Background Mavacamten, a first-in-class allosteric myosin inhibitor, has demonstrated efficacy and safety in obstructive hypertrophic cardiomyopathy (oHCM), notably reducing symptoms, left ventricular outflow obstruction, and wall thickness over 30 weeks. We recently reported that the MYBPC3 :c.772G>A variant causes HCM through cMyBP-C haploinsufficiency, leading to accelerated sarcomere kinetics and higher energy consumption in patient myocardium and hiPSC- derived cardiomyocytes (hiPSC-CMs). These effects are counterbalanced by prolonged action potentials and slower Ca²⁺ transients, which preserve twitch duration but may increase arrhythmic risk. Mavacamten may reduce myocardial energetic defects in HCM. Objectives To investigate the long-term effects of Mavacamten on sarcomere structure, contractility, and transcriptional remodeling using patient-specific and CRISPR-corrected isogenic hiPSC-derived cardiomyocyte models of HCM. Methods HiPSC-CMs and engineered heart tissues (EHTs) derived from a MYBPC3:c.772G>A patient and its CRISPR-corrected line were first exposed to increasing concentrations of Mavacamten to assess acute dose–response relationships and determine IC50 values. Based on these data, chronic treatments (0.3– 0.75 μM for 20 days) were performed mechanical, structural, electrophysiological, and transcriptomic adaptations. Results Acute exposure produced a rapid and fully reversible reduction in active force, while chronic treatment for 20 days induced a sustained decrease in contractility with incomplete recovery after 4 days of washout, indicating a two-phase mechanism of action. Long-term force reduction was paralleled by decreased cell area and sarcomere density, indicating that structural disassembly contributes to sustained functional depression and re-assembly after washout. Electrophysiological analysis confirmed the specific alterations of the MYBPC3 :c.772G>A mutation previously observed, with no detectable effects following treatment with Mavacamten. In addition, transcriptome analysis was used to study the molecular mechanisms underlying the long-term effect. Conclusions Mavacamten induces a biphasic, persistent-to-reversible, reduction of sarcomeric force associated with structural remodeling, providing mechanistic insight into its capacity to promote favorable cardiac remodeling in oHCM. ### Competing Interest Statement Iacopo Olivotto has received advisory board fees/research grants from Bristol Myers Squibb, Cytokinetics, Sanofi Chiesi, Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma and Edgewise and Lexeo. Sonette Steczina was a former graduate student at the University of Washington at the time of this work and is currently an employee at Cytokinetics HORIZON-HLTH-2023-TOOL-05, 101137115 European Union's Horizon 2020 research and innovation programme, 777204

