Effects Of Angiotensin Receptor Blockers Research Articles

Angiotensin receptor blockers and mineralocorticoid receptor antagonists therapy reaches better central haemodynamic parameters and avoid the episodes of atrial fibrillation

Abstract Introduction The goal of antihypertensive therapy is to prevent complications. The harmful effects of aldosterone are innumerable: induced cardiac/renal fibrosis, sodium and water retention, inflammation, oxidative stress, among others, that are involved in arterial/myocardium stiffness, remodelling, heart failure and new-onset atrial fibrillation (AF). Thiazide diuretics can activate the neurohormonal system, impair glucose metabolism, increase new-onset diabetes, and are potentially arrhythmogenic. Protective effect of Angiotensin Receptor Blockers (ARB) on major cardiovascular events might be partly independent of the degree of blood pressure reduction. Mineralocorticoid Receptor Antagonists (MRA) therapy reduce arterial stiffness, plasma volume, collagen/elastin ratio and vascular/myocardial fibrosis. Purpose The objective was to assess the levels reached in central haemodynamic parameters (CHP) and the presence of episodes of AF during ARB+hydrochlorothiazide (Hct) versus ARB+MRA therapy in hypertensive patients with normal kidney function. Methods For this cross-sectional retrospective study, data were entered from 108 hypertensive patients, female 62 (ARBs+MRA/ARB+Hctz average age 67/71), male 46 (average age ARB+MRA/ARB+Hctz 67/71), both p=ns). The average doses of Hct among female/male were 16/19 mg and the duration of the ARB+Hctz therapy were 37/47 months, while the ARB+MRA therapy were 36/49 months. 24-hours Holter monitoring was used in all patients. The group ARB+MRA before therapy had a history of AF episodes. The CHP (Central Aortic Pressure, End-Systolic Pressure, Mean Arterial Pressure, Pulse Pressure, Augmentation Pressure, Augmentation Index) were registered by the SphygmoCor System PVX (AtCor-Medical, Australia), according system's standard methods. Also was measured the difference between the normal levels, and the observed values of Augmentation Index (Diff-AIx) according age. Results The results of CHP, Diff-AIx, systolic and diastolic blood pressure during association of ARB+MRA therapy compared to ARB+Hct, both genders, showed the lowest values with a highly statistically significant difference. The episodes of AF during 24-hours Holter monitoring in the group ARB+Hct therapy in female/male were 55%/71%; instead, in the ARB+MRA treated they were not found. Conclusions These findings suggest that the dual block with ARB+MRA therapy giving better CHP, reducing the stress to arterial-ventricular coupling, it could be helpful to prevent, the harmful effects of angiotensin-aldosterone system such as the development of heart failure and atrial fibrillation. Funding Acknowledgement Type of funding source: None

Association of renin-angiotensin-aldosterone system inhibitors with mortality and testing positive of COVID-19: Meta-analysis.

Some have hypothesized that the use of angiotensin‐converting enzyme inhibitors (ACEI) and angiotensin‐receptor blockers (ARB) may modify susceptibility to coronavirus disease‐2019 (COVID‐19) in humans. Thus, we conducted two meta‐analyses to investigate the effect of ACEI and ARB on mortality and susceptibility to COVID‐19. Pubmed and EMBASE were searched through June 2020 to identify clinical trials that investigated the testing positive and in‐hospital mortality rates for COVID‐19 for those who were treated with ACEI and/or ARB and for those who were not treated with ACEI or ARB. The first analysis investigated the testing positive rate of COVID‐19. The second analysis investigated the in‐hospital mortality rate for patients with COVID‐19. Three eligible studies for the first analysis and 14 eligible studies for the second analysis were identified. The first analysis demonstrated that the use of ACEI or ARB did not affect the testing positive rates (odds ratio [OR] [confidence interval [CI]] = 0.96 [0.88–1.04]; p = .69, OR [CI] = 0.99 [0.91–1.08]; p = 0.35, respectively). The second analysis showed that the use of ACEI and/or ARB did not affect in‐hospital mortality (risk ratio [RR] 95% [CI]] = 0.88 [0.64–1.20], p = 0.42). The subgroup analysis by limiting studies of patients with hypertension showed ACEI and/or ARB use was associated with a significant reduction of in‐hospital mortality compared with no ACEI or ARB use (RR [CI] = 0.66 [0.49‐0.89], p = 0.004). Our analysis demonstrated that ACEI and/or ARB use was associated neither with testing positive rates of COVID‐19 nor with mortality of COVID‐19 patients.

