Safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy: A 36-week analysis from FOREST-HCM.

AIMS: The aim of this study was to report safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) over 36 weeks in the ongoing FOREST-HCM trial. METHODS AND RESULTS: Patients were started on aficamten 5 mg daily, with doses adjusted in 5-mg increments (5-20 mg) at ≥2-week intervals according to site-read left ventricular ejection fraction (LVEF). Aficamten dose was increased if LVEF ≥55%, maintained if LVEF 50-54%, decreased if LVEF 40-<50%, and temporarily interrupted if LVEF <40%. Safety and efficacy were assessed over 36 weeks. Overall, 34 patients were enrolled (mean age 57.2 ± 15.3 years, 62% female, 41% in New York Heart Association [NYHA] class III). Over 36 weeks, 82.3% achieved 15-20 mg daily dose and there was a modest reduction in LVEF by -4.3% ± 5.2 from 70% ± 6.1 (p < 0.0001). At Week 36, NYHA class improved by ≥1 class in 27 (79.4%) patients. Mean Kansas City Cardiomyopathy Questionnaire clinical summary score improved by 13.8 ± 12.5 points relative to baseline. Median (interquartile range) levels of N-terminal pro-B-type natriuretic peptide were significantly improved from baseline (-665.5 pg/ml [-1244.0, -232.0]; p < 0.0001), while high-sensitivity cardiac troponin I was unchanged (-2.7 ng/L [-11.3, 1.6]; p = 0.25). There were no drug discontinuations due to adverse events. LVEF <50% occurred in 2 (5.9%) patients, one following pulmonary vein isolation and one associated with atrial fibrillation. CONCLUSIONS: Over 36 weeks, aficamten appeared safe and effective in the studied patients with nHCM.

REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy.

BACKGROUND: LMNA (lamin A/C)-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. METHODS: REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA-related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23-72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences (P>0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, -24.2 to 34.1]; P=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; P=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; P=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; P=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; P=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; P=0.84) were similar between groups. No new safety findings were observed. CONCLUSIONS: Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA-related dilated cardiomyopathy. REGISTRATION: URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.

Clinical Relevance of the Systematic Analysis of Copy Number Variants in the Genetic Study of Cardiomyopathies.

Cardiomyopathies (CMs), one of the main causes of sudden death among the young population, are a heterogeneous group of myocardial diseases, usually with a genetic cause. Next-Generation Sequencing (NGS) has expanded the genes studied for CMs; however, the yield is still around 50%. The systematic study of Copy Number Variants (CNVs) could contribute to improving our diagnostic capacity. These alterations have already been described as responsible for cardiomyopathies in some cases; however, their impact has been rarely assessed. We analyzed the clinical significance of CNVs in cardiomyopathies by studying 11,647 affected patients, many more than those considered in previously published studies. We evaluated the yield of the systematic study of CNVs in a production context using NGS and a novel CNV detection software tool v2.0 that has demonstrated great efficacy, maximizing sensitivity and avoiding false positives. We obtained a CNV analysis yield of 0.8% that fluctuated depending on the type of cardiomyopathy studied (0.29% HCM, 1.41% DCM, 1.88% ARVC, 1.8% LVNC, 1.45% RCM), and we present the frequency of occurrence for 18 genes that agglutinate the 95 pathogenic/likely pathogenic CNVs detected. We conclude the importance of including in diagnostic tests a systematic study of these genetic alterations for the different cardiomyopathies.

Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

Phenotype and Clinical Outcomes in Desmin-Related Arrhythmogenic Cardiomyopathy.

BACKGROUND: Desmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce. OBJECTIVES: This study sought to provide information on the clinical phenotype and outcomes of patients with ACM caused by pathogenic variants of the DES gene in a multicenter cohort. METHODS: We collected phenotypic and outcomes data from 16 families with DES-related ACM from 10 European centers. We assessed in vitro DES aggregates. Major cardiac events were compared to historical controls with lamin A/C truncating variant (LMNA-tv) and filament C truncating variant (FLNC-tv) ACM. RESULTS: Of 82 patients (54% males, median age: 36 years), 11 experienced sudden cardiac death (SCD) (n = 7) or heart failure death (HFd)/heart transplantation (HTx) (n = 4) before clinical evaluation. Among 68 survivors, 59 (86%) presented signs of cardiomyopathy, with left ventricular (LV) dominant (50%) or biventricular (34%) disease. Mean LV ejection fraction was 51% ± 13%; 36 of 53 had late gadolinium enhancement (ring-like pattern in 49%). During a median of 6.73 years (Q1-Q3: 3.55-9.52 years), the composite endpoint (sustained ventricular tachycardia, aborted SCD, implantable cardioverter-defibrillator therapy, SCD, HFd, and HTx) was achieved in 15 additional patients with HFd/HTx (n = 5) and SCD/aborted SCD/implantable cardioverter-defibrillator therapy/sustained ventricular tachycardia (n = 10). Male sex (P = 0.004), nonsustained ventricular tachycardia (P = 0.017) and LV ejection fraction ≤50% (P = 0.012) were associated with the composite endpoint. Males with DES variants had similar outcomes to historical FLNC-tv and LMNA-tv controls. However, females showed better outcomes than those with LMNA-tv. In vitro experiments showed the characteristic finding of DES aggregates in 7 of 12 variants. CONCLUSIONS: DES ACM is associated with poor outcomes which can be predicted with potentially successful treatments, underscoring the importance of familial evaluation and genetic studies to identify at risk individuals.

