Genetics of canine myxomatous mitral valve disease.

Myxomatous mitral valve disease (MMVD) is the most common heart disease and cause of cardiac death in domestic dogs. MMVD is characterised by slow progressive myxomatous degeneration from the tips of the mitral valves onwards with subsequent mitral valve regurgitation, and left atrial and ventricular dilatation. Although the disease usually has a long asymptomatic period, in dogs with severe disease, mortality is typically secondary to left-sided congestive heart failure. Although it is not uncommon for dogs to survive long enough in the asymptomatic period to die from unrelated causes; a proportion of dogs rapidly advance into congestive heart failure. Heightened prevalence in certain breeds, such as the Cavalier King Charles Spaniel, has indicated that MMVD is under a genetic influence. The genetic characterisation of the factors that underlie the difference in progression of disease is of strong interest to those concerned with dog longevity and welfare. Advanced genomic technologies have the potential to provide information that may impact treatment, prevalence, or severity of MMVD through the elucidation of pathogenic mechanisms and the detection of predisposing genetic loci of major effect. Here we describe briefly the clinical nature of the disorder and consider the physiological mechanisms that might impact its occurrence in the domestic dog. Using results from comparative genomics we suggest possible genetic approaches for identifying genetic risk factors within breeds. The Cavalier King Charles Spaniel breed represents a robust resource for uncovering the genetic basis of MMVD.

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs.

Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography-mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax ) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2-4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.

[Patent ductus arteriosus in the dog: a retrospective study of clinical presentation, diagnostics and comparison of interventional techniques in 102 dogs (2003-2011)]. / Persisterende ductus arteriosus bij de hond: een retrospectieve studie naar klinische presentatie, diagnostiek, en vergelijking van toegepaste therapeutische mogelijkheden bij 102 honden (2003-2011).

A left-to-right shunting patent ductus arteriosus (PDA) is a common congenital heart defect in dogs. If it is left uncorrected, life expectancy in most cases is decreased due to the development of left-sided congestive heart failure. The aim of this study was to describe the dogs diagnosed with PDA in the Utrecht University Companion Animal Clinic from 2003 to 2011. The medical records of 102 patients were retrieved, and the clinical presentation and outcome of PDA closure by surgical ligation or transarterial catheter occlusion (TCO) were reviewed. In the TCO group, the result of coiling was compared with the placement of an Amplatz Canine Duct Occluder (ACDO). A predisposition to PDA was found in the German Brak, Stabyhoun, and Schapendoes. Dogs treated with surgical ligation were significantly older and heavier than those treated with TCO; within the TCO group, dogs treated with ACDO were significantly older and heavier The initial success rate (complete disappearance of the audible murmur in a patient that survived the procedure) was not significantly different between the different treatment modalities. Major complications were more common with surgical ligation, but the incidence of minor complications was not significantly different. There was no diference in survival between dogs treated with surgical ligation and dogs treated with TCO. This study shows a previously unreported predisposition to PDA in certain breeds. Both surgical ligation and TCO are suitable techniques for PDA closure, although major complications were more common with surgical ligation. ACDO appears to be the method with the least complications and thus can be considered the safest method.

Suspect 'baggage canine heartworm' case: canine heartworm disease in a dog from Sydney, New South Wales.

Locally acquired canine heartworm (Dirofilaria immitis) infection in the temperate southern climate zones of Australia is currently rare. We report a case of locally acquired canine heartworm from Sydney, New South Wales in a 12-year-old Fox Terrier × Jack Russell female that presented with coughing and breathing difficulties. Absence of heartworm prevention and no travel outside Sydney was noted. Blood sample was D. immitis positive using antigen test, but negative on Modified Knott's testing. PCR confirmed the presence of D. immitis DNA in circulating blood. Echocardiographic examination revealed multiple parallel echogenic lines separated by a hypoechoic region ('tram-tracks') in the right pulmonary artery. The patient was treated and clinical condition gradually improved over the following 12 months. Antigen test remained positive for D. immitis at ~7 months and became negative at ~15 months after the start of the treatment. The most plausible scenario is importation of infected mosquito(s) in the luggage arriving from Queensland, Australia, common holiday destination for many Sydney-siders. We consider this a case of 'baggage canine heartworm'. Canine heartworm in dogs who did not travel should be considered in the differential diagnosis and D. immitis antigen test coupled with Modified Knott's test or PCR must be considered.

