•Current treatment of obstructive hypertrophic cardiomyopathy is targeted at symptom relief by means of beta-blockers, calcium channel blockers and disopyramide, with invasive septal-reduction ...therapy considered as the only definitive therapy for those with refractory symptoms. Mavacamten, a cardiac myosin modulator, reduces the pathologic actin-myosin interactions that are characteristic of hypertrophic cardiomyopathy, leading to improved cardiac energetics and reduction in hypercontractility.•EXPLORER-HCM and VALOR-HCM were groundbreaking trials in hypertrophic cardiomyopathy that demonstrated that mavacamten improves exercise capacity, left ventricular outflow tract obstruction and symptoms in patients with obstructive hypertrophic cardiomyopathy; however, long-term safety and efficacy data are needed.•Hypertrophic cardiomyopathy is a complex and heterogeneous disease, and not all patients will respond to mavacamten, nor is it accessible to all patients, given its cost, frequency of required monitoring and pharmacological properties.
For many years, treatment of hypertrophic cardiomyopathy (HCM) has focused on non-disease-specific therapies. Cardiac myosin modulators (ie, mavacamten and aficamten) reduce the pathologic actin-myosin interactions that are characteristic of HCM, leading to improved cardiac energetics and reduction in hypercontractility. Several recently published randomized clinical trials have demonstrated that mavacamten improves exercise capacity, left ventricular outflow tract obstruction and symptoms in patients with obstructive HCM and may delay the need for septal-reduction therapy. Long-term data in real-world populations will be needed to fully assess the safety and efficacy of mavacamten. Importantly, HCM is a complex and heterogeneous disease, and not all patients will respond to mavacamten; therefore, careful patient selection and shared decision making will be necessary in guiding the use of mavacamten in obstructive HCM.
•Doses of aficamten were assessed for nonobstructive hypertrophic cardiomyopathy.•Treatment with aficamten was well tolerated.•Improvements in symptoms and angina were observed.•Changes in clinical ...status paralleled improvements in cardiac biomarkers.•Our findings support a larger pivotal phase 3 trial (ACACIA-HCM, NCT06081894).
This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM).
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.
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.
Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers.
ClinicalTrials.gov Identifier: NCT04219826
Summary of results from REDWOOD-HCM Cohort 4: Data in panel C are presented as mean and 95% CI; data in panel D are presented as mean and SD. Horizontal dotted lines represent the thresholds at which IP was down-titrated to the previous dosage (yellow) or was discontinued (red). CI, confidence interval; HCM, hypertrophic cardiomyopathy; hs-cTnI, high-sensitivity cardiac troponin T and I; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire clinical summary score; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow gradient; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SD, standard deviation. Display omitted
In symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, mavacamten is commercially approved to help improve left ventricular (LV) outflow tract (LVOT) gradients, symptoms, and reduce ...eligibility for septal reduction therapy (SRT) under the risk evaluation and mitigation strategy (REMS) program. We sought to prospectively report the initial real-world clinical experience with the use of commercially available mavacamten in a multi-hospital tertiary healthcare system.
We studied the first 150 consecutive oHCM patients (mean age 65 years, 53% women, 83% on betablockers and 61% in New York Heart Association NYHA class III) who were initiated on 5 mg of mavacamten with dose titrations using symptom assessment and echocardiographic measurements of LVOT gradient and LV ejection fraction (LVEF) measurements. We measured changes in NYHA class, LVEF, LVOT gradients (resting and Valsalva) at baseline, 4, 8 and 12 weeks.
At 261 ± 143 days (range of 31–571 days), 69 (46%) patients had ≥1 NYHA class, and 27 (18%) additional patients had ≥2 NYHA class improvement. The mean Valsalva LVOT gradient decreased from 72 ± 43 mmHg at baseline to 29 ± 31 mmHg at 4 weeks, 29 ± 28 mmHg at 8 weeks and 30 ± 29 mmHg at 12 weeks (p < 0.001). At baseline, 100% patients had Valsalva LVOT gradients ≥30 mmHg, which reduced to 29% at 4 weeks, 28% at 8 weeks and 30% at 12 weeks. In 40 patients who reported no symptomatic improvement, the mean Valsalva LVOT gradient decreased from 73 ± 39 mmHg at baseline to 34 ± 27 mmHg at 4 weeks, 35 ± 28 mmHg at 8 weeks and 30 ± 24 mmHg at 12 weeks (P < 0.001). The mean LVEF at baseline was 66 ± 6% and changed to 64 ± 5% at 4 weeks, 63 ± 5% at 8 weeks and 62 ± 7% at 12 weeks (p < 0.0001). No patient underwent SRT, developed LVEF ≤30% or developed heart failure requiring admission. Three (2%) patients needed temporary interruption of mavacamten due to LVEF<50%.
In a real-world study in symptomatic oHCM patients at a multi-hospital tertiary care referral center, we demonstrate the efficacy and safety, along with the logistic feasibility of prescribing mavacamten under the REMS program.
