INTRODUCTION

Various sequelae have been described after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Some patients continue to suffer from heterogeneous symptoms after the acute phase of critical illness. Such persisting symptoms lasting for at least 2 months after SARS-CoV-2 infection have been defined as ‘postcoronavirus disease 2019 (COVID-19) condition’ [1]. Along with persisting symptoms, various organ dysfunctions have been observed [2].

Cardiovascular diseases are among the most prominent of these postacute COVID-19 sequelae and include cerebral, kidney, vascular as well as ischemic and nonischemic heart diseases [3,4]. Importantly, these consequences can also occur after mild and moderate COVID-19 resulting in an important concern for a large part of the world-wide population [3,4].

Hypertension is closely associated with various cardiovascular diseases, which have been observed after COVID-19 [5], and could therefore constitute another feature within the post-COVID-19 condition complex. However, little is known about blood pressure outcomes after COVID-19. This particularly applies for nonsevere SARS-CoV-2 infections, representing the vast majority of COVID-19 courses. Few observational studies show an increase in blood pressure after severe COVID-19 [6–8], but these studies often lack standardized blood pressure measurements and might not be transferable to nonsevere and outpatient COVID-19 courses. A large retrospective analysis on the United States Department of Veterans Affairs healthcare database supports the hypothesis of a post-COVID-19 sequela by showing an excess in prescriptions of antihypertensive medication as well as an increase in registered diagnosis of hypertension after COVID-19 [2]. However, these data were based on coded diagnoses and prescribed medication but not on blood pressure measurements. Additional molecular linkage between COVID-19 and blood pressure derives from the bifunctional role of the angiotensin-converting enzyme 2 (ACE-2) as SARS-CoV-2 uptake mediator as well as regulator in blood pressure homeostasis [9–11].

These observations underline the need of a rigorous and standardized blood pressure investigation after nonsevere COVID-19 to assess possible hypertensive long-term effects. This study investigates the association of COVID-19 with subsequent hypertension in the long term by comparing individuals after mild or moderate COVID-19 to a matched population-based cohort without prior COVID-19 by state-of-the-art blood pressure measurements and a very precise assessment of competing risk factors.

MATERIALS AND METHODS Study design and population

Data for this cross-sectional analysis were derived from the Hamburg City Health Study (HCHS) and its associated post-COVID-19 program as described previously [4,12]. The HCHS is a prospective, population-based cohort study including residents of Hamburg, Germany, between 45 and 74 years of age, who are randomly identified from the local residents’ registration office. The study is ongoing since 2016, and until now, information on baseline investigations are available for about 18 000 individuals. During the pandemic, the study also recruited individuals after SARS-CoV-2 infections in a post-COVID-19 program via newspaper announcements and a local COVID-19 test center. Inclusion criteria for the post-COVID-19 program were laboratory-confirmed PCR SARS-CoV-2 infections at minimum 4 months prior to the study visit. PCR results were verified by the study personal, and all tests were obtained between March 1, and December 30, 2020. In accordance with the main HCHS program, participants had to be between 45 and 74 years of age at inclusion. On the basis of self-reported information, COVID-19 courses were categorized into mild (corresponding to flu-like symptoms), moderate (any other symptoms but no hospital admission) as well as nonsevere hospitalized courses (hospital admission but no need for intensive or intermediate care unit treatment). Post-COVID-19 individuals were matched with a k-nearest neighbors approach by age using a caliper of 2 years, sex, education, and preexisting hypertension in a 1 : 4 ratio to individuals from the main HCHS program using a logistic regression propensity score. To preclude prior COVID-19 in matched controls, individuals were only eligible as control if study visits were performed before December 30, 2019, which is before occurrence of the first COVID-19 case in Germany [13].

Both the HCHS and its associated post-COVID-19 program were approved by the local ethics committee (Landesärztekammer Hamburg, PV5131) and conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent before study participation. The HCHS is registered at ClinicalTrials.gov under the identifier NCT03934957.

