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.

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 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.

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.

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.

This post hoc analysis aimed to assess and characterise adverse events (AEs) related to the triple whammy (i.e., combination therapy of ACE inhibitors, ACE-I, and/or angiotensin receptor blockers, ARBs, with diuretics and non-steroidal anti-inflammatory drugs, NSAIDs) leading to emergency department (ED) visits and/or hospitalisations in the Italian setting. The MEREAFaPS database was analysed. ED visits related to co-treatment with ACE-I and/or ARBs, diuretics, and NSAIDs were considered. Information on the AE (including classification, seriousness, and outcome), suspected and concomitant drugs, and concomitant conditions was retrieved and analysed. Logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation associated with the drugs of interest. Between 1 January 2007, and 31 December 2018, 80 patients visited the ED for AEs related to the triple whammy, and a total of 261 suspected drugs were involved. Patients were mostly Caucasian females, with a median age of 85 years, and only 9 of them had renal manifestations. In this subset, drug-drug interaction contributed to kidney injury. Most patients presented a Charlson comorbidity index of 4-5. Overall, 47 patients were hospitalised (58.75%), but no significant differences in the risk of hospitalisation were found according to demographic, clinical, or therapeutic features.

One of the most relevant and differentiating aspects provided by the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure is the retraction of the historical stepped and vertical pharmacological treatment scheme for heart failure with reduced ejection fraction (HFrEF). Subsequently, it was replaced by an updated algorithm that places four therapeutic families in the same initial horizontal step with an equally high degree of recommendation (class I). In this context, these four pillars, which have demonstrated a significant reduction in mortality and hospitalizations in patients with HFrEF, include (1) angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB)/angiotensin II receptor-neprilysin inhibitors (ARNi), (2) beta blockers, (3) mineralocorticoid receptor antagonists (MRA) and (4) sodium-glucose cotransporter 2 inhibitors (SGLT2is) as the main novelty. This manuscript reviews the current therapeutic algorithm with a special focus on the therapeutic value of adding an MRA (still underused in both clinical trials and real world), changing an ACEi/ARB for an ARNi and incorporating an SGLT2i in patients with HFrEF. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment.

N-nitrosamines (NA) impurities have unexpectedly been found in sartan products, angiotensin II receptor antagonists that are used to control hypertension, representing an urgent concern for industry, global regulators and for the patients. In this study, an HPLC-MS/MS method was developed and validated for the quantification of six NA (N-nitrosodimethylamine, N-Nitroso-N-methyl-4-aminobutyric acid, N-Nitrosodiethylamine, N-ethyl-N-nitroso-2-propanamine, N-nitroso-diisopropylamine and N-nitroso-di-n-butylamine) in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan products. The method was validated in terms of sensitivity, linearity, accuracy, precision, robustness and stability. The limits of quantification were 100, 31.25, 250, 33, 312.5 and 125 µg kg-1 in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan samples, respectively, which met the sensitivity requirements for the limits set by Food and Drug Administration of the United States. The standard curves showed good linearity. The recoveries ranged from 93.06 to 102.23% in losartan matrix, 83 to 85.9% in valsartan, 96.1 to 101.2% in olmesartan, 89.2 to 97.5% in irbesartan, 93.4 to 132.0% in candesartan and 62.3 to 106.2% in telmisartan matrix. The other parameters met the validation criteria, the good sensitivity and precision, high accuracy and simple and fast analysis provides a reliable method for quality control of NA in sartan pharmaceutical products. The developed method was successfully applied for the determination of N-nitrosamines in 71 sartan products marketed in Brazil.

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that interactions between the dopamine (DA) and renin-angiotensin system (RAS) may modulate learning and reward-related processes. The present study therefore examined the behavioral and neural effects of the Angiotensin II type 1 receptor (AT1R) antagonist losartan on social reward and punishment processing in humans. A preregistered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay (SID) functional MRI (fMRI) paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of losartan (50 mg, n = 43, female = 17) or placebo (n = 44, female = 20). We evaluated reaction times (RTs) and emotional ratings as behavioral and activation and functional connectivity as neural outcomes. Relative to placebo, losartan modulated the reaction time and arousal differences between social punishment and social reward. On the neural level the losartan-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation. Losartan increased the reward-neutral difference in the ventral tegmental area (VTA) and attenuated VTA associated connectivity with the bilateral insula in response to punishment during the outcome phase. Thus, losartan modulated approach-avoidance motivation and emotional salience during social punishment versus social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations.SIGNIFICANCE STATEMENT Social deficits and anhedonia characterize several mental disorders and have been linked to the midbrain-striato-frontal circuits of the brain. Based on initial findings from animal models we here combine the pharmacological blockade of the Angiotensin II type 1 receptor (AT1R) via losartan with functional MRI (fMRI) to demonstrate that AT1R blockade enhances the motivational salience of social rewards and attenuates the negative impact of social punishment via modulating the communication in the midbrain-striato-frontal circuits in humans. The findings demonstrate for the first time an important role of the AT1R in social reward processing in humans and render the AT1R as promising novel treatment target for social and motivational deficits in mental disorders.

