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Background: Vericiguat was developed to treat patients with heart failure (HF). Currently, limited data are available to characterize vericiguat-treated patients in real-world clinical settings. Methods: This retrospective cohort study was done using a Japanese hospital administrative database to describe the use of vericiguat in patients with HF in real-world settings. Adult patients diagnosed with HF prescribed vericiguat between 1 July 2021 and 30 September 2022 were included. Patient characteristics at the initiation of vericiguat treatment, patterns of HF medication use, and vericiguat dose titrations were assessed within the first 90 days of treatment. Results: The study included 829 patients who were initiated on vericiguat therapy. The mean age was 75.5 years and 69.0% were male. Hypertension, coronary artery disease, and diabetes mellitus were present in 91.7, 71.3, and 60.1% of patients, respectively. Most patients had previously received HF medications, with high percentages using angiotensin-receptor blocker neprilysin inhibitors (ARNI; 43.9%) and sodium-glucose cotransporter-2 inhibitors (54.4%). During the first 90 days of vericiguat treatment, 65.8% of the patients were uptitrated from their starting dose, and 32.3% had reached the maximal daily dose. The median time to reach the maximal daily dose was 34 days. The multivariable model identified that initiating vericiguat treatment in an outpatient setting and using ARNI before initiating vericiguat treatment were factors significantly associated with reaching the maximal daily dose of vericiguat at any given time, whereas older age, chronic kidney disease, hyperkalemia, and anemia were not associated. Conclusions: These findings provide early insights into the use of vericiguat, which aid in optimizing the combinations and/or sequences of HF treatment incorporating vericiguat therapy. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is the primary cause of death and disability worldwide. Although age-standardized CVD mortality rates decreased globally by 14.5% between 2006 and 2016, the burden of CVD remains disproportionately higher in low- and middle-income countries compared to high-income countries. Even though proven, effective approaches based on multiple-drug intake aimed at the prevention and treatment of CVD are currently available, poor adherence, early discontinuation of treatment, and suboptimal daily execution of the prescribed therapeutic regimes give rise to shortfalls in drug exposure, leading to high variability in the responses to the prescribed medications. Wald and Law, in their landmark paper published in BMJ 2003, hypothesized that the use of a fixed-dose combination of statins, β-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and aspirin (classic Polypill composition) may increase adherence and decrease CVD by up to 80% when prescribed as primary prevention or in substitution of traditional protocols. Since then, many clinical trials have tested this hypothesis, with comparable results. This review aims to describe the available clinical trials performed to assess the impact of fixed-dose combinations on adherence, cost-effectiveness, and the risk factors critical to the onset of CVD. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) is rare among athletes. However, hypertrophic cardiomyopathy is the leading cause of SCD among those <35 years of age. Meanwhile, coronary artery disease (CAD) is the primary SCD cause among those ≥35 years of age. CAD-induced plaque ruptures are believed to be a significant cause of cardiovascular diseases in middle-aged individuals who participate in extreme long-distance running activities such as marathons. A total of 1970 articles related to EIH were identified using search terms. Out of these, 1946 studies were excluded for reasons such as arterial hypertension, exercise-induced pulmonary hypertension, the absence of exercise stress testing (EST), and a lack of relevance to EIH. The study analyzed 24 studies related to both long-distance runners with exercise-induced hypertension (EIH) and the general public. Among these, 11 studies were quasi-experimentally designed studies used in randomized controlled trials (RCTs) on long-distance runners with EIH. Additionally, 12 studies utilized cohort designs, and one study with a quasi-experimental design was conducted among the general population. Recent studies suggest that an imbalance between oxygen demand and supply due to ventricular hypertrophy may be the actual cause of cardiovascular disease, regardless of CAD. Exercising excessively over an extended period can reduce endothelial function and increase arterial stiffness, which in turn increases afterload and leads to an excessive increase in blood pressure during exercise. Exercise-induced hypertension (EIH), which increases the morbidity rate of resting hypertension and is a risk factor for cardio-cerebro-vascular diseases, is more prevalent in middle-aged long-distance runners than in runners from other age groups, and it increases the prevalence of critical arrhythmias, such as atrial fibrillation or ventricular arrhythmias. EIH is associated with angiotensin II activity, and angiotensin II receptor blockers show promising effects in middle-aged runners. Further, guidelines for preventing excessive participation in races and restricting exercise intensity and frequency would be useful. This review identifies EIH as a potential risk factor for cardiovascular diseases and describes how EIH induces SCD. [ABSTRACT FROM AUTHOR]

Background: Medication use during acute illness increases the risk of experiencing drug related problems (DRPs), including acute kidney injuries. It is recommended that potentially nephrotoxic medications are withheld during acute illness, including sulfonylureas, angiotensin converting enzyme inhibitors, diuretics, metformin, angiotensin receptor blockers, non-steroidal anti-inflammatories and sodium glucose co-transporter 2 inhibitors (SADMANS). It is unknown if Australian pharmacists currently provide sick day medication management advice regarding SADMANS medications. Hence, we aimed to identify current DRPs and the recommendations made during residential medication management reviews (RMMRs), especially with SADMANS medications. Methods: A retrospective review of 408 RMMRs was conducted. DRPs and pharmacist recommendations were classified according to a modified DOCUMENT system. General practitioners' (GP) recommendations were also categorised. Results: Over 97% of residents experienced at least one DRP. Common problems for non-SADMANS medications were "toxicity or adverse drug reaction", "drug selection" and "over/underdosing" and those for SADMANS medications included "toxicity or adverse drug reaction", "monitoring" and "drug selection". GPs agreed with pharmacist recommendations approximately 40% of the time. No pharmacists provided sick day medication management advice for SADMANS medications. Conclusion: DRPs remain highly prevalent in aged care facilities. Medication reviews effectively identify and resolve DRPs approximately 40% of the time, but do not currently minimise the risk associated with using SADMANS medications during sick days, which is a potential area of improvement. [ABSTRACT FROM AUTHOR]

(1) Background: Coronary artery disease (CAD) remains the leading cause of death in both sexes. The male sex is considered a classical atherosclerosis risk factor, whereas females should be protected by hormonal effects until menopause. Although there are known differences in the development, type, and prognosis of chronic coronary syndrome (CCS) between both sexes, there are no differences in approach in the guidelines. (2) Methods: The sex-related differences in CAD risk factors, treatment, echocardiographic, and angiographic results were assessed among 3291 patients with CCS. (3) Results: Women were older and had a higher prevalence of hypertension, dyslipidaemia, and diabetes mellitus than men. Women were more often treated conservatively than men. There was no difference in the use of beta-blockers and statins among the sexes. The LDL cholesterol goal was less frequently reached by women. Women were treated less often with aspirin than men, but they were treated more often with angiotensin receptor blockers than men. The left ventricle ejection fraction was higher among females. The number of obstructed vessels was higher in men. (4) Conclusions: Women may be more exposed to the risk factors of CAD than men. Men are diagnosed with CAD earlier, and their prevention and therapy are more efficient. [ABSTRACT FROM AUTHOR]

Although various guidelines for cardiovascular disease prevention have been established, the optimal drug therapy is often not implemented due to poor medication adherence and the clinical inertia of healthcare practitioners. Polypill strategies are one solution to this problem. Previous studies have established the usefulness of polypills, i.e., combination tablets including three or more medications, for the prevention of cardiovascular disease. For this purpose, the polypills generally contain an antiplatelet medication, an antihypertensive medication, and a statin. For the specific management of hypertension, combination therapy including more than two classes of antihypertensive medications is recommended by most international guidelines. Combination tablets including two classes of antihypertensive medications, such as renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) and Ca-channel blockers or thiazide diuretics, have been reported to be useful for cardiovascular disease prevention and lowering blood pressure (BP) levels. The use of RAS inhibitors is recommended for a wide range of complications, including diabetes, chronic heart failure, and chronic kidney disease. The combination of an RAS inhibitor and diuretic or Ca-channel blocker is thus recommended for the management of hypertension. Finally, we expect that novel medications such as angiotensin receptor neprilysin inhibitors (ARNIs) and sodium glucose cotransporter 2 inhibitors (SGLT2i), which have a more diverse range of effects in hypertension, heart failure, or diabetes, may be a solution to the problem of polypharmacy. Evidence is accumulating on the benefits of polypill strategies in cardiovascular disease prevention. Combination tablets are also effective for the treatment of hypertension. [ABSTRACT FROM AUTHOR]

This study aimed to determine the role of oxidative stress produced by the renin–angiotensin system (RAS) in cataract formation in streptozotocin-induced diabetic rats (STZ) using angiotensin II receptor blockers (ARBs). Rats were treated with streptozotocin and orally administered candesartan (2.5 mg/kg/day) or a normal diet for 10 weeks until sacrifice. Cataract progression was assessed through a slit-lamp examination. Animals were euthanized at 18 weeks, and the degree of cataract progression was evaluated. Oxidative stress was also assessed. In STZ-treated rats, lens opacity occurred at 12 weeks. Cataract progression was inhibited in the ARB-treated group compared with the placebo group (p < 0.05). STZ-treated rats exhibited upregulated angiotensin-converting enzyme (ACE) gene expression than control rats. Oxidative stress-related factors were upregulated in the placebo-treated group but suppressed in the ARB-treated group. A correlation coefficient test revealed a positive correlation between ACE gene expression and oxidative stress-related factors and a negative correlation between ACE and superoxide dismutase. Immunostaining revealed oxidative stress-related factors and advanced glycation end products in the lens cortex of the placebo-treated group. The mechanism of diabetic cataracts may be related to RAS, and the increase in focal ACE and angiotensin II in the lens promotes oxidative stress-related factor production. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a modern epidemic worldwide. Introducing renin–angiotensin system (RAS) inhibitors (i.e., ACEi or ARB) not only as blood-pressure-lowering agents, but also as nephroprotective drugs with antiproteinuric potential was a milestone in the therapy of CKD. For decades, this treatment remained the only proven strategy to slow down CKD progression. This situation changed some years ago primarily due to the introduction of drugs designed to treat diabetes that turned into nephroprotective strategies not only in diabetic kidney disease, but also in CKD unrelated to diabetes. In addition, several drugs emerged that precisely target the pathogenetic mechanisms of particular kidney diseases. Finally, the role of metabolic acidosis in CKD progression (and not only the sequelae of CKD) came to light. In this review, we aim to comprehensively discuss all relevant therapies that slow down the progression of non-diabetic kidney disease, including the lowering of blood pressure, through the nephroprotective effects of ACEi/ARB and spironolactone independent from BP lowering, as well as the role of sodium–glucose co-transporter type 2 inhibitors, acidosis correction and disease-specific treatment strategies. We also briefly address the therapies that attempt to slow down the progression of CKD, which did not confirm this effect. We are convinced that our in-depth review with practical statements on multiple aspects of treatment offered to non-diabetic CKD fills the existing gap in the available literature. We believe that it may help clinicians who take care of CKD patients in their practice. Finally, we propose the strategy that should be implemented in most non-diabetic CKD patients to prevent disease progression. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is a rare genetic disorder caused by a deficiency in the α-galactosidase A enzyme, which results in the globotriaosylceramide accumulation in many organs, including the kidneys. Nephropathy is a major FD complication that can progress to end-stage renal disease if not treated early. Although enzyme replacement therapy and chaperone therapy are effective, other treatments such as ACE inhibitors and angiotensin receptor blockers can also provide nephroprotective effects when renal damage is also established. Recently, SGLT2 inhibitors have been approved as innovative drugs for treating chronic kidney disease. Thus, we plan a multicenter observational prospective cohort study to assess the effect of Dapagliflozin, a SGLT2 inhibitor, in FD patients with chronic kidney disease (CKD) stages 1–3. The objectives are to evaluate the effect of Dapagliflozin primarily on albuminuria and secondarily on kidney disease progression and clinical FD stability. Thirdly, any association between SGT2i and cardiac pathology, exercise capacity, kidney and inflammatory biomarkers, quality of life, and psychosocial factors will also be evaluated. The inclusion criteria are age ≥ 18; CKD stages 1–3; and albuminuria despite stable treatment with ERT/Migalastat and ACEi/ARB. The exclusion criteria are immunosuppressive therapy, type 1 diabetes, eGFR < 30 mL/min/1.73 m2, and recurrent UTIs. Baseline, 12-month, and 24-month visits will be scheduled to collect demographic, clinical, biochemical, and urinary data. Additionally, an exercise capacity and psychosocial assessment will be performed. The study could provide new insights into using SGLT2 inhibitors for treating kidney manifestations in Fabry disease. [ABSTRACT FROM AUTHOR]

