Search Results (145)

Hypertrophic cardiomyopathy (HCM) is a prevalent and often underdiagnosed genetic cardiac disorder characterized by left ventricular hypertrophy and, in many cases, dynamic left ventricular outflow tract obstruction (LVOTO). The development of cardiac myosin inhibitors (CMIs) represents an emerging therapeutic approach in the pharmacological management of obstructive HCM (oHCM). This review offers an integrated and up-to-date synthesis of the cardiac myosin inhibitor class, with a focus on mavacamten, aficamten, and the broader landscape of emerging agents. It also highlights recent clinical trial outcomes, pharmacokinetic and pharmacogenetic considerations, and potential future directions in therapy. Furthermore, we incorporate the most recent data up to May 2025, including late-breaking trial results and real-world safety findings, aiming to provide clinicians with a practical and comprehensive perspective on this evolving drug class. A narrative review was conducted by systematically searching PubMed, Scopus, Google Scholar, and ClinicalTrials.gov for English-language articles and trials published between January 2016 and May 2025. Keywords included “cardiac myosin inhibitor”, mavacamten”, “aficamten”, “MYK-224”, and “hypertrophic cardiomyopathy.” Inclusion criteria encompassed clinical trials and comprehensive reviews specifically addressing CMIs in cardiac applications. CMIs such as mavacamten and aficamten have demonstrated significant clinical benefits in reducing LVOT gradients, improving exercise capacity, and alleviating symptoms in patients with oHCM. Mavacamten is currently approved for clinical use, while aficamten is in advanced regulatory review. Comparative data suggest potential advantages of aficamten in the onset of action, pharmacokinetic profile, and tolerability. Emerging evidence supports the exploration of CMIs in pediatric populations, heart failure with preserved ejection fraction (HFpEF), and non-obstructive HCM (nHCM), although results are still preliminary. Cardiac myosin inhibitors offer a novel, pathophysiology-targeted approach to managing oHCM. While mavacamten has established efficacy, next-generation agents like aficamten may offer improved safety and versatility. Further long-term studies are needed to clarify their role across broader patient populations. Full article

Sudden cardiac death (SCD) is a major public health concern, being a leading cause of death worldwide. SCD is particularly alarming for individuals with apparently good health, as it often occurs without preceding warning signs. Unfortunately, traditional autopsy methods frequently fail to identify the precise cause of death in these cases, highlighting the need for advanced techniques to elucidate underlying mechanisms. Recent advances in molecular biology over the past few years, particularly in proteomics, transcriptomics, and metabolomics techniques, have led to an expanded understanding of gene expression, protein activity, and metabolic changes, offering valuable insights into fatal cardiac events. Combining multi-omics methods with bioinformatics and machine learning algorithms significantly enhances our ability to uncover the processes behind lethal cardiac dysfunctions by identifying new useful biomarkers (like cardiac myosin-binding protein C, acylcarnitines, or microRNAs) to reveal molecular pathways linked to SCD. This narrative review summarizes the role of multi-omics approaches in forensic diagnosis by exploring current applications in unexplained cases and the benefits of integrating merged techniques in otherwise negative autopsies. We also discuss the potential for developing personalized and preventive forensic medicine, the technical limitations of currently available methods, and the ethical considerations arising from these advancements. Full article

Chronic ethanol use can lead to alcoholic cardiomyopathy (ACM), while the impact on the molecular and cellular aspects of the myocardium is unclear. Accordingly, male Sprague-Dawley rats were exposed to an ethanol-containing diet for 16 weeks and compared with a control group that was fed an isocaloric diet. Histological measurements from H&E slides revealed no significant differences in cell size. A proteomic approach revealed that alcohol exposure leads to enhanced mitochondrial lipid metabolism, and electron microscopy revealed impairments in mitochondrial morphology/density. Cardiac myosin purified from the hearts of ethanol-exposed animals demonstrated a 15% reduction in high-salt ATPase activity, with no significant changes in the in vitro motility and low-salt ATPase or formation of the super-relaxed (SRX) state. A protein carbonyl assay indicated a 20% increase in carbonyl incorporation, suggesting that alcohol may impact cardiac myosin through oxidative stress mechanisms. In vitro oxidation of healthy cardiac myosin revealed a dramatic decline in ATPase activity and in vitro motility, demonstrating a link between myosin protein oxidation and myosin mechanochemistry. Collectively, this study suggests alcohol-induced metabolic remodeling may be the initial insult that eventually leads to defects in the contractile machinery in the myocardium of ACM hearts. Full article

Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease, with an estimated prevalence of 1:600 in the general population, and is associated with significant morbidity. HCM is characterized by left ventricular hypertrophy and interventricular septal thickening due to sarcomere protein gene mutations. The recent emergence of cardiac myosin inhibitors (CMIs), specifically mavacamten and aficamten, has introduced a paradigm shift in HCM management by directly targeting the hypercontractile state of the disease. This review comprehensively discusses the molecular mechanisms of mavacamten and aficamten, highlighting their biochemical similarities and differences from available data. It evaluates their reported efficacy in completed clinical trials, such as reducing left ventricular outflow tract (LVOT) obstruction, improving functional capacity, and enhancing quality of life in HCM. It further provides insight and updates to ongoing trials of both CMIs. Finally, it compares and elaborates on the safety profiles of mavacamten and aficamten, discussing their favorable safety profiles shown in completed studies. In current clinical practice, only mavacamten is approved for use, and clinical insights concerning both CMIs are limited, but encouraging. In summary, cardiac myosin inhibitors are a promising class of disease-modifying drugs for HCM with proven short-term safety and efficacy, but limited data are available to fully determine their long-term effects and efficacy in diverse patient populations. Ongoing research is necessary to further explore and define their role in HCM management. Full article

The hypertrophic cardiomyopathy (HCM) clinical phenotype includes sarcomeric HCM, which is the most common form of inherited cardiomyopathy with a population prevalence of 1:500, and phenocopies such as cardiac amyloidosis and Anderson–Fabry disease, which are considered rare diseases. Identification of cardiac and non-cardiac red flags in the context of multi-organ syndrome, multimodality imaging, including echocardiography, cardiac magnetic resonance, and genetic testing, has a central role in the diagnostic pathway. Identifying the specific disease underlying the hypertrophic phenotype is very important since many disease-modifying therapies are currently available, and phase 3 trials for new treatments have been completed or are ongoing. In particular, many chemotherapy agents (alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting clonal cells) allowing one to treat AL amyloidosis, transthyretin stabilizers (tafamidis and acoramidis), and gene silencers (patisiran and vutrisiran) are available in transthyretin cardiac amyloidosis, and enzyme replacement therapies (agalsidase-alpha, agalsidase-beta, and pegunigalsidase-alpha) or oral chaperone therapy (migalastat) can be used in Anderson–Fabry disease. In addition, the introduction of cardiac myosin inhibitors (mavacamten and aficamten) has deeply modified the treatment of hypertrophic obstructive cardiomyopathy. The aim of this review is to describe the new disease-modifying treatments available in HCM and phenocopies in light of current scientific evidence. Full article

Obesity has been implicated in the induction of oxidative stress, which is thought to contribute to the pathogenesis of various cardiovascular diseases, including cardiac hypertrophy. However, the redox status during the early stages of cardiac hypertrophy remains inadequately characterized. In this study, we administered a high-fat diet (HFD) to C57BL/6N mice for 12 weeks. We investigated the expression of biomarkers associated with hypertrophy and oxidative stress, including lipid peroxidation, protein carbonylation, and the redox couples NADH/NAD⁺, NADPH/NADP⁺, and GSH/GSSG. Additionally, we assessed the expression levels and enzymatic activities of catalase, glutathione peroxidase, glutathione reductase, and superoxide dismutase. Following 12 weeks on a HFD, mice exhibited obesity and a 10% increase in the heart weight/tibia length ratio, together with an upregulation in the mRNA levels of β-myosin heavy chain, brain natriuretic peptide, and regulator of calcineurin 1, isoform 4. There was also a significant increase in NOX4 content in the heart of these animals; however, we observed no rise in protein carbonylation and a decrease in lipid peroxidation products. As for the redox couples, the GSH/GSSG ratio nearly doubled, while the NADH/NAD⁺ and NADPH/NADP⁺ ratios remained stable. All antioxidant enzyme mRNAs examined showed increased expression; however, only glutathione reductase showed higher activity. Our findings suggest that reductive stress is predominant within the cardiac environment of these animals. Full article

Hypertrophic cardiomyopathy is the most prevalent inherited cardiac condition, distinguished by an autosomal dominant inheritance pattern. Diagnosis can be achieved through echocardiography, cardiac magnetic resonance imaging, and genetic testing. Recently, significant advancements have occurred in pharmacological and invasive therapies that are transforming the management of hypertrophic cardiomyopathy, including the introduction of cardiac myosin inhibitors, radiofrequency ablation, and gene editing. Additional trials are being conducted on investigational therapies, with the results anticipated in the near future. This review aims to provide a concise overview of both currently approved and investigational treatments for hypertrophic cardiomyopathy. Full article

