Cardiomiopatia 3

8/6/2019 Cardiomiopatia 3

1/3

Nutrition and Disease

Antioxidant Status in Dogs with Idiopathic Dilated Cardiomyopathy1,2

Lisa M. Freeman,3 Don J. Brown and John E. Rush

Department of Medicine, Tufts University School of Veterinary Medicine, North Grafton, MA 01536

EXPANDED ABSTRACT

KEY WORDS: antioxidant dilated cardiomyopathy glutathione peroxidase dogs

Free radicals, metabolites of oxygen metabolism, are pro-duced under normal conditions, but their rate of productiondoes not exceed the capacity of the body to catabolize them. Itis only when the natural defenses are overwhelmed that free

radical damage occurs. Therefore, the hosts endogenous anti-oxidant system plays a major role in the prevention or limi-tation of myocardial damage. Endogenous antioxidants in-clude enzymatic antioxidants (e.g., superoxide dismutase orglutathione peroxidase), free radical scavengers (e.g., vitaminsA, C or E) and metal chelators. Antioxidants also can bederived exogenously through the diet or through the use ofsupplements.

Free radical-induced injury has been implicated in thedevelopment of a number of cardiac diseases, including coro-nary artery disease, myocardial infarction and some forms ofcardiomyopathy in people and laboratory animals (Kaul et al.1993). Free radicals not only have cytotoxic effects on themyocardium, but also act as negative inotropes (Prasad et al.

1993). Altered antioxidant status has been identified in anaortic banding model of congestive heart failure, with elevatedlevels during cardiac hypertrophy and decreased levels in fail-ure (Dhalla and Singal 1994, Gupta and Singal 1989). Similarchanges have been seen in other human diseases such asinflammatory bowel disease and human immunodeficiency vi-rus (Delmas-Beauvieux et al. 1996, Hoffenberg et al. 1997).Elevated mean vitamin A concentration was found in catswith dilated cardiomyopathy compared with healthy controls(Fox et al. 1993). Whether these alterations contribute todisease progression or reflect a compensatory response to in-creased free radical stress is unclear at present.

The purpose of this pilot study was to determine antioxi-dant status in dogs with idiopathic dilated cardiomyopathy

(IDCM)4 compared with healthy controls.

Materials and methods. Antioxidant status in canine

IDCM. All dogs were client-owned animals. A diagnosis ofIDCM was based on the presence of left atrial enlargement anda fractional shortening28% (22% in Doberman pinschers)

on 2-D and M-mode echocardiography. Controls were age-and weight-matched to the IDCM dogs. Dogs with majorconcurrent diseases, such as cancer, chronic renal failure andhepatic failure were excluded from the study. Owners signed aconsent form before enrolling their dogs in the study. Thestudy was approved by the Tufts University Animal Care andUse Committee.

Blood (10 mL) was collected in EDTA, centrifuged andseparated within 20 min. Fasting levels of vitamins A (reti-nol), C (ascorbic acid) and E (-tocopherol) were measured inplasma; glutathione peroxidase and superoxide dismutase weremeasured in washed erythrocytes. Vitamins A, C and E weredetermined by reverse-phase HPLC, and glutathione peroxi-dase was analyzed using a Cobas Fara II centrifugal analyzer

(Roche Diagnostics Systems, Nutley, NJ). Superoxide dis-mutase was determined by a commercial spectrophotometricassay (SOD-525, Bioxytech, Cedex, France). Dietary vitaminsA and E were calculated based on manufacturers data (IU/kgdiet on a dry matter basis) for dogs eating commercial dogfoods. One dog, which ate a homemade diet, was excludedfrom determinations of dietary vitamins. Mean antioxidantconcentrations between the IDCM and control groups werecompared using Students t test; Pearson correlation was usedto identify potential correlations between disease severity andantioxidant concentrations. Results were considered signifi-cant when the two-tailed P- value was 0.05.

Results. Twelve dogs with IDCM and 11 healthy controlswere enrolled in the study. Mean age of the IDCM dogs was

8.9 2.5 y compared with 7.9 1.9 y in the control group (P 0.21). Body weight also was not different between thegroups (46.0 18.3 kg for the IDCM group vs. 40.2 6.9 kgfor the controls; P 0.57). All control dogs and 11 of the 12IDCM dogs ate commercial dry diets; one IDCM dog ate ahomemade diet. In the IDCM group, one dog was classified as New York Heart Association (NYHA) Class I, four were NYHA Class II, five were NYHA Class III, and two were NYHA Class IV. An arrhythmia was detected in 11 of 12IDCM dogs (and 0 of 11 controls). The arrhythmia was atrial

1 Presented as part of the Waltham International Symposium on Pet Nutritionand Health in the 21st Century, Orlando, FL, May 26 29, 1997. Guest editors forthe symposium publication were Ivan Burger, Waltham Centre for Pet Nutrition,Leicestershire, UK and DAnn Finley, University of California, Davis.