The main goal was to determine the impact of mental stress (MS) on blood flow regulation in overweight/obese men. Fourteen overweight/obese men (27 ± 7 years; 29.8 ± 2.6 kg/m2) participated in two randomized experimental sessions with oral administration of the AT1R blocker Olmesartan (40 mg; AT1RB) or placebo (PL). After 2 h, a 5-min acute MS session (Stroop Color Word Test) was administered. Blood flow was assessed at baseline and during the first 3 min of MS by vascular ultrasound in the brachial artery. Blood was collected before (baseline) and during mental stress (MS) for measurement of nitrite (chemiluminescence) and endothelin-1 (ELISA kit). The AT1R blocker was able to reverse the MS responses observed in the placebo session for retrograde flow (p < 0.01), retrograde SR (p < 0.01) and oscillatory shear index (p = 0.01). Regarding vasoactive substances, no differences were observed in ET-1 (p > 0.05) responses to MS between experimental sessions. However, for nitrite responses, the administration of the AT1R blocker was able to increase circulating levels of NO (p = 0.03) Blockade of AT1R appears to prevent the decrease in endothelial function by reducing low shear stress and maintaining the vasoactive substances balance after MS in overweight/obese men.

Heart failure is a chronic illness with a high prevalence and mortality rate. The aim of this article is to give an update on new treatment options for heart failure and the value of the left ventricular ejection fraction (LVEF) in the diagnosis and treatment of heart failure. Based on LVEF, three groups of heart failure can be distinguished: (1) heart failure with reduced ejection fraction (HFrEF; LVEF ≤ 40%), (2) heart failure with mildly reduced ejection fraction (HFmrEF; LVEF 41-49%) and (3) heart failure with preserved ejection fraction (HFpEF; LVEF ≥ 50%). The treatment of HFrEF consists of four pillars, the application of which leads to symptom reduction and better survival: (1) angiotensin converting enzyme inhibitor (ACE-i) or angiotensin receptor-neprilysin inhibitor (ARNI), (2) β-blocker, (3) mineralocorticoid receptor antagonist (MRA) and (4) sodium-glucose co-transporter 2 (SGLT2) inhibitor. ACE-I, β-blocker and MRA can be considered as treatment of HFmrEF. The treatment of HFpEF mainly focuses on symptom reduction.

An update on the degree to which patients with type 2 diabetes in Canada achieve treatment targets is needed to document progress and identify subgroups that need attention. We sought to estimate the frequency with which patients managed in primary care met treatment targets (i.e., HbA1c ≤ 7.0%, blood pressure < 130/80 mm Hg and low-density lipoprotein cholesterol [LDL-C] < 2.00 mmol/L), guideline-based use of statins and of angiotensin-convertingenzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and the effects of patient age and sex.

Heart failure is a growing global health concern with high mortality and morbidity. Beta-blockers, mineralocorticoid receptor antagonists, and angiotensin-converting-enzyme inhibitors are the treatments of choice for worsening clinical symptoms. In early 2021, the FDA approved a new oral soluble guanylate cyclase stimulator, Vericiguat, for the treatment of chronic heart failure. To evaluate the efficacy and safety of this approved drug, we conducted a systematic review of the available randomized controlled trials (RCTs). A literature search was conducted using PubMed, The Cochrane Library, and Clinicaltrials.gov from inception to June 6, 2022, without any language restriction. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The quality of the included studies was checked using the Cochrane Risk-of-Bias tool. After a thorough literature search, seven studies met our pre-defined criteria and were therefore included in this review. Our review suggests that vericiguat was better in preventing all causes of death, cardiovascular death, and hospitalizations due to heart failure irrespective of the atrial fibrillation status of the patients and was even beneficial for patients with NT-proBNP levels up to 8000 pg/ml. The safety of the vericiguat, according to our review, is not up to the standards, especially with a higher dosage of vericiguat. Despite all of this, vericiguat can be a breakthrough in the treatment of heart failure as it has great potential to improve the disease severity.