Hisham Ahamed

Background: Danon disease, caused by loss-of-function variants in LAMP2, is an X-linked cardioskeletal disorder with cardiac manifestations in heterozygous females that are often underrecognized. The co-occurrence of surgically corrected dextro-transposition of the great arteries (d-TGA) and subsequent Danon cardiomyopathy in a patient carrying a maternally inherited GDF1 variant of uncertain significance has not previously been reported. Case summary: We describe a girl with d-TGA repaired in the neonatal period who later presented at 12 years of age with progressive dyspnoea on exertion (New York Heart Association class III). She was found to have severe left ventricular hypertrophy (LVH), biventricular outflow tract obstruction, myocardial fibrosis, and non-sustained ventricular tachycardia on ambulatory electrocardiographic (ECG) monitoring. Whole-exome sequencing revealed a de novo pathogenic LAMP2 variant, c.98del (p.Leu33Ter), predicted to disrupt all LAMP2 isoforms, establishing the diagnosis of Danon disease. A maternally inherited GDF1 in-frame deletion, c.651_656del (p.Ala218_Leu219del), was also identified and classified as a variant of uncertain significance; while its clinical significance remains unresolved, it is biologically plausible that the GDF1 variant may have contributed to the congenital heart disease substrate. Discussion: This case highlights two mechanistically distinct genetic events operating across different developmental windows: a likely susceptibility allele for congenital heart disease and a de novo lysosomal cardiomyopathy causing Danon disease. In patients with repaired congenital heart disease who subsequently develop an otherwise unexplained hypertrophic cardiomyopathy (HCM) phenotype, comprehensive cardiomyopathy-focused genetic evaluation may reveal a second diagnosis with major prognostic, therapeutic, and family-screening implications.

BACKGROUND: Implanted cardioverter-defibrillators (ICDs) have been used in patients with hypertrophic cardiomyopathy (HCM) to prevent sudden death, and have proven lifesaving for many patients. However, experience with ICD therapy has largely been derived from relatively small HCM cohorts confined to specific countries or regions of the world. Therefore, we sought to determine the effectiveness of ICDs in preventing sudden death due to life-threatening ventricular arrhythmias in a large international multicenter HCM population. METHODS: Databases from 25 HCM centers (8 in the United States, 9 in Europe, 4 in Asia, and 1 each in Australia, Africa, Mexico, and South America) were retrospectively interrogated to identify consecutive patients with HCM with ICDs (1992 to 2024) followed for 7±6 years (up to 32 years) for clinical outcomes. RESULTS: A total of 3387 patients were identified (63% men). They had a mean left ventricular thickness of 22±7 mm. The participants had received ICDs at a mean age of 47±17 years. Over follow-up, 550 patients (16%) experienced ≥1 appropriate ICD therapy (2.6%/y), including 86 of the 247 implanted for secondary prevention (35% [6.4%/y]) and 464 of the 3140 implanted for primary prevention (15% [2.2%/y]). Appropriate therapy occurred in the 464 primary prevention patients at a mean age of 49±17 years, with a median time to first appropriate therapy of 4 years after ICD implantation; 16% of these received their first appropriate therapy ≥10 years after implantation, and 47% experienced multiple interventions. Independent predictors of appropriate ICD therapy included unexplained syncope, left ventricular apical aneurysms, left ventricular systolic dysfunction, and nonsustained ventricular tachycardia on ambulatory monitoring. Of the 3140 primary prevention patients, 2946 survived (94%) and 194 died (6%) (0.8%/y), including 68 due to HCM (0.3%/y), predominantly of end-stage heart failure (n=43) or stroke (n=9). In contrast, 11 patients (0.4%) died suddenly, with device failures occurring in 2.4% of those with life-threatening ventricular tachyarrhythmias. Survival free from HCM-related mortality at 10 and 20 years was 97% and 91%, respectively. CONCLUSIONS: In this international multicenter study, the largest to date, including >3300 consecutive patients with HCM and ICDs, device therapy terminated potentially lethal ventricular tachyarrhythmias in 1 of 6 patients, with low HCM-related mortality rates for patients with ICDs. These novel data demonstrate the effectiveness of the ICD initiative, which has probably favorably altered the natural history of many patients with HCM worldwide.

