Summary: 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.

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.

The most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually high prevalence of early-onset MMVD, and thus, potentially greater cardiac morbidity and mortality compared to other breeds. Previous research has suggested that selected candidate risk alleles for MMVD are fixed in CKCSs, including six locations within the Nebulette (NEBL) gene on CFA2. The current study analysed genotypes of 180 Australian CKCSs at the identified risk loci. Of these, 178 were phenotyped for severity of disease by echocardiographic measurements of left atrium to aortic root ratio (LA:Ao) and weight normalised left ventricular end diastolic diameter (LVIDdN). Genotyping array markers correctly predicted the genotype at the risk-variant loci in the CKCS population, and the NEBL1, NEBL2 and NEBL3 variants were observed to be in perfect linkage disequilibrium in this cohort. The CKCS cohort included 6/178 dogs being heterozygous for the protective/wild-type alleles at the NEBL locus. The mean LA:Ao and LVIDdN scores of these dogs heterozygous at NEBL1-3 variants were significantly smaller, and with significantly lower variance compared to age-matched CKCSs that were homozygous for risk alleles. The lower cardiac measurements in the heterozygous dogs indicate a significantly reduced risk of severe MMVD disease. Our analysis suggests that despite relative fixation of the NEBL risk alleles, healthy reference alleles at NEBL1-3 exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality.