Email this article The condition of target organs in patients with hypertension after new coronavirus infection
- Authors: Syuzeva N.M.1, Koziolova N.A.1, Chernyavina A.I.1, Masalkina O.V.1
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Affiliations:
- E.A. Vagner Perm State Medical University
- Issue: Vol 41, No 6 (2024)
- Pages: 5-23
- Section: Original studies
- Submitted: 23.01.2025
- Accepted: 23.01.2025
- Published: 15.12.2024
- URL: https://permmedjournal.ru/PMJ/article/view/646557
- DOI: https://doi.org/10.17816/pmj4165-23
- ID: 646557
Cite item
Abstract
Objective. To determine the risk factors for the development of new coronavirus infection (NCVI) in patients with hypertension (AH) and to assess the condition of target organs depending on the course of NCVI.
Materials and methods. A screening clinical observational comparative study is presented. For a 2-year period 186 patients with a history of AH or with a first-time BP increase who consulted a general practitioner in an outpatient department were sequentially included into the study in accordance with the inclusion and non-inclusion criteria. The patients were divided into two groups depending on the presence of NCVI: the first group consisted of 100 patients with AH or first-onset AH who had had NCVI; the second group contained 86 patients with AH or first-time AH without a history of NCVI. All patients with AHunderwent a comprehensive routine clinical examination with an assessment of target organ damage in accordance with clinical guidelines within 14 days after visiting the polyclinic with an assessment of the data of the outpatient card and other medical documents to register concomitant diseases and conditions, as well as the features of the course of NCVI.
Results. Vaccination against NCVI in patients with AH reduces the relative risk (RR) of the development not only of NCVI by 87 %, but NCVI-pneumonia with hospitalization and prolonged post-COVID syndrome as well. It has been proved that obesity with a body mass index of > 30 g/m2, atherosclerosis of any localization, type 2 diabetes mellitus increase the RR of the development of various forms of NCVI, including a prolonged course of more than 12 weeks. Newly diagnosed chronic heart failure (CHF), verified not only by clinical symptoms, but also by echocardiography and N-terminal fragment of brain natriuretic propeptide (Nt-proBNP) concentration in the blood, increases the RR of the development of NCVI by 48.2 %, NCVI- pneumonia with hospitalization, and the prolonged course of NCVI by more than 2 times. An increase in Nt-proBNP > 125 pg/ml in patients with AH even without CHF is associated with the development of various forms of NCVI, including post-COVID syndrome. The use of renin-angiotensin-aldosterone system (RAAS) blockers, dual combined antihypertensive therapy in patients with AH reduced the RR of the development of both NCVI, NCVI-pneumonia with hospitalization and the prolonged course of NCVI on an average by 30 to 50 %. The use of sulfonylureas and/or insulin therapy in patients with AH and type 2 diabetes mellitus was associated with an increase in the RR of the development of NCVI by 73.6 %, the RR of the development of NCVI-pneumonia with hospitalization was more than 4 times higher, and a prolonged course of NCVI almost 3 times higher. Average daily pulse blood pressure and abnormal patterns of circadian rhythm of SBP and DBP were associated with an increase in RR of both acute and chronic forms of long-term NCVI. NСVI- pneumonia with hospitalization and post-COVID syndrome are associated with an increase in the RR of pathological changes in all target organs in patients with AH in comparison with patients who did not have any complications after NCVI.
Conclusion. Known risk factors for the development of various forms of NCVI, including its prolonged course in patients with AH, have been confirmed and new ones have been revealed. It has been determined that NCVI with a severe course and post-COVID syndrome are associated with pathological changes in all target organs in patients with AH after NCVI.
Full Text
Introduction
Risk factors for the novel coronavirus disease (COVID-19) and its associated pneumonia have been the focus of extensive research, leading to the development of algorithms for their treatment [1; 2]. However, the course of the disease is constantly evolving due to a variety of factors, including vaccination, virus mutation, the adoption of novel early diagnostic systems, and the emergence of more effective treatment methods [3]. Consequently, it is essential to examine the evolving context and profile of risk factors for COVID-19 in patients with cardiovascular diseases, particularly those with arterial hypertension.
There is significant controversy regarding the etiology of long COVID-19, particularly among hypertensive individuals, which is the most prevalent medical condition associated with an adverse prognosis [4; 5].
The current literature offers evidence regarding shifts in individual values indicative of functional changes in the kidneys, heart, and blood vessels in hypertensive patients diagnosed with COVID-19 [6-8]. To date, there has been no comprehensive evaluation of the damage to all target organs in hypertensive patients, nor has there been any analysis of the relationship between their remodeling and the various variants of COVID-19 in scientific databases.
Therefore, the identification of risk factors for both COVID-19 and its more severe course, particularly long COVID, and their effect on target organ restructuring in hypertensive patients is deemed an essential scientific task. This will facilitate the development of early strategies for the prevention of cardiovascular complications in patients with elevated blood pressure and a history of COVID-19.
The study aimed to identify the risk factors for COVID-19 in patients with arterial hypertension and to assess their target organs based on their clinical features of COVID-19.
Materials and Methods
A screening clinical observational comparative study is presented, which was performed in accordance with the Good Clinical Practice and the principles of the Helsinki Declaration. The study protocol was approved by the ethics committee. Prior to inclusion in the study, all participants had provided written informed consent.
The study included 186 consecutive outpatients with known hypertension or a newly reported elevation in blood pressure (systolic blood pressure [SBP] >140 mmHg and/or diastolic blood pressure [DBP] >90 mmHg) over a two-year period. The patients were divided into two groups based on their medical history of SARS-CoV-2. Group 1 consisted of 100 individuals with known or newly diagnosed arterial hypertension and a history of previous COVID-19 infection. Group 2 included 86 patients with known or newly diagnosed arterial hypertension without COVID-19 infection in their past medical history. The diagnosis of arterial hypertension was verified in accordance with the Clinical Guidelines of the Russian Society of Cardiology (RSC), which were approved by the Russian Ministry of Health in 2020 [9]. COVID-19 was confirmed by polymerase chain reaction (PCR) for SARS-CoV-2 RNA from nasopharyngeal swabs (Vector Best, Russia).
