Nonobstructive Hypertrophic Cardiomyopathy Research Articles

Mavacamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Design, Rationale, and Baseline Characteristics ofODYSSEY-HCM.

There are no approved therapies for patients with symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM). The authors describe the baseline characteristics of ODYSSEY-HCM (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy), a phase 3, randomized, double-blind, placebo-controlled trial conducted worldwide at 201 sites evaluating mavacamten in symptomatic adult patients with nHCM. The 2 primary endpoints are the changes from baseline to week 48 in: 1) Kansas City Cardiomyopathy Questionnaire 23-item Clinical Summary Score; and 2) peak oxygen consumption (pVO2) on cardiopulmonary exercise testing. Dose titrations are made on blinded core laboratory assessments. Of 1,088 patients screened, 580 are randomized (mean age 56 ± 15 years, 46% women, 43% with family histories). All patients are nonobstructive and symptomatic (70% in NYHA functional class II and 30% class III), with a mean Kansas City Cardiomyopathy Questionnaire 23-item Clinical Summary Score of 58 ± 20, and 77% are on beta-blockers. The mean left ventricular ejection fraction and pVO2 are 66% ± 4% and 18±6mL/kg/min, respectively. ODYSSEY-HCM will report if mavacamten improves patient-reported health status and exercise capacity in patients with symptomatic nHCM. (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy (ODYSSEY-HCM); NCT05582395).

A new HCM heart sound classification method based on weighted bispectrum features.

Hypertrophic cardiomyopathy (HCM), including obstructive HCM and non-obstructive HCM, can lead to sudden cardiac arrest in adolescents and athletes. Early diagnosis and treatment through auscultation of different types of HCM can prevent the occurrence of malignant events. However, it is challenging to distinguish the pathological information of HCM related to differential left ventricular outflow tract pressure gradients. To address this issue, a classification method based on weighted bispectrum features of heart sounds (HSs) is proposed for efficient and cost-effective HCM analysis. Preprocessing is first applied to remove background noise during HS acquisition. Then, the bispectrum contour map is calculated, and 56-dimensional features are extracted to represent the pathological information of HCM. Next, an adaptive threshold weighting mutual information method is proposed for feature selection and weighted fusion. Finally, the CNN-RF classifier model is built to automatically identify different types of HCM cases. A clinical dataset of normal and two types of HCM HSs is utilized for validation. The results show that the proposed method performs well, with a classification accuracy reaching 94.4%. It provides a reliable reference for HCM diagnosis in young patients in clinical settings.

Differential diagnosis of hypertrophic cardiomyopathy, fabry cardiomyopathy and transthyretin cardiac amyloidosis: insights from right ventricular strain imaging echocardiography

Abstract Introduction Timely differential diagnosis between hypertrophic cardiomyopathy (HCM), Fabry cardiomyopathy (FC) and wild-type transthyretin cardiac amyloidosis (ATTR-CA) is crucial for appropriate treatment and family screening. Right ventricle (RV) involvement is common in these diseases, making the systematic RV assessment essential. Two-dimensional speckle-tracking echocardiography (2D-STE) offers potential for precise RV myocardial mechanics evaluation, however its utility in distinguishing these conditions remains uncertain. Methods This study retrospectively compared matched controls (n=30) with three patient cohorts of nonobstructive HCM (n=30), ATTR-CA (n=30) and FC (n=30) referred to cardiomyopathy consultation between 2014 and 2021. Two blinded researchers independently performed morfofunctional echocardiographic evaluation of RV and 2D-STE analysis of RV myocardial strain. Receiver operating characteristic (ROC) analysis assessed the diagnostic performance of these parameters. Inter- and intra-observer reproducibility used Bland-Altman analysis and intraclass correlation coefficients. Results Male gender predominated in all groups (ATTR-CA 50%; FC 63%; HCM 63%). ATTR-CA patients were older when compared to FC and HCM (Median [IQR]: 84 [5] vs. 64.5 [18.75] vs. 57 [18.25] years, p<0.001) and had higher NT-proBNP (Median [IQR]: 5841 [11742] vs. 467 [1203] vs. 812 [857] pg/ml, p<0.001). ATTR-CA patients had the highest RV wall thickness (RVWT) in comparison to FC (9.0 vs. 7.4 mm, p=0.001) and HCM (9.0 vs. 5.5 mm, p<0.001). Patients with ATTR-CA had lower TAPSE (p=0.001), RV S’ (p=0.001), and RV-FAC values (p=0.003) compared to FC, with no significant differences compared to HCM. RV global longitudinal strain (RV-GLS) and RV free wall strain (RV-FWS) were significantly reduced in ATTR-CA (11.6% ± 4.7 and 15.5% ± 7.6) comparing to FC (19.3% ± 3.2 and 24.7% ± 3.9) and HCM (18.9% ± 3.1 and 25.6% ± 5.2) (p<0.001). RV systolic dysfunction according to RV strain analysis (RV-FWS <23%) led to substantial reclassification and increased prevalence in all groups (ATTR-CA: 37% to 87%; FA 0% to 20%; HCM: 3% to 27%). In ROC analysis, RV-GLS emerged as the most effective parameter for distinguishing ATTR-CA from FC (AUC 0.91; 95% CI 0.81-0.97, p<0.001) with an optimal cut-off of 15.0% yielding 83% sensitivity and 93% specificity. RVWT was the best discriminative parameter for distinguishing ATTR-CA from HCM (AUC 0.98; 95% CI 0.90-0.99, p<0.001; optimal cut-off of 6.5mm; 97% sensitivity, 90% specificity) and FC from HCM (AUC 0.91, 95% CI 0.81-0.97, p<0.001; optimal cut-off of 6.5mm; 83% sensitivity, 90% specificity). RVWT and strain parameters analyses were consistent Intra- and inter-observer with excellent agreement. Conclusion This study underscores the importance of RV thickness and RV-GLS for the differential diagnosis of HCM from phenocopies.

