Evaluation of blood pressure variation in recovered COVID-19 patients at one-year follow-up: a retrospective cohort study

Hypertension, alongside diabetes mellitus and coronary artery disease, has been identified as a prevalent comorbidity in COVID-19 patients, affecting approximately 27–30%, 19%, and 6–8% of cases, respectively [21, 22]. Studies investigating blood pressure variations among COVID-19 patients, primarily focusing on hospitalized individuals over short follow-up periods, have yielded insightful findings. In accordance with the results of the present study, a recent observational cohort study revealed that the incidence of new-onset hypertension significantly rose during the pandemic to 5.20 per 100 person-years, compared to the pre-pandemic rate of 2.11. Remarkably, the trend remains positive even in 2023, post-pandemic termination, suggesting ongoing high levels of virus circulation [23]. Akpek et al. demonstrated increased systolic (120.9 ± 7.2 vs. 126.5 ± 15.0 mmHg) and diastolic (78.5 ± 4.4 vs. 81.8 ± 7.4 mmHg) blood pressure shortly after COVID-19 infection, potentially leading to new-onset hypertension among hospitalized patients [24]. Gameil et al. observed a rise in systolic blood pressure among COVID-19 survivors at three months post-infection compared to gender-matched controls [25]. De Lorenzo et al. reported that a significant portion (58.9%) of discharged COVID-19 patients required ongoing medical care, with uncontrolled hypertension accounting for 21.6% of cases [26]. Nandadeva et al. found no disparity in ambulatory and laboratory-measured blood pressure between COVID-19 patients and controls; however, there was a notable inverse relationship between blood pressure and time since infection, suggesting higher blood pressure levels with more recent disease onset [27]. Chen et al. noted elevated Ang II levels in COVID-19 patients without prior hypertension compared to healthy controls, along with significantly higher systolic blood pressure in the patient group. Moreover, a subgroup of patients developed hypertension post-COVID-19, characterized by heightened Ang II levels compared to non-hypertensive COVID-19 patients [28]. These observations imply that blood pressure fluctuations may stem from hormonal changes following SARS-CoV-2 infections.

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in regulating blood volume, vascular resistance, and blood pressure [29]. It operates through two primary axes: the angiotensin-converting enzyme/angiotensin-II/angiotensin type-I receptor (ACE/ANG-II/AT1R) and the angiotensin-converting enzyme 2/angiotensin- [1‐7]/MAS-receptor (ACE2/ANG- [1‐7]/MAS) axes [30]. ACE2, expressed in various tissues such as the heart, intestines, kidneys, testis, and gallbladder, acts not only as a modulator of RAAS but also as the cell entry receptor for both SARS-CoV-1 and SARS-CoV-2 [31]. During the initial stages of the COVID-19 pandemic, there were concerns regarding the use of ACE inhibitors and ARBs due to their potential upregulation of ACE2. This led to speculations that these antihypertensive drugs might increase the susceptibility and severity of COVID-19 [32]. However, subsequent reviews and cohort studies dismissed this hypothesis, affirming the safety of these medications and even suggesting potential protective effects against COVID-19-related complications [33, 34]. 2 Additionally, ADAM17 can cleave the extracellular juxta-membrane region of ACE2, leading to an increase in the soluble form of ACE2. This soluble isoform may compete with membrane-bound ACE2, potentially preventing viral entry into cells [35, 36]. SARS-CoV-2 enters host cells by binding to ACE2 and TMPRSS2, leading to a transient downregulation of ACE2 and disrupting the balance between ACE2 and angiotensin II [37‐39]. This disruption can increase ANG II, resulting in increased vasoconstriction, aldosterone release, and fluid retention, contributing to elevated blood pressure [40‐42]. Moreover, this peptide hormone causes an increase in endothelial and organ damage by producing reactive oxygen species (ROS) [43]. Furthermore, Human recombinant soluble ACE2 (hrsACE2) has emerged as a potential therapeutic candidate for COVID-19 due to its ability to bind SARS-CoV-2 and potentially reduce viral entry into host cells [44]. Reduced ACE2 levels may also downregulate the protective ACE2/ANG- [1‐7]/MAS axis. This axis has been shown to protect against conditions such as lung fibrosis and inflammation [45‐47] In summary, the dysregulation of RAAS, characterized by increased angiotensin II levels, sodium and water retention, vasoconstriction, and downregulation of protective pathways, may contribute to elevated blood pressure in COVID-19 patients (Fig. 3) [48].

