Sage Journals: Discover world-class research

Abstract

In the era of the coronavirus disease 2019 (COVID-19) pandemic, acute cardiac injury (ACI), as reflected by elevated cardiac troponin above the 99th percentile, has been observed in 8%-62% of patients with COVID-19 infection with highest incidence and mortality recorded in patients with severe infection. Apart from the clinically and electrocardiographically discernible causes of ACI, such as acute myocardial infarction (MI), other cardiac causes need to be considered such as myocarditis, Takotsubo syndrome, and direct injury from COVID-19, together with noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis. Acute coronary syndromes (ACS) with normal or near-normal coronary arteries (ACS-NNOCA) appear to have a higher prevalence in both COVID-19 positive and negative patients in the pandemic compared to the pre-pandemic era. Echocardiography, coronary angiography, chest computed tomography and/or cardiac magnetic resonance imaging may render a correct diagnosis, obviating the need for endomyocardial biopsy. Importantly, a significant delay has been recorded in patients with ACS seeking advice for their symptoms, while their routine care has been sharply disrupted with fewer urgent coronary angiographies and/or primary percutaneous coronary interventions performed in the case of ST-elevation MI (STEMI) with an inappropriate shift toward thrombolysis, all contributing to a higher complication rate in these patients. Thus, new challenges have emerged in rendering a diagnosis and delivering treatment in patients with ACI/ACS in the pandemic era. These issues, the various mechanisms involved in the development of ACI/ACS, and relevant current guidelines are herein reviewed.

Keywords

COVID-19 SARS-CoV-2 acute cardiac injury myocardial infarction acute coronary syndromes ACS-NNOCA MINOCA Takotsubo cardiomyopathy myocarditis

Introduction

In the era of the coronavirus disease 2019 (COVID-19) pandemic, new issues and challenges have arisen and/or are newly recognized in the diagnosis and treatment of patients presenting with symptoms of acute cardiac injury (ACI) or acute coronary syndromes (ACS).^1
-3 First, a pattern of ACI, defined as cardiac troponin (cTn) above the 99th percentile in the upper reference limit, has been observed in a variable number of patients with COVID-19 infection dependent on the severity of the infection, which portends an adverse prognosis and increased mortality in these patients^3
-5; second, a significant delay has been recorded in patients with ACS attending the emergency room or seeking advice for their symptoms.^6,7 Also, the routine of caring for patients with ACS has been sharply disrupted with regard to urgent coronary angiography and/or the performance of primary percutaneous coronary intervention (PCI) in the case of ST-elevation myocardial infarction (STEMI) vs administering thrombolytic therapy.⁸ Thus, new challenges have emerged in delivering treatment for ACI/ACS in the era of the COVID-19 pandemic.⁹ All these issues are herein reviewed, modified current guidelines are presented and potential mechanisms involved in COVID-19-induced ACI/ACS are discussed and pictorially illustrated.

Myocardial Injury in COVID-19

Patients with COVID-19 infection can present with acute cardiac injury (ACI) defined as elevated cTn >99th percentile, albeit mostly with stable and unchanging values, or with typical ACS (STEMI or NSTEMI or unstable angina) from atherosclerotic coronary plaque disruption (rupture or erosion) with a rise and fall of cTn in the case of STEMI/NSTEMI, either in the setting of obstructive or non-obstructive coronary artery disease (CAD); the latter group of patients may have angiographically normal-appearing coronary arteries or non-obstructive (<50%) coronary lesions, recently termed ACS with normal or near-normal coronary arteries (ACS-NNOCA) (Figure 1).¹⁰ On the other hand, non-COVID-19 patients may also present with ACS or ACS mimics associated with the COVID-19 pandemic, either triggered by the anxiety related to corona-phobia,¹¹ or to pandemic-associated financial and other emotional stress.^12,13 Furthermore, many patients with ACS symptoms may avoid or delay their visit to the emergency room for fear of contracting the virus, with ensuing grave consequences.¹⁴

Figure 1.

The schema illustrates the potential mechanisms involved in COVID-19-induced acute coronary syndromes (ACS) and acute cardiac injury (ACI), the inter-relationship among them and among the types of typical (atherosclerosis-related) and non-typical (ACS-NNOCA) ACS, and the delayed first medical contact (FMC) observed with its attendant dire consequences (higher complication rate) (see text for discussion). ACE2 indicates angiotensin converting enzyme type 2; ACI, acute cardiac injury; ACS-NNOCA, acute coronary syndrome with normal or near-normal coronary arteries; INOCA, ischemia with non-obstructive coronary artery disease; MINCA, myocardial infarction with normal coronary arteries; MINOCA, myocardial infarction with non-obstructive coronary artery disease; NSTEMI, non-ST elevation myocardial infarction; RAS, renin-angiotensin system; SNS, sympathetic nervous system; STEMI, ST-elevation myocardial infarction; TTC, Takotsubo cardiomyopathy (syndrome); UA, unstable angina.

Acute Cardiac Injury (ACI)

From the outset, it was noted that cTn was marginally elevated in all patients with COVID-19 infection, while values exceeding the 99th percentile in the upper reference limit were observed in >8-62% of cases consistent with ACI.^15,16 Acute cardiac injury, thus defined as elevated cTn levels >99th percentile, is the most often reported cardiac abnormality in COVID-19 and is strongly associated with mortality.¹⁷ According to a large retrospective cohort study of 1,020 COVID-19 patients (median age 63 years, 50% female, 40% white), ACI, defined by high-sensitivity cTnI (hs-cTnI) concentration >99th percentile, was found in 390 (38%) patients.¹⁸ These patients were older (median age 70 years), had a higher cardiovascular (CV) disease burden, in addition to higher serum concentrations of inflammatory markers. Adjusted multivariate analysis showed that peak hs-cTnI concentrations were significantly associated with mortality. Another large cohort study of 2,736 patients with COVID-19 (median age 66.4 years, 59.6% men) reported that 985 (36%) patients had elevated cTn concentrations.¹⁹ After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury were significantly associated with mortality (adjusted hazard ratio-HR: 1.75; P < 0.001).

Several systematic reviews and meta-analyses have reported their findings on ACI in COVID-19 patients (Table 1).^{4,20

-30} A systematic review of 8 studies comprising 1,229 patients showed that the frequency of ACI was 16% (95% CI: 9%-27%), albeit with high (93%) heterogeneity among the studies.⁴ A meta-analysis of 16 studies comprising 2224 patients indicated that the incidence of ACI was 24.4% in hospitalized COVID-19 patients.²⁰ Subsequently, it was felt that it is more plausible that ACI is attributable mostly to nonischemic causes of myocardial injury or type 2 myocardial infarction (MI) (myocardial oxygen supply–demand imbalance), rather than typical or type 1 MI.^5,31 The point differentiating this increase in cTn from typical MI was the fact that the majority of COVID-19 patients demonstrate stable cTn rather than the dynamically changing values with a rise and fall indicative of an ACS (STEMI/NSTEMI).³² Nevertheless, this type of ACI has been associated with worse prognosis and increased mortality.^16,22,33 Occasionally, it may follow the course of acute fulminant myocarditis with hemodynamic compromise and cardiogenic shock requiring mechanical support (e.g., with extracorporeal membrane oxygenation-ECMO) for recovery.^34,35 Recently, another review of 26 studies including 11,685 patients indicated that the weighted pooled prevalence of ACI was 20% (range 5%-38% depending on the criteria used).²¹

Table 1.

Meta-Analyses of Studies Regarding Acute Cardiac Injury (ACI) and COVID-19 Infection.

Author / Year	No. of Studies	No. of Patients	Results	Comments
De Lorenzo et al / 2020⁴	8 (case series or cohorts)	1229	Frequency of ACI: 16%	There was high (93%) heterogeneity among the studies
Zou F et al / 2020²⁰	16 (15 retrospective, 1 prospective)	2224	Incidence of ACI: 24.4% in hospitalized COVID-19 patients All-cause mortality in patients with ACI: 72.6% (OR = 17.32) compared to those without ACI (14.5%)	Factors associated with increased risk of developing ACI were older age and history of HTN, and COPD
Bavishi et al / 2020²¹	26	11,685	Weighted pooled prevalence of ACI: 20%	ACI prevalence ranged from 5% to 38% depending on the criteria used
Santoso et al / 2020²²	13 (retrospective observational)	2389	ACI was associated with: Higher mortality (RR 7.95, P < 0.001; I²: 65%) Higher need for ICU care (RR 7.94, P = 0.01; I²: 79%), and Severe COVID-19 (RR 13.81, P < 0.001; I²: 0%)	ACI was not significant for ↑ risk of ARDS (RR 2.57, P = 0.06; I²: 84%).
Zuin et al / 2020²³	8	1686 (data on outcome available for 1615 patients)	ACI: 23.9% Incidence of ACI: higher among non-survivors vs survivors (61.6% vs 6.7%, P < 0.0001)	Pooled analysis: ↑ risk of death in COVID-19 patients complicated with ACI (odds ratio-OR: 21.6, P < 0.0001, I² = 82%)
Li et al / 2020²⁴	28	4189	ACI was associated with higher mortality (summary risk ratio 3.85; P < 0.001)	ACI: more frequent in severe vs milder disease (risk ratio 5.99; P < 0.001)
Li et al / 2020²⁵	10 (2 case series, 8 cohort)	3118	ACI: was associated with higher in-hospital mortality (unadjusted odds 21.15; I² = 71%)	The presence of CVD (unadjusted OR 4.85; I² = 29%) and hypertension (unadjusted OR 3.67; I² = 57%) was also associated with higher in-hospital mortality
Figliozzi et al / 2020²⁶	49	20,211	ACI: conferred the highest risk for death (OR 16.55) and for the adverse composite endpoint of death, severe presentation, hospitalization in the ICU and/or mechanical ventilation (OR 10.58, P < 0.001)	History of CVD (OR 3.15), AKI (OR 5.13), high procalcitonin (OR 4.8) or D-dimer (OR 3.7), and thrombocytopenia (OR 6.23) also conveyed high risk for the adverse composite endpoint
Vakhshoori et al /2020²⁷	11	1394	Incidence of ACI: 15% Dead or severe patients had higher percentages of myocardial injury, compared to non-severe ones (44% vs 24% vs 5%, respectively) Mean total troponin: 10.23 pg/mL / 13% of patients had elevated levels	Mean BNP was 216.74 pg/mL
Prasitlumkum et al / 2020³⁰	27	8971	Incidence of ACI in hospitalized COVID-19 pts: 20%	Older age, male and comorbidities were associated with a higher risk of ACI
Bansal et al / 2021²⁸	14	3175	ACI was associated with higher risk of: Mortality (RR: 7.79; I² = 58%) ICU admission (RR: 4.06; I² = 61%) Mechanical ventilation (RR: 5.53; I² = 0%), and Coagulopathy (RR: 3.86; I² = 0%)	ACI was not associated with increased risk of ARDS (RR: 3.22; I² = 73%) or AKI (RR: 11.52; I² = 0%) Levels of hs-cTnI myoglobin, NT-pro BNP and CK-MB were higher in nonsurvivors compared with survivors
Dalia et al / 2021 ²⁹	20	5967	Non-survivors and pts with severe COVID-19 infection (fulminant group): 8-fold increased risk of ACI compared to survivors/non-severe pts (non-fulminant group) (pooled RR: 8.52 (P < 0.001) Risk of death was higher in HF pts; RR 3.38 (P = 0.004)	A trend of increased risk was observed for any cardiac arrhythmia; pooled RR was 3.61 (P = 0.001)

Abbreviations: ACI, acute cardiac injury; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; cTn, cardiac troponin; CVD, cardiovascular disease; HF, heart failure; hs-cTnI, high-sensitivity cardiac troponin I; HTN, hypertension; ICU, intensive care unit; OR, odds ratio; pts, patients; RR, risk ratio.

ACI and Mortality

As mentioned, evidence that ACI during COVID-19 significantly increases mortality during the infection has been provided by meta-analyses, as well (Table 1). A meta-analysis of 16 studies (N = 2224) indicated that the all-cause mortality in patients with ACI was 72.6% (odds ratio-OR = 17.32) compared to those without ACI (14.5%).²⁰ Patients who were older with hypertension (HTN) and chronic obstructive pulmonary disease (COPD) were prone to develop ACI. Another meta-analysis of 8 studies (N = 1686 COVID-19 patients; mean age 59.5 years; 387 patients or 23.9% experiencing ACI), indicated that the incidence of ACI was higher among non-survivors (61.6 vs 6.7%, P < 0.0001).²³ Another meta-analysis of 13 studies comprising 2389 patients showed that ACI was associated with higher mortality (risk ratio-RR 7.95, P < 0.001; I²: 65%), higher need for intensive care unit (ICU) care (RR 7.94, P = 0.01; I²: 79%), and severe COVID-19 (RR 13.81, P < 0.001; I²: 0%).²² A meta-analysis of 28 studies including 4189 confirmed COVID-19 patients indicated that more severe COVID-19 infection was associated with higher mean cTn, while ACI was more frequent in those with severe, compared to milder, disease (RR 5.99; P < 0.001).²⁴ Furthermore, COVID-19-related ACI was associated with higher mortality (RR 3.85; P < 0.001). A meta-analysis of 10 studies, among which 8 reported on ACI, indicated that ACI was associated with an unadjusted odds ratio of 21.15 for in-hospital mortality (I² = 71%).²⁵ Finally, a meta-analysis of 49 studies showed that ACI was associated with high odds (odds ratio-OR 10.58) for the adverse composite endpoint of death, severe presentation, hospitalization in the ICU and/or mechanical ventilation; a history of CV disease (CVD) (OR 3.15), acute kidney injury (AKI) (OR 5.13), increased procalcitonin (OR 4.8) or D-dimer (OR 3.7), and thrombocytopenia (OR 6.23) also conveyed high odds for the adverse composite endpoint.²⁶ Advanced age, male sex, CV comorbidities, ACI or AKI, lymphocytopenia and D-dimer conferred an increased risk of in-hospital mortality.

Shock and malignant arrhythmias have been reported as the most common outcomes of ACI.³⁶ The risk of in-hospital death among COVID-19 patients with ACI may be predicted by the peak levels of cTn during hospitalization.³⁷ In addition, advanced age, coagulopathy, acute respiratory distress syndrome (ARDS), and other comorbidities are associated with increased risk of in-hospital mortality in COVID-19 patients with ACI.^30,38 Pre-existence of heart failure and hypertension, and high cardiac biomarkers correlate with worse outcomes.²⁹

Differential Diagnosis

In addition to possible clinically- and ECG-discernible reasons of ACI, such as STEMI or NSTEMI, other causes, such as myocarditis, Takotsubo syndrome (stress cardiomyopathy), acute heart failure, and direct injury from COVID-19 are important etiologies of ACI; however, noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis need also be considered (Table 2).^5,39 The clinical picture of ACI may be confused with acute MI or an MI mimic, such as Takotsubo cardiomyopathy (TTC) or acute myocarditis, whereby coronary angiography and/or cardiac magnetic resonance (CMR) imaging are most helpful, but in certain cases only endomyocardial biopsy (EMB) could render the correct diagnosis, as it was the case in a patient with COVID-19 who was diagnosed with lymphocytic myocarditis only after an EMB was performed.^40,41 Nevertheless, COVID-19 viral myocarditis, i.e. myocarditis caused by direct virus invasion of the myocardium has not convincingly been demonstrated as yet,⁴¹ with possible rare exceptions,⁴² as myocardial injury is more likely related to systemic consequences rather than direct damage by COVID-19.^43,44 Thus, due to the low frequency of COVID-19-induced myocarditis and unclear therapeutic implications, investigators have advised against the use of EMB to diagnose myocarditis in the setting of COVID-19.⁴⁵ Anyhow, CMR is suggested as the preferred imaging modality for non-invasive evaluation in acute myocarditis, enabling risk stratification and prognostication.⁴⁶

Table 2.

Causes of Acute Cardiac Injury or Acute Coronary Syndrome in Patients With and Without COVID-19 Infection.

I. COVID-19 Patients

Cardiac

MI type I (STEMI/NSTEMI)

MI type II (coronary spasm, coronary embolus, SCAD)

ACI (elevated albeit mostly stable/unchanging cTn values; direct injury from COVID-19 [rare]; indirect from systemic consequences)

ACS-NNOCA

ACS/MI (CAD)

MI mimic (myocarditis, Takotsubo cardiomyopathy)

Coronary vasculitis

Acute heart failure

Acute arrhythmias

Non-Cardiac

Pulmonary embolism

Critical illness

Hypoxemia

Sepsis

Shock

Anemia

Kidney disease

II. Non-COVID-19 Patients

STEMI / NSTEMI / UA

ACS-NNOCA

CAD

Myocarditis

Takotsubo

MVD

SCAD

Abbreviations: ACI, acute cardiac injury; ACS, acute coronary syndrome; ACS-NNOCA, acute coronary syndrome with normal or near-normal coronary arteries; CAD, coronary artery disease (ruptured atherosclerotic plaque); cTn, cardiac troponin; MI, myocardial infarction; MVD, microvascular dysfunction; NSTEMI, non-ST elevation myocardial infarction; SCAD, spontaneous coronary artery dissection; STEMI, ST-elevation myocardial infarction; UA, unstable angina.

According to a recent systematic review of CMR imaging findings in 34 studies comprising 199 COVID-19 patients, 79% of the CMRs were abnormal.⁴⁷ Myocarditis (40%) was the most prevalent diagnosis. Other findings included perfusion deficits, extracellular volume mapping abnormalities, and pericardial effusion. In the majority of patients, gross left ventricular (LV) function was normal. Kawasaki-like involvement with myocardial edema without necrosis was seen in 4 of 6 children.

A recent review highlights the advantages of chest/cardiac CT and/or CT coronary angiography (CTCA) in evaluating patients with possible ACI vs MI, patients with acute or stable chest pain, patients with pulmonary embolism, patients with possible intracardiac thrombus and patients with valvular heart disease.⁴⁸ Thus, appropriate use of a multimodality imaging strategy is most useful to detect ACI and distinguish MI from myocarditis, TTC, pulmonary embolism and other cardiac and chest pathologies in COVID-19 patients.^49,50

Acute Myocarditis

There are case reports of COVID-19 patients presenting with presumed acute myocarditis, many times of the fulminant type, however, there is paucity of confirmatory data via EMB and/or CMR.^51

-56 As mentioned, among 112 COVID-19 patients with ACI, as evidenced by elevated cTn, only 14 (12.5%) patients had abnormalities similar to myocarditis, such as triple elevation in cTnI with values over 0.12 ng/mL, plus abnormalities on echocardiography and/or ECG, albeit without CMR confirmation.⁴³ A systemic review of 14 patients with COVID-19-related myocarditis (median age 50.4 years) indicated a male predominance (58%), with HTN as the most prevalent comorbid condition (33%).⁵⁷ ECG findings were variable, and cTn was reported elevated in 12 cases and creatine kinase-MB in the other 2 cases. Echocardiography, performed in 83% of cases, revealed reduced LV function in 60%. The majority of cases required intubation. Among therapeutic options, glucocorticoids were most commonly used (58%) with a survival rate of 81% (85% for those on steroids). A recent case series reported on 10 patients (8 females) with COVID-19-related myocarditis-like syndrome referred for CMR; 2 patients were diagnosed as TTC and 8 patients had CMR images consistent with myocarditis; all patients fared well with normalization of cTn and recovery of LV function.⁵⁸

Recently, in children and adolescents, a Kawasaki-like multisystem inflammatory syndrome with predominant myocarditis associated with COVID-19 infection has been reported.⁵⁹ The clinical features of this syndrome overlap with those of Kawasaki disease and toxic shock syndrome. However, myocardial involvement requiring vasopressor support is more common in these patients than in Kawasaki disease (∼50% vs ∼5%), while coronary-artery aneurysms develop less commonly (∼9% vs ∼25%). Data indicate that this syndrome is largely immune-mediated, triggered by COVID-19, with a hyperinflammatory response possibly due to post-infectious cytokine storm, rather than a result of direct myocardial cell injury caused by the virus.