Modulating energy metabolism to treat non-obstructive hypertrophic cardiomyopathy? Insights from IMPROVE-HCM.

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease worldwide and may present with or without dynamic left ventricular outflow tract obstruction (LVOTO). Significant advances have been made in the management of obstructive HCM. On the other hand, despite their significant symptomatic burden, patients with non-obstructive HCM (nHCM) (i.e., without LVOTO) still do not have evidence-based therapeutical options. The recent IMPROVE-HCM study, a phase 2 randomized, double-blinded trial, aims to place a first step in filling this gap in knowledge. The study assessed the safety (primary endpoint) and efficacy (secondary endpoint) of ninerafaxstat, a novel cardiac mitotrope drug that increases adenosine triphosphate production. We highlighted the main findings of the trial, contextualizing these results within the larger landscape of completed and ongoing trials in nHCM.

Erratum: Ninerafaxstat in the Treatment of Diabetic Cardiomyopathy and Nonobstructive Hypertrophic Cardiomyopathy.

Erratum: Ninerafaxstat in the Treatment of Diabetic Cardiomyopathy and Nonobstructive Hypertrophic Cardiomyopathy.

Diagnosis of decreased segmental deformation of the left ventricular myocardium in a teenager at the early stage of hypertrophic cardiomyopathy (clinical observation)

The article presents a clinical observation that revealed a decrease in segmental deformation of the left ventricular myocardium in a 15-year-old teenager at the early stage of asymmetric non-obstructive hypertrophic cardiomyopathy (HCM). To assess myocardial systolic function, the following were used: ejection fraction and shortening of the left ventricle, as well as indicators of global and segmental myocardial deformation, determined by echocardiographic study using the 2D speckle-tracking method. There was no change in ejection fractions and shortening of the left ventricle, global longitudinal deformation of the myocardium, but there was a decrease in longitudinal and circular deformation in individual segments of the left ventricle, which, in general, was the basis for prescribing cardioprotective therapy.

Differences in the Impact of Left Ventricular Outflow Tract Obstruction on Intraventricular Pressure Gradient in Feline Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common form of cardiomyopathy in cats, and heart failure occurs as diastolic dysfunction progresses. HCM in cats is broadly classified as non-obstructive and obstructive hypertrophic cardiomyopathy, depending on the presence or absence of outflow tract obstruction. Measurement of the intraventricular pressure differences (IVPD) using color M-mode (CMM) has attracted attention as a reliable diastolic index as it correlates with catheterization, the gold standard for the assessment of diastolic performance. Because IVPD is affected by the size of the heart, the intraventricular pressure gradient (IVPG) index, which is unaffected by heart size, is by calculated by dividing IVPD by LV length. In the present study, CMM IVPG was used to non-invasively assess diastolic impairment in cats with obstructive hypertrophic cardiomyopathy. This study was conducted on 10 control cats and 18 cats in the HCM group. Although no severe left atrial enlargement was observed in the HCM group, the basal IVPG was significantly increased in the HOCM group compared to the control group. Although IVPD typically suggests impaired diastolic function and reduced ventricular compliance, the significant increase observed in the HOCM group compared to controls may suggest an indirect elevation in left atrial pressure, likely secondary to left ventricular outflow tract obstruction. The increase in IVPG in HOCM, as shown in this study, is a pathological effect of left ventricular outflow tract obstruction that cannot be detected by conventional echocardiographic indices, and evaluating IVPG is useful to evaluate cardiac function from a perspective that differs from conventional methods.

Submucosal hemorrhage of the esophagus: a case report

BackgroundSubmucosal hemorrhage of the esophagus is relatively rare and the course of this disease remains unclear. We report a case of this disease.Case presentationThe patient was a 68-year-old man who visited a clinic complaining of sudden-onset epigastric and back pain. He had been taking warfarin and a statin due to non-obstructive hypertrophic cardiomyopathy, right subclavian artery stenosis, and chronic atrial fibrillation. Contrast-enhanced computed tomography showed esophageal submucosal hemorrhage. Detailed endoscopic examination was difficult because of the massive hemorrhage and progressive esophageal mucosal edema. He was transferred to our hospital due to progression of anemia. Fortunately, hemorrhagic anemia showed no progression with conservative fasting therapy after admission to our hospital. Esophageal mucosa over the submucosal hemorrhage detached and regenerative tissue was observed on endoscopic examination 1 week later.ConclusionsEsophageal submucosal hemorrhage should be included among the differential diagnoses for patients presenting with chest and back pain.

