Left Ventricular Outflow Tract Gradient Research Articles

Mitral regurgitation mechanisms related to systolic anterior motion in hypertrophic cardiomyopathy.

Systolic anterior motion (SAM) of the mitral valve can result in mitral regurgitation (MR) and adverse outcomes in patients with obstructive hypertrophic cardiomyopathy (HCM). However, the mechanism and characteristics of MR severity mediated by SAM are unresolved. This study aimed to elucidate the anatomic and hemodynamic associations of MR and the impact of septal myectomy on changes in MR severity in patients with HCM. We retrospectively reviewed patients who underwent septal myectomy with SAM and interpretable imaging between 2017-2022. Significant MR was defined as moderate or more MR. The mitral valve, papillary muscle, and left ventricular geometry were quantitatively evaluated via echocardiography and cardiac computed tomography. Out of 34 patients, two groups were identified: those with preoperative significant MR (n=16) and those without significant MR (n=18). Patients with significant preoperative MR exhibited worse heart failure symptoms at baseline than those without. Following myectomy, these patients showed higher residual left ventricular outflow tract (LVOT) gradients at rest and with provocative measures than those without preoperative MR. Multivariate regression analysis revealed a significant association between the tenting area and MR severity. Additionally, the chordal cutting procedure alleviated the tenting area [2.1 (1.8-2.6) vs. 1.4 (1.2-1.6) cm2] compared to those without it. Our preliminary data suggested that chordal cutting with septal myectomy was associated with an improvement in the tenting area, contributing to MR severity. This procedure may serve as an effective therapy for patients with SAM and significant MR.

Radiofrequency Catheter Septal Ablation via a Trans-Atrial Septal Approach Guided by Intracardiac Echocardiography in Hypertrophic Obstructive Cardiomyopathy: One-Year Follow-Up.

Percutaneous radiofrequency catheter ablation (RFA) in hypertrophic obstructive cardiomyopathy (HOCM) with intracardiac echocardiography (ICE) guidance is a novel method that has been proven to be safe and effective in a small sample size study. RFA of the interventricular septum through a trans-atrial septal approach in HOCM patients with a longer follow-up has not been reported. 62 consecutive patients from March 2019 to February 2022 were included in this study. The area between the hypertrophied septum and anterior mitral valve (MV) leaflet was established using the three-dimensional system (CARTO 3 system), and all patients received atrial septal puncture under the guidance of intracardiac echocardiography (ICE). Point-by-point ablation was performed to cover the contact area. After ablation, the patients were followed up for 1, 3, 6, and 12 months. Transthoracic echocardiography was performed at 1, 3, 6, and 12 months, and resting and exercise-provoked left ventricular outflow tract (LVOT) gradients were obtained. During the 1-year follow-up, most patients' symptoms improved. The NYHA grading of the patient decreased from 2 (2, 3) at baseline to 2 (1, 2) (p 0.001). LVOT peak gradient at rest was decreased from 59 ( 27) mmHg to 30 ( 24) mmHg (p 0.001), and the provoked peak gradient was decreased from 99 ( 33) mmHg to 59 ( 34) mmHg (p 0.001). The average maximum septal thickness was reduced from 21 ( 4) mm to 19 ( 4) mm (p 0.001). After a 1-year follow-up, ice-guided radiofrequency ablation for HOCM might be a safe, accurate, and effective method. The catheter might be reliably attached to the ablation target area via trans-atrial septal access.

The long-term results of using 3-patch technique for supravalvular aortic stenosis

The objective of this study evaluated the results of using 3-patch technique for supravalvular aortic stenosis [1]
 Methods: This was a review of seri cases: using 3-path technique for supravalvular aortic stenosis from 1/2012 to 12/2018
 Results: There were 8 patients who underwent using 3-patch technique, include 5 males and 3 females. The mean of age was 12,4 years (range 4 to 32 year), 7 childrents and 1 adult. The left ventricular outflow tract gradient was 62 mmHg. The time of cardiopulmonary bypass, aortic clamping and ventilator were: 104 minutes; 72 minutes. 7 patients were used pericardium path and 1 patient was another graft. There was not intrahospital mortality. Echocardiography post -operation: left ventricular outflow tract gradient was 11,8 mmHg. During follow-up time 7,8 years after surgery, there was no late death; there were 3 patients who had to reoperation include 2 patient with stenotic distal anastomosis postoperation 5 years and 1 patient with severe aortic valve stenosis postoperation 8 years Conclusion: The long-term of using 3-patch technique for supravalvular aortic stenosis were satisfaction and longer follow-up was essential to find-out about risks of reoperation.

Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy.

This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P=0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.

Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort

BackgroundData assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed. ObjectivesThe authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655). MethodsAfter mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms. ResultsBetween April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: −35.6 ± 32.6 mm Hg; Valsalva: −45.3 ± 35.9 mm Hg), N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels (median: −480 ng/L; Q1-Q3: −1,104 to −179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events. ConclusionsMavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.

Takotsubo Cardiomyopathy: Patients Characteristics, Mortality, and Clinical Significance of Left Ventricular Outflow Tract Gradient, Retrospective Study.

Takotsubo cardiomyopathy (TC) is a reversible left ventricular systolic dysfunction with apical ballooning. Left ventricular outflow tract (LVOT) obstruction may develop in these cases due to hyperdynamic state of the left ventricle. Limited data are available on the prevalence of LVOT gradient in TC and its association with patient outcomes and mortality. Data were collected retrospectively for patients diagnosed with TC in a single tertiary center, demographic information, blood analysis results, and imaging finding including ejection fraction, and LVOT gradient was obtained from medical records. Additionally, medical treatment and outcome during hospitalization were extracted. Follow-up was conducted through cardiology clinic or phone contact. A total of 59 patients diagnosed with TC were reviewed during hospitalization, and 40 patients were followed up after discharge by phone contact and cardiology clinic. Most patients were female (91.5%), and nonsignificant coronary artery disease was present in 16.9% of patients. Approximately two-third of the patients had a reduced ejection fraction on admission, and only two patients (5.4%) continued to have reduced ejection fraction on echocardiography follow-up within a period of 2-14 days. LVOT gradient was present in 17 patients (28.5%); patients with preserved ejection fraction had a higher probability of having an LVOT gradient. However, there was no association between LVOT gradient and shock or mortality. Four patients (6.7%) experienced 30-day mortality, while all-cause mortality was reported in eight patients (13.5%) over the follow-up period (mean (±SD) 20.8 months ± 16.2). LVOT obstruction may occur in TC patients; it has no correlation with shock or mortality. However, determining whether there is a gradient is important for deciding on specific treatment approach.

Hypertrophic Cardiomyopathy With Elongated Mitral Valve Leaflets: Clinical Characteristics and Surgical Results

Background: Hypertrophic cardiomyopathy (HCM) is commonly associated with mitral valve pathology. A large majority of patients with HCM have elongated anterior and posterior mitral leaflets. There remains debate regarding the necessity and role of concomitant mitral valve surgery at the time of septal myectomy. We aimed to describe the characteristics and share our surgical experiences with this specific group of patients.Methods: This retrospective single‐center study investigates adult patients with HCM, with or without elongated mitral valve leaflets (MVLs), who underwent elective septal myectomy with or without concomitant mitral valve intervention, between January 1, 2016, and June 30, 2020. Clinical data were obtained from institutional medical records as well as the Society of Thoracic Surgeons data registry. The clinical characteristics and in‐hospital surgical outcomes were compared between patients with an elongated MVL and those without.Results: In total, 379 patients underwent septal myectomy, and 22 patients with intrinsic mitral valve disease were excluded. In addition, 23 patients were excluded due to missing data. Of the remaining 334 patients, 131 (39.2%) had elongated MVL and concomitant MVL plication. Patients with elongated MVL had higher rates of preoperative mitral valve systolic anterior motion (SAM) (94.7% vs. 86.7%, p = 0.019) and higher preoperative provoked left ventricular outflow tract gradient (LVOTG) (134.5 mmHg versus 125.3 mmHg, p = 0.046). Post septal myectomy and mitral valve plication, they had lower rates of postoperative residual mitral regurgitation (3.8% vs. 12.8%, p = 0.006), comparable rates of residual SAM (28.2% vs. 31.5%, p = 0.524), postoperative provoked LVOTG (15.4 mmHg vs. 14.0 mmHg, p = 0.317), 30‐day major adverse cardiopulmonary events (2.3% vs. 3.9%, p = 0.409), and mortality (0% vs. 1.0%, p = 0.255).Conclusions: Elongated MVLs contribute more significantly to dynamic LVOT obstruction, as evidenced during provocative testing. Concomitant mitral valve intervention during septal myectomy can be performed safely and may provide an effective strategy to resolve SAM and stress‐induced LVOTG.

