Overexpression of copper/zinc superoxide dismutase in the median preoptic nucleus improves cardiac function after myocardial infarction in the rat.

Previous reports indicate that overexpression of copper/zinc superoxide dismutase (CuZnSOD), an intracellular superoxide (O2 (•-) ) scavenging enzyme, in the brain subfornical organ improves cardiac function in a mouse model of heart failure (HF). A downstream hypothalamic site, the MnPO, may act as a relay centre for O2 (•-) to serve as a mediator in the pathophysiology of HF. To test the hypothesis that elevated O2 (•-) in the MnPO contributes to the pathophysiology of HF and decreased cardiac function, we injected adenovirus encoding CuZnSOD (AdCuZnSOD, n=7) or control empty adenovirus vector (AdEmpty, n=7) into the MnPO of normal rats. Subsequently, rats were subjected to coronary artery ligation to create a myocardial infarct (MI) of the left ventricle. Cardiac function was monitored via echocardiography. Upon completion, rat brains were examined for CuZnSOD expression in MnPO via immunofluorescence and histopathological analyses of cardiac infarct size were conducted. Baseline (EF) ejection fractions (%) of AdCuZnSOD and AdEmpty rats were 73 ± 1 and 71 ± 1, respectively. Two weeks after MI, EF was significantly decreased in both groups of rats (AdCuZnSOD: 51 ± 3, AdEmpty: 46 ± 1). In contrast, by 4 weeks post MI, EF had improved to 64 ± 2 in AdCuZnSOD rats, yet was only 52 ± 1 in AdEmpty rats, and this was accompanied by lower plasma noradrenaline levels in AdCuZnSOD rats (0.49 ± 0.19 ng/mL) compared to AdEmpty rats (1.20 ± 0.32 ng/mL). In conclusion, despite decreases in EF early after MI, overexpression of CuZnSOD in the MnPO was related to an improvement in left ventricular function and concomitant decreased plasma noradrenaline levels 4 weeks post MI.

The interplay between genetic background and sexual dimorphism of doxorubicin-induced cardiotoxicity.

BACKGROUND: Doxorubicin (DOX) is a very effective anticancer medication that is commonly used to treat hematological malignancies and solid tumors. Nevertheless, DOX is known to have cardiotoxic effects that may lead to cardiac dysfunction and failure. In experimental studies, female animals have been shown to be protected against DOX-induced cardiotoxicity; however, the evidence of this sexual dimorphism is inconclusive in clinical studies. Therefore, we sought to investigate whether genetic background could influence the sexual dimorphism of DOX-induced cardiotoxicity. METHODS: Male and female Wistar Kyoto (WKY) and Spontaneous Hypertensive Heart Failure (SHHF) rats were used. DOX was administered in eight doses of 2 mg/kg/week and the rats were followed for an additional 12 weeks. Cardiac function was assessed by trans-thoracic echocardiography, systolic blood pressure was measured by the tail cuff method, and heart and kidney tissues were collected for histopathology. RESULTS: Female sex protected against DOX-induced weight loss and increase in blood pressure in the WKY rats, whereas it protected against DOX-induced cardiac dysfunction and the elevation of cardiac troponin in SHHF rats. In both strains, female sex was protective against DOX-induced nephrotoxicity. There was a strong correlation between DOX-induced renal pathology and DOX-induced cardiac dysfunction. CONCLUSIONS: This study highlights the importance of studying the interaction between sex and genetic background to determine the risk of DOX-induced cardiotoxicity. In addition, our findings suggest that DOX-induced nephrotoxicity may play a role in DOX-induced cardiac dysfunction in rodent models.

Patent ductus arteriosus occlusion in small dogs utilizing a low profile Amplatz® canine duct occluder prototype.

