CURRENT AND PAST RESEARCH PROJECTS
2007-2008 Update


Grant 106

Institution: University of Pennsylvania

Title of Project: 3-Dimensional Echocardiographic Reconstruction of Mitral Valve Leaflet and Mitral Annular Geometry in Healthy Dogs and Dogs with Mitral Valve Degeneration

Investigators: Mark A. Oyama, DVM; Robert C. Gorman, MD; Meg M. Sleeper, VMD; Steve G. Cole, DVM; Liam P. Ryan, MD; and Joseph H. Gorman, III, MD.

Duration: 2007-2008

Objectives: The investigators hypothesize that the valves of dogs with mitral valve disease (MVD) possess inherently different geometrical characteristics when compared to those of non-affected dogs. They propose to use a novel 3-D echocardiographic technique to correlate the valve geometry with disease severity, ventricular function and geometry, and conventional 2-D echocardiographic measurements of mitral valve disease.

Background: It is not known whether breeds (like CKCS) that are predisposed to spontaneous mitral valve disease (MVD) have inherent abnormalities in valve geometry that lead to, or promote, development of the disease. Any such geometric abnormalities cannot be adequately evaluated by currently standard techniques, such as 2-D echocardiography. The investigators plan to use new 3-D echocardiography techniques and specialized image reconstruction to visualize the geometry of the valve annulus and valve leaflets in greater detail. They will study Cavaliers with MVD, Cavaliers without clinical MVD (a “non-affected, predisposed” dog population), and unaffected dogs from other, large breeds (a “non-affected, non-predisposed” population). These results will be correlated with clinical and echocardiographic parameters of disease severity, and will be compared between the three study groups to determine whether dogs predisposed to MVD have inherent mitral valve abnormalities that predispose them to development of the disease.

Grant 105

Institution:
The Ohio State University

Title of Project: The Study of Caudal Occipital Malformation Syndrome (COMS) in Cavalier King Charles Spaniels

Investigators: Carley J. Abramson, DVM and Phil March, DVM.

Duration: 2005-2007

Objectives: The goals of this study were to assess the correlation between the severity of clinical signs and the MRI findings in dogs affected with caudal occipital malformation syndrome (COMS) and to evaluate potential objective, non-invasive markers of COMS that might be used to detect the disease, assess its severity, select patients for surgical correction, and follow the effectiveness of surgery.

Findings:

COMS is a serious condition in dogs that can have severe neurological consequences. At present, reliable diagnosis is only possible with magnetic resonance imaging (MRI), which is expensive, requires sedation, and adds complexity to the evaluation of dogs suspected of having COMS. The investigators evaluated seven other non-invasive tests and parameters in 52 dogs and compared those results to MRI findings. Analysis so far indicates that none of the proposed non-invasive, non-sedation-requiring screening tests for COMS that were hoped to evolve out of this study will produce sufficiently reliable results. However, they also evaluated novel MRI techniques to assess the patterns of flow of the cerebrospinal fluid around and within the spinal cord in Cavaliers with COMS. These results may be important in understanding this disease and assessing the effectiveness of surgery or other therapies. Dr. March is currently at Tufts University, where he hopes to continue these investigations.

Grant 104

Institution:
The Stone Lion Veterinary Centre, Wimbledon, England
        
The Centre for Applied Genomics, Hospital for Sick Children in Toronto
         The Centre for Research in Neuroscience, McGill University in Montreal
         The Comparative Neuromuscular Laboratory, UC San Diego

Title of Project: The Study of the Successful Collection and Archiving of DNA from Cavalier King
                  Charles Spaniels, Enabling a Genome Scan to be performed.

Investigators: Clare Rusbridge, BVMS; Penny Knowler, BSc; Berge A Minassian, MD, CM; Guy
               A. Rouleau, MD, PhD; Diane Shelton, DVM, PhD.

Duration: 2005-2007

Objectives: This was a pilot study of the collection and archiving of DNA from Cavalier King Charles Spaniels, with the eventual goal of enabling a genome scan to be performed. This study is part of a much larger investigation that is aimed at performing large-scale DNA archiving, and genomic and genealogical analysis, with the goal of localizing the genes associated with syringomyelia, mitral valve degeneration, and epilepsy. This is a large study, funded by several organizations and involving multiple breeds. The portion of this study funded by the Cavalier Health Foundation was the collection and archival of DNA samples for 400 CKCSs in North America, to supplement the investigators’ ongoing data collection in the United Kingdom and Australia.

Findings:

The investigators have collected DNA samples from over 1500 CKCS dogs, including the 400 funded by the Foundation. They have also constructed a genealogy of over 10600 related CKCS dogs from over 600 MRI-confirmed syringomyelia dogs, as well as 273 with mitral valve disease and 62 with epilepsy. Preliminary results have suggested six interesting regions on six associated chromosomes that warrant further investigation. The investigators are currently investigating these six candidate regions by further genetic analysis in additional affected sibling-pair dogs with syringomyelia. The investigators are pursuing additional funding to extend and expand their project.

