Objectives: To evaluate survival time in dogs with persistent atrial standstill after pacemaker implantation and to compare the survival times for cardiac-related vs. non-cardiac deaths. Secondary objectives were to evaluate the effects of breed and the presence of congestive heart failure (CHF) at the time of diagnosis on survival time.Animals: Twenty dogs with persistent atrial standstill and pacemaker implantation.Methods: Medical records were searched to identify dogs diagnosed with persistent atrial standstill based on electrocardiogram that underwent pacemaker implantation. Survival after pacemaker implantation was analyzed using the Kaplan Meier method.Results: The median survival time after pacemaker implantation for all-cause mortality was 866 days. There was no significant difference (p=0.573) in median survival time for cardiac (506 days) vs. non-cardiac deaths (400 days). The presence of CHF at the time of diagnosis did not affect the survival time (P=0.854). No difference in median survival time was noted between breeds (P=0.126).Conclusions: Dogs with persistent atrial standstill have a median survival time of 866 days with pacemaker implantation, though a wide range of survival times was observed. There was no difference in the median survival time for dogs with cardiac-related deaths and those without. Patient breed and the presence of CHF before pacemaker implantation did not affect median survival time. (C) 2017 Elsevier B.V. All rights reserved.

Background Doxorubicin is a common antineoplastic agent with dose‐dependent cardiotoxic adverse effects, and pre‐existing myocardial dysfunction is a contraindication to its use. Objectives To systematically define the hemodynamic and biochemical alterations in dogs undergoing chemotherapy for newly diagnosed lymphoma and assess the reversibility of these alterations with fluid administration. Animals Twenty‐one client‐owned dogs with newly diagnosed lymphoma were evaluated 1 week after induction of chemotherapy. Underlying degenerative valve disease was exclusionary. Eighteen healthy age‐ and weight‐matched dogs were used as controls. Methods Physical examination, blood pressure by Doppler, echocardiography, and biochemical evaluation (routine serum biochemistry, plasma renin activity and aldosterone concentrations, plasma and urine osmolalities, and urine electrolyte concentrations) were measured in dogs with lymphoma and compared to controls. Dogs with lymphoma received crystalloids IV at 6 mL/kg/h for 24 hours. All variables were reassessed at 4 and 24 hours. Deuterium oxide dilution and bromide dilution were used to determine total body water and extracellular water space, respectively. Results Baseline echocardiograms showed significantly smaller chamber dimensions in dogs with lymphoma compared to controls. These changes were reversed by fluid administration. Systolic blood pressure and urine sodium concentration were significantly increased, and bromide dilution space, PCV, urine specific gravity, and urine potassium concentration were significantly decreased compared to controls. Conclusion and Clinical Importance Echocardiographic and biochemical abnormalities in dogs with lymphoma appear consistent with volume depletion, and may be the result of systemic hypertension and subsequent pressure natriuresis.

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.

Background Subaortic stenosis ( SAS ) is one of the most common congenital cardiac defects in dogs. Severe SAS frequently is treated with a beta adrenergic receptor blocker (beta blocker), but this approach largely is empirical. Objective To determine the influence of beta blocker treatment on survival time in dogs with severe SAS . Methods Retrospective review of medical records of dogs diagnosed with severe, uncomplicated SAS (pressure gradient [PG] ≥80 mmHg) between 1999 and 2011. Results Fifty dogs met the inclusion criteria. Twenty‐seven dogs were treated with a beta blocker and 23 received no treatment. Median age at diagnosis was significantly greater in the untreated group (1.2 versus 0.6 years, respectively; P = .03). Median PG at diagnosis did not differ between the treated and untreated groups (127 versus 121 mmHg, respectively; P = .2). Cox proportional hazards regression was used to identify the influence of PG at diagnosis, age at diagnosis, and beta blocker treatment on survival. In the all‐cause multivariate mortality analysis, only age at diagnosis ( P = .02) and PG at diagnosis ( P = .03) affected survival time. In the cardiac mortality analysis, only PG influenced survival time ( P = .03). Treatment with a beta blocker did not influence survival time in either the all‐cause ( P = .93) or cardiac‐cause ( P = .97) mortality analyses. Conclusions Beta blocker treatment did not influence survival in dogs with severe SAS in our study, and a higher PG at diagnosis was associated with increased risk of death.

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.

