Breed-Specific Vertebral Heart Scale for the Dachshund.

The objectives of this study were to determine a breed-specific vertebral heart scale (VHS) range for the dachshund and compare results to the established reference range of 9.7 ± 0.5, calculate inter-observer variability, and correlate VHS with echocardiography. Fifty-one normal dachshunds had radiographs and an echocardiogram performed. Five observers measured VHS to the nearest 0.25 vertebra. The data was analyzed using one-way analysis of variance, Wilcoxon Rank Sum test, Mann-Whitney rank sum test, calculation of reference and confidence intervals, Spearman rank-order correlations, and generation of intra-class correlations and confidence intervals. P < .05 was considered significant. The median for right lateral VHS was significantly larger than left (10.3 [range 9.25-11.55] versus 10.1 [range, 8.7-11.31], p < .0001). VHS for females was significantly larger than for males (left: 10.56 [9.2-11.31] versus 9.74 [8.7-10.88] and right: 10.8 [9.5-11.55] versus 9.99 [9.25-10.8], p = .0002). Observer consistency was high with an intra-class correlation coefficient of 0.95. No significant correlation was found between left atrial echocardiographic parameters and VHS. Results indicate normal dachshunds have a median VHS above the published generic canine reference range, and VHS can be reliably performed by observers with varying degrees of clinical experience.

Remote monitoring of the progression of primary pneumonic plague in Brown Norway rats in high-capacity, high-containment housing.

Development of new vaccines, diagnostics, and therapeutics for biodefense or other relatively rare infectious diseases is hindered by the lack of naturally occurring human disease on which to conduct clinical trials of efficacy. To overcome this experimental gap, the U.S. Food and Drug Administration established the Animal Rule, in which efficacy testing in two well-characterized animal models that closely resemble human disease may be accepted in lieu of large-scale clinical trials for diseases with limited natural human incidence. In this report, we evaluated the Brown Norway rat as a model for pneumonic plague and describe the natural history of clinical disease following inhalation exposure to Yersinia pestis. In high-capacity, high-containment housing, we monitored temperature, activity, heart rate, and rhythm by capturing electronic impulses transmitted from abdominal telemeter implants. Using this system, we show that reduced activity and development of fever are sensitive indications of disease progression. Furthermore, we identified heart arrhythmias as contributing factors to the rapid progression to lethality following the fever response. Together, these data validate the Brown Norway rat as an experimental model for human pneumonic plague and provide new insight that may ultimately lead to novel approaches in postexposure treatment of this devastating infection.

The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling.

The identification of mutations in PTPN11 (encoding the protein tyrosine phosphatase Shp2) in families with congenital heart disease has facilitated mechanistic studies of various cardiovascular defects. However, the roles of normal and mutant Shp2 in the developing heart are still poorly understood. Furthermore, it remains unclear how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome (also termed Noonan Syndrome with multiple lentigines), which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). In normal hearts, Shp2 controls cardiomyocyte size by regulating signaling through protein kinase B (Akt) and mammalian target of rapamycin (mTOR). We hypothesized that Shp2 LOF mutations dysregulate this pathway, resulting in HCM. For our studies, we chose the Shp2 mutation Q510E, a dominant-negative LOF mutation associated with severe early onset HCM. Newborn mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth displayed increased cardiomyocyte sizes, heart-to-body weight ratios, interventricular septum thickness, and cardiomyocyte disarray. In 3-mo-old hearts, interstitial fibrosis was detected. Echocardiographically, ventricular walls were thickened and contractile function was depressed. In ventricular tissue samples, signaling through Akt/mTOR was hyperactivated, indicating that the presence of Q510E-Shp2 led to upregulation of this pathway. Importantly, rapamycin treatment started shortly after birth rescued the Q510E-Shp2-induced phenotype in vivo. If rapamycin was started at 6 wk of age, HCM was also ameliorated. We also generated a second mouse model in which cardiomyocyte-specific Q510E-Shp2 overexpression started after birth. In contrast to the first model, these mice did not develop HCM. In summary, our studies establish a role for mTOR signaling in HCM caused by Q510E-Shp2. Q510E-Shp2 overexpression in the cardiomyocyte population alone was sufficient to induce the phenotype. Furthermore, the pathomechanism was triggered pre- but not postnatally. However, postnatal rapamycin treatment could still reverse already established HCM, which may have important therapeutic implications.

