Quality of life and societal costs in hypertrophic cardiomyopathy:protocol of the AFFECT-HCM study

Background: Ever since the first description of hypertrophic cardiomyopathy (HCM), the most common genetic cardiac disease, tremendous progress has been made in the evaluation and management of HCM patients, but little attention has been focused on the impact of HCM on societal costs and quality of life (QoL). Aims: This paper describes the study protocol for the AFFECT-HCM study into burden of disease (BoD), which aims to estimate health-related QoL and societal costs in HCM patients and genotype-positive phenotype-negative (G+/P−) relatives during a one-year follow-up study, and relate this to the phenotypical HCM expression. Methods: A total of 400 Dutch HCM patients and 100 G+/P− subjects will be followed for one year in a prospective, multi-centre, prevalence-based BoD study. Societal costs will be measured via a bottom-up approach using the cost questionnaires iMCQ and iPCQ. For QoL, the generic EQ-5D-5L and disease-specific Kansas City Cardiomyopathy Questionnaire will be used. QoL and societal costs will be compared with phenotype-specific HCM characteristics and other determinants to identify factors that influence BoD. Accelerometry will test the correlation between BoD and physical activity. Conclusion: The AFFECT-HCM study will evaluate the BoD in HCM patients and G+/P− subjects to improve the understanding of the societal and economic impact of HCM.</p

Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by sarcomere gene mutations (genotype-positive HCM) in ≈50% of patients and occurs in the absence of mutations (genotype-negative HCM) in the other half of patients. We explored how alterations in the metabolomic and lipidomic landscape are involved in cardiac remodeling in both patient groups. METHODS: We performed proteomics, metabolomics, and lipidomics on myectomy samples (genotype-positive N=19; genotype-negative N=22; and genotype unknown N=6) from clinically well-phenotyped patients with HCM and on cardiac tissue samples from sex- and age-matched and body mass index-matched nonfailing donors (N=20). These data sets were integrated to comprehensively map changes in lipid-handling and energy metabolism pathways. By linking metabolomic and lipidomic data to variability in clinical data, we explored patient group-specific associations between cardiac and metabolic remodeling. RESULTS:HCM myectomy samples exhibited (1) increased glucose and glycogen metabolism, (2) downregulation of fatty acid oxidation, and (3) reduced ceramide formation and lipid storage. In genotype-negative patients, septal hypertrophy and diastolic dysfunction correlated with lowering of acylcarnitines, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines. In contrast, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines were positively associated with septal hypertrophy and diastolic impairment in genotype-positive patients. CONCLUSIONS: We provide novel insights into both general and genotype-specific metabolic changes in HCM. Distinct metabolic alterations underlie cardiac disease progression in genotype-negative and genotype-positive patients with HCM.</p

Cancer Treatment–Related Complications in Patients With Hypertrophic Cardiomyopathy

Objective: To describe the potential clinical cardiotoxicity of oncological treatments in a cohort of consecutive patients with hypertrophic cardiomyopathy (HCM), systematically followed-up at two national referral centers for HCM. Cardiotoxicity relates to the direct effects of cancer-related treatment on heart function, commonly presenting as left ventricular contractile dysfunction. However, limited data are available regarding cardiotoxic effects on HCM as most studies have not specifically analyzed the effects of oncological treatment in HCM populations. This gap in knowledge may lead to unjustified restriction of HCM patients from receiving curative cancer treatments. Methods: We retrospectively analyzed clinical and instrumental data of all consecutive HCM patients who underwent oncological treatment between January 2000 and December 2020 collected in a centralized database. Results: Of 3256 HCM patients, 121 (3.7%) had cancer; 110 (90.9%) underwent oncological surgery, 45 (37.2%) received chemotherapy, and 22 (18.2%) received chest radiation therapy (cRT). After a median follow-up of 5.2 years (Q1-Q3: 2-13 years) from oncological diagnosis, 32 patients died. The cumulative survival at 5 years was 79.9%. The cause of death was mainly attributed to the oncological condition, whereas four patients died of sudden cardiac death without receiving previous chemotherapy or cRT. No patient interrupted or reduced the dose of oncological treatment due to cardiac dysfunction. No sustained ventricular tachyarrhythmia was induced by chemotherapy or radiation therapy. Conclusion: Cancer treatment was well tolerated in HCM patients. In our consecutive series, none died of cardiovascular complications induced by chemotherapy or cRT and they did not require interruption or substantial treatment tapering due to cardiovascular toxic effects. Although a multidisciplinary evaluation is necessary and regimens must be tailored individually, the diagnosis of HCM per se should not be considered a contraindication to receive optimal curative cancer treatment.</p