Mas Receptor Activation Contributes to the Improvement of Nitric Oxide Bioavailability and Vascular Remodeling During Chronic AT1R (Angiotensin Type-1 Receptor) Blockade in Experimental Hypertension

Angiotensin (1-7) production increases during AT1R (angiotensin type-1 receptor) blockade. The contribution of Ang (1-7) (angiotensin [1-7]) and its receptor (MasR) to the favorable effect of angiotensin receptor blockers on remodeling and function of resistance arteries remains unclear. We sought to determine whether MasR contributes to the improvement of vascular structure and function during chronic AT1R blockade. Spontaneously hypertensive rats were treated with Ang (1-7) or olmesartan ± MasR antagonist A-779, or vehicle, for 14 days. Blood pressure was measured by tail cuff methodology. Mesenteric arteries were dissected and mounted on a pressurized micromyograph to evaluate media-to-lumen ratio (M/L) and endothelial function. Expression of MasR and eNOS (endothelial nitric oxide synthase) was evaluated by immunoblotting, plasma nitrate by colorimetric assay, and reactive oxygen species production by dihydroethidium staining. Independently of blood pressure, olmesartan significantly reduced M/L and improved NO bioavailability, A-779 prevented these effects. Likewise, Ang (1-7) significantly reduced M/L and NO bioavailability. MasR expression was significantly increased by Ang (1-7) as well as by olmesartan, and it was blunted in the presence of A-779. Both Ang (1-7) and olmesartan increased eNOS expression and plasma nitrite which were reduced by A-779. Superoxide generation was attenuated by olmesartan and Ang (1-7) and was blunted in the presence of A-779. These MasR-mediated actions were independent of AT2R activation since olmesartan and Ang (1-7) increased MasR expression and reduced M/L in Ang II (angiotensin II)-infused AT2R knockout mice, independently of blood pressure control. A-779 prevented these effects. Hence, MasR activation may contribute to the favorable effects of AT1R antagonism on NO bioavailability and microvascular remodeling, independently of AT2R activation and blood pressure control.

Irbesartan treatment does not influence plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3‐deoxyglucosone in participants with type 2 diabetes and microalbuminuria: An IRMA2 sub‐study

AimAngiotensin receptor blockers (ARBs) reduce vascular complications in diabetes independently of blood pressure. Experimental studies suggested that ARBs may restore the detoxifying enzyme glyoxalase 1, thereby lowering dicarbonyls such as methylglyoxal. Human data on the effects of ARBs on plasma dicarbonyl levels are lacking. We investigated, in individuals with type 2 diabetes, whether irbesartan lowered plasma levels of the dicarbonyls methylglyoxal, glyoxal, 3‐deoxyglucosone and their derived advanced glycation end products (AGEs), and increased d‐lactate, reflecting greater methylglyoxal flux.MethodsWe analysed a subset of the Irbesartan in Patients with T2D and Microalbuminuria (IRMA2) study. We measured plasma dicarbonyls methylglyoxal, glyoxal and 3‐deoxyglucosone, free AGEs and d‐lactate using ultra‐performance liquid chromatography tandem mass‐spectrometry (UPLC‐MS/MS) in the treatment arm receiving 300 mg irbesartan (n = 121) and a placebo group (n = 101) at baseline and after 1 and 2 years. Effect of treatment was analysed with repeated measurements ANOVA.ResultsThere was a slight, but significant difference in baseline median methylglyoxal levels [placebo 1119 (907–1509) nmol/l vs. irbesartan 300 mg 1053 (820–1427) nmol/l], but no significant changes were observed in any of the plasma dicarbonyls over time in either group and there was no effect of irbesartan treatment on plasma free AGEs or d‐lactate levels at either 1 or 2 years.ConclusionIrbesartan treatment does not change plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3‐deoxyglucosone, free AGEs or d‐lactate in type 2 diabetes. This indicates that increased dicarbonyls in type 2 diabetes are not targetable by ARBs, and other approaches to lower systemic dicarbonyls are needed in type 2 diabetes. (Clinical Trial Registry No: #NCT00317915).