A systematic review and meta-analysis of the efficacy and safety of Mavacamten therapy in international cohort of 524 patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common heritable myocardial disorder worldwide. Current pharmacological treatment options are limited. Mavacamten, a first-in-class cardiac myosin inhibitor, targets the main underlying pathology of HCM. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Mavacamten in patients with HCM. PRISMA flow chart was utilized using PubMed, SCOPUS, and Cochrane databases for all up-to-date studies using pre-defined keywords. Pre-specified efficacy outcomes comprised several parameters, including an improvement in peak oxygen consumption (pVO2) and ≥ 1 NYHA class, the need for septal reduction therapy (SRT), change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ), changes in biochemical markers and LVEF, along with peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Safety outcomes included morbidity and serious adverse events. This systematic review included five studies, four RCTs and one non-randomized control trial comprised a total of 524 (Mavacamten [273, 54.3%] vs placebo [230, 45.7%] adult (≥ 18 years) patients with a mean age of 56 years. The study. comprised patients with Caucasian and Chinese ethnicity and patients with obstructive (oHCM) and non-obstructive (nHCM) HCM. Most baseline characteristics were similar between the treatment and placebo groups. Mavacamten showed a statistically significant increase in the frequency of the primary composite endpoint (RR = 1.92, 95% CI [1.28, 2.88]), ≥ 1 NYHA class improvement (RR = 2.10, 95% CI [1.66, 2.67]), a significant decrease in LVEF, peak left ventricular outflow tract gradient at rest and after Valsalva maneuver. Mavacamten also showed a significant reduction in SRT rates (RR = 0.29, 95% CI [0.21, 0.40], p < 0.00001), KCCQ clinical summary scores (MD = 8.08, 95% CI [4.80, 11.37], P < 0.00001) troponin levels and N-terminal pro-B-type natriuretic peptide levels. However, there was no statistically significant difference between Mavacamten and placebo regarding the change from baseline peak oxygen consumption. Mavacamten use resulted in a small increase in adverse events but no statistically significant increment in serious adverse events.Our study showed that Mavacamten is a safe and effective treatment option for Caucasian and Chinese patients with HCM on the short-term. Further research is needed to explore the long-term safety and efficacy of Mavacamten with HCM. In addition, adequately powered studies including patients with nHCM is needed to ascertain befits of Mavacamten in those patients.

Transapical beating-heart septal myectomy for hypertrophic cardiomyopathy with latent obstruction.

A novel transapical beating-heart septal myectomy (TA-BSM) procedure was performed for patients with latent obstruction through the left intercostal incision and without cardiopulmonary bypass. This study aims to demonstrate the experience of the TA-BSM procedure for patients with latent obstruction and compare outcomes to patients with resting obstruction. We studied 120 symptomatic hypertrophic obstructive cardiomyopathy patients (33 with latent obstruction and 87 with resting obstruction) who underwent TA-BSM. Demographic profiles, echocardiogram-derived ventricular morphology and haemodynamics and clinical outcomes were analysed. There were no important differences in baseline clinical characteristics between patients with latent obstruction and resting obstruction, including age, symptoms, comorbidities and medical history. Patients with latent obstruction had lower basal septum thickness, higher midventricular wall thickness, smaller left atrial chamber size and more frequency of mitral subvalvular anomalies. There was no difference in early (<30 days) deaths (0/33 vs 1/87, P > 0.999) and mid-term survival between patients with latent obstruction and resting obstruction. At 6 months after surgery, 31 (93.9%) patients with latent obstruction and 80 (92.0%) with resting obstruction achieved optimal procedural success, which was defined as a maximal gradient (after provocation) <30 mmHg and mitral regurgitation ≤ grade 1+ without mortality. Maximal left ventricular outflow tract gradient, basal septum thickness, midventricular wall thickness, mitral regurgitation grade and left atrial chamber size were significantly decreased after TA-BSM. In the follow-up, the New York Heart Association class was significantly improved following surgery. TA-BSM preserved favourable gold-standard guideline desired outcomes through real-time echocardiographic-guided resection. Equipoise of outcomes for this procedure regardless of degree of resting left ventricular outflow tract gradients supports operative management with this approach in symptomatic patients with latent obstruction.

Pompe disease in China: clinical and molecular characteristics.

