2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy. METHODS: A comprehensive literature search was conducted from September 14, 2022, to November 22, 2022, encompassing studies, reviews, and other evidence on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through May 23, 2023, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Hypertrophic cardiomyopathy remains a common genetic heart disease reported in populations globally. Recommendations from the "2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy" have been updated with new evidence to guide clinicians.

Histone Modifications and miRNA Perturbations Contribute to Transcriptional Dysregulation of Hypertrophy in Obstructive Hypertrophic Cardiomyopathy.

Background: Recently, we demonstrated transcriptional downregulation of hypertrophy pathways in myectomy tissue derived from patients with obstructive hypertrophic cardiomyopathy (HCM) despite translational activation of hypertrophy pathways. The mechanisms and modifiers of this transcriptional dysregulation in HCM remain unexplored. We hypothesized that miRNA and post-translational modifications of histones contribute to transcriptional dysregulation in HCM. Methods: First, miRNA-sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) were performed on HCM myectomy tissue and control donor hearts to characterize miRNA and differential histone marks across the genome. Next, the differential miRNA and histone marks were integrated with RNA-sequencing (RNA-seq) data. Finally, the effects of miRNA and histones were removed in silico to determine their necessity for transcriptional dysregulation of pathways. Results: miRNA-analysis identified 19 differentially expressed miRNA. ChIP-seq analysis identified 2,912 (7%) differential H3K4me3 peaks, 23,339 (21%) differential H3K9ac peaks, 33 (0.05%) differential H3K9me3 peaks, 58,837 (42%) differential H3K27ac peaks, and 853 (3%) differential H3K27me3 peaks. Univariate analysis of concordance between H3K9ac with RNA-seq data showed activation of cardiac hypertrophy signaling, while H3K27me showed downregulation of cardiac hypertrophy signaling. Similarly, miRNAs were predicted to result in downregulation of cardiac hypertrophy signaling. In silico knock-out that effects either miRNA or histones attenuated transcriptional downregulation while knocking out both abolished downregulation of hypertrophy pathways completely. Conclusion: Myectomy tissue from patients with obstructive HCM shows transcriptional dysregulation, including transcriptional downregulation of hypertrophy pathways mediated by miRNA and post-translational modifications of histones. Cardiac hypertrophy loci showed activation via changes in H3K9ac and a mix of activation and repression via H3K27ac.

Outcomes of Surgical Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy After Prior Septal Reduction Therapy.

OBJECTIVE: To compare early and late outcomes of septal myectomy in patients with obstructive hypertrophic cardiomyopathy who presented with residual or recurrent left ventricular outflow tract (LVOT) obstruction following prior septal reduction therapy (SRT). METHODS: From January 1989 to March 2022, 145 patients underwent reintervention by septal myectomy for residual LVOT obstruction following prior SRT; 72 patients had prior alcohol septal ablation (ASA), and 73 had prior surgical septal myectomy (SM). Baseline patient characteristics, echocardiographic parameters, and surgical outcomes were compared between these two groups. RESULTS: Patients who had prior ASA were more likely to be male (50.0% vs 30.1%; P=0.015), older (median age 57.5 years vs. 48.3 years; P<0.001) and have a greater body mass index (32.7 kg/m2vs. 30.0 kg/m2; P=0.011). After repeat SRT by septal myectomy, there was no significant difference in the incidence of postoperative complete heart block (CHB), necessitating permanent pacemaker, between the two groups (8.3% vs. 2.7%; P=0.151). One (0.7%) patient died within 30 days of surgery. Over a median follow-up of 7.5 years (IQR 3.0-13.8), there were 20 deaths. Kaplan-Meier 5-, 10-, and 15-year survival rates were 100%, 91%, and 76% for the prior SM group, and 93%, 81%, and 64% for the prior ASA group (P=0.207). CONCLUSION: Septal myectomy for residual or recurrent LVOT obstruction in patients who had prior ASA is safe with an acceptably low rate of postoperative CHB. Surgical outcomes and late survival rates in patients with prior ASA were satisfactory and comparable to patients who underwent repeat myectomy.

2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy. METHODS: A comprehensive literature search was conducted from September 14, 2022, to November 22, 2022, encompassing studies, reviews, and other evidence on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through May 23, 2023, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Hypertrophic cardiomyopathy remains a common genetic heart disease reported in populations globally. Recommendations from the "2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy" have been updated with new evidence to guide clinicians.

