Long-Term Safety and Efficacy of Mavacamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results of the PIONEER-OLE Study.

BACKGROUND: The phase 2 PIONEER-HCM (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction) study showed that mavacamten improved left ventricular outflow tract gradients, exercise capacity, and symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), but the results of longer-term treatment are less well described. We report interim results from the PIONEER-OLE (PIONEER Open-Label Extension) study, the longest-term study of mavacamten in patients with symptomatic obstructive HCM. METHODS AND RESULTS: Patients who previously completed PIONEER-HCM (n=20) were eligible to enroll in PIONEER-OLE. Patients received oral mavacamten, 5 mg once daily (starting dose), with individualized dose titration at week 6. Evaluations included serial monitoring of safety, echocardiography, Kansas City Cardiomyopathy Questionnaire-Overall Summary Score, and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Thirteen patients enrolled and received mavacamten (median study duration at data cutoff, 201 weeks). Most patients (92.3%) received ß-blockers concomitantly. Treatment-emergent adverse events were predominantly mild/moderate. One patient had an isolated reduction in left ventricular ejection fraction to 47%, which recovered and remained normal with continued treatment at a reduced dose. At week 180, mavacamten was associated with New York Heart Association class improvements from baseline (class II to I, n=9; class III to II, n=1; and unchanged, n=2), sustained reductions in left ventricular outflow tract gradients (mean [SD] change from baseline: resting, -50 [55] mm Hg; Valsalva, -70 [41] mm Hg), and serum NT-proBNP levels (median [interquartile range] change from baseline: -498 [-2184 to -76] ng/L), and improved Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (mean [SD] change from baseline: +17 [16]). CONCLUSIONS: This long-term analysis supports the continued safety and effectiveness of mavacamten for >3 years in obstructive HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03496168.

Mildly Reduced Renal Function Is Associated With Increased Heart Failure Admissions in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: The association between renal dysfunction and cardiovascular outcomes has yet to be determined in patients with hypertrophic cardiomyopathy (HCM). We aimed to investigate whether mildly reduced renal function is associated with the prognosis in patients with HCM. METHODS: Patients with HCM were enrolled at two tertiary HCM centers. Patients who were on dialysis, or had a previous history of heart failure (HF) or stroke were excluded. Patients were categorized into 3 groups by estimated glomerular filtration rate (eGFR): stage I (eGFR ≥ 90 mL/min/1.73 m², n = 538), stage II (eGFR 60-89 mL/min/1.73 m², n = 953), and stage III-V (eGFR < 60 mL/min/1.73 m², n = 265). Major adverse cardiovascular events (MACEs) were defined as a composite of cardiovascular death, hospitalization for HF (HHF), or stroke during median 4.0-year follow-up. Multivariable Cox regression model was used to adjust for covariates. RESULTS: Among 1,756 HCM patients (mean 61.0 ± 13.4 years; 68.1% men), patients with stage III-V renal function had a significantly higher risk of MACEs (adjusted hazard ratio [aHR], 2.71; 95% confidence interval [CI], 1.39-5.27; P = 0.003), which was largely driven by increased incidence of cardiovascular death and HHF compared to those with stage I renal function. Even in patients with stage II renal function, the risk of MACE (vs. stage I: aHR, 2.21' 95% CI, 1.23-3.96; P = 0.008) and HHF (vs. stage I: aHR, 2.62; 95% CI, 1.23-5.58; P = 0.012) was significantly increased. CONCLUSION: This real-world observation showed that even mildly reduced renal function (i.e., eGFR 60-89 mL/min/1.73 m²) in patients with HCM was associated with an increased risk of MACEs, especially for HHF.

[Mid-ventricular Hypertrophic Obstructive Cardiomyopathy in a Patient Whose Hemodynamics Were Exacerbated by Forward Shift of the Posterior Leaflet Caused by Mitral Annular Calcification].

A 82-year-old woman came to our hospital because of orthopnea and cardiac cachexia. Echocardiography revealed a pressure gradient of 50 mmHg at the left ventricular outflow tract and that of 78 mmHg at the mid-ventricle. Systolic anterior motion of the mitral leaflet caused by mitral annular calcification and severe mitral regurgitation( MR) were observed. On the basis of the patient's age and poor general conditions, we resected abnormal myocardium on the septum from the outflow tract down to the apex via aortic valve and we left the mitral annular calcification. The pressure gradient in the left ventricle, systolic anterior motion and mitral regurgitation were relieved, and her postoperative course was uneventful. Two years after the surgery, she remains in New York Heart Association( NYHA) class Ⅰ and is well.

