COVID-19 and coronary artery disease; A systematic review and meta-analysis

Background and aim Patients with underlying cardiovascular disorders such as coronary artery disease (CAD) are more prone to severe forms and multiple complications of COVID-19. The present systematic review and meta-analysis aimed to investigate the impact of CAD on patients with COVID-19. Methods Main electronic databases, including Medline (via PubMed), EMBASE, and Web of Science, were carefully searched and reviewed for original research articles published between 2019 and 2021. One hundred nine studies that address CAD in patients with COVID-19 were selected and analyzed. Results Following search and screening processes, 109 relevant publications were selected for analysis. The meta-analysis of prevalence studies indicated that the frequency of CAD among patients with COVID-19 was reported in 10 countries with an overall frequency of 12.4% [(95% CI) 11.1–13.8] among 20079 COVID-19 patients. According to case reports/case series studies, 50.9% of COVID-19 patients suffered from CAD. Fever was the most common symptom in these patients (47%); 36.5% also had hypertension. Conclusion The results obtained during the present study show that the simultaneous presence of COVID-19 and CAD, especially in men and elderly patients, can increase the risks and complications of both diseases. Therefore, careful examination of the condition of this group of patients for timely diagnosis and treatment is strongly recommended.


Introduction
Coronavirus disease 2019 , caused by a coronavirus strain known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread over the world, affecting billions of people [1,2]. Comorbidities affect a large percentage of COVID-19 patients [3][4][5]. Chinese studies revealed that 15-40% of patients with COVID-19 had a history of cardiac disease. Laboratory indicators of cardiac injury and cardiovascular involvement are found in 2-5 and 10-30% of patients, respectively [6,7]. A link between COVID-19 and cardiovascular disease (CVD) has been observed in clinical studies. COVID-19 patients with preexisting CVDs tend to have more severe complications and a higher mortality rate [8].
On the other hand, COVID-19 may also contribute to the development of CVD [7]. The high level of systemic inflammation linked to  has been suggested to hasten the onset of subclinical problems or produce de novo cardiovascular damage, increasing the death risk in COVID-19 patients [9]. Different studies highlighted that the prevalence of cardiovascular conditions was higher in patients admitted to the intensive care unit (ICU) due to COVID-19 and those who died from this disease [6,10]. Coronary artery disease (CAD), the most common type of CVDs, is one of the major concerns of global health. As the third leading cause of mortality worldwide, it accounts for 17.8 million deaths annually [11,12]. Although CAD was thought to be caused by lipid accumulation, its pathophysiology is complex, and its exact underlying mechanisms are still unknown [13]. However, endothelial dysfunction may be the origin of this process, which is frequently caused by one or more of the following factors: stress, oxidative damage due to free radicals, genetic changes, persistent infection, or hypercholesterolemia [14]. Uncontrolled hypertension, diabetes, and smoking may also facilitate this process [15]. CAD symptoms range from asymptomatic, stable chest pain to acute coronary syndrome and sudden cardiac death [16]. Arrhythmias and heart failure are among the most common complications, and myocardial infarction (MI) is the most common manifestation of CAD. A coronary artery obstruction causes an inadequate blood supply to the heart, resulting in CAD symptoms [17]. Although patients with a history of cardiac disease appear to be more prone to become infected with SARS-CoV-2 and to have a more severe clinical course, their clinical features and outcomes have yet to be documented. Therefore, the present study aimed to investigate CAD in patients with COVID-19 through a comprehensive systematic review and meta-analysis.

Search strategy
A comprehensive systematic literature search was conducted by reviewing original research papers published in Medline, Web of Science, and Embase databases in May 2021. The following phrases were used in the search strategy: "COVID OR COVID-19 OR novel coronavirus OR new coronavirus OR coronavirus 2019 OR 2019-nCoV OR nCoV OR CoV-2 OR SARS-2 OR SARS-CoV-2 OR severe acute respiratory syndrome coronavirus 2", AND "coronary artery disease OR CAD". The search was restricted to original articles about CAD among patients with COVID- 19. To identify further studies, bibliographies of related articles were also screened.