Skeletal muscle changes occur in heart failure (HF). Despite the cardioprotective effects of sodium–glucose co-transporter 2 (SGLT2) inhibitors in HF, their impact on skeletal muscle remains poorly understood. We investigated the effects of the SGLT2 inhibitor empagliflozin (EMPA) on cardiac remodeling and the soleus muscle of rats with myocardial infarction (MI)-induced HF. Methods: One week after MI induction, rats were assigned to Sham, Sham + EMPA, MI, and MI + EMPA groups. EMPA was administered (5 mg/kg/day) for 12 weeks. Results: MI + EMPA and MI had dilated left cardiac chambers; the left atrium diameter and left ventricle end-diastolic area were smaller in MI + EMPA than MI. The ejection fraction did not differ between infarcted groups. MI + EMPA had a larger soleus cross-sectional area and higher Type II myosin heavy chain expression than MI. Carbonylated protein and malondialdehyde levels were lower and superoxide dismutase activity higher in MI + EMPA than MI. Respiratory Complex I expression was higher in MI + EMPA than MI. Metabolic enzyme activities, altered in MI, were normalized in MI + EMPA. EMPA up-regulated anabolic proteins and down-regulated catabolic proteins. Conclusion: Empagliflozin attenuates infarction-induced cardiac remodeling in rats. In soleus muscle, empagliflozin preserves cell trophism, reduces oxidative stress, normalizes muscle and mitochondrial metabolism, and positively modulates proteins involved in synthesis and degradation-related pathways. Full article

Hypertrophic cardiomyopathy (HCM) is often associated with left ventricular outflow tract (LVOT) obstruction, which affects a substantial proportion of patients. This obstruction results from a range of anatomical abnormalities involving both the valvular and subvalvular structures. Pharmacological therapies play a pivotal role in the management of LVOT obstruction, with a range of drug classes exhibiting distinct mechanisms of action. Beta-blockers, including atenolol and nadolol, are considered the first-line treatment due to their ability to reduce heart rate and myocardial contractility and enhance diastolic filling. Non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, are utilized as second-line agents when beta-blockers are ineffective or contraindicated. Disopyramid, a Class 1A antiarrhythmic agent, is employed for patients who do not respond to initial therapeutic interventions and can reduce LVOT gradients. Recent advancements in cardiac myosin modulators, such as Mavacamten and Aficamten, offer targeted therapies by modulating myosin–actin interactions to reduce LVOT gradients and improve symptoms, with promising results from clinical trials. Although gene therapy is still in its nascent stages, it has the potential to address the genetic basis of HCM by employing techniques such as genome editing, gene replacement, and the modulation of signaling pathways. For patients exhibiting severe symptoms or demonstrating unresponsiveness to medical treatment, invasive therapies, such as septal reduction therapy and alcohol septal ablation, are considered. Ultimately, the treatment and prevention of atrial fibrillation and sudden cardiac death are two key points of HCM management in both obstructive and non-obstructive forms. This review aims to provide an overview of current pharmacological and invasive strategies, as well as emerging therapies, in the management of HCM. Full article

Anthracyclines and human epidermal growth factor receptor 2 (HER-2) inhibitors are cornerstone therapies for breast cancer but are associated with significant cardiotoxicity. While sodium–glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin have demonstrated cardio–renal protective effects during anthracycline treatment, their efficacy in preventing cardiotoxicity from sequential anthracycline and HER-2 blockade remains poorly understood. This study investigates the cardioprotective role of dapagliflozin in a preclinical model of chemotherapy-induced cardiotoxicity. Female C57Bl/6 mice were divided into four groups and treated for 10 days as follows: (1) a normal control group receiving saline (sham); (2) a model control group receiving doxorubicin (2.17 mg/kg/day for 5 days) followed by HER-2-blocking monoclonal antibody (2.25 mg/kg/day for 5 days); (3) a dapagliflozin-only group (10 mg/kg/day via oral gavage); and (4) a treatment group receiving the combination of doxorubicin, HER-2 inhibitor, and dapagliflozin. Cardiac function was assessed using echocardiography (VEVO 2100). Biomarkers of myocardial injury and inflammation (NLRP3, MyD88, CXCR4, H-FABP, troponin-T, and cytokines) were quantified via ELISA and immunohistochemistry. Circulating markers such as mitofusin-2, cardiac myosin light chain, malondialdehyde (MDA), and 4-hydroxy-2-nonenal (4-HNE) were also measured. Dapagliflozin significantly preserved the ejection fraction and reduced both radial and longitudinal strain impairment in mice treated with the doxorubicin–HER-2 inhibitor combination (p < 0.001). Levels of myocardial NLRP3, MyD88, CXCR4, H-FABP, interleukin-1β, and troponin-T were significantly lower in the dapagliflozin-treated group compared to the chemotherapy-only group. Serum markers of oxidative stress and cardiac injury, including mitofusin-2, MDA, 4-HNE, BNP, and high-sensitivity C-reactive protein (hs-CRP), were also reduced by dapagliflozin treatment. Our findings demonstrate that dapagliflozin effectively mitigates early cardiac dysfunction and injury in a preclinical model of sequential doxorubicin and HER-2 inhibitor therapy. Full article

