Predicting heart failure in phospholamban p.(Arg14del)-positive individuals using vectorcardiographic information

Abstract Background/introduction Since the development of heart failure in PLN-associated cardiomyopathy is highly variable, accurate risk prediction in phospholamban (PLN) p.(Arg14del)-positive individuals is essential to identify patients who may benefit from and rely on future (gene) therapies. Vectorcardiographic data may improve heart failure predictions as it holds information on ventricular depolarization and repolarization patterns which are likely altered in this genetic variant due to fibrosis and fibrofatty replacement. Purpose To assess the prognostic value of vectorcardiograic data using repeated measurements for predicting heart failure in PLN p.(Arg14del)-positive individuals. Methods/Results Data were collected of 417 PLN p.(Arg14del)-positive individuals (mean age 44.3 ± 16 years, 45.6% male) with no history of heart failure. During a median follow-up of 6 years (Interquartile range 3.1-10.7 years) after first cardiological investigation, 61 (14.6%) carriers experienced a heart failure composite endpoint, consisting of heart failure hospitalization, left ventricular assist device implantation, heart transplantation and heart failure related death. Vectorcardiographic data was derived from 12-lead ECG and four vector parameters over time were included in a multivariable Cox regression model: spatial QRS amplitude, spatial T wave amplitude, QRS-T angle, and vector gradient. After backward selection two parameters remained significantly associated with heart failure events: spatial T wave amplitude (p-value = 0.002) and QRS-T angle (p-value < 0.001). These variables were then used in a joint model with repeated vector measurements to provide individualized risk predictions (Figure 1). The model yielded a C-statistic of 0.86 (95% confidence interval [CI], 0.85 – 0.87) after 10-fold cross validation in the training set and 0.86 (95% CI, 0.83-0.89) in the test set. Conclusion Vectorcardiographic data over time holds important prognostic information that can predict heart failure in phospholamban p.(Arg14del)-positive individuals. These results may identify individuals at highest risk for heart failure.Figure 1.Example individual trajectory