Tricuspid valve surgery following septal myectomy in patients with a cardiac implantable electronic device.

Background: Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of developing cardiac arrhythmias and have a high prevalence of cardiac implantable electronic device (CIED) use. Tricuspid regurgitation (TR) is a potential complication of device leads and can be severe enough to prompt surgical intervention. Methods: We identified 21 consecutive patients who underwent tricuspid valve (TV) surgery for device lead-induced TR late following septal myectomy (SM) for obstructive HCM. The primary endpoint was long-term all-cause mortality. Results: The median patient age was 63 years (range, 55-71 years), 19 patients (91%) had New York Heart Association class III or IV limitation, and all patients were receiving diuretics for right heart failure. The median interval between device implantation and TV surgery was 4 years (range, 1.5-8.5 years). Eight patients (38%) underwent pacemaker implantation due to complete heart block following SM. Preoperatively, TR was severe in 81% of the patients. The primary mechanism of lead-induced TR was leaflet impingement without adherence (n = 15; 75%). Nine patients (43%) underwent TV replacement, and 12 patients (57%) underwent repair. Only 1 patient died early postoperatively. Patients with lead-induced TR had markedly reduced long-term survival compared to the overall population of patients undergoing SM; 5-year survival was 58%, compared to 96% for the contemporary SM group. Conclusions: Late lead-induced TR is a potential complication of CIEDs in patients with HCM who have undergone SM. Although TV repair and replacement can be done with acceptable early mortality, late patient survival is poor.

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 1983 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.

Serial Changes in Ventricular Strain in Symptomatic Obstructive Hypertrophic Cardiomyopathy Treated With Mavacamten: Insights From the VALOR-HCM Trial.

BACKGROUND: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain. METHODS: VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-GLS. RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. RESULTS: At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were -14.7%, -22.2%, and -16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 (P=0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (-11.4%), with no significant worsening from baseline through week 56 (P=0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 (P=0.62 and P=0.56, respectively). CONCLUSIONS: In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04349072.

The impact of mavacamten dosing on wall thickness regression: an insight from longer term follow-up based on genetic profile.

INTRODUCTION: We have previously reported that genetically positive patients have a more profound early decrease in provocable left ventricular outflow tract gradient compared to genetically negative patients utilizing mavacamten in the first 12 weeks of therapy. METHODS AND RESULTS: In this current analysis, we found that genetically positive patients have less favorable remodeling as measured by left ventricular wall thickness regression when evaluated long-term as compared to genetically negative patients, despite an overall better early response to mavacamten. The majority of genetically positive patients were maintained on only 2.5 mg of mavacamten due to early robust response. CONCLUSION: We hypothesize that this lower dosing attenuated the long-term benefit of mavacamten in genetically positive patients. We believe that the long-term benefit of mavacamten on positive cardiac remodeling is dose-dependent and not solely related to the magnitude of left ventricular outflow gradient decrease.

Clinical Implications of Left Ventricular Apex Mechanics in Patients with Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) is a unique disease with pathological hypertrophy mainly at the left ventricular (LV) apex. Although previous studies have indicated apical dysfunction in ApHCM, how apical mechanics change during disease progression has not been thoroughly examined. We aimed to characterize the mechanics of the LV apex in ApHCM patients at different disease stages and explore the clinical significance of these alterations. METHODS: 104 ApHCM patients were divided into 3 subtypes based on LV apical maximum wall thickness (AMWT) and extent of hypertrophy: relative-type (isolated apical hypertrophy with AMWT <15 mm), pure-type (isolated apical hypertrophy with AMWT ≥15 mm), and mixed-type (both apical and midventricular hypertrophy with AMWT ≥15 mm). Two-dimensional speckle-tracking echocardiography was used to analyze LV segmental strain, global strain, and twist. Comparisons of these parameters were performed among ApHCM subtypes and 30 healthy controls. Logistic regression and Cox proportional hazard regression analyses were employed to explore associations between myocardial mechanics and clinical indicators. A composite outcome of new-onset atrial fibrillation, heart failure hospitalization, myectomy, and all-cause mortality was assessed. RESULTS: Even in relative ApHCM patients, apical longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) were significantly impaired compared to controls (LS: -14.6±4.1% vs.-20.0±1.7%, p=0.001; CS: -19.6±2.5% vs.-25.6±3.7%, p=0.002; RS: 26.6±7.4% vs. 35.6±11.1%, p=0.026), while apical rotation and LV twist remained unchanged. In patients with greater apical hypertrophy (mixed and pure patients), apical LS and RS were more abnormal. Moreover, apical rotation showed significant reductions compared to relative-type patients. After adjusting for clinical and myocardial mechanical parameters, apical rotation was independently associated with NYHA class ≥ II (odds ratio =0.81, 95% confidence interval [CI]: 0.66-0.99, p=0.036) and the composite outcome (hazard ratio =0.82, 95% CI: 0.73-0.91, p=0.001). CONCLUSIONS: Relative ApHCM demonstrates apical dysfunction but sparing of apical rotation, which was abnormal in more extensive phenotypes. LV apex mechanics were closely related to clinical patterns, with apical rotation correlated with both NYHA class ≥ II and clinical events.