Inclusion and exclusion criteria
All case reports/case series and prevalence studies about CAD among patients with COVID-19 were evaluated. These studies reported sufficient data for analysis, such as the number of patients with COVID-19, the number of patients with CAD and SARS-CoV-2 infection, clinical symptoms, and laboratory findings. In the next step, two authors independently evaluated the recorded papers' titles, abstracts, and full texts based on the inclusion and exclusion criteria. The exclusion criteria were as follows [1]: studies considering CAD only [2], studies considering patients with COVID-19 only [3], review articles [4], abstracts presented in conferences, and [5] duplicate studies. After considering all studies based on inclusion and exclusion criteria, BH, MGH, and NKH selected appropriate papers.

Data extraction and definitions
In each study, the following items were considered: first author's last name, time of the study, time of publication, region, number of COVID-19 patients, number of COVID-19 patients with CAD, clinical symptoms, laboratory findings, outcomes, diagnostic methods, and treatment. The data were extracted by two independent individuals and verified by another researcher.

Meta-analysis
Statistical analysis was performed using STATA software, version 14.0 (Stata Corporation, College Station, Texas, USA) to report the frequency of CAD among patients with COVID-19. The fixed-effects (FEM) [18] and the random-effects models (REM) were utilized for data collection. Statistical heterogeneity was assessed using the Q-test and the I2 statistical methods. P-value <0.05 was considered statistically significant.

Characteristics of included studies
Overall, 3501 citations were recorded in the initial database searches. Three databases were searched, and therefore many duplicate studies were selected. After removing duplicates, 2112 non-duplicate studies remained. Of these, 1735 non-relevant studies were removed from our review after checking titles and abstracts. In the step of full-text screening, 268 irrelevant articles were also excluded. Eventually, 109 publications were selected for the final analysis ( Fig. 1).

The frequency of CAD among patients with COVID-19 based on prevalence studies
Out of 109 publications that reported CAD among patients with COVID-19, 43 articles (20 from Asia, 12 from America, and 11 from Europe) were prevalence studies, and 66 (12 from Asia, 26 from Europe, 27 from America, and one from Oceania) were case reports/case series (Table 1 and 2). A meta-analysis of prevalence studies indicated that the frequency of CAD among patients with COVID-19 was reported in 10 countries (China, Oman, Italy, Norway, Turkey, Spain, Serbia, Morocco, France, and the USA) with an overall frequency of 12.4% (95% CI  (Table 3). Fig. 2 summarizes almost all of the necessary data for a meta-analysis. The heterogeneity among assessed articles can be seen in Figs. 3 and 4.

The frequency of CAD among patients with COVID-19 among different continents based on prevalence studies
The meta-analysis of prevalence studies showed that the frequency of CAD among patients with COVID-19 was 10.8% (95% CI 8.2-13.3) among 10880 patients in America, 12.4% (95% CI 9.6-15.2) among 5799 patients in Europe, and 11.7% (95% CI 9.6-13.8) among 3400 patients in Asia (Table 3). There was no data on CAD infection prevalence among COVID-19 patients from Africa and Oceania. As shown in Table 1, the most COVID-19 patients with CAD were reported in the USA.

The frequency of CAD among patients with COVID-19 based on case reports/case series
We assessed the CAD infection among cases with COVID-19, which was reported in the mentioned electronic databases. Characteristics of case reports/case series studies (which should have been considered during the analyses mentioned above) are shown in Table 2. According to these studies results, 84 (54.9%) CAD patients have been reported among patients with COVID-19 from 26 countries ( Table 2). Most of the cases were in the USA (33 cases), Italy (10 cases), France (6 cases), and Spain (5 cases) ( Table 2). Among the patients whose gender was mentioned, 24 patients with CAD were women, 58 were men, and one was unknown. Evaluation of case reports/case series revealed that out of 84 patients with COVID-19, 63 patients had the underlying disease; most were from America and Europe, respectively. The continents of Asia and Oceania were also in the next rank. It should be noted that at the time of this study, there were no reports of underlying disease in COVID-19 patients with CAD in Africa. According to the results of the present study, the most common underlying diseases were hypertension (31/84), diabetes (29/84), obesity (11/84), multisystem inflammatory syndrome (10/84), and dyslipidemia (10/84) ( Table 4). In COVID-19 patients with CAD, the clinical symptoms were also considered. Thirty forms of clinical symptoms have been identified in these patients, depending on the findings of the investigations (Table 5).    Table 8 as  were other drug combinations that were used more than others in the treatment of patients.