The influence of ACE inhibitors and ARBs on hospital length of stay and survival in people with COVID-19.

During the COVID-19 pandemic the continuation or cessation of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) has been contentious. Mechanisms have been proposed for both beneficial and detrimental effects. Recent studies have focused on mortality with no literature having examined length of hospital stay. The aim of this study was to determine the influence of ACEi and ARBs on COVID-19 mortality and length of hospital stay. COPE (COVID-19 in Older People) is a multicenter observational study including adults of all ages admitted with either laboratory or clinically confirmed COVID-19. Routinely generated hospital data were collected. Primary outcome: mortality; secondary outcomes: Day-7 mortality and length of hospital stay. A mixed-effects multivariable Cox's proportional baseline hazards model and logistic equivalent were used. 1371 patients were included from eleven centres between 27th February to 25th April 2020. Median age was 74years [IQR 61-83]. 28.6% of patients were taking an ACEi or ARB. There was no effect of ACEi or ARB on inpatient mortality (aHR=0.85, 95%CI 0.65-1.11). For those prescribed an ACEi or ARB, hospital stay was significantly reduced (aHR=1.25, 95%CI 1.02-1.54, p=0.03) and in those with hypertension the effect was stronger (aHR=1.39, 95%CI 1.09-1.77, p=0.007). Patients and clinicians can be reassured that prescription of an ACEi or ARB at the time of COVID-19 diagnosis is not harmful. The benefit of prescription of an ACEi or ARB in reducing hospital stay is a new finding.

Therapeutic effects of various renin angiotensin modulators on hyperglycemia-induced cataract formation in Sprague Dawley rats.

Our previous research work reported the beneficial effects of angiotensin receptor blockers (ARBs) for the treatment of diabetes associated cataract which was induced by streptozotocin (STZ). The current study, evaluated the effects of topical administration of various renin angiotensin modulators on STZ-induced cataracts in rats. Single dose of STZ (60 mg/kg, i.p.) was administered in the rats to induce diabetes. Animals were divided into normal and diabetic rats. Normal rats were administered with single dose of sodium citrate buffer (0.1 M, 10ml/kg, i.p.). Diabetic animals were divided into various treatment groups, each group contains six animals and received aliskiren, olmesartan, enalapril, and angiotensin 1-7 at a dose of 0.5% w/v topically on the cornea of the eye for a period of 8 weeks. During experimental protocol morphology of the eyes and lenticular opacity were monitored. Animals were sacrificed after 8 weeks of drug treatment, and various cataractogenic biochemical parameters were assessed. Topical administrations with aliskiren, enalapril, olmesartan, and angiotensin 1-7 showed non-significant alterations in the blood glucose level, but significantly decreased lenticular opacity, restored antioxidant level, restored MDA level and Nitrite content, and decreased the onset of cataract formation. Overall, our findings suggest that topical treatment with renin angiotensin modulators delayed the onset of diabetes-induced cataract formation.

Effects of ACEI and ARB on COVID-19 patients: A meta-analysis.

