Safety and efficacy of orally administered telmisartan for the treatment of systemic hypertension in cats: Results of a double-blind, placebo-controlled, randomized clinical trial.

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.

Efficacy of long-term oral telmisartan treatment in cats with hypertension: Results of a prospective European clinical trial.

BACKGROUND: Efficacy of telmisartan in treating hypertension (HT) in cats has not been largely investigated. OBJECTIVE: Telmisartan oral solution effectively controls systolic arterial blood pressure (SABP) in hypertensive cats. ANIMALS: Two-hundred eighty-five client-owned cats with systemic HT. METHODS: Prospective, multicenter, placebo-controlled, randomized, double-blinded study. Hypertensive cats diagnosed with SABP ≥160 mmHg and ≤200 mmHg without target-organ-damage were randomized (2 : 1 ratio) to receive 2 mg/kg telmisartan or placebo q24 PO. A 28-day efficacy phase was followed by a 120-day extended use phase. Efficacy was defined as significant difference in mean SABP reduction between telmisartan and placebo on Day 14 and group mean reduction in SABP of > 20 mmHg by telmisartan on Day 28 compared to baseline. RESULTS: Two-hundred fifty-two cats completed the efficacy and 144 cats the extended use phases. Mean SABP reduction at Day 14 differed significantly between groups (P < .001). Telmisartan reduced baseline SABP of 179 mmHg by 19.2 (95% confidence interval [CI]: 15.92-22.52) and 24.6 (95% CI: 21.11-28.14) mmHg at Days 14 and 28. The placebo group baseline SABP of 177 mmHg was reduced by 9.0 (95% CI: 5.30-12.80) and 11.4 (95% CI: 7.94-14.95) mmHg, respectively. Of note, 52% of telmisartan-treated cats had SABP <150 mmHg at Day 28. Mean SABP reduction by telmisartan in severe (≥180 mmHg) and moderate HT (160-179 mmHg) was comparable and persistent over time. CONCLUSIONS AND CLINICAL IMPORTANCE: Telmisartan solution (PO) was effective in reducing SABP in hypertensive cats with SABP ≥160 mmHg and ≤200 mmHg.

Profibrotic effects of angiotensin II and transforming growth factor beta on feline kidney epithelial cells.

OBJECTIVES: The aim of this study was to evaluate the role of angiotensin II (AT-II) and its main mediator, transforming growth factor beta 1 (TGF-ß1), in the development of feline renal fibrosis. METHODS: Expression of marker genes indicating epithelial-to-mesenchymal transition (EMT), profibrotic mediators and matricellular proteins was measured in feline kidney epithelial cells (Crandell Rees feline kidney [CRFK] cells) after incubation with AT-II and/or TGF-ß1. RESULTS: Cells incubated with TGF-ß1 or the combination of TGF-ß1 with AT-II showed clear EMT with more stretched fibroblastic cells, whereas the cells incubated without TGF-ß1 and AT-II (control) showed more epithelial cells. Gene expression of collagen type I (COL1), tenascin-C (TNC), trombospondin-1 (TSP-1), connective tissue growth factor (CTGF) and alpha-smooth muscle actin (α-SMA) increased significantly after incubation of the CRFK cells with TGF-ß1 or TGF-ß1 in combination with AT-II for 12 h. As incubation of the CRFK cells with only AT-II did not show any significant rise in gene expression of the above-mentioned genes, this was further investigated. In contrast to healthy feline kidney tissue, CRFK cells showed almost no expression of the AT-II type 1 (AT1) receptor. CONCLUSIONS AND RELEVANCE: TGF-ß1 significantly induced expression of the EMT marker gene α-SMA, profibrotic mediator CTGF, and fibrogenic proteins COL1, TNC and TSP-1 in CRFK cells. The effect of TGF-ß1 on myofibroblast formation was also observed by the stretched appearance of the CRFK cells. As CRFK cells expressed almost no AT1 receptors, this cell line proved not suitable for testing the efficacy of drugs that interact with the AT1 receptor. As AT-II stimulates the effects of TGF-ß1 in mammals, the results of this study suggest an indirect profibrotic effect of AT-II besides the demonstrated profibrotic effect of TGF-ß1 and thus the development of feline renal fibrosis. Modulation of EMT or proliferation of myofibroblasts could serve as a diagnostic tool and a novel therapeutic target to inhibit renal fibrogenesis, and could possibly serve in the therapy of feline renal fibrosis.

Evaluation of orally administered telmisartan for the reduction of indirect systolic arterial blood pressure in awake, clinically normal cats.

OBJECTIVES: The aim of this study was to compare the effects of multiple once- or twice-daily oral dosage rates of the angiotensin II, type-1 receptor blocker, telmisartan (TEL), or placebo (PLA) on indirect systolic arterial blood pressure (SBP) in awake, clinically normal cats. METHODS: Utilizing an incomplete crossover design and following a 14 day acclimation period, 28 healthy laboratory cats were randomized to undergo treatment with three of the following 14 day treatment protocols, each separated by a 1 week washout period: oral PLA q24h, oral TEL at a dosage of 1, 1.5, 2 or 3 mg/kg q24h, or oral TEL at a dosage of 1 or 1.5 mg/kg q12h. Using the Doppler ultrasound method, indirect SBP was measured daily during each treatment period, and daily during the first 5 days of each washout period, approximately 3 h after administration of the morning treatment. RESULTS: Each treatment protocol was administered to a total of 12 cats. A statistically significant effect of treatment period was identified for the entire study; therefore, only data from the first treatment period (four cats per treatment group) were used for further analysis. Compared with PLA, during the first treatment period, SBP values were significantly lower in cats treated with TEL at all tested dosages by the second week of treatment. SBP remained significantly lower than in PLA-treated animals for 2 days following administration of the last dose in all TEL treatment groups. No clinical signs of hypotension were noted in any group. CONCLUSIONS AND RELEVANCE: These results suggest that treatment with TEL at a total daily dose of 1-3 mg/kg - administered as a single dose, or split into two equal doses administered 12 h apart - results in a significant, relatively long-lasting reduction of SBP in clinically normal cats. TEL appears to be well tolerated by normal cats at the dosages tested.

