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Background— Moderate, regular alcohol consumption is generally associated with a lower risk of cardiovascular events but data in patients with chronic heart failure are scarce. We evaluated the relations between wine consumption, health status, circulating biomarkers, and clinical outcomes in a large Italian population of patients with chronic heart failure enrolled in a multicenter clinical trial. Methods and Results— A brief questionnaire on dietary habits was administered at baseline to 6973 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial. The relations between wine consumption, fatal and nonfatal clinical end points, quality of life, symptoms of depression, and circulating biomarkers of cardiac function and inflammation (in subsets of patients) were evaluated with simple and multivariable-adjusted statistical models. Almost 56% of the patients reported drinking at least 1 glass of wine per day. After adjustment, clinical outcomes were not significantly different in the predefined 4 groups of wine consumption. However, patients with more frequent wine consumption had a significantly better perception of health status (Kansas City Cardiomyopathy Questionnaire score, adjusted P P =0.01), and lower plasma levels of biomarkers of vascular inflammation (osteoprotegerin and C-terminal proendothelin-1, adjusted P P =0.01) after adjusting for possible confounders. Conclusions— We show for the first time in a large cohort of patients with chronic heart failure that moderate wine consumption is associated with a better perceived and objective health status, lower prevalence of depression, and less vascular inflammation, but does not translate into more favorable clinical 4-year outcomes. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT0033633.

Cardiomiopatia dilatativa

Dilated cardiomyopathy (DCM), a heart muscle disease characterized by ventricular dilation and dysfunction, is a leading cause of mortality and morbidity. In the present paper we will consider the main results of studies on the natural history of DCM in 581 consecutive patients prospectively enrolled and systematically followed in the Heart Muscle Disease Registry of Trieste in the last 25 years. In the last decades prognosis of DCM significantly improved over time, mainly as a consequence of optimized treatment with ACE-inhibitors and beta-blockers. However, a strong heterogeneity of prognosis was observed among patients both in familial and sporadic cases. Early diagnosis and treatment allowed to recognize two distinct subgroups, one with a rapidly progressive downhill course, high mortality and urgent indication to heart transplantation, another with a more favorable outcome. Long-term optimized treatment with ACE-inhibitors (in 90% of cases) and beta-blockers (in 87% of cases) was associated with a remarkable clinical improvement in 50% of patients and apparent "healing" in 16% of cases. A systematic and accurate echocardiographic follow-up showed in these cases a significant improvement of the left ventricular ejection fraction (LVEF) with "reverse remodeling", frequently associated with a decrease of severity of functional mitral regurgitation and regression of the restrictive filling pattern. The response to optimal treatment showed a strong relation to long-term outcome. The 8-year transplant-free survival, starting from the evaluation at 2 years, was 31% in patients with persistent NYHA class III-IV, 64% in NYHA class I-II and LVEFor = 40%, 83% in NYHA class I-II and LVEF40% and 94% in patients with apparent "healing" (p0.0001). Long-term follow-up showed a significant clinical progression of the disease in 33% of cases, independently of the initial clinical response to treatment. Predictive factors of a favorable response to beta-blocker treatment associated with ACE-inhibitors were a history of mild hypertension, an early diagnosis and treatment and the presence of sinus tachycardia. The risk of sudden death was increased particularly in patients with long-term persistent or progressive left ventricular dilation and dysfunction. A rigorous pharmacological approach (optimization of beta-blockers, withdrawal or decrease of dosage of digitalis), and selective non-pharmacological strategy (automated implantable cardioverter-defibrillators for primary prevention in high-risk patients) are potentially effective to decrease the incidence of sudden death during long-term follow-up. In conclusion, the Heart Muscle Disease Registry of Trieste gave us in the last 25 years new insights into the natural history of DCM, underlying the importance of a rigorous and systematic approach both at clinical presentation and during long-term follow-up on optimized medical treatment.

