The current global situation of nitrosamine contamination has expanded from angiotensin-II receptor blockers (ARBs) to wide range of medicines as the risk of contamination via the drug substances, formulation, manufacturing process, and packaging is possible for many drug products. The understanding of chemistry, toxicology, and root causes of nitrosamines are mandatory to effectively evaluate and mitigate the risks associated with the contaminated mutagen. Lessons learnt and scientific findings from previously identified root causes are good examples on how to perform effective risk assessments and establish control strategies. Addressing the risk of nitrosamine contamination in pharmaceuticals requires significant knowledge and considerable resources to collect the necessary information for risk evaluation. Examples of the resources required include a reliable laboratory facility, reference material, highly specific and sensitive instrumentation able handle trace levels of contamination, data management, and the most limited resource - time. Therefore, the supporting tools to assist with risk assessment e.g., shared databases for drug and excipients in concern, screening models for the determination of nitrosamine formation potential, and an in silico model to help with toxicity estimation, have proven to be beneficial to tackle the risk and concern of nitrosamine contamination in pharmaceuticals.

Hypertension (HT) is a modifiable risk factor for life-threatening cardiovascular diseases (CVDs) including coronary artery disease, heart failure or stroke. Despite significant progress in understanding of the pathophysiological mechanisms of the disease, the molecular pathways targeted by HT treatment still remain largely unchanged. This warrants the necessity for searching novel biomarkers, which are causally related to persistent high blood pressure (BP) and may be pharmacologically targeted. Data from large-scale biobanks, containing high-throughput genetic and biochemical data, such as OLINK and SomaScan-based proteomics or Nuclear Magnetic Resonance-based metabolomics, as well as novel analytical tools including Mendelian randomisation (MR) approach enabling genetic casual inference, may create new treatment opportunities for HT and related CVDs. MR analysis may constitute an additional proof for observational studies and facilitate selection of druggable targets for clinical testing and have been already used to nominate potentially causal biomarkers for HT and CVDs such as circulating glycine, branched-chain amino acids, insulin-like growth factor 1 or fibronectin 1. Using MR framework, genetic proxies for targets of already known drugs, such as statins, PCSK9 and ACE inhibitors, may additionally inform about potential side effects and eventually contribute to a more personalized medicine. Finally, genetic causal inference may disentangle independent, direct effects of correlated traits such as lipid classes or markers of inflammation on cardiovascular clinical outcomes such as atherosclerosis and HT. While several novel HT-targeting drugs are currently under clinical investigation (e.g. brain renin-angiotensin-aldosterone system inhibitors or endothelin-1 receptor antagonists), analysis of high-throughput proteomic and metabolomic data from well-powered studies may deliver novel druggable molecular targets for HT and associated CVDs.

Endothelial cell function is mediated by different mechanisms in different vascular beds. Moreover, in humans, endothelial cell dysfunction triggers and accelerates the progression of cardiovascular and chronic kidney diseases. Progression of such diseases can be in part mitigated by the control of cardiovascular risk factors and drugs targeting different systems, including endothelin receptor antagonists (ERAs), renin-angiotensin aldosterone antagonists and glucose metabolism, all of which were shown to improve endothelial cell function. In recent years, the microRNAs, which are endogenous regulators of gene expression, have been identified as transmitters of information from endothelial cells to vascular smooth muscle cells, suggesting that they can entail tools to assess the endothelial cell dysfunction in arterial hypertension and target for pharmacologic intervention. This article critically reviews current challenges and limitations of available techniques for the invasive and noninvasive assessment of endothelial function, and also discusses therapeutic aspects as well as directions for future research in the areas of endothelial cell biology and pathophysiology in humans.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

Chronic kidney disease (CKD) affects about 10-15% of the German population with a steady increase. It is assumed that CKD will become the 5th most common cause of death worldwide in 2040. CKD is associated with high risk of mortality, morbidity, related in particular to cardiovascular disease, as well as high healthcare costs. Clinical strategies to manage CKD should encompass extensive life-style modification including weight normalization, reduction of dietary protein and salt intakes, regular exercise and avoidance of nicotine. Pharmacologically it includes inhibition of the renin-angiotensin-aldosterone system (RAAS), sodium-glucose co-transporter‑2 (SGLT-2) inhibitors in both diabetes-related and non-diabetic CKD and strategies to control other risk factors such as proteinuria, hyperglycemia and lipid disturbances. Among the various measures aimed at slowing CKD progression, blood pressure control and in particular RAAS inhibitors have received the most attention. Another therapeutic option includes aldosterone inhibition, be it via classical aldosterone-antagonists or the new mineralocorticoid-receptor antagonists. Avoidance of nephrotoxic agents (e.g. non-steroidal anti-inflammatory drugs) seems self-explanatory. Overall, given the often asymptomatic course of CKD in particular in early phases, patient education and self-empowerment as well as treatment in a multidisciplinary team appear essential to stem the tide of patients with advanced kidney damage.