All hypertensive patients received comprehensive, routine clinical assessments based on the RSC Clinical Guidelines, as approved by the Russian Ministry of Health (2020) [9]. These assessments were conducted within 14 days following their visit to the outpatient clinic. A detailed review of the patients' medical charts and other pertinent medical records was conducted to document any concomitant diseases and conditions, and the clinical features of COVID-19.
To be included in the study, subjects had to be between the ages of 18 and 70 years, have a diagnosis of known or newly diagnosed hypertension with any elevation of blood pressure, and be part of any risk group at any stage.
Non-inclusion criteria were as follows: secondary hypertension, acute respiratory viral infection or pneumonia with a negative COVID-19 PCR test for up to three months; severe liver diseases requiring continuous medication; stage 5 chronic kidney disease (CKD) with glomerular filtration rate (GFR) determined by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, dialysis, kidney transplant, severe blood diseases and autoimmune diseases; active cancer; acute inflammatory and infectious diseases; severe dementia and mental disorders that may render patients incapable of providing informed consent.
All patients had 24-hour blood pressure monitoring for medical indications based on the RSC Clinical Guidelines, as approved by the Russian Ministry of Health (2020) [9].
Masked nocturnal hypertension was verified by the following criteria: mean daytime ambulatory blood pressure <135/85 mmHg, mean nighttime ambulatory blood pressure ≥120/70 mmHg with any mean 24-hour ambulatory blood pressure and office blood pressure <140/90 mmHg [10].
A damage of the kidneys as a target organ in hypertensive patients was identified based on the RSC Clinical Guidelines approved by the Russian Ministry of Health (2020) [9]. GFR was calculated using the CKD-EPI equation based on serum creatinine and urine albumin-creatinine ratio (UACR) measured from the first morning urine sample. Additionally, serum cystatin C was determined by enzyme immunoassay using Cystatin C Human ELISA reagent kit (Biovendor, Czech Republic) and Immulite 1000 analyzer (DPC, USA). GFR was calculated from creatinine and cystatin C levels. The reference values for cystatin C were 1.04 ± 0.11 mg/L.
Left ventricular hypertrophy (LVH), a disease of the heart as a target organ, in hypertensive patients was detected by transthoracic echocardiography (EchoCG) using Vivid S5 ultrasound system (GE Healthcare, USA). The scanning procedure was based on the RSC Clinical Guidelines approved by the Russian Ministry of Health (2020) [9]. Left ventricular mass index (LVMI), i.e. left ventricular myocardial mass (LVM) / body surface area (BSA), is one of the echocardiographic parameters used to diagnose LVH. For patients with normal body weight, LVH is defined by LVMI >115 g/m2 for males and >95 g/m2 for females. For overweight and obese patients, LVH was diagnosed by LVH >50 g/m2.7 for males, >47 g/m2.7 for females calculated using the equation of LVM/height, m2.7.
Arterial lesions as a target organ damage in hypertensive patients was diagnosed based on the RSC Clinical Guidelines approved by the Russian Ministry of Health (2020) [9] by conventional duplex ultrasound of the brachiocephalic arteries using Vivid S5 system (GE Healthcare, USA) and by volumetric sphygmographic measurements using VaSera VS-1000 (Fucuda Denshi, Japan). The following parameters were measured: cardio-ankle vascular index (CAVI1), carotid-femoral pulse wave velocity (PWVcf), right-side brachial-ankle pulse wave velocity (R-PWV), left-side brachial-ankle pulse wave velocity (L-PWV), brachial pulse wave velocity (B-PWV), aortic pulse wave velocity (PWVa), carotid pulse wave velocity (C-PWV), right-side ankle-brachial index (R-ABI), and left-side ankle-brachial index (L-ABI). An increased arterial stiffness was identified with PWVcf > 10 m/s and/or R-PWV and L-PWV > 18 m/s and/or CAVI1 > 9 and/or ABI <0.9.
A damage of the brain as a target organ in hypertensive patients was detected based on the RSC Clinical Guidelines, as approved by the Russian Ministry of Health (2020) [9], by a short version of the Mini Mental State Examination (MMSE) used for assessing mental status to identify cognitive impairments. The MMSE scores were interpreted as follows: 28, mild cognitive impairment; 25–27, moderate cognitive impairment; 20–24, mild dementia; 10–19, moderate dementia; <10, severe dementia.
Statistical data processing was performed using Statistica 10.0 software package. In the null hypothesis testing, the critical value of the significance level was established at 0.05. The normality of the data distribution was tested using the Shapiro–Wilk and Kolmogorov–Smirnov tests. For normally distributed quantitative variables, arithmetic means and standard deviations (M ± SD) were calculated, whereas medians (Med), 25th and 75th quartiles were determined for non-normal distributions. Categorical variables were described using absolute (n) and percentage (%) frequencies. Normally distributed mean quantitative variables were compared using the Student's test. For non-normal distributions, the Mann–Whitney test was used. Categorical variables were compared using χ2-test with the Yates continuity correction.
Spearman's correlation analysis established the relationship between quantitative variables, and the Chuprov contingency coefficient was used to identify relationships between qualitative variables. The performance of the derived relationships was examined as suggested by Rea and Parker. In the null hypothesis testing for the correlations, the critical significance level was established at p < 0.05. Contingency tables included hazard ratios (HRs) and 95% confidence intervals (CIs) for the assessed parameters.
Results and Discussion
The mean age of the study patients was 59.7 ± 12.8 years. The study included 126 (67.7%) women and 60 (32.3%) men. The mean time to the study enrollment was 4.5 ± 1.8 months after the onset of COVID-19. The characteristics of the clinical course of COVID-19 in Group 1 are presented in Table 1.
