Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation

We evaluated the long-term effect of early angiotensin-converting enzyme (ACE) inhibition (enalapril maleate) as monotherapy to postpone or prevent congestive heart failure (CHF) in asymptomatic dogs with mitral regurgitation (MR) attributable to myxomatous valvular disease (MVD) in a prospective, randomized, double-blinded, placebo-controlled multicenter trial involving 14 centers in Scandinavia. Two hundred twenty-nine Cavalier King Charles (CKC) Spaniels with MR attributable to MVD but no signs of CHF were randomly allocated to treatment with enalapril 0.25-0.5 mg daily (n = 116) or to placebo groups (n = 113). Each dog was evaluated by physical examination, electrocardiography, and thoracic radiography at entry and every 12 months (+/-30 days). The number of dogs developing heart failure was similar in the treatment and placebo groups (n = 50 [43%] and n = 48 [42%], respectively; P = .99). The estimated means, adjusted for censored observations, for the period from initiation of therapy to heart failure were 1,150 +/- 50 days for dogs in the treatment group and 1,130 +/- 50 days for dogs in the placebo group (P = .85). When absence or presence of cardiomegaly at the entrance of the trial was considered, there were still no differences between the treatment and placebo groups (P = .98 and .51, respectively). Multivariate analysis showed that enalapril had no significant effect on the time from initiation of therapy to heart failure (P = .86). Long-term treatment with enalapril in asymptomatic dogs with MVD and MR did not delay the onset of heart failure regardless of whether or not cardiomegaly was present at initiation of the study.     

Association between exogenous atrial natriuretic peptide and hemodynamics in dogs with congestive heart failure produced by experimental mitral regurgitation

Association between exogenous atrial natriuretic peptide (ANP) and hemodynamic changes was ascertained in 3 dogs with overt congestive heart failure (CHF(+)) and 3 dogs without congestive heart failure (CHF(-)) caused by experimental mitral regurgitation (MR). The hemodynamic measurements were recorded in all dogs during and after 1 hr infusion of ANP at the rate of 0.1 (low dose), 0.5 (medium dose) and 1.0 (high dose) microg/kg/min, respectively. Heart rate, mean arterial pressure, pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance decreased significantly during and after ANP infusion even with low dose in the CHF(+). Stroke volume, stroke volume index and cardiac output in the CHF(+) during and after ANP infusion showed an increasing trend as compared with the CHF(-). Double product, an indicator of myocardial oxygen consumption, significantly decreased during and after ANP administration at all doses in the CHF(+). These findings indicate that even at low dose, exogenous ANP improves cardiac performance and reduces myocardial oxygen consumption in the CHF(+), and suggest that ANP has beneficial effects in the treatment of dogs with overt congestive heart failure resulting from MR.     

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.     

Partial external mitral annuloplasty in dogs with myxomatous mitral valve degeneration and congestive heart failure: Outcome in 9 cases

Objective

To report the outcome of partial external mitral annuloplasty in dogs with congestive heart failure (CHF) due to mitral regurgitation caused by myxomatous mitral valve degeneration (MMVD).

Animals, materials and methods

Nine client-owned dogs with CHF due to mitral regurgitation caused by MMVD. Surgery consisted of a double row of pledget-butressed continuous suture lines placed into the left ventricle parallel and just ventral to the atrioventricular groove between the subsinuosal branch of the left circumflex coronary artery and the paraconal branch of the left coronary artery.

Results

Two dogs died during surgery because of severe hemorrhage. Two dogs died 12 and 36 h after surgery because of acute myocardial infarction. Three dogs were euthanized 2 and 4 weeks after surgery because of progression of CHF, 1 was euthanized 30 days after surgery for non-cardiac disease, and 1 survived for 48 months. In the 5 dogs that survived to discharge there was no significant change in the left atrium to aortic ratio with surgery (3.6 ± 0.56 before surgery; 3.1 ± 0.4 after surgery; p = 0.182), and no significant change in mitral regurgitant fraction in 4 dogs in which this measurement was made (78.7 ± 2.0% before surgery; 68.7 ± 7.5% after surgery; p = 0.09).

Conclusions

Partial external mitral annuloplasty in dogs with CHF due to MMVD was associated with high perioperative mortality and most dogs that survived to discharge failed to show clinically relevant palliation from this procedure. Consequently, partial external mitral annuloplasty is not a viable option for dogs with mitral regurgitation due to MMVD that has progressed to the stage of CHF.     

Spectral analysis of heart rate variability in dogs with mild mitral regurgitation

OBJECTIVE: To assess autonomic function in dogs with mild mitral regurgitation (MR) that did not have clinical signs of the condition. ANIMALS: 6 healthy adult Beagles. PROCEDURE: Mild MR was experimentally induced. A 24-hour ambulatory ECG was recorded before and after induction of MR. Heart rate variability was analyzed in frequency domains by use of the ambulatory ECG. Low-frequency (LF) and high-frequency (HF) power were calculated by integrating over their frequency intervals, and the ratio of LF to HF was also calculated. Measurements of frequency domains were analyzed for 4 time periods (midnight to 6 AM, 6 AM to noon, noon to 6 PM, and 6 PM to midnight). RESULTS: Dogs with experimentally induced MR were classified as International Small Animal Cardiac Health Council class Ia. The HF power of dogs with MR was significantly decreased between 6 AM and noon. The ratio of LF to HF in dogs with MR was significantly increased for the periods between midnight and 6 AM, 6 AM and noon, and noon and 6 PM. CONCLUSIONS AND CLINICAL RELEVANCE: Compensatory response through autonomic modulation was observed in dogs with mild MR that did not have abnormalities, except for cardiac murmur, during clinical examination. This result suggests that treatment during the early stages of mild MR may be beneficial. Additional studies are necessary to determine whether such treatment will delay the onset of congestive heart failure and prolong survival in dogs affected with mild MR.     

