The highest percentage of SCAD patients (approximately 90%) are perimenopausal women. The predominance of females among SCAD patients and its high prevalence in pregnancy suggest that sex hormones play a significant role in the pathophysiology of this condition. The precise mechanisms of this pathophysiology association are still undetermined. Female sex hormones have an impact on arterial connective tissue and microvasculature. The obtained results suggest that the risk factors for SCAD in pregnancy (P-SCAD) include having more than one pregnancy, using sex hormones for in vitro fertilization (IVF), and having pre-eclampsia (6, 10).

Most events are reported during the last trimester and during the first week of the postpartum period. SCAD may occur even in the late postpartum (6–12 months) period, and it is linked with breastfeeding (10). A comprehensive study conducted in Canada between 2008 and 2012 revealed a higher incidence of P-SCAD compared with the data from prior studies (1.8 cases per 100,000 pregnancies). In the same study, P-SCAD patients exhibited worse prognosis than SCAD females who were not pregnant (NP-SCAD) having more frequently STEMI (64%), cardiogenic shock (24%), cardiac arrest (14%), and death (4.5%). P-SCAD patients exhibited a higher incidence of proximal coronary artery dissection and a significantly decreased left ventricle ejection fraction (LVEF) of ≤35%. This data regarding the poor prognosis in P-SCAD compared with NP-SCAD patients was confirmed in another American study (10).

Patients with P-SCAD compared with NP-SCAD had a higher prevalence of black ethnicity, older, with a history of arterial hypertension and hyperlipidemia, more often had depression, migraines, and more frequently were treated for infertility (1).

The hormonal and hemodynamic changes that occur during pregnancy, along with the increased shear stress on the coronary arteries, may contribute in developing SCAD. Within the initial 6 weeks of pregnancy, hemodynamics starts to change, including an increase in blood volume and in red blood cell mass while systemic vascular resistance is decreasing, and consequently, the cardiac output is higher. These changes are expected, but they increase the oxygen demands of the myocardium and could lead to developing SCAD. As previously stated, the highest incidence of P-SCAD was observed in the first month after childbirth, with the peak of incidence observed within the first postpartum week. During this period, there is another rapid increase in cardiac output due to the fast return of blood from the contracted uterus. Progesterone and estrogen have the highest levels during this period, which could be important since the endothelium has the sex hormone receptors. Estrogen induces the release of nitric oxide, resulting in vasodilatation, but it also influences the function of matrix metalloproteinases, which degrades the components of the artery wall and therefore contributes to SCAD (2–6). SCAD was also reported during lactation when oxytocin is released, which affects vasculature. Importantly, one of the metabolic products of oxytocin degradation is cardiotoxic and is found to be responsible for the occurrence of peripartum cardiomyopathy. This could also be important for the pathophysiology of SCAD (2–6).

The use of oral estrogen and progesterone were linked to an increased risk of developing SCAD in few reports (one single-center study with case reports) (13). Estrogen replacement therapy has known effects on coagulation, microcirculation, increased release of reactive oxygen species, and triggering arrhythmias, all of which may potentially be associated with SCAD (13). However, in a study conducted by Saw et al. (14) on a group of 168 females with SCAD, no association was found between the active use of oral combined hormone therapy and the incidence of SCAD.

There is limited data available regarding SCAD occurrence after in vitro fertilization. In the United States, 9% of patients with P-SCAD underwent IVF. Women with P-SCAD more frequently underwent IVF treatment compared with women in childbearing age in the US population (28% vs. 12%) (15, 16). In this process, patients are administered gonadotropin therapy together with selective estrogen modulators and aromatase inhibitors to stimulate the production of follicles that secrete high levels of estrogen and progesterone. As previously mentioned, these hormones could cause weakening and vascular wall rupture. Clomiphene is the most frequently used selective estrogen receptor modulator in IVF, and previously, it has been linked with different pathological conditions such as MI and potentially with SCAD (16).

The role of estrogen and progesterone levels or their fluctuations in SCAD occurrence is unclear. A limited number of studies have explored SCAD development during menstruation, hormone replacement therapy, and in women undergoing or having undergone IVF treatment (17).

One hypotheses explaining the gender difference in SCAD is the various responses to androgens in the cardiovascular system and other organs. The X chromosome contains genes responsible for the expression of androgen receptors. In females, the different response to androgens is the result of autosomal mosaicism. It is known that estrogens are synthetized from androgen precursors, catalyzed by aromatase. Furthermore, women frequently exhibit specific coronary anatomy characterized by tortuous coronary vessels and a predisposition to microvascular dysfunction as a consequence of increased metalloprotease activity induced by estrogens (13).