Pulsatile plasma profiles of FSH and LH before and during medroxyprogesterone acetate treatment in the bitch.

The aim of this study was to investigate the effect of medroxyprogesterone acetate (MPA) on pulsatile secretion of gonadotropins in the bitch. Five intact Beagle bitches were treated with MPA in a dose of 10mg/kg body weight subcutaneously at intervals of 4 weeks for a total of 13 injections, starting during anestrus. The 6-h plasma profiles of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were determined before, and 3, 6, 9, and 12 months after the start of MPA treatment. After 6 months of MPA treatment basal plasma LH concentration was transiently increased significantly. Basal plasma FSH concentration and the area under the curve above the zero level (AUC0) for FSH were significantly higher after 3 months of MPA treatment than before or after 9 and 12 months of treatment. MPA treatment did not significantly affect pulse frequency, pulse amplitude, or AUC above the baseline for either LH or FSH. During treatment 58 significant LH pulses were identified, and although each LH pulse coincided with an increase in plasma FSH concentration, in 17 cases the amplitude of the increase was too small to be recognized as a significant FSH pulse. In conclusion, MPA treatment did not suppress basal plasma gonadotropin levels in the bitches. On the contrary, it caused a temporary rise in the basal concentration of both FSH and LH, which may have been due to a direct effect of MPA on the ovary. In addition, several LH pulses were not accompanied by a significant FSH pulse, suggesting that MPA treatment attenuated the pulsatile pituitary release of FSH.

Physiology of the canine anoestrus and methods for manipulation of its length.

Progression from early to late anoestrus is characterized by the appearance of a larger number of gonadotrophin-releasing hormone (GnRH) pulses with a higher amplitude, an increase in the sensitivity of the pituitary to GnRH, an increase in ovarian responsiveness to gonadotrophins, and an increase in basal plasma follicle-stimulating hormone (FSH) concentration. A period of increased luteinizing hormone (LH) pulsatility has been observed shortly before the onset of pro-oestrus. Apart from these changes in the hypothalamus-pituitary-ovary axis, the initiation of a new follicular phase in the bitch is also stimulated by dopaminergic influences other than the accompanying plasma prolactin decrease. Metergoline, a drug which in a low dosage lowers the plasma prolactin concentration via a serotonin-antagonistic pathway, does not shorten the anoestrus; while bromocriptine, in a dosage insufficient to cause a decrease in the plasma prolactin concentration, does prematurely induce a follicular phase. These observations indicate that it is not the decrease in the plasma prolactin concentration, but another dopamine-agonistic influence that plays a crucial role in the transition to a new follicular phase. The dopamine-agonist induced oestrus is associated with a rapid rise in the basal plasma FSH concentration, similar to what is observed during the physiological late anoestrus. Administration of GnRH, eCG and oestrogens may also be used to induce oestrus but with variable results. Oestrus can be prevented surgically or medically, for which purpose progestagens are the most important drugs. The mechanism is still unclear, although it has been demonstrated that with continuing medroxyprogesterone acetate (MPA) treatment the FSH response to GnRH stimulation decreases and changes occur in the pulsatile release of the gonadotrophins. In general, LH pulses coincide with a FSH pulse, but during MPA treatment, LH pulses were observed while there was such a small increase in FSH that it was not recognized as significant FSH pulse.

Adenohypophyseal function in bitches treated with medroxyprogesterone acetate.

