Findings on the relationship between cardiovascular disease and coronavirus disease 2019: a systematic review

Coronavirus disease 2019 (COVID-19) presents as the main cause of death, respiratory and heart failures, especially in the elderly, immunosuppressed, and those with cardiovascular comorbidities. Therefore, a better understanding of these findings is needed. A systematic review was carried out looking for articles published between December 2019 and May 2020 on the MEDLINE / PubMed search platform using the following descriptors : ((((((((("cardiovascular disease") OR ("acute myocardial infarction")) OR ("coronary artery disease")) OR ("acute coronary syndrome")) OR ("atherosclerosis")) OR ("cardiac insufficiency")) OR ("pericarditis")) OR ("myocarditis")) AND ("COVID-19")) OR ("SARS-CoV-2") and considering inclusion and exclusion criteria.40% of patients infected with SARS-CoV-2 had hypertension or other cardiovascular comorbidities, while 27% presented cardiovascular complications, mainly acute cardiac injury, arrhythmia and heart failure. The hypotheses of involvement of an intense inflammatory response, decreased immunity and greater expression of ACE2 in the heart, associated with more severe heart conditions, were discussed in this study. The increase in cardiac and inflammatory markers was associated with worse clinical outcomes and risk of death, confirming the need to evaluate them since admission to the hospital. The 10 articles analyzed presented as a limitation the small number of patients inserted, to the detriment of the pandemic state. We warned about the need for better clinical management of patients with cardiovascular comorbidities, and the importance of including this group among the first to be immunized, aiming at reducing the number of fatal cases due to infection. Studies with greater coverage are needed for a better comprehension of the topics discussed here.


Introduction
In 2019 the rst cases of a new betacoronavirus were reported, caused by the agent called SARS-CoV-2 cough, myalgia, or fatigue is more common. Studies show that the most present comorbidities in hospitalized patients are diabetes, hypertension, and cardiovascular diseases, the latter two being more frequent in ICU (intensive care units). Moreover, heart failure and acute heart injury are the most reported complications in deceased patients [9,10,11]. In this review, we discuss the association between cardiovascular diseases and COVID-19 considering risk factors and main complications found in infected patients.