Table 1
Clinical course of novel Coronavirus disease (COVID-19), group 1, n = 100
Parameter | Value, n/% |
COVID-19 without hospitalization | 21/21.0 |
COVID-19 pneumonia | 58/58.0 |
COVID-19 pneumonia with hospitalization | 44/44.0 |
COVID-19 pneumonia with lung involvement >50% | 32/32.0 |
COVID-19 pneumonia with ICU admission | 16/16.0 |
COVID-19 pneumonia with mechanical ventilation | 12/12.0 |
COVID-19 with other complications | 68/68.0 |
COVID-19 pneumonia with cytokine storm | 18/18.0 |
COVID-19 pneumonia + glucocorticoids | 39/39.0 |
COVID-19 pneumonia + target therapy | 12/12.0 |
COVID-19 pneumonia + statins | 36/36.0 |
Long COVID-19 (for 12 weeks or more) | 58/58.0 |
Long COVID-19 with asthenia (for 12 weeks or more) | 56/58.0 |
Long COVID-19 with general malaise (for 12 weeks or more) | 55/55.0 |
Long COVID-19 with fatigue (for 12 weeks or more) | 52/52.0 |
Long COVID-19 with impaired concentration (for 12 weeks or more) | 36/36.0 |
Long COVID-19 with dyspnea (for 12 weeks or more) | 27/27.0 |
Long COVID-19 with reduced quality of life (for 12 weeks or more) | 58/58.0 |
Note: COVID-19, novel coronavirus disease; ICU, intensive care unit.
Table 2 shows the clinical characteristics and medical history by study group.
Table 2
Clinical characteristics and medical history of patients by study group, n = 186
Parameter | Group 1 (hypertension + | Group 2 (hypertension without COVID-19, n = 86) | p |
COVID-19 vaccination, n/% | 13/13.0 | 86/100.0 | < 0.001 |
Sex, n (%), M/F | 27 (27.0)/73 (73.0) | 36 (41.9)/50 (58.1) | 0.048 |
Age, years | 60.2 ± 11.6 | 59.0 ± 13.6 | 0.945 |
Smoking, n/% | 22/22.0 | 42/48.8 | < 0.001 |
Waist, cm | 94.6 ± 10.9 | 89.9 ± 17.3 | 0.005 |
BMI, kg/m2 | 31.1 ± 8.9 | 28.0 ± 6.4 | 0.004 |
BMI >30 kg/m2, n/% | 53/53.0 | 29/33.7 | 0.009 |
Newly diagnosed hypertension, n/% | 13/13.0 | 7/8.1 | 0.287 |
Known hypertension, n/% | 87/87.0 | 79/91.9 | 0.287 |
Duration of known hypertension, years | 8.0 [4.5; 10.0] | 10.0 [1.0; 20.0] | 0.002 |
CHD, stable angina, n/% | 10/10.0 | 5/5.8 | 0.296 |
Angina FC | 2.000 ± 0.001 | 2.200 ± 0.420 | 0.459 |
History of MI, n/% | 5/5.0 | 2/2.3 | 0.340 |
History of PCI, n/% | 3/3.0 | 3/3.5 | 0.851 |
History of CABG, n/% | 0/0.0 | 2/2.3 | 0.126 |
Brachiocephalic atherosclerosis and lower | 18/18.0 | 5/5.8 | 0.022 |
Type 2 diabetes, n/% | 22/22.0 | 6/7.0 | 0.005 |
Asthma, n/% | 25/25.0 | 26/30.2 | 0.426 |
COPD, n/% | 3/3.0 | 13/15.1 | 0.004 |
History of stroke/TIA, n/% | 6/6.0 | 7/8.1 | 0.569 |
Atrial fibrillation, n/% | 7/7.0 | 4/4.7 | 0.499 |
Known CHF, n/% | 18/18.0 | 26/30.2 | 0.075 |
Newly diagnosed CHF, n/% | 18/18.0 | 6/7.0 | 0.044 |
CHF FC | 1.81 ± 0.52 | 1.65 ± 0.62 | 0.178 |
CHF with low LVEF, n/% | 2/2.0 | 0/0.0 | 0.188 |
CHF with moderately reduced LVEF, n/% | 3/3.0 | 1/1.2 | 0.390 |
CHF with preserved LVEF, n/% | 31/31.0 | 31/36.0 | 0.568 |
Note: BMI, body mass index; CABG, coronary artery bypass graft; CHD, is coronary heart disease; CHF, chronic heart failure; COPD, chronic obstructive pulmonary disease; COVID-19, novel coronavirus disease; FC, functional class; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIA, transient ischemic attack.
Among 11 parameters describing clinical and medical history data and significantly different between the groups, five parameters demonstrated an association with COVID-19, i.e. a statistically significant, strong negative correlation with vaccination (K = −0.470; p < 0.001); a statistically significant, moderate positive correlation with atherosclerosis affecting any artery (K = 0.222; p = 0.005) and type 2 diabetes (K = 0.209; p = 0.009); a statistically significant, weak positive correlation with body mass index (BMI) > 30 g/m2 (K = 0.190; p = 0.012) and newly diagnosed chronic heart failure (CHF) (K = 0.164; p = 0.044). COVID-19 vaccination in hypertensive patients was associated with an 87% reduction in the risk of infection (0.132; 95% CI 1.000–0.178). It also protected from COVID-19 pneumonia, requiring hospitalization (0.132; 95% CI 1.000–0.192), and progression to long COVID-19 (0.132; 95% CI 1.001–0.185). In this population, BMI >30 g/m2 contributed to more than two-, seven-, and nine-fold increase in risks of COVID-19 (2.037; 95% CI 1.457–2.828), COVID-19 pneumonia with hospitalization (7.279; 95% CI 3.306–18.228), and long COVID-19 (9.825; 95% CI 4.256–26.796), respectively.
In hypertensive patients, atherosclerosis affecting any artery increased the risk of COVID-19 by 54.4% (1.544; 95% CI 1.151–1.915), whereas the risks of COVID-19 pneumonia with hospitalization and of long COVID-19 rose to more than 5.5- (5.667; 95% CI 3.226–10.312) and almost 3-fold (2.904; 95% CI 1.954–4.067), respectively. Type 2 diabetes in hypertensive patients was associated with a 76.8% increase in the risk of COVID-19 (1.768; 95% CI 1.253–2.157) and contributed to more than 3.5- and 2.5-fold increase in the risks of COVID-19 pneumonia with hospitalization (3.643; 95% CI 2.322–4.943) and of long COVID-19 (2.532; 95% CI 1.714–3.224), respectively. De novo CHF (newly diagnosis at the time of enrollment) increased the risk of COVID-19 by 48.2% (1.482; 95% CI 1.012–1.838) with a more than two-fold increase in the risks of COVID-19 pneumonia with hospitalization and of long COVID-19 (2.096; 95% CI 1.117–3.087 and 2.251; 95% CI 1.468–2.918, respectively).
