ABSTRACT
Sudden cardiac death in the young (SCDY) is a devastating event that often has an underlying genetic basis. Manchester Terrier dogs offer a naturally occurring model of SCDY, with sudden death of puppies as the manifestation of an inherited dilated cardiomyopathy (DCM). We performed a genome-wide association study for SCDY/DCM in Manchester Terrier dogs and identified a susceptibility locus harboring the cardiac ATP-sensitive potassium channel gene ABCC9. Sanger sequencing revealed an ABCC9 p.R1186Q variant present in a homozygous state in all SCDY/DCM-affected dogs (n = 26). None of the controls genotyped (n = 398) were homozygous for the variant, but 69 were heterozygous carriers, consistent with autosomal recessive inheritance with complete penetrance (p = 4 × 10-42 for the association of homozygosity for ABCC9 p.R1186Q with SCDY/DCM). This variant exists at low frequency in human populations (rs776973456) with clinical significance previously deemed uncertain. The results of this study further the evidence that ABCC9 is a susceptibility gene for SCDY/DCM and highlight the potential application of dog models to predict the clinical significance of human variants.
Subject(s)
Cardiomyopathy, Dilated , Death, Sudden, Cardiac , Dog Diseases , Sulfonylurea Receptors , Animals , Dogs , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/veterinary , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/veterinary , Genome-Wide Association Study , Genotype , Mutation, Missense , Sulfonylurea Receptors/genetics , Dog Diseases/geneticsABSTRACT
Humans have a larger energy budget than great apes, allowing the combination of the metabolically expensive traits that define our life history. This budget is ultimately related to the cardiac output, the product of the blood pumped from the ventricle and the number of heart beats per minute, a measure of the blood available for the whole organism physiological activity. To show the relationship between cardiac output and energy expenditure in hominid evolution, we study a surrogate measure of cardiac output, the aortic root diameter, in humans and great apes. When compared to gorillas and chimpanzees, humans present an increased body mass adjusted aortic root diameter. We also use data from the literature to show that over the human lifespan, cardiac output and total energy expenditure follow almost identical trajectories, with a marked increase during the period of brain growth, and a plateau during most of the adult life. The limited variation of adjusted cardiac output with sex, age and physical activity supports the compensation model of energy expenditure in humans. Finally, we present a first study of cardiac output in the skeleton through the study of the aortic impression in the vertebral bodies of the spine. It is absent in great apes, and present in humans and Neanderthals, large-brained hominins with an extended life cycle. An increased adjusted cardiac output, underlying higher total energy expenditure, would have been a key process in human evolution.
Subject(s)
Hominidae , Neanderthals , Adult , Animals , Humans , Hominidae/physiology , Gorilla gorilla , Pan troglodytes , Aorta , Cardiac Output , Biological EvolutionABSTRACT
Captive chimpanzees (Pan troglodytes) mature earlier in body mass and have a greater growth rate compared to wild individuals. However, relatively little is known about how growth parameters compare between chimpanzees living in different captive environments. To investigate, body mass was measured in 298 African sanctuary chimpanzees and was acquired from 1030 zoological and 442 research chimpanzees, using data repositories. An analysis of covariance, adjusting for age, was performed to assess same-sex body mass differences between adult sanctuary, zoological, and research populations. Piecewise linear regression was performed to estimate sex-specific growth rates and the age at maturation, which were compared between sexes and across populations using extra-sum-of-squares F tests. Adult body mass was greater in the zoological and resarch populations compared to the sanctuary chimpanzees, in both sexes. Male and female sanctuary chimpanzees were estimated to have a slower rate of growth compared with their zoological and research counterparts. Additionally, male sanctuary chimpanzees were estimated to have an older age at maturation for body mass compared with zoological and research males, whereas the age at maturation was similar across female populations. For both the zoological and research populations, the estimated growth rate was greater in males compared to females. Together, these data contribute to current understanding of growth and maturation in this species and suggest marked differences between the growth patterns of chimpanzees living in different captive environments.
