key: cord-0995717-2eo4x06y
authors: Shojaei, Fahimehalsadat; Habibi, Zahra; Goudarzi, Sogand; Firouzabadi, Fatemeh Dehghani; Montazerin, Sahar Memar; Najafi, Homa; Kahe, Farima; Momenzadeh, Kaveh; Mir, Mahshid; Khan, Faris; Jamil, Umer; Jamil, Adeel; Lee, Jane J.; Chi, Gerald
title: COVID-19: A double threat to takotsubo cardiomyopathy and spontaneous coronary artery dissection?
date: 2020-11-22
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110410
sha: 2d01c643e42ebf77ffa062922839ceb01bf547d2
doc_id: 995717
cord_uid: 2eo4x06y

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic that has affected millions of individuals worldwide. Prior studies suggest that COVID-19 may be associated with an increased risk for various cardiovascular disorders, such as myocardial injury, arrhythmia, acute coronary syndrome, and venous thromboembolism. Early reports of non-COVID-19 patients have described the concurrence of takotsubo cardiomyopathy (TTC) and spontaneous coronary artery dissection (SCAD). However, the interplay between COVID-19, TTC and SCAD has not been well established. We herein propose two sets of two-hit hypotheses for the development of SCAD and TTC in the context of COVID-19. The first two-hit hypothesis explains the development of SCAD, in which TTC-associated formation of vulnerable coronary substrate serves as the first hit (predisposing factor), and COVID-19-associated inflammation and vascular disruption serves as the second hit (precipitating factor). Conversely, another two-hit hypothesis is proposed to explain the development of TTC, in which SCAD-associated formation of vulnerable myocardial substrate serves as the first hit, and COVID-19-associated sympathetic overactivity serves as the second hit. Under this conceptual framework, COVID-19 poses a double threat for the development of SCAD (among patients with underlying TTC) as well as TTC (among patients with underlying SCAD), thereby forming a reciprocal causation. This hypothesis provides a rationale for the joint assessment of TTC and SCAD in COVID-19 patients with pertinent cardiovascular manifestations.

Coronavirus disease 2019 (COVID- 19) is an ongoing pandemic that has affected millions of individuals worldwide. Prior studies suggest that COVID-19 may be associated with an increased risk for various cardiovascular disorders, such as myocardial injury, arrhythmia, acute coronary syndrome, and venous thromboembolism. Early reports of non-COVID-19 patients have described the concurrence of takotsubo cardiomyopathy (TTC) and spontaneous coronary artery dissection (SCAD). However, the interplay between COVID-19, TTC and SCAD has not been well established. We herein propose two sets of two-hit hypotheses for the development of SCAD and TTC in the context of COVID-19. The first two-hit hypothesis explains the development of SCAD, in which TTC-associated formation of vulnerable coronary substrate serves as the first hit (predisposing factor), and COVID-19-associated inflammation and vascular disruption serves as the second hit (precipitating factor). Conversely, another two-hit hypothesis is proposed to explain the development of TTC, in which SCAD-associated formation of vulnerable myocardial substrate serves as the first hit, and COVID-19-associated sympathetic overactivity serves as the second hit. Under this conceptual framework, COVID-19 poses a double threat for the development of SCAD (among patients with underlying TTC) as well as TTC (among patients with underlying SCAD), thereby forming a reciprocal causation. This hypothesis provides a rationale for the joint assessment of TTC and SCAD in COVID-19 patients with pertinent cardiovascular manifestations. COVID-19 is associated with significant morbidity and mortality, mostly due to pulmonary and cardiovascular complications. Preliminary reports have described the occurrence of takotsubo cardiomyopathy (TTC) and spontaneous coronary artery dissection (SCAD) in COVID-19 patients.

However, it remains unclear whether COVID-19 patients are predisposed to TTC or SCAD.

The pathogenesis of TTC has been considered to be mediated by catecholamine excess. In a normal physiological condition, β2-adrenergic receptor activation by epinephrine leads to a positive inotropic response via the G s protein-adenylyl cyclase-protein kinase A pathway. In contrast, at supraphysiological epinephrine levels, a process termed stimulus trafficking takes place, in which stimulation of β2 adrenergic receptor is switched from G s protein to G i protein signaling, resulting in a negative inotropic effect (1) . Thus, the manifestation of apical hypokinesis in TTC develops due to a higher density of β2-adrenergic receptor at the apical myocardium than the basal myocardium. With respect to SCAD, two possible mechanisms have been proposed. The first is the "inside-out" model, where the intimal tear allows blood to cross the internal elastic lamina and accumulate in the tunica media. The second is the "outside-in" model, where disruption of vasa vasorum results in hemorrhage into the tunica media. In both models, there is the formation of false lumen filled with intramural hematoma and subsequent compression of the true lumen (2, 3) . Intriguingly, both TTC and SCAD affect predominantly women and may be precipitated by emotional stress or strenuous exercise associated with sympathetic discharge.