The progression of cardiac electrical remodelling and the onset of proarrhythmic events are multifactorial processes, with many factors contributing to atrial electrical remodelling and the consequent development of atrial fibrillation (AF). Recently, miR-182 has been identified as causative factors of arrhythmogenesis in animal models but its potential relationship with proinflammatory mediators such as interleukin-6 (IL-6), emerged as new key player in independent preclinical evidence for atrial electrogenesis, remains unknown. Human induced pluripotent stem cells (hiPSCs) were differentiated into cardiomyocytes (CMs) to study the role of miR-182-overexpression (OE) in human cardiac background. Functional consequences were assessed by measuring spontaneous electrical activity by using MULTIPLE-High-Throughput and Intracell systems, with/without autonomic stimulation. Molecular analyses by RT-PCR/Elisa assays were performed. Hearts from the Tg(myl7:GAL4,EGFP)xTg(Sce.4xUAS: miR-182,cry: EGFP) zebrafish line [Tg(myl7 > miR-182)] were used to measure the expression of dre-il6. Human IL-6 protein (5,4 pg/nL) was microinjected in the pericardial region of 2dpf Tg(myl7:EGFP) wt-like zebrafish embryos and heart rate was recorded. Expression analyses were performed on human left atrial samples of 49 patients (11 controls, CT; 18 left atrial dilation (LA-D); 20 permanent AF). MiR-182-OE in hiPS-CMs significantly impact cardiac electrophysiology showing reduced and irregular spontaneous beating rate. Accordingly, MiR-182-OE downregulated the expression of HCN4, encoding for the pacemaker f-current, incrementing IL-6 expression and secretion and via ISL1. On the contrary, 24–48 h incubation with IL-6 (50ng/mL) did not change miR-182-5p expression levels in CT hiPS-CMs. The IL-6 receptor antagonist tocilizumab (TOC, 10 µg/mL) partially rescued HCN4 expression in miR-182-OE hiPS-CMs. Interestingly, miR-182-OE in hiPS-CMs enhanced response to acetylcholine and dysregulated genes associated with atrial pathology. Zebrafish heart samples from Tg(myl7 > miR-182) exhibited increased il6 expression levels. Pericardial injection of human IL-6 in wt zebrafish embryos decreased heart rate. Finally, miR-182-5p was found to be overexpressed in human biopsies from patients with LA-D, with the highest expression levels observed in patients with permanent AF; remarkably, miR-182 levels were positively correlated with IL-6 expression. The results support the hypothesis of a causative link between miR-182-OE and IL-6 production in the cardiac context. This molecular axis may represent an associated molecular signature predisposing to arrhythmogenesis. Overall, our findings reveal novel pathophysiological mechanisms concordant across models and suggest novel pharmacological targets within the complex AF setting.

Despite recent advances in cardiovascular pharmacotherapy, prevention and treatment of many cardiovascular diseases remain limited with a clear need for more effective and safer pharmacological strategies. Here, we summarize the most relevant advances in cardiovascular pharmacotherapy in 2025, including the approval of four new drugs (aficamten, etripamil, lerodalcibep, and plozasiran), the label expansions for five already approved drugs, and the results of major randomized clinical trials with already approved drugs, including those that met the prespecified primary endpoints (positive trials) representing new pharmacological options for cardiovascular diseases, those with neutral or negative results, which did not confirm the primary endpoints and the withdrawal from the US market of Andexanet-alfa for safety concerns. Finally, we present the most promising experimental cardiovascular drugs currently being investigated in ongoing Phase 2 and 3 clinical trials.

Environmental risk factors-air pollution, noise, heat, chemical contamination, and light pollution-are increasingly recognized as key contributors to cardiovascular disease but remain underrepresented in clinical guidelines and public health strategies. This comprehensive review, developed under the auspices of the European Society of Cardiology (ESC), synthesizes current evidence on the cardiovascular consequences of environmental exposures. Building on prior ESC recommendations on air pollution, the consensus statement extends the focus to include climate change, urban heat islands, chemical pollutants, noise, and light pollution, highlighting their shared pathophysiological mechanisms: oxidative stress, inflammation, endothelial dysfunction, and circadian disruption. Epidemiological and experimental studies confirm that these exposures exacerbate the incidence of coronary artery disease, stroke, heart failure, arrhythmias, and hypertension-even at levels below existing regulatory thresholds. It is proposed the exposome framework as a conceptual tool to understand the cumulative lifetime impact of environmental hazards on cardiovascular health. Special attention is given to vulnerable populations, including children, the elderly, socioeconomically disadvantaged groups, and patients with pre-existing cardiovascular disease. The document outlines urgent research needs, such as the need for high-resolution exposure data, exploration of gene-environment interactions and molecular pathways, and the development of real-world and mechanistic studies assessing interventions. Mitigation strategies are discussed across individual, clinical, and policy levels, with a call for heart-healthy urban design, stricter emissions legislation, and equitable access to clean environments. Cardiologists are uniquely positioned to advocate for environmental cardiovascular health, bridging the gap between science, clinical care, and policy. This statement aims to accelerate that translation by raising awareness and promoting action across disciplines.

