Acute stress disorder and C-reactive protein in patients with acute myocardial infarction

Inflammation is a critical component of tissue healing after acute myocardial infarction (AMI).1 However, inflammation-related processes, if not adequately modulated, contribute to adverse left ventricular (LV) remodelling after AMI in certain subgroups of patients. Despite timely reperfusion, increased levels of C-reactive protein (CRP), white blood cell (WBC) counts and fibrinogen are associated with decreased LV function and more pronounced myocardial damage.2 The baseline CRP level is also a powerful independent predictor of both early and late mortality in moderate- and high-risk AMI, despite successful revascularisation.3 Genome-wide association studies suggest a genetic link between inflammation, adverse LV remodelling and heart failure.4 Several cardioprotective medications, including angiotensin-converting enzyme inhibitors, aspirin and statins, have been associated with anti-inflammatory effects.1 On the other hand, anti-inflammatory medications like canakinumab5–7 and colchicine8,9 have been shown to reduce cardiovascular events. In AMI patients, interleukin-1b levels measured pre-, 2- and 7-day and 2-month post-percutaneous coronary intervention predicted adverse LV remodelling at 1 year.10 Myocardial infarction is a life-threatening disease that may lead to acute stress disorder (ASD) within 4 weeks of the index event in 4–18% of patients.11 It is characterised by symptoms of dissociation, re-experiencing, avoidance and hyperarousal. ASD is a risk factor for the development of post-traumatic stress disorder (PTSD), which occurs in 10–20% of AMI patients.12 PTSD is associated with impairments in social functioning and deterioration in quality of life as well as in cardiovascular and overall health. The perception of an overcrowded and hectic hospital environment during AMI admission and hospitalisation may lead to ASD, independently of demographic, peritraumatic and medical factors.11 Occurrence of ASD, however, does not correlate with objective markers of AMI severity like troponin T peak level or LV ejection fraction (LVEF). Furthermore, a history of prior AMI may increase the risk of PTSD, but not of ASD.13 Several studies have shown a buffering effect of trait resilience on the development of PTSD. Meister et al.14 revealed that patients with AMI and higher trait resilience experience relatively fewer ASD symptoms. Resilience was associated with re-experiencing and arousal. Therefore, it is important to identify patients with low resilience and to offer them adequate support. The higher levels of in-hospital dissociative symptoms independently predict all-cause mortality among AMI patients.15 ASD and PTSD can be also associated with pre-existing depression, female gender, age and education level of AMI patients.14,16 AMI patients with current or past depressive episodes develop more PTSD than non-depressed AMI patients.17 Although most patients demonstrate a trend of recovery, ASD after AMI is a marker of long-term adjustment difficulties. At the 8-year follow-up, 6% of ASD AMI patients still experience symptoms of PTSD.18 Elevated levels of PTSD symptoms predict the risk of future hospital readmissions for cardiovascular events and interventions.12 These events correlate with chronic systemic inflammation and neuroendocrine–immune abnormalities inherent to PTSD.19,20 The association between CRP levels and adverse outcomes in AMI patients is well established.21 In the study including 492 AMI patients, CRP was significantly higher among those who died within 30 days of admission (1.42 mg/L versus 0.18 mg/L, p < 0.001) and independently associated with 30-day mortality (odds ratio 1.39, 95% confidence interval 1.20–1.62, p < 0.001). However, Bielas and coworkers22 were the first to reveal a significant direct correlation between the ASD symptom severity and the inflammatory response in AMI. The authors used the ASD-Scale (ASDS) to assess the prevalence of psychiatric symptoms.23 This scale offers an index value from a 19-item self-report record divided into four subscales: symptoms of dissociation (five items), re-experiencing (four items), avoidance (four items) and arousal (six items). Each item is scored on a five-point Likert scale from 0 to 4. Summed scores range between 0 and 76, with higher values indicating more stress. All participants were asked to rate the questionnaire with respect to the AMI. An ASDS summed score of ≥9 for the dissociative symptoms in combination with a cumulative score of ≥28 in the remaining three symptom subscales indicates a diagnosis of ASD.23 A total of 10% of the patients met the cut-off for ASD in the study by Bielas et al.22 Perceived social support was assessed with the Enhancing Recovery in Coronary Heart Disease (ENRICHD) Patients Social Support program, including degrees of emotional, structural and instrumental support, with six items on a Likert scale from 0 to 4.24 Socioeconomic status was defined with reference to a high, medium or low level of education.24 Inflammation levels were categorised according to the prognostic cardiovascular risk of CRP: 0 to <5, 5 to <10, 10 to <20 and ≥20 mg/L.25 Almost half of the patients had the highest risk category with CRP ≥20 mg/L. In the fully adjusted analysis, the associations of ASD symptoms with very high CRP levels were particularly driven by dissociation, avoidance and arousal. Among all ASDS sub-scores, CRP risk categories correlated best with the dissociation sub-score (r = 0.25). Previous reports have also established that AMI-triggered dissociative symptoms predict early mortality, while social isolation and increased CRP levels predict long-term cardiovascular mortality.26,27 Importantly, social support was found to be a protective factor attenuating the development of arousal and avoidance symptoms in patients with AMI. This is in agreement with the well-established role of social support as a stress absorber28 and previous reports showing that its low level is a psychosocial cardiovascular risk factor.29,30 In addition to ASD severity, the risks for recurrent cardiovascular events and mortality were independently predicted by LVEF, body mass index (BMI), male gender and low education. Bielas et al. confirmed the relevance of a high BMI for CRP ≥20 mg/L separately of covariates.22 Reduced LVEF and higher WBC count were also correlated with excessive CRP levels, whereas peak troponin levels and the prognostic GRACE score were not (GRACE – the Global Registry of Acute Coronary Events31 calculator is available at www.gracescore.org). Male patients were at high risk with regard to CRP levels ≥20 mg/L, as shown for ASD symptomatology. This is in line with epidemiological data on symptoms of dissociation in PTSD.32 Such vulnerability is surprising considering that women are more prone to develop PTSD after AMI33 and demonstrate symptoms of anxiety and depression more frequently than men.34 The study of Bielas et al.22 confirmed that ASD in AMI is significantly associated with increased risk for inflammation. ASD severity predicted the presence of CRP levels ≥20 mg/L. Accordingly, early assessment of ASD severity in patients with AMI may indicate the need for immediate interventions, such as fostering resilience.14 However, since Bielas et al.22 selected highly distressed patients with rather low psychiatric burdens, the results should not be applied to the general population with ACS. In conclusion, the independent relationship between AMI-triggered ASD and CRP is an important new finding. This observation should initiate prospective clinical studies to confirm the contribution of inflammation in the increased risk of recurrent cardiovascular events in ASD.35 This might put inflammation in the focus as a potential target in the management of AMI patients with ASD. The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: PMS and ADR are supported by project no. 175080 of the Ministry of Education, Science and Technological Development of the Republic of Serbia.