Does Psychosocial Stress Lead to Spontaneous Coronary... : Heart and Mind (2024)

INTRODUCTION

Spontaneous coronary artery dissection (SCAD) is an acute event that produces “a false lumen within the coronary artery wall which may compromise coronary (blood) flow by external compression of the true lumen.”[¹] SCAD has been relatively overlooked yet can be a life-threatening condition causing myocardial infarction (MI), cardiac arrhythmias, or cardiac death.[²] SCAD cases have been subclassified according to their angiographic appearance and the extent or length of their involvement of the artery,[³] but the fundamental process is the spontaneous formation of an intramural hematoma within the outer third of the tunica media layer of a coronary artery.[²] In contrast, coronary artery thrombosis, often associated with rupture of a coronary artery plaque, is the most common kind of acute MI (AMI).[⁴] The cause of SCAD is unknown, but extrapolation from the greater amount of data in (spontaneous) dissections of the aorta has attributed the causes of SCAD to either (i) a “tear” in the inner lining of the coronary artery allowing blood to enter the arterial wall and accumulate in the middle layer of the artery or (ii) a disruption of the very small blood vessels on the outer layer of the artery leading to bleeding into a layer of the coronary artery.[²] The second proposal is favored as evidence of an intimal tear has not been convincingly demonstrated.[²]

While the actual cause of the dissection has not been identified, a large number of conditions have been associated with the occurrence of SCAD and have been proposed to be either the underlying predisposing factor or an acute trigger of SCAD [Figure 1].

These conditions include: (i) genetic polymorphisms of F11 receptor, TALIN-1 (TLN-1), TSR1 ribosome maturation factor, phosphatase and actin regulator-1, or endothelin 1; (ii) chest trauma; (iii) angioplasty and stenting; (iv) pregnancy; (v) atherosclerosis; (vi) Marfan's syndrome; (vii) Ehlers-Danlos syndrome type IV; (viii) systemic lupus erythematosus; (ix) Kawasaki's disease; (x) Takayasu's arteritis; (xi) angiitis; (xii) coronary ectasia; (xiii) apical hypertrophic cardiomyopathy; (xiv) fibromuscular dysplasia of the coronary arteries; (xv) coronary artery spasm; (xvi) remote aortic valve replacement; (xvii) contraceptives; (xviii) chronic emotional stress; (xiv) severe hypertension; (xv) septic emboli; (xvi) triptan use; (xvii) hyperthyroidism; (xviii) autoimmune thyroiditis; (xviiii) prednisone use in rheumatoid arthritis; (xix) drug hypersensitivity; (xx) active hepatitis C with cryoglobulinemia; (xxi) sarcoma; (xxii) remote exercise-induced injury; (xxi) rheumatic mitral stenosis; (xxii) renal transplantation; (xxiii) bromocriptine; (xxiv) migraine headaches, and (xxv) intense (isometric) exercise.[¹²⁵⁶⁷⁸] Abnormalities of matrix metalloproteinases have been identified as factors responsible for aortic aneurysms and dissection[⁹] and may be operative in SCAD as well. Such a large and diverse list of factors suggests that all these factors cannot reasonably be “true” causative factors. Many of these conditions are based on single case reports, small patient groups, or patient groups without controls or comparative groups. When studies included a control group, cases of SCAD did not have concomitant inflammatory disorders, or several risk factors for atherosclerosis.[¹⁰¹¹]

Brain-heart interconnections have been well described. Acute and chronic imbalances in brain-heart interactions have a negative impact on health.[¹²] For decades, acute emotional stress has been linked not only to cardiac arrhythmias but also to MI and heart failure.[¹³¹⁴] The neurocardiac pathways involved in the production of cardiac arrhythmias are well understood and involve brain activity and autonomic nervous system-mediated cardiac electrical instability.[¹³¹⁴¹⁵] Acute stress-induced cardiomyopathy (Takotsubo) often presents with the clinical picture of AMI and is triggered by intense emotional stress, the pathophysiology of which is beginning to be understood.[¹⁶] Whether emotional factors, which originate in the brain/mind, could produce or be a consequence of SCAD is a brain-heart connection that has been suggested but not critically reviewed. This article will critically examine the data that emotional stressors and posttraumatic stress disorder (PTSD), might be related to SCAD.

