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Cardiomyopathies are primary myocardial disorders, genetically determined, with clinical onset between the third and the fifth decade of life. They represent the main causes of sudden cardiac death and heart failure in the youth. The more common myocardial diseases in clinical practice are dilated cardiomyopathy, arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy. Next generation sequencing techniques, recently available for genetics researches, together with the diffusion of advanced imaging techniques, permitted in the last years a deeper knowledge of these pathologies. Nevertheless, diagnosis, etiology and several aspects of patients' clinical management remain complex and controversial. This review paper aims to propose some operative flow-charts, derived from scientific evidences and the internal protocol of the Cardiothoracovascular Department of Trieste Hospital, Italian referral Center for cardiomyopathies and heart failure, with more than 30 years of experience in diagnosis and management of patients who suffer from primary myocardial disorders.

Heart failure is still a major cause of morbidity and mortality in Europe and North America. In the last three decades, gene therapy emerged as a target in the molecular mechanisms implicated in heart failure encouraging preclinical gene therapy studies in small and large animal models. Prior studies documented a decreased expression of sarcoplasmic reticulum Ca2+-ATPase protein (SERCA2a), a major cardiac calcium cycling protein, in heart failure. These results paved the way to preliminary studies based on gene transfer strategies of SERCA2a. The encouraging results in terms of safety and surrogate clinical endpoints led to a large randomized clinical study, the CUPID trial, including patients with heart failure and reduced ejection fraction. This phase IIb trial enrolling 250 patients randomized to intracoronary delivery of adeno-associated virus 1 (AAV1)/SERCA2a or placebo concluded with a non-superiority of the studied therapy, thus not confirming the results of the previous experiences with the same approach. In the present manuscript, we provide an overview of the scientific experiences that preceded the design of this major trial, then critically revising its structure and results. Finally we tried to understand the reasons of this unexpected failure and which are the future perspectives of gene therapy for heart failure.

It is generally recognized that current guidelines, based on ejection fraction criteria, do not allow appropriate selection of patients for implantable cardioverter-defibrillator (ICD) therapy in the primary prevention of sudden death, thus hindering the optimal use of ICD in patients with left ventricular dysfunction of ischemic and nonischemic etiology. Ejection fraction alone has limitations in both sensitivity and specificity. Assessment of the risk for sudden death using a combination of multiple tests (ejection fraction associated with one or more different arrhythmic risk markers) could partially compensate for these limitations. In this position paper, the potential usefulness of a polyparametric assessment using some of the most investigated risk markers of sudden death is discussed, including late gadolinium enhancement cardiac magnetic resonance, programmed ventricular stimulation, T-wave alternans, autonomic tone, biomarkers, and genetic testing.

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 LVEF < or = 40%, 83% in NYHA class I-II and LVEF > 40% and 94% in patients with apparent "healing" (p < 0.0001). 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 LVEF < or = 40%, 83% in NYHA class I-II and LVEF > 40% and 94% in patients with apparent "healing" (p < 0.0001). 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.

There are a number of cardiomyopathies secondary to a more widespread striated muscle involvement. While in some conditions the heart is affected as part of a severe myopathy (such as the dilated cardiomyopathy found in Duchenne and Becker muscular dystrophies), there are examples in which the skeletal muscle involvement is subtle. From a classification point of view, some of these cardiomyopathies are secondary to muscular dystrophies, or to metabolic disorders, or to other myopathies. From a practical diagnostic point of view, metabolic conditions predominate in infancy, whereas the dystrophic forms are more frequently found from the third decade onwards. Useful clinical clues to suggest a skeletal muscle involvement are muscle hypertrophy or wasting and contractures, in addition to weakness. Serum creatine kinase should always be studied when suspecting a form secondary to a muscular dystrophy, although a normal serum creatine kinase does not exclude a muscular dystrophy. Electromyography and muscle imaging are additional useful investigations in these patients. This article is focused on practical clinical suggestions on when to suspect and how to investigate patients with a cardiomyopathy secondary to neuromuscular disorders.

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by impaired contractility and dilation of the left ventricle or both ventricles. In a large proportion of patients, the cause of the disease is unknown and DCM is considered to be the final common phenotype of a heterogeneous group of disorders. Molecular studies carried out in specific DCMs have identified several metabolic and structural defects leading to a common phenotype of myocardial damage. Viral infection and autoimmune disorder can cause DCM. However, a familial trait is present up to 50% of cases, indicating a major role of genetic factors. The analysis of the phenotype, the pattern of genetic transmission, and molecular genetic findings have allowed the characterization of different forms of familial DCM, suggesting genetic heterogeneity. Furthermore, the risk of disease has been estimated as high as 20% in relatives of familial DCM patients, which is significantly higher than the normal population. Taking into account that DCM can be clinically not evident due to its low penetrance (in particular in the young population), a reproducible and reliable method for the diagnosis of familial forms is critical in the management of the disease. To address this issue, consensus guidelines for the diagnosis and screening of familial DCM have been developed. The screening method for familial DCM is based on physical exam, electrocardiogram, and echocardiogram of first-degree relatives of affected subjects. The family screening should be followed-up every 2 to 3 years, in particular in unaffected relatives (in the absence of a molecular diagnosis), to exclude a late onset of the disease.

