Cardiovascular Risk Factors and the Severity of COVID-19 Disease

Background and objective Several cardiovascular risk factors have emerged as important determinants of severe illness and death among coronavirus disease 2019 (COVID-19) patients. However, the full impact of these cardiovascular risk factors is still under investigation. This study aimed to investigate the association between patients' level of cardiovascular risk and the severity of COVID-19. Materials and methods This observational study included all adult patients with COVID-19 hospitalized at Sheikh Khalifa Ibn Zaid International University Hospital from March 20 to May 10, 2020. The cardiovascular risk level was assessed by the doctor responsible for each patient based on the 2019 European Society of Cardiology (ESC), the European Atherosclerosis Society (EAS), and the European Association for the Study of Diabetes (EASD) guidelines. We examined the association between the patients' level of cardiovascular risk and their severity of COVID-19 disease by using a logistic regression model. Results Among 133 patients with confirmed COVID-19, 46.6% had a low cardiovascular risk level, 19.5% had a moderate risk level, 15.8% had a high risk level, and 18.1% was found to have a very high risk level. Patients with different cardiovascular risk levels had significantly different rates of complications including secondary infection (p-value: <0.001), acute respiratory distress syndrome (ARDS) (p-value = 0.017), intensive care unit (ICU) admission (p-value: <0.001), and death (p-value: <0.001). A patient's very high cardiovascular risk level versus low, moderate, or high cardiovascular risk level was independently associated with ICU admission [OR = 6.42, 95% CI: (1.45-28.30)]. Conclusion Based on our findings, an increased level of cardiovascular risk among patients was strongly associated with the severity of COVID-19. This study also highlights the need for assessing cardiovascular risk factors in all patients with COVID-19.


Introduction
The novel coronavirus disease 2019 (COVID- 19) was first identified in Wuhan, China in December 2019, and since then it has spread rapidly around the world. The World Health Organization (WHO) subsequently declared COVID-19 as a global pandemic on March 11, 2020 [1]. As of April 14, 2021, there have been 136,996,364 confirmed cases of COVID-19 globally, which have resulted in 2,951,832 deaths [2].
Previous studies on the condition have observed that elderly patients and those with comorbidities such as diabetes, hypertension, and cardiovascular diseases are more likely to develop severe forms of COVID-19, with more complications and/or more susceptibility to death from the disease [3,4]. However, the impact of these cardiovascular risk factors such as age, hypertension, diabetes, and cardiovascular diseases on the clinical outcomes and the prognosis of COVID-19 disease is still poorly understood.
This study investigated the association between the level of the patients' cardiovascular risk and the severity of COVID- 19. We hypothesized that patients with increased cardiovascular risk levels, compared to those with a lower level of cardiovascular risk, are more likely to develop severe forms of COVID-19.

Study design
This single-center observational study included all adult patients (aged 18 years and above) admitted with confirmed COVID-19 disease to the Sheikh Khalifa Ibn Zaid International University Hospital in Casablanca, Morocco, between March 20 and May 10, 2020. This hospital has been mandated by the Moroccan Ministry of Health to care for patients with COVID-19. Depending on the severity of COVID-19, patients were admitted to the intensive care unit (ICU) (severe patients) or provided non-ICU care (non-severe patients). Criteria of ICU admission were defined based on the WHO interim guidelines: respiratory rate of >30 breaths per minute, severe respiratory distress or oxygen saturation level of SpO 2 below 92% with 4 l of oxygen ventilation, or neurological or hemodynamic disorders [5]. Pregnant women and patients under the age of 18 were excluded from the study.

Data collection
Data were collected from the electronic medical records of patients by a trained team of physicians. These medical investigators gathered and reviewed the data of all patients.
For each patient, we collected data related to her/his cardiovascular risk level as well as demographic characteristics including age and gender; comorbidities including hypertension, diabetes, cardiovascular diseases (atherosclerotic cardiovascular disease, heart failure, arrhythmia, etc.), respiratory diseases (chronic obstructive pulmonary disease, asthma, etc.), dyslipidemia, and other diseases and risk factors (hyperuricemia, neoplasia, smoking, obesity, etc.); clinical symptoms including fever, general symptoms (dizziness, myalgias, asthenia, etc.), respiratory symptoms (dyspnea, cough, etc.), as well as ear, nose, and throat (ENT) and digestive symptoms; and clinical outcomes including intensive care unit (ICU) admission, invasive mechanical ventilation use, the onset of complications [acute respiratory distress syndrome (ARDS), secondary infection, multiple organ failure, thromboembolic disease], and deaths.

Outcomes definition
The diagnosis of COVID-19 was based on the WHO interim guidelines [6] and confirmed as per reverse transcription-polymerase chain reaction (RT-PCR) assays. Diabetes was defined as a self-reported medical history of diabetes. Newly diagnosed diabetes was defined based on the American Diabetes Association (ADA) criteria [7], including fasting plasma glucose of over 126 mg/dl and/or random glycemia higher than 200 mg/dl and classic signs of hyperglycemia and/or HbA1c of ≥6.5% during the hospital stay. Hypertension was defined as blood pressure above 140/90 mmHg, and ARDS was defined according to the Berlin definition [8].

Outcomes assessment
A cardiovascular risk assessment was performed for each patient by the doctor who had recommended her/his hospitalization. As shown in Table 1, doctors at the study hospital performed the cardiovascular risk stratification based on the 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines, and for patients with diabetes, as per the 2019 ESC and the European Association for the Study of Diabetes (EASD) guidelines [9,10]. This cardiovascular risk stratification is commonly used in many countries including Morocco [11]. Based on this, patients were classified into four cardiovascular risk level categories: very high risk level, high risk level, moderate risk level, and low risk level.