Numerous reports of non-COVID-19 patients have described the concurrence of TTC and SCAD, suggesting a potential reciprocal causal association between TTC and SCAD. This article discusses the speculative interplay between TTC and SCAD in the context of COVID-19.

As illustrated in Figure 1 , we propose that the development of SCAD or TTC could be explained by a two-hit hypothesis, in which the first hit represents the predisposing factor and the second hit represents the precipitating factor. It is speculated that formation of an anatomical substrate (such as vulnerable coronary artery or vulnerable myocardium) is a prerequisite for the subsequent development of SCAD or TTC, and the propensity of disease manifestation is increased by COVID-19. The anatomical coronary substrate is defined as the coronary artery wall tissue with altered structural properties characterized by inflammatory reactions (e.g., eosinophilic infiltrates) in the adventitia that predispose the coronary artery to dissection. The anatomical myocardium substrate is defined as the myocardial tissue with altered structural properties characterized by ischemia-related reactions that predispose the myocardium to wall motion abnormalities. For the development of SCAD, TTC-associated formation of vulnerable coronary substrate (due to increased shear stress and vasospasm) serves as the first hit, and COVID-19associated inflammatory cells infiltration and vasa vasorum disruption serve as the second hit ( Figure 1, Panel A) . Conversely, for the development of TTC, SCAD-associated formation of vulnerable myocardial substrate (due to post-ischemic myocardial stunning) serves as the first hit, and COVID-19-associated sympathetic overactivity serves as the second hit (Figure 1, Panel B) .

Under this conceptual framework, COVID-19 could pose a double threat for the development of SCAD (among patients with underlying TTC) as well as TTC (among patients with underlying SCAD) through distinctive mechanisms, and may support the reciprocal causation between SCAD and TTC.

Reported cases of TTC in patients with COVID-19 are summarized in Table 1 . A total of six cases of TTC have been reported in individuals with confirmed COVID-19. All of the patients were female, with an average age of 72 years. They presented with different symptoms such as chest pain, fever, chill, cough, myalgia, and altered mental status. TTC diagnosis was confirmed with echocardiography and managed with medical therapy. The pathophysiology of COVID-19associated TTC may share some features with non-infectious cardiomyopathy and viral myocarditis. The first theory emphasizes the role of high sympathetic activity in the pathogenesis of TTC, similar to non-infectious cardiomyopathy. Because of the COVID-19 pandemic, psychological and physical stress posed on the community can activate the hypothalamic-pituitary-adrenal axis, resulting in hypercortisolism state, and also active sympathetic system resulting in increased sympathetic activity. Overstimulation of the sympathetic nervous system has a negative inotropic effect on myocyte contraction through a process called stimulus trafficking, in which epinephrine stimulation of β2 adrenergic receptor, leads to Gi protein activation and myocardial stunning. The other mechanism of TTC in COVID-19 patients is through cytokine storm syndrome, similar to viral myocarditis. Increased number of inflammatory cytokines (such as IL-6 and IL-8), chemokines (such as CXCL1), and inflammatory markers (such as ferritin and D-dimer) can lead to a systemic and localized inflammatory state. Macrophage infiltration and elevated inflammatory markers may also cause direct myocardial injury and lead to TTC (4, 5) . For definitive diagnosis of TTC, left ventriculography or echocardiography is required (6, 7) .

Reported cases of SCAD in patients with COVID-19 are summarized in Table 2 . So far, only four cases of SCAD have been reported in patients with positive COVID-19 test, including three men (75%) and one woman (25%), with an average age of 53 years. They presented with chest pain with or without cough and fever. Lack of cardiovascular risk factors, and the presents of a stressor helps to differentiate SCAD from atherosclerotic coronary artery disease (ASCAD), but for definitive diagnosis of SCAD, coronary angiography is needed (8, 9) . Clinical course and follow-up survey with coronary angiography, left ventriculography, and/or echocardiography may be needed for differentiation. SCAD was managed with medical therapy (75%) or percutaneous coronary intervention (PCI) (25%). Multiple mechanisms have been implicated in the pathogenesis of SCAD among COVID-19 patients. There have been several case reports of acute coronary syndrome (ACS) following acute respiratory viral infections (such as influenza and coronavirus outbreaks), especially in patients with a history of cardiac disease. It has been suggested that systemic inflammation in response to the infection or localized vessel inflammation can be the underlying mechanism for the coronary event (10, 11) . Among patients with ACS, there is greater inflammatory activity and inflammatory infiltrates such as neutrophils, T-cells, and macrophages in the atherosclerotic plaques. Also, in patients with acute systemic infection, there is enhanced infiltration of macrophages and T-cell in the adventitia, and dendritic cell in the intima and media layers of coronary vessels (12, 13) . In the context of COVID-19, one of the potential mechanisms for SCAD is that SARS-CoV-2 viral infection can lead to T-cell activation and infiltration in adventitia and periadventitial fat, which in turn produce more cytokines and proteases, thereby increasing the risk of plaque rupture or erosion and subsequent dissection (inside-out mechanism of SCAD) (14) . Another mechanism is that SARS-CoV-2 may stimulate angiogenesis and lead to proliferation of the vasa vasorum. The newly formed vasa vasorum is relatively leaky, fragile, and prone to disruption, which results in intramural hematoma (outsidein mechanism of SCAD) (15) . Vasa vasorum can also serve as the conduit for the entry of inflammatory cells into the tunica media and adventitia, facilitating inflammation and disruption of vasa vasorum (16) .

Prior to the COVID-19 pandemic, several reports have described the concurrence of TTC and SCAD (17) (18) (19) (20) . In the setting of TTC, vigorous contraction of the left ventricular base in conjunction with adjacent dyskinetic segments could form a prerequisite anatomical substrate for the causation of SCAD. The coronary dissection plane may develop as a result of excessive movement of the epicardial vessels and increased shear stress on the vessel wall at the hinge point between the hyperdynamic and akinetic myocardium (21) . It has also been speculated that the coronary arteries traversing the anterior or anterolateral wall would be more vulnerable to dissection as this region marks the transition point of the hyperdynamic basal segment and the remaining hypokinetic left ventricular segments (21) . In addition, the vulnerable coronary substrate may occur as a consequence of coronary vasospasm due to catecholamine excess in TTC.

With the vulnerable coronary substrate, further insults associated with COVID-19 (such as inflammatory cell infiltration and vasa vasorum rupture) could subsequently trigger the dissection of the coronary artery. On the contrary, post-ischemic myocardial stunning associated with SCAD could render the myocardium more susceptible to wall motion abnormalities, thus forming the vulnerable myocardial substrate. Under the influence of sympathetic overactivity associated with COVID-19, TTC may manifest due to hypokinesia in stunned myocardium coupled with hyperkinesia in the stimulated myocardium. Interestingly, it is noteworthy that both TTC and SCAD patients faced enormous "stresses" (e.g., emotional, sickness-related, or drug-related) that may cause or potentiate catecholamine surge and inflammatory cells infiltration. Moreover, COVID-19 (either the disease itself or the fear it caused) may also serve as a stressor for the development of TTC and/or SCAD. In this framework, it could be speculated that COVID-19 not only triggers the development of SCAD among patients with underlying TTC, but also manifests the development of TTC among patients with underlying SCAD, thereby serving as a precipitating factor that supports the reciprocal causation between TTC and SCAD.

SCAD or TTC may occur as an extrapulmonary manifestation in the setting of COVID-19. Long-term treatment mostly comprised of administering an angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers. In case of concomitant atherosclerotic disease, statins and aspirin should also be included as part of the treatment regimen (23) . The European Society of Cardiology (ESC) taskforce statement on TTC suggested no or a short course of medical therapy in mild cases as well as early mechanical support in the cases with circulatory failure (24) . The reported cases of COVID-19 induced TTC have been managed conservatively with the goal of reducing the complications (5, 25) . In addition, in of the COVID-19 case that hydroxychloroquine was administered as the COVID-19 treatment, it was later discontinued due to its potential adverse effect on the cardiomyopathy as well as increasing the risk of QT interval prolongation that is a known complication of TTC (25) .

The American Heart Association (AHA) and ESC practice guidelines recommended early invasive treatment strategies with revascularization of the involved vessel as the foundation of acute coronary syndrome (ACS) management and advocated that this strategy has been associated with a better long-term outcomes and lower complication rates. However, current literature lacks any randomized controlled trial study comparing the efficacy of invasive versus conservative managements in the ACS caused by SCAD. The latest AHA statement regarding SCAD recommended conservative therapy only in clinically stable cases and in the absence of left main or proximal two-vessel coronary artery dissection (9) . However, a meta-analysis of observational studies reported similar in-hospital and long-term outcomes in SCAD patients who were managed medically comparted to those who received early revascularization in the absence of aforementioned criteria (26) . Patients with COVID-19-induced SCAD has been managed conservatively by dual antiplatelet therapy as well as beta-blockers and anti-arrhythmic medications to prevent the dysrhythmia (27) . Future studies should investigate the optimal treatment for SCAD and TTC in the context of COVID-19.

The work is not funded. The authors declare no conflicts of interest. Table 2 . Reported cases of spontaneous coronary artery dissection in patients with COVID-19 

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