OBJECTIVES: To develop procedural methodology and assess the safety, utility and effectiveness of a low profile Amplatz(®) canine duct occluder (ACDO) prototype in dogs deemed too small to undergo ductal occlusion with the commercially-available ACDO device. ANIMALS: Twenty-one dogs with left-to-right shunting patent ductus arteriosus (PDA). Dogs were ≥1.5 kg but considered too small to accommodate a 6 Fr catheter or 4 Fr sheath within the femoral artery. METHODS: Prospective canine study using a low profile ACDO prototype delivered through a 4 Fr catheter via a femoral arterial approach. Procedural methods, fluoroscopy time, perioperative complications, and residual ductal flow were evaluated, and angiographic ductal morphology and dimensions were tabulated. RESULTS: All 21 dogs underwent successful ductal occlusion using the prototype device, 4 Fr catheter, and right femoral artery approach. No perioperative complications or device embolization occurred. The median minimal ductal diameter was 1.9 mm (range, 0.4-3.4), and the median device size deployed was 4 mm (range, 3-6). Complete ductal occlusion was noted in 17 dogs (81%) on post-deployment angiography. Twenty dogs (95%) had no residual flow on echocardiography performed the following day. In the 17 dogs (81%) that returned for a long-term (≥3months) follow-up evaluation, all had complete ductal occlusion based on echocardiography. CONCLUSIONS: The low profile ACDO prototype is a safe and effective method of PDA occlusion in the small dog. The deployment procedure appears of similar technical difficulty to the commercially available ACDO.

Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats.

Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure or mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity.

Structural and functional cardiovascular changes and their consequences following interventional patent ductus arteriosus occlusion in dogs: 24 cases (2000-2006).

OBJECTIVE: To investigate cardiovascular changes and survival times following complete interventional device occlusion of uncomplicated left-to-right shunting patent ductus arteriosus in dogs. DESIGN: Retrospective cohort study. ANIMALS: 24 dogs with uncomplicated patent ductus arteriosus that was fully occluded and reevaluated within 24 hours, approximately 3 months, and 1 year after the procedure. PROCEDURES: Information on medical history, diagnostic imaging findings, treatment received, and survival times were obtained from medical records. Patients were allocated into 2 groups on the basis of age (< 1 year [n = 14] and ≥ 1 year [10]) at the time of the procedure. Additional follow-up information was obtained through interviews of owners and referral veterinarians. RESULTS: Following ductal occlusion, decreases were detected in vertebral heart scale size, left ventricular chamber diameter in diastole and in systole, left atrial dimension, fractional shortening, aortic velocity, and ventricular wall thickness. There were no differences between age groups for postocclusion changes except vertebral heart scale size. Systolic dysfunction was detected in 14 (58%) patients on the final visit. Median survival time for all dogs after ductal occlusion was > 11.5 years. CONCLUSIONS AND CLINICAL RELEVANCE: Complete ductal occlusion resulted in immediate removal of the volume overload state and eventual return of cardiac chamber dimensions to reference range, suggesting regression of eccentric hypertrophy. Systolic dysfunction persisted in some dogs but appeared to be clinically unimportant. Most cardiovascular changes were independent of patient age at the time of the procedure.

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.

Minimally invasive per-catheter occlusion and dilation procedures for congenital cardiovascular abnormalities in dogs.

With ever-increasing sophistication of veterinary cardiology, minimally invasive per-catheter occlusion and dilation procedures for the treatment of various congenital cardiovascular abnormalities in dogs have become not only available, but mainstream. Much new information about minimally invasive per-catheter patent ductus arteriosus occlusion has been published and presented during the past few years. Consequently, patent ductus arteriosus occlusion is the primary focus of this article. Occlusion of other less common congenital cardiac defects is also briefly reviewed. Balloon dilation of pulmonic stenosis, as well as other congenital obstructive cardiovascular abnormalities is discussed in the latter part of the article.

Caudal vena cava obstruction caused by redundant pacemaker lead in a dog.