Connective tissue disorders, such as Marfan syndrome, Ehlers–Danlos syndrome type 4, and Loeys–Dietz syndromes, as well as polycystic kidney disease, are found in <5% of patients with SCAD (18, 19). The diagnosis of these conditions is important as it can guide familial screening and careful follow-up of affected patients (19).

Patients with SCAD in whom arterial imaging for extra-coronary vascular abnormalities was performed frequently exhibited fibromuscular dysplasia (18). The DISCO study is the first European multicenter analysis of SCAD patients and one of the largest studies in the world. The prevalence of FMD in this large cohort of SCAD patients was found to be 45% (20).

Marfan syndrome is caused by mutations in the fibrillin-1 gene (FBN1), and, among other abnormalities, patients with this syndrome exhibit dilatation of the aortic sinus with an increased risk of type A aortic dissection. There is a limited number of case reports in the literature regarding SCAD in patients with Marfan syndrome, and these reports suggest that the association between these entities lies in the structural changes in the connective tissue of the artery wall, which predispose to vessel dissection (2, 21).

In vascular Ehlers–Danlos syndrome, mainly middle-sized muscular arteries are affected, namely, mutations in the alpha 1 gene (COL3A1) are the cause of this syndrome. Collagen type III synthesis is disrupted, and consequently, patients are at risk for vascular rupture. SCAD has been reported to be associated with this syndrome in a limited number of case reports (2, 22).

Loeys–Dietz syndrome is caused by mutations in genes encoding compounds involved in the TGF-beta signaling pathway. Patients with this syndrome have tortuous arteries and arterial aneurysms with a high risk of arterial dissection or rupture. The risk remains high even in arteries that have normal diameters (2, 23).

Autosomal dominant polycystic kidney disease (ADPKD) was associated with SCAD in a few case reports. Patients with ADPKD have mutations in the polycystic kidney disease-1 and 2 genes that encode the polycystin synthesis. Polycystin is important for the integrity of the vascular wall, and its absence leads to vascular wall rupture and hemorrhage (2, 13).

Fibromuscular dysplasia is the most frequently associated with SCAD in the literature. However, the most frequent clinical presentation of this arteriopathy is renovascular hypertension. The association with SCAD was first reported in 2011 by Saw et al. This is a disease of medium-sized artery walls that is not caused by atherosclerosis or inflammation. The highest incidence is found in middle-aged women who do not have many traditional risk factors. FMD is characterized by changes in the arteries, such as stenosis and aneurysms, which make arteries susceptible to dissection. The renal, cervico-cephalic, and visceral arteries are commonly involved (2, 10).

Angiographically, FMD has two types: multifocal, which is predominant, and unifocal. Between 41% and 86% of SCAD patients experience changes in other vascular beds, with the majority of them exhibiting changes in two or more extra-coronary vascular beds (29%–70%). The possible clinical manifestations of cervico-cephalic FMD could be ischemic stroke or subarachnoid bleeding due to arterial dissection or intra-cerebral aneurysm (2). Canadian authors reported the presence of cerebral aneurysm in 7.1% of SCAD patients (24).

In the American registry for FMD, the frequency of SCAD was less than 3%. Furthermore, in one large study with more than 60,000 ACS patients, it has been shown that 0.16% of cases caused by SCAD were linked with FMD. Even SLE, a specific systemic inflammatory disease, had a higher association rate with SCAD (13, 25, 26).

PHACTR1/EDN1 is a genetic locus on chromosome 6q24 which carries the risk for coronary artery disease and AMI (27). This gene is also associated with migraine and cervicocerebral artery dissection (CeAD) (28). The putative variant of the PHACTR1 locus was found near a putative regulatory genetic region for EDN1, the endothelin (ET)-1 gene. This putative PHACRT1 variant relates to the risk of FMD. Interestingly the rs9349379-A allele is linked with a higher risk for FMD, CeAD, and migraine, whereas the less common allele, rs9349379-G, is linked with an increased risk for atherosclerosis. Firstly, the determined genetic risk locus for SCAD is rs9349379. The link between SCAD and FMD was determined even on the genetic level. Gupta et al. found that the rs9349379-A allele is found more frequently in patients with lower levels of circulating ET-1 than in healthy population. Endothelin-1 is a potent vasoconstrictor, and its vascular effects could have an important role in the pathophysiology of SACD. Whether the ET-1 expression decreased in SCAD and FMD is still to be determined (7, 29, 30, 31).

In the literature, SCAD was closely linked with the systemic inflammatory conditions, and the highest incidence was reported in one Canadian series (in 8.9% of cases). However, the mechanistic link between those two pathological conditions is still unknown. Since 1982, SCAD has been associated with inflammatory processes. This connection was initially observed when arterial biopsies revealed a focal infiltration of the tunica adventitia with inflammatory cells, predominantly eosinophils (5). Hypothetically, they could release lytic enzymes, causing dissection (30, 31).

