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.

Severe Hypertrophic Cardiomyopathy Associated With Hydroxychloroquine in a Young Woman With Systemic Lupus Erythematosus: A Case Report and Review of the Literature.

The use of the antimalarial drug hydroxychloroquine is a standard treatment in patients with systemic lupus erythematosus. It helps reduce disease-associated damage, prevents disease flare, and improves overall survival. The mechanism of action of hydroxychloroquine includes interference with lysosomal degradation of cells leading to the accumulation of vacuoles. Retinopathy is a well-described adverse effect of hydroxychloroquine, thus requiring screening with an ophthalmologist after prolonged use. Although rarely reported, cardiac adverse effects of hydroxychloroquine can also occur. In this report, we present a case of a 23-year-old woman with systemic lupus erythematosus on hydroxychloroquine who presented with stroke possibly due to Libman-Sacks endocarditis and was found to have severe hypertrophic cardiomyopathy on transthoracic echocardiogram.

Simultaneous Ablation of Ventricular Tachycardia and Hemodynamic Improvement of Mid-ventricular Obstructive Hypertrophic Cardiomyopathy by Coronary Venous Ethanol Ablation.

Transvenous coronary ethanol ablation may be successfully applied to simultaneously treat ventricular arrhythmia superimposed within a segment of hypertrophic cardiomyopathy. This presentation nicely describes this emerging technique for ventricular tachycardia ablation and identifies potential additional benefits of venous ethanol administration in patients with left ventricular obstructive physiology.

Unmasking obstruction in hypertrophic cardiomyopathy with postprandial resting and treadmill stress echocardiography.

BACKGROUND: Latent left ventricular outflow tract obstruction (LVOTO) is an important cause of symptoms in patients with hypertrophic cardiomyopathy (HCM) but can be challenging to provoke. OBJECTIVES AND METHODS: To examine the value of postprandial resting and stress echocardiography and utilization of invasive or enhanced drug therapies (surgical myectomy, alcohol septal ablation, disopyramide and mavacamten) in patients with postprandial LVOTO. Consecutive HCM patients without LVOTO underwent routine and postprandial echocardiography at rest, with provocation (Valsalva and standing) and after symptom-limited treadmill stress. RESULTS: Among 252 patients (mean age 58 years, 39% women), postprandial LVOT gradients were higher compared with routine echocardiography at rest (median 9.0 [0-38.0] vs 0 [0-14.0] mmHg, p<0.0001) and with provocation (18.5 [0-70.3] vs 1.5 [0-41.0] mmHg, p<0.0001). Postprandial exercise (PPXSE) gradients were higher in a subset of 44 patients who underwent both postprandial and fasting stress echocardiography, (47.0 [5.3-81.0] vs 17.5 [0-46.0] mmHg, p<0.0001). In total, 49 (19.5%) patients achieved the ≥50 mmHg threshold under routine conditions (rest/provocation); 90 (35.7%) additional patients achieved postprandial gradients ≥50 mmHg (rest/provocation/exercise), 38 (15.1%) with PPXSE alone. A total of 71 patients were treated with 91 invasive or enhanced drug therapies, 32 (45.1%) of whom had gradients ≥50 mmHg only after eating (rest/provocation) and 8 (11.3%) only with PPXSE, with symptom relief in the majority. CONCLUSIONS: Postprandial echocardiography was useful at unmasking LVOTO in more than one third of patients who did not have high gradients otherwise. Eating before echocardiography is a powerful provocative tool in the evaluation of patients with HCM.

Changes in Left Ventricular-Aortic Angulation Are Associated with the Development of Obstruction in Hypertrophic Cardiomyopathy.