Background: 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., Methods: 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., Results: 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 couplets > 20/24h 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-up > 12 mo)., Conclusions: 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.

The pathogenesis of dilated cardiomyopathy (DCM) is still unknown; however, some factors that seem to play an important role in the development of the disease have recently been identified: they are enteroviral infections, immune mechanisms and genetic factors. Enteroviral infection (particularly due to Coxsackie virus B) has long been suspected to be the cause of myocarditis and subsequent DCM. However, only recent techniques of genetic engineering have been able to demonstrate the presence of enteroviral RNA in endomyocardial biopsy of patients with DCM. The role of the viral particles contained in the myocardium is still undetermined. Changes in the immune system concerning cell-mediated and humoral immunity have been recently detected. It has been suggested that an autoimmune process could be the actual cause of DCM in some patients, rather than the consequence. The immune system is strictly related to the major histocompatibility complex. As in some autoimmune diseases, a relationship between DCM and HLA class II phenotype has been found: particularly the DR4 antigen seems to be associated with a high risk of disease. Besides immunogenetic factors, other genetic factors seem to play a role in the pathogenesis of DCM. In 6-8% of cases a familial history of cardiomyopathy has been observed. In clinical studies on familial DCM different phenotypes have been shown, suggesting that different genetic mechanisms are involved in the pathogenesis of the disease. At least two main mechanisms can be hypothesized: the transmission of "predisposing" factors or a defect in proteins essential for the cardiac muscle cell function. Viral agents, autoimmune reactions, immunogenetic and genetic factors seem to cause myocardial damage individually or with complex interactions: the research should be devoted to these topics in the future.

A total of 138 patients with idiopathic dilated cardiomyopathy were assessed and followed-up between July 1973 and October 1985 in order to evaluate prognostic risk indicators. Of these 102 were male and 36 were female with a mean age of 49.1 years. Each patient underwent physical examination, electrocardiography, echocardiography, cardiac catheterization and coronary angiography. The mortality rate was low for the first 3 years (respectively 8, 12.5 and 20%) while it was 57.5 at the end of the 5-year follow-up period. Univariate analysis at the time of the diagnosis revealed that five factors were predictive of the clinical course at the end of the fifth year: the NYHA functional class IV (p less than 0.0001); LV ejection fraction less than 0.30 (p less than 0.01); left ventricular failure, bi-ventricular failure and left ventricular end-diastolic pressure greater than 20 mmHg (p less than 0.05). Multivariate analysis was used to determine which combination of factors could most accurately predict survival. The most important prognostic factor was again the IV NYHA functional class (p less than 0.01) and, to a lesser degree, left ventricular end-diastolic pressure (p less than 0.05). The present study underlines that the survival rate of patients with dilated cardiomyopathy depends upon the selection of patients. This can explain the low 3-year mortality found in our patients. The NYHA functional class may be a useful practical guide for cardiac transplantation.

Thirty patients with congestive cardiomyopathy (C.C.) have been studied for the prevalence of neutralizing antibodies to coxsackie B viruses in comparison with age and sex matched controls. Seropositivity toward each antigen was similar in cases and controls: an exception was coxsackie B5 virus, where a significantly seropositivity was found in the control group. As a whole, high antibody titers to any antigen were observed more frequently on sera of cardiopathic patients; however the difference between cases and controls of g.m.t. to each antigen tested was not statistically significant, with the exception of coxsackie B1 virus. The absence of a clear relationship between C.C. and viral infections might be explained through biological as well as epidemiological considerations; of particular relevance, the long duration of cardiac disease (average length 71 months, median 54). Final considerations are offered regarding the methodologic approach for a better understanding of the etiology of this elusive disease.

