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Background: Preclinical studies indicate that the concurrent use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) may improve outcomes in broad groups of patients with cancer. There are limited data on the association between the use of RAAS inhibitors and outcomes among patients treated with immune checkpoint inhibitors (ICIs)., Methods: We performed a retrospective study of all patients treated with an ICI in a single academic network. Of 10,903 patients, 5910 were on any anti-hypertensive medication. Of those on anti-hypertensive therapy, 3426 were prescribed a RAAS inhibitor during ICI treatment, and 2484 were prescribed other anti-hypertensive medications. The primary outcome was overall survival in the entire cohort and in sub-groups by cancer types., Results: Thoracic cancer (34%) and melanoma (16%) were the most common types of cancer. Those prescribed a RAAS inhibitor were older, more frequently male, and had more cardiovascular risk factors. In a Cox proportional hazard model, the concurrent use of RAAS inhibitors was associated with better overall survival (hazard ratio (HR):0.92, [95% Confidence Interval (CI):0.85-0.99], P = .032). Patients with gastrointestinal (HR:0.82, [95% CI: 0.67-1.01], P = .057) and genitourinary cancer (HR:0.81, [95% CI:0.64-1.01], P = .067) had a non-statistically significant better overall survival., Conclusions: In this large retrospective study, patients with hypertension who were concomitantly taking a RAAS inhibitor during ICI therapy had better overall survival. This benefit was primarily noted among patients with gastrointestinal and genitourinary cancers. Prospective randomized trials are warranted to further evaluate and specify the benefit of RAAS inhibitors in patients with cancer who receive ICI therapy., Competing Interests: Conflict of interest statement Dr. Neilan has been a consultant to and received fees from Parexel Imaging, Intrinsic Imaging, H3-Biomedicine, Amgen, Sanofi, Genentech, Roche and AbbVie, outside of the current work. Dr. Neilan also reports consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to immune checkpoint inhibitors and research support from AstraZeneca for work related to immune checkpoint inhibitors. Dr. Sullivan has been a consultant to Asana, AstraZeneca, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, Pfizer, Replimune; and received research funding from Amgen and Merck, all outside of the current work. Dr. Jain has received an Honorarium from Amgen; Consultant fees from Chugai, Elpis, Pfizer, SPARC, SynDevRx; Owns equity in Accurius, Enlight, SynDevRx; Served on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a research Grant from Boehringer Ingelheim. No funding or reagent from these organizations was used in this study. Dr. Reynolds has received research funding from Project Datasphere and consultant to Teladoc all outside of the current work. Dr. Michielin received fees for advisory roles from BMS, MSD, GSK, Novartis, Roche, Pierre-Fabre and Amgen and research funding from BMS, MSD and Amgen. Other authors have no conflicts of interest or financial disclosure., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hypertension has been listed in several case series and retrospective cohorts as a potential risk factor for the incidence and severity of the new coronavirus (SARS-CoV-2)-associated disease (COVID-19). The debate is noteworthy because almost one billion people around the globe are estimated to have hypertensive diseases, according to the Global Burden of Disease study. Considering the SARS-CoV-2's high infectivity rates, a possible interaction between COVID-19 and hypertension is worrisome. Additionally, antihypertensive drugs, especially the renin-angiotensin-aldosterone system (RAAS) inhibitors, could also influence the natural course of COVID-19 infection. Not only can these associations hold from an epidemiologic standpoint, a mechanistic scenario possibly exists. Hypertension and antihypertensive drugs can increase the expression of transmembrane angiotensin-converting enzyme (ACE)-2 receptors, the entry target of the viruses, thus facilitating infectivity. On the other hand, an increase in ACE-2 could be protective considering the anti-inflammatory, antithrombotic effects of the ACE-2-angiotensin 1-7/Mas pathway. So far, little is known about the whole picture. Observational studies appear to indicate at least a twofold increased risk of mortality for hypertensive patients with COVID-19; however, the previous and continued use of RAAS inhibitors may be protective in this subgroup of patients. The scarcity of randomized clinical trials precludes evidence-based decision-making. At least one randomized study in a non-specified sub-analysis demonstrated no relationship between an angiotensin-converting enzyme inhibitor and incidence or severity of the disease. It is reflected mainly by observational studies and, therefore, by international cardiology societies' guidelines, which state that antihypertensive drugs, particularly RAAS inhibitors, should not be discontinued unless necessary on a case-by-case basis.