Background:The clinical use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) in patients with COVID-19 infection remains controversial. Therefore, we performed a meta-analysis on the effects of ACEI/ARB on disease symptoms and laboratory tests in hypertensive patients infected with COVID-19 virus and those who did not use ACEI/ARB.Methods:We systematically searched the relevant literatures from Pubmed, Embase, EuropePMC, CNKI, and other databases during the study period of 31 December 2019 (solstice, 15 March 2020), and analyzed the differences in symptoms and laboratory tests between patients with COVID-19 and hypertension who used ACEI/ARB drugs and those who did not. All statistical analyses were performed with REVMAN5.3.Results:We included a total of 1808 patients with hypertension diagnosed with COVID-19 in six studies. Analysis results show that ACEI/ARB drugs group D-dimer is lower (SMD = −0.22, 95%CI: −0.36 to −0.06), and the chances of getting fever is lower (OR = 0.74, 95%CI: 0.55 to 0.98). Meanwhile, laboratory data and symptoms were not statistical difference, but creatinine tends to rise (SMD = 0.22, 95% CI: 0.04 to 0.41).Conclusion:We found that the administration of ACEI/ARB drugs had positive effect on reducing D-dimer and the number of people with fever. Meanwhile it had no significant effect on other laboratory tests (creatinine excepted) or symptoms in patients with COVID-19, while special attention was still needed in patients with renal insufficiency.

Effects of ACEIs and ARBs on the Residual Renal Function in Peritoneal Dialysis Patients: A Meta-Analysis of Randomized Controlled Trials.

Background In peritoneal dialysis (PD) patients, whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could protect residual renal function is still controversial. To assess the effects of ACEIs and ARBs on the residual renal function and cardiovascular (CV) events in peritoneal dialysis patients, we performed a meta-analysis of randomized controlled trials. Materials and Methods We searched PubMed, EMBASE, the Cochrane Library, the CNKI database, and the Wanfang database for relevant articles from database inception to November 30, 2019. Randomized controlled trials were included. The primary outcome was the decline in the residual renal function (RRF). Results Thirteen trials with 625 participants were included in the meta-analysis. The average residual GFR declined by 1.79 ml/min per 1.73 m2 in the ACEI/ARB group versus 1.44 ml/min per 1.73 m2 in the placebo or active control group at 3 mo. The average residual GFR declined by 2.02 versus 2.06, 2.16 versus 2.72, and -0.04 versus 2.74 ml/min per 1.73 m2 in the placebo or active control group at 6 months (mo), 12 mo, and 24 mo, respectively. The decline in residual GFR showed a significant difference between the ACEI/ARB group and the placebo or active control group at 12 mo (MD = −0.64 ml/min per 1.73 m2; 95% CI: -0.97~-0.32; I2 = 44%; P < 0.0001). No significant difference was observed in Kt/V, urinary protein excretion, weekly creatinine clearance, CV events, or serum potassium levels. Conclusions In the present study, we found that the use of ACEIs and ARBs, especially long-term treatment, decreased the decline of RRF in patients on PD. ACEIs and ARBs do not cause an additional risk of side effects.

Effects of Angiotensin Receptor Blockers (ARBs) on In-Hospital Outcomes of Patients With Hypertension and Confirmed or Clinically Suspected COVID-19.

BackgroundThere is an ongoing controversy about harms and benefits of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in hypertensive patients with coronavirus disease 2019 (COVID-19). Given the unresolved debate, we investigated the association of ARBs with in-hospital outcomes of these patients.MethodsIn this retrospective observational study, we studied patients with COVID-19 who referred to Sina Hospital in Tehran, Iran, from February 20 to May 29, 2020. Patients with either positive real-time reverse-transcriptase polymerase-chain-reaction test of swab specimens, or high clinical suspicion according to the World Health Organization's interim guidance were included. We followed-up patients for incurring death, severe COVID-19, and in-hospital complications.ResultsWe evaluated 681 patients with COVID-19 of whom 37 patients were excluded due to incomplete medical records and 8 patients who used ACEIs which left 636 patients in the analysis. In this cohort, 108 (17.0%) patients expired and 407 (64.0%) patients incurred severe COVID-19. Of 254 (39.9%) patients with hypertension, 122 (48.0%) patients were receiving an ARB. After adjustment for possible confounders, we found no independent association between taking ARBs and in-hospital outcomes except for acute kidney injury (AKI), in patients with confirmed or clinically suspected COVID-19, either hypertensive or not-hypertensive. We found that discontinuation of ARBs during hospitalization was associated with a greater risk of mortality, invasive ventilation, and AKI (All P˂0.002).ConclusionsWe found that taking ARBs by patients with hypertension and confirmed or clinically suspected COVID-19 is not associated with poorer in-hospital outcomes after adjustment for possible confounders.

