MARRIAGE: A Randomized Trial of Moxonidine Versus Ramipril or in Combination With Ramipril in Overweight Patients With Hypertension and Impaired Fasting Glucose or Diabetes Mellitus. Impact on Blood Pressure, Heart Rate and Metabolic Parameters.

BACKGROUND: Moxonidine, an imidazoline I1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic. AIMS: This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes. METHODS: Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment. RESULTS: Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average -3.5 bpm, p = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters. CONCLUSION: Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment.

Effect of thermal pretreatment and gastrointestinal digestion on the bioactivity of dry-cured ham bone enzymatic hydrolyzates.

This study reports the effect of thermal pretreatment and the use of different commercial proteolytic enzymes (Protamex, Flavourzyme, Protana prime, and Alcalase) on the free amino acid content (FAA), peptide profile, and antioxidant, antidiabetic, antihypertensive, and anti-inflammatory potential (DPPH, FRAP, and ABTS assay, DPP-IV, ACE-I, and NEP inhibitory activities) of dry-cured ham bone hydrolyzates. The effect of in vitro digestion was also determined. Thermal pretreatment significantly increased the degree of hydrolysis, the FAA, and the DPP-IV and ACE-I inhibitory activities. The type of peptidase used was the most significant factor influencing antioxidant activity and neprilysin inhibitory activity. Protana prime hydrolyzates failed to inhibit DPP-IV and neprilysin enzymes and had low values of ACE-I inhibitory activity. After in vitro digestion, bioactivities kept constant in most cases or even increased in ACE-I inhibitory activity. Therefore, hydrolyzates from dry-cured ham bones could serve as a potential source of functional food ingredients for health benefits.

Comparison between screening for primary aldosteronism with and without drug adjustment.

OBJECTIVE: Few studies have evaluated the performance of non-drug-adjusted primary aldosteronism (PA) screening. Therefore, we aimed to examine the consistency between PA screening results with and without drug adjustment and to explore the effectiveness of screening without drug adjustment. METHODS: This prospective study included 650 consecutive patients with a high risk of incidence PA. Patients who initially screened positive underwent rescreening with drug adjustments and confirmatory tests. Regarding the remaining patients, one of every three consecutive patients underwent rescreening with drug adjustments and confirmatory tests. The changes in aldosterone and renin concentrations were compared between patients with essential hypertension (EH) and those with PA before and after drug adjustment. Sensitivity and specificity were used to assess the diagnostic performance of screening without drug adjustment, using the confirmatory test results as the reference. RESULTS: We screened 650 patients with hypertension for PA. Forty-nine patients were diagnosed with PA and 195 with EH. Regarding drugs, 519 patients were taking angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), or diuretics alone or in combination. Forty-one patients were taking beta-blockers. Ninety patients were taking beta-blockers in combination with other drugs. In patients treated with ACEIs, ARBs, CCBs, or diuretics alone, or in combination, or beta-blockers alone, PA positivity was determined using the criteria, aldosterone-to-renin ratio (ARR) >38 pg/mL/pg/mL and plasma aldosterone concentration (PAC) >100 pg/mL, and negativity, using the criteria, ARR <9 pg/mL/pg/mL; the sensitivity and specificity were 94.7% and 94.5%, respectively. After drug adjustment, the sensitivity and specificity of screening were 92.1% and 89%, respectively. CONCLUSIONS: In patients not treated with beta-blockers combined with others, when ARR >38 pg/mL/pg/mL and plasma aldosterone concentration (PAC) >100 pg/mL, or, ARR <9 pg/mL/pg/mL, non-drug-adjusted screening results were identical to with drug adjustment. Non-drug-adjusted screening could reduce the chance of medication adjustment, enable patients to continue their treatments and avoiding adverse effects, is of clinical importance.