Heart failure (HF) and atrial fibrillation (AF) are major global health challenges with rising prevalence and significant morbidity, mortality, and healthcare burden. Despite advances in HF management, AF remains a critical comorbidity that worsens outcomes and requires ad hoc treatment strategies, increasing the risk of non-adherence and side effects. While rhythm control strategies in AF have gained attention for their prognostic benefits in HF, the pharmacological treatment of HF in patients with AF, including the benefit of rhythm versus rate control, remains underexplored. The relationship between HF and AF lacks sufficient evidence and targeted research to assess the optimal treatment strategies. This narrative review critically examines current HF pharmacotherapy in the context of AF, focusing on the four cornerstone treatments and modifiers of prognosis for HF with reduced ejection fraction: beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/sacubitril-valsartan, aldosterone antagonists, and sodium–glucose co-transporter 2 inhibitors. Although these therapies are well-established in HF patients, their efficacy in patients with concomitant AF requires further prospective investigation. The unique challenges posed by AF, including arrhythmia-induced remodelling and cardiomyopathy, necessitate a more individually tailored treatment. We also highlight critical knowledge gaps and the need for dedicated clinical trials specifically assessing HF therapies in AF subgroups, such as paroxysmal, long-standing persistent and permanent AF, and the benefit of heart rate and rhythm control strategies. The future of precision medicine in HF-AF management lies in bridging these evidence gaps through targeted research and interdisciplinary collaboration.

Obscurin is a large muscle protein whose multiple functions include providing mechanical strength to the M-band and linking the sarcomere to the sarcoplasmic reticulum. Mutations in obscurin are linked to various forms of muscle diseases. This study compares cardiac function in a murine model of obscurin deletion (KO) with wild-type (WT) in vivo and ex vivo. Echocardiography showed that KO hearts had larger (+20%) end-diastolic and end-systolic volumes, reduced fractional shortening, and impaired ejection fraction, consistent with dilated cardiomyopathy. However, stroke volume and cardiac output were preserved due to increased end-diastolic volume. Morphological analyses revealed reduced sarcoplasmic reticulum volume, with preserved T-tubule network. While myofilament function was preserved in isolated myofibrils and skinned trabeculae, experiments in intact trabeculae revealed that Obscn KO hearts compared with WT displayed (1) reduced active tension at high frequencies and during resting-state contractions, (2) impaired positive inotropic and lusitropic response to β-adrenergic stimulation (isoproterenol 0.1 μM), and (3) faster mechanical restitution, suggesting reduced sarcoplasmic reticulum refractoriness. Intracellular [Ca2+]i measurements showed reduced peak systolic and increased diastolic levels in KO versus WT cardiomyocytes. Western blot experiments revealed lower SERCA and phospholamban (PLB) expression and reduced PLB phosphorylation in KO mice. While action potential parameters and conduction velocity were unchanged, β-adrenergic stimulation induced more frequent spontaneous Ca2+ waves and increased arrhythmia susceptibility in KO compared with WT. Taken together, these findings suggest that obscurin deletion, in adult mice, is linked to compensated dilated cardiomyopathy, altered E-C coupling, impaired response to inotropic agents, and increased propensity to arrhythmias.

