J Vet Intern Med 2007;21:996–1001

Effects of Carvedilol Treatment in Dogs with Chronic Mitral Valvular Disease Ma´rio Marcondes-Santos, Flavio Tarasoutchi, Antonio P. Mansur, and Ce´lia M.C. Strunz Background: Stimulation of the sympathetic nervous system occurs during the development of heart failure in dogs with chronic mitral valvular disease (CMVD). Hypothesis: The use of beta-blockers to modulate the activation of the sympathetic nervous system would be useful in dogs with CMVD. Animals: Group A included 13 dogs who received the conventional treatment (digoxin, benazepril, a reduced sodium diet, and codeine, and a diuretic when indicated), and group B included 12 dogs who received the protocol above plus carvedilol (0.3 mg/kg q12h). Methods: Blinded, placebo, controlled study. Results: The main echodopplercardiographic variables, heart rate, biochemical data, functional classification (FC) (New York Heart Association) and quality of life score (functional evaluation of cardiac health questionnaire) were assessed at baseline (T0) and after 3 months (T1). Only group B showed improvement in score of quality of life (13.8 6 8.8 versus 6.0 6 6.3; P , .001), in FC (2.4 6 0.9 versus 1.8 6 0.7; P 5 .032) and a reduction in systolic blood pressure (151.2 6 18.3 versus 124.5 6 23.4; P 5 .021). Two deaths from group A and 1 from B were related to CMVD. Conclusion: The studied dose of carvedilol in this group did not improve the sympathetic activation and echocardiographic variables over 3 months of chronic oral treatment. However, the results suggested a beneficial effect on the quality of life score, functional classification, and a reduction on systolic blood pressure. Key words: Beta-blocker; Cardiology; Dog; Heart failure; Mitral valve; Quality of life.

ome neuroendocrine mechanisms are triggered during the development of heart failure (HF) and contribute to the progression of this disease in humans and other animals.1,2 Among the main mechanisms that are triggered are the stimulation of the sympathetic nervous system (SNS), activation of the renin-angiotensin system, and release of vasopressin.2,3 Activation of the SNS is one of the first mechanisms aroused in HF.2,4–16 This activation stimulates tachycardia and arrhythmias and also causes malfunction and necrosis of cardiomyocytes.13–18 Analysis of these results suggests that the use of beta-blockers to prevent sympathetic action on cardiomyocytes would be especially helpful in reducing progression of heart disease in dogs. Beta-blockers have become an established treatment for human patients with HF. Clinical studies19,20 conducted since 1992 have tested the effect of the beta-blocker carvedilol and found that it has the potential to enhance survival in human patients with HF, chiefly those with dilated cardiomyopathy (DC). In addition to sympathetic modulation, carvedilol demonstrated antihypertensive and antioxidant effects, which contribute to reducing the progression of HF in humans.6,8,14,18,19,21 Studies have been done in healthy dogs to establish an effective dose of carvedilol and the main hemodynamic

S

From the Heart Institute (InCor), University of Sa˜o Paulo, Medical School (Marcondes-Santos, Tarasoutchi, Mansur, Strunz); and Sena Madureira Veterinary Hospital (Marcondes-Santos), Sa˜o Paulo, Brazil. Reprint requests: Dr Marcondes Santos, Cardiology Service from the Sena Madureira Veterinary Hospital, Sa˜o Paulo, Brazil, Rua Sena Madureira 898, Vila Mariana, CEP 04021-001, Sa˜o Paulo, Brazil. Submitted: November 5, 2006; Revised February 3, 2007, March 30, 2007; Accepted May 8, 2007. Copyright E 2007 by the American College of Veterinary Internal Medicine 0891-6640/07/2105-0016/$3.00/0

