Hyperarousal Symptoms in Survivors of Cardiac Arrest Are Associated With 13 Month Risk of Major Adverse Cardiovascular Events and All-Cause Mortality

Abstract

Background

Key dimensions of cardiac arrest-induced posttraumatic stress disorder (PTSD) symptoms include reexperiencing, avoidance, numbing, and hyperarousal. It remains unknown which dimensions are most predictive of outcome.

Purpose

To determine which dimensions of cardiac arrest-induced PTSD are predictive of clinical outcome within 13 months posthospital discharge.

Methods

PTSD symptoms were assessed in survivors of cardiac arrest who were able to complete psychological screening measures at hospital discharge via the PTSD Checklist-Specific scale, which queries for 17 symptoms using five levels of severity. Responses on items for each symptom dimension of the four-factor numbing model (reexperiencing, avoidance, numbing, and hyperarousal) were converted to Z-scores and treated as continuous predictors. The combined primary endpoint was all-cause mortality (ACM) or major adverse cardiovascular events (MACE; hospitalization for myocardial infarction, unstable angina, heart failure, emergency coronary revascularization, or urgent defibrillator/pacemaker placements) within 13 months postdischarge. Four bivariate Cox proportional hazards survival models evaluated associations between individual symptom dimensions and ACM/MACE. A multivariable model then evaluated whether significant bivariate predictors remained independent predictors of the primary outcome after adjusting for age, sex, comorbidities, premorbid psychiatric diagnoses, and initial cardiac rhythm.

Results

A total of 114 patients (59.6% men, 52.6% white, mean age: 54.6 ± 13 years) were included. In bivariate analyses, only hyperarousal was significantly associated with ACM/MACE. In a fully adjusted model, 1 standard deviation increase in hyperarousal symptoms corresponded to a two-times increased risk of experiencing ACM/MACE.

Conclusions

Greater level of hyperarousal symptoms was associated with a higher risk of ACM/MACE within 13 months postcardiac arrest. This initial evidence should be further investigated in a larger sample.

Survivors of cardiac arrest who experienced greater hyperarousal symptoms at hospital discharge also experienced a higher risk of adverse cardiovascular events and death within 13-months post-hospital discharge.

Introduction

Cardiac arrest is the cessation of the heart’s mechanical activity, confirmed by the absence of signs of circulation (i.e., pulse or heart rate) (1), resulting in disrupted blood flow to the brain, lungs, and other major organs. It is currently estimated that more than half a million Americans experience cardiac arrest annually (1). The majority of cardiac arrests occur through some cardiac or medical etiology (2), though other common external causes of cardiac arrest include drowning, trauma, asphyxia, electrocution, or drug overdose (3). Due to these various precursors, cardiac arrest can occur in a wide spectrum of people of any health status, age, and sex (4). While short-term prognosis is largely determined by several arrest-related factors (e.g., age, sex, prearrest comorbidities, arrest location, whether the arrest was witnessed by bystanders, provision of bystander cardiopulmonary resuscitation (CPR) and defibrillation, initial cardiac rhythm determined by emergency personnel, time to return of spontaneous circulation, lifestyle factors, and socioeconomic status; see (1) for full list of risk factors), predictors of long-term prognosis remain unclear (5).

Although survival from cardiac arrest has greatly improved (6), hypoxic-ischemic encephalopathy secondary to cardiac arrest remains a major cause of neurological morbidity (7). As such, survivors experience a number of chronic “extracardiac” symptoms (8). For example, retrograde and anterograde amnesia secondary to cerebral hypoxia is a pervasive challenge among survivors (9). Additionally, posttraumatic stress disorder (PTSD) symptoms in response to the cardiac event and subsequent hospitalization experience are highly prevalent (8,10,11,12) and have been associated with greater all-cause mortality (ACM) and major adverse cardiovascular events (MACE) within 1 year of hospital discharge (12).