Cardiac fibrosis is a key factor in electrical conduction disturbances, yet its specific impact on conduction remains unclear, hindering predictive insight of cardiac electrophysiology and arrhythmogenesis. Among the different cardiac disorders, arrhythmogenic cardiomyopathy (ACM) is known to be associated with massive fibrotic remodelling of the myocardium, and it accounts for most cases of stress-related arrhythmic sudden death. To explore ACM further, we employed a Desmoglein-2-mutant mouse model and developed a correlative imaging approach to integrate macro-scale cardiac electrophysiology with 3D micro-scale reconstructions of the ventricles, to characterise the dynamics of conduction wavefronts and relate them to the underlying structural substrate. Our findings confirm that this ACM model shows localised replacement of cardiomyocytes with collagen and non-myocytes, contributing to electrical dysfunction. Moreover, we observed that conduction through fibrotic tissue areas shows a frequency-dependent behaviour, where conduction fails at high stimulation frequencies, promoting re-entrant arrhythmias, even in regions that were electrophysiologically inconspicuous at lower stimulation rates. Using a computational model, informed by high-resolution structural data, we found that frequency-dependent conduction through fibrotic tissue cannot be explained solely by collagen deposition or cardiomyocyte re-organisation. Indeed, fibrotic areas feature electrophysiological remodelling which acts as a low-pass filter for conduction, which can be quantitatively explained by electrotonic coupling of cardiomyocytes with non-myocytes. Collectively, our study provides a novel structure-function mapping pipeline and describes a previously unrecognised pro-arrhythmogenic mechanism in ACM, underscoring the need for dynamic assessment of functional conduction block in fibrotic myocardium using multiple diagnostic pacing protocols.

Cardiac fibrosis contributes to electrical conduction disturbances, yet its specific impact on conduction remains unclear, hindering predictive insight into cardiac electrophysiology and arrhythmogenesis. Arrhythmogenic cardiomyopathy is associated with fibrotic remodeling, and it accounts for most cases of stress-related arrhythmic sudden death. Here we develop a correlative imaging approach to integrate macroscale cardiac electrophysiology with three-dimensional microscale reconstructions of the ventricles. We apply this tool to a desmoglein-2 mutant mouse model to characterize the dynamics of conduction wavefronts and relate them to the underlying structural substrate. We observed that conduction through fibrotic tissue areas shows a frequency-dependent behavior, where conduction fails at high stimulation frequencies; this promotes reentrant arrhythmias, even in regions that were electrophysiologically inconspicuous at lower stimulation rates. We found that fibrotic areas undergo electrophysiological remodeling that acts as a low-pass filter for conduction, quantitatively explained by computational models informed by structural data. Collectively, our study provides a structure–function mapping pipeline and describes a pro-arrhythmogenic mechanism in arrhythmogenic cardiomyopathy. Giardini et al. present an imaging method that combines quantitative measurements of cardiac electrophysiology with high-resolution three-dimensional structural reconstructions, enabling the detection of arrhythmogenic electrical coupling between cardiomyocytes and non-myocytes in murine hearts.

Despite substantial advances in cardiovascular pharmacotherapy and devices in recent years, prevention and treatment of many cardiovascular diseases (CVDs) remain limited, thus reflecting the need for more effective and safer pharmacological strategies. In this review, we summarize the most relevant studies in cardiovascular pharmacotherapy in 2024, including the approval of first-in-class drugs for the treatment of resistant hypertension and pulmonary arterial hypertension, label expansions for bempedoic acid and semaglutide, and the results of major randomized clinical trials (RCTs) that have met the pre-specified primary endpoints, thereby filling some gaps in knowledge and opening new perspectives in the management of CVD, and those RCTs whose results did not confirm the proposed research hypotheses. We also include a section on drug safety, where we describe the newest data on adverse reactions and drug-drug interactions that may complicate treatment and/or reduce drug adherence with the consequent decrease in drug effectiveness. Finally, we present the most important ongoing phase 2 and phase 3 clinical trials assessing the efficacy and safety of cardiovascular drugs for the prevention and treatment of CVD.