changes promoted by this drug in canine species.22–25 In dogs with induced HF, when using a model of iatrogenic mitral regurgitation, the oral dose was less than 0.2 mg/ kg and titrated up to 0.4 mg/kg.26 Previous studies reported a significant improvement on the left ventricular function in dogs with experimentally induced mitral regurgitation treated with the beta-blocker atenolol.27,28 Its administration promoted a decrease in cardiac interstitial norepinephrine (NE) in dogs with experimentally induced mitral regurgitation.29 The proposed mechanism of systolic dysfunction characteristic of primary mitral valve regurgitation is related to the increase of the SNS tone, which results in a reduction of the absolute number of cardiomyocytes, as well as the number of contractile elements within each cardiomyocyte.30 Other investigators31,32,a mentioned, in their studies, the possible beneficial effects of carvedilol treatment in dogs with chronic mitral valvular disease (CMVD), which include dogs with CMVD with no clinical signs of the condition. Some of these investigators31,32 stated that studies to evaluate the effect of betablockers during the various phases of CMVD treatment should be conducted to confirm this hypothesis. Recently, a studyb with canine DC did not reveal any differences in the echocardiographic and neurohormonal variables after carvedilol treatment (0.3 mg/kg q12h). Similar results were noted in a retrospective study33 done with acquired DC or CMVD and revealed no improvement in functional classification or cardiac dimensions after treatment with another beta-blocker, metoprolol. However, the response to carvedilol might be different in dogs, depending on the type of heart disease (DC or CMVD, acquired or experimentally induced mitral disease, asymptomatic or symptomatic diseases) or in comparison with healthy dogs. The objective of this study was to evaluate the effects of a low dose of carvedilol in a group of client-owned dogs with CMVD. The primary study end points involved quality of life

Carvedilol in Dogs

and sympathetic activation. Secondary end points involved echocardiographic variables.

Materials and Methods Animals The clinical study was conducted on 25 client-owned dogs. The dogs were from the Cardiology Service of the Sena Madureira Veterinary Hospital in Sa˜o Paulo, Brazil and were diagnosed with CMVD.

Procedure The definitive diagnosis of CMVD was obtained during echocardiographic examination by use of an ultrasound systemc with a 5-MHz micro convex transducer and was performed by a veterinarian specialist in Doppler echocardiography from the Image Service of Sena Madureira Veterinary Hospital and blinded to the protocol treatment. Severity of mitral regurgitation of dogs with CMVD was estimated by spectral-pulsed Doppler. Only dogs with moderate-to-severe mitral regurgitation and left atrial enlargement were chosen, and were classified as grade I to IV according to New York Heart Association (NYHA) functional class scoring system modified for veterinary use3 on the basis of historical severity of HF signs and physical, radiographic, and echocardiographic findings. The radiographic examinations were performed by a veterinarian specialist in radiology from the same veterinary hospital and who was blinded to the protocol treatment. The NYHA functional class scoring system was transformed to arabica numeral for analysis. After the selection, the dogs were balanced to sex and functional classification, filling up 2 groups in an attempt to avoid the influence of different clinical conditions between the groups over the results. The data are presented as mean and standard deviation. The group A comprised 13 dogs (4 females and 9 males); mean age, 11.0 6 1.6 years; functional classes, 2.3 6 0.7; and left atrium dimension : aortic root dimension (LA : Ao) ratio, 1.79 6 0.39. Group B comprised 12 dogs (4 females and 8 males); mean age, 11.2 6 1.6 years; functional classes, 2.4 6 0.9; and LA : Ao ratio, 1.73 6 0.39. The breeds were as follow; in group A, 10 Poodles, 1 Fox, 1 Pinscher, and 1 mixed-breed dog; and in group B, 6 Poodles, 2 mixed-breed-dogs, 1 Beagle, 1 Lhasa Apso, 1 Cocker Spaniel, and 1 Pinscher. The animals under therapy before the study (8 from group A and 7 from group B) were receiving furosemide, with or without digoxin or a vasodilator. After the collection of baseline parameters (T0), the current treatment was discontinued and the new protocol was initiated (Table 1). All the included dogs had normal results for clinopathologic tests of renal and hepatic function. In addition, results of the cell blood count were within the respective reference ranges. Informed written consent was obtained from each owner. Each owner was informed about the drugs used in the treatment and the possible adverse effects, but the differences between the protocol treatments were omitted so each was blind to the name of the drug under study and the protocol treatment of the other studied dogs. The study was approved by the Ethic Committee of the Heart Institute (InCor), University of Sa˜o Paulo, Medical School. Clinical evaluation consisted of a physical examination; ECG; measurement of arterial blood pressure; thoracic radiography; CBC; serum biochemical analysis; and 2-dimensional, M-mode, and spectral-pulsed Doppler echocardiography. All dogs were submitted to the above evaluation at baseline (T0) and after 3 months (T1). The period of 3 months was chosen based in studies27,28 with atenolol in dogs with experimentally induced mitral regurgitation that reported an improvement of the left ventricular function after this time. The conventional treatment for group A