Older individuals are more likely to develop solid cancers, but at the same time are more sensitive to the side effects of chemotherapy. In addition, older adults are more likely to present with chronic diseases (comorbidities) and immunosenescence that may decrease immunosurveillance against cancer. Clinical outcomes for the older patient with cancer are different from the younger patient and require different research and treatment approaches. Thus, alternative therapeutic approaches tailored specifically to the older patients are required. Colorectal cancer (CRC) has a high incidence in older individuals and is the third leading cause of cancer death globally. Anti-hypertensives are used by a large proportion of older patients and some studies have pointed to a positive impact of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) on CRC outcomes. As we have previously shown in a mouse model, lung metastases express ACE and contain many infiltrating myeloid-derived suppressor cells (MDSC); particularly high levels of MDSC are also present in the blood of older patients with CRC and other cancers, and are associated with disease severity. In this Commentary, we hypothesize that one mechanism responsible for the positive impact of ACEi or ARB on the outcome of CRC is the modulation of myeloid cells contributing to their maturation to non-suppressive neutrophils/monocytes and diverting them away from retaining an immature MDSC phenotype.

Persons with diabetes and chronic kidney disease (CKD) have a high residual risk of developing cardiovascular (CV) complications despite treatment with renin-angiotensin system blockers and sodium-glucose cotransporter type 2 inhibitors. Overactivation of mineralocorticoid receptors plays a key role in the progression of renal and CV disease, mainly by promoting inflammation and fibrosis. Finerenone is a nonsteroidal selective mineralocorticoid antagonist. Recent clinical trials, such as FIDELIO-DKD and FIGARO-DKD and the combined analysis FIDELITY have demonstrated that finerenone decreases albuminuria, risk of CKD progression, and CV risk in subjects with type 2 diabetes (T2D) and CKD. As a result, finerenone should thus be considered as part of a holistic approach to kidney and CV risk in persons with T2D and CKD. In this narrative review, the impact of finerenone treatment on the CV system in persons with type 2 diabetes and CKD is analyzed from a practical point of view.Key messages:Despite inhibition of renin-angiotensin system and sodium-glucose cotransporter type 2, persons with type 2 diabetes (T2D) and chronic kidney disease (CKD) remain on high cardiovascular (CV) residual risk.Overactivation of mineralocorticoid receptors plays a key role in the progression of renal and CV disease, mainly by promoting inflammation and fibrosis that is not targeted by traditional treatments.Finerenone is a nonsteroidal selective mineralocorticoid antagonist that decreases not only albuminuria, but also the risk of CKD progression, and CV risk in subjects with T2D and CKD.

Background Angiotensin II type 1 receptor blockers (ARBs) have been shown to limit the growth of abdominal aortic aneurysm (AAA), but their efficacy is controversial. This study aimed to investigate the molecular mechanism underlying the protective effect of ARBs against AAA progression. Methods and Results Olmesartan, an ARB, was administered to wild-type and osteoprotegerin-knockout (Opg-KO) mice starting 2 weeks before direct application of CaCl2 to aortas to induce AAA. The protective effect of olmesartan against AAA in wild-type and Opg-KO mice was compared at 6 weeks after AAA induction. Olmesartan prevented AAA progression in Opg-KO mice, including excessive aortic dilatation and collapse of tunica media, but not in wild-type mice. Deficiency of the Opg gene is known to cause excessive activation of the tumor necrosis factor-related apoptosis-inducing ligand-induced c-Jun N-terminal kinase/matrix metalloproteinase 9 pathway, resulting in prolonged AAA progression. Olmesartan attenuated the upregulation of phosphorylated c-Jun N-terminal kinase and matrix metalloproteinase 9 expression in the aortic wall of Opg-KO mice. In cultured vascular smooth muscle cells, tumor necrosis factor-related apoptosis-inducing ligand-induced c-Jun N-terminal kinase phosphorylation and matrix metalloproteinase 9 expression were inhibited by angiotensin (1-7), the circulating levels of which are increased by ARBs. Furthermore, administering an angiotensin (1-7) antagonist to Opg-KO mice diminished the protective effect of olmesartan against AAA progression. Conclusions Olmesartan prevented AAA progression in Opg-KO mice by upregulating angiotensin (1-7), suggesting that angiotensin (1-7) may be a key factor that mediates the protective effect of ARBs.

