肥大型心筋症

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder that can lead to heart failure or sudden death. Family-based identification of rare sarcomeric variants can support molecular diagnosis and cascade screening in inherited HCM. This study aimed to identify and evaluate a novel TPM1 variant found in a Vietnamese family with HCM. The proband, a 3-year-old boy diagnosed with HCM, and eight relatives from three generations underwent clinical and genetic evaluation. A candidate variant initially identified by targeted next-generation sequencing was validated by PCR and Sanger sequencing. Familial segregation analysis was performed, and variant pathogenicity was assessed according to ACMG guidelines with support from in silico prediction and structural modeling. Sanger sequencing confirmed a heterozygous missense variant in exon 6 of TPM1 NM_001018005.2:c.576G > C, p.(Glu192Asp), in the proband, his father, and paternal grandfather, all of whom exhibited clinical signs of HCM. The variant was absent in unaffected relatives and in public population databases. Based on ACMG criteria (PM1, PM2, PM5, and PP3), the variant was classified as likely pathogenic. This novel TPM1 variant segregated with HCM in a Vietnamese family, expands the known mutational spectrum of TPM1 in hypertrophic cardiomyopathy, and warrants further functional investigation and familial genetic evaluation.

AIMS: Non-sustained ventricular tachycardia (NSVT) is a well-established risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). However, its characteristics have been overlooked. This study evaluates the prognostic value of NSVT characteristics, particularly coupling intervals, for HCM risk stratification. METHODS AND RESULTS: This retrospective, multicentre study included 2625 HCM patients. Twenty-four-hour Holter recordings were assessed for NSVT and its characteristics (frequency, duration, and coupling intervals). The primary endpoint was SCD; the secondary endpoints were cardiovascular and all-cause death. Two thousand five hundred and eighty-four patients were analysed (49.6 ± 15.2 years; 62.4% male). Non-sustained ventricular tachycardia occurred in 320 (12.4%). During the median follow-up of 4.4 years, there were 221 all-cause deaths (8.6%), 159 cardiovascular deaths (6.2%), and 64 SCDs (2.5%). Among characteristics, the second coupling interval best predicted adverse outcomes (optimal cut-off = 394 ms). Non-sustained ventricular tachycardia frequency and duration were not prognostic. In univariable and multivariable analyses, a second coupling interval < 394 ms markedly increased the risk of SCD [hazard ratio (HR) 8.36, 95% confidence interval (CI) 4.33-16.12, P < 0.001], cardiovascular death (HR 3.64, 95% CI 2.07-6.37, P < 0.001), and all-cause death (HR 3.26, 95% CI 1.97-5.41, P < 0.001) vs. absence of NSVT, whereas a second coupling interval ≥ 394 ms did not. Replacing NSVT with malignant NSVT (NSVT with short second coupling interval) significantly improved SCD risk algorithms. CONCLUSION: A short second coupling interval of NSVT poses a higher SCD risk in HCM than a long one. Detailed dissection of NSVT characteristics may improve decision-making for implantable cardioverter-defibrillator implantation in HCM.

BACKGROUND: High-intensity ultrasound (HIU) ablation can produce deep myocardial lesions but has been limited by the directional, side-facing transducer orientation, yielding inconsistent myocardial targeting with lesion efficiencies <75% and transmurality <60%. OBJECTIVE: We designed HIU catheters and a real-time contact sensing method to guide energy delivery, aiming for a device capable of deep ventricular tachycardia (VT) ablation and septal reduction therapy in hypertrophic cardiomyopathy (HCM). We hypothesized that contact sensing guided HIU (CSG-HIU) would create larger, deeper, and more transmural lesions than standard HIU (Std-HIU) in a terminal swine model. METHODS: Transducer dimensions (5x6 mm) and frequency (5 MHz) were selected from 3D acoustic simulations. Three contact sensing modalities (pulse-echo, and bipolar or unipolar impedance via transducer-side microelectrodes) were validated ex-vivo. The best method was then used in a prospective in-vivo swine study comparing Std-HIU (n=10) to CSG-HIU (n=13) ablation of the ventricular septum. RESULTS: Ex-vivo, bipolar impedance performed best, with a 600 Ω threshold showing 100% sensitivity and specificity for stable contact. In-vivo, versus Std-HIU, CSG-HIU improved lesion efficiency (100 vs 50%, p=0.007), with larger volumes (2071±1231 vs. 568±890 mm3, p=0.005), deeper lesions (15±3 vs. 6±6 mm, p<0.001), and transmurality in 69 vs 20% of swine (p=0.030). No sustained atrioventricular block, ventricular septal defects, or procedural mortality occurred. CONCLUSIONS: Real-time bipolar impedance CSG-HIU overcomes historical directional limitations, achieving 100% lesion efficiency and more predictable transmurality.