Study on the Effects of Angiotensin Receptor/Neprilysin Inhibitors on Renal Haemodynamics in Healthy Dogs.

An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a vascular receptor blocker. No human or veterinary studies regarding the effect of ARNI on renal haemodynamics in the absence of cardiac or renal issues exist. Therefore, we investigated the effect of ARNI on renal haemodynamics in five healthy dogs. ARNI was administered to all five dogs at an oral dose of 20 mg/kg twice daily for 4 weeks. Renal haemodynamics were assessed on the day before ARNI administration (BL), on Day 7, and on Day 28. The glomerular filtration rate (GFR) significantly increased on Day 28 compared to BL and Day 7, whereas renal plasma flow increased on Day 7 and Day 28 compared to BL. Systolic blood pressure significantly decreased between BL and Day 28. Plasma atrial natriuretic peptide (ANP) concentrations increased on Day 7 compared to BL. Additionally, ANP concentrations increased on Day 28 in three of the five dogs. Different ANP concentrations were observed in the remaining two dogs. Both urine output volume and heart rate remained relatively stable and did not exhibit significant change. In conclusion, ARNI may enhance renal haemodynamics in healthy dogs. ARNI could be a valuable drug for treating both heart and kidney disease in dogs.

A pilot study of the proarrhythmic effects of pimobendan injection in clinically healthy cats.

Pimobendan is not currently approved for use in cats, although its usefulness in feline hypertrophic cardiomyopathy has been suggested. Reports indicate an increase in arrhythmic events following oral administration to healthy cats. Given the greater potency of intravenous administration compared to oral intake, it is conceivable that the incidence of arrhythmias may be increased following pimobendan injection. Therefore, this study aimed to investigate the proarrhythmic effects of pimobendan injection in cats. Five clinically healthy cats underwent physical examination, echocardiography, blood pressure measurements, and 24-hour Holter electrocardiography immediately before and after receiving pimobendan as an intravenous bolus dose of 0.15 mg/kg twice daily for 3 days. Additionally, a 24-hour Holter electrocardiography recording was conducted on the third day of pimobendan or placebo IV administration to assess heart rate, arrhythmias, and heart rate variability. Following pimobendan administration, there was a significant increase in total 24-hour heart rate. Echocardiography revealed a significant increase in mitral valve annulus systolic velocity (S') on the ventricular septal wall side, indicative of enhanced contractility. Only one cat exhibited paroxysmal ventricular tachycardia and an increase in the frequency of arrhythmic events. Conversely, in the remaining cats, a decreasing trend in the number of arrhythmias was observed. These findings indicate that intravenous administration of pimobendan may not be implicated in the onset of arrhythmias. Nevertheless, further research is warranted to explore the effects of intravenous pimobendan administration in cats with myocardial disease.

Plasma N-terminal pro-atrial natriuretic peptide concentrations are affected by dehydration in healthy dogs.

Background: Plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations may be affected by the hydration status. Aim: This study aimed to evaluate the effect of dehydration on plasma NT-proANP and NT-proBNP concentrations in healthy dogs. Methods: This prospective study included five clinically healthy dogs. Furosemide was administered intravenously at 2-4 mg/kg every 1-2 hours until completion of the dehydration model. The dehydration model was considered complete when weight loss was ≥5% and findings of dehydration on physical examination were observed. Plasma NT-proANP and NT-proBNP concentrations were compared at three-time points: before the dehydration model was created (point 1), at the completion of the dehydration model (point 2), and when dehydration was judged to have improved (point 3). Association between plasma NT-proANP and NT-proBNP concentrations, and each clinical variable (physical examination, blood pressure, blood chemistry, blood gases, and echocardiography) was assessed using linear regression analysis. Results: Plasma NT-proANP concentration decreased significantly from point 2 to point 1 (p < 0.05), whereas plasma NT-proBNP concentration showed a decreasing trend but did not differ significantly between points 1 and 2. Plasma NT-proANP concentration correlated significantly with body weight (R2 = 0.178) and plasma NT-proBNP concentration (R2 = 0.284) (p < 0.05, respectively), and plasma NT-proBNP concentration correlated significantly with electrolytes (sodium, R2 = 0.439; potassium, R2 = 0.444; and chloride, R2 = 0.419), and echocardiographic parameters [diastolic left ventricular internal diameter (LVIDd) R2 = 0.519; weight-standardized LVIDd, R2 = 0.535] (p < 0.01, respectively). Conclusion: The plasma NT-proANP concentrations decreased with dehydration. However, the plasma NT-proBNP concentration did not change with mild dehydration and reflected left ventricular morphology.