2 Supported in part by Hills Pet Nutrition.3 To whom correspondence should be addressed.4 Abbreviations used: ACEI, angiotensin converting-enzyme inhibitor; IDCM,

idiopathic dilated cardiomyopathy; NYHA, New York Heart Association.

0022-3166/98 $3.00 1998 American Society for Nutritional Sciences. J. Nutr. 128: 2768S2770S, 1998.

2768S

byonO

ctober23,2006

jn.nutrition.org

Downloadedfrom
http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/http://jn.nutrition.org/


2/3

fibrillation in six dogs and ventricular premature complexes infive dogs. Medication regimens included an angiotensin-con-verting enzyme inhibitor (ACEI) and a -blocker (n 3);ACEI, furosemide, digoxin and a -blocker (n 6); and

ACEI, furosemide, digoxin and diltiazem (n

3). Meanechocardiographic measurements in the IDCM group areshown in Table 1.

Circulating antioxidant levels are shown in Table 2. Eryth-rocyte glutathione perioxidase concentrations were measuredin only 21 of 23 dogs due to technical difficulties (11 dogs withIDCM and 10 controls). Mean erythrocyte glutathione perox-idase concentration was significantly higher in IDCM dogs(159.5 19.8 U/g Hb) compared with controls (138.4 14.4U/g Hb; P 0.01). There was a trend for higher concentra-tions of plasma vitamin A and vitamin C in the IDCM groupas well, but these did not reach significance (P 0.12 and P 0.11, respectively). There was no difference between groupsin plasma vitamin E or erythrocyte superoxide dismutase.There was a trend for higher levels of dietary vitamin A in theIDCM group (32488 11481 IU/kg) compared with the con-trols (22775 3005 IU/kg; P 0.07), although there was nocorrelation between dietary vitamin A and circulating vitaminA. There was no difference between groups in dietary vitaminE levels (343 222 IU/kg for IDCM dogs vs. 275 124 IU/kgfor controls; P 0.48).

Disease severity (NYHA Class) was related to circulatingantioxidants. There was a significant correlation betweendisease severity and erythrocyte glutathione peroxidase,both when severity was measured by NYHA Class (r 0.52, P 0.02) and when severity was measured by end-systolic volume index (r 0.60; P 0.009; Fig. 1). New

York Heart Association Class was associated with plasmavitamin C (r 0.49; P 0.02). Class also was correlatedwith dietary vitamin A (r 0.47; P 0.05). There was nosignificant correlation between disease severity and plasmavitamin A, plasma vitamin E, erythrocyte superoxide dis-mutase or dietary vitamin A.

Discussion. The results of this pilot study suggest thatalterations in some aspects of the endogenous antioxidantsystem exist in dogs with IDCM, especially for circulatingglutathione peroxidase and vitamin C. These results con-tradict those found using a rodent model of cardiac hyper-trophy, in which reduced levels of antioxidants were foundin animals with congestive heart failure (Gupta and Singal1989). The cause for this discrepancy is unknown, but it islikely related to the disease model because at least twohuman studies demonstrated elevated antioxidant concen-trations in inflammatory bowel disease and human immu-nodeficiency virus (Delmas- Beauvieux et al 1996, Hoffen-berg et al 1997). Whether these alterations, similar to thosein our study, are a primary or secondary occurrence is

currently unknown. Elevations in antioxidant levels may bea marker of a compensatory response to increased oxidantstress. The elevations also may be secondary to medicationsused in the therapy of IDCM. On the other hand, thesealterations in antioxidant status may play a role in thedevelopment or progression of disease. Either way, furtherstudy of these changes is warranted.

This study also identified trends for higher dietary intakes ofvitamin A in dogs with IDCM and a correlation betweendietary vitamin A and disease severity. The most likely causefor these weak relationships is that as cardiac disease becomesmore severe, a reduced-sodium cardiac diet is more likely to beprescribed. These diets tend to contain high levels of vitaminA. Additional studies will be necessary to determine whether

circulating levels of antioxidants accurately reflect tissue con-centrations. For example, there are known to be some differ-

TABLE 1

Mean echocardiographic measurements in dogs with

idiopathic dilated cardiomyopathy (n 12).

