Adult Hypertrophic Cardiomyopathy Research Articles

Abstract 4122024: Fibroblasts Are the Primary Contributors to a Disrupted Micro-Environment in End-Stage Pediatric Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a relatively rare but debilitating diagnosis in pediatric patients. This represents a vulnerable population who often require heart transplantation. Here, we examine the transcriptome in ventricular tissue to identify underlying cellular processes unique to pediatric HCM (pHCM). Methods: We performed single-nucleus RNA sequencing on explanted hearts at transplant in female patients with end-stage pHCM (n=3) and compared findings to pediatric control (n=2) and adult HCM (n=5; Figure 1A-1B). Results: We generated 91,682 single-cell transcriptomes from 8 tissue samples. Principal component analysis exhibited the largest source of transcriptional variation separated pHCM and controls (Figure 1C). We identified distinct underlying cellular processes in cardiomyocytes, fibroblasts, endothelial cells, and myeloid cells in pHCM. pHCM was enriched in cardiomyocytes with stressed signatures and pathways associated with hypertrophy (Figure 1D); we noted depletion of tissue-resident macrophages (Figure 1D) and increased vascular remodeling in endothelial cells in pHCM. Fibroblasts exhibited activation signatures and compared to adult HCM, showed heightened fibrotic processes and a unique pro-fibrotic cluster with increased metabolic stress, mitochondrial turnover, and anti-apoptotic properties (Figure 2). In cell-to-cell communication, the differential number and weight of interactions were higher in pHCM compared to controls and fibroblasts had the highest strength of outgoing interactions. Conclusions: Our analysis provides the first single-nuclei analysis focused on pHCM. Fibroblast-mediated cellular processes contributed most to the disrupted micro-tissue environment; they had more downstream processes associated with fibrosis and may respond to metabolic stress differently compared to adult HCM. This advances our understanding of the early presentation of pHCM, providing a crucial steppingstone toward improved patient outcomes.

Follow-Up Study of Percutaneous Intramyocardial Septal Radiofrequency Ablation in the Treatment of Hypertrophic Obstructive Cardiomyopathy With HFpEF.

The study aimed to evaluate the changes of left ventricular diastolic function and the improvement of clinical symptoms in hypertrophic cardiomyopathy (HCM) patients with heart failure with preserved ejection fraction (HFpEF) after percutaneous intramyocardial septal radiofrequency ablation (PIMSRA). This study enrolled 31 adult HCM patients with HFpEF who underwent PIMSRA treatment. Electrocardiogram, imaging, and blood biochemical examinations were performed on these patients during a 6-month follow-up. Compared with the baseline, at 6 months after PIMSRA, patients showed significant reductions in peak left ventricular outflow tract pressure gradients (resting gradient: from a mean of 83.24 to 23.40mmHg, p < 0.001; postexercise gradient: from a mean of 109.70 to 33.39mmHg, p< 0.001). The interventricular septal thickness reduced from a mean of 22.90 to 17.48mm, p < 0.001. The E/e' decreased from a median of 18.67 to 11.54, p < 0.001. The 6-minute walk distance (6MWD) increased from a mean of 359.03 to 435.81 m, p < 0.001. The Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ OS) increased from a mean of 57.57 to 71.93, p < 0.001. The number of HFpEF patients diagnosed according to the European Society of Cardiology's Heart Failure Association HFA-PEFF score decreased from 31 to 23. None of the patients had new-onset bundle branch block or complete heart block after PIMSRA. PIMSRA is a safe and effective treatment. It can improve left ventricular diastolic function and quality of life in HCM patients.

Genotype-phenotype relationship in hypertrophic cardiomyopathy

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is an inherited highly heterogeneous disease with variable penetrance and expression, but the exact relationship between the underlying genetic cause and the clinical course remains elusive. Purpose The aim of our study was to analyse the phenotypic and molecular characteristics of individuals with HCM examined and treated at our University Hospital. Methods Clinical data from adult HCM patients treated at our hospital between 2005 and 2023 were analysed. Informed consents to participate in the study were obtained from all participants. Clinical manifestation, instrumental examination and next generation sequencing (NGS) data of HCM related genes were collected. The Mann–Whitney U for two groups and Kruskal–Wallis tests for more than two groups were used to compare continuous variables. Univariate logistic regression was used to analyze categorical variables. Results The study involved 191 unrelated individuals, 58.6% males, the median age at HCM diagnosis was 50, interquartile range 37 – 60 years. A median follow-up was 3.9 [1.6-6.4] years. Pathogenic and likely pathogenic (P/LP) variants were identified in 45.5% (N=87) of affected individuals. Truncating variants were observed in 31 individuals. MYBPC3 P/LP variants were the most common (N=47), following by MYH7 (N=22) and other (N=18). Individuals with MYBPC3 P/LP truncating variants had higher HCM estimated 5-year risk of sudden cardiac death (SCD) during primary evaluation (3.1 [2.5-4.6]) compared to individuals with P/LP variants in other genes (2.4 [1.9-3.7]) and individuals with negative NGS results (1.8 [1.5-2.7], p&amp;lt;0,001). Patients with MYBPC3 P/LP variants experienced the earliest onset of symptoms (median age 37.0 [30.5-50.0] years) and HCM diagnosis (median age 38.0 [31.0-51.5] years) compared to individuals with other genes P/LP variants (median age 46.0 [31.0-56.2] years and 47.5 [31.5 – 59.5] years, respectively) and genotype negative individuals (median age 51.5 [44.0-61.0] years and 52.0 [45.0-63.2] years, respectively), p&amp;gt;0,001). The presence of P/LP variant was associated with significantly thicker left ventricular wall (maximal thickness) on cardiac imaging in comparison with negative NGS results (18.0 [15.0-21.0] mm vs. 16.0 [14.0-18.0] mm, p=0.002 on transthoracic echocardiography and 20.0 [17.0-22.5] mm vs. 18.0 [16.0-20.0] mm, p&amp;lt;0,001 on cardiac magnetic resonance). The presence of MYBPC3 truncating variants were associated with the greatest risk of ventricular tachycardia in comparison with negative NGS results (OR 3.05, 95% CI:1.3, 8.0, p=0.025). Conclusion More severe HCM phenotype is associated with detection of P/LP variants in HCM related genes. The presence of the MYBPC3 P/LP variant is associated with an earlier onset of the disease and truncating variants of this gene are related to a higher risk for ventricular tachycardia and an estimated 5-year risk of SCD.

