|Year : 2021 | Volume
| Issue : 1 | Page : 45-53
Lesion types, pathogenesis, pathological manifestations, and imaging findings of cardiovascular complications induced by coronavirus disease 2019: Current status
Feiran Yu1, Qimin Zhou2, Dexin Yu3
1 School of Medical Imaging, Weifang Medical University, Weifang, China
2 Department of Radiology, Changle Hospital of Traditional Chinese Medicine, Changle, Fujian, China
3 Department of Radiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
|Date of Submission||22-Nov-2020|
|Date of Acceptance||15-Feb-2021|
|Date of Web Publication||18-Nov-2021|
Prof. Dexin Yu
Department of Radiology, Qilu Hospital of Shandong University, Jinan City, 250012 Shandong
Source of Support: None, Conflict of Interest: None
The coronavirus disease 2019 (COVID-19) has formed a worldwide pandemic trend. Despite the virus usually invades lungs and presents with various respiratory symptoms, it can also affect the cardiac function in multiple ways and result in high mortality. Various possible mechanisms have been proposed to explain these manifestations at present, including cytokine storm and direct invasion of the virus. There are a series of feasible schemes in clinical work to reduce the incidence of complications now, but the layered management of hospitalized patients, the early prevention, and the early detection of complications seem to be more important. Cardiac imaging examinations (such as computed tomography coronary angiography, magnetic resonance imaging multi-parameter scan, and enhanced scan, etc.) are very essential in these aspects. However, radiological data of the cardiac complications are not comprehensive enough in accessing the prognosis due to the limitation of examination. This paper summarized the imaging findings of cardiac complications of COVID-19, providing the possible morphological basis or hypothesis for cardiac multimode imaging by analyzing the pathological manifestations retrospectively.
Keywords: Cardiovascular complications, COVID-19, pathological findings, radiologic manifestations
|How to cite this article:|
Yu F, Zhou Q, Yu D. Lesion types, pathogenesis, pathological manifestations, and imaging findings of cardiovascular complications induced by coronavirus disease 2019: Current status. Radiol Infect Dis 2021;8:45-53
|How to cite this URL:|
Yu F, Zhou Q, Yu D. Lesion types, pathogenesis, pathological manifestations, and imaging findings of cardiovascular complications induced by coronavirus disease 2019: Current status. Radiol Infect Dis [serial online] 2021 [cited 2021 Dec 8];8:45-53. Available from: http://www.ridiseases.org/text.asp?2021/8/1/45/330567
| Introduction|| |
Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the past few months, it has spread in many countries rapidly, and the number of patients is still rising steadily now. According to the publishing reports, the severity of these patients with COVID-19 is diverse, ranging from completely asymptomatic to severe pneumonia. Part of the patients did not have any specific manifestations, and other parts of patients could have fever, cough, fatigue, and other symptoms. Besides, there is a growing number of evidence that patients can also have many other organ complications except lung, in which cardiovascular complications have a higher mortality rate.,, This review retrospectively summarized the impact of SARS-CoV-2 on the cardiovascular system as well as the pathological development and imaging characteristics of cardiovascular complications, which may help clinicians and radiologists to improve diagnostic rate at an early stage and reduce the incidence of clinical adverse events.
| Cardiovascular Complications of the COVID-19|| |
Although COVID-19 usually affects the respiratory system, the symptoms it caused in the cardiovascular system are also common and associated with adverse outcomes closely. Abnormal changes of cardiac-specific biomarkers can not only detect the changes of cardiac function but also be an important means to judge the prognosis of patients. The following are several common cardiovascular complications induced by COVID-19.
Since the outbreak of COVID-19, many researchers had found that part of patients with COVID-19 presented as the manifestations of myocardial injury including the reduction of left ventricular ejection fraction, the increasing myocardial injury markers, and the abnormal changes of the electrocardiogram., However, the pathogenesis of pneumonia-related heart injury is unclear at present. Guo et al. conducting a single-center study collecting and analyzing the medical data of 187 patients found that the patients with potential cardiovascular diseases (such as high blood pressure, coronary heart disease [CHD], cardiomyopathy, etc.) or elevated level of Troponin T (TnT) had significantly higher mortality rates (69.4%) than those without these potential diseases. In addition, the level of TnT was correlated with plasma C-reactive protein, which may be related to the inflammatory response. Another study showed that the mortality of patients with cardiac injuries was higher than that without heart damage (51% vs. 4.5%). However, it was uncertain whether the cause of death is caused by heart damage directly in the two studies. Furthermore, there is no denying that heart damage is related to poor prognosis in the setting of SARS-CoV-2 infection, and the connection between them is not yet clear, which still needs further study in future.
