eplerenone and Atrial-Fibrillation

Aldosterone has been implicated in atrial remodelling representing a potential target for upstream therapies. Accumulating evidence suggests that mineralocorticoid receptor blockade may have favourable effects on atrial fibrillation (AF) development, although some controversial results have been published. We, therefore, conducted a meta-analysis of randomized clinical trials (RCTs) and observational studies in order to examine the protective role of mineralocorticoid receptor antagonists (MRAs) on AF.. Of the 1337 initially identified records, 3 RCTs and 2 observational studies with 3640 patients were finally analysed. The pooled analysis of the included studies demonstrated that patients treated with MRAs have 31% lower risk of AF compared with controls [relative ratio (RR): 0.69; 95% confidence interval (CI): 0.58-0.83] without any heterogeneity across the studies (I(2) = 0%). This effect was consistent across RCTs (RR: 0.72; 95% CI: 0.55-0.94) and observational studies (RR: 0.67; 95% CI: 0.53-0.84) without heterogeneity. Also, MRAs reduce the risk of AF in both heart failure (HF) (RR: 0.63; 95% CI: 0.50-0.80) and after cardiac surgery (RR: 0.77; 95% CI: 0.61-0.98). Analysing the relative impact of eplerenone and spironolactone, we showed that only eplerenone significantly reduces AF burden (RR: 0.64; 95% CI: 0.44-0.90).. Our meta-analysis suggests that MRAs may be effective in AF prevention especially in the HF setting. However, there are insufficient data for the widespread use of aldosterone antagonists solely for AF prevention. Larger RCTs with long-term follow-up in different clinical settings are needed to clarify the impact of MRAs on AF.

Topics: Aldosterone; Atrial Fibrillation; Cardiac Surgical Procedures; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Spironolactone

Upstream therapy is the promising issue in the treatment of atrial fibrillation (AF) especially in patients with arterial hypertension and heart failure. The possible beneficial effects of renin-angiotensin-aldosterone system blockade with ACE-inhibitors and angiotensin receptor antagonists in AF prevention have been demonstrated in experimental and clinical studies. There is growing mass of evidence, from both theoretical and experimental research studies, to suggest that upstream therapy using spironolactone or eplerenone may reduce the deleterious effect of excess aldosterone secretion and further modify the environment of AF including inhibition of atrial muscle fibrosis. It refers to patients with different forms of AF, including chronic AF. Aldosterone antagonists treatment may be a simple and valuable additional option in low-risk, hypertensive and heart failure patients in primary and secondary prevention of refractory paroxysmal and persistent AF.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone

Eplerenone is reported to reduce the development of atrial fibrillation (AF). The aim of this study was to clarify the mechanism of eplerenone for AF prevention from the viewpoint of P wave morphology, which is reported to correlate with atrial fibrosis.. Thirty-five patients with hypertension, who were randomized to receive eplerenone (n = 16) or amlodipine (n = 19) for 1 year, were evaluated. P wave signal-averaged electrocardiography was recorded at baseline and 1 year after entry, and P wave duration (Ad) and P wave dispersion (P-disp) were obtained. Serum levels of intact procollagen type I N-terminal propeptide (PINP) and N-terminal procollagen-III peptide (PIIIP) were also measured.. There were no significant differences in baseline clinical characteristics including Ad, P-disp, and the decrease in blood pressure at 1-year follow-up between the two groups. Ad and P-disp (mean ± standard deviation) significantly increased in patients on amlodipine after 1 year (140 ± 21 ms to 139 ± 19 ms vs 132 ± 10 ms to 136 ± 12 ms, P < 0.01 and 14 ± 7 ms to 9 ± 4 ms vs 12 ± 5 to 16 ± 8, P < 0.01, respectively). PINP was significantly more decreased in patients with eplerenone than amlodipine (56.6 ± 30.4 μg/mL to 46.6 ± 19.4 μg/mL vs 41.5 ± 16.2 μg/L to 48.7 ± 21.3 μg/L, P < 0.01). Percent changes of Ad, P-disp, PINP, and PIIIP were significantly smaller in patients with eplerenone than amlodipine (0.0 ± 4.7% vs 3.2 ± 4.4%, P < 0.05, - 28.6 ± 31.0% vs 46.3 ± 73.0%, P < 0.01, - 5.6 ± 38.1% vs 22.7 ± 42.7%, P < 0.05, and - 9.2 ± 25.1% vs 7.4 ± 19.0%, P < 0.05, respectively).. Eplerenone reduced the increase of Ad and P-disp with a decrease of PINP and PIIIP, which might translate into reduction of atrial fibrosis. This study showed that eplerenone may be useful as upstream therapy for AF in patients with hypertension.

