PO-05-202 FIRST DRAFT OF A NOVEL PLN P.ARG14DEL HEART FAILURE RISK MODEL TO POTENTIALLY AID PATIENT SELECTION FOR FUTURE GENE THERAPY.

Abstract

Gene therapy is a rapidly developing treatment option that will alleviate heart disease by directly targeting pathophysiological mechanisms underlying hereditary heart disease. As it stands today, patient selection is focused on the early-stage, young patients with severe and lethal cardiomyopathies for whom other treatment options are lacking. Many severely affected PLN p.Arg14del carriers precisely fit in this characterization, but risk stratification is needed to select patients as this genetic cardiomyopathy is characterized by incomplete penetrance. To develop a prediction model for heart failure in PLN p.Arg14del carriers to help future patient selection for gene therapy. Data were collected of PLN p.Arg14del mutation carriers with no history or presentation of left ventricular ejection fraction (LVEF) <30%, heart failure hospitalization, left ventricular assist device (LVAD), heart transplantation (HTX) or heart failure (HF) death. The composite endpoint of HF included a LVEF <30%, hospitalization, LVAD, HTX or HF death. Cox regression was performed with lasso penalty for selection of covariates. Cross validation was used to select the penalty and predictors were chosen based on the number of events in a 10:1 ratio. Model performace was estimated using C-statistic. This study included 500 PLN p.Arg14del carriers, aged 39.7 ± 16 years and 42.8% male. During a median follow-up of 6 years (Interquartile range 2.9-9.2) after first MRI, 43 (8.6%) carriers experienced a composite endpoint of HF. We included atrial fibrillation (HR 2.31 [95% CI, 1.57-3.04]; p=0.064), NYHA class ≥2 at presentation (HR 2.74 [95% CI, 1.83-3.65], p=0.037), low-voltage ECG (HR 1.70 [95% CI, 0.99-2.41], p=0.15) and late gadolinium enhancement on MRI (HR 2.18 [95% CI, 1.40-2.97], p=0.064) in the final multivariable Cox regression model. The 5-year risk for HF was calculated for each carrier, after which the cohort was divided into two risk groups. Carriers in the high risk group had one or more risk factors and experienced most events and carriers in the low risk group experienced the least events. This resulted in a C-statistic of 0.76 (95% CI, 0.67-0.85). It should be noted, however, that the number needed to treat at 5 year is still 20 and only after 9 years its declines towards 6 in the high risk group. This is the first outline of a novel PLN p.Arg14del risk prediction model for heart failure to potentially aid patient selection for gene therapy in the future when validated.