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1 Idiopathic Dilated Cardiomyopathy in Dogs: Survival and Prognostic Indicators Eric Monnet, E. Christopher Orton, Mo Salman, and June Boon To further define the prognosis and identify clinical findings predictive for survival in dogs with dilated cardiomyopathy (DCM), we performed Kaplan Meier survival analysis of 37 dogs with idiopathic DCM. Survival analysis showed that the 50% probability of survival occurred at.3 months. Probability of survival at 1 year was 37.5% and at years was 8%. Bivariate Cox proportional hazard ratios identified pleural effusion and pulmonary edema, both signs of congestive heart failure, as independent prognostic indicators for dogs with DCM (P <.01). Hazard ratios for these prognostic indicators were.354 and 3.91, respectively. Multivariate Cox stepwise regression identified pleural effusion, left ventricular free-wall thickening fraction, ventricular ectopy, and weight loss as significant prognostic indicators for dogs with DCM. Because of the retrospective nature of this study, the effects of different drug treatments were not evaluated. The type of cardiac-related death, progressive failure versus sudden death, was not addressed in this study and requires further evaluation. J Vet Intern Med 1995;9:1-17. Copyright by the American College of Veterinary Internal Medicine. diopathic dilated cardiomyopathy (DCM) is a pri- I mary myocardial disorder characterized by left ventricular dilation without wall thickening, poor left ventricular systolic hnction, and ventricular ectopy. 1-3 DCM occurs most commonly in certain medium and large breed dogs and causes progressive congestive heart failure (CHF) or sudden death in these breeds.34 The etiology of DCM in dogs is unknown and could be different among the various breeds. The prognosis for survival of dogs with DCM reportedly is p ~or.~,~ Several factors potentially predictive of survival in dogs with DCM have been suggested including breed, class of heart failure, presence of cardiac arrhythmias, and echocardiographic in dice^.^.^ To further define the prognosis and identify potential prognostic factors predictive of survival, we performed survival analysis of 37 dogs meeting diagnostic criteria for idiopathic DCM. Materials and Methods \ Medical records of dogs diagnosed with idiopathic DCM at Colorado State University Veterinary Teaching Hospital between 1986 and were evaluated retrospectively. En- From the Department of Clinical Sciences, Colorado State University, Fort Collins, CO. Accepted April 1, Reprint requests: E. Christopher Orton, DVM, PhD, Department of Clinical Sciences, Colorado State University, Fort Collins, CO Copyright 0 I995 by the American College of Veterinary Internal Medicine /95/ $3.00/0 try criteria for inclusion in this study were (1) radiographic or M-mode echocardiographic evidence of left ventricular heart enlargement (left ventricular end-diastolic dimension >44 mm/m), () decreased left ventricular shortening fraction (<5%) on M-mode echocardiography, (3) normal or less than normal left ventricular free-wall thickness on M- mode echocardiography, and (4) absence of imaging lesions of the cardiac valves on two-dimensional echocardiography. Dogs with doxorubicin-induced cardiomyopathy were excluded from this study. Entry time was established as the time ofthe first echocardiogram confirming the diagnosis of DCM. Survival times were determined from records of clinic visits or by telephone contact with the owner or referring veterinarian. The cause of death was recorded as related or unrelated to cardiac disease. Dogs that died from causes unrelated to cardiac disease or that were alive at the end of the study period were censored in the analysis. Dogs euthanized because of progressive heart failure were counted as deaths related to cardiac disease and were not censored. Animals with stable heart disease at the time of euthanasia were not included in the study. The cut-off date for survival analysis was January 199. The product limit method of Kaplan Meier was used to construct a survival curve.6 The 50% probability of survival time point and mortality rates at 1 and years were determined from the survival curve. Twenty-seven discrete and continuous diagnostic vanables from the signalment, cardiac history, physical examination, thoracic radiographs, electrocardiogram (ECG), and echocardiogram obtained at the time of initial diagnosis were evaluated as potential prognostic indicators of survival (Tables 1 and ). Modified New York Heart Association classification of heart failure at presentation was evaluated according to the following: class I, cardiac disease but no evidence of heart failure; class 11, cardiac-related exercise intolerance; class 111, signs of heart failure during normal activity; class IV, signs of heart failure at rest, syncope, or cardiogenic shock.7 Cox proportional hazard analysis was 1 Journal of Veterinary Internal Medicine, Vol9, No 7 (January-February), 7 995: pp 1-7 7