Methodology
The study is a systematic review of the literature in search of an updated answer to a central and guiding question: what relationships have been found so far between cardiovascular diseases and COVID-19?
The descriptors were organized using the Boolean operators "AND" and "OR" according to the sequence: ((((((((("cardiovascular disease") OR ("acute myocardial infarction")) OR ("coronary artery disease")) OR ("acute coronary syndrome")) OR ("atherosclerosis")) OR ("cardiac insu ciency")) OR ("pericarditis")) OR ("myocarditis")) AND ("COVID-19")) OR ("SARS-CoV-2"). The following lters were applied as inclusion criteria: full text, case reports, classical article, clinical study, clinical trial, comparative study, controlled clinical trial, journal article or multicenter study, articles published between January 2019 and May 8, 2020, research with humans, in English, MEDLINE. The exclusion criteria used were: duplicate articles, reviews, meta-analyzes, and those that presented a main theme or methodologies that did not contribute to the study proposal. So, the descriptors together with the Boolean operators were entered on the MEDLINE platform via PubMed, inclusion criteria were selected in the search for eligible articles and, exclusion criteria were observed by reading abstracts and full text.
Results And Discussion 10 articles were selected using the lters on the PubMed platform and by consensus between two researchers after reading the abstracts or full texts ( Figure 1). Table 1 shows a brief description of the selected articles. A limitation that we can observe in these studies is the small number of patients inserted in the face of a pandemic. Probably, the rapid spread of the virus found the medical scienti c community with insu cient tools to deal with the problem more widely. The urgent interest in understanding COVID-19 in several aspects such as comorbidities, complications, transmission, treatment, among others, has accelerated publications, including many preliminary studies. This can be monitored daily by increasing the number of publications available per day on digital platforms since the beginning of the pandemic. Considering the 848 patients of the 10 articles included in this review, it was observed that approximately 40% of the cases presented cardiovascular comorbidities, while cardiac complications were reported in about 27% of the patients, being distributed in 17% of Acute Heart Injury and 10% of Heart Failure. In study 7, a retrospective and single-center case series of the 138 COVID-19 patients reported that 16.7% patients had arrhythmia. We also observed that the male gender was more prevalent, representing 62% of the patien Cardiovascular comorbidities and worse prognosis in COVID-19   The ndings from studies 1, 2, 3, 6, 7, 8, and 9 in table 1 show clinical outcomes (transfer to the ICU,  respiratory and cardiac complications, for example, and death) in patients with COVID-19 and history of hypertension or another cardiovascular disease. Considering the studies that presented data, which enabled a joint assessment (comorbidities and cardiovascular complications compared between groups of patients with the better and worse clinical outcome), it can be noted that heart failure, acute cardiac injury, and elevation of the QTcF interval on the electrocardiogram of patients tend to be directly proportional to the presence of cardiovascular comorbidities ( Figure 2). These ndings reinforce the inclusion of patients with such comorbidities in the risk group for SARS-CoV2 infection.
In study 7 (Table 1), the group of patients who presented NT-proBNP> 88.64pg / mL had a higher percentage of cardiovascular comorbidities and elevations in other markers of cardiac injury (myoglobin, CKMB, and Hs-TnI). Mortality in this group was 60%, while in the group of patients with NT-proBNP <88.64pg / mL there was no death. Although NT-proBNP was related to cardiac injury, it was also an independent factor for the risk of in-hospital death, as well as other markers of cardiac injury and hypertension. In study 10 (Table 1), it is observed that among the fatal cases analyzed, the percentage of cardiovascular comorbidities (hypertension and other heart diseases such as myocardial infarction) was 8% more in the group of people over 70 years of age and the increase in mortality was mainly related to males in this age group. However, the main symptoms, biochemical tests, and complications that led patients to death were not detailed.
The ACE2 is an aminopeptidase bound to the cell membrane that is involved in cardiac function and the development of hypertension. This enzyme also functions as a receptor for entry into the cell for both SARS-CoV and SARS-CoV-2 [2]. The expression of ACE2 in human cardiac tissues was evaluated and it was noted that those obtained from patients with muscle heart disease showed greater expression of the enzyme, indicating in this group of patients a greater vulnerability to SARS-CoV-2 infection, which may develop lesions, more severe cardiac conditions, and contribute to a worse prognosis [7]. However, it is still unclear in the literature whether hypertensive patients with COVID-19 and treatment with an ACE inhibitor or angiotensin receptor blocker can contribute to an increase in ACE2 and consequently lead to an increased risk of infection in the myocardium by SARS-CoV-2 [2]. Despite that, it has been recommended that these patients should continue treatment unless a change in therapy is made on medical advice [20].
Another point to be considered is that hypertensive patients have high levels of plasminogen, which increases the ability of many viruses to bind to ACE2. The envelope proteins in SARS-CoV-2 are cleaved by furin-like intracellular proteases and this increases the ability of viruses to enter host cells. A type of non-furin cleavage can be exerted by plasmin, generated through plasminogen cleavage. However, despite the participation of plasmin in the entry of various viruses into cells, further in vivo studies are needed to prove this participation concerning SARS-CoV-2 [21].