SARS-CoV-2 infection affects the respiratory system but also many tissues and organs that may be adversely compromised. Accordingly, recent evidence has assessed virus ability to infect different cell phenotypes, translate viral proteins and promote virus replication. Among them, Envelope (E) proteins sustain virus replication, promote inflammatory processes and remodelling of host cells. However, despite advances on structure and sequence, E-protein specific location and effects in human host cells are still controversial and poorly investigated.Using lentiviral vectors, we established HEK293 and hiPS cell lines stably expressing E-protein. Immunocytochemistry showed E-protein mainly locates within the endoplasmic reticulum, the ERGIC and the Golgi compartments, while only HEK293 cells display some protein staining in cell periphery suggesting a possible insertion into the plasmalemma. Electrophysiological recordings in HEK293 cells revealed E-protein self-assembles in the plasma membrane to mediate a cation efflux pore that is sensitive to amantadine blockade. Calcium fluorescence imaging in HEK293 and hiPS cells demonstrated E-protein expression induces a marked depletion of thapsigargin-sensitive intracellular calcium stores. The altered calcium homeostasis associates to reduced cell metabolic activity, mitochondrial potential, proliferation rate and promotes ER stress. Finally, trilineage differentiation of hiPS cells indicated E-protein expression preserves cell pluripotency while selectively impairs mesodermal differentiation. These results unveil a critical role of stable E-viroporin expression that through alteration of ER Ca²⁺ homeostasis, metabolic activity and induction of ER stress affects important cellular functions, including the differentiative process from pluripotent to mesodermal progenitors, a critical cell population in self-repair and homeostasis of most human tissue and organs.

Aims Direct oral anticoagulants (DOACs) are increasingly used off-label to treat patients with left ventricular thrombus (LVT). We analysed available meta-data comparing DOACs and vitamin K antagonists (VKAs) for efficacy and safety.Methods We conducted a systematic search and meta-analysis of observational and randomized data comparing DOACs vs. VKAs in patients with LVT. Endpoints of interest were stroke or systemic embolism, thrombus resolution, all-cause death, and a composite bleeding endpoint. Estimates were pooled using a random-effects model meta-analysis, and their robustness was investigated using sensitivity and influential analyses.Results We identified 22 articles (18 observational studies, 4 small randomized clinical trials) reporting on a total of 3587 patients (2489 VKA vs. 1098 DOAC therapy). The pooled estimates for stroke or systemic embolism [odds ratio (OR): 0.81; 95% confidence interval (CI): 0.57, 1.15] and thrombus resolution (OR: 1.12; 95% CI: 0.86, 1.46) were comparable, and there was low heterogeneity overall across the included studies. The use of DOACs was associated with lower odds of all-cause death (OR: 0.65; 95% CI: 0.46, 0.92) and a composite bleeding endpoint (OR: 0.67; 95% CI: 0.47, 0.97). A risk of bias was evident particularly for observational reports, with some publication bias suggested in funnel plots.Conclusion In this comprehensive analysis of mainly observational data, the use of DOACs was not associated with a significant difference in stroke or systemic embolism, or thrombus resolution, compared with VKA therapy. The use of DOACs was associated with a lower rate of all-cause death and fewer bleeding events. Adequately sized randomized clinical trials are needed to confirm these findings, which could allow a wider adoption of DOACs in patients with LVT.

Inflammatory cytokines, including interleukin 6 (IL6), are associated with ion channel remodeling and enhance the propensity to alterations in cardiac rhythm generation and propagation, in which the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role. Hence, we investigated the consequences of exposure to IL6 on HCN channels in cell models and human atrial biopsies. In murine atrial HL1 cells and in cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs), IL6 elicited STAT3 phosphorylation, a receptor-mediated downstream signaling. Downregulation of HCN1,2,4 by IL6 was observed after 24-48 h; in hiPS-CMs, this effect was reverted by 24 h of application of tocilizumab, a human IL6 receptor antagonist. In parallel, hiPS-CM action potentials (APs) showed a reduced spontaneous frequency. Moreover, we assessed IL6 and HCN expression in dilated left atrial samples from patients with mitral valve disease, an AF-prone condition. IL6 levels were increased in dilated atria compared to controls and positively correlated with echocardiographic atrial dimensions. Interestingly, the highest IL6 transcript levels and the lowest HCN4 and HCN2 expression were in these samples. In conclusion, our data uncovered a novel link between IL6 and cardiac HCN channels, potentially contributing to atrial electrical disturbances and a higher risk of dysrhythmias in conditions with elevated IL6 levels.

