Angiotensin II Receptor Blockers Group Research Articles

Effect of angiotensin-converting enzyme inhibitors versus that of angiotensin receptor blockers on survival in patients undergoing hemodialysis: a nationwide observational cohort study

Background This study aimed to evaluate the patient survival rates based on the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in a large cohort of patients undergoing maintenance hemodialysis (HD). Methods Data from a national HD quality assessment program were used in this retrospective study. The patients were classified into four groups based on the use of renin-angiotensin system blockers (RASBs) as follows: No group, patients without a prescription of any anti-hypertensive drugs including RASBs; Other group, patients with a prescription of anti-hypertensive drugs excluding RASBs; ACEI group, patients with a prescription of an ACEI; and ARB group, patients with a prescription of an ARB. Results The 5-year survival rates in the no, other, ACEI, and ARB groups were 68.6%, 67.8%, 70.6%, and 69.2%, respectively. The ACEI group had the best patient survival trend among the four groups. In multivariable Cox regression analyses, no differences were observed between the ACEI and ARB groups. Among young patients and patients without diabetes or heart disease, the ACEI group had the best patient survival among the four groups. However, among patients with DM or heart disease, the ARB group had the best patient survival. Conclusions Our study found that patients receiving ACEI and ARB had comparable survival. However, patients receiving ARB had better survival in the subgroups of patients with DM or heart disease, and patients receiving ACEI had better survival in the subgroup of young patients or patients without diabetes or heart disease.

Investigation of the efficacy of beta-blockers and reninangiotensin-aldosterone system inhibitors in chronic heart failure with preserved ejection fraction

Purpose: To investigate the clinical effectiveness of beta-blockers (BBs) and renin-angiotensinaldosterone system (RAAS) inhibitors in chronic heart failure with preserved ejection fraction (HFpEF).
 Methods: 100 patients with HFpEF admitted to The Third Affiliated Hospital of Qiqihar Medical University, China, between April and June 2023 were stratified into five groups. Beta-blocker (BB) group received bisoprolol, angiotensin-converting enzyme inhibitor (ACEI) group received benazepril hydrochloride, angiotensin II receptor blocker (ARB) group received candesartan, angiotensin receptor neprilysin inhibitor (ARNI) group received sacubitril valsartan, and mineralocorticoid receptor antagonist (MRA) group received spironolactone. Differences in clinical effectiveness, six-minute walking distance (6MWD), cardiac functionality, quality of life, and survival rate were compared among the groups.
 Results: Beta-blocker group showed the highest efficacy. After treatment, all groups except MRA showed significant improvement in 6MWD. Also, ACEI, ARB, and ARNI groups exhibited significantly longer 6 MWD than MRA group (p < 0.05). Left ventricular ejection fraction levels showed significant improvement in the ACEI, ARNI, and MRA groups (p < 0.05), while pulmonary artery pressure (PAP) decreased in the BB, ACEI, ARNI, and MRA groups (p < 0.05). After treatment, the Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores of BB, ACEI, ARB, and ARNI groups were significantly lower than before treatment (p < 0.05). All five groups significantly exhibited decline in NTproBNP levels after treatment (p < 0.05). However, at 18-month follow-up, there was no significant difference in survival rates among the groups (p > 0.05).
 Conclusion: Beta-blockers (BBs) and RAAS inhibitors show promising activity in HFpEF, bisoprolol enhances cardiac function, benazepril improves symptoms, candesartan aids exercise and sacubitril valsartan elevates cardiac class. However, none of these drugs significantly improves clinical outcomes.

Angiotensin II Receptor Blockers Cause Changes in Prostate-specific Antigen Levels: A Retrospective Cohort Study.

We previously reported a decrease in prostate-specific antigen (PSA) levels in patients with castration-resistant prostate cancer treated with angiotensin II receptor blockers (ARBs). However, no studies have reported the effect of ARBs on PSA variability in patients without a history of prostate cancer. Therefore, we conducted a population-based, retrospective study to determine whether ARBs have an inhibitory effect on elevated PSA levels in Japanese patients without a history of prostate cancer. This study was conducted using a large-scale Japanese claim database, including male patients aged ≥60 years who had two or more PSA measurements with an interval between measurements of 3 months to 2 years between April 2008 and June 2019. Patients who had been prescribed ARBs were grouped into the ARB group, and those who were prescribed antihypertensive drugs other than ARBs were grouped into the non-ARB group. We compared the proportions of patients with second PSA levels greater than the first. The numbers of eligible patients in the ARB and non-ARB groups were 777 and 527, respectively. Multivariate logistic regression analysis revealed that the proportion of patients with elevated PSA levels was significantly lower in the ARB group than in the non-ARB group (adjusted odds ratio=0.80, 95% confidence interval=0.64-0.99, p=0.047). ARBs may suppress elevated PSA levels in patients without a history of prostate cancer. This contributes to the prevention of prostate cancer.

