Coronary Implications of COVID-19

Abstract

Patients with SARS-CoV-2 infection carry an increased risk of cardiovascular disease encompassing various implications, including acute myocardial injury or infarction, myocarditis, heart failure, and arrhythmias. A growing volume of evidence correlates SARS-CoV-2 infection with myocardial injury, exposing patients to higher mortality risk. SARS-CoV-2 attacks the coronary arterial bed with various mechanisms including thrombosis/rupture of preexisting atherosclerotic plaque, de novo coronary thrombosis, endotheliitis, microvascular dysfunction, vasculitis, vasospasm, and ectasia/aneurysm formation. The angiotensin-converting enzyme 2 receptor plays pivotal role on the cardiovascular homeostasis and the unfolding of COVID-19. The activation of immune system, mediated by proinflammatory cytokines along with the dysregulation of the coagulation system, can pose an insult on the coronary artery, which usually manifests as an acute coronary syndrome (ACS). Electrocardiogram, echocardiography, cardiac biomarkers, and coronary angiography are essential tools to set the diagnosis. Revascularization is the first-line treatment in all patients with ACS and obstructed coronary arteries, whereas in type 2 myocardial infarction treatment of hypoxia, anemia and systemic inflammation are indicated. In patients presenting with coronary vasospasm, nitrates and calcium channel blockers are preferred, while treatment of coronary ectasia/aneurysm mandates the use of antiplatelets/anticoagulants, corticosteroids, immunoglobulin, and biologic agents. It is crucial to untangle the exact mechanisms of coronary involvement in COVID-19 in order to ensure timely diagnosis and appropriate treatment. We have reviewed the current literature and provide a detailed overview of the pathophysiology and clinical spectrum associated with coronary implications of SARS-COV-2 infection.

Highlights of the Study

• SARS-CoV-2 affects the coronary arterial bed with various mechanisms including rupture of coronary plaque, de novo coronary thrombosis, endotheliitis, microvascular dysfunction, vasculitis, vasospasm, and coronary artery ectasia/aneurysm formation.

• Acute coronary syndrome is the main presentation.

• Electrocardiogram, echocardiography, cardiac biomarkers, and coronary angiography are essential diagnostic tools.

• Untangling the mechanisms of coronary involvement in COVID-19 ensures timely diagnosis and appropriate treatment.

Introduction

The outbreak of the novel coronavirus disease 2019 (COVID-19) resulted in a major burden for healthcare professionals and systems worldwide [1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrated high rates of transmission and contamination even at low levels of viral load, facilitating its pandemic effect [2]. Its overall mortality rate approaches 1% and increases substantially over the age of 60 years [3, 4]. Clinical manifestations of COVID-19 include mostly symptoms from the respiratory tract, varying form slight flu-like signs to acute respiratory distress syndrome. Moreover, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including acute myocardial injury and myocarditis, heart failure and cardiac arrest, arrhythmias, acute myocardial infarction (MI), cardiogenic shock, and takotsubo cardiomyopathy [5–7].

A growing volume of evidence correlates COVID-19 with myocardial injury, exposing patients to higher mortality risk. Additionally, SARS-CoV-2 has been reported to affect the coronary arterial bed with various mechanisms including acute coronary syndrome (ACS) with obstructive or nonobstructive coronary arteries (MINOCA), microvascular dysfunction, vasculitis, endotheliitis, vasospasm, coronary aneurysm in the context of multisystem inflammatory syndrome in children (MIS-C) and adults (MIS-A) and in-situ thrombosis [8–11]. It is crucial to identify patients with COVID-19-related coronary complications, especially atypical ones, in order to provide appropriate treatment. In this narrative review, we aimed to provide a detailed overview of the pathophysiologic mechanisms and clinical spectrum associated with coronary implications of SARS-COV-2 infection.

