Abstract 12787: In Silico Cardiac Risk Assessment of Long QT Patients: Clinical Predictability of Cardiac Models
Background: Although several attempts have been made to correlate decrease in ion channel function associated with specific mutations with patient phenotype in Long QT syndrome, these attempts have been largely unsuccessful. Systems level computational models are highly developed in the field of cardiac physiology and can be used to predict consequences of complex changes in channel function to the overall heart rhythm.
Methods: 633 LQT1 genotyped subjects with 34 different mutations from multinational LQTS registries were studied. Cellular electrophysiology function was determined for each of the mutations and introduced in a transmural ECG computer model. The effect of the mutation on transmural repolarization was determined for each mutant (transmural repolarization prologation (TRP) [Figure]) and related to the risk of cardiac events (comprising syncope, aborted cardiac arrest and sudden cardiac death) among study patients.
Results: Multivariate analysis showed that the mutation-specific TRP was associated with increased risk of cardiac events mutations (32% per 10ms increment [p<0.0001]; >25ms (mean) HR=1.98 p<0.001; upper quartile [Q4] HR=3.71 [p<0.0001]) independently of the patient's individual QTc (Figure). Subgroup analysis showed that among patients with moderate to normal QTc duration (<500 msec) the risk associated with TRP was maintained (36% per 10ms [p<0.0001; >25ms HR=2.00 [p=0.0025]; Q4: HR=3.77 [p<0.0001])), whereas the patient's individual QTc was not associated with a statistically significant risk increase after adjustment for TRP (all corresponding p-values >0.10).
Conclusions: Our findings suggest that simulated repolarization can be used to predict clinical outcomes and to improve risk stratification in LQT1 patients, with a more pronounced effect among patients with a lower-range QTc, in whom the patient's individual QTc may provide less incremental prognostic information.
- © 2011 by American Heart Association, Inc.