Hemostatic biomarkers in dogs with chronic congestive heart failure

BACKGROUND: Chronic congestive heart failure (CHF) in humans is associated with abnormal hemostasis, and abnormalities in hemostatic biomarkers carry a poor prognosis. Alterations in hemostatic pathways can be involved in the pathogenesis of CHF in dogs, and microthrombosis in the myocardium could contribute to increased mortality. HYPOTHESIS: That plasma concentration or activity of hemostatic biomarkers is altered in dogs with CHF and that these factors predict mortality. ANIMALS: Thirty-four dogs with CHF caused by either dilated cardiomyopathy (DCM, n=14) or degenerative valvular disease (CDVD, n=20) compared with 23 healthy age-matched control dogs were included in this study. Dogs with CHF were recruited from 2 referral cardiology clinics, and control dogs were owned by friends or colleagues of the investigators. METHODS: Clinical examination and echocardiography were performed in all dogs. Plasma fibrinogen and D-dimer concentrations, antithrombin and protein C activity, and thrombin-antithrombin complex (TAT) were measured in all dogs. RESULTS: Dogs with CHF had significantly higher fibrinogen (P = .04), D-dimer (P = .002), and TAT concentration (P < .0001), lower antithrombin (P < .0001) and protein C activity (P < .001) compared with control dogs. None of the hemostatic biomarkers were associated with risk of death. CONCLUSIONS AND CLINICAL IMPORTANCE: There is evidence of a procoagulant state in dogs with CHF. The lack of predictive value for survival might be due to the small number of dogs examined. Further studies are necessary to investigate the presence and importance of microthrombosis in dogs with CHF.     

A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog

Guyonnet, J., Elliott, J., Kaltsatos, V. A preclinical pharmacokinetic and pharmacodynamic approach to determine a dose of spironolactone for treatment of congestive heart failure in dog. J. vet. Pharmacol. Therap. 33 , 260–267. Fifteen Beagle dogs were used to describe the anti‐aldosterone effect of spironolactone (0, 0.8, 2 and 8 mg/kg) in a hyperaldosteronism model. The magnitude of the aldosterone response observed in this model was very similar to the one described in a dog with congestive heart failure (CHF). Each dog was allocated to a treatment group according to a 5 × 5 Latin square crossover design for five periods with a washout period of 7 days between each period. A maximal possible effect (E_max) model was employed to determine the basic pharmacodynamic parameters of spironolactone, measured by high‐performance liquid chromatography, in antagonizing the renal effects of aldosterone. The change in urinary sodium/potassium ratio in response to a single dose of aldosterone was calculated. The inhibition of this response by oral spironolactone administration was assessed. Aldosterone alone decreased sodium excretion by approximately 35% and urinary potassium concentrations increased by 25%, whereas the urine volume decreased, as expected. The effect of aldosterone on the Na⁺/K⁺ ratio was completely reversed (88% inhibition) at a dose of 2 mg spironolactone/kg, while at the dose of 0.8 mg/kg, partial reversal was seen (27.5% inhibition). Urine flow rate was not significantly modified by either aldosterone treatment or aldosterone with spironolactone. The dose of spironolactone required to inhibit the action of aldosterone by 50% (ED₅₀) was estimated to be 1.08 ± 0.28 mg/kg. The E_max was a ratio of 1.089 ± 0.085, close to the observed value in negative control group (1.00 ± 0.18). The proposed spironolactone dose using this E_max model was 2 mg/kg b.w. once daily for the management.     

Prospective clinical trial evaluating spironolactone in Doberman pinschers with congestive heart failure due to dilated cardiomyopathy

