Selective Aldosterone Blockades Suppress Atrial Tachyarrhythmias
Introduction: Renin-angiotensin-aldosterone system activation may be involved in the pathogenesis of atrial arrhythmias in congestive heart failure (CHF). The effects of aldosterone blockade on atrial tachyarrhythmias have not been evaluated. This study's aim was to determine whether selective aldosterone blockade suppresses atrial tachyarrhythmia inducibility and modifies atrial electrical and/or structural remodeling in a canine model of rapid ventricular pacing (RVP)-induced CHF.
Methods and Results: Dogs were assigned randomly to treatment with oral placebo or eplerenone (50 mg/day) and divided into four groups: two sham-operated (no RVP) and two RVP groups. After 5 weeks of no RVP or RVP at 230 beats/min along with concurrent placebo or eplerenone treatment, dogs underwent electrophysiologic and echocardiographic studies. Sustained atrial tachyarrhythmia inducibility (>10-minute duration), atrial effective refractory periods (ERPs), systolic and diastolic function, and left atrial and left ventricular (LV) chamber sizes were assessed. Placebo-treated RVP dogs developed CHF with LV systolic and diastolic dysfunction, left atrial and LV enlargement, increased atrial ERPs, and inducible sustained atrial tachyarrhythmias. Eplerenone treatment in RVP dogs significantly suppressed sustained atrial tachyarrhythmia inducibility, nonuniformly prolonged atrial ERPs and attenuated LV diastolic dysfunction without modifying left atrial or LV dilation or ejection fractions in CHF. Isoproterenol (2-4 μg/min) reversed eplerenone's atrial antiarrhythmic and ERP prolonging effects in CHF. Eplerenone did not alter atrial ERPs in sham (no RVP) dogs without CHF.
Conclusions: Eplerenone suppresses inducibility of sustained atrial tachyarrhythmias, selectively prolongs atrial ERPs, and attenuates LV diastolic remodeling in RVP-induced CHF. Aldosterone blockade may be a promising new approach for atrial tachyarrhythmia prevention in CHF.
Recent accumulating evidence suggests that suppression of the renin-angiotensin-aldosterone system has beneficial effects in the prevention of atrial tachyarrhythmias. This stems from clinical reports suggesting a reduction in atrial fibrillation (AF) in patients with congestive heart failure (CHF) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Similarly, data from the rapid ventricular pacing (RVP) animal model indicate that enalapril reduces duration of AF episodes induced in CHF by attenuating atrial fibrosis and heterogeneous conduction velocity slowing.
Surprisingly however, the potential antiarrhythmic benefits of aldosterone blockade (AB) for the prevention of atrial tachyarrhythmias in CHF have received little attention. Serum aldosterone levels are elevated in patients with persistent AF and decline after sinus rhythm is restored. Patients with primary hyperaldosteronism have an increased incidence of AF compared with age-, gender-, and blood pressure-matched controls with essential hypertension. Aldosterone released in CHF promotes adverse cardiac structural remodeling via cellular proliferation and myocardial and vascular fibrosis. Independent of profibrotic effects, aldosterone produces electrical remodeling with some notable similarities to electrophysiological ion channel alterations that occur during cardiac remodeling in CHF. Beneficial effects of AB have been seen in experimental models and in patients with CHF with favorable influences on remodeling, fibrosis, baroreceptor function, heart rate variability, and QT dispersion. Two recent clinical trials established that addition of AB to standard CHF neurohormonal inhibitor therapy reduces sudden death mortality in patients with severe CHF or myocardial infarction with left ventricular (LV) dysfunction. The potential mechanisms involved in antiarrhythmic benefits of AB in CHF might be related to attenuation of structural and/or electrical remodeling by antagonizing deleterious effects of aldosterone excess. Alternatively, direct actions of aldosterone receptor antagonists on ion channels independent of and unrelated to their effects at mineralocorticoid receptors also might be involved in arrhythmia prevention in CHF.
This study's objectives were to determine whether treatment with eplerenone, a selective AB, suppresses inducibility of sustained atrial tachyarrhythmias in the canine model of RVP-induced CHF and to correlate antiarrhythmic effects of eplerenone in CHF with changes in the electro-anatomic substrate. Eplerenone was selected for AB rather than spironolactone, a nonselective blocker, because spironolactone and canrenoic acid, its major metabolite, prolong atrial action potential duration (APD) and directly block K currents in normal ventricular myocytes. To our knowledge, no previous reports have shown that eplerenone directly prolongs repolarization or blocks K currents, and no active metabolites of eplerenone have been identified.