Grant 103

Institution:
University of Tennessee

Title of Project: Quantitative, Functional, and Morphologic Characterization of Platelets in the 
                  Cavalier King Charles Spaniel

Investigator: Sarah M. Cowan, DVM

Duration: 2002-2003

Objectives: This was a pilot study designed as an effort to characterize the commonly reported, inherited abnormalities of platelets (macrothrombocytosis and thrombocytopenia) in Cavalier King Charles Spaniels.

Findings:

Thrombocytopenia (low platelet count) and macrothrombocytosis (abnormally large platelet cells) are commonly-encountered blood-count abnormalities in Cavaliers. This study was aimed at quantifying this problem and assessing its clinical significance. Thrombocytopenia was present in 51% of the 69 CKCSs in the study, and macrothrombocytes were present in one-third.  Co-incidentally, 38% of the dogs in this study had cardiac murmurs, though any linkage between the two will require much further study. However, overall platelet function appeared normal. The investigators termed the disorder “Benign Inherited Giant Platelet Disorder” (IGPD). Significantly, the investigators noted that platelet counting by automated instruments is particularly prone to error in this condition and that platelet counts in affected animals should always be performed manually. Several abstracts and one published paper have originated from this study, which won the award for best resident abstract at the 2002 Meeting of the American College of Veterinary Internal Medicine. Dr. Cowan is now located at The Veterinary Specialist Centre in Sidney, Australia and is continuing her research on platelet function in Cavaliers and the possible genetic relationship of this abnormality with mitral valve disease.

Awarded Best Resident Abstract at the ACVIM Forum in 2002

Grant 102

Institution:
North Carolina State University

Title of Project: Identification of Mitogenic Receptors Associated with Chronic Valvular Heart
                  Disease in Cavalier King Charles Spaniels

Investigators: Bruce W. Keene, DVM, MSc; Natasha J. Olby, VetMB, PhD; Sharon C. Hinkle PhD;
               David Malarkey, DVM, PhD; Francis W.K. Smith III, DVM; Teresa C. DeFrancesco,
               DVM; William Rausch, DVM; Jens Haggstrom, DVM; Clarke E. Atkins, DVM.

Duration: 2001-2002

Objectives: This was a pilot study designed to identify specific receptors on heart valves that may be involved in the development of Cavalier heart valve disease.

Findings:

Special microscopic staining of heart valve tissues from dogs with and without mitral valve disease was performed to assess the levels of several types of receptors. These types of receptors are triggered by a variety of specific molecules that play many roles within the body, including the regulation of cell numbers within tissues, cell activity, and the balance between cell division and programmed cell death. Such molecules, called mitogens, have been implicated by some investigators in human valvular disease associated with certain drugs, like fenfluramine. The investigators in this study found mitogen receptor levels in valvular tissues somewhat different from those reported in earlier publications by other authors. The investigators have proposed several possible causes for the discrepancy between their results and previous studies. They suggest that further studies be performed, using valvular tissues from larger numbers of affected and control animals, as well as testing for additional subtypes of these mitogenic receptors

Grant 101

Institution:
Texas A&M University

Title of Project: Effect of Carvedilol in Dogs with Chronic Degenerative Valve Disease

Investigators: Sonya G. Gordon, BSc, DVM, DVSc; Dawn M. Boothe, DVM, PhD; Matthew W.
               Miller, DVM, MS; Anne Bahr, DVM, MS; and Wendy Arsenault, DVM.

Duration: 2001-2004

Objectives:

This study was a pilot project to evaluate the use of a beta-blocker, carvedilol, in Cavaliers with mitral valve disease (MVD).  Beta blockers are often used in humans to improve the heart's pumping ability.   The primary goal of this study was to determine the most effective dosing for carvedilol in CKCS dogs, and to lay a foundation for future studies to determine if carvedilol will slow the progression of MVD in affected dogs.

Findings:

The investigators have completed the assessment of the biological effects and metabolism of carvedilol in normal dogs, and have established safe and effective dosage regimens. They have developed an oral suspension of carvedilol that allows for precise dosing of canine cardiac patients – a requirement for rigorous clinical trials. Their early clinical results suggest that carvedilol improves the heart’s pumping action in Cavaliers with MVD that have not yet developed symptoms. So far, six abstracts and two scientific papers have been published from this work.  One of these abstracts was awarded “Best Resident Abstract” at the 2003 American College of Veterinary Internal Medicine Forum. The investigators are continuing their research in this field and are planning a larger study to determine whether treatment of asymptomatic Cavaliers with MVD will delay onset of clinical signs and symptoms of congestive heart failure.

Awarded Best Resident Abstract at the ACVIM Forum in 2003


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