Impact of Genetic Testing on the Diagnosis, Management, and Prognosis of Hypertrophic Cardiomyopathy: A Systematic Review.

Hypertrophic cardiomyopathy (HCM) is a hereditary cardiovascular condition marked by heart muscle thickening, fibrosis, and myocardial disorders. It is often inherited in an autosomal dominant pattern. Symptoms include dyspnea, fatigue, palpitations, dizziness, syncope, and an increased risk of sudden cardiac death (SCD). Genetic studies have identified many asymptomatic carriers, indicating a higher prevalence of HCM. Advances in genetic testing (GT) and novel therapies, such as cardiac myosin inhibitors, have significantly impacted the diagnosis and management of HCM. This integrative review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and aimed to synthesize information regarding the impact of GT on the diagnosis and management of HCM patients. An electronic search was conducted on May 17, 2024, across PubMed, Embase, Scopus, Web of Science, and Cochrane databases, covering January 2020 to May 2024. Inclusion criteria were studies involving adult HCM patients who underwent GT and follow-up. Exclusion criteria included non-human studies, pediatric cases, non-HCM-related GT, non-peer-reviewed articles, systematic reviews, conference abstracts, and editorials. From 1,155 articles identified, 42 met the inclusion criteria after applying filters and removing duplicates. GT identified pathogenic variants in a significant proportion of HCM patients, enhancing diagnostic accuracy and management. Key mutations were found in myosin binding protein C3 and myosin heavy chain 7 genes. GT facilitated personalized management strategies, including risk stratification for SCD and family screening. Patients with identified mutations often required closer monitoring and tailored treatments. GT has revolutionized the diagnosis and management of HCM. The integration of genetic data has improved risk stratification, facilitated early intervention, and enhanced patient outcomes. Despite these advances, challenges remain in identifying genetic variants in some patients, emphasizing the need for continuous improvement in genetic panels and diagnostic methods. This review highlights the significant role of GT in optimizing HCM care through precise risk assessment and tailored treatment strategies.

Novel Cardiac Myosin Inhibitor Therapy for Hypertrophic Cardiomyopathy in Adults: A Contemporary Review.

Hypertrophic cardiomyopathy (HCM) affects as many as 1 in 200 people in the adult population globally. Patients may present with exertional dyspnea, presyncope or syncope, atrial and ventricular arrhythmias, heart failure, and even sudden cardiac death. Current guideline-based therapy involves medical therapy for treatment of symptoms in milder forms of the disease and surgical or catheter-based septal reduction therapies in obstructive HCM. Until recently, there has existed a gap between these two approaches that is now being filled by a new class of drugs, cardiac myosin inhibitors, which directly target the underlying disease process in HCM. Current investigations examine the effects of two cardiac myosin inhibitors on reported symptoms, echocardiographic evidence of disease, and the associated need for septal reduction. This paper reviews the contemporary evidence for the use of cardiac myosin inhibitors in HCM in adults and highlights future directions for this exciting field of cardiovascular medicine.

Trends of hypertrophic cardiomyopathy-related mortality in United States young adults: a nationwide 20-year analysis.