Abstract 4140118: Identification of Obstructive and Non-Obstructive Hypertrophic Cardiomyopathy Patients Using Natural Language Processing in a Large Integrated Healthcare System

Introduction: Accurately identifying and characterizing patients with hypertrophic cardiomyopathy (HCM) is critical for population management and care optimization. Research Question: To develop natural language processing (NLP) algorithms to identify and characterize obstructive (oHCM) and non-obstructive (nHCM) HCM patients directly from echocardiograms, and to compare with the presence or absence of HCM-related diagnosis codes. Methods: We developed and validated NLP algorithms to identify HCM from all adult (age≥18yrs) echocardiograms performed from 2010-2019 in Kaiser Permanente Northern CA (KPNC), capturing measures of any HCM, HCM subtype, hypertrophy subtype, septal and posterior LV wall thickness, resting and stress/Valsalva LVOT gradients, and systolic anterior motion. We developed a rules-based algorithm (following AHA/ACC criteria) to classify patients as having HCM, including oHCM or nHCM subtypes, and possible HCM (defined as wall thickness ≥2cm without other criteria meeting an HCM definition). We evaluated the presence of HCM-related ICD-9/10 diagnosis codes among patients classified as HCM/non-HCM from echocardiograms using NLP, and linked baseline demographics and clinical parameters from our integrated electronic medical record. Results: Among 472,405 adults with echocardiograms, we identified 2,892 patients with HCM based upon NLP-derived measures (all NLP measures achieved >95% positive predictive value and >95% negative predictive value), including 1,585 (55%) with oHCM, 1,145 (40%) with nHCM, and 162 (6%) which could not be classified (Figure). Among those 2,892 patients, 1,283 did not have any associated HCM ICD-9/10 diagnosis codes (Table). Among 469,513 patients with no identified HCM from NLP-based algorithms, HCM ICD-9/10 diagnosis codes existed in 1,567 patients (Table). We also identified 4,593 patients with possible HCM by NLP, only 4.5% of whom had an associated HCM code. Among confirmed HCM patients by NLP, oHCM patients were slightly older (66 vs 61 yrs), more likely female (53% vs 43%), had similar mean septal wall thickness (1.7cm vs 1.7cm), but were more likely to have a septal hypertrophy subtype (46% vs 28%) compared to nHCM patients. Conclusions: Echocardiogram-based NLP methods can improve the identification of and care for HCM patients. Many patients with possible HCM may be underdiagnosed, representing an opportunity for quality improvement.

Abstract 4134685: Cardiopulmonary Exercise Testing for Characterization and Prognostication in Hypertrophic Cardiomyopathy: A Meta-Analysis

Background: Hypertrophic cardiomyopathy (HCM) carries substantial risk of adverse cardiac events. Consequently, detailed physiologic assessment and accurate risk stratification in HCM are of high clinical importance. Aim: To synthesize current evidence on the utility of cardiopulmonary exercise testing (CPET) for characterization and prognostication of HCM. Methods: PubMed, Embase, Scopus, and Web of Science were systematically searched for eligible studies from database inception to November 2023. Studies that had at least one CPET performed in HCM patients, with corresponding test data reported, were included. Abstracts with no full-text and studies focused on pediatric populations were excluded. The primary outcome was a composite endpoint of cardiovascular adverse events. Hazard ratios (HR) and 95% confidence interval (CI) from Cox proportional hazard model were meta-analyzed. This study was performed following the PRISMA guidelines and registered under PROSPERO (CRD42023487759). Results: Sixty full-length manuscripts focused on CPETs performed in HCM patients were included, comprising 12,914 patients. Despite male predominance (66%) and average age of 48 years, peak VO 2 was only 6.2 [95% CI, 6.0-6.4] metabolic equivalents (21.8 [20.9-22.6] mL/kg/min), consistent with significant functional limitation. In subanalyses, peak VO 2 was 18.9 [18.0-19.9] mL/kg/min in obstructive HCM and 22.5 [20.8-24.2] mL/kg/min in non-obstructive HCM. Compared to commonly used metrics such as NYHA Class, CPET markedly enhances sensitivity to detect impaired cardiac performance ( Figure ). This meta-analysis highlights several easily-derived CPET variables that consistently predict HCM prognosis. An increase of 1 mL/kg/min in peak VO 2 was associated with a lower HR of 0.83 [0.76-0.90] for adverse cardiac events, while a 1 unit increase in the VE/VCO 2 slope was associated with a higher HR of 1.12 [1.03-1.23]. Abnormal blood pressure response to exercise conferred a 2.5-fold [2.0-3.1] increase in adverse events. Conclusion: CPET is a valuable objective method for multi-dimensional physiologic assessment and prognostication in HCM. With further standardization, CPET is well suited for more widespread clinical utilization in HCM patients.

Loss of quality of life and increased societal costs in patients with hypertrophic cardiomyopathy: the AFFECT-HCM study.

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. The impact of HCM on quality of life (QoL) and societal costs remains poorly understood. This prospective multi-centre burden of disease study estimated QoL and societal costs of genotyped HCM patients and genotype-positive phenotype-negative (G+/P-) subjects. Participants were categorized into three groups based on genotype and phenotype: 1) G+/P- (left ventricular (LV) wall thickness <13 mm), 2) non-obstructive HCM (nHCM, LV outflow tract (LVOT) gradient <30 mmHg), and 3) obstructive HCM (oHCM, LVOT gradient ≥30 mmHg). We assessed QoL with EQ-5D-5L and Kansas City Cardiomyopathy Questionnaires (KCCQ). Societal costs were measured using medical consumption (iMCQ) and productivity cost (iPCQ) questionnaires. We performed subanalyses within three age groups: <40, 40-59, and ≥60 years. From three Dutch hospitals, 506 subjects were enrolled (84 G+/P-, 313 nHCM, 109 oHCM; median age 59 years, 39% female). HCM (both nHCM and oHCM) patients reported reduced QoL vs G+/P- subjects (KCCQ: 88 vs 98, EQ-5D-5L: 0.88 vs 0.96; both p<0.001). oHCM patients reported lower KCCQ scores than nHCM patients (83 vs 89, p=0.036). Societal costs were significantly higher in HCM patients (€19,035/year vs €7,385/year) compared to G+/P- controls, mainly explained by higher healthcare costs and productivity losses. Being symptomatic and of younger age (<60 years) particularly led to decreased QoL and increased costs. HCM is associated with decreased QoL and increased societal costs, especially in younger and symptomatic patients. oHCM patients were more frequently symptomatic than nHCM patients. This study highlights the substantial disease burden of HCM and can aid in assessing new therapy cost-effectiveness for HCM in the future.

Incidence of infective endocarditis in patients with hypertrophic cardiomyopathy

BackgroundData on the incidence of infective endocarditis (IE) in patients with hypertrophic cardiomyopathy (HCM) is sparse. This study evaluated a HCM cohort with aim to study the incidence of IE in these patients. MethodsAll patients entering the HCM cohort from May 2003 to June 2022 of a tertiary care hospital with at least one follow-up visit were included and followed up till June 2023. This was a retrospective cohort analysis. Only individuals who were diagnosed with IE after entry into the cohort were included. ResultsThe study cohort consisted of 529 HCM patients with a total follow up duration of 3244.6 years. The mean and median follow-up durations were 6.1±4.7 and 5.3 (range 31 days to 20.1) years respectively. Three (0.57%) patients in the cohort developed IE. Incidence of IE in HCM patients was 0.92/1000 patient years. Two patients had left ventricular outflow tract obstruction while one had non-obstructive HCM. None of the patients with isolated mid-cavity gradients developed IE. The incidence of IE in the obstructive and nonobstructive groups was 1.39 and 0.55 per 1000 patient years respectively. Two had vegetations on mitral valve while one had vegetations on aortic valve. Both patients with mitral valve endocarditis developed severe residual mitral regurgitation and heart failure. ConclusionsIE is a rare complication in HCM patients with an incidence of 0.92/ 1000 patient years. However, when it occurs, IE is associated with high morbidity and mortality.

Epidemiology and prognosis of obstructive and non-obstructive hypertrophic cardiomyopathy in Finland: a nationwide cohort study

Abstract Background Hypertrophic cardiomyopathy (HCM) is an often hereditary myocardial disease. The Finnish population has a specific genetic background, which may influence and even predispose people to various hereditary diseases. Whilst advances in genetic testing and imaging techniques may have influenced the detection of HCM and associated subtypes, contemporary data on incidence and prevalence remain limited. Purpose This study aimed to evaluate the current trends in the incidence, prevalence, and prognosis of obstructive and non-obstructive HCM in a nationwide cohort in Finland. Methods A population-based registry study was conducted using data from Finnish nationwide healthcare registries (HILMO/avoHILMO) including individuals aged at least 12 years with recorded HCM diagnosis between 2000 and 2021. The incidence was calculated by dividing the number of newly diagnosed HCM patients by the Finnish background population. Furthermore, the mean incidence per age-group was calculated by dividing the sum of age-group specific incidences by the number of age groups. The date and cause of death were obtained from national registries (Statistics Finland). Mortality was computed by dividing the number of deaths by follow-up length. Patients were followed from 2014 to 2021, and incident cases were defined as new diagnoses after 2014. HCM cases were stratified into obstructive HCM and non-obstructive HCM based on ICD-10 codes I42.1 and I42.2, respectively. Results Among 5,834 documented patients with HCM, the overall mean incidence by age-group was 2.64/100,000, with incidence increasing with age, peaking in those aged ≥85 years (6.22/100,000 patient-years [PY]). Annual incidence of obstructive HCM decreased from 2.2 to 1.4/100,000 PY, while non-obstructive HCM increased from 4.6 to 5.4/100,000 PY between 2014 and 2021 (Fig 1). Prevalence of non-obstructive HCM rose from 40 to 56/100,000 PY, while obstructive HCM prevalence remained stable (23-24/100,000 PY). All-cause mortality was 5.5/100 PY, with obstructive and non-obstructive HCM mortality at 5.7 and 4.6/100 PY, respectively. HCM-specific deaths accounted for 16% and 12% of all deaths in patients with non-obstructive and obstructive HCM, respectively. Conclusions This nationwide study in Finland revealed an increasing incidence and prevalence of non-obstructive HCM over time, contrasting with stable rates among patients with obstructive HCM. Incidence and prevalence were strongly age dependent. Non-HCM-related deaths were predominant in both HCM subtypes.