Pompe disease (PD) is a rare, progressive, and autosomal recessive lysosomal storage disorder caused by mutations in the acid α-glucosidase gene. The clinical course and molecular mechanism of this disease in China have not been well defined. In this single-center cohort study, we investigated a total of 15 Chinese patients with Pompe disease to better understand the clinical manifestations, echocardiographic imaging and genetic characteristics in this population. The median age of 15 patients at symptom onset was 5.07 months (1-24 months). The median age at diagnosis was 19.53 months (range: 3 to 109 months, n = 15). Average diagnostic delay was 13.46 months. None of the patients had received enzyme replacement therapy (ERT). Fifteen patients died at a median age of 24.80 months due to cardiorespiratory failure (range 3-120 months). Myasthenia symptoms and severe hypertrophic cardiomyopathy were universally present (15/15 = 100%). Global longitudinal strain (GLS) by echocardiography was significantly lower in these patients. After adjusting for gender, body surface area (BSA), left ventricular ejection fraction (LVEF), E/e'ratio, maximum left ventricular wall thickness (MLVWT), left ventricular posterior wall (LVPW), left ventricular outflow tract (LVOT)gradient, GLS was independently correlated with survival time (hazard ratio (HR) = 0.702, 95% confidence Interval (CI): 0.532-0.925, P = 0.012). In our cohort, we identified 4 novel GAA mutation: c.2102T > C (p.L701P), c.2006C > T (p.P669l), c.766T > A (p.Y256N), c.2405G > T (p.G802V). 12 patients were compound heterozygotes, and 4 homozygotes. Our study provides a comprehensive examination of PD clinical course and mutations of the GAA gene for patients in China. We showed clinical utility of echocardiography in quantifying heart involvement in patients with suspected PD. GLS can provide prognostic information for mortality prediction. We reported four novel mutations in the GAA gene for the first time. Our findings may improve early recognition of PD characteristics in Chinese patients.

A systematic review and meta-analysis of sex differences in clinical outcomes of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is recognized as the most prevalent form of genetic cardiomyopathy, and recent investigations have shed light on the existence of sex disparities in terms of clinical presentation, disease progression, and outcomes. This study aimed to systematically review the literature and perform a meta-analysis to comprehensively compare the clinical outcomes between female and male patients with HCM. A thorough search was conducted in databases including PubMed, Embase, Cochrane Library, and Web of Science, encompassing literature from inception until June 2023. The primary endpoints examined were: (1) all-cause mortality; (2) an arrhythmic endpoint comprising sudden cardiac death (SCD), sustained ventricular tachycardia, ventricular fibrillation, or aborted SCD; and (3) a composite endpoint incorporating either (1) or (2), in addition to hospitalization for heart failure or cardiac transplantation. Pooled estimates were derived using a random-effects meta-analysis model. The analysis encompassed a total of 29 observational studies, involving 44,677 patients diagnosed with HCM, of which 16,807 were female. Baseline characteristics revealed that the female group exhibited an advanced age [55.66 ± 0.04 years vs. 50.38 ± 0.03 years, pooled mean difference (MD) = 0.31, 95% CI: 0.22-0.40, p = 0.000, I2 = 88.89%], a higher proportion of New York Heart Association class III/IV patients [pooled odds ratio (OR) = 1.94, 95% CI: 1.55-2.43, p = 0.000, I2 = 85.92%], and a greater prevalence of left ventricular outflow tract gradient greater than or equal to 30 mmHg (pooled OR = 1.48, 95% CI: 1.27-1.73, p = 0.000, I2 = 68.88%) compared to the male group. The female group were more likely to have a positive genetic test (pooled OR = 1.27, 95% CI: 1.08-1.48, p = 0.000, I2 = 42.74%) and to carry the myosin heavy chain beta 7 mutation (pooled OR = 1.26, 95% CI: 1.04-1.54, p = 0.020, I2 = 0.00%) compared to the male group. Female sex exhibited a significant association with increased risks of all-cause mortality (pooled OR = 1.62, 95% CI: 1.38-1.89, p = 0.000, I2 = 72.78%) and the composite endpoint (pooled OR = 1.47, 95% CI: 1.20-1.79, p = 0.000, I2 = 84.96%), while no substantial difference was observed in the arrhythmic endpoint (pooled OR = 1.08, 95% CI: 0.87-1.34, p = 0.490, I2 = 55.48%). The present findings suggest that female patients with HCM tend to experience poorer clinical outcomes. It is imperative to critically reevaluate disease definitions and enhance awareness to mitigate delays in the diagnosis and treatment of HCM in women, thereby fostering equitable healthcare practices. https://www.crd.york.ac.uk/, PROSPERO (CRD42023431881).