Data regarding hypertrophic cardiomyopathy (HCM)-related mortality in United States young adults, defined as those aged between 25 and 44 years, are lacking. We sought to assess the trends in HCM-related mortality among US young adults between 1999 and 2019 and determine differences by sex, race, ethnicity, urbanization and census region. Mortality data were retrieved by the Centers for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiologic Research (WONDER) dataset from January 1999 to December 2019. Age-adjusted mortality rates (AAMRs) were assessed using the Joinpoint regression modeling and expressed as estimated average annual percentage change (AAPC) with relative 95% confidence intervals (95% CIs). Over 20-year period, the AAMR from HCM in US young adults linearly decreased, with no differences between sexes [AAPC: -5.3% (95% CI -6.1 to -4.6), P < 0.001]. The AAMR decrease was more pronounced in Black patients [AAPC: -6.4% (95% CI -7.6 to -5.1), P < 0.001], Latinx/Hispanic patients [AAPC: -4.8% (95% CI -7.2 to -2.36), P < 0.001] and residents of urban areas [AAPC: -5.4% (95% CI -6.2 to -4.6), P < 0.001]. The higher percentages of HCM-related deaths occurred in the South of the country and at the patient's home. HCM-related mortality in US young adults has decreased over the last two decades in the United States. Subgroup analyses by race, ethnicity, urbanization and census region showed ethnoracial and regional disparities that will require further investigation.

Anatomical, functional and prognostic correlates of resting coronary flow velocity in patients with hypertrophic cardiomyopathy

Abstract Background The clinical significance of baseline peak diastolic coronary flow velocity (CFV) in the left anterior descending coronary artery (LAD) has not been investigated yet in patients with hypertrophic cardiomyopathy (HCM). Aim To assess the anatomical, functional and prognostic correlates of baseline LAD CFV in HCM. Methods 384 consecutive adult HCM patients (age=52+15 years, 164 [43%] females) with no known coronary artery disease from 8 centers in 5 countries were prospectively analyzed. All patients underwent comprehensive transthoracic echocardiography including CFV measurement with pulse wave Doppler in the mid-distal LAD. All patients had preserved left ventricular (LV) function. LV force was calculated as (peak instantaneous LV outflow tract gradient+systolic blood pressure)/LV end-systolic volume. Patients were followed for a median of 50 months (IQ range 18-97 months), the outcome measure was a composite endpoint of all-cause death and acute heart failure. Results The mean CFV was 36±11 cm/s. CFV was positively correlated with LV maximal wall thickness (r=0.375, p&amp;lt;0.001), LV maximal septal thickness (r=0.320, p&amp;lt;0.001), resting LV outflow tract gradient (r=0.274, p&amp;lt;0.001), LV force (r=0.227, p&amp;lt;0.001), mean E/e’ (r=0.479, p&amp;lt;0.001) and heart rate (r=0.221, p&amp;lt;0.001). During follow-up, 54 events occurred (33 all-cause deaths and 21 acute heart failures). Receiver operating characteristic analysis was used to determine the best cut-off value of CFV (&amp;gt;31 cm/s) to predict the composite endpoint. Patients with CFV &amp;gt;31 cm/s had a significantly worse 10-year event-free survival compared to those with CFV ≤31 cm/s, see Figure. Conclusion Higher resting LAD CFV is associated with greater LV wall thickness, higher LV outflow tract gradient, faster heart rate and more elevated left ventricular filling pressures in HCM. Elevated resting CFV may indicate a coronary microcirculation dysfunction either primary or secondary to anatomical (septal hypertrophy), functional (increased myocardial oxygen demand), or autonomic (increased sympathetic drive) determinants. Whatever the underlying endotype, high resting CFV is related to worse prognosis in the long term.Figure.

The importance of vasodilator stress echocardiography in predicting all-cause mortality and acute heart failure in hypertrophic cardiomyopathy

Abstract Background Reduced coronary flow velocity reserve (CFVR) in the left anterior descending coronary artery (LAD) during vasodilator stress echocardiography (VSE) is a marker of poor outcome and is associated with higher baseline coronary flow velocity (CFV) in hypertrophic cardiomyopathy (HCM). However, whether resting CFV has additive predictive value to CFVR during VSE in HCM is unknown. Aim To assess the prognostic value of baseline CFV and CFVR during VSE in HCM. Methods 325 adult HCM patients (age=52+15 years, 147 [45%] females) with preserved left ventricular function and no known coronary artery disease who underwent VSE in 6 certified centers between 1999 and 2021 were prospectively analyzed. VSE modality was adenosine (0.14 mg/kg/min in 2', n=232) or dipyridamole (0.84 mg/kg in 6', n=93). CFVR in the LAD was assessed by transthoracic (n=306) or transoesophageal (n=19) echocardiography. Patients were followed for a median of 67 months (IQ range 31-103 months), the primary endpoint was a composite of all-cause mortality and acute heart failure (HF). Results Receiver operating characteristic analysis was used to determine the best cut-off value of CFV (&amp;gt;31 cm/s, elevated) and CFVR (≤2.0, reduced) to predict the primary endpoint. Patients with reduced CFVR had more frequently elevated baseline CFV (75% vs 49%, p&amp;lt;0.001). Elevated resting CFV was a predictor of composite endpoint at univariable (HR 2.04, 95% CI 11.05-3.97, p=0.035) but not at multivariable analysis. A reduced CFVR was an independent predictor of all-cause mortality (HR 5.50, 95% CI 1.94-15.59, p=0.001), acute HF (HR 5.80, 95% CI 1.60-21.00, p=0.007), and the composite end-point (HR 4.95, 95% CI 2.39-10.25, p&amp;lt;0.001). The 5-year event rate was 6-fold higher in patients with reduced CFVR compared to patients with preserved CFVR (19% vs 3%, p&amp;lt;0.001), with no additional impact of resting CFV (see Figure). Conclusion LAD CFVR ≤2.0 during VSE is a strong and independent predictor of all-cause mortality and acute HF in HCM. Elevated resting CFV is more frequent in patients with reduced CFVR, but has no independent prognostic value when CFVR is considered.Kaplan-Meier event-free survival curves