Background: Immune checkpoint inhibitors (ICI) usage has increased in recent years, along with it the associated adverse effects. Objective: To conduct an observational study on immune checkpoint usage and adverse drug reactions associated with its use in a tertiary care center from coastal south India. Methodology: 228 patients were enrolled in this ambispective study, patient’s data was collected from the year 2020 2024. Patients were selected based on inclusion criteria. Results: While adverse effects such as pruritus, tachycardia, and thyroiditis occurred infrequently, their clinical significance necessitates careful monitoring. A statistically significant association (p = 0.022) between treatment response and adverse events indicated a potential relationship between therapeutic effectiveness and toxicity. The instance of myocarditis was found to be 0.4%. Conclusion: These findings emphasize the significance of accurate monitoring, management, which includes various fields, and individualized therapies to maximize the outcomes for patients and reduce potential risks associated with Immune Checkpoint inhibitors (ICI).

Background: Primary hypertrophic cardiomyopathy ( HCM ) is predominantly a genetic disease causing left ventricular hypertrophy in the absence of other cardiac and systemic metabolic diseases. Currently, limited data exist on the prevalence of clinically actionable gene variants for primary HCM in South Asian Indian ( SAI ) patients, which are necessary for minimizing disparities in interpreting ancestry‐specific variants. The ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel categorized HCM ‐causing genes into 5 categories according to their clinical relevance: definitive, strong, moderate, limited, and disputed. However, comprehensive studies examining this classification in SAI patients are lacking. Methods: Whole‐exome sequencing was performed for 335 primary SAI patients with HCM, including all known cardiovascular genes and clinically actionable gene categories to determine their allele frequencies. Results: SAI HCM exomes revealed a total of 193 pathogenic/likely pathogenic variants and variants of uncertain significance across 26 clinically actionable genes in 119 (35.52%) of 335 cases. The SAI HCM exhibited significantly fewer variants in the 12 definitive category genes compared with other global HCM cohorts (15.77% versus 43.23%; P P =0.3499). Among the 21 limited and disputed genes, MYH6 showed a significantly higher prevalence of pathogenic/likely pathogenic variants in the SAI HCM than in the other global HCM cohorts (0.897% versus 0%; P =0.0287). Conclusions: The clinically actionable gene variants in SAI HCM differed significantly from other global HCM cohorts, specifically MYBPC3 , MYH7 , and MYH6 .

To correlate extracellular volume (ECV) measurement at diagnosis with sudden cardiac death in patients with AL amyloidosis from South Asia. This ambispective study included 188 AL amyloidosis patients from January 2000 to October 2024 at Amrita Institute of Medical Sciences, Kochi. Patients had serum free light chain restriction (FLC-diff ≥ 18 mg/dL) and biopsy-proven amyloidosis and/or cardiac amyloidosis phenotype. ECV was calculated from T1 mapping in cardiac MRI. Normal ECV was defined as < 25%.Of 188 patients (median age 64.5 years, male: female 2:1), 43 underwent cardiac MRI with 22 having evaluable ECV. Five patients had normal ECV (< 25%) and 17 had abnormal ECV (≥ 25%). Patients with abnormal ECV showed significantly higher baseline lambda light chains (558 vs. 46 mg/dL) and NT-proBNP (5587 vs. 1254 pg/mL). All 10 deaths occurred in the abnormal ECV group versus none in the normal ECV group (p < 0.05). ECV values were significantly higher in patients with sudden cardiac death (p = 0.03). Abnormal ECV demonstrated perfect sensitivity (100%) but lower specificity (41.67%) for predicting mortality. Although limited by its sample size, ECV mapping can be a useful tool predicting survival in AL amyloidosis patients, with abnormal ECV predicting sudden cardiac death in this South Asian cohort.