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Background The influence of aldosterone breakthrough (ABT) on proteinuria reduction during renin‐angiotensin system (RAS) inhibition for spontaneous proteinuric chronic kidney disease (CKDP) has not been determined in dogs. Objectives Determine whether ABT occurs in dogs with CKDP and if it is associated with decreased efficacy in proteinuria reduction during RAS inhibitor treatment. Animals Fifty‐six client‐owned dogs with CKDP and 31 healthy client‐owned dogs. Methods Prospective, multicenter, open‐label clinical trial. Dogs were treated with an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker alone or in combination at the attending clinician's discretion and evaluated at 5 time points over 6 months. Healthy dogs were used to determine the urine aldosterone‐to‐creatinine ratio cutoff that defined ABT. The relationship of ABT (present at ≥50% of visits) and proteinuria outcome (≥50% reduction in urine protein‐to‐creatinine ratio from baseline at ≥50% of subsequent visits) was evaluated. Mixed effects logistic regression was used to evaluate the relationship between clinical variables and outcomes (either successful proteinuria reduction or ABT). Results Thirty‐six percent (20/56) of dogs had successful proteinuria reduction. Between 34% and 59% of dogs had ABT, depending on the definition used. Aldosterone breakthrough was not associated with proteinuria outcome. Longer duration in the study was associated with greater likelihood of successful proteinuria reduction (P = .002; odds ratio, 1.6; 95% confidence interval [CI], 1.2‐2.2). Conclusions and Clinical Importance Aldosterone breakthrough was common in dogs receiving RAS inhibitors for CKDp but was not associated with proteinuria outcome.

Angiotensinogen, the unique precursor of all angiotensin hormones of the renin‐angiotensin‐aldosterone system (RAAS), is now a potential target in a novel pharmacological approach to hypertension. Investigating the factors that influence angiotensinogen levels, including sex hormones, may have important therapeutic implications. Plasma angiotensinogen and sex hormones levels were measured in 5171 Multi‐Ethnic Study of Atherosclerosis (MESA) participants. Linear models were employed to determine the associations of angiotensinogen with sex hormones. Angiotensinogen levels were significantly higher in postmenopausal women receiving hormone therapy (HT, n = 760) compared to women not receiving HT (n = 1675) and in men (n = 2736). A positive association was present between angiotensinogen and estrogen levels that differed in magnitude between sexes and by HT status among postmenopausal women (women on HT: r = 0.44, p < 0.0001; women not on HT: r = 0.09, p = 0.0002; and men: r = 0.07, p = 0.0003). The type of HT formulation (estrogen or estrogen/progesterone) and its duration of use did not significantly affect angiotensinogen levels. This study suggests a significant role of sex, estrogen, and HT in the pathophysiology of angiotensinogen, which is important given the development and testing of angiotensinogen‐targeting therapeutics.

Background Information regarding efficacy of the angiotensin II receptor blocker, telmisartan, for treatment of proteinuria in dogs is limited. Objective To evaluate the antiproteinuric efficacy of telmisartan, as compared to enalapril, in dogs with chronic kidney disease and persistent, renal proteinuria. Animals Thirty‐nine client‐owned dogs with chronic kidney disease and urinary protein‐to‐creatinine ratio (UPC) > 0.5 (if azotemic) or ≥ 1.0 (if nonazotemic). Methods In this prospective, randomized, double‐masked clinical trial, dogs were block randomized, according to presence or absence of azotemia and systemic arterial hypertension, to receive telmisartan (1.0 mg/kg PO q24h), or enalapril (0.5 mg/kg PO q12h), and followed for 120 days. Up‐titration of study drug dosage on days 30 and 60, and addition of the other study drug at day 90, were performed if UPC > 0.5 was noted at these visits. Percentage change in UPC relative to baseline was calculated for all time points. Data are presented as median (range). Results Thirty‐nine (20 telmisartan‐treated, 19 enalapril‐treated) dogs were included. At day 30, percentage change in UPC was greater for telmisartan‐treated (−65% [−95% to 104%]) vs enalapril‐treated (−35% [−74% to 87%]) dogs (P = .002). Among dogs persistently proteinuric at earlier visits, telmisartan remained superior to enalapril at days 60 (P = .02) and 90 (P = .02). No difference in percentage change in UPC between study groups was observed at day 120, when combination therapy was allowed. Combination therapy resulted in relevant azotemia in 4/13 (31%) dogs. Conclusions and Clinical Importance Telmisartan might be a suitable first‐line therapy for dogs with renal proteinuria.