The prevalence of CAD-COVID-19 patients based on detection methods
Diagnosis of CAD-COVID-19 patients in most eligible studies was performed using real-time PCR, Echocardiography, Chest radiology, Angiography, and CT scan (Table 9). Based on the evaluated studies, Real-time PCR (48 studies) and echocardiography (17 studies) were the most common methods used to detect CAD-COVID-19 patients. The use of CT coronary angiogram (one study), electrocardiography, and CT angiography (Two studies for each) methods were also mentioned in fewer studies (Table 9).

Discussion
Increased risk of COVID-19 and subsequent exacerbation of the disease and even death from the virus appear to be associated with certain conditions, including heart disease, especially coronary artery problems. However, there is still little evidence on how coronary heart disease and COVID-19 relate. In various studies examining the role of cardiovascular disease during respiratory virus epidemics, people with cardiovascular disease have been associated with an increased risk of respiratory infections, including influenza. Patients were often at a greater risk of death [19]. In the present study, the first systematic review and meta-analysis about COVID-19 patients with coronary artery disease, prevalence studies, case reports, and case series were analyzed. Accordingly, a total of 20079 patients with COVID-19 were screened in prevalence studies; in addition, 84 patients in case reports and case series studies were also evaluated. Meta-analysis of prevalence studies showed that most COVID-19 patients were from continental Europe (mainly Italy, Norway, France, Serbia, Morocco, and Spain), and the prevalence of this disease was 12.4% (9.6-15.2). Also, the prevalence of this infection, according to studies published in Asia, was 11.7% (9.6-13.8), which was mainly reported in China and Oman. Studies conducted in the Americas found that the prevalence of COVID-19 was 10.8% (8.2-13.3), mainly in the United States. According to case reports and case series, the USA has the highest number of patients with simultaneous COVID-19 and CAD, with 35 reported cases. According to case reports and case series studies, it was found that the number of men was 2.52 times higher than women, and the average age of all patients was 52.3 years. These studies showed that the most common clinical symptoms in patients with COVID-19, who also had CAD, were fever, cough, dyspnea, and chest pain. On the other hand, cases such as decreased appetite, aphasia, hemiplegia, weakness, nocturia, and collapse were among the least reported symptoms in these patients. In a retrospective study conducted by Lian et al. [20] on 788 patients with COVID-19, the manifestations of the disease were examined   in two groups: <60 years (n ¼ 652) and 60 years (n ¼ 136). It was noteworthy that most of the clinical symptoms of the infection were similar in both groups and included fever, cough, sputum, and fatigue. In the present study, evaluation of laboratory results of patients with CAD and COVID-19 revealed that there was a change in some important laboratory factors, including increased D-dimer, increased troponin, increased ferritin, and also an elevation in CRP levels. Evaluation of cardiac troponin I (cTnI) and cardiac troponin T (cTnT) necrotic biomarker is the gold standard for assessing myocardial damage worldwide. Elevated cardiac biomarkers are common in COVID-19 patients and it appears that an increase in cardiac troponin may be associated with disease severity and mortality from COVID-19 [21,22]. In a study by Guo et al. [23] on 187 hospitalized COVID-19 patients, cTnT levels were increased in 52 patients, all of whom had developed a myocardial injury. Mortality was higher in these patients compared to patients with normal cTnT levels (59.6% compared to 8.9%). Interestingly, a positive linear relationship was also observed in their study between cTnT and CRP, indicating an association between the severities of inflammation observed in COVID-19 and myocardial damage. The results of the study performed by Guan et al. [24] on 1099 COVID-19 patients showed an increase in D-dimer levels in 46% of all patients and, most importantly, in 60% of those with severe disease. According to a study by Shah et al. [25], out of 309 hospitalized COVID-19 patients, an increase in cTnI levels was observed in more than 1/3 of them (37.5%), most of whom had a mean age of 68.2 years and were male (53.5%). In an observational cohort study by Manocha et al. [26], the laboratory parameters of 446 out of 1053 COVID-19 patients in the USA were examined. Abnormal values and increases in TnI, CRP, Ferritin, and D-dimer were reported (50.7%, 97.8%, 90.6%, and 94%, respectively). Patients with severe TnI increase were elderly patients with significant coronary heart disease and prior stroke. Notably, in 112 patients with TnI level 0.34 ng/Ml, there was a significant increase in atrial