Mean SD

Left atrium, cm 3.5 0.7

Aorta, cm 2.9

0.4Left ventricular internal dimension in diastole, cm 5.7 0.9Left ventricular internal dimension in systole, cm 4.6 0.9End-diastolic volume index,1 mL/m2 175 118End-systolic volume index,2 mL/m2 86 54Fractional shortening, % 18.1 6.3

1 (Left ventricular internal dimension in diastole)3/body surface area.2 (Left ventricular internal dimension in systole)3/body surface area.

TABLE 2

Mean circulating antioxidant concentrations in dogs with

idiopathic dilated cardiomyopathy (IDCM) and controls1

IDCM(n 12)

Controls(n 11)

P-value

Vitamin A, mol/L 4.0 1.7 3.1 1.1 0.12 Vitamin C, mol/L 43.15 16.47 34.07 7.38 0.11 Vitamin E, mol/L 49.6 23.1 50.4 18.8 0.92Superoxide dismutase,

U/g Hb 2280 470 2071 412 0.27Glutathione peroxidase,

U/g Hb 159.5 19.8 138.4 14.4 0.01

1 Values are mean SD.

FIGURE 1 Comparison of disease severity [based on end-systolic

volume index (ESVI)] and glutathione peroxidase (GPX) concentrations

in dogs with idiopathic dilated cardiomyopathy (n 11) and controls

(n 10); *ESVI (left ventricular internal dimension in systole)3/body

surface area.

ANTIOXIDANT STATUS IN CANINE IDCM 2769S

byonO

ctober23,2006

jn.nutrition.org

Downloadedfrom


3/3

ences in the myocardial vs. the circulating antioxidant systembecause catalase is produced only in very low levels in theheart (Janssen et al. 1993).

In summary, dogs with IDCM had elevated concentrationsof erythrocyte glutathione peroxidase, which were correlatedwith disease severity. Plasma vitamin C and dietary vitamin Aalso correlated with disease severity. Future studies will berequired to determine the significance of these findings, whichmay be secondary to IDCM and its therapy or may play animportant role in the development and progression of thedisease.

LITERATURE CITED

Delmas-Beauvieux, M, Peuchant, E., Couchouron, A., Constans, J., Sergeant, C.,Simonoff, M., Pellegrin, J., Leng, B., Conri, C. & Clerc, M. (1996) Theenzymatic antioxidant system in blood and glutathione status in human

immunodeficiency virus (HIV)-infected patients: effects of supplementation

with selenium or -carotene. Am. J. Clin. Nutr. 64: 101107.Dhalla, A. K. & Singal, P. K. (1994) Antioxidant changes in hypertrophied and

failing guinea pig hearts. Am. J. Physiol. 266: H1280H1285.Fox, P. R., Trautwein, E. A., Hayes, K. C., Bond, B. R., Sisson, D. D. & Moise, N. S.

(1993) Comparison of taurine, -tocopherol, retinol, selenium, and totaltriglycerides and cholesterol concentrations in cats with cardiac disease and

in healthy cats. Am. J. Vet. Res. 54: 563569.Gupta, M. & Singal, P. K. (1989) Higher antioxidant capacity during a chronic

stable heart hypertrophy. Circ. Res. 64: 398406.

Hoffenberg, E. J., Deutsch, J., Smith, S. & Sokol, R. J. (1997) Circulatingantioxidant concentrations in children with inflammatory bowel disease.

Am. J. Clin. Nutr. 65: 14821488.

Janssen, M., Van der Meer, P. & De Jong, J. W. (1993) Antioxidant defensesin rat, pig, guinea pig, and human hearts: comparison with xanthine oxi-

doreductase activity. Cardiovasc. Res. 27: 20522057.Kaul, N., Siveski-Iliskovic, N., Hill, M., Slezak, J. & Singal, P. K. (1993) Free

radicals and the heart. J. Pharmacol. Toxicol. Methods 30: 5567.Prasad, K., Kalra, J. & Bharadwaj, L. (1993) Cardiac depressant effects of

oxygen free radicals. Angiology 44: 257270.

SUPPLEMENT2770S

byonO

ctober23,2006

jn.nutrition.org

Downloadedfrom

Cardiomiopatia 3

Documents

Transcript of Cardiomiopatia 3