Table 3 shows the laboratory values by study group.
Table 3
Laboratory values of patients by study group, n = 186
Parameter | Group 1 (hypertension + COVID-19, n = 100) | Group 2 (hypertension without COVID-19, n = 86) | p |
Platelets, 103/mL | 259.5 ± 73.4 | 266.4 ± 88.4 | 0.585 |
White blood cells, 1,000 cells/mL | 7445.3 ± 2956.5 | 8092.6 ± 3049.5 | 0.077 |
Lymphocytes, % | 31.9 ± 9.56 | 31.1 ± 10.6 | 0.784 |
ESR, mm/h | 17.0 [9.0; 30.0] | 15.0 [7.0; 24.0] | 0.101 |
CRP, mg/L | 3.3 [1.3; 7.2] | 2.6 [1.1; 7.2] | 0.492 |
Fasting blood glucose, mmol/L | 5.7 ± 1.6 | 5.5 ± 1.5 | 0.184 |
HbA1c, % | 6.03 ± 0.99 | 6.37 ± 1.02 | 0.851 |
Total cholesterol, mmol/L | 5.6 ± 1.5 | 5.0 ± 1.2 | 0.057 |
LDLC, mmol/L | 3.5 ± 1.3 | 3.2 ± 1.1 | 0.082 |
HDLC, mmol/L | 1.37 [1.00; 1.6]2 | 1.45 ± 0.50 | 0.083 |
TG, mmol/L | 1.44 [0.93; 2.04] | 1.14 [0.95; 1.64] | 0.068 |
Uric acid, mmol/L | 288.3 ± 78.9 | 308.1 ± 109.8 | 0.707 |
Potassium, mmol/L | 4.20 ± 0.55 | 4.44 ± 0.44 | 0.124 |
Sodium, mmol/L | 141.7 ± 4.1 | 140.0 ± 15.8 | 0.856 |
Nt-proBNP, pg/mL | 82.3 [31.3; ± 215.2] | 72.8 [26.7 ± 136.4] | 0.007 |
Nt-proBNP >125 pg/mL, n/% | 48/44.0 | 26/30.2 | 0.021 |
Note: COVID-19, novel coronavirus disease; CRP, C–reactive protein; ESR, erythrocyte sedimentation rate; HbA1c, glycated hemoglobin, type A1c; HDLC, high-density lipoprotein cholesterol; LDLC, low–density lipoprotein cholesterol; Nt-proBNP, N-terminal pro-brain natriuretic peptide; TG, triglycerides.
Correlation analysis demonstrated a weak positive correlation between Nt-proBNP >125 pg/mL and the frequency of COVID-19. Regardless of CHF, Nt-proBNP >125 pg/mL was associated with a 39.8% increase in the risk of COVID-19 (1.398; 95% CI 1.052–1.813), whereas the risks calculated for COVID-19 pneumonia with hospitalization and for long COVID-19 increased by almost two-fold (1.982; 95% CI 1.1210–3.186) and more than 4.5-fold (4.541; 95% CI 2.528–8.778), respectively.
Continuous medications received at the time of enrollment are presented in Table 4 by study group.
Table 4
Continuous medications by study group, n = 186
Parameter | Group 1 (hypertension + | Group 2 (hypertension without COVID-19, n = 86) | p |
ACE inhibitors/ARBs/ARNIs, n/% | 68/68.0 | 75/87.2 | 0.002 |
Beta-adrenergic blocking agents, n/% | 50/50.0 | 29/33.7 | 0.026 |
Thiazide/thiazide-like diuretics, n/% | 15/15.0 | 20/23.3 | 0.151 |
Loop diuretics, n/% | 4/4.0 | 4/4.7 | 0.828 |
MCRA, n/% | 14/14.0 | 5/5.8 | 0.067 |
Dihydropyridine calcium channel antagonists, n/% | 30/30.0 | 20/23.3 | 0.301 |
Centrally acting antihypertensive agents, n/% | 2/2.0 | 0/0.0 | 0.188 |
Without antihypertensive therapy, n/% | 24/24.0 | 10/11.6 | 0.047 |
Antihypertensive monotherapy, n/% | 14/14.0 | 18/20.9 | 0.212 |
Combination of two antihypertensive agents, n/% | 31/31.0 | 42/48.8 | 0.020 |
Combination of three or more antihypertensive | 31/31.0 | 16/18.6 | 0.077 |
Anticoagulants, n/% | 6/6.0 | 4/4.7 | 0.685 |
Antiplatelet agents, n/% | 35/35.0 | 38/44.2 | 0.201 |
Statins, n/% | 36/36.0 | 39/45.4 | 0.196 |
Antianginal agents (calcium channel blockers, nitrates, trimetazidine, ivabradine, ranolazine, nicorandil), n/% | 2/2 | 0/0 | 0.188 |
Sulfonylurea/insulin, n/% | 22/22.0 | 4/4.7 | 0.002 |
Metformin, n/% | 16/16.0 | 5/5.8 | 0.051 |
SGLT2 inhibitors, n/% | 4/4.0 | 4/4.7 | 0.828 |
Inhaled glucocorticoids, including combinations, n/% | 26/26.0 | 32/37.2 | 0.100 |
Note: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ARNI, angiotensin II receptor/neprilysin inhibitor; COVID-19, novel coronavirus disease; MCRA, mineralocorticoid receptor antagonist; SGLT2, sodium/glucose cotransporter 2.
A total of five categories of medications demonstrated significant differences between the study groups. Among them, three categories were associated with the risk of COVID-19, i.e. a moderate negative correlation for renin-angiotensin-aldosterone system (RAAS) inhibitors and a combination of two antihypertensive agents (K = 0.557, p < 0.001 and K = 0.205, p = 0.009, respectively), and a strong positive correlation for sulfonylurea/insulin (K = 0.737, p = 0.002).