Association between hospital volume, clinical events, resource utilization, and costs of septal myectomy and alcohol septal ablation procedures in US patients with hypertrophic cardiomyopathy

Abstract Background Prior studies have evaluated the relationship between hospital procedural volumes of septal reduction therapies (SRT) for obstructive hypertrophic cardiomyopathy (HCM) and outcomes. Other analyses, including economic outcomes, are needed to support clinical decisions among adult patients diagnosed with HCM. Objective The objective of this study was to reconfirm the relationship between higher SRT procedural volume, including septal myectomy (SM) -with and without mitral valve repair or replacement (MVRR)- and alcohol septal ablation (ASA), and clinical events, healthcare resource utilization, and hospitalization costs using more contemporary hospitalization data. Data &amp; Methods This cross-sectional study utilizes retrospective observational data from the PINC AI™ Healthcare Database (PHD), a US hospital administrative database. The study population consists of adult patients with HCM undergoing ASA or SM procedures between January 1, 2012, and March 31, 2022. Hospital volume was determined by tertiles of total SRT performed for ASA, SM separately during the study period. We compare clinical events (including death, stroke, acute renal failure, and pacemaker implantation), readmission, index length of stay, and hospitalization costs across tertiles. We present p-values between tertiles and within procedure types. Results A total of 3,068 adult HCM patients in 315 US hospitals underwent SRT during the study period, including 1,400 with ASA and 1,668 with SM. Table 1 shows the patient and hospital characteristics by tertiles of hospital volume. The median age of patients was 66 years for ASA and 62 years for SM. Medicare coverage accounted for 59.9% of ASA and 44.9% of SM, followed by commercial coverage (28.5% of ASA and 39% of SM). Most hospitals in the study were teaching hospitals (74% for ASA and 67% for SM). In the highest SRT volume tertile (5% of hospitals performing SRT) the average annual number of procedures was 3.5 ASA and 4.9 SM. Table 2 presents the outcomes by hospital volume (low-, mid-, and high-volume). Recorded in-hospital death rates for ASA were 1.4%, 1.4%, and 1.1%, respectively (not statistically different); for SM, 5.1%, 3.4% and 2.9%, respectively (not statistically different). For ASA and SM, index hospital costs, and 30-day readmission rates had an inverse relationship to hospital volume, with statistically significant differences for both procedures between the low- and high-volume hospitals (p&amp;lt;0.05). Conclusion The annual number of SRT procedures for obstructive HCM remains low, even for higher volume hospitals. This study shows high variability in clinical events, resource utilization, and in-hospital costs by hospital procedure volume and type of SRT. We reconfirmed that higher hospital procedure volume is associated with fewer adverse clinical events and lower costs.

Comparing indices of systemic inflammation and cardiac phenotype between hypertensive and non-hypertensive hypertrophic cardiomyopathy

Abstract Background Arterial hypertension (HTN) is associated with excess mortality in hypertrophic cardiomyopathy (HCM), but underlying mechanisms are largely elusive. Purpose The purpose of this study was to investigate the association between HTN and indices of systemic inflammation and cardiac function in a HCM cohort. Methods This was a single-center cross-sectional case-control study comparing 30 adult HCM patients with HTN (HTN+) and 30 sex- and age-matched HCM patients without HTN (HTN-). Echocardiographic measures were assessed using post-processing analyses by a blinded investigator. Results Mean age of the total sample was 54.6±10.1 years, 30% were women. Mean end-diastolic interventricular septum (IVSd) thickness was 2.1±0.4 cm, 18% previously underwent septal reduction therapy, and 47% had left ventricular outflow tract obstruction. HTN+ portrayed more severe IVSd thickness than HTN- [2.2±0.3 cm vs. 2.0±0.4 cm; p = 0.017], while echocardiographic measures of systolic and diastolic function, including speckle-tracking derived parameters, did not differ between groups. Moreover, levels of N-terminal pro B-type natriuretic peptide were balanced between groups. Compared with HTN-, HTN+ patients exhibited higher circulating plasma levels of interleukin-6 [2.8 pg/ml (2.0, 5.4) vs. 2.1 pg/ml (1.5, 3.4); p = 0.008] and high-sensitivity C-reactive protein [2.6 mg/l (1.4, 6.5) vs. 1.1 mg/l (0.9, 2.4); p = 0.004] Conclusion This study demonstrates that HTN is associated with low-grade systemic inflammation among HCM patients. Moreover, this analysis indicates that HTN+ do not exhibit an altered systolic and diastolic function compared to HTN-. Accordingly, the adverse impact of HTN in HCM patients may be a consequence of systemic effects rather than alterations of cardiac function.TableFigure

