The acute phase of COVID-19 has been explored extensively, including factors affecting its incidence, severity, mortality, and patient survival; however, data about the disease’s sequelae are limited. With the prolongation of the pandemic, the short-term and long-term effects of COVID-19 on different body systems began to move into the research spotlight. In an unprecedented undertaking, we examined the long-term effects of COVID-19 on BP among 5,355 non-hospitalized patients who were followed up 12.5 ± 0.4 months after recovering from COVID- 19. Both systolic and diastolic BPs were significantly higher post-infection. There were 456 (17%) patients with new-onset hypertension and 456 (14%) with exacerbated hypertension requiring an intensified antihypertensive regimen. Age, previous history of HTN, DM, or cardiac events, and smoking were the predictors of BP increase.
In addition to ARDS and AKI, SARS-CoV-2 can also result in cardiovascular complications (15). A number of studies have shown that cardiac tissue contains SARS-CoV-2 genetic material (16). The virus can penetrate small blood vessel walls in the heart, leading to myocardial ischemia and potentially causing arrhythmia (17). Moreover, SARS-CoV-2 has been found within endothelial cells, leading to endotheliitis responsible for the systemic complications observed in COVID-19 (18).
Hypertension (27–30%), along with DM (19%) and coronary artery disease (6–8%), has been recognized as a fairly common comorbidity in COVID-19 patients since early in the pandemic (19, 20). Several studies have looked at variations in BP among COVID-19 patients, mainly examining hospitalized patients for a short follow-up period. Akpek indicated that COVID-19 increases systolic (120.9 ± 7.2 vs. 126.5 ± 15.0 mmHg) and diastolic (78.5 ± 4.4 vs. 81.8 ± 7.4 mmHg) BP and might cause new-onset hypertension shortly after infection in hospitalized patients (21). Gameil et al. compared 120 COVID-19 survivors with 120 gender-matched controls and found that the systolic BP increased only in the case group at three months of follow-up (22). De Lorenzo et al. found that 109 (58.9%) COVID-19 patients needed further medical care after being discharged from the hospital; 40 (21.6%) were due to uncontrolled BP (23). Nandadeva et al. found no difference between ambulatory and laboratory-measured BP between COVID-19 patients and a control group. However, there was a significant reverse relationship between blood pressure and time of infection (i.e., a higher BP with more recent disease) (24). The Chen et al. study reported that angiotensin II (Ang II) was significantly higher in COVID-19 patients without prior hypertension compared with healthy controls. They also found that systolic BP was significantly higher in COVID-19 patients vs. healthy controls. Among them, 16 patients were characterized as hypertensive after COVID-19; their angiotensin II levels were elevated more than other COVID-19 patients (25). Hence, it seems that such BP changes reflect hormonal variations occurring following SARS-CoV-2 infections.
The renin-angiotensin-aldosterone system (RAAS) is a crucial regulator of blood volume, vascular resistance, and blood pressure (26). It has two axes on which BP regulation depends on the interaction of them: 1-angiotensin-converting enzyme/angiotensin-II/angiotensin type-I receptor (ACE/ANG-II/ AT1R) and 2- angiotensin-converting enzyme 2/angiotensin-(1–7)/MAS-receptor (ACE2/ANG-(1–7)/MAS) (15). Many drugs interfere with this system. ACE 2 is an enzyme expressed in the intestines, kidney, testis, gallbladder, and heart, which modulates the RAAS; however, it acts as the cell entry receptor of both SARS-CoV-1 and SARS-CoV-2 (27). At the beginning of the COVID-19 pandemic, the prescription of ACE inhibitors and ARBs was challenging due to their role in the upregulation of ACE 2. It was believed that using these antihypertensive drugs would increase the level of ACE 2 and, subsequently, the incidence and severity of COVID-19 (28). Several review and cohort studies rejected this hypothesis, declared these drugs safe, and encouraged patients to use them if indicated (29, 30). It was suggested that the physiological expression of ACE 2 in the lungs or heart reaches saturation for binding with SARSCoV-2 spike protein; thus, further upregulation of ACE2 expression by RAAS inhibitors would not enhance infection but would rather protect the lungs and heart (31). ADAM17 can also cleave the extracellular juxta-membrane region of ACE2, increasing the soluble form of ACE 2 (32). The soluble isoform of ACE 2 may compete with membrane-bound ACE 2 and bind to the spike protein of the virus, preventing its cell entry (33). The European Society for Cardiology and American Heart Association confirmed this issue (34, 35). Nonetheless, some hypertensive patients might have lost their adherence to these drugs early during the pandemic, increasing their BP.