Topics: Aged; Atrial Fibrillation; Electrocardiography; Eplerenone; Female; Fibrosis; Heart Atria; Humans; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Spironolactone

The purpose of this study was to analyze the incidence of new atrial fibrillation or flutter (AFF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) database.. Aldosterone antagonism in heart failure might influence atrial fibrosis and remodeling and, therefore, risk of developing AFF. The development of new AFF was a pre-specified secondary endpoint in the EMPHASIS-HF study.. Patients in New York Heart Association functional class II and with ejection fraction ≤35% were eligible for EMPHASIS-HF. History of AFF at baseline was reported by investigators using the study case report form. New onset AFF (in those with no history of AFF at baseline) was reported using a specific endpoint form; in a sensitivity analysis we also examined the effect of eplerenone on AFF reported as an adverse event.. New onset AFF was significantly reduced by eplerenone: 25 of 911 (2.7%) versus 40 of 883 (4.5%) in the placebo group (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.35 to 0.96; p = 0.034). The reduction in the primary endpoint with eplerenone was similar among patients with and without AFF at baseline (HR: 0.60, 95% CI: 0.46 to 0.79 vs. HR: 0.70, 95% CI: 0.57 to 0.85, respectively; p for interaction = 0.41). The risk of cardiovascular (CV) death or hospital admission for worsening heart failure, the primary endpoint, was not significantly different in subjects with and without AFF at baseline (both study groups combined: HR: 1.23, 95% CI: 0.81 to 1.86; p = 0.33).. In patients with systolic heart failure and mild symptoms, eplerenone reduced the incidence of new onset AFF. The effects of eplerenone on the reduction of major CV events were similar in patients with and without AFF at baseline.

Topics: Aged; Atrial Fibrillation; Disease Progression; Dose-Response Relationship, Drug; Electrocardiography; Eplerenone; Female; Heart Failure, Systolic; Heart Rate; Hospitalization; Humans; Incidence; Male; Mineralocorticoid Receptor Antagonists; Prognosis; Spironolactone; Survival Rate; United States

Topics: Adenosine; Angioplasty, Balloon, Coronary; Anti-Arrhythmia Agents; Antihypertensive Agents; Atherectomy, Coronary; Atrial Fibrillation; Azithromycin; Chlamydophila Infections; Coronary Disease; Defibrillators, Implantable; Double-Blind Method; Eplerenone; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy, Left Ventricular; Myocardial Reperfusion; Pyridines; Radiology, Interventional; Spironolactone; Stents; Thiazepines; Thrombolytic Therapy

Atrial fibrillation (AF) is the most common progressive cardiac arrhythmia and is often associated with rapid contraction in both atria and ventricles. The role of atrial energy and metabolic homeostasis in AF progression is under-investigated.. To determine the remodeling of energy metabolism during persistent AF and the effect of eplerenone (EPL), an aldosterone inhibitor, on metabolic homeostasis.. A nonsustained atrial pacing sheep model was developed to simulate the progression of AF from paroxysmal to persistent. Metabolomic and proteomic analyses at termination of the experiment were used to analyze atrial tissues obtained from sheep in sham, sugar pill (SP) and EPL-treated groups.. Proteomic analysis indicated that compared to the sham group, in SP group, fatty acid (FA) synthesis, FA oxidation, tricarboxylic acid (TCA) cycle processes and amino acids (AAs) transport and metabolism were reduced, while glycolytic processes were increased. In metabolomic analysis, the levels of intermediate metabolites of the glycolytic pathways, including 2-phosphoglyceric acid (2 PG), 1,3-bisphosphoglyceric acid (1,3 PG), and pyruvate, HBP (uridine diphosphate-N-acetylglucosamine, UDP-GlcNAc), TCA (citrate) and AAs were greater while the levels of the majority of lipid classes, including phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), glycerophosphoglycerophosphates (PGP), glycerophosphoinositols (PI) and glycerophosphoserines (PS), were decreased in the atria of SP group than in those of sham group. EPL-pretreatment decreased the expression of glut4 and increased the content of acylcarnitines and lipids, such as lyso phospholipids, phospholipids and neutral lipids.. In the metabolic remodeling during AF, glucose and lipid metabolism were up- and down-regulated, respectively, to sustain TCA cycle anaplerosis. EPL partialy reversed the metabolic shifting.