Age-matched comparison reveals early electrocardiography and echocardiography changes in dystrophin-deficient dogs.

The absence of dystrophin in the heart leads to Duchenne cardiomyopathy. Dystrophin-deficient dogs represent a critical model to translate novel therapies developed in mice to humans. Unfortunately, little is known about cardiophysiology changes in these dogs. We performed prospective electrocardiographic and echocardiographic examinations at 3, 6 and 12 months of age in four normal and three affected dogs obtained from the same litter. Affected dogs showed growth retardation and serum creatine kinase elevation. Necropsy confirmed cardiac dystrophin deficiency and histopathology. Q/R ratio elevation and diastolic left ventricular (LV) internal diameter reduction were the most consistent findings in affected dogs at all ages. At 6 and 12 months, dystrophic dogs also showed significant reduction of PR intervals, LV end diastolic/systolic volumes and systolic LV internal diameters. Epicardial and endocardial slope times were significantly reduced in affected dogs at 12 months. These results establish the baseline for evaluating experimental therapies in the future.

Coil embolization of an aorticopulmonary fistula in a dog.

An 8-year-old, castrated male Basset Hound was evaluated for congestive heart failure and atrial fibrillation. Echocardiography and angiography demonstrated a left-to-right shunting aorticopulmonary fistula. Coil embolization of the fistula was initially successful in reducing the volume of blood flow through the vascular network. The dog was medically managed for congestive heart failure until it was euthanized 6 months after initial presentation. The physiology and treatment of centrally located arteriovenous fistulae are discussed.

Cardiovascular manifestations of iatrogenic hyperthyroidism in two dogs.

Two dogs were diagnosed with iatrogenic thyrotoxicosis (1 definitive, 1 presumptive). Both showed physical examination findings of agitation, tachypnea, and tachycardia. Sinus tachycardia with supraventricular ectopy was diagnosed in one case, and syncope and atrial flutter was present in the other. Both dogs had concurrent cardiac disease that might have contributed to the severity of their clinical signs. Excessive thyroid hormone supplementation in humans causes supraventricular arrhythmias including sinus tachycardia, supraventricular tachycardia, atrial fibrillation, and atrial flutter. Clinical signs and rhythm abnormalities resolved in both dogs with resolution of the thyrotoxicosis.

TEAD-1 overexpression in the mouse heart promotes an age-dependent heart dysfunction.

TEA domain transcription factor-1 (TEAD-1) is essential for proper heart development and is implicated in cardiac specific gene expression and the hypertrophic response of primary cardiomyocytes to hormonal and mechanical stimuli, and its activity increases in the pressure-overloaded hypertrophied rat heart. To investigate whether TEAD-1 is an in vivo modulator of cardiac specific gene expression and hypertrophy, we developed transgenic mice expressing hemagglutinin-tagged TEAD-1 under the control of the muscle creatine kinase promoter. We show that a sustained increase in TEAD-1 protein leads to an age-dependent dysfunction. Magnetic resonance imaging revealed decreases in cardiac output, stroke volume, ejection fraction, and fractional shortening. Isolated TEAD-1 hearts revealed decreased left ventricular power output that correlated with increased betaMyHC protein. Histological analysis showed altered alignment of cardiomyocytes, septal wall thickening, and fibrosis, although electrocardiography displayed a left axis shift of mean electrical axis. Transcripts representing most members of the fetal heart gene program remained elevated from fetal to adult life. Western blot analyses revealed decreases in p-phospholamban, SERCA2a, p-CX43, p-GSK-3alpha/beta, nuclear beta-catenin, GATA4, NFATc3/c4, and increased NCX1, nuclear DYKR1A, and Pur alpha/beta protein. TEAD-1 mice did not display cardiac hypertrophy. TEAD-1 mice do not tolerate stress as they die over a 4-day period after surgical induction of pressure overload. These data provide the first in vivo evidence that increased TEAD-1 can induce characteristics of cardiac remodeling associated with cardiomyopathy and heart failure.

Cardiac expression of a mini-dystrophin that normalizes skeletal muscle force only partially restores heart function in aged Mdx mice.

