Covid-19 and Heart Involvement: A Systematic Review of Literature

Abstract Background Recent reports in the literature have indicated that infection by coronavirus disease 2019 (COVID-19) causes cardiac complications, such as heart failure, arrhythmia, myocardial infarction, and even fulminant myocarditis. These complications have been identified as the cause of death in some patients infected with SARS-CoV-2. Objectives To analyze echocardiographic and electrocardiographic changes, treatments used, and clinical outcomes in patients with myocarditis and COVID-19. Methods The items described for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed. This review included articles in English, Portuguese, and Spanish that reported cardiac involvement, injury, or myocardial inflammation in patients who acquired COVID-19 (SARS-CoV-2). Results Five databases were consulted to find 1,726 articles. After applying the eligibility criteria, a total of 22 studies were considered qualified. ST-segment (section of the electrocardiogram corresponding the end of the S wave to the beginning of the T wave) elevation and tachyarrhythmia were the most common changes found in the electrocardiographic analysis of patients affected with COVID-19. Concerning echocardiography, there was a high frequency of decreased ejection fraction and occurrence of pericardial effusion. Conclusion This systematic review provides a potential tool for the analysis of cardiac changes and implications caused in patients affected by SARS-CoV-2 infection, with emphasis on the presence of tachyarrhythmia on electrocardiogram (ECG) and decreased ejection fraction on echocardiogram.

system, which is important for regulating blood pressure and other functions related to the cardiovascular and renal systems. 6,7 COVID-19 can cause myocarditis, which leads to serious damage to the cardiovascular health of patients with coronary artery disease. The main mechanisms involved in the pathogenesis are the hyperinflammatory state mediated by pro-inflammatory cytokines such as the interleukins IL-2, IL-10, IL-6, IL-8 and tumor necrosis factor (TNF-α); endothelial dysfunction resulting from the interaction between ACE2 and SARS-CoV-2; processes of macro-and microthrombotic arterial occlusion induced by stress in the autonomic nervous system; and endothelial, coronary, and smooth muscle cell dysfunction associated with macrophages and platelet activation, precipitating instability and rupture of the atheromatous plaque that leads to thrombus formation. These factors together lead to myocardial injury, hypoxia, and cardiotoxicity, which cause myocarditis and aggravation in patients with preexisting coronary artery disease. [6][7][8][9] Viral infection is described as one of the most common infectious causes of myocarditis onset, particularly influenza and parvovirus B19. However, cardiac involvement as a complication of SARS-CoV-2 infection is still poorly understood. It appears that it affects the cardiovascular system because of an elevation of cardiac biomarkers such as troponin T and type B natriuretic peptide. 10,11 Cardiac dysfunction does not present as a common sequela in patients affected by SARS-CoV-2; however, a significant number of patients were observed with myocardial injury. COVID-19 infection can cause cardiac complications, such as heart failure, arrhythmia, myocardial infarction, and even fulminant myocarditis. The literature also reports the occurrence of acute myopericarditis and pericardial effusion in patients with COVID-19, even in the absence of severe pulmonary disease. Myocarditis has already been identified as the cause of death in some patients infected with SARS-CoV-2. The highest frequency of cardiac involvement is in the focal myocardium, with risk of arrhythmia, progression to fulminant heart failure, and cardiogenic shock. 3,[12][13][14] The objective of this systematic review is to map the clinical changes in electrocardiogram (ECG) and echocardiogram of patients with COVID-19 confirmed by reverse-transcriptase chain reaction (RT-PCR), who developed myocarditis, as well as the clinical outcomes and treatments employed in each case.