The authors previously demonstrated that acute administration of sildenafil-a phosphodiesterase 5 (PDE5) inhibitor-improves hemodynamic parameters in patients with resistant hypertensive (RH), but its effect on ambulatory blood pressure monitoring (ABPM) is unknown. This interventional, nonrandomized, single-blinded, placebo-controlled, crossover trial included 26 patients with RH. A dose of sildenafil (187.5mg) was given, and after a washout period of 14 days the patients received a single oral dose of placebo and the protocol was repeated. The patients underwent 24-hour ABPM recordings the day before and immediately after the protocols. The reduction of systolic (-8.8±1.4 vs 1.3±1.2 mm Hg, P=.02), diastolic (-5.3±3.3 vs 1.8±1.1 mm Hg, P=.03), and mean (-7.9±3.6 vs 0.8±0.9 mm Hg, P=.01) 24-hour BP were found after the use of sildenafil compared with placebo. Improvement in daytime BP levels was also observed (systolic -6.0±4.7 vs 4.4±1.5 mm Hg [P=.02] and mean -4.8±3.9 vs 3.5±1.4 mm Hg [P=.02] for sildenafil vs placebo, respectively). Considering its antihypertensive effect, sildenafil may represent a therapeutic option for RH treatment., (©2016 Wiley Periodicals, Inc.)

Purpose: Failure to control blood pressure (BP) despite the use of three or more drugs characterizes resistant hypertension (RHTN). Impaired endothelial function is associated with this condition and phosphodiesterase-5 inhibitors (PDE5i)-inhibiting cGMP breakdown-reduce BP in RHTN patients. We hypothesized that acute administration of PDE5i could ameliorate hemodynamic, endothelial parameters and left ventricular diastolic function (LVDF) in RHTN patients. Also, an exploratory analysis was performed to assess the influence of the T-786C endothelial NO synthase polymorphism on those responses., Methods: Subjects (n = 26) underwent a 6-month clinical screening for RHTN diagnosis. Increasing doses of oral sildenafil were given at 30 min intervals (37.5, 50 and 100 mg) while continuous non-invasive hemodynamic measures were assessed. LVDF, flow mediated dilation (FMD), nitrite and cGMP levels were also determined., Results: Mean arterial pressure and total peripheral resistance decreased in all patients (84.17 ± 21.04 to 75 ± 17.21 mmHg; 1149 ± 459.7 to 1037 ± 340 dyn.s/cm(-5), respectively). Likewise, sildenafil improved diastolic dysfunction parameters (Left atrial volume: 25 ± 5.8 to 20 ± 4.4; IVRT: 104 ± 19.33 to 88 ± 15.22; E/e' septal: 9.7 ± 3.8 to 7.9 ± 2.9; E/e' lateral: 7.7 ± 3.4 to 6.4 ± 3.2). No statistical changes were found in FMD, nitrite and cGMP with PDE5i., Conclusion: Our data suggest PDE5i acutely improves diastolic function and hemodynamic profile in RHTN subjects, despite unchanging endothelial dysfunction.

