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Background: Hypertension among persons with childbearing potential is on the rise. Maintaining proper blood pressure during pregnancy is vital to prevent maternal and neonatal complications. Yet, limited evidence on the risk-benefit of various antihypertensives presents challenges for informed decision-making during this critical period. This study aimed to examine the utilization patterns of different classes of antihypertensives among persons with pre-existing hypertension before, during, and after pregnancy. Methods: We used MarketScan® Commercial Database 2011−2020 to analyze antihypertensive utilization among pregnant persons aged 12 to 55 identified via a validated algorithm. Pre-existing hypertension was defined as ≥1 inpatient or ≥2 outpatient encounters for hypertension within the 180 days preceding the LMP. Antihypertensive utilization was described during target periods: 0–3 months (0-3M) before pregnancy, 1st/2nd/3rd trimester (T1/2/3), 0-3M, and 4-6M after pregnancy. Results: We identified 1,950,292 pregnancies, of which 20,576 (12,978 live and 7,598 non-live) had pre-existing hypertension. Both groups had similar antihypertensive use (80.1% and 81.0%, respectively) during the 6 months before pregnancy (baseline). For live-birth pregnancies, 13.9% of baseline users discontinued treatment during pregnancy, while 28.9% of non-users initiated antihypertensives during pregnancy, and 17.2% started postpartum. Before pregnancy, the predominant antihypertensives included thiazide diuretics (21.9%), combined α- and β-blockers (18.4%), and dihydropyridines (16.2%). During pregnancy, thiazide diuretics, cardioselective β-blockers, and ACE inhibitors declined (T3: 3.0%, 4.2%, and 0.8%). Dihydropyridine use was steady during pregnancy, but preference shifted from amlodipine to nifedipine in T3 (2.2.% vs.10.8%). Central α2‐agonists increased during pregnancy (up to 15.2% in T3) compared to both pre- (9.8%) and post-pregnancy (5.7%). ARBs mirrored ACE inhibitors, with less than 1% utilization in later trimesters. Combination agents dropped from 10.8% pre-pregnancy to 0.8% in T3, then rebounded to 7.3% post-pregnancy. Conclusion: Research is warranted to evaluate the choice of antihypertensives and optimal timing to switch to safer alternatives, considering maternal and fetal outcomes. [ABSTRACT FROM AUTHOR]

The renin–angiotensin system (RAS)—a classical blood pressure regulator—largely contributes to healthy organ development and function. Besides, RAS activation promotes age‐related changes and age‐associated diseases, which are attenuated/abolished by RAS‐blockade in several mammalian species. RAS‐blockers also increase rodent lifespan. In previous work, we discussed how RAS‐blockade downregulates mTOR and growth hormone/IGF‐1 signaling, and stimulates AMPK activity (together with klotho, sirtuin, and vitamin D‐receptor upregulation), and proposed that at least some of RAS‐blockade's aging benefits are mediated through regulation of these intermediaries and their signaling to mitochondria. Here, we included RAS‐blockade's impact on other aging regulatory pathways, that is, TGF‐ß, NF‐kB, PI3K, MAPK, PKC, Notch, and Wnt, all of which affect mitochondria. No direct evidence is available on RAS/RAS‐blockade‐aging regulatory pathway–mitochondria interactions. However, existing results allow to conjecture that RAS‐blockers neutralize mitochondrial dysfunction by acting on the discussed pathways. The reviewed evidence led us to propose that the foundation is laid for conducting clinical trials aimed at testing whether angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)—even at subclinical doses—offer the possibility to live longer and in better health. As ACEi and ARB are low cost and well‐tolerated anti‐hypertension therapies in use for over 35 years, investigating their administration to attenuate/prevent aging effects seems simple to implement. [ABSTRACT FROM AUTHOR]

Background: Previous experimental and clinical studies suggested a beneficial effect of statins, metformin, angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers (RASi) on portal hypertension. Still, their effects on hard cirrhosis-related clinical endpoints, such as variceal bleeding and bleeding-related mortality, remain to be investigated. Methods: Thus, we recorded the use of statins, metformin and RASi in a large cohort of cirrhotic patients undergoing endoscopic band ligation (EBL) for primary (PP, n = 440) and secondary bleeding prophylaxis (SP, n = 480) between 01/2000 and 05/2020. Variceal (re-) bleeding and survival rates were compared between patients with vs. without these co-medications. Results: A total of 920 cirrhotic patients with varices were included. At first EBL, median MELD was 13 and 515 (56%) patients showed ascites. Statins, metformin and RASi were used by 49 (5.3%), 74 (8%), and 91 (9.9%) patients, respectively. MELD and platelet counts were similar in patients with and without the co-medications of interest. Rates of first variceal bleeding and variceal rebleeding at 2 years were 5.2% and 11.7%, respectively. Neither of the co-medications were associated with decreased first bleeding rates (log-rank tests in PP: statins p = 0.813, metformin p = 0.862, RASi p = 0.919) nor rebleeding rates (log-rank tests in SP: statin p = 0.113, metformin p = 0.348, RASi p = 0.273). Similar mortality rates were documented in patients with and without co-medications for PP (log-rank tests: statins p = 0.630, metformin p = 0.591, RASi p = 0.064) and for SP (statins p = 0.720, metformin p = 0.584, RASi p = 0.118). Conclusion: In clinical practice, variceal bleeding and mortality rates of cirrhotic patients were not reduced by co-medication with statins, metformin or RASi. Nevertheless, we recommend the use of these co-medications by indication, as they may still exert beneficial effects on non-bleeding complications in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study. Methods: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies. Results: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C. Conclusion: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC. [ABSTRACT FROM AUTHOR]

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]

Heart failure poses a global health challenge affecting millions of individuals, and access to guideline-directed medical therapy is often limited. This limitation is frequently attributed to factors such as drug availability, slow adoption, clinical inertia, and delayed diagnosis. Despite international recommendations promoting the use of guideline-directed medical therapy for heart failure management, personalized approaches are essential in settings with resource constraints. In India, crucial treatments like angiotensin II receptor blocker neprilysin inhibitors and sodium-glucose co-transporter 2 inhibitors are not fully utilized despite their established safety and efficacy. To address this issue, an expert consensus involving 150 specialists, including cardiologists, nephrologists, and endocrinologists, was convened. They deliberated on patient profiles, monitoring, and adverse side effects and provided tailored recommendations for guideline-directed medical therapy in heart failure management. Stressing the significance of early initiation of guideline-directed medical therapy in patients with heart failure, especially with sodium-glucose co-transporter 2 inhibitors, the consensus also explored innovative therapies like vericiguat. To improve heart failure outcomes in resource-limited settings, the experts proposed several measures, including enhanced patient education, cardiac rehabilitation, improved drug access, and reforms in healthcare policies. [ABSTRACT FROM AUTHOR]