Data collection and blood pressure measurements

A deep multiorgan assessment including standardized blood pressure measurements, investigation of biomaterial as well as exploration of socioeconomic factors was performed for all individuals according to the recently published HCHS protocol [12]. Preexisting comorbidities including information on preexisting hypertension, social and lifestyle information, current medication as well as range of physical activity were assessed by highly standardized patient interviews. On the basis of recently published definitions [1], symptomatic post-COVID-19 condition was defined as at least one persisting symptom since SARS-CoV-2 infection, reported at study visit. Laboratory analyses were performed according to routine clinical practice on an Atellica COAG 360 System analyzer (Siemens Healthineers, Erlangen, Germany). The estimated glomerular filtration rate (eGFR) was calculated with the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) formula for creatinine [14]. Second morning spot urine sodium and creatinine were investigated on frozen samples from the HCHS biobank in a blinded fashion and used to calculate the daily urine sodium concentration according to the Kawasaki formula as an estimate for daily dietary sodium intake [15]. All other laboratory analyses were directly performed during study visits. SARS-CoV-2 antibody titers against the nucleocapsid protein were quantified with the Elecsys anti-SARS-CoV2 assay (Roche, Mannheim, Germany; analyzer: Cobas e411), and against the spike protein with the Liason SARS-CoV-2 S1/S2 IgG (Diasorine, Saluggia, Italy; analyzer: Liaison XL) or Elecsys Anti-SARS-CoV-2 S assay (Roche; analyzer: Cobas e411). Antispike antibody titers were normalized according to the first WHO international standard for anti-SARS-CoV-2 immunoglobulin [16].

Blood pressure was measured with digital, automatic monitors (boso-medicus uno, BOSCH + SOHN, Jungingen, Germany) under attendance of a study personal. All readings were performed in duplicates by specially trained assistant medical technicians. Measurement procedures were performed according to current guidelines [17]. Briefly, participants were seated in a silent room and a comfortable upright position with the feet touching ground and the undressed arm resting on a table. The same facilities were used for all participants. Three cuff sizes were available, chosen according to the circumference of the upper arm (BOSO CA03, CA01, and CA02 for circumferences of 17–22, 22–32, and 32–42 cm, respectively) and placed 2.5 cm above the inside of the elbow. Measurements were performed after at least 3 min of rest with 2 min between the readings. Per the protocol, the right arm was used for all readings, while a switch to the left arm was only allowed for documented medical reasons. Participants were blinded to the results during the procedure.

Outcome measures

Outcome measures were SBP and DBP, calculated by the mean of the two readings, as well as the frequency of hypertension defined by a SBP at least 130 mmHg or a DBP at least 80 mmHg according to the 2017 American College of Cardiology (ACC) and American Heart Association guideline (AHA) [18]. As the definition of hypertension varies between different guidelines, we additionally assessed the effect on hypertension as defined by the 2018 European Society of Cardiology (ESC) and European Society of Hypertension (ESH) guideline as secondary outcome (SBP ≥ 140 mmHg or a DBP ≥ 90 mmHg) [19]. Further, the single definitions of elevated SBP (≥ 130 and ≥ 140 mmHg) and DBP (≥ 80 and ≥ 90 mmHg) were investigated as secondary outcomes. Blood pressure readings were performed at a random timepoint but at least 4 months after PCR-confirmed SARS-CoV-2 infections for post-COVID-19 individuals.