The aim of this study was to investigate the effects of treatment with medroxyprogesterone acetate (MPA) on canine adenohypophyseal function. Five Beagle bitches were treated with MPA (10mg/kg, every 4 weeks) and their adenohypophyseal function was assessed in a combined adenohypophyseal function test. Four hypophysiotropic hormones (CRH, GHRH, GnRH, and TRH) were administered before and 2, 5, 8, and 11 months after the start of MPA treatment, and blood samples for determination of the plasma concentrations of ACTH, cortisol, GH, IGF-1, LH, FSH, prolactin, alpha-MSH, and TSH were collected at -15, 0, 5, 10, 20, 30, and 45 min after suprapituitary stimulation. MPA successfully prevented the occurrence of estrus, ovulation, and a subsequent luteal phase. MPA treatment did not affect basal and GnRH-induced plasma LH concentrations. The basal plasma FSH concentration was significantly higher at 2 months after the start of MPA treatment than before or at 5, 8, and 11 months after the start of treatment. The maximal FSH increment and the AUC for FSH after suprapituitary stimulation were significantly higher before treatment than at 5, 8, and 11 months of MPA treatment. Differences in mean basal plasma GH concentrations before and during treatment were not significant, but MPA treatment resulted in significantly elevated basal plasma IGF-1 concentrations at 8 and 11 months. MPA treatment did not affect basal and stimulated plasma ACTH concentrations, with the exception of a decreased AUC for ACTH at 11 months. In contrast, the maximal cortisol increment and the AUC for cortisol after suprapituitary stimulation were significantly lower during MPA treatment than prior to treatment. MPA treatment did not affect basal plasma concentrations of prolactin, TSH, and alpha-MSH, with the exception of slightly increased basal plasma TSH concentrations at 8 months of treatment. MPA treatment did not affect TRH-induced plasma concentrations of prolactin and TSH. In conclusion, the effects of chronic MPA treatment on adenohypophyseal function included increased FSH secretion, unaffected LH secretion, activation of the mammary GH-induced IGF-I secretion, slightly activated TSH secretion, suppression of the hypothalamic-pituitary-adrenocortical axis, and unaffected secretion of prolactin and alpha-MSH.

Basal and GnRH-induced secretion of FSH and LH in anestrous versus ovariectomized bitches.

The basal and gonadotropin releasing hormone (GnRH)-induced plasma concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were studied in four anestrous and four ovariectomized (OVX) bitches. Blood samples were obtained via jugular venipuncture 40min before and 0, 10, 20, 30, 60, 90, and 120min after the i.v. administration of synthetic GnRH in a dose of 10microg/kg body weight. The basal plasma FSH and LH concentrations were significantly higher in the OVX bitches than in the anestrous bitches. In the anestrous bitches, the plasma FSH concentration was significantly higher than the pretreatment level at 10, 20, and 30min, whereas the plasma LH concentration was significantly elevated at 10 and 20min. The maximal GnRH-induced plasma FSH concentration in the anestrous bitches did not surpass the lowest plasma FSH concentration in the OVX bitches, whereas the GnRH-induced plasma LH concentrations in the anestrous bitches overlapped with the basal plasma LH concentrations in the OVX bitches. In the OVX bitches, GnRH administration did not induce a significant change in the plasma FSH concentration, whereas the plasma LH concentration increased significantly at 10 and 20min. In conclusion, the results of the present study indicate that in anestrous bitches GnRH challenge results in increased plasma levels of both FSH and LH, whereas in the OVX bitches, in which the basal plasma FSH and LH concentrations are higher, only a rise in the plasma LH concentration is present after GnRH stimulation. The results also suggest that a test to measure plasma concentration of FSH in single samples appears to have potential in verification of neuter status in bitches.

NT-proBNP and cardiac troponin I concentrations in dogs with tick paralysis caused by Ixodes holocyclus.