Assessment of the measurement of canine and feline serum fibroblast growth factor-23 concentrations by automated chemiluminescence immunoassay.

This study compared canine and feline fibroblast growth factor (FGF)-23 concentration measurements between automated chemiluminescence assay (CLEIA) and enzyme-linked immunosorbent assay (ELISA). Seventy serum samples each from dogs and cats were evaluated. FGF-23 measurements by CLEIA significantly correlated with those of ELISA in both dogs and cats. The Bland-Altman test showed that FGF-23 between CLEIA and ELISA had fixed and proportional biases, respectively, in both dogs and cats. Measurements by CLEIA were lower than those of ELISA, especially in higher serum FGF-23 concentrations. This study showed that FGF-23 concentrations in dogs and cats can be evaluated by automated CLEIA. However, FGF-23 cannot be directly compared between CLEIA and ELISA.

A dog presenting with syncope due to two different etiologies.

Objective: The treatment of syncope depends largely on its possible etiology. Therefore, identifying the cause of syncope is very important in treatment planning. Herein, we report an etiology of syncope caused by pulmonary hypertension (PH) associated with canine filariasis, followed by syncope due to bradyarrhythmia 1 year later. Materials and Methods: An 8-year-old male English Cocker Spaniel was referred to our hospital for a second opinion regarding syncope that the dog had started experiencing approximately 2 months prior. Based on the examination findings, we diagnosed that the fainting was due to heartworm disease and associated PH. After increasing the dose of pimobendan (0.50 mg/kg, q12h), the syncope subsided. However, syncope recurred on the 215th day of the first episode. Results: The findings that differed from those during the initial examination were that cardiac arrest was observed for approximately 5 sec during auscultation, along with sinus arrest. Therefore, to further investigate for syncope, a Holter electrocardiograph was obtained for 3 days. Consequently, sinus arrest was identified as the etiology of the recurrent syncope, and the patient was diagnosed with sick sinus syndrome, Rubenstein classification type II. Following cilostazol (10 mg/kg, q12h) administration, the syncope subsided. Conclusion: This case reports syncope in a dog, which typically occurs due to different etiologies. When a dog has PH, it may be important to think about the possibility of arrhythmias caused by a bigger right heart.

Evaluation of the association between electrocardiogram parameters and left cardiac remodeling in dogs with myxomatous mitral valve disease.

Background and Aim: Electrocardiography (ECG) is an adjunct for cardiac enlargement diagnosis. However, its efficacy in assessing left cardiac remodeling (left atrial and left ventricular enlargement) in dogs with myxomatous mitral valve disease (MMVD) remains unclear. This study aimed to evaluate the association between ECG parameters and left cardiac remodeling and to investigate whether the rate of change in ECG waveforms in the same individual reflected left cardiac remodeling in dogs with MMVD. Materials and Methods: This retrospective study included 20 healthy dogs and 140 dogs with MMVD. Data on clinical variables were obtained through physical examination, thoracic radiography, and echocardiography. The ECG parameters were the P-wave duration, PR interval, QRS complex duration, P-wave amplitude, R-wave amplitude, and mean electrical axis. Dogs with examination data that could be obtained multiple times during the study period were classified into the non-progressive and progressive groups. Results: Only the P-wave and QRS complex durations were selected as significant variables associated with imaging test parameters (p < 0.05); they had a relatively higher discriminatory ability for the left cardiac remodeling than other ECG parameters. The rates of change in the PR interval and R-wave amplitude were significantly higher in the progressive group than in the non-progressive group. Conclusion: In dogs with MMVD, the P-wave and QRS complex durations were significantly correlated with the left cardiac remodeling indicators. Furthermore, an increased rate of change in the PR interval and R-wave amplitude in the same individual may indicate left cardiac remodeling.