Abstract 15539: Outcomes of a Multidisciplinary Approach to Management of Mavacamten in Obstructive Hypertrophic Cardiomyopathy

Background: Mavacamten treats obstructive hypertrophic cardiomyopathy in adults, improving symptoms and functional capacity. Its complex management process involves frequent echocardiograms, dose adjustments based on Valsalva left ventricular outflow tract (VLVOT) gradient changes, and screening for drug interactions. The high cost of mavacamten poses a financial burden to patients, and the management process lacks adequate simplification. Real-world workflow descriptions are needed for successful patient outcomes. Methods: We retrospectively analyzed patients prescribed mavacamten from May 2022 to May 2023 through a multidisciplinary workflow. Patients were referred to a pharmacist after an initial clinic visit with a cardiologist. Pharmacists counseled patients, enrolled them in the online Risk Evaluation and Mitigation Strategies program, and facilitated enrollment in the manufacturer's patient support program for cost reduction options and prior authorization. Echocardiogram dates were determined using a calculator created by the authors and coordinated with the echocardiography staff. Pharmacists adjusted doses based on finalized echocardiogram reports. Outcomes included ejection fraction (EF), LVOT, and VLVOT which were analyzed using a generalized linear mixed model controlling for time. Additional outcomes were out-of-pocket cost, time to approval, and time to first dispense. Results: Among 34 patients considered, 21 received mavacamten. Reasons for non-receipt included cost (6 patients), unwillingness to follow-up (4 patients), drug interactions (1 patient), absence of mavacamten on insurance formulary (1 patient), and awaiting insurance approval (1 patient). Patients on mavacamten received therapy for 2-48 weeks. They experienced significant decreases in average LVOT (P&lt;0.001) and VLVOT (P&lt;0.001) over time. Average EF showed a non-significant decrease (P=0.097), with one patient recovering from a decline below 50% upon discontinuing mavacamten. Conclusion: Mavacamten faces barriers such as echocardiogram follow-up, complex dosing, drug interaction screening, and cost. However, the described workflow effectively addresses many of these barriers, serving as a template for mavacamten management.

Abstract 14514: Hypertrophic Cardiomyopathy - Genotype Distribution and Genotype-Phenotype Correlations - A Unique Perspective From a Single Center Study

Background: The role of genotype in risk stratification of hypertrophic cardiomyopathy (HCM) is unclear. Hypothesis: Genotype status affects phenotype and associated outcomes. Aims: To evaluate genotype-phenotype correlations in all adult HCM patients seen at our Cardiac Specialty Center over 13 years and associated outcomes. Methods: We evaluated genotype-phenotype correlations, all-cause mortality, and a composite outcome, including mortality, stroke, implantable cardioverter-defibrillator placement, heart failure hospitalization, LV assist device implantation, heart transplant, septal myectomy, and alcohol septal ablation. Results: Of 827 HCM patients, genotyping was completed in 754 (91.2%), which included 27% genotype-positive (Gen-P), 22% variants of unknown significance (VUS), and 51% genotype-negative (Gen-N) patients with a mean age of 47, 57, and 58 years, respectively. The most common gene implicated was MYBPC3 (63%). LV hypertrophy on electrocardiogram was more frequent in Gen-N than Gen-P patients. Gen-P patients had more frequent non-sustained ventricular tachycardia on Holter monitoring (25% vs 10%), grade III diastolic dysfunction (12% vs 7%), elevated ProBNP (71% vs 61%), and lower ejection fraction (66% vs 69%) than Gen-N patients (P &lt;.05 for all comparisons). All heart transplantations (N=5) were performed in Gen-P patients. LVOT obstruction was more frequent in Gen-N than Gen-P patients (48% vs 26%, P &lt;.01). Distribution of outcomes is shown in Panels A-H. The composite outcome was worse in Gen-P vs Gen-N patients (HR 1.84, P &lt;.01). The other independent predictors of poor composite outcome were old age, male sex, obesity, and atrial fibrillation. A separate analysis of mortality showed similar survival in all groups. Conclusion: Differences exist in phenotype and outcomes based on the genotype status, with more severe phenotype and poorer outcomes in Gen-P patients in our single-state single-center experience.

Clinical profile and outcomes of pediatric hypertrophic cardiomyopathy in a South Indian tertiary care cardiac center: a three decade experience