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Table 1. Number of animals divided according to drugs before the study (discontinued) and at the beginning of the study in both groups (A and B). Drugs before the study (discontinued) Vasodilator Digoxin Furosemide Drugs in the beginning of the study Benazepril Digoxine Codeine Furosemide Spironolactone Hydrochlorothiazide Carvedilol

A (n 5 13)

B (n 5 12)

8 2 5

7 2 4

13 12 10 12 1 1 0

12 10 9 10 1 1 12

was the benazepril (0.3–0.5 mg/kg q24h) for dogs in functional class I. In dogs with functional class $II, the protocol was benazepril (0.3–0.5 mg/kg q24h), digoxin (0.0055 mg/kg q12h, with therapeutic concentrations of serum digoxin of 1–2 ng/mL measured 1 week after the initiating therapy; blood samples were collected 6–8 hours after the last dose) and 1 reduced sodium dietd,e,f during the 3 months of evaluation. Codeine (0.3 mg/kg q8h) and a diuretic were used only when necessary in dogs with functional classes $II. The diuretic protocol used in the study was as follows: only furosemide (mean dose, 2.5 mg/kg q12h in both groups) for dogs with functional classification II and III, and the association of spironolactone (2 mg/kg q12h) and hydrochlorothiazide (2 mg/kg q12h) for dogs with functional class IV (only 1 dog in group A and 1 in group B). All dogs in group B received the same protocol mentioned above plus carvedilol (0.3 mg/kg q12h) (Table 1). The initial dose of carvedilol was 0.15–0.2 mg/kg q12h during 1 week. After evaluating the arterial blood pressure and the heart rate, the dose was raised to 0.3 mg/kg q12h. Only 1 dog in group B kept receiving carvedilol at initial doses because of the lower values (#100 mm Hg) of systolic arterial blood pressure after the beginning of treatment. The purpose of using client-owned dogs in this study was because the owners could more accurately evaluate the quality of life of their dogs than could other viewers. The functional evaluation of cardiac health (FETCH) questionnaire score used to evaluate the quality of life34 was established through the information obtained from the owner during the anamnesis on T0 and T1. The questionnaire consisted of 17 questions answered by the owner, who graded the severity of clinical signs on a scale from 0 to 5, the higher score being the poorest health-related quality of life. To check the questionnaire applied, the comparison between the FETCH score and the HF functional classification was assessed for the 25 dogs at baseline conditions (T0) by using the Spearman rank test. To confirm the homogeneity of the clinical condition of the groups in the beginning of the study, the FETCH score (Student’s t-test) and the functional classification (Mann Whitney U-test) were compared at T0. By revealing similar results (with P 5 not significant [NS]) (Table 2), we assumed that the clinical conditions at T0 were not interfering in these data. Blood samples for the measurement of plasma concentrations of NE were collected early in the morning. An appropriately sized heparinized catheterg was inserted into a saphenous vein of each dog. Then, the dog was positioned in lateral recumbence on a table with minimal restraint for 20 minutes.21,35 The first milliliter of blood collected via the catheter was discarded. The subsequent 3– 5 mL of blood were collected and immediately transferred into icechilled tubes that contained a mixture of ethylene glycol tetracetic

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Table 2. Mean 6 standard deviation of quality of life score (FETCH questionnaire), functional class, biochemical data, heart rate, blood pressure, and main echodopplercardiographic parameters at 2 treatment times in dogs with CMVD. Group Aa A (T0) Quality of life (FETCH score) Functional class (NYHA)c Norepinephrine (pg/mL) Sodium (mEq/L) Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LVIDd (cm) LVIDs (cm) LVIDd : Ao LVIDs : Ao FS (%) Ao (cm) LA (cm) LA : Ao

12.3 2.3 579 146.9 146.5 124.2 80 3.2 1.6 2.3 0.7 49.9 1.4 2.5 1.79

6 9.1 6 0.7 6 409.4 6 2.9 6 35.1 6 16.5 6 12.9 6 0.8 6 0.4 6 0.3 6 0.1 6 5.3 60.2 6 0,9 6 0.39