BACKGROUND The Glasgow prognostic score (GPS) consists of a combination of serum C-reactive protein and albumin levels as indicators of systematic inflammatory response and nutritional status, respectively. The present retrospective study aimed to evaluate the association between the GPS and atrial fibrillation, stroke, and mortality at 30 days and 1 year after coronary artery bypass graft (CABG) surgery. MATERIAL AND METHODS Patients with chronic coronary syndromes who underwent CABG surgery between 2012 and 2019 in a single center were included. Preoperative GPS was calculated. Then, patients were grouped according to postoperative atrial fibrillation (POAF) development. Further, groups were formed to evaluate the relationship between GPS and 30-day and 1-year cardiovascular mortality as well as stroke development. RESULTS Patients who developed POAF had higher GPS, higher European System for Cardiac Operative Risk Evaluation (EuroSCORE II) score, advanced age, lower angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) use, lower left ventricular ejection fraction, and were more likely to be female and to have a history of carotid artery disease (P<0.05, for all). Additionally, GPS, EuroSCORE II, advanced age, and lower left ventricular ejection fraction were detected as independent risk factors for POAF development. When adverse outcomes were assessed, cardiovascular mortality at 30 days or 1 year, and stroke development at 1 year, were more frequent in patients with POAF. Moreover, POAF development was found to be an independent risk factor for adverse outcomes. Also, GPS was established as an independent risk factor both for 30-day and 1-year cardiovascular mortality (P<0.0001 and P=0.001, respectively). CONCLUSIONS GPS is an easy-to-calculate score that has reasonable diagnostic accuracy in determining the risk of POAF and stroke as well as 30-day and 1-year cardiovascular mortality.

The mineralocorticoid receptor antagonist spironolactone has been shown to improve cardiac function and reverse left ventricular hypertrophy in heart failure patients, but there are no consistent findings on the efficacy and safety in hemodialysis patients. Abnormal aldosterone secretion plays a critical role in the formation of left ventricular hypertrophy. Because of the existence of "aldosterone escape", the routine use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers does not completely inhibit aldosterone secretion. Low-dose spironolactone (25 mg/d) has been found in small-sample clinical studies to have a significant positive impact with respect to decreasing left ventricular mass index, increasing left ventricular ejection fraction, reversing left ventricular hypertrophy, and improving cardiovascular function while still being safe. More prospective multicenter clinical trials with large sample sizes are needed, however, to provide convincing evidence.

Introduction: Since the coronavirus disease 2019 (COVID-19) pandemic, the use of angiotensin II receptor blockers (ARBs) in hypertensive patients with COVID-19 has been controversial. Following our previous study, after one year, we intended to extend our sample size and results to investigate the effects of ARBs with both in-hospital outcomes and 7-month follow-up results in patients with COVID-19. Methods: Patients with a diagnosis of COVID-19 who were admitted to Sina Hospital, Tehran, Iran, from February to October 2020 participated in this follow-up cohort study. The COVID-19 diagnosis was based on a positive polymerase chain reaction test or chest computed tomography scan according to guidelines. Patients were followed for disease severity, incurring in-hospital mortality, complications, and 7-month all-cause mortality. Results: We evaluated 1413 patients with COVID-19 in this study. After excluding 124 patients, 1289 including 561(43.5%) hypertensive patients, entered the analysis. During the study, 875(67.9%) severe disease, 227(17.6%) in-hospital mortality, and 307(23.8%) 7-month all-cause mortality were observed. After adjusting for possible confounders, ARB was not associated with severity, in-hospital and 7-month all-cause mortality, and in-hospital complications except for acute kidney injury. Discontinuation of ARBs was significantly associated with higher in-hospital mortality and 7-month all-cause mortality (both P values<0.006). We observed a better 7-month outcome in those who continued their ARBs after discharge. Conclusion: The results of this study, along with the previous studies, provide reassurance that taking ARBs is not associated with the risk of mortality, complications, and poorer outcomes in hypertensive COVID-19 patients after adjustment for possible confounders.