A Multi-Omics Atlas of Sex-Specific Differences in Obstructive Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Women with HCM tend to have a later onset but more severe disease course. However, the underlying pathobiological mechanisms for these differences remain unknown. Methods: Myectomy samples from 97 patients (53 males/44 females) with symptomatic obstructive HCM and 23 control cardiac tissues were included in this study. RNA-sequencing was performed on all samples. Mass spectrometry-based proteomics and phosphoproteomics was performed on a representative subset of samples. Results: The transcriptome, proteome, and phosphoproteome was similar between sexes and did not separate on PCA plotting. Overall, there were 482 differentially expressed genes (DEGs) between control females and control males while there were only 53 DEGs between HCM females and HCM males. There were 1963 DEGs between HCM females and control females compared to 1064 DEGs between HCM males and control males. Additionally, there was increased transcriptional downregulation of hypertrophy pathways in HCM females and in HCM males. HCM females had 119 differentially expressed proteins compared to control females while HCM males only had 27 compared to control males. Finally, the phosphoproteome showed females had 341 differentially phosphorylated proteins (DPPs) compared to controls while males only had 184. Interestingly, there was hypophosphorylation and inactivation of hypertrophy pathways in females but hyperphosphorylation and activation in males. Conclusion: There are subtle, but biologically relevant differences in the multi-omics profile of HCM. This study provides the most comprehensive atlas of sex-specific differences in the transcriptome, proteome, and phosphoproteome present at the time of surgical myectomy for obstructive HCM.

Re-evaluating the Incidence and Prevalence of Clinical Hypertrophic Cardiomyopathy: An Epidemiological Study of Olmsted County, Minnesota.

OBJECTIVE: To contemporaneously reappraise the incidence-rate, prevalence, and natural history of hypertrophic cardiomyopathy (HCM) in Olmsted County, Minnesota, from 1984 to 2015. PATIENTS AND METHODS: A validated medical-record linkage system collecting information for residents of Olmsted County was used to identify all cases of HCM between January 1, 1984, and December 31, 2015. After adjudication of records from Mayo Clinic and Olmsted Medical Center, data relating to diagnoses and outcomes were abstracted. The calculated incidence rate and prevalence were standardized to the US 1980 White population (age- and sex-adjusted) and compared with a prior study examining the years 1975-1984. RESULTS: Two hundred seventy subjects with HCM were identified. The age- and sex-adjusted incidence rate was 6.6 per 100,000 person-years, and the point prevalence of HCM on January 1, 2016, was 89 per 100,000 population. The incidence rate and point prevalence of HCM on January 1, 2016, standardized to the US 1980 White population (age- and sex-adjusted), were 6.7 (95% CI, 7.1 to 8.8) per 100,000 person-years and 81.5 per 100,000 population, respectively. The incidence rate of HCM increased each decade since the index study. Individuals with HCM had a higher overall standardized mortality rate than the general population with an observed to expected HR of 1.44 (95% CI, 1.21 to 1.71; P<.001) which improved by each decade. CONCLUSION: The incidence and prevalence of HCM are higher than rates reported from a prior study in the same community examining the years 1975-1984, but lower than other study cohorts. The risk of mortality in HCM remains higher than expected, albeit with improvement in rates of mortality observed each decade during the study period.

Improvement in gastrointestinal bleeding after septal myectomy for hypertrophic cardiomyopathy.

OBJECTIVE: Patients with obstructive hypertrophic cardiomyopathy may have occult gastrointestinal bleeding. In this study, we analyzed outcomes of septal myectomy in patients who had a history of gastrointestinal bleeding preoperatively to understand patient characteristics and impact of septal reduction on recurrent gastrointestinal bleeding. METHODS: We analyzed 73 adult patients who had a history of gastrointestinal bleeding before transaortic septal myectomy for obstructive hypertrophic cardiomyopathy and compared outcomes to 219 patients without gastrointestinal bleeding preoperatively. RESULTS: Patients with preoperative history of gastrointestinal bleeding were older (median (IQR) age, 65 (59-69) years, P < .001) and were more likely to have systemic hypertension (70% vs 53%, P = .020) and coronary artery disease (25% vs 13%, P = .026). Preoperatively, patients with gastrointestinal bleeding had a larger left atrial volume index (median, 53 mL/m2; interquartile range, 42-67; P = .006) and greater right ventricular systolic pressure (median, 36 mm Hg; interquartile range, 32-49; mm Hg, P = .005) but no significant difference in severity of outflow tract obstruction (P = .368). There were no perioperative deaths. The estimated 5- and 10-year survivals were 96.6% and 81.8%, respectively. At a median of 3.4 (interquartile range, 1.9-9.1) years after septal myectomy, 11 patients (15%) had recurrence of gastrointestinal bleeding, which was attributed to angiodysplasia or unknown causes in 6 patients (8%). CONCLUSIONS: Patients with a preoperative history of gastrointestinal bleeding have favorable short- and long-term outcomes after septal myectomy for obstructive hypertrophic cardiomyopathy. Remission of gastrointestinal bleeding was observed in 85% of patients postprocedure, and only 8% of the patients had recurrent gastrointestinal bleeding due to angiodysplasia or unknown causes.

Persistence of left atrial thrombus in patients with hypertrophic cardiomyopathy and atrial fibrillation.

BACKGROUND: We recently demonstrated that patients with atrial fibrillation (AF) and hypertrophic cardiomyopathy (HCM) have an increased risk of left atrial (LA) thrombus. In this study, we aimed to evaluate thrombus management, thrombus persistence, and thromboembolic events for HCM and non-HCM patients with AF and LA thrombus. METHODS: From a cohort of 2,155 AF patients undergoing transesophageal echocardiography (TEE) for any indication, this study included 122 patients with LA thrombus (64 HCM patients and 58 non-HCM controls). RESULTS: There was no difference in mean CHA2DS2-VASc scores between HCM and control patients (3.9 ± 2.2 vs 3.8 ± 2.0, p = 0.88). Ten (16%) and 4 (7%) patients in the HCM and control groups, respectively, were in sinus rhythm at the time of TEE identifying the LA thrombus (p = 0.13). In all patients, the anticoagulation strategy was modified after the LA thrombus diagnosis. A total of 36 (56%) HCM patients and 34 (59%) control patients had follow-up TEE at median 90 and 62 days, respectively, after index TEE. The HCM group had significantly higher 90-day rates of persistent LA thrombus compared to the control group (88% vs 29%; p < 0.001). In adjusted models, HCM was independently associated with LA thrombus persistence. Among patients with LA thrombus, the 5-year cumulative incidence of thromboembolic events was 11% and 2% in HCM and control groups, respectively (p = 0.22). CONCLUSIONS: Among patients with AF with LA thrombus identified by TEE, those with HCM appear to have a higher risk of LA thrombus persistence than non-HCM patients despite anticoagulation.

Proteomic and phosphoproteomic analyses of myectomy tissue reveals difference between sarcomeric and genotype-negative hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetically heterogenous condition with about half of cases remaining genetically elusive or non-genetic in origin. HCM patients with a positive genetic test (HCMSarc) present earlier and with more severe disease than those with a negative genetic test (HCMNeg). We hypothesized these differences may be due to and/or reflect proteomic and phosphoproteomic differences between the two groups. TMT-labeled mass spectrometry was performed on 15 HCMSarc, 8 HCMNeg, and 7 control samples. There were 243 proteins differentially expressed and 257 proteins differentially phosphorylated between HCMSarc and HCMNeg. About 90% of pathways altered between genotypes were in disease-related pathways and HCMSarc showed enhanced proteomic and phosphoproteomic alterations in these pathways. Thus, we show HCMSarc has enhanced proteomic and phosphoproteomic dysregulation observed which may contribute to the more severe disease phenotype.

Art and science of risk stratification of sudden cardiac death in hypertrophic cardiomyopathy: Current state, unknowns, and future directions.

The progress in the management of hypertrophic cardiomyopathy (HCM) over the last several decades has resulted in great improvements in quality of life and overall survival for HCM patients. Yet, sudden cardiac death (SCD) due to ventricular tachyarrhythmias is among the common causes of HCM-related mortality. SCD risk stratification is a central and often challenging domain in the care of the HCM patient. Distinguishing the individuals most likely to benefit from a primary prevention implantable-cardioverter defibrillator (ICD) from those truly at a low risk of SCD in whom an ICD is not necessary is a nuanced process. Clinicians need to carefully balance the potential benefit and risks of ICDs, particularly in young patients. Because of intense investigations in diverse HCM cohorts globally, two main approaches to SCD risk stratification in HCM have emerged, one based on major SCD risk factors and one based on a mathematically derived risk score. In this overview, we discuss the current state, latest advances and remaining unknowns about established and novel markers of risk of SCD in HCM. We also review how the risk factor- and risk score-based assessments can and should be used in conjunction to enhance rather than contradict each other in facilitating informed ICD decision-making in contemporary clinical practice.