Group Bb A (T1) 9.1 2.1 483.6 144.9 140.9 127.7 80.9 3.3 1.7 2.3 0.7 48.7 1.4 2.5 1.75

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

8.3 0.7 310.4 4.4 22.6 16.9 12.2 0.9 0.5 0.4 0.2 3.7 0.2 0.9 0.34

B (T0) 13.8 2.4 515.1 145.5 145 151.2 90.8 3.7 1.9 2.3 1.2 48.5 1.6 2.8 1.73

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

8.8 0.9 405.8 3.1 23.9 18.3 14.4 0.8 0.5 0.4 0.2 6.1 0.3 0.7 0.39

B (T1) 6.0 1.8 393.3 146.6 127.3 124.5 85.5 3.6 1.9 2.3 1.2 48.1 1.6 2.7 1.75

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

6.3* 0.7** 231.4 3.5 24.1 23.4*** 11.3 0.8 0.5 0.4 0.2 5.3 0.4 0.7 0.39

Ao, aortic root dimension; CMVD, chronic mitral valvular disease; FETCH, functional evaluation of cardiac health; FS, fractional shortening; LA, left atrium dimension; LVIDd, diastolic left ventricular internal dimension; LVIDs, systolic left ventricular internal dimension; NYHA, New York Heart Association; T0, baseline condition; T1, after 3 months of treatment. a Thirteen dogs who received conventional treatment for CMVD. b Twelve dogs with conventional treatment plus carvedilol for CMVD. c Functional class (NYHA) was transformed to arabic numeral for analysis: I, 2; II, 2; III, 3; IV, 4. Within a row, values differ significantly (*P , .001; Student’s t-test; **P 5 .032; ***P 5 .021; Wilcoxon signed rank test) from T0 value in the group.

acid (EGTA)-glutathione (20 mL of anticoagulant/mL of blood). Within 1 hour after blood collection, plasma was separated by cold centrifugation and was immediately frozen at 270uC. NE was determined by high-performance liquid chromatography36–39,h and sodium was analyzed by selective electrode.i To confirm the contribution of the sympathetic activation on the severity of clinical signs in this group of HF dogs, the correlation between NE and HF functional classes was calculated for the 25 dogs at T0 by using the Spearman rank test. The arterial blood pressure was measured indirectly by vascular Doppler,j with the dog in lateral recumbence. The cuff width was approximately 40% of the limb circumference. Each value of systolic and diastolic arterial blood pressure was calculated by the mean of 3 to 4 measurements. The heart rate evaluation was performed by ECG.k The M-mode echocardiographic variables studied were the following: diastolic left ventricular internal dimension (LVIDd), systolic left ventricular internal dimension (LVIDs), fractional shortening (FS), aortic root dimension (Ao), left atrium dimension (LA), and LVIDd : Ao, LVIDs : Ao, LA : Ao ratios. Values for FS were calculated by the equation: FS 5 ([LVIDd 2 LVIDs]/LVIDd) 3 100. The intraobserver variability for the M-mode echocardiographic variables was calculated by means of 15 measurements in each variable in 5 dogs40 (coefficients of variation ranged from 2.6 to 6.5%). The severity of mitral regurgitation was estimated by the use of spectral-pulsed Doppler ultrasonography, with careful placement of the pulsed-wave Doppler gate at various depths within the left atrium to provide information on the width and depth of the regurgitant jet in the left atrium. An aliased signal was generated at points where the gate revealed a regurgitant jet; the signal was generated on the basis of the percentage of the left atrium occupied by the regurgitant jet (mild ,20%; moderate, 20–50%; and severe, .50%).32,41–43

Statistical Analysis Data were expressed as mean, median 6 SD. The KolmogorovSmirnov normality test was used to test for normal distribution of data for the variables. On the basis of those results, the parametric Student’s t-test was used for results with normal distribution. When the normal distribution was rejected, the nonparametric MannWhitney U test was used to compare the independent groups; the nonparametric Wilcoxon signed-rank test to measure the dependent samples, and the Spearman rank test to measure the degree of association between variables. Results were considered significant at values of P , .05.

