Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected ...tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.
•Aficamten is a next-generation cardiac myosin inhibitor (CMI)•CMIs are a novel treatment for obstructive hypertrophic cardiomyopathy (oHCM)•We report efficacy and safety of aficamten with ...disopyramide for refractory oHCM•In Cohort 3 of REDWOOD-HCM, aficamten plus disopyramide was well tolerated•Patients had improved left ventricular outflow tract gradient and NYHA class
Hypertrophic cardiomyopathy (HCM) is the most common heritable myocardial disorder worldwide. Current pharmacological treatment options are limited. Mavacamten, a first-in-class cardiac myosin ...inhibitor, targets the main underlying pathology of HCM. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Mavacamten in patients with HCM. PRISMA flow chart was utilized using PubMed, SCOPUS, and Cochrane databases for all up-to-date studies using pre-defined keywords. Pre-specified efficacy outcomes comprised several parameters, including an improvement in peak oxygen consumption (pVO2) and ≥ 1 NYHA class, the need for septal reduction therapy (SRT), change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ), changes in biochemical markers and LVEF, along with peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Safety outcomes included morbidity and serious adverse events. This systematic review included five studies, four RCTs and one non-randomized control trial comprised a total of 524 (Mavacamten 273, 54.3% vs placebo 230, 45.7% adult (≥ 18 years) patients with a mean age of 56 years. The study. comprised patients with Caucasian and Chinese ethnicity and patients with obstructive (oHCM) and non-obstructive (nHCM) HCM. Most baseline characteristics were similar between the treatment and placebo groups. Mavacamten showed a statistically significant increase in the frequency of the primary composite endpoint (RR = 1.92, 95% CI 1.28, 2.88), ≥ 1 NYHA class improvement (RR = 2.10, 95% CI 1.66, 2.67), a significant decrease in LVEF, peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Mavacamten also showed a significant reduction in SRT rates (RR = 0.29, 95% CI 0.21, 0.40, p < 0.00001), KCCQ clinical summary scores (MD = 8.08, 95% CI 4.80, 11.37, P < 0.00001) troponin levels and N-terminal pro–B-type natriuretic peptide levels. However, there was no statistically significant difference between Mavacamten and placebo regarding the change from baseline peak oxygen consumption. Mavacamten use resulted in a small increase in adverse events but no statistically significant increment in serious adverse events. Our study showed that Mavacamten is a safe and effective treatment option for Caucasian and Chinese patients with HCM on the short-term. Further research is needed to explore the long-term safety and efficacy of Mavacamten with HCM. In addition, adequately powered studies including patients with nHCM is needed to ascertain befits of Mavacamten in those patients.
Catalogues of pathogenic genetic mutations in hypertrophic cardiomyopathy (HCM) are disproportionately small when compared to that of the size of the population with South Asian ancestry and their ...collective increased risk of heart disease.
We conducted clinical exome sequencing of 200 HCM patients to identified cardiomyopathy-associated genetic mutations. The clinical and echocardiographic characteristics of genotype-positive and genotype-negative patients were compared, and the likelihood of detecting a positive genetic test result was evaluated. Allelic burden analysis was done to compare the minor allele frequencies (MAF) of the pathogenic or likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) identified in the cohort against various population genomics databases.
The genetic yield was 40% for P/LP variants, with MYBPC3 and MYH7 as the predominant sarcomere genes. Younger age-at-diagnosis, family history of HCM, asymmetric hypertrophic (ASH) pattern, the ratio of the interventricular septum to posterior wall thickness (IVS/PW ratio), left atrial (LA) dimensions, severe mitral regurgitation grade (MR grade), late gadolinium enhancement (LGE) detected fibrosis and absence of hypertension were associated with an increased likelihood of HCM-associated variants. Patients who experienced ventricular tachycardia and premature cardiovascular death were significantly likely to carry MYBPC3 or loss-of-function variants. LA and interventricular septal (IVS) dimensions were associated with MYH7 variants. The rare variant burden for P/LP variants and VUSs was significantly enriched in HCM cases compared to population controls.
Our study provides a comprehensive evaluation of HCM-associated genetic mutations from an Indian population. The identified genotype-phenotype associations could improve the yield of targeted genetic testing in HCM.
•The genetic yield of clinical exome sequencing in a cohort of hypertrophic cardiomyopathy patients of South Asian ancestry was 40% for pathogenic or likely pathogenic variants.•The MYBPC3 and MYH7 were the predominant sarcomere genes that carried HCM-associated mutations.•Younger age-at-diagnosis, family history of HCM, asymmetric hypertrophic (ASH) pattern, the ratio of the interventricular septum to posterior wall thickness (IVS/PW ratio), left atrial (LA) dimensions, severe mitral regurgitation grade (MR grade), late gadolinium enhancement (LGE) detected fibrosis and absence of hypertension were associated with an increased likelihood of HCM-associated variants.•Identification of HCM-associated mutations and genotype-phenotype associations provides impetus to improve rates of genetic testing in populations of South Asian ancestry.