OBJECTIVE: To characterize changes in ventricular morphology in patients with hypertrophic cardiomyopathy(HCM) who develop left ventricular outflow tract(LVOT) obstruction. METHODS: We reviewed HCM patients with LVOT obstruction who underwent septal myectomy from May 2012 to June 2023. Among 68 patients initially without obstruction, documented up to 7.6 years (IQR,6.3-9.4) before the operation, a comparison was made with 78 nonobstructive HCM patients over a similar period. Patients who did not develop obstruction were matched with those who did on sex, age, and maximum septal wall thickness during the initial echocardiography, identifying 41 matched pairs. Echocardiographic data, including 5 measures of angulation, were compared between the groups. RESULTS: The median interval between echocardiographic assessments was 7.5 years (IQR,6.3-8.1) among obstructive versus 7.3 years (IQR,6.2-9.0) in nonobstructive patients. Obstructive patients were more likely to have hypertension at both times. The maximum septal wall thickness increased within both groups (both p<0.001), but the magnitude of increase was not different between groups (p=0.130). Obstructive patients exhibited a greater increase in left ventricular (LV) mass (p<0.001) compared to nonobstructive patients (p=0.004). Aortic angulation significantly increased in 4 of the 5 measurements(all p<0.001) in obstructive patients, while nonobstructive patients showed no change. Anterior and posterior mitral valve(MV) leaflet lengths and coaptation lengths remained similar in both groups over time. CONCLUSIONS: The development of LVOT obstruction in patients with HCM was associated with progressive LVOT angulation and increased LV hypertrophy, as reflected by LV mass. Progression to obstruction was not related to changes in the MV leaflet morphology.

Evaluation of clopidogrel response in healthy cats using a novel viscoelastic test and thromboelastography.

Introduction: Cats with cardiomyopathy face an increased risk of arterial thromboembolism (ATE). Although clopidogrel is frequently utilized to mitigate this risk, feline responses to this therapy exhibit variability. This study evaluated 2 viscoelastic devices, thromboelastography (TEG) and Viscoelastic Coagulation Monitor (VCM), for monitoring clopidogrel in cats in comparison to light transmission aggregometry (LTA). Methods: Twenty-eight healthy cats received clopidogrel for 7 days. Blood was collected at baseline and after treatment for analysis by TEG, VCM, and LTA. Results: On LTA, maximum amplitude, slope, and area under the curve (AUC) significantly decreased after treatment (p < 0.0001). On VCM, maximum clot firmness (MCF) significantly increased after treatment (p = 0.002). On TEG, R-time significantly prolonged (p = 0.024), while K and alpha angle significantly changed (p = 0.0002 and p = 0.0014, respectively). There was a moderate negative correlation between TEG R-time and LTA AUC (r = -0.39, p = 0.042). Eight cats were identified as non-responders to clopidogrel. Of the 8 non-responders, 6 (75%) had shortened R time after treatment. VCM appeared to be less discriminatory in identifying non-responders. Discussion: LTA remained the gold standard of monitoring clopidogrel treatment in cats. Unexpected changes on VCM and TEG were likely related to high interindividual and assay variability and increased sensitivity of feline platelets. R-time on TEG may have potential utility for point-of-care monitoring of clopidogrel response in cats.

Genetics of hypertrophic cardiomyopathy: established and emerging implications for clinical practice.

Pathogenic variation in genes encoding proteins of the cardiac sarcomere is responsible for 30%-40% of cases of hypertrophic cardiomyopathy. The main clinical utility of genetic testing is to provide diagnostic confirmation and facilitation of family screening. It also assists in the detection of aetiologies, which require distinct monitoring and treatment approaches. Other clinical applications, including the use of genetic information to inform risk prediction models, have been limited by the challenge of establishing robust genotype-phenotype correlations with actionable consequences, but new data on the interaction between rare and common genetic variation, as well as the emergence of therapies targeting disease-specific pathogenic mechanisms, herald a new era for genetic testing in routine practice.

Hypertrophic Cardiomyopathy: From Medical Treatment to Advanced Heart Failure Therapies.

PURPOSE OF REVIEW: There has been much debate surrounding novel medical therapies and heart transplantation listing challenges in patients with hypertrophic cardiomyopathy (HCM). RECENT FINDINGS: Recent clinical trials led to FDA approval of mavacamten (a cardiac myosin inhibitor), offering symptom relief and potentially delaying/avoiding invasive septal reduction therapies for some patients with HCM and left ventricular outflow obstruction (LVOTO). For those with refractory symptoms and end-stage heart failure, heart transplantation remains the gold standard. However, the concern for the organ allocation system failing to prioritize those individuals persists. HCM is a heterogeneous genetic condition with variable penetration and clinical presentation. Even though a large portion of patients remain asymptomatic, an important minority develops debilitating symptoms refractory to medical therapy. Post-HT short- and long-term outcomes are favorable. However, HT waitlist mortality remains high. For highly selected patients with HCM, a left ventricular assist device is a viable option.

Relationship between obesity and hypertrophic or dilated cardiomyopathy: The role of sex.