Penetrance of Dilated Cardiomyopathy in Genotype-Positive Relatives.

BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.

Pregnancy in women with dilated cardiomyopathy genetic variants.

INTRODUCTION AND OBJECTIVES: Limited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients. METHODS: We studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month. RESULTS: A total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy. CONCLUSIONS: Cardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.

BACKGROUND: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219826.

Impact of SARS-CoV-2 infection in patients with cardiac amyloidosis: Results of a multicentre registry / Impacto de la infección por SARS-CoV-2 en pacientes con amiloidosis cardiaca: resultados de un registro multicéntrico

Background Descriptions on impact of SARS-CoV-2 infection in patients with cardiac amyloidosis (CA) are lacking. Our aim was to describe the prognosis of those patients. Methods Retrospective observational study of unvaccinated patients with CA who developed SARS-CoV-2 infection enrolled in eleven centres (March 2020 to May 2021). Descriptive analysis of basal characteristics, hospitalization, mortality, and severe clinical course was performed. Comparisons to a population-based control group were made. Results Forty-one patients were identified. Most patients had wild-type transthyretin CA (61%) and were on NYHA Class II–III (80.5%). CA patients were commonly hospitalized (73.2%) and those were more symptomatic than outpatients (p=0.035). The 24.4% of CA patients died as consequence of SARS-CoV-2 infection. Patients with CA had an increased risk of hospitalization [OR 6.23 (3.05–12.74), p<0.001] and mortality [OR 2.18 (1.01–4.68), p=0.047] when compared to control population after adjustment by age and sex. After a medium follow-time of 311 days, 41.5% of the CA cohort died. Conclusions SARS-CoV-2 infection is associated with high mortality and hospitalization rates in patients with CA, which exceed that expected by their sex and advanced age (AU)

Antecedentes El impacto de la infección por SARS-CoV-2 en pacientes con amiloidosis cardíaca (AC) es desconocido. El principal objetivo de este estudio es describir el pronóstico de estos pacientes. Métodos Estudio observacional retrospectivo de pacientes con AC no vacunados que desarrollaron infección por SARS-CoV-2 identificados en 11 centros (marzo 2020/mayo 2021). Se realiza un análisis descriptivo de características basales, hospitalización, mortalidad y curso clínico grave, y se comparan los resultados con una cohorte poblacional. Resultados Cuarenta y un pacientes fueron identificados. La mayoría eran AC por transtirretina wild-type (61%) y estaban en clase NYHA II-III (80,5%). La mayoría de los pacientes fueron hospitalizados (73,2%), los cuales tenían peor clase funcional que los ambulatorios (p=0,035). El 24,4% de los pacientes fallecieron como consecuencia de la infección. Los pacientes con AC tenían un mayor riesgo de hospitalización (OR: 6,23; 3.05-12.74; p<0,001) y fallecimiento (OR: 2,18; 1,01-4,68; p=0,047) que la cohorte poblacional tras ajuste por sexo y edad. Tras un seguimiento medio de 311 días, el 41,5% de los pacientes fallecieron. Conclusiones La infección por SARS-CoV-2 presenta alto riesgo de mortalidad y hospitalización en pacientes con AC, mayor que la esperada por su sexo y edad (AU)

Giant ascending aortic aneurysm with impending rupture as presentation of cutis laxa 1B: a case report.

Background: Thoracic aortic aneurysms are rarely symptomatic but can result in acute aortic syndromes, associated with a high mortality rate. While most cases may be acquired, a genetic basis is evident in approximately 20-25% of the cases, especially among patients under 50 years of age, and those exhibiting syndromic features or family history. Although autosomal dominant inheritance is predominant in familial aortopathies, exceptions exist, such as cutis laxa 1B (CL1B)-related aortic disease, caused by variants in EFEMP2 gene, that follows an autosomal recessive inheritance pattern. Case summary: We present the case of a 26-year-old male with a giant ascending aorta aneurysm and massive pericardial effusion, which was ultimately diagnosed of CL1B due to the p.Ser137Cys variant in the EFEMP2 gene in homozygosis. The patient underwent successful ascending aorta replacement (Bentall´s procedure). There were not complications or further events after 2 years of follow-up. Discussion: This case underscores the importance of genetic testing in young patients presenting with aortopathies, syndromic features, or atypical presentations, irrespective of family history.