Protocol and Registration
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), which consists of a checklist with 27 items and a four-step flowchart to assist the construction of systematic reviews and meta-analyses. 15

Inclusion Criteria
Only case reports and case series that recorded cardiac involvement, injury, or myocardial inflammation in patients who acquired COVID-19 confirmed by RT-PCR were chosen for this study. The articles were in English, Portuguese, and Spanish, and only studies that presented information on clinical manifestations, with or without changes in the ECG and echocardiogram were included. Alterations considered abnormal in the ECG were based on the Recommendations for the Standardization and Interpretation of the Electrocardiogram Guidelines from the American Heart Association/American College of Cardiology/Heart Rhythm Society, consisting of atrial or ventricular arrhythmias, conduction disorders, or other electrophysiological information indicated in the exam as suggestive of pathology. Abnormalities in echocardiogram followed recommendations from the American Society of Echocardiography and included reduced ejection fraction, motility disorders, wall or ventricle thickening, presence of blood clots, or other morphological and non-morphological changes that imply abnormal heart functioning. [16][17][18][19][20][21][22]

Exclusion Criteria
In this study, articles that were not case reports, series of cases, or observational studies were excluded. Articles from literature reviews, encyclopedias, editorials, book chapters, conference summaries, correspondence, reviews, news, and small communications were also excluded. Studies that did not present data regarding age, sex, ECG, echocardiogram, RT-PCR result, and myocarditis related to SARS-CoV-2 infection were excluded.
The articles used are indexed in the Medical Literature Analysis and Retrieval System Online (Medline) databases, consulted in PubMed, Scientific Electronic Library Online (SciELO), Cochrane CENTRAL, LILACS, and Science Direct.

Study Selection
The screening of the articles included in this work was performed based on the analysis of whether the title and abstract met the eligibility criteria, which were elected by fulfilling the inclusion criteria and not meeting any of the exclusion criteria. Articles that met the inclusion criteria were read in full, while the articles that met any of the exclusion criteria were excluded from the selection of this review.

Data Collection Process and Data Items
Among the articles included, the authors' names, year, place of publication, and methodology were removed. For case reports, information on age, sex, and possible complaints presented by the patient during the admission period were removed. Diagnostic strategies, laboratory tests performed, treatment, outcomes, and complications were extracted.

Synthesis of Results and Summary of Measures
For the analysis of the results obtained, the data were tabulated and duly described regarding their absolute frequency and relative frequency.

Risk of Bias of the Included Studies
To reduce the risk of bias, all studies included in this work underwent peer review.

Study Selection
Five databases were consulted to find 1,726 articles, and, of these, 266 duplicated articles were excluded from more than one database, resulting in 1,075 articles. In addition, 363 articles were not included in the analysis because of the non-association between COVID-19 and myocarditis. Thus, out of a total of 1,726 articles, 22 were selected, according to the eligibility criteria for the study, which represents 0.01% of all the articles found ( Figure 1).

Risk of Bias within the Studies
Descriptive studies, such as case reports and case series are subject to bias, due to their format, methods, and level of evidence.

Results of Individual Studies
Twenty-two case reports were selected for the systematic review. Al-Assaf et al. 23 described an atypical presentation of COVID-19 as subclinical myocarditis with persistent high-degree atrioventricular block treated with pacemaker implant, in a 58-year-old man in the United Arab Emirates. Nikoo et al. 24 presented a case of systolic dysfunction and complete heart block as complications of fulminant myocarditis in a case of recovered COVID-19 in a 38-year-old woman from Iran. Fischer et al. 25 described a case report of isolated myocarditis due to COVID-19 infection in a pediatric patient in France. The study from Iran by Malekrah et al. 26 reported a rare cardiac complication caused by novel coronavirus disease in a 76-year-old man. The article by Purdy et al. 27 registered a case series of myocarditis in COVID-19 presenting with cardiogenic shock, in the United States of America, in two patients age 53 and 30 years old. The article by Tiwary et al. 28 34 described the feasibility of prone position coronary angiography in a patient with COVID-19 pneumonia and refractory hypoxemia from France and its consequences for the heart. Faraj et al. 35  Articles with no association between COVID-19 and myocarditis (n=363) Full-text articles assessed for elefibility (n=385) Articles included in systematic review (n=22) infection in the United States of America was described by Haddadin et al. 39 Loghin et al., 40 in an article from the United States of America, described a pseudo-acute myocardial infarction in a young COVID-19 patient. The Spanish study by Rey et al. 41 registered COVID-19 infection and simultaneous thrombosis of two coronary arteries in a 59-year-old man. Nicol et al. 42 described delayed acute myocarditis and COVID-19-related multisystem inflammatory syndrome in a 40-year-old male patient from France. The Brazilian study by Yokoo et al. 43 described COVID-19 myocarditis in an 81-year-old man. Finally, Bernal-Torres et al. 44 reported COVID-19 fulminant myocarditis in a 38-year-old female Colombian patient with recent history of travel to Spain. Table 1 exhibits the identification of the articles included in the study.