Results The severity of mitral regurgitation was estimated by the use of spectral-pulsed Doppler ultrasonography, which revealed in group A: 5 dogs with mild regurgitation, 3 with mild-to-severe regurgitation, and 5 with severe regurgitation. In group B, mild regurgitation was observed in 5 dogs and was severe in 7 dogs. The results of the FETCH quality of life score, which ranged from 2 to 30 when compared with HF functional classification, revealed a positive and significant correlation (r 5 0.579, P 5 .003, Spearman rank test; Fig 1), which allowed us to assume that this questionnaire could reflect the health-related quality of life in this group of dogs. The difference in the quality of life FETCH score between T0 and T1 was not statistically significant for dogs in group A (12.3, 7.0 6 9.1 versus 9.1, 6.0 6 8.3; P 5 .38). However, a statistically significant improvement

Carvedilol in Dogs

Fig 1. Comparison of the functional evaluation of cardiac health score of quality of life with the New York Heart Association functional class of heart failure at T0. The values were significantly and positively correlated (r 5 0.579; P 5 .003, Spearman rank test).

of quality of life FETCH score for dogs treated with the evaluated dose of carvedilol in group B was detected with higher scores at T0 in comparison with T1 (13.8, 12.0 6 8.8 versus 6.0, 4.0 6 6.3; P , .001, Student’s ttest) (Table 2, Fig 2). The better results for the score of quality of life presented by group B after 3 months of treatment could be confirmed by the improvement of functional class (2.4, 2.5 6 0.9 versus 1.8, 2.0 6 0.7; P 5 .032, Wilcoxon signed-rank test). For group A, the mean values of functional class were similar at the 2 studied times (2.3, 2.0 6 0.72 versus 2.1, 2.0 6 0.7; P 5 NS, Wilcoxon signed-rank test). Plasma NE results for all dogs at the beginning of treatment revealed a moderate positive correlation with HF functional classification (r 5 0.52; P 5 .008, Spearman rank test ). Although the results pointed to a trend for lower values of plasma NE in group B after 3 months of beta-blocker therapy, they were not statistically significant. No differences between T1 and T0 for the 2 drug protocols were observed for sodium values. Even with no differences being detected for the mean heart rate measured by ECG at the 2 studied times for the groups A and B, there was a trend for lower values in group B at T1. The results from blood pressure data revealed a statistical difference only for systolic blood pressure of group B (151.2, 160 6 18.3 versus 124.5, 125 6 23.4, P 5 .021, Wilcoxon signed-rank test). The mean of diastolic blood pressure was similar at T0 and T1 for both groups. The M-mode echocardiographic variables LVIDd, LVIDs, FS, Ao, LA, LVIDd : Ao, LVIDs : Ao, and LA : Ao at the 2 periods of evaluation (T0 and T1) were

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Fig 2. Comparison of means, quality of life functional evaluation of cardiac health score questionnaire in the baseline condition (T0) and after 3 months of treatment (T1) in group A (conventional treatment, n 5 13) and group B (conventional treatment plus carvedilol, n 5 12) in dogs with CMVD. *Values at T1 differed significantly (P , .001, Student’s t-test) from values at T0.

compared in each group, and no statistical difference was found.

Discussion Because of the controversial data from the literature about the effective dose of carvedilol in healthy dogs and the absence of clinical studies in dogs with symptomatic CMVD having previous hemodynamic changes, we chose a relatively low oral dose of 0.3 mg/kg carvedilol q12h, according to the study by Uechi et al,26 to better control the effects of this drug in a small group of clientowned dogs with CMVD in this preliminary study. The results of this study with the evaluated carvedilol dose revealed an improvement in the quality of life score (estimated by the FETCH questionnaire)34 and the functional class (Table 2, Fig 2), which suggested that the use of this beta blocker could be beneficial for the treatment of dogs with CMVD. However, although the quality of life (FETCH) questionnaire was answered by owners blinded to the object of this analysis, we cannot exclude some degree of subjectivity in this evaluation, and this is a limitation of this study. New research must be performed with a larger number of animals to evaluate the real impact of this therapy in the progress of the HF in canine CMVD. Another limitation was that some of the dogs were under drug therapy before the beginning of the protocol, meaning that these other drugs could have influenced the results, not only the beta-blocker. Otherwise it must be emphasized that the ingestion of drugs, except for carvedilol in group B, was