Remimazolam-based anesthesia in a patient with hypertrophic obstructive cardiomyopathy undergoing radical colorectal cancer surgery: A case report.

BACKGROUND: The goal of anesthesia in patients with hypertrophic obstructive cardiomyopathy (HOCM) is to reduce the risk of left ventricular outflow tract obstruction triggered by anesthetics. Remimazolam is a newly developed anesthetic that has been reported to have superior hemodynamic stability. There have been no reports on the completion of non-cardiac surgery with remimazolam in patients with HOCM. METHODS: Here we report the case of a 49-year-old man diagnosed with hypertrophic obstructive cardiomyopathy who underwent resection of colon cancer with remimazolam and remifentanil anesthesia. A bolus 0.3 mg/kg remimazolam was administered for anesthesia induction, and then adjusted to 2 mg/kg/h to maintain anesthesia. Set the pain threshold index to 50 to auto-control the infusion speed of remifentanil. RESULTS: No hypotension occurred during anesthesia, and norepinephrine was not administered. After conversion to open surgery, the patient's blood pressure elevated and reduced with urapidil and esmolol. CONCLUSION: In this patient with HOCM, remimazolam and remifentanil provided adequate anesthesia for induction and maintenance to complete the right hemicolectomy.

Evaluation the relationship between myocardial fibrosis and left ventricular torsion measured by cardiac magnetic resonance feature-tracking in hypertrophic cardiomyopathy patients with preserved ejection fraction.

The relationship between left ventricular (LV) torsion and myocardial fibrosis (MF) in hypertrophic cardiomyopathy (HCM) patients with preserved ejection fraction was still not well understood. New developments in cardiac magnetic resonance (CMR) enable a much fuller assessment of cardiac characteristics. This study sought to assess the impact of HCM on myocardial function as assessed by LV torsion and its relationship with MF. HCM (n = 79) and healthy controls (n = 40) underwent CMR. According to whether there was late gadolinium enhancement (LGE), patients were divided into LGE+ group and LGE- group. LV torsion and torsion rate were measured by CMR feature-tracking (CMR-FT). MF was quantitatively evaluated through LGE imaging. LGE was present in 44 patients (56%). Compared with healthy controls, torsion increased in the LGE- group (P < 0.001). Compared with LGE+ group, torsion was higher in the LGE- group (P < 0.001). There was no significant difference in torsion between LGE+ group and healthy controls. Correlation analysis showed that torsion was correlated with LGE% (r = - 0.443) and LGE mass (r = - 0.435) respectively. On multivariable logistic regression analysis, LV torsion was the only feature that was independently associated with the presence of LGE (OR 0.130; 95% CI 0.040 to 0.420, P = 0.01). The best torsion value associated with MF was 1.91 (sensitivity 60.0%, specificity 77.3%, AUC = 0.733). In HCM patients with preserved ejection fraction, CMR-FT derived LV torsion analysis holds promise for myocardial fibrosis detection.

Transcatheter Myotomy to Reduce Left Ventricular Outflow Obstruction.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a source of morbidity in hypertrophic cardiomyopathy (HCM) and a life-threatening complication of transcatheter mitral valve replacement (TMVR) and transcatheter aortic valve replacement (TAVR). Available surgical and transcatheter approaches are limited by high surgical risk, unsuitable septal perforators, and heart block requiring permanent pacemakers. OBJECTIVES: The authors report the initial experience of a novel transcatheter electrosurgical procedure developed to mimic surgical myotomy. METHODS: We used septal scoring along midline endocardium (SESAME) to treat patients, on a compassionate basis, with symptomatic LVOT obstruction or to create space to facilitate TMVR or TAVR. RESULTS: In this single-center retrospective study between 2021 and 2023, 76 patients underwent SESAME. In total, 11 (14%) had classic HCM, and the remainder underwent SESAME to facilitate TMVR or TAVR. All had technically successful SESAME myocardial laceration. Measures to predict post-TMVR LVOT significantly improved (neo-LVOT 42 mm2 [Q1-Q3: 7-117 mm2] to 170 mm2 [Q1-Q3: 95-265 mm2]; P < 0.001; skirt-neo-LVOT 169 mm2 [Q1-Q3: 153-193 mm2] to 214 mm2 [Q1-Q3: 180-262 mm2]; P < 0.001). Among patients with HCM, SESAME significantly decreased invasive LVOT gradients (resting: 54 mm Hg [Q1-Q3: 40-70 mm Hg] to 29 mm Hg [Q1-Q3: 12-36 mm Hg]; P = 0.023; provoked 146 mm Hg [Q1-Q3: 100-180 mm Hg] to 85 mm Hg [Q1-Q3: 40-120 mm Hg]; P = 0.076). A total of 74 (97.4%) survived the procedure. Five experienced 3 of 76 (3.9%) iatrogenic ventricular septal defects that did not require repair and 3 of 76 (3.9%) ventricular free wall perforations. Neither occurred in patients treated for HCM. Permanent pacemakers were required in 4 of 76 (5.3%), including 2 after concomitant TAVR. Lacerations were stable and did not propagate after SESAME (remaining septum: 5.9 ± 3.3 mm to 6.1 ± 3.2 mm; P = 0.8). CONCLUSIONS: With further experience, SESAME may benefit patients requiring septal reduction therapy for obstructive hypertrophic cardiomyopathy as well as those with LVOT obstruction after heart valve replacement, and/or can help facilitate transcatheter valve implantation.

Hypertrophic Cardiomyopathy: Preadolescence, Mitral Valve Disease, and Midventricular Obstruction.

Septal myectomy is indicated in patients with obstructive hypertrophic cardiomyopathy (HCM) who have persistent symptoms despite medical therapy, intolerance of medication side effects, or severe resting or provocable gradients. Septal myectomy at high volume centers is safe, with low operative mortality (1%) and low rates of complications such as complete heart block or ventricular septal defect (3% and 0.5%, respectively). Additionally, improved survival following myectomy has been observed when compared to patients with obstructive HCM managed medically or those with nonobstructive HCM. As a longstanding, quaternary referral center for septal myectomy, our institution has built significant experience and expertise in the surgical and medical management of HCM, including atypical HCM, defined as preadolescent patients, those with mitral valve disease, and those with isolated midventricular obstruction. The most important factor of septal myectomy in achieving complete resolution of obstruction and avoiding recurrence is the apical extent of the myectomy trough, which must extend to the septum opposite the papillary muscles. If this cannot be fully achieved via a transaortic exposure, especially in preadolescents and patients with midventricular obstruction, then a transapical approach may be needed. Mitral valve repair is rarely necessary as SAM-mediated MR resolves with adequate myectomy alone, but mitral repair is performed in cases of intrinsic valvular disease. In this manuscript we provide a summary of current operative techniques and outcomes data from our institution on the management of these various categories of HCM.

Implication of sleep apnea for cardiac remodeling in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Cardiac remodeling is a life-long process in hypertrophic cardiomyopathy (HCM), and if uncontrolled, would cause substantial morbidity and mortality. Sleep apnea (SA) is a common comorbidity in HCM. This study aimed to investigate the relationship between SA and cardiac remodeling in a large series of patients with HCM. METHODS: A total of 606 patients with HCM who underwent sleep evaluations at Fuwai Hospital were included. Parameters of cardiac remodeling were evaluated by echocardiographic studies. RESULTS: SA was present in 363 (59.9%) patients. Left ventricular (LV) end-diastolic diameter (P < 0.001), left atrial (LA) diameter (P = 0.024), ascending aortic diameter (P < 0.001) all increased and maximal end-diastolic wall thickness (P < 0.001) decreased with the severity of SA. After adjustment for sex, age, body mass index, hypertension, hyperlipidemia, diabetes, coronary artery disease and cigarette use, log (apnea-hypopnea index+1) was independently correlated with increasing LV end-diastolic diameter (ß = 0.729, P = 0.003) and deceasing maximal end-diastolic wall thickness (ß = -0.503, P = 0.009). Log (percentage of total sleep time spent with oxygen saturation<90% + 1) was independently correlated with increasing LV end-diastolic diameter (ß = 0.609, P = 0.004) and LA diameter (ß = 0.695, P = 0.006). Severity of SA (severe SA with odds ratio, 2.38; 95% CI, 1.20-4.70; P = 0.013), log (apnea-hypopnea index+1) (OR, 1.28; 95% CI, 1.01-1.63; P = 0.045) and log (percentage of total sleep time spent with oxygen saturation<90% + 1) (OR, 1.31; 95% CI, 1.08-1.59; P = 0.006) were also independently associated with LV enlargement. CONCLUSIONS: Severity of SA is independently associated with cardiac remodeling indicating a trend toward enlarged chamber size and thinned wall. Clinical trials are required to determine whether treatment of SA improves cardiac remodeling and long-term outcomes in patients with HCM.