Risk level Description
Very high risk level Documented ASCVD DM with target organ damage a , or at least three major risk factors, or early onset of T1DM of long duration (>20 years

Ethical considerations
The study was approved by the Institutional Ethics Board of the Sheikh Khalifa Ibn Zaid International University Hospital (approval number: CE_UM6SS/1/06/2020 -April 3, 2020). Patient consent was waived as the study included only unidentifiable data, in accordance with the national law.

Statistical analysis
For descriptive analysis, we presented continuous variables as medians with interquartile ranges (IQRs) (small sample) and categorical variables as percentages. Patients with different cardiovascular risk level categories were compared in terms of demographics characteristics, comorbidities, clinical symptoms, and clinical outcomes, using the nonparametric k-sample test on the equality of medians for continuous variables and using the Fisher's exact test for categorical variables.
Secondly, univariate analysis was performed to study the association between all available variables, as described above, and ICU admissions. Finally, multivariate logistic regression was performed to examine the association between cardiovascular risk level and ICU admissions. Since cardiovascular risk might be highly correlated with many variables, particularly those related to comorbidities, we used a stepwise multivariate model based on a bidirectional elimination, with a p-value of <0.05 and including all significant control variables as found in the univariate analysis. Results were reported as odds ratios (ORs) with their 95% confidence intervals (CIs).
All statistical analyses were performed using the STATA software (StataCorp LLC, College Station, TX). Pvalues were two-sided, and those <0.05 were considered statistically significant.

Results
A total of 133 adult patients who were hospitalized at Sheikh Khalifa Ibn Zaid International University Hospital with confirmed COVID-19 infection from March 20 to May 10, 2020, were included in the study.  The characteristics of the study population as per their cardiovascular risk levels are presented in Table 3.

Discussion
In this study, we investigated the association of cardiovascular risk levels of the patients with the severity of COVID-19 disease; this is the first major study involving an African population with COVID-19. The patients' level of cardiovascular risk was assessed by the doctor who had recommended their hospitalization, following the 2019 ESC, EAS, and EASD guidelines [9,10].
Patients with a very high level of cardiovascular risk had a significantly higher rate of complications including secondary infection and ARDS. In addition, these patients also showed generally poorer clinical outcomes. More than four-fifths of them were admitted to the ICU and about one-third of them required invasive mechanical ventilation. The death rate was also higher among patients with a very high cardiovascular risk level. Interestingly, we found that a patient's very high cardiovascular risk level was strongly and independently associated with ICU admissions.
These findings are in agreement with previous reports that have linked worse outcomes in COVID-19 infection with cardiovascular risk factors such as advanced age, hypertension, and diabetes, as well as with cardiovascular diseases such as coronary heart disease, heart failure, and cerebrovascular infarction. Indeed, Wang et al. have reported higher rates of ICU admissions in patients with several comorbidities [12]. Furthermore, a recent prospective study involving an American cohort of 5,279 patients with COVID-19 has shown that advanced age followed by heart failure were the strongest risk factors for severe COVID-19 illness [13].
Similarly, a study that involved an Italian cohort of 1,591 infected patients with COVID-19 in the Lombardy region has shown that 68% of the patients admitted in ICU units were elderly individuals and had at least one comorbidity. The most common comorbidities in this study were hypertension (49%) followed by cardiovascular disease (21%) and hypercholesterolemia (18%) [14].
Moreover, Guan et al. have reported that among 1,099 patients with laboratory-confirmed COVID-19 disease from 552 hospitals in 30 Chinese provinces, hypertension and diabetes were strongly associated with admission to the ICU unit, the use of mechanical ventilation, and death as a composite endpoint [15]. Likewise, the reported mortality rate was higher in patients with underlying cardiovascular diseases than patients without comorbidities [16].  [17]. Similarly, an Italian study that described the characteristics of patients who died as a result of COVID-19 has observed that deceased patients were predominantly elderly males with multiple comorbidities [18].
Several mechanisms may be attributed to the association of cardiovascular risk factors with worse clinical outcomes in patients with COVID-19. Patients with a higher level of cardiovascular risk may have a lower grade of vascular inflammation, which combines with the immune response induced by the virus and leads to an aggravation of the inflammatory state [19]. Secondly, the procoagulant state reported in COVID-19 may increase the risk of thromboembolic and acute cardiovascular events, by activating prothrombotic factors in atheromatous plaque [20]. Finally, previous studies have reported a significant association of myocardial injury with fatal outcomes of COVID-19 [21]. Consequently, patients with cardiovascular risk factors are more likely to have a severe form of COVID-19.

Limitations
Our study has some limitations. Firstly, it was observational by design, and hence further multicentric prospective and/or retrospective studies are required to validate our results. Secondly, only 133 patients were included in the study, and a larger study including more participants is highly recommended in order to verify our results. Thirdly, our assessment of COVID-19 severity was based on ICU admissions, and factors related to disease progression were not analyzed extensively. Finally, this was a single-center study, and this may have led to some biases in the results. Therefore, further multicenter studies are recommended to rectify this issue.

Conclusions
This study found that an increased level of cardiovascular risk seems to be associated with the severity of COVID-19 disease. Further studies need to be conducted in order to study the mechanisms that induce and aggravate the severity of COVID-19 in patients with cardiovascular risk factors. Our findings also highlight the need for early assessment of cardiovascular risk levels in all patients with COVID-19, as well as implementing a priority vaccination strategy for patients with cardiovascular diseases.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Board of Cheikh Khalifa Ibn Zaid International University Hospital issued approval CE_UM6SS/1/06/2020 -April 3, 2020. This study was approved by the Institutional Ethics Board of Cheikh Khalifa Ibn Zaid International University Hospital. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.