Cardiac markers and prognosis
The studies from 1 to 4, 6 to 9 of Table 1 presented laboratory ndings, among which some markers stand out, such as hypersensitive cardiac troponin I (hs-cTnI); Creatine Kinase MB (CK-MB); Creatine Kinase (CK); B-type Natriuretic Peptide (NT-proBNP); Lactate Dehydrogenase (LDH); High Sensitivity Reactive C Protein (hsCRP) and Myoglobin (MYO). It is observed that these markers were higher in the group of patients who presented more severe cases or who died as a result of infection, than in groups of moderate or recovered cases, thus showing the correlation of the high level of these markers with poor prognosis. It is also observed that cardiac markers had higher levels in elderly patients [16].
It is worth noting that advanced age is associated with the risk of death of patients infected by SARS-CoV-2, and in this age group, among the main comorbidities are hypertension and coronary heart disease [11]. Age-related dysfunctions also reverberate in the T-cell function, making it di cult to recognize new antigens and making the elderly more susceptible to infections. Additionally, an increase in the expression of pro-in ammatory cytokines is also observed in this group [22]. Both contribute negatively to the control of the replication of the coronavirus, besides prolonging the in ammatory response that demonstrates to be one of the main causes of the severity of COVID-19, that is, the cytokine storm is part of the pathological process of infection [9,11].
The studies 2 and 7 (Table 1) demonstrate that the levels of in ammatory markers such as hsCRP and Procalcitonin (PCT) are higher in critically ill or deceased patients compared to the group of recovered patients, as well as markers of cardiac injury -hs-cTnI, NT-proBNP, MYO, and CK-MB are also there. These ndings indicate a possible association between in ammation and cardiac injury in COVID-19. Linked to this, as patients with cardiac comorbidities present a greater expression of ACE2 [7], this may favor the mechanism of direct injury to the cardiac tissue, caused by the toxicity induced by the virus [23].
In studies 7 and 9 (Table 1), the cardiac markers hs-cTnI, CK-MB, MYO, LDH, and NT-proBNP were associated with mortality. Already in study 8 (Table 1) an association was also found between changes in hs-cTnI levels and the risk of death, with a rapid increase in its concentration after the 16th day of the disease being observed in deceased patients, as well as being present in more than half of them. The trials with hs-cTnI are effective in the diagnosis of Acute Coronary Syndrome (ACS), and its use allows a more precise report in the indication of myocardial injury. However, despite the alteration of the levels of this enzyme to predict suspicion of ACS, it was observed in patients with COVID-19 without heart symptoms, even though its elevation is more common after the onset of symptoms [24]. This raises the possibility of secondary cardiac injury related to an increase in oxygen demand caused by sepsis in subclinical coronary artery disease. Sepsis would lead to ischemia resulting in type 2 acute myocardial infarction [25]. This sequence of events may contribute to the elucidation of the ndings of study 3 (Table   1), which included 113 patients who died as a result of the COVID-19, among which 100% had sepsis and 49% had heart failure. The same study points to higher levels of hs-cTnI, NT-proBNP, and LDH in deceased patients compared to survivors. In study 9 (Table 1), the values of these markers, including the CKMB, were also higher at the admission of non-survivors.
Interestingly, study 4 (Table 1) found changes in the concentration of CK-MB in 66.7% of children and 14.3% of adults. None of the children required intensive treatment or presented serious complications, although the increase in CKMB indicates cardiac injury. This nding can be explained by the fact that the ACE2 enzyme is less expressed in children, which can lead to a milder course of the disease [26]. Myocardium seems to be a target of infection also in children [27], but further studies on the effect of SARS-CoV-2 infection on the child's cardiovascular system are necessary. In study 7 (Table 1) the NT-proBNP was an independent factor of risk of death in severe cases of infection, although it correlates with the other markers of acute myocardial injury and in ammatory markers. The elevation of cardiac markers seems to represent an adverse prognosis for the SARS-CoV2 patient, evidencing the need for their laboratory request since the patient's admission, aiming at the most appropriate clinical management.