Relationship between six-minute walk distance and cardiopulmonary exercise testing in non-obstructive hypertrophic cardiomyopathy

Abstract Background Recent studies have shown the promise of new approaches to the management of hypertrophic cardiomyopathy (HCM) symptoms. However, as HCM is a chronic disorder that evolves slowly over decades with low annual event rates, therapeutic trials in the disease rely on surrogate measures of disease severity and progression rather than hard endpoints such as mortality. Exercise capacity is one potential surrogate endpoint. Purpose To examine the relationship between peak oxygen uptake (VO2) and six-minute walk test distance (6MWD) in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) and describe the association with clinical parameters and quality of life. Methods We examined baseline data from patients with nHCM enrolled in a randomised placebo-controlled trial of trimetazidine therapy. The study was conducted in a single European centre. Cardiopulmonary exercise testing (CPET) was performed to assess peak oxygen consumption (pVO2), ventilatory anaerobic threshold (VAT) and ventilatory equivalent for carbon dioxide (minute ventilation to carbon dioxide production (VEVCO2). Health related quality of life was assessed with the Minnesota Living with Heart Failure Questionnaire (MLHFQ). ECG and echocardiography were performed on the same day and biomarkers (NT-proBNP and cardiac Troponin T, cTnT) were measured prior to exercise testing. Results In 51 patients (age 50 ± 13 years; 71% male) with nHCM, pVO2 ranged from 10 to 24.3 ml/kg/min and 6MWD from 188 to 650 metres. 6MWD correlated with peak VO2 (Pearson r=0.41, 95% CI 0.15 to 0.67, p=0.003) and anaerobic threshold (r=0.32, 95%CI 0.04 to 0.55, p=0.024). After adjusting for age and sex, NT-proBNP concentration correlated with peak VO2 (radi=-0.35, 95% CI -0.69 to -0.01, p=0.042) but not 6MWD (radj=-0.05, 95% CI -0.42 to 0.32, p=0.779). Health related quality of life assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) correlated moderately with 6MWD (radi=-0.54, 95% CI -0.79 to -0.29, p&amp;lt;0.001) but weakly with peak VO2 (radi 0.28, 95% CI -0.55 to -0.01, p=0.042). I Conclusions There is a modest correlation between peak VO2 and 6MWD in nHCM. The pVO2 correlates more strongly with NT-proBNP whereas 6MWD better reflects quality of life. These data suggest pVO2 and 6MWD provide complementary information about health status in nHCM.Relationship between 6MWD and CPETCharacteristics of study cohort

Characterizing disease burden and health care resource utilization in patients with hypertrophic cardiomyopathy: a nationwide real-world study in Finland

Abstract Background Hypertrophic cardiomyopathy (HCM) is an often hereditary myocardial disease with an estimated prevalence of 1:500 in the general population. Purpose This study aimed to investigate healthcare resource utilization (HCRU) and associated costs in patients diagnosed with HCM (and the associated subtypes: obstructive or non-obstructive) in a nationwide cohort in Finland. Methods This retrospective, registry-based cohort study included all Finnish patients diagnosed with HCM between 2000 and 2021, who were 12+ years old at the time of diagnosis, as identified from the national care registers for healthcare. HCRU data were collected between 2014 and 2021 from the Finnish national care registers for health care and the social insurance institution. Data pertaining to New York Heart Association (NYHA) classification were collected from three Finnish university hospitals. Results The study cohort comprised 5,834 patients with an HCM diagnosis; obstructive HCM accounted for 34% of cases. Mean per patient-year costs were €6638, 95% confidence interval (CI) €6472-€7415, and €6112, 95% CI €5957-€6560 for those with obstructive and non-obstructive HCM respectively. All-cause hospitalizations at specialized care were the most prominent cost associated with patients with obstructive and non-obstructive HCM equating to 46.3% and 46.1% of the total cost respectively (Fig 1.). Comorbidity burden, as measured by Charlson comorbidity index (CCI) score, was greater in patients with the obstructive than non-obstructive phenotype of the disease (CCI ≥4: 2.2 and 1.8, p&amp;lt;0.01, respectively). The highest utilization of invasive procedures was found for patients with NYHA class III-IV. Conclusion This population-based study, utilizing real-world data, provides novel insights into HCRU and related costs among Finnish patients with HCM (and associated subtypes). HCRU appears to be primarily driven by hospitalizations at specialized care. Furthermore, the data indicate that patients with obstructive HCM are likely to have a more severe disease, with higher comorbidity burden and requiring more invasive procedures than patients with the non-obstructive form of the disease. However, there were no statistically significant differences in health care costs between those with obstructive and non-obstructive HCM.