Statistical analysis

Data are presented as mean with standard deviation (SD) for continuous and number with percentage for categorical variables. Blood pressure outcomes were investigated in crude analyses using unpaired t-test for comparison between groups as well as in multivariable-adjusted linear regression models. Multivariable-adjusted logistic regression models were used to compare the frequency of hypertension between groups. Association of SARS-CoV-2 antispike or antinucleocapsid antibody levels with outcome parameters was analyzed with multivariable-adjusted linear regression models. Regression analyses were calculated without adjustment (model 1) or adjusted for (model 2): BMI, smoking status (three categories: never, former, or current smoker), physical activity (self-reported hours of weekly sport activity), number of antihypertensives, the calculated daily urine sodium excretion as an estimate of daily dietary sodium intake, dyslipidemia, sleep apnea, congestive heart failure, chronic kidney disease, and diabetes. Results for logistic regression models are presented as odds ratio (OR) with 95% confidence intervals (95% CIs) and for linear regression models as beta with 95% CI. Missing values (see suppl. Table 1, https://links.lww.com/HJH/C237 for numbers of missing values) were imputed by random forest-based imputations (R package missforest, V 1.4) [20] and R version 4.2.2 (2022–10-31) was used for statistical analyses.

RESULTS Matching and baseline characteristics

Four hundred and thirty-two individuals were identified in the post-COVID-19 cohort and matched to 1728 controls without prior COVID-19 (see suppl. Table 2, https://links.lww.com/HJH/C237 for matching characteristics). Mean age was 56.1 (SD 7.1) years in the post-COVID-19 and 56.2 (SD 7.10) years in the non-COVID-19 cohort with 47.5 and 46.4% women, respectively (Table 1). Nearly all participants were white Caucasians. Preexisting hypertension based on self-reported information was present in 23.6% of post COVID-19 and 23.7% of control individuals. Social, anthropometric, and medical conditions including known risk factors for hypertension were comparable between the two cohorts with little disparities. This also applied for laboratory data including the calculated daily sodium excretion indicating dietary sodium consumption. Although current smoking was less common (6.2% in the post-COVID-19 and 17.8% in the non-COVID-19 cohort), there were more former smokers in the post-COVID-19 cohort (44.0 versus 34.2%). Mean number of antihypertensives per individual was 0.4 (SD 0.9) in both cohorts.

TABLE 1 - Baseline characteristics Non COVID-19 Post COVID-19 SMD Characteristics (n = 1728) (n = 432) Sex, no. (%) 0.022  Female 801 (46.4) 205 (47.5)  Male 927 (53.6) 227 (52.5) Anthropometry, mean (SD)  Age 56.2 (7.0) 56.1 (7.1) 0.010  BMI 26.1 (4.4) 26.6 (4.6) 0.094 Education, no. (%) 0.013  High 1038 (60.1) 257 (59.5)  Medium 340 (19.7) 87 (20.1)  Low 350 (20.3) 88 (20.4) Employment, no. (%) 0.134  Full-time 921 (55.5) 246 (56.9)  Part-time 429 (25.9) 126 (29.2)  None 308 (18.6) 60 (13.9) Ethnicity, no. (%) 0.151  White 1700 (98.4) 430 (99.5)  Hispanic 7 (0.4) 0 (0.0)  Black 6 (0.3) 1 (0.2)  Asian 4 (0.2) 0 (0.0)  Other 11 (0.7) 1 (0.2) Vitals, mean (SD)  Heart rate (beats per minute) 69.4 (10.4) 69.4 (11.9) 0.001 Lifestyle  Current smoking, no. (%) 307 (17.8) 27 (6.2) 0.360  Former smoking, no. (%) 591 (34.2) 190 (44.0) 0.201  Weekly sport activity, hours 3.1 (3.0) 3.2 (2.5) 0.029 Comorbidities  Hypertension 409 (23.7) 102 (23.6) 0.001  Dyslipidemia 281 (16.3) 89 (20.6) 0.112  Malignancy 200 (11.6) 42 (9.7) 0.060  Chronic kidney disease 144 (8.3) 48 (11.1) 0.094  Chronic obstructive pulmonary disease 96 (5.6) 19 (4.4) 0.053  Diabetes 79 (4.6) 27 (6.2) 0.074  Coronary artery disease 32 (1.9) 13 (3.0) 0.030 Sleep apnea 55 (3.2) 25 (5.8) 0.126 Congestive heart failure 22 (1.3) 8 (1.9) 0.047  Peripheral vascular disease 25 (1.4) 7 (1.6) 0.077 Labs, mean (SD)  Hemoglobin (g/dl) 14.3 (1.1) 14.5 (1.1) 0.154  Sodium (mmol/l) 139.1 (2.0) 139.1 (1.7) 0.006  Potassium (mmol/l) 3.9 (0.3) 3.7 (0.2) 0.405  eGFR (ml/min per 1.73 m2) 101 (23.6) 99.2 (23.1) 0.076  hsCRP (mg/dl) 0.20 (0.38) 0.17 (0.24) 0.093  HbA1c, % 5.5 (0.6) 5.5 (0.5) 0.019  Daily urine sodium excretion (mg/day) 4717 (1393) 4870 (1602) 0.102 Antihypertensive medication, no. (%)  Beta blocker 169 (9.8) 34 (7.9) 0.067  ACE-I/ARB 300 (17.4) 87 (20.1) 0.071  Thiazide diuretic 117 (6.8) 19 (4.4) 0.103  Calcium antagonist 88 (5.1) 27 (6.2) 0.050  Loop diuretic 14 (0.8) 5 (1.2) 0.035  MRA 7 (0.4) 3 (0.7) 0.039  SGLT-2-I 1 (0.1) 4 (0.9) 0.124 Number of antihypertensives per individual, mean (SD) 0.4 (0.9) 0.4 (0.9) 0.009

