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Hypothyroidism is the most common endocrine disease in dogs and has been shown to have a hereditary nature in many breeds. Previous studies have documented decreased fertility in bitches with experimentally-induced hypothyroidism, decreased viability at birth, increased periparturient mortality, and reduced birth weight in pups born to hypothyroid dogs. Hypothyroid women have an increased demand for exogenous thyroxine throughout gestation in order to maintain normal plasma concentrations of thyroid hormones and produce neuropsychologically normal children. This study was performed to determine if pregnancy causes a similar need for increased levothyroxine dosages in dogs to maintain a euthyroid state. Serum was harvested from blood collected from six bitches with experimentally-induced hypothyroidism that were receiving standard thyroid hormone replacement therapy and from four euthyroid control bitches. Thyroid function tests performed on these samples included total thyroxine (T4), free T4 (FT4), thyroid stimulating hormone (TSH), and 3,5,3'-triiodinine (T3). Thyroid concentrations were measured from ovluation through the end of pregnancy. All bitches whelped normal litters. Euthyroid bitches had no significant alterations in their hormone concentrations throughout pregnancy. None of the supplemented hypothyroid bitches had clinical signs of hypothyroidism throughout the study. Serum concentrations of T4 and FT4 were elevated at multiple sample points during gestation. The results from this study indicate that standard levothyroxine supplementation is adequate to maintain a euthyroid state during pregnancy in experimentally-induced hypothyroid dogs. In addition, there is no evidence that canine thyroid profiles in euthyroid dogs are altered during gestation. / Master of Science

Development of pulmonary hypertension is an independent predictor of poor outcome in dogs affected by myxomatous valvular degeneration (MMVD). Systolic pulmonary arterial pressure is routinely estimated by Doppler echocardiography applying the simplified Bernoulli equation to the velocity of tricuspid regurgitation (sPAP_D). The accuracy of this estimation is unknown in dogs with MMVD, but experimental studies suggest that the method is imperfect. In order to fill this knowledge gap we prospectively enrolled dogs affected by MMVD and cardiac remodeling - American College of Veterinary Internal Medicine (ACVIM) stages B2 and C MMVD for which treatment had been unchanged for at least one month. A flow-directed thermodilution monitoring catheter was percutaneously placed in the right jugular vein and advanced to the main pulmonary artery. Pulmonary arterial systolic pressure was recorded through this catheter connected to a pressure-transducer and data acquisition-analysis system (sPAP_C). A second operator simultaneously acquired tricuspid regurgitant velocity spectra to calculate sPAP_D. Each operator was blinded to the result of the other technique. Twenty dogs were enrolled. Technical difficulties prevented catheterization in 2 dogs. Eighteen measurement pairs were therefore used for comparison of sPAP_C and sPAP_D through Bland-Altman analysis and linear regression. A statistically significant bias between sPAP_C and sPAP_D (mean difference=0.5mmHg; Confidence interval: -6.5mmHg, +7.5mmHg) was not detected. The limits of agreement between the techniques were wide (-27.3mmHg, +28.2mmHg). Regression analysis failed to identify a significant linear association between the two techniques (r=0.11, p=0.17). In conclusion, sPAP_D poorly agrees with sPAP_C measurement in dogs affected by MMVD in ACVIM stages B2 and C. In these dogs, sPAP_D could under- or over-estimate sPAP_C by more than 20mmHg, and therefore caution should be used when interpreting PASP_D. / Master of Science / The most common heart disease of dogs is myxomatous mitral valve disease (MMVD). In many affected dogs, this disease can be complicated by the development of high pressure in the vessels of the lungs, a condition called pulmonary hypertension (PH). On average, dogs with MMVD and PH have shorter survival compared to dogs affected solely by MMVD. The pulmonary pressure in dogs is usually estimated using cardiac ultrasound (echocardiography). This technique has the advantage of being "non-invasive" but it is not a direct measurement of pressure, therefore it may not be accurate. In order to evaluate the accuracy of echocardiography in measuring pulmonary pressure, in this study we compared direct measurements of pulmonary pressure obtained through cardiac catheterization to the measurements estimated using echocardiography, in dogs affected by MMVD. We performed this on 18 dogs affected by MMVD, with one person performing the direct measurements and another performing the echocardiographic ones; the two people were not aware of the measurements obtained with the other technique. We found that the echocardiographic estimated pressures can be very different from the real pressures measured with cardiac catheterization. Particularly, echocardiography resulted both in relevant over- and under-estimation of the real pressure, in an unpredictable way. This study therefore suggests that pulmonary pressures estimated by echocardiography should be interpreted cautiously in dogs affected by MMVD.

Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. However, prospectively acquired data describing the natural history and prognostic factors in a large population of dogs affected by this disease are sparse. Thus, the Longitudinal Outcome of canine (K9) myxomatous mitral valve disease registry (LOOKmitral) was established to prospectively collect clinical and diagnostic data from a large population of dogs affected by MMVD. A total of 6,102 dogs were enrolled in the LOOK-mitral registry from November 1st, 2015, to October 31st, 2018, in thirteen cardiology specialty practices. We first described the baseline characteristics of the dogs enrolled in the registry, which mainly confirmed previous findings. Moreover, we provided new additional results, such as the presence of systolic dysfunction in some small breed dogs and how the intensity of the murmur correlates with the severity of MMVD also in large breed dogs. Second, we described the baseline treatment characteristics at the time of enrollment. These data showed that the results of the "Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly" (EPIC) trial and left atrial and left ventricular dimensions, assessed by echocardiography, influenced veterinary cardiologist's prescription of cardiovascular drugs in affected dogs. Lastly, we evaluated predictors of reoccurrence of congestive signs within 180 days after successfully treating the first episodes of heart failure in dogs enrolled in the LOOKMitral registry. While this study failed to identify accurate predictors of recurrence, dogs with larger left ventricular internal dimensions at end-diastole were more likely to present with reoccurrence of clinical signs suggesting that closer monitoring of these dogs may be recommended. / Doctor of Philosophy / Despite being the most common heart disease in dogs, data on a large group of dogs affected by myxomatous mitral valve disease (MMVD) are currently sparse in veterinary medicine. The Longitudinal Outcome Of canine (K9) Mitral valve disease (LOOK-Mitral) was established in 2015 to collect data on a large population of dogs affected by MMVD. A total of 6,102 dogs were enrolled in thirteen referral centers over three years. First, the baseline characteristics of dogs enrolled in the registry were described. These data mainly confirmed previous findings. Moreover, they provided some new insight like the possible presence of contractile dysfunction in some small breed dogs and the correlation between the intensity of the heart murmur and the severity of the disease also in large breed dogs. Second, we described the medical treatment prescribed or modified by veterinary cardiologists at the enrollment visit. These data showed that the "Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly" (EPIC) trial, a clinical trial published during the enrollment period, and the heart ultrasound (echocardiography) data influence cardiologist prescription habits. Lastly, we evaluated if any clinical or echocardiographic variable could predict the reoccurrence of clinical signs of heart failure within 180 days from the first manifestation of those clinical signs in dogs enrolled in the LOOK-Mitral registry. While this study failed to accurately identify predictors of reoccurrence, dogs with larger left ventricular chamber sizes were more likely to present reoccurrence of clinical signs suggesting that closer monitoring of these dogs may be recommended.

