TEST OF A NEW THEORY TO EXPLAIN EXCESS RISK IN CARDIAC POST-TRAUMATIC STRESS DISORDER

Principal Investigator:  William Whang, M.D.; Co-Investigator, Richard P. Sloan, Ph.D.

The goal of the proposed research is to identify targets for new interventions to reduce the doubled cardiac event recurrence and mortality risk faced by the 1 in 8 survivors of non-ST elevation myocardial infarction (NSTEMI) and unstable angina (UA) who develop PTSD secondary to their life-threatening cardiac event. Research on the mechanisms likely to carry that risk is converging on autonomic dysregulation as the culprit. PTSD is associated with high heart rate (HR) and low heart rate variability (HRV), both established secondary risk markers in NSTEMI/UA patients. In our recently offered Enduring Somatic Threat (EST) model, we propose a vicious cycle in which PTSD intrusion symptoms cause acute autonomic imbalance, leading to heart rhythm alterations that are perceived as threatening by the patient, causing further autonomic imbalance. Further, the model proposes that this vicious cycle is exacerbated by non-adherence to beta-blockers (medications that blunt sympathetic influences on HR), a common avoidance behavior in patients with PTSD. Surprisingly, although autonomic imbalance is the leading candidate for PTSD's influence on cardiovascular morbidity and mortality in populations from young veterans to older adults with cardiovascular disease, its candidacy is based almost solely on research conducted in the clinic or the laboratory. No study has ever tested the association of PTSD symptoms and cardiovascular parameters in the real world.

We propose to test the EST model in our Reactions to Acute Care and Hospitalization observational cohort study of 1,741 NSTEMI/UA patients. We will enroll 100 participants with NSTEMI/UA-induced PTSD, and 100 without, at 1-month after hospital discharge. For 1 week, participants will (1) report on PTSD intrusion symptoms in the 30 minutes prior to each of 10 daily electronic momentary assessments (EMA); (2) wear an ambulatory smart shirt embedded with ECG and an accelerometer, from which we will derive heart rate and heart rate variability (HRV); and (3) have their adherence to beta blockers electronically monitored. We will test whether NSTEMI/UA patients with PTSD have higher 24-hr HR and lower 24-hr HRV than those without PTSD and, if so, whether the frequency and intensity of intrusive thought(s) explains the difference. Further, we will test whether HR is higher, and HRV lower, for epochs in which patients report intrusions relative to those in which they do not and whether the difference is more pronounced in patients with PTSD. Finally, we will test whether patients with PTSD are less adherent to beta-blockers, and explore whether associations of intrusions with HR/HRV are more pronounced on days that patients miss their dose. More than 150,000 Americans develop PTSD secondary to NSTEMI/UA each year, and they are at high risk for adverse outcomes. This research will determine whether autonomic dysregulation in the real world is truly a candidate mechanism, describe the dynamics by which PTSD causes it, identify the factors most important to target and the point in the vicious cycle to intervene, and suggest new interventions to offset risk.

The Enduring Somatic Threat (EST) model of PTSD due to cardiovascular events posits that the recurrent distressing intrusive thoughts characteristic of PTSD cause repeated episodes of autonomic dysregulation leading to increased heart rate (HR; an index of sympathetic nervous system activation) and decreased heart rate variability (HRV; an index of parasympathetic nervous system withdrawal) – both established predictors of adverse outcomes. The EST model further posits

Specific Aims. We propose testing a new theory to explain the excess risk associated with posttraumatic stress disorder (PTSD) due to non ST-elevation myocardial infarction and unstable angina (NSTEMI/UA; the two most common forms of acute coronary syndrome).As many as 16% of the 1 million patients who survive NSTEMI/UA go on to develop PTSD in response to the event, and those who develop PTSD are at double the risk of their counterparts without PTSD for recurrent cardiac events and mortality in the subsequent 1-3 years. However, the mechanisms by which PTSD worsens prognosis are unknown. We have demonstrated that the intrusive thoughts that are characteristic of PTSD are strongly associated with cardiac event recurrence and mortality in two large observational cohorts of NSTEMI/UA survivors, and that PTSD due to cardiovascular events is strongly associated with nonadherence to secondary prevention medication that the experience of intrusive thoughts initiates behavioral avoidance of cardiovascular risk reminders – in particular, medications that are necessary for secondary prevention. Beta-blockers, widely prescribed for secondary prevention in NSTEMI/UA patients, dampen many cardiac effects of sympathetic activation. Accordingly, in patients who are nonadherent to beta-blockers, the HR response to intrusive thoughts is not blocked, resulting in increased HR. Finally, the model posits that awareness of sympathetic activation serves as a reminder of the NSTEMI/UA event which, in turn, further exacerbates intrusive thoughts, resulting in a vicious cycle.

We propose to test this vicious cycle model across time in our Reactions to Acute Care and Hospitalization (REACH; R01 HL117832) observational cohort study of 1,741 NSTEMI/UA patients enrolled in the emergency department and followed for 1 month for PTSD status and 1 year for recurrent cardiac events/mortality. To conduct this intensive, in-depth examination of the complex vicious cycle we propose, we will select 100 patients with NSTEMI/UA-induced PTSD, and 100 without, at 1 month after hospital discharge. For 1 week (week 6 post-discharge), participants will (1) report on PTSD intrusion symptoms in the 30 minutes prior to each of 10 daily electronic momentary assessments (EMA); (2) wear an ambulatory smart shirt embedded with ECG and accelerometry, from which we will derive HR and HRV adjusted for posture and movement; and (3) have their adherence to beta blockers electronically monitored.

Aim 1. Determine the association of EMA PTSD intrusion symptoms and cardiac autonomic dysregulation.

Hypothesis 1. PTSD participants will have higher 24-hour mean HR and lower 24-hour mean HRV than non-PTSD participants, and the difference will be partially attributable to the greater frequency and intensity of intrusive thoughts in the PTSD participants.

Hypothesis 2. EMA reports of intrusive thoughts will be associated with higher HR and lower HRV within-person, compared to EMA reports without intrusive thoughts, and this association will be stronger in participants with PTSD than in those without.

Aim 2. Determine the association of EMA PTSD symptoms with nonadherence to cardioprotective medication.

Hypothesis 3. PTSD participants will have worse adherence to beta-blockers than non-PTSD participants, and the difference will be partially attributable to greater frequency and intensity of intrusive thoughts.

Exploratory Hypothesis. HR increases that occur during epochs in which participants report intrusive thoughts will be significantly greater on days that participants miss their beta-blocker dose.

Public Health Significance.  More than 150,000 NSTEMI/UA patients develop PTSD in the U.S. each year, but the mechanisms for their increased recurrence and mortality risk are unknown. This study will be the first to simultaneously assess the momentary experience of PTSD symptoms, behavior, and autonomic function outside the laboratory, and in so doing may identify the dynamic processes by which PTSD symptoms increase risk in NSTEMI/UA patients. This theory-driven investigation could lead to new insights into the cardiovascular, autonomic, and behavioral consequences of PTSD in cardiac patients, and may identify novel treatment targets and suggest novel interventions for reducing their cardiovascular risk. As such, we expect that this research will exert a powerful, sustained impact on research and NSTEMI/UA patient management.

Marna Freed