ACE-I, angiotensin-converting-enzyme-inhibitors; ARB, angiotensin II receptor blockers; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; hsCRP, high-sensitive C-reactive protein; MRA, Mineralocorticoid receptor antagonist; SD, standard deviation; SGLT2-I, sodium-glucose linked transporter 2-inhibitors; SMD, standardized mean difference.

Individuals of the post-COVID-19 cohort were investigated in mean 251 (SD 84) days after SARS-CoV-2 infections (Table 2). About 62.5% had experienced mild and 30.3% moderate, nonhospitalized COVID-19 courses. Only 7.2% had suffered from nonsevere hospitalized courses, but no patient was treated on an intensive or intermediate care unit. Mean titer of antispike and antinucleocapsid antibodies was 758 (SD 2701) binding antibody units (BAU)/ml and 72 (SD 100) times the cut off index (COI), respectively. About 64.6% had post-COVID-19 condition with at least one persisting symptom since the initial infection.

TABLE 2 - COVID-19 characteristics Post COVID-19 Characteristics (n = 432) Latency to infection, mean (SD)  Days since infection 251 (84) Severity, no. (%)  Mild 270 (62.5)  Moderate 131 (30.3)  Nonsevere, hospitalization 31 (7.2) Antibody titers, mean (SD)  Antispike (BAU/ml) 758 (2701)  Antinucleocapsid, /COI 72 (100) Post-COVID-19 condition, no. (%)  At least one persisting symptom 279 (64.6)  Fatigue 230 (53.2)  Shortness of breath 140 (32.4)  Pain 116 (26.9)

BAU, binding antibody units; COI, cut off index; SD, standard deviation.

SBP and DBP

SBP was 137.9 (SD 17.0) mmHg in post-COVID-19 individuals compared with 135.6 (SD 17.7) mmHg in matched controls (P = 0.013). DBP was 5.2 mmHg higher (P < 0.001) in the post-COVID-19 cohort with a mean of 87.2 (SD 10.1) mmHg versus 82.0 (SD 10.0) in matched controls (Fig. 1). We further compared SBP and DBP between the two cohorts by multiple linear regression models to adjust for relevant hypertensive risk factors (Fig. 1, model 2). Although there only was a nonsignificant trend toward a higher SBP in the post COVID-19 cohort after adjustment for various confounders and competing risk factors (beta coefficient 1.6, 95% CI -0.2 to 3.4, P = 0.073), DBP remained significantly increased in post COVID-19 individuals compared with matched controls (beta coefficient 4.6, 95% CI 3.6–5.6, P < 0.001). Similar results were seen in an available case analysis (suppl. Table 3, https://links.lww.com/HJH/C237).