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similar in the 2 groups at T0 and T1 (Table 1), making us believe that differences noted between the 2 moments for group B could be attributed to the beta-blocker. Another point was that the groups were composed of different breeds, which could be interpreted as a source of bias for the study. It must be mentioned also that the 2 groups of dogs were balanced according to sex and functional classification, not truly random. However, we do not believe that these 2 points compromised the results, because of the homogeneity at the baseline clinical conditions in the 2 groups when compared. The NE data correlated with the functional classes at baseline for all dogs, as already described by other investigators,2 but these neurohormone concentrations did not follow the differences observed in the functional classification after carvedilol therapy. This paper also failed to detected differences in heart rate after 3 months of beta-blocker treatment. However, the values obtained for both of these parameters had a trend to be lower in the dogs after treatment with carvedilol (Table 2). The inclusion of a larger number of dogs and a longer period of treatment is likely to allow us to better investigate the effect of carvedilol treatment on NE and HR values. With regard to blood pressure, the basal systolic values (T0) were lower in group A in comparison with group B, but all animals began the study with values considered normal for the species according to previous studies when using the same method.44,45 After treatment, we obtained lower values at T1 moment compared with T0 for group B. This decrease is in agreement with previous studies that described the antihypertensive effect (a1-adrenergic blocking effect) of carvedilol.6,8,18,19,21,22,46 The decrease of systolic blood pressure observed in this study is very similar to the result reported by Uechi et al.26 These investigators noted a decrease on blood pressure and heart rate in dogs with HF with iatrogenic mitral regurgitation treated with 0.4 mg/kg carvedilol. The use of the beta-blocker atenolol, as demonstrated by other investigators, promoted the improvement on left ventricular function in dogs with experimentally induced mitral regurgitation.27,28 Other investigatorsa describe a reduction in the left atrial size (estimated by maximum diastolic left atrial area in cm2), as well as an improvement in the left ventricular function in 5 asymptomatic dogs with CMVD after 5 months of treatment with higher doses of carvedilol. Yet, in the same study, when the M-mode parameters LVIDd, LVIDs, and LA : Ao ratio were evaluated, the values were similar (without statistical differences), both before and after 5 months of treatment. These data did not reveal any different measurements for the main M-mode echocardiographic parameters before and after 3 months of treatment. This observation was the same as the one described by Rush et al33 in a retrospective study with metoprolol in acquired heart disease in dogs. In fact, the utilization of other methods with different sensibilities to evaluate the remodeling effects during the carvedilol treatment could be the explanation for these different results. Another limitation of the study could be the short period of follow-up or the controversial therapeu-

tic dose of carvedilol used in this preliminary study, or both, compelling us to, in the future, extend the time of treatment and use different doses to better evaluate the carvedilol treatment in dogs with CMVD.

Footnotes a

Gordon SG, Bahr A, Miller MW, et al. Short-term hemodynamic effects of chronic oral carvedilol in Cavalier King Charles Spaniels with asymptomatic chronic degenerative valve disease. Proceedings of the 23rd Annual ACVIM forum 2005 b Oyama MA, Sisson DD, Bulmer BJ, et al. Effect of carvedilol in dogs with dilated cardiomyopathy: results from a prospective placebo-controlled randomized clinical trial. Proceedings of the 24th Annual ACVIM forum 2006 c Aloka SSD 650 ultrasound system, Aloka Inc, Tokyo, Japan d Hill’s canine h/d, Pet Nutrition, Topeka, KS e Purina cardiovascular formula, Ralston Purina do Brasil, SP, Brasil f Royal Canin early cardiac, Royal Canin, SP, Brasil g Angiocath, Becton Dickinson, Juiz de Fora, Brazil h High-performance liquid chromatography, 515, with electrochemical detector, Waters Corp, Milford, MA i Cobas Integra 700, Roche, Mannheim, Germany j Medmega DV-610, Medmega, Sa˜o Paulo, Brazil k Ecafix model E.C.G.-6, Ecafix , Sa˜o Paulo, Brazil

Acknowledgments We thank Lilian Caram Petrus, DVM, MSc, from Sena Madureira Veterinary Hospital for the Doppler echocardiographic examinations; Elizaˆngela Rodrigues Lima, DVM, Sena Madureira Veterinary Hospital, for the radiographic examinations, and Vilma Zaidan Dagli for the English revision of this paper. Supported by the Research Fund from Clinical Laboratory—Heart Institute (InCor), University of Sa˜o Paulo, Medical School, Sa˜o Paulo, Brazil.

References 1. Levine TB, Francis GS, Goldsmith SR, et al. Activity of sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982;49:1659–1666. 2. Ware WA, Lund DD, Subieta AR, et al. Sympathetic activation in dogs with congestive heart failure caused by chronic mitral valve disease and dilated cardiomyopathy. J Am Vet Med Assoc 1990;197:1475–1481. 3. Sisson D, Kittleson MD. Management of heart failure: principles of treatment, therapeutics strategies and pharmacology. In: Fox PR, Sisson D, Moı¨se NS, eds. Textbook of Canine and Feline Cardiology—Principles and Clinical Practice, 2nd ed. Philadelphia: WB Saunders; 1999:216–250. 4. Ishise H, Asanoi H, Ishizaka S, et al. Time course of sympathovagal imbalance and left ventricular dysfunction in conscious dogs with heart failure. J Appl Physiol 1998;84: 1234–1241. 5. Sisson DD. Neuroendocrine evaluation of cardiac disease. Vet Clin North Am Small Anim Pract 2004;34:1105–1126.

Carvedilol in Dogs 6. Dorn GW. Adrenergic pathways and left ventricular remodeling. J Card Fail 2002;8(Suppl):S370–S373. 7. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978;41:233–243. 8. Francis GS, Goldsmith SR, Cohn JN. Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure. Am Heart J 1982;104:725–731. 9. Bristow MR. The adrenergic nervous system in heart failure. N Engl J Med 1984;311:850–851. 10. Ross RD, Daniels SR, Schwartz DC, et al. Plasma norepinephrine levels in infants and children with congestive heart failure. Am J Cardiol 1987;59:911–914. 11. Rector TS, Olivari MT, Levine TB, et al. Predicting survival for an individual with congestive heart failure using the plasma norepinephrine concentration. Am Heart J 1987;114:148–152. 12. Abraham WT, Hensen J, Schrier RW. Elevated plasma noradrenaline concentrations in patients with low-output cardiac failure: dependence on increased noradrenaline secretion rates. Clin Sci (Lond) 1990;79:429–435. 13. Patel MB, Stewart JM, Loud AV, et al. Altered function and structure of the heart in dogs with chronic elevation in plasma norepinephrine. Circulation 1991;84:2091–2100. 14. Sato N, Vatner SF, Shen YT, et al. Effects on cardiac denervation on development of heart failure and catecholamine desensitization. Circulation 1997;95:2130–2140. 15. Houle MS, Billman GE. Low-frequency component of heart rate variability spectrum: a poor marker of sympathetic activity. Am J Physiol 1999;276:H215–H223. 16. Ohtsuka S, Suzuki S, Ishikawa K, et al. Norepinephrine release is increased in the hibernating heart, studied in a chronic model of myocardial hibernation. J Cardiovasc Pharmacol 2000;36(Suppl 2):S35–S41. 17. Stewart JM, Patel MB, Wang J, et al. Chronic elevation of norepinephrine in conscious dogs produces hypertrophy with no loss of LV reserve. Am J Physiol 1992;262:H331–H339. 18. Mann DL, Kent RL, Parsons B, et al. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992;85:790–804. 19. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349–1355. 20. Bristow MR. Mechanism of action of beta-blocking agents in heart failure. Am J Cardiol 1997;80:26L–40L. 21. Benedict CR, Shelton B, Johnstone DE, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. Circulation 1996;94:690–697. 22. Sawangkoon S, Miyamoto M, Nakayama T, Hamlin RL. Acute cardiovascular effects and pharmacokinetics of carvedilol in healthy dogs. Am J Vet Res 2000;61:57–60. 23. Abbott JA, Broadstone RV, Ward DL, Pyle RL. Hemodynamic effects of orally administered carvedilol in healthy conscious dogs. Am J Vet Res 2005;66:637–641. 24. Arsenault WG, Boothe DM, Gordon SG, et al. Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs. Am J Vet Res 2005;66:2172–2176. 25. Gordon SG, Arsenault WG, Longnecker M, et al. Pharmacodynamics of carvedilol in conscious, healthy dogs. J Vet Intern Med 2006;20:297–304. 26. Uechi M, Sasaki T, Ueno K, et al. Cardiovascular and renal effects of carvedilol in dogs with heart failure. J Vet Med Sci. 2002;64:469–475. 27. Tsutsui H, Spinale FG, Nagatsu M, et al. Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest 1994;93:2639–2648.

