blockade of IKCa promotes ventricular arrhythmias in human HF and a non-ischemic rabbit Ventricular IKCa shortens repolarization and promotes peri-infarct arrhythmias in rats. [12] blockade of IKCa promotes ventricular arrhythmias in human HF and a non-ischemic rabbit
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