Mavacamten-Associated Temporal Changes in Left Atrial Function in Obstructive HCM: Insights From the VALOR-HCM Trial.

BACKGROUND: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) trial showed that mavacamten reduced the eligibility for septal reduction therapy with sustained improvement in left ventricular outflow tract gradients. Mavacamten also resulted in favorable cardiac remodeling, including improvement in biomarkers (eg, N-terminal pro-B-type natriuretic peptide and troponin T). However, the impact of mavacamten on left atrial (LA) function is unknown. OBJECTIVES: The aim of this study was to assess serial changes in LA strain measures in patients enrolled in the VALOR-HCM trial. METHODS: VALOR-HCM included 112 symptomatic patients with obstructive HCM (mean age 60 years; 51% male). Patients assigned to receive mavacamten at baseline (n = 56) continued therapy for 56 weeks and those assigned to placebo transitioned to mavacamten (n = 52) from week 16 to week 56. Echocardiographic LA strain (reservoir, conduit, and contraction) was measured by using a vendor-neutral postprocessing software. RESULTS: At baseline, the mean LA volume index (LAVI) and LA strain values (conduit, contraction, and reservoir) were 41.3 ± 16.5 mL/m2, -11.8% ± 6.5%, -8.7% ± 5.0%, and 20.5% ± 8.7%, respectively (all worse than reported normal). LAVI significantly improved by -5.6 ± 9.7 mL/m2 from baseline to week 56 (P < 0.001). There was a significant (P < 0.05) improvement in absolute LA strain values from baseline to week 56 (conduit [-1.7% ± 6%], contraction [-1.2% ± 4.5%], and reservoir [2.8% ± 7.7%]). Patients originally receiving placebo had no differences in LA measurements up to week 16. There was no significant improvement in LA strain values (conduit [-0.9% ± 3.8%], contraction [-0.4% ± 3.4%], and reservoir [1.4% ± 6.1%]; all; P = NS) from baseline to week 56 in patients with history of atrial fibrillation. CONCLUSIONS: In VALOR-HCM, mavacamten resulted in an improvement in LAVI and LA strain at week 56, suggesting sustained favorable LA remodeling and improved function, except in the atrial fibrillation subgroup. Whether the advantageous LA remodeling associated with long-term treatment with mavacamten results in a favorable impact on the observed high burden of atrial tachyarrhythmias in HCM remains to be proven. (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy [VALOR-HCM]; NCT04349072).

Changes in left ventricular-aortic angulation are associated with the development of obstruction in hypertrophic cardiomyopathy.

OBJECTIVE: To characterize changes in ventricular morphology in patients with hypertrophic cardiomyopathy who develop left ventricular (LV) outflow tract obstruction. METHODS: We reviewed patients with hypertrophic cardiomyopathy with LV outflow tract obstruction who underwent septal myectomy from May 2012 to June 2023. Among 68 patients initially without obstruction documented up to 7.6 years (interquartile range, 6.3-9.4 years) before the operation, a comparison was made with 78 patients with nonobstructive hypertrophic cardiomyopathy over a similar period. Patients who did not develop obstruction were matched with those who did on sex, age, and maximum septal wall thickness during the initial echocardiography, identifying 41 matched pairs. Echocardiographic data, including 5 measures of angulation, were compared between the groups. RESULTS: The median interval between echocardiographic assessments was 7.5 years (interquartile range, 6.3-8.1 years) among patients with obstruction versus 7.3 years (interquartile range, 6.2-9.0 years) in patients without nonobstruction. Patients with obstruction were more likely to have hypertension at both times. The maximum septal wall thickness increased within both groups (both P values < .001), but the magnitude of increase was not different between groups (P = .130). Patients with obstruction exhibited a greater increase in LV mass (P < .001) compared with patients without obstruction (P = .004). Aortic angulation significantly increased in 4 of the 5 measurements (all P values < .001) in patients with obstruction, whereas patients with no obstruction showed no change. Anterior and posterior mitral valve leaflet lengths and coaptation lengths remained similar in both groups over time. CONCLUSIONS: The development of LV outflow tract obstruction in patients with hypertrophic cardiomyopathy was associated with progressive LV outflow tract angulation and increased LV hypertrophy, as reflected by LV mass. Progression to obstruction was not related to changes in the mitral valve leaflet morphology.

