key: cord-0799071-371we9wc
authors: Nakou, Eleni; De Garate, Estefania; Liang, Kate; Williams, Matthew; Pennell, Dudley J.; Bucciarelli-Ducci, Chiara
title: Imaging Findings of COVID-19-Related Cardiovascular Complications
date: 2021-10-30
journal: Card Electrophysiol Clin
DOI: 10.1016/j.ccep.2021.10.008
sha: e233b5c992ded36513512ee729f144745a11c73f
doc_id: 799071
cord_uid: 371we9wc

Other than respiratory disease, patients with coronavirus disease 2019 (COVID-19) commonly have cardiovascular manifestations, which are recognised as significant risk factors for increased mortality. COVID-19 patients may present with a wide spectrum of clinical presentations ranging from asymptomatic heart disease detected incidentally by cardiac investigations (troponin, BNP, imaging) to cardiogenic shock and sudden cardiac death. In this broad clinical course, advanced imaging plays an important role in the diagnosis of different patterns of myocardial injury, risk stratification of COVID-19 patients, and in detecting potential cardiac side effects of the current treatments and vaccines against the severe acute respiratory syndrome.

At the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as a novel cause of respiratory infection in Wuhan, which spread rapidly resulting in the global pandemic of coronavirus disease (COVID-19) 1 . It is widely recognised that patients with cardiovascular (CV) risk factors, or established CV disease (CVD), are at increased risk of developing severe COVID-19 disease, and those with myocardial injury have Kinase (MAPK) pathway promoting thrombotic events 21 and might also induce the production of reactive oxygen species (ROS) causing myocardial injury 22 .

c. Endothelial cell damage and thrombo-inflammation. The direct invasion of the vascular endothelial cells via ACE2 receptors may result in inflammation and endothelial dysfunction contributing to thrombosis. There is early histological evidence of direct toxic effects to endothelial cells caused by SARS-CoV-2 23 . In this case series, there was evidence of lymphocytic endotheliitis in the lungs, heart and kidneys in a patient who died from COVID-19 and multiorgan failure. This was also observed in the lungs, heart, kidneys and liver in a patient who died with COVID-19, multisystem inflammatory response (MIS) and myocardial infarction with ST elevation.

can induce an excessive activation of immune cells and inflammatory response causing a cytokine storm. The overproduction of pro-inflammatory cytokines can lead to endothelial dysfunction and the activation of complement pathways, platelets, von Willebrand factor and tissue factor; increasing the risk of thrombosis in the circulation including in the coronary system and therefore increasing the risk of an acute coronary syndrome 24, 25 . SARS-CoV-2 infection can also promote a disproportionate production of factor VIII and neutrophil extracellular traps (NETs), which can facilitate the development of thrombotic events [24] [25] [26] . Apart from type I myocardial infarction (MI), the exaggerated systemic inflammatory response increases the metabolic demand causing myocardial mismatch in oxygen demand and supply and, as a consequence, a type II MI 25-27 . J o u r n a l P r e -p r o o f e. Hypoxic injury. Hypoxia caused by SARS-CoV-2 infection induces intracellular acidosis and the release of ROS from mitochondria in cardiomyocytes, which destroys the cell membrane contributing to cardiomyocyte apoptosis 4,28 .

f. Cardiovascular side effects of drugs and vaccines. It is widely known that antiretroviral therapy and other drugs used in the management of COVID-19 patients (azithromycin, tocilizumab, chloroquine and hydroxychloroquine) can induce arrhythmias, or interact with some cardiovascular treatments 29 . Additionally, cases of thromboembolic events have been reported following ChAdOx1 nCov-19 /AZD1222 (AstraZeneca COVID-19 vaccine) the Ad26.COV2.S (Janssen COVID-19 vaccine) 30, 31 vaccinations. More recently, there is a potential association of the mRNA vaccines, BNTb162b (Pfizer) and mRNA-1273 (Moderna) with myocarditis 32 . It is currently believed that the thrombotic events have been associated with autoantibodies directed against the platelet factor 4 (PF4) antigen 33 .

The underlying pathophysiological mechanisms causing COVID-19 related cardiovascular complications are presented in Figure 1 .