Inferior vena cava obstruction, a rare but serious complication of transvenous pacemaker lead placement in humans, has not been reported in dogs. We describe this complication in a dog that developed ascites 8 months after pacemaker implantation. Radiography disclosed a loop of redundant lead within the caudal vena cava (CVC), and angiography demonstrated obstruction to blood flow. Withdrawal of the loop from the CVC did not restore blood flow. Persistent obstruction was suspected secondary to fibrosis resulting from vascular damage caused by the loop of lead. Angioplasty of the CVC obstruction restored blood flow and resolved the dog's clinical signs.

Evaluation of serum cardiac troponin I concentration in dogs with renal failure.

OBJECTIVE: To determine whether dogs with renal failure have higher serum cardiac troponin I (cTnI) concentrations than healthy dogs. DESIGN: Case-control study. ANIMALS: 31 dogs with renal failure and 51 healthy dogs. PROCEDURES: Serum concentrations of creatinine and cardiac troponin I, urine specific gravity, and systolic arterial blood pressure were measured for all dogs. Dogs underwent a standardized physical examination, and any dog with evidence of cardiovascular disease or other nonrenal disease was excluded from final analyses. Dogs were considered to be in renal failure when the serum creatinine concentration was >or= 3.0 mg/dL, urine specific gravity was between 1.007 and 1.030, and renal failure had been clinically diagnosed. RESULTS: Dogs with renal failure had significantly higher serum cTnI concentrations (median, 0.35 ng/mL) than did healthy dogs (0.20 ng/mL). The renal failure group also had a significantly higher median systolic blood pressure (156 mm Hg) than did healthy dogs (138 mm Hg), although serum cTnI concentration was not correlated with systolic blood pressure in dogs with renal failure. There was no significant difference in age between dogs with renal failure and healthy dogs, but dogs with renal failure had significantly higher serum creatinine concentration and lower urine specific gravity. CONCLUSIONS AND CLINICAL RELEVANCE: Although dogs with renal failure did not have overt clinical signs of cardiac disease, they had high serum cTnI concentrations, which may have been associated with subclinical cardiovascular disease. The cause of the high serum cTnI concentration in these dogs requires additional investigation.

The Amplatz canine duct occluder: a novel device for patent ductus arteriosus occlusion.

The Amplatz canine duct occluder (ACDO) is a nitinol mesh device with a short waist that separates a flat distal disc from a cupped proximal disc. The device is designed to conform to the morphology of the canine patent ductus arteriosus (PDA). PDA dimensions are determined by angiography, and a guiding catheter is advanced into the main pulmonary artery via the aorta and PDA. An ACDO with a waist diameter approximately twice the angiographic minimal ductal diameter (MDD) is advanced via the catheter using an attached delivery cable until the flat distal disc deploys within the main pulmonary artery. The partially deployed ACDO, guiding catheter, and delivery cable are retracted until the distal disc engages the pulmonic ostium of the PDA. With the delivery cable stabilized, the catheter is retracted to deploy the waist across the pulmonic ostium and cupped proximal disc within the ductal ampulla. Tension on the delivery cable is released, and correct ACDO positioning and stability are confirmed by observing that the device assumes its native shape, back-and-forth maneuvering of the delivery cable, and a small contrast injection made through the guiding catheter. The delivery cable is detached and removed with the guiding catheter. To assess for any residual ductal flow, an angiogram is performed at the conclusion of the procedure, followed by Doppler echocardiography at 1 day and 3 months post-procedure. PDA occlusion in dogs with the ACDO is straightforward and extremely effective across a wide range of body weights, somatotypes, MDDs, and ductal morphologies.

Effects of a single injection of methylprednisolone acetate on serum biochemical parameters in 11 cats.