Patient Profiles
In the respective studies, the age group ranged from 15 to 81 years, with the mean age of 51 years. In addition, the male sex (63.6%) was the most prevalent.

Risk of Bias across the Studies
Due to the nature of the descriptive studies, the results presented are liable to investigator bias, selection procedure bias, and selection bias.

Discussion
SARS-CoV-2 is a beta coronavirus that presents the composition of a positive enveloped RNA simple tape structure. It belongs to the subfamily Coronavirinae. The virus invades the human cell by binding with ACE2, a protein present in the cell membrane that is present in the cardiovascular epithelium. With its entry into the cellular environment, it migrates to the inside of the core for replication and apoptosis. 10,45 The pathophysiology of severe COVID- 19 has not yet been fully elucidated. However, the presence of a pro-inflammatory peak, known as a cytokine storm has been observed. 43 The damage caused by COVID-19 to the cardiovascular system is multifactorial, and it can result in a disorder between the high metabolic demand of cardiac tissue and low cardiac reserve, thrombogenesis, inflammation on a systemic level, and injury to cardiac tissue by the invasion of the virus to the myocardium. Generally, the most severe cases of acute cardiac injury occur in patients with preexisting comorbidities, such as diabetes mellitus, systemic arterial hypertension, chronic kidney disease, and cardiovascular disease, which are linked to a worse clinical prognosis. 46,47 These characteristics were observed in this study where we noticed that, in 31.8% (n = 7) of the studies in which the patients died, 32,34,36,[38][39][40][41] 71.4% (n = 5) had registered comorbidities. 32,36,38,39,41 Myocarditis presents various clinical manifestations, from mild symptoms, such as chest pain, palpitations, and fatigue, to cardiogenic shock or sudden cardiac death   due to association with ventricular arrhythmias. 4,[12][13][14]47 In myocarditis, there is focal or global myocardial inflammation, necrosis, and even ventricular dysfunction. The suspicion of focal myocarditis is raised in the presence of chest pain after a syndrome that is similar to influenza, thus presenting clinical evidence that points to an ACS for ECG or laboratory tests, or even with the presentation of cardiac wall movement abnormalities, but without evidence of an obstructive coronary artery disease for coronary angiography. 2,5,11,46,[48][49][50][51][52] The mechanisms and manifestations of cardiac arrhythmia are variable and include supraventricular tachycardia, polymorphic ventricular tachycardia, and torsade. However, the etiology of these abnormalities is still unclear. They may come from the disease itself through the inflammatory cascade, myocarditis, and hypoxia, or from the therapies based on chloroquine, hydroxychloroquine, moxifloxacin, and azithromycin. [47][48][49] In our study, the use of these medications was reported in 54.5% of the studies in which there was cardiac involvement after diagnosis of COVID-19. [26][27][28][29]33,[35][36][37][41][42][43][44] Acute respiratory infection caused by SARS-CoV-2 may be linked to an increased risk for classic myocardial infarction, as it is already known that inflammatory responses in the endothelium, such as that occurring in COVID-19, can increase the occurrence of plaque rupture. 48 Transthoracic echocardiography is more likely to detect changes in contractility of the ventricular segment, perfused by the coronary artery, which is involved in patients with ACS. Therefore, echocardiography may be an aid tool for differential diagnosis between myocarditis and ACS resulting from COVID-19 infection. 45,46,53,54 For myocarditis, we usually find diffuse hypokinesis with a reduction of ventricular ejection fraction, with possible presentation of a slightly associated pericardial effusion; however, segmental dyskinesia may also occur with even a hypodynamic state. Myocarditis may also clinically present with preserved ventricular function, with no change to segmental ventricular contractility in echocardiography. 