IntroductionAlthough much research has been done on adult hypertrophic cardiomyopathy, data on pediatric hypertrophic cardiomyopathy is still limited.Methods and resultsThe study enrolled all patients with cardiomyopathy who presented to us between 1990 to 2020 and were younger than 18 yrs. During the thirty-year study period, we identified 233 cases of pediatric cardiomyopathy. Sixty-three cases (27%) had hypertrophic cardiomyopathy. Out of the 63 HCM cases, 12% presented in the neonatal period and 37% presented in the first year of life. The median age of presentation was 7 yrs (Range 0.1–18 yrs). Sixteen patients had proven syndromic, metabolic, or genetic disease (25%). LV outflow obstruction was present in 30 patients (47%). Noonan syndrome was present in 9 of the 63 patients (14%). Dyspnea on exertion was the most common mode of presentation. Cardiac MRI was done in 28 patients, out of which 17 had late gadolinium enhancement (LGE). Mid myocardial enhancement was the most common pattern. Four patients had LGE of more than 15%. Over a mean follow-up period of 5.6 years (0.1–30 years), twenty-one were lost to follow-up (33%). Among the patients whose outcome was known, eleven died (26%), and thirty-one (73%) were alive. The 5-year survival rate of HCM patients was 82%, and the 10-year survival rate was 78%. Seven died of sudden cardiac death, three from heart failure, and one from ventricular arrhythmias. Sustained ventricular arrhythmias were seen in three patients and atrial arrhythmias in two. First-degree AV block was seen in 10 patients (15%) and bundle branch blocks (BBB) in five (8%). Eight patients required ICD or transplant (12.7%). Two patients underwent ICD for primary prevention, and one underwent PPI for distal AV conduction disease. Among the various clinical, echocardiographic, and radiological risk factors studied, only consanguinity showed a trend towards higher events of death or ventricular arrhythmias (P-value 0.08).ConclusionMore than one-third of our HCM cohort presented in infancy. LV outflow tract obstruction is common (47%). Mid myocardial enhancement was the most common pattern of late gadolinium enhancement. SCD was the most common cause of death. The outcome in our HCM cohort is good and similar to other population cohorts. Only Consanguinity showed a trend towards higher events of death or ventricular arrhythmias.

Efficacy and Safety of Mavacamten in the Treatment of Hypertrophic Cardiomyopathy: A Systematic Review.

Current pharmacological options for hypertrophic cardiomyopathy (HCM) are not disease-specific; while it treats symptoms, mavacamten targets the underlying pathology. We aim to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive HCM. This systematic review of the literature followed the PRISMA guidelines. Title/abstract and topics were searched using the following term: "mavacamten". The electronic research literature databases included the Cochrane Library, MedLine, and clinicaltrials.gov from July to August 2022. Primary efficacy endpoint was to assess clinical response at the end of treatment compared with baseline, defined as, at least one New York Heart Association (NYHA) class reduction. Two secondary endpoints from baseline were determined. The first was defined as improvement in mixed venous oxygen pressure (pVO2). The second was defined as reduction of the post-exercise left ventricular outflow tract (LVOT) gradient. We included in our analyses data from four studies that met our review eligibility criteria. There were three randomised placebo-controlled clinical trials and one non-randomised open-label clinical trial. All four studies showed a reduction in NYHA class from mavacamten use. Three out of four studies demonstrated >1 NYHA functional class improvement ranging from 34% to 80%, while only one study showed a smaller percentage of patients remaining at class 3. Three out of four studies measured pVO2 as an outcome, and all three studies noticed an increase in peak oxygen consumption after mavacamten treatment. Additionally, three out of four studies measured post-exercise LVOT gradient reduction as an outcome and all three found significant reduction in the post-exercise LVOT gradient after treatment. The most commonly observed adverse side effects were atrial fibrillation and decreased left ventricular ejection fraction, but all participants recovered without long-term sequelae and only one patient dropped out of the trial. Mavacamten has a greater efficacy than placebo in the treatment of HCM. It also showed promising tolerability and efficacy profiles in the treatment of HCM in adults. The three endpoints used in the evaluation of studies were reduction in NYHA class, increase in pVO2, and post-exercise LVOT gradient reduction. Mavacamten showed greater reduction in NYHA, larger effects on increase of pVO2, and significant reduction of the LVOT gradient. Mavacamten was also found to be well tolerated, like the placebo. The side effect profile was limited for the majority of individuals taking mavacamten. In the future, authors recommended dose-optimisation studies, and studies that evaluate mavacamten both in comparison to, and in conjunction with other current treatments.

Abstract P2138: Long-Term Clinical Value And Impact Of Mavacamten In Symptomatic Obstructive Hypertrophic Cardiomyopathy: A Systematic Review And Meta-Analysis

Introduction: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder involving the cardiac sarcomere. Mavacamten is the first-in-class oral cardiac myosin inhibitor approved for treating HCM in adults targeting sarcomere hypercontractility. We aimed to evaluate the efficacy and safety of mavacamten in symptomatic obstructive HCM. Methods: We conducted a systematic literature search in Embase, PubMed, Scopus, and Web of Science databases from inception until March 05, 2023. Results: After screening 349 studies, our final analysis included 5 studies with 843 obstructive HCM patients and an average follow-up of 27.2 weeks. A fixed effects model was used to calculate risk ratios (RRs). Our meta-analysis revealed a significant improvement in NYHA functional class from baseline in patients on mavacamten compared to placebo [RR, 4.59 (95% CI: 2.94-7.16), p&lt;0.00001]. Mavacamten use in obstructive HCM patients also resulted in significantly lower rates of septal reduction therapy (SRT) or patients who were guideline-eligible for SRT versus placebo [RR, 0.29 (95% CI: 0.22-0.39), p&lt;0.00001]. There was no significant effect of mavacamten use on the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (p = 0.22). Also, no significant difference was observed in the occurrence of ≥1 serious adverse event (p = 0.77), atrial fibrillation (p = 0.98), and non-sustained ventricular tachycardia (p = 0.44) between mavacamten and placebo group. Conclusions: A substantial improvement in NYHA functional class without any serious adverse events, and a significant reduction in the number of patients requiring SRT, makes mavacamten a promising drug for obstructive HCM.

