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Cardiac K[sub.v]4.3 channels contribute to the transient outward K[sup.+] current, I[sub.to], during early repolarization of the cardiac action potential. Two different isoforms of K[sub.v]4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both K[sub.v]4.3 isoforms to explore their potential for isoform-specific therapy. K[sub.v]4.3 isoforms were expressed in Xenopus laevis oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two K[sub.v]4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked K[sub.v]4.3 L by 77 ± 2% and K[sub.v]4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (K[sub.v]4.3 L) and 35 ± 4% (K[sub.v]4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K[sub.v]4.3 protein expression. Carvedilol inhibited K[sub.v]4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K[sub.v]4.3. Blockade of repolarizing K[sub.v]4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.

Trials of β blockers in patients undergoing non-cardiac surgery have reported conflicting results. This randomised controlled trial, done in 190 hospitals in 23 countries, was designed to investigate the effects of perioperative β blockers. We randomly assigned 8351 patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery to receive extended-release metoprolol succinate (n=4174) or placebo (n=4177), by a computerised randomisation phone service. Study treatment was started 2–4 h before surgery and continued for 30 days. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal cardiac arrest. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00182039. All 8351 patients were included in analyses; 8331 (99·8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group reached the primary endpoint (244 [5·8%] patients in the metoprolol group vs 290 [6·9%] in the placebo group; hazard ratio 0·84, 95% CI 0·70–0·99; p=0·0399). Fewer patients in the metoprolol group than in the placebo group had a myocardial infarction (176 [4·2%] vs 239 [5·7%] patients; 0·73, 0·60–0·89; p=0·0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3·1%] vs 97 [2·3%] patients; 1·33, 1·03–1·74; p=0·0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1·0%] vs 19 [0·5%] patients; 2·17, 1·26–3·74; p=0·0053). Our results highlight the risk in assuming a perioperative β-blocker regimen has benefit without substantial harm, and the importance and need for large randomised trials in the perioperative setting. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol. Canadian Institutes of Health Research; Commonwealth Government of Australia's National Health and Medical Research Council; Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo), Spain; British Heart Foundation; AstraZeneca.

Hospitalized patients with acute myocardial infarction and preserved EF were assigned to receive open-label long-term beta-blocker therapy or not. Beta-blockers did not lead to a lower risk of death or MI.

Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV ) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Background Guidelines recognized dual combination in initial antihypertensive therapy. Studies found that low-dose quadruple combination were superior to monotherapy. However, whether low-dose quadruple therapy is better than dual combination is unknown. Methods A randomized blinded crossover trial was conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23.75 mg + amlodipine 2.5 mg + indapamide 1.25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg), both in a single pill, in the initial treatment of patients with mild to moderate hypertension. Patients were randomly assigned in a 1:1 ratio to two crossover sequences. Each sequence received four-weeks of either half-dose quadruple antihypertensives or standard-dose dual antihypertensives, followed by a two-week washout and crossover for four-weeks. Participants and researchers were blinded. The main outcomes were the reduction of blood pressure and safety outcomes. Analyses were per intention to treat. Results A total of 90 eligible participants were randomized between July 13, 2022, and April 20, 2023. The mean age was 43.88 years (SD 10.31), and 25.6% were women. The mean baseline 24-h blood pressure was 145.59/93.84 mm Hg. Compared to the standard-dose dual treatment, the half-dose quadruple treatment resulted in a further reduction in mean 24-h blood pressure by 4.72/4.17 mm Hg ( P  < 0.001 for both systolic and diastolic blood pressure), mean daytime blood pressure by 5.52/4.73 mm Hg ( P  < 0.001 for both), mean nighttime blood pressure by 2.37/2.25 mm Hg ( P  = 0.034 and 0.014, respectively), and mean office blood pressure by 2.91/1.73 mm Hg ( P  < 0.001 and 0.014, respectively). Apart from significant increases of fasting blood glucose ( P  = 0.029) and blood uric acid ( P  < 0.001) in the half-dose quadruple group, no other adverse events or changes in laboratory values differed significantly between the two treatments. Conclusions Initiating treatment with half-dose quadruple combination therapy was more effective in lowering blood pressure than standard-dose dual therapy. The safety of half-dose quadruple therapy was comparable. Trial registration ClinicalTrials.gov Identifier: NCT05377203.