Sound recording and digital phonocardiography of cardiac murmurs in dogs by using a sensor-based electronic stethoscope.

The goals of this study were to present a technique of digitalised sound recordings and phonocardiograms (dPCGs), and to analyse its diagnostic capabilities. Heart sounds of 20 dogs were auscultated in vivo (on-line) and recorded with dPCGs by two authors using a Welch Allyn Meditron Stethoscope System. Sound recordings were auscultated off-line and blindly by four different observers having various auscultatory experiences, then listened to while viewing dPCGs. The results were compared to echocardiographic diagnoses. There was a significant agreement (p < 0.001) between on-line and off-line auscultatory findings regarding the four observers, ranging from 45% to 75% (weighted kappa values: 0.72 to 0.87). The best agreement was achieved by Observer 1 having the highest experience. Significant differences (p < 0.05) were found between Observer 1 and Observer 4 (with the lowest experience) in judging the quality of the murmurs during the off-line and blind auscultation. However, there were only minimal differences (95% to 100% agreements) in dPCG analyses among the four observers regarding intensity and quality of the murmurs while simultaneously listening to and viewing the dPCGs. Significant correlations were found between the traditional '0 to 6 scale' and a new '0 to 3 scale' murmur intensity gradings by all observers (correlation coefficients 0.640 to 0.908; p < 0.01 to p < 0.001). Analysis of dPCGs might be a valuable, additional tool helping with the diagnosis of canine cardiac murmurs, especially for those with less cardiological experience.

Evaluation of the association between plasma concentration of N-terminal proatrial natriuretic peptide and outcome in cats with cardiomyopathy.

OBJECTIVE: To determine whether plasma N-terminal proatrial natriuretic peptide (NT-proANP) concentration could predict the outcome (survival duration) of cats with cardiomyopathy (CM). DESIGN: Case-control study. ANIMALS: 51 cats with CM (25 with and 26 without congestive heart failure [CHF]) and 17 healthy cats. PROCEDURES: Cats were thoroughly examined and assigned to 1 of 3 groups (control, CM with CHF, and CM alone). Plasma NT-proANP concentrations were measured by use of a human proANP(1-98) ELISA. Survival durations were compared between CM groups. RESULTS: Plasma NT-proANP concentrations differed significantly among the 3 groups, and survival durations differed significantly between the 2 CM groups. Median (range) NT-proANP concentration was 413 fmol/mL (52 to 940 fmol/mL) in the control group, 1,254 fmol/mL (167 to 2,818 fmol/mL) in the CM alone group, and 3,208 fmol/mL (1,189 to 15,462 fmol/mL) in the CM with CHF group. At a cutoff of 517 fmol/mL, NT-proANP concentration had a sensitivity of 90% and specificity of 82% for detecting CM. Multivariate analysis revealed that only the variable left atrium-to-aortic diameter ratio was a significant predictor of survival duration. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma NT-proANP concentration may have potential as a testing marker for distinguishing healthy cats from cats with CM. It may also be useful for distinguishing CM cats with CHF from those without CHF The value of NT-proANP concentration as a predictor of survival duration was not supported in this study and requires further evaluation.

Measurement of N-terminal proatrial natriuretic peptide in plasma of cats with and without cardiomyopathy.

OBJECTIVE: To determine whether plasma N-terminal proatrial natriuretic peptide (Nt-proANP) concentrations in cats with cardiomyopathy (CM) differ from values in healthy cats and evaluate whether plasma Nt-proANP concentrations can be used to discriminate cats with CM and congestive heart failure (CHF) from CM-affected cats without CHF. ANIMALS: 16 cats that had CM without CHF, 16 cats that had CM with CHF, and 11 healthy control cats. PROCEDURES: All cats underwent a physical examination, assessment of clinicopathologic variables (including plasma thyroxine concentration), thoracic radiography, and echocardiography. On the basis of findings, cats were assigned to 1 of 3 groups (control cats, cats with CM and CHF, and cats with CM without CHF). Venous blood samples were obtained from all 43 cats, and plasma Nt-proANP concentrations were measured by use of a human proANP(1-98) ELISA. RESULTS: Plasma Nt-proANP concentrations differed significantly among the 3 groups. Median Nt-proANP concentration was 381 fmol/mL (range, 52 to 450 fmol/mL), 763 fmol/mL (range, 167 to 2,386 fmol/mL), and 2,443 fmol/mL (range, 1,189 to 15,462 fmol/mL) in the control group, in cats with CM without CHF, and in cats with CM and CHF, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Measurement of plasma Nt-proANP concentration could be of benefit in the assessment of cats with naturally occurring CM and might have potential as a screening marker for the disease. Furthermore, measurement of plasma NtproANP concentration may be useful for distinguishing cats with CM and CHF from those with CM and no CHF.