Subject(s)
Animals, Wild , Pan troglodytes , Animals , Male , Female , Animals, Zoo , Sex CharacteristicsABSTRACT
Assessing and treating cardiovascular disease (or heart disease) is a growing concern for institutions housing great apes, as it is a major cause of mortality in all four taxa managed in human care. As part of a proactive monitoring plan, zoological managers and veterinarians often elect to perform electrocardiograms (ECGs) on their great ape populations. ECGs noninvasively evaluate cardiac electrical activity, and are thereby capable of providing information regarding heart function. This electrical signature is transcribed as a visual display of waveforms, referred to as telemetry strips, and can detect irregularities in heart rhythm, also known as arrhythmia. While traditional 6- or 12-lead ECGs are recommended periodically as part of a thorough heart performance evaluation, here we discuss the KardiaMobile (KM) device as an additional primate welfare tool. KM is a small, Food and Drug Administration-cleared, clinical-grade mobile ECG monitor that requires only 30 s of pressure to flag heart rate or arrhythmic abnormalities. We detail the training process and applicability to great apes in human care.
Subject(s)
Ape Diseases/diagnosis , Cardiovascular Diseases/veterinary , Electrocardiography/veterinary , Monitoring, Physiologic/veterinary , Animal Welfare , Animals , Animals, Zoo , Cardiovascular Diseases/diagnosis , Electrocardiography/instrumentation , Electrocardiography/methods , Hominidae , Monitoring, Physiologic/instrumentation , Monitoring, Physiologic/methodsABSTRACT
Cardiovascular disease (CVD) has been identified as a major cause of mortality in all four great ape taxa in zoologic institutions. In an effort to better understand and treat CVD in captive great apes, a program called the Great Ape Heart Project (GAHP), based at Zoo Atlanta, collects and maintains a database of echocardiograms and other relevant medical information relating to the cardiac health status of great apes. Cardiac health assessments have become standard practice among North American zoos that house great apes and are recommended by all four great ape Species Survival Plans (SSP) for the assessment of CVD in captive great apes. As of December 31, 2017, more than 70 ape-holding institutions have submitted approximately 1,100 cardiac examinations of great apes to the GAHP, information from which is stored in the GAHP database. Transthoracic echocardiography is one of the most practical and cost-effective diagnostic imaging techniques for the evaluation of cardiac function in great apes. Standardization of echocardiographic measurements is critical for maximizing the diagnostic value of an echocardiographic exam and for utilization of stored information in comparative studies within and between the great ape taxa. The following manuscript offers suggestions for standardization of nomenclature, imaging technique, echocardiographic measurements, data storage, and reporting of cardiac exams for submission into the GAHP database with the goal of promoting consistency and quality in data collection.
Subject(s)
Ape Diseases/diagnostic imaging , Echocardiography/veterinary , Heart Diseases/veterinary , Hominidae , Practice Guidelines as Topic , Animals , Animals, Zoo , Echocardiography/methods , Heart Diseases/diagnostic imagingABSTRACT
OBJECTIVES: The aim of this study was to determine the pharmacokinetics of furosemide in cats following intravenous (IV), oral and transdermal administration. METHODS: This study used six healthy adult cats in a three-phase design to compare plasma furosemide concentrations in cats that received one IV 2 mg/kg dose of furosemide, one oral 2 mg/kg dose of furosemide and 3 days of q12h dosing with 2 mg/kg furosemide transdermally applied to the ear pinna. RESULTS: After IV administration the elimination half-life was (mean and coefficient of variation) 2.25 h (72%), systemic clearance was 149 ml/kg/h (27.4%) and volume of distribution was 227 ml/kg (22%). After oral administration the terminal half-life was 1.2 h (18.7%), peak concentration was 3.4 µg/ml (51.7%) and bioavailability was 48.4%. The transdermal plasma concentrations were undetectable or very low at most time points, and pharmacokinetics were not determined from the transdermal dose. CONCLUSIONS AND RELEVANCE: Furosemide was rapidly eliminated in cats after oral and IV administration and is probably best administered orally at least q12h in cats with heart failure. The oral dose absorbed was approximately 50%, but the absorption from transdermal administration was negligible.