tachyarrhythmias and ventricular tachyarrhythmias as well as mortality rate. The mean age of these patients was 69.7 years, and 70% were male. This study also revealed that a sharp increase in D-dimer and ferritin levels was associated with increased patient mortality. Evidence suggests that D-dimer levels rise during COVID-19, leading to coagulation disorders. D-dimer is a marker of fibrinolysis, and its increase is associated with venous thromboembolism and inflammation. The increase in this factor is associated with ICU hospitalization and increased risk of in-hospital mortality and acute myocardial injury [27]. These findings suggest that the severe form of SARS-CoV-2 infection is a systemic disease that involves multiple organs and subsequently leads to thrombosis and heart damage following inflammation. It can also be argued that changes in laboratory findings may be related to disease severity. However, the exact origin and cause of these laboratory changes in patients with COVID-19 cannot be ascertained. So far, despite countless efforts to control the COVID-19 pandemic, the disease remains a major challenge to the global community and a threat to public health, especially to susceptible individuals, including those with coronary artery disease. Although extensive research has been conducted worldwide to combat SARS-CoV-2, there is Table 5 Sign and symptoms in COVID-19 patients with CAD based on case report/series studies. n, number of patients with any variables; N, the total number of patients with CAD. no definitive cure for the disease. However, supportive therapies such as oxygen therapy, control of fluid accumulation in the lungs, broad-spectrum antibiotics to prevent secondary bacterial infections, fluid intake to prevent dehydration, and medication for reducing fever may be helpful in the early stages of the disease. Umifenovir is a hemagglutinin inhibitor that can prevent fusion and virus entry into target cells. It can also inhibit viral RNA synthesis and regulate the immune system by inducing interferon production and activating phagocytes. A systematic review and meta-analysis by Huang et al. [28] on the efficacy and safety of Umifenovir in patients with COVID-19 showed that it had good tolerability and safety but limited efficacy. They stated that taking Umifenovir was associated with more reports of negative PCR on day 14 of COVID-19. In addition, they noted that Umifenovir could not significantly reduce hospital stays, improve symptoms, or reduce the risk of disease progression. The study conducted by Lian et al. had similar results [29]. However, according to a retrospective cohort study performed by Huang et al. [30] on COVID-19 patients, administration of chloroquine and Umifenovir reduced viral shedding intervals, reduced hospital stay, and consequently reduced hospital costs. They also found that taking Lopinavir/Ritonavir increased the viral shedding interval, increased hospital stay, and subsequently increased hospitalization costs and side effects. In a retrospective cohort study, Deng et al. [31] found that Umifenovir combined with Lopinavir/Ritonavir had a more favorable clinical response than Lopinavir/Ritonavir alone. Therefore, according to the results of most studies, there is no evidence to support the use of Umifenovir to improve disease outcomes in patients with COVID-19. The present study showed that in addition to antiviral drugs, other drugs such as azithromycin and HCQ were among the most widely used drugs in people with COVID-19. In addition, aspirin and clopidogrel were the most commonly used drugs in patients with CAD. Unfortunately, there is not enough information about the exact efficacy of most of the drugs listed in Table 8, so the efficacy of these drugs in the control and management of COVID-19 patients cannot be accurately determined.
One of the most important aspects of the present study is the evaluation of underlying diseases in people with COVID-19 and coronary artery disease. According to the results of the present study, the most common  n, number of patients with any variables; N, the total number of patients with CAD. underlying diseases in these individuals were hypertension, type 2 diabetes, and obesity (36.5%, 34.1%, and 12.9%, respectively). In a study conducted by Koutsoukis et al. [32] in France on 237 patients with myocardial infarction, some underlying diseases (mainly diabetes and hypertension) were more common in patients with myocardial infarction and COVID-19 than patients without COVID-19 (53.8% compared to 25.6%). In a systematic review and meta-analysis by Ssentongo et al. [33] on underlying diseases and their impact on COVID-19-induced death, the most common underlying diseases were cardiovascular disease, hypertension, high blood pressure, diabetes, and congestive heart failure. It has been shown that COVID-19 patients with underlying diseases have a higher mortality rate than those without underlying