Improvement in Sexual Dysfunction in Patients With Hypertrophic Cardiomyopathy Undergoing Septal Myectomy: A Prospective Study.

Background: Septal myectomy improves symptoms in the majority of patients with obstructive hypertrophic cardiomyopathy (HCM), but there are limited prospective data on functional outcomes after operation. Objectives: The authors investigated quality of life measures and prevalence of sexual dysfunction before and after septal myectomy for obstructive HCM. Methods: Between January 2018 and October 2019, 436 patients underwent transaortic septal myectomy at our clinic. All patients were screened for eligibility, and 197 (45.2%) were enrolled in this prospective survey study. Patients received a questionnaire pertaining to quality of life and sexual health before and within 4 to 6 months postoperatively, and 113 (57.4%) completed the follow-up survey. Results: The mean age of the 54 (47.8%) women and 59 (52.2%) men was 54.7 ± 14.1 years. Quality of life, including both mental and physical components, improved significantly in both men (P < 0.001) and women (P < 0.001). Women reported mild sexual dysfunction at baseline, and following septal myectomy, they experienced significant (P < 0.05) improvement in most domains pertaining to sexual health. In men, the International Index of Erectile Function median score was 23 (IQR: 7.0-29.5), which is consistent with mild dysfunction at baseline, and there was significant improvement following surgery in young (age ≤55 years) men (P < 0.001). Conclusions: Quality of life is significantly improved following septal myectomy in patients with obstructive HCM. Both women and men reported mild sexual dysfunction at baseline, and women and younger men (age ≤55 years) experienced significant improvements in sexual health.

Sex-Related Differences in Patients With Hypertrophic Cardiomyopathy Undergoing Alcohol Septal Ablation.

BACKGROUND: Previous studies have shown that women with hypertrophic obstructive cardiomyopathy (HCM) have worse long-term outcomes irrespective of intervention. However, the outcomes of patients undergoing alcohol septal ablation (ASA) based on sex have not been described. Hence, this study aimed to evaluate pressure changes and long-term mortality in patients with HCM undergoing ASA based on sex. METHODS AND RESULTS: This is a single-center retrospective study evaluating hemodynamic changes and long-term mortality in patients with HCM treated with ASA according to sex. A total of 259 patients were included (aged 68.4±11.9 years, 62.2% women). Women had higher age and baseline pressures at the time of ASA, with a greater percent reduction in mean left atrial pressure (men versus women: 2.2% versus 15.9%, respectively; P=0.02). Women had better survival (median survival rate of men versus women: 8.6 versus 12.5 years, respectively; P=0.011). On Cox multivariable regression, predictors of mortality were age (per group change <60 years, 61-70 years, 71-80 years, and >80 years; hazard ratio [HR], 1.45 [95% CI, 1.10-1.91], P=0.008), female sex (HR, 0.59 [95% CI, 0.35-0.99], P=0.048), chronic kidney disease (HR, 1.88 [95% CI, 1.06-3.33], P=0.031), and left ventricular outflow tract gradient reduction ≤86% (HR, 1.91 [95% CI, 1.14-3.19], P=0.014). CONCLUSIONS: Women with HCM undergoing ASA are older and have higher left-sided baseline pressures compared with men yet have better survival. Further studies exploring the mechanisms of differential outcomes according to sex in patients with HCM undergoing ASA are needed.

