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.     

Clinical, echocardiographic, and neurohormonal effects of a sodium-restricted diet in dogs with heart failure

The use of low-sodium diets in dogs with heart failure is common practice, but randomized, double-blind studies have not been conducted to examine the benefits or problems with this approach. The purpose of this study was to determine the effects of a low-sodium diet on clinical, echocardiographic, and neurohormonal parameters in dogs with heart failure. Dogs with stable chronic heart failure were fed exclusively a low-sodium (LS) and a moderate-sodium (MS) diet for 4 weeks each in a randomized, double-blind, crossover design. At days 0, 28, and 56, echocardiography and thoracic radiography were performed, and blood was analyzed for electrolytes and neurohormones. Fourteen dogs completed the study (9 with chronic valvular disease and 5 with dilated cardiomyopathy). Electrolyte abnormalities were common during the study, and serum sodium and chloride concentrations decreased significantly on the LS diet. Neurohormones did not change significantly between diet groups. Maximum left atrial (P = .05) and standard left atrial (P = .09) size decreased on the LS diet. For dogs with chronic valvular disease, vertebral heart score (P = .05), left ventricular internal dimension in diastole (P = .006) and systole (P = .02), standard left atrial dimension (P = .03), maximum left atrial dimension (P = .02), end-diastolic volume index (P = .02), and end-systolic volume index (P = .04) decreased significantly on the LS diet compared to the MS diet. Although analysis of these data suggests some benefits of a low-sodium diet, future studies with improved study design are needed to further evaluate the advantages and disadvantages of sodium restriction in dogs with heart failure.     

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.     

Evaluation of acute congestive heart failure in dogs and cats: 145 cases (2007–2008)

Objective – To characterize the clinical presentation, management, and in‐hospital outcomes of dogs and cats diagnosed with acute congestive heart failure (CHF). Design – Retrospective study of animals seen between January 2007 and May 2008. Setting – Emergency service at a university teaching hospital. Animals – Ninety dogs and 55 cats with CHF. Measurements and Main Results – Patient characteristics, including age, clinical signs, clinicopathologic abnormalities, diagnostic testing, and outcome were recorded. Forty‐eight of the animals already were receiving cardiac medications at the time of presentation. The most common diseases represented were chronic valvular disease and cardiomyopathies. Cats had significantly lower median body temperature at admission compared with dogs (P<0.001). The most common abnormalities were elevated lactate (64%), elevated BUN (52%), hypochloremia (31%), hyperglycemia (27%), and elevated liver enzymes (26%). Many of these became even more prevalent during hospitalization. One hundred and sixteen animals were discharged from the hospital, for a survival rate of 80%. There was no survival difference between dogs and cats (P=0.39). Dogs that developed hypokalemia during hospital stay (P=0.04) were more likely to survive compared with those without hypokalemia and initial body temperature was lower for those cats that did not survive (P=0.02). Of those that did not survive, the majority were euthanized (n=25), while 4 dogs died. Conclusions – Dogs and cats presented to the emergency service with CHF had a high survival rate. In cats, initial body temperature was lower for those cats that did not survive. Although clinicopathologic abnormalities were common in both species, only dogs with hypokalemia had improved survival to hospital discharge.     

Increased NT-proANP predicts risk of congestive heart failure in Cavalier King Charles spaniels with mitral regurgitation caused by myxomatous valve disease

ObjectivesTo evaluate the predictive value of plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) and nitric oxide end-products (NOx) as markers for progression of mitral regurgitation caused by myxomatous mitral valve disease.AnimalsSeventy-eight privately owned Cavalier King Charles spaniels with naturally occurring myxomatous mitral valve disease.MethodsProspective longitudinal study comprising 312 measurements over a 4.5 year period. Clinical values were recorded, NT-proANP concentrations were measured by radioimmunoassay, and NOx were analyzed colorimetrically. To predict congestive heart failure (CHF), Cox proportional hazards models with time-varying covariates were constructed.ResultsThe hazard ratio for NT-proANP (per 1000 pmol/l increase) to predict future CHF was 6.7 (95% confidence interval, 3.6–12.5; p < 0.001). The median time to CHF for dogs with NT-proANP levels >1000 pmol/l was 11 months (95% confidence interval, 5.6–12.6 months), compared to 54 months (46 – infinity) for dogs with concentrations ≤1000 pmol/l (p < 0.001). Due to intra- and inter-individual variability, most corresponding analyses for NOx were insignificant but dogs reaching CHF had a lower mean NOx concentration than dogs not reaching CHF (23 vs. 28 μmol/l, p = 0.016). Risk of CHF increased with increase in heart rate (>130 beats per minute) and grade of murmur (≥3/6).ConclusionsThe risk of CHF due to mitral regurgitation is increased in dogs with blood NT-proANP concentrations above 1000 pmol/l. Measurement of NT-proANP can be a valuable tool to identify dogs that may develop CHF within months.     