Evidence suggests an association between obesity and the risk for cardiomyopathy development; however, robust evidence is still lacking. In this study we sought to explore the relationship of obesity with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) and possible interactions with sex using large-scale epidemiological real-world data. We analysed data from the Nationwide Inpatient Sample of US hospitalisations for the years 2015-2019. There were a total of 46 934 admissions with diagnosis of HCM and 170 924 with DCM. There was a significant interaction between cardiomyopathies' diagnosis with sex and age subgroups; the rates of both DCM and HCM increased with age (p < .001 for both); DCM diagnosis was significantly higher in males compared with females (0.85% vs. 0.35%, p < .001). After adjustment for age, sex, race and presence of arterial hypertension there was a significant stepwise positive association between obesity and the population rates of both cardiomyopathy subtypes. For hospitalised patients with a body mass index (BMI) ≥30 kg/m2 there was an odds ratio (OR) of 1.68 (95% CI: 1.55-1.81, p < .001) for HCM and OR = 1.82 (95% CI: 1.79-1.84, p < .001) for DCM. More importantly, the positive relationship between a cardiomyopathy diagnosis (HCM or DCM) with increasing BMI was driven by the male sex (p < .001 for both) and it was non-significant in females. The findings from this nationwide observational analysis support a sexual dimorphism in the relationship between obesity and HCM or DCM, which should be further investigated.

Is Type 2 Diabetes Mellitus an Independent Risk Factor for Mortality in Hypertrophic Cardiomyopathy?

Background: The mortality rate of hypertrophic cardiomyopathy (HCM) has decreased between 1999 and 2020. The risk factors for sudden cardiac death (SCD) in HCM were updated in the American Heart Association (AHA)/American College of Cardiology Foundation (ACCF) 2020 guidelines by adding new risk factors, like the late gadolinium enhancement on cardiac magnetic resonance imaging (MRI). Type 2 diabetes mellitus (T2DM) is a major risk factor for most cardiac diseases; however, it is not included in these guidelines due to a lack of strong evidence of a correlation between T2DM and mortality in HCM. Therefore, we sought to investigate if T2DM increases the 5-year risk rate for adverse outcomes, such as heart failure and all-cause mortality in patients with HCM. Methods: We collected patient data from January 1, 2018, to March 1, 2023, using the TriNetX database. The sample included 80,502 individuals with HCM, then divided into two cohorts based on the absence (58,573; cohort 1) or presence (15,296; cohort 2) of T2DM. The two matched groups then underwent survival and risk analyses for all-cause mortality or the first incidence of heart failure diagnosis within 5 years from the point in time when the selection criteria were first met. Results: We found a statistically significant increase in all-cause mortality and new-onset heart failure in HCM patients with diabetes compared to those without diabetes after adjusting for major risk factors. Conclusions: This is one of the largest retrospective cohort studies that examined the correlation between T2DM and adverse outcomes in patients with HCM. This underlines the need for future prospective studies investigating the effects of T2DM on HCM outcomes.

Morphological anomalies in obstructive hypertrophic cardiomyopathy: Insights from four-dimensional computed tomography and surgical correlation.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder in which left ventricular outflow tract obstruction critically affects symptoms and prognosis. Traditionally, left ventricular outflow tract obstruction was primarily attributed to septal hypertrophy with systolic anterior motion of the mitral valve. However, recent evidence highlights significant contributions from the mitral valve and papillary muscle anomalies, as well as an apical-basal muscle bundle observed in HCM patients. Accurate morphological assessment is essential when considering septal reduction therapy. While transesophageal echocardiography and cardiac magnetic resonance are recommended for assessing the anomalous structures, four-dimensional computed tomography offers superior spatial resolution and multiplanar reconstruction capabilities. These features enable the evaluation of details of the morphological anomalies, such as the apical-basal muscle band, papillary muscle anomalies, subaortic stenosis, and right ventricular outflow tract obstruction. Based on the detailed assessment of these morphological features, four-dimensional computed tomography has been utilized for planning of surgical correction in a comprehensive HCM center. This approach facilitates the intervention strategies and may improve outcomes in septal reduction therapy for obstructive HCM.

Machine Learning in Hypertrophic Cardiomyopathy: Nonlinear Model From Clinical and CMR Features Predicting Cardiovascular Events.