Background: The role of antihypertensive drugs in inducing hyperuricaemia and gout has been a long-term concern in clinical practice. However, clinical studies regarding this issue are limited in number and have yielded inconsistent results. We comprehensively evaluated the association between various antihypertensive drugs and the occurrences of hyperuricaemia, gout and related adverse events (AEs) using the FDA Adverse Event Reporting System (FAERS), aiming to guide the selection of antihypertensive drugs with a goal of minimizing the risk of hyperuricaemia, gout and related AEs. Methods: We used OpenVigil 2.1 to query the FAERS database. Hyperuricaemia, gout and related AEs were defined by 5 Preferred Terms: hyperuricaemia, gout, gouty arthritis, gouty tophus and urate nephropathy. Disproportionality analysis was performed, and a positive signal indicated an association between AEs and antihypertensive drugs. Results: The numbers of antihypertensive drugs with positive signals for hyperuricaemia, gout, gouty arthritis, gouty tophus and urate nephropathy were 46, 66, 27, 8 and 6, respectively. These drugs included diuretics, antihypertensive drugs with central action, α blockers, β blockers, α and β blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, vasodilators, and compound preparations. Furthermore, 42 antihypertensive drugs had positive signal for more than one AEs. Conclusion: Our study suggests that some potassium-sparing diuretics, calcium channel blockers and losartan may be associated with increased risk of hyperuricaemia, gout or related AEs, which is inconsistent with most previous studies. Moreover, Our study also suggests that some antihypertensive drugs with central action, α and β blockers, renin inhibitors and vasodilators may be associated with increased risk of hyperuricaemia, gout or related AEs, which has not been reported in previous studies. These findings complement real-world evidence on the potential risks of hyperuricaemia, gout and related AEs associated with antihypertensive drugs.

The new 2021 guidelines of the European Society of Cardiology (ESC) have broken with the old step by step treatment of heart failure and have fundamentally revised the strategy in the pharmacotherapy setting. For patients with heart failure and reduced ejection fraction ≤ 40%, the 4 substance groups angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor-neprilysin inhibitors (ARNI), beta blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose transporter 2 (SGLT2) inhibitors are now recommended as early as possible after diagnosis. Completing the substance groups has priority over increasing the dosage of the individual substances. This makes it necessary to rethink current clinical practice, especially as the guidelines are reluctant to give concrete instructions for implementation.

The wide overlap between the syndromes of chronic kidney disease and chronic heart failure means that familiarity with the 2021 European Society of Cardiology guidelines is of importance to nephrologists. The common risk factors for the two syndromes together with the adverse cardiac structural remodelling associated with chronic kidney disease means that many kidney disease patients are breathlessness and fall within the heart failure phenotypes categorised in the guidelines. The management of heart failure is evolving rapidly leading to significant changes in the latest guideline iteration. The 2021 guideline has changed from the 2016 version firstly by an increased focus on identifying the three phenotypes of heart failure to guide appropriate evidence based management. Secondly a new and simplified treatment algorithm for heart failure with reduced ejection fraction involving the rapid sequential initiation and up-titration of 4 'pillars' of drug treatment-ACE inhibitors or angiotensin-neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and now, thanks to convincing trial data, sodium-glucose co-transporter-2 inhibitors. Thirdly, guidelines for device therapy have been changed with down-graded advice on indications for primary prevention implantable cardioverter defibrillator therapy for patients with non-ischaemic heart failure and for cardiac resynchronisation therapy with left bundle branch block and a QRS duration < 150 ms. There are updated treatment plans for heart failure associated with non-cardiovascular co-morbidities including chronic kidney disease.

A deep interaction between the endometrium and the invading trophoblast occurs during implantation in humans, with the acquisition of uterine receptivity to the invading embryo promoted by an elevation of pro-inflammatory cytokines in the endometrium, and the invasiveness of decidualizing endometrial stromal cells, augmented by trophoblast-derived signals. Considering that usage of angiotensin II type 1 (AT1) receptor blockers, among other renin-angiotensin system (RAS) antagonists, is associated with adverse pregnancy outcomes, here we aim to analyse the involvement of AT1 receptor in the reciprocal dialogue occurring between endometrial stroma and trophoblast cells. In human endometrial stromal cells (T-HESC) pre-incubated with a decidualization cocktail, angiotensin (Ang) II increased protein expression of prolactin and FOXO1, markers of endometrial decidualization, while promoting nuclear translocation of FOXO1. In addition, Ang II treatment increased CXCL8, and matrix metalloprotease (MMP)-2 levels in T-HESC. Incubation with the AT1 receptor blocker losartan or with an NFAT signalling inhibitor, decreased Ang II-induced secretion of prolactin, CXCL8, and MMP-2 in T-HESC. In a wound healing assay, conditioned medium (CM) obtained from Ang II-treated T-HESC, but not CM from losartan-pre-incubated T-HESC, increased migration of HTR-8/SVneo trophoblasts, effect that was inhibited in the presence of a CXCL8-neutralizing antibody. An increased secretion of CXCL8 and MMP-2 was observed after treatment of T-HESC with CM obtained from HTR-8/SVneo cells, which was not observed in T-HESC pre-incubated with losartan or with the NFAT inhibitor. This study evidenced a reciprocal RAS-coded messaging between trophoblast and ESC which is affected by the AT1 receptor blocker losartan.