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. In particular, how Shp2 loss-of-function (LOF) mutations cause LEOPARD Syndrome, which is characterized by congenital heart defects such as pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM), remains unclear. We employed both in vitro and in vivo models to investigate signaling mechanisms downstream of Q510E-Shp2, a particularly aggressive mutation leading to early-onset HCM. In cultured rat neonatal cardiomyocytes, Q510E-Shp2 expression significantly increased cell size. This increase was accompanied by hyperactivation of signaling through mammalian target of rapamycin (mTOR). mTOR inhibition with rapamycin reversed the pro-hypertrophic effects of Q510E-Shp2 in culture. Mice with cardiomyocyte-specific overexpression of Q510E-Shp2 starting before birth also showed up-regulation of signaling through Akt/mTOR/p70S6K and developed HCM in the early neonatal period. Q510E-Shp2 expression increased cardiomyocyte sizes and septum thickness, and caused cardiomyocyte disarray and fibrosis. Echocardiographically, hearts were hypocontractile and displayed increased wall thicknesses. Importantly, rapamycin administration rescued the Q510E-Shp2-induced phenotype in vivo. Our studies establish a role for mTOR signaling in HCM caused by the LOF mutation Q510E-Shp2. Pharmacological inhibition of mTOR was sufficient to rescue the HCM phenotype in both models. These findings have important implications not only for the development of novel therapeutic approaches for LEOPARD Syndrome patients, but also for closely related forms of congenital heart disease such as Noonan Syndrome.

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.

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.

BACKGROUND:Hydration status is important to the cardiovascular system because of its effects on preload. Decreased preload can alter echocardiographic measurements of systolic and diastolic function, potentially confounding interpretation of results.HYPOTHESIS/OBJECTIVES:Mild fluid deficits are associated with measurable echocardiographic changes that are validated by physical and biochemical markers of decreased intravascular volume.ANIMALS:Twenty-five healthy staff/student-owned dogs with no evidence of cardiac or renal disease.METHODS:Prospective, interventional laboratory study. Dogs were randomly assigned to water deprivation (WD) alone for 8 hours (n = 13) or to furosemide treatment (FTx, 2.5mg/kg IV) followed by WD for 8 hours (n = 12). Echocardiograms, biochemical sampling, and physical parameters were measured at baseline, and after 4 and 8 hours.RESULTS:Both protocols induced fluid deficit as indicated by significant (P < .00001) decreases in weight at 4 hours (WD, 1.1%; FTx, 3.7%) and 8 hours (WD, 2.7%; FTx, 4.5%). Furosemide significantly decreased left ventricular end-diastolic volume (54.3 +/- 19.3-42.1 +/- 17.3 mL, P < .0001), cardiac index (4.2 +/- 1.1-2.9 +/- 0.9 L/min/M2, P < .0001), and mitral valve E wave velocity (0.79 +/- 0.2-0.66 +/- 0.2 m/s, P = .0004). These changes were accompanied by significant increases in blood urea nitrogen concentration (13.8 +/- 2.6-14.8 +/- 2.7 mg/dL, P = .04), vasopressin concentration (1.4 +/- 1.2-3.3 +/- 1.9 pg/mL, P = .045), and PCV (49.8 +/- 4.5-53.2 +/- 6.5%, P = .006). Effects of water deprivation alone were similar, but less pronounced.CONCLUSIONS AND CLINICAL IMPORTANCE:Mild fluid deficits have measurable hemodynamic effects in dogs. Hydration status should be considered when evaluating cardiac function by echocardiogram.

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.

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.

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 beta MyHC 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-3 alpha/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.

Duchenne cardiomyopathy is a heart disease resulting from the loss of cardiac dystrophin. It significantly reduces the life quality and shortens lifespan in Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy patients and carriers. Gene replacement therapy with adeno-associated viral vector (AAV) and gene repair therapy with exon skipping hold great promise for restoring dystrophin expression and ameliorating cardiomyopathy. The last few years have witnessed tremendous advances towards Duchenne cardiornyopathy gene therapy. The infrastructure (animal models and functional assays) is now available for comprehensive preclinical studies. Essential parameters, such as the therapeutic threshold, have also been defined. Together with the recent developments in novel AAV vectors and modified antisense oligo-nucleotides, clinical application of Duchenne cardiornyopathy gene therapy may become a reality in the near future.