In hypertensive patients, RAAS inhibitors were associated with a 30.4%, 47.2%, and 43.6% reduction in the risk of COVID-19 (0.696; 95% CI 0.499–0.947), COVID-19 pneumonia with hospitalization (0.528; 95% CI 0.278–0.947), and long COVID-19 (0.564; 95% CI 0.415–0.852), respectively. The use of dual antihypertensive combinations reduced the risk of COVID-19, COVID-19 pneumonia with hospitalization, and long COVID-19 by 30.4% (0.696; 95% CI 0.499–0.947), 51.5% (0.485; 95% CI 0.248–0.886), and 43.5% (0.565; 95% CI 0.333–0.916), respectively. Sulfonylurea and/or insulin therapy increased the risks by 73.6% (1.736; 95% CI 1.267–2.016) for COVID-19, by more than 4-fold (4.001; 95% CI 2.606–5.091) for COVID-19 pneumonia with hospitalization, and by almost 3-fold (2.774; 95% CI 1.917–3.356) for long COVID-19.
Table 5 shows the blood pressure values for the study groups.
Table 5
Office blood pressure, heart rate measurements and 24-hour blood pressure
monitoring by study group, n = 186
Parameter | Group 1 (hypertension + COVID-19, n = 100) | Group 2 (hypertension without COVID-19, n = 86) | p |
Office SBD, mmHg | 140.0 ± 19.5 | 163.9 ± 21.0 | 0.584 |
Office DBP, mmHg | 86.0 ± 12.7 | 87.4 ± 12.5 | 0.568 |
Resting HR, bpm | 68.90 ± 11.39 | 69.17 ± 13.54 | 0.822 |
Target SBD/DBP achieved, n/% | 12/12.0 | 5/5.8 | 0.145 |
Only target SBD achieved, n/% | 14/14.0 | 2/2.3 | 0.011 |
Only target DBP achieved, n/% | 9/9.0 | 2/2.3 | 0.055 |
Mean 24-hour SBP, mmHg | 138.4 ± 13.9 | 128.6 ± 15.0 | < 0.001 |
Maximum morning SBP, mmHg | 146.5 ± 21.5 | 150.0 ± 20.8 | 0.393 |
Mean daytime SBP, mmHg | 132.6 ± 6.3 | 134.4 ± 18.8 | 0.828 |
Mean nighttime SBP, mmHg | 127.2 ± 19.4 | 120.7 ± 15.7 | 0.014 |
Mean 24-hour DBP, mmHg | 83.9 ± 9.1 | 84.5 ± 9.0 | 0.975 |
Maximum morning DBP, mmHg | 91.7 ± 16.0 | 97.0 ± 22.0 | 0.060 |
Mean daytime DBP, mmHg | 89.3 ± 12.6 | 90.6 ± 12.6 | 0.441 |
Mean nighttime DBP, mmHg | 75.6 ± 11.6 | 78.2 ± 9.7 | 0.295 |
Mean 24-hour pulse pressure, mmHg | 54.0 ± 9.5 | 46.1 ± 11.0 | < 0.001 |
Mean 24-hour pulse pressure >53 mmHg, n/% | 59/59.0 | 32/37.2 | 0.007 |
Dipper pattern, SBP, % | 8.0 [-7.0; 15.0] | 10.0 [4.0; 15.0] | 0.121 |
Dipper pattern, DBP, % | 10.0 [2.0; 20.0] | 13.0 [6.5; 20.0] | 0.230 |
Dipper SBP, n/% | 49/49.0 | 69/80.2 | < 0.001 |
Dipper DBP, n/% | 55/55.0 | 67/77.9 | 0.002 |
Non-dipper SBP, n/% | 31/31.0 | 12/14.0 | 0.011 |
Non-dipper DBP, n/% | 19/19.0 | 12/14.0 | 0.470 |
Night-peaker SBP, n/% | 24/24.0 | 1/1.2 | < 0.001 |
Night-peaker DBP, n/% | 10/10.0 | 0/0 | 0.008 |
Over-dipper SBP, n/% | 4/4.0 | 4/4.7 | 0.886 |
Over-dipper DBP, n/% | 16/16.0 | 7/8.1 | 0.162 |
SBP variability, mmHg | 14.5 [5.8; 18.2] | 13.1 [10.0; 20.3] | 0.267 |
DBP variability, mmHg | 11.3 [8.5; 16.0] | 10.6 [9.1; 14.5] | 0.184 |
Masked nocturnal hypertension, n/% | 12/12.0 | 2/2.3 | 0.027 |
Note: DBP, diastolic blood pressure; HR, heart rate; COVID-19, novel coronavirus disease; SBP, systolic blood pressure.
The 24-hour blood pressure monitoring yielded 11 parameters that were found to be significantly different between the study groups. Correlation analysis demonstrated only three parameters that showed a correlation with the risk COVID-19. These were: a moderate positive correlation for pulse pressure >53 mmHg (K = 0.217; p = 0.004), a strong positive correlation for Non-dipper/Night-peaker circadian SBP patterns (K = 0.413; p < 0.001), a weak positive correlation for Non-dipper/Night-peaker circadian DBP patterns (K = 0.181; p = 0.014). Pulse pressure >53 mmHg was associated with more than 1.5-, 3.5-, and almost 2.5-fold increase in the risk of COVID-19 (1.503; 95% CI 1.125–1.999), COVID-19 pneumonia with hospitalization (3.657; 95% CI 1.902–7.620), and long COVID-19 (2.484; 95% CI 1.531–4.169), respectively. In Non-dipper/Night-peaker circadian SBP patterns, the risks increased by more than two-fold (2.121; 95% CI 1.634–2.615) for COVID-19, by more than three-fold (3.371; 95% CI 2.056–5.283) for COVID-19 pneumonia with hospitalization, and by more than more than 2.5-fold (2.708; 95% CI 1.816–3.816) for long COVID-19. Non-dipper/Night-peaker circadian DBP patterns contributed to a 14.5%, 86.7%, and 71.1% increase in the risk of COVID-19 (1.145; 95% CI 1.057–1.814), COVID-19 pneumonia with hospitalization (1.867; 95% CI 1.063–2.904), and long COVID-19 (1.711; 95% CI 1.075–2.438), respectively.
Table 6 demonstrates the renal filtration measurements by study group.