Tropomodulin (Tmod) is an actin-binding protein that interacts with tropomyosin and the actin filament at the pointed end. The influence of Tmod on the thin filament activation in the myocardium is not clear. We studied the interactions of Tmod1 and Tmod4 with the cardiac tropomyosin isoforms Tpm1.1 and Tpm1.2 using size-exclusion chromatography, a pull-down assay, and cross-linking with glutaraldehyde. We found that Tmod1 and Tmod4 form complexes with both Tpm1.1 and Tpm1.2, indicating durable interactions between these proteins. The effects of both Tmods on the actin–myosin interaction were studied using an in vitro motility assay. Tmod did not affect the sliding velocity of bare F-actin. Tmod1 slightly dose-dependently decreased the sliding velocity of F-actin–Tpm1.1 filaments and had no effect on the velocity of F-actin–Tpm1.2 filaments. With ventricular myosin, Tmod1 reduced the calcium sensitivity of the sliding velocity of thin filaments containing Tpm1.1 but did not affect it with filaments containing Tpm1.2. With atrial myosin, Tmod1 decreased the calcium sensitivity of the sliding velocities of thin filaments containing both Tpm1.1 and Tpm1.2. We can conclude that Tmod takes part in the regulation of actin–myosin interactions in the myocardium through interactions with Tpm. The effect of Tmod on the activation of thin filaments depends on the protein isoforms. Full article

(1) Background: Prompt acute coronary syndrome (ACS) recognition remains challenging. This study evaluated the diagnostic and prognostic performance of novel biomarkers for non-ST-elevation myocardial infarction (NSTEMI). (2) Methods: Patients with suspected ACS presenting to Heidelberg University Hospital’s Emergency Department between August 2014 and February 2023 were analyzed. The biomarker panel included high-sensitivity cardiac troponin T (hs-cTnT), cardiac myosin-binding protein C (cMyBP-C), pro-B-type natriuretic peptide (proBNP), total N-terminal pro-B-type natriuretic peptide (t-NtproBNP), Angiotensin II (Ang2), Bone morphogenetic protein 10 (BMP10), Endothelial cell-specific molecule 1 (ESM1), fatty acid-binding protein 3 (FABP3), Fibroblast growth factor 23 (FGF23), Growth differentiation factor 15 (GDF15), and Copeptin. Negative predictive values (NPVs), sensitivities, and area under the curve (AUC) values were calculated for NSTEMI discrimination. Effectiveness and prognostic performance were assessed based on cardiovascular events at 30 days and 1 year. (3) Results: Of 1765 patients, 212 (12%) were diagnosed with NSTEMI. The European Society of Cardiology (ESC) 0/1 h and 0/3 h algorithms achieved sensitivities of 100% and 96.8%, NPVs of 100% and 99.3%, and effectiveness values of 54.8% and 66.0%. Hs-cTnT (AUC: 0.922) and cMyBP-C (AUC: 0.917) exhibited the highest diagnostic accuracy, followed by FABP3 (AUC: 0.759) and Copeptin (AUC: 0.624). Other biomarkers had lower performance (AUC: 0.516–0.617). At 1 year, event rates ranged from 0.0% to 3.4%, with the ESC algorithms demonstrating superior prognostic performance (0.8%, 2.4%). (4) Conclusions: The ESC 0/1 h and 0/3 h algorithms remain the most effective NSTEMI diagnostic strategies, balancing high sensitivity, prognostic reliability, and effectiveness. Among novel biomarkers, only cMyBP-C demonstrated comparable accuracy to hs-cTnT, supporting its potential as an adjunct to troponin assays. Full article

