Fulvio Camerini

Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology.

Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology.

Spectrum of Clinicopathologic Manifestations of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: A Multicenter Study☆

OBJECTIVES The aim of the present investigation was to redefine the clinicopathologic profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), with special reference to disease progression and left ventricular (LV) involvement. BACKGROUND Long-term follow-up data from clinical studies indicate that ARVC is a progressive heart muscle disease that with time may lead to more diffuse right ventricular (RV) involvement and LV abnormalities and culminate in heart failure. METHODS Forty-two patients (27 male, 15 female; 9 to 65 years old, mean [+/-SD] age 29.6 +/- 18) from six collaborative medical centers, with a pathologic diagnosis of ARVC at autopsy or heart transplantation, and with the whole heart available, were studied according to a specific clinicomorphologic protocol. RESULTS Thirty-four patients died suddenly (16 during effort); 4 underwent heart transplantation; 2 died as a result of advanced heart failure; and 2 died of other causes. Sudden death was the first sign of disease in 12 patients; the other 30 had palpitations, with syncope in 11, heart failure in 8 and stroke in 3. Twenty-seven patients experienced ventricular arrhythmias (ventricular tachycardia in 17), and 5 received a pacemaker. Ten patients had isolated RV involvement (group A); the remaining 32 (76%) also had fibrofatty LV involvement that was observed histologically only in 15 (group B) and histologically and macroscopically in 17 (group C). Patients in group C were significantly older than those in groups A and B (39 +/- 15 years vs. 20 +/- 8.8 and 25 +/- 9.7 years, respectively), had significantly longer clinical follow-up (9.3 +/- 7.3 years vs. 1.2 +/- 2.1 and 3.4 +/- 2.2 years, respectively) and developed heart failure significantly more often (47% vs. 0 and 0, respectively). Patients in groups B and C had warning symptoms (80% and 87%, respectively, vs. 30%) and clinical ventricular arrhythmias (73% and 82%, respectively, vs. 20%) significantly more often than patients in group A. Hearts from patients in group C weighed significantly more than those from patients in groups A and B (500 +/- 150 g vs. 328 +/- 40 and 380 +/- 95 g, respectively), whereas hearts from both group B and C patients had severe RV thinning (87% and 71%, respectively, vs. 20%) and inflammatory infiltrates (73% and 88%, respectively, vs. 30%) significantly more often than those from group A patients. CONCLUSIONS LV involvement was found in 76% of hearts with ARVC, was age dependent and was associated with clinical arrhythmic events, more severe cardiomegaly, inflammatory infiltrates and heart failure. ARVC can no longer be regarded as an isolated disease of the right ventricle.

Familial dilated cardiomyopathy ☆: Evidence for genetic and phenotypic heterogeneity

OBJECTIVES This study was performed to evaluate the characteristics, mode of inheritance and etiology of familial dilated cardiomyopathy (FDC). BACKGROUND A genetic form of disease transmission has been identified in a relevant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients. METHODS Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed. RESULTS Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific. CONCLUSIONS Familial dilated cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.OBJECTIVES This study was performed to evaluate the characteristics, mode of inheritance and etiology of familial dilated cardiomyopathy (FDC). BACKGROUND A genetic form of disease transmission has been identified in a relevant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients. METHODS Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed. RESULTS Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific. CONCLUSIONS Familial dilated cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.

Persistence of Restrictive Left Ventricular Filling Pattern in Dilated Cardiomyopathy: An Ominous Prognostic Sign

OBJECTIVES We sought to assess the prognostic implications of the evolution of restrictive left ventricular filling pattern (RFP) in dilated cardiomyopathy (DCM). BACKGROUND Previous work has demonstrated that a RFP in DCM is associated with a poor prognosis. Few data are available on the prognostic implications of the evolution of this pattern. METHODS The evolution of left ventricular filling was studied by Doppler echocardiography in 110 patients with DCM. According to the left ventricular filling pattern at presentation and after 3 months of treatment, the patients were classified into three groups: Group 1A (n = 24) had persistent restrictive filling; Group 1B (n = 29) had reversible restrictive filling; and Group 2 (n = 57) had nonrestrictive filling. RESULTS During follow-up (41 +/- 20 months), mortality plus heart transplantations was significantly higher in Group 1A than in Groups 1B and 2 (p < 0.0001). On multivariate analysis, the model incorporating E wave deceleration time at 3 months was more powerful at predicting mortality with respect to this variable at baseline (p = 0.0039). Clinical improvement at 1 and 2 years was significantly more frequent in Groups 1B and 2 than in Group 1A (p < 0.0001 at 2 years). CONCLUSIONS In patients with DCM, the persistence of restrictive filling at 3 months is associated with a high mortality and transplantation rate. The patients with reversible restrictive filling have a high probability of improvement and excellent survival. Doppler echocardiographic reevaluation of these patients after 3 months of therapy gives additional prognostic information with respect to the initial study.