Aim of this study is the analysis of clinical, morphologic and haemodynamic features of cardiac amyloidosis. Cardiac amyloidosis was demonstrated histologically in 7 of our patients: in 6 by endomyocardial biopsy during cardiac catheterization, in one at autopsy. The clinical picture was characterized in every patient by signs and symptoms of congestive heart failure. The electrocardiogram showed several non specific signs: low voltage of the QRS complexes, both in peripheral (4/7) and precordial leads (7/7 cases); marked leftward and upward deviation of the QRS axis (6/7 cases); first degree A-V block (5/7); abnormal Q waves (7/7). M-mode and two-dimensional echocardiography invariably demonstrated a typical pattern: a non dilated left ventricle with thickened and hyper-refractile walls, and usually a slight-moderate diffuse hypokinesia. Other common features were a thickening of right ventricular walls, interatrial septum, and atrioventricular and semilunar valves. Computerized analysis of the M-mode tracings disclosed a marked impairment of the indexes of both systolic and diastolic ventricular function in all patients. By correlating electrocardiographic and echocardiographic data, we found in every case a striking disproportion between the low QRS voltage and the high muscle cross-sectional area (an echocardiographic index of left ventricular mass): this pattern appears to be highly suggestive of infiltrative heart disease. Cardiac catheterization (performed in 6 cases) showed an increase of left ventricular (6/6) and right ventricular (5/6) end-diastolic pressure, with a dip plateau pattern in some cases (4/6 of the left, 2/6 in the right ventricle). The cardiac index was decreased in 3/6 cases. Left ventricular angiography confirmed the echocardiographic data of normal volumes and a slight-moderate decrease of the ejection fraction. We conclude that cardiac amyloidosis usually mimics a restrictive cardiomyopathy (severe congestive heart failure with increased ventricular filling pressures, in the absence of severe systolic ventricular dysfunction). This disease can be suspected clinically by the correlation of the clinical, electrocardiographic and echocardiographic data. The final diagnosis requires an endomyocardial biopsy.

The electrocardiogram (ECG) of 80 patients with dilated cardiomyopathy was studied. An abnormal ECG was present in 100% of our patients, and in 25% it was the first sign of the disease. Thirty-eight cases (47.5%) showed left atrial enlargement, 22 (27.5%) prolonged PR interval, 33 (41.2%) left bundle branch block, 15 (18.7%) abnormal Q waves, 9 (11.2%) primary S-T and T changes. There were significant differences in ejection fraction and in left ventricular end-diastolic volume between patients with right bundle branch block (p less than 0.05 and p = 0.05 respectively). Patients were followed for a period of 29.5 +/- 28.8 months (min. 2 days, max. 10 years): during the observation period the ECG showed in 28 cases an increasing left ventricular conduction delay and a leftward shifting of mean QRS axis. Patients with left ventricular conduction delays showed a worse prognosis. ECG in dilated cardiomyopathy is a nonspecific but sensitive tool, which may be related to different degrees of myocardial impairment and may be useful in the definition of a prognostic profile.

DILATED CARDIOMYOPATHY - Conduction and rhythm disturbances are frequent findings in dilated cardiomyopathy. 65 patients with dilated cardiomyopathy underwent 24-hour electrocardiographic monitoring: 95.4% showed ventricular arrhythmias, 80% complex ventricular arrhythmias and 44% runs of non-sustained ventricular tachycardia. Over 1000 ventricular extrasystoles in 24 hours were present in 44% of cases. Ventricular tachycardia and multiform and paired ventricular extrasystoles correlated significantly with the severity of cardiac dysfunction and with a worse prognosis. Patients undergoing antiarrhythmic therapy (amiodarone) showed a significant reduction in the number of ventricular extrasystoles and in the incidence of complex ventricular arrhythmias. HYPERTROPHIC CARDIOMYOPATHY - The high incidence of arrhythmias, particularly ventricular arrhythmias (approx. 70% of cases) in hypertrophic cardiomyopathy is well recognized: episodes of ventricular tachycardia are present in 20% of cases and are related to an elevated risk of sudden death. Antiarrhythmic treatment with amiodarone significantly reduces the number of ventricular extrasystoles and the episodes of ventricular tachycardia, may prevent sudden death and improve survival. RESTRICTIVE CARDIOMYOPATHY - Very little information is present in literature concerning this extremely rare form, in which every type of rhythm and conduction disturbance has been observed. CONCLUSIONS - Electrocardiographic monitoring is nowadays a very important tool in the management of cardiomyopathy patients, to identify possible patients at risk and to monitor the antiarrhythmic treatment.

Acute and chronic effects of captopril (C) were studied in 14 patients (12 males, 2 females; mean age 56 +/- 15 years) with chronic congestive heart failure (CCHF) refractory to digitalis and diuretics. All patients underwent hemodynamic evaluation before and after increasing doses of C (6.25-100 mg). Nine patients were evaluated during long term therapy by means of clinical examination, exercise testing, chest-X-ray and echocardiography. After C the following acute haemodynamic changes were observed. Mean right atrial pressure: -25% (p less than 0.01), left ventricular filling pressure: -22% (p less than 0.01), mean systemic arterial pressure: -15% (p less than 0.01), systemic vascular resistance: -31% (p less than 0.01), cardiac index: +36% (p less than 0.01). Of the 9 patients who were evaluated during long term C treatment, 7 (group A, mean follow up 6.4 +/- 4.2 months) improved in 1 or 2 NYHA functional classes and showed an increased exercise tolerance during the first 3-6 months of therapy. In this period, however, two sudden deaths and one drop-out were observed. Moreover, after the seventh month two patients of this group deteriorated clinically. Two patients (group B) developed a progressively weight gain during the first 15 days of C treatment. In the majority of our patients with refractory CCHF, captopril improves cardiac performance in the acute phase and in the first 3-6 months of therapy. Controlled studies and longer follow up are needed to understand better the long term effects of C in CCHF patients.