It has been reported that clinical manifestations of COVID-19 could be palpitations. Case reports showed that the number of COVID-19 patients with arrhythmia is increasing, especially in intensive care unit patients. Si et al. retrospectively analyzed 1284 cases with the severe respiratory symptom, finding that 44 (25.9%) of 170 patients with heart damage had ventricular arrhythmia. There may be a certain connection between arrhythmias and heart damage, but this study selected critical patients as research subjects, and the patients with arrhythmia but no heart damage were not included. Bhatla et al. analyzed the clinical data of 700 admitted patients to assess the impact of potential risk factors on arrhythmia. They also found that intensive care patients were more likely to develop arrhythmia and cardiac arrest. Cardiac arrhythmia may be the result of systemic disease, rather than simple myocardial damage.
In the process of disease, researchers observed that the level of D-dimer increased significantly in some severe patients with COVID-19, which predicted a higher incidence of thrombosis and poor outcomes. Thrombosis is another new concern in cardiac complications now. The study of Zhang et al. involved 143 COVID-19 patients, and they found 66 patients (46.1%) had lower extremity deep vein thrombosis (DVT), these people were older than those without DVT. Moreover, the researchers also conducted a multivariate analysis, they found the chronic disease may also be the cause of DVT in patients, since most patients were admitted at an advanced stage of illness, which may cause the high prevalence of DVT in the study, so there is indeed a link between DVT and COVID-19. In the prospective study of Helms et al., thrombus was detected in 64/150 patients with COVID-19, the patients with pulmonary embolism accounted for 16.7%, among them, the thrombotsis rate was significantly high in the patients receiving continuous renal replacement therapy (96.6%) and in the patients receiving extracorporeal membrane oxygenation (25%), although they also received anticoagulant therapy already. Therefore, they believed that the anticoagulant target for critical patients should be higher than that for general patients. COVID-19 seems to have an additional stimulant effect on thrombus formation in hospitalized patients, but the exact of mechanism thrombus formation in COVID-19 patients needs further study in future.
Researchers have reported suspected cases of myocarditis continually in some single-case reports. The incidence of myocarditis in hospitalized COVID-19 patients is uncertain, and myocardial pathological data are scanty now. In Tavazzi et al.'s study, a 69-year-old COVID-19 patient with high inflammatory markers and lymphopenia was treated, the echocardiography showed the left ventricle of the patient was dilated and motor function declined, his heart muscle biopsies revealed that virus particles were observed in the cardiac interstitium, rather than in the myocardial cells. In the report of Sala et al., virus particles were also not found in the cardiomyocytes of patients, they thought what COVID-19 caused were inflammation of the myocardial tissue, and it is not a real sense of myocarditis. Two studies both showed that myocardial inflammation was related to cardiac function and the prognosis of patients, but its mechanism is unclear now.
| Pathogenesis of COVID-19 Cardiac Complications|| |
The cardiac complications of COVID-19 are varied, and the incidence is high, its exact pathogenesis is still unclear now. However, cellular and molecular analyses seemed to explain several possible pathogenesis pathways such as angiotensin-converting enzyme 2 (ACE2)-mediated viral invasion, excessive cytokine release, and vWF antigen release. Some researchers also deemed that it might be the result of a multi-factor combination.
Severe acute respiratory syndrome coronavirus 2 invades human cells through angiotensin-converting enzyme 2 receptor
Some studies have indicated that SARS-CoV-2, SARS-CoV, and MERS-CoV were members of the β family virus genus, they still differed in some aspects with a homology of only 80% (SARS-CoV) and 50% (MARS-CoV)., Nevertheless, Lu et al. found that SARS-CoV-2 and SARS-CoV had similar receptor domains after exploring three kinds of the virus with homology modeling. Previous studies have shown that the spines protein on the surface of coronavirus could bind to the ACE2 of human cells specifically after being cleaved by the host protease, then the virus completed the invasion into cells through intracellular endocytosis. ACE2 not only transmitted signals as a receptor but also could be a part of negative regulation in the renin–angiotensin system (RAS). In another previous study, it was found that coronavirus could reduce the expression of the ACE2 receptor, and it may be self-regulation of the body, which induced relative enhancement of the RAS system meanwhile., The signal activated the expression of the fibrosis-associated chemokine (C-C motif) ligand 2(CCL2) through the Ras-Erk-AP-1 pathway to promote the occurrence of fibrosis, which caused heart damage and even the occurrence of heart failure finally. Recently, Liu et al. conducted a single-cell level analysis and found that the expression of ACE2 in the heart more than lungs, but the expression of S-protein cleaving enzyme is few, like transmembrane protease serine protease-2 (TMPRSS2), it may be used to explain the reason why the virus particles could rarely be found in the myocardial cells. These studies also explained the etiology of some extracardiac diseases and provided evidence for clinical treatment, but it was difficult to explain why COVID-19 patients were easier to develop thrombus.
