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.).

iPSC-Based Modeling of Variable Clinical Presentation in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and a frequent cause of heart failure and sudden cardiac death. Our understanding of the genetic bases and pathogenic mechanisms underlying HCM has improved significantly in the recent past, but the combined effect of various pathogenic gene variants and the influence of genetic modifiers in disease manifestation are very poorly understood. Here, we set out to investigate genotype-phenotype relationships in 2 siblings with an extensive family history of HCM, both carrying a pathogenic truncating variant in the MYBPC3 gene (p.Lys600Asnfs*2), but who exhibited highly divergent clinical manifestations. METHODS: We used a combination of induced pluripotent stem cell (iPSC)-based disease modeling and CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR-associated protein 9)-mediated genome editing to generate patient-specific cardiomyocytes (iPSC-CMs) and isogenic controls lacking the pathogenic MYBPC3 variant. RESULTS: Mutant iPSC-CMs developed impaired mitochondrial bioenergetics, which was dependent on the presence of the mutation. Moreover, we could detect altered excitation-contraction coupling in iPSC-CMs from the severely affected individual. The pathogenic MYBPC3 variant was found to be necessary, but not sufficient, to induce iPSC-CM hyperexcitability, suggesting the presence of additional genetic modifiers. Whole-exome sequencing of the mutant carriers identified a variant of unknown significance in the MYH7 gene (p.Ile1927Phe) uniquely present in the individual with severe HCM. We finally assessed the pathogenicity of this variant of unknown significance by functionally evaluating iPSC-CMs after editing the variant. CONCLUSIONS: Our results indicate that the p.Ile1927Phe variant of unknown significance in MYH7 can be considered as a modifier of HCM expressivity when found in combination with truncating variants in MYBPC3. Overall, our studies show that iPSC-based modeling of clinically discordant subjects provides a unique platform to functionally assess the effect of genetic modifiers.

Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy.

BACKGROUND AND AIMS: Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. METHODS: Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion. RESULTS: At the latest data cut-off, 211 (91.3%) of 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0-228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the week 156 and 180 visits, respectively. Sustained reductions from baseline to week 180 occurred in left ventricular outflow tract gradients (mean [standard deviation]: resting, -40.3 [32.7] mmHg; Valsalva, -55.3 [33.7] mmHg), NT-proBNP (median [interquartile range]: -562 [-1162.5, -209] ng/L), and EQ-5D-5L score (mean [standard deviation]: 0.09 [0.17]). Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (week 24) and 63.9% (week 180). At week 180, 74 (77.9%) of 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten). CONCLUSIONS: Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up.

Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial.

BACKGROUND AND AIMS: The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy (oHCM) is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate effect of treatment with aficamten on biomarker concentrations. METHODS: Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and to evaluate whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. RESULTS: Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% CI 83%-76%, P < .001) and hs-cTnI by 41% (95% CI 49%-32%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. NT-proBNP reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. CONCLUSIONS: NT-proBNP and hs-cTnI concentrations are associated with key variables in oHCM. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy.

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.

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.

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.

AIMS: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. CONCLUSION: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.

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.

Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.

An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease.

Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life.

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.

The impact of diabetes mellitus on the clinical phenotype of hypertrophic cardiomyopathy.

AIMS: Diabetes mellitus (DM) aggravates the clinical features of ischaemic and hypertensive heart diseases and worsens the prognosis of heart failure patients. Hypertrophic cardiomyopathy (HCM) and diabetes coexist fairly frequently in elderly patients but the impact of DM on the clinical phenotype of HCM is yet unknown. We sought to describe if predominant features of heart failure in DM patients exist independently in HCM. METHODS AND RESULTS: We reviewed clinical characteristics of 937 patients, age ≥40, diagnosed with HCM, from two tertiary medical centres in Spain and Israel. A propensity score matched cohort of 294 patients was also analysed. Our cohort comprised 102 HCM patients with diabetes (8.7%). Patients with DM were older at diagnosis {median 56 [interquartile range (IQR) 47-67] vs. 53 (IQR 43-63), P = 0.02} and had a higher prevalence of comorbidities. Hypertrophic cardiomyopathy patients with DM had a higher prevalence of diastolic dysfunction, pulmonary hypertension, significant mitral regurgitation, and pacemaker implantation. Hypertrophic cardiomyopathy patients with DM had a higher New York Heart Association (NYHA) class (P < 0.001) and lower exercise capacity [7.0 METS (IQR 5.0-10.0) vs. 9.0 METS (IQR 6.6-11.0), P = 0.002]. These findings were independent of age, gender, country of origin, hypertension, and coronary artery disease. Patients with diabetes had a significantly higher 15-year mortality (22% vs. 15%, P = 0.03), with no differences in sudden cardiac death, appropriate implanted cardioverter-defibrillator therapy, or heart transplantation. CONCLUSION: Hypertrophic cardiomyopathy patients with diabetes are older and have a higher cardiovascular risk profile. They have a lower functional capacity and more heart failure symptoms due to diastolic dysfunction.

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.

Prevalence and characteristics of transthyretin amyloid cardiomyopathy in hypertrophic cardiomyopathy.

AIMS: Recognition of transthyretin amyloid cardiomyopathy is increasing due to advances in cardiac imaging and diagnostic strategies, but questions remain regarding disease frequency and characteristics. We examined the prevalence and characteristics of transthyretin amyloid cardiomyopathy in older patients with hypertrophic cardiomyopathy of unascertained aetiology. METHODS AND RESULTS: TTRACK was a multicentre, non-interventional, cross-sectional epidemiologic study funded by Pfizer and conducted in 20 hospitals and medical centres in 11 countries (NCT03842163). Eligible patients were aged ≥50 years, had hypertrophic cardiomyopathy (maximal end-diastolic left ventricular wall thickness ≥15 mm on echocardiogram) without an identified genetic or alternative origin at study enrolment, and underwent 99mTechnetium bone scintigraphy, with or without single photon emission computed tomography (SPECT). Cardiac-versus-bone uptake on scans was visually scored from 0 to 3 (Perugini scoring). Patients with grades 1-3 underwent monoclonal protein and laboratory testing and transthyretin (TTR) gene sequencing. Of 766 eligible patients, 691 (90.2%) had scintigraphy alone and 75 (9.8%) scintigraphy plus SPECT. Two hundred and eight patients (27.2%) had grade 2 or 3 cardiac uptake on scintigraphy; 144 (18.8%) had grade 2 or 3 cardiac uptake and no evidence of plasma cell dyscrasia and were diagnosed with transthyretin amyloid cardiomyopathy. Of patients with transthyretin amyloid cardiomyopathy, 11 (7.6%) had a pathogenic TTR gene variant and 34 (23.8%), 74 (51.7%), and 35 (24.5%) had New York Heart Association class I, II, and III/IV heart failure (HF) symptoms, respectively. Clinical and laboratory diagnostic characteristics were observed in ≥90% of patients with transthyretin amyloid cardiomyopathy. The characteristics most strongly associated with transthyretin amyloid cardiomyopathy on multivariable analysis were carpal tunnel syndrome (odds ratio [OR] 54.3; P < 0.0001) and male sex (OR 7.9; P < 0.0001). CONCLUSIONS: In the TTRACK study, almost one in five patients ≥50 years of age with hypertrophic cardiomyopathy had transthyretin amyloid cardiomyopathy. Greater awareness of the frequency and characteristics of transthyretin amyloid cardiomyopathy in older patients with hypertrophic cardiomyopathy are needed to help improve early detection of this debilitating but treatable disease.

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.

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.