Is there any role of renin-angiotensin system inhibitors in modulating inflammatory bowel disease outcome?

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been associated with improved outcomes in inflammatory bowel disease. We aimed to investigate any possible effect of antihypertensive medications on inflammatory bowel disease course. One hundred and fifty inflammatory bowel disease patients with hypertension were compared using a 1:1 ratio with age- and gender-matched control patients with inflammatory bowel disease. The class of antihypertensive medication, traditional risk factors for atherosclerosis, inflammatory bowel disease characteristics, and history (surgery, hospitalizations, and treatment) were retrospectively analyzed. Of 150 (44.7% Crohn's disease) patients with hypertension, 46.7% were on angiotensin receptor blockers, 30.6% on angiotensin-converting enzyme inhibitors, 40% on β-blockers, and 40.7% on calcium channel blockers. Univariate analysis revealed significantly higher rates of traditional risk factors for atherosclerosis among antihypertensive users. When analyzing by class of antihypertensive medication, angiotensin receptor blockers were significantly associated with milder course as indicated by less frequent immunomodulator (P = 0.039) and steroid use (P = 0.041). Rates of lifetime steroids were statistically significantly lower among angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (odds ratio = 1.191, 95% confidence interval, 1.005-1.411). After adjustment with confounding factors, only angiotensin receptor blockers were associated with milder inflammatory bowel disease course (P = 0.037) and lower rates of immunomodulator use (P = 0.038). Our study suggests a possible protective effect of angiotensin receptor blockers on overall inflammatory bowel disease course by targeting the renin-angiotensin system. Their effect on inflammatory bowel disease needs to be studied in larger cohorts.

Children’s use of value information is characterized by differential autonomic reactivity during learning

The Marfan syndrome (MFS) patients are highly predisposed to thoracic aortic aneurysm and/or dissection, with virtually every patient having evidence of aortic disease at some point during their lifetime. We conducted a meta-analysis to investigate the efficacy of angiotensin receptor blockers (ARBs) in slowing down the progression of aortic dilatation in MFS patients. PUBMED, EMBASE, and COCHRANE databases were searched for relevant articles published from inception to February 1, 2020. We included randomized clinical trials evaluating the effect of ARBs on aortic root size in patients with MFS with a follow-up period of at least 2.5 years. Seven studies were included with a total of 1,510 patients. Our analysis demonstrated a significantly smaller change in aortic root and ascending aorta dilation in the ARBs treated group when compared with placebo (mean difference 0.68; 95% confidence interval [CI] −1.31 to −0.04; p = 0.04, I2 = 94%, and mean difference −0.13, 95% CI −0.17 to −0.09; p < 0.00001, I2 = 0%, respectively). ARBs as an add-on therapy to beta-blockers resulted in a significantly smaller change in aortic root dilation when compared with the arm without ARBs (mean difference −2.06, 95% CI −2.54 to −1.58; p < 0.00001, I2 = 91%). However, there was no statistically significant difference in the number of clinical events (aortic complications/surgery) observed in the ARBs arm when compared with placebo (Risk ratio of 1.01, 95% CI 0.74 to 1.38; p = 0.94, I2 = 0%). In conclusion, ARBs therapy is associated with a slower progression of aortic root dilation when compared with placebo and as an addition to beta-blocker therapy.

ANGIOTENSIN RECEPTOR BLOCKERS PROVIDE BETTER GLOMERULAR FILTRATION RATES THAN ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN KIDNEY TRANSPLANT RECIPIENTS WITH PROTEINURIA

Introduction: Kidney transplantation is the best renal replacement therapy in CKD whereas preventing measures of kidney function still remains a major problem after transplantation. Proteinuria and hypertension are two major determinants of worsening of kidney function in graft kidneys. Angiotensin converting enzyme inhibitors (ACEI) and Angiotensin receptor blockers (ARB) are the choice of treatment in proteinuria and hypertension. The aim of our study is to compare and evaluate the effectiveness of ACEIs and ARBs in patients with proteinuria higher than 1 gram per day. Materials & Methods: 62 kidney transplant (KT) recipients who have proteinuria over 1 g/day who have been followed up in Baskent University between 2009-2015 were enrolled to our study. The data of 2 years follow-up has been recorded. Patients using ACE-Is (Group 1), patients using ARBs (Group 2) have been compared. The demographic, clinical and laboratory values of the patients were recorded prospectively. At least 1 year of stable kidney function and proteinuria higher than 1 g/day was the inclusion criteria. Results: The initial 24 hours proteinuria levels showed statistically significant decrease in the follow up of 2 years period. The mean proteinuria at the initiation of the study was 2914 ± 2501 mg/d whereas the mean proteinuria declined to 1331 ± 2088 mg/d at the 24th month of the study. Both ACEI group (Group 1)and ARB group (Group 2) showed statistically significant decreasing effect on proteinuria. After 24 months follow-up, the ACEI group showed a significant loss of kidney function that was confirmed as the reducing of creatinine clearance from 88.8 ± 38.1 to 76.9 ± 36.1 mL/min whereas the ARB group maintained the kidney function that was confirmed as preventing the creatinine clearance from 65.2 ± 29.0 to 61.2 ± 29.1 mL/min. Conclusion: Patients who have proteinuria higher than 1 g per day should receive ACEI or ARB therapies. ARBs showed better results in prevention of GFR compared to ACE inhibitors while both protocols showed significant decline in proteinuria regardless of primary etiology.

Coronavirus Disease-2019 Conundrum: RAS Blockade and Geriatric-Associated Neuropsychiatric Disorders.

Coronavirus Disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which primarily targets the human respiratory system and may lead to severe pneumonia and ultimately death. Mortality rate is particurlarly high among people beyond the sixth decade of life with cardiovascular and metabolic diseases. The discovery that the SARS-CoV-2 uses the renin-angiotensin system (RAS) component ACE2 as a receptor to invade host epithelial cells and cause organs damage resulted in a debate regarding the role of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) therapies during COVID-19 pandemic. Some authors proposed the discontinuation of ACEIs and ARBs for cardiovascular, kidney, and metabolic diseases, while expert opinions have discouraged that due to limited empirical evidence of their negative effect on COVID-19 outcomes, and that withdrawing treatment may contribute to clinical decompensation in high-risk patients. Moreover, as cardiovascular and metabolic diseases are associated with neurodegenerative and psychiatric disorders, especially among older adults, a critical appraisal of the potential positive effects of ACEIs and ARBs is highly needed. Herein, we aim to discuss the conundrum of ACEIs and ARBs use in high-risk patients for COVID-19, and their potential protective role on the development and/or progression of geriatric neuropsychiatric disorders.

ACE2, Metformin, and COVID-19.