Background: Telmisartan is considered more potent than valsartan. Hemodynamic response during anesthesia induction may be influenced by anti-hypertension (HTN) medication. The present study compared the effect of anti-HTN medications on post-induction hypotension during noncardiac surgeries. Methods: This observational study standardized the anesthetic regimen across patients, with hypotension defined as mean blood pressure (BP) of less than 65 mmHg. The hemodynamic changes within 5 min before and after endotracheal intubation, and within 10 min before and after surgical incision were measured. Transthoracic echocardiographic evaluation of the left ventricle (LV) during anesthesia induction was performed. The primary endpoint was the decline in mean BP after anesthetic administration in telmisartan and valsartan groups. Multivariate logistic regression analysis was used to identify predictors of post-induction hypotension. Results: Data from 157 patients undergoing noncardiac surgery were analyzed. No significant differences were found in mean BP decline between the two groups during anesthesia induction. Hemodynamic changes and LV ejection fraction (EF) during anesthesia induction were similar between the groups. Age and preoperative initial mean BP in operation room (OR) were associated with post-induction hypotension in both groups. Conclusions: The angiotensin receptor blocker (ARB) type did not influence post-induction hypotension during anesthesia induction. Age and preoperative initial mean BP in OR were associated with post-induction hypotension in patients taking ARBs. [ABSTRACT FROM AUTHOR]

Losartan, an angiotensin II receptor antagonist frequently detected in wastewater effluents, poses considerable risks to both aquatic ecosystems and human health. Seeking to address this challenge, advanced oxidation processes (AOPs) emerge as robust methodologies for the efficient elimination of such contaminants. In this study, the degradation of Losartan was investigated in the presence of activated peroxymonosulfate (PMS), leveraging ferrous iron as a catalyst to enhance the oxidation process. Utilizing advanced analytical techniques such as NMR and mass spectrometry, nine distinct byproducts were characterized. Notably, seven of these byproducts were identified for the first time, providing novel insights into the degradation pathway of Losartan. The study delved into the kinetics of the degradation process, assessing the degradation efficiency attained when employing the catalyst alone versus when using it in combination with PMS. The results revealed that Losartan degradation reached a significant level of 64%, underscoring the efficacy of PMS/Fe(II) AOP techniques as promising strategies for the removal of Losartan from water systems. This research not only enriches our understanding of pollutant degradation mechanisms, but also paves the way for the development of sustainable water treatment technologies, specifically targeting the removal of pharmaceutical contaminants from aquatic environments. [ABSTRACT FROM AUTHOR]

Olmesartan medoxomil (OLM) is a selective angiotensin II receptor antagonist used in the treatment of hypertension. Its therapeutic potential is limited by its poor water solubility, leading to poor bioavailability. Encapsulation of the drug substance by two methylated cyclodextrins, namely randomly methylated β-cyclodextrin (RM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD), was carried out to overcome the limitation related to OLM solubility, which, in turn, is expected to result in an improved biopharmaceutical profile. Supramolecular entities were evaluated by means of thermoanalytical techniques (TG—thermogravimetry; DTG—derivative thermogravimetry), spectroscopic methods including powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier-transform infrared (UATR-FTIR) and UV spectroscopy, saturation solubility studies, and by a theoretical approach using molecular modeling. The phase solubility method reveals an AL-type diagram for both inclusion complexes, indicating a stoichiometry ratio of 1:1. The values of the apparent stability constant indicate the higher stability of the host–guest system OLM/RM-β-CD. The physicochemical properties of the binary systems are different from those of the parent compounds, emphasizing the formation of inclusion complexes between the drug and CDs when the kneading method was used. The molecular encapsulation of OLM in RM-β-CD led to an increase in drug solubility, thus the supramolecular adduct can be the subject of further research to design a new pharmaceutical formulation containing OLM, with improved bioavailability. [ABSTRACT FROM AUTHOR]

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and β-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of β-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a β-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS. [ABSTRACT FROM AUTHOR]

Background This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin–angiotensin–aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K+) binder. Methods Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K+ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K+ binder cohorts. Results The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K+ binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K+ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K+ binder cohort was 2.56 (95% confidence interval 1.92–3.41; P  < .0001). Conclusions In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K+ binder treatment. [ABSTRACT FROM AUTHOR]

Aims Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin–angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. Methods and results In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10−6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1 , Ammecr1l , Hs6st1 , Nfil3 , Fam221a , Lmo4 , Adamts1 , Cish , Hif3a , Bcl6 , Rad54l2 , Adap1 , Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys. Conclusion Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks. [ABSTRACT FROM AUTHOR]

The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment. [ABSTRACT FROM AUTHOR]

Currently, the utilization patterns of medications for heart failure (HF) after worsening HF events remain unelucidated in Japan. Here, we conducted a retrospective cohort study evaluating the changes in HF drug utilization patterns in 6 months before and after hospitalizations for HF. The adherence to newly initiated HF medications was evaluated based on the proportion of days covered (PDC) and persistence as continuous treatment episodes among new users. The study included 9091 patients hospitalized for HF between January 2016 and September 2019, including 2735 (30.1%) patients who were newly prescribed at least one HF medication after hospitalization. Despite increases in the use of foundational HF therapy (beta-blockers, angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers, or mineralocorticoid receptor antagonists), 35.6% and 7.6% of patients were treated with the HF foundational monotherapy or diuretics alone after hospitalization, respectively. The mean PDC of newly initiated HF medications ranged from 0.57 for thiazide diuretics to 0.77 for sodium-glucose cotransporter-2 inhibitors. Continuous use of HF medications during the first year after initiation was observed in 30–60% of patients. The mean PDC and one-year continuous HF medication use were consistently lower in patients aged ≥ 75 years and in patients with a history of HF hospitalization for all HF medication classes except for tolvaptan and digoxin. Despite the guideline recommendations of HF pharmacotherapy, both treatment and adherence were suboptimal after HF hospitalization, especially in vulnerable populations such as older patients and those with prior HF hospitalizations. [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]

Here, we target the high-density lipoprotein (HDL) proteome in a case series of 16 patients with post-COVID-19 symptoms treated with HMG-Co-A reductase inhibitors (statin) plus angiotensin II type 1 receptor blockers (ARBs) for 6 weeks. Patients suffering from persistent symptoms (post-acute sequelae) after serologically confirmed SARS-CoV-2 infection (post-COVID-19 syndrome, PCS, n = 8) or following SARS-CoV-2 vaccination (PVS, n = 8) were included. Asymptomatic subjects with corresponding serological findings served as healthy controls (n = 8/8). HDL was isolated using dextran sulfate precipitation and the HDL proteome of all study participants was analyzed quantitatively by mass spectrometry. Clinical symptoms were assessed using questionnaires before and after therapy. The inflammatory potential of the patients' HDL proteome was addressed in human endothelial cells. The HDL proteome of patients with PCS and PVS showed no significant differences; however, compared to controls, the HDL from PVS/PCS patients displayed significant alterations involving hemoglobin, cytoskeletal proteins (MYL6, TLN1, PARVB, TPM4, FLNA), and amyloid precursor protein. Gene Ontology Biological Process (GOBP) enrichment analysis identified hemostasis, peptidase, and lipoprotein regulation pathways to be involved. Treatment of PVS/PCS patients with statins plus ARBs improved the patients' clinical symptoms. After therapy, three proteins were significantly increased (FAM3C, AT6AP2, ADAM10; FDR < 0.05) in the HDL proteome from patients with PVS/PCS. Exposure of human endothelial cells with the HDL proteome from treated PVS/PCS patients revealed reduced inflammatory cytokine and adhesion molecule expression. Thus, HDL proteome analysis from PVS/PCS patients enables a deeper insight into the underlying disease mechanisms, pointing to significant involvement in metabolic and signaling disturbances. Treatment with statins plus ARBs improved clinical symptoms and reduced the inflammatory potential of the HDL proteome. These observations may guide future therapeutic strategies for PVS/PCS patients. [ABSTRACT FROM AUTHOR]

Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some approaches such as combination therapy may be applicable for increasing therapeutic efficacy of PFD. Losartan (LOS), an angiotensin II receptor antagonist, could be a suitable candidate for combination therapy because of its stabilizing effect on the pulmonary function of IPF patients. Therefore, this study aimed to investigate the effects of LOS in combination with PFD on bleomycin (BLM)-induced lung fibrosis in rats. BLM-exposed rats were treated with LOS alone or in combination with PFD. The edema, pathological changes, level of transforming growth factor-β (TGF-β1), collagen content, and oxidative stress parameters were assessed in the lung tissues. Following BLM exposure, the inflammatory response, collagen levels, and antioxidant markers in rat lung tissues were significantly improved by PFD, and these effects were improved by combination with LOS. The findings of this in vivo study suggest that the combined administration of PFD and LOS may provide more potent protection against IPF than single therapy through boosting its anti-inflammatory, anti-fibrotic, and anti-oxidant effects. These results hold promise in developing a more effective therapeutic strategy for treating of lung fibrosis. [ABSTRACT FROM AUTHOR]

Dapagliflozin, a sodium–glucose cotransporter 2 inhibitor (SGLT2i), has shown demonstrated benefits for renal and cardiovascular outcomes in large clinical trials. However, short-term concerns regarding its impact on renal function and electrolyte balance exist. This study aimed to evaluate the short-term effects of dapagliflozin on renal function and electrolyte balance in patients newly prescribed the medication. A retrospective analysis of 246 patients who initiated dapagliflozin therapy was conducted. Serum creatinine, sodium, and potassium levels were measured at baseline (before dapagliflozin) and 5–8 days after initiation (endpoint). A Wilcoxon signed-rank test, Pearson's chi-square test, and Fischer's exact test were used for the data analysis. Glycemia and sodium levels were significantly higher at the baseline compared to the endpoint (p < 0.001). Conversely, creatinine and potassium levels were significantly higher at the endpoint than at the baseline (p < 0.001). The prevalence of hyponatremia and hyperkalemia were increased at the endpoint (17.5% vs. 10.2% and 16.7% vs. 8.9%, respectively). Although not statistically significant, a trend towards increased hyponatremia with the co-administration of furosemide was observed (p = 0.089). No significant association was found between potassium-sparing medications (p > 0.05) and hyperkalemia, except for angiotensin receptor blockers (p = 0.017). The combination of dapagliflozin and furosemide significantly increased the risk of acute kidney injury (AKI) at the endpoint (p = 0.006). Age, gender, and chronic kidney disease status did not significantly influence the occurrence of AKI, hyponatremia, or hyperkalemia (p > 0.05). These findings emphasize the importance of the close monitoring of renal function and electrolyte balance, particularly in the early stages of dapagliflozin therapy, especially in patients receiving diuretics or renin–angiotensin–aldosterone system inhibitors. [ABSTRACT FROM AUTHOR]

Aims: There is a lack of specific studies assessing the impact of natriuretic peptide monitoring in the post‐discharge management of patients with heart failure (HF) and preserved ejection fraction (HFpEF), throughout the vulnerable phase following acute HF hospitalization. The NICE study aims to assess the clinical benefit of incorporating N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) into the post‐discharge management of HFpEF patients. Methods and results: Individuals admitted with HFpEF (left ventricular ejection fraction >50%) were included in a multicentre randomized controlled study employing an open‐label design with event blinding (NCT02807168). Upon discharge, 157 patients were randomly allocated to either NT‐proBNP monitoring (n = 79) or no access to NT‐proBNP (control group, n = 78) during pre‐scheduled visits at 2, 4 and 12 weeks. Clinical endpoints were evaluated at 6 months. The primary endpoint of HF rehospitalizations occurred in 12.1% patients, without significant differences observed between the NT‐proBNP monitoring group (12.8%) and the control group (11.4%) (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.47–2.81, p = 0.760). Regarding secondary endpoints, the NT‐proBNP monitoring group demonstrated a significantly lower risk of death (1.3% vs. 10.1%; HR 0.12, 95% CI 0.02–0.98; p = 0.048), whereas non‐HF hospitalizations (12.8% vs. 19.0%, p = 0.171) and any adverse clinical event (26.9% vs. 36.7%, p = 0.17) did not reach statistical significance [Correction added on 29 April 2024, after first online publication: In the preceding sentence, "95% CI 0.02 ‐ 0.09" has been corrected to "95% CI 0.02 ‐ 0.98; p = 0.048" in this version.]. Awareness of NT‐proBNP levels were associated with higher doses of diuretics and renin–angiotensin system inhibitors (angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers) in the NT‐proBNP monitoring group. Conclusions: Post‐discharge monitoring of NT‐proBNP in HFpEF patients did not exhibit an association with reduced rates of HF hospitalization in this study. Nonetheless, it appears to enhance global clinical management by optimizing medical therapies and contributing to improved overall survival. [ABSTRACT FROM AUTHOR]

Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin–angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS‐induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain‐derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non‐classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation. [ABSTRACT FROM AUTHOR]

Objectives: Drug-induced liver injury is a common adverse reaction that frequently occurs with chemotherapeutic agents, such as cisplatin (CIS). This study seeks to enhance our understanding of drug actions and their associated adverse effects by examining the toxicity of CIS on rat liver tissue. We aimed to investigate the potential hepatoprotective effects of irbesartan (IRB), an easily accessible angiotensin II receptor blocker, in mitigating CIS-induced hepatotoxicity. Materials and Methods: Wistar albino rats were divided into four groups. These groups included a control group [saline, per oral (p.o.)] for seven days, and 1 mL saline intraperitoneal [(i.p.) on the fourth day]; a CIS group (1 mL saline for seven days and 7.5 mg/kg CIS i.p. on the fourth day); a CIS + IRB group (IRB: 50 mg/kg p.o. for seven days and 7.5 mg/kg CIS i.p. on the fourth day), and an IRB group (50 mg/kg IRB p.o. for seven days). The effect of IRB on interleukin-1 beta (IL-1ß) and caspase 3 levels was evaluated by immunohistochemical analysis, and its effects on mRNA expression levels of CCAAT/enhancer-binding protein homologous protein (CHOP) and immunoglobulin-heavy-chain-binding protein (BiP) were tested by quantitative real-time polymerase chain reaction. Results: IRB administration mitigated CIS-induced liver toxicity by inhibiting endoplasmic reticulum (ER) stress. Specifically, this drug reduced the mRNA expression of ER stress markers, including CHOP and BiP. In addition, IRB treatment decreased oxidative stress, inflammatory responses, and apoptotic markers. Conclusion: These findings suggest that IRB is a promising therapeutic option for preventing CIS-induced liver injury, potentially by modulating ER stress-related pathways. [ABSTRACT FROM AUTHOR]