Outcomes of surgical septal myectomy for obstructive hypertrophic cardiomyopathy after previous 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 after previous septal-reduction therapy (SRT). METHODS: From January 1989 to March 2022, 145 patients underwent reintervention by septal myectomy for residual LVOT obstruction after previous SRT; 72 patients had previous alcohol septal ablation (ASA) and 73 had previous surgical septal myectomy. Baseline patient characteristics, echocardiographic parameters, and surgical outcomes were compared between these 2 groups. RESULTS: Patients who had previous ASA were more likely to be male (50.0% vs 30.1%; P = .015), be older (median age 57.5 years vs 48.3 years; P < .001), and have a greater body mass index (32.7 kg/m2 vs 30.0 kg/m2; P = .011). After repeat SRT by septal myectomy, there was no significant difference in the incidence of postoperative complete heart block, necessitating permanent pacemaker, between the 2 groups (8.3% vs 2.7%; P = .151). One (0.7%) patient died within 30 days of surgery. Over a median follow-up of 7.5 years (interquartile range, 3.0-13.8), there were 20 deaths. Kaplan-Meier 5-, 10-, and 15-year survival rates were 100%, 91%, and 76% for the previous septal myectomy group, and 93%, 81%, and 64% for the previous ASA group (P = .207). CONCLUSIONS: Septal myectomy for residual or recurrent LVOT obstruction in patients who had previous ASA is safe, with an acceptably low rate of postoperative complete heart block. Surgical outcomes and late survival rates in patients with complete heart block ASA were satisfactory and comparable with patients who underwent repeat myectomy.

Invasive Cardiac Hemodynamics in Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Symptomatic limitations in apical hypertrophic cardiomyopathy may occur because of diastolic dysfunction with resultant elevated left ventricular filling pressures, cardiac output limitation to exercise, pulmonary hypertension (PH), valvular abnormalities, and/or arrhythmias. In this study, the authors aimed to describe invasive cardiac hemodynamics in a cohort of patients with apical hypertrophic cardiomyopathy. METHODS AND RESULTS: Patients presenting to a comprehensive hypertrophic cardiomyopathy center with apical hypertrophic cardiomyopathy were identified (n=542) and those who underwent invasive hemodynamic catheterization (n=47) were included in the study. Of these, 10 were excluded due to postmyectomy status or incomplete hemodynamic data. The mean age was 56±18 years, 16 (43%) were women, and ejection fraction was preserved (≥50%) in 32 (91%) patients. The most common indication for catheterization was dyspnea (48%) followed by suspected PH (13%), and preheart transplant evaluation (10%). Elevated left ventricular filling pressures at rest or exercise were present in 32 (86%) patients. PH was present in 30 (81%) patients, with 6 (20%) also having right-sided heart failure. Cardiac index was available in 25 (86%) patients with elevated resting filling pressures. Of these, 19 (76%) had reduced cardiac index and all 6 with right-sided heart failure had reduced cardiac index. Resting hemodynamics were normal in 8 of 37 (22%) patients, with 5 during exercise; 3 of 5 (60%) patients had exercise-induced elevation in left ventricular filling pressures. CONCLUSIONS: In patients with apical hypertrophic cardiomyopathy undergoing invasive hemodynamic cardiac catheterization, 86% had elevated left ventricular filling pressures at rest or with exercise, 81% had PH, and 20% of those with PH had concomitant right-sided heart failure.

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.

Obstruction in Hypertrophic Cardiomyopathy: Many Faces.

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, exhibits left ventricular hypertrophy not secondary to other causes, with varied phenotypic expression. Enhanced actin-myosin interaction underlies excessive myocardial contraction, frequently resulting in dynamic obstruction within the left ventricle. Left ventricular outflow tract obstruction, occurring at rest or with provocation in 75% of HCM patients, portends adverse prognosis, contributes to symptoms, and is frequently a therapeutic target. Transthoracic echocardiography plays a crucial role in the screening, initial diagnosis, management, and risk stratification of HCM. Herein, we explore echocardiographic evaluation of HCM, emphasizing Doppler assessment for obstruction. Echocardiography informs management strategies through noninvasive hemodynamic assessment, which is frequently obtained with various provocative maneuvers. Recognition of obstructive HCM phenotypes and associated anatomical abnormalities guides therapeutic decision-making. Doppler echocardiography allows monitoring of therapeutic responses, whether it be medical therapies (including cardiac myosin inhibitor therapy) or septal reduction therapies, including surgical myectomy and alcohol septal ablation. This article discusses the hemodynamics of obstruction and practical application of Doppler assessment in HCM. In addition, it provides a visual atlas of obstruction in HCM, including high-quality figures and complementary videos that illustrate the many facets of dynamic obstruction.