A pilot study of patch Holter electrocardiograph recordings in healthy cats.

Background: A patch Holter electrocardiograph (P-Holter) is cordless, making it lightweight, unlike the conventional Holter electrocardiograph (C-Holter). A P-Holter can also take continuous measurements for up to 14 days without replacing the battery or SD card. Aim: To compare the performance of the P-Holter and the C-Holter in healthy cats. Additionally, we aimed to investigate whether multiday recordings with the P-Holter decrease sympathetic nerve activity or improve the accuracy of arrhythmia detection. Methods: Five healthy domestic short-haired cats were used for this study. Both a P-Holter and C-Holter were used on the first day, but only the P-Holter was used on days 2-6. The evaluated variables were the analyzable time of both Holter types, heart rate (HR), HR variability (HRV), and the number of arrhythmia occurrences. Results: For two out of the five cats, measurement of P-Holter was interrupted. Eventually, continuous recordings using the P-Holters were able to be collected from all individuals for 6 days. The 24 hours analyzable time from the P-Holter and C-Holter was almost identical (p = 0.94). The 24 hours mean HR did not differ across Holter types (p = 0.67). In addition, the timing of the occurrences of arrhythmias was almost identical to the P-Holter and C-Holter. Results of HRV suggested that sympathetic nerve activity was likely to decrease and vagal nerve activity was likely to increase after 4-5 days of measurement, compared to the second day of measurement (p < 0.05). When only the P-Holter was installed, the number of arrhythmia occurrences was similar on days 2-6. Conclusion: In this study, the P-Holter may be as useful as the C-Holter in cats with suspected intermittent arrhythmias, although the P-Holters were placed on cats without a clinical indication. However, cats may have individual differences in their adaptation to the device. P-Holter recordings taken for more than 4-5 days may allow the cat to acclimate to the device and reduce sympathetic nerve activity. The accuracy of arrhythmia detection across multiday P-Holter recordings requires further investigation using clinical cases.

Upper urolithiasis in cats with chronic kidney disease: prevalence and investigation of serum and urinary calcium concentrations.

OBJECTIVES: This study aimed to define the prevalence of upper urolithiasis in cats with chronic kidney disease (CKD) in a referral population, and to compare urinary calcium:creatinine ratio (UCa:Cr), and total and ionised calcium between cats with CKD with and without upper urolithiasis. METHODS: The medical records of cats diagnosed with CKD were reviewed for signalment, body weight, diet and prevalence of upper urolithiasis. Cats with preserved urine samples were further classified into two groups: urolithiasis group (upper urolithiasis identified by abdominal ultrasonography) and control group (CKD of unknown origin). Serum biochemical analysis, CKD stage, blood gas analysis, urine specific gravity and UCa:Cr were compared between groups using a two-sample t-test or Mann-Whitney U-test for continuous variable and a χ2 test or Fisher's exact test for categorical variables. Multivariable binary logistic regression analysis was used to identify risk factors. RESULTS: Among the 140 cats with CKD, the prevalence of upper urolithiasis was 73%. Fifty cats (5, 29 and 16 cats with CKD stages 1, 2 and 3, respectively) with urine samples met the inclusion criteria and were included in the analysis. Among cats with CKD, being purebred (odds ratio [OR] = 81.56; P = 0.03) and being fed dry food only (OR = 25.06; P = 0.001) were identified as independent upper urolithiasis risk factors; those with upper urolithiasis were more likely to be exclusively fed with urine-acidifying food (P <0.001) and have increased serum ionised calcium (iCa) (P = 0.044), fractional excretion of calcium (P = 0.45) and UCa:Cr (P = 0.005) than cats with CKD without upper urolithiasis. CONCLUSIONS AND RELEVANCE: Cats with CKD that were purebred, fed dry food and fed urine-acidifying food only often had upper urolithiasis. A higher UCa:Cr may be a result of increased serum iCa and may cause 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 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.

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 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.