Effects of ivabradine and atenolol on heart rate and heart rate variability in healthy cats over a 24 h period: A pilot study.

BACKGROUND: Ivabradine is used to treat tachycardia; unlike atenolol, it does not affect blood pressure or myocardial contractility. This study compared the impact of ivabradine and atenolol on heart rate (HR) and HR variability (HRV) during a 24 h period, feeding and sleeping times, via a Holter electrocardiogram in healthy cats. We hypothesised that ivabradine and atenolol would lower the HRs equally well, even at times of excitement and rest, such as during feeding and sleep; that ivabradine, unlike atenolol, would have an effect on HRV. METHODS: Five clinically healthy cats were used in the prospective blinded crossover study receiving 3 days of ivabradine (0.30 mg/kg per os twice daily) followed by atenolol (6.25 mg/cat per os twice daily, range 1.3-2.0 mg/kg) or receiving atenolol followed by ivabradine. A placebo period was initiated before the start of the crossover test, data obtained during that period were used as a baseline (BL). Evaluation parameters included HR and HRV, for the whole 24 h period and for feeding and sleeping times, comparing the effect of ivabradine and atenolol with BL. RESULTS: The HR for the whole 24 h, feeding and sleeping times, were significantly lower with ivabradine and atenolol, compared to BL (p < 0.05). The HRV for the whole 24 h and sleeping time were significantly higher after ivabradine compared with BL and after atenolol. CONCLUSIONS: In healthy cats, ivabradine and atenolol significantly reduced the HR regardless of excitement and rest; their effects were comparable. Ivabradine significantly increased HRV in comparison to BL whereas atenolol did not.

Association between serum fibroblast growth factor-23 concentrations and blood calcium levels in chronic kidney disease cats with upper urolithiasis.

OBJECTIVES: This study investigated whether serum fibroblast growth factor (FGF)-23 concentrations are associated with serum total calcium (tCa) and blood ionised calcium (iCa) concentrations in cats with chronic kidney disease (CKD) and upper urolithiasis. METHODS: Serum samples and the medical records of cats with CKD with nephroliths, ureteroliths or both were investigated retrospectively. Cats with a serum creatinine concentration >250 µmol/l and/or a serum phosphorus concentration ⩾1.50 mmol/l were excluded. Based on cut-offs for serum tCa (2.70 mmol/l) or blood iCa (1.40 mmol/l), cats were divided into the following groups: total hypercalcaemia (H-tCa) (>2.70 mmol/l) and total normocalcaemia (N-tCa) (⩽2.70 mmol/l) groups, or ionised hypercalcaemia (H-iCa) (>1.40 mmol/l) and ionised normocalcaemia (N-iCa) (⩽1.40 mmol/l) groups, respectively. Serum FGF-23 concentrations were compared between groups and correlation analysis was performed. RESULTS: Thirty-two cats with CKD and upper urolithiasis were included. Serum FGF-23 concentrations in the H-tCa group (median 573 pg/ml [range 125-3888]; n = 12) were significantly higher compared with the N-tCa group (median 245 pg/ml [range 94-627]; n = 20) (P = 0.001). Serum FGF-23 concentrations in the H-iCa group (median 1479 pg/ml [range 509-3888]; n = 6) increased significantly compared with the N-iCa group (median 245 pg/ml [range 94-637]; n = 26) (P <0.001). Serum FGF-23 concentrations significantly correlated with serum tCa (r = 0.511, P = 0.003) and blood iCa concentrations (r = 0.425, P = 0.015) but not serum creatinine (r = 0.279, P = 0.122) or phosphorus concentrations (r = 0.208, P = 0.253).Conclusions and relevance Increased serum FGF-23 concentrations were associated with hypercalcaemia independently of creatinine and phosphate status in cats with CKD and upper urolithiasis.

Serum fibroblast growth factor-23 concentrations in young and mature adult cats with chronic kidney disease.