The concomitant presence of memory impairment and PTSD in survivors of cardiac arrest poses a conceptual paradox when considering current diagnostic criteria for PTSD. To meet diagnosis, exposure to an activating traumatic event and at least one form of reexperiencing symptom anchored to that trauma is needed (13). Given the memory impairments implicated in cardiac arrest, it is unclear how certain hallmark reexperiencing symptoms, such as flashback and intrusive memories, manifest in these patients. Instead, there is the possibility that the PTSD symptoms are not anchored toward a discrete traumatic event per se but rather through daily somatic reminders of patients’ near-death experience and mortality (e.g., increased heart rate, chest pain, and restricted mobility). In turn, this can lead to a chronic maladaptive fear of experiencing a subsequent arrest (8,10; see Edmondson et al. (14) for enduring somatic threat model). This may be especially true for survivors whose cardiac arrest rhythm was precipitated by somatic experiences, such as tachycardia, chest pain, and dizziness (i.e., “shockable rhythms”; ventricular fibrillation or ventricular tachycardia), though not necessarily for those who experienced pulseless electrical activity or asystole. Notably, research on patients with traumatic brain injury who develop amnesia and PTSD symptoms has found the two not to be mutually exclusive; however, the likelihood of developing reexperiencing symptoms is low (15,16).

We recently conducted a confirmatory factor analysis (CFA) and demonstrated that cardiac arrest-induced PTSD symptoms are characterized by a four-factor model that includes dimensions for reexperiencing, avoidance, numbing, and hyperarousal symptoms (17). This four-factor numbing model, developed by King et al. (18), has been found to characterize PTSD symptoms from a variety of nonmedical traumatic experiences as well (19). Our CFA, thus, added to a growing understanding of how PTSD symptoms manifest after acute cardiovascular events (20,21), but it is not clear if certain PTSD symptom dimensions may be associated with a particularly pernicious prognosis for cardiac arrest patients. Previous work in cardiac patients has found that specific symptoms of a psychiatric disorder can largely impact later cardiovascular disease (CVD) risk (22), but this work did not focus on PTSD. Intrusive reexperiencing symptoms predicted 42 month risk of ACM and MACE in patients with acute coronary syndrome (ACS) (23); however, there has yet to be an examination of the independent relationships between specific cardiac arrest-induced PTSD symptoms and future CVD risk. In survivors of cardiac arrest, the association of intrusive reexperiencing may be less potent than that in ACS patients due to the concomitant presence of memory impairments postarrest. The relationship between avoidance symptoms and long-term outcomes is also unclear; some have suggested a link between lower medication adherence and consequent poor outcome (24), though others have found avoidance symptoms to be associated with lower ambulatory blood pressure (25). Numbing symptoms could lead to worse outcomes through the mechanism of social isolation; however, that relationship remains to be demonstrated. Conversely, hyperarousal symptoms have been linked to dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, greater cardiovascular reactivity, and disordered sleep quality (26), all of which could ultimately impose greater secondary cardiovascular risk.

In the present inquiry, we examined the association of individual PTSD symptom dimensions, as represented by the four-factor numbing model, on 13 month ACM/MACE. We hypothesized that (a) the hyperarousal symptom dimension would be a stronger predictor of clinical outcome compared to the other dimensions due to its implications with dysregulated sympathetic activity and (b) the reexperiencing symptom dimension would not be a predictor of clinical outcome due to survivors’ memory impairments.

Method

Participants

This is a post hoc secondary analysis of an observational, prospective cohort study evaluating the evolution of cognitive, functional, and psychological sequelae experienced by survivors of cardiac arrest over 1 year (5). In the parent study, inclusion criteria are ≥18 years of age, resuscitated following in- or out-of-hospital cardiac arrest, and admitted to a large tertiary medical center in New York, NY. From these initially included patients, those who survive to hospital discharge and have sufficient mental status at discharge are asked to complete neuropsychological, functional, and psychological measures. Patient flow for inclusion in the present analysis can be found in Supplementary Fig. 1. Cardiac arrest was defined as a loss of pulse requiring chest compressions, rescue shock, or both.

Details regarding the screening procedure have been described previously (27) (see also Supplementary Methods). Briefly, daily intensive care unit screening identified potential participants per diagnostic codes, who were then approached for written consent. Participation was contingent on sufficient mental status, defined as having a Cerebral Performance Category score (CPC) (28) of 3 or less, being alert and oriented to person, place, and date, and having no presence of delirium, agitation, or sedation according to the Confusion Assessment Method for the ICU (CAM-ICU) (29) and the Richmond Agitation-Sedation Scale (RASS) (30). If sufficient mental status per our inclusion criteria was not present on admission, written consent to monitor the patient’s status was obtained by a surrogate. If at any point during the hospitalization the patient regained sufficient mental status, they were then approached again for written consent. The study was approved by the local institutional review board. The analytic sample for the current study included 114 individuals who met inclusion criteria, consented to participate in the parent study, and completed psychological screening at hospital discharge.