Association between clinical phenotypes of hypertrophic cardiomyopathy and Ca2+ gene variation gene variation

Objective: To observe the association between clinical phenotypes of hypertrophic cardiomyopathy (HCM) patients and a rare calcium channel and regulatory gene variation (Ca2+ gene variation) and to compare clinical phenotypes of HCM patients with Ca2+ gene variation, a single sarcomere gene variation and without gene variation and to explore the influence of rare Ca2+ gene variation on the clinical phenotypes of HCM. Methods: Eight hundred forty-two non-related adult HCM patients diagnosed for the first time in Xijing Hospital from 2013 to 2019 were enrolled in this study. All patients underwent exon analyses of 96 hereditary cardiac disease-related genes. Patients with diabetes mellitus, coronary artery disease, post alcohol septal ablation or septal myectomy, and patients who carried sarcomere gene variation of uncertain significance or carried>1 sarcomere gene variation or carried>1 Ca2+ gene variation, with HCM pseudophenotype or carrier of ion channel gene variations other than Ca2+ based on the genetic test results were excluded. Patients were divided into gene negative group (no sarcomere or Ca2+ gene variants), sarcomere gene variation group (only 1 sarcomere gene variant) and Ca2+ gene variant group (only 1 Ca2+ gene variant). Baseline data, echocardiography and electrocardiogram data were collected for analysis. Results: A total of 346 patients were enrolled, including 170 patients without gene variation (gene negative group), 154 patients with a single sarcomere gene variation (sarcomere gene variation group) and 22 patients with a single rare Ca2+ gene variation (Ca2+ gene variation group). Compared with gene negative group, patients in Ca2+ gene variation group had higher blood pressure and higher percentage of family history of HCM and sudden cardiac death (P<0.05); echocardiographic results showed that patients in Ca2+ gene variation group had thicker ventricular septum ((23.5±5.8) mm vs. (22.3±5.7) mm, P<0.05); electrocardiographic results showed that patients in Ca2+ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (400.6±47.2) ms, P<0.05) and higher RV5+SV1 ((4.51±2.26) mv vs. (3.50±1.65) mv, P<0.05). Compared with sarcomere gene variation group, patients in Ca2+ gene variation group had later onset age and higher blood pressure (P<0.05); echocardiographic results showed that there was no significant difference in ventricular septal thickness between two groups; patients in Ca2+ gene variation group had lower percentage of left ventricular outflow tract pressure gradient>30 mmHg (1 mmHg=0.133 kPa, 22.8% vs. 48.1%, P<0.05) and the lower early diastolic peak velocity of the mitral valve inflow/early diastolic peak velocity of the mitral valve annulus (E/e') ratio ((13.0±2.5) vs. (15.9±4.2), P<0.05); patients in Ca2+ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (399.0±43.0) ms, P<0.05) and lower percentage of ST segment depression (9.1% vs. 40.3%, P<0.05). Conclusion: Compared with gene negative group, the clinical phenotype of HCM is more severe in patients with rare Ca2+ gene variation; compared with patients with sarcomere gene variation, the clinical phenotype of HCM is milder in patients with rare Ca2+ gene variation.

An evaluation of mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy in adults

ABSTRACT Introduction Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder leading to hypertrophy of the left ventricle excluding other etiologies. Patients can experience exertional chest pain, dyspnea, syncope or even sudden cardiac death (SCD). Traditional medical management consists of beta blockers (BB), nondihydropyridine calcium channel blockers and disopyramide. Mavacamten, a novel cardiac myosin inhibitor, has recently been shown to improve both quantitative and qualitative measures of obstructive HCM allowing some patients to defer septal reduction therapy. Areas covered This review delves into the pharmacotherapy of mavacamten, the evidence behind this first-in-class drug for HCM, guidance for clinical usage, and possible future uses for cardiac myosin inhibitors. Expert opinion Mavacamten should be incorporated into the standard armamentarium of medications used to treat obstructive HCM. PIONEER-HCM, EXPLORER-HCM and VALOR-HCM demonstrated improvements in peak LVOT gradient both at rest and post-exercise, cardiac biomarkers, New York Heart Association (NYHA) functional class and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Unlike other medications utilized for treatment, mavacamten can delay or even obviate the need for septal reduction therapy.