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder marked by abnormal thickening of the left ventricular myocardium, often leading to arrhythmias and heart failure. Mutations in sarcomeric protein genes, particularly MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), are major contributors to HCM pathogenesis. This study aims to investigate the structural and functional effects of two HCM-associated missense mutations, p.S236G and p.E334K, located within the C0–C2 domains of cMyBP-C. Methods: Following in silico analysis, a bacterial expression system was applied, enabling the discrete C0–C2 domains of wild-type (cMyBP-C^WT) and mutant (cMyBP-C^S236G and cMyBP-C^E334K) cMyBP-C proteins to be expressed and purified as recombinant proteins. Structural and stability changes were assessed using circular dichroism (CD), differential scanning calorimetry (DSC), and chemical denaturation assays. Functional impact on actin binding was also evaluated in vitro. Results: CD analysis revealed altered secondary structure in both mutants compared to the wild-type protein. Thermal and chemical stability assays indicated increased stability in the cMyBP-C^E334K mutant, suggesting that it exhibits a more rigid conformation. This increased rigidity corresponded with a significant reduction in the actin-binding affinity relative to the wild-type protein. Conclusions: Our findings demonstrate specific detrimental effects of the p.E334K mutation and underscore the importance of understanding the structural and functional consequences of HCM-associated mutations to assist the development of targeted therapeutic strategies. Full article

Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy marked by increased left ventricular wall thickness, leading in some cases to left ventricular outflow tract (LVOT) obstruction, heart failure, and arrhythmias. Mavacamten, a selective allosteric inhibitor of cardiac myosin, has demonstrated benefits in improving hemodynamics and reducing LVOT obstruction. However, its impact on arrhythmic burden remains unclear, with reports of early atrial fibrillation (AF) risk contrasting with long-term reductions in arrhythmias. This study assesses the temporal patterns of Holter-detected arrhythmias in HCM patients treated with mavacamten. Methods: This retrospective study included HCM patients from three Mayo Clinic sites. Baseline demographic, clinical, and echocardiographic data were collected. Holter monitoring was performed at baseline, short-term (<6 months), and long-term (>6 months) follow-up. Arrhythmic events, including premature atrial contractions (PACs), premature ventricular contractions (PVCs), and supraventricular tachycardia (SVT), were analyzed using standardized rates per 24 h. Statistical comparisons utilized the Wilcoxon signed-rank test. Results: Twenty-seven patients (56% female, median age 66 years) were included. PACs, PVCs, and SVT duration transiently but not significantly increased at short-term follow-up but returned to baseline at long-term follow-up. No sustained or high-risk ventricular arrhythmias were observed. Conclusions: Mavacamten is associated with transient arrhythmic fluctuations early in treatment, followed by stabilization. These findings support its long-term electrophysiological safety and underscore the need for early rhythm monitoring. Further research should explore its role in arrhythmic risk stratification in HCM patients. Full article

17β-estradiol (E2) is the most active metabolite of estrogen with a wide range of physiological action on cardiac muscle. Previous studies have reported E2 effects predominantly for the ventricles, while the E2 impact on the atria has been less examined. In this study, we focused on the direct E2 effects on atrial and ventricular contractility at the cellular and molecular levels. Single atrial and ventricular cardiomyocytes (CM) from adult (24 weeks-old) female Wistar rats were incubated with 10 nM E2 for 15 min. Sarcomere length and cytosolic [Ca²⁺]_i transients were measured in mechanically non-loaded CM, and the tension–length relationship was studied in CM mechanically loaded by carbon fibers. The actin–myosin interaction and sarcomeric protein phosphorylation were analyzed using an in vitro motility assay and gel electrophoresis with Pro-Q Diamond phosphoprotein stain. E2 had chamber-specific effects on the contractile function of CM with a pronounced influence on ventricular CM. The characteristics of [Ca²⁺]_i transients did not change in both atrial and ventricular CM. However, in ventricular CM, E2 reduced the amplitude and maximum velocity of sarcomere shortening and decreased the slope of the passive tension–length relationship that was associated with increased TnI and cMyBP-C phosphorylation. E2 treatment accelerated the cross-bridge cycle of both atrial and ventricular myosin that was associated with increased phosphorylation of the myosin essential light chain. This study shows that E2 impairs the mechanical function of the ventricular myocardium while atrial contractility remains mostly preserved. Hormonal replacement therapy (HRT) with estrogen is by far the most effective therapy for treating climacteric symptoms experienced during menopause. Here we found a chamber specificity of myocardial contractile function to E2 that should be taken into account for the potential side effects of HRT. Full article