Value of a comprehensive exercise echocardiography assessment for patients with hypertrophic cardiomyopathy.

BACKGROUND: Exercise echocardiography (ExE) may assess left ventricular (LV) systolic and diastolic function, LV outflow tract (LVOT) obstruction, and mitral regurgitation (MR). We aimed to evaluate the prognostic value of these assessments during exercise in patients with hypertrophic cardiomyopathy (HCM). METHODS: LV systolic function, LV-derived filling pressures, LVOT gradients, and MR were prospectively evaluated during treadmill ExE in 285 patients with HCM and preserved LV ejection fraction (EF) (≥50%). Recordings were obtained at rest and peak exercise for LV systolic function and at rest and post-exercise for LVOT gradients, MR, and ratio of early LV inflow velocity to early tissue Doppler annulus velocity (E/e´). RESULTS: Thirty-seven patients (13%) had LVOT obstruction at rest, and 76 (27%) developed exercise-induced LVOT obstruction. New wall motion abnormalities were detected in 38 patients (13%). E/e´>14 was observed in 129 patients at rest (45%) and in 134 at post-exercise (47%). Corresponding figures for significant MR (moderate or severe) were 21 (7%) and 17 (6%). During follow-up (3.9 ± 2.5 years), 27 patients had a hard event, 39 a combined event (hard plus new atrial fibrillation or syncope), and 58 a combined event or intervention. Exercise electrocardiographic testing, exercise LVEF, and the combination of positive ExE and increased E/e´ with exercise predicted outcome. The worst event rate corresponded to patients with raised E/e' values at post-exercise and positive ExE (annualized hard event-rate of 5.9%). CONCLUSIONS: A comprehensive assessment during ExE is feasible for patients with HCM and preserved LV systolic function, and provides significant incremental prognostic information.

The impact of diabetes mellitus on the clinical phenotype of hypertrophic cardiomyopathy.

AIMS: Diabetes mellitus (DM) aggravates the clinical features of ischaemic and hypertensive heart diseases and worsens the prognosis of heart failure patients. Hypertrophic cardiomyopathy (HCM) and diabetes coexist fairly frequently in elderly patients but the impact of DM on the clinical phenotype of HCM is yet unknown. We sought to describe if predominant features of heart failure in DM patients exist independently in HCM. METHODS AND RESULTS: We reviewed clinical characteristics of 937 patients, age ≥40, diagnosed with HCM, from two tertiary medical centres in Spain and Israel. A propensity score matched cohort of 294 patients was also analysed. Our cohort comprised 102 HCM patients with diabetes (8.7%). Patients with DM were older at diagnosis {median 56 [interquartile range (IQR) 47-67] vs. 53 (IQR 43-63), P = 0.02} and had a higher prevalence of comorbidities. Hypertrophic cardiomyopathy patients with DM had a higher prevalence of diastolic dysfunction, pulmonary hypertension, significant mitral regurgitation, and pacemaker implantation. Hypertrophic cardiomyopathy patients with DM had a higher New York Heart Association (NYHA) class (P < 0.001) and lower exercise capacity [7.0 METS (IQR 5.0-10.0) vs. 9.0 METS (IQR 6.6-11.0), P = 0.002]. These findings were independent of age, gender, country of origin, hypertension, and coronary artery disease. Patients with diabetes had a significantly higher 15-year mortality (22% vs. 15%, P = 0.03), with no differences in sudden cardiac death, appropriate implanted cardioverter-defibrillator therapy, or heart transplantation. CONCLUSION: Hypertrophic cardiomyopathy patients with diabetes are older and have a higher cardiovascular risk profile. They have a lower functional capacity and more heart failure symptoms due to diastolic dysfunction.

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.

BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.

Direct oral anticoagulants in patients with hypertrophic cardiomyopathy and atrial fibrillation.

