Rare Genetic Variants in Young Adults Requiring Pacemaker Implantation.

BACKGROUND: Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled. OBJECTIVES: This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups. METHODS: We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects). RESULTS: Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%). CONCLUSIONS: Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated.

The importance of variant reinterpretation in inherited cardiovascular diseases: Establishing the optimal timeframe.

Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.

Penetrance of Dilated Cardiomyopathy in Genotype-Positive Relatives.

BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.

Respuesta de los autores: Estrategias de reperfusión en los pacientes con IAMCEST: el debate no cesa / Authors' reply: Reperfusion strategies in patients with ST elevation myocardial infarction: the debate goes on

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Angioplastia primaria frente a fibrinolisis en pacientes alejados de un centro con hemodinámica / Primary angioplasty versus fibrinolysis in patients at a distance from a hospitalwith a catheterization laboratory

Objetivo: En los pacientes con infarto agudo de miocardio con elevación del ST (IAMEST) sometidos a angioplastia primaria (AP), la distancia al centro de hemodinámica alarga los tiempos y empeora el pronóstico. En estos pacientes, la estrategia fármaco-invasiva podría ser una alternativa. Nuestro objetivo fue establecer si el pronóstico es diferente en función del tipo de tratamiento de reperfusión en los pacientes alejados de un laboratorio de hemodinámica. Método: Registro prospectivo durante 5 años de los pacientes con IAMEST ingresados en la unidad de cuidados críticos cardiológicos. Se seleccionaron pacientes que recibieron terapias de reperfusión y estaban a más de 50 Km del centro con hemodinámica. Se recogieron las características del infarto, tiempos de tratamiento y la mortalidad a corto y largo plazo. Finalmente se realizó un modelo de supervivencia. Resultados: Se registraron 584 pacientes; 194 recibieron AP y 390 fibrinolisis (FL). En los pacientes sometidos a AP, la mediana del tiempo desde el primer contacto médico (PCM)-balón fue 160 minutos. Los tratados con FL presentaron un PCM-aguja de 30 minutos. La mortalidad en el seguimiento a dos años fue superior en los pacientes tratados con AP (12,2%) frente a los que recibieron FL (7,0%) (p = 0,04). Existió un aumento del riesgo de mortalidad en el grupo tratado con AP con hazard ratio (HR) de 1,97 (IC 95%: 1,04-3,70; p = 0,035). Conclusiones: En los pacientes que sufren un IAMEST a más de 50 Km de un centro con hemodinámica, la reperfusión mediante AP tiene importantes retrasos y se asocia con mayor mortalidad respecto a la FL (AU)

Background and objective: Long distance from a hospital with a catheterization laboratory is associated with a poorer prognosis in patients who undergo primary angioplasty for ST-elevation myocardial infarction (STEMI). An invasive pharmacologic strategy could offer an alternative treatment for these patients. We aimed to establish whether prognosis was better with primary angioplasty or fibrinolysis for reperfusion in cases of STEMI occurring far from a catheterization laboratory. Methods: Prospective registry study of patients with STEMI admitted to our cardiology critical care unit. Patients were included over a 5-year period if they received reperfusion therapy and had required transport of more than 50 km to reach a hospital with a catheterization laboratory. We recorded characteristics of the STEMI event, treatment times, and short- and long-term mortality. The data was used for survival analysis. Results: We registered 584 patients; 194 were treated with primary angioplasty and 390 with fibrinolysis. The mean time between first physician contact and balloon insertion was 160 minutes. The mean time between first physician contact and needle insertion for fibrinolysis was 30 minutes. The 2-year mortality rate was higher in patients treated with angioplasty (12.2%) than with those who underwent fibrinolysis (7.0%) ) (P=.04). Survival analysis showed that risk for death was higher in the primary angioplasty group (hazard ratio, 1.97 (95% CI, 0.64-0.95; P=.001). Conclusion: When STEMI occurs more than 50 km from a catheterization laboratory, reperfusion by means of balloon angioplasty delays care considerably and is associated with a higher mortality rate than reperfusion by fibrinolysis (AU)