Duchenne muscular dystrophy (DMD) affects both skeletal and cardiac muscle. It is currently unclear whether the strategies developed for skeletal muscle can ameliorate cardiomyopathy. Synthetic mini-/micro-dystrophin genes have yielded impressive skeletal muscle protection in animal models. The 6-kb DeltaH2-R19 minigene is particularly promising because it completely restores skeletal muscle force to wild-type levels. Here, we examined whether expressing this minigene in the heart, but not skeletal muscle, could normalize cardiac function in the mdx model of DMD cardiomyopathy. Transgenic mdx mice were generated to express the DeltaH2-R19 minigene under the control of the alpha-myosin heavy-chain promoter. Heart structure and function were examined in adult and very old mice. The DeltaH2-R19 minigene enhanced cardiomyocyte sarcolemmal strength and prevented myocardial fibrosis. It also restored the dobutamine response and enhanced treadmill performance. Surprisingly, heart-restricted DeltaH2-R19 minigene expression did not completely normalize electrocardiogram and hemodynamic abnormalities. Overall, systolic function and ejection fraction were restored to normal levels but stroke volume and cardiac output remained suboptimal. Our results demonstrate that the skeletal muscle-proven DeltaH2-R19 minigene can correct cardiac histopathology but cannot fully normalize heart function. Novel strategies must be developed to completely restore heart function in DMD.

Evaluation of circulating amino terminal-pro-B-type natriuretic peptide concentration in dogs with respiratory distress attributable to congestive heart failure or primary pulmonary disease.

OBJECTIVE: To evaluate assessment of circulating amino terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration as a means to discriminate between congestive heart failure and primary pulmonary disease in dogs. DESIGN: Prospective case series. ANIMALS: 46 dogs with signs of respiratory distress or coughing. PROCEDURES: All dogs underwent physical and thoracic radiographic examinations. Dogs with evidence of heart disease (eg, murmur, arrhythmia, or large cardiac silhouette detected by radiography) also underwent echocardiography. Dogs with no evidence of heart disease or failure were included if they underwent bronchoalveolar lavage (with cytologic examination and bacterial culture of the lavage fluid). Blood samples for NT-proBNP assay were obtained within 12 hours of the diagnosis of heart failure or prior to bronchoalveolar lavage in dogs with primary pulmonary disease. Circulating concentrations of NT-proBNP were compared between groups and correlated with radiographic and echocardiographic measures of cardiac size. RESULTS: Congestive heart failure and primary pulmonary disease were diagnosed in 25 and 21 dogs, respectively. Dogs with congestive heart failure had significantly higher median serum or plasma NT-proBNP concentration (2,554 pmol/L; interquartile [25% to 75%] range, 1,651.5 to 3,475.5 pmol/L) than dogs with primary pulmonary disease (357 pmol/L; interquartile range, 192.5 to 565.5 pmol/L). Radiographic vertebral heart score and echocardiographic left atrial-to-aortic diameter ratio were not correlated with NT-proBNP concentration. Left ventricular end-diastolic diameter (measured echocardiographically) and NT-proBNP concentration were weakly correlated. CONCLUSIONS AND CLINICAL RELEVANCE: Serum or plasma NT-proBNP concentration assessment may be useful for discrimination of congestive heart failure from primary pulmonary disease in dogs with respiratory distress or cough.

Cardiovascular device infections in dogs: report of 8 cases and review of the literature.

BACKGROUND: Infection is an infrequent but major complication of cardiovascular device implantation. HYPOTHESIS: Treatment of patients with cardiovascular implant infection with antibiotic therapy and removal of the device is superior to antibiotic therapy alone. METHODS: Medical records were reviewed for dogs that received a cardiovascular device from June 2001 to August 2006 at the University of Minnesota Veterinary Medical Center and the University of Missouri Veterinary Medical Teaching Hospital. RESULTS: Six of 63 (9.5%) pacemaker systems and 2 of 47 (4.3%) patent ductus arteriosus (PDA) occlusion devices became infected. Median time from procedure to diagnosis of implant infection was 62 days (range, 5 to 419). Median age of dogs with pacemaker infections was 8.5 years (range, 6.2 to 11.9). Pseudomonas aeruginosa and Staphylococcus spp were the most commonly cultured isolates. Four dogs were treated with antibiotics and pacemaker replacement. All 4 recovered completely from their infections. One was alive at the end of the study period, and 3 had been euthanized. However, the reasons for euthanasia were unrelated to pacemaker infection. In contrast, both dogs with infected pacemakers that were treated with antibiotics alone were euthanized because of complications attributable to infection. Infection of PDA occlusion devices occurred in puppies < 16 weeks of age, and Pasteurella spp were isolated from both. One was successfully treated with a combination of antibiotics and surgery, and the other was euthanized without treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Antibiotic therapy alone is associated with chronic complications in patients with cardiovascular implants and is unlikely to effect a cure.