FIGURE 1:

Effect on systolic and diastolic blood pressure shown by crude comparison of SBP (a) and DBP (b) as well as multivariable-adjusted linear regression analysis (c) between the non-COVID-19 and post-COVID-19 cohort. Each grey dot in panels (a) and (b) is one individual, blue dots and lines represent mean and standard deviation, respectively. Adjustments in regression models were performed for BMI, smoking status, physical activity, number of antihypertensives per individual, the calculated daily dietary sodium intake, dyslipidemia, sleep apnea, employment, congestive heart failure, chronic kidney disease, and diabetes.

Frequency of hypertension

Hypertensive blood pressure, defined as values at least 130/80 mmHg according to the ACC/AHA guidelines [18], was frequent in both cohorts and occurred in 82.4% of post COVID-19 individuals and 69.0% in control individuals (Fig. 2, see suppl. Table 3, https://links.lww.com/HJH/C237 for available-case analysis). Even after adjustment for BMI, smoking status, physical activity, number of antihypertensives per individual, the calculated daily dietary sodium intake, dyslipidemia, sleep apnea, congestive heart failure, chronic kidney disease, and diabetes, hypertensive blood pressures were significantly more frequent in post-COVID-19 individuals (OR 2.0, 95% CI 1.5–2.7, P < 0.001). This effect was also observed for a blood pressure threshold at least 140/90 mmHg (OR 1.7, 95% CI 1.3–2.1, P < 0.001), defined as hypertensive values by the ESC/ESH guideline [19]. Analyses of the single systolic and diastolic definitions for hypertensive values showed that there was a nonsignificant trend for an increase in SBP values at least 130 mmHg (OR 1.2, 95% CI 0.9–1.5, P = 0.145) or at least 140 mmHg (OR 1.2, 95% CI 1.0–1.5, P = 0.091) in the post COVID-19 cohort in the fully adjusted model (Fig. 2). However, DBPs at least 80 mmHg (OR 2.1, 95% CI 1.7–2.8, P < 0.001) or at least 90 mmHg (OR 2.3, 95% CI 1.8–2.9, P < 0.001) occurred significantly more frequent in individuals after COVID-19 than in matched controls.

FIGURE 2:

Frequency of hypertensive blood pressure in the non-COVID-19 and post-COVID-19 cohort with comparison by multivariable-adjusted logistic regression analysis. Adjustments were performed for BMI, smoking status, physical activity, number of antihypertensives per individual, the calculated daily dietary sodium intake, dyslipidemia, sleep apnea, employment, congestive heart failure, chronic kidney disease, and diabetes.

Subgroup analysis

Subgroup analyses were performed according to self-reported preexisting hypertension, COVID-19 severity, and the presence of a symptomatic post-COVID-19 condition (Fig. 3 and suppl. Table 4, https://links.lww.com/HJH/C237). There were no obvious differences in the effect on SBP and DBP in individuals with and without preexisting hypertension with a similar increase in the frequency of hypertensive blood pressure readings in both subgroups (OR 2.4, 95% CI 1.0–6.5, P = 0.065 for individuals with and OR 2.0, 95% CI 1.5–2.8, P < 0.001 without preexisting hypertension, Fig. 3). However, hypertensive effects increased with COVID-19 severity. Although individuals with prior mild COVID-19 already showed a significant increase in the frequency of hypertensive blood pressure (OR 1.6, 95% CI 1.2–2.3, P = 0.006), this effect was augmented in individuals after moderate COVID-19 (OR 3.0, 95% CI 1.7–5.4, P < 0.001) and was strongest in individuals after nonsevere, hospitalized COVID-19 (OR 24.2, 95% CI 3.4–5.48, P = 0.008). A significantly higher prevalence of hypertensive blood pressures was also observed for individuals with and without a self-reported symptomatic post-COVID-19 condition as compared to matched controls (OR 2.3, 95% CI 1.6–3.4, P ≤ 0.001 and OR 1.6, 95% CI 1.0–2.6, P = 0.040, respectively). SARS-CoV-2 antispike or antinucleocapsid antibody titers did not correlate with SBP and DBP (suppl. Figure 1, https://links.lww.com/HJH/C237).