Background: The prognostic effect of concomitant hypertrophic cardiomyopathy (HCM) on adverse events in patients with atrial fibrillation (AF) has not been evaluated in a multicenter prospective ...cohort study in Japan.Methods and Results: Using the Hokuriku-Plus AF Registry, 1,396 patients with nonvalvular AF (1,018 men, 72.3±9.7 years old) were assessed prospectively; 72 (5.2%) had concomitant HCM. During a median follow-up of 5.0 years (interquartile range 3.5–5.3 years), 79 cases of thromboembolism (1.3 per 100 person-years) and 192 of heart failure (HF) (3.2 per 100 person-years) occurred. Kaplan-Meier analysis revealed that the HCM group had a significantly greater incidence of thromboembolism (P=0.002 by log-rank test) and HF (P<0.0001 by a log-rank test) than the non-HCM group. The Cox proportional hazards model demonstrated that persistent AF (adjusted hazard ratio 2.98, 95% confidence interval 1.56–6.21), the CHA2DS2-VASc score (1.35, 1.18–1.54), and concomitant HCM (2.48, 1.16–4.79) were significantly associated with thromboembolism. Conversely, concomitant HCM (2.81, 1.72–4.43), older age (1.07, 1.05–1.10), lower body mass index (0.95, 0.91–0.99), a history of HF (2.49, 1.77–3.52), and lower left ventricular ejection fraction (0.98, 0.97–0.99) were significantly associated with the development of HF.Conclusions: Concomitant HCM predicts the incidence of thromboembolism and HF in AF patients.
We present 3 heart transplant recipients who developed hypertrophic cardiomyopathy years after transplantation. In all 3 cases, the diagnosis was initially made based on echocardiography and ...confirmed using cardiac magnetic resonance imaging. (Level of Difficulty: Advanced.)
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This study sought to examine the diagnostic ability of radiomic texture analysis (TA) on quantitative cardiovascular magnetic resonance images to differentiate between hypertensive heart disease ...(HHD) and hypertrophic cardiomyopathy (HCM).
HHD and HCM are associated with increased left ventricular wall thickness (LVWT). Contemporary guidelines define HCM as LVWT ≥15 mm that is unexplained by other disease, which complicates diagnosis in cases of co-occurrences. Conventional global native T1 mapping involves calculation of mean T1 values as a surrogate for fibrosis. However, there may be differences in its spatial localization, such as diffuse and more focal fibrosis in HHD and HCM, respectively.
This study identified 232 subjects (53 with HHD, 108 with HCM, and 71 control subjects) for TA who consecutively underwent free-breathing multislice native T1 mapping. Four sets of texture descriptors were applied to capture spatially dependent and independent pixel statistics. Six texture features were sequentially selected with the best discriminatory capacity between HHD and HCM and were tested using a support vector machine (SVM) classifier. Each disease group was randomly split 4:1 (feature selection/test validation), in which the reproducibility of the pattern was analyzed in the test validation dataset.
The selected texture features provided the maximum diagnostic accuracy of 86.2% (c-statistic: 0.820; 95% confidence interval CI: 0.769 to 0.903) using the SVM. For the test validation dataset, the accuracy of the pattern remained high at 80.0% (c-statistic: 0.89; 95% CI: 0.77 to 1.00). Global native T1, with an accuracy of 64%, separated HHD and HCM patients modestly (c-statistic: 0.549; 95% CI: 0.452 to 0.640).
Radiomics analysis of native T1 images discriminates between HHD and HCM patients and provides incremental value over global native T1 mapping.
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To characterize changes in ventricular morphology in patients with hypertrophic cardiomyopathy(HCM) who develop left ventricular outflow tract(LVOT) obstruction.
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.
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.
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.
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Introduction: Apical Hypertrophic Cardiomyopathy (AHCM) is a unique variant with distinct clinical presentation, genetics, treatment, complications and outcome. Case: A 52 year non-hypertensive Asian ...male presented with exertional shortness of breath for two years without chest pain, palpitation or syncope. The apex beat was heaving. Electrocardiogram revealed non q wave deep symmetrical T wave inversion in anterolateral leads and echocardiography demonstrated hypertrophied apical septum. Coronary angiogram showed normal coronaries with typical “Ace of Spade” configuration during ventriculography. Conclusion: Characterization of various forms of hypertrophic cardiomyopathy is essential for management purpose as apical hypertrophic cardiomyopathy usually have benign course.
The HSP70 co-chaperone BAG3 targets unfolded proteins to degradation via chaperone assisted selective autophagy (CASA), thereby playing pivotal roles in the proteostasis of adult cardiomyocytes ...(CMs). However, the complex functions of BAG3 for regulating autophagy in cardiac disease are not completely understood. Here, we demonstrate that conditional inactivation of Bag3 in murine CMs leads to age-dependent dysregulation of autophagy, associated with progressive cardiomyopathy. Surprisingly, Bag3-deficient CMs show increased canonical and non-canonical autophagic flux in the juvenile period when first signs of cardiac dysfunction appear, but reduced autophagy during later stages of the disease. Juvenile Bag3-deficient CMs are characterized by decreased levels of soluble proteins involved in synchronous contraction of the heart, including the gap junction protein Connexin 43 (CX43). Reiterative administration of chloroquine (CQ), an inhibitor of canonical and non-canonical autophagy, but not inactivation of Atg5, restores normal concentrations of soluble cardiac proteins in juvenile Bag3-deficient CMs without an increase of detergent-insoluble proteins, leading to complete recovery of early-stage cardiac dysfunction in Bag3-deficient mice. We conclude that loss of Bag3 in CMs leads to age-dependent differences in autophagy and cardiac dysfunction. Increased non-canonical autophagic flux in the juvenile period removes soluble proteins involved in cardiac contraction, leading to early-stage cardiomyopathy, which is prevented by reiterative CQ treatment.
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•Inactivation of Bag3 in CMs initiates hypertrophic cardiomyopathy in juvenile mice•Juvenile but not late stage Bag3-deficient CMs show increased autophagic flux•Inactivation of Atg5 does not improve cardiac function in juvenile Bag3-cKO mice•Treatment with chloroquine normalizes cardiac function in juvenile Bag3-cKO mice•Human BAG3P209L heart samples show similar changes as in Bag3-cKO mice
Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected ...tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.
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