Clinical characteristics and burden of non-obstructive hypertrophic cardiomyopathy: a real-world survey in Italy and Spain

Abstract Background Research describing non-obstructive hypertrophic cardiomyopathy (nHCM) and the associated burden of illness is sparse. Purpose This research aimed to describe the clinical characteristics of patients with nHCM and the associated clinical and societal burden of illness in Italy (IT) and Spain (ES). Methods Data were from the Adelphi HCM Disease Specific Programme (DSP), a cross-sectional survey with retrospective data collection in IT and ES (July 2022–January 2023). Ethics approval was obtained from the Pearl Institutional Review Board. Cardiologists provided data on patient demographics, employment, clinical characteristics, symptoms, support needs and treatment for up to ten consecutively consulting adult HCM patients. Patients voluntarily completed a survey containing the Kansas City Cardiomyopathy Questionnaire-23 (KCCQ). Analyses were descriptive and the mean [SD] was summarized for continuous variables. Results Overall, 112 cardiologists provided data for 483 patients with nHCM from IT (243) and ES (240). The mean age [SD] was 54.3 [14.1] and 58.0 [16.0], with 66.3% and 61.7% of patients being male, in IT and ES respectively. Eighty-four percent and 92.1% of patients were classified as New York Heart Association (NYHA) II, 14.8% and 7.1% were NYHA III, and 1.2% and 0.8% were NYHA IV, in IT and ES respectively. Among patients who completed the KCCQ, the mean [SD] KCCQ-clinical summary score was 84.9 [12.9] in IT and 81.8 [20.7] in ES. Regarding work-related impact, 30.8% (IT) and 16.7% (ES) of patients had taken time off work due to nHCM in the last three months, and 41.6% (IT) and 48.4% (ES) were not working full-time, of which 5.6% (IT) and 11.0% (ES) were not working full time due to nHCM. Additionally, 17.6% and 18.2% of patients experienced a delayed diagnosis in IT and ES respectively, with 24.0% (IT) and 25.0% (ES) having multiple delays to diagnosis. The most common symptoms reported by physicians were dyspnoea when active (83.7%), palpitations (29.3%) and fatigue (25.7%). The most prevalent concomitant conditions were hypertension (20.5%), anxiety (18.6%), and atrial fibrillation (18.4%). In IT and ES, respectively, 77.8% and 74.2% of patients were currently prescribed treatment for nHCM. The most frequently prescribed treatments were beta-blockers (83.3%), diuretics (32.1%) and angiotensin converting enzyme inhibitors (20.5%), alone or in combination. In IT and ES respectively, 14.4% and 18.8% of patients required caregiver support, at a mean [SD] of 46.3 [52.4] and 44.2 [47.5] hours per week. Conclusions While the majority of patients with nHCM were classified as NYHA II, a considerable clinical and societal burden is evident. Burden was demonstrated by the high prevalence of symptoms, comorbidities, disruptions to employment and the requirement for caregiver support among these patients, highlighting the need for new treatment and management approaches to enhance health outcomes and reduce societal impact.

AFFECT-HCM: quality of life and costs in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, characterised by increased wall thickness. Pathogenic DNA variants in sarcomeric genes are identified in about half of HCM patients, enabling pre-symptomatic testing in family members. Since the first description of HCM tremendous progress has been made in the evaluation and management of HCM patients. However, little is known on the impact of HCM on quality of life (QoL) and costs. Purpose The AFFECT-HCM study evaluates the QoL, healthcare and societal costs in HCM patients and genotype-positive phenotype-negative (G+/P-) subjects. Methods The AFFECT-HCM is a multi-centre prospective study including genotyped HCM patients aged 18-80 years and G+/P- subjects. The study cohort is divided into three groups based on phenotype: G+/P- (wall thickness &amp;lt;13 mm), non-obstructive HCM (nHCM, maximal left ventricular outflow tract (LVOT) gradient &amp;lt;30 mmHg) and obstructive HCM (oHCM, LVOT gradient ≥30 mmHg). For QoL, the generic five-domain five-level EQ-5D-5L with the attached visual analogue scale and disease-specific Kansas City Cardiomyopathy Questionnaire are used. Healthcare and societal costs are measured via a bottom-up approach using the cost questionnaires iMCQ and iPCQ and expressed with means (the standard in healthcare cost reporting despite non-normality) in 2023 Euro per patient per year (€ PPPY). QoL and costs are compared between phenotypes. Results Results are summarised in the table. Between November 2022 - December 2023, 506 subjects (mean age 55 years, 39% female) were included in three Dutch hospitals. The study included 84 G+/P-, 307 nHCM and 115 oHCM subjects. Questionnaire response rate was 92%. Compared to G+/P- subjects; HCM patients were older (57 vs 46 yrs), more often male (67% vs 32%) and had more cardiovascular risk factors. Compared to nHCM patients, oHCM patients were more often symptomatic (58% vs 34%), more often in NYHA class III (19% vs 2%) and used more HCM-related medications (79% vs 64%). HCM patients, and particularly oHCM patients, reported decreased QoL with lower QoL-related questionnaire scores (Figure). The utilities (EQ-5D-5L) of HCM patients were lower than G+/P- subjects and the Dutch overall average (0.87±0.17), and for oHCM comparable with another study (0.82±0.18). Costs were higher for HCM patients than G+/P- subjects (€14374 vs €5888 PPPY) and higher in oHCM patients compared to nHCM patients (€19672 vs €12419 PPPY). The leading between-group difference is higher productivity losses in oHCM patients. Conclusion HCM is associated with reduced QoL and increased costs, especially in oHCM patients. The primary cost driver are healthcare costs, but the difference between oHCM and nHCM patients is mainly caused by indirect costs due to productivity losses. These data provide novel insights in the BoD of HCM and can aid in assessing cost-effectiveness analyses of new therapies for HCM in the future.Baseline characteristics and resultsQuality of life-related questionnaires