This study evaluated the effects of allisartan isoproxil combined with amlodipine besylate tablets (Group A+C) or metoprolol succinate extended‐release tablets (Group A+B) on sexual function and nighttime blood pressure (nBP) in 130 male patients with essential hypertension (EH). Patients were randomized to two groups. After 6‐month, the IIEF‐15 total score (ITS) of sexual function significantly improved in Group A+C (p = 0.015), including intercourse satisfaction (IS) (p = 0.003), orgasmic function (OF) (p = 0.021), and overall satisfaction (OS) (p = 0.019), while erectile function (EF) (p = 0.081) and sexual desire (SD) (p = 0.08) were unchanged. In contrast, the ITS was decreased (p = 0.008), including EF (p = 0.005), IS (p = 0.048), SD (p = 0.003), and OS (p = 0.010), but OF remained unchanged (p = 0.076) in Group A+B. Between‐group comparisons confirmed significant differences across IIEF‐15 domains (all p < 0.05). Compared to baseline, office systolic BP (OSBP), office diastolic BP (ODBP), nighttime average SBP (nSBP), and nighttime average DBP (nDBP) were significantly reduced at 6 months in two groups (all p < 0.05). Although nSBP fall (nSBPF) (p = 0.010) and nDBP fall (nDBPF) (p = 0.002) significantly increased in Group A+C. In Group A+C, the nighttime‐daytime BP fall ratio of SBP was 1.04 (0.45, 1.70) and that of DBP was 1.13 (0.38, 1.44) after treatment, with a median value > 1, indicating that nBP fall after treatment was greater than dBP fall. Compared to Group A+B, ODBP (difference = −4.00 mmHg, 95% CI [−7.64, −0.36], p = 0.032), daytime average DBP (difference = −5.47 mmHg, 95% CI [−10.05, −0.79], p = 0.023) and 24‐h average DBP (difference = −5.77 mmHg, 95% CI [−10.31, −1.24], p = 0.014) decreased more significantly in Group A+C, nDBPF increased significantly (difference = 4.99 mmHg, 95% CI [0.04, 9.93], p = 0.048), and the decrease in the nighttime‐daytime BP fall ratio of SBP and DBP was higher (p < 0.05). It was concluded that combined antihypertension of allisartan isoproxil with amlodipine besylate tablets improved sexual function in male hypertensive patients in terms of the ITS, IS, OF, and OS, but there was no significant improvement in EF and SD. Both combined antihypertensive regimens were effective in lowering BP, but allisartan isoproxil combined with amlodipine besylate tablets demonstrated more advantageous in lowering DBP and nBP.

β blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II–IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0·35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. The mean study duration was 58 months (SD 6). The mean ejection fraction was 0·26 (0·07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0·83 [95% CI 0·74–0–93], p=0–0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0·94 [0·86–1–02], p=0·122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. Our results suggest that carvedilol extends survival compared with metoprolol.

Beta-blockers have been the initial treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM) despite limited evidence of their efficacy. Aficamten is a cardiac myosin inhibitor that reduces left ventricular outflow tract gradients, improves exercise capacity, and decreases HCM symptoms when added to standard medications. Whether aficamten as monotherapy provides greater clinical benefit than beta-blockers as monotherapy remains unknown. We conducted an international, double-blind, double-dummy trial in which adults with symptomatic obstructive HCM were randomly assigned in a 1:1 ratio to receive aficamten (at a daily dose of 5 mg to 20 mg) plus placebo or metoprolol (at a daily dose of 50 mg to 200 mg) plus placebo. The primary end point was the change in peak oxygen uptake at week 24; secondary end points were improvement at week 24 in New York Heart Association (NYHA) functional class and changes at week 24 in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient after the Valsalva maneuver, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, left atrial volume index, and left ventricular mass index. A total of 88 patients were assigned to the aficamten group and 87 to the metoprolol group. The mean age of the patients was 58 years, 58.3% were men, and the mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. At 24 weeks, the change in the peak oxygen uptake was 1.1 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.5 to 1.7) in the aficamten group and -1.2 ml per kilogram per minute (95% CI, -1.7 to -0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; P<0.001). Patients who received aficamten had significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index than patients who received metoprolol. No significant difference in left ventricular mass index was observed. Adverse events appeared to be similar in the two treatment groups. Among patients with symptomatic obstructive HCM, aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics and decreasing symptoms. (Funded by Cytokinetics; MAPLE-HCM ClinicalTrials.gov number, NCT05767346.).