SummaryCOVID-19 is becoming a leading cause of mortality throughout the world, and few effective therapies are currently available. Angiotensin converting enzyme 2 (ACE2) is essential to COVID-19 pathogenesis, as the binding of SARS-CoV-2 spike protein (S protein) is required for viral entry and development of COVID-19. ACE2 regulates the protective arm of the renin-angiotensin-aldosterone system (RAAS) that endows anti-hypertensive and anti-inflammatory effects in the cardiovascular and pulmonary systems. Preclinical data suggest ACE2 might be downregulated after SARS-CoV-2 binding, and treatments that increase ACE2 may prevent cardiopulmonary injury. Development, testing, and mass production of novel ACE2 therapies may take years, whereas more effective treatments for COVID-19 are needed urgently. Metformin is a widely available anti-diabetic agent that has an excellent safety profile, and clinical and preclinical data suggest metformin may offer cardiopulmonary protection in COVID-19 via enhanced ACE2 expression.

Chronotherapy of Hypertension with Angiotensin Receptor Blockers–A Meta-Analysis of Blood Pressure Measured by Ambulatory Blood Pressure Monitoring in Randomized Trials

BackgroundWe performed this meta-analysis evaluating the efficacy of chronotherapy of hypertension with angiotensin receptor blockers (ARBs). MethodsWe searched Pubmed, Web of Science, and Cochrane for all published randomized trials that compare antihypertensive effects of ARBs between bedtime dosing and awakening dosing. Blood pressure (BP) was measured by ambulatory BP monitoring in patients with mild or moderate essential hypertension. ResultsThe effects of ARBs on BP were assessed in 805 essential hypertensive patients included in 8 trials with a follow-up of 12 ± 3 weeks. The sleep-time systolic and diastolic BP (SBP, DBP) with bedtime dosing greatly decreased as compared with awakening dosing (weighted mean differences [WMD] for SBP WMD −5.23 [95% confidence intervals (CI), −7.27, −3.20] mm Hg, p < 0.001; WMD for DBP −2.94 [95% CI, −4.52, −1.36] mm Hg, p < 0.001). The reduction of daytime SBP (WMD 0.98 [95% CI, −0.20, 2.17] mm Hg, p = 0.10), DBP (WMD 0.11 [95% CI, −0.68, 0.89] mm Hg, p = 0.79), 24 hour SBP (WMD −0.75 [95% CI, −1.93, 0.42] mm Hg, p = 0.21) and DBP (WMD −0. 77 [95% CI, −1.55 0.01] mm Hg, p = 0.05) with bedtime dosing was similar with awakening dosing. ConclusionsBedtime dosing with ARBs is more effective in lowering sleep-time BP than awakening dosing in patients with essential hypertension, suggesting a utilization of chronotherapy of hypertension with ARBs to reduce sleep-time high BP. Larger multi-ethnic studies are needed to investigate the efficacy of chronotherapy of hypertension.

Mendelian randomization in COVID-19: Applications for cardiovascular comorbidities and beyond.

Mendelian randomization in COVID-19: Applications for cardiovascular comorbidities and beyond.

Meta-analysis Examining the Usefulness of Angiotensin Receptor blockers for the Prevention of Aortic Root Dilation in Patients With the Marfan Syndrome

The Marfan syndrome (MFS) patients are highly predisposed to thoracic aortic aneurysm and/or dissection, with virtually every patient having evidence of aortic disease at some point during their lifetime. We conducted a meta-analysis to investigate the efficacy of angiotensin receptor blockers (ARBs) in slowing down the progression of aortic dilatation in MFS patients. PUBMED, EMBASE, and COCHRANE databases were searched for relevant articles published from inception to February 1, 2020. We included randomized clinical trials evaluating the effect of ARBs on aortic root size in patients with MFS with a follow-up period of at least 2.5 years. Seven studies were included with a total of 1,510 patients. Our analysis demonstrated a significantly smaller change in aortic root and ascending aorta dilation in the ARBs treated group when compared with placebo (mean difference 0.68; 95% confidence interval [CI] -1.31 to -0.04; p = 0.04, I2 = 94%, and mean difference -0.13, 95% CI -0.17 to -0.09; p < 0.00001, I2 = 0%, respectively). ARBs as an add-on therapy to beta-blockers resulted in a significantly smaller change in aortic root dilation when compared with the arm without ARBs (mean difference -2.06, 95% CI -2.54 to -1.58; p < 0.00001, I2 = 91%). However, there was no statistically significant difference in the number of clinical events (aortic complications/surgery) observed in the ARBs arm when compared with placebo (Risk ratio of 1.01, 95% CI 0.74 to 1.38; p = 0.94, I2 = 0%). In conclusion, ARBs therapy is associated with a slower progression of aortic root dilation when compared with placebo and as an addition to beta-blocker therapy.