Effect of metoprolol in hypertrophic obstructive cardiomyopathy patients after alcohol septal ablation

BackgroundThe use of beta-blockers in hypertrophic obstructive cardiomyopathy (HOCM) patients after alcohol septal ablation (ASA) lacks data support. We aimed to evaluate the effect of metoprolol on exercise capacity, hemodynamic and laboratory parameters, and quality of life in HOCM patients after ASA. MethodsThis was a prospective randomized single-center open-label crossover trial in 21 HOCM patients after ASA. Patients received metoprolol and no beta-blocker for two periods of three months. The endpoints were: peak oxygen uptake (pVO2), maximal left ventricular outflow tract (LVOT) pressure gradient at peak exercise, a ratio of mitral peak velocity of the early filling (E) to early diastolic mitral annular velocity (e′) (E/e′) at rest, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) plasmatic concentration. ResultsNo significant association was found between the treatment and any of the endpoints in the assessed patients: 1) pVO2 (19.5 ± 5.3 ml/kg/min vs. 19.4 ± 4.1 ml/kg/min, p = 0.90), 2) exercise-induced pressure gradient in LVOT 32 ± 37 mmHg vs. 32 ± 30 mmHg, p = 0.84, 3) E/e′ ratio at rest (11 ± 4 vs. 10 ± 4, p = 0.23), 4) KCCQ overall summary score (78 ± 11 vs. 77 te ± 15, p = 0.56), 5) NT-proBNP (215 pg/ml [121–333] vs. 153 pg/ml [102–228], p = 0.19). ConclusionsIn HOCM patients after successful ASA, metoprolol treatment did not improve exercise capacity, hemodynamic and laboratory parameters, or quality of life.

Fractal analysis in cardiovascular magnetic resonance: prognostic value of biventricular trabecular complexity in hypertrophic cardiomyopathy.

Trabecular complexity can be quantified by fractal analysis based on cine images of cardiovascular magnetic resonance (CMR), yielding fractal dimension (FD) index. We aimed to investigate the prognostic value of biventricular FD in patients with hypertrophic cardiomyopathy (HCM). This retrospective study included 284 (192 men, median age 53 years) patients with HCM who underwent CMR, with median follow-up of 24 months. Biventricular trabeculae complexity was quantified as FD using short-axis cine images. The primary end point included sudden cardiac death (SCD) events. The secondary end point included both SCD events and rehospitalization due to heart failure. Cox regressions were performed. Prediction models were established by adding ventricular FDs to ESC predictors and late gadolinium enhancement (LGE) percentage and the C indices were calculated. Cox regressions revealed that left ventricular (LV) maximal apical FD (HR range 1.114-1.133; all P<0.05) and right ventricular (RV) global FD (HR range 1.135-1.150; all P<0.05) were significant prognostic factors of both end points after adjustment for the European Society of Cardiology (ESC) predictors (age, maximum LV wall thickness, LV atrial size, peak left ventricular outflow tract (LVOT) gradient, family history of SCD, unexplained syncope, non-sustained ventricular tachycardia), and LGE percentage. The prediction model with the addition of biventricular FDs (C-index: 0.864-0.877) had the best performance. LV maximal apical FD and RV global FD were independent predictors of SCD events and rehospitalization due to heart failure in patients with HCM. The addition of biventricular FDs to the conventional prediction model contributed incremental prognosis value in HCM.

Heart failure in patients with hypertrophic obstructive cardiomyopathy

Hypertrophic cardiomyopathy is a hereditary cardiac disease, diverse in clinical manifestations, cardiac structure and natural progression. Patients with disease are associate with a broad range of clinical presentations, from patients who are asymptomatic, accidentally discovered during routine examination, to patients with chest pain, dyspnea, syncope, and even sudden death. We are presenting the clinical case of a young male patient with hypertrophic cardiomyopathy with rather large left ventricular wall thickness about 37mm who was hospitalized with severe dyspnea accompanied by tachycardia episodes and hypotension. The patient underwent electrical cardioversion, Doppler echocardiography, stress Doppler echocardiography with treadmill, cardiac MRI, basic blood tests, coronary CT angiography and ventriculography. The results showed the patient had a very high NT-proBNP level of 16,271 pg/mL; echocardiography showed asymmetric left ventricular hypertrophy, a maximum resting LVOT gradient of 28 mmHg, increasing to 64mmHg at peak stress, preserved left ventricular systolic function and grade III left ventricular diastolic dysfunction; greatly increased left ventricular mass of 199.6 g/m2, and delayed contrast enhancement involving the subendocardium of both ventricles and transecting the left ventricular free wall on cardiac MRI. We also discuss various treatment option for this young man.

Effect of Mavacamten in Women Compared With Men With Obstructive Hypertrophic Cardiomyopathy: Insights From EXPLORER-HCM.