Subject(s)
Analgesics, Opioid/pharmacokinetics , Cats/metabolism , Furosemide/pharmacokinetics , Administration, Cutaneous , Administration, Oral , Administration, Topical , Analgesics, Opioid/administration & dosage , Animals , Biological Availability , Female , Furosemide/administration & dosage , Half-Life , Infusions, Intravenous/veterinary , Injections, Intravenous/veterinary , MaleABSTRACT
A 2-year-old male intact Belgian Malinois was presented for exercise intolerance. A grade III/VI left basilar systolic murmur was detected. Echocardiography revealed moderate right atrial and ventricular dilation and increased pulmonic outflow velocity. Thoracic radiographs showed right heart enlargement and a dilated caudal vena cava. In addition, on the left lateral projection, an enlarged aberrant right cranial pulmonary lobar vein was suspected to be diverging ventrally from the course of the right cranial lobar bronchus and inserting more ventrally than normal in the region of the right atrium. A left-to-right pulmonary vascular shunt was suspected, and the patient underwent further diagnostics under general anesthesia. An agitated saline study was positive, suggestive of a concurrent right to left shunt. A right heart catheterization was performed. Angiography was inconclusive. Oximetry testing revealed an increase in oxygen saturation within the right atrium at the level of the caudal cava supportive of a left-to-right shunt in this region. Computed tomography angiography revealed a large single pulmonary vein that anomalously entered into the caudolateral aspect of the right atrium (left-to-right shunt) and was suspicious for a small arteriovenous malformation between the right caudal pulmonary artery and the right pulmonary vein returning to the left atrium (right to left shunt). The patient was diagnosed with a partial anomalous pulmonary venous connection and a possible arteriovenous malformation.
Subject(s)
Arteriovenous Malformations/veterinary , Dog Diseases/diagnosis , Heart Atria/abnormalities , Pulmonary Artery/abnormalities , Abnormalities, Multiple/veterinary , Animals , Arteriovenous Malformations/diagnosis , Arteriovenous Malformations/diagnostic imaging , Diagnosis, Differential , Dog Diseases/diagnostic imaging , Dogs , Echocardiography/veterinary , Male , Tomography, X-Ray Computed/veterinaryABSTRACT
Gene therapy is a procedure resulting in the transfer of a gene into an individual's cells to treat a disease. One goal of gene transfer is to express a functional gene when the endogenous gene is inactive. However, because heart failure is a complex disease characterized by multiple abnormalities at the cellular level, an alternate gene delivery approach is to alter myocardial protein levels to improve function. This article discusses background information on gene delivery, including packaging, administration, and a brief discussion of some of the candidate transgenes likely to alter the progression of naturally occurring heart disease in dogs and cats.
Subject(s)
Cardiovascular Diseases/veterinary , Cat Diseases/therapy , Dog Diseases/therapy , Gene Transfer Techniques/veterinary , Genetic Therapy/veterinary , Animals , Cardiovascular Diseases/therapy , Cat Diseases/genetics , Cats , Dog Diseases/genetics , Dogs , Genetic Therapy/methods , TransgenesABSTRACT
Heart disease can be defined as any abnormality of the heart whether it is a cardiac dysrhythmia or structural heart disease, either congenital or acquired. Heart failure occurs when a cardiac abnormality results in the inability of the heart to pump enough blood to meet the body's needs. Heart disease can be present without leading to heart failure. Heart failure, however, is a consequence of heart disease. There are 4 main areas where the clinician can intervene to improve cardiac output with heart failure: preload, afterload, myocardial contractility, and heart rate.