Hypertension and type 2 diabetes mellitus (T2DM) are important, intertwined public health issues. People with both conditions face significantly elevated risks of cardiovascular (CV) and renal complications. To optimize patient care, a multidisciplinary expert panel met to review recent evidence on optimal blood pressure (BP) targets, implications of albuminuria, and treatment regimens for hypertensive patients with T2DM, with the aim of providing recommendations for physicians in Hong Kong. The panel reviewed the relevant literature, obtained by searching PubMed for the publication period from January 2015 to June 2021, to address five discussion areas: (i) BP targets based on CV/renal benefits; (ii) management of isolated systolic or diastolic hypertension; (iii) roles of angiotensin II receptor blockers; (iv) implications of albuminuria for CV/renal events and treatment choices; and (v) roles and tools of screening for microalbuminuria. The panel held three virtual meetings using a modified Delphi method to address the discussion areas. After each meeting, consensus statements were derived and anonymously voted on by every panelist. A total of 17 consensus statements were formulated based on recent evidence and expert insights regarding cardioprotection and renoprotection for hypertensive patients with T2DM. [ABSTRACT FROM AUTHOR]

The aim of this study is to assess the use of high-risk medications in patients with community-acquired acute kidney injury (CA-AKI) and the differences in the characteristics and outcomes of CA-AKI based on the use of these medications. This is a retrospective audit of adults (≥35 years) with CA-AKI admitted to a large tertiary care hospital over a two-year period. We investigated the prevalence of SADMANS (sulfonylureas; angiotensin converting enzyme inhibitors; diuretics; metformin; angiotensin receptor blockers; nonsteroidal anti-inflammatory drugs; and sodium glucose co-transporter 2 inhibitors) medications use in people with CA-AKI prior to hospitalisation. Outcomes including CA-AKI severity, kidney function recovery and in-hospital mortality were examined and stratified by use of SADMANS medications. The study included 329 patients, with a mean (SD) age of 75 (12) years and a 52% proportion of females, who were hospitalised with CA-AKI. Most patients (77.5%) were taking at least one regular SADMANS medication upon admission. Overall, 40% of patients (n = 132) and 41% of those on SADMANS (n = 104) had hypovolaemia or associated symptoms such as vomiting and diarrhoea during admission. Over two-thirds (68.1%) had mild AKI on admission and patients who were taking SADMANS medications were more likely to have mild AKI. Patients on SADMANS had more comorbidities and a higher medication burden, but there were no differences in AKI severity on admission or outcomes such as length of hospitalisation, ICU admission, need for dialysis, recovery rates and mortality between the two groups. However, the high prevalence of SADMANS medications use among patients with CA-AKI indicates a potential for preventability of CA-AKI-led hospitalisations. Future studies are needed to gain better insights into the role of withholding this group of medications, especially during an acute illness. [ABSTRACT FROM AUTHOR]

Additional studies are needed to confirm whether the use of renin-angiotensin system blockers (RASBs) induces survival benefits in patients on hemodialysis (HD). This study aimed to evaluate patient survival with the use of RASBs in a large sample of maintenance HD patients. This study used data from the national HD quality assessment program and claim data from South Korea (n = 54,903). A patient using RASBs was defined as someone who had received more than one prescription during the 6 months of each HD quality assessment period. The patients were divided into three groups as follows: Group 1, no prescription for anti-hypertensive drugs; Group 2, prescription for anti-hypertensive drugs other than RASBs; and Group 3, prescription for RASBs. The five-year survival rates in Groups 1, 2, and 3 were 72.1%, 64.5%, and 66.6%, respectively (p < 0.001 for Group 1 vs. Group 2 or 3; p = 0.001 for Group 2 vs. Group 3). Group 1 had the highest patient survival rates among the three groups, and Group 3 had higher patient survival rates compared to Group 2. Group 3 had higher patient survival rates than Group 2; however, the difference in patient survival rates between Group 2 and Group 3 was relatively small. Multivariate Cox regression analyses showed similar trends as those of univariate analyses. The highest survival rates from our study were those of patients who had not used anti-hypertensive drugs. Between patients treated with RASBs and those with other anti-hypertensive drugs, patient survival rates were higher in patients treated with RASBs. [ABSTRACT FROM AUTHOR]

Ischemic heart failure (HF) is one of the most common causes of morbidity and mortality in the world-wide, but sex-specific predictors of mortality in elderly patients with ischemic cardiomyopathy (ICMP) have been poorly studied. A total of 536 patients with ICMP over 65 years-old (77.8 ± 7.1 years, 283 males) were followed for a mean of 5.4 years. The development of death during clinical follow up was evaluated, and predictors of mortality were compared. Death was developed in 137 patients (25.6%); 64 females (25.3%) vs. 73 males (25.8%). Low-ejection fraction was only an independent predictor of mortality in ICMP, regardless of sex (HR 3.070 CI = 1.708–5.520 in female, HR 2.011, CI = 1.146–3.527 in male). Diabetes (HR 1.811, CI = 1.016–3.229), elevated e/e' (HR 2.479, CI = 1.201–5.117), elevated pulmonary artery systolic pressure (HR 2.833, CI = 1.197–6.704), anemia (HR 1.860, CI = 1.025–3.373), beta blocker non-use (HR2.148, CI = 1.010–4.568), and angiotensin receptor blocker non-use (HR 2.100, CI = 1.137–3.881) were bad prognostic factors of long term mortality in female, whereas hypertension (HR 1.770, CI = 1.024–3.058), elevated Creatinine (HR 2.188, CI = 1.225–3.908), and statin non-use (HR 3.475, CI = 1.989–6.071) were predictors of mortality in males with ICMP independently. Systolic dysfunction in both sexes, diastolic dysfunction, beta blocker and angiotensin receptor blockers in female, and statins in males have important roles for long-term mortality in elderly patients with ICMP. For improving long-term survival in elderly patients with ICMP, it may be necessary to approach sex specifically. [ABSTRACT FROM AUTHOR]

Introduction: Aortic dissection (AD) is a life-threatening disease. However, the effectiveness of different strategies of antihypertensive therapies in non-operated AD patients is still unclear. Materials and methods: Patients were classified into five groups (groups 0–4) based on the number of classes of antihypertensive drugs, including β-blockers, renin-angiotensin system (RAS) agents (angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and the renin-inhibitors), calcium channel blockers (CCBs), and other antihypertensive drugs, were prescribed within 90 days after discharge. The primary endpoint was a composite outcome of re-hospitalization associated with AD, referral for aortic surgery, and all-cause death. Results: A total of 3932 non-operated AD patients were included in our study. The most prescribed antihypertensive drugs were CCBs, followed by β-blockers and ARBs. Within group 1, compared to other antihypertensive drugs, patients using RAS agents (aHR, 0.58; p = 0.005) had a significantly lower risk of occurrence of the outcome. Within group 2, the risk of composite outcomes was lower in patients using β-blockers + CCBs (aHR, 0.60; p = 0.004) or CCBs + RAS agents (aHR, 0.60; p = 0.006) than in those using RAS agents + others. Conclusion: For non-operated AD patients, RAS agents, β-blockers, or CCBs should be given in a different strategy of combinations to reduce the hazard of AD-related complications compared to other agents. [ABSTRACT FROM AUTHOR]