Compared with men, women with hypertrophic cardiomyopathy (HCM) have a higher incidence of heart failure and worse outcomes. We investigated baseline clinical and echocardiographic characteristics and response to mavacamten among women compared with men in the EXPLORER-HCM study (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy). A prespecified post hoc analysis of sex from the blinded, randomized EXPLORER-HCM trial of mavacamten versus placebo in symptomatic patients with obstructive HCM was performed. Baseline characteristics were compared with t tests for continuous variables (expressed as mean values) and χ2 tests for categorical variables. Prespecified primary, secondary, and exploratory end points and echocardiographic measurements from baseline to end of treatment (week 30) were analyzed with ANCOVA for continuous end points and a generalized linear model with binomial distribution for binary end points, with adjustment for each outcome's baseline value, New York Heart Association class, β-blocker use, and ergometer type. At baseline, women (n=102) were older (62 years versus 56 years; P<0.0001), had lower peak oxygen consumption (16.7 mL·kg-1·min-1 versus 21.3 mL·kg-1·min-1; P<0.0001), were more likely to be assigned New York Heart Association class III (42% versus 17%; P<0.0001), had worse health status (Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score 64 versus 75; P<0.0001), and had higher baseline plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels (1704 ng/L versus 990 ng/L; P=0.004) than men (n=149). After 30 weeks of mavacamten treatment, similar improvements were observed in women and men in the primary composite end point (percentage difference on mavacamten versus placebo, 22% versus 19%, respectively; P=0.759) and in the secondary end points of change in postexercise left ventricular outflow tract gradient (-42.4 mm Hg versus -33.6 mm Hg; P=0.348), change in peak oxygen consumption (1.2 mL·kg-1·min-1 versus 1.6 mL·kg-1·min-1; P=0.633), and percentage achieving ≥1 New York Heart Association class improvement (41% versus 28%; P=0.254). However, women had greater improvement in health status (Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score 14.8 versus 6.1; P=0.026) and in the exploratory end point of NT-proBNP levels (-1322 ng/L versus -649 ng/L; P=0.0008). Although at baseline women with symptomatic obstructive HCM enrolled in EXPLORER-HCM were older and had worse heart failure and health status than men, treatment with mavacamten resulted in similar improvements in the primary and most secondary EXPLORER-HCM end points and greater improvements in health status and NT-proBNP. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.

Long-term effects of mavacamten treatment in obstructive hypertrophic cardiomyopathy (HCM): updated cumulative analysis of the EXPLORER cohort of MAVA-long-term extension (LTE) study up to 120 weeks

Abstract Introduction Mavacamten was efficacious and well tolerated in patients (pts) with obstructive HCM over a median follow-up of 62 weeks in a previous interim analysis of the ongoing MAVA-LTE study (NCT03723655) (data cut-off; August 31, 2021). Here, we report an updated cumulative analysis of the EXPLORER cohort of MAVA-LTE up to 120 weeks. Methods Pts who completed EXPLORER-HCM (NCT03470545) could enroll in MAVA-LTE. All pts initiated the study with mavacamten 5 mg/day per protocol; dose adjustments to 2.5, 10, or 15 mg were based on site-read Valsalva left ventricular outflow tract (LVOT) gradient and LV ejection fraction (LVEF). Results In total, 231 pts (median age, 61 years; 39% female) enrolled in the EXPLORER cohort of MAVA-LTE. Median time on study was 101 weeks at data cut-off (May 31, 2022) with variations due to differences in enrollment timing. At data cut-off, 215 pts remained on treatment (total adjusted exposure: 475 pt-years). Mavacamten dosing of pts who reached week 120 (n=80) was: 2.5 mg (27.5%); 5 mg (31.3%); 10 mg (26.3%); 15 mg (12.5%). Between weeks 48–120, 34 of 231 (14.7%) pts underwent dose adjustments. Mavacamten treatment showed sustained improvements in mean [SD] change from baseline to week 120 in LVOT gradients (resting, −35.3 [33.0] mmHg; Valsalva, −47.0 [37.3] mmHg), left atrial volume index (−8.5 [10.3] mL/m2) and E/e’ average (−3.9 [5.0]) (Table). At week 120, 83.5% of pts had a Valsalva LVOT gradient ≤30 mmHg. Mavacamten was associated with sustained reduction from baseline to week 120 in N-terminal pro B-type natriuretic peptide (NT-proBNP) level (Table); 75.9% of pts improved by ≥1 class New York Heart Association class (Figure). Mean (SD) LVEF decreased by 9.1% (7.1) from baseline to week 120 but remained in the normal range. Since the previous interim analysis (data cut-off: August 31, 2021), 1 additional transient reduction in LVEF &amp;lt;50% occurred resulting in temporary treatment interruption (a total of 13 pts [5.6%] experienced LVEF &amp;lt;50% from study initiation). The pt resumed treatment at a lower dose 4 weeks after the event. In total, 74 serious adverse events (SAE) were reported in 47 pts (20.3%), with 18 new SAEs and 13 additional pts (5.6%) with SAEs since the previous interim analysis, including 1 new SAE (atrial fibrillation) considered drug related. No new safety signals were identified. One additional death (leading to a total of 4) occurred, due to intracranial hemorrhage. Like the previous 3 deaths (due to acute myocardial infarction, cardiac arrest, and bacterial endocarditis) the event was considered unrelated to the study drug. Conclusions Long-term mavacamten treatment up to 120 weeks showed sustained improvements in LVOT obstruction, symptoms, and NT-proBNP levels in pts with symptomatic obstructive HCM consistent with the findings of the parent study. Mavacamten treatment continues to be well tolerated with no new safety signals observed.

