Beta-blockers are traditionally considered a cornerstone of the pharmacological therapy in heart failure (HF) post-myocardial infarction (MI) and their use in this setting recognizes a pathophysiological rationale. However, most of evidence supporting their administration in ischemic HF is dated and was conceived before the introduction of modern reperfusion therapies (the so-called “pre-reperfusion era”). The introduction of cutting-edge techniques for revascularization and pharmacological strategies changed the history of MI, reducing mortality and allowing to many patients to overcome the acute event without residual ventricular dysfunction. In the “reperfusion era”, the impact of beta-blocker therapy is different than previously observed and evidence coming from new studies lead to question their role as inevitable drugs after acute events, principally in patients with preserved left ventricular ejection fraction. Consequently, the clinical need of prescribing beta-blockers across the full spectrum of ischemic HF patients has become a debated question. This review aims to retrace the history of beta-blockers in ischemic HF, focusing on recent and ongoing trials, that will offer new and update evidence to guide clinical practice in the next future. Since a “one-size-fits-all” approach cannot be justified, our aim is to propose a tailored approach to each patient’s profile, based on left ventricular ejection fraction, comorbidities, arrhythmic burden and quality of life. Furthermore, we propose an algorithm to guide the therapeutic decision of begin, withhold or withdrawn therapy with beta-blockers from the MI onset to the chronical phase of ischemic HF.

Non-obstructive hypertrophic cardiomyopathy (nHCM) is defined by exertional limitation without left ventricular outflow tract obstruction and lacks approved targeted therapies. ODYSSEY-HCM was a phase 3, randomized, double-blind, placebo-controlled trial that enrolled adults with symptomatic nHCM and left ventricular ejection fraction ≥ 60% to receive mavacamten, a selective cardiac myosin inhibitor, or placebo for 48 weeks with dose titration guided by serial echocardiography. The co-primary endpoints were the change in peak oxygen uptake and the 23-item Kansas City Cardiomyopathy Questionnaire clinical summary score. Mavacamten produced clear pharmacodynamic effects manifested by reductions in circulating markers of myocardial stress and imaging indices consistent with modest reverse remodelling, but it did not produce statistically significant improvement in the prespecified co-primary clinical endpoints at 48 weeks. Treatment was associated with an increased incidence of reversible reductions in ejection fraction necessitating protocol-mandated dose interruption, indicating a constrained therapeutic window in this cohort. Collectively, the data demonstrate target engagement without definitive patient-centered benefit over the study interval. Further evaluation is required, including randomized trials of agents with alternative pharmacokinetic and titration properties, studies with extended exposure, and phenotype-enriched enrollment, to determine whether biomarker and imaging responses can be translated into sustained improvements in functional capacity and health-related quality of life in patients with nHCM.

Chronic heart failure with reduced ejection fraction (HFrEF) is a progressive syndrome associated with substantial residual morbidity and mortality despite contemporary guideline-directed medical therapy (GDMT) - angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs)/angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) [1]. Consequently, the need for novel therapeutic strategies has led to the exploration of new drug classes and pathways. In HF, impaired nitric-oxide (NO) signaling, reduced soluble guanylate cyclase (sGC) responsiveness/abundance, and downstream attenuation of cyclic guanosine monophosphate (cGMP) contribute to disease progression [2]. Vericiguat-an oral sGC stimulator-sensitizes sGC to endogenous NO and directly stimulates the enzyme, thereby restoring cGMP signaling in vascular smooth muscle and cardiomyocytes.

Subcutaneous glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce risk of major adverse cardiac events (MACE) for patients with type 2 diabetes (T2DM) who have or are at high risk of cardiovascular disease, but the evaluation of cardiovascular efficacy of oral GLP-1 RAs has yet to be performed. This article reviews results from the SOUL (Semaglutide Cardiovascular Outcomes) trial, whose aim was to assess the cardiovascular benefit in oral semaglutide in high-risk individuals. SOUL was a randomized, double blind, parallel-group, placebo-controlled superiority trial that enrolled 9,650 adults with T2DM who had established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both, to receive a maximum daily dose of 14 mg oral semaglutide or placebo. The primary outcome in this study was a composite of time to first CV death, non-fatal MI, or non-fatal stroke. In prespecified secondary analyses, treatment groups were analyzed for an expanded list of CV, CKD, PAD, and HF outcomes. Over a median follow-up of 49.5 months, the risk for MACE was significantly lower in the oral semaglutide compared with the placebo group (HR 0.86; 95% CI, 0.77; 0.96; p = 0.006), and these results were consistent across subgroup analysis, including by sodium glucose co-transporter 2 inhibitor (SGLT2i) drug use. Oral semaglutide reduces the risk of MACE in high-risk patients with T2DM.

Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left-ventricular (LV) filling pressures largely owing to diastolic dysfunction and stiffness. The measurement of filling pressure presents unique challenges as cardiac structures live within the context of the thorax. The heart and pulmonary vasculature are therefore subjected to the same changes in external volume as the lung. Here, we review the mechanisms by which LV filling pressure interacts with the thoracic space, with a particular focus on patients with HFpEF during rest and exercise. Specifically, we discuss the means by which intrathoracic volume impacts ventricular filling and function. We outline the interacting compliances within the thoracic cavity which can alter intrathoracic and therefore cardiac filling pressures. We also detail means by which intrathoracic pressure can be modulated by different conditions and body positions, such as supine posture, gravity, and obesity. Throughout, we highlight gaps in the literature as well as perspective towards possible future directions.

Left ventricular assist device (LVAD) implantation is an important surgical option for patients with advanced heart failure (HF) who are not eligible for heart transplantation (destination therapy) or who are not expected to survive to transplant without durable mechanical circulatory support (bridge-to-transplant). Despite the hemodynamic support provided by LVAD, both atrial and ventricular arrhythmias (AAs and VAs, respectively) are prevalent and contribute to morbidity and mortality, primarily due to right ventricular failure and arrhythmic storm. Management strategies are extrapolated from recommendations for patients with HF with reduced ejection fraction, since available data are limited. Controlling heart rate is a crucial therapeutic approach for AAs since restoration of sinus rhythm often has a minimum effect on hemodynamics. Management of VAs is further complicated by factors unique to LVAD patients, such as suction events. Antiarrhythmic drugs may not work for both AAs and VAs, necessitating escalation therapy or catheter ablation. Given the technical challenges of catheter ablation, a strict cooperation between HF specialists and electrophysiologists is warranted. This review aims to summarize the current scientific evidence and provide clinical guidance for managing arrhythmias in this complex patient group, characterized by significant knowledge gaps.