The evidence to support a causal or cause-and-effect relationship between a factor and an event, condition, or disease is strict. The strongest clinical evidence to support a causal relationship between a factor and a disease or condition is a combination of a number of randomized control trials with specific interventions on the factor to determine whether it prevented or reduced the disease or outcome of interest. For example, multiple clinical trials on the treatment of hypertension or elevated cholesterol established that hypertension and elevated cholesterol contribute in a causative manner to the development of atherosclerotic cardiovascular disease. For factors where there are no such data, reliance is placed on different kinds of evidence such as that conceptualized and developed by Hill in 1965.[¹⁷] First, the presence of the factor in individuals without the condition to determine that the factor is an antecedent (and not a consequence) of the medical disease. There should be a specific control group not affected by the factor. Next, there should be a gradient of risk such that the higher the level of that factor, the greater the likelihood of the occurrence of the disease. In addition, the factor should make “biological sense,” taking into consideration the biology of the medical condition. A critically important consideration for clinical medicine is an intervention strategy that reduces the risk factor leading to a reduction in disease incidence. We have previously utilized this construct to establish causality between several risk factors and atherosclerosis.[¹⁸]

METHODOLOGY

A systematic search was conducted of Medline and EMBASE. The search was conducted from the inception of each database to June 30, 2022. Search terms “coronary artery dissection or spontaneous coronary artery dissection AND the terms psychological stress, anxiety, or depression” were used in conjunction with Boolean operators to identify articles reporting SCAD and emotional stress, depression, or anxiety. Because there was no primary patient or animal contact, there was no requirement for approval from our research ethics committee. Titles and abstracts were screened to identify articles for full-text review. The exclusion criteria were: (i) not published in English; (ii) involved nonhuman subjects; (iii) nonprimary articles (reviews, editorials, or letters commenting on an article; and (iv) unrelated to the investigated topic, i.e., no cases of SCAD and/or psychological factors. There were 22 articles, of which 4 were eliminated because they were nonprimary articles, 1 was not in English, 1 did not have SCAD, and 1 was not related to the acute SCAD event. There were 8 case reports. The other articles were discussed in the text and the three with control groups were included for data analysis. Data analysis was performed using Comprehensive Meta-Analysis (Biostat Inc., NJ, USA).

Emotional stress and spontaneous coronary artery dissection

The association of emotional or psychological stress with SCAD has been reported in a number of case reports [Table 1]. These case reports describe the occurrence of SCAD in an individual who had recently had psychological or emotional distress. While case reports are interesting, they do not establish causality. Because SCAD is rare, and many people experience significant psychological or emotional stress, so that the SCAD and an emotional event may have coincided at random.

Studies without a comparison group

Early, retrospective analysis of cases with SCAD reported that SCAD was associated with stress-psychological or emotional stress,[⁵²⁶²⁷] especially in women compared to men.[⁸] Those initial studies usually did not have a control group, and included self-reported data, rather than detailed externally validated questionnaires. Nakashima et al. conducted a retrospective study of patients with AMI, identified 63 patients with SCAD, and obtained information about emotional stress and extreme physical activity from the medical records and, when necessary, a mailed questionnaire and telephone follow-up.[²⁷] They reported emotional stress in 18 (29%) patients (illness of a family member [n = 1]; argument [n = 3]; interrogation at a police station [n = 1]; excessive work [n = 8]; stress associated with raising children [n = 2]; panic attack [n = 1]; postoperative stress [n = 1]; and postearthquake stress [n = 1]).[²⁷]

Saw et al. in a combined retrospective and prospective study of 50 patients with nonatherosclerotic SCAD found that emotional stress was reported in 26.0% of cases before their MI.[²⁶] Saw et al. extended their study to include 48 patients who were retrospectively identified and 120 patients who were prospectively identified.[⁵] Patient data were obtained from a combination of patient interviews, hospital records, and patient-completed questionnaires.[⁵] Intense emotional stress was reported in 40.5% of patients preceding their SCAD event.[⁵]