Exploring the effects of mavacamten through hemodynamic force analysis in patients with obstructive hypertrophic cardiomyopathy

Abstract Introduction Mavacamten is a first-in-class allosteric myosin inhibitor effective in relieving left ventricular (LV) outflow tract obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). To date, however, its effect on cardiac mechanics is still unclear. Hemodynamic force (HDF) analysis represents the fluid dynamics correlate of deformation imaging, showing a greater sensitivity in detecting early mechanical abnormalities or response to treatment [1]. Purpose To explore the in vivo effect of mavacamten on cardiac mechanics in patients with HCM after a 3 year-treatment, using HDF analysis. Methods LV HDF analysis was performed in 6 patients with oHCM (representing a cohort of the MAVA-LTE study) at baseline and after 3 years of treatment. Apical 4-, 2-, and 3-chamber echocardiographic views were analysed using a dedicated and sofisticated software. Base-apex forces (where positive deflections represent a force directed from the apex to the base of LV, whilst negative ones are directed toward the LV apex) were assessed in terms of timing indexed to cardiac cycle duration. HDF curves from the 6 patients treated with macavamten were compared to those obtained from oHCM patients (n=20), non-obstructive HCM (noHCM) patients (n=20), and healthy controls (n=22). Results Figure 1 shows a different pattern of transition between diastole and systole in HCM patients compared to controls. Specifically, HCM patients exhibited an earlier onset of the systolic phase, expressed as a fusion of late diastolic deceleration and systolic thrust. This was numerically represented as a decrease in diastolic-systolic transition time, which is 0.22 [0.20-0.24] for oHCM, 0.23 [0.21-0.25] for noHCM and 0.26 [0.26-0.30] for controls (p ≤0.001 for control vs oHCM, p ≤0.01 for control vs noHCM). Additionally, HCM patients showed an increased rate of force generation. The time to systolic peak (i.e., time interval from the onset of systole to the maximum force) was reduced in HCM patients compared to controls, and was shorter in oHCM than in noHCM patients (0.13 [0.11-0.15] vs 0.16 [0.14-0.17], p ≤0.01), thus reflecting an increased clinotropism in HCM. After 3 years of mavacamten treatment, the diastolic-systolic transition time and the time to systolic peak returned to a level similar to that of healthy controls (0.30 [0.27-0.30] in mavacamten group vs 0.26 [0.26-0.30], p &amp;gt;0.05, and 0.21 [0.20-0.22] vs 0.19[0.17-0.20], p=0.04, respectively) (Figure 2). Conclusion HDF analysis reveals that mavacamten affects the duration of transition from diastole to systole and prolongs time from the onset to the peak in systole. These findings may explain the removal of the mechanical coupling substrate responsible for the systolic anterior movement of mitralic leaflets and the subsequent resolution of LV outflow tract obstruction by mavacamten.Distribution of time parameters

Mavacamten in a real-world hypertrophic cardiomyopathy population: how many may be eligible?