Cytokine storm and immunosuppression
Previous studies have found that the cellular immunity was mussy, and the level of cytokine was elevated in COVID-19 patients; researchers collected the venous blood of patients with COVID-19 for biochemical and cellular analysis and found the level of IL-6, IL-10 in severe patients was higher than that in mild patients, while the level of CD4+ T cells and CD8+ T cells was low in severe patients. These studies prompted cytokines may be one of the important factors of cardiac injury., In Guo's research, they found that the high levels of TnT and C-reactive protein were significantly related to the level of IL-6, which may suggest that the heart injury and the degree of inflammation were associated with the degree of cytokines. Novel coronavirus would multiply quickly after entering the body cell, CD4+ T cells would be quickly activated and differentiated into Th1 cells, then the Th1 cells secreted IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and other cytokines, the GM-CSF could stimulate monocytes to release cytokines IL-6 ulteriorly, the cytokine storm would be formed in this cycle. At the same time, IL-6 promoted vascular leakage and interstitial edema, which weaken the contraction of papillary muscle and caused cardiac insufficiency, elevated cytokine levels can also lead to immune dysfunction., At present, the specific mechanism of immune dysfunction caused by cytokine storm still needs further study to design a new therapeutic method.
| Pathological Findings of Cardiac Complications|| |
Pathological findings are the basis of imaging studies and provide an important theoretical support for diagnosis. Autopsies have shown that reverse transcription-polymerase chain reaction (RT-PCR) could detect the presence of viruses in many organs including myocardial tissues.,
Fox et al. performed autopsy on ten patients who died of COVID-19, they found the most prominent manifestation in these patients was cardiac hypertrophy, and the right ventricular expansion was larger than the left ventricle, it may be associated with the rise of the BNP. Furthermore, mild-to-moderate hemorrhagic pericardial effusion and edema of pulmonary parenchyma were observed in several patients. In the research of Edler et al., some patients had the myocardial scar. Some characteristics of cardiac histopathology were also worthy of attention. For example, researchers just found the scattered single-cell necrosis under light microscopy, rather than large patchy necrosis, and the viral RNA could be detected in the myocardial interstitium; the viral particles were not found in the myocardial cells of patients under the electron microscope., Cardiac histology examination showed single-cell necrosis was not accompanied by lymphocyte infiltration, which did not consistent with the typical manifestation of lymphocytic myocarditis.
In consecutive cases of COVID-19, the researchers found that viral invasion was confined in the mesenchymal cells and the related inflammatory cells did not increase, these manifestations were not consistent with clinical myocarditis. The specific molecular mechanisms still require further study in future. In addition, the long-term consequences of these viral activities are unclear now.
| Radiologic Manifestations of Cardiac Complications of COVID-19|| |
Cardiac computed tomography (CT) can not only be used to show respiratory lesions caused by COVID-19, but also effectively identify the high-risk cardiac risks (such as atherosclerotic plaques, valvular dysfunction) in COVID-19 patients. The value of coronary CT angiography (CTA) imaging in guiding risk stratification and differential diagnosis of angina pectoris has been well established. Besides, multistage coronary CTA imaging is of great significance in assessing cardiac function and regional motion. Compared with CT, cardiac magnetic resonance imaging (CMR) is easier to show the organic changes of the heart caused by COVID-19 such as myocarditis and abnormal valve function, and it has unique advantages in evaluating the degree of cardiac ischemia and the viability of cardiomyocytes. The combination of myocardial perfusion, advanced gadolinium enhancement, and tissue mapping can evaluate cardiac function and display myocardial characteristics. In addition, the combination of CMR and CT can be used to diagnose the underlying cause of chest pain in patients. During the pandemic, CMR can be used in place of esophageal echocardiography, and the cardiac cine magnetic resonance imaging (MRI) can evaluate structural abnormalities of the left atrium and detect adnexal thrombosis with efficiency and safety.