Introduction/objectivesWhether the aldosterone antagonist spironolactone has beneficial survival effects in dogs with dilated cardiomyopathy (DCM) is not known. The primary objective of the study was to evaluate the effect of spironolactone, when added to conventional therapy, on survival time in Doberman pinschers with congestive heart failure (CHF) due to DCM.AnimalsSixty-seven client-owned Doberman pinschers with CHF due to DCM.Materials and methodsThe trial design was prospective, randomized, blinded, and placebo controlled. Dogs were randomized to receive 50–75 mg of spironolactone twice daily (n = 34) or a placebo (n = 33), in addition to standard CHF therapy. Follow-up visits were targeted every one–six weeks until endpoint. Quality-of-life questionnaire and physical examination were performed at every visit, while renal biochemistry, ECG, echocardiography, and thoracic radiography were reassessed as needed. The primary endpoint was time to cardiac death, defined as death or euthanasia from CHF or sudden death.ResultsMedian time to primary endpoint in the spironolactone group (183 days) was not statistically significantly different than that for the placebo group (124 days) (P = 0.254). The development of atrial fibrillation (AF) was significantly less frequent in the spironolactone group (n = 7) than the placebo group (n = 15, P = 0.037).ConclusionsWhile median time to cardiac death in the spironolactone group was not statistically significantly different than that in the placebo group, adding spironolactone to conventional therapy resulted in reduced occurrence of AF.     

Short-term effects of ecadotril in dogs with induced congestive heart failure

OBJECTIVE: To evaluate short-term hemodynamic effects of ecadotril in a model of congestive heart failure in dogs. ANIMALS: 6 conscious adult male dogs. PROCEDURES: Instruments were placed in dogs to measure left ventricular, aortic, and atrial blood pressures. Heart failure was induced by repeated coronary embolization with latex microspheres. Four times, and in random order, dogs were given vehicle or active drug (3, 10, or 30 mg/kg of body weight) orally. Hemodynamic variables, urine flow, and urinary electrolyte excretion were measured before and 30, 90, and 150 minutes, and 10 and 21 hours after drug administration. RESULTS: Changes in urine flow, heart rate, mean arterial pressure, or peak positive and negative rate of change in ventricular pressure were not apparent. Urinary sodium excretion significantly increased in response to the low and high doses of ecadotril but not in response to the 10 mg/kg dose. Left ventricular end diastolic pressure (LVEDP) consistently decreased in dose- and time-dependent manner. Maximal group-averaged reductions in LVEDP were 5.2, 8.1, and 10 mm Hg for the low, middle, and high doses, respectively. The magnitude of the decrease in LVEDP was not related to cumulative change in urine flow. CONCLUSIONS AND CLINICAL RELEVANCE: Orally administered ecadotril reduced left ventricular filling pressures in these dogs by a mechanism that does not require a substantial diuretic effect. Ecadotril may be effective for alleviating clinical signs in dogs with left-sided heart failure and may be particularly beneficial for use in dogs that are refractory to traditional diuretic therapy.     

Brain natriuretic peptide concentration in dogs with heart disease and congestive heart failure

Plasma brain natriuretic peptide concentration ([BNP]) is high in humans with cardiac disease and is further increased with congestive heart failure (CHF). The hypotheses of this study were that dogs with moderate to severe mitral regurgitation due to myxomatous mitral valve disease (MVD) would have increased plasma [BNP] compared to normal dogs, that plasma [BNP] would be higher in dogs with CHP, and that plasma [BNP] would predict premature death from cardiovascular disease. The study population consisted of 34 dogs: 9 normal dogs and 25 dogs with MVD. Patients were divided into 4 groups: group 1-10 dogs with moderate to severe MVD and no radiographic evidence of CHF; group II--6 dogs with severe MVD and mild CHF; group III--7 dogs with severe MVD and moderate CHF; and group IV--2 dogs with severe MVD and severe CHF. Diagnostic tests included thoracic radiographs, an echocardiogram, a serum chemistry profile, and the measurement of plasma [BNP] by a canine-specific radioimmunoassay. There was a significant positive correlation between the plasma [BNP] and heart disease/failure groups (P = .0036). Plasma [BNP] increased with progressively increasing severity of MVD and CHE Group I dogs had higher plasma [BNP] than did control dogs (P < .0001), and plasma [BNP] was higher in dogs with CHF (groups II-IV versus group I; P = .012). Plasma [BNP] was also weakly positively correlated with left atrial size (r = 0.43, P = .04). For every 10-pg/mL increase in plasma [BNP], the mortality rate over 4 months' time increased approximately 44%.     