BACKGROUND: The cumulative burden of hypertrophic cardiomyopathy (HCM) is significant, with a noteworthy percentage (10%-15%) of patients with HCM per year experiencing major adverse cardiovascular events (MACEs). A current risk stratification scheme for HCM had only limited accuracy in predicting sudden cardiac death (SCD) and failed to account for a broader spectrum of adverse cardiovascular events and cardiac magnetic resonance (CMR) parameters. OBJECTIVES: This study sought to develop and evaluate a machine learning (ML) framework that integrates CMR imaging and clinical characteristics to predict MACEs in patients with HCM. METHODS: A total of 758 patients with HCM (67% male; aged 49 ± 14 years) who were admitted between 2010 and 2017 from 4 medical centers were included. The ML model was built on the internal discovery cohort (533 patients with HCM, admitted to Fuwai Hospital, Beijing, China) by using the light gradient-boosting machine and internally evaluated using cross-validation. The external test cohort consisted of 225 patients with HCM from 3 medical centers. A total of 14 CMR imaging features (strain and late gadolinium enhancement [LGE]) and 23 clinical variables were evaluated and used to inform the ML model. MACEs included a composite of arrhythmic events, SCD, heart failure, and atrial fibrillation-related stroke. RESULTS: MACEs occurred in 191 (25%) patients over a median follow-up period of 109.0 months (Q1-Q3: 73.0-118.8 months). Our ML model achieved areas under the curve (AUCs) of 0.830 and 0.812 (internally and externally, respectively). The model outperformed the classic HCM Risk-SCD model, with significant improvement (P < 0.001) of 22.7% in the AUC. Using the cubic spline analysis, the study showed that the extent of LGE and the impairment of global radial strain (GRS) and global circumferential strain (GCS) were nonlinearly correlated with MACEs: an elevated risk of adverse cardiovascular events was observed when these parameters reached the high enough second tertiles (11.6% for LGE, 25.8% for GRS, -17.3% for GCS). CONCLUSIONS: ML-empowered risk stratification using CMR and clinical features enabled accurate MACE prediction beyond the classic HCM Risk-SCD model. In addition, the nonlinear correlation between CMR features (LGE and left ventricular pressure gradient) and MACEs uncovered in this study provides valuable insights for the clinical assessment and management of HCM.

Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.

Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1L580P by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1L580P-specific disease mechanism provoking cardiac hypertrophy. The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers. LZTR1 complex dysfunction results in the accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data show that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Uni- or biallelic genetic correction of the LZTR1L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies.

Patterns of Left Ventricular Remodelling in Children and Young Patients with Hypertrophic Cardiomyopathy.

Introduction: The aim of this study was to evaluate the age at onset, clinical course, and patterns of left ventricular (LV) remodelling during follow-up in children and young patients with hypertrophic cardiomyopathy (HCM). Methods: We included consecutive patients with sarcomeric or non-syndromic HCM below 18 years old. Three pre-specified patterns of LV remodelling were assessed: maximal LV wall thickness (MLVWT) thickening; MLVWT thinning with preserved LV ejection fraction; and MLVWT thinning with progressive reduction in LV ejection fraction (hypokinetic end-stage evolution). Results: Fifty-three patients with sarcomeric/non-syndromic HCM (mean age 9.4 ± 5.5 years, 68% male) fulfilled the inclusion criteria. In total, 32 patients (60%) showed LV remodelling: 3 patients (6%) exhibited MLVWT thinning; 16 patients (30%) showed MLVWT thickening; and 13 patients (24%) progressed to hypokinetic end-stage HCM. Twenty-one patients (40%) had no LV remodelling during follow-up. In multivariate analysis, MLVWT was a predictor of the hypokinetic end-stage remodelling pattern during follow-up (OR 1.17 [95%CI 1.01-1.36] per 1 mm increase, p-value 0.043), regardless of sarcomeric variants and New York Heart Association class. Two patients with sarcomeric HCM, showing a pattern of MLVWT regression during childhood, experienced progression during adolescence. Conclusions: Different patterns of LV remodelling were observed in a cohort of children with sarcomeric/non-syndromic HCM. Interestingly, a pattern of progressive MLVWT thinning during childhood, with new progression of MLVWT during adolescence, was noted. A better understanding of the remodelling mechanisms in children with sarcomeric HCM may be relevant to defining the timing and possible efficacy of new targeted therapies in the preclinical stage of the disease.