Urinary angiotensinogen as a surrogate marker predicting the antiproteinuric effects of angiotensin receptor blockers in patients with overt proteinuria: a\xa0multicenter prospective study

BackgroundAlthough urinary angiotensinogen (AGT) and renin reflect intrarenal renin-angiotensin system activity and are enhanced in proteinuric chronic kidney disease, the clinical value of urinary AGT and renin levels during antiproteinuric treatment has yet to be determined. We investigated the clinical usefulness of initial urinary AGT or renin to determine the antiproteinuric effects of angiotensin receptor blockers (ARBs).MethodsThis multicenter, prospective, single-arm study included 205 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] ≥ 1 mg/mg) enrolled between April 2009 and December 2011. All patients were treated with valsartan. The urinary AGT/creatinine ratio (uAGT/Cr) was measured at the baseline and 24 weeks, and the renin/creatinine ratio (uR/Cr) was measured at the baseline. Fifty-six patients were followed-up for 5 years.ResultsThe mean age was 47.6 years and 51.2% were male. The mean uPCR was 2.32 mg/mg and the mean eGFR was 63.2 mL/min/1.73m2. Natural logarithms (ln) (uAGT/Cr), ln(uR/Cr), and diabetes mellitus were associated with proteinuria decrement (decrease in uPCR ≥1 mg/mg). Ln(uAGT/Cr) was an independent predictor for proteinuria decrement (OR 1.372, 95% CI, 1.068–1.762, P = 0.013). Among the 56 patients followed-up for 5 years, Δln(uAGT/Cr) at 24 weeks was an independent predictor for uPCR < 1 mg/mg at 5 years (OR 0.379, 95% CI, 0.20–0.715, P = 0.003).ConclusionsOur study demonstrates the potential role of both baseline urinary AGT and changes in urinary AGT during the initial 24 weeks as surrogate markers predicting the antiproteinuric effects of ARBs in patients with overt proteinuria.

Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19.

The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.

Kynurenine/Tryptophan Ratio Predicts Angiotensin Receptor Blocker Responsiveness in Patients with Diabetic Kidney Disease.

Albuminuria is a measurement and determinant factor for diabetic kidney disease (DKD). Angiotensin receptor blocker (ARB) is recommended for albuminuria in DKD with variable response. To find surrogate markers to predict the therapeutic effect of ARB, we carried out a prospective study to correlate plasma metabolites and the progression of renal function/albuminuria in DKD patients. A total of 56 type 2 diabetic patients with various stages of chronic kidney disease and albuminuria were recruited. ARB was prescribed once albuminuria was established. Urinary albumin-to-creatinine ratio (UACR) was determined before and six months after ARB treatment, with a ≥30% reduction of UACR considered an ARB responder. Plasma levels of 145 metabolites were measured before ARB treatment; only those associated with albuminuria were selected and compared between ARB responders and non-responders. Both lower tryptophan (Trp ≤ 46.75 μmol/L) levels and a higher kynurenine/tryptophan ratio (KTR ≥ 68.5 × 10−3) were significantly associated with macroalbuminuria (MAU), but only KTR (≥54.7 × 10−3) predicts ARB responsiveness (sensitivity 90.0%, specificity 50%) in MAU. Together, these data suggest that the kynurenine/tryptophan ratio predicts angiotensin receptor blocker responsiveness in patients with diabetic kidney disease.