FIGURE 3:

Subgroup analysis of hypertensive blood pressure by preexisting hypertension, COVID-19 severity and presence of post-COVID-19 condition between the non-COVID-19 and post-COVID-19 cohort with multivariable-adjusted logistic regression analysis. Adjustments were performed for BMI, smoking status, physical activity, number of antihypertensives per individual, the calculated daily dietary sodium intake, dyslipidemia, sleep apnea, employment, congestive heart failure, chronic kidney disease, and diabetes.

DISCUSSION

This study characterizes blood pressure outcomes in 432 individuals after nonsevere COVID-19 compared with 1728 matched controls and reveals two important findings. First, hypertensive blood pressures occurred more frequently in individuals after nonsevere COVID-19 as compared to matched controls without prior COVID-19. Second, the higher prevalence of hypertension in the post-COVID-19 cohort was mainly due to differences in diastolic blood pressure.

Although the observed absolute differences were small for DBP and SBP, this resulted in a significant increase in individuals with de-novo or uncontrolled hypertension after nonsevere COVID-19. Such observation is not surprising given the high prevalence of high-normal blood pressures [21,22]. Although small differences in blood pressure as indicated by our study probably have limited effects on an individual level, it can translate into a relevant impact on cardiovascular outcomes on a population level [23,24]. It has to be noted that differences in the frequency of hypertension in the investigated cohort were mostly driven by changes in DBP, while there only was a trend towards higher SBPs. The relevance of increases in DBP for cardiovascular outcomes remains controversial, especially in middle-aged and older individuals [25–28]. Thus, effects on cardiovascular outcomes and mortality are likely smaller than suggested by the considerable rise in hypertension after COVID-19. This observation also puts recent studies into new perspectives showing a major increase in registered hypertension diagnoses after COVID-19 [2]. Still, the observed increase in blood pressure could be a driver of observed adverse cardiovascular outcomes after nonsevere COVID-19 such as kidney, cerebrovascular, or cardiac diseases [3]. Importantly, we also observed relevant changes in subgroup analyses of individuals with mild COVID-19 defined as a course with no more than flu-like symptoms as well as of individuals without a symptomatic post-COVID-19 condition. Due to the tremendous prevalence of mild SARS-CoV-2 infections, such adverse effects could have significant implications on general cardiovascular care [29,30]. Although our study investigated individuals in mean more than 8 months after the acute SARS-CoV-2 infection arguing against temporary effects, future studies with long-term follow-up are needed to clarify effects beyond the observed mid-term consequences.

The potential mechanisms of higher blood pressure after nonsevere COVID-19 are still unclear. Increasing evidence indicates that hypertension is not only mediated by a direct increase in hydrostatic pressure through salt concentration, hormonal signaling, or peripheral vascular resistance but that inflammation also plays an important role in the pathophysiology and contributes to the deleterious consequences of this disease. Cells of the innate immune system, including monocyte, macrophages, and dendritic cells, can promote blood pressure elevation via effects mostly on kidney and vascular function. Moreover, convincing evidence shows that T and B cells from the adaptive immune system are involved in hypertension and hypertensive end-organ damage [31,32]. Therefore, COVID-19 induced inflammation could play a role in hypertensive sequela. SARS-CoV-2 mediated inflammatory effects on the microcirculation and activation of endothelial cells could contribute to such linkage between SARS-CoV-2 and subsequent hypertension [33–35]. ACE-2 might also be a potential mediator, as it controls blood pressure as well as the cellular uptake of SARS-CoV-2 [9–11]. However, accelerated aging has also been described after COVID-19 [36] and usually leads to a decline in DBP. The observed effects with a predominantly higher DBP in the post-COVID-19 cohort could thus rather point to vascular constriction of resistance vessels as a possible mechanism. Indeed, enhanced vasoconstriction and reduced vasorelaxation has been observed after COVID-19 [37]. The vascular inflammation described following COVID-19 with the involvement of innate and adaptive immunity may contribute to the increased DBP [38]. Still, future experimental studies are needed to clarify the molecular background of a SARS-CoV-2 blood pressure axis as well as a predominant effect on DBP. Further, comparisons to other viral infections can help to elucidate whether the observed effects are specific for SARS-CoV-2.