Another hypothesis proposed for how COVID-19 increases blood pressure is that the balance between ACE 2 and angiotensin II is disturbed by SARS-CoV-2 (36). It was confirmed that one of the complications of SARS-CoV infection is decreased ACE2 expression (37). SARS-CoV- 2 resembles SARS-CoV, share 80% of sequence identity but with significantly higher binding affinity to ACE2, As a result, the number of virus particles required to infect a cell is reduced (38, 39). SARS-CoV-2 binds to the ACE II receptor and serine protease transmembrane serine protease 2 (TMPRSS2) through its S1 and S2 subunits of spike protein to enter the host cell, leading to transient ACE II downregulation via these two host protease enzymes (40). The alternative SARS-Cov- 2 cell entry mechanism is through interaction with AT2R and CD147 (15). ACE 2 counter-regulates the RAAS by facilitating angiotensin (Ang) II and Ang I cleavage to Ang 1–9 and Ang 1–7, respectively, resulting in the accumulation of Ang II in different tissues (41). Plasma-ANG-II levels were found to be linearly related to viral load and lung injury (42). When ANG-II binds to the ANG II type 1 receptor (AT1R) in various tissues throughout the body, it causes vasoconstriction, increases aldosterone release, and activates the thirst reflex, resulting in the secretion of antidiuretic hormone (ADH). As a result, Aldosterone promotes sodium and water reabsorption in the kidney's distal tubules and collecting ducts. ADH binds to receptors in the renal collecting ducts and reduces urine loss at the same time. The combined effects of ANG-II, aldosterone, and ADH raise both the preload and afterload on the heart, resulting in an increase in blood pressure. Furthermore, the ACE/ ANG-II/ AT1R axis is associated with oxidative stress, fibrosis, inflammation and cellular proliferation. (43–45) Moreover, this peptide hormone causes an increase in endothelial and organ damage by producing reactive oxygen species (ROS) (46). ANG 2 also binds to the ANG 2 type 2 receptor (AT2R), causing the opposite effects as when the type 1 receptor is activated. Additionally, ACE 2 activity was reported to be reduced in patients with pulmonary arterial hypertension (32). Due to essential role of ACE 2 in regulation of RAAS and SARS-Cov- 2 host cell entrance it has been proposed that Human recombinant soluble ACE2 (hrsACE2) can be a potential candidate for treatment of COVID-19 (47).
Following the decrease of ACE 2 levels, the protective axis of Ang 1–7, Ang 1–9, and MAS receptors is downregulated (41). There are pieces of evidence that the ACE2/ANG-(1–7)/MAS axis protects rats from lung fibrosis and pulmonary hypertension (48). Deletion of MasR can induce proinflammatory phenotypes of macrophages in mice, which indicate its anti-inflammatory effect (49). Moreover, its activation causes a variety of effects, including antiarrhythmic effects and vasodilation via the release of nitric oxide (NO) and prostaglandins (50). In summary, dysregulation of RAAS, increasing Ang II, promoting sodium and water retention, and vasoconstriction lead to increased BP (Fig. 3) (36).