PTSD Symptom Dimensions in Response to Cardiac Arrest

PTSD symptomatology was assessed in survivors of cardiac arrest at hospital discharge via the PTSD Checklist-Specific (PCL-S) scale (31). The PCL-S was developed by the National Center for PTSD to assess symptom severity for all 17 Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV) symptoms for PTSD (32). Patients rated the degree to which they experienced each symptom in the past month, with reference to the acute cardiac arrest event and subsequent hospitalization, on a scale from 1 (“Not at all”) to 5 (“Extremely”). A suggested cutoff of 36 for specialized medical settings was used to identify positive PTSD screens (33). Internal consistency of the PCL-S in the current sample was high (Cronbach’s alpha = .90). The PCL-S has demonstrated acceptable test–retest reliability (34), and excellent sensitivity and specificity for predicting PTSD clinical diagnosis (35).

For our primary analysis, we created four continuous variables from total scaled scores for each PTSD symptom dimension in the four-factor numbing model of PTSD (i.e., reexperiencing, avoidance, numbing, and hyperarousal). Because the four dimensions did not have the same score ranges, we converted the total scaled scores to Z-scores. The allocation of each PCL-S item on respective symptom dimensions can be seen in Table 1.

Table 1.

PCL-S items and corresponding four-factor model symptom dimensions

PTSD symptoms	Symptom dimensions
1. Intrusive thoughts of trauma	Reexperiencing
2. Recurrent dreams of trauma	Reexperiencing
3. Flashbacks	Reexperiencing
4. Emotional reactivity to trauma cues	Reexperiencing
5. Physiological reactivity to trauma cues	Reexperiencing
6. Avoidance of thoughts of trauma	Avoidance
7. Avoidance of reminders of trauma	Avoidance
8. Inability to recall aspects of trauma	Numbing
9. Loss of interest	Numbing
10. Detachment	Numbing
11. Restricted affect	Numbing
12. Sense of foreshortened future	Numbing
13. Insomnia	Hyperarousal
14. Irritability	Hyperarousal
15. Impaired concentration	Hyperarousal
16. Hypervigilance	Hyperarousal
17. Exaggerated startle response	Hyperarousal

PCL-S, PTSD Checklist-Specific; PTSD, posttraumatic stress disorder.

Assessment of Clinical Outcome

The primary outcome was either (a) recurrence of a MACE which included: hospitalization for nonfatal myocardial infarction, unstable angina, congestive heart failure exacerbation, urgent/emergency coronary revascularization procedures (percutaneous coronary intervention or coronary artery bypass grafting), or urgent implantable cardio-defibrillator/pacemaker placements or (b) ACM within 13 months of the hospital discharge interview (reported via telephone or in person conducted at 6 and 12 month study follow-ups with a research coordinator). All clinical outcomes were adjudicated by a board-certified neurointensivist. For patient-reported hospitalization with MACE, supporting documentation of the event was confirmed in 25 (86%) patients from hospital electronic medical records. All deaths were verified using the Social Security National Death Index.

Statistical Analysis Plan

A bivariate correlation matrix evaluated correlations between PTSD symptom dimensions. Four bivariate Cox proportional hazards survival models evaluated associations between continuous Z-scores on individual symptom dimensions (i.e., reexperiencing, avoidance, numbing, and hyperarousal) with ACM/MACE. A final multivariable model included all four symptom dimensions as predictors and important potentially confounding covariates (i.e., age, sex, medical comorbidities via the Charlson Comorbidity Index (36), preexisting psychological disorder, and nonshockable rhythm) as previously used by the research team (12) based on literature on cardiac arrest prognosis (1), PTSD in response to cardiac arrest (11), and the risk of PTSD on major adverse cardiovascular events (37). Secondary analyses following the same data plan examined the associations of individual symptom dimensions with ACM separately and with MACE separately.

We then examined the differential associations of PTSD symptom dimensions on ACM/MACE by including all four dimensions in a model with the above covariates to investigate the effect of hyperarousal over and above the other symptom dimensions. We first ran a model consisting of the four symptom dimensions without covariates, followed by a fully adjusted model.

