Spontaneous coronary artery dissection in patients with prior psychophysical stress: a systematic review of case reports and case series

Spontaneous coronary artery dissection (SCAD) is becoming an increasingly recognized etiology of acute coronary syndrome (ACS), cardiac arrest, and sudden cardiac death [1]. SCAD is characterized by a non-atherosclerotic, non-iatrogenic, and non-traumatic spontaneous tear in coronary arteries, which leads to a collapsed arterial lumen (true lumen) due to the formation of an intramural hematoma (IMH) (false lumen), resulting in compromised coronary blood flow and myocardial infarction (MI) [2].

SCAD is responsible for 1–4% of ACS cases in the general population but is estimated to affect as many as 35% of women under 50 [3]. It is one of the leading causes of pregnancy-associated myocardial infarction (PAMI) [4]. Nevertheless, owing to its underdiagnosis and misdiagnosis with atherosclerotic ACS, its actual prevalence is higher than previously reported [5]. Despite this, the etiology of SCAD remains uncertain. There is increasing interest in discovering the main risk factors and triggers behind its pathogenesis. The current knowledge of SCAD has mainly remained limited to single-center case reports and case series data, with only a handful of large-scale cohorts and no randomized clinical trials investigating its pathogenesis, management, and prognosis [6‐9]. Thus, exploring case reports and case series regarding SCAD could provide helpful information regarding disease characteristics and management. In addition, case reports and case series can provide insight into uncommon conditions that may be challenging for practitioners to diagnose and treat, offering guidance on how to manage these conditions.

Previous studies have suggested a minor role of traditional cardiovascular risk factors, except hypertension, in SCAD occurrence [2]. Some factors that are believed to contribute to SCAD pathogenesis potentially include underlying arteriopathies (such as fibromuscular dysplasia (FMD)), female sex, pregnancy/other hormonal changes, systemic inflammatory conditions, and connective tissue disorders [10]. One important predisposing factor includes psychophysical stress, and its role in SCAD has been introduced as a research priority and a key question by the American Heart Association [2]. More than half of the patients afflicted with SCAD had experienced emotional (including the demise of a family member or marriage and workplace-related issues) or physical stress (including extreme aerobic or anaerobic physical activities, lifting heavy objects, intense Valsalva or coughing) preceding the presentation. The stress experienced by women was predominantly emotional, while that experienced by men was primarily physical [2, 11].

In light of this information, despite the large existing cohorts of SCAD patients, we included only case series and case reports of SCAD patients because more detailed information is available in these types of studies. This systematic review aimed to exclusively evaluate the characteristics and management of patients experiencing SCAD following psychophysical stress.

In this systematic review, we studied SCAD patients in whom emotional or physical stress was known as a possible trigger of SCAD. Here, we aimed to compare our findings with the overall data about SCAD from previous studies.

It is hypothesized that a combination of predisposing factors leads to higher susceptibility to having a SCAD event following a trigger. Female sex, pregnancy, physical or emotional stress, and FMD are among the known risk factors proposed by a large number of studies and are more likely to have underlying roles in its pathophysiology. The suggested hypothesis proposes that during physical or emotional stress a sudden catecholamine surge can cause an increase in arterial shear stress and lead to a stress tear of the vasa vasorum [11]. However, this mechanism has not been fully investigated. A similar mechanism has been proposed in other stress-related cardiovascular conditions such as Takotsubo syndrome [11, 108]. Endothelial dysfunction, the initial stage of atherosclerosis, is independently linked to cardiovascular events. Even individuals with few traditional risk factors but with peripheral endothelial dysfunction are at higher risk. Studies have shown mental stress impacts endothelial function, leading to oxidative stress and inflammation, which increase cardiovascular risk [109]. This suggests that the endothelium plays a critical role in translating the physiological effects of mental stress into measurable cardiovascular risk. Additionally, study of Martin et al. [110] showed that individuals with a history of apical ballooning syndrome exhibit abnormal microvascular function when stressed, leading to excessive blood vessel constriction and impaired dilation afterward. Further study revealed impaired responses to acetylcholine in the coronary arteries during mental stress, while responses to nitroglycerin remain intact, indicating endothelial dysfunction [111].

SCAD tends to predominantly affect young or middle-aged women, most often in the peripartum period [2]; surprisingly, in our study, 41.9% of reported stress-related SCAD occurred in men. This discrepancy might be potentially due to the exclusion of pregnancy-associated SCAD in our methods. In our study, the mean age of female patients was significantly higher than that of males likely due in part to excluding women in the peripartum period in the study methodology. However, a study has also reported this age difference [112]. Consistent with the results of other studies [112, 113], we found that SCAD patients whose attacks were precipitated by emotional stress were predominantly women, while physical stressors were reported more frequently in men. The study of Jaskanwal et al. [114] examined a large group of patients with chest pain and nonobstructive CAD. It found that individuals with anxiety disorders, especially women, were more likely to have coronary endothelial dysfunction. This association persisted even after adjusting for traditional cardiovascular risk factors and medication use. The findings suggest that anxiety disorders may contribute to the development of coronary endothelial dysfunction, particularly in women [114]. We witnessed that the presence of coronary artery disease risk factors was consistent with other studies [11, 112, 113, 115‐118], wherein hypertension was the most common cardiovascular risk factor reported, and other classic risk factors for MI were not common.