Abstract Introduction Mavacamten is a newly approved drug for obstructive hypertrophic cardiomyopathy (oHCM) and is currently being studied in non-obstructive HCM (nHCM). Our goal was to evaluate how often patients with oHCM and nHCM in a real-world cohort would be eligible for the main mavacamten trials: EXPLORER-HCM, VALOR-HCM and MAVERICK-HCM. Methods Single-centre retrospective study enrolling consecutive patients with confirmed HCM, as per the 2023 ESC Guidelines, with at least yearly follow-up in our center, from 2017-2023. Key inclusion criteria from the three trials were considered: NYHA class II-III for all; obstructive forms (defined as peak left ventricle outflow tract [LVOT] gradient ≥50 mmHg at rest, after Valsalva manoeuvre or exercise) for EXPLORER-HCM and VALOR-HCM; left ventricular ejection fraction (LVEF) ≥55% for EXPLORER-HCM and MAVERICK-HCM; LVEF ≥60% and formal criteria for septal reduction therapy for VALOR-HCM, and NT-proBNP ≥300pg/mL for MAVERICK-HCM. Key exclusion criteria (estimated glomerular filtration rate [eGFR] &amp;lt;30mL/kg/1.73m2, QTc using the Fridericia’s formula &amp;gt;500ms, paroxysmal or intermittent atrial fibrillation present on screening electrocardiograph) were also considered. Results Overall, 410 patients were diagnosed with HCM, of whom 361 (88%) were alive at follow-up and included in the analysis: mean age of 63 ± 16 years, 196 (54%) were male, 272 (75%) with septal HCM and 60 (17%) with oHCM. According to the criteria of EXPLORER-HCM, VALOR-HCM and MAVERICK-HCM, 35 (10%), 6 (2%) and 27 (7%) patients would be eligible for enrolment, respectively. In patients with oHCM, 35 (58%) would be eligible for the EXPLORER-HCM trial. In the overall cohort, 65 (18%) would have criteria for at least one of the trials. The main reasons for exclusion were as follows: 191 (53%) NYHA I, 43 (12%) with NYHA IV, 12 (3%) had a LVEF &amp;lt;55%, 8 (2%) had both HCM and infiltrative myocardial disease and/or moderate-to-severe aortic stenosis and 8 (2%) had an eGFR &amp;lt;30mL/kg/1.73m2. In patients with nHCM, 16 (5%) would have been excluded due to NT-proBNP &amp;lt;300pg/mL and 8 (3%) due to paroxysmal atrial fibrillation. Conclusion In a real-word HCM cohort, we found that approximately 1 in every 5 patients would have criteria for either of the mavacamten trials, with more than half of oHCM being potential candidates for the EXPLORER-HCM. The main reasons for non-eligibility were NYHA I and LVEF &amp;lt;55%.

Impaired myocardial energetics in both sarcomere positive and negative HCM are linked to arrhythmic risk

Abstract Background Impaired myocardial energetics play a pivotal role in the complex pathophysiology of hypertrophic cardiomyopathy (HCM), and are thought to be mediated by energy-costly sarcomeric mutations and mitochondrial dysfunction (1). Two thirds of HCM patients, however, do not possess pathogenic sarcomeric mutations (2) and instead develop the condition due to a combination of increased polygenic susceptibility and comorbidities. Whether energetic impairment, a target of novel HCM treatments (e.g., myosin modulators such as Mavacamten), similarly affects sarcomere mutation positive (Sarc+) and negative (Sarc-) HCM remains unclear, as does the association between impaired energetics and markers of arrhythmic risk such as hypertrophy severity, cardiac function and non-sustained ventricular tachycardia (NSVT). This study aimed to investigate differences in resting myocardial energetics between Sarc+ and Sarc- HCM by measuring the phosphocreatine-to-adenosine triphosphate (PCr/ATP) ratio using phosphorus magnetic resonance spectroscopy (31P-MRS) and explore the association between impaired energetics and markers of arrhythmic risk in HCM. Methods We recruited one hundred (100) participants (80 non-obstructive HCM patients and 20 age- and sex-matched controls). Myocardial energetics were assessed using 31P-MRS to measure the PCr/ATP ratio. Cardiac magnetic resonance (CMR) imaging including cine, T1 (ShMOLLI), quantitative pixel-wise perfusion mapping (3) and late gadolinium enhancement (LGE) imaging was also performed. In addition, HCM patients underwent 7-day ECG monitoring to document NSVT episodes (3 beats ≥120 bpm). Results HCM patients had impaired myocardial energetics (PCr/ATP ratio) relative to controls (HCM 1.64±0.36 vs controls 1.97±0.32 p&amp;lt;0.001). PCr/ATP ratios did not differ between Sarc+ and Sarc- HCM even after adjustment for confounders including age, hypertrophy and fibrosis burden (Sarc+ 1.64 [1.50-1.78] vs Sarc- 1.64 [1.52-1.77], p=0.993). PCr/ATP ratio showed no correlation with maximum wall thickness (p=0.257), left ventricular ejection fraction (p=0.727) or myocardial perfusion reserve (p=0.851), but did inversely correlate with global longitudinal strain (r=-0.3, p=0.025). Reduced PCr/ATP was associated with presence of fibrosis (LGE+ 1.58±0.35 vs LGE- 1.79±0.37 p=0.025) and with NSVT, independent of age or fibrosis burden (NSVT+ 1.54 [1.40-1.67] vs NSVT- 1.73 [1.62-1.86], p=0.046). Conclusion Myocardial energetics are similarly impaired in Sarc+ and Sarc- HCM, and are independently associated with impaired contractility, greater fibrosis severity and heightened arrhythmic risk. Our findings provide novel mechanistic insights into the potentially favourable response of HCM patients to energy-sparing myosin modulator therapies irrespective of genotype and highlight the potential for cardiac energetics to serve as a marker of arrhythmic risk.