Background: It has been demonstrated in previous studies that red blood cell distribution width (RDW) is correlated with the severity and prognosis of cardiovascular disease. The target of our study was to assess the relationship between RDW and the prognosis of ischemic cardiomyopathy (ICM) patients undergoing percutaneous coronary intervention (PCI). Methods: The study retrospectively enrolled 1986 ICM patients undergoing PCI. The patients were divided into three groups by RDW tertiles. The primary endpoint was major adverse cardiovascular events (MACE) and the secondary endpoints were each of the components of MACE (all-cause mortality, nonfatal myocardial infarction (MI) and any revascularization). Kaplan–Meier survival analyses were conducted to show the association between RDW and the incidence of adverse outcomes. The independent effect of RDW on adverse outcomes was determined by multivariate Cox proportional hazard regression analysis. In addition, the nonlinear relationship between RDW values and MACE was explored using restricted cubic spline (RCS) analysis. The relationship between RDW and MACE in different subgroups was determined using subgroup analysis. Results: As RDW tertiles increased, the incidences of MACE (Tertile 3 vs. Tertile 1: 42.6 vs. 23.7, p < 0.001), all-cause death (Tertile 3 vs. Tertile 1: 19.3 vs. 11.4, p < 0.001) and any revascularization (Tertile 3 vs. Tertile 1: 20.1 vs. 14.1, p < 0.001) increased significantly. The K–M curves showed that higher RDW tertiles were related to increased incidences of MACE (log-rank, p < 0.001), all-cause death (log-rank, p < 0.001) and any revascularization (log-rank, p < 0.001). After adjusting for confounding variables, RDW was proved to be independently associated with increased risks of MACE (Tertile 3 vs. Tertile 1: HR, 95% CI: 1.75, 1.43–2.15; p for trend < 0.001), all-cause mortality (Tertile 3 vs. Tertile 1: HR, 95% CI: 1.58, 1.17–2.13; p for trend < 0.001) and any revascularization (Tertile 3 vs. Tertile 1: HR, 95% CI: 2.10, 1.54–2.88; p for trend < 0.001). In addition, the RCS analysis suggested nonlinear association between RDW values and MACE. The subgroup analysis revealed that elderly patients or patients with angiotensin receptor blockers (ARBs) had a higher risk of MACE with higher RDW. Patients with hypercholesterolemia or without anemia also had a higher risk of MACE. Conclusions: RDW was significantly related to the increased risk of MACE among ICM patients undergoing PCI. [ABSTRACT FROM AUTHOR]

Background: Antihypertensive pharmacological therapy includes diuretics, beta-blockers, ACE inhibitors, calcium channel blockers and angiotensin II receptor blockers. Besides their use in arterial hypertension, these drugs also play a major role in the therapy of portal hypertension, heart failure and coronary artery disease. Systematic analyses on the possible influence of these medications on cancer incidence are lacking. Methods: By utilizing the Disease Analyzer database (IQVIA), 349,210 patients with antihypertensive drug prescriptions between 2010 and 2020 without a diagnosis of cancer prior to or at the date of initial drug prescription were included. Propensity score matching was carried out by 1:1:1:1:1 according to the five antihypertensive treatments. Cox regression analyses were performed to investigate an association between antihypertensive drugs and the incidence of cancer. Results: Patients who were diagnosed with cancer were treated with diuretics in 19.9% of cases, calcium channel blockers in 16.9% of cases, and angiotensin II receptor blockers, ACE inhibitors, or beta-blockers in 13.9%, 13.2% and 12.8% of cases, respectively. Cox regression models revealed that diuretic use positively correlated with liver cancer incidence (HR: 1.31, 95%CI: 1.12–2.63) and lymphoid/haematopoietic tissue cancer incidence (HR: 1.27, 95%CI: 1.10–1.46). Use of diuretics negatively correlated with the incidence of prostate (HR: 0.64, 95%CI: 0.53–0.78) and skin cancer (HR: 0.81, 95%CI: 0.72–0.92). Finally, a positive association was found between angiotensin II receptor inhibitors and prostate cancer incidence (HR: 1.50, 95%CI: 1.28–1.65). Conclusions: These data suggest that diuretic use might be associated with liver cancer and lymphoid/haematopoetic tissue cancer development. [ABSTRACT FROM AUTHOR]

Hence, the question of whether the impact of disease activity and related systemic inflammation on atherosclerosis is indeed larger in patients with RA compared to those with spondyloarthritis requires further study. Importantly in the present context, in patients with rheumatoid arthritis (RA), a ~60% increase in cardiovascular mortality is observed [[4]]. Compared to patients with RA remission, those with moderate or high RA activity were at increased risk of developing carotid plaque, with an OR (95% CI) of 2.26 [1.02-5.00] ( I p i = 0.04). Disease activity was assessed using the DAS28-CRP in patients with RA and the Ankylosing Spondylitis Disease Activity Score using C-reactive protein concentrations (ASDAS-CRP) in those with spondyloarthritis. [Extracted from the article]

Patients with heart failure (HF) and associated chronic kidney disease (CKD) are a population less represented in clinical trials; additionally, subjects with more severe estimated glomerular filtration rate reduction are often excluded from large studies. In this setting, most of the data come from post hoc analyses and retrospective studies. Accordingly, in patients with advanced CKD, there are no specific studies evaluating the long-term effects of the traditional drugs commonly administered in HF. Current concerns may affect the practical approach to the traditional treatment, and in this setting, physicians are often reluctant to administer and titrate some agents acting on the renin angiotensin aldosterone system and the sympathetic activity. Therefore, the extensive application in different HF subtypes with wide associated conditions and different renal dysfunction etiologies remains a subject of debate. The role of novel drugs, such as angiotensin receptor blocker neprilysin inhibitors and sodium glucose linked transporters 2 inhibitors seems to offer a new perspective in patients with CKD. Due to its protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. In this review, we discussed the largest trials reporting data on subjects with HF and associated CKD, while suggesting a practical stepwise algorithm to avoid renal and cardiac complications. [ABSTRACT FROM AUTHOR]