To evaluate the relationship between Renin-Angiotensin-Aldosterone System (RAAS) activity and Perfusion Index (PI) in children with Postural Tachycardia Syndrome (POTS), and to assess the diagnostic performance of Angiotensin II (AngII) and PI for POTS status. A total of 65 children with POTS and 65 age- and sex-matched healthy controls were enrolled. Plasma renin, angiotensin I (AngI), AngII, and aldosterone were quantified via enzyme-linked immunosorbent assay, and PI was measured using a pulse oximetry-based monitor during head-up tilt testing. Statistical analyses included Receiver Operating Characteristic (ROC) curve analysis of AngII and PI for POTS status, binary logistic regression, and Pearson correlation. Compared to controls, children with POTS demonstrated a significantly lower PI (4.64 ± 1.54 vs 6.19 ± 1.64%; adjusted < 0.005) and higher AngII levels (114.07 ± 7.69 vs 109.20 ± 10.44 pg/mL; adjusted = 0.012). ROC analysis indicated that PI had a stronger diagnostic value (AUC = 0.753, 95% CI: 0.670-0.836) than AngII (AUC = 0.654, 95% CI: 0.559-0.749) in identifying POTS. In logistic regression, only PI remained an in nt predictor of POTS (Odds Ratio = 0.577, 95% CI: 0.442-0.755, < 0.001). A significant inverse correlation was observed between AngII and PI (r = -0.459, < 0.001). PI is a valuable, noninvasive clinical marker for POTS in children, demonstrating superior diagnostic utility compared to AngII. While elevated AngII retains clinical significance by reflecting underlying pathophysiology and disease severity, its independent predictive value is limited. The combined assessment of PI and AngII may enhance the pathophysiological understanding and management strategies for pediatric POTS.

Background Angiotensin‐converting enzyme 2 (ACE2) is a homologue of angiotensin‐converting enzyme (ACE) and produces angiotensin peptides (APs), such as angiotensin 1‐9 and 1‐7 that are vasodilatory and natriuretic, and act to counterbalance angiotensin II. Hypothesis Evidence of ACE2 can be found in tissues and plasma of dogs. Equilibrium concentrations of renin angiotensin aldosterone system (RAAS) APs differ in dogs with heart disease compared to healthy dogs and recombinant human ACE2 (rhACE2) alters relative concentrations of APs. Animals Forty‐nine dogs with and 34 dogs without heart disease. Methods Immunohistochemistry and assays for tissue and plasma ACE2 activity and equilibrium concentrations of plasma RAAS APs were performed. Results Immunolabeling for ACE2 was present in kidney and myocardial tissue. Median plasma ACE2 activity was significantly increased in dogs with congestive heart failure (CHF; 6.9 mU/mg; interquartile range [IQR], 5.1‐12.1) as compared to control (2.2 mU/mg; IQR, 1.8‐3.0; P = .0003). Plasma equilibrium analysis of RAAS APs identified significant increases in the median concentrations of beneficial APs, such as angiotensin 1‐7, in dogs with CHF (486.7 pg/mL; IQR, 214.2‐1168) as compared to those with preclinical disease (41.0 pg/mL; IQR, 27.4‐45.1; P < .0001) or control (11.4 pg/mL; IQR, 7.1‐25.3; P = .01). Incubation of plasma samples from dogs with CHF with rhACE2 increased beneficial APs, such as angiotensin 1‐9 (preincubation, 10.3 pg/mL; IQR, 4.4‐37.2; postincubation, 2431 pg/mL; IQR, 1355‐3037; P = .02), while simultaneously decreasing maladaptive APs, such as angiotensin II (preincubation, 53.4 pg/mL; IQR, 28.6‐226.4; postincubation, 2.4 pg/mL; IQR, 0.50‐5.8; P = .02). Conclusions and Clinical Importance Recognition of the ACE2 system expands the conventional view of the RAAS in the dog and represents an important potential therapeutic target.