Primary aldosteronism (PA) is the most common form of endocrine hypertension. The risk of stroke, myocardial infarction, heart failure, atrial fibrillation, and deterioration of kidney function is higher in PA than in essential hypertension (EH), even with the same blood pressure (BP) levels. However, many patients remain undiagnosed because most antihypertensive drugs substantially interfere with PA screening results, which makes drug adjustment necessary. This can be a time-consuming and unsafe process, requiring 4­6 weeks, and could lead to a hypertensive crisis and other complications. Some studies have suggested that certain antihypertensive drugs can be continued during PR screening. However, few studies have evaluated the performance of non-drug-adjusted PA screening. Therefore, in this prospective study, we aimed to compare patients with hypertension and a high risk of PA before and after drug adjustment and to use confirmatory test results as a reference to explore the diagnostic or exclusion effect. We found that non-drug-adjusted screening performs similarly to drug-adjusted screening in a particular group of patients. Our findings could aid in preventing unnecessary drug adjustment for PA screening, thereby reducing the risk in these patients.

Investigating the Relationship Between Acne and Vasodilatory Medications in a Hospital-Wide Adult Population.

Acne vulgaris is a common chronic dermatological condition characterized by obstruction and inflammation of pilosebaceous units. Recent research on a different dermatologic condition has demonstrated that the use of vasodilatory medications is associated with a decreased relative risk of rosacea. This finding is significant due to the overlapping inflammatory pathways involved in rosacea and acne. Herein, a retrospective cohort study was designed to determine the correlation between vasodilator usage and the risk of developing acne within 5 years, contrasting it with thiazide diuretics, chosen as a control due to its non-vasodilatory antihypertensive mechanism and availability of data. Angiotensin-converting enzyme (ACE) inhibitors (RR, 0.775; 95% CI, 0.727-0.826; P<0.05), angiotensin receptor blockers (ARBs) (RR, 0.739; 95% CI, 0.685-0.797; P<0.05), beta-blockers (BB) (RR, 0.829; 95% CI, 0.777-0.885; P<0.05), and calcium channel blockers (CCB) usage (RR, 0.821, 95% CI, 0.773-0.873; P<0.05) were associated with a significantly lower risk of developing acne within 5 years of initiating therapy compared to thiazide diuretics. It is unclear if thiazide diuretics are more likely to cause acne within the adult population or if vasodilators are protective against the development of acne. Finding mechanisms and therapeutics that lower the risk of developing acne is of significant public health interest, and this study provides a step toward this endeavor. Further research is required to uncover the underlying mechanisms for this reduction in the development of acne.  J Drugs Dermatol. 2024;23(6):446-449.     doi:10.36849/JDD.8362.

Vicinal diaryl pyrazole with tetrazole/urea scaffolds as selective angiotensin converting enzyme-1/cyclooxygenase-2 inhibitors: Design, synthesis, anti-hypertensive, anti-fibrotic, and anti-inflammatory.

As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 µM, respectively). 17b (IC50 0.078 µM) and 17 f (IC50 0.094 µM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 µM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to  l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.

Efficacy of astragalus combined with renin-angiotensin-aldosterone system blockers in the treatment of stage III diabetic nephropathy: a systematic review and meta-analysis.