Table 6
Renal filtration measurements by study group, n = 186
Parameter | Group 1 (hypertension + COVID-19, n = 100) | Group 2 | p |
Serum creatinine, mmol/L | 88.1 ± 12.0 | 83.9 ± 21.2 | 0.093 |
Blood urea nitrogen, mmol/L | 5.9[4.1; 6.5] | 5.5[4.4; 6.8] | 0.406 |
GFR (CrCl), mL/min/1.73m2 | 72.7 ± 20.5 | 80.4 ± 21.8 | 0.014 |
GFR (CrCl) >60 mL/min/1.73m2, n/% | 69/69.0 | 70/81.4 | 0.077 |
GFR (CrCl) 45–59 mL/min/1.73m2, n/% | 28/28.0 | 11/12.8 | 0.019 |
GFR (CrCl) 30–44 mL/min/1.73m2, n/% | 3/3.0 | 5/5.8 | 0.562 |
Cystatin C, mg/L | 1.24 [0.98; 1.52] | 1.09 [0.87; 1.21] | < 0.001 |
GFR (CrCl-CysC), mL/min/1.73m2, n/% | 63.2 ± 16.4 | 71.5 ± 13.9 | < 0.001 |
GFR (CrCl-CysC) >60 mL/min/1.73m2, n/% | 59/59.0 | 73/84.9 | < 0.001 |
GFR (CrCl-CysC) 45–59 mL/min/1.73m2, n/% | 31/31.0 | 12/14.0 | 0.011 |
GFR (CrCl-CysC) 30–44 mL/min/1.73m2, n/% | 6/6.0 | 1/1.2 | 0.180 |
GFR (CrCl-CysC) 15–29 mL/min/1.73m2, n/% | 4/4.0 | 0/0.0 | 0.172 |
UACR, mg/g | 172.7 [25.4; 450.6] | 68.3 [21.3; 236.2] | < 0.001 |
UACR <30 mg/g, n/% | 56/56.0 | 60/70.0 | 0.075 |
UACR 30–299 mg/g, n/% | 23/23.0 | 19/22.1 | 0.978 |
UACR >300 mg/g, n/% | 21/21.0 | 7/8.1 | 0.026 |
Note: COVID-19, novel coronavirus disease; CrCl, creatinine clearance; CysC, cystatine C; GFR, glomerular filtration rate; UACR, urine albumin-creatinine ratio.
Correlation analysis showed that the risk of COVID-19 was moderately negatively correlated with GFR (CrCl-CysC) < 60 mL/min/1.73m2 (K = 0.284; p < 0.001) and weakly positively correlated with UACR > 300 mg/g (K = 0.179; p = 0.026).
Echocardiographic heart parameters are presented in Table 7 by study group.
Table 7
Echocardiographic parameters by study group, n = 186
Parameter | Group 1 (hypertension + COVID-19, n = 100) | Group 2 (hypertension without COVID-19, n = 86) | p |
LVEF, % | 62.1 ± 7.0 | 61.9 ± 5.8 | 0.530 |
LVEF >50%, n/% | 93/93.0 | 86/100.0 | 0.035 |
LVEF 41–49%, n/% | 7/7.0 | 0/0.0 | 0.035 |
Mean E/e’ | 13.2[7.8; 15.6] | 11.6[6.4; 14.1] | < 0.001 |
Mean E/e’ >14 | 41/41.0 | 16/18.6 | 0.002 |
LVM, g | 215.7 ± 77.7 | 217.6 ± 78.9 | 0.710 |
LVMI, females, g/m2 | 107.4 ± 42.7 | 116.8 ± 52.0 | 0.178 |
LVMI, males, g/m2 | 120.9 ± 38.5 | 115.8 ± 35.3 | 0.350 |
LVMI, females, g/m2,7 | 43.3[13.4; 30.1] | 40.0[12.3; 24.7] | 0.005 |
LVMI, males, g/m2,7 | 58.9[18.0; 39.2] | 52.0[14.1; 27.4] | < 0.001 |
LVH, n/% | 68/68.0 % | 37/43.0 % | 0.002 |
Note: COVID-19, novel coronavirus disease; E, maximum early filling velocity; e’, early diastolic mitral annular velocity; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; LVM, left ventricular mass; LVMI, left ventricular mass index.
Correlation analysis of seven echoCG parameters showing significant differences between the study groups demonstrated that the risk of COVID-19 correlated with only two of them, with moderate positive correlations with left ventricular diastolic dysfunction (mean E/e’ >14) (K = 0.242; p = 0.002) and LVH (K = 0.251; p = 0.002).
Table 8 shows the values of volumetric sphygmography by study group.
Table 8
Volumetric sphygmographic parameters by study group, n = 186
Parameter | Group 1 (hypertension + | Group 2 (hypertension without COVID-19, n = 86) | p |
R-ABI | 1.04 ± 0.06 | 1.03 ± 0.07 | 0.296 |
R-ABI <0.9, n/% | 3/3.0 | 0/0.0 | 0.301 |
L-ABI | 1.06 ± 0.07 | 1.05 ± 0.06 | 0.301 |
L-ABI <0.9, n/% | 1/1.0 | 1/1.2 | 0.545 |
PWVcf, m/s | 13.9 ± 4.7 | 12.6 ± 6.1 | 0.094 |
PWVcf >10 m/s, n% | 61/61.0 | 44/51.2 | 0.230 |
R-PWV, m/s | 14.8 ± 3.3 | 14.5 ± 2.9 | 0.514 |
R-PWV >18 m/s, n/% | 28/28.0 | 12/14.0 | 0.032 |
L-PWV, m/s | 15.4 ± 5.4 | 14.8 ± 3.2 | 0.368 |
L-PWV >18 m/s, n/% | 33/33.0 | 16/18.6 | 0.040 |
B-PWV | 7.6 [5.3; 8.4] | 7.4 [4.4; 8.1] | 0.371 |
C-PWV, m/s | 5.7[1.7; 12.4] | 6.5[2.3; 16.5] | 0.173 |
PWVа, m/s | 8.4 [4.4; 12.5] | 10.1[4.3; 14.1] | 0.089 |
CAVI1 | 9.5 ± 2.0 | 8.4 ± 1.8 | < 0.001 |
CAVI1 ³ 9 | 63/63.0 | 32/37.2 | < 0.001 |
Note: B-PWV, brachial pulse wave velocity; CAVI1, cardio-ankle-vascular index; COVID-19, novel coronavirus disease; C-PWV, carotid pulse wave velocity; L-ABI, left-side ankle–brachial index; L-PWV, left-side brachial-ankle pulse wave velocity; PWVа, aortic pulse wave velocity; PWVcf, carotid-femoral pulse wave velocity; R-ABI, right-side ankle–brachial index; R-PWV, right-side brachial-ankle pulse wave velocity.