Background We aimed to evaluate the effect of early intravenous metoprolol treatment, microvascular obstruction (MVO), intramyocardial hemorrhage (IMH) and adverse left ventricular (LV) remodeling on the evolution of infarct and remote zone circumferential strain after acute anterior ST-segment elevation myocardial infarction (STEMI) with feature-tracking cardiovascular magnetic resonance (CMR). Methods A total of 191 patients with acute anterior STEMI enrolled in the METOCARD-CNIC randomized clinical trial were evaluated. LV infarct zone and remote zone circumferential strain were measured with feature-tracking CMR at 1 week and 6 months after STEMI. Results In the overall population, the infarct zone circumferential strain significantly improved from 1 week to 6 months after STEMI (− 8.6 ± 9.0% to − 14.5 ± 8.0%; P  < 0.001), while no changes in the remote zone strain were observed (− 19.5 ± 5.9% to − 19.2 ± 3.9%; P  = 0.466). Patients who received early intravenous metoprolol had significantly more preserved infarct zone circumferential strain compared to the controls at 1 week ( P  = 0.038) and at 6 months ( P  = 0.033) after STEMI, while no differences in remote zone strain were observed. The infarct zone circumferential strain was significantly impaired in patients with MVO and IMH compared to those without ( P  < 0.001 at 1 week and 6 months), however it improved between both time points regardless of the presence of MVO or IMH ( P  < 0.001). In patients who developed adverse LV remodeling (defined as ≥ 20% increase in LV end-diastolic volume) remote zone circumferential strain worsened between 1 week and 6 months after STEMI ( P  = 0.036), while in the absence of adverse LV remodeling no significant changes in remote zone strain were observed. Conclusions Regional LV circumferential strain with feature-tracking CMR allowed comprehensive evaluation of the sequelae of an acute STEMI treated with primary percutaneous coronary intervention and demonstrated long-lasting cardioprotective effects of early intravenous metoprolol. Trial registration ClinicalTrials.gov, NCT01311700 . Registered 8 March 2011 - Retrospectively registered.

Despite previous randomised trials of early β-blocker therapy in the emergency treatment of myocardial infarction (MI), uncertainty has persisted about the value of adding it to current standard interventions (eg, aspirin and fibrinolytic therapy), and the balance of potential benefits and hazards is still unclear in high-risk patients. 45 852 patients admitted to 1250 hospitals within 24 h of suspected acute MI onset were randomly allocated metoprolol (up to 15 mg intravenous then 200 mg oral daily; n=22 929) or matching placebo (n=22 923). 93% had ST-segment elevation or bundle branch block, and 7% had ST-segment depression. Treatment was to continue until discharge or up to 4 weeks in hospital (mean 15 days in survivors) and 89% completed it. The two prespecified co-primary outcomes were: (1) composite of death, reinfarction, or cardiac arrest; and (2) death from any cause during the scheduled treatment period. Comparisons were by intention to treat, and used the log-rank method. This study is registered with ClinicalTrials.gov, number NCT 00222573. Neither of the co-primary outcomes was significantly reduced by allocation to metoprolol. For death, reinfarction, or cardiac arrest, 2166 (9·4%) patients allocated metoprolol had at least one such event compared with 2261 (9·9%) allocated placebo (odds ratio [OR] 0·96, 95% CI 0·90–1·01; p=0·1). For death alone, there were 1774 (7·7%) deaths in the metoprolol group versus 1797 (7·8%) in the placebo group (OR 0·99, 0·92–1·05; p=0·69). Allocation to metoprolol was associated with five fewer people having reinfarction (464 [2·0%] metoprolol vs 568 [2·5%] placebo; OR 0·82, 0·72–0·92; p=0·001) and five fewer having ventricular fibrillation (581 [2·5%] vs 698 [3·0%]; OR 0·83, 0·75–0·93; p=0·001) per 1000 treated. Overall, these reductions were counterbalanced by 11 more per 1000 developing cardiogenic shock (1141 [5·0%] vs 885 [3·9%]; OR 1·30, 1·19–1·41; p<0·00001). This excess of cardiogenic shock was mainly during days 0–1 after admission, whereas the reductions in reinfarction and ventricular fibrillation emerged more gradually. Consequently, the overall effect on death, reinfarction, arrest, or shock was significantly adverse during days 0–1 and significantly beneficial thereafter. There was substantial net hazard in haemodynamically unstable patients, and moderate net benefit in those who were relatively stable (particularly after days 0–1). The use of early β-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day or so after admission. Consequently, it might generally be prudent to consider starting β-blocker therapy in hospital only when the haemodynamic condition after MI has stabilised.