OBJECTIVE: To determine the efficacy and safety of Astragalus combined with renin-angiotensin-aldosterone system (RAAS) blockers in treating stage III diabetic nephropathy (DN) by meta-analysis. METHODS: PubMed, Embase, Cochrane Library, Wiley, and Web of Science databases were searched for articles published between August 2007 and August 2022. Clinical studies on Astragalus combined with RAAS blockers for the treatment of stage III DN were included. Meta-analysis was performed by RevMan 5.1 and Stata 14.3 software. RESULTS: A total of 32 papers were included in this meta-analysis, containing 2462 patients from randomized controlled trials, with 1244 receiving the combination treatment and 1218 solely receiving RAAS blockers. Astragalus combined with RAAS blockers yielded a significantly higher total effective rate (TER) (mean difference [MD] 3.63, 95% confidence interval [CI] 2.59-5.09) and significantly reduced urinary protein excretion rate (UPER), serum creatinine (Scr), blood urine nitrogen (BUN) and glycosylated hemoglobin (HbAlc) levels. In subgroup analysis, combining astragalus and angiotensin receptor blocker significantly lowered fasting plasma glucose (FPG) and 24 h urinary protein (24hUTP) levels, compared with the combined astragalus and angiotensin-converting enzyme inhibitor treatment. Meanwhile, the latter significantly decreased the urinary microprotein (ß2-MG). Importantly, the sensitivity analysis confirmed the study's stability, and publication bias was not detected for UPER, BUN, HbAlc, FPG, or ß2-MG. However, the TER, SCr, and 24hUTP results suggested possible publication bias. CONCLUSIONS: The astragalus-RAAS blocker combination treatment is safe and improves outcomes; however, rigorous randomized, large-scale, multi-center, double-blind trials are needed to evaluate its efficacy and safety in stage III DN.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are commonly used to treat diabetic neuropathy (DN) and Astragalus membranaceus components are known to improve DN symptoms.We aimed to establish the efficacy and safety of using Astragalus combined with RAAS inhibitors.Astragalus combined with RAAS inhibitors enhances the total effective rate of diabetic neuropathy response to treatment and reduces urinary protein excretion rate, serum creatinine, blood urea nitrogen and HbAlc.Sensitivity analysis affirms study stability, while publication bias was detected for total effective rate, serum creatinine, and 24 h urinary protein levels.

A novel ACE inhibitory peptide from Pelodiscus sinensis Wiegmann meat water-soluble protein hydrolysate.

Pelodiscus sinensis meat is a nutritional food and tonic with angiotensin-converting enzyme (ACE) inhibitory activities. To identify the bioactive substances responsible, several bioinformatics methods were integrated to enable a virtual screening for bioactive peptides in proteins identified within a water-soluble protein fraction of Pelodiscus sinensis meat by Shotgun proteomics. The peptides were generated from the identified proteins by in silico proteolysis using six proteases. A comparison of the numbers of proteins suitable for digestion with each enzyme and the iBAQ (intensity-based absolute quantification) values for these proteins revealed that bromelain and papain were the most suitable proteases for this sample. Next, the water solubility, toxicity, and ADMET (absorption/distribution/metabolism/excretion/toxicity) properties of these peptides were evaluated in silico. Finally, a novel ACE inhibitory peptide IEWEF with an IC50 value of 41.33 µM was identified. The activity of the synthesized peptide was verified in vitro, and it was shown to be a non-competitive ACE inhibitor. Molecular docking revealed that IEWEF could tightly bind to C-ACE, and N-ACE with energies less than 0 kJ mol-1, and the peptide IEWEF can form hydrogen bonds with C-ACE and N-ACE respectively. These results provide evidence that bioactive peptides in the water-soluble protein fraction account for (at least) some of the ACE inhibitory activities observed in Pelodiscus sinensis meat. Furthermore, our research provides a workflow for the efficient identification of novel ACE inhibitory peptides from complex protein mixtures.

Sacubitril-valsartan vs ACE/ARB in pediatric heart failure: A retrospective cohort study.

BACKGROUND: The first angiotensin receptor/neprilysin inhibitor on the market, sacubitril-valsartan, has shown marked improvements in death and hospitalization for heart failure among adults, and is now approved for use in pediatric heart failure. While the ongoing PANORAMA-HF trial is evaluating the effectiveness of sacubitril-valsartan for pediatric patients with a failing systemic left ventricle, the enrollment criteria do not include the majority of pediatric heart failure patients. Additional studies are needed. METHODS: Using the TriNetX database, we performed a propensity score matched, retrospective cohort study to assess the incidence of a composite of all-cause mortality or heart transplant within 1 year. The 519 patients who received sacubitril-valsartan were compared to 519 matched controls who received an angiotensin converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB). RESULTS: There was no significant difference in the incidence of the composite outcome with sacubitril-valsartan over an ACE/ARB (13.3% vs 13.2%, p = 0.95), or among the components of mortality (5.0% vs 5.8%, p = 0.58) or heart transplantation (8.7% vs 7.5%, p = 0.50). Patients who were receiving full goal-directed medical therapy (14.4% vs 16.0%, p = 0.55) also showed no difference in the composite outcome. We observed a significantly increased incidence of hypotension (10% vs 5.2%, p = 0.006) and a trend toward reduced number of hospitalizations per year (mean (SD) 1.3 (4.4) vs 2.0 (9.1), p = 0.09). CONCLUSIONS: Sacubitril-valsartan is not associated with a decrease in the composite of all-cause mortality or heart transplantation within 1 year. Future studies should evaluate the possible reduction in hospitalizations and optimal dosing to minimize hypotension.