Correlation analysis of four significant differences of the volumetric sphygmographic parameters between the groups showed the only one correlation for the risk of COVID-19, i.e. a moderate positive correlation with CAVI1 (K = 0.257; p < 0.001).
MMSE scores are presented in Table 9.
Table 9
MMSE scores by study group, n = 186
Parameter | Group 1 (hypertension + COVID-19, n = 100) | Group 2 (hypertension without COVID-19, n = 86) | p |
MMSE score | 27.8[25.2; 30.0] | 29.2[26.5; 29.9] | < 0.001 |
MMSE score 29–30, n/% | 62/62.0 | 70/81.4 | 0.007 |
MMSE score 28, n/% | 28/28.0 | 12/14.0 | 0.032 |
MMSE score 25–27, n/% | 5/5.0 | 2/2.3 | 0.570 |
MMSE score 20–24, n/% | 3/3.0 | 2/2.3 | 0.865 |
MMSE score 10–19, n/% | 2/2.0 | 0/0.0 | 0.545 |
Cognitive impairment with dementia, n/% | 38/38.0 | 16/18.6 | 0.007 |
Note: COVID-19, novel coronavirus disease; MMSE, Mini Mental State Examination.
Correlation analysis of MMSE scores that were significantly different between the study groups revealed that the risk of COVID-19 was moderately negatively correlated with any cognitive impairment and/or mild dementia (K = −0.213; p = 0.007).
Table 10 demonstrates the calculated hazard ratios for target organ involvement in hypertensive patients, based on the clinical course of COVID-19.
Table 10
Hazard ratios for target organ involvement in hypertensive patients, based on clinical course of COVID-19, n = 186
Parameter | COVID-19 in hypertensive patients (HR, 95% CI) | COVID-19 pneumonia with hospitalization in hypertensive | Long COVID-19 >12 weeks |
GFR (CrCl-CysC) <60 mL/min/1.73m2 | 1.699 (1.294–2.093) | 2.579 (1.571–3.938) | 2.188 (1.454–3.056) |
UACR >300 mg/g | 1.501 (1.056–1.853 | 2.075 (1.133–3.082) | 2.005 (1.261–2.695) |
Mean E/e’ >14 | 1.573 (1.189–1.973) | 2.176 (1.306–3.412) | 1.770 (1.148–2.546) |
LVH | 1.640 (1.203–2.265) | 2.175 (1.229–4.026) | 1.934 (1.214–3.175) |
CAVI1 ³ 9 | 1.465 (1.089–1.983) | 1.875 (1.084–3.347) | 1.749 (1.113–2.808) |
Cognitive impairment with dementia | 1.499 (1.124–1.887) | 1.851 (1.085–2.924) | 1.642 (1.050–2.380) |
Note: CAVI1, cardio-ankle vascular index; COVID-19, novel coronavirus disease; E, maximum early filling velocity; e’, early diastolic mitral annular velocity; GFR, glomerular filtration rate; LVH, left ventricular hypertrophy; UACR, urine albumin-creatinine ratio.
Our findings are consistent with previous studies, which established a positive correlation between COVID-19 vaccination and a reduced risk of the disease, whereas obesity, atherosclerosis, and type 2 diabetes demonstrated a negative correlation [11-13]. An original finding of our study was the demonstration of the association between various forms of COVID-19 and newly diagnosed CHF, with the diagnosis made not only by clinical symptoms, as observed in other studies, but also by echocardiographic data and blood levels of Nt-proBNP. Therefore, our findings differ from those reported by Maestre-Muñiz et al. (2021), who demonstrated that the incidence of de novo CHF was only 2.0% one year after the onset of COVID-19 among 766 patients [14]. Using the Russian clinical guidelines for verification, newly diagnosed CHF was detected in 18% of hypertensive patients at 4.5 months after the onset of COVID-19. Higher HRs were demonstrated for both severe COVID-19 and long COVID-19. As evidenced by available literature, long COVID-19 occurs in 10%–35% of patients with various phenotypes [15; 16]. The identification of risk factors and pathogenetic mechanisms for these phenotypes plays a critical role in supporting the selection of appropriate therapeutic strategies for these patients [17].
It has been demonstrated that elevated Nt-proBNP with or without underlying CHF was associated with an increased risk of various forms of COVID-19. Our findings are consistent with those of several studies that have found that infection with the SARS-CoV-2 virus may increase serum levels of NT-proBNP and BNP, both in individuals with CHF and in those with infectious complications, lung damage, and kidney damage [18; 19].
The negative effect of the insulin therapy on the course of COVID-19 in patients with type 2 diabetes has been corroborated by the meta-analysis of 66 observational studies, where it was shown that the use of insulin can pose a high risk of various complications of COVID-19, especially in elderly patients, therefore caution is necessary [20]. In contrast to the findings of our study, the authors suggested that the use of sulfonylurea has a neutral effect. These findings must be validated through further clinical studies.
As was demonstrated in our study, a meta-analysis of 33 observational studies found that patients receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) have a reduced risk of hospitalization, reduced severity of COVID-19 pneumonia, lower need for mechanical ventilation, and an overall reduction in mortality [21]. The available data on the potential preventive effect of angiotensin II receptor / neprilysin inhibitors (ARNIs) in patients with COVID-19 remains limited. This study included a combined group of patients who received ACE inhibitors, ARBs, and ARNIs. Therefore, it may be assumed that the ARNIs have at least a neutral effect on the risk of severe forms of COVID-19 and long COVID-19. The meta-analysis has further elucidated that the Omicron variant of SARS-CoV-2 is potentially more transmissible and has been associated with an increased incidence of unfavorable clinical outcomes in patients who have not received adequate treatment with ACE inhibitors / ARBs. The majority of available literature aligns with current guidelines in this aspect.