Background Little is known about the effect of renin angiotensin aldosterone system‐inhibiting (RAASi) drugs on alternative angiotensin peptides (APs) such as angiotensin 1‐7 (Ang1‐7), which are mediated by angiotensin‐converting enzyme 2 (ACE2). Hypothesis/Objectives Angiotensin receptor blockers (ARBs) would alter balance of APs and differences would be magnified in vitro by incubation of plasma samples with recombinant human ACE2 (rhACE2). Animals Six cats with cardiomyopathy (CM), 8 healthy cats. Methods Prospective open label trial. Plasma equilibrium concentrations of APs were measured in healthy cats as well as in CM cats that first received no RAASi drugs (CMnoRAASi) and then after 14 days of PO telmisartan (CMARB). Plasma APs also were measured after in vitro incubation with rhACE2. Results No significant differences were found between healthy and CMnoRAASi groups. Concentrations of several APs, including angiotensin I (AT1) and angiotensin II (AT2) were significantly different between CMnoRAASi and CMARB groups. Incubation with rhACE2 decreased AT1 and AT2 in both groups. The geometric mean concentration of Ang1‐7 was significantly higher in CMARB (4.9 pg/mL; 95% confidence interval [CI], 3.7‐6.4 pg/mL) vs CMnoRAASi (3.2 pg/mL; 95% CI, 2.2‐4.7 pg/mL; P = .01) and in CMARB + ACE2 (5.0 pg/mL; 95% CI, 3.9‐6.4 pg/mL) vs CMnoRAASi + ACE2 (3.0 pg/mL; 95% CI, 1.7‐5.5 pg/mL; P = .01). The most favorable theoretical AP profile that maximized Ang1‐7 and other alternative APs was CMARB + ACE2. Conclusions and Clinical Importance Balance between traditional and alternative APs can be favorably shifted using ARBs and in vitro incubation with rhACE2. These data shed light on new AP‐targeting strategies in cats with CM.

This study aimed to investigate the role of let‐7a‐5p in the pathogenesis of essential hypertension (EH) and its correlation with the renin‐angiotensin‐aldosterone system (RAAS) biomarkers. Ninety‐eight EH patients and 24 healthy controls (HC) enrolled in the study were assayed for the relative expression of let‐7a‐5p in plasma by quantitative real‐time polymerase chain reaction (Q‐PCR), and biomarkers of the RAAS system, including angiotensin‐converting enzyme 2 (ACE2), Ang (1‐7), MAS1, angiotensin‐converting enzyme (ACE), angiotensin II (Ang II), and angiotensin II type 1 receptor (AT1R), were determined by enzyme‐linked immunosorbent assay (ELISA) The expression levels of the biomarkers of RAAS system were determined. The results showed that the expression levels of let‐7a‐5p in the plasma of EH patients were remarkably higher than those of HC. The prediction model of combined let‐7a‐5p showed high accuracy by constructing a subject operating characteristic (ROC) curve with an area under the curve (AUC) of 0.885, and the reliability of the model was further verified by the Hosmer–Lemeshow (H–L) goodness‐of‐fit test, the Model Calibration Curve, and the Decision Curve Analysis. Spearman correlation analysis revealed that the expression of let‐7a‐5p was positively correlated with ACE (r = 0.352, p < 0.001), and mediation analysis indicated that ACE partially mediated between let‐7a‐5p and the development of hypertension. The present study concludes with the potential of let‐7a‐5p as a companion diagnostic biomarker for EH. It suggests that there may be a complex regulatory mechanism between it and specific RAAS biomarkers, which provides a new perspective on the pathogenesis and diagnosis of EH.

Background Information regarding the efficacy of telmisartan for feline systemic arterial hypertension is limited. Objectives To evaluate the safety and efficacy of PO administered telmisartan solution in hypertensive cats. Animals Client‐owned cats with indirect systolic arterial blood pressure (SBP) of 160‐200 mm Hg, based on multiple measurements. Methods This multicenter trial consisted a 28‐day, prospective, randomized, double‐blind, placebo‐controlled, parallel group, efficacy phase and a 154‐day extended‐use telmisartan phase. Hypertensive cats were randomly assigned to receive 1.5 mg telmisartan/kg PO q12h for 14 days, followed by 2 mg telmisartan/kg PO q24h, or equivalent volume of placebo. Systolic blood pressure was measured on days 0, 14, and 28. Change in SBP compared to baseline was calculated for days 14 and 28. Telmisartan efficacy was defined as significant decrease in SBP at day 14 compared to placebo and a clinically relevant (>20 mm Hg) decrease in SBP at day 28. Results Two‐hundred twenty‐one cats were included. On day 14, least squares mean (95% confidence interval) SBP decrease was significantly larger in telmisartan‐treated (−23.3 mm Hg [−28.2 to −18.3]) versus placebo‐treated (−7.5 mm Hg [−13.6 to −1.5]) cats (P = .0005). On day 28, telmisartan treatment resulted in a clinically relevant SBP decrease (−23.9 mm Hg [−27.8 to −20.0]), whereas placebo did not (−11.6 mm Hg [−17.4 to −5.9 mm Hg]). The decrease in SBP persisted over the 6‐month trial in telmisartan‐treated cats. Conclusions and Clinical Importance Telmisartan significantly decreased SBP to a clinically relevant extent and was well tolerated in hypertensive cats.