Anti-Hypertensive Drugs Moderate the Relationship of Blood Pressure with Alzheimer's Pathologies and Neurodegenerative Markers in Non-Demented Hypertensive Older Adults.

BACKGROUND: We aimed to explore whether the relationships of blood pressures (BPs) with Alzheimer's disease (AD) endophenotypes varied by usage of antihypertensive drugs (AHDs). METHODS: A total of 765 non-demented older adults (mean age: 74.4 years; female: 43.1%) with a self-reported history of hypertension were followed for 6 years. Multiple linear regression and linear-mixed effect models were used to investigate the interaction effects of five categories of AHDs (angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARBs], ß-blocker, calcium channel blockers [CCB], diuretic) with BPs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse pressure [PP]) on AD core pathology and neurodegenerative markers. RESULTS: After Bonferroni correction, significant interaction effects of BPs with AHDs were observed. Elevated SBP or PP in late-life was associated with higher levels of cerebral Aß burden (diuretic alone/ß-blocker × SBP), higher levels of CSF tau proteins (diuretic × SBP/PP, ARBs/CCB × SBP), and lower volume of entorhinal region (ß-blocker × SBP, diuretic × PP) only among hypertensive patients who received no anti-hypertensive treatments, while these associations became compromised or null for users of specific AHDs except for ACEI. Compared to taking other classes of AHDs, elevated SBP in late-life was associated with lower cerebral Aß burden in diuretic users (padjusted = 0.08) and was associated with higher CSF tau proteins in ACEI alone users (padjusted = 0.03). Longitudinal data validated the above-mentioned interaction effects on changes of cerebral Aß burden (padjusted < 0.05), CSF tau proteins (padjusted < 0.10), and brain atrophy (padjusted < 0.05). CONCLUSIONS: The relationships of late-life BP with AD pathology and neurodegeneration could be modified by anti-hypertensive treatments and varied by AHD classification. These findings provide preliminary evidence for tailored BP management strategy for preventing AD among late-life hypertensive adults.

Pharmacological Research Progress of Novel Antihypertensive Drugs.

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely ß-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.

A retrospective prognostic evaluation using unsupervised learning in the treatment of COVID-19 patients with hypertension treated with ACEI/ARB drugs.

Introduction: This study aimed to evaluate the prognosis of patients with COVID-19 and hypertension who were treated with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor B (ARB) drugs and to identify key features affecting patient prognosis using an unsupervised learning method. Methods: A large-scale clinical dataset, including patient information, medical history, and laboratory test results, was collected. Two hundred patients with COVID-19 and hypertension were included. After cluster analysis, patients were divided into good and poor prognosis groups. The unsupervised learning method was used to evaluate clinical characteristics and prognosis, and patients were divided into different prognosis groups. The improved wild dog optimization algorithm (IDOA) was used for feature selection and cluster analysis, followed by the IDOA-k-means algorithm. The impact of ACEI/ARB drugs on patient prognosis and key characteristics affecting patient prognosis were also analysed. Results: Key features related to prognosis included baseline information and laboratory test results, while clinical symptoms and imaging results had low predictive power. The top six important features were age, hypertension grade, MuLBSTA, ACEI/ARB, NT-proBNP, and high-sensitivity troponin I. These features were consistent with the results of the unsupervised prediction model. A visualization system was developed based on these key features. Conclusion: Using unsupervised learning and the improved k-means algorithm, this study accurately analysed the prognosis of patients with COVID-19 and hypertension. The use of ACEI/ARB drugs was found to be a protective factor for poor clinical prognosis. Unsupervised learning methods can be used to differentiate patient populations and assess treatment effects. This study identified important features affecting patient prognosis and developed a visualization system with clinical significance for prognosis assessment and treatment decision-making.