Plasma endothelin-1 immunoreactivity in normal dogs and dogs with acquired heart disease

We sought to measure plasma endothelin-1 (ET-1) concentrations in normal dogs and to compare them with those measured in dogs with acquired heart disease with or without pulmonary edema. A sandwich enzyme-linked immunosorbent assay kit was validated and used to measure ET-1 immunoreactivity in plasma samples obtained from 32 normal dogs and 46 dogs with either dilated cardiomyopathy (DCM, n = 27) or degenerative valvular disease (CDVD, n = 19) with (n = 30) or without (n = 16) overt congestive heart failure (CHF). Plasma ET-1 concentrations (geometric mean, 95% confidence interval of geometric mean) were 1.17 (1.04-1.32) fmol/mL in the 32 normal control dogs, 1.25 (0.981-1.60) fmol/mL in 16 dogs with DCM (n = 9) or CDVD (n = 7) without CHF, and 2.51 (2.10-3.01) fmol/mL in 30 dogs with DCM (n = 18) and CDVD (n = 12) with CHE Plasma immunoreactivity of ET-1 was significantly higher in dogs with CHF in comparison with normal dogs (P < .001) and dogs with heart disease without CHF (P < .001). No significant difference was found between normal dogs and dogs with heart disease but without CHF (P > .05). Significant correlations were between plasma ET-I concentrations and left atrial:aortic ratio (P < .0001, r2 = .39), left ventricular internal dimension at end-diastole indexed to aortic diameter (P < .0001, r2 = .30) or body surface area (BSA) (P = .0071, r2 = .10), and left ventricular internal dimension at end-systole indexed to aortic diameter (P = .0003, r- = .17) or BSA (P = .0008, r2 = .15).     

Serum concentrations of cardiac troponin I and cardiac troponin T in dogs with class IV congestive heart failure due to mitral valve disease

Objective: The objective of this study was to evaluate the incidence of circulating detectable serum levels of cardiac troponin I (CTnI) and circulating detectable serum levels of cardiac troponin T (CTnT) in dogs with class IV congestive heart failure (CHF) due to mitral valve disease (MVD) at admission. An additional study aim was to determine if detectable troponin levels correlated with the magnitude of several clinical parameters. Design: Prospective clinical investigation. Setting: Small animal emergency and critical care referral hospital. Interventions: Blood was collected before emergency treatment from 15 dogs presenting in class IV CHF due to MVD. Measurements: Serum concentrations of CTnI, CTnT at presentation. Main results: Six dogs (40%) had a detectable CTnI (median 0.24, range 0.12–0.31 ng/mL), and the remainder were less than 0.1 ng/mL and deemed non‐detectable. The one dog (7%) that had a detectable CTnT (0.02 ng/mL) also had a detectable CTnI (0.23 ng/mL). There was no statistical difference in survival to discharge between dogs with non‐detectable troponin levels and those with detectable troponin levels; however, dogs with detectable troponin levels had shorter overall survival times. Dogs with a detectable level of CTnI had a median survival of 67.5 days (range 1–390 days), and dogs with a non‐detectable level of CTnI had a median survival time of 390 days (range 20–912 days) (P=0.02). Conclusion: This study suggests that CTnI can be detected at admission in the blood of 40% of dogs with class IV CHF due to MVD. Dogs with non‐detectable levels of cardiac troponins had a significantly longer overall survival time. The encouraging results of this small pilot study warrant further investigation.     

Comparisons of 3‐, 2‐Dimensional,and M‐Mode Echocardiographical Methods for Estimation of Left Chamber Volumes in Dogs with and without Acquired Heart Disease

Background: Real‐time 3‐dimensional echocardiography (RT3D) is a recent technique based on volumetric scanning, eliminating the need for geometric modeling of the cardiac chambers and minimizing the errors caused by foreshortened views. Hypothesis: Estimations of left ventricular (LV) end‐diastolic (EDV) and end‐systolic volume (ESV), and left atrial (LA) size, differ depending on the echocardiographic technique of estimation. Animals: Fifty‐one dogs with acquired heart disease and 34 healthy control dogs. Methods: Prospective observational study by M‐mode (Teichholz method), Simpson's modified 2‐dimensional (2D) method, and RT3D methods for estimation of LV volumes. LA size was evaluated by 2D and RT3D methods. Results: RT3D showed good agreement with 2D for EDV and ESV, whereas Teichholz method overestimated LV volumes in comparison with the other 2 methods by approximately a factor 2. There were no statistically significant differences among the 3 methods in estimating ejection fraction. Comparison between RT3D assessment of LA end‐systolic volume per kilogram (LAs/kg) and LA to aortic ratio (LA/Ao) measured by 2D relative to each other showed that the RT3D method underestimated LAs/kg at lower values, and overestimated it at higher values. The difference between methods increased with increasing LA size. Conclusions and Clinical Importance: There was good agreement between RT3D and 2D methods of estimating EDV and ESV, whereas the Teichholz method overestimated LV volumes by approximately a factor 2. In comparison with RT3D, LA/Ao underestimated LA size, especially when LA was enlarged.     