Common systemic inflammatory disorders associated with SCAD include systemic lupus erythematosus (SLE), rheumatoid arthritis, celiac disease, Crohn's disease, and ulcerative colitis (19). A sub-analysis of the Framingham offspring study reported that women with SLE have a 50-fold increased risk of MI compared with age-matched control. Having said that, only several case reports documenting the occurrence of SCAD in SLE patients were published. SCAD can be the first manifestation of SLE, and therefore, screening for this disease is prudent in these patients (2, 19). In the literature, we found different inflammatory diseases in patients with SCAD such as sarcoidosis and infective hepatitis. Polyarteritis nodosa with pathological changes in small- and medium-sized arteries has also been associated with SCAD (2, 32–34). In these case reports or case series, coronary vasculitis or systemic inflammation may explain the increased risk for SCAD. In the larger cohort studies, a rather small percentage of patients had inflammatory conditions or short-term increases in inflammatory markers. This systemic inflammatory disease could only be a coincidental finding (1). The authors did not find a connection between SCAD and vasculitis in systemic arteries in the conducted studies. Coronary arteritis is a rare pathological condition, and it is characterized by the stenosis or occlusion of the proximal parts of arteries accompanied by skip lesions or aneurysms. This finding is not characteristic of SCAD (31).

Recently, a case report of SCAD in COVID-19-infected patient was published. It is known that COVID-19 is inducing a marked inflammatory and immune response which can damage endothelial and smooth muscle cells in blood vessels. Theoretically, the inflammatory response induced by the infection could promote the fragility of coronary vessels and lead to SCAD (35).

Patients with autoimmune disorders have an increased risk for SCAD (1). The frequency of autoimmune diseases in SCAD patients is comparable with the frequency in the general population (approximately 9%) (36). A recent study using population-based data from the Rochester Epidemiology Project showed that patients with autoimmune diseases did not have an increased risk for SCAD (31).

In SCAD cohort studies, the reported prevalence rate of migraine ranged from 37% to 46%, contrasting with a lifetime migraine prevalence rate of 24% in women from the Women's Ischemia Syndrome Evaluation (WISE) cohort in the United States. Female SCAD patients have an estimated 37% higher age-adjusted 1-year migraine prevalence rate, as reported (37). Migraine is characterized by headache, typically unilateral in location, accompanied by nausea/vomiting and sensitivity to loud sounds and lights (38). Studies showed that endothelial dysfunction in migraines could be involved in developing stroke and in the pathogenesis of cervical artery dissection. It is postulated that a similar association could be present in SCAD. In a study conducted by the Mayo Clinic research group found that migraines were highly prevalent among the female population with SCAD, as previously reported. The same researchers found that migraineurs with SCAD were younger with more prevalent arterial abnormalities. They more frequently complained of chest pain and depression. In a large US national cohort study with 66,360 SCAD patients, only 0.8% of patients had migraine (13).

Patients with SCAD had a higher prevalence of hypothyroidism when compared with individuals with atherosclerosis who develop ACS. Among SCAD patients with hypothyroidism, there was a higher incidence among women, and they exhibited frequent dissection in the distal segments of coronary arteries as well as dissections in the corkscrew arteries. Therefore, they were more often treated conservatively. Thyroid hormones have a significant role in the heart and blood vessels. Hypothyroidism is accompanied by conduction disturbances, different types of arrhythmias, rapid atherogenesis, and coronary artery disease. The results from studies conducted on a small number of patients indicate that hypothyroidism may somehow be involved in SCAD pathophysiology. In those patients, even iatrogenic coronary artery dissection is more frequent (39). Also, Spanish authors found a high percentage of autoimmune thyroid dysfunction in the population with SCAD (40).

In ≤5% of SCAD cases, we found hereditary arteriopathies and connective tissue disorders (18). However, Goel et al. (41) published a case series with five pairs of relatives with angiographically confirmed SCAD.

Several studies investigating the susceptibility genes for SCAD were published in 2018 and 2019. The genes associated with the risk for SCAD were the F11R (the gene responsible for F11 receptor which is a regulator of tight junction assembly), TLN1 ( the gene encoding Talin 1 which is responsible for linking the actin cytoskeleton to the extracellular matrix), TSR1 (the gene which influences ribosome maturation factor and RNA formation), already mentioned PHACTR1 (the gene important for cytoskeleton actine), and EDN1 (encoding endothelin 1 which is a circulating vasoactive peptide) (17).