Revealing the ACE receptor binding properties and interaction mechanisms of salty oligopeptides from Stropharia rugosoannulata mushroom by molecular simulation and antihypertensive evaluation.

The salty oligopeptides from Stropharia rugosoannulata have been proven to be potential ACE inhibitors. To investigate the ACE receptor binding properties and interaction mechanisms of salty oligopeptides, the molecular interaction, dynamics simulation, and antihypertensive evaluation cross-validation strategy were employed to reveal the oligopeptides' binding reactions and modes with the ACE receptor. Single oligopeptide (ESPERPFL, KSWDDFFTR) had exothermic and specific binding reactions with the ACE receptor, driven by hydrogen bonds and van der Waals forces. The coexistence of the multiple oligopeptide molecules did not produce the apparent ACE receptor competition binding reactions. The molecular dynamics simulation verified that the two oligopeptides disturbed the ACE receptor's different residue regions. Both oligopeptides could form stable complexes with the ACE receptor. Based on the classification of 50 oligopeptides' binding modes, ESPERPFL and KSWDDFFTR belonged to different classes, and their receptor binding modes and sites complemented, resulting in a potential synergistic effect on ACE inhibition. The antihypertensive effect of KSWDDFFTR and its distribution in the body were evaluated using SHR rats orally and ICR mice by tail vein injection, and KSWDDFFTR had antihypertensive effects within 8 h. The study provides a theoretical basis for understanding salty oligopeptides' ACE receptor binding mechanism and their antihypertensive effects.

Novel Angiotensin-Converting Enzyme-Inhibitory Peptides Obtained from Trichiurus lepturus: Preparation, Identification and Potential Antihypertensive Mechanism.

Peptides possessing antihypertensive attributes via inhibiting the angiotensin-converting enzyme (ACE) were derived through the enzymatic degradation of Trichiurus lepturus (ribbonfish) using alkaline protease. The resulting mixture underwent filtration using centrifugation, ultrafiltration tubes, and Sephadex G-25 gels. Peptides exhibiting ACE-inhibitory properties and DPPH free-radical-scavenging abilities were isolated and subsequently purified via LC/MS-MS, leading to the identification of over 100 peptide components. In silico screening yielded five ACE inhibitory peptides: FAGDDAPR, QGPIGPR, IFPRNPP, AGFAGDDAPR, and GPTGPAGPR. Among these, IFPRNPP and AGFAGDDAPR were found to be allergenic, while FAGDDAPRR, QGPIGPR, and GPTGPAGP showed good ACE-inhibitory effects. IC50 values for the latter peptides were obtained from HUVEC cells: FAGDDAPRR (IC50 = 262.98 µM), QGPIGPR (IC50 = 81.09 µM), and GPTGPAGP (IC50 = 168.11 µM). Peptide constituents derived from ribbonfish proteins effectively modulated ACE activity, thus underscoring their therapeutic potential. Molecular docking and modeling corroborated these findings, emphasizing the utility of functional foods as a promising avenue for the treatment and prevention of hypertension, with potential ancillary health benefits and applications as substitutes for synthetic drugs.

Generalizable Approach to Quantifying Guideline-Directed Medical Therapy.