Some authors believe that COVID-19 has not been fully recognized as a modifier of cardiovascular risk, including the risk factors such as hypertension [22]. The present study corroborates the association between hypertension and COVID-19, as evidenced by previous studies [23]. However, a novel aspect of the present study is that it considers not only the association between hypertension or elevated blood pressure and various forms of COVID-19. We further investigate the correlation of the elevated mean 24-hour pulse pressure and abnormal circadian patterns, including Non-dipper, Night-peaker, and masked nocturnal hypertension, with severe
COVID-19 and long COVID-19. These observations are, however, rarely documented in the relevant literature.
A decline in renal filtration during the acute phase of COVID-19 has been documented in numerous studies. A growing body of evidence indicates a decrease in glomerular filtration rate between 6 and 12 months of follow-up, even in patients without acute renal injury during the acute phase of COVID-19 [24]. This phenomenon has also been observed in hypertensive patients in this study. The authors of the review express concern that there are no guidelines in place to establish a follow-up period or to determine therapeutic alternatives for these patients. They also believe that the impact of COVID-19 on the renal health has yet to be determined. Future large-scale studies with long-term follow-up periods are necessary to assess renal function through biopsy, urinalysis, serum creatinine and cystatin C measurements, and renal tubular function evaluation.
The process by which the cardiovascular system remodels in patients with a history of COVID-19 remains a significant scientific concern. This study has shown that hypertensive patients with any clinical form of COVID-19 experience an increase in diastolic dysfunction and the risk of LVH increases with no significant decrease in LVEF as early as 4.5 months from the onset of the disease. As previously demonstrated, CHF in patients with dyspnea is associated with right ventricular dysfunction [25]. Some of our findings are consistent with a meta-analysis of 21 observational studies that established the association of long COVID-19 with increased LVM and right ventricular dysfunction [26]. However, the authors also reported a decrease in LVEF in patients with a history of intensive care unit admission. It is particularly significant to emphasize that CHF persisted in recovered patients even after a year following SARS-CoV-2 infection. Future studies are required to elucidate the biological mechanisms underlying the long-term cardiovascular effects of COVID-19.
In the present study, we demonstrated that the true arterial stiffness, as measured by CAVI1, displayed a statistically significant increase in patients with any clinical form of COVID-19, including long COVID-19. Other clinical studies have also revealed that brachial-ankle and carotid-femoral pulse wave velocities and arterial stiffness are significantly higher in patients with COVID-19 compared to the control participants without the acute phase of COVID-19 [27; 28]. The exact mechanisms underlying endothelial dysfunction in patients with COVID-19 remain to be fully elucidated; however, this dysfunction may be attributable to a combination of direct effects of SARS-CoV-2 and secondary effects of systemic inflammation caused by COVID-19 on the vascular endothelium. [29]. Several observational studies have demonstrated the potential for vascular dysfunction resulting from SARS-CoV-2 infection to partially improve, though not fully return to baseline, thereby causing persistent vascular dysfunction following the infection [30–32], a finding that aligns with the present study. It can be expected that lifestyle changes in patients with a history of COVID-19 will also improve vascular function, depending on blood pressure, thereby preventing the progression of atherosclerosis [33; 34]. Skow et al. (2022) demonstrated that vascular function was not impaired in participants who had received a vaccine against COVID-19 and subsequently infected with the Omicron variant of SARS-CoV-2 [35].
Conclusions
COVID-19 vaccination in hypertensive patients was associated with an 87% reduction in the risk of infection and protected from COVID-19 pneumonia, requiring hospitalization, and progression to long COVID-19. It has been demonstrated that BMI >30 g/m2, atherosclerosis affecting any artery, and type 2 diabetes increased the risk of various forms of COVID-19, including long COVID-19 of more than 12 weeks. Newly diagnosed CHF verified not only by clinical symptoms, but also by echocardiography and Nt-proBNP levels increased the risk of COVID-19 by 48.2% and contributed to more than two-fold increase in the risks of COVID-19-pneumonia with hospitalization and of long COVID-19. Nt-proBNP > 125 pg/mL in hypertensive patients, even without underlying CHF, was associated with various forms of COVID-19, including long COVID-19. RAAS inhibitors and dual antihypertensive combinations in this population reduced the risk of COVID-19, COVID-19 pneumonia with hospitalization, and long COVID-19 by an average of 30%–50%. In hypertensive patients with type 2 diabetes, the use of sulfonylurea and/or insulin therapy was associated a 73.6% increase in the risk of COVID-19, whereas the risks of COVID-19 pneumonia with hospitalization and of long COVID-19 increased by more than 4- and 3-fold, respectively. Pulse pressure and abnormal SBP and DBP circadian patterns were associated with higher HRs for both acute and chronic forms of long COVID-19. COVID-19 pneumonia with hospitalization and long COVID-19 has been shown to be associated with elevated HRs for the involvement of all target organs in hypertensive patients compared to those who had uncomplicated COVID-19.
About the authors
N. M. Syuzeva
E.A. Vagner Perm State Medical University
Email: nakoziolova@mail.ru
ORCID iD: 0000-0001-8754-2950
Assistant of the Department of Propaedeutics of Internal Diseases №2
Russian Federation, Perm
N. A. Koziolova
E.A. Vagner Perm State Medical University
Author for correspondence.
Email: nakoziolova@mail.ru
ORCID iD: 0000-0001-7003-5186
DSc (Medicine), Professor, Head of the Department of Propaedeutics of Internal Diseases № 2
Russian Federation, PermA. I. Chernyavina
E.A. Vagner Perm State Medical University
Email: nakoziolova@mail.ru
ORCID iD: 0000-0002-0051-6694
DSc (Medicine), Associate Professor of the Department of Propaedeutics of Internal Diseases №2
Russian Federation, PermO. V. Masalkina
E.A. Vagner Perm State Medical University
Email: nakoziolova@mail.ru
ORCID iD: 0009-0006-3364-0591
PhD (Medicine), Associate Professor of the Department of Propaedeutics of Internal Diseases №2
Russian Federation, PermReferences
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