Subject(s)
Heart Diseases/veterinary , Horse Diseases/therapy , Animals , Heart Diseases/diagnosis , Heart Diseases/therapy , Horse Diseases/diagnosis , Horses , HumansABSTRACT
Cardiovascular disease is a leading cause of death in captive chimpanzees and is often associated with myocardial fibrosis, which increases the risk of cardiac arrhythmias. In this case report, we present a 36-y-old male chimpanzee (Pan troglodytes) diagnosed with frequent ventricular premature complexes (VPC). We placed a subcutaneous implantable loop recorder for continual ECG monitoring to assess his arrhythmias without the confounding effects of anesthetics. During his initial treatment with the antiarrhythmia medication amiodarone, he developed thrombocytopenia, and the drug was discontinued. After reviewing other potential therapies for the treatment of cardiac arrhythmias, we elected to try acupuncture and laser therapy in view of the positive results and the lack of adverse side effects reported in humans. We used 2 well-known cardiac acupuncture sites on the wrist, PC6 (pericardium 6) and HT7 (heart 7), and evaluated the results of the therapy by using the ECG recordings from the implantable loop recorder. Although periodic increases in the animal's excitement level introduced confounding variables that caused some variation in the data, acupuncture and laser therapy appeared to decrease the mean number of VPC/min in this chimpanzee.
Subject(s)
Acupuncture Therapy/veterinary , Ape Diseases/diagnosis , Ape Diseases/therapy , Electrocardiography, Ambulatory/veterinary , Laser Therapy/veterinary , Pan troglodytes , Ventricular Premature Complexes/veterinary , Animals , Ape Diseases/physiopathology , Electrocardiography, Ambulatory/instrumentation , Equipment Design , Heart Rate , Male , Predictive Value of Tests , Time Factors , Treatment Outcome , Ventricular Premature Complexes/diagnosis , Ventricular Premature Complexes/physiopathology , Ventricular Premature Complexes/therapyABSTRACT
Computed Tomography (CT) and Echocardiography (EC) are two imaging modalities that produce critical longitudinal data that can be analyzed for radiation-induced organ-specific injury to the lung and heart. The Medical Countermeasures Against Radiological Threats (MCART) consortium has a well established animal model research platform that includes nonhuman primate (NHP) models of the acute radiation syndrome and the delayed effects of acute radiation exposure. These models call for a definition of the latency, incidence, severity, duration, and resolution of different organ-specific radiation-induced subsyndromes. The pulmonary subsyndromes and cardiac effects are a pair of interdependent syndromes impacted by exposure to potentially lethal doses of radiation. Establishing a connection between these will reveal important information about their interaction and progression of injury and recovery. Herein, the authors demonstrate the use of CT and EC data in the rhesus macaque models to define delayed organ injury, thereby establishing: a) consistent and reliable methodology to assess radiation-induced damage to the lung and heart; b) an extensive database in normal age-matched NHP for key primary and secondary endpoints; c) identified problematic variables in imaging techniques and proposed solutions to maintain data integrity; and d) initiated longitudinal analysis of potentially lethal radiation-induced damage to the lung and heart.
Subject(s)
Echocardiography/standards , Heart Injuries/diagnosis , Lung Injury/diagnosis , Multimodal Imaging/standards , Radiation Injuries/diagnosis , Tomography, X-Ray Computed/standards , Algorithms , Animals , Guidelines as Topic , Longitudinal Studies , Macaca mulatta , Male , Radiation Dosage , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
A 10-year-old male neutered cavalier King Charles Spaniel with a 1-year history of degenerative mitral valve disease presented for dyspnea and severe weakness. He was diagnosed with congestive heart failure, systolic dysfunction, presumptive myocardial infarction and a left atrial thrombus based on thoracic radiographs, electrocardiogram and echocardiographic findings. Clinical signs also suggested right foreleg embolism. The dog was euthanized due to the grave prognosis and a postmortem evaluation was performed. The postmortem examination confirmed myocardial infarction and was thought to be due to embolic showering from the thrombus attached to a partial thickness left atrial endocardial tear.