diseases. In the present study, the most common types of CAD were acute coronary syndrome, acute thrombotic occlusion of the right coronary artery, stenosis of the proximal left anterior descending coronary artery, occluded artery, and STEMI. There were also the fewest reports of ALCAPA, coronary aneurysms, Wellens syndrome, and stress cardiomyopathy. According to a review study by Helal et al. [34], a 28.1% decrease in the rate of hospitalization of patients with acute coronary syndrome during the COVID-19 pandemic was reported in 2020 compared to the same time in 2019 (61328 patients in 2020 compared to with 22539 patients in 2019). Also, a decrease of 21.9% in STEMI cases was reported in 2020 compared to 2019. Notably, this decrease was mainly observed in types of acute coronary syndrome with milder manifestations/symptoms (including NSTEMI and UA). This study also reported increased in-hospital cardiac arrest and frequent left ventricular systolic impairment. Another review study conducted by Roshdy et al. [35] on cardiac tissue autopsy in COVID-19-induced deaths found that cardiac abnormalities were common among these individuals. However, acute myocarditis changes were uncommon (1.5% of cases). The highest outcomes related to autopsy in COVID-19 patients included myocardial ischemia, thrombosis, and cardiac dilatation. These researchers also stated that SARS-CoV-2 was present in the hearts of almost half of the dead patients, but true myocarditis was observed in only 1.5% of the deceased patients. The results of the Kermani-Alghoraishi study [36] suggest that COVID-19, especially in severe forms, may play a role in the progression and development of acute coronary syndromes, especially STEMI, during increased thrombogenicity. Coronary artery angiography in these patients shows significantly large thrombosis and simultaneous involvement of several vessels. Given that in pandemics caused by Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome coronavirus (MERS-CoV), we have seen an increase in the rate of acute cardiovascular events in infected patients, hence such results in the SARS-CoV-2 pandemic was expected, but the results of many studies did not show such an event. Suggested factors that may explain this reduction in acute Coronary Syndrome during the COVID-19 pandemic include an increased commitment to medication, dietary changes, reduction in strain following quarantine in most communities, and increased people's cooperation in observing prevention and treatment protocols. Another important issue in the field of COVID-19 is the use of appropriate and accurate diagnostic methods. RT-PCR is the gold standard molecular diagnostic method for detecting this virus. This technique can be suitable for diagnosing infection in patients as well as screening infected carriers. However, it should be noted that this test is not very sensitive, so it will be very useful to combine several diagnostic methods to achieve sufficient sensitivity and specificity [37,38]. According to the present study's analysis, the most common diagnostic methods for identifying patients infected with COVID-19 were PCR, Chest radiology, CT scan, and ELISA. Additionally, based on published studies, echocardiography and angiography were the most frequently used methods to assess and control patients with CAD. Finally, it is important to note the limitations of the present study. First, only information about patients referred to the hospital was analyzed based on published articles. Second, some published articles failed to meet the inclusion criteria for our survey due to inadequate information (including clinical evidence, laboratory findings, and underlying diseases). Third, because there is no accurate and extensive information on COVID-19 patients with CAD in many parts of the world, we have not been able to fully document the exact prevalence of this group of patients worldwide. Fourth, in many studies, the outcome of COVID-19 in patients was not mentioned and therefore is not present in our study.

Conclusion
SARS-CoV-2 infection can be a burden for people with CAD. Due to the importance of assessing the status of people with CAD and COVID-19, various studies have been conducted in this field that has provided different information. The results of the present meta-analysis highlighted that in people with a history of CAD, especially men and elderly patients, it is important to note that if COVID-19-related symptoms occur and abnormal laboratory findings present, they should immediately refer to medical centers for on-time confirmation of the infection and time management to prevent the deterioration of their clinical condition. Investigation of the exact link between COVID-19 and CAD requires more extensive research. However, physicians should be aware of the potential effects of COVID-19 on patients with CAD and the consequences of viral infection.

Funding
No funding.

Ethical Approval
Not required.