14,45 The most frequent alterations and characteristics found in echocardiography of patients with cardiac impairment are reduced left ventricular ejection fraction, pericardial effusion, global hypokinesis, left ventricular hypertrophy, diastolic dysfunction, pulmonary hypertension, and reduced overall longitudinal deformation. In the most severe cases, the following manifestations were observed: hyperdynamic phase, in which there is an increase in parameters for cardiac output and the left ventricular ejection fraction, with a consequent decrease in peripheral vascular resistance; acute cardiomyopathy generated by stress, which presents abnormalities for segmental contraction and ballooning of the apical region of the left ventricle (known as Takotsubo cardiomyopathy); acute pulmonary hypertension and right ventricular hypertrophy; and systolic and/or diastolic global dysfunction resulting from long-term anoxia, severe hypoxia, or systemic inflammation. 46,[53][54][55][56] Regarding our study, we noticed that the most frequent manifestations on echocardiogram were similar to those already described in the literature, with significant presence of hypokinesis (31.9%), 24,25,27,31,34,36,44 reduced left ventricular ejection fraction (45.5%), 24,27,30,31,33,34,38,[42][43][44] pericardial effusion (27.3%), 27,28,33,35,42,44 ventricular dysfunction (9.0%), 27,36 and ventricular hypertrophy (13.6%). 28,29,31 Therefore, transthoracic echocardiography has been shown to be a means of early clinical evaluation of patients with SARS-CoV-2, since this method allows the visualization of hemodynamic evidence, capable of guiding the appropriate management. For patients with the most severe form of COVID-19, it is recommended to perform and evaluate daily echocardiography, as well as guidance for treatment that presents inotropic and/ or circulatory support. In this study, echocardiographic analysis proved to be of fundamental importance for the determination of the therapeutic strategies aimed at intervening favorably in the cardiac picture of the patient affected by the disease. We have observed the use of pacemakers (18.1%), 23,24,26,39 beta-blockers and other antiarrhythmics (31.8%), 24,25,27,29,34,42,44 ACE inhibitors (9.0%), 25,42 diuretics (18.1%), [27][28][29]44 in patients depending on the specific clinical need of each case, thus contributing to and corroborating previous analyses. 23,46 The causative factors of the alterations observed in ECG induced by COVID- 19 are not yet fully described. However, studies indicate that the virus can have a direct action on cardiomyocytes through an infiltration process with a consequent breakdown of the action potential of cells and structures, such as communicating junctions, causing several changes in the electrical conduction process. [57][58][59] Some of these abnormalities are still considered nonspecific but are highlighted in studies before the high frequency of STsegment abnormalities; others that are more nonspecific, with variable appearance include: sinus tachycardia, atrioventricular block, occasional branch block, atrial Int J Cardiovasc Sci. 2023;36:e20220035 fibrillation, bradycardia, premature atrial contractions, intraventricular block, and right branch block. [55][56][57][58][59][60] In our study, the elevation of the ST segment (31.9%) was the most characteristic change, 25,34,36,38,40,41,44 followed by atrioventricular or branch block (22.7%) 23,26,28,39,41 and sinus tachycardia (18.1%). 27,38,40,42 Notably, many cases showed sinus rhythm (27.3%). 24,30,32,35,37,42 CMRI is an extremely useful imaging exam for analyzing myocardial structure and function, in addition to providing information about the composition of cardiac tissue less invasively than myocardial biopsy. 61 As for its use in cardiac impairment caused by COVID-19 evaluation, studies by Petersen et al., 61 Ojha et al., 62 and Shafiabadi Hassani et al. 63 described findings, such as myocarditis according to the Lake Louise criteria, 64 LGE (an imaging finding indicating tissue inflammation and early fibrosis), 65 edema, areas of nonischemic necrosis, pericardial effusion, and myocardial inflammatory activity causing damage to heart tissue. [61][62][63] Our study was similar to those described; CMRI was performed in 40.9% of studies, [23][24][25]29,31,40,[42][43][44] reporting myocarditis (88.8% of those who performed CMRI) 23,25,29,31,40,[42][43][44] edema (66.6% of those who performed CMRI) 23,25,31,40,44 description of myocardial inflammation (66.6% of those who underwent CMRI) 23,24,29,42,43 and LGE (55.5% of those who underwent CMRI). 