OBJECTIVES: The aim of this study was to investigate serum fibroblast growth factor (FGF)-23 concentrations in young and mature adult cats with chronic kidney disease (CKD). METHODS: The present study retrospectively investigated the serum samples and medical records of 1-8-year-old clinically healthy cats (control group, n = 7) and cats with CKD (n = 54). Cats with CKD were divided into four stages based on serum creatinine concentrations, according to the International Renal Interest Society (IRIS) CKD guidelines. Serum FGF-23 concentrations were compared between cats in the control group, IRIS stages 1, 2 and 3-4 CKD. Continuous variables were analysed using correlations and multiple linear regression. RESULTS: Serum FGF-23 concentrations were significantly higher in cats with IRIS stages 1, 2 and 3-4 CKD, compared with those in the control group (P = 0.02, P = 0.002 and P = 0.002, respectively). Additionally, serum FGF-23 concentrations in cats with IRIS stages 3-4 CKD had higher serum FGF-23 concentrations than those with IRIS stages 1 and 2 CKD (P = 0.04 and P = 0.02, respectively). In the multiple linear regression analysis, serum urea nitrogen concentration, serum phosphorus concentration and blood ionised calcium concentration were independent variables predicting serum FGF-23 concentration. CONCLUSIONS AND RELEVANCE: Serum FGF-23 concentrations in younger cats with CKD increased in early-stage CKD and were associated with mineral metabolic markers, as also occurs in geriatric cats.

Association between serum fibroblast growth factor-23 concentration and development of hyperphosphatemia in normophosphatemic dogs with chronic kidney disease.

BACKGROUND: Fibroblast growth factor (FGF)-23 is increased first in the sequence of changes associated with chronic kidney disease (CKD)-mineral and bone disorder. Thus, its measurement may serve as a predictive indicator of incident hyperphosphatemia. OBJECTIVES: To investigate whether serum FGF-23 concentration in normophosphatemic dogs with CKD is associated with the risk of the subsequent development of hyperphosphatemia and CKD progression. ANIMALS: Forty-two normophosphatemic dogs with CKD. METHODS: Blood samples and medical records were retrospectively investigated. Hyperphosphatemia was defined as a serum phosphorous concentration >5.0 mg/dL. Progression was defined as a >1.5-fold increase in serum creatinine concentration. The time periods and hazard ratios for these outcomes were assessed using Kaplan-Meier analysis, log-rank test, and univariate Cox regression analysis. The variables associated with the outcomes in the univariate analysis were included in the multivariate Cox regression model with backward selection. RESULTS: Serum FGF-23 concentration >528 pg/mL was associated with a shorter time to development of hyperphosphatemia (P < .001) and CKD progression (P < .001). In multiple Cox regression analysis, increased FGF-23 concentration remained a significant variable associated with these outcomes (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Increased FGF-23 concentration in normophosphatemic dogs with CKD was associated with significant risk of development of hyperphosphatemia, independent of CKD stage, and of the progression of CKD. Future research focusing on whether interventions that decrease FGF-23 secretion will slow the development of hyperphosphatemia and CKD progression is needed.

Comparison of N-terminal pro-atrial natriuretic peptide and three cardiac biomarkers for discriminatory ability of clinical stage in dogs with myxomatous mitral valve disease.

Plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) concentration increases with progression of myxomatous mitral valve disease (MMVD) in dogs. This multicentre, prospective study compared plasma NT-proANP, N-terminal pro-brain natriuretic peptide (NT-proBNP), ANP, and cardiac troponin I (cTnI) concentrations in dogs with MMVD for their characteristics and discriminatory ability to detect cardiac dilatation and congestive heart failure (CHF). Thirty-six healthy dogs and 69 dogs with MMVD were included. Clinical variables were obtained via physical examination, thoracic radiography, and echocardiography. The discriminatory ability of each cardiac biomarker (CB) to determine the presence or absence of cardiac dilatation (event 1) and CHF (event 2) was evaluated using the receiver operating characteristic curves. Plasma NT-proANP, NT-proBNP, and ANP concentrations showed a significant association with the left atrium/aorta ratio (P<0.01). The area under the curve of plasma NT-proANP and NT-proBNP concentrations were 0.72 and 0.75, respectively in event1 and 0.72 and 0.76, respectively in event2. Plasma NT-proANP and NT-proBNP concentrations showed sensitivity 80.0 and 80.0%; specificity 67.6 and 64.7% in event1 (cutoff value; 8,497.81 pg/ml and 1,453.00 pmol/l, respectively) and sensitivity 85.7 and 81.0%; specificity 60.4 and 64.6% in event2 (cutoff value; 8,684.33 pg/ml and 1,772.00 pmol/l, respectively). In dogs with MMVD, plasma NT-proANP, NT-proBNP, and ANP concentrations increase with left atrial enlargement. Particularly, plasma NT-proANP and NT-proBNP concentrations appeared to be equally useful in the discriminatory ability to detect cardiac dilatation and CHF.