Subject(s)
Dog Diseases/pathology , Heart Atria/pathology , Mitral Valve Insufficiency/veterinary , Myocardial Infarction/veterinary , Animals , Dogs , Heart Diseases/complications , Heart Diseases/veterinary , Male , Myocardial Infarction/pathology , Rupture/pathology , Rupture/veterinary , Thrombosis/complications , Thrombosis/veterinaryABSTRACT
This study evaluated whether acepromazine or methadone reduced behavioral parameters, overall excitement, and activity associated with midazolam administration to healthy dogs. Dogs received midazolam (M) alone [M: 0.25 mg/kg body weight (BW)] or with methadone (MM) (MM: 0.75 mg/kg BW) or acepromazine (MA) (MA: 0.03 mg/kg BW) or saline (S) solution alone, all intramuscularly. Two blinded observers evaluated behavioral parameters using video recordings 30 min before and after injection of drugs. Accelerometery was used to evaluate "total activity counts" (TAC) at baseline and post-treatment. Post-treatment excitement scores were significantly higher in M and MA compared to baseline, M and MM compared to S, and M compared to MA. Behavioral parameters showed significantly higher proportions of "pacing" post-treatment in all groups receiving midazolam, and "restlessness," "chewing/licking," and "sniffing" in M. No significant differences were found for TAC at baseline and post-treatment. Midazolam-induced paradoxical behavioral changes (excitation, panting, pacing, restlessness, licking/chewing, and vocalization) were not prevented by acepromazine or methadone in healthy dogs.
Effets de l'acépromazine ou de la méthadone sur les réactions comportementales induites par le midazolam chez les chiens. Cette étude a évalué si l'acépromazine ou la méthadone réduisait les paramètres comportementaux, le niveau d'excitation général et l'activité associée à l'administration de midazolam chez des chiens en santé. Les chiens ont reçu le midazolam (M) seul (M : 0,25 mg/kg poids corporel [PC]) ou avec de la méthadone (MM) (MM : 0,75 mg/kg PC) ou de l'acépromazine (MA) (MA : 0,03 mg/kg PC) ou une solution saline (S) seule, tous administrés par voie intramusculaire. Deux observateurs à l'aveugle ont évalué les paramètres comportementaux à l'aide d'enregistrements vidéo 30 minutes avant et après l'injection des médicaments. Un accéléromètre a été utilisé pour évaluer les «numérations de l'activité totale¼ (NAT) comme données de référence et après le traitement. Les notes d'excitation après le traitement étaient significativement supérieures pour M et MA comparativement aux données de référence, M et MM comparativement à S et M comparativement à MA. Les paramètres comportementaux ont montré des proportions significativement supérieures de «va-et-vient¼ après le traitement dans tous les groupes qui avaient reçu midazolam et une «agitation¼, de «mastication et léchage¼ et de «reniflement¼ dans M. Aucune différence significative n'a été constatée pour NAT aux données de référence et après le traitement. Les changements comportementaux paradoxes induits par le midazolam (excitation, halètement, va-et-vient, agitation, lèchage et mastication et vocalisation) n'ont pas été prévenus par l'acépromazine ni la méthadone chez les chiens en santé.(Traduit par Isabelle Vallières).
Subject(s)
Behavior, Animal/drug effects , Conscious Sedation/veterinary , Dogs/physiology , Hypnotics and Sedatives/pharmacology , Midazolam/pharmacology , Acepromazine/administration & dosage , Acepromazine/pharmacology , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacology , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/pharmacology , Cross-Over Studies , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Hypnotics and Sedatives/administration & dosage , Injections, Intramuscular/veterinary , Methadone/administration & dosage , Methadone/pharmacology , Midazolam/administration & dosage , Prospective Studies , Treatment OutcomeABSTRACT
OBJECTIVE: To determine whether echocardiographic variables differed between successful (elite) and less successful (nonelite) Arabian endurance horses. ANIMALS: 34 Arabian horses that competed in endurance racing. PROCEDURES: Horses were assigned to either an elite or nonelite group on the basis of results of a previous competition, and a standardized echocardiographic examination was performed on each horse within 1 to 4 weeks after that competition. Multivariable logistic regression with backward stepwise elimination was used to create a prediction model for the determination of horse status (elite or nonelite) as a function of the measured echocardiographic variables. RESULTS: The elite and nonelite groups consisted of 23 and 11 horses, respectively. One horse in the nonelite group had a frequent ventricular dysrhythmia that could have negatively affected its performance and rider's safety, whereas none of the horses in the elite group had remarkable cardiac abnormalities. The left ventricular internal diameter during systole and diastole and left ventricular mass and stroke volume were significantly greater for horses in the elite group, compared with those for horses in the nonelite group. The final logistic regression model correctly predicted the horse status for all of the horses in the elite group and 8 of 11 horses in the nonelite group. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that heart size was significantly associated with performance for Arabian endurance horses in a manner similar to findings for Thoroughbred and Standardbred racehorses in active competition.