Background: Accurately predicting post-discharge mortality risk in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) remains a complex and critical challenge. The primary objective of this study was to develop and validate a robust risk prediction model to assess the 12-month and 24-month mortality risk in STEMI patients after hospital discharge. Methods: A retrospective study was conducted on 664 STEMI patients who underwent PPCI at Xiangtan Central Hospital Chest Pain Center between 2020 and 2022. The dataset was randomly divided into a training cohort (n = 464) and a validation cohort (n = 200) using a 7:3 ratio. The primary outcome was all-cause mortality following hospital discharge. The least absolute shrinkage and selection operator (LASSO) regression model was employed to identify the optimal predictive variables. Based on these variables, a regression model was constructed to determine the significant predictors of mortality. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA). Results: The prognostic model was developed based on the LASSO regression results and further validated using the independent validation cohort. LASSO regression identified five important predictors: age, Killip classification, B-type natriuretic peptide precursor (NTpro-BNP), left ventricular ejection fraction (LVEF), and the usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (ACEI/ARB/ARNI). The Harrell's concordance index (C-index) for the training and validation cohorts were 0.863 (95% CI: 0.792–0.934) and 0.888 (95% CI: 0.821–0.955), respectively. The area under the curve (AUC) for the training cohort at 12 months and 24 months was 0.785 (95% CI: 0.771–0.948) and 0.812 (95% CI: 0.772–0.940), respectively, while the corresponding values for the validation cohort were 0.864 (95% CI: 0.604–0.965) and 0.845 (95% CI: 0.705–0.951). These results confirm the stability and predictive accuracy of our model, demonstrating its reliable discriminative ability for post-discharge all-cause mortality risk. DCA analysis exhibited favorable net benefit of the nomogram. Conclusion: The developed nomogram shows potential as a tool for predicting post-discharge mortality in STEMI patients undergoing PPCI. However, its full utility awaits confirmation through broader external and temporal validation. [ABSTRACT FROM AUTHOR]

Prescribing cascade is a significant clinical problem but is often overlooked. We explore the incidence of the prescribing cascades of antigout medications related to thiazide treatment in gout-naïve hypertensive adults newly exposed to the pharmacological treatment. This population-based, retrospective cohort study used the Taiwan National Health Insurance Registry Database. Gout-naïve hypertensive adults who were newly dispensed first-line antihypertensive drugs between January 1, 2000, and December 31, 2016, were enrolled. Patients were divided into the thiazide group (n = 4192) and the non-thiazide group (n = 81,083). The non-thiazide group included patients who received an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, calcium channel blocker, or beta-blocker. The study utilized propensity score matching and multivariable Cox regression models to investigate the prescribing cascade of antigout agents following antihypertensive treatment, adjusting for factors like age, sex, comorbidities, and concurrent medications. After propensity score matching, each group consisted of 4045 patients, with the thiazide group exhibiting a higher risk of being prescribed antigout medications across different time intervals post-treatment initiation. Specifically, adjusted hazard ratios (aHRs) for the thiazide group were 2.23, 2.07, and 2.41 for < 30 days, 31–180 days, and > 180 days, respectively, indicating a sustained and significant risk over time. Comparative analyses revealed thiazide diuretics were associated with a higher risk of antigout medication prescriptions compared to other antihypertensive classes, particularly evident after 180 days. Subgroup analyses across various demographics and comorbidities consistently showed an increased risk in the thiazide cohort. Gout-naïve hypertensive adults newly dispensed thiazide had a higher risk of subsequently adding antigout agents than those taking other first-line antihypertensive medications. The awareness and interruption of these prescribing cascades are critical to improving patient safety. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association of several antihypertensive medication classes with incidence of Parkinson's disease (PD), taking into account possible underlying conditions. Methods: In a case-control study based on a large primary care database and including 21,981 PD cases and 21,981 non-PD controls matched for age, sex, and possible treatment indications associations with different antihypertensive medication groups, including diuretics, betablockers, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin-II receptor-blockers and PD were examined. Results: Antihypertensive medications overall were associated with a lower risk of subsequent diagnosis of PD (OR: 0.94, 95% CI 0.90–0.97), with the negative association most significant for medications acting on the renin–angiotensin–aldosterone system. A positive association with diagnosis of PD was only seen for betablockers and restricted to those with relatively young age and not in those with longer treatment duration. Conclusion: When taking into account underlying diagnoses, antihypertensive medications overall were associated with a reduced incidence of PD. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future. [ABSTRACT FROM AUTHOR]

Background: Despite declining mortality in most countries and in Lithuania, ovarian cancer burden has remained high. Studies have indicated that antihypertensive medications use may help to improve ovarian cancer survival, however findings remain controversial. The aim of the study was to analyse the association between post-diagnosis antihypertensive medications intake and cancer-specific survival in ovarian cancer patients. Methods: This retrospective cohort study included 588 ovarian cancer cases diagnosed between 2013 and 2015. Hazard ratios (HR) and corresponding 95% confidence intervals (95%CI) were estimated using multivariable Cox proportional hazards models to assess associations between antihypertensive medications and ovarian cancer-specific mortality. Results: In total, 279 (47%) patients died during the follow-up; 242 (87%) of them died due to ovarian cancer. The risk of ovarian cancer death was reduced in angiotensin-converting enzyme inhibitors (ACE inhibitors) users vs. non-users (HR 0.55, 95% CI: 0.36–0.83). Subgroup analysis showed better ovarian cancer survival in higher dose ACE inhibitors users (HR 0.46, 95% CI: 0.28–0.77, p for trend 0.002); the effect was also stronger in age 51–65 years, stage I–III, surgery or chemotherapy treatment, pre-diagnosis ACE inhibitor users' and pre-diagnosis hypertension subgroups. The risk of cancer-specific death was slightly lower among calcium-channel blocker and angiotensin-receptor blocker users and higher among beta-blocker users as compared to non-users, however chance and confounding could not be ruled out. We found no association between the use of centrally and peripherally acting antiadrenergic agents and diuretics and risk of ovarian cancer-specific mortality. Conclusions: Our findings imply that post-diagnosis use of ACE inhibitors may be associated with reduced ovarian cancer-specific mortality; however, further research is needed for the comprehensive assessment. [ABSTRACT FROM AUTHOR]

Introduction: An oxidative stress and angiotensin II (Ang II) contribute significantly in the pathogenesis of diabetic nephropathy (DN). Therefore, interventions targeting these factors are anticipated to significantly contribute to inhibiting the progression of diabetic kidney disease. Objectives: The aim of this study was to assess the impact of a combination of rosmarinic acid (RA) and angiotensin receptor blockers (ARBs) in preventing mesangial expansion and reducing glomerular volume in streptozotocin (STZ)-induced diabetic rats. Materials and Methods: We observed experimental animals, 16 adults male Wistar rats, which were randomly grouped into 4 groups (n=4 per group): negative and positive control groups and diabetic rats treated with RA 75 mg/kg and candesartan 1 mg/kg (treatment group 1) and RA therapy 75 mg/kg and losartan 2.5 mg/kg (treatment group 2). Following 8 weeks of therapy, the renal histology was assessed to evaluate mesangial expansion and glomerular volume. Results: In comparison to the positive control, treatment group 1 demonstrated a significant inhibition of mesangial expansion (MD: -19.92; 95% CI: -21.97, -17.87; P < 0.001) and decreased glomerular volume (MD: 2669.06; 95% CI: 2066.31, 3271.80; P < 0.001). Similarly, treatment group 2 significantly inhibited mesangial expansion (MD: -19.21; 95% CI: -21.26, -17.16; P < 0.001) and decreased glomerular volume (MD: 2488.04; 95% CI: 1885.29, 3090.78; P < 0.001) compared to the positive control. While treatment group 1 exhibited better effects than treatment group 2, although the difference was not statistically significant. Conclusion: In STZ-induced diabetic rats, combination therapy of RA with candesartan or losartan can inhibit mesangial expansion and decrease glomerular volume. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme (ACE) inhibitors are used primarily in the treatment of hypertension, heart failure, and in the acute phase of myocardial infarction. Lisinopril [N2-[(1S)-1-car-boxy-3-phenylpropyl]-L-lysyl-L-proline], enalapril [(S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline] and ramipril [2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid] are all five-membered heterocycles and three of the most prevalent ACE inhibitors in clinical use worldwide. ACE inhibitor-induced angioedema (AE) is clinically characterized by self-limited edema of the dermis and subcutaneous lipid tissue, localized on face skin, oral mucosa and tongue in most cases. However, severe episodes of intestinal AE misdiagnosed as acute appendicitis and laryngeal AE requiring incubation have been reported. The pathophysiology of ACE inhibitor-induced angioedema is attributed to the accumulation of bradykinin, which is a potent vasodilator with proinflammatory activity that is normally degraded by angiotensin-converting enzyme (ACE) and aminopeptidase P; however, a small proportion of treated patients is affected. Given that patients do not respond to anti-H1 antihistamines and steroids, early clinical recognition and discontinuation of the ACE inhibitors are the treatments of choice for the long-term management of ACE inhibitor- induced angioedema. The search period of the present review was set up until November 2023, and its aim is to shed light on the broader context of ACE inhibitor-induced angioedema, exploring aspects such as clinical presentation, pathophysiology, and therapeutic considerations in this potentially life-threatening condition. The exploration of alternative drug options such as angiotensin II receptor blockers, the potential association of coadministration of DPP-4 inhibitors with ACE inhibitors, the presentation of angioedema and the significant clinical importance of this condition are also discussed. By focusing on the chemical structure of ACE inhibitors, specifically their nitrogen-based heterocycles—an attribute shared by over 880 drugs approved by the FDA within the pharmaceutical industry—this review emphasizes the pivotal role of nitrogen scaffolds in drug design and underscores their relevance in ACE inhibitor pharmacology. [ABSTRACT FROM AUTHOR]

