eplerenone and Arrhythmias--Cardiac

The role of the renin-angiotensin-aldosterone system (RAAS) in hypertension has since long been recognized and aldosterone has been acknowledged as one of the key hormones in the pathophysiology, not only in primary aldosteronism but also in essential hypertension and drug-resistant hypertension. Aldosterone-receptor antagonists (ARAs) are increasingly used in patients with resistant hypertension, often with impressive results. However, definitive evidence for the benefit of ARAs in these patients from randomized, controlled trials is lacking. This review gives an overview of the current data on this topic. Future studies should focus on the identification of factors that are able to predict the response to treatment, as to select patients who will benefit most from treatment with ARAs. On the basis of the current knowledge, we recommend prescription of ARAs to patients with primary aldosteronism, resistant hypertension and patients with hypertension and hypokalemia.

Topics: Albuminuria; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Drug Therapy, Combination; Electrocardiography; Eplerenone; Fibrosis; Glomerular Filtration Rate; Humans; Hypertension; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; Myocardium; Spironolactone

Topics: Arrhythmias, Cardiac; Drug Interactions; Eplerenone; Evidence-Based Medicine; Heart Failure; Humans; Hypertension; Myocardial Infarction; Patient Selection; Quality of Life; Risk Factors; Spironolactone; United States

Topics: Animals; Arrhythmias, Cardiac; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Eplerenone; Female; Fibrosis; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Mineralocorticoid receptor(MR) antagonism reduces sudden cardiac death in heart failure, but the underlying mechanism remains poorly understood. Concurrent treatment with an MR antagonist during rapid ventricular pacing (RVP) prevents development of adverse ventricular electrophysiological remodeling, interstitial fibrosis, inflammatory cytokine gene activation, and ventricular tachyarrhythmia inducibility without diminishing the extent of systolic dysfunction. We hypothesized that attenuating preexistent inflammatory pathways and myocardial fibrosis with eplerenone after systolic heart failure is established by rapid pacing can reduce electrical activation delays and arrhythmia vulnerability.. Dogs subjected to RVP for 8 weeks in the absence or presence of eplerenone treatment during the final 4 weeks of pacing were assessed by echocardiography, electrophysiology study,ventricular fibrosis measurements, and inflammatory cytokine mRNA expression analysis. Eplerenone reversed preexistent ventricular activation delays, interstitial fibrosis, inflammatory cytokine (interleukin-6, tumor necrosis factor-α) gene overexpression, and arrhythmia vulnerability in ventricular paced dogs with heart failure. Eplerenone failed to improve left ventricular systolic dysfunction or chamber enlargement. A correlation between severity of fibrosis and ventricular arrhythmia inducibility was found.. MR antagonism regresses rapid pacing-induced electrical delays, inflammatory cytokine gene activation, and fibrosis in heart failure. Ventricular arrhythmia vulnerability in heart failure is correlated with extent of fibrosis and electrical activation delays during premature excitation.

Topics: Action Potentials; Animals; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Cardiovascular Agents; Disease Models, Animal; Dogs; Eplerenone; Fibrosis; Heart Failure; Hypertrophy, Left Ventricular; Inflammation Mediators; Interleukin-6; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Spironolactone; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Myocardial fibrosis increases arrhythmia vulnerability of the diseased heart. The renin-angiotensin-aldosterone system (RAAS) governs myocardial collagen synthesis. We hypothesized that reducing cardiac fibrosis by chronic RAAS inhibition would result in reduced arrhythmia vulnerability of the senescent mouse heart. Wild-type mice (52 wk old) were treated for 36 wk: 1) untreated control (C); 2) eplerenone (E); 3) losartan (L); and 4) cotreatment with eplerenone and losartan (EL). Ventricular epicardial activation mapping was performed on Langendorff-perfused hearts. Arrhythmia inducibility was tested by one to three premature stimuli and burst pacing. Longitudinal and transverse conduction velocity and dispersion of conduction were determined during pacing at a basic cycle length of 150 ms. Sirius red staining (collagen) was performed. As a result, in the RV of mice in the E, L, and EL groups, transverse conduction velocity was significantly increased and anisotropic ratio was significantly decreased compared with those values of mice in the C group. Anisotropic reentrant arrhythmias were induced in 52% of untreated mice and significantly reduced to 22%, 26%, and 16% in the E, L, and EL groups, respectively. Interstitial fibrosis was significantly decreased in both the RV and LV of all treated groups. Scattered patches of replacement fibrosis were found in 90% of untreated hearts, which were significantly reduced in the E, L, and EL groups. A strong correlation between the abundance of patchy fibrosis and arrhythmia inducibility was found. In conclusion, chronic RAAS inhibition limited aging-related interstitial fibrosis. The lower arrhythmogeneity of treated mice was directly correlated to the reduced amount of patchy fibrosis.

Topics: Age Factors; Aging; Angiotensin II Type 1 Receptor Blockers; Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Cell Communication; Cellular Senescence; Connexin 43; Disease Models, Animal; Echocardiography, Doppler; Electrocardiography; Epicardial Mapping; Eplerenone; Female; Fibrosis; Heart Conduction System; Heart Diseases; Losartan; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Myocardium; Renin-Angiotensin System; Spironolactone; Ventricular Function, Left; Ventricular Function, Right

Topics: Arrhythmias, Cardiac; Defibrillators, Implantable; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Spironolactone; Stroke Volume