Post hoc analyses further elaborated on the results of the primary analysis by examining the relationship between individual symptom items within the significant symptom dimension and ACM/MACE. Five bivariate Cox proportional hazards survival models evaluated associations between individual symptom items within the significant symptom dimension with ACM/MACE. Due to concern for high collinearity between individual symptom items of the same dimension, we did not assess differential associations between individual symptom items in a multivariable model. A final set of post hoc analyses examined associations between the significant symptom dimension and individual components of the composite ACM/MACE outcome through bivariate Cox proportional hazard survival models.

Results

Characteristics of Cohort

A total of 114 individuals were included; patient characteristics can be found in Table 2. Nearly one third (n = 36; 31.6%) of patients screened positive for cardiac arrest-induced PTSD as has been reported previously (12). During the median follow-up period of 12.4 months (range 10.2–13.5), 10 (8.8% overall; 6 [5.3%] with PTSD) died and 29 (25.4% overall; 14 [12.3%] with PTSD) experienced a recurrent MACE. Correlations between the PTSD symptom dimensions were each moderate in size (Table 3).

Table 2.

Demographics, clinical characteristics, and discharge outcomes of analytic sample

Demographics
Age, mean ± SD	55 ± 13
Gender—Male, % (n)	59.6 (68)
Race, % (n)
White	52.6 (60)
Black	20.2 (23)
Hispanic	18.4 (21)
Asian	8.7 (10)
Insurance, % (n)
Medicare	28.1 (32)
Medicaid	20.2 (23)
Combined	9.6 (11)
Private	31.6 (36)
Uninsured	7.9 (9)
Annual income, % (n)
<$45,000	69.3 (79)
>$45,000	25.4 (29)
Smoking, % (n)
Current smoker	48.2 (55)
Former smoker	30.7 (35)
Never smoker	16.6 (19)
Recent alcohol consumption, % (n)	22.8 (26)
Premorbid information
Obese, % (n) [BMI ≥ 30 kg/m2]	29.8 (34)
Charlson Comorbidity Index, median (IQR)	2 (1–4)
Preexisting hypertension, % (n)	58.8 (67)
Preexisting diabetes, % (n)	27.1 (31)
Preexisting coronary artery disease, % (n)	23.7 (27)
Premorbid Psych, % (n)	17.5 (20)
Depression	11.4 (13)
Anxiety	3.5 (4)
Both depression and anxiety	2.6 (3)
Premorbid CPC, % (n)
CPC 1	91.2 (104)
CPC 2	3.5 (4)
CPC 3	4.4 (5)
Preliving environment
Home unassisted	71.1 (81)
Home assisted with ADLs	20.2 (23)
Institutionalized partially dependent ADLs	4.4 (5)
Institutionalized fully dependent ADLs	1.8 (2)
Arrest-related factors
In-hospital arrests, % (n)	61.4 (70)
Witnessed arrest, % (n)	89.5 (102)
CPR, % (n)
No CPR	7.9 (9)
Bystander CPR	16.7 (19)
CPR provided by EMS or medical personnel	71.1 (81)
Defibrillation, % (n)
No defibrillation	21.9 (25)
Bystander defibrillation	2.6 (3)
Defibrillation provided by EMS or medical personnel	70.2 (80)
Initial cardiac rhythm, % (n)
Shockable (VT/VFib)	49.1 (56)
Nonshockable (PEA)	31.6 (36)
Nonshockable (Asystole)	18.4 (21)
ROSC (minutes), median (IQR)	8 (3–15)
Admission ph, mean ± SD
Targeted temperature management, % (n)	36 (41)
Therapeutic Intervention Scoring System, median (IQR)	32 (26–37)
Length of ICU Stay (days), median (IQR)	11 (5–20)
Length of hospital stay (days), median (IQR)	21 (11–36)
Discharge CPC, % (n)
CPC 1	28.9 (33)
CPC 2	24.5 (28)
CPC 3	45.6 (52)
Discharge disposition, % (n)
Home	45.6 (52)
Inpatient rehabilitation	37.7 (43)
Skilled nursing	14 (16)
Clinical Frailty Score at discharge, median (IQR)	6 (5–7)
Total number of significant other family members at home, median (IQR)	1 (1–3)
Medications and procedures before discharge
Antiarrhythmic medication use, % (n)	47.4 (54)
Statin medication use, % (n)	29 (33)
Antithrombotic medication use, % (n)	34.2 (39)
ICD/PM placement, % (n)	36.8 (42)
Discharge assessment
PTSD severity scorea mean, SD	32.1 + 13.7
Positive screen for PTSDb	31.6 (36)

ADLs, activities of daily living; BMI, body mass index; CPC, Cerebral Performance Category scale; CPR, cardiopulmonary resuscitation; EMS, emergency medical services; ICU, intensive care unit; ICD/PM, implantable cardioverter-defibrillators or pacemakers; IQR, interquartile range; PEA, pulseless electrical activity; PTSD, posttraumatic stress disorder; ROSC, return of spontaneous circulation; SD, standard deviation; VT/VFib, ventricular tachycardia/ventricular fibrillation.