Recurrent pericarditis is a problematic clinical condition that impairs the quality of life of the affected patients due to the need for repeated hospital admissions, emergency department visits, and complications from medications, especially glucocorticoids. Unfortunately, available treatments for recurrent pericarditis are very limited, including only a handful of medications such as aspirin/NSAIDs, glucocorticoids, colchicine, and immunosuppressants (such as interleukin-1 (IL-1) blockers, azathioprine, and intravenous human immunoglobulins). Until recently, the clinical experience with the latter class of medications was very limited. Nevertheless, in the last decade, experience with IL-1 blockers has consistently grown, and valid clinical data have emerged from randomized clinical trials. Accordingly, IL-1 blockers are a typical paradigm shift in the treatment of refractory recurrent pericarditis with a clearly positive cost/benefit ratio for those unfortunate patients with multiple recurrences. A drawback related to the above-mentioned medications is the absence of universally accepted and established treatment protocols regarding the full dose administration period and the need for a tapering protocol for individual medications. Another concern is the need for long-standing treatments, which should be discussed with the patients. The above-mentioned unmet needs are expected to be addressed in the near future, such as further insights into pathophysiology and an individualized approach to affected patients. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known for its pivotal role in enhancing insulin secretion and reducing glucagon release from the pancreas. Diabetic nephropathy, which is characterized by albuminuria, represents a significant microvascular complication of diabetes. Most of the previous studies mainly focused on the therapeutic renal protective effect in clinical trials after the administration of GLP-1 receptor agonists (GLP-1 RAs), rather than before administration. Hence, this study aimed to investigate the association between fasting plasma GLP-1 levels and albuminuria before GLP-1 RA administration. A cross-sectional study was designed to evaluate the association between fasting plasma GLP-1 levels and albuminuria in patients with type 2 diabetes mellitus (T2DM). A cohort of 68 participants with T2DM was analyzed using data collected at Wonkwang University Hospital in Iksan, Korea. Logistic regression analysis was employed to determine the odds ratio (OR) and 95% confidence interval (CI) of the incidence of albuminuria between two groups categorized by fasting GLP-1 levels, low (Group L) and high GLP-1 (Group H). The OR (95% CI) for the incidence of albuminuria comparing Group L with Group H of fasting plasma GLP-1 levels was 3.41 (1.16–10.02), p = 0.03 after adjustment for relevant variables including age, gender, fasting plasma glucose, HbA1c, C-peptide, creatinine, and medication use [angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors]. When analyzed as a continuous variable, each 1 pmol/L reduction in fasting plasma GLP-1 levels was associated with an OR (95% CI) of 1.67 (1.17–1.87), p = 0.02, following full adjustment. These results highlight a negative association between fasting plasma GLP-1 levels and the incidence of albuminuria in Korean patients with T2DM, before GLP-1 RA administration. These findings suggest that endogenous GLP-1 may have a beneficial impact in mitigating albuminuria. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course. Background: Angioedema is non-pitting edema that occurs in the deep layers of the skin and subcutaneous tissue due to vascular leakage of plasma resulting from 1 of 2 major pathophysiological processes: mast cell-mediated angioedema and bradykinin-mediated angioedema. While it is a well-recognized adverse reaction of angiotensin-converting enzyme inhibitors, the association of angioedema with angiotensin receptor blockers is relatively less studied. Direct local trauma, although rarely, has been suggested to induce angioedema under certain conditions. We present a unique case of direct, local, trauma-related angioedema in a patient on an angiotensin receptor blocker. Case Report: The patient, an 83-year-old woman on telmisartan for hypertension, hit her neck against the edge of a chair during a fall. Shortly thereafter, she developed progressive airway compromise due to airway angioedema, as noted on direct laryngoscopy. A contrast CT scan of the neck also noted edema of the periglottic and supraglottic regions. She required intravenous corticosteroid administration and intubation in the emergency room and was successfully extubated 3 days after admission. She had no prior history of angioedema or allergy. We hypothesize that increased levels of circulatory bradykinin in the setting of telmisartan, combined with a local release of bradykinin from trauma, was the main pathophysiologic cause of the angioedema. Conclusions: This case report highlights the rare and often forgotten adverse reaction of angioedema with use of angiotensin receptor blockers and confirms the finding of local trauma as a possible trigger. [ABSTRACT FROM AUTHOR]

The core symptoms of attention deficit hyperactivity disorder (ADHD) are due to the hypofunction of the brain's adrenergic (NE) and dopamine (DA) systems. Drugs that enhance DA and NE neurotransmission in the brain by blocking their transporters or receptors are the current therapeutic strategies. Of late, the emerging results point out the serotonergic (5-HT) system, which indirectly modulates the DA activity in reducing the core symptoms of ADHD. On this basis, second-generation antipsychotics, which utilize 5-HT receptors, were prescribed to children with ADHD. However, it is not clear how serotonergic receptors modulate the DA activity to minimize the symptoms of ADHD. The present study investigates the efficacy of serotonergic and alpha-2 adrenergic receptor manipulation in tackling the core symptoms of ADHD and how it affects the DA neuroreceptors in the brain regions involved in ADHD. Fifteen-day-old male spontaneously hypertensive rats (SHRs) received 5-HT1A agonist (ipsapirone) or 5-HT2A antagonist (MDL 100907) (i.p.) or alpha-2 agonist (GFC) from postnatal days 15 to 42 along with age-matched Wistar Kyoto rats (WKY) (n = 8 in each group). ADHD-like behaviors were assessed using a battery of behavioral tests during postnatal days 44 to 65. After the behavioral tests, rat brains were processed to estimate the density of 5-HT1A, 5-HT2A, DA-D1, and DA-D2 neuroreceptors in the prefrontal cortex, the striatum, and the substantia nigra. All three neuroreceptor manipulations were able to minimize the core symptoms of ADHD in SHRs. The positive effect was mainly associated with the upregulation of 5-HT2A receptors in all three areas investigated, while 5-HT1A was in the prefrontal cortex and the substantia nigra. Further, the DA-D1 receptor expression was downregulated by all three neuroreceptor manipulations except for alpha-2 adrenergic receptor agonists in the striatum and 5-HT2A antagonists in the substantia nigra. The DA-D2 expression was upregulated in the striatum while downregulated in the prefrontal cortex and the substantia nigra. In this animal model study, the 5-HT1A agonist or 5-HT2A antagonist monotherapies were able to curtail the ADHD symptoms by differential expression of DA receptors in different regions of the brain. [ABSTRACT FROM AUTHOR]