There is increasing evidence that patients with pre-existing cardiovascular disease (CVD) are at an increased risk of developing acute myocardial injury, with high troponin levels associated with poorer prognosis 2,3 . Studies show that 12%-15% of hospitalised COVID-19 patients had an elevated troponin suggestive of myocardial damage, while up to 31% with severe COVID-19 presentation had cardiac involvement 34, 35 . Another study with 112 patients with COVID 19 showed that troponin levels were mostly normal at admission. Troponin J o u r n a l P r e -p r o o f increased during hospitalisation in 37.5% of the patients, especially in those who died, while typical signs of myocarditis were not detected on echocardiography 36 . These findings suggested that myocardial injury might be the consequence of the systemic inflammatory response rather than the direct invasion and damage by SARS-CoV-2.

In a study of 305 hospitalised patients with COVID 19, myocardial injury (defined by elevated troponin levels) was observed in 190 patients 37 . Echocardiographic abnormalities, including global or regional left ventricular (LV) wall motion abnormalities, LV diastolic dysfunction, right ventricular (RV) dysfunction and pericardial effusions were noted in almost two-thirds of patients with myocardial injury. In the same study the detection of structural abnormalities by transthoracic echocardiography (TTE) was an independent predictive factor of mortality in the subgroup with myocardial injury. An international prospective study of 1216 patients from 69 countries revealed the spectrum of echocardiographic abnormalities with clinical indication for TTE 38 . Abnormal TTE was found in 55%, including LV and RV abnormalities at 39% and 33% respectively, while the prevalence of echocardiographic abnormalities was slightly lower (46%) in the subgroup with no pre-existing CVD. The LV abnormalities were predominantly non-specific in nature and the mechanism of dysfunction was often not identified unless the TTE findings were suggestive of acute MI (3%), myocarditis (3%), and stress cardiomyopathy (2%). In the same study severe LV, RV or biventricular systolic dysfunction was observed in 14% and cardiac tamponade occurred in 1%. In contrast, another study showed that RV dilatation and systolic dysfunction were more common (39%) compared to LV systolic dysfunction (10%) in 100 hospitalised patients with COVID-19 39 . The J o u r n a l P r e -p r o o f most common echocardiographic findings among those with subsequent clinical deterioration were worsening RV (12 patients) and LV function (5 patients).

Myocardial infarction, myocarditis or acute pulmonary hypertension might be the cause of isolated RV dysfunction in COVID-19 patients 40 . Acute cor pulmonale precipitated by acute pulmonary embolism or adult respiratory distress syndrome (ARDS) has also been reported [41] [42] [43] . Additionally, the implementation of positive end-expiratory pressure in the respiratory support of critically ill COVID-19 patients can contribute to RV dysfunction 44 

J o u r n a l P r e -p r o o f Cardiovascular Magnetic Resonance imaging is increasingly recognised as an essential tool in the assessment of COVID-19 induced myocardial injury due to the unique capability of CMR for non-invasive tissue characterisation. Figure 2 shows the specific CMR techniques used for the characterisation of tissue damage in clinical practice. Guidelines have been published for safe CMR scanning during the COVID-19 pandemic 56,57 and the Society for Cardiovascular Magnetic Resonance (SCMR) recommends a specific protocol to perform in patients with suspected COVID-19 cardiac involvement 58 . The primary advantage of CMR is the ability to differentiate between ischaemic and non-ischaemic pathologies 59 . Although endomyocardial biopsy (EMB) remains the gold standard for the diagnosis of acute myocarditis, its use in routine clinical practice is limited due to low diagnostic accuracy and peri-procedural risks. patients with severe symptoms requiring hospitalisation. Comparisons were made with healthy controls as well as with risk factor-matched controls 65 . CMR was performed 2-3 months after the initial positive COVID-19 test. Significant high-sensitivity troponin I (hs-cTnI) elevation at the time of CMR was noted in 5% of the patients. Notably, high myocardial native T1 (73%), elevated myocardial native T2 (60%), myocardial LGE (32%), and pericardial LGE (22%) was detected in patients who recovered from COVID-19, while CMR abnormalities found in the risk-factor matched controls were less frequent including high native T1 and T2 (40% and 9% respectively), myocardial LGE (17%), and pericardial LGE (15%). There was also mild LV and RV systolic dysfunction compared with healthy and risk-factor matched controls (LVEF 56% versus 60% and 61% respectively; RVEF 56% versus 60% and 59%). Similarly, a smaller study of 26 patients who remained symptomatic after recovery from COVID-19 found myocardial oedema in 54%, LGE 31% and decreased RV functional parameters in the subgroup with positive conventional CMR findings 66 . A larger study included 148 patients with severe COVID-19, (all requiring hospital admission, 48 of whom (32%) requiring ventilatory support) and troponin elevation who underwent CMR at a median 68 days post discharge 67 . LV function was normal in 89% , myocarditis-like scar noted in 26%, infarction and/or ischaemia in 22% and dual pathology in 6%. However, whether these abnormalities represent de novo COVID-J o u r n a l P r e -p r o o f 19 associated changes or pre-existed in the context of clinically silent disease remains unclear.