Wager et al. sent a questionnaire to 409 women who reported that they had had SCAD.[²⁸] The limitations of that study were that “medical verification of SCAD diagnosis was not required for entry into this study,” and there was no control group.[²⁸] Stressful life events experienced 1 year and 2 weeks prior to the incident SCAD were endorsed. The most commonly cited stressful events in the 1 year before the event were “change in employment or responsibilities at work,” and the next three most frequently cited events were “change in health of a family member,” “intimate partner conflict,” and “death of a close family member or friend.”[²⁸] The most common source of stress in the 2 weeks prior to SCAD was “extreme or unusual physical exertion.” The next three most frequently cited events were “intimate partner conflict,” “change in employment status/responsibilities,” and “conflict with a close family member or friend.”[²⁸]

Subsequent studies used validated questionnaires to assess psychological stress. Smaardijk et al. obtained questionnaire data from 172 women with SCAD from a SCAD database in The Netherlands.[²⁹] The psychological assessment indicated high levels of perceived stress. The 10-item Perceived Stress Scale (PSS-10) was used to measure the severity of psychological distress in the past month, and a PSS-10 ≥14 was found in 50% of cases. Fatigue, assessed by the Fatigue Assessment Scale (FAS-10), was reported (FAS-10 ≥22) in 56% of cases, and a history of burnout was reported in 25% of cases. The prevalence of depression, assessed by depressive symptoms using the 9-item Patient Health Questionnaire (PHQ-9), was reported in 9%, and anxiety assessed by the 7-item Generalized Anxiety Disorder Questionnaire (GAD-7) was reported in 12% of cases. Type D personality was assessed using the Type D scale containing 7-item negative affectivity (NA) and social inhibition (SI) subscales. A cutoff of 10 (NA ≥10 and SI ≥10) was used to identify Type D and was present in 19% of cases.[²⁹] The time interval between the SCAD and the psychological assessment is not known. Because individuals were already in the database, it can be reasonably assumed that the questionnaires were completed a meaningful time after the SCAD event.[²⁹] Recall data are subject to considerable ambiguity.

Liang et al. administered questionnaires to 158 patients who survived a SCAD event using the PHQ-9 and the GAD-7, a mean 3.7 years after SCAD.[³⁰] One-third of patients had received treatment with medications or counseling for depression and 37% for anxiety.[³⁰] The long duration of time between the SCAD event and the assessment of psychological stress raises questions concerning the patients' memory of the event.

These studies, similar to the case reports, did not have a control group without SCAD to determine whether the association was a significant one. In addition, there was no consideration of the gradient of risk between SCAD and psychological stress, i.e., whether the occurrence of SCAD was increased with greater compared to lesser emotional stress.

STUDIES WITH A COMPARISON GROUP

Studies with a control group are more instructive. Adams et al. conducted a retrospective study and identified 22 patients with SCAD who were matched on a 1:3 basis with 66 acute coronary syndrome (ACS) patients selected from the local database of coronary angiograms admitted during the same timeframe.[³¹] The presence of anxiety, depression, or any other formally diagnosed psychiatric disorder (assessed as a composite variable of any psychiatric history) was quantified through medical records and detailed medical interviews.[³¹] The presence of anxiety, depression, or other neuropsychiatric illness among SCAD patients was significantly higher than in the ACS group (52.4% vs. 1.5%, P < 0.0001).[³¹] However, the presence of anxiety and depression in ACS was unusually low in that study and may have been due to the retrospective nature of the selection procedure.

Smaardijk et al. administered several standardized psychological tests to 172 patients with SCAD and 76 age- and sex-matched individuals with atherosclerosis-related ACS.[³²] Patients with SCAD were recruited from a Dutch SCAD database. The time interval between the SCAD and the psychological assessment is not known. Because individuals were already in the database, it can be reasonably assumed that the questionnaires were completed a meaningful length of time after the SCAD event. Online questionnaires and medical records were used to investigate psychological factors. Patients with SCAD were more likely to have experienced an emotional precipitant in the 24 h prior to the event (56%), compared with the ACS group (39%) (odds ratio [OR] =1.98, 95% confidence interval [CI], 1.14–3.44). The prevalence of other emotional precipitants, however, did not differ between groups.[³²] The prevalence of extreme or unusual emotional distress, moderate or severe depression, anxiety, or Type D personality was not significantly more common in patients with SCAD compared to the control group.[³²] Even after age matching, patients with a history of SCAD were significantly younger at the time of their event and were more often married, employed, had a higher education level and were more often on hormonal therapy compared to the ACS group.[³²] After adjustment for age, education level, physical inactivity, and gestational hypertension, the OR for reporting an emotional precipitant was 2.23 (95% CI, 1.12–4.44) times higher for SCAD compared to ACS.[³²]

