Cardiac manifestations in COVID‐19 patients—A systematic review

Abstract Objectives The coronavirus disease‐2019 (COVID‐19) pandemic has resulted in the worst global pandemic of our generation, affecting 215 countries with nearly 5.5 million cases. The association between COVID‐19 and the cardiovascular system has been well described. We sought to systematically review the current published literature on the different cardiac manifestations and the use of cardiac‐specific biomarkers in terms of their prognostic value in determining clinical outcomes and correlation to disease severity. Methods A systematic literature review across PubMed, Cochrane database, Embase, Google Scholar, and Ovid was performed according to PRISMA guidelines to identify relevant articles that discussed risk factors for cardiovascular manifestations, cardiac manifestations in COVID‐19 patients, and cardiac‐specific biomarkers with their clinical implications on COVID‐19. Results Sixty‐one relevant articles were identified which described risk factors for cardiovascular manifestations, cardiac manifestations (including heart failure, cardiogenic shock, arrhythmia, and myocarditis among others) and cardiac‐specific biomarkers (including CK‐MB, CK, myoglobin, troponin, and NT‐proBNP). Cardiovascular risk factors can play a crucial role in identifying patients vulnerable to developing cardiovascular manifestations of COVID‐19 and thus help to save lives. A wide array of cardiac manifestations is associated with the interaction between COVID‐19 and the cardiovascular system. Cardiac‐specific biomarkers provide a useful prognostic tool in helping identify patients with the severe disease early and allowing for escalation of treatment in a timely fashion. Conclusion COVID‐19 is an evolving pandemic with predominate respiratory manifestations, however, due to the interaction with the cardiovascular system; cardiac manifestations/complications feature heavily in this disease, with cardiac biomarkers providing important prognostic information.


| RESULTS
A total of 1602 articles were found. Following the removal of duplicates, 798 articles were screened. Of these, 616 articles were excluded after applying the inclusion and exclusion criteria. The remaining 182 articles were analyzed in full, of which 61 articles met our inclusion criteria and were included in our analysis. The complete PRISMA flow chart is reported in Figure 1. Results are divided into risk factors for cardiovascular manifestations, cardiac manifestations, and cardiac-specific biomarkers.

| Risk factors for cardiovascular manifestations
Several risk factors for cardiovascular manifestation in COVID-19 patients have been described and summarized in Table 2. One of the most important risk factors is the presence of pre-existing cardiovascular comorbidities. Patients with hypertension or any other cardiovascular comorbidity were more likely to develop a cardiovascular complication due to SARS-CoV-2 infection, with a higher proportion of hypertensive patients developing acute heart injury and heart failure. 9 In a study by Yang et al 10 patients with diabetes, the cerebrovascular, and cardiovascular disease had inferior outcomes with an acute cardiac injury one of the common complications, leading to death. An analysis of 150 patients with COVID-19 demonstrated that hypertension, diabetes, pre-existing CVD, and cerebrovascular disease were responsible for 43%, 18%, 19%, and 10% of all deaths respectively. Of these deaths, 39% were attributed to heart failure or respiratory failure. 11 Other studies have linked hypertension and diabetes as significant risk factors for developing cardiovascular complications. 13,14 Guo et al 15  Patients with elevated troponin levels had more frequent malignant arrhythmias and higher levels of other cardiac biomarkers.
An Italian retrospective study showed hypercholesterolemia was another significant comorbidity that can predict worse outcomes involving cardiovascular implications. One hundred eighty-eight patients present in Intensive Care Units across hospitals in Lombardy had hypercholesterolemia, indicating the importance as a risk factor. 16 The commonest risk factor associated with an adverse cardiovascular complication in COVID-19 patients was hypertension (27%) comorbidity which contributed towards cardiac manifestations. CVD and diabetes was seen in 12.1% and 11.5% of patients, respectively.

| Heart failure and cardiogenic shock
Heart failure as a complication of pneumonia is common in hospital patients. However, several studies have identified heart failure as a significant manifestation of COVID-19. 14,17,18 One of the first studies linking heart failure and COVID-19 involved 191 patients with Heart failure is postulated to occur in COVID-19 patients due to the severe immune system over-reaction resulting in cytokine storm. The virus downregulates the angiotensin-converting enzyme 2 (ACE2), leading to increased levels of Angiotensin II causing increased inflammation, hypertension, and thrombosis. 21 As further data becomes available, the mechanism of heart failure in COVID-19 patients will become clearer and help provide a standard approach to its treatment.