Recently, Adlam et al. performed a meta-analysis of genome-wide association studies (GWAS) with approximately 2,000 patients with SCAD. The authors reported 17 risk genes and therefore polygenic inheritance for this disease. The genetics for atherosclerosis and SCAD showed some overlaps but in opposite directions. The genetic association was again confirmed for SCAD and FMD, but also for migraine and SCAD. Among the so-called new genes for SCAD, those associated with arterial hypertension gained more attention. It seems that there is a genetic link between arterial hypertension and the risk for developing SCAD. Strict control of arterial blood pressure could be pivotal in decreasing the risk of SCAD recurrence (42–44).

Published genetic data do not explain the female dominance demonstrated in this condition. This could be due to autosomal genes that have sex-related regulators (genes with estrogen-responsive structures) (17). Genetic testing for SCAD is not a standard practice, but it may be considered in situations where connective tissue diseases are suspected, as mentioned previously (18).

Patients with SCAD have less percentage of the traditional cardiovascular risk factors for ischemic heart disease. New publications indicate that those patients could have traditional factors as well. In majority of them, hypertension, smoking, and dyslipidemia have been reported. However, no causal relationship has been found thus far (10, 18). According to a recently published study, SCAD patients exhibit arterial hypertension in approximately 37% of cases, while 35% have hyperlipidemia, which is almost identical as those observed in the population without SCAD (17, 45). Reasonably, those traditional risk factors for coronary artery disease are more common findings in older SCAD patients (10). It was reported that in a population involving over 600 SCAD patients, diabetes mellitus was identified in 0.9%–4.6% of cases, while smoking habits were observed in 0.6%–10% of patients. Consistent with earlier findings, hypertension was prevalent in 27%–36% of patients. Notably, obesity was not present in this population (46).

Arterial hypertension is highly prevalent in the general population. Also, high arterial systolic pressure and pulsatory pressure could cause SCAD by increasing the shear stress on the vessels. Notably, some psychosocial factors that are present predominantly in females could indirectly act by increasing the risk for hypertension, smoking, or abdominal obesity and therefore the risk for SCAD (46, 47).

In younger women, fat deposits primarily accumulates in the subcutaneous tissue, while in menopausal women, fat is starting to accumulate in visceral depots which is characteristic for men. In this way, the metabolic risk is increasing. Hormone replacement therapy with estrogen seems to recover the endothelial function in postmenopausal women (48). Visceral fat is an endocrine organ that releases adipokines and influences many metabolic pathways. Perivascular adipose tissue has effects on the development of atherosclerosis through inflammatory mechanisms, and it is also believed to play a significant role in SCAD development (49).

The so-called mechanical stressors such as intense Valsalva-like maneuvers and factors that provoke coronary spasm have been reported in SCAD. In a recently published prospective studies with SCAD patients, the males in 11.9% of cases experienced chest pain immediately after isometric or intense physical activity (10). This physical stressor could induce a rise in catecholamine levels and a further increase in coronary artery shear stress, resulting to SCAD (18). Interestingly, the authors found retrograde SCAD on the coronary angiograms in Takotsubo syndrome associated with this type of stress (9). Sympathomimetic drugs such as amphetamines and cocaine have probably the same pathophysiology mechanisms in developing SCAD (15). The use of anabolic steroids, which could lead to the weakness of the arterial medial wall, in combination with intense physical activity (lifting weights) was reported in one case report as the cause of SCAD in a male patient (50). These substances enhance blood coagulability by reducing the production of plasminogen activator and influencing platelet function as well (51).

Preceding emotional stress has been described in a significant percentage of SCAD cases, particularly in women (10). Emotional distress, 24 h before ACS, was significantly more frequent in the SCAD group, but not in patients with type 1 MI. A high percentage of SCAD patients, 41%–55% in some published papers, have reported experiencing some kind of uncommon psychological stress prior to the occurrence of the event (3, 10).

It was reported that 40.5% of participants from a large prospective cohort study had some level of emotional stress followed by ACS, and 24% of patients were involved in physical activity, of whom 12.5% were engaged in isometric exercise. A smaller number of patients reported minor activities prior to SCAD such as severe coughing or vomiting. More recent studies reported that females with concomitant FMD and psychological stressors were at risk for SCAD. On the other part, men without FMD and physical stressors were at high risk for developing SCAD (13).

The results from a large Canadian study showed that men with SCAD were younger than females and that they more frequently had some physical but not psychological stressor preceding the ACS caused by SCAD (10). As mentioned, women with SCAD had a higher self-reported prevalence of anxiety and depression. Psychiatric disorders are known risk factors for bad prognosis and are linked with adverse cardiovascular events. There is a theory that women are more prone to psychological stressors which can lead to a rise in coronary artery shear stress and SCAD (12).