Importantly, the extent of these abnormalities were quite limited and with minimal functional consequences.

CMR findings have also been reported among athletes who have recovered from COVID-19 [68] [69] [70] . In a study of 145 university student athletes who were asymptomatic or experienced mild to moderate symptoms, CMR was performed at a median of 15 days after the positive COVID- CMR abnormalities detected in convalescent COVID-19 raised concerns for long-term CV complications even in asymptomatic patients. However, the clinical significance of these findings remain uncertain and further studies are needed to confirm the clinical role of imaging in a long-term setting. The potential role of CMR in screening athletes is debated in the literature 71 . The COVID-HEART trial is an ongoing multi-centre UK trial which will clarify the association of COVID-19 related cardiac involvement with co-morbidity, genetics, patientreported quality of life measures and functional capacity 72 . Table 1 summarizes the studies of TTE and CMR findings in patients with COVID-19.

(NSTEMI), non-invasive diagnostic testing prior to catheterisation was recommended during the pandemic 73 . In haemodynamically stable cases with low or intermediate cardiovascular risk, Computed Tomography Coronary angiography (CTCa) could be considered as an alternative to invasive coronary angiogram 74 . CTCa also provides information on lung parenchyma and pulmonary vessels, while excluding significant coronary artery disease (CAD) with almost 100% negative predictive value 75 .

A retrospective study of 100 COVID-19 patients who underwent CT pulmonary angiography (CTPA) showed that 23% had acute pulmonary embolism (PE) 76 . Those with PE had more severe disease requiring more intensive care admissions and mechanical ventilation (PE vs non-PE: 74% versus 22%, and 65% versus 25%, respectively, p=0.001 for both comparisons) 76 . However, presentations were mild, none with evidence of acute SARS-CoV-2 infection, nor met criteria for MIS. The CMR findings were consistent with myocarditis in all cases highlighting the role of CMR in detecting pathology even in less aggressive disease. Figure 5 shows the CMR findings of a patient admitted with acute myocarditis one-week post mRNA-1273 vaccination. Greater proportions of patients with ischemic (32% vs 17%) and non-ischemic (20% vs 7%) LGE patterns than the risk factor matched control group.

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AUC: area under the receiver operating characteristic curve (ROC) curve; CI: confidence interval; CMR: cardiac magnetic resonance

DVT: deep vein thrombosis; ECG: electrocardiogram; GLS: global longitudinal strain; HR: hazard ratio; ECV: extracellular volume fraction

LLC: Lake Louise Criteria; LS: longitudinal strain; LV: left ventricular; LVEDVi: left ventricular end-diastolic volume index; LVEF: left ventricular ejection fraction; LVESVi: left ventricular end-systolic volume index; NPs: natriuretic peptides; OR: odds ratio; RV: right ventricular; RVCI: right ventricular cardiac index; RVCO: right ventricular cardiac output; RVEDVi: right ventricular end-diastolic volume index; RVEF: right ventricular ejection fraction; RVESVi: right ventricular end-systolic volume index; RVLS: right ventricular longitudinal strain; RVSV: right ventricular stroke volume

There was greater proportion of cases with pericardial enhancement (22% vs 14%) and pericardial effusion (20% vs 7%) compared with the risk factor matched control group. Huang L, et al 66 Retrospective