Dilated cardiomyopathy (DCM), a heart muscle disease characterized by ventricular dilation and dysfunction, is a leading cause of mortality and morbidity. In the present paper we will consider the main results of studies on the natural history of DCM in 581 consecutive patients prospectively enrolled and systematically followed in the Heart Muscle Disease Registry of Trieste in the last 25 years. In the last decades prognosis of DCM significantly improved over time, mainly as a consequence of optimized treatment with ACE-inhibitors and beta-blockers. However, a strong heterogeneity of prognosis was observed among patients both in familial and sporadic cases. Early diagnosis and treatment allowed to recognize two distinct subgroups, one with a rapidly progressive downhill course, high mortality and urgent indication to heart transplantation, another with a more favorable outcome. Long-term optimized treatment with ACE-inhibitors (in 90% of cases) and beta-blockers (in 87% of cases) was associated with a remarkable clinical improvement in 50% of patients and apparent "healing" in 16% of cases. A systematic and accurate echocardiographic follow-up showed in these cases a significant improvement of the left ventricular ejection fraction (LVEF) with "reverse remodeling", frequently associated with a decrease of severity of functional mitral regurgitation and regression of the restrictive filling pattern. The response to optimal treatment showed a strong relation to long-term outcome. The 8-year transplant-free survival, starting from the evaluation at 2 years, was 31% in patients with persistent NYHA class III-IV, 64% in NYHA class I-II and LVEFor = 40%, 83% in NYHA class I-II and LVEF40% and 94% in patients with apparent "healing" (p0.0001). Long-term follow-up showed a significant clinical progression of the disease in 33% of cases, independently of the initial clinical response to treatment. Predictive factors of a favorable response to beta-blocker treatment associated with ACE-inhibitors were a history of mild hypertension, an early diagnosis and treatment and the presence of sinus tachycardia. The risk of sudden death was increased particularly in patients with long-term persistent or progressive left ventricular dilation and dysfunction. A rigorous pharmacological approach (optimization of beta-blockers, withdrawal or decrease of dosage of digitalis), and selective non-pharmacological strategy (automated implantable cardioverter-defibrillators for primary prevention in high-risk patients) are potentially effective to decrease the incidence of sudden death during long-term follow-up. In conclusion, the Heart Muscle Disease Registry of Trieste gave us in the last 25 years new insights into the natural history of DCM, underlying the importance of a rigorous and systematic approach both at clinical presentation and during long-term follow-up on optimized medical treatment.

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The aim of this study was to evaluate whether small left ventricular (LV) volumes increase the negative prognostic impact of a restrictive filling pattern (RFP) and that of mitral regurgitation (MR) in patients with nonischemic heart failure (HF). The Meta-analysis Research Group in Echocardiography (MeRGE) is a meta-analysis that collated individual patient data from several prospective echocardiography outcome studies. This analysis was restricted to 10 studies and 601 patients with nonischemic HF. The role of MR was tested in a subgroup of 252 patients. A total of 106 deaths occurred during a median follow-up of 32 months. At multivariate analysis, RFP (hazard ratio [HR], 4.16; 95% confidence interval [CI], 1.54-11.23; P=.005) and New York Heart Association class III or IV (HR, 2.15; 95% CI, 1.33-3.47; P=.001) were the independent predictors of poor prognosis, and there was no statistically significant interaction between LV dilation and RFP. Moderate/severe MR was associated with poorer outcome in the group of patients with normal volumes, whereas it was not a significant predictor of mortality in patients with any degree of LV dilation. In patients with nonischemic HF, RFP is the most important indicator of poor prognosis, irrespective of the degree of LV dilation. Normal LV volumes increase the negative prognostic impact of moderate to severe MR.

Eight-hundred thirty patients (pts) with suspected myocardial disease of undefined etiology were observed from 1978 to 1996. In 350 pts, the clinical diagnosis was of dilated cardiomyopathy (DCM) or myocarditis. An endomyocardial biopsy was performed on all patients and in 54 of them (15%), an active myocarditis was identified. In six cases, myocarditis was detected at autopsy. There were 37 male patients and 23 females, with an average age of 35.5 +/- 15 years (range 1.67). Mean time interval between clinical onset and diagnosis was 4 +/- 10 months. Clinical presentation was characterized in 4 cases by fulminant myocarditis (Group I), in 8 cases by chest pain (Group II), in 14 cases by arrhythmia (Group III: hypokinetic in 9 pts and hyperkinetic in 5) and, in the last 34 pts, by congestive heart failure (CHF) (Group IV). Improvement was defined at 9 +/- 3 months according to a clinical score based on left ventricular shortening fraction (increaseor = 5 units), New York Heart Association Class improvement by (at least one Class) and left ventricular end-diastolic diameter (decreaseor = 10%). The main clinical and instrumental parameters characterizing the groups were: a more severe dilatation and left ventricular dysfunction in the pts belonging to Group I or IV with respect to those in Group II and III; a significantly worse prognosis in terms of evolution in DCM or death/cardiac transplantation (CT) in the pts from the Group II and III. After a follow-up period of 48 +/- 46 months, the mortality in the four groups was: 100% (4/4), 0% (0/8), 21% (3/14), 38% (13/34). Fifty percent of deaths were concentrated in the first 2 years of follow-up. Left ventricular end-diastolic diameter (OR 1.09, p0.05), age (OR 0.95), presence of left ventricular bundle branch block (OR 2.32), right ventricular function (OR 2.43) at clinical onset and the status of improvement at 9 +/- 3 months of follow-up (OR 0.24, p0.05) are predictors of evolution in DCM or death/CT for the pts with onset from CHF (Group IV). Immunosuppressive treatment has been utilized for the 76% of the pts. No conclusion can be drawn on the efficacy of this therapy, but no adverse events significantly related to therapy have been observed in a 9 +/- 3 months follow-up period. In conclusion, myocarditis can show a clinical presentation polymorphism, which influences the prognosis and natural history of the disease. Evolution in DCM and adverse events (death/CT) are more common in Groups I and IV. Some simple parameters evaluated at clinical presentation and the proposed classification as "improved" or "not improved" after a short-term follow-up (9 +/- 3 months) show good predictive accuracy. The present study does not allow us to draw any conclusion about the efficacy of immunosuppressive treatment. A randomized, controlled, large-scale trial, with adequate follow-up and advanced histological diagnosis techniques will help define the role of immunosuppressive therapy and patient eligibility criteria for this treatment.