OBJECTIVE: The purpose of this study was to determine through measurement of cardiac biomarkers whether there was cardiac involvement in dogs infested with Ixodes holocyclus. METHODS: Dogs with tick paralysis and no-mild (group 1; n = 44) or moderate-severe respiratory compromise (group 2; n = 36) and a control group of dogs (n = 31) were enrolled. Plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), serum cardiac troponin I (cTnI) and serum creatinine concentrations were determined. For most of the affected dogs SpO2 was determined. RESULTS: SpO2 readings did not differ between groups 1 and 2. Three animals in group 2 had an SpO2 reading <90%. NT-proBNP concentrations were lower in both groups 1 and 2 compared with the control group. There was no difference in cTnI concentrations among groups, although they were elevated in four dogs, including the three dogs in group 2 with SpO2 readings <90%. Creatinine concentrations were within the reference interval for all dogs, but did differ among the groups, with control dogs having the highest values, followed by group 1 and then group 2. CONCLUSION: This study did not detect significant cardiac involvement in dogs with tick paralysis induced by I. holocyclus. Evidence for reduced preload in dogs with tick paralysis was provided by lower NT-proBNP concentrations compared with control dogs. Severe hypoxaemia may not be a significant component of the clinical picture in many of the dogs presenting with tick paralysis. Dogs with severe hypoxaemia may have loss of cardiomyocyte integrity, reflected by elevated cTnI concentrations.

Single-dose pharmacokinetics and cardiovascular effects of oral pimobendan in healthy cats.

INTRODUCTION: To investigate the pharmacokinetics and pharmacodynamics of oral pimobendan in conscious, healthy cats. ANIMALS: Eight healthy adult cats. MATERIALS AND METHODS: A randomised, single-blinded, crossover design was used. Two oral doses of pimobendan (0.625-mg [LD], 1.25-mg [HD]) and a control substance (3-mL water) were administered to each cat. Blood collection, echocardiography, and oscillometric blood pressure measurements were performed repeatedly for 12 h following each dose. Plasma concentrations of pimobendan and the active metabolite, O-desmethylpimobendan (ODMP), were quantified using ultra-high-performance liquid chromatography tandem mass spectrometry. Cardiovascular parameters were evaluated for between- and within-treatment effects over time using linear mixed modelling. RESULTS: Pimobendan was rapidly absorbed and converted to ODMP with the pimobendan AUC0-∞ greater than ODMP AUC0-∞ (ODMP:pimobendan AUC0-∞ ratio 0.6 [LD] and 0.5 [HD]) despite a longer elimination half-life of ODMP (pimobendan t1/2 0.8 h vs. ODMP t1/2 1.6 h [LD]; pimobendan t1/2 0.7 h vs. ODMP t1/2 1.3 h [HD]). Averaged across all time points, pimobendan increased several measures of systolic function; however, its effect could not be further characterised. Although treatment was well-tolerated, two cats vomited following HD and another had a ventricular premature beat recorded following LD. CONCLUSIONS: The lower ODMP:pimobendan AUC0-∞ ratio compared to that observed previously in dogs suggests reduced metabolism in cats. Treatment effects were observed in measures of systolic function; however, the duration of action and differences in effects between the two pimobendan doses could not be characterised. Further studies are required to evaluate pimobendan in feline cardiovascular medicine.

Low doses of bromocriptine shorten the interestrous interval in the bitch without lowering plasma prolactin concentration.

In order to investigate the effect of different doses of bromocriptine on plasma prolactin concentration and the interestrous interval, beagle bitches were treated twice daily with 5 microg (5-group), 20 microg (20-group), or 50 microg (50-group) bromocriptine per kg body weight orally, starting 28 days after ovulation. In the 5-group, the difference between the mean plasma prolactin concentration before and that during bromocriptine treatment was not significant. In contrast, mean plasma prolactin concentration decreased significantly after the start of bromocriptine treatment in the 20- and 50-groups. The mean interestrous interval was significantly shorter in all three groups than in untreated bitches in the same colony. The mean interestrous interval in the 20-group and that in the 50-group were similar, but both were significantly shorter than that in the 5-group. The results of this study indicate that bromocriptine shortens the interestrous interval in the bitch even when the dose is so low that it does not lower plasma prolactin concentration. Induction of estrus in the bitch by bromocriptine therefore involves a mechanism other than via the lowering of plasma prolactin concentration. Furthermore, this study shows that the extent of shortening of the interestrous interval by bromocriptine is dose dependent.