Subject(s)
Echocardiography/veterinary , Heart/anatomy & histology , Heart/physiology , Horses/anatomy & histology , Horses/physiology , Physical Conditioning, Animal , Physical Endurance/physiology , Animals , Female , Heart Function Tests/veterinary , MaleABSTRACT
OBJECTIVE: To generate reference ranges for echocardiographic variables in clinically normal adult chimpanzees (Pan troglodytes). DESIGN: Retrospective cohort study. ANIMALS: 88 clinically normal adult chimpanzees. PROCEDURES: Echocardiographic data obtained between 2002 and 2011 from chimpanzees at the Alamogordo Primate Facility were reviewed (263 echocardiograms obtained from 158 individuals). Data from clinically normal individuals (33 females and 55 males) were analyzed. Basic cardiac parameters measured in all individuals included aortic root diameter and left atrial diameter in the short and long axis during diastole. Left ventricular measurements included left ventricular internal diameter in systole and diastole and diastolic septal and posterior wall thickness. The E point to septal separation was also measured. Spectral Doppler measurements included the peak flow velocity of the pulmonary artery and aorta and diastolic transmitral flow. The presence of arrhythmias was also noted. RESULTS: Standard echocardiographic findings for a large group of adult female and male chimpanzees were obtained. Female and male chimpanzees were grouped by age in 10-year blocks, and echocardiographic findings were analyzed statistically by 10-year block. In male chimpanzees, cardiac arrhythmias were noted to increase with age. CONCLUSIONS AND CLINICAL RELEVANCE: Cardiovascular disease is an important cause of morbidity and death in captive chimpanzees; however, basic echocardiographic measurements from a large cohort of clinically normal animals have not previously been reported. The number of animals in the present study was insufficient to generate reference ranges; however, data from a large cohort of clinically normal animals are presented. This information will be useful for veterinarians working in clinical and research settings with this species.
Subject(s)
Animals, Zoo , Echocardiography/veterinary , Pan troglodytes/anatomy & histology , Aging , Animals , Ape Diseases/pathology , Arrhythmias, Cardiac/veterinary , Female , Male , Reference Values , Retrospective Studies , Sex FactorsABSTRACT
OBJECTIVE: To determine whether measurement of blood cardiac troponin I (cTnI) concentrations with a cage-side analyzer could be used to differentiate cardiac from noncardiac causes of dyspnea in cats. DESIGN: Prospective, multicenter study. ANIMALS: 44 client-owned cats with dyspnea and 37 healthy staff-owned cats. PROCEDURES: Affected cats were examined because of dyspnea; treatment was administered in accordance with the attending clinician's discretion. Cats were judged to have a cardiac or noncardiac cause of dyspnea on the basis of results of physical examination, thoracic radiography, and echocardiography. Blood cTnI concentrations were determined with a cage-side analyzer on samples collected within 12 hours after admission of affected cats. Concentrations for healthy cats were obtained for comparison. RESULTS: 5 enrolled cats were excluded from the study because of concurrent cardiac and respiratory disease. Of the remaining 39 cats with dyspnea, 25 had a cardiac cause and 14 had a noncardiac cause. The 25 cats with a cardiac cause of dyspnea had a significantly higher blood cTnI concentration than did the 37 healthy cats or the 14 cats with a noncardiac cause of dyspnea. CONCLUSIONS AND CLINICAL RELEVANCE: Measurement of cTnI concentrations with a cage-side assay in emergency settings may be useful for differentiating cardiac from noncardiac causes of dyspnea in cats.