BACKGROUND: Quantifying guideline-directed medical therapy (GDMT) intensity is foundational for improving heart failure (HF) care. Existing measures discount dose intensity or use inconsistent weighting. METHODS: The Kansas City Medical Optimization (KCMO) score is the average of total daily to target dose percentages for eligible GDMT, reflecting the percentage of optimal GDMT prescribed (range, 0-100). In Change the Management of Patients With HF, we computed KCMO, HF collaboratory (0-7), and modified HF Collaboratory (0-100) scores for each patient at baseline and for 1-year change in established GDMT at the time (mineralocorticoid receptor antagonist, ß-blocker, ACE [angiotensin-converting enzyme] inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor). We compared baseline and 1-year change distributions and the coefficient of variation (SD/mean) across scores. RESULTS: Among 4532 patients at baseline, mean KCMO, HF collaboratory, and modified HF Collaboratory scores were 38.8 (SD, 25.7), 3.4 (1.7), and 42.2 (22.2), respectively. The mean 1-year change (n=4061) for KCMO was -1.94 (17.8); HF collaborator, -0.11 (1.32); and modified HF Collaboratory, -1.35 (19.8). KCMO had the highest coefficient of variation (0.66), indicating greater variability around the mean than the HF collaboratory (0.49) and modified HF Collaboratory (0.53) scores, reflecting higher resolution of the variability in GDMT intensity across patients. CONCLUSIONS: KCMO measures GDMT intensity by incorporating dosing and treatment eligibility, provides more granularity than existing methods, is easily interpretable (percentage of ideal GDMT), and can be adapted as performance measures evolve. Further study of its association with outcomes and its usefulness for quality assessment and improvement is needed.

Population pharmacokinetics of ramipril in patients with chronic heart failure: A real-world longitudinal study.

In patients with chronic heart failure (CHF), the use of angiotensin-converting enzyme inhibitors, including ramipril, is recommended to reduce the risk of heart failure worsening, hospitalisation, and death. Our aim was to investigate the influence of body composition on the pharmacokinetics of ramipril and its active metabolite ramiprilat and to evaluate the changes in pharmacokinetics after prolonged therapy. Twenty-three patients with CHF who were on regular therapy with ramipril participated at the first study visit ( median age 77 years, 65 % male, and 70 % New York Heart Association Class II); 19 patients attended the second study visit and the median time between the two visits was 8 months. Pharmacokinetics were assessed using a nonlinear mixed-effects parent-metabolite model comprising two compartments for ramipril and one compartment for ramiprilat. The influence of body size and composition was best described by an allometric relationship with fat-free mass. In addition, ramipril clearance was related to patient age and daily ramipril dose, while clearance of ramiprilat was influenced by glome rular filtration rate and daily ramipril dose. There were no clinically relevant changes in the pharmacokinetics of ramipril and ramiprilat between the study visits. Due to the relatively stable pharmacokinetics of ramipril, regular outpatient visits at 6-month intervals seem appropriate to evaluate ramipril therapy.

Screening and rational identification of a novel angiotensin-converting enzyme C-domain inhibitory peptide from Fabaceae food peptide library.

Angiotensin-converting enzyme (ACE), consisting of N-domain and C-domain, is a key regulator of blood pressure. The use of cACE-specific inhibitors helps minimize side effects in clinical applications. Legumes are a good source of proteins containing ACE inhibitory peptides; however, no studies have reported the identification of cACE-specific inhibitory peptides from Fabaceae. In this study, thermal hydrolysates from seeds, sprouts, pods, seedlings, and flowers of legumes were analyzed. Flowers of legumes exhibited a C-domain-preference ACE inhibition and anti-hypertensive effect in rats. Screening the legume peptide library identified a novel cACE inhibitory peptide, SJ-1. This study reported the first identification of cACE inhibitory peptide from Fabaceae foods. SJ-1, identified from the legume flowers, interacted with active site residues of cACE, leading to the inhibition of ACE activity, downregulation of bradykinin levels, and reduction of blood pressure. These findings also suggested the potential of legume proteins as a source of cACE inhibitory peptides.

Beta blockers are associated with lower all-cause mortality among HFpEF patients.