Comparing clinical outcomes of ARB and ACEi in patients hospitalized for acute COVID-19

Continued receipt of Renin–Angiotensin–Aldosterone inhibitors in patients with COVID-19 has shown potential in producing better clinical outcomes. However, superiority between ACEi (angiotensin-converting enzyme inhibitors) and ARB (angiotensin II receptor blockers) regarding clinical outcomes in this setting remains unknown. We retrospectively collected data on patients hospitalized for acute COVID-19 using the nationwide administrative database (Diagnosis and Procedure Combinations, DPC). The DPC data covered around 25% of all acute care hospitals in Japan. Patient outcomes, with focus on inpatient mortality, were compared between patients previously prescribed ACEi and those prescribed ARB. Comparisons based on crude, multivariate and propensity-score adjusted analysis were conducted. We examined a total of 7613 patients (ARB group, 6903; ACEi group 710). The ARB group showed lower crude in-hospital mortality, compared to the ACEi group (5% vs 8%; odds ratio, 0.65; 95% CI 0.48–0.87), however not in the multivariate-adjusted model (odds ratio, 0.95; 95% CI 0.69–1.3) or propensity-score adjusted models (odds ratio, 0.86; 95% CI 0.63–1.2). ARB shows potential in reducing hospital stay duration over ACEi in patients admitted for COVID-19, but does not significantly reduce in-hospital mortality. Further prospective studies are needed to draw a definitive conclusion, but continuation of either of these medications is warranted to improve clinical outcomes.

PS-C26-8: UNIQUE PROPERTIES OF DEPRESSOR, RENAL, AND ALDOSTERONE RESPONSES TO ALISKIREN THERAPY IN HYPERTENSIVE PATIENTS WITH NEPHROPATHY

Objective: Blood pressure (BP) control using renin-angiotensin system (RAS) inhibitor as a first choice is recommended in hypertension accompanied by chronic kidney disease (CKD), and RAS localized in the kidney is known to exist independent of circulating RAS. Aliskiren, direct renin inhibitor (DRI), is most excellent in kidney tissue migration among RAS inhibitors despite it has been reported to cause aldosterone breakthrough like angiotensin II receptor blocker (ARB) in essential hypertension. Therefore, DRI-induced antihypertensive, renoprotective and aldosterone-suppressing effects were investigated as compared to those of ARB in hypertensive CKD patients. Design and method: 168 hypertensive patients with CKD (stage G1–4) were employed in this study. Home BP in the morning, estimated glomerular filtration rate (eGFR), urinary protein/creatinine ratio (UPCR), urinary liver-type fatty-acid-binding protein (U-LFABP) as an indicator of tubular dysfunction, plasma and urinary aldosterone concentration (PAC and UAC) were measured before and 0.5 to 5 years after administration of ARB or DRI and assessed retrospectively. Aldosterone breakthrough was defined as any increase in PAC from the baseline level following treatment with a RAS inhibitor. Results: In ARB-treated group, BP and UPCR decreased significantly at 6 months, but sufficient declines were not observed 1st year onward. In DRI-treated group, a significant reduction in BP was sustained until 3 years and BP unchanged decreasing tendency even 4 years later, meanwhile UPCR decreased significantly for 2 years and was below the pretreatment value 3 years after. ARB raised BP and UPCR again in patients with CKD G3–4 prior to those with CKD G1–2, however, DRI expressed no difference between stages. Although PAC diminished up to 6 months in ARB group and 1 year in DRI group, it turned up 1 year and 2 years after, respectively. PAC-ascensive rate and maximum elevation in PAC were higher and greater in ARB group than in DRI group (48.7 vs 22.6%, 56.1 vs 29.3pg/ml). All significant differences in rising PAC cases disappeared by 5 years, whereas in non-rising PAC cases, only DRI reduced U-LFABP without deterioration in eGFR and UAC further lowered while PAC was maintained. Conclusions: In comparison with ARB, aliskiren prolongs hypotensive and proteinuria-lowering effects with retained eGFR regardless of CKD severity possibly via improvement of tubular disorders and less PAC reascent in hypertensive nephropathy. Aliskiren given to CKD patients might elicit mild and delayed aldosterone breakthrough rather than ARB due to a direct action against aldosterone derived from the kidney.