Natural history and predictors of all-cause mortality and major arrhythmic cardiac events in pediatric RASopathy associated hypertrophic cardiomyopathy

Abstract The RASopathies are a group of developmental disorders caused by germline variants in components of the RAS-MAPK pathway, commonly associated with hypertrophic cardiomyopathy (HCM). The aim of this study was to describe the natural history and predictors of all-cause mortality and major arrhythmic cardiac events (MACE) in a large, multi-centre cohort of paediatric patients with a RASopathy syndrome and HCM. One-hundred-and-forty-nine patients were included (111 (74.5%) Noonan Syndrome (NS); 12 (8.05%) Noonan Syndrome with Multiple Lentigines (NSML); 6 (4.03%) Costello Syndrome (CS); 6 (4.03%) Cardiofaciocutaneous Syndrome (CFCS); and 14 (9.4%) with Noonan-like syndrome patients). NSML patients had higher maximal left ventricular wall thickness (MLVWT) (z score 17.02 (10.57-32.78), p=0.004] and higher left ventricular outflow tract (LVOT) gradient values (60mmHg, 36-80, p=0.019), with no other significant echocardiographic differences between RASopathy syndromes. Over a median follow up of 197.5 months (93.58-370), 23 patients (15.43%) died, at a median age of 48.94 months (3.29-175.84). Overall survival was 96.45% (91.69-98.51), 90.42% (84.04-94.33) and 84.12 (75.42-89.94) at 1, 5 and 10 years, respectively, but this was varied according to RASopathy syndrome. RASopathy syndrome, specifically Noonan-like syndrome (Hazard ratio 4.18, p=0.032) and congestive cardiac failure admission (Hazard ratio 7.35, p=0.037) were independent predictors of all-cause mortality and LVOT gradient was an independent predictor for MACE (Hazard ratio 1.02, p=0.025). These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify predictors of adverse outcome in patients with RASopathy-related HCM.

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.

Transthyretin amyloid cardiomyopathy among patients with hypertrophic cardiomyopathy: clinical, cardiac imaging, and electrocardiographic findings from the TTRACK study