Subject(s)
Cat Diseases/blood , Dyspnea/veterinary , Heart Diseases/veterinary , Point-of-Care Systems , Troponin I/blood , Animals , Cat Diseases/diagnosis , Cats , Dyspnea/blood , Dyspnea/diagnosis , Dyspnea/etiology , Female , Heart Diseases/blood , Heart Diseases/complications , Heart Diseases/diagnosis , MaleABSTRACT
Mucopolysaccharidosis VII (MPS VII) is due to the deficient activity of ß-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs) in lysosomes and multisystemic disease with cardiovascular manifestations. The goal here was to determine the pathogenesis of mitral valve (MV) disease in MPS VII dogs. Untreated MPS VII dogs had a marked reduction in the histochemical signal for structurally-intact collagen in the MV at 6 months of age, when mitral regurgitation had developed. Electron microscopy demonstrated that collagen fibrils were of normal diameter, but failed to align into large parallel arrays. mRNA analysis demonstrated a modest reduction in the expression of genes that encode collagen or collagen-associated proteins such as the proteoglycan decorin which helps collagen fibrils assemble, and a marked increase for genes that encode proteases such as cathepsins. Indeed, enzyme activity for cathepsin B (CtsB) was 19-fold normal. MPS VII dogs that received neonatal intravenous injection of a gamma retroviral vector had an improved signal for structurally-intact collagen, and reduced CtsB activity relative to that seen in untreated MPS VII dogs. We conclude that MR in untreated MPS VII dogs was likely due to abnormalities in MV collagen structure. This could be due to upregulation of enzymes that degrade collagen or collagen-associated proteins, to the accumulation of GAGs that compete with proteoglycans such as decorin for binding to collagen, or to other causes. Further delineation of the etiology of abnormal collagen structure may lead to treatments that improve biomechanical properties of the MV and other tissues.
Subject(s)
Heart Valve Diseases/etiology , Mitral Valve/pathology , Mucopolysaccharidosis VII/complications , Animals , Chordae Tendineae/metabolism , Collagen/metabolism , Dogs , Extracellular Matrix/genetics , Extracellular Matrix/metabolism , Female , Glycosaminoglycans/metabolism , Heart Valve Diseases/metabolism , Male , Mitral Valve/metabolism , Mucopolysaccharidosis VII/metabolism , Peptide Hydrolases/genetics , Peptide Hydrolases/metabolism , Signal TransductionABSTRACT
Mucopolysaccharidosis VII (MPS VII) is due to deficient activity of the lysosomal enzyme ß-glucuronidase (GUSB) and results in the accumulation of glycosaminoglycans (GAGs). This study determined the long-term effect of neonatal intravenous injection of a gamma retroviral vector (RV) on cardiac valve disease in MPS VII dogs. Transduced hepatocytes secreted GUSB into the blood for up to 11 years at levels similar to or greater than those achieved with enzyme replacement therapy (ERT). Valve regurgitation and thickening were scored from 0 (normal) to +4 (severely abnormal). At 1 year, untreated MPS VII dogs had mitral regurgitation, mitral valve thickening, aortic regurgitation, and aortic valve thickening scores of 2.3 ± 0.7, 2.3 ± 0.6, 1.8 ± 0.5, and 1.6 ± 0.7, respectively, which were higher than the values of 0.6 ± 0.1, 0.1 ± 0.4, 0.3 ± 0.8, and 0.1 ± 0.4, respectively, in treated MPS VII dogs. Treated MPS VII dogs maintained low aortic regurgitation and aortic valve thickening scores in their lifetime. Although mitral regurgitation and mitral valve thickening scores increased to 2.0 at ≥ 8 years of age in the treated MPS VII dogs, older normal dogs from the colony had similar scores, making it difficult to assess mitral valve disease. Older treated dogs had calcification within the mitral and the aortic valve annulus, while GUSB staining demonstrated enzyme activity within the mitral valve. We conclude that neonatal RV-mediated gene therapy reduced cardiac valve disease in MPS VII dogs for up to 11 years, and propose that neonatal initiation of ERT should have a similar effect.