BACKGROUND: Chronic anticoagulation with vitamin K antagonists (VKAs) is recommended in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF). Direct oral anticoagulants (NOACs) are an alternative to VKAs but there are limited data to support their use in HCM. We sought to describe the pattern of use, thromboembolic events, bleeding and quality of life in patients with HCM and AF treated with NOACs. METHODS: Data from patients treated with NOACs (n=99) and VKA (n=433) at 9 inherited cardiac diseases units were retrospectively collected. Annual rates of embolic events, serious bleeding and death were analysed and compared. Quality of life and treatment satisfaction were evaluated with SF-36 and SAFUCA questionnaires in 80 NOAC-treated and 57 VKA-treated patients. RESULTS: After median follow-up of 63 months (IQR: 26-109), thromboembolic events (TIA/stroke and peripheral embolism) occurred in 10% of patients on oral anticoagulation. Major/clinically relevant bleeding occurred in 3.8% and the global mortality rate was 23.3%. Thromboembolic event rate was 0.62 per 100patient-years in the NOAC group vs. 1.59 in the VKA group [subhazard ratio (SHR) 0.32;95%CI:0.04-2.45; p=0.27]. Major/clinically relevant bleeding occurred in 0.62 per 100person-years in the NOAC group vs. 0.60 in the VKA group (SHR 1.28;95%CI 0.18-9.30; p=0.85). Quality of life scores were similar in both groups; however, NOAC-treated patients achieved higher scores in the SAFUCA. CONCLUSIONS: HCM patients with AF on NOACs showed similar embolic and bleeding rates to those on VKA. Although quality of life was similar in both groups, the NOAC group reported higher treatment satisfaction.

Extensa familia con síndrome de Marfan en la que se demuestra la patogenicidad de una variante «sinónima» (p. Ile2118=) en el gen de la fibrilina 1 / A large family with Marfan syndrome demonstrating the pathogenicity of a «synonymous» variant (p. ile2118=) in the fibrillin-1 gene

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Severe cardiac conduction disturbances and pacemaker implantation in patients with hypertrophic cardiomyopathy.

The aims of this study were to determine the prevalence of severe cardiac conduction disturbances in a cohort of 451 patients with hypertrophic cardiomyopathy and to describe the characteristics of, and outcomes in, those who required a permanent pacemaker. A pacemaker was implanted in 48 patients (11%): 20 had sinus node dysfunction and 28 had an atrioventricular conduction disturbance. Primary bradyarrhythmia (which was not related to iatrogenic atrioventricular block or therapeutic ablation of the atrioventricular node) was the reason for permanent pacemaker implantation in 36 patients (8%). In 18% of cases, at least one other family member had a permanent pacemaker. In this patient series, a high prevalence of severe cardiac conduction disturbance leading to permanent pacemaker implantation was observed. Severe cardiac conduction disturbance in hypertrophic cardiomyopathy may also have a familial component.

Trastornos graves de la conducción cardiaca e implante de marcapasos en pacientes con miocardiopatía hipertrófica / Severe cardiac conduction disturbances and pacemaker implantation in patients with hypertrophic cardiomyopathy

El objetivo de este estudio es analizar la prevalencia de trastornos graves de la conducción cardiaca en una cohorte de 451 pacientes con miocardiopatía hipertrófica, describiendo las características y la evolución de aquellos que requirieron marcapasos. En 48 pacientes (11%) se implantó un marcapasos: 20 casos por disfunción del nodo sinusal y 28 casos por trastorno de la conducción auriculoventricular. Las bradiarritmias primarias (las no relacionadas con bloqueo auriculoventricular iatrogénico o ablación terapéutica del nodo auriculoventricular) fueron causa de implante en 36 pacientes (8%). En un 18% se detectó un marcapasos en al menos otro miembro de la familia. En nuestra serie, encontramos una elevada prevalencia de trastornos graves de la conducción cardiaca que determinaron el implante de marcapasos. Los trastornos severos de la conducción en la miocardiopatía hipertrófica tienen también una presentación familiar (AU)

The aims of this study were to determine the prevalence of severe cardiac conduction disturbances in a cohort of 451 patients with hypertrophic cardiomyopathy and to describe the characteristics of, and outcomes in, those who required a permanent pacemaker. A pacemaker was implanted in 48 patients (11%): 20 had sinus node dysfunction and 28 had an atrioventricular conduction disturbance. Primary bradyarrhythmia (which was not related to iatrogenic atrioventricular block or therapeutic ablation of the atrioventricular node) was the reason for permanent pacemaker implantation in 36 patients (8%). In 18% of cases, at least one other family member had a permanent pacemaker. In this patient series, a high prevalence of severe cardiac conduction disturbance leading to permanent pacemaker implantation was observed. Severe cardiac conduction disturbance in hypertrophic cardiomyopathy may also have a familial component (AU)