Particular study strengths exist. The entire study population had been evaluated by a very comprehensive and rigorous study protocol applying the exact same investigative procedures to all participants. Blood pressure was measured by specially trained assistant medical technicians according to current guidelines [17] and competing risk factors were vigorously assessed. Participants after mild to moderate COVID-19 qualified with at least one positive PCR test and antibody status was obtained. Matched controls had been randomly recruited from the same geographic region via registration office within the frame of the HCHS. Important confounders such as preexisting medical conditions, medication, anthropometry including measures of obesity, physical activity, and social aspects are addressed by the matching approach or adjustments in regression analyses. Also, we control for the calculated daily dietary sodium intake, an important confounder given that COVID-19 is known to affect smell and taste ability [39]. Interestingly, no difference was found in the calculated sodium uptake between the two cohorts suggesting no increased salt intake due to loss of taste in individuals after nonsevere COVID-19. Also, the blood pressure distribution and the observed frequency of hypertension in our study are in line with other studies [21,40]. Still, the high prevalence of hypertension in both cohorts calls for further confirmatory and explanatory investigations.

Limitations of our study include its cross-sectional nature. Thus, the definition of preexisting hypertension had to be based on patient interviews. Also, residual confounding due to secondary effects such as antipyretic medication with NSAIDS during the acute SARS-CoV-2 infection phase or a restrain towards medical contacts after infections cannot be excluded. Despite the rigorous matching and adjustment of competing risk factors, a possible selection bias due to the comparison with historic controls also constitutes a limitation. Also, the study collective is mainly restricted to white Caucasians. As the study was conducted during the early pandemic when SARS-CoV-2 vaccination was not yet available, effect of prior vaccination but also of newer SARS-CoV-2 variants still has to be investigated. However, the absence of prior vaccination also excludes confounding, as reports have linked SARS-CoV-2 vaccination to new-onset hypertension [41,42].

In conclusion, this study found significantly higher blood pressures in individuals after nonsevere COVID-19 as compared to matched controls with predominant differences in DBP. These findings suggest a hypertensive sequela, which might contribute to adverse cardiovascular events after COVID-19 and constitute a potential therapeutic target. Future studies are needed to clarify the cause and the relevance of this SARS-CoV-2 blood pressure axis for the observed cardiovascular outcomes after COVID-19 and identify possible treatment options including hypertensive surveillance and control.

ACKNOWLEDGEMENTS

C.S.-L. and T.B.H. were supported by the City of Hamburg, Germany (LFF-OS 95–2021). T.B.H. was supported by the Deutsche Forschungsgemeinschaft (CRC1192, HU 1016/8–2, HU 1016/11-1, HU 1016/ 12-1), the Bundesministerium für Bildung und Forschung (STOP-FSGS-01GM1901C, NephrESA-031L0191E), the Else-Kröner Fresenius Stiftung (Else Kröner-Promotionskolleg–iPRIME), and the H2020-IMI2 consortium BEAt-DKD (115974); this joint undertaking receives support from the European Union's Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations and Juvenile Diabetes Research Foundation. This work was partially funded by the Else Kröner-Fresenius-Stiftung and the Eva Luise und Horst Köhler Stiftung – Project No: 2019_KollegSE.04. U.O.W. is supported by the Deutsche Forschungsgemeinschaft (We 1688/19-1 and SFB 1192).

The data will be shared on reasonable request to the corresponding author.

Conflicts of interest

None.

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