Topics: Animals; Atrial Fibrillation; Citric Acid Cycle; Disease Models, Animal; Energy Metabolism; Eplerenone; Glucose; Homeostasis; Lipid Metabolism; Male; Metabolic Networks and Pathways; Mineralocorticoid Receptor Antagonists; Myocardium; Sheep

Topics: Atrial Fibrillation; Atrial Remodeling; Eplerenone; Heart Atria; Humans; Spironolactone

The aldosterone inhibitor eplerenone (EPL) has been shown to reduce the incidence of atrial fibrillation (AF) in patients with systolic heart failure, but the mechanism is unknown.. This study hypothesized that by reducing atrial dilation and fibrosis in the absence of heart failure, EPL also reduces AF burden and prevents AF perpetuation.. The authors conducted a randomized controlled study in 34 sheep that were atrially tachypaced (13 ± 1 week). They compared daily oral EPL (n = 19) versus sugar pill (SP) treatment (n = 15) from the start of tachypacing. The endpoint was a continuous 7-day stretch of persistent AF (n = 29) or completion of 23 weeks tachypacing (n = 5).. EPL significantly reduced the rate of left atrial dilation increase during AF progression. Atria from EPL-treated sheep had less smooth muscle actin protein, collagen-III expression, interstitial atrial fibrosis, and cell hypertrophy than SP-treated sheep atria did. However, EPL did not modify the AF-induced increase in the rate of dominant frequency and ion channel densities seen under SP treatment, but rather prolonged the time to persistent AF in 26% of animals. It also reduced the degree of fibrillatory conduction, AF inducibility, and AF burden.. In the sheep model, EPL mitigates fibrosis and atrial dilation, modifies AF inducibility and AF complexity, and prolongs the transition to persistent AF in 26% of animals, but it does not prevent AF-induced electrical remodeling or AF persistence. The results highlight structural remodeling as a central upstream target to reduce AF burden, and the need to prevent electrical remodeling to avert AF perpetuation.

Topics: Animals; Atrial Fibrillation; Atrial Remodeling; Cardiac Pacing, Artificial; Eplerenone; Fibrosis; Male; Mineralocorticoid Receptor Antagonists; Sheep; Spironolactone

Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery. There exist consistent experimental and clinical data suggesting that aldosterone antagonists (AAs) may exert beneficial effects regarding electrical and structural remodeling in failing myocardium. Recently, eplerenone (EPL) has been found to reduce the incidence of nonsurgical AF when added to guideline-recommended therapy in patients with systolic heart failure. Based on these findings, we primarily aimed to evaluate by retrospective analysis the impact of the two AAs, EPL and spironolactone (SPL), given at standard therapeutic doses in preventing new-onset POAF in patients the majority of which had a preoperative ejection fraction (EF) below 40%. A total of 332 patients (298 men/34 women, mean age 64.3 ± 9 years) without history of AF were included in this analysis; 132 of these patients received long-term EPL or SPL in addition to beta-blockade/statins therapy and 200 patients received neither EPL nor SPL. All patients underwent on-pump coronary artery bypass graft (80%) and/or valvular surgery (20%). In the nonAA group (EF = 35.8 ± 6%) 90/200 patients (45%) had POAF, while in the AA group (EF = 36.2 ± 5%) only 40/132 patients (30.3%) developed POAF (P < 0.01, χ (2) test). Multivariate logistic regression analysis revealed that only AAs and left atrial diameter significantly affected the development of POAF even when adjusted for other clinical variables (P < 0.05). In conclusion, AAs significantly reduced the incidence of POAF when added to standard heart failure therapy in patients undergoing on-pump cardiac surgery.