| Arrhythmias
Patients affected with COVID-19 are at an increased risk of arrhythmias due to underlying comorbidities, polypharmacy, and disease progression. In a study of 137 patients, 7.3% reported palpitations as one of their symptoms. 27 Several studies have concluded that the prevalence of cardiac arrhythmias is higher in critically ill patients compared to non-critically ill patients. 7,28,29  Of note, non-specialized clinicians may use multiple concurrent medications that could potentially (synergistically, in some cases) contribute to an increased arrhythmic risk. Several trials are underway testing combination therapies, for instance, a Brazilian study compared low vs high dose chloroquine, in combination with ceftriaxone and azithromycin with or without oseltamivir. 33 This study amongst others was terminated due to safety concerns as 25% of patients in the high-dose arm showed QT prolongation and two experienced ventricular tachycardia before death. Table 4 summarizes the studies used in analyzing the occurrence of arrhythmias in COVID-19 patients.

| Cardiac inflammatory and coronary manifestations of COVID-19
Myocardial injury in COVID-19 is a recognized phenomenon. Case series include reports of myocarditis, ACS, and spontaneous coronary artery dissection (SCAD) (

| Cardiac-specific biomarkers
Cardiac biomarkers are important in recognizing patients that might be presenting with early signs of myocardial injury secondary to COVID-19, 50 as the presence of myocardial injury was associated with over 50% mortality. 14 We summarized studies looking at cardiac-specific biomarkers (CK, CK-MB, Troponin, Myoglobin, and BNP) in Table 6.
MYO raised in 29 patients, Ultra-TnI raised in 27 patients, NT-proBNP raised in 34 patients. No. of cases with raised MYO, ultra Tn-I and NT-proBNP significantly higher in severe and critical cases compared to mild (P < .05) NT-proBNP and MYO significantly increased in severe and critical cases compared to mild (P < .0167), but no difference between severe and critical cases.
The increased ultra-TnI significant between mild and severe cases only (P < .0167).
The increased level of MYO, Ultra-TnI, and NT-proBNP was associated with the severity of COVID-19.
The case fatality rate was 22.81% (13/57) in the group with abnormal parameters compared to 5.09% (11/216) in the normal parameter group.
All four parameters significantly higher in the death group compared to alive group (P < .001) Zhao et al, 76 China Retrospective, single-center CK raised more in severe compared to mild group (26.7% vs 9.8%, P = .018) Severe group tended to suffer damage to the cardiovascular system (26.7% vs 9.8%, P = .04)

Zheng et al, 77 China
Retrospective study 99 (32 critical, 67 noncritical) Mean age in critical group of 63.8 and 42.5 in noncritical group (P < .001), Overall mean age 63.8

CKMB Myoglobin
High sensitivity troponin T (TNTHSST) NT-proBNP CKMB raised in critical group compared to noncritical group (P = .053) Myoglobin raised in critical group compared to noncritical group (P = .026) TNTHSST raised in critical group compared to noncritical group (P = .000) NT-proBNP raised in critical group compared to noncritical group (P = .022) Critically ill patients showed significant laboratory evidence of myocardial damage compared to noncritical group, TNTHSST (P < .001), CKMB, myoglobin, and NT-proBNP (P < .05). Critically ill patients had increased myocardial damage and cardiac function indexes. High sensitivity troponin I (hs tnI) NT-proBNP higher in the NT-proBNP >0/88.64 pg/mL (P < .001) Myoglobin was higher in the group in the NT-proBNP >0/ 88.64 pg/mL (P < .001) CK-MB was higher in the NT-proBNP >0/88.64 pg/mL (P < .001) Hs-TnI was higher in the NT-proBNP >0/88.64 pg/mL (P = .001) Univariate analysis showed a hazard ratio (HR) of NT-proBNP associated to in-hospital death was 1.369 (95% CI, 1.217-1.541; P < .001) for an increase of 100 pg/mL Theories addressing the association between COVID-19 and the The lack of large-scale data on cardiogenic shock and COVID-19 makes it difficult to draw any firm conclusions. However, current data informs us that cardiogenic shock is a cardiovascular manifestation that doctors must look out for in COVID-19 patients. Finally, further studies are required to characterize the nature and classification of arrhythmias amidst the COVID-19 pandemic. 61 Ruan et al 11 showed patients that died from COVID-19 the cause of death was respiratory failure and cardiac injury in 33%, supported by Shi et al. 13 The presence of myocardial injury was associated with a significantly worse prognosis. A meta-analysis by Li et al cardiac biomarkers were significantly higher in severe cases compared to milder cases (P < .001), this included troponin (P < .001), CK-MB (P < .001) and NT-proBNP (P = .009) but myoglobin was not (P = .052).
Additionally, death was also higher in patients with acute cardiac injury (P < .001). 62

Results
Both TnT and NT-proBNP levels increased significantly during the course of hospitalization in those who ultimately died, but no such dynamic changes of TnT or NT-proBNP levels were evident in survivors.
Fan et al 85  | 2005 more rapid escalation of treatment. With a second wave expected by many experts to be worse than the initial wave, clinicians must be aware of the risk factors, the manifestations, and the investigations that could help in preventing such predictions becoming reality.