2 ~~ IDIOPATHIC DILATED CARDIOMYOPATHY 13 Table 1. Frequency of Analyzed Discrete Variables Obtained From Signalment, Cardiac History, Physical Examination, ECG, Thoracic Radiographs, and Class of Heart Failure in 37 Dogs With Dilated Cardiomyopathy Variable Number of Dogs Frequency (%) Signalment Breeds Doberman Pincher Great Dane Labrador Retriever Cocker Spaniel Male Cardiac History Weight loss Syncope Exercise intolerance Physical Examination Gallop rhythm Ascites Systolic murmur ECG Atrial fibrillation Ventricular ectopy Ventricular tachycardia Thoracic Radiographs Left ventricular enlargement Biventricular enlargement Pulmonary venous congestion Pulmonary edema Pleural effusion Functional Class of Heart Failure I II Ill IV \ performed on each variable to determine its association with survival.' A proportional hazard ratio was calculated for each variable as a measure of the magnitude of the effect that the variable had on survival. A 90% confidence interval was calculated for each hazard ratio. Hazard ratio intervals Table. Mean f SD of Echocardiographic Variables Analyzed From 37 Dogs With Dilated Cardiomyopathy Variable Left ventricular end-diastolic diameter (mm/m)* Left ventricular end-systolic diameter (mm/m) Shortening fraction (%) Ejection fraction (%) Left ventricular end-diastolic wall thickness (mm/m) Left ventricular end-systolic wall thickness (mrn/m) Thickening fraction (%) Left ventricular end-diastolic wall thickness/ diameter * Mean body surface area was: mz. Mean i SD 56.4i t k i t.04 Table 3. Cardiac Drugs Used in the Management of 37 Dogs With Dilated Cardiomyopathy Drug No ofdogs Frequency (%) Digoxin Furosemide Captopril Hydralazine Propranolol Procainamide 54 that did not include 1.O were considered significant. A forward stepwise Cox regression analysis was used to construct a multivariate model predictive of survival. The Epidemiology, Graphics, Estimation, and Testing (EGRET, Statistic and Epidemiology Research Corporation, 909 Northerst Road St, Suite 3 10, Seattle, WA) package was used to construct the Kaplan Meier survival curves and to calculate the proportional hazard ratios. Cardiac drugs used during the course of therapy for CHF and cardiac arrhythmias were recorded, but no attempt was made to correlate therapy with survival. Therapy included rest, digoxin, low sodium diet, furosemide, captopril, hydralazine, propranolol, and procainamide (Table 3). Digoxin was administered to all dogs that survived for 1 week or more after presentation. Dogs in atrial fibrillation were administered digoxin with or without propranolol, as needed to reduce the ventricular rate below 150 beats/min. Congestive heart failure was treated with a low sodium diet, furosemide, captopril, or combinations of these. Some dogs received afterload reduction with captopril or hydralazine at the discretion of the attending veterinarian. Two dogs with ventricular ectopy received procainamide. Results Thirty-seven dogs met diagnostic criteria for DCM during the time period of this study. Twenty-six dogs died during the study period for reasons related to cardiac disease, 4 dogs died for reasons unrelated to cardiac disease, 6 dogs were alive at the end of the study period, and 1 dog was lost to follow up after 15 days. Median survival time was 65 days. The 50% probability of survival for dogs with DCM occurred at.3 months (Fig 1). Probability of survival at 1 year was 37:5%, and at years it was 8%. The frequency of discrete diagnostic variables obtained from the signalment, cardiac history, physical examination, ECG, and thoracic radiographs, as well as the class of heart failure, is shown in Table 1. The median age for dogs in this study was 7 years (range 1 to I3 years). The mean values of continuous echocardio-

3 14 MONNET ET AL =I m 1.oo n - > cc > v) TIME (MONTHS) Fig 1. Actuarial survival curve for 37 dogs with idiopathic dilated cardiomyopathy. The 50% and 1 -year probabilities of survival are indicated by dotted lines. Censored animals are indicated with vertical bars. graphic variables are reported in Table. The distribu- - - tion of the shortening fraction (SF) was 8 dogs with SF <5%, 6 dogs with SF between 6% and lo%, 1 dogs with SF in between 1 1 % and 15%, 9 dogs with SF between 16% and 0%, and 4 dogs with SF in between 1% and 5%. The frequency of cardiac drugs used in treatment of these dogs are reported in Table 3. Hazard ratios and 90% confidence intervals calculated from bivariate Cox proportional htzard analysis of diagnostic variables are reported in table 4. Of the 7 discrete and continuous diagnostic variables evaluated, only pleural effusion and pulmonary edema were significant independent prognostic indicators for survival. Kaplan Meier survival curves for these two prognostic indicators are shown in Figs and 3. Multivariate Cox stepwise regression analysis showed that the most significant independent predictive variable, pleural effusion, was strengthened by the addition of left ventricular thickening fraction, ventricular ectopy, and weight loss to the equation. Hazard ratios and 95% confidence intervals for the multivariate model are shown in Table 5. Discussion Entry criteria for this study were based on those previously reported for the diagnosis of DCM in the d~g.'.~.