Association of RASis and HMG-CoA reductase inhibitors with clinical manifestations in coronavirus disease 2019 patients: Results from the Khorshid Coronavirus Disease Cohort Study.

Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEinhs) may deteriorate or improve the clinical manifestations in severe acute respiratory syndrome coronavirus 2 infection. A comparative, cross-sectional study was conducted to evaluate the association of ARBs/ACEinhs and hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (HMGRis) with clinical outcomes in coronavirus disease 2019 (COVID-19). From April 4 to June 2, 2020, 659 patients were categorized according to whether they were taking ARB, ACEinh, or HMGRi drugs or none of them. Demographic variables, clinical and laboratory tests, chest computed tomography findings, and intensive care unit-related data were analyzed and compared between the groups. The ARB, ACEinh, and HMGRi groups significantly had lower heart rate (P < 0.05). Furthermore, a lower percent of O2 saturation (89.34 ± 7.17% vs. 84.25 ± 7.00%; P = 0.04) was observed in the ACEis group than non-ACEinhs. Mortality rate and the number of intubated patients were lower in patients taking ARBs, ACEinhs, and HMGRis, although these differences failed to reach statistical significance. Our findings present clinical data on the association between ARBs, ACEinhs, and HMGRis and outcomes in hospitalized, hypertensive COVID-19 patients, implying that ARBs/ACEinhs are not associated with the severity or mortality of COVID-19 in such patients.

Assessment of the comparative efficiency of treatment with angiotensin-converting enzyme inhibitor and angiotensin II receptor blockers in patients who are old and senile with stage 3, grade 2–3 hypertension

BACKGROUND: The problem of sex differences in the treatment of hypertension is currently relevant because of the different disease course in men and women. Particular attention should be paid to the age aspect of the problem, since the clinical and hemodynamic parameters of arterial hypertension (AH) in patients who are old and senile have their specifics.&#x0D; AIM: This study aimed to assess the sex aspect of the comparative efficiency of the angiotensin-converting enzyme inhibitor (ACEI) perindopril and angiotensin II receptor blockers (ARB) losap, losartan, and lorista patients who are old and senile with stage 3, grade 23 hypertension.&#x0D; MATERIALS AND METHODS: A total of 185 patients with stage 3, grade 23 hypertension were examined. Two randomized groups of patients were formed depending on the therapy received. Group 1 received ACEI (perindopril), and group 2 patients received ARBs (lozap, losartan, and lorista). Patients kept a diary in which the amount and types of pain, dizziness, and heart palpitations were noted. In addition, the Health, Activity, and Mood Questionnaire and daily self-monitoring of blood pressure every 3 h during the hospital stay and for 23 months after discharge were used. The obtained information was processed using variation statistics and the difference method.&#x0D; RESULTS: The analysis of the comparative efficiency of ARBs and ACEIs revealed significant sex differences in hemodynamic parameters. The ARB group of drugs showed a more pronounced decrease in 24-h blood pressure monitoring (24-h BPM) and the number of pain episodes in the heart area in women compared with men. When using ACEI, no sex difference in the decrease in 24-h BPM indicators was observed. However, significant differences in clinical symptoms of both men and women were found. In women, compared with men, ACEIs had a greater positive effect on the subjective state in points (according to the Health, Activity, and Mood Questionnaire).&#x0D; CONCLUSIONS: The results suggest that ARB therapy for women who are old and senile with stage 3, grade 23 hypertension. For men of a similar age with this pathology, therapy with both ACEIs and ARBs may be recommended.

Actual impact of angiotensin II receptor blocker or calcium channel blocker monotherapy on renal function in real-world patients.