X-linked dilated cardiomyopathy (XLDC) is a familial heart disease presenting in young males as a rapidly progressive congestive heart failure, without clinical signs of skeletal myopathy. This condition has recently been linked to the dystrophin gene in some families and deletions encompassing the genomic region coding for the first muscle exon have been detected. In order to identify the defect responsible for this disease at the molecular level and to understand the reasons for the selective heart involvement, a family with a severe form of XLDC was studied. In the affected members, no deletions of the dystrophin gene were observed. Analysis of the muscle promoter, first exon and intron regions revealed the presence of a single point mutation at the first exon-intron boundary, inactivating the universally conserved 5' splice site consensus sequence of the first intron. This mutation introduced a new restriction site for Msel, which cosegregates with the disease in the analyzed family. Expression of the major dystrophin mRNA isoforms (from the muscle-, brain- and Purkinje cell-promoters) was completely abolished in the myocardium, while the brain- and Purkinje cell- (but not the muscle-) isoforms were detectable in the skeletal muscle. Immunocytochemical studies with anti-dystrophin antibodies showed that the protein was reduced in quantity but normally distributed in the skeletal muscle, while it was undetectable in the cardiac muscle. These findings indicate that expression of the muscle dystrophin isoform is critical for myocardial function and suggest that selective heart involvement in dystrophin-linked dilated cardiomyopathy is related to the absence, in the heart, of a compensatory expression of dystrophin from alternative promoters.

Recent studies have demonstrated that genetic factors are likely to play a major role in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). In clinical surveys, a familial trait has been demonstrated in 20 to 30\% of idiopathic dilated cardiomyopathy patients (familial dilated cardiomyopathy). Molecular genetic studies have confirmed the clinical hypothesis of genetic heterogeneity in familial dilated cardiomyopathy, and are currently producing relevant advances in the understanding of this disease. The autosomal dominant form is considered to be the most frequent form of inherited idiopathic dilated cardiomyopathy. After the exclusion of a large series of candidate genes, the first familial dilated cardiomyopathy gene has been mapped to the long arm of chromosome 9. A second locus has been found on chromosome 1. Moreover, in two large families, characterized by a peculiar form of conduction delays and later development of myocardial dysfunction, the disease loci have been mapped to chromosome 1 and 3, respectively. The identification of the disease genes is in progress. In families with X-linked dilated cardiomyopathy, the disease gene has been identified as the dystrophin gene. The 5' end of the gene appears to be the critical region for the development of dilated cardiomyopathy without clinical evidence of muscle dystrophy. Furthermore, other cytoskeletal proteins, such as adhalin, could be involved in the pathogenesis of familial dilated cardiomyopathy. In familial right ventricular cardiomyopathy (or arrhythmogenic right ventricular dysplasia) characterized by isolated or prevalent right ventricular involvement, three different disease loci have been identified so far: two localized on the long arm of chromosome 14 and one on chromosome 1. The disease genes are still unknown and are currently under investigation. The study of the genetic factors at the molecular level is starting to elucidate the pathogenetic mechanisms of idiopathic dilated cardiomyopathy. These findings will also have relevant clinical and therapeutic implications.

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.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 (LVEFor = 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; p0.05). 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 (p0.01), congestive heart failure score (p0.04) and right ventricular function (p0.05).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 classor = 2 and in 9 LVEF wasor = 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.

In a prospective study on 340 cases with primary myocardial disease, eight patients (six males, two females, mean age 36 years, range 24-47) with an idiopathic left ventricular aneurysm were observed. All patients had normal coronary arteries, no angina or history of myocardial infarction; all but one had no risk factors for ischaemic heart disease; all had normal right ventricles; one patient had a history of familial dilated cardiomyopathy, two of 'flu-like' syndrome at the time of first symptom and two of alcohol abuse. All patients had ventricular tachycardia (VT), five sustained (of right bundle branch block morphology in three, and of different morphologies in two), three non-sustained. Patients with sustained VT had inducible VT (resembling the clinical one) on electrophysiological study. Electrocardiogram (ECG) showed an infarction pattern in three cases. Aneurysms were of limited size (2.1 +/- 1/11 segments on echocardiography) and were located in the septum, apex or posterior wall. Left ventricular ejection fraction (LVEF) was reduced (0.50) in six patients and was not correlated with the aneurysm size. The duration of illness was inversely correlated with LVEF (P0.05). Endomyocardial biopsy showed evidence of diffuse pathological changes in all cases (cell hypertrophy, myofibrillar lysis, mitochondriosis). During follow-up (64 +/- 32 months), patients were successfully treated with anti-arrhythmic drugs: no patients required surgical treatment to control ventricular arrhythmia. Considering the clinical and pathological features of idiopathic left ventricular aneurysm, this primary myocardial disease could be classified as a novel peculiar form of cardiomyopathy.

