Myocardial ischemia/reperfusion (I/R) injury has been extensively studied, yet the underlying neuroinflammatory mechanisms are not fully understood. While toll-like receptor 4 (TLR4) is known to be involved in neuropathic pain and neurodegeneration, its role in the central nervous system during myocardial I/R injury, as well as how it modulates neuronal activity to influence cardiac function, remains unclear. In this study, we established a rodent model of myocardial I/R injury by ligating the left anterior descending artery. We found that myocardial I/R injury significantly upregulated TLR4 expression in the spinal dorsal horn, with enhanced TLR4 levels predominantly localized to spinal neurons rather than astrocytes or microglia. Upregulation of TLR4 exhibited functional crosstalk with the calcitonin gene-related peptide (CGRP) receptor, facilitating the transmission of nociceptive signals from the injured myocardium and leading to hyperexcitation of spinal neurons. Both pharmacological inhibition and genetic manipulation of TLR4 signaling resulted in a marked reduction in neuronal activity and attenuated myocardial ischemic injury, accompanied by decreased nociceptive input from the heart to the spinal dorsal horn. Collectively, our findings reveal classic neuroinflammatory signals derived from TLR4 that contribute to neuronal hyperexcitation following myocardial I/R injury. Targeting spinal neuronal TLR4 signaling represents a promising therapeutic strategy for patients with acute myocardial injury.

Beta-blockers are the cornerstone of first-line therapy for symptomatic obstructive hypertrophic cardiomyopathy (oHCM), whereas mavacamten has recently emerged as an effective disease-specific treatment targeting the underlying hypercontractile state. However, the optimal management of concomitant beta-blocker therapy following mavacamten initiation remains uncertain. Available evidence indicates that beta-blockers do not diminish the favorable effects of mavacamten on left ventricular outflow tract obstruction or symptom relief but may attenuate improvements in exercise capacity due to chronotropic limitation. This work reviews the current evidence regarding beta-blocker use during mavacamten therapy and discusses the pathophysiological mechanisms underlying this interaction. Based on the available data, we propose a practical, physiology-guided approach in which continuation of beta-blockers is reserved for patients with specific clinical indications, including atrial fibrillation requiring rate control, myocardial ischemia, or increased ventricular arrhythmic risk, while cautious dose reduction or withdrawal may be considered in selected patients with persistent chronotropic incompetence after effective relief of obstruction. Prospective studies are needed to define the optimal strategy for integrating beta-blockers with cardiac myosin inhibition in oHCM.

Venous thromboembolism (VTE), including deep-vein thrombosis and pulmonary embolism, is the third most common cause of vascular death worldwide and a major contributor to costly and debilitating non-fatal complications. Despite the changing landscape of risk factors, preventive and diagnostic strategies, risk stratification and therapies, no contemporary global summary of the burden of VTE is available. In a collaborative, multinational effort, we provide a global overview of the incidence and outcomes of VTE. Reliable data were available for only a limited number of countries (predominantly in Northern America, Western Europe and Oceania), with notable regional differences. During 2012-2016, the global annual incidence of deep-vein thrombosis ranged from 25.1 to 131.5 per 100,000 of the population. The incidence of pulmonary embolism rose from 2012-2016 to 2017-2022 in Northern America and Asia but remained stable in Oceania. Among patients with pulmonary embolism, 30-day all-cause mortality ranged globally from 1.0% to 9.0%, and the 1-year cumulative incidence of recurrent VTE ranged from 2.9% to 8.1%. These findings reveal the substantial global burden of VTE, sources of heterogeneity and stark regional gaps in the data, demanding coordinated surveillance, standardized reporting and research into local and global drivers to curb worldwide morbidity and mortality.