This observational retrospective cohort study investigates the effect of antihypertensive therapy with angiotensin II receptor blockers (ARBs) or dihydropyridine calcium channel blockers (dCCBs) monotherapy on renal function using longitudinal real-world health data of a drug-naive, hypertensive population without kidney disease. Using propensity score matching, we selected untreated hypertensive participants ( n = 10 151) and dCCB ( n = 5078) or ARB ( n = 5073) new-users based on annual health check-ups and claims between 2008 and 2020. Participants were divided by the first prescribed drug. The mean age was 51 years, 79% were men and the mean estimated glomerular filtration rate (eGFR) was 78 ml/min per 1.73 m 2 . Blood pressure rapidly decreased by approximately 10% in both treatment groups. At the 1-year visit, eGFR levels decreased in the ARB group by nearly 2% but increased in the dCCB group by less than 1%. However, no significant difference was apparent in the annual eGFR change after the 1-year visit. The risk for composite kidney outcome (new-onset proteinuria or eGFR decline ≥30%) was lowest in the ARB group owing to their robust effect on preventing proteinuria: hazard ratio (95% confidence interval) for proteinuria was 0.91 (0.78-1.05) for the dCCB group and 0.54 (0.44-0.65) for the ARB group, compared with that for the untreated group after ending follow-up at the last visit before changing antihypertensive treatment. From the present findings based on the real-world data, ARBs can be recommended for kidney protection even in a primary care setting. Meanwhile, dCCB treatment initially increases eGFR with no adverse effects on proteinuria.

Real-world experience of angiotensin receptor neprilysin inhibitor on the glucose-lowering effect

We investigated the effect of angiotensin receptor neprilysin inhibitor (ARNI) on glycemic control in Korean patients. This retrospective cohort study was conducted at a single tertiary hospital. We compared the HbA1c level reduction between the ARNI and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in chronic heart failure patients with diabetes. We also examined whether the target HbA1c level was reached and the time to start insulin between the two groups. Over the study period, ARNI did not significantly lower the HbA1c level after adjusting confounding factors compared to ACEIs or ARBs. However, as a result of a simple comparison using Mann–Whitney U test, ARNI group showed significant decrease in HbA1c at 6, 12, and 24 months compared to ACEIs or ARBs group (p = 0.003, 0.009, and 0.026, respectively). The initiation of insulin was delayed in the ARNI group, but this difference was not significant based on the result of hazard ratio, but cumulative incidence was significantly lower in the ARNI group. In the real world, the blood glucose-control effects of ARNI were not superior to those of ACEIs or ARBs. However, long-term studies are needed as ARNI use increases to obtain more statistically significant results.

Efficacy and safety of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers in diabetic nephropathy: a systematic review and meta-analysis.

Diabetic nephropathy (DN) is one of the most typical microangiopathies caused by diabetes. It often leads enormous physiological and psychological burdens for patients and seriously affects their quality of life. Therefore, effective combination therapy is necessary for these patients. In this study, we performed a meta-analysis to systematically evaluate and discuss the efficacy and safety of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in the treatment of DN. The PubMed, Embase, Web of Science, and Medline databases were selected as the sources of the literature search, and the search was limited to studies published in English. Studies related to ACEIs and ARBs in the treatment of DN published from January 2001 to January 2021 were included in this analysis. Meta-analysis was performed to calculate the reinforcement mean difference. In total, eight articles involving 1,893 cases with DN were included in this study. The results of this systematic review and meta-analysis showed that for patients with diabetic nephropathy，there were significant differences in 24-hour proteinuria [mean difference (MD) =-78.46, 95% confidence interval (95% CI): -80.25 to -76.66, P<0.00001], systolic blood pressure (MD =-9.11, 95% CI: -13.44 to -4.78, P<0.0001), and diastolic blood pressure (MD =-3.39, 95% CI: -5.68 to -1.11, P=0.004) between the combined ACEI and ARB group and the single ACEI or ARB group (P<0.05). In terms of safety, in addition to the significant difference in serum potassium (MD =0.1, 95% CI: 0.05 to 0.15, P=0.0001) between the combined ACEI and ARB group and the single drug group (P<0.1), there were no notable differences in serum creatinine (MD =0.66, 95% CI: -8.0 to 2.12, P=0.37), creatinine clearance (MD =-0.25, 95% CI: -0.62, 0.11, P=0.17), or the incidence of adverse reactions [odds ratio (OR) =1.19, 95% CI: 0.81 to 1.75, P=0.37]. A total of eight studies were included in this meta-analysis. The results showed that for patients with diabetic nephropathy, the combination of ACEI and ARB was more effective than ACEI or ARB alone, and also had higher safety.

