Metoprolol in dilated cardiomyopathy: is it possible to identify factors predictive of improvement? The Heart Muscle Disease Study Group.

BACKGROUND: Some controlled clinical trials showed a beneficial effect of beta-blockers on symptoms, exercise tolerance, and left ventricular function in dilated cardiomyopathy. The purpose of this study was to investigate if there are clinical variables at baseline that could predict a favorable response to long-term metoprolol therapy. METHODS AND RESULTS: Since November 1987, 94 consecutive patients with dilated cardiomyopathy and left ventricular ejection fraction less than 0.40 were treated with metoprolol (mean final dosage, 136 +/- 32 mg) associated with tailored medical therapy with digitalis, diuretics, and angiotensin-converting enzyme inhibitors. Eighty-four surviving patients had a complete 2-year noninvasive follow-up period. Ten patients died or were transplanted before the final assessment. Improvement was defined according to a clinical score based on left ventricular ejection fraction (increase > or = 10 U), left ventricular end-diastolic diameter (decrease > or = 10%), regression of restrictive filling pattern, New York Heart Association functional class, exercise tolerance (increase > or = 2 minutes), and cardiothoracic ratio (decrease > or = 10%). According to these criteria, 48 patients (51.1%) were classified as improved. Multivariate analysis identified a group of patients with a history of mild hypertension (blood pressure between 140/90 and 170/100 mmHg) and significantly higher probability of improvement with longterm metoprolol (odds ratio [OR], 2.22; 95% confidence interval, 1.25-3.94; P = .007). Among the 71 patients with normal blood pressure (< 140/90 mmHg), heart rate in upright position (100 vs 75 beats/min: OR, 2; 95% confidence interval, 1.38-4.94; P = .003), left ventricular ejection fraction 0.20-0.33 versus less than 0.20 (OR, 4.72; 95% confidence interval, 1.06-21.04; P = .042), and New York Heart Association class I-II versus III-IV (OR, 2.74; 95% confidence interval, 0.97-7.75; P = .05) were significantly associated with a positive response to metoprolol. At baseline, both supine and upright heart rate were significantly higher in patients who improved, but heart rate in the upright position was the most significant predictor of improvement in patients with normal blood pressure at multivariate analysis. CONCLUSIONS: According to the authors' logit model, patients with a history of mild hypertension or with a higher resting heart rate, associated with controlled symptoms of heart failure (New York Heart Association class I-II) or moderate to severe left ventricular ejection fraction (range, 0.20-0.33) showed a remarkable probability of long-term (2-year) improvement on metoprolol.

Nonpredictive value of fibrosis in dilated cardiomyopathy treated with metoprolol.

Therapy with ß-adrenergic blocking agents has been advocated as a potential useful approach in heart failure. Recent studies suggest that histologic parameters may be helpful in assessing the effectiveness of ß-blocker treatment in dilated cardiomyopathy (DCM). In order to predict the response to ß-blockers in DCM, fibrous tissue was evaluated at endomyocardial biopsy (EMB) in 45 patients (pts) with a mean left ventricular ejection fraction of 0.28 ± 0.07, who were successively long-term treated with metoprolol (M) (mean dosage 138 ±26 mg/die). EMB was performed from left (n = 32) or right (n = 13) ventricle by means of a King's bioptome or the Cordis adaptation of this instrument. Quantification of fibrous tissue was performed at 9 × magnification and with a computerized morphometric system. Qualitative evaluation at light microscopy distinguished four types of fibrosis: pericellular, perivascular, focal, and endocardial. Volume fraction of fibrous tissue ranged from 1.3 to 35.5% (mean 12.1 ± 9.3%) and was not significantly correlated with any clinical variable considered. After 24 ± 12 months of treatment, 25 pts were considered improved (group A), whereas the remaining 20 pts were considered not improved (group B), according to criteria based on ejection fraction, left ventricular end-diastolic diameter, filling pattern at Doppler-Echocardiography, cardiothoracic ratio, NYHA functional class, and exercise duration at ergometric test. Volume fraction of fibrous tissue did not differ significantly between the two groups (group A = 12.1 ± 9.1%; group B = 11.3 ± 9.6%;p = NS). Dominant pericellular type of fibrosis was equally distributed between the two groups (group A = 9 25 pts, 36%; group B = 10 20 pts, 50%), whereas a perivascular and/or focal replacement fibrosis was more frequent in group A (group A = 10 20 pts, 50%; group B = 2 20 pts, 10%; p = .05, OR 5.55 at univariate analysis). At multivariate analysis mean aortic blood pressure was the only variable discriminating the two groups; the type of fibrosis, although not statistically significant, maintained a high value of odds-ratio (5.23). In conclusion, extent of total fibrosis assessed by EMB may range widely in patients with DCM, is not correlated with the most important clinical variables, and is not predictive of long-term response to ß-blocker treatment. Otherwise, prevalent perivascular and/or focal replacement fibrosis could be associated with a higher probability of improvement after long-term ß-blocker treatment.