In addition to ARDS and AKI, SARS-CoV-2 can also result in complications affecting other systems, including cardiovascular issues [30]. Increasing evidence suggests that SARS-CoV-2 has a systemic impact, causing vascular damage and dysfunction, particularly affecting the endothelium and potentially linking various organs and systems [49, 50]. The virus can indirectly affect microvascular endothelial cells, leading to changes in endothelial functions. Oxidative stress initiates endothelial damage [51, 52], exacerbating alterations in cell permeability. Additionally, modifications in the expression of adhesion molecules and receptors related to angiogenesis can lead to an increased neutrophil count, the formation of neutrophil extracellular traps, inflammation, blood clotting, and reduced oxygen levels [53]. The virus has been detected in the myocardium during autopsy analysis [54, 55], and it has been reported to induce endotheliitis, myocardial ischemia, and arrhythmia by penetrating the small blood vessel walls in the heart [56, 57]. Furthermore, the disruption of arteriolar endothelial walls, crucial for regulating blood flow and vascular resistance, contributes to blood pressure variations following infection [58]. However, the duration and long-term impact of these disturbances on the cardiovascular system in patients remains uncertain.

Concerns regarding the safety of SARS-CoV-2 vaccines have arisen due to reported incidents of thromboembolic events, hypersensitivity reactions, and tachycardia post-vaccination [43, 59, 60]. Additionally, reports have highlighted BP elevation following COVID-19 vaccination. In a systematic review and meta-analysis by Angeli et al., encompassing six studies and 357,387 subjects, incidence rates of abnormal/increased BP and stage III hypertension/hypertensive urgencies and emergencies were found to be 3.20% and 0.6%, respectively [61]. Meylan et al. documented instances of stage III hypertension in nine patients shortly after mRNA-based SARS-CoV-2 vaccination, with eight having a history of hypertension; all recovered following monitoring and antihypertensive treatment [43]. These findings are supported by Zappa et al., who observed an average increase in systolic or diastolic BP by ≥ 10 mmHg at home during the first five days after the initial vaccine dose, particularly among individuals with a prior COVID-19 history [62]. Moreover, the vaccine recipients with pre-existing immunity exhibited a higher frequency and severity of systemic reactions compared to those without immunity [63]. This observed increase in BP post-vaccination suggests a potential association with elevated BP post-COVID-19 infection, possibly linked to RAAS overactivation.

Immune system activation and subsequent inflammation are determinants of systolic, diastolic, and pulse pressure in COVID-19 patients [64, 65]. Inflammatory cytokines released by viral and bacterial infections cause microvascular dysfunction, disrupting kidney microcirculation and potentially leading to BP variation [66]. The role of inflammation in aortic stiffness and BP has been confirmed in previous studies; it induces endothelial injuries and dysregulation, reducing nitric oxide production [67]. This vasodilator is a promising remedy in the treatment of HTN, but its bioavailability decreases in COVID-19 patients [49]. A randomized clinical trial indicated that the immune response against pathogens increases aortic stiffness—a pivotal basis of systolic BP [68]. Incubation of COVID-19 serum has been shown to induce endothelial damage, including apoptosis and impaired angiogenic capacity as well as triggering thrombotic events [13, 69].

Despite the present study evaluating non-hospitalized patients, some hospitalized COVID-19 may experience prolonged periods of mechanical ventilation, associated sedation, volume overload, inotropic use, increased adrenergic tone, fever, hypoxia, inflammation, cytokine storm, ischemia, and vasculitis. These factors may contribute to an excessive cardiovascular response and worsening of hypertension [7]. ICU-admitted COVID-19 patients tend to develop hyperreninemia combined with hypernatremia and hyperchloremia [70]. It has been also indicated that three months after hospitalization due to COVID-19, patients experience sympathetic neural overdrive, vascular dysfunction, increased arterial stiffness, and reduced exercise capacity. These factors may contribute to clinical manifestations such as elevated blood pressure [15, 71].