Leptin and aldosterone have been associated with the pathophysiological mechanisms of hypertension. However, despite studies showing the association of leptin with intima-media thickness, arterial distensibility and sympathetic nerve activation, the relationship between leptin and blood pressure (BP) in resistant hypertension (RHTN) is unknown. We aimed to assess the correlation of plasma leptin and aldosterone levels with BP in uncontrolled controlled RHTN (UCRHTN) and CRHTN patients. Plasma leptin and aldosterone levels, office BP, ambulatory BP monitoring and heart rate were measured in 41 UCRHTN, 39 CRHTN and 31 well-controlled HTN patients. No differences were observed between the three groups regarding gender, body mass index and age. The UCRHTN group had increased leptin when compared with CRHTN and well-controlled HTN patients (38.2±21.4, 19.6±8.7 and 20.94±13.9 ng ml(-1), respectively; P<0.05). Aldosterone levels values were also statistically different when comparing RHTN, CRHTN and well-controlled HTN patients (9.6±3.8, 8.1±5.0 and 8.0±4.7 ng dl(-1), respectively; P<0.05). As expected, UCRHTN patients had higher heart rate values compared with CRHTN and well-controlled HTN patients (86.2±7.2, 83.5±6.7 and 83.4±8.5, respectively; P<0.05). Plasma leptin positively correlated with systolic (SBP) and diastolic BP (DBP), and aldosterone (r=0.43, 0.35 and 0.47, respectively; all P<0.05) in UCRHTN, but neither in the CRHTN nor in the HTN group. Simple linear regression showed that SBP, DBP and aldosterone may be predicted by leptin (r(2)=0.16, 0.15 and 0.19, respectively; all P<0.05) only in the UCRHTN subgroup. In conclusion, UCRHTN patients have higher circulating leptin levels associated with increased plasma aldosterone and BP levels when compared with CRHTN and HTN subjects.

Resistant hypertension (RHTN) includes both patients whose blood pressure (BP) is uncontrolled on three or more medications (uncontrolled RHTN (UCRH)) and patients whose BP is controlled with use of four or more drugs (controlled RHTN (CRH)). It is unknown whether endothelial function and nocturnal drop demonstrate a similar pattern in patients with CRH and UCRH. We examined circadian BP patterns and vascular function in these patients. In all, 40 CRH and 26 UCRH patients, and 25 normotensives underwent biochemical testing, ambulatory BP monitoring, determination of brachial artery responses to endothelial-dependent (flow-mediated; dilation (FMD)) and independent (nitroglycerin mediated) stimuli. The nighttime drop in systolic BP (SBP) and diastolic BP (DBP) was less pronounced in UCRH than in CRH (SBP, 1.9±1.6 versus 4.9±1.7%; DBP, 7.5±1.8 versus 10.9±1.8%, UCRH and CRH, respectively; P<0.05). FMD was greater in control group compared with RHTN patients. Patients with UCRH had significantly impaired FMD compared with CRH (5.9±2.3% versus 7.1±5.1%; P<0.0001). Therefore, UCRH patients have less nocturnal dipping and a more impaired endothelial response compared with CRH patients. These findings suggest that important differences among patients with RHTN may allow identify subgroups with increased cardiovascular risk.

Resistant hypertension (RHTN) includes patients whose blood pressure (BP) is controlled with the use of four or more antihypertensive medications, and is referred to as 'controlled resistant hypertension' (CRH). While specifically comparing patients with CRH and uncontrolled resistant hypertension (UCRH), we hoped to identify distinguishing characteristics that would provide insight into factors contributing to resistance to antihypertensive therapies. RHTN patients were identified as controlled (CRH, n=43) or uncontrolled (UCRH, n=47). No statistical differences were observed between the CRH and UCRH subgroups with respect to age and gender. The body mass index, aldosterone-renin ratio and pulse wave velocity (PWV) were significantly higher in UCRH patients. Although both subgroups showed increased cardiac mass, left ventricular mass index was significantly higher in UCRH compared with CRH patients. Multivariate linear regression analysis indicated that PWV was significantly dependent on age in both UCRH and CRH patients; however, the influence of ageing was more pronounced in the former subgroup. Older age, greater vascular stiffness, higher aldosterone levels and greater left ventricular hypertrophy were significantly associated with lack of BP control in patients with RHTN. These findings suggest important possibilities in terms of preventing and better treating RHTN.