Abstract and Introduction
Abstract
Introduction: Renin-angiotensin-aldosterone system activation may be involved in the pathogenesis of atrial arrhythmias in congestive heart failure (CHF). The effects of aldosterone blockade on atrial tachyarrhythmias have not been evaluated. This study's aim was to determine whether selective aldosterone blockade suppresses atrial tachyarrhythmia inducibility and modifies atrial electrical and/or structural remodeling in a canine model of rapid ventricular pacing (RVP)-induced CHF.
Methods and Results: Dogs were assigned randomly to treatment with oral placebo or eplerenone (50 mg/day) and divided into four groups: two sham-operated (no RVP) and two RVP groups. After 5 weeks of no RVP or RVP at 230 beats/min along with concurrent placebo or eplerenone treatment, dogs underwent electrophysiologic and echocardiographic studies. Sustained atrial tachyarrhythmia inducibility (>10-minute duration), atrial effective refractory periods (ERPs), systolic and diastolic function, and left atrial and left ventricular (LV) chamber sizes were assessed. Placebo-treated RVP dogs developed CHF with LV systolic and diastolic dysfunction, left atrial and LV enlargement, increased atrial ERPs, and inducible sustained atrial tachyarrhythmias. Eplerenone treatment in RVP dogs significantly suppressed sustained atrial tachyarrhythmia inducibility, nonuniformly prolonged atrial ERPs and attenuated LV diastolic dysfunction without modifying left atrial or LV dilation or ejection fractions in CHF. Isoproterenol (2-4 μg/min) reversed eplerenone's atrial antiarrhythmic and ERP prolonging effects in CHF. Eplerenone did not alter atrial ERPs in sham (no RVP) dogs without CHF.
Conclusions: Eplerenone suppresses inducibility of sustained atrial tachyarrhythmias, selectively prolongs atrial ERPs, and attenuates LV diastolic remodeling in RVP-induced CHF. Aldosterone blockade may be a promising new approach for atrial tachyarrhythmia prevention in CHF.
Introduction
Recent accumulating evidence suggests that suppression of the renin-angiotensin-aldosterone system has beneficial effects in the prevention of atrial tachyarrhythmias. This stems from clinical reports suggesting a reduction in atrial fibrillation (AF) in patients with congestive heart failure (CHF) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Similarly, data from the rapid ventricular pacing (RVP) animal model indicate that enalapril reduces duration of AF episodes induced in CHF by attenuating atrial fibrosis and heterogeneous conduction velocity slowing.
Surprisingly however, the potential antiarrhythmic benefits of aldosterone blockade (AB) for the prevention of atrial tachyarrhythmias in CHF have received little attention. Serum aldosterone levels are elevated in patients with persistent AF and decline after sinus rhythm is restored. Patients with primary hyperaldosteronism have an increased incidence of AF compared with age-, gender-, and blood pressure-matched controls with essential hypertension. Aldosterone released in CHF promotes adverse cardiac structural remodeling via cellular proliferation and myocardial and vascular fibrosis. Independent of profibrotic effects, aldosterone produces electrical remodeling with some notable similarities to electrophysiological ion channel alterations that occur during cardiac remodeling in CHF. Beneficial effects of AB have been seen in experimental models and in patients with CHF with favorable influences on remodeling, fibrosis, baroreceptor function, heart rate variability, and QT dispersion. Two recent clinical trials established that addition of AB to standard CHF neurohormonal inhibitor therapy reduces sudden death mortality in patients with severe CHF or myocardial infarction with left ventricular (LV) dysfunction. The potential mechanisms involved in antiarrhythmic benefits of AB in CHF might be related to attenuation of structural and/or electrical remodeling by antagonizing deleterious effects of aldosterone excess. Alternatively, direct actions of aldosterone receptor antagonists on ion channels independent of and unrelated to their effects at mineralocorticoid receptors also might be involved in arrhythmia prevention in CHF.
This study's objectives were to determine whether treatment with eplerenone, a selective AB, suppresses inducibility of sustained atrial tachyarrhythmias in the canine model of RVP-induced CHF and to correlate antiarrhythmic effects of eplerenone in CHF with changes in the electro-anatomic substrate. Eplerenone was selected for AB rather than spironolactone, a nonselective blocker, because spironolactone and canrenoic acid, its major metabolite, prolong atrial action potential duration (APD) and directly block K currents in normal ventricular myocytes. To our knowledge, no previous reports have shown that eplerenone directly prolongs repolarization or blocks K currents, and no active metabolites of eplerenone have been identified.
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