Subject(s)
Gammaretrovirus/genetics , Genetic Therapy , Genetic Vectors/genetics , Heart Valve Diseases/etiology , Heart Valve Diseases/therapy , Mucopolysaccharidosis VII/complications , Mucopolysaccharidosis VII/genetics , Animals , Animals, Newborn , Aortic Valve/diagnostic imaging , Aortic Valve/pathology , Disease Models, Animal , Dogs , Echocardiography , Female , Glucuronidase/genetics , Glucuronidase/metabolism , Heart Valve Diseases/diagnostic imaging , Male , Mitral Valve/diagnostic imaging , Mitral Valve/pathologyABSTRACT
Dystrophin-deficient muscles suffer from free radical injury, mitochondrial dysfunction, apoptosis, and inflammation, among other pathologies that contribute to muscle fiber injury and loss, leading to wheelchair confinement and death in the patient. For some time, it has been appreciated that endurance training has the potential to counter many of these contributing factors. Correspondingly, numerous investigations have shown improvements in limb muscle function following endurance training in mdx mice. However, the effect of long-term volitional wheel running on diaphragm and cardiac function is largely unknown. Our purpose was to determine the extent to which long-term endurance exercise affected dystrophic limb, diaphragm, and cardiac function. Diaphragm specific tension was reduced by 60% (P < 0.05) in mice that performed 1 yr of volitional wheel running compared with sedentary mdx mice. Dorsiflexor mass (extensor digitorum longus and tibialis anterior) and function (extensor digitorum longus) were not altered by endurance training. In mice that performed 1 yr of volitional wheel running, plantarflexor mass (soleus and gastrocnemius) was increased and soleus tetanic force was increased 36%, while specific tension was similar in wheel-running and sedentary groups. Cardiac mass was increased 15%, left ventricle chamber size was increased 20% (diastole) and 18% (systole), and stroke volume was increased twofold in wheel-running compared with sedentary mdx mice. These data suggest that the dystrophic heart may undergo positive exercise-induced remodeling and that limb muscle function is largely unaffected. Most importantly, however, as the diaphragm most closely recapitulates the human disease, these data raise the possibility of exercise-mediated injury in dystrophic skeletal muscle.
Subject(s)
Diaphragm/physiology , Heart Ventricles/physiopathology , Physical Conditioning, Animal/physiology , Physical Endurance/physiology , Running/physiology , Animals , Exercise Therapy/methods , Extremities/physiology , Mice , Mice, Inbred mdx , Muscle Contraction/physiology , Muscle, Skeletal/physiology , Muscular Dystrophy, Animal/physiopathology , Organ Size/physiology , Stroke Volume/physiologyABSTRACT
OBJECTIVE: To assess the effectiveness of the vertebral heart scale (VHS) system to differentiate congestive heart failure from other causes of dyspnea in cats. DESIGN: Retrospective case series. ANIMALS: 67 cats with acute respiratory distress. PROCEDURES: Medical records of client-owned cats evaluated on an emergency basis because of acute respiratory distress during a 1-year period were reviewed. For study inclusion, cats must have undergone evaluation with echocardiography and thoracic radiography within 12 hours after hospital admission. The VHS was calculated for each cat by 2 investigators. Signalment, physical examination, and echocardiographic findings were reviewed for each patient. RESULTS: There was 83% agreement overall between the 2 investigators in assessment of cardiomegaly in cats with dyspnea (κ = 0.49). The VHS cutpoints were the same for both observers in terms of optimizing sensitivity and specificity. A VHS of > 8.0 vertebrae was the best cutpoint when screening for heart disease, whereas a VHS of > 9.3 vertebrae was very specific for the presence of heart disease. Measurements between 8.0 and 9.3 vertebrae suggested the cause of dyspnea was equivocal (ie, secondary to congestive heart failure or respiratory disease), in which case echocardiography would be most useful in providing additional diagnostic information. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that the VHS system may be a useful tool to help differentiate cardiac from noncardiac causes of respiratory distress in cats in an emergency situation when an echocardiogram is not available or is not plausible in an unstable patient.