25,31,[42][43][44] Thus, this corroborates the usefulness of this test in assessing the degree of cardiovascular impairment in patients infected with SARS-CoV-2. [61][62][63] COVID-19 can affect several organs and systems of the human body and cause hemodynamic impact. 66 The main characteristics described in the studies conducted by Sastry, Cuomo, and Muthusamy 67 and by Jasiński and Stefaniak 68 include the occurrence of thromboembolic events, hypercoagulability, microangiopathies, respiratory failure, septic shock, cardiogenic shock, hypoxia, metabolic acidosis, renal injury, and myocardial stress. From this perspective, the results of our research corroborate with previous studies, since these characteristics were also recorded in the description of increased levels of cardiac troponins (63.6%), 24,25,[28][29][30][31][32][33][34][36][37][38][42][43][44] indicating possible damage to myocardial function; 69 SaO 2 below 95% (40.9 %); 24,26,31,34,35,37,38,41,43 increased D-dimer (31.8%), 27,29,32,36,37,41,42 which is an important biochemical marker whose increased serum levels indicate increased predisposition to thromboembolism; 70 evolution of patients to cardiogenic shock (22.7%); 27,31,36,38,44 and occurrence of metabolic acidosis (18.1%). 27,31,37,44 This combination of factors has been reported to be directly involved in the pathogenesis of myocardial damage in the form of myocarditis and in infarction with and without atheroma plaque formation. 6,8,9,61 Moreover, cytokines also play an important role in this aspect, with a different activity, since they are related to changes in the expression of calcium and potassium channels resulting from disturbances in the duration of the action potential. 58 Most patients with SARS-CoV-2 show nonspecific characteristics for the manifestation of myocarditis, with a presentation of sinus tachycardia, including ST-segment elevation, nonspecific intraventricular conduction delay, and T-wave abnormalities, with inversion in the previous leads, and the occasional appearance of atrioventricular block, corroborating the results of our study. One of the possible factors indicated in previous studies as related to ECG alterations would be due to the effect of antivirals used. 49,52,[57][58][59] Thakore et al. 57 observed the relevance of QT interval (period of the ECG from the beginning of the Q wave to the end of the T wave) analysis among patients infected with COVID-19. In this retrospective study, it was observed that an increase of 10 ms in corrected QT interval was related to a 16% increase in the patient's chance of having a higher severity index and, therefore, a higher risk of fatal evolution, given that, among patients who died during hospitalizations, a significant portion had a longer corrected QT interval on baseline ECG. In other studies, ECG findings were also frequently found to be associated with echocardiogram demonstrating ejection fraction lower than 50%, hypokinesis, and slight wall thickening. 57,[71][72][73]

Conclusion
We conclude that the current systematic review provides a potential tool for the analysis of cardiac changes and implications of SARS-CoV-2 infection, with an emphasis on the main ECG and echocardiographic findings, but also with coverage of clinical characteristics, treatment, and outcomes. ST-segment and tachyarrhythmias are the most frequent changes in the ECG, while diffuse hypokinesis, reduced ejection fraction, and pericardial effusion are more present on the echocardiogram.
The results obtained in this article corroborate previous studies' conclusions on the subject. Further epidemiological and clinical research is needed to better understand these conditions, as well as to establish therapies to provide a better prognosis.