Serum cystatin C concentration can be used to evaluate glomerular filtration rate in small dogs.

Serum cystatin C levels (CysC) are used in human medicine to document progressive kidney failure. Although CysC are not thought to be useful for the diagnosis of kidney dysfunction in dogs, there has been no specific consideration of body weight as a confounding issue. The aim of this study was to assess that the utility of CysC for the diagnosis of decreased glomerular filtration rate (GFR) in smaller vs. larger dogs. In clinically healthy dogs, serum creatinine (Cre) and CysC correlate directly with body weight; we found that dogs weighing <20 kg had significantly lower CysC than those weighing ≥20 kg (0.27 ± 0.07 vs. 0.34 ± 0.05 mg/l, respectively, P<0.001). In dogs weighing <20 kg, CysC had superior diagnostic accuracy for the detection of mildly decreased plasma iohexol clearance (PCio) (<1.8 ml/min/kg) compared with Cre (sensitivity 100% vs. 80.9% and specificity 100% vs. 85.7%); this was not true for dogs weighing ≥20 kg. Additionally, using a cut-off PCio of <1.8 ml/min/kg, the area under receiver-operating characteristics curve (AUC) of CysC was significantly higher than that of Cre in dogs weighing <20 kg (P<0.05); this was not true for dogs weighing ≥20 kg (P=0.695). In conclusion, CysC is a useful marker for the detection of a mild decreasing GFR compared with Cre in dogs weighing <20 kg.

Effects of telmisartan on proteinuria and systolic blood pressure in dogs with chronic kidney disease.

Renal proteinuria is associated with promoted renal dysfunction and a shorter survival period in dogs with chronic kidney disease (CKD). Renin angiotensin- aldosterone system inhibitors are primarily used to treat renal proteinuria. In this retrospective, open-label study, we aimed to evaluate the anti-proteinuric and anti-hypertensive effects of telmisartan (angiotensin II receptor blocker) in dogs with proteinuric CKD. A total of 28 dogs with proteinuric CKD were included in the study, all dogs received telmisartan 1 mg/kg q24h, PO. The urine protein-to-creatinine ratio (UPC), urine albumin-to-creatinine ratio (UAC) and systolic blood pressure (SBP) decreased significantly after telmisartan administration (P < 0.05). The median rate of change in UPC, UAC and SBP at Day 120 were - 65.1%, -75.9% and - 9.7%. Ten dogs (36.7%) achieved UPC < 1.0 at Day 120, of which six dogs had UPC < 0.5. A reduction of UPC to ≥50% was achieved in 10 dogs (36%) at Day 45 and 17 dogs (61%) at Day 120. Seventeen dogs (61%) had hypertension at baseline, of which 10 dogs (59%) had SBP < 160 mmHg at Day 120. Two-way repeated measures analysis of variance did not attribute the observed changes in SBP, UPC or UAC to feeding with a renal diet. In conclusion, telmisartan therapy provides anti-proteinuric and anti-hypertensive effects in dogs with proteinuric CKD.

The effect of sildenafil on pulmonary haemodynamics in a canine model of chronic embolic pulmonary hypertension.

The effects of different doses of orally administered sildenafil on pulmonary haemodynamics in dogs with pulmonary hypertension (PH) have not been documented in an invasive and quantitative manner. In this study, we examined the effects of oral sildenafil using a canine model of chronic embolic PH (CEPH). This CEPH model was created by repeatedly injecting microspheres through a catheter into the pulmonary artery under general anaesthesia at regular weekly intervals over several months. The CEPH dogs received 1, 2 or 4 mg/kg of sildenafil orally twice a day for seven days. Then, haemodynamic measurements including pulmonary artery pressure (PAP), systemic artery pressure (SAP), pulmonary artery wedge pressure (PAWP), right atrial pressure (RAP) and cardiac output (CO) were obtained after seven days of sildenafil administration via right heart catheterisation and oscillometric blood pressure measurements. Sildenafil was well tolerated in this study. Sildenafil administered at doses of 2 and 4 mg/kg significantly decreased systolic PAP compared with before administration. In addition, all doses of sildenafil significantly decreased the mean and diastolic PAP. Furthermore, 4 mg/kg of sildenafil significantly decreased PAP compared with 1 mg/kg. Sildenafil also significantly decreased pulmonary vascular resistance without notable changes in SAP or systemic vascular resistance. The PAWP, RAP and CO did not increase significantly at any doses. In conclusion, the oral administration of sildenafil to CEPH models decreased PAP in a dose-dependent manner.