Effects of gonadotrophin releasing hormone administration on the pituitary-ovarian axis in anoestrous vs ovariectomized bitches.

The aim of this study was to determine the effects of gonadotrophin releasing hormone (GnRH) administration on the plasma concentrations of reproductive hormones in intact and ovariectomized (OVX) bitches. Therefore, blood samples were collected at multiple times before and after the administration of 10 microg/kg GnRH (Fertagyl)) for the determination of the plasma concentrations of luteinizing hormone (LH), oestradiol, progesterone and testosterone in six anoestrus and in six OVX bitches. The mean plasma LH concentrations before and 60 min after GnRH administration were significantly lower in the anoestrous bitches than in the OVX bitches. In both groups GnRH administration resulted in a significant increase in the plasma LH concentration. The highest plasma LH concentrations were found at 10 min after GnRH administration and these values did not differ significantly between the two groups. Only in the anoestrous bitches a significant increase in plasma oestradiol concentrations was found after GnRH administration and these values were significantly higher than those in the OVX bitches. The plasma concentrations of progesterone and testosterone were low (close to or below the limit of quantitation) both before and after GnRH administration and the differences between anoestrous and OVX bitches were not significant. It can be concluded that (i) basal plasma LH concentration is significantly higher in OVX bitches than in anoestrous bitches, (ii) plasma LH concentration increases after GnRH administration in both anoestrous and OVX bitches, (iii) GnRH administration causes a significant rise in plasma oestradiol concentration only if ovarian tissue is present and (iv) measurement of plasma progesterone and testosterone concentrations before and after GnRH administration does not aid in distinguishing between anoestrous and OVX bitches. The results of this study may provide a basis for the diagnosis of remnant ovarian tissue and verification of neuter status in the bitch.

Serotonin antagonist-induced lowering of prolactin secretion does not affect the pattern of pulsatile secretion of follicle-stimulating hormone and luteinizing hormone in the bitch.

Dopamine agonists decrease plasma prolactin concentration and shorten the duration of anoestrus in the bitch. In order to determine whether this shortening results from decreased prolactin release or is due to another dopamine agonistic effect on the pulsatile release of FSH and LH, eight anoestrous beagle bitches were treated with a low dose of the serotonin antagonist metergoline (0.1 mg per kg body weight, twice daily) starting 100 days after ovulation. Six-hour plasma profiles of LH and FSH were obtained 7 days before, immediately before, 1 week after, and then at 2-week intervals after the start of the treatment with the serotonin antagonist until signs of pro-oestrus appeared. Plasma prolactin concentration was measured three times weekly from 75 to 142 days after ovulation and thereafter once weekly until the next ovulation, and was observed to decrease significantly after the start of treatment. The length of the interoestrous interval in the treated dogs was, however, not different from that in the preceding pretreatment cycle or from that in a group of untreated bitches. During the first weeks of treatment no changes were observed in the pulsatile plasma profiles of FSH and LH. Four weeks after the start of the treatment with the serotonin antagonist there was an increase in the mean basal plasma FSH concentration and the mean area under the curve for FSH, without a concurrent increase in LH secretion. The increase in FSH secretion continued until late anoestrus. In conclusion, the serotonin antagonist-induced lowering of plasma prolactin concentration was not associated with shortening of the interoestrous interval. The plasma profiles of LH and FSH were similar to those observed during physiological anoestrus, but different from those observed during anoestrus shortened by treatment with a dopamine agonist. Hence the prematurely induced oestrus observed during administration of dopamine agonists cannot be explained by a decreased plasma prolactin concentration but must be due to some other dopamine agonistic effect, probably increased FSH secretion. The observations in this study further strengthen the hypothesis that an increase in circulating FSH is essential for ovarian folliculogenesis and consequently the termination of anoestrus in the bitch.