Exercise training prevents development of cardiac contractile dysfunction in hypertensive TG (mREN-2)27 rats.

BACKGROUND: Angiotensin-II (Ang-II) contributes to cardiac remodeling and left ventricular dysfunction. In contrast, exercise may have beneficial effects on left ventricular structure and function. METHODS AND RESULTS: We investigated the effects of low-intensity exercise training (ET) on in vivo cardiac function in hypertensive TG (mREN-2)27 rats (Ren-2) which develop left ventricular hypertrophy and dysfunction. Ren-2 rats and Sprague Dawley (SD) controls (4-5 weeks) began treadmill exercise every day for 5-6 weeks. Cardiac function was evaluated by echocardiography. Cardiac output and stroke volume were increased by ET in both 8-wk-old SD and Ren-2. Slope of mitral deceleration time, a non-invasive measure of diastolic function, was lower in the Ren-2 rats, but not changed by ET. LV collagen deposition, as assessed by hydroxyproline assay, was not affected by rat strain or ET at 10-11 weeks of age. Left ventricular B-type natriuretic peptide mRNA levels were higher in the Ren-2 rats (100%), but not affected by ET. Both alpha (~14.5 fold) and beta (~2.5 fold) myosin heavy chain mRNA were higher in the LV of Ren-2 rats (p < 0.05), but were not changed by ET. CONCLUSION: Low-intensity exercise training in Ren-2 rats, a model of Ang-II-mediated hypertension, maintains cardiac index and stroke volume in the presence of impaired diastolic function at 8 wks of age.

Effect of combined simvastatin and cyclosporine compared with simvastatin alone on cerebral vasospasm after subarachnoid hemorrhage in a canine model.

OBJECT: The object of this study was to determine whether the combination of cyclosporine and simvastatin could ameliorate cerebral vasospasm after subarachnoid hemorrhage (SAH) in a canine model to a greater extent than simvastatin alone. METHODS: Animals were assigned to one of three groups: control (five dogs), simvastatin alone (four), or simvastatin and cyclosporine (four). A double SAH model was used. Baseline basilar artery (BA) angiograms were obtained. These were repeated at Days 3, 7, and 10. Measurement of the BA diameter was performed. Decreased BA diameter was seen on Day 3 in the control and simvastatin/cyclosporine group. A return to baseline diameters was seen by Day 7. An increase from baseline diameter was seen in the simvastatin group at Day 10. CONCLUSIONS: Cyclosporine may interfere with the vasodilatory effects of simvastatin. Vasodilation greater than baseline is seen at Day 10 in the simvastatin group. The combination of simvastatin and cyclosporine does not ameliorate cerebral vasospasm in a canine model to a greater extent than simvastatin alone.

Septicemia in a young dog following treatment of patent ductus arteriosus via coil occlusion.

CASE DESCRIPTION-A 12-week-old female English Springer Spaniel was evaluated for lethargy, vomiting, and pyrexia 1 week after treatment of patent ductus arteriosus (PDA) via coil occlusion. CLINICAL FINDINGS-Test results were consistent with septicemia, and the assumption was made that the PDA occlusion coils were infected. Radiography revealed partial migration of the coil mass into the pulmonary artery and signs of congestive heart failure. TREATMENT AND OUTCOME-After successful treatment of the septicemia and heart failure, surgical removal of the coils and resection of the PDA were undertaken. Although the coil that embolized to the pulmonary vasculature was left in place, the dog's clinical signs resolved. CLINICAL RELEVANCE-This case highlights the fact that as PDA coil occlusion devices become more widely used in dogs, practitioners must be prepared to treat implant infections aggressively, with both medical and surgical interventions if necessary.

Pulmonary hypertension and right-sided heart failure in an adult llama with hepatic disease.