Krittanawong et al. examined data from the United States (US) Nationwide Inpatient Sample collected from January 1, 2004 to September 30, 2015, and compared 66,360 patients diagnosed with SCAD to a control group who had ACS without SCAD.[¹⁰] The mean age was 63.1 years and 44.2% were women. A total of 3,415 (5.14%) had depression in the SCAD group, which was significantly lower than the control group who had ACS without SCAD. Anxiety was present in 0.96% and depression in 5.1%, which was significantly lower than the control group. Krittanawong et al. also examined the data from the Mount Sinai Health System's electronic medical records from January 1, 2008 to December 31, 2018, and compared 375 patients with acute coronary syndrome and SCAD with 30,500 patients with ACS but no SCAD.[³³] While self-reported emotional stress was significantly more (5.1% vs. 3.0%) in SCAD patients, there was no significant differences in reported anxiety (1.1% vs. 0.8%) or depression (8.5% vs. 6.6%) between the two groups.[³³]

Murugiah et al. compared patients with SCAD to patients with AMI.[³⁴] Using data from the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients study, which prospectively enrolled 3,572 AMI patients between 18 and 55 years of age in hospitals in the US, Spain, and Australia; they identified 67 SCAD cases.[³⁴] They administered the PHQ-9 and the PSS-14. The PSS-14 inquires about patients' feelings over the past month, with examples such as “in the last month, how often have you been upset because of something that happened unexpectedly?,” and “each item was scored as 0 for never and 4 for very often, with the overall score ranging from 0 to 56 (greater scores = greater stress).” As SCAD predominantly affects women, they conducted a sub-analysis comparing PHQ-9 and PSS-14 scores between women with SCAD and women with other types of AMI. Patients with SCAD had lower PHQ-9 scores (6.1 + 6.0 vs. 7.7 + 6.4) than patients with AMI, a small but significant difference (P = 0.03). Patients with SCAD had similar PSS-14 scores to patients with AMI. After adjustment for cardiovascular risk factors, comorbidities, and clinical acuity, no differences in PHQ-9 or PSS-14 scores remained between SCAD and AMI. Similar results were obtained in a subgroup analysis of only women with SCAD and AMI. They concluded that “patients with SCAD had a relatively lower burden of depression and perceived stress than other patients with AMI.”[³⁴]

Kok et al. examined the Mayo Clinic SCAD “Virtual” Multi-Center Registry and compared those with a history of migraine to those without migraine headaches and found a significantly higher rate of reported depression in those with migraine (27% vs. 17%).[⁷] As there was no control group without SCAD in this study, and patients with migraine represented a subset of patients with SCAD, it was not included in the analysis.

Combining the three clinical studies demonstrates that there was no excess perceived stress or depression in patients with SCAD compared to a control group [Figure 2]. There was considerable heterogeneity between the studies based on the results of one small study, which was at variance with the other two larger studies. Removing that study from the analysis, eliminated any heterogeneity that is the Cochrane Q and I² values were nonsignificant. The one large database study supports this conclusion.[³³]

All of these studies were retrospective, conducted after the SCAD event which limits the strength of the conclusions. However, the data support the contention that chronic stress is not associated with SCAD, but an acute emotional event may be a precipitator of SCAD.

While acute episodes of emotional stress can occur in patients with chronic anxiety, depression, and other common stress factors, the absence of a relationship between chronic perceived stress or depression and SCAD suggests that the chronic condition is not a predisposing factor for SCAD and focus should be on acute emotional stress. The linkage of these cardiac abnormalities to acute emotional stress provides a supportive basis for the suggestion that acute emotional stress might produce SCAD. However, there is considerable research that remains to be done. First, proof is necessary that the finding of the association of acute stress and SCAD does not represent an ascertainment bias, i.e., that individuals with acute emotional stress are more likely to be included in SCAD population by the nature of the presence of emotional stress. Second, a well-detailed biological basis/model for emotional stress and SCAD is necessary.