Diagnostic yield of head-up tilt table test in hypertrophic cardiomyopathy and unexplained syncope: the knot does not seem to be unraveling.

BACKGROUND: Conflicting results have been published considering the diagnostic performance of head-up tilt test (HUTT) in patients with hypertrophic cardiomyopathy (HCM). We aimed to conduct a meta-analysis to evaluate the diagnostic value of HUTT in the evaluation of unexplained syncope in patients with HCM. METHODS: We performed a structured systematic database search using the following keywords: hypertrophic cardiomyopathy, syncope, unexplained syncope, head-up tilt test, tilt table test, tilt testing, orthostatic stress, autonomic function, autonomic response. Studies in which the HUTT was used to define autonomic dysfunction in patients with syncope at baseline or without syncope were included in the final analysis. RESULTS: A total of 252 HCM patients from 6 studies (159 patients without a history of syncope and 93 with a history of syncope, respectively) were evaluated. HUTT was positive in 50 (19.84%) of 252 patients (in 21 of 93 patients (22.58%) with a history of syncope and in 29 of 159 patients (18.24%) without a history of syncope, respectively). The pooled total sensitivity and specificity of the HUTT for detecting syncope were 22.1% (14.8-35.1%) and 83.6% (73.2-91.6%), respectively. The summary receiver operator curve showed that HUTT had an only modest discriminative ability for syncope with an area under the curve value of 0.565 (0.246-0.794). CONCLUSION: Although HUTT has significant limitations in diagnosis of unexplained syncope in patients with HCM, it may still be used to determine hypotensive susceptibility. Other autonomic tests can be used in diagnostic workflow in this population.

Metabolic remodeling and calcium handling abnormality in induced pluripotent stem cell-derived cardiomyocytes in dilated phase of hypertrophic cardiomyopathy with MYBPC3 frameshift mutation.

Hypertrophic cardiomyopathy (HCM) is an inherited disorder characterized by left ventricular hypertrophy and diastolic dysfunction, and increases the risk of arrhythmias and heart failure. Some patients with HCM develop a dilated phase of hypertrophic cardiomyopathy (D-HCM) and have poor prognosis; however, its pathogenesis is unclear and few pathological models exist. This study established disease-specific human induced pluripotent stem cells (iPSCs) from a patient with D-HCM harboring a mutation in MYBPC3 (c.1377delC), a common causative gene of HCM, and investigated the associated pathophysiological mechanisms using disease-specific iPSC-derived cardiomyocytes (iPSC-CMs). We confirmed the expression of pluripotent markers and the ability to differentiate into three germ layers in D-HCM patient-derived iPSCs (D-HCM iPSCs). D-HCM iPSC-CMs exhibited disrupted myocardial sarcomere structures and an increased number of damaged mitochondria. Ca2+ imaging showed increased abnormal Ca2+ signaling and prolonged decay time in D-HCM iPSC-CMs. Cell metabolic analysis revealed increased basal respiration, maximal respiration, and spare-respiratory capacity in D-HCM iPSC-CMs. RNA sequencing also showed an increased expression of mitochondrial electron transport system-related genes. D-HCM iPSC-CMs showed abnormal Ca2+ handling and hypermetabolic state, similar to that previously reported for HCM patient-derived iPSC-CMs. Although further studies are required, this is expected to be a useful pathological model for D-HCM.

[Bibliometrics Analysis of Studies on Hypertrophic Cardiomyopathy From 2018 to 2022].

Objective To analyze the research progress and hot topics in hypertrophic cardiomyopathy from 2018 to 2022.Methods The publications in the field of hypertrophic cardiomyopathy from January 1,2018 to December 31,2022 were retrieved from Web of Science core collection database and included for a bibliometric analysis.Results A total of 6355 publications were included,with an average citation frequency of 7 times.The year 2021 witnessed the most publications (1406).The analysis with VOSviewer showed that the research on sudden death related to hypertrophic cardiomyopathy,especially the predictive value of late gadolinium-enhanced cardiac MRI in sudden death,was a hot topic.In addition,gene detection and the new drug mavacamten became hot research topics.The United States was the country with the largest number of publications and the highest citation frequency in this field.Chinese scholars produced the second largest number of publications,which,however,included few high-quality research results.Conclusions Risk stratification and prevention of sudden death is still an important and hot research content in the field of hypertrophic cardiomyopathy.Chinese scholars should carry out multi-center cooperation in the future to improve the research results.