Background: The association between antihypertensive medication and schizophrenia has received increasing attention; however, evidence of the impact of antihypertensive medication on subsequent schizophrenia based on large-scale observational studies is limited. We aimed to compare the schizophrenia risk in large claims-based US and Korea cohort of patients with hypertension using angiotensin-converting enzyme (ACE) inhibitors versus those using angiotensin receptor blockers (ARBs) or thiazide diuretics. Methods: Adults aged 18 years who were newly diagnosed with hypertension and received ACE inhibitors, ARBs, or thiazide diuretics as first-line antihypertensive medications were included. The study population was sub-grouped based on age (> 45 years). The comparison groups were matched using a large-scale propensity score (PS)-matching algorithm. The primary endpoint was incidence of schizophrenia. Results: 5,907,522; 2,923,423; and 1,971,549 patients used ACE inhibitors, ARBs, and thiazide diuretics, respectively. After PS matching, the risk of schizophrenia was not significantly different among the groups (ACE inhibitor vs. ARB: summary hazard ratio [HR] 1.15 [95% confidence interval, CI, 0.99–1.33]; ACE inhibitor vs. thiazide diuretics: summary HR 0.91 [95% CI, 0.78–1.07]). In the older subgroup, there was no significant difference between ACE inhibitors and thiazide diuretics (summary HR, 0.91 [95% CI, 0.71–1.16]). The risk for schizophrenia was significantly higher in the ACE inhibitor group than in the ARB group (summary HR, 1.23 [95% CI, 1.05–1.43]). Conclusions: The risk of schizophrenia was not significantly different between the ACE inhibitor vs. ARB and ACE inhibitor vs. thiazide diuretic groups. Further investigations are needed to determine the risk of schizophrenia associated with antihypertensive drugs, especially in people aged > 45 years. [ABSTRACT FROM AUTHOR]

Summary: Background: Although enteropathy due to angiotensin II receptor blockers (ARBs) has been known for over 10 years, clinicians' awareness of this condition is still low. Aims: To systematically review the literature about clinical phenotypes, distribution of mucosal changes throughout the gastrointestinal tract and prognosis of enteropathy due to ARBs. Methods: According to PRISMA guidelines, we searched PubMed and Embase for relevant articles up to November 6, 2023. We included full‐text papers, letters, case reports and case series describing enteropathy due to ARBs. Patients were classified into subgroups based on endoscopic and histological findings of different regions of the gastrointestinal tract. The protocol was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/TK67C). Results: We included 94 articles reporting 183 cases (101 female, mean age at diagnosis 69 ± 10 years). The clinical picture at diagnosis was characterised by severe diarrhoea (97%) and weight loss (84%, median −13 kg), leading to hospital admission in 167 (95%) patients. Olmesartan (90%) was most frequently implicated. Villous atrophy (VA) was reported in 164/183 (89%) patients. One hundred and nine had only VA, 12 had pan‐gastrointestinal involvement, 23 had VA and gastric involvement and 19 had VA and colon involvement (predominantly microscopic colitis). Outcomes were reported for 178/183 (97%) patients, who all recovered clinically on ARBs withdrawal. Histological recovery occurred in all 96 patients with VA at baseline who underwent follow‐up duodenal biopsy. Conclusions: Enteropathy due to ARBs is characterised by severe malabsorption often requiring hospital admission and can involve the entire gastrointestinal tract. Clinician awareness can lead to prompt diagnosis and excellent prognosis. [ABSTRACT FROM AUTHOR]

Sparsentan is a dual endothelin/angiotensin II receptor antagonist indicated to reduce proteinuria in patients with primary IgA nephropathy at high risk of disease progression. In vitro data indicate that sparsentan is likely to inhibit or induce various CYP enzymes at therapeutic concentrations. Sparsentan as a victim and perpetrator of CYP3A4 mediated drug–drug interactions (DDIs) has been assessed clinically. A mechanistic, bottom‐up, physiologically‐based pharmacokinetic (PK) model for sparsentan was developed based on in vitro data of drug solubility, formulation dissolution and particle size, drug permeability, inhibition and induction of metabolic enzymes, and P‐glycoprotein (P‐gp) driven efflux. The model was verified using clinical PK data from healthy adult volunteers administered single and multiple doses in the fasted and fed states for a wide range of sparsentan doses. The model was also verified by simulation of clinically observed DDIs. The verified model was then used to test various DDI simulations of sparsentan as a perpetrator and victim of CYP3A4 using an expanded set of inducers and inhibitors with varying potency. Additional perpetrator and victim DDI simulations were performed using probes for CYP2C9 and CYP2C19. Simulations were conducted to predict the effect of complete inhibition of P‐gp inhibition on sparsentan absorption and clearance. The predictive simulations indicated that exposure of sparsentan could increase greater than two‐fold if co‐administered with a strong CYP3A4 inhibitor, such as itraconazole. Other potential DDI interactions as victim or perpetrator were all within two‐fold of control. The effect of complete P‐gp inhibition on sparsentan PK was negligible. [ABSTRACT FROM AUTHOR]

Aim: Persistent symptoms despite guideline‐directed medical therapy (GDMT) and poor tolerance of GDMT are hallmarks of patients with advanced heart failure (HF) with reduced ejection fraction (HFrEF). However, real‐world data on GDMT use, dose, and prognostic implications are lacking. Methods and results: We included 699 consecutive patients with HFrEF and at least one 'I NEED HELP' marker for advanced HF enrolled in a multicentre registry. Beta‐blockers (BB) were administered to 574 (82%) patients, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor–neprilysin inhibitors (ACEi/ARB/ARNI) were administered to 381 (55%) patients and 416 (60%) received mineralocorticoid receptor antagonists (MRA). Overall, ≥50% of target doses were reached in 41%, 22%, and 56% of the patients on BB, ACEi/ARB/ARNI and MRA, respectively. Hypotension, bradycardia, kidney dysfunction and hyperkalaemia were the main causes of underprescription and/or underdosing, but up to a half of the patients did not receive target doses for unknown causes (51%, 41%, and 55% for BB, ACEi/ARB/ARNI and MRA, respectively). The proportions of patients receiving BB and ACEi/ARB/ARNI were lower among those fulfilling the 2018 HFA‐ESC criteria for advanced HF. Treatment with BB and ACEi/ARB/ARNI were associated with a lower risk of death or HF hospitalizations (adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.48–0.84, and HR 0.74, 95% CI 0.58–0.95, respectively). Conclusions: In a large, real‐world, contemporary cohort of patients with severe HFrEF, with at least one marker for advanced HF, prescription and uptitration of GDMT remained limited. A significant proportion of patients were undertreated due to unknown reasons suggesting a potential role of clinical inertia either by the prescribing healthcare professional or by the patient. Treatment with BB and ACEi/ARB/ARNI was associated with lower mortality/morbidity. [ABSTRACT FROM AUTHOR]