~ The criterion of left ventricular dilation was based on radiographic interpretation and the upper 95% confidence limit for left ventricular end diastolic Table 4. Ninety Percent Confidence Intervals and Bivariate Cox Proportional Hazard Ratios for Discrete and Continuous Variables From 37 Dogs With Cardiomyopathy Variable 90% Confidence Interval Hazard Ratio Pulmonary edema ' Pleural effusion ' Ventricular tachycardia Gallop rhythm Heart failure class IV Dobgrman Ventricular ectopy Ascites Syncope Male Heart failure class Ill or IV Weight loss Left ventricular end diastolic wall thickness Left ventricular end systolic wall thickness Biventricular enlargement (Radiographic) Age (vr) Left ventricular end-systolic diameter Pulmonary venous congestion Left ventricular end-diastolic diameter Thickening fraction ,9966 Ejection fraction ,9954 Shortening fraction ,9891 Atrial fibrillation.41.16,944 Murmur ,7390 Left ventricular enlargement (Radiographic) Exercise intolerance ,6374 Significant variable (P <.1). m B a.oo 1 I PLEURAL EFFUSION I EFFUSION TIME (MONTHS) Fig. Actuarial survival curves for dogs (idiopathic dilated cardiomyopathy) with and without pleural effusion. The curves were significantly different (P<.01).

4 IDIOPATHIC DILATED CARDIOMYOPATHY 15 dimension as determined from 65 normal dogs. The upper confidence limit of 44 mm/mz is consistent with previously published values for normal A shortening fraction of <5% was chosen as an entry criterion because this value was relatively conservative among the various published criteria for diagnosing DCM in dogs. This study confirmed the clinical impression of many authors that DCM in dogs generally carries a poor prognosis, considering that median survival occurred at just over months. However, this study also suggests that dogs that survive more than 7 months have a good probability of becoming long-term survivors, with some living as long as 40 months after the diagnosis. The biphasic nature of the survival curve for dogs with DCM is interesting and suggests that there may be disparity in the severity of disease at the time of initial diagnosis. This may reflect in part different degrees of awareness of cardiac signs by owners. It also may relate to the probable multifactorial nature of DCM. Limitations of the current study include the inability to absolutely exclude concurrent cardiac conditions that could have effected outcome, the inclusion of euthaqasia as an endpoint for cardiacrelated death, the retrospective nature of the study and lack of a standardized treatment protocol, and the relatively small sample size. Dogs with obvious aortic or mitral valve lesions identified on two-dimensional echocardiography were excluded from the study. Further, left ventricular wall thickness was considered an entry criterion in an attempt to identify dogs with primary volume overload and secondary myocardial failure. Dogs with 1.00n TIME (MONTHS) Fig 3. Actuarial survival curves for dogs (idiopathic dilated cardiomyopathy) with and without pulmonary edema. The curves were significantly different (P<.01). Table 5. Multivariate Cox Regression Model of Survival for Dogs With Dilated Cardiornyopathy 95% Confidence Hazard Parameter Interval Ratio Pleural effusion Thickening fraction.94.99,9663 Ventricular ectopy Weight loss mitral insufficiency judged to be secondary to dilation of the valve annulus were included in the study. It is possible that dogs with concurrent primary volume overload and primary myocardial failure could have been included in the study. Special studies to identify specific myocardial metabolic defects such as L-carnitine deficiency were not undertaken. The issue of how to handle euthanasia in a veterinary survival study is difficult and controversial, and raises an important potential limitation of this study. One way to deal with this issue is to exclude all animals that were euthanized. However, because euthanasia is often prompted by progressive CHF, this approach would eliminate many cases, even those dogs that were treated aggressively but failed to respond. Another approach is to include but censor dogs that were euthanized. Censoring treats these dogs statistically the same way survivors or dogs that die from causes unrelated to cardiac disease are treated. This also could be misleading since dogs that are euthanized because owners and veterinarians felt they were hours or days away from death are not counted as true cardiac deaths. In this study, dogs that were euthanized because of their cardiac condition were counted as cardiac-related deaths. This approach may have influenced survival times because different owners may have been committed to treatment to different degrees. Another limitation of this retrospective study is that therapy was not standardized. Two drugs used in this study, hydralazine and captopril, have been shown to improve survival in humans with chronic heart failure.i,i3 These drugs were not routinely administered during the period of this study, and this could have affected survival in some cases. A prospective study with a standardized treatment protocol would be necessary to determine the effect of therapy on survival. Pleural effusion, identified by thoracic radiography, was the most significant prognostic indicator of survival in this study, even though the amount of effusion in each case was considered mild. Pleural effusion is