BACKGROUND: Therapeutic use of corticosteroids has been implicated in a variety of serum biochemical abnormalities in dogs; however, the effects in cats are less well characterized. OBJECTIVE: The objective of this brief communication is to report serum biochemical changes in response to methylprednisolone acetate (MPA) in adult cats. METHODS: Serum biochemical profiles were performed on 11 cats with dermatologic diseases at baseline, 3-6 days, and 16-24 days after a single intramuscular dose of 5 mg/kg MPA. RESULTS: Median serum albumin and bicarbonate concentrations and amylase activity were increased compared to baseline at both post-treatment time points; aspartate aminotransferase activity and magnesium concentration were increased at 3-6 days post-treatment only; and alkaline phosphatase activity and total calcium concentration were increased at 16-24 days post-treatment only. Median serum creatinine concentration was decreased compared to baseline at both post-treatment time points. Examination of data from individual cats revealed significant variability in serum biochemical changes in response to MPA. No adverse clinical reactions to the drug were reported. CONCLUSIONS: A single dose of MPA results in significant changes in some serum biochemical values in cats, although individual responses will vary.

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.

Hemodynamic effects of methylprednisolone acetate administration in cats.

OBJECTIVE: To investigate the mechanisms by which corticosteroid administration may predispose cats to congestive heart failure (CHF). ANIMALS: 12 cats receiving methylprednisolone acetate (MPA) for the treatment of dermatologic disorders. PROCEDURE: The study was conducted as a repeated-measures design. Various baseline variables were measured, after which MPA (5 mg/kg, IM) was administered. The same variables were then measured at 3 to 6 days and at 16 to 24 days after MPA administration. Evaluations included physical examination, systolic blood pressure measurement, hematologic analysis, serum biochemical analysis, thoracic radiography, echocardiography, and total body water and plasma volume determination. RESULTS: MPA resulted in a substantial increase in serum glucose concentration at 3 to 6 days after administration. Concurrently, RBC count, Hct, and hemoglobin concentration as well as serum concentrations of the major extracellular electrolytes, sodium and chloride, decreased. Plasma volume increased by 13.4% (> 40% in 3 cats), whereas total body water and body weight slightly decreased. All variables returned to baseline by 16 to 24 days after MPA administration. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that MPA administration in cats causes plasma volume expansion as a result of an intra to extracellular fluid shift secondary to glucocorticoid-mediated extracellular hyperglycemia. This mechanism is analogous to the plasma volume expansion that accompanies uncontrolled diabetes mellitus in humans. Any cardiovascular disorders that impair the normal compensatory mechanisms for increased plasma volume may predispose cats to CHF following MPA administration.

Cardiac lymphoma and pericardial effusion in dogs: 12 cases (1994-2004).

OBJECTIVE: To determine clinical characteristics and clinicopathologic findings, including results of pericardial fluid analysis, and determine the outcome associated with pericardial effusion caused by cardiac lymphoma in dogs. DESIGN: Retrospective case series. ANIMALS: 12 dogs. PROCEDURE: Medical records of affected dogs were reviewed for echocardiographic findings, radiographic findings, results of pericardial fluid analysis, clinicopathologic findings, treatment protocols, and outcomes. RESULTS: Pericardial effusion was detected by echocardiography in all 12 dogs, and lymphoma was detected by cytologic examination of the effusion (11/12 dogs) or histologic examination of pericardium (3/12). Large-breed dogs were overrepresented; median weight was 40.5 kg (89.1 lb). Most hematologic and biochemical changes were mild and non-specific. Survival time for dogs treated with combination chemotherapeutic agents was 157 days and for dogs that did not receive chemotherapy survival time was 22 days. This difference was not significant, but several dogs had long-term survival. CONCLUSIONS AND CLINICAL RELEVANCE: Cardiac lymphoma is an uncommon cause of pericardial effusion, and results suggest that cardiac lymphoma does not always warrant the poor prognosis of other stage V, substage b lymphomas.

Feline arterial thromboembolism: an update.