Some concerns have been raised regarding the safety of SARS-CoV-2 vaccines based on reports of thromboembolic events, hypersensitivity reactions, and tachycardia following vaccination (46, 51, 52). There are also some reports about BP rising after COVID-19 vaccination. In a systematic review and meta-analysis by Angeli et al. evaluating six studies with 357,387 subjects and 13,444 events of abnormal or increased BP, the researchers found 3.20% and 0.6% of patients with abnormal/increased BP and stage III hypertension or hypertensive urgencies and emergencies, respectively (53). Meylan et al. found stage III hypertension in 9 patients minutes after mRNA-based SARS-CoV-2 vaccination; 8 had a history of hypertension. All of them recovered after some hours of monitoring and antihypertensive medications (46). These findings extend those by Zappa et al., who described six patients with an average rise in systolic or diastolic BP at home by ≥ 10 mmHg during the first five days after the first dose of the vaccine when compared with the five days before the vaccine. They concluded that a history of previous COVID-19 is associated with a higher rise in BP after vaccination (54). The rise in BP following COVID-19 vaccination indirectly supports the increase in BP after COVID-19; both occur by RAAS overactivation.( Fig. 4)
Immune system activation and subsequent inflammation are determinants of systolic, diastolic, and pulse pressure in COVID-19 patients (55, 56). Inflammatory cytokines released by viral and bacterial infections cause microvascular dysfunction, increased vascular permeability, tissue damage, and hypoperfusion, which disturb kidney microcirculation, so BP variation is probable (57). The role of inflammation on aortic stiffness and BP has been confirmed in previous studies; it causes endothelial injuries, and dysregulation reduces nitric oxide production (58). This vasodilator is a promising remedy in the treatment of HTN and covid-19. A randomized clinical trial indicated that the immune response against pathogens increases aortic stiffness—a pivotal basis of systolic BP (59). Hospitalized COVID-19 patients may experience a prolonged period of mechanical ventilation and associated sedation, volume overload, inotropic use, increased adrenergic tone, fever, hypoxia, inflammation, cytokine storm, ischemia, and vasculitis, which may contribute to an excessive cardiovascular response and worsening of hypertension (6). It was shown that ICU-admitted COVID-19 patients tend to develop hyperreninemia combined with hypernatremia and hyperchloremia (60). These events may trigger sympathetic, RAAS, or other reactive responses that mediate systemic vasoconstriction and affect BP and cardiovascular events (61).
Our investigation suggested that patients with older age and comorbidities (including HTN, DM, smoking, and a history of cardiovascular events) are at higher risk of BP increase after COVID-19 recovery. Previous meta-analyses and observational studies cite these characteristics as predictors of COVID-19 severity and mortality (62, 63). RAAS dysregulation (decreased ACE 2 and Ang 1–7; increased Ang II) can potentially explain the abovementioned associations. Also, it has been hypothesized that endothelial dysfunction in patients with such comorbidities and vascular damage induced by COVID-19 can predict severe morbidity and mortality following COVID-19. Age, history of hypertension, diabetes, and previous cardiac events were predictors of uncontrolled hypertension in the COVID-19 group in the Angeli study (13). Similarly, Nam et al. associated advanced age and a history of hypertension with increased BP variability (64). Thus, the comorbidities such as DM and HTN must be controlled to prevent a severe COVID-19 course and subsequent sequelae.
Blood pressure changes over a long period are influenced by quite diverse factors; besides the effect of COVID-19, other factors may change the BP during the pandemic. According to studies worldwide, lockdowns have been linked with several adverse long-term effects on cardiovascular diseases due to increased stress, anxiety, isolation, obesity, and decreased physical activity (65, 66). In a survey in Vietnam, 3.3% and 2.6% of participants reported a reduction and cessation of exercise during the pandemic lockdown, respectively. Moreover, 12.4% of patients had difficulty controlling their BP; decreased medication adherence, inaccessibility of medical facilities, and a sedentary lifestyle could be possible etiologies (67, 68). According to Di Renzo et al., outdoor physical activities such as walking, jogging, and swimming decreased significantly during the pandemic (69).
Limitations and strengths
The current study has some limitations. First, the BP levels were measured at the clinic, and ambulatory daytime, nighttime, and 24-hour BP were unavailable. While such measurements would be more accurate, white-coat hypertension seems unlikely to affect our results as the BP was measured in a quiet room in a comfortable position, and initial and final measurements from the same person were compared using paired statistical analysis. Secondly, serial BP measurements across multiple follow-up sessions would have allowed the persistence of possible changes to be determined. Third, this study was a single-center experience representing a limited racial, ethnic, and geographical area. On the other hand, the large sample size of non-hospitalized patients is a strength of this study as it may be more representative of the general population affected by COVID-19 than a hospitalized population. Another strength was that BP measurements were not taken during the acute disease phase of COVID-19, eliminating the effects of acute disease processes and related psychological factors. Nonetheless, multicenter prospective studies with longer follow-up periods should be planned to overcome the limitations of the present work.