The use of angiotensin II receptor blocker is associated with greater recovery of cardiac function than angiotensin-converting enzyme inhibitor in dilated cardiomyopathy.

AimsAngiotensin‐converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) have been shown to be associated with recovery of cardiac function in patients with dilated cardiomyopathy (DCM). The aim of this study was to assess comparative effectiveness of ACEis vs. ARBs on recovery of left ventricular ejection fraction (LVEF) among patients with DCM.Methods and resultsWe analysed the clinical personal records of DCM, a national database of the Japanese Ministry of Health, Labour and Welfare, from 2003 to 2014. Patients with LVEF < 40% and on either ACEis or ARBs were included. Eligible patients were divided into two groups according to the use of ACEis or ARBs. A one‐to‐one propensity case‐matched analysis was used. The primary outcome was defined as LVEF ≥ 40% at 3 years of follow‐up. Out of 4618 eligible patients, 2238 patients received ACEis and 2380 patients received ARBs. Propensity score matching yielded 1341 pairs. Mean age was 56.0 years, 2041 (76.1%) were male, median duration of heart failure was 1 year, and mean LVEF was 27.6%. The primary outcome was observed more frequently in ARB group than in ACEi group (59.8% vs. 54.1%; odds ratio 1.26; 95% confidence interval 1.08–1.47; P = 0.003). The per‐protocol analysis showed similar results (62.0% vs. 54.0%; odds ratio 1.39; 95% confidence interval 1.17–1.66; P < 0.001). The change in LVEF from baseline to 3 years of follow‐up was greater in ARB group than in ACEi group (15.8 ± 0.4% vs. 14.0 ± 0.4%, P = 0.003). The subgroup analysis showed that this effect was observed independently of systolic blood pressure, heart rate, LVEF, chronic kidney disease, and concomitant use of beta‐blockers and mineralocorticoid receptor antagonists.ConclusionsThe use of ARBs was associated with LVEF recovery more frequently than ACEis among patients with DCM and reduced LVEF.

Angiotensin II receptor blockers in modulation of transforming growth factor-beta effects on mitral valve myxomatous degeneration

Abstract Growing evidence supports role transforming growth factor-β (TGF-β) as a mediator of the myxomatous changes in the mitral valve prolapse. Recently, angiotensin II receptor blockers (ARB) emerged as a potentially effective inhibitor of TGF-β signaling. Treatment of valvular interstitial cells (VICs) with ARB resulted in effective inhibition of TGF-β-induced ECM expression. Our aim was to evaluate the effect of preoperative ARB therapy in modulation of transforming growth factor-β effects on mitral valve myxomatous degeneration. Methods A total of 233 asymptomatic patients (mean age: 53.8±12.9) undergoing mitral valve surgery for severe mitral regurgitation due to mitral valve prolapse were enrolled in our retrospective, non-randomized, single-center study. Resected abnormal segments of the mitral leaflets (segment of the posterior leaflet or the entire valve) were obtained during mitral valve repair/replacement surgery and examined by experienced pathologists. Immunohistochemical characterization of mitral valve sections was performed with the primary antibodies. Quantification was performed by counting TGF-β1 and TGF-β2 positive cells within 10 random high-power fields divided by the total number of cells in specimens. Quantification of immunohistochemical staining for collagen III was performed by measurement of staining area divided by the total area of the specimens. Results Two hundred thirty-three consecutive patients (66% males, mean age 53.8±12.9 years, range 19–80) with severe MR were enrolled in the study. According to the case reports, 43 patients (18.5%) received losartan or telmisartan before surgery and were included in study group. 190 patients (81.5%) did not receive any ARB and were enrolled in the control group. Histological examination showed disorganized collagen and elastin fibers, expansion of the spongiosa layer in both groups. However, MV specimens' immunohistochemistry revealed a lower expression of type III collagen in ARB group as compared to controls (31.3% ± 10.8% vs. 43.8% ± 15.3%; p&amp;lt;0.001). MV leaflets in control group showed the increased VICs density (95.3±39.9 vs. 70.0±21.7/high-power field, p=0.0001). TGF-β1 and TGF-β2 positive cells were significantly rare in the ARB than in control MV specimens (18% vs. 33%, p=0.012 and 16% vs. 38%, p&amp;lt;0.ehab724.15541, respectively). Expression of type III collagen and TGF-β2 positive cells count showed a weak, but significant correlation (r=0.28; p=0.ehab724.155414). The multivariate Cox analysis showed a decrease in the relative risk of valvular thickening (myxomatous degeneration) with ARB therapy (0.85; 95% CI: 0.61 – 1.17; p=0.01). Conclusions We indicate a beneficial effect of ARB treatment through the inhibition of TGF-β pathway on valvular myxomatous degeneration in patients with MVP. Modulation of the progression of MVP with such therapeutic agents may have great clinical significance. Funding Acknowledgement Type of funding sources: None.

Effect of Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor on Kidney Function and Blood Potassium Level in Indonesian Type 2 Diabetes Mellitus with Hypertension: A Three-Month Cohort Study.

PurposeNational formulary restrictions in Indonesia (2019) require estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 to be able to prescribe telmisartan and valsartan and ACE-I intolerance to be able to prescribe irbesartan and candesartan. These restrictions are based on economic considerations and differ from American Diabetes Association (ADA) (2020) guidelines which allow equal use of angiotensin II receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACE-I) without restriction. Since there is a need to evaluate the different effects of ACE-I and ARB in the Indonesian hypertensive type 2 diabetes mellitus (T2DM) population, we compare their effects on urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and blood potassium level.Patients and MethodsA prospective cohort study at RSUPN Dr. Cipto Mangunkusumo Hospital was conducted in 123 T2DM patients. We followed the study subjects prospectively for three months using a validated questionnaire, health record, and laboratory data.ResultsAfter 3 months of observation, there were no significant changes, except increased BMI values (p = 0.046) in the ACE-I group, and decreased LDL value (p = 0.016) and HDL value (p = 0.004) in the ARB group. Multivariate analysis showed that the consumption of ACE-I or ARB was not associated with a decrease/constant of UACR or increase potassium level, even after adjusting by confounding variables. Interestingly, we found ARB was more likely to increase eGFR, but the significance was lost once the duration of ACE-I/ARB use was entered into the model. In addition, BMI >25 kg/m2 was a significant factor associated with decreased/constant UACR, maleness was significant for increased eGFR, and declining systolic blood pressure for increase in potassium level.ConclusionACE-I and ARB have a similar effect on UACR and blood potassium level, but ARB slightly increased eGFR compared to ACE-I within three months of consumption.

Effect of ACEI and ARB treatment on nitric oxide-dependent endothelial function.

Background: Angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are widely used as a first-line therapy for the treatment of cardiovascular disease. Here, ACEI modulate the bradykinin receptor (BDKRB1 and BDKRB2) system and NO-dependent endothelial function, thus determining cardiovascular health and regenerative arteriogenesis. The current study aims at evaluating nitric oxide-dependent endothelial function, and gene expression of bradykinin receptors in peripheral blood mononuclear cells (PBMC) from patients with ACEI or ARB treatment. Patients and methods: The WalkByLab has been established to screen cardiovascular patients for peripheral artery disease and coronary artery disease. In total 177 patients from WalkByLab with heterogenous disease and risk status were randomly selected, divided according to their medication history into the following groups: 1. ACEI group, 2. ARB group or 3. non-ACE/ARB group. Total plasma nitrite/nitrate (NO) levels were measured, endothelial function was evaluated by assessing flow meditated dilation (FMD). PBMC were isolated from peripheral whole blood, and gene expression (qRT-PCR) of bradykinin receptors and angiotensin converting enzyme were assessed. Results: Plasma total NO concentration in the ACEI group (24.66±16.28, µmol/l) was increased as compared to the ARB group (18.57±11.58, µmol/l, P=0.0046) and non-ACE/ARB group (16.83±8.64, µmol/l, P=0.0127) in patients between 40 to 90 years of age. However, FMD values (%) in the ACEI group (7.07±2.40, %) were similar as compared to the ARB (6.35±2.13, %) and non-ACE/ARB group (6.51±2.15, %), but significantly negatively correlated with age. Interestingly, BDKRB1 mRNA level was significantly higher and BDKRB2 mRNA level lower in the ACEI group (BDKRB1 3.88-fold±1.05, BDKRB2 0.22-fold±0.04) as compared to the non-ACE/ARB group (BDKRB1 1.00-fold±0.39, P<0.0001, BDKRB2 1.00-fold±0.45, P=0.0136). Conclusions: ACEI treatment enhances total nitrite/nitrate concentration, furthermore, upregulates BDKRB1 in PBMC, but downregulates BDKRB2 mRNA expression. FMD is a strong determinant of vascular aging and is sensitive to underlying heterogenous cardiovascular diseases.

Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia.

IntroductionDespite considerable scientific debate, there have been no prospective clinical studies on the effects of angiotensin II receptor blockers (ARBs) on the course of COVID-19 infection. Losartan is the ARB that was chosen to be tested in this study.MethodsPatients with COVID-19 and mild hypoxia (receipt of ≤ 3 L/min O2 by nasal cannula) admitted to three hospitals were randomized in a 1:1 ratio within 72 h of SARS-CoV-2 nucleic acid testing confirmation to prospectively receive standard of care (SOC) alone or SOC plus losartan 12.5 mg orally every 12 h for 10 days or until hospital discharge, with the option to titrate upward dependent on blood pressure tolerability. Primary composite endpoint was receipt of mechanical ventilation or death before receiving ventilation. Subjects were followed until discharge to home or until an endpoint was met in the hospital.ResultsSixteen subjects received an ARB plus SOC and 15 subjects received SOC alone. The median age was 53 years for both groups. Median time from hospital admission to study enrollment was 2 days (range 1–6) for the ARB group and 2 days (range 1–4) for the SOC group. Mean Charlson comorbidity index was 2 for both groups. One subject in each group achieved the composite endpoint.ConclusionThis small prospective randomized open-label study showed no clinically significant impacts of ARB therapy in mildly hypoxemic patients hospitalized with COVID-19 early in the pandemic. A larger prospective randomized placebo-controlled trial would be needed to confirm these findings or capture less pronounced effects and probably should focus on outpatients earlier in disease course.Trial Registrationclinicaltrials.gov; March 27, 2020; NCT04340557.

Comparison Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers for Incidence of Lung Cancer: A Retrospective Study.

Introduction: Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blockers (ARBs) are taken as the first treatment option for hypertensive patients. The various global trials have suggested that ACEIs and ARBs may increase risk of lung cancer; however, the results are contradictory and there is no local study available. This study is conducted to compare the incidence of lung cancers in patients on ACEIs and ARBs.Methods: This retrospective study, conducted in a major cardiology unit of a tertiary care hospital in Pakistan, included patients diagnosed with hypertension, between 2005 and 2010, who were prescribed either ACEIs or ARBs. During the period of 2005 to 2010, 47,823 naïve hypertensive patients were reported in the outpatient department of the cardiology unit. Of which, 22,241 were prescribed ACEI and 25,582 were prescribed ARBs. After sorting patient data based on our inclusion criteria, n = 14,891 participants were included in the ACEI group and n = 19,112 participants were included in the ARB group.Results: The incidence of lung cancer in the ACEI and ARB group was n = 165 and n = 160, respectively. In this study, the overall incidence rates of lung cancer in the ACEI and ARB cohorts were 12.2 and 16.6 per 10,000 person-years, respectively. The hazard ratio was 1.32 (95% confidence interval: 1.06-1.64; p-value: 0.01).Conclusion: In this study, the incidence of lung cancer was relatively more among people using ACEIs than ARBs. Hence, patients undergoing long-term treatment with ACEIs need regular follow-up and proper scanning to avoid grave complications.

Effects of angiotensin II receptor blocker usage on viral load, antibody dynamics, and transcriptional characteristics among COVID-19 patients with hypertension.