Cardiac complications in COVID-19
After an average incubation period of approximately 4 to 5 days, the symptoms begin to appear and COVID-19 tends to last for two weeks with worsening in the second week due to the in ammatory response that follows the virus's replication period. In this short time, the most severe complications of the disease can happen [28]. Acute cardiac injury and heart failure were the main cardiovascular complications found in patients infected with SARS-CoV-2 among studies selected for this review ( Figure  2). In addition to the involvement of ACE2, which possibly can contribute to increasing the risk of cardiac complications in COVID-19, especially in the presence of cardiovascular comorbidities, as previously described, other hypotheses have been discussed, such as those mentioned by Adão and Guzik [29]. The highlight was given to in ammatory cytokines and hypoxia generated by the impairment of the respiratory system in COVID-19.
The rapid replication of the virus can cause massive death of epithelial and endothelial cells, and vascular leakage, triggering the exuberant production of pro-in ammatory cytokines and chemokines [30]. In studies 1, 2, 7 and 8 (Table 1), higher levels of in ammatory markers were found (IL-6, IL-10, and TNF-α; IL-6, IL-18, IL-10, IL-2, and TNF-α receptors; PCR; ferritin, and IL-6, respectively) in the group of patients with more severe cases of the disease. TNF-α, IL-1, IL-6, IL-8, IL-12, IL-18, and interferon-gamma (IFNγ) are pro-in ammatory cytokines, which act as mediators of the immune system. Anti-in ammatory cytokines, such as interleukins 4, 5, 10, 11, and 13, are also produced and the regulation of this balance is complex. The pro-in ammatory cytokines effectively initiate the in ammatory process against infectious agents. TNF-α, IL-1, IL-6 are responsible for raising protein levels in the acute in ammatory phase, which includes C-reactive protein (CRP) during infection [31,32].
When a set of cytokines is considered, the predictive value for cardiac complications increases, since it is known that cytokines work together leading to a complex in ammatory response [33]. IL-6 participates in the activation of T lymphocytes and the cytotoxicity of these cells leads to an intense in ammatory response that can damage the heart muscle [34]. The T-lymphocytes present a cardiotropism by an interaction between the heart-produced hepatocyte growth factor (HGF) and c-Met, the HGF receptor on naïve T-cells [35]. Also, clinical trials showed that both TNF-α and IL-1 are associated with impaired systolic and diastolic function and, also leading to adverse cardiac remodeling and decreased contractility of the heart muscle due to a reduction in oxygen consumption of the respiratory chain [36,37,38,39]. The 77-year-old man (with obesity and a history of hypertension) in study 5 (Table 1) had an acute ischemic injury (coronary artery atherosclerosis), but no evidence of myocarditis was found. So, in patients in whom heart failure is caused by in ammatory mechanisms, there is an expectation that welltargeted anti-in ammatory therapies can be used to obtain a better clinical outcome for patients [40].
One of the therapeutic options being analyzed for COVID-19 are chloroquine (CQ) and hydroxychloroquine (HCQ), antimalarial drugs and also used in treating some chronic rheumatic condictions due to immunomodulatory properties, for example, the inhibition of the production of proin ammatory cytokines such as IL-1, IL-6 and TNF-α [41,42,43]. Although CQ has antiviral properties tested in vitro, it has not always been con rmed during the treatment of patients with viral infections and the mechanisms of action of this drug may vary according to the pathogen. Among these mechanisms stand out the alkalinization of endosomes affecting the proper maturation of the viral protein and the recognition of the viral antigen by dendritic cells. This recognition occurs through a pathway that involves the Toll-like receptor that requires endosomal acidi cation. And nally, QC showed an anti-SARS-CoV-1 effect in vitro, decreasing the glycosylation of ACE2 [43,44].
In study 6 ( Figure 2), which included patients in severe COVID-19, was observed that the group of patients who received higher doses of QC had a higher percentage of acute cardiac injury, but it should be taken into account that this group also presented a higher percentage of cardiovascular comorbidities and a higher mean age. Added to this, the group that received high doses of QC (ie, 600mg twice daily for 10 days) presented more instance of QTc interval greater than 500 milliseconds compared with the lowdosage group (ie, 450mg twice daily on day 1 and once daily for 4 days). Therefore, suggesting that the QC should be administered with caution, especially in severe cases of the infection. At doses beyond the safety margin, chloroquine can show pro-arrhythmic activity mainly because of its ability to inhibit the cardiac potassium current from the internal recti er and, consequently, induce lethal ventricular arrhythmias [45].

Conclusion
The presence of cardiovascular comorbidity points to an increased risk of complications in COVID-19, such as heart failure and acute cardiac injury. Besides, higher levels of in ammatory and cardiac markers were associated with a worse prognosis of infected patients. These ndings seem to support the hypothesis that the probable higher expression of ACE2 in the heart of patients with such comorbidities allows greater entry of the virus into the cell, an intense in ammatory response that leads to decreased oxygen consumption and less contractibility. However, it is important to note that the studies discussed in this systematic review, included a small number of infected patients, considering a pandemic. These studies reinforce the need for attention to the group of cardiac patients, both for better clinical management and for new studies, given the poor prognosis that the infection promotes to these patients.
We emphasize the importance of including this group among those who will receive the rst doses of immunization, certainly contributing to a decrease in fatal cases due to SARS-CoV-2.

Declarations
Our numbering.