Heart failure with reduced ejection fraction (HFrEF) is a complex and progressive clinical condition characterized by dyspnea and functional impairment. HFrEF has a high burden of mortality and readmission rate making it one of the most significant public health challenges. Basic treatment strategies include diuretics for symptom relief and use of quadruple therapy (Angiotensin receptor blocker/neprilysin inhibitors, evidence-based beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors) for reduction in hospitalizations, all-cause mortality, and cardiovascular mortality. Despite compelling evidence of clinical benefit, guideline directed medical therapy is vastly underutilized in the real-world clinical practice. Other medications such as intravenous iron, ivabradine, hydralazine/nitrates and vericiguat may also have a role in certain subgroup of HFrEF patients. Specific groups of patients with HFrEF may also be candidates for various device therapies such as implanted cardioverter defibrillators, cardiac resynchronization therapy and transcatheter mitral valve repair. This review provides a comprehensive overview of drug and device management approaches for patients with HFrEF, recommendations for initiation and titrations of therapies, and challenges associated with guideline directed medical therapy in the management of patients with HFrEF.

Tobacco smoking is deleterious to the lungs because it exposes them to many toxic substances. These include transition metal ions, such as cadmium. However, there is a lack of information about the influence of endogenous metal-binding peptides, such as His-Leu (HL), on the lung distribution of transition metals in smokers. To address this, we administered HL subcutaneously to rats exposed to tobacco smoke for six weeks, then we measured the concentrations of transition metal ions in the lungs. We found that exposure to tobacco smoke elevates the concentrations of Cd(II) and Cu(II). Administration of the HL peptide, whose elevation is a consequence of angiotensin receptor blocker anti-hypertension therapy, increases the concentration of Fe in the lungs of rats exposed to smoke. These findings suggest that smoking is a risk factor for patients receiving angiotensin receptor blockers to treat hypertension.

Many studies have shown that alterations in the gut microbiota are associated with hypertension. Our study aimed to observe the characteristics of the gut microbiota in hypertension and to further explore whether drug molecules can play a therapeutic role in hypertension by interfering with the gut microbiota. We evaluated the differences in the composition of the gut microbiota in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Meanwhile, three first-line cardiovascular disease (CVD) drugs, losartan, atorvastatin, and aspirin, were used to treat the SHR in order to observe their effects on the gut microbiota in SHR. The 16S rDNA results showed that the diversity and richness of the gut microbiota in SHR were significantly reduced compared with that of the WKY, the Firmicutes/Bacteroidetes ratio was increased, the abundances of Bifidobacterium and short chain fatty acids (SCFAs)-producing bacteria decreased, and the abundance of lactate-producing bacteria increased. In addition to lowering the blood pressure, losartan increased the abundances of Alistipes, Bacteroides, and Butyricimonas in SHR, reduced the abundances of Ruminococcaceae, Streptococcus, and Turicibacter, reduced the Firmicutes/Bacteroidetes ratio, and rebalanced the gut microbiota. Losartan also increased the abundances of Bifidobacterium and SCFAs-producing bacteria and reduced the abundance of lactate-producing bacteria. However, atorvastatin and aspirin had no significant effect on the gut microbiota in SHR. The above results showed that losartan could change the characteristics of the gut microbiota in hypertension and rebalance the gut microbiota, which may be related to lowering the blood pressure. Atorvastatin and aspirin have no significant influence on the gut microbiota in SHR.

Heart failure (HF) is categorized arbitrarily based on the left ventricular ejection fraction (LVEF) in HF with reduced (HFrEF; LVEF < 40%), mildly reduced (HFmrEF; LVEF 40-49%), or preserved ejection fraction (HFpEF; LVEF ≥ 50%). In this opinion paper, based on (patho)physiological considerations, we contend that the neurohormonal overactivity syndrome (NOHS), which is present in all symptomatic HF patients irrespective of their LVEF, not only contributes to the development of signs and symptoms but it is also a major determinant of patients' outcomes. In this regard, NHOS is the only currently available treatment target in HF and should be combatted in most patients with the combined use of diuretics and neurohormonal inhibitors (β-blockers, angiotensin receptor-neprilysin inhibitor/angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoid antagonists, and sodium-glucose co-transporter 2 inhibitors). Unfortunately, despite the advances in therapeutics, HF mortality remains high. Probably machine learning approaches could better assess the multiple and higher-dimension interactions leading to the HF syndrome and define clusters of HF treatment efficacy.