^aPTSD total severity score based on the PTSD Checklist-Specific (scale range 17–79).

^bPositive screen based on a cutoff of >36.

Table 3.

Bivariate correlations between posttraumatic stress disorder symptom dimensions

Reexperiencing	Avoidance	Numbing	Hyperarousal
Reexperiencing	–	.54	.65	.56
Avoidance	.54	–	.53	.49
Numbing	.65	.53	–	.63
Hyperarousal	.56	.49	.63	–

All correlations significant at the .01 level (two-tailed).

Associations Between Symptom Dimensions with ACM/MACE

Details on unadjusted and adjusted associations between symptom dimensions with ACM/MACE are presented in Table 4. In unadjusted bivariate models, hyperarousal was associated with ACM/MACE (hazard ratio [HR]: 1.8; 95% confidence interval [CI]: 1.3, 2.4). In this model, a 1 standard deviation (SD) increase in hyperarousal symptoms was associated with a 1.8 times higher risk of experiencing ACM/MACE. Reexperiencing (HR: 1.2; 95% CI: 0.9, 1.6), avoidance (HR: 1.1; 95% CI: 0.8, 1.4), and numbing (HR: 1.3: 95% CI: 0.9, 1.7) were not significantly associated with ACM/MACE in unadjusted bivariate models.

Table 4.

Associations between symptom dimensions with 13 month ACM/MACE

Variable	ACM/MACE (n = 39)		MACE only (n = 29)		ACM only (n = 10)
	Unadjusted HR (95% CI)	Adjusted HR (95% CI)	Unadjusted HR (95% CI)	Adjusted HR (95% CI)	Unadjusted HR (95% CI)	Adjusted HR (95% CI)
Hyperarousal	1.8 (1.3–2.4)*	2.0 (1.4–2.8)*	1.5 (1.2–1.9)*	1.5 (1.1–2.0)*	2.8 (1.5–5.0)*	3.6 (1.8–7.3)*
Reexperiencing	1.2 (0.9–1.6)	–	1.2 (0.9–1.5)	–	1.3 (0.8–2.3)	–
Avoidance	1.1 (0.8–1.4)	–	0.9 (0.8–1.2)	–	1.0 (0.5–1.9)	–
Numbing	1.3 (0.9–1.7)	–	1.2 (0.9–1.5)	–	1.5 (0.9–2.4)	–
All dimensions in a single model (estimates are for hyperarousal)	2.0 (1.4–2.9)*	1.9 (1.3–2.9)*	1.6 (1.2–2.1)*	1.6 (1.2–2.2)*	3.4 (1.7–7.0)*	5.2 (1.9–14)*

Covariates included in adjusted analyses include age, sex, Charlson Comorbidity Index, preexisting psychological diagnosis, and nonshockable rhythm.

ACM/MACE, all-cause mortality/major adverse cardiovascular events; HR, hazard ratios; CI, confidence interval.

*p < .05.

In the adjusted model, patients with greater hyperarousal symptoms (HR: 2.0; 95% CI: 1.4, 2.8) and older age (HR: 1.0; 95% CI: 1.0, 1.1) were more likely to experience ACM/MACE after adjusting for sex (HR: 1.2; 95% CI: 0.6, 2.4), Charlson Comorbidity Index (HR: 0.9; 95% CI: 0.8, 1.2), preexisting psychological disorder (HR: 1.1; 95% CI: 0.5, 2.4), and nonshockable rhythm (HR: 1.5; 95% CI: 0.5, 4.2). In this model, a 1 SD increase in hyperarousal symptoms was associated with a two-times higher risk of experiencing ACM/MACE. Secondary analyses of the association of individual symptoms on ACM separately and MACE separately are presented in Table 4.