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 indirectly. 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 [72, 73]. Evaluating these factors was not the purpose of the present study, but their effects cannot be ignored. According to Di Renzo et al., outdoor physical activities such as walking, jogging, and swimming decreased significantly during the pandemic [74]. 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; a sedentary lifestyle, decreased medication adherence, and inaccessibility of medical facilities could be possible etiologies [75]. The pandemic has had a significant impact on the continuity of care, medication adherence, and blood pressure management among individuals with hypertension, exacerbating challenges in achieving optimal blood pressure control. Pandemic-related disruptions, such as lockdowns and healthcare system strain, have led to interruptions in medication adherence, as evidenced by a decline from 86.0 to 80.8% according to a retrospective cohort study involving 64,766 individuals. Concurrently, in-person primary care visits decreased from 2.7 to 1.4 per year during the pandemic [76]. In the present study, no patients experienced remote BP management. Despite this, as a result of the pandemic’s disruption to traditional healthcare services, there has been a notable increase in the adoption of remote management programs aimed at addressing the widespread issue of poorly controlled hypertension [77]. This shift towards remote management has shown promising results; notably, the proportion of patients with sustained hypertension reaching their blood pressure goals increased from 75.8 to 94.6% during the pandemic period, facilitated by remote monitoring and frequent patient-provider communication [78]. Moreover, maintenance of blood pressure was achieved earlier during the pandemic, indicating the effectiveness of remote management strategies coupled with enhanced patient support and engagement.

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 [79, 80]. It was suggested that the upregulation of fibroblasts in COVID-19 patients with HTN and DM may contribute to lung fibrosis and a decline in lung function [81]. RAAS dysregulation (decreased ACE 2 and Ang 1–7; increased Ang II) can potentially explain the abovementioned associations. Endothelial dysfunction in patients with hypertension, diabetes, obesity, or aging, combined with vascular damage induced by COVID-19, has been linked to severe morbidity and mortality. This suggests that the direct effects of SARS-CoV-2 on the vascular system may amplify the mortality risk in COVID-19 patients [82]. Age, history of hypertension, diabetes, and previous cardiac events were predictors of uncontrolled hypertension in the COVID-19 group in the Angeli study [19]. Similarly, Nam et al. associated advanced age and a history of hypertension with increased BP variability [83]. Thus, comorbidities such as DM and HTN must be controlled to prevent a severe COVID-19 course and subsequent sequelae. (Fig. 4, graphical abstract)

The current study has some limitations. First, due to the retrospective nature of the study, we could not establish a control group to compare BP levels between cases and controls, which limits our ability to draw causal conclusions about the observed variations in BP. Additionally, the retrospective design means controlling for confounding factors is challenging, making it difficult to distinguish whether the fluctuations in blood pressure are directly related to the pathophysiological effects of the virus or indirectly influenced by factors prevalent during the COVID-19 era, such as a sedentary lifestyle, psychological factors, or decreased adherence to treatment. Information bias may be present due to reliance on medical records, potentially introducing inaccuracies or omissions in recorded data. Moreover, recall bias might affect the accuracy of reported information about medication and past medical history, as it relies on patients’ recall of past events and medication details. Second, the BP levels were measured at the clinic, and ambulatory daytime, nighttime, and 24-hour BP measurements were unavailable for the majority of the patients. While such measurements would provide a more comprehensive assessment, the likelihood of white-coat hypertension influencing our results seems minimal. BP was measured in a quiet room under comfortable conditions, and initial and final measurements from the same individual were compared using paired statistical analysis, enhancing the reliability of our findings. Third, serial BP measurements across multiple follow-up sessions would have enabled us to determine the persistence of any observed changes over time. Fourth, this study was conducted at a single center, representing a limited racial, ethnic, and geographical area, which may limit the generalizability of the findings. On the other hand, the large sample size of non-hospitalized patients is a significant strength of this study, potentially offering insights that are more representative of the broader population affected by COVID-19 compared to studies focusing solely on hospitalized patients. Another strength is that BP measurements were not taken during the acute phase of COVID-19, eliminating the potential confounding effects of acute disease processes and related psychological factors on BP readings. Nonetheless, multicenter prospective studies with longer follow-up periods are warranted to overcome the limitations of the present work and provide more robust evidence.