Mechanisms of Myocardial Injury

Myocardial injury related to SARS-CoV-2 infection is defined as elevation of high-sensitivity cardiac troponin (hsT) and/or creatinine kinase MB above the 99th percentile of the reference upper limit, irrespective of electrocardiographic and/or echocardiographic abnormalities [7, 12]. It appears that the magnitude of elevation of hsT may be associated with severity of disease and prognosis [7]. The plausible mechanisms of myocardial injury in COVID-19 include:

• 1.Downregulation of the angiotensin-converting enzyme 2 (ACE-2) receptor [13, 14]. ACE-2 receptors are expressed beyond the airway and alveolar epithelial cells, also in the intestinal epithelial, renal epithelial, vascular endothelial and myocardial cells. COVID-19 induces systemic inflammation via systemic ACE-2 receptors [15]. The affinity of SARS-CoV-2 spike protein for ACE-2 receptors facilitates the entry of the virus into cells; thus, extrapulmonary manifestations, such as direct myocardial invasion by SARS-CoV-2, are often recognized in tissues that express ACE-2 receptors [16–19]. It is also widely seen in cardiac valves, especially the human aortic valve. ACE-2 cells in heart valves can be attacked by COVID-19 and may provoke disruption of normal blood flow [20]. It has been found that the spike protein of SARS-CoV-2 reduces ACE-2 expression by decreasing ACE-2 receptor activity [15]. The internalization of the virus with ACE-2 results in the loss of ACE-2 on the cell surface, causing increased levels of angiotensin II and decreased levels of angiotensin-(1–7), leading to vasoconstriction, inflammation, increased oxidative stress, and fibrosis [21]. Therefore, it is supported that the downregulation of ACE-2 expression may be a principal cause of cardiovascular injury [22–24].
• 2.Provocation of inflammation, apoptosis, and necrosis of myocardial tissue and cytokine storm mediated by hyperactivation of the immune system [24]. Inside the cardiomyocytes, SARS-CoV-2 rapidly replicates and causes a strong reaction of the immune system, resulting in cytokine storm and cardiovascular tissue damage [24]. In addition, immune cell activation (dendritic cells and macrophages) and upregulation of inflammatory mediators such as interleukin (IL)-6, IL-1 beta, IL-2, IL-8, IL-17, interferons (IFNs), chemokines, colony-stimulating factors, and tumor necrosis factors (TNFs), favor the apoptosis of epithelial lung and endothelial cells and increase capillary permeability. Furthermore, the cytokines IFN-α/β favor T-cell apoptosis, thus reducing viral clearance [25]. Moreover, IFN-α/β and IFN-γ mediate the inflammatory cell infiltration via the Fas-Fas ligand or TRAIL-death receptor 5 (DR5) mechanisms leading to apoptosis of airway and alveolar epithelial cells [26–28]. Increased cytokine activation in acute respiratory distress syndrome (ARDS) leads to the “cytokine storm” impairing lung function and augmenting the hyper-inflammation syndrome [29, 30].
• 3.Respiratory failure and hypoxia induced myocardial damage [31]. It is noteworthy that ARDS induced by COVID-19 may provoke extended vascular disorders, such as capillary congestion with thrombotic elements on micro- and macro-vascular level, dilation and abnormal angiogenesis [32–35]. These data suggest that COVID-19 lung injury may participate in a larger spectrum of generalized vascular dysfunction [36].

Coronary Implications

A growing volume of evidence correlates COVID-19 with myocardial injury, exposing patients with or without preexisting cardiovascular disease to higher mortality risk [37, 38]. Coronary arteries can be affected in COVID-19 infection through various mechanisms. In particular, coronary involvement of COVID-19 may be associated with thrombosis/rupture of preexisting atherosclerotic plaque, de novo coronary thrombosis, endotheliitis, microvascular dysfunction, vasculitis, vasospasm, and ectasias/aneurysms (Fig. 1) [39]. Coronary insult usually manifests clinically as an ACS [39]. Traditional cardiovascular risk factors such as diabetes mellitus, obesity, and hypertension are associated with worse outcomes and increased mortality in patients with COVID-19 [40]. Unraveling the potential mechanisms of COVID-19-associated coronary insult is of utmost importance in order to differentiate other types of myocardial injury (e.g., myocarditis) and provide the appropriate treatment. In the next few paragraphs, we summarize the principal mechanisms of coronary manifestations of COVID-19.

Fig. 1.

Coronary implications of COVID-19: the spike protein of SARS-CoV-2 attacks the vascular cells via the ACE-2 receptor. The activation of proinflammatory cytokines and the renin-angiotensin-aldosterone system along with platelet aggregation cause thrombosis/rupture of preexisting atherosclerotic plaque, whereas de novo coronary thrombosis-endotheliitis is mediated by increased levels of interleukin (IL)-1b, IL-8 and TNF-a. IL-6 and matrix metalloproteinases play a pivotal role in the formation of coronary artery ectasia. Accumulation of reactive oxygen species and immune complexes cause microvascular dysfunction and vasculitis, respectively. Extensive catecholamine release coupled with nitric oxide depletion induce coronary vasospasm.

Coronary Thrombosis with Preexisting Atherosclerotic Disease

Studies indicate that 8%–17% of patients with COVID-19 had a history of coronary artery disease [41, 42]. ACS may develop in patients infected by SARS-COV-2 with a history of chronic or undiagnosed coronary artery disease and classical risk factors. In this group of patients, underlying cardiovascular disease can increase the severity of symptoms and impair prognosis [42]. Most patients with COVID-19 and signs of myocardial damage present with typical symptoms of SARS-CoV-2 infection, while the diagnosis of ACS may be delayed, and medical personnel should focus on the entire complex of clinical manifestations and examination data (electrocardiography [ECG], echocardiography, troponins) [43, 44]. In this subset, ACS is the consequence of atherothrombosis through the activation of the proinflammatory cascade, platelet aggregation, and RAAS activation triggered by the SARS-COV-2 infection. Therefore, COVID-19 potentially plays a role in exacerbation of a preexisting epicardial coronary artery disease leading to plaque erosion or rupture and ACS [45].

De Novo Coronary Thrombosis-Endotheliitis

Many patients present with ACS in the absence of obstructive atherosclerotic disease [44]. COVID-19 systemic inflammation is related to thromboembolic events and coagulation disorders, as presented by the increased levels of d-dimers, von Willebrand factor, and interleukin IL-6 [46]. Recent literature suggests two possible pathophysiologic mechanisms related to COVID-19 coagulopathy [47]. First, the virus affects the endothelium, the natural “barrier” between the circulating blood and vessel wall elements, resulting in thromboembolic events [48, 49]. Endothelial dysfunction is a systematic and continuous process which may persist after the acute phase, in the post-COVID period [50]. Endothelial damage creates an inflammatory environment favoring platelet activation and the increase of cytokines IL-1β and IL-8. Increased activation of platelets, tissue factor, neutrophils and neutrophil extracellular traps, and the compliment factors C5–9 has been detected in the serum of patients with COVID-19 [51, 52].

The second mechanism suggests a more indirect viral involvement through the induction of cytokine storms [53]. Overproduction of immune cells and proinflammatory cytokines results in reduced peripheral blood flow, multiorgan failure, and ARDS [54, 55].

Coronary Microvascular Dysfunction

Coronary microvascular bed is a common target of myocardial insult in patients with COVID-19 [56]. In the study of Bilge et al. [57], microvascular dysfunction was more profound in male population with history of COVID-19 and may persist 3 months after the disease onset [58]. Of note, coronary angiographies from COVID-19 patients with acute MI demonstrated more frequently no-reflow phenomenon and significantly reduced left ventricular function after revascularization, probably indicating microvascular dysfunction [6]. Nevertheless, some cases of patients with ACS have been described with normal epicardial artery coronary imaging [58, 59]. Post-mortem analysis revealed extensive thrombus formation in the microvascular circulation, rich in fibrin and terminal complement part C5-9, depicting an inflammatory process [60].

The literature highlights some possible pathophysiologic pathways of microvascular dysfunction which include luminal stenosis, vascular remodeling, impaired endothelial and smooth muscle cell function, and automatic dysregulation [61]. Endothelial dysfunction remains one the most detrimental pathways of COVID-19 inflammation [62]. Damage-associated molecular patterns and pathogen associated molecular patterns are activated by endothelial TLRs inducing the activation, aggregation, and adhesion of leukocytes, platelets, the formation of neutrophil extracellular traps, and the production of proinflammatory cytokines, particularly IL-1, IL-6, and TNF-a [60, 63]. The inflammatory response is amplified by the renin-angiotensin-aldosterone system, which is mediated through downregulation of ACE-2 [8]. Consequently, neurohormonal activation, increased angiotensin II and aldosterone levels, vasoconstriction, oxidative stress, and reduction of endothelial nitric oxide synthetase, further aggravate endothelial function [43, 64–66].

Emerging evidence support the role of the vascular glycocalyx, the natural protector of endothelium from shear stress, in the COVID-19-induced endothelial dysfunction [67]. Coronary microvascular dysfunction may be the result of oxidative stress and increased sympathetic activity through the catecholamine release resulting in vasoconstriction and reduced coronary blood flow, especially in diabetics [68]. The alteration of microvascular circulation depletes coronary flow reserve and increases microvascular resistance [9].

Coronary Vasculitis

COVID-19 is capable of inducing vascular inflammation, also known as vasculitis. Autoimmune conditions, such as lymphocytic vasculitis, leukocytoclastic vasculitis, central nervous system vasculitis, and Kawasaki syndrome (KS) may be present not only during the acute infection but also in the post-COVID period [69, 70]. The most common histologic finding includes features of necrotizing vasculitis with mononuclear intima infiltration of small and medium-sized vessels [71]. ACE-2 expression and lymphomonocytic inflammation in COVID-19 disease increases crescentically toward the small vessels suggesting that COVID-19-induced endotheliitis is a small vessel vasculitis not involving the main coronaries [72]. COVID-19 patients with suspected myocarditis may exhibit vasculitis and intramural vessel microaneurysms in cardiac magnetic resonance (CMR) imaging [73].

COVID-19 is associated with hyperactive humoral immune response and evolution to type 3 hypersensitivity. This type of reaction includes excessive accumulation of immune complexes unable to be removed from the circulation and invasion of the coronary endothelium. The severe inflammation mediated by C3a and C5a complement lays the setting of endothelial edema and vascular barrier erosion that further result in karyorrhexis, fibrinoid deposition, and necrotizing vasculitis [74]. Overall, COVID-19 vasculitis is a rising autoimmune disorder affecting multiple organs, requiring further investigation.

Coronary Vasospasm

Coronary spasm is the consequence of impaired coronary endothelial function [75]. Almost 30% of patients with COVID-19 and ST‐segment elevation myocardial infarction (STEMI) show angiographically normal coronary arteries. Genetic predisposition on the level of endothelial nitric oxide (NO) synthase, ACE, angiotensin II receptor, and environmental interactions may hold a role in arterial spasm [76]. Endothelial impairment and dysregulation of the vasomotor tone are significantly associated with vasospasm [77]. The deficiency of the vasodilatory NO along with the increased vascular tone caused by elevated levels of the vasoconstrictive mediator endothelin-1 is of major importance [78, 79]. COVID-19 may also reduce the concentrations of arachidonic acid, thus stimulating the production of thromboxane, which favors vasoconstriction and platelet aggregation [80]. The activation of catecholamines is another interesting pathway affecting the coronary artery tone, the microvascular resistance, and the myocardial oxygen demand [24]. It has been observed that sympathetic activation in COVID-19 patients may be triggered by mental, physical, or physiological stress, such as depression, fear, stress, and anxiety, which may be clinically evident as takotsubo syndrome [81, 82].

Coronary Ectasia-Aneurysm

Coronary artery ectasia (CAE) describes a focal enlargement of the coronary artery exceeding 1.5-fold diameter of the adjacent normal segment, mainly caused by atherosclerosis in adults and KS in children [83]. CAE and aneurysms have been described in 6–24% of patients with MIS-C/A [84]. This entity has also been associated with congenital anomalies, arteritis, infections, and connective tissue disease [85].

MIS-C/A is defined as a clinically serious condition involving fever, laboratory evidence of inflammation, and multisystem organ involvement without alternative plausible diagnoses, as well as evidence of COVID-19 infection or recent exposure to a COVID-19 case [84]. MIS-C and MIS-A are an emerging pathology caused by COVID-19 and are strongly associated to CAE and aneurysm formation. There are reports of MIS-C occurring in 15% of patients with giant aneurysms and 6–24% with coronary artery dilation or aneurysms [84]. They describe a systemic hyper-inflammation disorder presenting 4–6 weeks in children and 2–12 weeks on adults after the initial SARS-COV-2 infection [86]. Although most cases revealed artery z-scores (how much larger [or smaller] a coronary artery diameter is compared to the average diameter for a healthy child of the same size) between 2 and 2.5, there have also been reports of large and giant coronary artery aneurysms classified as z-scores ≥10 [87]. These lesions have significant risk of thrombotic coronary occlusion [15].

Clinical manifestations may resemble KS and toxic shock syndrome, increasing the diagnostic difficulty. Symptoms include unexplained persistent fever, diffuse erythematous polymorphic rash, non-purulent conjunctivitis, gastrointestinal symptoms, mucosal changes, and peripheral edema. Young adults with COVID-19 may also demonstrate moderate cardiac dysfunction [11, 88]. The massive activation of proinflammatory cytokines in MIS-C patients leads to cytokine storm and macrophage activating syndrome overlapping the features of KS [89]. IL-6 secreted by T-helper cells enhances the upregulation and activation of matrix metalloproteinases, which lead to the degradation of extracellular matrix, and coronary artery dilatation [83].

Diagnosis

History taking and clinical examination is the first step for diagnosing cardiovascular involvement in COVID-19 patients. Patients usually present as an ACS, with symptoms including chest pain, angina, dyspnea, clinical signs of heart failure, syncope, or even shock [44, 45]. Diagnostic workup includes ECG, which may illustrate ST-segment or T-wave abnormalities, tachy- or bradyarrythmias, bundle branch or atrioventricular block and echocardiography which may show wall motion abnormalities and reduced ejection fraction [45, 90]. Moreover, biomarkers of myocardial injury such as hsTnT/I and N-terminal B-type natriuretic peptide are essential for differential diagnosis and are linked to severe prognosis and increased mortality. In patients presenting with symptoms, rapid rule-in or rule-out protocols apply as in other special populations with higher baseline concentrations of myocardial biomarkers. Troponin levels in patients with COVID-19 infection and myocardial injury seem to be lower than in most cases of ACS or acute myocarditis. In case of notable increase (e.g., >5 times the upper normal limits) in patients not critically ill, it could indicate myocarditis, takotsubo syndrome, spontaneous coronary dissection, or type 1 MI [91]. Lower levels of hsTnI in non-critically ill patients should be carefully taken into consideration in association with previous medical history of cardiovascular disease and presence of related symptoms. In addition, d-dimers levels representing active coagulation may be increased and should be considered in combination with other biomarkers. CRP and IL-6 levels, although significantly increased in COVID-19 infection, seem to indicate the extent of coronary plaque inflammation and the vulnerability to rupture [44, 45].

Noninvasive cardiovascular imaging further assists in setting the diagnosis. Echocardiogram is readily available for all hospitalized patients in the emergency setting and provides valuable information regarding regional wall motion abnormalities and left ventricular systolic and diastolic dysfunction. Moreover, CT coronary angiography (CTCA) may be considered to evaluate coronary involvement in patients without regional wall motion abnormalities in echocardiogram, mildly elevated levels of hsTnI and low pretest probability. CMR helps differentiate MI from myocarditis in patients with elevated hsTnl levels and unobstructed coronary arteries [44, 45].

It is of utmost importance to differentiate patients with COVID-19 and type 1 MI from other COVID-19 patients, who might present with troponin elevation and/or ST changes, without coronary etiology. In conjunction with the aforementioned diagnostic tools, invasive coronary angiography (ICA) is the cornerstone of diagnosing ACS. In patients with typical symptoms and ST-segment elevation in the ECG, emergency ICA is essential. In non-ST-segment elevation ACS, risk stratification is recommended for proper coronary intervention and optimal medical management [92].