A cost-effectiveness analysis of hypertrophic cardiomyopathy sudden cardiac death risk algorithms for implantable cardioverter defibrillator decision-making.

AIMS: To conduct a contemporary cost-effectiveness analysis examining the use of implantable cardioverter defibrillators (ICD) for primary prevention in patients with hypertrophic cardiomyopathy (HCM). METHODS: A discrete-time Markov model was used to determine the cost-effectiveness of different ICD decision-making rules for implantation. Several scenarios were investigated including the reference scenario of implantation rates according to observed real world practice. A 12-year time horizon with an annual cycle length was used. Transition probabilities used in the model were obtained using Bayesian analysis. The study has been reported according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Using a 5-year SCD risk threshold of 6% was cheaper than current practice and has marginally better total quality adjusted life years (QALYs). This is the most cost-effective of the options considered, with an incremental cost effectiveness ratio of £834 per QALY. Sensitivity analyses highlighted that this decision is largely driven by what health related quality of life (HRQL) is attributed to ICD patients and time horizon. CONCLUSION: We present a timely new perspective on HCM ICD cost-effectiveness, using methods reflecting real-world practice. While we have shown that a 6% 5-year SCD risk cut-off provides the best cohort stratification to aid ICD decision-making, this will also be influenced by the particular values of costs and HRQL for subgroups or at a local level. The process of explicitly demonstrating the main factors which drive conclusions from such an analysis will help to inform shared decision-making in this complex area for all stakeholders concerned.

Impact of SARS-CoV-2 infection in patients with cardiac amyloidosis: Results of a multicentre registry.

BACKGROUND: Descriptions on impact of SARS-CoV-2 infection in patients with cardiac amyloidosis (CA) are lacking. Our aim was to describe the prognosis of those patients. METHODS: Retrospective observational study of unvaccinated patients with CA who developed SARS-CoV-2 infection enrolled in eleven centres (March 2020 to May 2021). Descriptive analysis of basal characteristics, hospitalization, mortality, and severe clinical course was performed. Comparisons to a population-based control group were made. RESULTS: Forty-one patients were identified. Most patients had wild-type transthyretin CA (61%) and were on NYHA Class II-III (80.5%). CA patients were commonly hospitalized (73.2%) and those were more symptomatic than outpatients (p=0.035). The 24.4% of CA patients died as consequence of SARS-CoV-2 infection. Patients with CA had an increased risk of hospitalization [OR 6.23 (3.05-12.74), p<0.001] and mortality [OR 2.18 (1.01-4.68), p=0.047] when compared to control population after adjustment by age and sex. After a medium follow-time of 311 days, 41.5% of the CA cohort died. CONCLUSIONS: SARS-CoV-2 infection is associated with high mortality and hospitalization rates in patients with CA, which exceed that expected by their sex and advanced age.

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure.

BACKGROUND AND AIMS: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. METHODS: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). CONCLUSIONS: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants.

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

Lamin A/C Ablation Restricted to Vascular Smooth Muscle Cells, Cardiomyocytes, and Cardiac Fibroblasts Causes Cardiac and Vascular Dysfunction.

Mutations in the LMNA gene (encoding lamin A/C proteins) cause several human cardiac diseases, including dilated cardiomyopathies (LMNA-DCM). The main clinical risks in LMNA-DCM patients are sudden cardiac death and progressive left ventricular ejection fraction deterioration, and therefore most human and animal studies have sought to define the mechanisms through which LMNA mutations provoke cardiac alterations, with a particular focus on cardiomyocytes. To investigate if LMNA mutations also cause vascular alterations that might contribute to the etiopathogenesis of LMNA-DCM, we generated and characterized Lmnaflox/floxSM22αCre mice, which constitutively lack lamin A/C in vascular smooth muscle cells (VSMCs), cardiac fibroblasts, and cardiomyocytes. Like mice with whole body or cardiomyocyte-specific lamin A/C ablation, Lmnaflox/floxSM22αCre mice recapitulated the main hallmarks of human LMNA-DCM, including ventricular systolic dysfunction, cardiac conduction defects, cardiac fibrosis, and premature death. These alterations were associated with elevated expression of total and phosphorylated (active) Smad3 and cleaved (active) caspase 3 in the heart. Lmnaflox/floxSM22αCre mice also exhibited perivascular fibrosis in the coronary arteries and a switch of aortic VSMCs from the 'contractile' to the 'synthetic' phenotype. Ex vivo wire myography in isolated aortic rings revealed impaired maximum contraction capacity and an altered response to vasoconstrictor and vasodilator agents in Lmnaflox/floxSM22αCre mice. To our knowledge, our results provide the first evidence of phenotypic alterations in VSMCs that might contribute significantly to the pathophysiology of some forms of LMNA-DCM. Future work addressing the mechanisms underlying vascular defects in LMNA-DCM may open new therapeutic avenues for these diseases.