[Safety and tolerability of beta-blockers in severe cardiac decompensation from dilated cardiomyopathy]. / Tollerabilità ed effetti dei betabloccanti nello scompenso cardiaco severo da cardiomiopatia dilatativa.

BACKGROUND: Several reports from controlled and uncontrolled studies, mainly in the setting of heart failure due to dilated cardiomyopathy (DCM), indicate that chronic betablockade may improve hemodynamics and clinical function. There are few reports on the effects of betablockers in patients with severe heart failure. METHODS: Thirty-five patients (27 M; 8 F; mean age 44.3 +/- 16.7 years; range 14-66 years) with DCM, advanced functional (NYHA III-IV) and severe left ventricular dysfunction (LVEF < or = 25%) underwent a test dosage with metoprolol (5 mg b.i.d.). Five patients (14%) did not tolerate the drug; 30 were chronically treated with metoprolol (mean dosage 127 +/- mg/die). No differences in baseline characteristics were observed between tolerant and not tolerant patients, except for the E-deceleration time (103 +/- 42 ms vs 84 +/- 17 ms; p<0.05). Seven alive patients did not reach a minimum follow up of 18 months. Nineteen patients (54.3%) had a follow up of at least 18 months. They were classified as ¿improved¿ (11 pts; and ¿not improved¿ (8 pts; 42%) on the basis of a score, which included left ventricular ejection fraction (> or = 0.10), left ventricular end diastolic diameter (> or = 10%), regression of restrictive filling pattern, NYHA functional class (> or = 1), cardio-thoracic ratio (> or = 10%) and exercise time (> or = 2 min). No differences were observed at baseline between ¿improved¿ and ¿not improved¿ patients, with exception for a history of slight hypertension (p<0.01), congestive heart failure score (p<0.04) and right ventricular function (p<0.05). RESULTS: An overall improvement of all the main clinical-instrumental parameters were observed in the 19 long term treated patients. At the end of follow up 16 long term treated patients were in NYHA class > or = 2 and in 9 LVEF was > or = 40%. During follow up, among the 30 patients who tolerated the drug, 1 pt died suddenly after 12 months of betablocker therapy and 5 pts were transplanted. No major events occurred among ¿improved¿ patients, after 24 +/- 6 months of follow-up. The actuarial survival curve of our study population shows that survival at 1, 2, 3 and 4 years was respectively 87%, 75%, 67% and 66%. These results confirm previous trials evidence that a progressively increasing dose of beta-blockers confers functional benefit in DCM with severe heart failure.

Changing mortality in dilated cardiomyopathy. The Heart Muscle Disease Study Group.

OBJECTIVE: To analyse the changes in mortality in dilated cardiomyopathy over the past 15 years and to identify the factors that might have influenced survival. DESIGN: Follow up study of 235 patients (aged 16-70) systematically enrolled on a register from 1 January 1978 to 31 December 1992. SETTING: Hospital department of cardiology. PATIENTS: Three groups corresponding to three periods of 5 years: group 1 (diagnosis between 1 January 1978 and 31 December 1982) 26 patients; group 2 (diagnosis between 1 January 1983 and 31 December 1987) 65 patients; and group 3 (diagnosis between 1 January 1988 and 31 December 1992) 144 patients. MAIN OUTCOME MEASURES: Death or heart transplantation. RESULTS: Two and four year survival was 73.8% and 53.8% in group 1, 87.7% and 72.3% in group 2, and 90.3% and 82.9% in group 3 (P = 0.02). During the 15 years of the study period the number of cases increased progressively and the baseline clinical characteristics changed (that is, patients were younger and less severely affected), partly explaining the improvement in survival. None the less, the three mortality curves tended to diverge progressively and the improvement in survival in the different groups was still significant after stratification for the severity of the disease, suggesting that treatment had a sustained effect. A progressively higher proportion of patients were treated with angiotensin converting enzyme (ACE) inhibitors and more recently with beta blockers. In group 2, after stratification for the severity of heart failure, patients who were treated with ACE inhibitors showed a better survival than patients who were not. Furthermore, analysis of group 3 showed that beta blockers had a significant additive effect with conventional therapy both by intention to treat and actual treatment. Four year survival in patients with mild and moderate to severe heart failure treated with beta blockers, and usually digitalis and ACE inhibitors, was respectively 90% and 87.5%. CONCLUSIONS: The improvement in the survival of patients with dilated cardiomyopathy over the past 15 years may be explained by earlier diagnosis, new treatments, and a change in the clinical characteristics of the patients at enrolment.