BACKGROUND: The evidence regarding beta blocker (BB) benefit in heart failure with preserved ejection fraction (HFpEF) remains inconclusive, leading to consideration of BB withdrawal in this population. OBJECTIVES: In this study, we retrospectively analyzed the association of BB on all-cause mortality in HFpEF patients. METHODS: This is a single-center retrospective cohort study of 20,206 patients with left ventricular ejection fraction (EF) ≥ 50% who were hospitalized with decompensated HF between January 2011 and March 2020. Survival is reported at 30 days, 1 year, and 3 years. A secondary analysis comparing mortality for patients on BB with additional indications including hypertension (HTN), coronary artery disease (CAD), and atrial fibrillation (AF) was completed. Mortality was compared between patients on BB and additional therapies of spironolactone or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs). RESULTS: BB showed lower all-cause mortality at 30 days, 1 year, and 3 years (p < 0.0001). This association with lower all-cause mortality was validated by a supplementary propensity score-matched analysis. At 3 years, there was significant mortality reduction with addition of BB to either spironolactone (p = 0.0359) or ACEi/ARBs (p < 0.0001). CONCLUSION: In a large single-center retrospective registry, BB use was associated with lower mortality in HFpEF patients with a recent decompensated HF hospitalization. The mortality benefit persisted in those treated with spironolactone or ACEi/ARBs, and in those with AF. This provocative data further highlights the uncertainty of the benefit of BB use in this cohort and calls for re-consideration of BB withdrawal, especially in those tolerating it well, without conclusive, large, and randomized trials showing lack of benefit or harm.

What to do with foundation therapies for heart failure for patients with end-stage kidney disease on haemodialysis.

There is a significant burden of cardiovascular disease morbidity and mortality in the end-stage kidney disease population, driven by traditional and non-traditional risk factors. Despite its prevalence, heart failure is difficult to diagnose in the dialysis population due to overlapping clinical presentations, limitations of investigations, and the impact on the cardiorenal axis. 'Foundation therapies' are the key medications which improve patient outcomes in heart failure with reduced ejection fraction and include beta-blockers, renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors. They are underutilised in the dialysis population due to the exclusion of chronic kidney disease patients from major trials and legitimate clinical concerns e.g. hyperkalaemia, intradialytic hypotension and residual kidney function preservation. A coordinated cardiorenal multidisciplinary approach can guide appropriate diagnostic considerations (biomarkers interpretation, imaging, addressing unique complications of kidney disease), optimise dialysis management (prescription length, frequency and ultrafiltration targets) and when at euvolaemia facilitate the stepwise introduction of appropriate foundation therapies.

Correlation between Angiotensin Inhibitor Administration and Longer Survival in Patients Who Underwent Curative Resection for Pancreatic Cancer.

PURPOSE: The microenvironment of pancreatic ductal adenocarcinoma (PDAC) with extensive desmoplastic stroma contributes to aggressive cancer behavior. Angiotensin system inhibitors (ASIs) reduce stromal fibrosis and are a promising therapeutic strategy. The purpose of this study was to examine how ASIs affected the oncological results of patients who had their PDAC removed. MATERIALS AND METHODS: A retrospective assessment was conducted on the clinicopathological and survival data of patients who received curative resection for PDAC at Severance Hospital between January 2012 and December 2019. RESULTS: A total of 410 participants (228 male and 182 female), with a median follow-up period of 12.8 months, were included in this study. Patients were divided into three groups, based on ASI use and history of hypertension: group 1, normotensive and never used ASI (n=210, 51.2%); group 2, ASI non-users with hypertension (n=50, 12.2%); and group 3, ASI users with hypertension (n=150, 36.6%). The three groups did not differ significantly in terms of age, sex, kind of operation, T and N stages, or adjuvant and neoadjuvant therapy. Moreover, there was no discernible difference in disease-free survival between those who used ASI and those who did not (p=0.636). The 5-year overall survival (OS) rates in groups 1, 2, and 3 were 52.6%, 32.3%, and 38.0%, respectively. However, the OS rate of ASI users was remarkably higher than that of non-users (p=0.016). CONCLUSION: In patients with resected PDAC, ASI is linked to longer survival rates. Furthermore, for individuals with hypertension, ASI in conjunction with conventional chemotherapy may be an easy and successful treatment option.