Drug-Drug Interactions, Medication Adherence, and Stroke Should Be Considered When Approaching the Impact of Acid Suppression Therapy on Chronic Kidney Disease Patients. We also considered proton pump inhibitor (PPI)-clopidogrel drug-drug interaction in the multivariate analysis because the use of concomitant PPI, which can inhibit cytochrome P450, may attenuate the effectiveness of clopidogrel and increase potential for adverse cardiovascular events [[4]]. Drug-Drug Interactions, Medication Adherence, and Stroke Should Be Considered When Approaching the Impact of Acid Suppression Therapy on Chronic Kidney Disease Patients. [Extracted from the article]

Sacubitril/valsartan represents the combination that became " I sine qua non i " in the treatment of heart failure with reduced ejection fraction (HFrEF) with significant positive effect on major cardiovascular events [[1]], and it was included in the guidelines about the therapy in these patients [[2]]. In patients with resistant hypertension the composite outcome that included number of total hospitalizations for HF and death from cardiovascular causes was significantly higher than in patients with well-controlled hypertension [[5]]. The I post hoc i analysis of PARAGON-HF trial showed that 731 HFpEF patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension [[5]]. [Extracted from the article]

Reference 1 Kohsaka S., Okami S., Morita N., Yajima T. Risk-Benefit Balance of Renin-Angiotensin-Aldosterone Inhibitor Cessation in Heart Failure Patients with Hyperkalemia. Footnotes 1 B Disclaimer/Publisher's Note: b The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). Risk-Benefit Balance of Renin-Angiotensin-Aldosterone Inhibitor Cessation in Heart Failure Patients with Hyperkalemia. [Extracted from the article]

Objective: We aimed to investigate the demographic, clinical and hemodynamic characteristics of patients who underwent percutaneous mitral valve (MV) repair over the last decade, as well as to determine the potential changes in trends of these parameters among patients with structural and functional MR (SMR and FMR). Methodology: We analyzed all patients who underwent interventional MV repair in our institution between January 2010 and March 2021. Our study included both SMR and FMR patients. All data were obtained from a local registry. Results: Nine hundred and seventeen patients (357 SMR patients and 563 FMR patients) were involved in this study. We did not find significant differences in demographical, clinical and hemodynamic characteristics among SMR and FMR patients. Left ventricular remodeling and systolic dysfunction were more pronounced in FMR patients. Systemic vascular resistance was the only hemodynamic parameter that differed between SMR and FMR patients; it was higher in SMR group. An evaluation of the trend between the first and last five years of our experience revealed that the number of patients treated with this technique is constantly increasing, but that this is more pronounced in SMR patients. It was also found that the operative risk of SMR and FMR patients was significantly higher in the first five years. Additionally, our results showed change in medical therapy in MR patients over the last decade in terms of increased use of angiotensin II receptor blockers and the introduction of angiotensin receptor II blocker-neprilysin inhibitor. Conclusion: SMR and FMR patients who underwent interventional MV repair have similar clinical and hemodynamic characteristics. The percentage of SMR patients increased more significantly than FMR patients over the last five years. [ABSTRACT FROM AUTHOR]

Hyperkalaemia is a growing concern in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) as it limits the use of some prognostic-modifying drugs and has a negative impact on prognosis. The objective of the present study was to estimate the prevalence of hyperkalaemia in outpatients with HFrEF and its impact on achieving optimal medical treatment. For this purpose, a multicentre, prospective, and observational study was carried out on consecutive HFrEF patients who were monitored as outpatients in heart failure (HF) units and who, in the opinion of their doctor, received optimal medical treatment. A total of 565 HFrEF patients were included from 16 specialised HF units. The mean age was 66 ± 12 years, 78% were male, 45% had an ischemic cause, 39% had atrial fibrillation, 43% were diabetic, 42% had a glomerular filtration rate < 60 mL/min/1.7 m2, and the mean left ventricular ejection fraction was 31 ± 7%. Treatment at the study entry included: 76% on diuretics, 13% on ivabradine, 7% on digoxin, 18.9% on angiotensin-conversing enzyme inhibitors (ACEi), 11.3% on angiotensin receptors blockers (ARBs), 63.8% on angiotensin-neprilysin inhibitors (ARNi), 78.5% on mineralocorticoid receptor antagonists (MRAs), and 92.9% on beta-blockers. Potassium levels in the baseline analysis were: ≤5 mEq/L = 80.5%, 5.1–5.4 mEq/L = 13.8%, 5.5–5.9 mEq/L = 4.6%, and ≥6 mEq/L = 1.06%. Hyperkalaemia was the reason for not prescribing or reaching the target dose of an MRAs in 34.8% and 12.5% of patients, respectively. The impact of hyperkalaemia on not prescribing or dropping below the target dose in relation to ACEi, ARBs, and ARNi was significantly less. In conclusion, hyperkalaemia is a frequent problem in the management of patients with HFrEF and a limiting factor in the optimisation of medical treatment. [ABSTRACT FROM AUTHOR]

(1) Background: This observational study aimed to verify the association between serum potassium levels and hospitalization days in patients with chronic kidney disease in a follow up of nine months. (2) Methods: Patients with chronic kidney disease were divided into group A (180 patients, potassium ≤ 5.1 mEq/L) and B (90 patients, potassium > 5.1 mEq/L). Student's t-test, Mann–Whitney test, Pearson's Chi-Square test, Pearson/Spearman's correlation test and linear regression test were performed in the entire sample and in stage-G4/5 subsample. (3) Results: Groups A and B differed for estimated glomerular filtration rate (eGFR) (34.89 (IQR, 16.24–57.98) vs. 19.8 (IQR, 10.50–32.50) mL/min/1.73 m2; p < 0.0001), hemoglobin (11.64 ± 2.20 vs. 10.97 ± 2.19 g/dL, p = 0.048), sum of hospitalization days (8 (IQR, 6–10) vs. 11 (IQR, 7–15) days; p < 0.0001) and use of angiotensin II receptor blockers (40.2% vs. 53.3%; p = 0.010). Considering patients with eGFR 6–30 mL/min/1.73 m2, differences in the sum of hospitalization days were confirmed. Multivariable regression analysis showed that hyperkalemia is an independent risk factor of increased hospital length. In stage G4-G5, regression analysis showed that hyperkalemia is the only independent risk factor (β = 2.93, 95% confidence interval, 0.077–5.794, p = 0.044). (4) Conclusions: We observed significantly greater odds of increased length of hospital stay among patients with higher potassium, mostly in stages G4–G5 chronic kidney disease. [ABSTRACT FROM AUTHOR]