CASE DESCRIPTION: A 13-year-old llama was examined because of lethargy, inappetence, and syncope. CLINICAL FINDINGS: Physical examination revealed muffled heart and lung sounds and peripheral edema. Clinicopathologic abnormalities included lymphopenia, hyperglycemia, prerenal azotemia, mild hyponatremia, mild hypoalbuminemia, and high gamma-glutamyltransferase and creatine kinase activities. On ultrasonography, the liver appeared hyperechoic and ascites and pleural effusion were seen. Echocardiography revealed severe dilatation of the right atrium, right ventricle, and pulmonary artery; severe tricuspid regurgitation; and high right ventricular systolic pressure consistent with right-sided heart failure secondary to pulmonary hypertension. TREATMENT AND OUTCOME: Treatment with furosemide was attempted, but because of failing health, the llama was euthanized 4 weeks later. Macronodular cirrhosis of the liver, glomerulonephritis, and intimal fibrosis and medial hypertrophy of muscular pulmonary arteries were seen on histologic examination of postmortem specimens. CLINICAL RELEVANCE: Findings in this case were similar to those reported for human patients with portopulmonary hypertension secondary to hepatic cirrhosis. Pulmonary hypertension secondary to hepatic disease should be considered in the differential diagnosis of right-sided heart failure.

Does whole body autoregulation mediate the hemodynamic responses to increased dietary salt in rats with clamped ANG II?

The present study was conducted to test the hypothesis that salt-dependent hypertension, in rats with an unresponsive renin-angiotensin system, is characterized by a "whole body autoregulation" hemodynamic profile. To test this hypothesis, rats were chronically instrumented to continuously measure cardiac output (CO) and arterial pressure (AP). A venous catheter was implanted for infusion of saline vehicle (Veh; n = 8) or treatment [enalapril (2 mg.kg-1.day-1) plus ANG II: ANG-NORM (5 ng.kg-1.min-1 ANG II, n = 8) or ANG-HI (10 ng.kg-1.min-1 ANG II, n = 9)] to pharmacologically clamp plasma ANG II. After a 10-day recovery period on a 0.1% NaCl diet, AP and CO were measured continuously for 5 days of control (0.1% NaCl), 7 days of high salt (4.0% NaCl), and 5 days of recovery (0.1% NaCl). Hemodynamics did not change in the Veh group at any time. AP increased by approximately 20 mmHg in the ANG-NORM and ANG-HI groups when NaCl was increased. Hypertension was mediated by an increase in CO of approximately 12% at steady state, with no change in total peripheral resistance (TPR) during the high salt period. AP returned to control levels when dietary sodium was decreased, mediated by a approximately 10% decrease in TPR, with CO remaining elevated. There was no difference in the hemodynamic responses to increased salt between the ANG-HI and ANG-NORM groups. We conclude that the whole body autoregulation hypothesis does not explain the hemodynamic profile of salt-dependent hypertension in rats with an unresponsive renin-angiotensin system.

Use of pericardial fluid pH to distinguish between idiopathic and neoplastic effusions.

Pericardial effusion (PE) resulting from neoplasia usually is associated with a poor prognosis, whereas idiopathic PE frequently has a good prognosis. This study examined the utility of pH measurement to distinguish between these 2 etiologies. Dogs were classified as having idiopathic PE (n = 12) if pericarditis was diagnosed on histopathology (n = 4) or if no historical, physical, or echocardiographic evidence of recurrent PE was present for at least 6 months after pericardiocentesis (n = 8). Dogs were classified as having neoplastic PE (n = 25) if pericardial or myocardial neoplasia was detected on histopathology (n = 11) or a discrete mass associated with the right atrium, right ventricle, or the aorta was visualized on echocardiography (n = 14). Samples of PE were centrifuged and the supernatant pH was measured with a portable pH meter. The lowest pH (6.40) was found in a dog with idiopathic PE and the highest pH (7.85) was found in a dog with neoplastic PE. However, data from the 2 groups overlapped in 33 out of 37 (89%) instances, and median pH from the idiopathic and neoplastic groups was not significantly different (7.40 and 7.47, respectively; P = 0.28; difference in medians = -0.7; 95% CI, -0.26-0.06). Because of the degree of overlap, our data provide little justification for the use of pH measurement as a diagnostic test in cases of PE.