Differential Associations of Symptom Dimensions on ACM/MACE

Details on the differential associations of symptom dimensions on ACM/MACE are presented in Table 4. In an unadjusted model with all four symptom predictors, hyperarousal was associated with ACM/MACE over and above the other three symptom dimensions (HR: 2.0; 95% CI: 1.4 to 2.9). In this model, a 1 SD increase in hyperarousal symptoms was associated with a two-times higher risk of experiencing ACM/MACE. No other symptom dimensions were significantly associated with ACM/MACE.

After adjusting for covariates, hyperarousal remained associated with ACM/MACE over and above the other three symptom dimensions and covariates (HR: 1.9; 95% CI: 1.3 to 2.9). In this model, a 1 SD increase in hyperarousal symptoms was associated with a 1.9 times higher risk of experiencing ACM/MACE. No other symptom dimension was significantly associated with ACM/MACE. Secondary analysis of the association of symptom dimensions on ACM separately and MACE separately are presented in Table 4.

Post Hoc Analysis of Hyperarousal Symptoms on ACM/MACE

In bivariate models, insomnia (HR: 2.5; 95% CI: 1.2, 3.7) and exaggerated startle response (HR: 2.4; 95% CI: 1.1, 2.6) were each individually associated with ACM/MACE. In these models, a 1 SD increase in insomnia and exaggerated startle response were associated with a 2.5 and 2.4 times higher risk of experiencing ACM/MACE, respectively.

Post Hoc Analysis of Hyperarousal Symptoms on Individual Components of ACM/MACE

In bivariate models, hyperarousal was significantly associated with each individual component of the composite ACM/MACE outcome (HRs: 1.4–2.8) except for rehospitalization for revascularization procedures or implantable cardioverter-defibrillator or permanent pacemaker placement alone. Details of each bivariate model are presented in Table 5.

Table 5.

Bivariate models between the hyperarousal symptom dimension and individual components of the primary outcome ACM/MACE

Outcomes	n (%)	HR (95% CI)
ACM only	10 (8.8)	2.8 (1.5–5.0)*
MACE only	29 (25.4)	1.5 (1.0–2.2)*
Rehospitalization for MI, UA, and CHF alone	16 (14)	1.7 (1.0–2.7)*
Rehospitalization for revascularization procedures or ICD/PPM placement alone	13 (11.4)	1.4 (0.8−2.3)*
ACM and all MACE combined	39 (34.2)	1.8 (1.3–2.4)*
ACM and all confirmed MACE only	34 (29.8)	1.9 (1.4–2.6)*

ACM, all-cause mortality; MACE, major adverse events; MI, myocardial infarction; UA, unstable angina; CHF, congestive heart failure; ICD, implantable cardioverter-defibrillator; PPM, permanent pacemaker.

*p < .001.

Discussion

Cardiac arrest-induced PTSD may be distinct from PTSD resulting from other life-threatening medical events, perhaps due to the profound amnesia survivors experience regarding the event. The present study examined how particular PTSD symptom dimensions, as characterized by the four-factor numbing model of PTSD, are associated with 13 month ACM/MACE. We found that hyperarousal symptoms, but not reexperiencing, numbing, or avoidance symptoms, were associated with a higher risk of ACM/MACE within 13 months posthospital discharge after adjusting for clinically important covariates. Additionally, we found that hyperarousal symptoms were uniquely associated with a higher risk of ACM/MACE over and above the other symptom dimensions. Finally, post hoc analyses revealed that, within the hyperarousal symptom dimension, insomnia and exaggerated startle response were each individually associated with a higher risk of ACM/MACE. These results provide initial evidence for a potential relationship between hyperarousal symptoms and future clinical outcomes in survivors of cardiac arrest.