Objectives: To determine the effects of prednisone and prednisone plus ultralow-dose aspirin on coagulation in healthy dogs, and to determine intra-individual variation in thromboelastography (TEG). Animals: 14 healthy experimental dogs and 10 healthy client-owned dogs Procedures: Prospective, randomized, blinded study. TEG was performed twice three days apart on each experimental dog prior to treatment and intra-individual variation was calculated. Dogs were given prednisone (2 mg/kg/day) plus aspirin (0.5 mg/kg/day) or prednisone (2 mg/kg/day) plus placebo for 14 days, after which TEG and other baseline tests were repeated. Changes from baseline between and within each group were compared using t-tests or Wilcoxon 2 sample tests. Client owned dogs had TEG performed twice three days apart to determine intra-individual variation. Results: Intra-individual variation in TEG parameters were <10% for MA (maximum amplitude) and angle. For experimental dogs, MA and fibrinogen significantly increased from baseline whereas Ly30 (percent lysis 30 minutes after MA) and antithrombin activity significantly decreased within each group. For the prednisone plus placebo group, Ly60 (percent lysis 60 minutes after MA) significantly decreased from baseline. For all parameters, there was no difference between groups for change from baseline. Conclusions and Clinical Relevance: Prednisone caused hypercoagulability in healthy dogs evidenced by increased MA and fibrinogen and decreased antithrombin activity. Concurrent use of ultra-low dose aspirin had no effect on measured TEG parameters. Intra-individual variation in some TEG parameters is high and may preclude routine clinical utility. / Master of Science

Background: Biliary sludge is associated with gallbladder (GB) dysmotility and mucus hypersecretion suggesting that these factors could lead to GB mucoceles. If biliary sludge does progress to GB mucoceles, treatments to reduce the production and progression of sludge are warranted. Objectives: The aim of this study was to determine the natural history of biliary sludge in dogs. Animals: Healthy, client-owned dogs (n=74) screened for biliary sludge; 42 affected dogs identified Methods: Prospective, observational design. Serial ultrasound examinations and biochemistries were evaluated over 1 year. The following were determined: percentage of the GB filled with sludge (mild (0.01%-24.4%), moderate (24.5%-49.4%), moderate to severe (49.5%-74.4%), severe (74.5%-100%)), gravity dependency of sludge, GB dimensions, and biochemical indices (ALT, GGT, ALP, total bilirubin, albumin, total calcium, triglycerides, and cholesterol). Mixed model ANOVA, Friedman chi-square, Mantel-Haenzsel chi-square tests, and Kruskal-Wallis test were performed to detect significant changes in these parameters. Significance at P <0.05. Results: After 1 year of follow-up, the percentage of the GB filled by sludge was mild (34%), moderate (47%), moderate to severe (13%), severe (3%), or absent (3%) with no significant difference in the median degree of biliary sludge within 1 year (P=0.36). There was no significant change in the gravity dependency of sludge over 1 year. Dogs had resolved (2%), decreased (19%), static (40%), increased (29%), or recurrent (10%) sludge at the conclusion of the study. Biochemical indices or GB volume were not significantly different over time or among groups. Conclusion: Biliary sludge is prevalent, affected dogs remain asymptomatic, and it rarely resolves in healthy dogs over a period of 1 year. Some dogs developed non-gravity dependent sludge within 1 year, which may indicate changes in consistency. / Master of Science

Background: The pathogenesis of gallbladder mucocele is unknown in the dog. It has been proposed that hyperlipidemia could impair gallbladder motility and contribute to gallbladder mucocele formation. Objectives: The objective of this study was to compare gallbladder motility in dogs with hyperlipidemia to healthy, control dogs using ultrasonography. We hypothesized that hyperlipidemic dogs have decreased gallbladder motility, defined by increased fasting gallbladder volume (GBV) and decreased gallbladder ejection fractions at 60 (EF60) and 120 minutes (EF120) compared to controls. Animals: 26 hyperlipidemic dogs, 28 healthy control dogs Methods: Twenty-six hyperlipidemic and 28 healthy, age-matched control dogs were prospectively enrolled. Hyperlipidemia