The aim of this study was to comparatively evaluate clinical, laboratory and hemodynamic effects on the long term of different triple combination antihypertensive medications in a well-characterized Italian cohort. We considered the data of a subset of Brisighella Heart Study (BHS) participants who were consecutively evaluated in three epidemiological surveys between 2012 and 2020. For the current analysis, we excluded normotensive subjects, patients treated with <3 or ≥3 antihypertensive drugs without taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium-channel blockers (CCB) and/or thiazide/thiazide-like diuretics. The remaining participants were divided into three groups depending on whether they were treated with Perindopril/Amlodipine/Indapamide, ACE-inhibitors (other than perindopril)/CCBs/Thiazide or ARBs/CCBs/Thiazide, either with separate drugs or fixed pill combinations. A further group of age- and sex-matched volunteers was selected as control and included patients receiving other antihypertensive treatments. The long-term (12 years) effects of the different antihypertensive treatments were compared among the pre-defined groups. During the observation period, there was a trend towards increase in both systolic and diastolic blood pressure (BP) in all the investigated subgroups (p for trend <0.05), but in the subgroup of patients treated with Perindopril/Amlodipine/Indapamide, such increase was significantly lower than in the other groups (p < 0.05). The combination treatment with renin-angiotensin system (RAS) modulators, CCBs and thiazide/thiazide-like diuretics was associated with significantly lower diastolic BP (p < 0.05) and more strictly controlled lipid pattern than other triple combination of anti-hypertensive medications. Patients treated with Perindopril/Amlodipine/Indapamide did not experience any age-related increase in serum levels of total cholesterol. Moreover, during the follow up none of them developed type 2 diabetes, nor had a need for a greater number of antihypertensive drugs to improve BP control, mainly because of a more stable BP control. Based on our observations, combination treatment with RAS modulators, amlodipine and thiazides/thiazide-like diuretics is more effective than other triple antihypertensive medications for lowering the diastolic BP and has a better impact on serum lipids. Perindopril/Amlodipine/Indapamide is associated with more protective metabolic profile than any other considered combination antihypertensive medications. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to evaluate the relationship between renin-angiotensin-aldosterone (RAA) system activity and reactivity, and the endothelial function profile in normotensive subjects (N), and in essential hypertensives (H), followed by analysis of the modulatory role of an angiotensin receptor blocker (ARB): valsartan, administered in the management of hypertension. Methods: A total of 101 male subjects were enrolled to the study: 31H and 70N. The nitric-oxide (NO) bioavailability (l-Arginine, asymmetric dimethylarginine (ADMA)), symmetric dimethylarginine (SDMA), endothelial vasodilative function (flow mediated dilation (FMD)), oxidative-stress markers (malonyldialdehyde (MDA), thiol index (GSH/GSSG), nitrotyrozine (N-Tyr)), and pro-inflammatory/angiogenic parameters (sICAM-1, sVCAM-1, PAI-1, sE-selectin, PAI-1, thromboxane -B2) were assessed at baseline, then after intravenous -l-arginine administration, which was repeated after the 4-day acetylsalicylic acid (ASA) administration (75 mg/24 h). In hypertensives, this whole protocol was repeated following 2 weeks of valsartan therapy. Results: No effect of valsartan and ASA on the flow-mediated vasodilation (FMD) and the NO bioavailability in hypertensives was observed. Administration of valsartan increased plasma renin activity (PRA), but without a decrease in the aldosterone levels. ASA treatment minimized the pre-existing differences between the groups, and increased the PRA in the N-subgroup with the highest ARR values. The blood concentrations of proinflammatory sICAM-1, sE-selectin, sVCAM-1, and PAI-1 were higher, whereas the anti-inflammatory 6-keto-PGF1 alpha level was lower in hypertensive subjects. The levels of angiogenic VEGF did not differ between groups. Conclusions: Our study does not confirm the modulative effect of valsartan on endothelial function. Normotensive men showed an increase in FMD after l-arginine administration, possibly indicating baseline impairment of the NO synthesis. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is common after cardiac surgery. To date, there are no specific pharmacological therapies. In this review, we summarise the existing evidence for prevention and management of cardiac surgery-associated AKI and outline areas for future research. Preoperatively, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be withheld and nephrotoxins should be avoided to reduce the risk. Intraoperative strategies include goal-directed therapy with individualised blood pressure management and administration of balanced fluids, the use of circuits with biocompatible coatings, application of minimally invasive extracorporeal circulation, and lung protective ventilation. Postoperative management should be in accordance with current KDIGO AKI recommendations. [ABSTRACT FROM AUTHOR]

Iatrogenic sexual dysfunction (SD) caused by antihypertensive (AH) compounds, provoking sexual desire, orgasm or arousal dysfunction, is a common clinical adverse event. Unfortunately, it is often underestimated and underreported by clinicians and prescribers in clinical practice, deteriorating the adherence and patient quality of life. The objective of this study was to investigate the frequency of SD in patients treated with different antihypertensive compounds; a real-life naturalistic and cross-sectional study in patients receiving AH treatment was carried out. Method: A total of 256 patients were included in the study (188 males and 68 females who met the inclusion and exclusion criteria). The validated Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX) was transversally applied once at least every two months following the onset of the treatment in order to measure possible AH-related SD. Although the spontaneous reporting of SD was very low (6.81% females/24.8% males), 66.40% of the patients reported impaired sexual function through the SALSEX questionnaire after the treatment onset, as follows: decreased desire (55.8% females/54.2% males), delayed orgasm (42.6%/45.7%), anorgasmia (42.6%/43.6%) and arousal difficulties (53%/59.6%). The average frequency of moderate to severe iatrogenic SD was 66.4% with AH in monotherapy as follows: angiotensin II receptor antagonists (ARBs), 29.8%; calcium antagonists, 40%; diuretics, 42.9%; beta blockers, 43.8%; and angiotensin-converting enzyme (ACE) inhibitors, 77.8%. Combined treatments showed a higher percentage of main SD (70.3%): diuretic + ACE inhibitor, 42.3%; ARB + calcium antagonist, 55.6%; diuretic + calcium antagonist, 68.8%; and diuretic + ARB, 74.2%. The greatest risk factors associated with SD were poor general health, age over 60 with a comorbid coronary or musculoskeletal disease, mood disorder and diuretic +ARB combined therapy. Conclusion: SD is common in patients treated with antihypertensive drugs, and it is still underreported. The most harmful treatment deteriorating sexual function was the combination of diuretic +ARB, while the least harmful was monotherapy with ARBs. More research is needed on the clinical management of this problem to preserve the quality of life of patients and their partners. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is associated with dementia. Angiotensin receptor blockers (ARBs) have been widely used for delaying CKD progression; however, their effect on dementia prevention in patients with CKD remains unclear. We designed a retrospective cohort study to investigate the effects of ARBs on the incidence of dementia in patients with CKD. We selected 21,208 patients from the Taiwan nationwide database from 1 January 2006 to 31 December 2006. We identified ARB users (n = 17,466) and ARB non-users (n = 3742) and their medication possession ratio (MPR). The Cox proportional hazard model was used to estimate hazard ratios (HRs) for the incidence of dementia in ARB users in the CKD population. During the 11-year follow-up period, 2207 dementia events were recorded; multivariate-adjusted hazard ratios for dementia by ARB usage and ARB usage per MPR were 0.578 (95% CI: 0.52–0.643) and 0.996 (95% CI: 0.995–0.998), respectively. This association was observed in almost all subgroups. Dose frequency effect of ARBs was noted; patients with higher MPRs of ARBs generally had higher protection from dementia. Patients with hypertension and CKD who received ARBs had a decreased risk of dementia. Protective effects of ARBs on dementia increased with the frequency of ARB use. [ABSTRACT FROM AUTHOR]

The gastrointestinal tract is the body's largest interface between the host and the external environment. People infected with SARS-CoV-2 are at higher risk of microbiome alterations and severe diseases. Recent evidence has suggested that the pathophysiological and molecular mechanisms associated with gastrointestinal complicity in SARS-CoV-2 infection could be explained by the role of angiotensin-converting enzyme-2 (ACE2) cell receptors. These receptors are overexpressed in the gut lining, leading to a high intestinal permeability to foreign pathogens. It is believed that SARS-CoV-2 has a lesser likelihood of causing liver infection because of the diminished expression of ACE2 in liver cells. Interestingly, an interconnection between the lungs, brain, and gastrointestinal tract during severe COVID-19 has been mentioned. We hope that this review on the molecular mechanisms related to the gastrointestinal disorders as well as neurological and hepatic manifestations experienced by COVID-19 patients will help scientists to find a convenient solution for this and other pandemic events. [ABSTRACT FROM AUTHOR]

33143005 16 Esposito P., Conti N.E., Falqui V., Cipriani L., Picciotto D., Costigliolo F., Garibotto G., Saio M., Viazzi F. New Treatment Options for Hyperkalemia in Patients with Chronic Kidney Disease. Hyperkalemia is commonly observed in patients with chronic heart failure [CHF], in CKD stage 3-5, and in patients with diabetes mellitus. Keywords: chronic kidney disease; CKD-MBD; hyperkalemia; vascular calcification EN chronic kidney disease CKD-MBD hyperkalemia vascular calcification 3840 1 09/14/21 20210901 NES 210901 Chronic kidney disease (CKD) is now an enormous worldwide health problem. Recent progress in our understanding of CKD pathophysiology together with the development of novel therapeutic agents has led to a renewed attention on the treatment of CKD and its associated metabolic complications which are now amenable to intervention. [Extracted from the article]

Our main aim was to describe the effect on the severity of ACEI (angiotensin-converting enzyme inhibitor) and ARB (angiotensin II receptor blocker) during COVID-19 hospitalization. A retrospective, observational, multicenter study evaluating hospitalized patients with COVID-19 treated with ACEI/ARB. The primary endpoint was the incidence of the composite outcome of prognosis (IMV (invasive mechanical ventilation), NIMV (non-invasive mechanical ventilation), ICU admission (intensive care unit), and/or all-cause mortality). We evaluated both outcomes in patients whose treatment with ACEI/ARB was continued or withdrawn. Between February and June 2020, 11,205 patients were included, mean age 67 years (SD = 16.3) and 43.1% female; 2162 patients received ACEI/ARB treatment. ACEI/ARB treatment showed lower all-cause mortality (p < 0.0001). Hypertensive patients in the ACEI/ARB group had better results in IMV, ICU admission, and the composite outcome of prognosis (p < 0.0001 for all). No differences were found in the incidence of major adverse cardiovascular events. Patients previously treated with ACEI/ARB continuing treatment during hospitalization had a lower incidence of the composite outcome of prognosis than those whose treatment was withdrawn (RR 0.67, 95%CI 0.63–0.76). ARB was associated with better survival than ACEI (HR 0.77, 95%CI 0.62–0.96). ACEI/ARB treatment during COVID-19 hospitalization was associated with protection on mortality. The benefits were greater in hypertensive, those who continued treatment, and those taking ARB. [ABSTRACT FROM AUTHOR]

(1) Background: Type 2 diabetes mellitus (T2DM) is the main cause of chronic kidney disease (CKD). In Greece, in a population from hospital-based diabetes clinics (n = 1759), the overall prevalence of diabetic chronic kidney disease (DCKD) was 45% including mild, moderate, and severe CKD. The aim of this study was to describe and analyze how T2DM patients with mild-to-severe CKD are managed by diabetologists in Greece and assess the achievement rates in glycemic, blood pressure and low-density lipoprotein-cholesterol (LDL-C) control. (2) Methods: This cross-sectional multicenter study took place from June 2015 to March 2016 and collected data from diabetes centers in public hospitals all over Greece. (3) Results: With regard to the anti-diabetes treatment, most participants were on metformin, DPP-4 (Dipeptidyl Peptidase-4 inhibitors) inhibitors and insulin. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were the most prescribed medications for hypertension. For the management of dyslipidemia, most participants were on statins. For patients with DCKD, the levels of HbA1c, blood pressure and LDL-C were 7.2%, 137.7/76.9 mmHg and 95.9 mg/dL, respectively (mean values). (4) Conclusions: The outcomes of this study suggest that management of DCKD can be further improved and should be enhanced. These results may contribute to the whole health care system in Greece. In addition, the better understanding of therapeutic strategies used by diabetologists treating these patients offers educational benefits to primary care physicians, which can result in an overall more successful and efficient management of subjects with T2DM and DCKD. [ABSTRACT FROM AUTHOR]