Cancer Treatment–Related Complications in Patients With Hypertrophic Cardiomyopathy

Objective: To describe the potential clinical cardiotoxicity of oncological treatments in a cohort of consecutive patients with hypertrophic cardiomyopathy (HCM), systematically followed-up at two national referral centers for HCM. Cardiotoxicity relates to the direct effects of cancer-related treatment on heart function, commonly presenting as left ventricular contractile dysfunction. However, limited data are available regarding cardiotoxic effects on HCM as most studies have not specifically analyzed the effects of oncological treatment in HCM populations. This gap in knowledge may lead to unjustified restriction of HCM patients from receiving curative cancer treatments. Methods: We retrospectively analyzed clinical and instrumental data of all consecutive HCM patients who underwent oncological treatment between January 2000 and December 2020 collected in a centralized database. Results: Of 3256 HCM patients, 121 (3.7%) had cancer; 110 (90.9%) underwent oncological surgery, 45 (37.2%) received chemotherapy, and 22 (18.2%) received chest radiation therapy (cRT). After a median follow-up of 5.2 years (Q1-Q3: 2-13 years) from oncological diagnosis, 32 patients died. The cumulative survival at 5 years was 79.9%. The cause of death was mainly attributed to the oncological condition, whereas four patients died of sudden cardiac death without receiving previous chemotherapy or cRT. No patient interrupted or reduced the dose of oncological treatment due to cardiac dysfunction. No sustained ventricular tachyarrhythmia was induced by chemotherapy or radiation therapy. Conclusion: Cancer treatment was well tolerated in HCM patients. In our consecutive series, none died of cardiovascular complications induced by chemotherapy or cRT and they did not require interruption or substantial treatment tapering due to cardiovascular toxic effects. Although a multidisciplinary evaluation is necessary and regimens must be tailored individually, the diagnosis of HCM per se should not be considered a contraindication to receive optimal curative cancer treatment.</p

Phenotypic variability of filamin C–related cardiomyopathy:Insights from a novel Dutch founder variant

Background: Dilated cardiomyopathy (DCM) can be caused by truncating variants in the filamin C gene (FLNC). A new pathogenic FLNC variant, c.6864_6867dup, p.(Val2290Argfs∗23), was recently identified in Dutch patients with DCM. Objectives: The report aimed to evaluate the phenotype of FLNC variant carriers and to determine whether this variant is a founder variant. Methods: Clinical and genetic data were retrospectively collected from variant carriers. Cardiovascular magnetic resonance studies were reassessed. Haplotypes were reconstructed to determine a founder effect. The geographical distribution and age of the variant were determined. Results: Thirty-three individuals (of whom 23 [70%] were female) from 9 families were identified. Sudden cardiac death was the first presentation in a carrier at the age of 28 years. The median age at diagnosis was 41 years (range 19–67 years). The phenotype was heterogeneous. DCM with left ventricular dilation and reduced ejection fraction (&lt;45%) was present in 11 (33%) individuals, 3 (9%) of whom underwent heart transplantation. Cardiovascular magnetic resonance showed late gadolinium enhancement in 13 (65%) of the assessed individuals, primarily in a ringlike distribution. Nonsustained ventricular arrhythmias were detected in 6 (18%), and 5 (15%) individuals received an implantable cardioverter-defibrillator. A shared haplotype spanning 2.1 Mb was found in all haplotyped individuals. The variant originated between 275 and 650 years ago. Conclusion: The pathogenic FLNC variant c.6864_6867dup, p.(Val2290Argfs∗23) is a founder variant originating from the south of the Netherlands. Carriers are susceptible to developing heart failure and ventricular arrhythmias. The cardiac phenotype is characterized by ringlike late gadolinium enhancement, even in individuals without significantly reduced left ventricular function.</p