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28. Nemoto S, Hamawaki M, De Freitas G, Carabello B. A. Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation. J Am Coll Cardiol 2002;40:149–154. 29. Tallaj J, Wei CC, Hankes GH, et al. Beta 1-adrenergic receptor blockade attenuates angiotensin II-mediated catecholamine release into the cardiac interstitium in mitral regurgitation. Circulation 2003;108:225–230. 30. Ha¨ggstro¨m J, Kvart C, Pedersen HD. Acquired valvular heart disease. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. St. Louis: Elsevier Saunders; 2005:1022–1036. 31. Fuji Y, Wakao Y. Spectral analysis of heart rate variability in dogs with mild mitral regurgitation. Am J Vet Res 2003;64:145–148. 32. Marcondes Santos M, Strunz CM, Larsson MH. Correlation between activation of the sympathetic nervous system estimated by plasma concentrations of norepinephrine and Doppler echocardiographic variables in dogs with acquired heart disease. Am J Vet Res 2006;67:1163–1168. 33. Rush EJ, Freeman LM, Hiler C, Brown DJ. Use of metoprolol in dogs with acquired cardiac disease. J Vet Cardiol 2002;4:23–28. 34. Freeman LM, Rush JE, Farabaugh AE, Must A. Development and evaluation of a questionnaire for assessing healthrelated quality of life in dogs with cardiac disease. J Am Vet Med Assoc 2005;226:1864–1868. 35. Bu¨hler HU, da Prada M, Haefely W, et al. Plasma adrenaline, noradrenaline and dopamine in man and different animal species. J Physiol 1978;276:311–320. 36. Yui Y, Fujita T, Yamamoto T, et al. Liquid-chromatographic determination of norepinephrine and epinephrine in human plasma. Clin Chem 1980;26:194–196. 37. Krstulovic AM. Investigations of catecholamine metabolism using high-performance liquid chromatography. J Chromatogr 1982;229:1–34. 38. Davies CL, Molyneux SG. Routine determination of plasma catecholamines using reversed-phase ion-pair high-performance liquid chromatography with electrochemical detection. J Chromatogr 1982;231:41–51. 39. Bouloux P, Perrett D, Besser GM. Methodological considerations in the determination of plasma catecholamines by highperformance liquid chromatography with electrochemical detection. Ann Clin Biochem 1985;22:194–203. 40. Chetboul V, Tidholm A, Nicolle A, et al. Effects of animal position and number of repeated measurements on selected twodimensional and M-mode echocardiographic variables in healthy dogs. J Am Vet Assoc 2005;227:743–747. 41. Thomas WP, Gaber CE, Jacobs GJ, et al. Recommendations for standards in transthoracic two-dimensional echocardiography in the dog and cat. J Vet Intern Med 1993;7:247–252. 42. Boon JA. The echocardiographic examination. In Boon JA, ed. Manual of Veterinary Echocardiography. Baltimore: Williams & Wilkins; 1998:151–260. 43. Brown DJ, Rush JE, MacGregor J, et al. M-mode echocardiographic ratio indices in normal dogs, cats, and horses: a novel quantitative method. J Vet Intern Med 2003;17:653–662. 44. Remillard RL, Ross JN, Eddy JB. Variance of indirect blood pressure measurements and prevalence of hypertension in clinically normal dogs. Am J Vet Res 1991;52:561–565. 45. Stepien RL, Rapoport GS. Clinical comparison of three methods to measure blood pressure in nonsedated dogs. J Am Vet Med Assoc 1999;215:1623–1628. 46. McTavish D, Campoli-Richards D, Sorkin EM. Carvedilol: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1993;45:232–258.