Evaluation of the Autonomic Nervous System in a Canine Model of Chronic Embolic Pulmonary Hypertension.

BACKGROUND: Sildenafil improves autonomic dysfunction caused by pulmonary hypertension (PH) in humans, but its effect is unknown in dogs with PH. This prospective study aimed to evaluate the autonomic nervous system function of a canine model of chronic embolic PH (CEPH) and the autonomic nervous system function of a canine model of CEPH in which sildenafil was administered. METHODS: This study used five clinically healthy female beagle dogs. Evaluation parameters included hemodynamic parameters, heart rate (HR) and heart rate variability (HRV). Each evaluation parameter was compared before and after creating the CEPH model (before, BL; after, CEPHBL) and between the CEPHBL model and after the administration of sildenafil (1 mg/kg, BID) in the CEPH model dogs (CEPHSil). RESULTS: In the CEPHBL model, the hemodynamic parameters indicated cardiac hypofunction, and HR was significantly increased and HRV was significantly decreased compared with BL. Further, in the CEPHSil model, the hemodynamic parameters suggested improvement in cardiac function, and HRV was significantly increased. CONCLUSIONS: From the results of the CEPH model dogs, autonomic dysfunction was shown to occur in PH dogs. In addition, the administration of 1 mg/kg of sildenafil to CEPH model dogs may improve autonomic dysfunction.

Pharmacokinetics of single dose sildenafil orally administered in canine models of chronic embolic pulmonary hypertension.

Information regarding the pharmacokinetics of oral sildenafil in dogs with pulmonary hypertension is limited. In this study, we examined the pharmacokinetics of oral sildenafil in a canine model of chronic embolic pulmonary hypertension (CEPH). The CEPH model was developed by repeatedly injecting microspheres into the pulmonary arteries. The pharmacokinetics of oral sildenafil at 1, 2 and 4 mg/kg was evaluated using four dogs with pulmonary hypertension in the fasted state. The plasma concentrations of sildenafil were determined using high-performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil was well tolerated in this study. Proportional increments in the maximum plasma concentration and area under the curve extrapolated to infinity at drug doses of 1, 2 and 4 mg/kg were detected using a power model analysis. No significant differences were observed among the three doses in the time to maximum plasma concentration. The mean residence time and elimination half-life were slightly but significantly higher at a dose of 4 mg/kg than at a dose of 1 mg/kg.

Relationship between right heart echocardiographic parameters and invasive pulmonary artery pressures in canine models of chronic embolic pulmonary hypertension.

Basic information related to the association between right heart echocardiographic parameters and invasive pulmonary artery pressure (PAP) in dogs with pulmonary hypetension (PH) is scarce. The aim of this study was to examine the association between conventional right heart echocardiographic parameters and invasive PAP by right heart catheterization (RHC) before and after PH. Five female beagle dogs regarded as clinically healthy were used. Echocardiography and RHC were conducted before and after creating chronic embolic pulmonary hypertension (CEPH) models. The acceleration time to ejection time ratio in pulmonary artery flow profile (AT/ET), the ratio of the pulmonary artery and aortic diameter in diastole (PA/Ao), the right pulmonary artery distensibility index by M-mode method (RPAD M-mode), the normalized right ventricular internal diameter in diastole (RVIDdn), and the normalized tricuspid annular plane systolic excursion (TAPSEn) were correlated with the invasive systolic PAP (sPAP), mean PAP (mPAP) and diastolic PAP (dPAP). Multiple linear regression analysis identified AT/ET and RVIDdn as independent predictors of sPAP, PA/Ao and RVIDdn as independent predictors of mPAP, and PA/Ao and RPAD M-mode as independent predictors of dPAP. AT/ET and PA/Ao had high sensitivity and specificity for predicting CEPH. In conclusion, AT/ET, PA/Ao, RPAD M-mode, RVIDdn and TAPSEn were significantly correlated with invasive PAP and alterations in PA/Ao or AT/ET might enable clinicians to predict PH, even if tricuspid regurgitation is not observed.