Hypertension, also known as high or raised blood pressure, is a common condition in which the force of circulating blood pushing against the walls of the body's arteries is excessive. Antihypertensive drugs such as angiotensin II receptor blockers (ARBs) and angiotensinconverting enzyme (ACE) inhibitors, which target different proteins in the same pathway of the renin-angiotensin system, are usually recommended for first-line treatment. Identifying potential off-target proteins and possible side effects correlated with these antihypertensives can help shed light on the potential additional differences of these drugs and yield helpful information for the design and development of future antihypertensives. MAPK8 was identified as a potential off-target protein of valsartan, the chosen representative for ARB, through reverse docking and molecular dynamics. Valsartan exhibited similar binding as the known cocrystallized inhibitor, whereas lisinopril - an ACE inhibitor used for comparison - was unable to form a stable complex with MAPK8. Network analysis further identified E73 and K166 as key residues for valsartan binding while still maintaining the same signaling network as the apo structure. These observations may assist in future studies for the potential polypharmacology of valsartan and for the identification of new indications of already marketed drugs to facilitate drug discovery for other diseases. [ABSTRACT FROM AUTHOR]

Renin-Angiotensin-System (RAS) inhibitors remained the only effective nephro-protective treatments until recent landmark trials showed that sodium-glucose co-transporter 2 (SGLT2) inhibitors and non-steroid mineral receptor antagonists added-on RAS inhibitor therapy dramatically slowed renal disease progression in patients with chronic kidney disease (CKD). However, despite this impressive advancement, a substantial proportion of patients remains at high risk of renal and cardiovascular events. Thus, we are still far from achieving the therapeutic ceiling in CKD. However, we are entering a new era in the management of patients with CKD with innovative methodological approaches to test disease-modifying medications in the context of personalized medicine. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is increasing in prevalence worldwide, posing major implications for public health such as kidney failure requiring dialysis, and increased risk of cardiovascular and all-cause mortality. Diabetic and hypertensive kidney disease represent the two most common causes of CKD. Until a few years ago, lifestyle modifications, blood pressure, glycaemic and lipid control, along with angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker monotherapy were the only measures for retarding these two diseases and were the cornerstone of treatment for CKD of any aetiology. Effective application of all these measures could reduce the estimated glomerular filtration rate (eGFR) decline in proteinuric CKD roughly from 10–12 to 5–6 mL/min/1.73 m2/year, hence leaving a large unmet need in CKD treatment. In recent years, major kidney outcome trials showed that the addition of sodium–glucose cotransporter-2 inhibitors (SGLT2i) in patients with CKD with or without type 2 diabetes (T2D) and of the non-steroidal mineralocorticoid receptor antagonist finerenone in patients with CKD with T2D can largely improve kidney and cardiovascular outcomes. Elegant analyses of these trials shed further light on these effects, showing that SGLT2i or finerenone use on top of standard-of-care treatment in patients with albuminuric CKD can further reduce chronic eGFR annual loss to 2–2.5 mL/min/1.73 m2, while SGLT2is in normoalbuminuric CKD can reduce this loss <0.5 mL/min/1.73 m2, i.e. well below the aging-related GFR loss. Therefore, current evidence suggests that available treatments, if properly implemented, can help us reach the therapeutic ceiling in the majority of CKD patients. [ABSTRACT FROM AUTHOR]

This article discusses the potential benefits of inhibiting the renin-angiotensin system (RAS) in preventing hypertension. Hypertension is a global health problem that increases the risk of cardiovascular diseases. The RAS plays a crucial role in the development of hypertension, and pharmacological inhibition of the RAS can lower blood pressure. However, long-term treatment with RAS inhibitors can lead to side effects and poor compliance. The article explores the epigenetic mechanisms behind the long-term effects of RAS inhibition and identifies potential gene targets for future treatments. While animal studies have shown promising results, clinical trials have not yet confirmed the same effects in humans. Further research is needed to fully understand and utilize the potential of RAS inhibition in preventing hypertension. [Extracted from the article]

Background: Current hypertension guidelines recommend combination of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker with a calcium-channel blocker or thiazide diuretic as initial antihypertensive therapy in patients with monotherapy uncontrolled hypertension. However, to what extent these two different combinations are comparable in blood pressure (BP)-lowering efficacy and safety remains under investigation, especially in the Chinese population. We investigated the BP-lowering efficacy and safety of the amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies in Chinese patients. Methods: In a multi-center, randomized, actively controlled, parallel-group trial, we enrolled patients with stage 1 or 2 hypertension from July 2018 to June 2021 in 20 hospitals and community health centers across China. Of the 894 screened patients, 560 eligible patients were randomly assigned to amlodipine/benazepril 5/10 mg (n = 282) or benazepril/hydrochlorothiazide 10/12.5 mg (n = 278), with 213 and 212 patients, respectively, who completed the study and had a valid repeat ambulatory BP recording during follow-up and were included in the efficacy analysis. The primary outcome was the change from baseline to 24 weeks of treatment in 24-h ambulatory systolic BP. Adverse events including symptoms and clinically significant changes in physical examinations and laboratory findings were recorded for safety analysis. Results: In the efficacy analysis (n = 425), the primary outcome, 24-h ambulatory systolic BP reduction, was − 13.8 ± 1.2 mmHg in the amlodipine/benazepril group and − 12.3 ± 1.2 mmHg in the benazepril/hydrochlorothiazide group, with a between-group difference of − 1.51 (p = 0.36) mmHg. The between-group differences for major secondary outcomes were − 1.47 (p = 0.18) in 24-h diastolic BP, − 2.86 (p = 0.13) and − 2.74 (p = 0.03) in daytime systolic and diastolic BP, and − 0.45 (p = 0.82) and − 0.93 (p = 0.44) in nighttime systolic and diastolic BP. In the safety analysis (n = 560), the incidence rate of dry cough was significantly lower in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group (5.3% vs 10.1%, p = 0.04). Conclusions: The amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies were comparable in ambulatory systolic BP lowering. The former combination, compared with the latter, had a greater BP-lowering effect in the daytime and a lower incidence rate of dry cough. Trial registration: ClinicalTrials.gov, NCT03682692. Registered on 18 September 2018. [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]

Given possible involvement of the central and peripheral angiotensin system in pain processing, we conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent diabetic peripheral neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the preclinical study, the nociceptive sensitivity was determined in leptin-deficient ob/ob mice, a T2DM model. A clinical retrospective cohort study was conducted, using the medical records of T2DM patients receiving antihypertensives at three hospitals for nearly a decade. In the ob/ob mice, daily treatment with perindopril, an angiotensin-converting enzyme inhibitor (ACEI), or telmisartan, an angiotensin receptor blocker (ARB), but not amlodipine, an L-type calcium channel blocker (CaB), significantly inhibited DPN development without affecting the hyperglycemia. In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni's test indicated significantly later DPN development in the ARB and ACEI groups than the others group. The multivariate Cox proportional analysis detected significant negative association of the prescription of ACEIs or ARBs and β-blockers, but not CaBs or diuretics, with DPN development. Thus, our study suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM. [ABSTRACT FROM AUTHOR]