Sympathetic activation in dogs with congestive heart failure caused by chronic mitral valve disease and dilated cardiomyopathy

Baseline plasma norepinephrine (NE) and epinephrine (EPI) concentrations were measured in dogs with naturally acquired heart failure (HF) caused by either degenerative mitral valve disease and mitral regurgitation (MR) or idiopathic dilated cardiomyopathy (DCM). Compared with controls (clinically normal), dogs with HF had increased plasma NE concentration, which was correlated positively with clinical severity of HF. Dogs with the most severe degree of HF (New York Heart Association functional class IV) had mean NE concentration significantly (P less than 0.05) greater than that of dogs with all other functional classes of HF. Overall, mean NE concentration in dogs with DCM was greater than that in dogs with MR. Plasma EPI concentration was not different between control dogs and dogs with HF or between dogs with DCM or MR. Correlations were not found between the echocardiographically derived end systolic volume index (used as an estimate of myocardial function) and plasma NE and EPI concentrations or serum sodium or potassium concentration. Dogs with DCM, as a group, had a small but significant (P less than 0.05) decrease in serum sodium concentration, compared with dogs with MR. This difference was maintained only for class-IV HF when dogs were separated according to functional HF class. In dogs with DCM, significant inverse correlation was found between plasma NE and serum sodium concentrations. When grouped together, all dogs with HF maintained this relationship; however, dogs with MR did not have correlation between plasma NE and serum sodium concentrations. Plasma EPI and serum sodium concentrations were not correlated for any group. It was concluded that in dogs, plasma NE, but not EPI, concentration is high in relation to the clinical severity of naturally acquired HF.(ABSTRACT TRUNCATED AT 250 WORDS)     

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%.     

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.     

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.     

Pulmonary function in dogs with mitral valve regurgitation

Mitral valve regurgitation was created in 2 groups of dogs. Groups were selected on absence (group 1) or presence (group 2) of clinical signs of congestive left ventricular failure. Group-2 dogs, in which mean left atrial pressures were greater than 30 mm of Hg, had increases in heart rate, pulmonary arterial mean pressure, left atrial diameter, and left ventricular diastolic diameter. These changes were associated with decreased arterial O2 tension, decreased static and dynamic compliance, reduced lung volumes, and increased pulmonary resistance. Group-1 dogs, in which mean left atrial pressure was less than 30 mm of Hg, had moderate changes in hemodynamics, but no changes in pulmonary function, except during exercise when arterial O2 tension decreased.     

Platelet aggregation in dogs with mitral valve regurgitation

OBJECTIVE: To compare platelet aggregation in healthy dogs and dogs with mitral valve regurgitation (MVR) to determine whether regurgitation had an effect on platelet function. ANIMALS: 32 dogs with MVR and 43 healthy dogs. PROCEDURE: Platelet aggregation was measured with an aggregometer, using adenosine 5'-diphosphate as the aggregating agent, and the maximum aggregation and the enhancement of platelet sensitivity (EPS) values were calculated. RESULTS: Platelet count and maximum aggregation were not significantly different between healthy dogs and dogs with MVR. However, EPS values in dogs with MVR were significantly higher than values in healthy dogs. Platelet count and maximum aggregation were not significantly different between dogs classified as New York Heart Association functional class I or II and dogs classified as functional class III or IV; however, EPS values were significantly higher in dogs classified as functional class III or IV. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that platelet aggregation is decreased in dogs with MVR and that the EPS value may be more sensitive to differences in disease severity than in measurement of maximum aggregation.     

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.     

Prediction of first onset of congestive heart failure in dogs with degenerative mitral valve disease: The PREDICT cohort study

ObjectiveTo identify risk factors for first-onset congestive heart failure (CHF) in dogs with degenerative mitral valve disease (DMVD).AnimalsEighty-two dogs with and without CHF secondary to DMVD were retrospectively assigned to a derivation cohort. Sixty-five dogs with asymptomatic DMVD were recruited into a prospective validation cohort.MethodsVariables associated with risk of CHF in dogs were identified in a derivation cohort and used to construct a predictive model, which was then prospectively tested through longitudinal examination of a validation cohort.ResultsLogistic regression analysis of the derivation cohort yielded a predictive model that included the left atrial to aortic root dimension ratio (LA:Ao) and plasma concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP). When this model was prospectively applied to the validation cohort, it correctly predicted first-onset of CHF in 69.2% of cases. Analysis of the validation cohort revealed that plasma NT-proBNP concentration and indexed left ventricular end-diastolic diameter (LVIDd:Ao) were independent risk factors for development of first-onset CHF in dogs with DMVD (NT-proBNP ≥1500 pmol/L, odds ratio (OR), 5.76, 95% confidence interval (CI), 1.37–24.28, P = 0.017; LVIDd:Ao ≥3, OR, 6.11, 95% CI, 1.09–34.05, P = 0.039).ConclusionsMeasures of left heart size and plasma NT-proBNP concentration independently estimate risk of first-onset of CHF in dogs with DMVD. These parameters can contribute to the management of dogs with DMVD.