Although cardiovascular diseases (CVDs) are the leading cause of death worldwide, their pharmacotherapy remains suboptimal. Thus, there is a clear unmet need to develop more effective and safer pharmacological strategies. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2023, including the approval of first-in-class drugs that open new avenues for the treatment of atherosclerotic CVD and heart failure (HF). The new indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy, hypercholesterolaemia, type 2 diabetes, obesity, and HF; the impact of polypharmacy on guideline-directed drug use is highlighted as well as results from negative clinical trials. Finally, we end with a summary of the most important phase 2 and 3 clinical trials assessing the efficacy and safety of cardiovascular drugs under development for the prevention and treatment of CVDs.

Obesity and underweight are a growing health problem worldwide and a challenge for clinicians concerning antithrombotic therapy, due to the associated risks of thrombosis and/or bleeding. This clinical consensus statement updates a previous one published in 2018, by reviewing the most recent evidence on antithrombotic drugs based on body size categories according to the World Health Organization classification. The document focuses mostly on individuals at the extremes of body weight, i.e. underweight and moderate-to-morbid obesity who require antithrombotic drugs, according to current guidelines, for the treatment or prevention of cardiovascular diseases or venous thromboembolism. Managing antithrombotic therapy or thromboprophylaxis in these individuals is challenging, due to profound changes in body composition, metabolism and organ function, altered drug pharmacokinetics and pharmacodynamics, as well as weak or no evidence from clinical trials. The document also includes artificial intelligence simulations derived from in silico pharmacokinetic/pharmacodynamic models, which can mimic the pharmacokinetic changes and help identify optimal regimens of antithrombotic drugs for severely underweight or severely obese individuals. Further, bariatric surgery in morbidly obese subjects is frequently performed worldwide. Bariatric surgery causes specific and additional changes in metabolism and gastrointestinal anatomy, depending on the type of the procedure, which can also impact the pharmacokinetics of antithrombotic drugs and their management. Based on existing literature, the document provides consensus statements on optimising antithrombotic drug management for underweight and all classes of obese patients, while highlighting the current gaps in knowledge in these complex clinical settings, which require personalized medicine and precision pharmacology.

Polypharmacy is often necessary in complex, chronic, comorbid and cardiovascular patients and is a known risk factor for potential drug-drug interaction (DDI) that can cause adverse reactions (toxicity or therapeutic failure). Anti-thrombotic drugs (largely low-dose aspirin and a platelet P2Y12 receptor inhibitor) and statins are among the most co-administered drugs in cardiovascular patients. Ticagrelor is a selective antagonist of the platelet P2Y12-receptor, highly effective in inhibiting platelet aggregation and bio-transformed by the CYP3A4 and substrate of transporters, such as the breast cancer resistance protein (BCRP). Statins have different pharmacokinetic profiles; some undergo CYP3A4-mediated metabolism; rosuvastatin is primarily metabolized by the CYP2C9; and they have different affinities for drug transporters. Rhabdomyolysis is a very rare but severe adverse event, which is specific for statins which can be triggered by DDIs that increase statin’s concentrations through blockade of their biotransformation and/or elimination. Large pharmacovigilance and small observational studies reported increased rhabdomyolysis in patients treated with some statins and ticagrelor but not aspirin, clopidogrel or prasugrel. Recent studies in vitro, pharmacokinetic trials and in silico drug modelling identified and validated the BCRP inhibition by ticagrelor, as a mechanism contributing to the DDI with statins, as ‘victim’ drugs, leading to increased rhabdomyolysis. While the clinical impact of this DDI deserves further investigation, a careful evaluation should be advised when ticagrelor is co-prescribed with some statins.