Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction.

BACKGROUND: Most trials that have shown a benefit of beta-blocker treatment after myocardial infarction included patients with large myocardial infarctions and were conducted in an era before modern biomarker-based diagnosis of myocardial infarction and treatment with percutaneous coronary intervention, antithrombotic agents, high-intensity statins, and renin-angiotensin-aldosterone system antagonists. METHODS: In a parallel-group, open-label trial performed at 45 centers in Sweden, Estonia, and New Zealand, we randomly assigned patients with an acute myocardial infarction who had undergone coronary angiography and had a left ventricular ejection fraction of at least 50% to receive either long-term treatment with a beta-blocker (metoprolol or bisoprolol) or no beta-blocker treatment. The primary end point was a composite of death from any cause or new myocardial infarction. RESULTS: From September 2017 through May 2023, a total of 5020 patients were enrolled (95.4% of whom were from Sweden). The median follow-up was 3.5 years (interquartile range, 2.2 to 4.7). A primary end-point event occurred in 199 of 2508 patients (7.9%) in the beta-blocker group and in 208 of 2512 patients (8.3%) in the no-beta-blocker group (hazard ratio, 0.96; 95% confidence interval, 0.79 to 1.16; P = 0.64). Beta-blocker treatment did not appear to lead to a lower cumulative incidence of the secondary end points (death from any cause, 3.9% in the beta-blocker group and 4.1% in the no-beta-blocker group; death from cardiovascular causes, 1.5% and 1.3%, respectively; myocardial infarction, 4.5% and 4.7%; hospitalization for atrial fibrillation, 1.1% and 1.4%; and hospitalization for heart failure, 0.8% and 0.9%). With regard to safety end points, hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker occurred in 3.4% of the patients in the beta-blocker group and in 3.2% of those in the no-beta-blocker group; hospitalization for asthma or chronic obstructive pulmonary disease in 0.6% and 0.6%, respectively; and hospitalization for stroke in 1.4% and 1.8%. CONCLUSIONS: Among patients with acute myocardial infarction who underwent early coronary angiography and had a preserved left ventricular ejection fraction (≥50%), long-term beta-blocker treatment did not lead to a lower risk of the composite primary end point of death from any cause or new myocardial infarction than no beta-blocker use. (Funded by the Swedish Research Council and others; REDUCE-AMI ClinicalTrials.gov number, NCT03278509.).

Design and rationale of randomized evaluation of decreased usage of beta-blockers after acute myocardial infarction (REDUCE-AMI).

AIMS: Most trials showing benefit of beta-blocker treatment after myocardial infarction (MI) included patients with large MIs and are from an era before modern biomarker-based MI diagnosis and reperfusion treatment. The aim of the randomized evaluation of decreased usage of beta-blockers after acute myocardial infarction (REDUCE-AMI) trial is to determine whether long-term oral beta-blockade in patients with an acute MI and preserved left ventricular ejection fraction (EF) reduces the composite endpoint of death of any cause or recurrent MI. METHODS AND RESULTS: It is a registry-based, randomized, parallel, open-label, multicentre trial performed at 38 centres in Sweden, 1 centre in Estonia, and 6 centres in New Zealand. About 5000 patients with an acute MI who have undergone coronary angiography and with EF ≥ 50% will be randomized to long-term treatment with beta-blockade or not. The primary endpoint is the composite endpoint of death of any cause or new non-fatal MI. There are several secondary endpoints, including all-cause death, cardiovascular death, new MI, readmission because of heart failure and atrial fibrillation, symptoms, functional status, and health-related quality of life after 6-10 weeks and after 1 year of treatment. Safety endpoints are bradycardia, AV-block II-III, hypotension, syncope or need for pacemaker, asthma or chronic obstructive pulmonary disease, and stroke. CONCLUSION: The results from REDUCE-AMI will add important evidence regarding the effect of beta-blockers in patients with MI and preserved EF and may change guidelines and clinical practice.

Effects of estrogen plus progesterone on hemodynamic and vascular reactivity in hypertensive postmenopausal women.

AIMS: To investigate the medium-term effects of estrogen plus progesterone therapy (EPT) on vascular reactivity, endothelial function and hemodynamic responses in 20 hypertensive postmenopausal women. METHODS: This randomized, double-blind, cross-over, placebo-controlled study investigates the effect of 6 months of EPT (conjugated equine estrogen plus medroxyprogesterone). Blood pressure (office and ambulatory), heart rate and heart rate variability (HRV) were measured at baseline and following EPT/placebo treatment. In eight women, we used a wire-myograph to assess endothelial function and contractile response of subcutaneous arteries to transmural nerve stimulation (TNS) and exogenous noradrenaline. RESULTS: EPT decreased vascular reactivity to cumulative TNS compared with baseline (p<0.01) and placebo (p<0.05). Moreover, EPT diminished sensitivity to exogenous noradrenaline (p<0.05). Although EPT reinforced response to acetylcholine, we observed no difference in maximal relaxation induced by substance P or acetylcholine. EPT did not affect ambulatory blood pressure, heart rate or HRV. CONCLUSIONS: Oral combined medium-term EPT reduces adrenergic reactivity in subcutaneous arteries from treated hypertensive postmenopausal women. EPT might act postjunctionally at the adrenergic vascular receptor level. In the present study, EPT neither reduces sympathetic activity nor increases vagal tone, and thus does not support an effect on the central hemodynamic system.

Oestrogen modulates vascular adrenergic reactivity of the spontaneously hypertensive rat.

BACKGROUND: Male spontaneously hypertensive rats (SHRs) show an increased vascular neurogenic response compared with normotensive Wistar-Kyoto (WKY) control rats. OBJECTIVE: To study the vascular adrenergic response in hypertensive and normotensive female rats, with a focus on the influence of oestrogen. METHODS: Female SHRs and WKY rats were allocated randomly to a control group or to groups to undergo ovariectomy or ovariectomy combined with oestrogen supplementation (17beta-oestradiol 150 microg/kg per day) for either 1 day (group 1E2) or 10 days (group 10E2). Mean arterial pressure (MAP) was recorded and small mesenteric arteries were mounted in a Multi Myograph 610M. Vascular reactivities to transmural nerve stimulation (TNS), exogenous noradrenaline and acetylcholine were analysed. RESULTS: MAP was significantly greater in SHRs than in WKY rats in all groups studied. Sensitivity to cumulative TNS (0.12-32 Hz) did not differ between vessels from control SHRs and WKY rats, expressed as the frequency giving 50% of maximal neurogenic response (Ef(50): 4.1 +/- 1.1 and 4.0 +/- 1.6 Hz, respectively). However, there was a greater reactivity to TNS in ovariectomized SHRs than in ovariectomized WKY rats (Ef(50) 1.8 +/- 0.7 and 6.8 +/- 2.2 Hz, respectively; P < 0.05). Oestradiol treatment significantly decreased the sensitivity to TNS in ovariectomized SHRs (P < 0.05), and after 10 days the frequency-response curves were almost identical (Ef(50) 6.3 +/- 1.9 Hz for group 10E2 SHRs and 5.6 +/- 0.8 Hz for group 10E2 WKY rats). The increased adrenergic reactivity in ovariectomized SHRs was inhibited by prazosin, an alpha(1)-adrenergic antagonist, and could not be explained by differences in endothelial function or sensitivity to applied noradrenaline. CONCLUSION: Increased adrenergic reactivity is not present in small arteries from female SHRs. The findings of this study suggest that oestrogen acts on prejunctional mechanisms, reducing full expression of hypertension and peripheral vascular pathology.

Acute effects of transdermal estrogen on hemodynamic and vascular reactivity in elderly postmenopausal healthy women.

OBJECTIVE: The acute effects of estrogen on hemodynamic responses were studied with emphasis on the sympathoadrenal system and peripheral circulation. DESIGN: Eleven healthy postmenopausal women recruited from the population-based study BEDA were included in this randomized, double-blind, cross-over, placebo-controlled hypothesis-generating pilot study, where the effect of transdermal estrogen (17 beta-estradiol, 100 microg/24 h) was tested. METHODS: Twenty-four hours after the patch with estrogen/placebo was attached, the blood pressure during rest and mental stress test was measured, together with blood samples for analysis of P-adrenaline and P-noradrenaline. Twenty-four-hour ambulatory registration of blood pressure and heart rate were recorded. Contractile properties and endothelial function of subcutaneous small arteries from gluteal biopsies were studied with the wire-myograph technique. RESULTS: Estrogen treatment reduced both ambulatory systolic blood pressure (5 mmHg, P = 0.05), diastolic blood pressure (3 mmHg, P < 0.05) and heart rate (6-8 beats/min during morning hours, P < 0.01). Diastolic blood pressure during and after mental stress was significantly reduced after estrogen treatment (p < 0.01). The levels of P-adrenaline and P-noradrenaline were similar in both treatment protocols. The contractile properties of the arteries were not significantly influenced by estrogen. Substance P induced nitric oxide-dependent relaxation in both estrogen-treated and placebo-treated precontracted arteries. Acetylcholine, on the other hand, induced a non-nitric oxide, non-prostanoid-dependent hyperpolarization, which was inhibited by potassium-induced depolarization after placebo but not after estrogen treatment. CONCLUSIONS: Acute administration of transdermal estrogen in clinically relevant doses modulates hemodynamics, probably by an altered parasympathetic balance, which might involve changes at the muscarinic receptor level.

Interactive effects of growth hormone and oestrogen on vascular responses in hypophysectomised female rats.

OBJECTIVE: Growth hormone (GH) and oestrogen (E(2)) are associated with beneficial effects on the cardiovascular system and it is therefore of great interest to study their interactive effects on haemodynamics and vascular function. DESIGN AND METHODS: Female hypophysectomised (Hx) rats were treated for seven days with GH, E(2) or a combination of the hormones. Systolic blood pressure (SBP), heart rate (HR) and plasma insulin-like growth factor-I (IGF-I) were measured. Contractile properties and endothelial function were studied in isolated resistance arteries using the wire-myograph technique. RESULTS: Hypophysectomy, per se, caused a fall in SBP and HR, while vascular adrenergic reactivity (sensitivity to applied noradrenaline) was enhanced. Impaired acetylcholine-induced relaxation and basal release of nitric oxide, suggests endothelial dysfunction after Hx. After supplementation with GH, SBP remained low while HR increased towards the control level. GH increased plasma IGF-I, but had no effect on vascular contractility or endothelial responses. E(2) replacement resulted in blunted plasma IGF-I, while the vascular adrenergic and serotonergic responses were reinforced. Endothelial function was not improved after E(2) treatment. When GH and E(2) were given in combination, the GH-induced increase in body weight, plasma IGF-I levels and HR were counteracted by E(2). Moreover, the anticipated reinforcement of the vascular serotonergic response by E(2) was reduced. Neither E(2) nor GH+E(2) affected SBP. CONCLUSIONS: The results suggest that GH and E(2) might have interactive effects on haemodynamic and metabolic parameters, but not on the contractility or endothelial function of resistance arteries, in Hx female rats.