was defined as hypercholesterolemia (>332 mg/dL) and/or hypertriglyceridemia (>143 mg/dL). Dogs with both primary and secondary causes of hyperlipidemia were included. All dogs were fasted for at least 12 hours prior to collection of plasma biochemistry and pre-prandial ultrasound. Ultrasound was performed on dogs in the fasted state as well as at 60 and 120 minutes after being fed 10g/kg of a high fat diet (Hill's a/d diet; Hill's Pet Nutrition, Topeka, Kansas, USA). GBVs and EFs were calculated using the following formulas: GBV = (0.52 x L x W x H)/kg and EF = ((GBV0- GBV60,120)/GBV0) x 100, respectively. GBV0, GBV60, GBV120, EF60 and EF120 were compared between dogs with hyperlipidemia and controls using the Wilcoxon rank sum test. Statistical significance was set to p<0.05. Results: Hypercholesterolemia and hypertriglyceridemia were present in 15/26 (58%) and 21/26 (81%) hyperlipidemic dogs, respectively and 10/26 (38%) had elevations in both parameters. The median age in both groups was 10 years. Median (range) cholesterol concentration was 346 mg/dL (181-1372 mg/dL) and 238 mg/dL (153-324) in hyperlipidemic and control dogs, respectively. Median triglyceride concentration was 330 mg/dL (52-2213) and 65.5 mg/dL (32-142) in hyperlipidemic and control dogs, respectively. Eleven (42%) hyperlipidemic dogs were considered severely hyperlipidemic based on the triglyceride and/or cholesterol concentrations above 500 mg/dL. There were significant differences in GBV0 and GBV60 between hyperlipidemic and control dogs. Dogs with severe hyperlipidemia had significantly larger GBVs at all time points. Dogs with hypercholesterolemia also had significantly greater GBVs at all times compared to dogs without hypercholesterolemia. Median EF60 and EF120 were not significantly different between hyperlipidemic and control dogs nor severely hyperlipidemic and mildly hyperlipidemic dogs. Conclusions: Hyperlipidemic dogs have significantly greater fasting and postprandial GBVs but similar ejection fractions when compared to control dogs. Gallbladder emptying is unaltered in hyperlipidemic dogs, but gallbladder volume is higher in hyperlipidemic dogs after feeding. This distention could contribute to bile retention of bile and potentially gallbladder disease. / Master of Science / The gallbladder (GB) is a reservoir for bile. The GB contracts to deliver bile to the intestines after a meal to help with digestion of nutrients and fats, and to rid the body of harmful waste. When the GB becomes diseased, abnormal bile flow can become toxic to the liver and endanger the patient's health. One of the most common GB diseases in dogs is GB mucocele (buildup of mucus in the GB). The cause of GB mucocele formation is not well understood. One proposed cause is decreased contractions of the GB related to increased cholesterol and/or elevated triglycerides (hyperlipidemia). Our study investigated whether hyperlipidemia leads to poor gallbladder contraction, possibly explaining GB mucocele formation. We used ultrasound scans before and after eating to compare gallbladder motility in dogs with hyperlipidemia to healthy, control dogs. We hypothesized that hyperlipidemic dogs would have decreased gallbladder motility compared to controls. Twenty-six dogs with elevated cholesterol and/or elevated triglycerides and 28 healthy, age-matched control dogs were enrolled. Ultrasound was performed on dogs in the fasted state as well as 60 and 120 minutes after being fed. There were significant differences in findings between affected dogs and control dogs. Dogs with very high blood lipid levels had significantly larger gall bladder volumes (GBVs). Dogs with high cholesterol also had significantly greater GBVs at all times compared to normal dogs. This finding indicates that excessive bile may be retained in the gall bladders of dogs with hyperlipidemia, possibly affecting the function of the organ. Our study also looked at difference between the two groups in measures of ejection fraction, which can gage how efficiently the gall bladder releases bile. No differences were noted between the healthy group and the affected group. Conclusions and Outcomes: Hyperlipidemic dogs have significantly greater GBVs than control dogs both before and after eating, but similar ejection fractions. This study provides a clearer understanding of the mechanisms of gall bladder disfunction in dogs.