Cardiac computed tomography
Previous studies have shown that the appearance of ground-glass opacities (GGO) and pleural thickening sign could be seen in most patients with COVID-19 on plain CT, and the CT manifestations changed with the progress of the disease constantly. In addition, the CT scan could be used for diagnosing cardiovascular complications at all stages of the COVID-19 including coronary stenosis and acute heart failure. Moreover cardiopulmonary CT scanning for admitted patients can be performed simultaneously, which may be convenient to stratify patients according to the radiological data for effective and planned management.
According to the research, the detection rate of coronary artery disease by CT was significantly higher than that by echocardiography. Computed tomographic coronary angiography should be considered for the patients who had elevated level of troponin and BNP and a history of CHD. CTA of coronary was used to evaluate the stenosis degree and plaque stability of the coronary arteries to prevent adverse events. During the period of the COVID-19, coronary CTA has an important predictive value for myocardial infarction caused by obstructive coronary stenosis. In addition, the distribution of COVID-19-related coronary lesions seemed to have certain patterns. Theocharis et al. found that all 12 (60%) patients had left coronary system involvement after performing coronary CTA in 20 patients with COVID-19, in which the left main coronary artery and the left anterior descending branch were dilated in 9 patients. Myocardial infarction with nonobstructive coronary arteries (MINOCA) was also common in patients with COVID-19., The negative predictive value of coronary CTA for luminal stenosis was up to 98.1%, it could be used to exclude CAD when combined with the evaluation of pulmonary artery and thoracic aorta. It is also useful in the diagnosis of chest pain caused by MINOCA., In conclusion, coronary CTA may identify a wide range of CHD caused by COVID-19, from mild non-obstructive plaque to extensive vascular changes.
CT pulmonary angiography (CTPA) is an important tool in the diagnose of thromboembolism for patients with COVID-19 due to its noninvasion. It has been reported that the incidence of venous thrombosis in patients with COVID-19 was more than 25%, and the incidence of pulmonary embolism was significantly increased., In Colombo's report, a COVID-19 patient was admitted with dyspnea and chest pain, researchers found a large number of filling defects in pulmonary vessels after undergoing CT examination, the patient was discharged after active anticoagulant treatment [Figure 1]. They thought that CTPA and thrombobiomarker detection were necessary for hospitalized patients with chest pain, and CTPA was also useful for the systematic evaluation of thromboembolism. Furthermore, researchers also found that the pulmonary embolus was mostly located in the branch of the pulmonary lobe, while the central pulmonary artery was rarely found in patients with COVID-19. However, in recent studies, researchers found that the incidence of parameter estimate (PE) in COVID-19 patients receiving CTA was more than 23%., Therefore, the indications of the CTA examination in COVID-19 patients should be further explored now.
|Figure 1: Computed tomography pulmonary angiography showed thromboembolic occlusion is observed in the right branch of the pulmonary artery. Reproduced with permission from ref|
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There have been many reports about myocardial inflammation so far, and the possible mechanism and pathological performance have been mentioned above. Some researchers thought that the late iodine enhancement or extracellular mapping with CT could be used to identify myocarditis. However, the myocardial biopsy of COVID-19 patients showed single-cell necrosis, rather than patchy necrosis, it may be difficult to discern on CT. Compared with CMR and echocardiography, CT may be not a good measure to evaluate the myocardial function and detect myocardial inflammation.
At present, CT had great value in the diagnosis of thromboembolism and evaluation of the cardiac structure, and there have been many CT imaging reports on related complications already. However, the research assessing the prognosis of COVID-19 patients with CT imaging is still lacking now.
Cardiac magnetic resonance imaging
Compared with CT, CMR may show the cardiac complications caused by COVID-19 better. It is an important measure to combine morphology with function, CMR also has a unique advantage in assessing the cardiac function, the degree of local inflammation, and the valve function., In addition, CMR may partly replace transesophageal echocardiography to detect mural thrombus in the heart during the epidemic, which could reduce direct exposure of medical staff.
CMR is an important way to assess the function and structure of the heart. It is of great significance in detecting gross and histological abnormalities of the heart. In Riccardo's report, he observed enlargement of the right ventricular cavity and significant pericardial effusion on CMR of the COVID-19 patient, but no evidence of pericardial thickening could be found [Figure 2]. It seemed that the right ventricle was more susceptible to pulmonary vascular resistance. CMR was also the key method to show myocardial damage and myocardial inflammation because of the extremely high detection rate of myocardial edema and myocardial fibrosis. Esposito found that the myocardial inflammation caused by COVID-19 was characterized by diffuse myocardial edema after conducting CMR examination on 10 COVID-19 patients, the edema region presented as increased T2 signal and delayed gadolinium enhancement on CMR, the thickening ventricular wall was also found at the junction of myocardial edema [Figure 3]. In addition, researchers also found that the edema area was mostly located in the inferior lateral wall and the apex of the heart, which was different from acute viral myocarditis.,, Some studies have shown that CMR was also extremely important for the assessment of myocardial injury and prognosis, the degree of cardiac fibrosis on CMR was positively correlated with the risk of ventricular arrhythmia.,, Cardiac complications caused by COVID-19 showed no specificity in CMR images, and the existing methods to judge prognosis were difficult to use in patients with COVID-19 at acute stage.
|Figure 2: Cardiac magnetic resonance show enlargement of the right ventricular cavity and significant pericardial effusion is observed in the COVID-19 patient. Reproduced with permission from ref|
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|Figure 3: Cardiac magnetic resonance show myocarditis-like syndrome is observed in the COVID-19 patients. Reproduced with permission from ref|
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Myocardial inflammation can lead to local cell necrosis and fibrosis, resulting in myocardial damage and dysfunction. CMR has irreplaceable advantages in evaluating cardiac function. It can calculate the function parameters of left and right ventricular such as end-systolic volume, end-diastolic volume, stroke output, ejection fraction, and so on., In Riccardo's report, he found diffuse hypokinesia in both ventricles (LVEF reached 35%), without symptoms of valvular heart disease. After treating for a week, the patient's LVEF increased to 44%. In Esposito's study, he used multiplanar cine imaging to find that patients had normal left ventricular end-diastolic volume despite the cardiac function was abnormal. In both studies, the cardiac function of patients was restored and pericardial effusion decreased after receiving supportive treatment. The reason for the transient cardiac dysfunction remains unknown now.
There was a certain correlation between cardiac dysfunction, the changes in hemodynamics and thrombosis, COVID-19 patients had high incidence of thrombosis even they got regular thrombolytic therapy timely. In previous research, researchers found DE-CMR has the highest sensitivity, specificity, and diagnostic accuracy after comparing the sensitivity of two means in thrombosis detection. In the report of Alcoberro Torres et al., a mass with a smooth edge was found on the roof of the right heart during follow-up despite the patient was treated with Bemiparin to prevent thrombosis, then the mass disappeared after increasing the dose of anticoagulant. Patients with COVID-19 should be on highly alert to thrombosis. The thrombosis formed in the heart may be one of the causes of pulmonary embolism in COVID-19 patients; PE should be excluded in combination with CT findings.
CMR may be a safe and highly sensitive means for the diagnosis and detection of cardiac diseases in patients who did not need intensive care or in patients who have recovered. However, there are few studies on the prognosis of patients recovering from COVID-19-related cardiac complications now.
Positron emission tomography of the heart
Myocardial perfusion imaging (MPI) with single-photon emission computed tomography (SPECT) is of great importance in the diagnosis of CHD, the judgment of myocardial infarction area, as well as the evaluation of myocardial ischemia.,, Myocardial necrosis related to COVID-19 is not extensive patchy necrosis but single-cell scattered death; these manifestations are easily found by SPECT-MPI. In the area of low coronary perfusion, the intake of 201Tl showed perfusion defects in the first 10-15 min, delayed imaging (after 3–4 h) is characterized by radioactive concentration, these differences in the imaging are useful to distinguish the area of ischemia clearly. Besides, previous research has shown that SPECT-MIP could predict myocardial function recovery with a high accuracy, which played a critical role in clinical management and guided the recovery of cardiac function in patients.
| Conclusion|| |
The worldwide pandemic trend of COVID-19 has been formed, the situation remains serious at present. Although its performance in the respiratory system is very serious, it influences the cardiovascular system through various mechanisms, the fatality rate is extremely high. The multimode imaging plays an important role in the process of diagnosis and treatment now; it is also useful for hierarchical management, so as to achieve the best clinical treatment.
We thank our colleagues in the research group for their help in critically reading the manuscript and language proofreading. All authors have participated sufficiently in the collection, analysis, and interpretation of the data.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]