Topics: Aged; Atrial Fibrillation; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Chi-Square Distribution; Coronary Artery Bypass; Eplerenone; Female; Greece; Heart Failure, Systolic; Heart Valves; Humans; Incidence; Logistic Models; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Multivariate Analysis; Odds Ratio; Retrospective Studies; Risk Factors; Spironolactone; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left

Several studies have demonstrated a relation between the rennin-angiotensin-aldosterone system and atrial fibrillation (AF), but there are no reports on the effect of eplerenone, a selective aldosterone blocker, on the prevention of AF recurrence after radiofrequency catheter ablation (RFCA). The aim of this study was to evaluate the effects of eplerenone on clinical outcomes after RFCA in patients with long-standing persistent AF. A total of 161 consecutive patients with long-standing persistent AF (sustained AF duration 1 to 20 years, mean 3.4 ± 3.8) who underwent RFCA were investigated. Eplerenone was used in 55 patients and not used in the remaining 106 patients. Other conventional pharmacologic agents, including angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers, were used equally in the 2 groups. After 24 months of follow-up, 47% of the patients were free from AF recurrence. The rate of freedom from AF recurrence was significantly greater in the eplerenone group (60%) than in the noneplerenone group (40%) (p = 0.011). By univariate analysis, the duration of sustained AF (p <0.001), left atrial diameter (p = 0.010), left atrial volume index (p = 0.017), and early AF recurrence (p <0.001) were significantly associated with AF recurrence, and the use of eplerenone was associated with maintenance of sinus rhythm after RFCA (p = 0.022). Multivariate Cox regression analysis showed that longer duration of sustained AF (>3 years) (p <0.001) and early AF recurrence (p <0.001) were significantly associated with AF recurrence, and only eplerenone therapy significantly improved maintenance of sinus rhythm (p = 0.017). In conclusion, eplerenone significantly improved maintenance of sinus rhythm after RFCA in patients with long-standing persistent AF.

Topics: Atrial Fibrillation; Biomarkers; Catheter Ablation; Chi-Square Distribution; Combined Modality Therapy; Electrocardiography, Ambulatory; Eplerenone; Female; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Proportional Hazards Models; Retrospective Studies; Risk Factors; Spironolactone; Treatment Outcome

Topics: Antihypertensive Agents; Aortic Valve Stenosis; Asymptomatic Diseases; Atrial Fibrillation; Eplerenone; Heart Ventricles; Humans; Hypertension; Spironolactone

Topics: Antihypertensive Agents; Aortic Valve Stenosis; Asymptomatic Diseases; Atrial Fibrillation; Eplerenone; Humans; Hypertension; Spironolactone

Hypertension is well known to increase atrial fibrillation (AF) and the development of AF is associated with atrial chamber remodeling. Although mineralocorticoid receptor (MR) inhibition provides cardiovascular protection, the role of MR on atrial structural remodeling and inducibility of AF in hypertension remains unclear. Here, we investigated roles of the MR on atrial structural remodeling and inducibility of AF in hypertensive rats by using MR antagonist eplerenone (EPL). Dahl salt-sensitive (DS) rats were fed a normal-salt or a high-salt (HS) diet from 7 weeks, and a non-antihypertensive dose of EPL or vehicle was administrated from 13 weeks, at which time myocytes hypertrophy, interstitial fibrosis in the atrium and AF inducibility had increased, until 20 weeks. There was no significant difference in systolic blood pressure between DS+HS (186 ± 4 mm Hg) and DS+HS+EPL (184 ± 5 mm Hg) at 20 weeks. Burst atrial pacing demonstrated decreased AF inducibility in DS+HS+EPL (0 of 10) compared with DS+HS (7 of 10). Fibrosis and myocytes hypertrophy in the atrium were decreased in DS+HS+EPL with the reduction of atrial inflammatory cytokines. These beneficial effects of EPL were associated with less atrial oxidative stress, as assessed by 4-hydroxy-2-nonenal staining, and reduced activation of the Rho GTPase Rac1 in the atrium. Thus, MR has important roles in atrial structural remodeling and AF inducibility in Dahl rats. The effects of MR are associated, at least in part, with activation of Rac1-oxidative stress/inflammatory axis.