Although an underlying disturbance in cardiac function can be identified in most patients with congestive heart failure, manifestations of the disease are greatly influenced by other factors, particularly neurohumoral and peripheral adaptive responses which occur secondary to impaired cardiac function. Until recently diuretic agents and digoxin formed the basis of conventional treatment of this condition. The majority of clinical trials published since 1980, indicate that digoxin lessens symptoms and reduces morbidity associated with congestive heart failure particularly in patients with more advanced symptoms and ventricular dysfunction. The efficacy of digitalis in congestive heart failure may in part result from sympathoinhibitory properties such as the activation of baroreceptorial mechanisms. At present there is no conclusive evidence that cardiac glycosides improve survival. Several trials clearly indicate that angiotensin converting enzyme inhibitors (enalapril, captopril) can reduce both morbidity and mortality in symptomatic congestive heart failure. Asymptomatic patients like those with severe left ventricular dysfunction and those who are at high risk for left ventricular remodeling after anterior wall myocardial infarction may also benefit from ACE-inhibition therapy. Increasing evidence suggests that beta-adrenergic blockade can produce symptomatic and hemodynamic improvement in heart failure of idiopathic and ischemic aetiology. Appropriately powered randomized controlled trials are required to determine the impact on survival of beta-blockers.

Several reports suggest that chronic beta blockade, most often with the beta 1 selective agent metoprolol, may improve hemodynamic and clinical function in patients with idiopathic dilated cardiomyopathy. However, controlled trials are limited and some studies have not shown beneficial effects in short term trials. Mechanisms of effectiveness are still debated and probably concern the capacity to avoid toxic myocardial damage by catecholamines, to induce receptor up-regulation, to contribute to the control of arrhythmias, to improve diastolic relaxation and other mechanisms.After a revision of the literature, a preliminary clinical experience with metoprolol in dilated cardiomyopathy diagnosed according to the WHO definition is reported. Sixty-seven patients symptomatic for congestive heart failure or with complex ventricular arrhythmias associated with severe left ventricular dysfunction were submitted to test dose with metoprolol 5 mg bid for 2-7 days. All patients were completely studied, including coronary angiography and endomyocardial biopsy to exclude ischemic heart disease and active myocarditis. Four pts (6%) did not tolerate the first test dosage of metoprolol and twenty-two patients were excluded from analysis because of inadequate follow-up or because they were enrolled in an international trial. Forty-one patients underwent long-term treatment with metoprolol at a final mean dosage of 150 mg a day (range 50-200 mg) and are presently analyzed. The dosage was gradually increased during the first seven weeks.After 6 +/- 2 months and 12 +/- 2 months, 34 patients were stable or ameliorated (Group 1) and experienced an overall significant improvement of functional class (all pts in class I-II NYHA), of left and right ventricular ejection fraction (from 28 +/- 8.8% to 35.8 +/- 13.7% to 33.2 +/- 12.3% and from 38.6 +/- 11.8% to 42.4 +/- 5.8% to 45.2 +/- 12.2% respectively), of clinical signs of congestive heart failure, of cardiothoracic index, of left ventricular diameters and of arrhythmic pattern. Furthermore, the rate of ventricular couplets20/24h and of non-sustained ventricular tachycardia changed respectively from 46% and 54% to 4% and 21% at 12 +/- 2 months. None in Group 1 died nor is any waiting for heart transplantation. Eleven patients (Group 2) did not tolerate the drug acutely (4 pts) or deteriorated during the first 6 +/- 2 months (7 pts) of the treatment. In this group a worsening or an insignificant variation of all clinical and instrumental parameters was observed. During follow-up four patients of this group underwent heart transplantation (one died shortly after the operation because of infective complications), one died while waiting, two are currently waiting for heart transplantation, and three are still in heart failure (class III NYHA). No cases of sudden death occurred in any group of patients (15 pts with follow-up12 mo).Our uncontrolled study seems to confirm the beneficial effect of betablockers in a subgroup of patients with idiopathic dilated cardiomyopathy. The characterization of responders to this therapy is still undefined and will constitute the aim of future analyses.