As hypothesized, the hyperarousal symptom dimension was the strongest predictor of ACM/MACE within 13 months. For every 1 SD increase in hyperarousal symptoms, patients had a two times greater likelihood of experiencing ACM/MACE after adjusting for clinically important covariates. Further, hyperarousal symptoms were uniquely associated with ACM/MACE over and above the other three symptom dimensions. Within the four-factor numbing model of PTSD, the hyperarousal dimension consists of symptoms for insomnia, irritability, impaired concentration, hypervigilance, and exaggerated startle response. Post hoc analyses revealed that insomnia and exaggerated startle response were each individually associated with the composite outcome. Edmondson’s enduring somatic threat model (14) posits that PTSD after life-threatening medical events manifests through repeated and chronic somatic reminders of the traumatic event. These “somatic threats” serve to remind patients of their vulnerability and help cultivate a maladaptive fear of event recurrence. When considering this model with survivors of cardiac arrest, a particularly potent hyperarousal manifestation may result from continual somatic reminders of survivors’ near-death experience and subsequent maladaptive fear of cardiac arrest recurrence. Another plausible explanation could be that a perpetual state of hyperarousal would keep survivors hypervigilant to somatic sensations and, subsequently, lead them to catastrophize these sensations (e.g., perceiving increased heart rate as a sign of a recurrent cardiac arrest). In other patient populations, hyperarousal has been associated with dysregulated sympathetic responses, including dysregulated HPA activity, heightened cardiovascular reactivity, and disordered sleep quality (26). Thus, a potential mechanism for elevated risk of 13 month ACM/MACE in survivors of cardiac arrest could be the upsurge of sympathetic activity resulting from chronic hyperarousal. Further study incorporating underlying biomarkers is needed to confirm this mechanistic hypothesis in survivors of cardiac arrest.

The reexperiencing symptom dimension was not associated with the primary outcome, which supports our second hypothesis. Previous research has demonstrated that the likelihood of developing reexperiencing symptoms in the context of amnesia and traumatic brain injury is possible; however, it is less likely compared to developing other PTSD symptoms (15,16). The present findings support this notion as a hallmark cognitive complication of cardiac arrest is retrograde and anterograde amnesia (9). Importantly, although each patient included in the present analysis experienced some degree of memory impairment, all had sufficient mental status and adequate memory function to engage in psychological screening at hospital discharge. Patients with severe amnesia were not included in this analysis. Thus, in the absence of full amnesia, these patients were able to develop reexperiencing symptoms per se, but these symptoms’ association on ACM/MACE was not as potent as the other symptom dimensions. It is possible that amnesia experienced during the cardiac arrest event may have reduced the potentially traumatic impact of that discrete event. Previous conceptualizations of cardiac arrest-induced PTSD have described the symptoms to be anchored by daily reminders of newfound cognitive and functional debilitations, followed by enduring somatic threats (10). Thus, instead of cardiac arrest-induced PTSD being anchored toward one activating trauma, it is likely implicated in repeated events similar to complex trauma. As such, reexperiencing symptoms in survivors of cardiac arrest may not be as clinically important as compared to survivors of discrete traumatic episodes.

The dimensions for avoidance and numbing symptoms were also not predictive of ACM/MACE in adjusted analyses. In other CVDs, the link between avoidance and long-term clinical outcome is conflicting (e.g., (24, 25)). The present findings add to this ambiguity, warranting further study to clarify the role of avoidance symptoms and long-term cardiovascular outcomes. Similarly, there has yet to be a firmly demonstrated link between numbing symptoms and clinical outcomes in CVDs. In cardiac arrest, emotional numbing symptoms could be protective of cardiovascular reactivity through mechanisms of disengagement and withdrawal; however, this has yet to be observed empirically. Taken together, continued study is needed to parse out the present inquiry’s null findings.

These present, preliminary, results require further comprehensive inquiry. The forthcoming study in a larger sample should consider physiological correlates of noncardiac-related PTSD to comprehensively identify points for risk prediction and targets for intervention. For example, recent meta-analytic results indicated that people diagnosed with PTSD have lower respiratory sinus arrhythmia (the beat-to-beat variability in heart rate associated with respiration; RSA (38)) than those without PTSD (39). This is particularly important as RSA serves as a reliable proxy of cardiac vagal control (i.e., the heart’s natural pacemaker (40)); therefore, in the context of PTSD, lower RSA is indicative of unhealthy parasympathetic activity. Other evidence suggests that PTSD is associated with poor health behaviors, such as medication nonadherence, smoking, and physical inactivity, all of which contribute to greater cardiovascular health risks (41,42). Finally, socially, PTSD has been associated with physical and psychological intimate relationship problems (43), which in turn have important implications for subsequent health problems (44).