Factors contributing to the decision for euthanasia of dogs with congestive heart failure

OBJECTIVE: To determine the prevalence of clinical signs that affect quality of life in dogs with congestive heart failure (CHF), and to characterize the role of these clinical signs in the decision for euthanasia. DESIGN: Prospective study. ANIMALS: 38 dogs with CHF that had been euthanatized within the preceding 22 months. PROCEDURE: Clinical information and factors affecting the decision for euthanasia were reviewed and recorded from medical records of dogs with CHF. Each owner was then interviewed via telephone to determine whether their dog had anorexia or other clinical signs of disease prior to euthanasia, their perception of their dogs' quality of life, and the most important factor and contributing factors that influenced the decision to euthanatize their dog. RESULTS: Of the 38 dogs with CHF, > 70% had weakness (35 dogs), coughing (33), anorexia (32), weight loss (32), dyspnea (30), or exercise intolerance (28) reported by their owners. Factors often named by owners as most important in the decision for euthanasia were poor prognosis given by the attending veterinarian, recurrent clinical signs of CHF (ie, coughing, dyspnea, or ascites), and poor quality of life. Weakness, anorexia, and recurrent clinical signs of CHF were the most common contributing factors in the decision for euthanasia. CLINICAL IMPLICATIONS: Anorexia, weight loss, and exercise intolerance are common in dogs euthanatized because of CHF. The importance of quality of life and poor prognosis in making a decision for euthanasia suggests that addressing these factors may improve patient management.     

Lymphocyte subpopulations and hematologic variables in dogs with congestive heart failure

Alterations in lymphocyte subpopulations and in other hematologic variables have been documented in people with heart failure. The purpose of the current study was to compare flow cytometric and hematologic variables in dogs with congestive heart failure (CHF) to healthy controls. CD4+ peripheral blood mononuclear cells (PBMC) and CD8+ lymphocytes were analyzed by flow cytometry, and white blood cell count, platelet count, hematocrit, and hemoglobin were determined by a complete blood count. Twenty-five dogs with CHF (International Small Animal Cardiac Health Council [ISACHC] class 2 [n = 12] and ISACHC class 3a [n = 13]) and 13 healthy controls were enrolled in the study. Compared with the controls, dogs with CHF had markedly lower percentages of CD4+ PBMC, CD8+ lymphocytes, hematocrit, and hemoglobin, but markedly higher leukocytes, neutrophils, and platelets. There were no differences in these variables between dogs with dilated cardiomyopathy (n = 6) and those with chronic valvular disease (n = 19). Dogs in ISACHC class 3a had a markedly lower total lymphocyte number, CD4+ and CD8+ cells, and hematocrit, but markedly higher leukocyte and neutrophil numbers relative to the control group. CD4+ and CD8+ subpopulations and other blood cell variables are altered in dogs with CHF. Future studies to determine possible clinical implications of these changes are warranted.     

Rate of change of heart size before congestive heart failure in dogs with mitral regurgitation

Objectives : The objective of the study was to examine the changes in vertebral heart scale, and left atrial and ventricular dimensions before and at onset of congestive heart failure in cavalier King Charles spaniels with mitral regurgitation. Methods : Records and radiographs from 24 cavalier King Charles spaniels with mitral regurgitation were used. Vertebral heart scale (24 dogs), and left atrial dimension and left ventricular end diastolic and end systolic diameters (18 dogs) and their rate of increase were measured at intervals over years to the onset of congestive heart failure. They were plotted against time to onset of congestive heart failure. Results : Dimensions and rates of change of all parameters were highest at onset of congestive heart failure, the difference between observed and chance outcome being highly significant using a two-tailed chi-square test (P<0·001). Clinical significance : The left heart chambers increase in size rapidly only in the last year before the onset of congestive heart failure. Increasing left ventricular end systolic dimension is suggestive of myocardial failure before the onset of congestive heart failure. Rate of increase of heart dimensions may be a useful indicator of impending congestive heart failure.     

Thyroid function in dogs with spontaneous and induced congestive heart failure.