A case of hypertrophic cardiomyopathy with previous aortic valve replacement.

We describe a 45-year-old patient who was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) after the aortic valve replacement surgery. Enlarged left atria, thickened ventricular septum, left ventricular outflow tract stenosis, moderate mitral regurgitation and mild tricuspid regurgitation in the echocardiography were found. We offered the patient the new minimally invasive treatment modality: percutaneous intra-myocardial septal radiofrequency ablation (PIMSRA). We demonstrate the safety and efficacy with pictures. One month after surgery, the patient recovered well with improved symptoms of chest tightness, and no LVOT obstruction or arrhythmia.

Scar architecture affects the electrophysiological characteristics of induced ventricular arrhythmias in hypertrophic cardiomyopathy.

AIMS: Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) detects myocardial scarring, a risk factor for ventricular arrhythmias (VAs) in hypertrophic cardiomyopathy (HCM). The LGE-CMR distinguishes core, borderzone (BZ) fibrosis, and BZ channels, crucial components of re-entry circuits. We studied how scar architecture affects inducibility and electrophysiological traits of VA in HCM. METHODS AND RESULTS: We correlated scar composition with programmed ventricular stimulation-inducible VA features using LGE intensity maps. Thirty consecutive patients were enrolled. Thirteen (43%) were non-inducible, 6 (20%) had inducible non-sustained, and 11 (37%) had inducible sustained mono (MMVT)- or polymorphic VT/VF (PVT/VF). Of 17 induced VA, 13 (76%) were MMVT that either ended spontaneously, persisted as sustained monomorphic, or degenerated into PVT/VF. Twenty-seven patients (90%) had LGE. Of these, 17 (57%) had non-sustained or sustained inducible VA. Scar mass significantly increased (P = 0.002) from non-inducible to inducible non-sustained and sustained VA patients in both the BZ and core components. Borderzone channels were found in 23%, 67%, and 91% of non-inducible, inducible non-sustained, and inducible sustained VA patients (P = 0.003). All 13 patients induced with MMVT or monomorphic-initiated PVT/VF had LGE. The origin of 10/13 of these VTs matched scar location, with 8/10 of these LGE regions showing BZ channels. During follow-up (20 months, interquartile range: 7-37), one patient with BZ channels and inducible PVT had an ICD shock for VF. CONCLUSION: Scar architecture determines inducibility and electrophysiological traits of VA in HCM. Larger studies should explore the role of complex LGE patterns in refining risk assessment in HCM patients.

Pathological causes of sudden death in autopsied children with reference to peculiar findings: An Egyptian perspective.

Childhood is a long period extending up to the age of 18 years. Childhood encompasses different developmental stages; each stage has specific characteristics. This 5-year study included 244 autopsied children who died unexpectedly due to natural causes. This study was conducted in the forensic pathology unit of the Egyptian Forensic Medicine Authority (EFMA). Pathological causes of death were diagnosed in 181 cases, representing nearly three-quarters (74.2 %) of cases. Males represented 60.8 % of these cases. More than half (51.4 %) of deaths due to natural disease occurred within the first month of life. The diagnosis was established for the first-time during autopsy in 58 % of cases. Prematurity complications and infections were the cause of death in 35.9 % and 30.4 % of deaths attributed to natural pathologies, respectively. Prematurity complications are the most common cause of death in perinatal (63.6) and neonatal (71.4 %) periods. Whereas infection is the most common cause of death during infancy (55 %), childhood (52.8 %), and adolescence (43.8 %). Pneumonia was the most common infection (61.8 %). This study highlighted cases with peculiar pathologies that include cardiomyopathies (idiopathic dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and Arrhythmogenic right ventricular cardiomyopathy (ARVD)), Waterhouse-Friderichsen syndrome (WFS), ruptured cerebral cavernous hemangioma, and cerebellar medulloblastoma.