Abstract 14817: Machine Learning Computer Vision for Point of Care Decision Support of Echocardiographic Identification of Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) has an estimated prevalence of 1/500 but remains underdiagnosed. Echocardiography is the primary diagnostic modality but requires recognition of varied patterns of hypertrophy. Point of care tools to facilitate improved identification of HCM are needed. Methods: We identified 400 study cases of HCM in adults meeting professional society guideline diagnostic criteria from 2000-2020 at Duke University Medical Center. 900 study controls matched on age, sex, year of echo, and ejection fraction were also identified. Multi-vendor echocardiographic examinations performed within 12 months of initial diagnosis were used to train a convolutional neural network (CNN) to identify HCM. The model consisting of a 18-layer deep R(2+1)D residual network was developed on 60% of the data (training), 20% of the data (validation) was used to select model hyperparameters and to monitor for overfitting, and the remaining 20% (test) was used for performance estimation. CNN performance was evaluated by the receiving operating characteristic (ROC) and precision-recall curve and their summaries, namely, area under the ROC (AUROC) and average precision (AP, i.e. , average positive predictive value). We report performance characteristics at the study level. Results: Among 400 HCM cases and 900 controls, the median age was 65, with 48.1% male. Hypertension was present in 44.9%, with heart failure in 16.3% and Atrial Fibrillation in 12%. Median EF was 55% with 14.5% having an EF &lt; 50%. Median diastolic dimension was 4.4 cm and moderate or severe MR was present in 8.4%. Study-level AUCROC for the CNN was 0.853 and the average precision was 0.698 (Figure 1). Conclusion: A machine learning CNN is able identify study-wise HCM with an AUC of 0.853. Further work will be necessary to ensure explainability of results and similar multi-institutional performance as a point of care tool for the echocardiographic identification of HCM on diagnostic rates.

Abstract 12104: Pediatric Hypertrophic Cardiomyopathy With Left Ventricular Systolic Dysfunction: Insights From the Sarcomeric Human Cardiomyopathy Registry (SHaRe)

Introduction: Left ventricular systolic dysfunction (LVSD, LV ejection fraction (LVEF) &lt;50), occurs in ~8% of adults with hypertrophic cardiomyopathy (HCM) and is associated with poor prognosis. However, the incidence and prognosis of LVSD in pediatric patients with HCM (&lt;18 years old) is poorly understood. Methods: Patients in SHaRe with pediatric HCM were included. Time-to-event analyses were performed to estimate 1) cumulative incidence of LVSD in pediatric vs adult HCM (Kaplan Meier), 2) predictors of incident LVSD in pediatric HCM (Cox-proportional hazards) and 3) a composite outcome of all-cause mortality, heart transplant and left ventricular assist device implant in pediatric HCM. Results: In total, 1296 pediatric HCM patients (34% females, median 12.2 years at diagnosis, median 8.3 years follow-up) were included. LVSD occurred in 155 (12%) of patients with 29% (n=45) having LVSD at the first SHaRe visit and 22% (n=34) developing LVSD &lt;18 years old. At 5-year follow-up, the cumulative incidence of LVSD was 9% [8-11%]. Predictors of incident pediatric LVSD included HCM before age 12 (HR 2.0 [1.3-3.0]), female sex (HR 0.49 [0.32-0.77]), P/LP variants in thick filament genes (HR 2.6 [1.1-4.2], multiple P/LP variants (HR 9.1 [CI 2.9-29.1]) and baseline LVEF (HR 0.63 [0.58-0.68], per 5 %-points increase). Pediatric HCM was associated with higher rate of LVSD compared to adult-onset HCM (n=6428, median HCM at age 49 years, median follow-up of 7.1 years), p=0.05 (Figure 1). The composite endpoint occurred in 41% (n= 63/155) of children with HCM and subsequent LVSD. In patients with LVSD, female sex (HR 2.44 [1.41-4.17]) and baseline LVEF &lt;35% (HR 4.0 [2.4-6.9]) were independently associated with the composite outcome. Conclusion: Females were less likely to develop LVSD but more likely to have adverse outcomes once they do. Clinical outcomes are adverse, and greater recognition of and surveillance for LVSD in pediatric HCM are warranted.

Extended Myectomy for Hypertrophic Cardiomyopathy: Early Outcomes From a Nascent Centre of Excellence in Canada

Hypertrophic cardiomyopathy (HCM) is one of the commonest inherited cardiac abnormalities. The disorder is clinically and genetically heterogeneous and is characterized by left ventricular wall thickening that is not explained by abnormal loading conditions. HCM is estimated to affect between 1 in 200 and 1 in 500 people in the general population. In the majority of cases, HCM patients have a relatively benign course; however, if left untreated, this abnormality can lead to sudden cardiac death, especially in young adults and athletes. Therefore, early diagnosis is crucial to help implement the proper management for patients with HCM. In response to the growing need for more HCM centres of excellence in Canada, we developed one such centre at the University of Ottawa Heart Institute from the start of 2018. This centre will help in the early diagnosis and management of HCM patients, especially those with left ventricular outflow tract obstruction who might benefit from myectomy surgery. This paper describes our early experience with surgical myectomy in adult HCM patients between January 2018 and December 2020. We report the results of 27 patients with HCM who underwent myectomy surgery during the study period. All 27 patients survived to discharge, and all were still alive at 6 months postdischarge. Our experience highlights the crucial role that preoperative and perioperative imaging play in the management of this condition, in addition to the vital role of having a committed “heart team” of cardiologists, surgeons, and anesthesiologists.