ABSTRACT
Importance: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia. Objective: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). Design, Setting, and Participants: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. Main Outcomes and Measures: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. Results: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). Conclusions and Relevance: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.
Subject(s)
Cardiomyopathy, Dilated/genetics , Death, Sudden, Cardiac/prevention & control , Filamins/genetics , Heart Failure/genetics , Tachycardia, Ventricular/genetics , Ventricular Dysfunction, Left/genetics , Adult , Cardiomyopathy, Dilated/mortality , Cardiomyopathy, Dilated/physiopathology , Cardiomyopathy, Dilated/therapy , Codon, Nonsense , Connectin/genetics , Defibrillators, Implantable , Female , Heart Failure/mortality , Heart Failure/physiopathology , Heart Failure/therapy , Heart Transplantation/statistics & numerical data , Humans , Male , Middle Aged , Mutation , Stroke Volume , Tachycardia, Ventricular/epidemiology , Tachycardia, Ventricular/physiopathology , Ventricular Dysfunction, Left/physiopathologyABSTRACT
Las alteraciones metabólicas secundarias al tratamiento antirretroviral (dislipemia, resistencia a la insulina, cambios en la distribución de la grasa) unido al incremento de la edad media de la población infectada por virus de la inmunodeficiencia humana (VIH) en el mundo desarrollado pueden aumentar el riesgo de eventos cardiovasculares en estos pacientes.Como en la población general, en los pacientes con infección VIH, los factores tradicionales de riesgo predicen la mayor parte del riesgo cardiovascular; sin embargo, es un proceso multifactorial en el que intervienen los fármacos antirretrovirales, y en el que influyen factores genéticos, ambientales y el propio VIH. Este artículo revisa las alteraciones metabólicas producidas por la infección VIH y la terapia antirretroviral, las técnicas de detección de aterosclerosis subclínica, los estudios clínicos observacionales y prospectivos que estudian la epidemiología de los factores de riesgo cardiovascular y de los eventos cardiacos en esta población, la estimación del riesgo cardiovascular y el manejo terapéutico de los factores de riesgo cardiovascular en estos pacientes.