Our study is not without limitations. First, cardiac arrest-induced PTSD symptoms were measured via diagnostic inventory rather than the gold standard clinical interview. Next, the PTSD screener used assessed DSM-IV PTSD symptoms as a conception of the parent study was prior to the publication of DSM-5. However, DSM-IV PTSD symptoms have been found to approximate DSM-5 estimates of the disorder (45). Additionally, PTSD screening was conducted 24 hr before hospital discharge, which coincided with a number of patients being excluded due to refusal, lack of interest, and cognitive impairment. Given our limited sample size and the relatively few ACM/MACE events observed, our results should be interpreted tentatively. Future studies should consider implementing PTSD screening in survivors of cardiac arrest at a later time point when they may be more willing to participate, such as after they complete rehabilitation. Furthermore, because of our limited sample size, we were especially selective in choosing covariates for our adjusted models so as to avoid model overfitting. Subsequent inquiries should further investigate the relative associations between cardiac arrest clinical variables (e.g., arrest location, whether the arrest was witnessed by bystanders, provision of bystander CPR, and time to return of spontaneous circulation) and PTSD symptoms on long-term clinical outcomes. Finally, our study was not designed to examine biological or behavioral mechanisms underlying the associations between PTSD symptoms and future ACM/MACE. As such, unmeasured covariates may offer alternative explanations to our findings. Despite these limitations, this was the first study to prospectively examine the independent relationships between individual PTSD symptom dimensions and future clinical outcomes. Finally, we suggest that future study designs compare survivors who have clinically significant hyperarousal symptoms from those without to better discern the causality of ACM/MACE.

Conclusions

Within the context of cardiac arrest-induced PTSD, hyperarousal symptoms were associated with an elevated risk for future CVD and ACM. These preliminary results should be further investigated in a large sample. Additionally, the forthcoming study should also examine the upregulation of sympathetic activity as a potential underlying mechanism, which could inform early interventions for cardiac arrest-induced PTSD.

Compliance with Ethical Standards

Funding Dr. Sumner acknowledges support from the National Institutes of Health (K01HL130650 award). Dr. Elkind received compensation for providing consultative services for Vascular Dynamics; receives research funding from Roche for an NINDS-funded clinical trial of atrial cardiopathy; receives study medication in kind but no personal compensation from the BMS-Pfizer Alliance for Eliquis for an NINDS-funded clinical trial of atrial cardiopathy; gives expert legal opinions on behalf of LivaNova (cardiac surgery and stroke); receives royalties from UpToDate for chapters related to stroke; and serves on the National, Founders Affiliate, and New York City chapter boards of the American Heart Association/American Stroke Association. Dr. Elkind’s institution, Columbia University, receives compensation through service agreements with Medtronic for Dr. Elkind’s effort on analyses of clinical trials related to cardiac monitoring and from Biogen for his effort as lead Principal Investigator for a Biogen study of Tysabri and stroke. Dr. Park acknowledges support from the National Institute of Neurological Disorders and Stroke (K01ES026833 award). Dr. Claassen reports grants from DANA, grants from McDonell, personal fees from SAGE, grants from SHINE, grants from I-SPOT, grants from ESETT, grants from SAGE, other from iCE Neurosystems, outside the submitted work. Dr. Edmondson acknowledges support from the National Heart, Lung, and Blood Institute (HL132347 and HL128497 awards). The funding sources had no role in study design, collection, analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication.

Authors’ Statement of Conflict of Interest and Adherence to Ethical Standards The authors declare that they have no conflict of interest.

Authors’ Contributions A.P.: conception and design, acquisition of data, analysis and interpretation of data, drafting and critically revising the article for important intellectual content, and final approval of the version to be published. J.S.: conception and design, critical revising the article for important intellectual content, and final approval of the version to be published J.A.S.: conception and design, analysis and interpretation of data, critically revising the article for important intellectual content, and final approval of the version to be published. M.S.V.E.: analysis and interpretation of the data, critically revising the article for important intellectual content, and final approval of the version to be published. D.J.R.: acquisition of data, critically revising the article for important intellectual content, and final approval of the version to be published. S.P.: acquisition of data, critically revising the article for important intellectual content, and final approval of the version to be published. J.C.: acquisition of data, critically revising the article for important intellectual content, and final approval of the version to be published. D.E.: analysis and interpretation of the data, critically revising the article for important intellectual content, and final approval of the version to be published. S.A.: acquisition of data, analysis and interpretation of data, critically revising the article for important intellectual content, and final approval of the version to be published.

Ethical Approval All procedures performed in this study involving human participants was in accordance with the ethical standards of the local institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent Informed consent was obtained from all individual participants included in this study.