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as hypertrophic cardiomyopathy (HCM). Identifying ATTR-CM in patients with HCM is essential because treatment approaches vary, especially with the availability of disease-modifying therapies for ATTR-CM. In this analysis of the TTRACK study, we investigated clinical, cardiac imaging, and electrocardiogram (ECG) features of ATTR-CM that may heighten suspicion of amyloid disease and prompt further screening in patients with HCM. Purpose Explore the clinical, echocardiogram (echo), magnetic resonance imaging (MRI), and ECG findings of patients with HCM screened for ATTR-CM in the TTRACK study. Methods In this global, multicentre, non-interventional epidemiological study, the prevalence of ATTR-CM was assessed in patients ≥50 years of age with HCM of unknown aetiology (left ventricular [LV] maximum wall thickness ≥15 mm [echo]) using 99mTc-DPD/99mTc-PYP/99mTc-HMDP-labeled bone scintigraphy. Nuclear images were graded based on cardiac vs bone radiotracer uptake following the Perugini system. Monoclonal protein testing was performed to exclude light chain amyloidosis. Results Of 766 eligible patients with scintigraphy data, 521 (68.0%) had no cardiac uptake; 37 (4.8%) had low uptake (grade 1); and 208 (27.2%) had moderate/high uptake (grade 2/3). Among patients with moderate/high uptake (cardiac amyloidosis [CA]), 137 (65.9% of patients with CA; 17.9% of the overall cohort) had confirmed ATTR-CM. Comparing NYHA classification of patients with no cardiac uptake vs those with ATTR-CM, 33.8% and 25.0% were asymptomatic (NYHA class I). Marked numerical differences were observed in some echo findings of patients with no cardiac uptake vs ATTR-CM, including mean LV mass index (155.6 vs 177.0 g/m2) and the proportions of patients with preserved apical strain (57.9% vs 74.2%) and concentric hypertrophic pattern (38.8% vs 77.8%) (Table [A]). Although a smaller percentage of patients with ATTR-CM exhibited LV outflow tract (LVOT) obstruction than patients with no cardiac uptake, 12.5% of patients with ATTR-CM had LVOT obstruction (LVOT gradient &amp;gt;30 mmHg). A substantially lower proportion of patients with no cardiac uptake (54.7%) had late gadolinium enhancement on MRI than those with ATTR-CM (84.6%). Notable ECG differences were seen in PR interval (179.4 vs 196.9 ms) and the proportion with poor precordial R wave progression (21.9% vs 47.9%) (Table [B]). Conclusions In the TTRACK study, conducted in the largest cohort of patients with HCM ever screened for ATTR-CM, approximately 18% of patients ≥50 years of age with HCM had findings indicative of ATTR-CM. Noteworthy differences in some clinical, cardiac imaging, and ECG findings were seen between patients with HCM with and without ATTR-CM, but none appeared to be definitive. These findings suggest that broader screening for amyloid disease with scintigraphy should be considered among all patients with HCM.

Changes in standard of care (SOC) medication during long-term mavacamten treatment for obstructive hypertrophic cardiomyopathy (HCM): results from the EXPLORER cohort of MAVA-Long-Term Extension (LTE)

Abstract Introduction Mavacamten is efficacious and well tolerated in patients with obstructive HCM in the ongoing MAVA-LTE study (NCT03723655) as shown in previous interim analyses. Here, we present exploratory data from the EXPLORER cohort of MAVA-LTE investigating the effect of changes in SOC treatment on the efficacy and safety of mavacamten. Methods Patients who completed EXPLORER-HCM (NCT03470545) could enroll in MAVA-LTE and comprised the EXPLORER cohort. All patients in the EXPLORER cohort received mavacamten. Patients could receive beta blockers or nondihydropyridine calcium channel blockers (verapamil/diltiazem) as SOC treatment. After 24 weeks on study, SOC treatment could be adjusted. A cumulative interim analysis (data cut-off: May 31, 2022) was performed on patients who: received no SOC, discontinued SOC, had any reduction in SOC and had ≥50% reduction in SOC from baseline to data cut-off. Results In total, 231 patients (mean age, 60 years; 39% female) comprised the EXPLORER-LTE cohort (median time on study: 101 weeks at data cut-off). At baseline, 176 patients (76.2%) received beta blockers and 38 (16.5%) received nondihydropyridine calcium channel blockers. At data cut-off, 12 (5.2%) patients had received no SOC treatment from baseline, 11 (4.8%) patients had discontinued SOC, 27 (11.7%) patients had any dose reduction in SOC, 18 (7.8%) patients had a ≥50% reduction in SOC and 14 (6.1%) patients had an increase in SOC. In the no SOC subgroup, mavacamten treatment was associated with improvements from baseline to last visit in resting and Valsalva left ventricular outflow tract (LVOT) gradients, left atrial volume index (LAVI), and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels (Table 1). Improvements in these parameters were also observed in the SOC discontinuation and SOC dose reduction subgroups (Table 1). In the SOC discontinuation subgroup, improvements in resting and Valsalva LVOT gradients, LAVI, and NT-proBNP levels from baseline were maintained after SOC discontinuation (Table 1). SOC medications were discontinued or reduced over a mean (range) period of 63 (9–96) and 62 (3–133) weeks, respectively. At data cut-off, left ventricular ejection fraction remained within the normal range for all patients regardless of the SOC subgroup. Patients who reduced SOC medication had small increases in heart rate (within normal range) from baseline to last visit (Table 2). Overall, blood pressure remained stable across subgroups throughout the observation period (Table 2). No patients experienced worsening of NYHA class from baseline to last visit or from withdrawal to last visit. Conclusions Beneficial and sustained effects on LVOT obstruction, NT-proBNP levels and symptoms in patients with symptomatic obstructive HCM were observed with long-term mavacamten treatment alone or after SOC discontinuation or dose reduction.