Epidemiological evidence suggests that patients with hypertension infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at increased risk of acute lung injury. However, it is still not clear whether this increased risk is related to the usage of renin-angiotensin system (RAS) blockers. We collected medical records of coronavirus disease 2019 (COVID-19) patients from the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), and evaluated the potential impact of an angiotensin II receptor blocker (ARB) on the clinical outcomes of COVID-19 patients with hypertension. A total of 30 hypertensive COVID-19 patients were enrolled, of which 17 were classified as non-ARB group and the remaining 13 as ARB group based on the antihypertensive therapies they received. Compared with the non-ARB group, patients in the ARB group had a lower proportion of severe cases and intensive care unit (ICU) admission as well as shortened length of hospital stay, and manifested favorable results in most of the laboratory testing. Viral loads in the ARB group were lower than those in the non-ARB group throughout the disease course. No significant difference in the time of seroconversion or antibody levels was observed between the two groups. The median levels of soluble angiotensin-converting enzyme 2 (sACE2) in serum and urine samples were similar in both groups, and there were no significant correlations between serum sACE2 and biomarkers of disease severity. Transcriptional analysis showed 125 differentially expressed genes which mainly were enriched in oxygen transport, bicarbonate transport, and blood coagulation. Our results suggest that ARB usage is not associated with aggravation of COVID-19. These findings support the maintenance of ARB treatment in hypertensive patients diagnosed with COVID-19.

Sphingosine-1-phosphate: A mediator of the ARB-MI paradox?

BackgroundAngiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are important in the prevention of cardiovascular disease. The “ARB-MI paradox” implies that no risk reduction of myocardial infarction (MI) was found in ARB-treated patients despite target blood pressure control. Sphingosine-1-phosphate (S1P) is a cardioprotective sphingolipid which is released by platelets during activation. In this study we aimed to investigate differences of S1P homeostasis mediated by bradykinin and sphingosine kinases during ACEI/ARB treatment. MethodsIn this hypothesis generating pilot study, we investigated S1P plasma concentrations in 34 patients before and 3 months after ARB/ACEI medication. S1P levels were measured via liquid chromatography–tandem mass spectrometry. Bradykinin levels were measured by an enzyme-linked immunosorbent assay. ResultsPatient characteristics were not different between the ACEI and ARB group. Baseline S1P plasma concentrations were similar before ARB and ACEI treatment (7.4 SD 1.9 pmol vs. 7.8 SD 2.7 pmol, p = 0.54). After 3 months, S1P plasma levels were significantly higher in ACEI (9.3 SD 2.2 pmol) as compared to ARB treated patients (7.4 SD 2.4 pmol, p = 0.001). Pearson correlation showed no significant association between bradykinin and S1P levels before (r = −0.219; 95% CI [−0.54–0.15]; p = 0.245) or after three months of treatment with ACEI or ARB (r = −0.015; 95% CI [−0.48–0.45]; p = 0.95). ConclusionsS1P plasma concentrations are higher in ACE treated patients as compared to ARB treatment. This leads to the hypothesis, that differences in S1P metabolism might partially explain the ARB-MI paradox. This needs to be tested in clinical trials.

Effects of angiotensin II receptor blockers on serum levels of epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids in patients admitted to a cardiovascular center

PurposeSeveral clinical studies have demonstrated that angiotensin-converting enzyme inhibitors, but not angiotensin II receptor blockers (ARBs), reduce the risk of non-fatal myocardial infarction and cardiovascular mortality. We found that ARBs inhibited the activity of various cytochrome enzymes in arachidonic acid metabolism, resulting in decreased in vitro production of epoxyeicosatrienoic acids (EETs), which exhibit vasodilation and anti-inflammatory effects, and their subsequent metabolites, dihydroxyeicosatrienoic acids (DHETs). The present study examined the effects of ARBs on serum levels of EETs and DHETs in patients admitted to a cardiovascular center.MethodsA total of 223 patients were enrolled, of which 107 were exposed to ARBs in this study. ARB-free individuals were defined as the control group (n = 116). Serum levels of EETs and DHETs were measured by liquid chromatography–tandem mass spectrometry. Multiple linear regression analyses were carried out to identify covariates for total serum levels of EETs and DHETs.ResultsA significant negative association was observed between ARB use and serum EET and DHET levels (p = 0.034), whereas a significant positive association was observed between the estimated glomerular filtration rate (eGFR) and serum EET and DHET levels (p = 0.007). The median serum total EET and DHET level in the ARB group tended to become lower than that in the control group, although the difference was not significant.ConclusionARB use and eGFR were significantly associated with total serum levels of EETs and DHETs. Our results suggest that ARBs could affect the concentration of EETs in vivo.

Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin II Receptor Blockers

Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin II Receptor Blockers