Ultrasound Enhancing Agents with Transthoracic Echocardiography for Maximal Wall Thickness in Hypertrophic Cardiomyopathy.

Objectives: To determine whether ultrasound enhancing agent (UEA) changes maximal wall thickness (WT) in hypertrophic cardiomyopathy (HCM), and if it improves correlation with magnetic resonance imaging (MRI). Patients and Methods: A total of 107 patients with HCM were prospectively enrolled at a single tertiary referral center between July 10, 2014, and August 31, 2017, and underwent transthoracic echocardiography (TTE) with and without UEA and MRI. Maximal WT measurements were compared, and variability among the 3 modalities was evaluated using a simple linear regression analysis and paired t tests and Bland-Altman plots. Interobserver variability for each technique was assessed. Results: Most (63%) of cardiac imagers found UEA helpful in determining maximal WT by TTE, with 49% reporting change in WT. Of 52 patients where UEA changed WT measurement, 32 (62%) reported an increase and 20 (38%) reported a decrease in WT. The UEA did not alter the median discrepancy in WT between MRI and TTE. However, where UEA increased reported WT, the difference between MRI and TTE improved in 79% of cases (P=.001) from 2.0-0.5mm. In those with scar on MRI, UEA improved agreement of WT between TTE and MRI compared with that of TTE without UEA (79% vs 39%; P=.011). Interclass correlation coefficient for WT for TTE without UEA, with UEA, and MRI was 0.84; (95% CI, 0.61-0.92), 0.88; (95%CI, 0.82-0.92), and 0.97; (95%CI, 0.96-0.98), respectively. Conclusion: Although use of UEA did not eliminate differences in WT discrepancy between modalities, the addition of UEA to TTE aided in WT determination and improved correlation with MRI in those with greater WT and in all patients with myocardial scars.

Aortic valve regurgitation following transaortic septal myectomy for obstructive hypertrophic cardiomyopathy: Incidence and influence on late outcomes.

OBJECTIVE: In this study, we describe the incidence, sites of valve injury, and the influence of aortic valve regurgitation (AR) on outcomes of septal myectomy for obstructive hypertrophic cardiomyopathy. METHODS: We analyzed patients who underwent transaortic septal myectomy for obstructive hypertrophic cardiomyopathy from 2001 to 2022. The primary study end point was incidence of procedure-related AR, defined as the need for an unplanned aortic valve (AV) procedure or new-onset moderate AR on early postoperative echocardiography. RESULTS: There were 2807 patients who underwent transaortic septal myectomy for hypertrophic cardiomyopathy and had pre- and postoperative transthoracic echocardiograms. Procedure-related AR was observed in 55 (2%) patients; 27 (1%) required unplanned AV procedures at the time of myectomy, and 29 (1%) additional patients developed moderate AR postoperatively. During follow-up, 9 total patients underwent late AV reoperation, 1 patient who developed new moderate AR postoperatively required late AVR due to severe calcific AS, and none of the patients who had unplanned AV procedures required late reoperation. The overall cumulative incidence of AV reoperation at 10 and 15 years was 1% and 5%. The predicted probability of moderate or severe AR at 5 and 10 years was 1.4% and 1.8%, respectively. There was no difference in survival comparing patients with or without early postoperative mild or worse AR (P = .69). CONCLUSIONS: Procedure-related AR was observed in 2% of patients undergoing transaortic septal myectomy, and unplanned AV procedures were necessary for half of these patients. Intraoperative identification and valve repair mitigate the impact of cusp injury on late reintervention and survival.