5 16 MONNET ET AL reported to be a frequent finding in dogs with DCM; however, no relationship between this finding and prognosis has been established previo~sly.~ Studies in dogs suggest that pleural effusion is most likely to occur when systemic interstitial pressures are e1e~ated.i~ It is tempting to suggest that pleural effusion may be a prognostic indicator for dogs with DCM because it is most likely to occur in dogs with biventricular CHF. Pulmonary edema was also found to be predictive of survival in dogs with DCM, suggesting that dogs presenting with this problem may have a poorer prognosis than dogs presented for other problems such as exercise intolerance, collapse, or syncope. Pulmonary edema, which may be a sign of advanced DCM, has been suggested to indicate a poor prognosis in Doberman Pinchers with DCM.3 Increased pulmonary wedge pressure has been reported as a significant risk factor in humans with DCM Other clinical findings thought to be important based on clinical impression, including the Doberman Pincher breed and echocardiographic indices of systolic function, were not found to be significant independent prognostic indicators in this study. Because the number of dogs studid was relatively small, it is possible that a larger study would identify significant breed-related prognostic indicators. Decreased shortening fraction, an essential criterion for diagnosis of DCM, was not a significant prognostic indicator for dogs in this study. This finding was in agreement with studies of human patients with dilated cardiomyopathy that show that echocardiographic indices of cardiac function are not good predictors of survival Increased E point to septa1 separation, which has been recognized as a consistent finding in Doberman Pinchers with DCM,3 was not evaluated in this study. Ventricular ectopy may increase mortality in both humans and dogs with DCM,3,4,18,19 but was not an independent prognostic indicator in this study. There are some limitations to the use of the in-hospital ECG. The in-hospital ECG could overestimate ventricular ectopy if recorded during a period of stress or, very likely, could underestimate ventricular ectopy because information is collected over just a few minutes. Holter ECG analysis would more accurately evaluate ventricular ectopy in dogs with DCM. Interestingly, although echocardiographic variables and ventricular ectopy were not independent indicators of prognosis, both left ventricular free-wall thickening fraction and presence of ventricular ectopy strengthened the overall predictive value of pleural effusion in a multivariate model of survival. Dilated cardiomyopathy can lead to two distinct cardiac-related outcomes; sudden cardiac death or death from progressive heart failure. It is entirely possible that these two outcomes may have different prognostic indicators. In this regard, indices related to ventricular ectopy might be expected to be predictive of sudden cardiac death, whereas indices of cardiac function might be predictive of nonsudden cardiac death. In a study of human patients with severe heart failure, nonsustained ventricular tachycardia recorded by Holter ECG examination was an independent predictor of sudden death.'' Interestingly, in the same study, hemodynamic and echocardiographic measurements did not predict nonsudden cardiac death. In the present retrospective study, it was not possible to reliably determine whether death in each dog was sudden or not. The criteria for sudden cardiac death in human patients are quite specific: patients must be clinically stable 1 week before death and must be observed to have no acute symptoms 1 hour before death.'' A prospective study of dogs with DCM that included Holter ECG information would be valuable to determine prognostic indicators for sudden cardiac death. In summary, Kaplan Meier survival analysis of dogs with DCM confirmed the overall guarded prognosis for this condition. However, the analysis also suggests that dogs surviving beyond 7 months have a reasonable probability of becoming long-term survivors. Bivariate Cox proportional hazard ratios identified pleural effusion and pulmonary edema as independent prognostic indicators for dogs with DCM. Multivariate Cox stepwise regression implicated pleural effusion, left ventricular free-wall thickening fraction, ventricular ectopy, and weight loss as significant prognostic indicators for dogs with DCM. References 1. Abelman W. Classification and natural history of primary myocardial disease. Prog Cardiovasc Dis 1984;7: Calvert CA. Dilated congestive cardiomyopathy in Doberman pinchers. Compend Contin Educ Prac Vet 1986;8: Calvert CA, Brown J. Use of M-mode echocardiography in the diagnosis ofcongestive cardiomyopathy in Doberman Pinchers. J Am Vet Med Assoc 1986; 189: Calvert CA, Chapman WL, Total RL. Congestive cardiomyopathy in doberman pincher dogs. J Am Anim Hosp Assoc 198; 181: Calvert CA. Cardiomyopathy in the Doberman Pincher dog. California Vet 1984;38:7-1.

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