Background: Keratoconjunctivitis sicca (KCS) is a chronic ocular disease of both dogs and humans that can result in ocular discomfort, corneal opacification, and vision loss. Lacritin, a protein found in the tears of many species, has been shown to play a role in lacrimation and corneal health. Because of its role as a potential lacrimostimulant, assessment of endogenous lacritin levels could reveal a correlation between lacritin and tear production in the dog. Objectives: To determine if tear lacritin concentrations are decreased in canine eyes affected by KCS. Animals: 58 client-owned dogs (tear samples from 55 eyes with normal tear production and 55 eyes diagnosed with KCS). Methods: All eyes underwent an ophthalmic exam, including Schirmer Tear Testing (STT), anterior segment assessment, and tear sample collection. Tear samples were evaluated for their total protein concentrations via BCA assay and lacritin concentrations via ELISA. Results: Total protein of canine tears is increased in KCS-affected eyes as compared to normal eyes. Tear lacritin as a component of total tear protein is significantly decreased in tears from KCS-affected eyes. When measured as a concentration (mass per volume of aqueous tears), lacritin is not significantly different between KCS-affected eyes and normal eyes, nor were they strongly correlated to STT values. Conclusions and Clinical Importance: Total tear protein levels were significantly increased in canine KCS. When quantified as a proportion of total tear sample protein, tear lacritin levels are decreased in KCS-affected eyes. Relative to tear volume, tear lacritin levels are not significantly different between KCS-affected eyes and normal eyes. Assessment of lacritin supplementation in canine KCS is warranted to evaluate potential effects on lacrimation and ocular surface health. / Master of Science / Keratoconjunctivitis sicca describes a syndrome of inadequate pre-ocular tear film, due to decreased quantity or quality of tears on the ocular surface. A multitude of clinical signs and sequelae result, including ocular discomfort, ocular discharge, and corneal opacification that may lead to vision loss. Current therapies aim at improving endogenous tear production; standard therapy, however, may not significantly improve disease in up to 30% of canine patients and 40% of human patients. Development of additional therapies could improve the vision and comfort of patients with KCS. Lacritin, a protein found in the tears of many species, has been shown to play a role in lacrimation and corneal health. Because of its role as a potential stimulant of tear production, assessment of endogenous lacritin levels could reveal a correlation between lacritin and tear production in the dog. This project aims to compare tear lacritin concentrations in dogs with normal tear production versus dogs with KCS. Tear samples were collected from normal dogs (n=55) and those affected with KCS (n=55). Samples were analyzed for their total tear protein levels via BCA assay and for their lacritin levels via ELISA analysis. Total tear protein levels and tear lacritin levels were compared to Schirmer Tear Test results, a routine method of diagnosing KCS in dogs. Tear lacritin was significantly decreased in KCS, relative to the quantity of total tear proteins. As a portion of the total volume of tears, lacritin was not significantly different in KCS-affected eyes as compared to normal eyes. Further investigation is warranted to determine the effects lacritin supplementation may have on canine KCS, in regard to tear production and clinical signs of KCS.

The objective of this prospective cohort study is to assess the use of neurofilament light chain (NfL) as a biomarker for diagnostic and therapeutic monitoring in dogs with idiopathic and structural epilepsy. A total of 50 dogs (36 idiopathic epilepsy and 14 structural epilepsy) were enrolled to contribute a total of 58 samples (52 serum and 6 cerebrospinal fluid (CSF)). Dogs diagnosed with structural epilepsy received magnetic resonance imaging (MRI). Dogs were grouped into acute seizures when they had a generalized seizure within the last 7 days and chronic seizures when they had no observed generalized seizures for the previous 30 days. Both serum and CSF NfL concentrations were measured using single molecule array technology (Simoa). The median serum concentration of NfL in dogs with structural epilepsy was 109 [11.4-741.3] pg/mL and 17.7 [5.8-188] pg/mL in dogs with idiopathic epilepsy regardless of the interictal interval. Serum NfL concentration was significantly increased in dogs with structural epilepsy when compared with dogs with idiopathic epilepsy (p < 0.001). There was no significant difference in NfL concentration in dogs with an interictal interval of 7 days compared to dogs with an interictal interval of 30 days. In dogs with seizures, serum NfL concentration may help discriminate between structural and idiopathic epilepsy. Future studies are needed to determine its role in differentiating true seizure events from seizure mimics. / Master of Science / Generalized seizures due to epilepsy is the most frequent neurologic problem in dogs presenting to veterinary hospitals. Idiopathic epilepsy is the most common underlying cause for seizures to occur in young dogs. Structural epilepsy occurs due to a brain tumor, encephalitis or stroke and is more common in dogs greater than six years of age. A diagnosis of structural epilepsy typically requires an identifiable structural abnormality on magnetic resonance imaging (MRI) and / or cerebrospinal fluid (CSF) analysis. A diagnosis of idiopathic epilepsy is suggested when these tests are normal. Performing these diagnostics is not always feasible for a variety of reasons (accessibility, cost, anesthetic safety). Therefore, it is important to investigate alternative options for the diagnosis of idiopathic epilepsy. It can also be difficult for pet owners to witness and document every seizure for an accurate seizure frequency history. Investigating new methods for assessing seizure control is also warranted. This study was performed to gain knowledge about the measurement of a neuron specific biomarker that can be measured in both blood and CSF for the diagnosis of structural epilepsy and therapeutic monitoring of seizure control. It appears that the measurement of serum neurofilament light chain (NfL) can serve as an alternative for the differentiation of idiopathic and structural epilepsy as NfL concentration was significantly increased in dogs with structural epilepsy. There was no difference in NfL concentration between dogs with recent seizures and dogs with well-controlled seizures. Additional research is needed to assess its use in differentiating true seizures from other neurologic or cardiac episodes that can appear similar.