ATE remains a devastating complication of cardiac disease. Despite some improvements in our understanding of the underlying causes and clinical features of this disease, short-term management remains a challenge, and mortality is high. Long-term mortality is primarily attributable to the severe underlying cardiac disease. Many questions remain to be answered regarding the ideal management approach for feline ATE. The authors' preferred diagnostic and therapeutic approaches for these difficult patients are detailed in Box. 1.

Cellular and molecular mechanisms of systolic and diastolic dysfunction in an avian model of dilated cardiomyopathy.

We investigated the cellular and molecular mechanisms of systolic and diastolic dysfunction in a furazolidone (Fz)-induced model of dilated cardiomyopathy (DCM) in turkey poults. Serial echocardiograms disclosed marked systolic dysfunction in the Fz-treated poults, and ventricular weight and left ventricular (LV)/body weight ratio were significantly increased. Isolated heart experiments were performed to determine LV pressure-volume (P-V) relationships. In addition, LV sarcomere lengths (SLs) were measured after hearts had been fixed, and wall stress (sigma)-SL relationships were determined. When compared to control hearts, LV chamber volume in DCM hearts was approximately 3-fold increased, the active or developed LV P-V relationship was markedly depressed, the passive or diastolic P-V relationship was steeper, and SLs were significantly shorter. However, the developed sigma-SL relationships of DCM and control hearts were not different indicating that intrinsic myocardial capacity to generate active force is unaffected in this model of DCM. In contrast, passive sigma, and passive tension in trabecular muscle preparations increased much more steeply with SL in DCM than normal hearts. Trabecular muscle experiments disclosed that the increase in passive myocardial stiffness was primarily collagen based. Titin, the giant sarcomeric molecule, which is an important determinant of passive myocyte properties in normal myocardium, did not contribute significantly to increased passive myocardial stiffness in DCM. We conclude that increased collagen-based passive myocardial stiffness is the major cause of the steeper passive or diastolic P-V relationship in DCM. Further, altered passive myocardial properties and ventricular geometry in DCM play a critical role to reduce ventricular systolic function by limiting SL extension during diastole, thereby limiting the use of the myocardial length-tension relationship.

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.

Arterial thromboembolism in cats: acute crisis in 127 cases (1992-2001) and long-term management with low-dose aspirin in 24 cases.

Records of 127 cats with arterial thromboembolism (ATE) were reviewed. Abyssinian, Birman, Ragdoll, and male cats were overrepresented. Tachypnea (91%), hypothermia (66%), and absent limb motor function (66%) were common. Of 90 cats with diagnostics performed, underlying diseases were hyperthyroidism (12), cardiomyopathy (dilated [8], unclassified [33], hypertrophic obstructive [5], hypertrophic [19]), neoplasia (6), other (4), and none (3). Common abnormalities were left atrial enlargement (93%), congestive heart failure (CHF, 44%), and arrhythmias (44%). Of cats without CHF, 89% were tachypneic. Common biochemical abnormalities were hyperglycemia, azotemia, and abnormally high serum concentrations of muscle enzymes. Of 87 cats treated for acute limb ATE, 39 (45%) survived to be discharged. Significant differences were found between survivors and nonsurvivors for temperature (P < .00001), heart rate (P = .038), serum phosphorus concentration (P = .024), motor function (P = .008), and number of limbs affected (P = .001). No significant difference was found between survivors and nonsurvivors when compared by age, respiratory rate, other biochemical analytes, or concurrent CHE A logistic regression model based on rectal temperature predicted a 50% probability of survival at 98.9 degrees F (37.2 degrees C). Median survival time (MST) for discharged cats was 117 days. Eleven cats had ATE recurrences, and 5 cats developed limb problems. Cats with CHF (MST: 77 days) had significantly shorter survival than cats without CHF (MST: 223 days; P = .016). No significant difference was found in survival or recurrence rate between cats receiving high-dose aspirin (> or = 40 mg/cat q72h) and cats receiving low-dose aspirin (5 mg/cat q72h). Adverse effects were less frequent and milder for the lower dosage.