Background: Keloid is a skin disorder that results from excessive fibrous tissue growth in the area of the initial trauma. Treating keloids can be challenging since the success of various treatments varies from one study to another. Triamcinolone acetonide injection, a standard treatment, can cause undesirable side effects. Meanwhile, the effectiveness of existing topical therapies for keloids is not always reliable. The pro-inflammatory, pro-proliferative, and pro-fibrotic effects of angiotensin II in human skin contribute to keloid formation. Losartan potassium, an angiotensin II blocker, has the potential to act as an anti-keloid agent. Due to the thicker skin structure of a keloid and ease of application, ethosome gel is chosen as a safe and comfortable carrier for losartan potassium, making it a good choice for treating keloids. Methods: In this randomised clinical trial, 46 adults with keloids were divided into two treatment groups. One group of 23 participants received 5% losartan potassium loaded in ethosomal gel, while the other group of 23 participants received intralesional injections of 10% triamcinolone acetonide. Over 12 weeks, changes in POSAS 3.0 scores, degree of erythema and pigmentation, surface area, thickness, and pliability of the keloids will be measured at four different times: baseline, 4 weeks, 8 weeks, and 12 weeks. Statistical analysis will be conducted using SPSS software version 24, with a significance level of p < 0.05. Discussion: Losartan potassium is believed to be beneficial for keloid management because it inhibits the angiotensin II receptor, which plays a role in inflammation, proliferation, and fibrosis. This study examines the efficacy of 5% losartan potassium loaded in ethosomal gel for human keloids. Trial registration: Clinicaltrial.gov identifier NCT05893108. Registered on 7 June 2023. [ABSTRACT FROM AUTHOR]

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active. [ABSTRACT FROM AUTHOR]

Background: The therapeutic efficacy of renin-angiotensin system inhibitors (RASi) in elderly patients with hypertension and at risk of fractures has been in the limelight because of accumulating evidence that localized RAS activation in bone tissue leads to osteoclastic bone resorption, resulting in osteoporosis. This study set out to investigate the association between RASi use and fracture incidence in a large cohort. Methods: We employed a nested case–control design to investigate the association between RASi use and newly developed fractures. A case was defined as a patient newly diagnosed with a fracture between January 2004 and December 2015. We selected 1,049 cases and controls using 1:1 propensity score matching. Conditional logistic regression analysis was conducted to estimate the association between RASi exposure and fracture incidence. Results: Overall, RASi usage was significantly associated with lower odds for fracture incidence (ever-users vs never-users: OR, 0.73; 95% CI, 0.59–0.91). We found that ARB-only users experienced fewer fractures than RASi-never users (OR, 0.65; 95% CI, 0.49–0.86), whereas ACEi-only users or ARB/ACEi-ever users did not. In subgroup analysis, RASi-ever users without cerebrovascular disease, those with a BMI exceeding 23, and statin exposure had significantly lower ORs. Conclusions: The present study established a significant association between RASi use and reduced fracture incidence, thus highlighting the potential clinical utility of RASi use as a preventive strategy in elderly patients at risk for osteoporotic fractures. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical effectiveness of beta-blockers (BBs) and renin-angiotensin-aldosterone system (RAAS) inhibitors in chronic heart failure with preserved ejection fraction (HFpEF). Methods: 100 patients with HFpEF admitted to The Third Affiliated Hospital of Qiqihar Medical University, China, between April and June 2023 were stratified into five groups. Beta-blocker (BB) group received bisoprolol, angiotensin-converting enzyme inhibitor (ACEI) group received benazepril hydrochloride, angiotensin II receptor blocker (ARB) group received candesartan, angiotensin receptor neprilysin inhibitor (ARNI) group received sacubitril valsartan, and mineralocorticoid receptor antagonist (MRA) group received spironolactone. Differences in clinical effectiveness, six-minute walking distance (6MWD), cardiac functionality, quality of life, and survival rate were compared among the groups. Results: Beta-blocker group showed the highest efficacy. After treatment, all groups except MRA showed significant improvement in 6MWD. Also, ACEI, ARB, and ARNI groups exhibited significantly longer 6 MWD than MRA group (p < 0.05). Left ventricular ejection fraction levels showed significant improvement in the ACEI, ARNI, and MRA groups (p < 0.05), while pulmonary artery pressure (PAP) decreased in the BB, ACEI, ARNI, and MRA groups (p < 0.05). After treatment, the Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores of BB, ACEI, ARB, and ARNI groups were significantly lower than before treatment (p < 0.05). All five groups significantly exhibited decline in NTproBNP levels after treatment (p < 0.05). However, at 18-month follow-up, there was no significant difference in survival rates among the groups (p > 0.05). Conclusion: Beta-blockers (BBs) and RAAS inhibitors show promising activity in HFpEF, bisoprolol enhances cardiac function, benazepril improves symptoms, candesartan aids exercise and sacubitril valsartan elevates cardiac class. However, none of these drugs significantly improves clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke is one of the prevalent neurodegenerative disorders; it is generally characterized by sudden abruption of blood flow due to thromboembolism and vascular abnormalities, eventually impairing the supply of oxygen and nutrients to the brain for its metabolic needs. Oxygen-glucose deprived conditions provoke the release of excessive glutamate, which causes excitotoxicity. Summary: Recent studies suggest that circulatory angiotensin-II (Ang-II) has an imperative role in initiating detrimental events through binding central angiotensin 1 (AT1) receptors. Insufficient energy metabolites and essential ions often lead to oxidative stress during ischemic reperfusion, which leads to the release of proinflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and cytokines like interleukin-18 (IL-18) and interleukin- 1beta (IL-1β). The transmembrane glutamate transporters, excitatory amino acid transporter-2 (EAAT-2), which express in astroglial cells, have a crucial role in the clearance of glutamate from its releasing site and convert glutamate into glutamine in normal circumstances of brain physiology. Key Message: During cerebral ischemia, an impairment or dysfunction of EAAT-2 attributes the risk of delayed neuronal cell death. Earlier studies evidencing that angiotensin receptor blockers (ARB) attenuate neuroinflammation by inhibiting the Ang-II/AT1 receptor-mediated inflammatory pathway and that ceftriaxone ameliorates the excitotoxicity-induced neuronal deterioration by enhancing the transcription and expression of EAAT-2 via the nuclear transcriptional factor kappa-B (NF-kB) signaling pathway. The present review will briefly discuss the mechanisms involved in Ang-II/AT1-mediated neuroinflammation, ceftriaxone-induced EAAT-2 expression, and the repurposing hypothesis of the novel combination of ARBs and ceftriaxone for the treatment of cerebral ischemia. [ABSTRACT FROM AUTHOR]

Introduction: Olmesartan, an angiotensin II receptor antagonist, is associated with an uncommon complication of enteropathy that presents insidiously, usually months to years after initial commencement of anti-hypertensive therapy which can be dose-dependent. It has a variable spectrum of clinical presentation but commonly presents as a moderate to severe malabsorptive process with potential severe complications related to poor end-organ perfusion. Lymphocytic gastritis and microscopic colitis are often noted in patients presenting with olmesartan-induced enteropathy; however, hepatic involvement has been less frequently observed. Case Presentation: We illustrate a case of a 43-year-old female presenting with 2 weeks of profuse non-bloody diarrhea in the context of olmesartan enteropathy which was complicated by an acute severe ischemic and enteropathic hepatopathy. Conclusion: Our case prompts clinicians to maintain a high index of suspicion in cases presenting with a seronegative enteropathy and concurrent acute liver injury while on olmesartan therapy. Cessation of olmesartan therapy resulted in prompt resolution of diarrheal symptoms and normalization of the acute transaminitis on subsequent three-week follow-up. [ABSTRACT FROM AUTHOR]