Diagnosing type 2 MI in the context of SARS-CoV-2 infection can be challenging. Implementation of high-sensitivity (hs)-cTn assays, along with the application of the 4th Universal Definition of Myocardial Infarction, has led to an increased accuracy in the differentiation between type 1 MI and type 2 MI. However, no cutoff values for cardiac troponin can reliably differentiate between acute myocardial injury and different types of MI [91]. Additionally, the very low adoption rate of ICA due to associated risks in such critically ill patients hampers prompt diagnosis, whereas CTCA could be a safe alternative.

In cases of nonobstructive epicardial coronaries, functional assessment of the coronary microcirculation during ICA can reveal microvascular dysfunction and/or vasospam [93] Setting the diagnosis of coronary vasculitis is a cumbersome process requiring histological findings [72]. CAE and aneurysm formation can be depicted with the use of ICA or CTCA in MIS-A and echocardiography is MIS-C patients [87, 91].

Treatment

During the pandemic, significant delays were reported to reperfusion therapy. Tam et al. [94] reported longer delays of symptom onset to first medical contact (318 vs. 82.5 min), door to balloon time (110 vs. 84.5 min), and catheterization laboratory to balloon time (33 vs. 20.5 min) compared with the prepandemic era. Delays in presentation, absence of adequate COVID-19 testing, potential occupational hazard to staff members, prolonged evaluation times in the emergency department resulted in longer door to balloon times; therefore, potential loss of primary percutaneous coronary intervention (PCI) benefit led to the suggestion that fibrinolysis could be the first approach in a selected patients with STEMI [95]. STEMI patients with COVID-19 were more likely to receive medical therapy alone compared with controls (20% vs. 2%) and less likely to undergo interventional treatment with primary PCI (71% vs. 93%) [96]. Stefanini et al. [97] reported that in 40% of STEMI patients with COVID-19, no culprit lesion could be identified in ICA; therefore, a fibrinolytic-first approach is not justified because reperfusion is not required in a significant percentage of these patients. Moreover, other cardiac pathologies, such as stress-induced cardiomyopathy, SARS-CoV-2 infection-induced myocarditis, or pericarditis, are common in this subset, and fibrinolysis may add additional bleeding risk. The adoption of enhanced prophylactic measures in the cardiac catheterization laboratories, easy access to rapid testing, and wider availability of personal protective equipment for staff, the ESC later recommended primary PCI for all STEMI patients with COVID-19. Thrombolysis is recommended only for patients for whom transfer to PCI-capable hospital is not possible within 120 min from first medical contact or alternatively when primary PCI cannot be performed or is not judged to be the best option [91].

Revascularization is the first-line therapy in all patients with ACS and obstructed coronary arteries [44, 92]. “Emergent (do not postpone) coronary intervention is indicated in the setting of STEMI, very high risk/high risk non-ST elevation ACS (NSTE-ACS), and cardiogenic shock. Urgent (within days) coronary intervention should be performed in intermediate risk NSTE-ACS patients, unstable angina, left main PCI, last remaining vessel PCI, decompensated ischemic heart failure, angina pectoris class IV, and CABG in patients with NSTE-ACS unsuitable for PCI. Lower priority (perform within <3 months) includes the subset of patients with advanced coronary artery disease with angina class III or NYHA III symptoms, staged PCI of non-infarct related artery in STEMI in patients hemodynamically stable and without >90% lesions in proximal segments of major epicardial coronary arteries, proximal LAD PCI. Elective coronary intervention (may be postponed >3 months) in cases related to CTO interventions and CCS with angina class II or NYHA II symptoms” [91].

Primary PCI is indicated in all COVID-19 patients presenting with STEMI. Depending on the angiographic findings, balloons, drug-coated balloons, drug-eluting stents and thrombus aspiration techniques can be implemented. Fibrinolysis can be considered only if the target time delay cannot be met (120 min plus 60 min delay) [89]. Very high risk NSTE-ACS patients should be managed similarly to STEMI. In addition, optimal medical therapy with antiplatelets, b-blockers, ACE-i or AT-II antagonists and statins is recommended. The choice of the appropriate medications should be very meticulous since drug-drug interactions between cardiovascular and antiviral agents used for COVID-19 are common [98]. Bleeding risk is substantially increased with IIb/IIIa inhibitors, unfractioned/low molecular weight heparin, fibrinolysis, and by the concomitant use of the P2Y₁₂ inhibitor ticagrelor with the protease inhibitor lopinavir/ritonavir, let alone COVID-19-related coagulopathy [98]. In patients with cardiogenic shock, percutaneous mechanical circulatory support devices (intra-aortic balloon pump, Impella, extracorporeal membrane oxygenation) can be considered [91].

In patients presenting with vasospasm, nitrates and calcium channel antagonists are indicated [99]. In type 2 MI, therapeutic management includes treatment of hypoxia, anemia, and systemic inflammation control [92]. Treatment of MIS-C/MIS-A includes the use of antiplatelet/anticoagulant therapy, corticosteroids, immunoglobulin, and biologic agents, as shown in Figure 2 [100]. Immunoglobulin reduces the risk and mortality of coronary aneurysm. Immediate treatment accelerates the recovery of vessels to normal luminal dimension in less than a week [101].

Fig. 2.

Treatment of COVID-19-related coronary complications. Percutaneous or surgical revascularization is indicated in patients with acute coronary syndromes and obstructed coronary arteries alongside optimal medical therapy. Coronary vasospasm responds to nitrates and calcium channel antagonists. In type 2 myocardial infarction, treatment of hypoxia, anemia, and systemic inflammation control is essential. Treatment of multisystem inflammatory syndrome in children (MIS-C) and adults (MIS-A) mandates the use of antiplatelets/anticoagulants, corticosteroids, immunoglobulin, and/or biologic agents.

Prognosis

Myocardial injury is an independent risk factor for inhospital mortality in patients with COVID-19 [102]. Patients with ACS and COVID-19 present a significantly increased risk of short and 1-year mortality compared to ACS patients without COVID-19 due to advanced age, comorbidities, higher inflammatory milieu, prolonged time to PCI, or even no access to PCI [103, 104]. Saad et al. [105] also compared inhospital STEMI patients with COVID-19 to inhospital STEMI patients without COVID-19 from prior years and reported a strikingly higher mortality rate for the STEMI and COVID-19 subset. In a meta-analysis by Chew et al. [106], the overall mortality of STEMI patients was reported 27% higher during the pandemic as compared with prepandemic counterparts. Additionally, type 2 MI in COVID-19 patients is associated with a dismal long-term prognosis compared to type 1 MI [89]. More research is essential to establish the long-term outcomes of COVID-19 patients and microvascular dysfunction, vasculitis, vasospasm, and CAE.

Conclusions

COVID-19-associated myocardial insult exposes patients to a higher mortality risk. SARS-CoV-2 has been reported to attack the coronary arterial bed with various mechanisms including thrombosis/rupture of preexisting atherosclerotic plaque, de novo coronary thrombosis, endotheliitis, microvascular dysfunction, vasculitis, vasospasm, and ectasia/aneurysm formation. It is crucial to untangle the exact mechanisms of coronary involvement in COVID-19 in order to ensure timely diagnosis, appropriate treatment, and favorable prognosis.

Statement of Ethics

No permission was required from the Ethical Committee (review article).

Conflict of Interest Statement

The authors declare that there are no potential conflicts of interest to report.

Funding Sources

The study did not receive funding.

Author Contributions

Andreas S. Triantafyllis: conceptualization, writing – review and editing, visualization, methodology, and resources; Danai Sfantou: writing – original draft, methodology, and resources; Eleni Karapedi, Katerina Peteinaki, Sotirios C. Kotoulas, Richard Saad, and Petros N. Fountoulakis: writing – original draft, methodology, visualization, and resources; Dimitrios Tsiptsios, Konstantinos Tsamakis, Loukianos Rallidis, James N. Tsoporis, Dimitrios Varvarousis, Eftychia Hamodraka, Andreas Giannakopoulos, and Leonidas E. Poulimenos: writing – review and editing; Ignatios Ikonomidis: conceptualization and writing – review and editing. All authors contributed to the article and approved the submitted version.

Funding Statement

The study did not receive funding.

Data Availability Statement

Data are available for review.