Effect of pimobendan on case fatality rate in Doberman Pinschers with congestive heart failure caused by dilated cardiomyopathy

BACKGROUND: Despite traditional therapy of a diuretic, angiotensin converting enzyme inhibitor, digoxin, or a combination of these drugs, survival of dogs with dilated cardiomyopathy (DCM) is low. Pimobendan, an inodilator, has both inotropic and balanced peripheral vasodilatory properties. HYPOTHESIS: Pimobendan when added to conventional therapy will improve morbidity and reduce case fatality rate in Doberman Pinschers with congestive heart failure (CHF) caused by DCM. ANIMALS: Sixteen Doberman Pinschers in CHF caused by DCM. METHODS: A prospective randomized, double-blind, placebo-controlled study with treatment failure as the primary and quality of life (QoL) indices as secondary outcome variables. Therapy consisted of furosemide (per os [PO] as required) and benazepril hydrochloride (0.5 mg/kg PO q12h) and dogs were randomized in pairs and by sex to receive pimobendan (0.25 mg/kg PO q12h) or placebo (1 tablet PO q12h). RESULTS: Pimobendan-treated dogs had a significant improvement in time to treatment failure (pimobendan median, 130.5 days; placebo median, 14 days; P= .002; risk ratio = 0.35, P= .003, lower 5% confidence limit = 0.13, upper 95% confidence limit = 0.71). Number and rate of dogs reaching treatment failure in the placebo group precluded the analysis of QoL. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan should be used as a first-line therapeutic in Doberman Pinschers for the treatment of CHF caused by DCM.     

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%.     

Effect of thyroid hormone supplementation on survival of euthyroid dogs with congestive heart failure due to systolic myocardial dysfunction: a double-blind, placebo-controlled trial

Nineteen euthyroid dogs of 12 breeds with echocardiographic signs of dilated cardiomyopathy (DCM) and radiographic and clinical signs of congestive heart failure (CHF) were evaluated in a randomised, double-blind, and placebo-controlled study. The dogs received either thyroxine or placebo as an adjunct to digoxin, furosemide and propranolol. The group assignment of individual dogs and serum concentrations of thyroid hormones remained unknown to owners and investigators during the entire study period. Dogs were evaluated clinically and with electrocardiography (ECG), thoracic radiography, echocardiography and measurement of total thyroxine (tT4) and thyroid stimulating hormone (TSH) before beginning of the trial, and then one week, 2 months, 6 months and yearly after initial examination, and, when applicable, at the time of euthanasia. End-point of the study was euthanasia (n = 17) due to severe congestive heart failure or sudden death (n = 2). Survival times ranged from 17 to 1030 days (median 187 days) in the placebo group, and from 18 to 1000 days (median 73 days) in the treatment group. There was no statistically significant difference in survival times between the treatment group and the placebo group (p = 0.46). Post mortem and histopathologic examinations revealed the attenuated wavy fiber type of DCM in 11 dogs, and myocardial infarcts, arteriosclerosis and chronic valvular disease in one dog. In conclusion, there was a wide range in survival times of dogs treated with digoxin, furosemide and propranolol. Adding thyroid hormones to the treatment did not significantly influence survival.     

Atrial natriuretic peptide concentration in dogs with congestive heart failure, chronic renal failure, and hyperadrenocorticism.

The function of atrial natriuretic peptide (ANP) is claimed to be control of salt and water homeostasis, and thus, the hormone may be involved in the pathogenesis of certain diseases with impaired volume regulation. We, therefore, studied plasma ANP concentration in dogs with chronic renal failure, congestive heart failure, and hyperadrenocorticism. Dogs with chronic renal failure had twofold higher plasma ANP concentration (16.2 +/- 5.8 fmol/ml), compared with healthy dogs (8.3 +/- 3.5 fmol/ml). An even more distinct increase (sixfold) of plasma ANP concentration was found in dogs with congestive heart failure (52.9 +/- 29.7 fmol/ml). In contrast, dogs with hyperadrenocorticism did not have high ANP plasma concentration (5.5 +/- 2.0 fmol/ml). High-performance liquid chromatographic analysis of plasma from dogs with congestive heart failure indicated that, in addition to the normal circulating form of ANP (99-126), the unprocessed precursor ANP (1-126) is detectable in the circulation. These qualitative and quantitative alterations of plasma ANP concentration in dogs further suggest involvement of this peptide in the development and/or maintenance of diseases associated with impaired volume regulation.     

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.     

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.