Limitations of proof of causality concepts for spontaneous coronary artery dissection

Studies of the role of psychological factors in the pathophysiology of SCAD are challenging. It would be unethical to induce SCAD in humans. There are no intermediate models, such as the presence of myocardial ischemia on exercise stress testing or myocardial imaging, that permit the evaluation of interventions on myocardial ischemia. There are no good animal models of SCAD which would permit experiments on the effect of stress. Prospective studies of persons with anxiety, depression, or PTSD and monitoring them for the development of SCAD would require very large populations considering the very low incidence of SCAD. An appropriate control group also needs to be similarly monitored. These kinds of studies are necessary in order to determine whether psychological factors or PTSD might be causally related to SCAD.

SPONTANEOUS CORONARY ARTERY DISSECTION AS A CAUSE OF MENTAL HEALTH ISSUES

Wager et al. evaluated a questionnaire they gave to 409 women who reported that they had SCAD. Participants experienced the SCAD event as highly stressful and frightening, and their heart health was reported to be a moderate-to-severe source of physiological stress.[²⁸] Thirty percent of persons with SCAD described the event as “scary,” followed by “surprising” (14%), “life changing” (12%), and “traumatic” (10%).[²⁸] In the study by Smaardijk et al., after an average of 3.2 years posthospitalization for the SCAD or ACS event, both patient groups had similarly high levels of perceived stress (50% vs. 45%, P = 0.471) and fatigue (56% vs. 53%, P = 0.643).[³²]

Johnson et al. utilized the Mayo Clinic SCAD database and sent individuals with SCAD a questionnaire – “the PTSD Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; PHQ-9; Generalized Anxiety Disorder-7; Anxiety Sensitivity Index; Connor-Davidson Resilience Scale; 36-Item Short-Form Health Survey; and a SCAD-specific questionnaire.”[³⁵] Among 782 patients contacted, 512 surveys were returned. Most respondents were women (97.5%). They found significant rates of PTSD, depression, and anxiety, which were associated with lower quality of life, especially among those with lower resiliency.[³⁵] Over 95% of patients found their symptoms of PTSD to be bothersome on a regular basis, with at least 86% finding their symptoms to be bothersome at least once weekly.

Edwards et al. studied a small sample of patients, and their conclusion was similar.[³⁶] Fourteen women with SCAD, mean age of 51 years, responded to standardized psychosocial questionnaires at a median of 35 months post-SCAD. PTSD was reported in 43% of cases. “Eight of the 11 women who reported having a mental health history (72.7%) indicated that their symptoms were related to having experienced SCAD.”[³⁶]

High rates of depression and anxiety are found in patients following MI,[³⁷] regardless of whether it is due to SCAD or coronary thrombosis. Johnson et al. suggested that the prevalence of anxiety and depression in their cohort was similar to the published prevalence of these conditions in patients after MI.[³⁵]

Depression and anxiety after MI can be associated with a worse outcome.[³⁸] These findings have led to the integration of psychosocial services within cardiac rehabilitation programs, and specific programs have been tailored to patients with SCAD.[³⁹]

CONCLUSION

The evidence to date suggests that chronic psychological stress, anxiety, or depression is not associated with SCAD. This finding is different from the relationship of chronic psychological factors and atherosclerotic coronary artery disease.[⁴⁰] The data for this conclusion on SCAD, however, are based on retrospective evaluation of patients with SCAD compared to individuals with comparable conditions. In order to satisfy the rigorous criteria for causality, prospective studies are necessary. These studies would be challenging to conduct because of the low incidence of SCAD in the population. Until those kinds of studies are performed, current studies support the contention that there is no relationship between chronic psychological stress, anxiety, or depression and SCAD. Acute emotional stress may be a factor related to SCAD because some patients report a severe emotional event immediately before their SCAD. More importantly, a study with a control group found that patients with SCAD were almost twice as likely to have experienced an emotional precipitant in the 24 h prior to the event compared with patients with ACS. These findings must be tempered by the high frequency of acute emotional stress and the low incidence of SCAD. Further research is needed to provide mechanistic data on the pathophysiology of SCAD in relation to acute psychological distress. It is important to recognize that clinical events such as SCAD can potentially have a significant impact on psychological well-being.

Ethical statement

The ethical statement is not applicable for this article.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Simon W. Rabkin is an Editorial Board Member of Heart and Mind. The article was subject to the journal's standard procedures, with peer review handled independently of Dr. Simon W. Rabkin and their research groups. There are no conflicts of interest.

REFERENCES