Myxomatous mitral valve degeneration (MMVD) is the most common canine cardiac disease. In the studies presented in this dissertation, we used advanced echocardiographic techniques to elucidate several aspects of MMVD in dogs. Our hypothesis was that the mitral valve (MV) morphology could have a role in the development of MMVD. First, we tested whether we could use real time three-dimensional transthoracic echocardiography (RT-3DTTE), and an offline software for MV analysis to evaluate canine MV. We described that the technique was feasible and repeatable, we evaluated the morphology of the MV in healthy dogs, and we provided reference values for MV morphologic variables in this species. Then, we used the same technique to compare healthy dogs to dogs affected by MMVD. We found that dogs affected by MMVD have more circular and flatter valve. We then analyzed the MV of healthy Cavalier King Charles Spaniels (CKCSs), given the high predisposition of this breed for MMVD. Our findings indicate that compared to healthy dogs of other breeds, the MV of healthy CKCSs is flatter and has less leaflet tenting, corroborating our hypothesis that an altered MV morphology could represent a predisposing factor for disease development. We also used RT–3DTTE to characterize the area of the regurgitant MV orifice of dogs affected with MMVD, finding that the technique requires further standardization in order to become clinically useful. The elevation of pulmonary venous pressure caused by MMVD can, in some dogs, cause pulmonary arterial hypertension (PH), which is a risk factor associated with worse outcome in dogs with MMVD. Diagnosis of PH in dogs with MMVD is usually made by estimating pulmonary pressure using Doppler echocardiography. We are currently evaluating the accuracy of this technique, compared to invasive measurement of pulmonary pressure. Only preliminary data are presented regarding this study, as the disclosure of the blinding would have infringed the power of the study. Our preliminary results demonstrate that there is only moderate agreement between the two techniques, indicating that caution should be used when deriving the non-invasive estimation of systolic pulmonary pressure in order to make clinical decisions. / Ph. D. / The studies collected in this dissertation focus on myxomatous mitral valve disease (MMVD), which is the most common heart disease in dogs, and the most common cause of cardiac-related death in this species. This disease mainly affects one of the heart valves, i.e. the mitral valve (MV), impeding its normal functionality. In the studies presented in this dissertation, we used advanced non-invasive ultrasonographic techniques to investigate the mechanisms involved in this disease. We hypothesized that a different shape of the MV in some dogs could contribute to the development of the disease. We used 3D ultrasounds to build models of the MV and analyze the shape of it. We first demonstrated that using this technique in dogs was feasible and repeatable, and that the MV of normal dogs was elliptical and saddle-shaped. We then compared the shape of the MV of normal dogs, to the shape of the MV of dogs affected with MMVD. We found that dogs with the disease have a MV that is flatter and more circular. In our next study, we examined the shape of the MV of a breed of dogs that is predisposed to develop MMVD: Cavalier King Charles Spaniels (CKCSs). Our study found that healthy CKCSs have an overall flatter MV when compared with the other breeds, and that the normal MV of CKCSs is similar to the MV of affected dogs of other breeds. This finding support our hypothesis that an abnormal shape of the MV could contribute to the development of the disease. In another study, we saw to evaluate whether we could use 3D ultrasounds for investigating the shape of the hole that creates on affected MV. We concluded that this technique still requires more standardization before being used for evaluation of dogs. In another study, of which some preliminary results are presented in this dissertation, we are testing how accurate it is to evaluate the pressure of the pulmonary artery using ultrasonography. We are doing this by comparing this technique to a direct measurement of the pressures with a catheter in the pulmonary artery. We found that measurements obtained with the two techniques do not agree very well, which most likely indicates the evaluation of the pulmonary artery pressure using ultrasonography requires caution.