Outcomes of concomitant myectomy and left ventricular apical aneurysm repair in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Hypertrophic cardiomyopathy with left ventricular apical aneurysm is a phenotype associated with a 4-fold increase in the risk for sudden cardiac death. In this study, we describe the surgical outcome of concomitant apical aneurysm repair in patients undergoing transapical myectomy for hypertrophic cardiomyopathy. METHODS: We identified 67 patients with left ventricular apical aneurysms who underwent transapical myectomy and apical aneurysm repair between July 2000 and August 2020. Long-term survival was compared with that of 2746 consecutive patients undergoing transaortic septal myectomy for obstructive hypertrophic cardiomyopathy with subaortic obstruction. RESULTS: Transapical myectomy was indicated for midventricular obstruction (n = 44) or left ventricular remodeling for diastolic heart failure (n = 29). Preoperatively, 74.6% (n = 50) of patients were in New York Heart Association class III/IV heart failure, and 34.3% (n = 23) of patients had experienced syncope or presyncope. Atrial fibrillation was documented in 22 patients (32.8%), and episodes of ventricular arrhythmias were recorded in 30 patients (44.8%). Thrombus was present in the apical aneurysm in 6 patients. During a median (interquartile range) follow-up of 4.9 (1.8-7.6) years, the estimated 1- and 5-year survivals were 98.5% and 94.5%, respectively, which were not significantly different from that of patients undergoing transaortic septal myectomy for obstructive hypertrophic cardiomyopathy (P = .52) or an age- and sex-matched US general population (P = .40). CONCLUSIONS: Apical aneurysm repair in conjunction with septal myectomy is a safe procedure, and the good long-term survival of patients suggests that the procedure may reduce cardiac-related death in this high-risk hypertrophic cardiomyopathy population.

High-Sensitivity Cardiac Troponin T Elevation in Hypertrophic Cardiomyopathy Is Associated With Ventricular Arrhythmias.

OBJECTIVE: To investigate the relationship between high-sensitivity cardiac troponin T (hs-cTnT) levels and sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). METHODS: A referral HCM population with prospectively obtained hs-cTnT concentration from March 1, 2018, to April 23, 2020, was reviewed. Patients with end-stage renal disease or an abnormal hs-cTnT level not collected in an outpatient protocolled fashion were excluded. The hs-cTnT level was compared with demographic characteristics, comorbidities, conventional HCM-associated SCD risk factors, imaging, exercise testing, and prior cardiac events. RESULTS: Of 112 included patients, 69 (62%) had an elevated hs-cTnT concentration. The level of hs-cTnT correlated with known risk factors for SCD, including nonsustained ventricular tachycardia (P=.049) and septal thickness (P=.02). When patients were stratified by having a normal vs an elevated hs-cTnT concentration, patients with elevated hs-cTnT concentration were more likely to have experienced an implantable cardioverter-defibrillator discharge for ventricular arrhythmia, ventricular arrhythmia with hemodynamic instability, or cardiac arrest (incidence rate ratio, 2.96; 95% CI, 1.11 to 10.2). When sex-specific hs-cTnT cutoffs were removed, this association was no longer present (incidence rate ratio, 1.50; 95% CI, 0.66 to 3.60). CONCLUSION: In a protocolized, outpatient HCM population, hs-cTnT elevations were common and were associated with more arrhythmic expressivity of the HCM substrate as indicated by previous ventricular arrhythmias and appropriate implantable cardioverter-defibrillator shocks only when sex-specific hs-cTnT cutoffs were used. Further research should use different hs-cTnT reference values by sex to determine whether an elevated hs-cTnT value is an independent risk factor for SCD in patients with HCM.

Clinical course of patients with hypertrophic cardiomyopathy away from tertiary referral care.

AIMS: Data on the clinical course of hypertrophic cardiomyopathy (HCM) are mainly derived from tertiary HCM centre studies, and knowledge of clinical outcomes of patients leaving specialty care and returning to local physicians is limited due to gaps between clinical encounters or complete loss of follow-up. This survey aims to describe the clinical course of HCM in patients following their evaluation at a tertiary referral centre. METHODS AND RESULTS: A comprehensive outcomes survey was developed and sent to 4495 eligible patients with HCM previously evaluated at Mayo Clinic. Questions assessed general well-being, New York Heart Association class, procedures performed, and probable HCM-triggered ventricular arrhythmic events (VAEs) since last visit. In total, 2058 patients (mean age 63 ± 15 years; 42% female) responded to the survey covering a total of 10 510 patient-years with an average of 5.4 ± 6.4 years of follow-up since their last on-campus/virtual visit to Mayo Clinic. During their time away from specialty care, 20% of patients reported having cardiac-related hospitalizations and 25% reported having cardiac-related procedures. Similar to high-risk referral cohorts, 5% of patients reported VAEs with an event rate of 0.98 events/100 patient-years. The prevalence of atrial fibrillation, syncope, pre-syncope, cardiac-related hospitalizations, and VAEs during time away from specialty care increased significantly with increasing New York Heart Association class (P < 0.001). CONCLUSIONS: Acknowledging ascertainment bias, the clinical course of patients away from tertiary care may be more severe than previously anticipated. Among those with exertional symptoms, HCM-related morbidity increased substantially. Higher risk HCM patients should remain in contact with HCM specialty care.