Presently, SCAD patients are routinely screened for FMD due to a strong association, with FMD predicting major adverse cardiovascular events (MACEs) [2, 119]. In the study of Fahmy et al., approximately one-half of the male patients with SCAD had concomitant FMD [112], whereas in our study, all of the FMD cases were women. Takotsubo syndrome and SCAD share key characteristics, prompting questions about a common pathophysiology [120]. Moreover, some articles have proposed a chicken or egg causality between SCAD and Takotsubo syndrome [120]. Recent research indicates that individuals diagnosed with Takotsubo syndrome tend to be older and have a higher prevalence of specific cardiovascular risk factors when compared to those with SCAD. Additionally, Takotsubo syndrome patients, despite their older age and greater cardiovascular risk factors, exhibit lower occurrences of depressive disorder or emotional triggers than SCAD patients [121, 122]. Remarkably individuals with Takotsubo syndrome have a poorer prognosis in terms of in-hospital, mid-term, and long-term outcomes, with higher noncardiac mortality rates compared to SCAD patients [121, 122]. However, it is worth noting that in propensity score-matched cohorts of middle-aged women, SCAD diagnosis resulted in worse long-term outcomes compared to Takotsubo syndrome, primarily due to an elevated risk of cardiac-related rehospitalization [123]. Accordingly, in our study, four patients with stress-related SCAD had concomitant Takotsubo syndrome, and one was initially misdiagnosed with Takotsubo syndrome.

Regarding the clinical manifestations, some studies have reported non-ST elevation myocardial infarction (NSTEMI) as the most common presentation of SCAD [124, 125], but ST elevation myocardial infarction (STEMI) has been more prevalent in SCAD patients in other studies [112, 126]. Similarly, in our selected cases, ST elevation was the most common ECG finding. Additionally, some patients had arrhythmias, cardiogenic shock, cardiac tamponade, and cardiac arrest. These presentations were also reported in previous studies [127].

Coronary angiography has remains the diagnostic gold standard for SCAD [128], yet instances of misdiagnosis (12.4% in this study) emphasize its limitations. Intracoronary imaging (IVUS or OCT) in SCAD poses potential risks, complicating the decision on their application in diagnosis or treatment alongside PCI [129, 130]. Intracoronary imaging can be helpful for diagnostic confirmation of doubtful cases, especially type 3 SCAD [130]. In our study, seven patients had multivessel SCAD. Although one study stated that clinical outcomes and long-term follow-up were similar between single-vessel and multivessel SCAD, the stroke rate was significantly higher in patients with multivessel SCAD [131]. Overall, LAD is reported as the most frequently involved artery in SCAD [8, 125], which was also true in our study. Saw et al. reported type 2 SCAD as the most prevalent angiographic appearance of SCAD [125]. Similarly, the most common type of SCAD in stress-related cases was type 2, accounting for 64.7% of the cases in whom the SCAD type was reported.

Medical management versus revascularization in SCAD patients depends on hemodynamic stability and their thrombolysis in myocardial infarction (TIMI) flow grade found on angiography [132]. Prior meta-analyses indicated that conservative management of SCAD had similar outcomes comparing to the invasive management [133, 134], but in our study, less than one-half of the patients received medical management. It is worth noting that PCI in SCAD patients is technically challenging, given that it can lead to a propagation of dissection and cutoff of coronary flow, putting patients at a higher risk for ischemia and myocardial damage. Despite large cohorts in which SCAD patients are more managed conservatively [119], we witnessed conservative and revascularization strategies used in approximately equal numbers of patients. Therefore, this raises the question of whether this is either a bias of smaller case reports/series or whether patients with a predisposing psychosocial trigger have a slightly more severe phenotype at presentation. Studies have revealed that performing PCI in SCAD patients is challenging, and its success rate is lower than that of PCI in atherosclerotic disease [9, 127].

The incidence of early post discharge readmission following MI and SCAD is considerable. Most readmissions are because of cardiac causes [135]. Recurrence in SCAD occurs more frequently than recurrence in atherosclerotic MI [8, 136]. In our study, 16 patients experienced recurrent SCAD during a median follow-up of 2 months. This observation is consistent with prior literature [137], highlighting the importance of rigorous follow-up in the early post-SCAD period. In a large cohort of SCAD patients with low vascularization rates and high medical management, the recurrence rate was low [119]. However, in our selected SCAD cases, 18 out of 22 recurrences were in individuals who received medical therapy. This discrepancy might be due to the small size of the study population, different demographics, or probably better aggressive treatment results. Investigating the reasons behind this and finding susceptible patients is of utmost importance to reduce the associated morbidity and mortality and prevent unnecessary interventions and hospitalizations. In a meta-analysis by Gerald et al. [138], hypertension and FMD were major stressors for recurrence. In our series, stress-related SCAD recurrences were associated with neither arterial hypertension nor FMD. Additionally, Ehlers–Danlos syndrome, ADPKD, and Loeys–Dietz syndrome were present in patients with SCAD recurrence.

There were some limitations in our study. To evaluate detailed information of each individual, we included only case reports and case series. We excluded other observational studies due to insufficient data on each individual, although they had larger populations. This is considered as the major limitation of the present study. Additionally, it should be noted that having heterogeneous follow-up durations could impact data consistency and analysis in our study and we were unable to provide a complete and comprehensive evaluation of follow-up events.

In the present systematic review of case reports and case series, we described the stress type, clinical features, and angiographic findings of SCAD in patients with prior psychophysical stress (see Fig. 2). While physical stress seems to precede SCAD in most cases, emotional stress is implicated in females more than males. Further studies are needed to confirm these findings.