Hypertrophic cardiomyopathy (HCM) is believed to have low overall mortality rate, that could be influenced by gender, particularly among probands. We aimed to evaluate the survival rates and possible ...gender differences in a homogeneous cohort of HCM proband patients, referred for genetic testing, from the same geographical area, without differences in medical care access nor clinical referral pathways.
we compared the mortality rates of a cohort of consecutive HCM probands referred for genetic testing (2000−2022), from a Spanish region (xxx1) with a centralized genetic testing pathway, with its control reference population by Ederer II method. Gender differences were analyzed.
Among the 649 HCM probands included in this study, there were significantly more men than women (61.3% vs 38.7, p < 0.05), with an earlier diagnosis (53.5 vs 61.1 years old, p < 0.05). Clinical evolution or arrhythmogenic HCM profile did no show no significant gender differences. Mean follow up was 9,8 years ±6,6 SD (9,9 ± 7 vs 9,6 ± 6,1, p = 0.59). No statistically significant differences in observed mortality, expected survival and excess mortality were found in the general HCM proband cohort. However, we found a significant excess mortality in female probands with HCM. No additional differences in analysis by genetic status were identified.
Expected survival in our HCM probands did not differ from its reference population. However, despite no gender differences in phenotype severity were identified, proband HCM women did present a diagnosis delay and worse mortality outcomes.
•Hypertrophic cardiomyopathy (hcm) patients have low overall mortality rate.•Expected survival rates in our hcm probands did not differ from its reference population.•Despite no gender differences in phenotype severity were identified among hcm probands, women did present a diagnosis delay and worse mortality outcomes.
This study was conducted to determine the influence of early septal reduction therapy (SRT) after referral on survival in patients with obstructive hypertrophic cardiomyopathy.
We reviewed the ...patients with obstructive hypertrophic cardiomyopathy (resting pressure gradient ≥30 mm Hg or provoked pressure gradient ≥50 mm Hg) who were evaluated at our clinic from 2000 to 2012. Early SRT was defined as undergoing septal myectomy or alcohol septal ablation during the 6 months after index evaluation. Survival after the 6-month landmark period was analyzed in a multivariable Cox model.
A total of 1351 patients were included in the landmark analysis. Patients who were more symptomatic and had received more medical treatment at index evaluation were more likely to undergo early SRT. Over a median follow-up period of 10.2 years, the survival was comparable (P = .207) but patients undergoing early SRT had, on average, improved survival compared with the medical treatment group (hazard ratio, 0.66; 95% confidence interval, 0.48-0.90) after adjustment by age and comorbidities. Further analysis revealed significant treatment heterogeneity, with increased benefit of early SRT seen in women (hazard ratio, 0.51; 95% confidence interval, 0.35-0.75), those who are in New York Heart Association functional class III or IV (hazard ratio, 0.52; 95% confidence interval, 0.36-0.76), and patients without diabetes (hazard ratio, 0.59; 95% confidence interval, 0.42-0.82).
In experienced hypertrophic cardiomyopathy centers, early SRT is similar to continued medical treatment for patients with obstructive hypertrophic cardiomyopathy. It appears to improve survival of female patients and those who are in New York Heart Association functional class III or IV.
Hypertrophic cardiomyopathy (HCM) is a relatively common often inherited global heart disease, with complex phenotypic and genetic expression and natural history, affecting both genders and many ...races and cultures. Prevalence is 1:200-1:500, largely based on the disease phenotype with imaging, inferring that 750,000 Americans may be affected by HCM. However, cross-sectional data show that only a fraction are clinically diagnosed, suggesting under-recognition, with most clinicians exposed to small segments of the broad disease spectrum. Highly effective HCM management strategies have emerged, altering clinical course and substantially lowering mortality and morbidity rates. These advances underscore the importance of reliable HCM diagnosis with echocardiography and cardiac magnetic resonance. Family screening with noninvasive imaging will identify relatives with the HCM phenotype, while genetic analysis recognizes preclinical sarcomere gene carriers without left ventricular hypertrophy, but with the potential to transmit disease. Comprehensive initial patient evaluations are important for reliable diagnosis, accurate portrayal of HCM and family history, risk stratification, and distinguishing obstructive versus nonobstructive forms.
Patients with hypertrophic cardiomyopathy (HCM) often have atrial fibrillation, and empiric anticoagulation is recommended in these patients, regardless of other risk factors. However, ...anticoagulation is not recommended for patients who require hemodialysis (HD) because of the high bleeding risk. We herein report a case of left atrial appendage closure (LAAC) using the Watchman FLX system for a dilated phase HCM patient complicated by persistent atrial fibrillation and requiring HD. LAAC with the Watchman FLX system may be an alternative to antithrombotic medications in patients with dilated HCM complicated by atrial fibrillation and requiring HD.
The MYH7 R453 variant has been identified in inherited hypertrophic cardiomyopathy (HCM) and is associated with sudden death and a poor prognosis. The detailed clinical course of HCM with the MYH7 ...R453 variant, from a preserved to a reduced left ventricular ejection fraction, has not been reported. We identified the MYH7 R453C and R453H variants in three patients who progressively developed advanced heart failure requiring circulatory support and summarized the clinical course and echocardiographic parameters of these patients over the years. Because of the rapid disease progression, we consider genetic screening for patients with HCM imperative for future prognosis stratification.
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