Objectives: Besides their proven effectivity in decreasing the risk of cardiovascular events, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARBs) are likely to possess anti-inflammatory properties as well. This study aims to investigate whether the use of ACEi and ARBs additionally lowers disease activity in patients with rheumatoid arthritis (RA). Methods: In this cross-sectional study, we used ARBs or ACEi to study RA patients who had at least one DAS28-CRP measurement during a one-year period. A control group of RA patients without ACEi/ARBs was randomly selected. The primary outcome was the difference between the DAS28-CRP scores of ACEi/ARBs users and controls. The secondary outcomes were the differences between administered dosages of csDMARDs and bDMARDs for users and controls, respectively; these were expressed in defined daily dose (DDD). Confounders were included in the multiple regression analyses. Results: A total of 584 ACEi/ARBs users and 552 controls were finally examined. Multiple linear regression analyses showed no association between the use of ACEi or ARBs and the DAS28-CRP scores (ACEi factor 1.00, 95% CI 0.94–1.06; ARBs 1.02, 95% CI 0.96–1.09), nor with the dosage of csDMARDs (ACEi 0.97, 95% CI 0.89–1.07; ARBs 0.99, 95% CI 0.90–1.10). Furthermore, the use of ACEi was not associated with reduced dosages of bDMARDs (OR 1.14, 95% CI 0.79–1.64), whereas ARBs users tended to use less bDMARDs (1.46, 95% CI 0.98–2.18, p = 0.06). Conclusion: In this study, the use of either ACEi or ARBs in RA patients had no impact on disease activity as measured by the DAS28-CRP. A trend towards lower bDMARD dosages was observed in ARBs users, but the significance of this finding is still unclear. [ABSTRACT FROM AUTHOR]

With advances in critical care, patients who would have succumbed in previous eras now survive through hospital discharge. Many survivors suffer from chronic organ dysfunction and induced frailty, representing an emerging chronic critical illness (CCI) phenotype. Persistent and worsening cardiovascular and renal disease are primary drivers of the CCI phenotype and have pathophysiologic synergy, potentiating one another and generating a downward spiral of worsening disease and clinical outcomes manifest as cardio-renal syndromes. In addition to pharmacologic therapies (e.g., diuretics, beta adrenergic receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and blood pressure control), special consideration should be given to behavioral modifications that avoid the pitfalls of polypharmacy and suboptimal renal and hepatic dosing, to which CCI patients may be particularly vulnerable. Smoking cessation, dietary modifications (e.g., early high-protein nutrition and late low-sodium diets), and increased physical activity are advised. Select patients benefit from cardiac re-synchronization therapy or renal replacement therapy. Coordinated, patient-centered care bundles may improve compliance with standards of care and patient outcomes. Given the complex, heterogeneous nature of cardiovascular and renal disease in CCI and the dismal long-term outcomes, further research is needed to clarify pathophysiologic mechanisms of cardio-renal syndromes in CCI and develop targeted therapies. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme 2 (ACE2) is the recognized host cell receptor responsible for mediating infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 bound to tissue facilitates infectivity of SARS-CoV-2; thus, one could argue that decreasing ACE2 tissue expression would be beneficial. However, ACE2 catalytic activity towards angiotensin I (Ang I) and II (Ang II) mitigates deleterious effects associated with activation of the renin-angiotensin-aldosterone system (RAAS) on several organs, including a pro-inflammatory status. At the tissue level, SARS-CoV-2 (a) binds to ACE2, leading to its internalization, and (b) favors ACE2 cleavage to form soluble ACE2: these actions result in decreased ACE2 tissue levels. Preserving tissue ACE2 activity while preventing ACE2 shredding is expected to circumvent unrestrained inflammatory response. Concerns have been raised around RAAS modulators and their effects on ACE2 expression or catalytic activity. Various cellular and animal models report conflicting results in various tissues. However, recent data from observational and meta-analysis studies in SARS-CoV-2-infected patients have concluded that RAAS modulators do not increase plasma ACE2 levels or susceptibility to infection and are not associated with more severe diseases. This review presents our current but evolving knowledge of the complex interplay between SARS-CoV-2 infection, ACE2 levels, modulators of RAAS activity and the effects of RAAS modulators on ACE2 expression. [ABSTRACT FROM AUTHOR]

An important stage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) life cycle is the binding of the spike (S) protein to the angiotensin converting enzyme-2 (ACE2) host cell receptor. Therefore, to explore conserved features in spike protein dynamics and to identify potentially novel regions for drugging, we measured spike protein variability derived from 791 viral genomes and studied its properties by molecular dynamics (MD) simulation. The findings indicated that S2 subunit (heptad-repeat 1 (HR1), central helix (CH), and connector domain (CD) domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the receptor binding domain (RBD) domain, which is typically targeted in drug discovery programs, exhibits more sequence variability and flexibility. Interpretations from MD simulations suggest that the monomer form of spike protein is in constant motion showing transitions between an "up" and "down" state. In addition, the trimer cavity may function as a "bouncing spring" that may facilitate the homotrimer spike protein interactions with the ACE2 receptor. The feasibility of the trimer cavity as a potential drug target was examined by structure based virtual screening. Several hits were identified that have already been validated or suggested to inhibit the SARS-CoV-2 virus in published cell models. In particular, the data suggest an action mechanism for molecules including Chitosan and macrolides such as the mTOR (mammalian target of Rapamycin) pathway inhibitor Rapamycin. These findings identify a novel small molecule binding-site formed by the spike protein oligomer, that might assist in future drug discovery programs aimed at targeting the coronavirus (CoV) family of viruses. [ABSTRACT FROM AUTHOR]

The renin–angiotensin–aldosterone system (RAAS) has been studied extensively, and with the inclusion of novel components, it has become evident that the system is much more complex than originally anticipated. According to current knowledge, there are two main axes of the RAAS, which counteract each other in terms of vascular control: The classical vasoconstrictive axis, renin/angiotensin-converting enzyme/angiotensin II/angiotensin II receptor type 1 (AT1R), and the opposing vasorelaxant axis, angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor (MasR). An abnormal activity within the system constitutes a hallmark in hypertension, which is a global health problem that predisposes cardiovascular and renal morbidities. In particular, essential hypertension predominates in the hypertensive population of more than 1.3 billion humans worldwide, and yet, the pathophysiology behind this multifactorial condition needs clarification. While commonly applied pharmacological strategies target the classical axis of the RAAS, discovery of the vasoprotective effects of the opposing, vasorelaxant axis has presented encouraging experimental evidence for a new potential direction in RAAS-targeted therapy based on the G protein-coupled MasR. In addition, the endogenous MasR agonist angiotensin-(1-7), peptide analogues, and related molecules have become the subject of recent studies within this field. Nevertheless, the clinical potential of MasR remains unclear due to indications of physiological-biased activities of the RAAS and interacting signaling pathways. [ABSTRACT FROM AUTHOR]

Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients' clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis. [ABSTRACT FROM AUTHOR]