PROJECT SUMMARY/ABSTRACT Posttraumatic stress disorder (PTSD) is a chronic disabling psychiatric condition characterized by a persistent maladaptive reaction to the exposure to severe psychological stress, including trauma re-experiencing, hypervigilance, and hyperarousal. Our group has conducted seminal work to establish PTSD as a risk factor for coronary heart disease and autonomic dysfunction. A major concern, based on these findings, is that PTSD could increases the risk of ventricular arrhythmia and sudden cardiac death (SCD) through autonomic dysregulation. This has important clinical implications on management of cardiovascular risk in PTSD. Two important metrics that are potentially useful for risk stratification are T-wave alternans (TWA) and Morphological Beat Variability (MVB). We have found in preliminary investigations that TWA may be linked to acute stress and PTSD, but additional study is needed. In this R03 application, we seek to collaborate with Dr. Gari Clifford in Biomedical Informatics to create a custom program that measures TWA and MVB with state-of- the-art signal processing in a recently recruited cohort of male veteran twins with high-resolution ECG data. We will also study for genetic influences with twin modeling and the effects of acute stress with laboratory- based trauma reminder challenges. Our aims are to 1) Examine the relationship of PTSD with MVB and TWA a) over 24 hours, and b) during trauma recall challenge; 2) Evaluate the potential role for familial and genetic factors by comparing the within-pair difference in MVB and TWA between monozygotic and dizygotic twin pairs discordant for PTSD. We hypothesize that MVB and TWA will be higher, on average, during a 24 hour period, and will increase during trauma recall challenge in PTSD subjects compared to those without PTSD. In addition, we hypothesize that the relationship of PTSD with MVB and TWA will be stronger within DZ pairs than MZ pairs, implying that there is a common genetic pathway linking PTSD and SCD risk. The development of methods to measure these factors, as well as the study of these important mechanisms, will accelerate Dr. Shah’s progress towards research independence, and help to establish him as an expert in the field of mental stress and SCD.