Topics: Animals; Atrial Fibrillation; Cardiomegaly; Eplerenone; Fibrosis; Heart Atria; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Oxidative Stress; rac1 GTP-Binding Protein; Rats; Rats, Inbred Dahl; Receptors, Mineralocorticoid; Sodium Chloride, Dietary; Spironolactone

Topics: Antihypertensive Agents; Atrial Fibrillation; Diuretics; Eplerenone; Humans; Hypertension; Spironolactone; Sulfonamides; Torsemide

Recent research provided important insights into the development of atrial fibrillation (AF)-maintaining substrate and suggested targeting of the underlying molecular mechanisms, 'upstream' of the electrical aspects of AF, as a novel strategy for AF treatment ('upstream' therapy). Upstream therapies for AF include drugs targeting the renin-angiotensin II-aldosterone system (angiotensin converting enzyme inhibitors and AT(1) receptor antagonists and aldosterone antagonists), statins, steroids and omega-3 fatty acids (fish oil). Aldosterone causes volume retention, cardiac hypertrophy and fibrosis, and systemic inflammation and coagulation that promote AF development and its complications and blockade of aldosterone receptors with spironolactone or eplerenone suppresses inducible AF. Although the clinical impact of spironolactone treatment requires validation in randomized clinical trials in AF patients, further understanding of the molecular mechanisms by which aldosterone causes atrial remodelling is likely to lead to development of novel therapeutic approaches to AF.

Topics: Atrial Fibrillation; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Spironolactone

Over the past years, the importance of the renin-angiotensin-aldosterone system in atrial fibrillation (AF) pathophysiology has been recognised. Lately, the role of aldosterone in AF pathophysiology and mineralocorticoid receptor (MR) antagonism in "upstream" AF treatment is discussed. Hypothesising that selective MR antagonism might also influence atrial ion currents (L-type calcium current [I (Ca,L)], transient outward potassium current [I (to)], sustained outward potassium current [I (sus)]) and their tachycardia-induced remodelling, the effects of an eplerenone treatment were studied in a rabbit model. Six groups each with four animals were built. Animals of the control group received atrial pacing leads, but in contrast to the pacing groups, no atrial tachypacing (600 per minute for 24 and 120 h immediately before heart removal) was applied. Animals of the eplerenone groups were instrumented/paced as the corresponding control/pacing groups, but were additionally treated with eplerenone (7 days before heart removal). Atrial tachypacing was associated with a reduction of I (Ca,L). I (to) was decreased after 24 h of tachypacing, but returned to control values after 120 h. In the absence of rapid atrial pacing, MR antagonism reduced I (Ca,L) to a similar extent as 120 h of tachypacing alone. Based on this lower "take-off level", I (Ca,L) was not further decreased by high-rate pacing. I (to) and its expected tachycardia-induced alterations were not influenced by MR antagonism. In our experiments, selective MR antagonism influenced atrial I (Ca,L) and its tachycardia-induced alterations. As changes of I (Ca,L) are closely linked with atrial calcium signalling, the relevance of these alterations in AF pathophysiology and, accordingly, AF treatment is likely and has to be further evaluated.

Topics: Animals; Atrial Fibrillation; Calcium Channels, L-Type; Cardiac Pacing, Artificial; Disease Models, Animal; Electric Conductivity; Eplerenone; Female; Heart Atria; Heart Conduction System; Ion Channel Gating; Mineralocorticoid Receptor Antagonists; Potassium Channels; Rabbits; Spironolactone; Tachycardia

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Atrial Fibrillation; Black People; Eplerenone; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone