A COVID-19 infection, which primarily affects the lungs, has a wide clinical spectrum, from asymptomatic infection to mild upper respiratory illness, severe viral pneumonia, respiratory failure, shock and, in some cases, death . The COVID-19 pandemic has had a serious impact on our understanding of the traditional course of ACS. However, the course and outcomes of ACS in coronavirus infections remain unclear. It is assumed that it is possible to develop both acute myocardial infarction (AMI) type 1 or 2, and myocardial infarction with non-obstructive coronary arteries (MINOCA) . It is important to be able to recognise ACS concealers, especially atypical ones, in order to provide adequate treatment and avoid additional risks or even harm (for example, fibrinolysis in the case of myocarditis or stress cardiomyopathy which will expose patients to the risk of bleeding or possible invasive coronary angiography for unresolved ST elevation, which would be inappropriate) .
There is no doubt that with the typical course of ACS and a background of COVID-19 infection pathogenetic factors of type 1 and 2 MI are present. With MINOCA, patients are less susceptible to traditional risk factors. Age, male sex, obesity, smoking, and diabetes are not significant predictors of MINOCA, while peripheral vascular disease, cerebrovascular disease, liver disease, kidney disease, and malignant neoplasms are identified as significant predictors . At the same time, SARS-CoV-2 presents a separate problem and it is evident that the viral infection itself, the presence of hypoxia and systemic inflammation are independent risk factors and can lead to destabilisation of existing cardiovascular diseases (CVD).
Classic acute myocardial injury in COVID-19 patients has multiple mechanisms, including direct damage to angiotensin-converting enzyme receptors on myocytes, resulting in damage to angiotensin-converting enzyme 2 (ACE2) signalling pathways .
Another possible mechanism is myocardial ischaemia caused by systemic hypoxia. In the setting of severe COVID-19 infection with acute respiratory distress syndrome (ARDS), multiple microthrombosis, coronary spasm, systemic inflammatory response due to cytokine storm and vasculitis-like vessel damage can be likely triggers, which in severe cases of COVID-19 leads to rupture of the atherosclerotic plaque . Some studies highlight the association between infections and vascular inflammation in atherosclerotic risk .
After internalisation and duplication of SARS-CoV-2 in epithelial cells, multiple cytokines and chemokines are released into the blood, in particular IL6, INFγ and chemotactic protein 1 of monocytes. As angiotensin II levels decrease, vascular permeability increases and vasodilatation capacity decreases also due to an unbalanced angiotensin II/bradykinin equilibrium. Systemic inflammation changes coronary blood flow, leading to the activation and rupture of pre-existing atherosclerotic plaques and causes type 1 myocardial infarction. In addition, the degree of microvascular resistance in patients with coronary syndrome X increases. Thus, in COVID-19, ACS without atherothrombosis also occurs .
An example is the information by Tedeschi et al about a case of acute massive coronary thrombosis in a patient with COVID-19 without pre-existing coronary atherosclerosis (confirmed by coronary angiography). While inflammatory and prothrombotic markers were normal on admission, with the development of ACS they became clearly elevated , indicating the role of COVID-19 vasculitis in the development of type 2 MI. The prothrombotic or endothelitis-inducing effects of SARS-CoV-2 infection can also cause either local coronary thrombosis or distal embolism and contribute to the development of MINOCA. On the other hand, MINOCA and oligosymptomatic infection with SARS-CoV-2 could accidentally arise simultaneously as independent pathological processes .
Clinical peculiarities of ACS in COVID-19
The difficulty lies in the fact that the clinical picture of acute coronary syndrome in a patient with COVID-19 can be masked by the peculiarities of the course of the infectious disease itself. Most patients with COVID-19 and signs of myocardial damage are admitted to the hospital with typical symptoms of SARS-CoV-2 infection: fever, cough, shortness of breath, and bilateral lung infiltrates. The diagnosis of ACS, in this case, may be delayed, and medical personnel should focus on the entire complex of clinical manifestations and examination data (ECG, echocardiography, troponins).
Patients with a COVID-19 infection can be conditionally divided into two groups. The first group includes patients where SARS-CoV-2 is detected in those patients with chronic cardiovascular diseases and classic risk factors. In this case, ACS is a consequence of atherothrombosis, classical pathogenetic mechanisms take place, and the COVID-19 infection happened independently of these, which is a normal course of the disease. The second group includes those patients with a primary infection. Such patients are usually sick for at least two weeks with SARS-CoV-2, and ACS develops against the background of this infection: that is, there is immune vasculitis and hypercoagulation, which are so often talked about in light of the discussion of the pathogenesis of a new viral infection . In this case, there may be several pathogenetic mechanisms: spasm of the coronary artery, dissection of the artery wall, coronary embolism, and/or coronary microcirculation disorders. The presence of an imbalance between myocardial oxygen demand and oxygen supply (type 2 heart attack) as a result of acute respiratory failure and tachyarrhythmia, or even sepsis is important. In some cases, it presents as transient thrombotic lesions of the artery, which occur as a result of cracks or ulceration of the atherosclerotic plaque, which insignificantly narrows the lumen of the artery. Thus, the attention of the clinician in ACS with a background SARS-CoV-2 infection, in addition to the classic risk factors, should be aimed at assessing the mechanisms involved in the development of type 2 MI and the presence of vasospasm. It is also important to exclude the consequences of COVID-19 vasculitis (coronaritis) in the form of dissection of the coronary artery, non-traumatic rupture of the intima and the formation of a false lumen. Wall dissection can occur in both intact and atherosclerotic coronary arteries.
The differential diagnosis of COVID and MI has indeed become a challenge for clinicians. Symptoms of chest pain or tightness are common in patients with an active COVID-19 infection. Pain is usually not well localised and may be associated with shortness of breath due to COVID-19 pneumonia. Associated with this condition is deep hypoxemia, which together with tachycardia, can lead to chest pain and electrocardiographic changes indicating myocardial ischaemia. The presence of a COVID-19 infection can make a differential diagnosis difficult, as shortness of breath and respiratory symptoms may be present, which may precede or precipitate cardiac signs and symptoms.
The most frequently used blood tests useful in COVID-19 patients with cardiovascular involvement are:
- N-terminal (NT)-pro Brain Natriuretic Peptide (BNP),
- D-dimer and ferritin.
Biomarkers indicating rapid deterioration in COVID-19 patients are mostly represented by troponin I (TnI), C-reactive protein (CRP), D-dimer, progressive deterioration of lymphocyte counts and elevated inﬂammatory markers (IL-6, TNF-α) .
It is recognised that elevated troponin levels are an important prognostic factor that must be determined initially and monitored during the treatment of patients with severe coronavirus infection, as well as when complications from the cardiovascular system appear or worsen. At the same time, an early and mild elevation of hs-troponin during the early pulmonary phases (stage I and II) is followed by a marked increase in troponin in the case of further deterioration and a hyperinflammatory course (stage III) of the disease . As troponin elevation in patients with a COVID-19 infection seem to be lower than in most cases of ACS or acute myocarditis, the European Association of Percutaneous Cardiovascular Interventions (EAPCI) suggests considering marked elevation (e.g., >5 times the upper normal limit) in a patient who is not critically ill to suspect COVID-19 and AMI .
In addition, plasma concentrations of IL-6 and CRP appear to reflect the intensity of occult plaque inflammation and the vulnerability to rupture. So, CRP and IL-6 resulted as independent predictors of future clinical events such as myocardial infarction, unstable angina, stroke, and peripheral vascular disease in symptomatic and in apparently asymptomatic patients .
Non-invasive imaging may aid diagnosis
The main problem with ACS management in COVID-19 is the issue of increased time duration to decide on the need for a percutaneous coronary intervention (PCI). For patients whose diagnosis of ST-elevation myocardial infarction (STEMI) is questionable due to atypical symptoms, diffuse ST elevation, or an abnormal ECG, an additional non-invasive assessment, including further risk stratification of COVID-19, is warranted.
Cardiogoniometry (CGM) is a new electrodiagnostic tool that uses 3D computer information about cardiac potentials. It consists of a simple computerised vector cardiography with a lead system obtained to construct three orthogonal projections. Using these three-dimensional projections, the cardiogoniometer, a microprocessor-based system, measures and calculates the maximum depolarisation vectors (QRS) and repolarisation (T) vectors .
The use of echocardiography, which has always been regarded as the “gatekeeper” for diﬀerential diagnosis of cardiovascular disease, should be reconsidered in this emergency period. The presence of a regional wall motion abnormality in echocardiography increases the likelihood of acute atherothrombotic lesion and may prompt clinicians to perform coronary angiography. The absence of regional changes can provide confidence and lead to alternative non-invasive imaging techniques such as CT coronary angiography or cardiac MRI. Since STEMI is more common in patients with recent respiratory infection, we would like to reiterate the recommendations of the European Society of Cardiology (ESC) Guidelines for the Diagnosis and Management of Cardiovascular Disease During the COVID-19 pandemic to quickly evaluate ST-segment elevation patients according to existing treatment protocols and consider urgent coronary angiography if acute coronary syndrome is suspected .
The use of computed tomography (CT) scans completed with contrast enhanced sequences has been proposed by Hendren et al to exclude acute myocarditis. This avoids the additional use of cardiac magnetic resonance (CMR) and invasive endomyocardial biopsy, since patterns of delayed myocardial enhancement consistent with acute myocarditis revealed by cardiac CT have also been described .
Regarding patients hospitalised for COVID-19 with suspected ACS, EACVI recommends evaluating the pre-test probability (PTP) based on symptoms, ECG signs, age, sex, previous history, and cardiovascular risk factors; to use coronary CT angiography for intermediate PTP, and to reserve ICA only for cases with very high PTP or STEMI, high-risk non-STEMI (NSTEMI) or crescendo angina .
Revascularisation is a cornerstone therapy for AMI-CAD however, it is not a therapeutic option in patients without atherothrombosis. In clinical practice, it may be reasonable to administer angiotensin converting enzyme inhibitors (ACEi)/ angiotensin-receptor blockers (ARBs), statins, and antiplatelet agents to most patients with MINOCA. Optimum therapy with calcium channel blockers is the treatment of choice for coronary spasm in patients with vasospastic angina.
Therapies targeting angiotensin converting enzyme 2 (ACE2) with blocking agents may be detrimental, with the risk of worsening hypertension, while boosting ACE2 activity could be a good treatment of COVID-19 , as previously described for SARS. The upregulation of proinflammatory cytokines observed in COVID-19 patients that induces a severe inflammation leads to a marked increase of D-dimers and the fibrinolysis .
Heparin may also be helpful in microvascular dysfunction; it has been postulated that ischaemic hypoxia in the subendocardial layer can make it lose its natural anticoagulant properties .
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been identified as a potential risk factor for serious clinical presentation of SARS-CoV-2 infection. Potential impact of chronic aspirin therapy has been questioned. However, at the low dose administered in chronic coronary syndrome (CCS), aspirin has very limited anti-inflammatory effect. Therefore, CCS patients should not withdraw aspirin for secondary prevention.
Statin therapy has been variably associated with favourable outcomes in patients admitted with influenza or pneumonia. On the other hand, patients with COVID-19 have been reported to develop severe rhabdomyolysis or increased liver enzymes. In these latter cases, it may be prudent to temporarily withhold statin therapy.
There is no formal consensus on the optimal treatment of patients with MINOCA resulting from COVID-19 infection . Most importantly, treatment should depend on the underlying cause. In cases with evidence of thrombosis, therapeutic anticoagulation would be a logical treatment; in the absence of thrombosis, the INSPIRATION trial demonstrated that it should not be used for routine prophylaxis in intensive care patients with COVID-19 , with decreased thrombotic complications balanced by increased bleeding events.
Undoubtedly, an important aspect in ACS against the background of COVID-19 is maintaining saturation above 95%, ensuring proper blood gas composition and acid-base balance.
Conclusions and take-home messages
The COVID-19 pandemic has had a serious impact on our understanding of the traditional course of ACS, which can be either a consequence of the infection itself in infected individuals or an independent disease where it is possible to develop both AMI type 1 or 2, and AMI without coronary artery disease (MINOCA). In the presence of SARS-CoV-2 infection, the combination in one patient of the classic risk factors for atherosclerosis and COVID-19 suggests the presence of vasculitis and puts them in a group with a very high risk of cardiovascular complications.
Patients with a COVID-19 infection can be conditionally divided into two groups. In the first, ACS is a consequence of atherothrombosis, classic pathogenetic mechanisms take place, and COVID infection occurs later, thus there is a normal disease course. The second group includes primarily infected patients. Usually, such patients are sick for at least two weeks of SARS-CoV-2, and ACS develops against the background of this infection: that is, there is immune vasculitis and hypercoagulation. With ACS against the background of COVID-19, the problem of coronaritis, which is an inflammation of the coronary vessels with the development of secondary thrombosis, should not be ruled out.
Also, the clinician's attention in ACS in patients with a SARS-CoV-2 infection should be focused on assessing the mechanisms of the development of MI types 1 and 2, and the presence of vasospasm. It is also important to exclude the effects of COVID-19 vasculitis (coronaritis) with dissection of the coronary artery, non-traumatic rupture of the intima and the formation of false lumen.
Biomarkers indicating a rapid deterioration in the condition of patients with COVID-19 are mainly represented by troponin I (TnI), CRP, erythrocyte sedimentation rate (ESR), D-dimer, progressive deterioration in the number of lymphocytes and increased markers of inflammation (IL-6, TNF- α).
Concerning non-invasive methods, in addition to ECG, additional assessment is advisable, including cardiogoniometry (CGM), echocardiography or optical coherence tomography (OCT).