Acute Coronary Syndromes in Patients With COVID-19 Infection

In a prospective multicenter cohort study of 187 patients admitted for acute MI (111 STEMI, 76 NSTEMI), 32 (17%) were diagnosed with COVID-19.⁶⁰ GRACE score, Killip classification, and levels of inflammatory markers were significantly higher in COVID-19 patients. Total (25% vs 3.8%; P < 0.001) and CV mortality (15.2% vs 1.8%; P = 0.001) were also higher in COVID-19-patients. GRACE score >140 (OR, 23.45; P = 0.005) and COVID-19 (OR, 6.61; P = 0.02) were independent predictors of in-hospital death.

Another prospective study of 26 STEMI patients admitted during the pandemic reported that 7 (26.9%) of these patients tested positive for COVID-19.⁶¹ Median time from symptom onset to hospital admission was significantly longer in 2020 as compared to the historical cohort (15 vs 2 h; P < 0.01); also, more patients presented late compared with the historical cohort (50% vs 4.8%; P < 0.01). Primary PCI was performed in fewer patients (80.8% vs 100% in the historical cohort; P = 0.06). A multicenter retrospective study of 78 patients with COVID-19 infection and STEMI (median age 65 years, 63% men) reported that during hospitalization, 8 (10%) developed acute respiratory distress syndrome (ARDS), 14 (18%) required mechanical ventilation, 19 (24%) were treated with primary PCI and 59 (76%) were treated with fibrinolytic therapy.⁶² A total of 13 (17%) patients required cardiac resuscitation, and 9 (11%) died. Among those treated with PCI (n = 19), a high rate of stent thrombosis (21%) was reported. Finally, a report from Italy of 547 patients hospitalized for ACS (45% STEMI) indicated that the mean admission rate for ACS during the study period was 13.3 admissions per day compared to 18.9 admissions per day during the previous year (incidence rate ratio, 0.70; P < 0.001).⁶³ The authors also reported a significant increase in mortality during this period that was not fully explained by COVID-19 cases alone.

Thus, in the COVID-19 era, STEMI patients with concurrent COVID-19 infection seem to represent ∼17%-27% of patients admitted with STEMI. Patients admitted with any type of ACS present relatively late to the hospital compared to pre-pandemic periods; fewer patients are submitted to PCI; for a variety of reasons to be discussed later, ACS patients have worse prognosis in the pandemic era compared to the pre-pandemic era.

Acute Coronary Syndromes With Normal or Near-Normal Coronaries

Acute coronary syndromes with normal or near-normal coronary arteries (ACS-NNOCA), comprising MI with non-obstructive coronary arteries (MINOCA) or MI with normal coronary arteries (MINCA) and ischemic syndromes with non-obstructive coronaries (INOCA),¹⁰ are being increasingly reported in patients with COVID-19 infection (Table 2).^64
-66 In a case series of 18 COVID-19 patients presenting with STEMI, 3 of 9 (33%) patients undergoing coronary angiography did not have obstructive coronary artery disease (CAD).⁶⁷ In an observational study of 118 consecutive confirmed COVID-19 patients (median age 66 years, all men) undergoing transthoracic echocardiography, 5 (4.2%) patients had features compatible with TTC; however, these patients had no coronary angiography to exclude CAD.⁶⁸ There have been several case reports of TTC in patients with COVID-19; ^69

-75 one particular case with reverse TTC (akinesia of the LV basal and midventricular wall with apex sparing) was reported to complicate the course of fulminant COVID-19 associated with cytokine release syndrome, whereby inotropic therapy failed, and the patient responded well to therapeutic plasma exchange.⁷⁶ In a literature review that yielded 16 COVID-19 patients with TTC (median age 57; 50% male) of which 11/16 patients’ individual data were available, 4 out of 11 (36.4%) patients had cardiac complications such as atrial fibrillation, pericardial effusion, cardiogenic shock, and heart failure.⁷⁴ A recent case report described a COVID-19 patient who presented with MINOCA (NSTEMI) and CTCA showed signs of vasculitis with diffuse wall irregularities and focal thickening, which was considered to have triggered endothelial dysfunction and vasospasm.⁶⁵

A prospective study enrolled all STEMI patients who underwent primary PCI during the COVID-19 period (83 patients) and compared them with a previous cohort of STEMI patients (2008-2017, n = 1,552 patients); non-COVID-19 patients (n = 72) were also compared with COVID-19 patients (n = 11).⁶⁶ Patients during the outbreak period were older, significantly delayed seeking care and sustained a two-fold higher in-hospital mortality. Higher biological markers of inflammation (C-reactive protein), fibrinolysis (D-dimer), and antiphospholipid antibodies in 4 cases were observed in the COVID-19 group. In the COVID-19 group, MINOCA (defined as thrombotic MI non-atherosclerotic coronary occlusion) was observed in 6 of 11 cases (54.5%) vs 5 of 72 cases in the non-COVID-19 group (1.4%) (P < 0.001) and associated with higher post-procedure distal embolization (72.7% vs 30.6%, P = 0.007). The in-hospital mortality was higher in the COVID-19 group (27.3% vs 5.6%, P = 0.016).

Thus, in patients with COVID-19 infection, a garden variety of ACS-NNOCA may be observed ranging from ruptured pre-existing or new atherosclerotic plaques to other ischemic or non-ischemic syndromes, like TTC or acute myocarditis.^{57,64,73
-75,77
-79} Importantly, compared with the non-COVID-19 patients, the prevalence of ACS-NNOCA in COVID-19 patients appears to be much higher, reported at ∼33%-55% of patients with COVID-19 presenting with STEMI,^66,67,80 when ACS-NNOCA has been reported to occur in 3.5%-14.5% in non-COVID patients presenting with ACS; ¹⁰ the reasons behind this discrepancy have not been elucidated (see discussion on mechanisms below). Notably, the risk of sudden cardiac death (SCD) in patients with ACS-NNOCA remains a major concern; myocardial ischemia, inflammation, and fibrosis are probably at the core of the SCD risk in these patients.⁸¹

Non-COVID-19 Patients

On the other hand, the pandemic may also account for cases of ACS-NNOCA in patients without COVID-19 infection. Interestingly, in these patients, the fear or stress that this pandemic instigates appears to be the trigger for ACS-NNOCA. These may include cases of coronary spasm, TTC, myocarditis, etc. (Table 2).^{10,12,65,82,83}

A retrospective cohort study of 1914 patients presenting with ACS (1656 in the pre-COVID-19 period and 258 patients during the COVID-19 pandemic period) indicated that there was a significant increase in the incidence of stress cardiomyopathy (TTC) during the COVID-19 period compared with the pre-pandemic period (20 patients or 7.8% vs 5-12 patients or 1.5%-1.8% in the pre-COVID-19 period).¹² Patients with TTC during the COVID-19 pandemic had a longer median hospital length of stay (8 vs 4-5 days; P = 0.006), while mortality was similar (1 patient in each period).

Thus, it becomes apparent that there may be an increase in the numbers of MI/ACS mimickers in the era of COVID-19 and caution is due to render proper diagnosis in patients with or without COVID-19 presenting to the emergency room with chest pain. Multimodality CV imaging including standard and newer echocardiography techniques, CTCA, and CMR may guide diagnosis and management (Figure 2).^84
-86 Cardiovascular imaging may offer several advantages in non-invasively evaluating COVID and non-COVID patients with cardiac symptoms during the COVID-19 pandemic (Figure 2).^48,87,88 Newer echocardiography techniques, such as LV global longitudinal strain, may uncover subclinical myocardial dysfunction in a large proportion (∼80%) of patients hospitalized with COVID-19, while gross LV dysfunction with decreased LV ejection fraction and wall motion abnormalities are less frequent findings (22%-23%).⁸⁷ Myocardial strain imaging may detect myocardial dysfunction in almost all critically ill COVID-19 patients.⁸⁹ Nevertheless, in the majority, if not all, patients, coronary angiography will be needed to visualize the coronary arteries; in those with non-significant or absent coronary lesions, it would be advisable to perform LV angiography that could hasten and confirm certain diagnoses, like TTC.¹⁰

Figure 2.

An algorithm is proposed to investigate the causes of Acute Cardiac Injury (ACI) in patients with COVID-19 infection that includes clinical assessment, ECG, echocardiography and newer strain imaging techniques, high-sensitivity cardiac troponin (cTn), invasive and noninvasive coronary angiography, chest computed tomography and cardiac magnetic resonance (CMR) imaging. N.B.: CMR stands out as the preferred imaging modality for non-invasive evaluation in ACI, also enabling risk stratification and prognostication (see text for discussion). ACS-NNOCA indicates Acute Coronary Syndrome with Normal or Near-Normal Coronary Arteries; CAD, (atherosclerotic) coronary artery disease; CMR, cardiac magnetic resonance imaging; CT, computed tomography; CTCA, computed tomography coronary angiography; cTn, cardiac troponin; ECG, electrocardiogram; LV, left ventricular; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; PE, pulmonary embolism; STEMI, ST-elevation myocardial infarction; TTC, Takotsubo cardiomyopathy; Δs, changes.

Mechanisms for COVID-19-Related ACS and ACI

Acute Coronary Syndrome

Various mechanisms may be involved in the development of ACS in patients with COVID-19 infection (Figure 1).^1,90 Of course, stress and increased sympathetic activity associated with the viral disease may precipitate the ACS event in a patient with pre-existing CAD.^13,91,92 Sepsis, primarily originating from the lower respiratory tract, is also a most common precipitating factor for MI type II (coronary insufficiency not related to acute plaque rupture).⁹³ Importantly, coronary atherosclerosis is a thrombo-inflammatory atherosclerotic disease,⁹⁴ and COVID-19 also instigates a thrombo-inflammatory process, and as such, COVID-19-disease-specific mechanisms may well account for the development of ACS, like a cytokine storm, leading to accelerated formation of new coronary plaques and destabilization and rupture of pre-existing plaques caused by hyperinflammation and/or stress together with the initiation and perpetuation of a pro-thrombotic milieu; ^1,95,96 furthermore, direct myocardial injury secondary to acute systemic viral infection might also play a role.⁹⁰ Importantly, COVID-19 infection is characterized by infiltration of inflammatory cells that cause excessive production of cytokines, proteases, coagulation factors, oxygen radicals and vasoactive molecules leading to endothelial dysfunction and injury, disruption of fibrous cap, initiation of the coagulation cascade leading to a hypercoagulable state and thrombus formation. In addition, the viral disease may cause vasoconstriction and stimulation of platelet activation, further contributing to the deleterious vascular effects. A higher thrombus burden involving the coronary vessels, as well as the cardiac cavities, has been reported in COVID-19 patients presenting with STEMI.^95,97 Finally, significant hypoxia in the setting of a thrombo-inflammatory milieu may lead to atherosclerotic plaque rupture and coronary thrombosis and acute MI. Thus, a “cytokine storm” along with or without direct myocardial damage, together with “endotheliitis” combined with hypercoagulability, hypoxia and sympathetic activation, all leading to destabilization of pre-existing plaques and/or de novo formation of new plaques, plaque rupture and coronary thrombosis, may be responsible for ACS events in COVID-19.^{1,21,90,98,99}

Acute Cardiac Injury

The pathogenesis of COVID-19 infection-related ACI in the absence of an apparent ACS event, remains to be elucidated. Nevertheless, one suggestion points to hyperinflammation and cytokine storm mediated through pathologic T-cells and monocytes leading to myocarditis.²¹ Another suggestion concerns the direct infection and invasion of myocardial cells by the virus, causing myocardial cell damage and viral myocarditis.¹⁰⁰ The virus enters human cells through binding of spike (S) protein with angiotensin converting enzyme (ACE) 2, an ACE homologue, which is highly expressed in myocardial tissue and plays an important role in the CV system.^3,101 Although ACI biomarkers (cTn) in all patients with ACI and ECG changes in some patients highly suggest that the virus directly infects the myocardium and leads to myocarditis, direct pathological and imaging evidence remains scarce.^102,103 Some investigators have even suggested that COVID-19 infection does not cause myocarditis, and myocardial ischemia is the most probable explanation of the ACI.¹⁰⁴ Others have proposed hypercoagulability and development of coronary microvascular thrombosis, as a possible cause of ACI in some patients, while diffuse endothelial injury and “endotheliitis” in several organs including the heart, has also been considered in other cases.^{21,95,105,106} Indeed, cardiac histopathology studies have shown scattered individual cell myocyte necrosis suggestive of pericytes infection by SARS-CoV-2 causing capillary endothelial cell or microvascular dysfunction.¹⁰⁷ Other investigators have pointed to microthrombi as the most common pathological cause of myocyte necrosis; these microthrombi appear different in composition from intramyocardial thromboemboli from COVID-19 negative individuals and from coronary thrombi retrieved from COVID-19 positive and negative STEMI patients.¹⁰⁸

Another mechanism of myocardial injury may relate to cardiomyocyte damage from severe hypoxemia and hypoperfusion, both complicating COVID-19 infection via pulmonary infection and hemodynamic compromise induced by viral sepsis (imbalance of oxygen supply and demand; type II MI).¹⁰⁹ This mechanism may be accentuated in patients with underlying CV disease such as CAD and heart failure. Finally, as already mentioned, the associated hyperinflammatory state, the cytokine storm, may lead to myocardial damage, as well as to other organ (multi-organ) damage and failure, especially in severe COVID cases with the attendant excessive inflammatory response.¹¹⁰

In the end, the interplay between the inflammatory, coagulation, complement and endothelial systems in COVID-19 may account for the ensuing CV complications.^111,112 COVID-19-induced inflammation may involve primary vessel inflammation, possible sepsis and a secondary reaction to tissue damage caused by the virus, leading to generation and release of inflammatory mediators.¹¹³ In addition to acute lung injury and multi-organ failure, a cytokine storm, typically associated with concurrent serum ferritin rises and hemodynamic instability, may also lead to vascular damage.¹¹⁴ Pulmonary thrombosis, not necessarily preceded by deep venous thrombosis, but rather originating primarily in the lungs, may account for the observed “pulmonary embolism” cases.⁹⁵ COVID-19 can confer a hypercoagulable state via activation of the contact and tissue factor pathways¹¹⁵; direct viral myocardial and microvascular injury leads to exposure to subendothelium and collagen, producing platelet and possibly contact pathway activation.¹¹¹ SARS-CoV-2–platelet interactions result in platelet activation and aggregation in COVID-19, further enhancing the pro-thrombotic vascular milieu.¹¹⁶ Evidence suggests that COVID-19 leads to excessive production of neutrophil extracellular traps (NETs) (NETosis), especially in patients with severe disease, which is a key mechanism that predisposes to untoward effects including thromboembolic complications and damage to surrounding tissues and organs.¹¹⁷ COVID-19 microthrombus formation seems to be more closely related to endothelial damage and complement-mediated thrombotic microangiopathy, rather than sepsis-induced coagulopathy or disseminated intravascular coagulation (DIC).¹¹⁸

Acute cardiac injury in COVID-19 may be due to virus-mediated lysis of myocardial cells, also observed in other viral infections, or as a consequence of COVID-binding ACE2 receptors in the heart, thus reducing the activity of ACE2 and dampening the cardioprotective effects of this enzyme.¹¹⁹ COVID-19-induced inflammation resulting in substantial cytokine release can also result in atherosclerotic plaque instability, rupture and subsequent arterial thrombus formation, leading to coronary thrombosis and acute MI.¹²⁰ Finally, COVID-19-induced endothelial dysfunction may play a key role in the development of micro- and macro-vascular complications in the CV system.¹⁰⁶

Patient Delay in Seeking Care and Visiting the Emergency Department/Re-Emergence of Post-MI Mechanical and Other Complications in the COVID-19 Era

In the era of the COVID-19 pandemic, patients hesitate or are reluctant to seek medical care wishing to avoid hospital admission for their health problems lest they contract COVID. Among them, patients with chest pain delay their visit to the emergency room with resultant significant delay in first medical contact, including patients suffering from acute STEMI.^66,121 Thus, a surge of case reports emerges of delayed presentation of STEMI complicated by ventricular septal or LV free wall rupture or acute mitral regurgitation from papillary muscle rupture, mechanical complications that we used to see in the era when thrombolysis and/or primary PCI were not available.^122

-126 A case series of 10 acute MI patients with delayed presentation reported complications such as heart failure and cardiogenic shock, but also complications rarely seen in the primary PCI era including ventricular septal rupture, LV pseudoaneurysm, and right ventricular infarction.¹²⁷ Another series of 4 cases of post-MI mechanical complications also warns about the delayed access to healthcare for fear of contracting COVID-19 which led to excessively high mortality (75%).¹²⁸ A case of post-MI pericarditis has also been reported.¹²⁹

As mentioned, another case series of 78 COVID-19 positive patients presenting with STEMI found a high rate (76%) of thrombolysis vs primary PCI (24%), a high rate of stent thrombosis (21%), and 11% in-hospital mortality.⁶²

According to a UK study, during lockdown, a greater than 50% drop was noted in the number of patients presenting to cardiology and those diagnosed with MI.¹³⁰ Similarly, a study from China indicated a 51.4% decrease in hospital admissions of STEMI patients during the peak period of COVID-19 epidemic.¹³¹ Importantly, lack of reperfusion therapy for STEMI patients was >10% higher in 2020 than the previous 2 years; 2-3 times more STEMI patients received fibrinolysis in 2020 than the 2 previous years, while the volume of primary PCI dropped by more than half. This led to highest mortality rate recorded in February 2020.

A similar study from Greece indicated a lowest number of acute MI cases in March 2020 compared to the number of MI cases in the same month in the preceding 3-year period (P < 0.001); also, there was a significant 30%-40% reduction in the visits to the cardiac emergency room of the hospital during the first 3 months of the pandemic period.¹³²

According to a large cohort study from China comprising 28,189 STEMI patients, the COVID-19 outbreak reduced the number of STEMI cases reported to China chest pain centers, the percentage of patients undergoing primary PCI declined, while the percentage of patients undergoing thrombolysis increased.⁸ With an average delay of ∼20 min for reperfusion therapy, the rate of in-hospital mortality and in-hospital heart failure increased during the outbreak; the rate of in-hospital hemorrhage remained the same.

In the same context, a recent report of data from 18 hospitals or healthcare systems in the US from January 2019 to April 2020 indicated that the COVID-19 pandemic adversely affected many aspects of STEMI care, including timely access to the cardiac catheterization laboratory for primary PCI.⁷ There was a marked reduction in the number of activations for STEMI (29%), which drove a significant decline in the number of activations leading to angiography (34%) and number of activations leading to primary PCI (20%). Similarly, a large US cohort study analyzing 15,244 MI hospitalizations between December 30, 2018, and May 16, 2020 (4955 for STEMI [33%] and 10,289 for NSTEMI [67%]) indicated that beginning February 23, 2020, MI-associated hospitalizations decreased during the early COVID-19 period, while thereafter they started to increase again.¹³³ The observed to expected mortality ratio for MI increased during the early period, disproportionately associated with patients with STEMI. In the same context, a report from Israel pointed to a resurge of MIs with rebound increase in STEMI hospitalizations coinciding with the fading of the first wave of the COVID-19 pandemic.¹³⁴

Finally, a French population-based, observational study assessing the incidence and outcomes of out-of-hospital cardiac arrest (OOHCA) in an urban region during the COVID-19 pandemic, indicated that, compared with non-pandemic periods, the maximum weekly OOHCA incidence increased from 13.42 to 26.64 per million inhabitants (P < 0.0001), before returning to normal in the final weeks of the pandemic period.¹³⁵ There was a higher rate of OOHCA occurring at home (90.2% vs 76.8%; P < 0.0001), less bystander cardiopulmonary resuscitation (47·8% vs 63·9%; P < 0.0001) and shockable rhythm (9·2% vs 19·1%; P < 0.0001), and longer delays to intervention (median 10.4 min vs 9.4 min; P < 0.0001). The number of patients with resuscitated OOHCA admitted alive decreased from 22.8% to 12.8% (P < 0.0001) in the pandemic period. COVID-19 infection accounted for about a third of the increase in OOHCA incidence during the pandemic. This is in keeping with the noted higher incidence of life-threatening arrhythmias incurred by COVID-19-associated ACI and ACS.⁹² Furthermore, ACS-NNOCA may also trigger malignant arrhythmias and sudden cardiac death.⁸¹

Thus, there is a reduced number of admissions for ACS but also a significant delay in ACS presentation consistently reported during the COVID-19 pandemic era.^{7,130,131,136} There is fear supported by important preliminary evidence that this observed pattern may lead to increases in OOHCA, acute mechanical and long-term complications of MI and missed chance to implement secondary prevention therapies for patients with CAD.^{127,128,135,136}

Coronary Thrombus and Coronary Stent Thrombosis

According to an observational study of 115 consecutive patients admitted with STEMI and managed with primary PCI, those presenting with concurrent COVID-19 infection had higher rates of multivessel thrombosis, stent thrombosis, higher thrombus burden, higher use of glycoprotein IIb/IIIa inhibitors and thrombus aspiration; myocardial tissue perfusion, as reflected by myocardial blush grade, and LV function were significantly lower in patients with COVID-19 with STEMI.⁹⁷ Multiple coronary thromboses causing STEMI were reported in a patient with COVID pneumonia who was managed with thrombo-aspiration, coronary stenting and combined antiplatelet and anticoagulant therapy.¹³⁷

Furthermore, a recent case report of STEMI indicated the presence of microvascular thrombi accounting for the dismal course of this STEMI patient in the absence of epicardial vessel occlusion.¹³⁸ On the other hand, a COVID-19 patient presenting with STEMI was found to have LV thrombus despite receiving anticoagulation; D-dimer levels were excessively elevated and the patient succumbed to his disease.¹³⁹

Case reports and series of acute and late stent thrombosis are increasingly being presented in patients with COVID-19 infection.^62,140
-142 In a case series of 78 patients with STEMI, of whom 19 were treated with primary PCI and stenting, 4 patients (21%) developed stent thrombosis.⁶²

Thus, a heavy thrombus burden involving the coronary macro- and micro-vessels, as well as the cardiac cavities, has been reported in COVID-19 patients presenting with STEMI, who also have a higher risk of stent thrombosis.⁹⁵ Whether selective thromboaspiration might improve procedural and clinical outcome in these patients remains to be proven.¹⁴³

Guidelines

STEMI/ Mode of Reperfusion in the COVID-19 Era

As mentioned, a high rate of thrombolysis (76%) was reported in an early series of 78 COVID-19 patients presenting with STEMI.⁶² Similarly, in a large cohort study from China comprising 28,189 STEMI patients, the percentage of patients undergoing primary PCI declined (OR 0.76; P < 0.001), while the percentage of patients undergoing thrombolysis increased (OR: 1.66; P < 0.001). These results are in accordance with early national STEMI protocols in China and Taiwan that recommended prioritizing thrombolysis.^8,144 However, although a decreasing trend toward primary PCI and an increasing use of thrombolysis as first approach to patients with STEMI had become apparent during the early phase of the pandemic, current guidelines still support primary PCI as the preferred strategy.^145,146

In keeping with objections to thrombolysis as first approach to STEMI in the COVID-19 era and in accordance with the established superiority of primary PCI in managing STEMI patients, a recent European Society of Cardiology (ESC) guidance document recommends primary PCI for all STEMI patients.¹⁴⁷ Specifically, the guidance indicates that primary PCI remains the reperfusion therapy of choice if feasible within the time frame of 120 min and performed in facilities approved for the treatment of COVID-19 patients in a safe manner for healthcare providers and other patients; primary PCI may be delayed during the pandemic (up to 60 minutes) for reasons of logistics; if the target time cannot be met and fibrinolysis is not contraindicated, fibrinolysis should then become first line therapy.¹⁴⁷ They also point out that any STEMI patient should be considered potentially infected since commonly the COVID-19 test results are not immediately available.

Similarly, the American Heart Association (AHA) indicates that in the absence of significant system resource constraints, PCI should remain the primary and preferred reperfusion strategy for patients with STEMI based on superior outcomes with PCI including preservation of LV function and lower rates of reinfarction, stroke, and death.¹⁴⁵ Furthermore, the AHA states that testing for COVID-19 should not delay primary PCI for those with clear STEMI. Fibrinolysis should be considered for patients with STEMI who cannot receive PCI and coronary reperfusion within 120 minutes.

A recent Consensus Statement from the Society for Cardiovascular Angiography and Interventions (SCAI), American College of Cardiology (ACC), and the American College of Emergency Physicians (ACEP) emphasizes the need for primary PCI to remain the standard of care for STEMI patients during the COVID-19 pandemic at PCI-capable hospitals when it can be provided in a timely fashion, with an expert team fitted with personal protection equipment (PPE) in a dedicated catheterization laboratory.¹⁴⁸ They recommend a fibrinolysis-based strategy at non-PCI capable hospitals or in specific situations where primary PCI cannot be performed or is not considered the best option.

Myocarditis

The ESC recommends treating patients with acute myocarditis complicated by cardiogenic shock with inotropes and/or vasopressors and mechanical ventilation.¹⁴⁹ Additionally, in patients requiring longer-term support, extracorporeal membrane oxygenation (ECMO) and LV assist devices should be used.

By and large, glucocorticoids and immunoglobulin therapy are not supported for routine therapy in acute myocarditis, especially in infection-positive forms, as based on prior studies, reviews and the ESC recommendation.^149
-151 However, there are case reports of successful treatment of COVID-19 fulminant myocarditis using antiviral therapy (lopinavir-ritonavir), immune-modulators (interferon alpha-1β, methylprednisolone, immunoglobulin) and supportive measures (inotropes, ECMO).^152
-154 As mentioned, a recent review of 14 patients showed favorable outcomes in COVID-19 patients with myocarditis treated with steroid therapy.⁵⁷ In a pediatric series of 20 children presenting with fulminant myocarditis and shock, all children but one received inotropic/vasoactive drug support, all received IV immunoglobulin (with adjuvant corticosteroids administered in 2), and all children survived and were afebrile with a full LV function recovery at discharge from the ICU.¹⁵⁵

Conclusion

Acute cardiac injury (ACI), defined by elevated cTn levels above the 99th percentile, constitutes the most commonly reported CV abnormality in COVID-19 infection, associated with high mortality rates. In addition to clinically and electrocardiographically discernible causes of ACI, such as STEMI or NSTEMI, other causes need to be considered such as myocarditis, Takotsubo syndrome, acute heart failure, and direct injury from COVID-19; furthermore, noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis need also be taken into account (Table 2). ACS-NNOCA appears to have a higher prevalence in both COVID-19 positive and negative patients in the pandemic era, likely due to associated stress incurred by the pandemic, with most data particularly supporting an increased incidence of TTC. Echocardiography with its new strain imaging techniques, chest CT, CTCA or invasive coronary angiography and/or CMR imaging are most helpful in the differential diagnosis (Figure 2), obviating the need for endomyocardial biopsy to render a diagnosis of myocarditis and/or differentiate from other causes of ACI detailed in this review. CMR is singled out as the preferred imaging modality for non-invasive evaluation in ACI, also enabling risk stratification and prognostication.⁴⁶

Several studies have now documented a significant reduction of hospital access for patients with STEMI or any type of ACS in the COVID-19 era with an increase in treatment delay, longer hospitalization, higher levels of cTn, higher rates of LV dysfunction, higher rates of thrombolytic treatment of STEMI vs primary PCI and worse clinical outcomes.^{6,8,9,60,62,156}

Despite a tendency of preferring less invasive approaches in ACS patients during the pandemic, e.g. by administering thrombolysis to more STEMI patients, professional societies still emphasize the need for primary PCI to remain the standard of care for STEMI patients at PCI-capable hospitals when it can be provided in a timely fashion, with an expert team fitted with PPE in a dedicated catheterization laboratory, leaving fibrinolysis-based strategies for non-PCI capable hospitals or in situations where primary PCI cannot be performed within standard timelines.

Perspective

Acute cardiac injury with cTn levels >99th percentile occurs in a considerable percentage of patients afflicted by COVID-19 due to a variety of causes related to this viral pandemic and portends a poor prognosis. Improved understanding of the acute and chronic sequelae of ACI and CV involvement incurred by COVID-19 infection with use of CMR and other CV imaging techniques (e.g., newer echo techniques) may help us to better monitor these patients and devise preventive and therapeutic strategies and finally teach us how to prevent similar calamities in the future. Newer therapies and effective vaccination may hopefully halt a downward spiral and restrain and contain this disease.

In this pandemic era, digital health services, with telemetry via either standard, mobile or wearable monitoring systems, are quickly expanding to protect both patients and health care personnel.¹⁵⁷ However, patient access issues need to be urgently addressed during this pandemic in order to reduce inordinate delays for COVID and non-COVID patients to receive appropriate cardiac (e.g., primary PCI for acute STEMI) and other therapies that may lead to worse clinical outcome with increased morbidity and mortality.

Footnotes

Author Contributions

All authors contributed to the preparation of this manuscript and approved the final version. ASM conceived and designed the project, analyzed the data, wrote the initial draft, and edited the final product; AAM conducted literature search, constructed the Tables and edited/revised the manuscript; TAM conducted literature search, designed the Figures and edited/revised the manuscript; HM analyzed the data, reviewed, revised, and edited the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Antonis S. Manolis

Helen Melita

References

Schiavone

Gobbi

Biondi-Zoccai

, et al. Acute coronary syndromes and Covid-19: exploring the uncertainties. J Clin Med. 2020;9(6):1683.

Boukhris

Hillani

Moroni

, et al. Cardiovascular implications of the COVID-19 pandemic: a global perspective. Can J Cardiol. 2020;36(7):1068–1080.

Manolis

. Cardiovascular complications of the coronavirus (COVID-19) infection. Rhythmos. 2020;15(2):23–28.

De Lorenzo

Kasal

Tura

Lamas

Rey

. Acute cardiac injury in patients with COVID-19. Am J Cardiovasc Dis. 2020;10(2):28–33.

Sandoval

Januzzi

Jr Jaffe

. Cardiac troponin for the diagnosis and risk-stratification of myocardial injury in COVID-19: JACC review topic of the week. J Am Coll Cardiol. 2020;76(10):1244–1258.

Cammalleri

Muscoli

Benedetto

, et al. Who has seen ST-segment elevation myocardial infarction patients? First results from Italian real world COVID-19. J Am Heart Assoc. 2020;9(19):e017126.

Garcia

Stanberry

Schmidt

, et al. Impact of COVID-19 pandemic on STEMI care: an expanded analysis from the United States [published online August 7, 2020]. Catheter Cardiovasc Interv. 2020. doi:10.1002/ccd.29154

Xiang

Zhang

, et al. Management and outcomes of patients with STEMI during the COVID-19 pandemic in China. J Am Coll Cardiol. 2020;76(11):1318–1324.

Nijjer

Petraco

Sen

. Optimal management of acute coronary syndromes in the era of COVID-19. Heart. 2020;106(20):1609–1616.

10.

Manolis

Melita

. Acute coronary syndromes in patients with angiographically normal or near normal (non-obstructive) coronary arteries. Trends Cardiovasc Med. 2018;28(8):541–551.

11.

Lee

Jobe

Mathis

Gibbons

. Incremental validity of coronaphobia: coronavirus anxiety explains depression, generalized anxiety, and death anxiety. J Anxiety Disord. 2020;74:102268.

12.

Jabri

Kalra

Kumar

, et al. Incidence of stress cardiomyopathy during the coronavirus disease 2019 pandemic. JAMA Netw Open. 2020;3(7):e2014780.

13.

Edmondson

Newman

Whang

Davidson

. Emotional triggers in myocardial infarction: do they matter? Eur Heart J. 2013;34(4):300–306.

14.

Moroni

Gramegna

Ajello

, et al. Collateral damage: medical care avoidance behavior among patients with myocardial infarction during the COVID-19 pandemic. JACC Case Rep. 2020;2(10):1620–1624.

15.

Lippi

Lavie

Sanchis-Gomar

. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): evidence from a meta-analysis. Prog Cardiovasc Dis. 2020;63(3):390–391.

16.

Lombardi

Carubelli

Iorio

, et al. Association of troponin levels with mortality in Italian patients hospitalized with coronavirus disease 2019: results of a multicenter study. JAMA Cardiol. 2020;5(11):1274–1280.

17.

Anupama

Chaudhuri

. A review of acute myocardial injury in coronavirus disease 2019. Cureus. 2020;12(6):e8426.

18.

Raad

Dabbagh

Gorgis

, et al. Cardiac injury patterns and inpatient outcomes among patients admitted with COVID-19. Am J Cardiol. 2020;133:154–161.

19.

Lala

Johnson

Januzzi

, et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. J Am Coll Cardiol 2020;76(5):533–546.

20.

Zou

Qian

Wang

Zhao

Bai

. Cardiac injury and COVID-19: a systematic review and meta-analysis. CJC Open. 2020;2(5):386–394.

21.

Bavishi

Bonow

Trivedi

, et al. Acute myocardial injury in patients hospitalized with COVID-19 infection: a review. Prog Cardiovasc Dis. 2020;63(5):682–689.

22.

Santoso

Pranata

Wibowo

, et al. Cardiac injury is associated with mortality and critically ill pneumonia in COVID-19: a meta-analysis [published online April 19, 2020]. Am J Emerg Med. 2020;S0735–S6757. doi:10.1016/j.ajem.2020.04.052

23.

Zuin

Rigatelli

Zuliani

, et al. Incidence and mortality risk in coronavirus disease 2019 patients complicated by acute cardiac injury: systematic review and meta-analysis. J Cardiovasc Med (Hagerstown). 2020;21(10):759–764.

24.

Han

Woodward

, et al. The impact of 2019 novel coronavirus on heart injury: a systematic review and meta-analysis. Prog Cardiovasc Dis. 2020;63(4):518–524.

25.

Guan

, et al. Impact of cardiovascular disease and cardiac injury on in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis. Heart 2020;106(15):1142–1147.

26.

Figliozzi

Masci

Ahmadi

, et al. Predictors of adverse prognosis in COVID-19: a systematic review and meta-analysis. Eur J Clin Invest 2020;50(10):e13362.

27.

Vakhshoori

Heidarpour

Shafie

, et al. Acute cardiac injury in COVID-19: a systematic review and meta-analysis. Arch Iran Med. 2020;23(11):801–812.

28.

Bansal

Kumar

Patel

, et al. Meta-analysis comparing outcomes in patients with and without cardiac injury and coronavirus disease 2019 (COVID 19). Am J Cardiol. 2021;141:140–146.

29.

Dalia

Lahan

Ranka

, et al. Impact of congestive heart failure and role of cardiac biomarkers in COVID-19 patients: a systematic review and meta-analysis. Indian Heart J. 2021;73(1):91–98.

30.

Prasitlumkum

Chokesuwattanaskul

Thongprayoon

, et al. Incidence of myocardial injury in Covid-19-infected patients: a systematic review and meta-analysis. Diseases. 2020;8(4):40.

31.

Chapman

Bularga

Mills

. High-sensitivity cardiac troponin can be an ally in the fight against COVID-19. Circulation. 2020;141:1733–1735.

32.

Gaze

. Clinical utility of cardiac troponin measurement in COVID-19 infection. Ann Clin Biochem. 2020;57(3):202–205.

33.

Huang

Wang

, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.

34.

Tavazzi

Pellegrini

Maurelli

, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail. 2020;22(5):911–915.

35.

Kociol

Cooper

Fang

, et al. Recognition and initial management of fulminant myocarditis: a scientific statement from the American Heart Association. Circulation. 2020;141(6):e69–e92.

36.

Moayed

Rahimi-Bashar

Vahedian-Azimi

, et al. Cardiac injury in COVID-19: a systematic review. Adv Exp Med Biol. 2021;1321:325–333.

37.

Wang

Shu

Liu

, et al. The peak levels of highly sensitive troponin I predicts in-hospital mortality in COVID-19 patients with cardiac injury: a retrospective study. Eur Heart J Acute Cardiovasc Care. 2021;10(1):6–15.

38.

Zheng

Jiang

. Key factors leading to fatal outcomes in COVID-19 patients with cardiac injury. Sci Rep. 2021;11(1):4144.

39.

Thygesen

Alpert

Jaffe

, et al. Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol. 2018;72(18):2231–2264.

40.

Sala

Peretto

Gramegna

, et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J. 2020;41(19):1861–1862.

41.

Peretto

Sala

Caforio

ALP

. Acute myocardial injury, MINOCA, or myocarditis? Improving characterization of coronavirus-associated myocardial involvement. Eur Heart J. 2020;41(22):2124–2125.

42.

Hudowenz

Klemm

Lange

, et al. Case report of severe PCR-confirmed COVID-19 myocarditis in a European patient manifesting in mid January 2020. Eur Heart J Case Rep. 2020;4:1–6.

43.

Deng

Zhang

, et al. Suspected myocardial injury in patients with COVID-19: evidence from front-line clinical observation in Wuhan, China. Int J Cardiol. 2020;311:116–121.

44.

Castiello

Georgiopoulos

Finocchiaro

, et al. COVID-19 and myocarditis: a systematic review and overview of current challenges [published online March 24, 2021]. Heart Fail Rev. 2021:1–11. doi:10.1007/s10741-021-10087-9

45.

Kawakami

Sakamoto

Kawai

, et al. Pathological evidence for SARS-CoV-2 as a cause of myocarditis: JACC review topic of the week. J Am Coll Cardiol. 2021;77(3):314–325.

46.

Sanghvi

Schwarzman

Nazir

. Cardiac MRI and myocardial injury in COVID-19: diagnosis, risk stratification and prognosis. Diagnostics (Basel). 2021;11(1):130.

47.

Ojha

Verma

Pandey

, et al. Cardiac magnetic resonance imaging in coronavirus disease 2019 (COVID-19): a systematic review of cardiac magnetic resonance imaging findings in 199 patients. J Thorac Imaging. 2021;36(2):73–83.

48.

Singh

Choi

Leipsic

, et al. Use of cardiac CT amidst the COVID-19 pandemic and beyond: North American perspective. J Cardiovasc Comput Tomogr. 2020;15(1):16–26.

49.

Citro

Pontone

Bellino

, et al. Role of multimodality imaging in evaluation of cardiovascular involvement in COVID-19. Trends Cardiovasc Med. 2021;31(1):8–16.

50.

Goerlich

Minhas

Mukherjee

, et al. Multimodality imaging for cardiac evaluation in patients with COVID-19. Curr Cardiol Rep. 2021;23(5):44.

51.

El-Assaad

Hood-Pishchany

Kheir

, et al. Complete heart block, severe ventricular dysfunction, and myocardial inflammation in a child with COVID-19 infection. JACC Case Rep. 2020;2(9):1351–1355.

52.

Garot

Amour

Pezel

, et al. SARS-CoV-2 fulminant myocarditis. JACC Case Rep. 2020;2(9):1342–1346.

53.

Joshi

Kaplan

Bakar

, et al. Cardiac dysfunction and shock in pediatric patients with COVID-19. JACC Case Rep. 2020;2(9):1267–1270.

54.

Lara

Young

Del Toro

, et al. Acute fulminant myocarditis in a pediatric patient with COVID-19 infection. Pediatrics. 2020;146(2):e20201509.

55.

Khalid

Dasu

. A case of novel coronavirus (COVID-19)-induced viral myocarditis mimicking a takotsubo cardiomyopathy. HeartRhythm Case Rep. 2020;6(8):473–476.

56.

Hussain

Fadel

Alwaeli

Guardiola

. Coronavirus (COVID-19) fulminant myopericarditis and acute respiratory distress syndrome (ARDS) in a middle-aged male patient. Cureus. 2020;12(6):e8808.

57.

Sawalha

Abozenah

Kadado

, et al. Systematic review of COVID-19 related myocarditis: insights on management and outcome. Cardiovasc Revasc Med. 2021;23:107–113.

58.

Esposito

Palmisano

Natale

, et al. Cardiac magnetic resonance characterization of myocarditis-like acute cardiac syndrome in COVID-19. JACC Cardiovasc Imaging. 2020;13(11):2462–2465.

59.

Manolis

. Pediatric inflammatory multisystem syndrome temporally associated with SARS-Cov-2 infection (PIMS-TS): Kawasaki-like multisystem inflammatory syndrome in children (MIS-C) during the COVID-19 pandemic with predominant myocarditis. Rhythmos. 2020;15:42–46.

60.

Solano-López

Zamorano

Pardo Sanz

, et al. Risk factors for in-hospital mortality in patients with acute myocardial infarction during the COVID-19 outbreak. Rev Esp Cardiol (Engl Ed). 2020;73(12):985–993.

61.

Gramegna

Baldetti

Beneduce

, et al. ST-segment-elevation myocardial infarction during COVID-19 pandemic: insights from a regional public service healthcare hub. Circ Cardiovasc Interv. 2020;13(8):e009413.

62.

Hamadeh

Aldujeli

Briedis

, et al. Characteristics and outcomes in patients presenting with COVID-19 and ST-segment elevation myocardial infarction. Am J Cardiol. 2020;131:1–6.

63.

De Filippo

D’Ascenzo

Angelini

, et al. Reduced rate of hospital admissions for ACS during Covid-19 outbreak in northern Italy. N Engl J Med. 2020;383(1):88–89.

64.

Rivero

Antuña

Cuesta

Alfonso

. Severe coronary spasm in a COVID-19 patient. Catheter Cardiovasc Interv. 2021;97(5):E670–E672.

65.

Feuchtner

Barbieri

Luger

, et al. Myocardial injury in COVID-19: the role of coronary computed tomography angiography (CTA). J Cardiovasc Comput Tomogr. 2020;15(1):e3–e6.

66.

Popovic

Varlot

Metzdorf

, et al. Changes in characteristics and management among patients with ST-elevation myocardial infarction due to COVID-19 infection. Catheter Cardiovasc Interv. 2021;97(3):E319–E326.

67.

Bangalore

Sharma

Slotwiner

, et al. ST-segment elevation in patients with Covid-19—a case series. N Engl J Med. 2020;382(25):2478–2480.

68.

Giustino

Croft

Oates

, et al. Takotsubo cardiomyopathy in COVID-19. J Am Coll Cardiol. 2020;76(5):628–629.

69.

Kariyanna

Chandrakumar

Jayarangaiah

, et al. Apical takotsubo cardiomyopathy in a COVID-19 patient presenting with stroke: a case report and pathophysiologic insights. Am J Med Case Rep. 2020;8(10):350–357.

70.

Bottiroli

De Caria

Belli

, et al. Takotsubo syndrome as a complication in a critically ill COVID-19 patient. ESC Heart Fail. 2020;7(6):4297–4300.

71.

Minhas

Scheel

Garibaldi

, et al. Takotsubo syndrome in the setting of COVID-19. JACC Case Rep. 2020;2(9):1321–1325.

72.

Bernardi

Calvi

Cimino

, et al. COVID-19 pneumonia, takotsubo syndrome, and left ventricle thrombi. JACC Case Rep. 2020;2(9):1359–1364.

73.

Taza

Zulty

Kanwal

Grove

. Takotsubo cardiomyopathy triggered by SARS-CoV-2 infection in a critically ill patient. BMJ Case Rep. 2020;13(6):e236561.

74.

Desai

Jadeja

Sharma

. Takotsubo syndrome a rare entity in patients with COVID-19: an updated review of case-reports and case-series. Int J Cardiol Heart Vasc. 2020;29:100604.

75.

Pasqualetto

Secco

Nizzetto

, et al. Stress cardiomyopathy in COVID-19 disease. Eur J Case Rep Intern Med. 2020;7(6):001718.

76.

Faqihi

Alharthy

Alshaya

, et al. Reverse takotsubo cardiomyopathy in fulminant COVID-19 associated with cytokine release syndrome and resolution following therapeutic plasma exchange: a case-report. BMC Cardiovasc Disord. 2020;20(1):389.

77.

Meyer

Degrauwe

Van Delden

Ghadri

Templin

. Typical takotsubo syndrome triggered by SARS-CoV-2 infection. Eur Heart J. 2020;41(19):1860.

78.

Courand

Harbaoui

Bonnet

Lantelme

. Spontaneous coronary artery dissection in a patient with COVID-19. JACC Cardiovasc Interv. 2020;13:e107–e108.

79.

Agdamag

ACC

Edmiston

Charpentier

, et al. Update on COVID-19 myocarditis. Medicina (Kaunas). 2020;56(12):678.

80.

Stefanini

Montorfano

Trabattoni

, et al. ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes. Circulation. 2020;141(25):2113–2116.

81.

Kosmas

Manolis

Dagres

Iliodromitis

. Myocardial infarction or acute coronary syndrome with non-obstructive coronary arteries and sudden cardiac death: a missing connection. Europace. 2020;22(9):1303–1310.

82.

Chadha

. ‘COVID-19 pandemic’ anxiety-induced takotsubo cardiomyopathy. QJM. 2020;113(7):488–490.

83.

O’Keefe

Torres-Acosta

O’Keefe

, et al. Takotsubo syndrome: cardiotoxic stress in the COVID era. Mayo Clin Proc Innov Qual Outcomes. 2020;4(6):775–785.

84.

Rudski

Januzzi

Rigolin

, et al. Multimodality imaging in evaluation of cardiovascular complications in patients with COVID-19. J Am Coll Cardiol. 2020;76(11):1345–1357.

85.

Hausvater

Smilowitz

, et al. Myocarditis in relation to angiographic findings in patients with provisional diagnoses of MINOCA. JACC Cardiovasc Imaging. 2020;13(9):1906–1913.

86.

Sivakumar

Amancharla

RKG

Murthy

. ACS like presentation with normal coronaries: are they all MINOCA? Utility of cardiac MRI. IHJ Cardiovasc Case Rep. 2017;1:132–134.

87.

Shmueli

Shah

Ebinger

, et al. Left ventricular global longitudinal strain in identifying subclinical myocardial dysfunction among patients hospitalized with COVID-19. Int J Cardiol Heart Vasc. 2021;32:100719.

88.

Panchal

Kyvernitakis

Mikolich

Biederman

RWW

. Contemporary use of cardiac imaging for COVID-19 patients: a three center experience defining a potential role for cardiac MRI. Int J Cardiovasc Imaging. 2021:1–13.

89.

Wang

, et al. Widespread myocardial dysfunction in COVID-19 patients detected by myocardial strain imaging using 2-D speckle-tracking echocardiography [published online January 28, 2021]. Acta Pharmacol Sin. 2021;1–8. doi:10.1038/s41401-020-00595-z

90.

Sheth

Grewal

Patel

, et al. Possible mechanisms responsible for acute coronary events in COVID-19. Med Hypotheses. 2020;143:110125.

91.

Manolis

Apostolopoulos

, et al.

The role of the autonomic nervous system in cardiac arrhythmias: the neuro-cardiac axis, more foe than friend [published online May 17, 2020]?

Trends Cardiovasc Med. 2020;S1050–1738(20)30066–9. doi:10.1016/j.tcm.2020.04.011

92.

Manolis

Apostolopoulos

Papatheou

Melita

. COVID-19 infection and cardiac arrhythmias. Trends Cardiovasc Med. 2020;30(8):451–460.

93.

Pillai

Trikkur

Farooque

, et al. Type II myocardial infarction: predisposing factors, precipitating elements, and outcomes. Cureus. 2020;12(7):e9254.

94.

Manolis

Melita

. Atherosclerosis: an athero-thrombo-inflammatory disease. Hosp Chronicles. 2012;7(4):195–201.

95.

Manolis

Papatheou

Melita

. COVID-19 infection: viral macro- and micro-vascular coagulopathy and thromboembolism / prophylactic and therapeutic management. J Cardiovasc Pharmacol Ther. 2021;26(1):12–24.

96.

Singhania

Bansal

Nimmatoori

, et al. Current overview on hypercoagulability in COVID-19. Am J Cardiovasc Drugs. 2020;20(5):1–11.

97.

Choudry

Hamshere

Rathod

, et al. High thrombus burden in patients with COVID-19 presenting with ST-elevation myocardial infarction. J Am Coll Cardiol. 2020;76(10):1168–1176.

98.

Jenab

Rezaei

Hedayat

, et al. Occurrence of acute coronary syndrome, pulmonary thromboembolism, and cerebrovascular event in COVID-19. Clin Case Rep. 2020;8(12):2414–2417.

99.

Tedeschi

Rizzi

Biscaglia

Tumscitz

. Acute myocardial infarction and large coronary thrombosis in a patient with COVID-19. Catheter Cardiovasc Interv. 2021;97(2):272–277.

100.

Abdelnabi

Eshak

Saleh

Almaghraby

. Coronavirus disease 2019 myocarditis: insights into pathophysiology and management. Eur Cardiol. 2020;15:e51.

101.

Manolis

Melita

. The controversy of renin-angiotensin-system blocker facilitation versus countering COVID-19 infection. J Cardiovasc Pharmacol. 2020;76(4):397–406.

102.

Lindner

Fitzek

Bräuninger

, et al. Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiol. 2020;5(11):1281–1285.

103.

Bradley

Maioli

Johnston

, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series. Lancet. 2020;396(10247):320–332.

104.

Beigmohammadi

Jahanbin

Safaei

, et al. Pathological findings of postmortem biopsies from lung, heart, and liver of 7 deceased COVID-19 patients. Int J Surg Pathol. 2021;29(2):135–145.

105.

Vrints

CJM

Krychtiuk

Van Craenenbroeck

Segers

Price

Heidbuchel

. Endothelialitis plays a central role in the pathophysiology of severe COVID-19 and its cardiovascular complications [published online November 19, 2020]. Acta Cardiol. 2020:1–16.

106.

Evans

Rainger

Mason

, et al. Endothelial dysfunction in COVID-19: a position paper of the ESC working group for atherosclerosis and vascular biology, and the ESC council of basic cardiovascular science. Cardiovasc Res. 2020;116(14):2177–2184.

107.

Fox

Akmatbekov

Harbert

, et al. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir Med. 2020;8(7):681–686.

108.

Pellegrini

Kawakami

Guagliumi

, et al. Microthrombi as a major cause of cardiac injury in COVID-19: a pathologic study. Circulation. 2021;143(10):1031–1042.

109.

Zheng

Zhang

Xie

. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259–260.

110.

Wei

Zhang

Cui

Jiang

. Progress in treatment of myocardial injury in patients with 2019-nCoV: a Chinese experience. Heart Surg Forum. 2020;23(4):E426–E429.

111.

Page

Ariëns

RAS

. Mechanisms of thrombosis and cardiovascular complications in COVID-19. Thromb Res. 2021;200:1–8.

112.

Liu

. The roles and potential therapeutic implications of C5a in the pathogenesis of COVID-19-associated coagulopathy. Cytokine Growth Factor Rev. 2021;58:75–81.

113.

Pearce

Davidson

Yellon

. The cytokine storm of COVID-19: a spotlight on prevention and protection. Expert Opin Ther Targets. 2020;24(8):723–730.

114.

Ragab

Salah Eldin

Taeimah

Khattab

Salem

. The COVID-19 cytokine storm; what we know so far. Front Immunol. 2020;11:1446.

115.

Bautista-Vargas

Bonilla-Abadía

Cañas

. Potential role for tissue factor in the pathogenesis of hypercoagulability associated with in COVID-19. J Thromb Thrombolysis. 2020;50:479–483.

116.

Manne

Denorme

Middleton

, et al. Platelet gene expression and function in patients with COVID-19. Blood. 2020;136(11):1317–1329.

117.

Janiuk

Jabłońska

Garley

. Significance of NETs formation in COVID-19. Cells. 2021;10(1):151.

118.

Wang

Sahu

Cerny

. Coagulopathy, endothelial dysfunction, thrombotic microangiopathy and complement activation: potential role of complement system inhibition in COVID-19. J Thromb Thrombolysis. 2021;51(3):657–662.

119.

Manolis

Melita

. Cardiovascular implications and complications of the coronavirus disease-2019 pandemic: a world upside down. Curr Opin Cardiol. 2021;36(2):241–251.

120.

Fatkhullina

Peshkova

Koltsova

. The role of cytokines in the development of atherosclerosis. Biochemistry (Mosc). 2016;81(11):1358–1370.

121.

Coughlan

Chongprasertpon

Arockiam

Arnous

Kiernan

. COVID-19 and STEMI: a snapshot analysis of presentation patterns during a pandemic. Int J Cardiol Heart Vasc. 2020;30:100546.

122.

Ahmed

Nautiyal

Kapadia

Nissen

. Delayed presentation of STEMI complicated by ventricular septal rupture in the era of COVID-19 pandemic. JACC Case Rep. 2020;2(10):1599–1602.

123.

Atreya

Kawamoto

Yelavarthy

, et al. Acute myocardial infarction and papillary muscle rupture in the COVID-19 era. JACC Case Rep. 2020;2(10):1637–1641.

124.

Albiero

Seresini

. Subacute left ventricular free wall rupture after delayed STEMI presentation during the COVID-19 pandemic. JACC Case Rep. 2020;2(10):1603–1609.

125.

Joshi

Kazmi

Sadiq

Azemi

. Post-MI ventricular septal defect during the COVID-19 pandemic. JACC Case Rep. 2020;2(10):1628–1632.

126.

Alsidawi

Campbell

Tamene

Garcia

. Ventricular septal rupture complicating delayed acute myocardial infarction presentation during the COVID-19 pandemic. JACC Case Rep. 2020;2(10):1595–1598.

127.

Shah

Tang

Ibrahim

, et al. Surge in delayed myocardial infarction presentations: an inadvertent consequence of social distancing during the COVID-19 pandemic. JACC Case Rep. 2020;2(10):1642–1647.

128.

Qureshi

Al-Drugh

Ogunsua

, et al. Post myocardial infarction complications during the COVID-19 pandemic—a case series. Cardiovasc Revasc Med. 2020;S1553-8389(20):30474–30477. doi:10.1016/j.carrev.2020.08.005

129.

Otero

Singam

NSV

Barry

, et al. Complication of late presenting STEMI due to avoidance of medical care during the COVID-19 pandemic. JACC Case Rep. 2020;2(10):1610–1613.

130.

Fersia

Bryant

Nicholson

, et al. The impact of the COVID-19 pandemic on cardiology services. Open Heart. 2020;7(2):e001359.

131.

Zhang

Song

Dang

. Experience of ST segment elevation myocardial infarction management during COVID-19 pandemic from the mainland of China. Cardiovasc Revasc Med. 2020;S1553-8389(20):30453–X. doi:10.1016/j.carrev.2020.07.027

132.

Tsioufis

Chrysohoou

Kariori

, et al. The mystery of “missing” visits in an emergency cardiology department, in the era of COVID-19; a time-series analysis in a tertiary Greek General Hospital. Clin Res Cardiol. 2020;109:1483–1489.

133.

Gluckman

Wilson

Chiu

, et al. Case rates, treatment approaches, and outcomes in acute myocardial infarction during the coronavirus disease 2019 pandemic. JAMA Cardiol. 2020;5(12):1–6.

134.

Fardman

Oren

Berkovitch

, et al. Post Covid-19 acute myocardial infarction rebound. Can J Cardiol. 2020;36(11):1832. e15-32. e16.

135.

Marijon

Karam

Jost

, et al. Out-of-hospital cardiac arrest during the COVID-19 pandemic in Paris, France: a population-based, observational study. Lancet Public Health. 2020;5(8):e437–e443.

136.

Mafham

Spata

Goldacre

, et al. COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England. Lancet. 2020;396(10248):381–389.

137.

Kurdi

Obaid

UlHaq

Ionescu

Sekar

. Multiple spontaneous coronary thrombosis causing ST-elevation myocardial infarction in a patient with COVID-19. Br J Hosp Med (Lond). 2020;81(7):1–6.

138.

Guagliumi

Sonzogni

Pescetelli

Pellegrini

Finn

. Microthrombi and ST-segment elevation myocardial infarction in COVID-19. Circulation. 2020;142(8):804–809.

139.

Fenton

Siddavaram

Sugihara

Husain

Lessons of the month 3: ST-elevation myocardial infarction and left ventricular thrombus formation: an arterial thrombotic complication of severe COVID-19 infection. Clin Med (Lond). 2020;20(4):437–439.

140.

Prieto-Lobato

Ramos-Martínez

Vallejo-Calcerrada

Corbí-Pascual

Córdoba-Soriano

. A case series of stent thrombosis during the COVID-19 pandemic. JACC Case Rep. 2020;2(9):1291–1296.

141.

Lacour

Semaan

Genet

Ivanes

. Insights for increased risk of failed fibrinolytic therapy and stent thrombosis associated with COVID-19 in ST-segment elevation myocardial infarction patients. Catheter Cardiovasc Interv. 2021;197(2):E241–E243.

142.

Hinterseer

Zens

Wimmer

, et al. Acute myocardial infarction due to coronary stent thrombosis in a symptomatic COVID-19 patient. Clin Res Cardiol. 2021;110(2):302–306.

143.

Manolis

. Is atherothromboaspiration a possible solution for the prevention of no-reflow phenomenon in acute coronary syndromes? Single centre experience and review of the literature. Curr Vasc Pharmacol. 2018;17(2):164–179.

144.

Wang

Huang

Hwang

. Management of acute coronary syndrome in patients with suspected or confirmed coronavirus disease 2019: consensus from Taiwan Society of Cardiology. J Formos Med Assoc. 2021;120(1 Pt 1):78–82.

145.

Temporary Emergency Guidance to STEMI Systems of Care During the COVID-19 Pandemic: AHA’s Mission: lifeline. Temporary Emergency Guidance to STEMI Systems of Care During the COVID-19 Pandemic: AHA’s Mission: lifeline. Circulation. 2020;142(3):199–202.

146.

Kow

Hasan

. Revascularization strategy in patients with acute ST-elevation myocardial infarction amid COVID-19 pandemic. J Formos Med Assoc. 2020;120(1 Pt 3):772–773.

147.

The European Society for Cardiology. ESC Guidance for the Diagnosis and Management of CV Disease During the COVID-19 Pandemic. Published 2020. Updated May 28, 2020. Accessed February 26, 2021. https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance

148.

Mahmud

Dauerman

Welt

, et al. Management of acute myocardial infarction during the COVID-19 pandemic: a position statement from the Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology (ACC), and the American College of Emergency Physicians (ACEP). J Am Coll Cardiol. 2020;96(2):1375–1384.

149.

Caforio

Pankuweit

Arbustini

, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(33):2636–2648, 48a-48d.

150.

Chen

Wang

Liu

. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev. 2013;(10):CD004471.

151.

Robinson

Hartling

Crumley

Vandermeer

Klassen

. A systematic review of intravenous gamma globulin for therapy of acute myocarditis. BMC Cardiovasc Disord. 2005;5(1):12.

152.

Zeng

Liu

Yuan

, et al. First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Infection. 2020;48(5):773–777.

153.

Wei

Fang

. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Eur Heart J. 2021;42(2):206.

154.

Inciardi

Lupi

Zaccone

, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):1–6.

155.

Grimaud

Starck

Levy

, et al. Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children. Ann Intensive Care. 2020;10(1):69.

156.

Suryawan

IGR

Bakhriansyah

Puspitasari

, et al. To reperfuse or not to reperfuse: a case report of Wellens’ syndrome with suspected COVID-19 infection. Egypt Heart J. 2020;72(1):58.

157.

Varma

Marrouche

Aguinaga

, et al. HRS/EHRA/APHRS/LAHRS/ACC/AHA worldwide practice update for telehealth and arrhythmia monitoring during and after a pandemic. J Am Coll Cardiol. 2020;76:1363–1374.

COVID-19 and Acute Myocardial Injury and Infarction: Related Mechanisms and Emerging Challenges

Abstract

Keywords

Introduction

Myocardial Injury in COVID-19

Acute Cardiac Injury (ACI)

ACI and Mortality

Differential Diagnosis

Acute Myocarditis

Acute Coronary Syndromes in Patients With COVID-19 Infection

Acute Coronary Syndromes With Normal or Near-Normal Coronaries

Non-COVID-19 Patients

Mechanisms for COVID-19-Related ACS and ACI

Acute Coronary Syndrome

Acute Cardiac Injury

Patient Delay in Seeking Care and Visiting the Emergency Department/Re-Emergence of Post-MI Mechanical and Other Complications in the COVID-19 Era

Coronary Thrombus and Coronary Stent Thrombosis

Guidelines

STEMI/ Mode of Reperfusion in the COVID-19 Era

Myocarditis

Conclusion

Perspective

Footnotes

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iDs

References