Background Use of telmisartan for the treatment of proteinuria in dogs has not been thoroughly investigated. Hypothesis/Objectives Telmisartan can be effective for the treatment of proteinuria in dogs. Animals Forty‐four client‐owned dogs with proteinuria. Methods Retrospective study. Dogs diagnosed with clinically relevant proteinuria (nonazotemic dogs with a urine protein‐to‐creatinine ratio [UPC] ≥2 and azotemic dogs with UPC ≥0.5) were separated into 3 groups: telmisartan alone, with benazepril, or with mycophenolate. The UPC was recorded before treatment and at subsequent follow‐ups (1, 3, 6, and 12 months, as available). Response to treatment was categorized as complete (UPC ˂0.5), partial (UPC decreased by ≥50% but still ≥0.5), or no response (UPC decreased by <50%). Serum creatinine and potassium concentrations and arterial pressure also were recorded. Results In the telmisartan group, treatment response (UPC ˂0.5 or decreased by ≥50%) was observed in 70%, 68%, 80%, and 60% of dogs at 1, 3, 6, and 12 months follow‐up, respectively. No significant changes were noted in serum creatinine or potassium concentrations, or in arterial blood pressure at all follow‐up times. Adverse effects consisted of mild self‐limiting gastrointestinal signs in 5 dogs. Two dogs developed clinically relevant azotemia that required discontinuation of the treatment before the first follow‐up. Conclusions and Clinical Importance Telmisartan can be considered for treatment of proteinuria in dogs, alone or in combination with other treatments for proteinuria.

Aims At present, the clinical burden of hypokalaemia and hyperkalaemia among European heart failure patients, and relationships between serum potassium and adverse clinical outcomes in this population, is not well characterized. The aim of this study was to investigate associations between mortality, major adverse cardiac events, and renin–angiotensin–aldosterone system inhibitor (RAASi) discontinuation across serum potassium levels, in a UK cohort of incident heart failure patients. Methods and results This was a retrospective observational cohort study of newly diagnosed heart failure patients listed in the Clinical Practice Research Datalink, with a first record of heart failure (index date) between 2006 and 2015. Hypokalaemia and hyperkalaemia episodes were defined as the number of serum potassium measurements exceeding each threshold (<3.5, ≥5.0, ≥5.5, and ≥6.0 mmol/L), without such a measurement in the preceding 7 days. Risk equations developed using Poisson generalized estimating equations were utilized to estimate adjusted incident rate ratios (IRRs) relating serum potassium and clinical outcomes (death, major adverse cardiac event, and RAASi discontinuation). Among 21,334 eligible heart failure patients, 1969 (9.2%), 7648 (35.9%), 2725 (12.8%), and 763 (3.6%) experienced episodes of serum potassium <3.5, ≥5.0, ≥5.5, and ≥6.0 mmol/L, respectively. The adjusted IRRs for mortality exhibited a U‐shaped association pattern with serum potassium. Relative to the reference category (4.5 to <5.0 mmol/L), adjusted IRRs for mortality were estimated as 1.98 (95% confidence interval: 1.69–2.33), 1.23 (1.12–1.36), 1.35 (1.14–1.60), and 3.02 (2.28–4.02), for patients with serum potassium <3.5, ≥5.0 to <5.5, ≥5.5 to <6.0, and ≥6.0 mmol/L, respectively. The adjusted IRRs for major adverse cardiac events demonstrated a non‐statistically significant relationship with serum potassium. Discontinuation of RAASi therapy exhibited a J‐shaped trend in association with serum potassium. Compared with the reference category (4.5 to <5.0 mmol/L), adjusted IRRs were estimated as 1.07 (0.89–1.28) in patients with serum potassium <3.5 mmol/L, increasing to 1.32 (1.14–1.53) and 2.19 (1.63–2.95) among those with serum potassium ≥5.5 to <6.0 and ≥6.0 mmol/L, respectively. Conclusions In UK patients with new onset heart failure, both hypokalaemia and hyperkalaemia were associated with increased mortality risk, and hyperkalaemia was associated with increased likelihood of RAASi discontinuation. Our results demonstrate the potential importance of serum potassium monitoring for heart failure outcomes and management.