The effects of spontaneous and experimentally induced congestive heart failure on serum thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3'5'-triiodothyronine (reverse T3), free T4, free T3 concentrations, and the serum T4 and T3 concentrations in response to administration of thyrotropin were studied. Serum thyroid hormone concentrations were not different between eight dogs with spontaneous congestive heart failure and normal age matched control dogs. Seven dogs with experimental heart failure were tested before and after induction of congestive heart failure by rapid ventricular pacing. Mean serum T4 and free T3 concentrations were decreased and mean serum reverse T3 concentration was increased following induction of heart failure. The serum T4 and T3 responses to thyrotropin were not altered. Thyroid gland morphology appeared normal in dogs with experimental heart failure. Experimental congestive heart failure, similar to some other nonthyroidal illnesses, alters thyroid hormone secretion and metabolism in dogs.     

Association of hyponatremia and hyperglycemia with outcome in dogs with congestive heart failure

Objective: To evaluate plasma sodium and glucose concentrations in dogs with congestive heart failure (CHF) prior to treatment and evaluate the differences between survivors and non‐survivors. Design: Retrospective study. Animals: Fifty‐nine dogs with CHF prior to receiving cardiac medication. Interventions: None. Measurements and main results: The mean plasma sodium concentration in dogs with CHF was below the reference range (144–156 mmol/L) and significantly lower (P=0.009) in non‐survivors (141±6 mmol/L) compared with survivors (147±4 mmol/L). The mean plasma glucose concentration was above the reference range (76–117 mg/dL) and significantly higher (P=0.004) in non‐survivors (128±52 mg/dL) compared with survivors (100±13 mg/dL). Forty‐four percent of non‐survivors had concurrent low plasma sodium and high plasma glucose concentrations, whereas no survivors had both abnormalities (P<0.0001). Conclusions: Lower plasma sodium and higher plasma glucose are associated with a worse outcome in dogs with CHF.     

Antioxidant status and biomarkers of oxidative stress in dogs with congestive heart failure

Alterations in antioxidant status and oxidative stress have been documented in dogs with dilated cardiomyopathy (DCM). The purpose of this study was to more broadly assess this relationship in dogs with congestive heart failure (CHF). Malondialdehyde (MDA), 8-F(2alpha)-isoprostane, protein carbonyls, reduced (GSH) and oxidized (GSSG) glutathione, vitamins A, C, and E, and oxygen radical absorbance capacity (ORAC) were measured from a single venous blood sample from dogs with CHF secondary to DCM or chronic valvular disease (CVD) and in healthy controls. Nineteen dogs with CHF (14 CVD and 5 DCM) and 12 healthy controls were enrolled in the study. Concentrations of 8-F(2alpha)-isoprostane (CHF: 44.6 pg/mL [range, 27.1-98.0 pg/mL], controls: 25.3 pg/ mL [range, 11.1-80.4 pg/mL]) but not MDA (CHF: 4.11 microM [range, 1.89-6.39 microM], controls: 3.88 microM [range, 2.14-4.72 microM]) or protein carbonyls (0.69 nmol/mg protein [range, 0.37-1.67 nmol/mg protein], controls: 0.80 nmol/mg protein [range, 0.40-1.14 nmol/mg protein]) were significantly higher in the dogs with CHF than in the controls. Vitamin E concentration (CHF: 2,215 microg/ dL [range, 916-3,499 microg/dL], controls: 2,820 microg/dL [range, 1,738-3,775 microg/dL]) and GSH:GSSG (CHF: 12.0 [range, 3.69-30.1], controls: 22.7 [range, 12.5-227]) were significantly lower, whereas ORAC (CHF: 824 micromol Trolox equivalent/L [range, 304-984], controls: 497 micromol Trolox equivalent/L [range, 258-759]) and vitamin C (CHF: 0.90 mg/dL [range, 0.55-2.02 mg/dL], controls: 0.72 mg/dL [range, 0.43-0.85 mg/dL]) concentrations were higher in dogs with CHF than in controls. Vitamin A concentrations were not different between dogs with CHF and controls. No differences in any of the parameters were detected between dogs with DCM versus those with CVD. Some antioxidant defenses are decreased in dogs with CHF, and some biomarkers of oxidative stress are increased in dogs with CHF. The effect of dietary interventions to correct this imbalance in antioxidant defenses warrants further study.