SARS-CoV-2 infection is triggered when the S-protein of the virus binds to angiotensin-converting enzyme 2 (ACE2), which is highly expressed in the heart, lungs, kidney, and gastrointestinal tract, and plays an important role in several cardiovascular and immune pathways. 20 SARS-CoV-2 binds to ACE2 with much higher affinity compared to SARS-CoV. 21 Additionally, SARS-CoV-2 shows its pathogenic activity by attacking type II alveolar epithelial cells that are expressing ACE2. Previous studies of coronavirus that causes SARS demonstrated that this virus binds to ACE2 in pulmonary alveoli through their superficial spike proteins, which causes lung damage and even lung function failure. 21 The loss of ACE2, caused by binding SARS-CoV-2, may shift the system to an overall higher angiotensin II and lower angiotensin- (1) (2) (3) (4) (5) (6) (7) tone. The role of angiotensin II in COVID-19 hypertensive patients seems to be crucial due to its role in functioning of the renin-angiotensin-aldosterone system (RAAS) that promotes vasoconstriction, sodium retention, oxidative stress, inflammation, and fibrosis and increases the bioactive peptide angiotensin-(1-7). 22 
Epidemiological data coming from China indicate that arterial hypertension, cardiovascular diseases, diabetes, and chronic obstructive pulmonary disease are the most prevalent concomitant diseases in patients with COVID-19 [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] 23 (Table 1 ). The number of investigations that provided at least short follow-up with intrahospital outcome is limited. Even though these data demonstrated that the prevalence of hypertension in COVID-19 patients with lethal outcome was high, [7] [8] [9] [10] 14, 17 it has still been debated whether hypertension was a predictor of mortality independently of other cardiovascular risk factors (age, obesity, diabetes) and comorbidities (coronary artery disease, heart failure, atrial fibrillation, cerebrovascular disease, renal impairment).
The prevalence of hypertension among patients with COVID-19, between different studies, ranged from 15%-20% 3, 4, 11, 12, 16, 17 to 30%-35%. [5] [6] [7] 9, 13 There are several reasons for these variations.
Average age was significantly higher in patients with elevated prevalence of hypertension, [3] [4] [5] [6] [7] [13] [14] [15] [16] which might be the most important reason for different prevalence of hypertensive patients among studies. Advanced age was associated with higher prevalence of other comorbidities such as diabetes, renal impairment, arterial hypertension, and obesity, which altogether increased proportion of hypertensive patients. 5, 6, 9, 13, 15 The prevalence of overweight and obesity was not reported in available studies about COVID-19. This "circulus vitiosus" between hypertension, obesity, and diabetes is difficult to break, and therefore, conclusion cannot be made without detailed data of all links of chain. The impact of smoking should not be forgotten in the relation between COPD, hypertension, and higher propensity to COVID-19. 3,6-9,11,12 However, results are conflicting, but majority of authors did not find higher prevalence of smoking in patients with adverse outcome. [7] [8] [9] The level of renal damage cannot be excluded as one of contribute factor for higher percentage of hypertension and advance stage of COVID-19 in hypertensive patients. Most of studies reported the large prevalence of cardiovascular diseases in COVID- 19 patients, but they also did not classified them and therefore it is difficult to estimate the individual effect of coronary artery disease, heart failure, and atrial fibrillation on occurrence and severity of COVID-19.
Li et al summarized the findings from 6 studies and showed that the prevalence of hypertension, cardio-, and cerebrovascular disease and diabetes in patients with COVID-19 was 17.1%, 16.4%, and 9.7%, respectively. 17 The incidences of hypertension, cardio-cerebrovascular diseases, and diabetes were two-to threefolds higher in patients with severe type of COVID-19 than in their non-severe counterparts. Yang et al included 46,248 COVID-19 patients from 8 studies and reported that the most prevalent comorbidities were hypertension, diabetes, cardiovascular diseases, and respiratory system disease. 18 The most frequent comorbidities in severe patients were hypertension, respiratory system disease, and cardiovascular disease. The large meta-analysis that included 76,993 patients with COVID-19 found that the pooled prevalence of hypertension, cardiovascular disease, smoking history, and diabetes was 16.37%, 12.11%, 7.63%, and 7.87%, respectively 19 (Table 1 ). The authors of meta-analyses agreed about the large heterogeneity between studies, which obviously limited the quality of their study. This can be partly explained by different designs and large variation in sample size among studies. 18, 19 Some essential data are still missing, and it would be dangerous to ascribe the large portion of risk for SARS-CoV-2 infection or severity of COVID-19 to any risk factor, including hypertension. It would be reasonable to hypothesize that uncontrolled comorbidities, as well as combination of concomitant diseases, may increase the risk of infection and severity of COVID-19, but this has to be examined.
There are many controversies about the effect of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in COVID-19 patients. 24 Some authors expressed their concern that the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and variation in ACE2 expression may be partly responsible for SARS-CoV-2 virulence. 25 
Limited number of studies provided outcome data after a short follow-up. Therefore, one should be careful in interpretation of these findings. Guan 6 In this study, chronic renal dysfunction and usage of RAAS were also more prevalent in patients with cardiac injury. However, patients with cardiac injury were almost 20 years older and more frequently men than those without injury, which also have to be taken into account. It was also reported that underlying cardiovascular disease was worsening outcome only in patients with myocardial injury. 6 Defining myocardial injury only by elevation of troponin I in these circumstances could be questionable because this biomarker may be increased in many conditions such as inflammation and/or sepsis/systemic inflammatory response syndrome and kidney injury.
The authors did not clearly stated which disorders were included under the term "cardiovascular disease" and it is not clear whether hypertension was included in this term. Furthermore, it is difficult to understand which cardiomyopathies were included and whether patients with heart failure were included.
Chen et al reported that hypertension, cardiovascular disease, and diabetes were more prevalent among COVID-19 patients who died in comparison with survivors. 7 However, there was a large difference in age and sex distribution between groups and authors did not investigate the effect of comorbidities on outcome in this population 7 ( More importantly, the duration of follow-up was short and some patients remained in the hospital at the time of publishing these studies, which means that real outcome was unknown. Obesity was not reported in available studies, and its influence could not be inves- 
Recent findings reported that arterial hypertension represented one of the most common comorbidities in patients with COVID-19. This prevalence ranged between 10% and 34%. The impact of hypertension on outcome and particularly on mortality in COVID-19 patients is not clear due to lack of data. Studies did not provide evidence that RAAS inhibitors should be avoided or switched in these patients. Large studies that will consider all potential sources of bias and confounding factors, as well as longer follow-up, are necessary.
The public pressure to find all answers is very high, but physicians' duty is to stay rational and has scientific approach to available and upcoming data.
Marijana Tadic https://orcid.org/0000-0002-6235-5152