Left ventricular involvement in right ventricular dysplasia

Right ventricular dysplasia, a heart muscle disease of unknown cause, anatomically characterized by variable replacement of myocardial muscle with adipose or fibroadipose tissue, is usually considered a selective disorder of the right ventricle. However, concomitant left ventricular involvement has been noted in a few cases. The aim of this study was to evaluate the prevalence and characteristics of left ventricular involvement in right ventricular dysplasia, as well as possible progression of the disease. Thirty-nine patients with right ventricular dysplasia were studied by M-mode and two-dimensional echocardiography; 28 of them also underwent cardiac catheterization, and in 25 endomyocardial biopsy was performed. On first examination the left ventricle was normal in 25 patients, whereas in the remaining 14 right ventricular abnormalities were associated with left ventricular involvement, characterized by asynergic areas (12 patients) or diffuse mild hypokinesis (two patients). During follow-up (27 patients, 84.1 +/- 66.1 months) 10 patients showed worsening of right ventricular function; in nine the appearance or worsening of left ventricular abnormalities was observed. Five patients died (four in congestive heart failure and one suddenly). Results of postmortem examination (available in two patients) showed atrophy of myocells and a massive fatty and fibrous infiltration of the right ventricular wall, associated with degenerative changes and fibrosis of the left ventricle. In conclusion, right ventricular dysplasia may be associated with left ventricular involvement and the disorder appears to be progressive in some instances.

Magnetic resonance imaging in right ventricular dysplasia

Fifteen patients with right ventricular dysplasia were investigated by T1-weighted spin- and gradient-echo pulse sequences, using a protocol that enabled both a subjective analysis of myocardial signal intensity and a quantitative/qualitative analysis of right and left ventricular function. In 8 patients, 3 investigators independently recognized abnormally hyperintense areas in the anatomic sites usually affected by the disease. In 7 of these patients, these areas showed an overlap with a-dyskinetic areas imaged by both magnetic resonance imaging (MRI) and echocardiography. In 1 patient who underwent a cardiac transplant, MRI of the explanted heart showed an excellent correlation between the distribution of the lesions and the in vivo/in vitro features. The data were compared with those from an equivalent sample of patients affected by dilated cardiomyopathy. In the latter patients, no focal hyperintensities were attributed to any anatomic sites in the right ventricule, and no focal a-dyskinetic foci were observed. Furthermore, the 2 groups of patients were significantly different in regard to dimensional and functional quantitative parameters. The results suggest that MRI is useful in integrating echocardiographic data and can be helpful in diagnosing this disease in late stages.

Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol

OBJECTIVES The purpose of this study was to analyze whether long-term treatment with the nonselective beta-adrenergic blocking agent carvedilol may have beneficial effects in patients with dilated cardiomyopathy (DCM), who are poor responders in terms of left ventricular (LV) function and exercise tolerance to chronic treatment with the selective beta-blocker metoprolol. BACKGROUND Although metoprolol has been proven to be beneficial in the majority of patients with heart failure, a subset of the remaining patients shows long-term survival without satisfactory clinical improvement. METHODS Thirty consecutive DCM patients with persistent LV dysfunction (ejection fraction #40%) and reduced exercise tolerance (peak oxygen consumption ,25 ml/kg/min) despite chronic (.1 year) tailored treatment with metoprolol and angiotensin-converting enzyme inhibitors were enrolled in a 12-month, open-label, parallel trial and were randomized either to continue on metoprolol (n 5 16, mean dosage 142 6 44 mg/day) or to cross over to maximum tolerated dosage of carvedilol (n 5 14, mean dosage 74 6 23 mg/day). RESULTS At 12 months, patients on carvedilol, compared with those continuing on metoprolol, showed a decrease in LV dimensions (end-diastolic volume 28 6 7 vs. 17 6 6 ml/m 2 ,p 5 0.053; end-systolic volume 27 6 5 vs. 16 6 4 ml/m 2 ,p 5 0.047), an improvement in LV ejection fraction (17 6 3% vs. 21 6 2%, p 5 0.045), a reduction in ventricular ectopic beats (212 6 9 vs. 162 6 50 n/h, p 5 0.05) and couplets (20.5 6 0.4 vs. 11.5 6 0.6 n/h, p 5 0.048), no significant benefit on symptoms and quality of life and a negative effect on peak oxygen consumption (20.6 6 0.6 vs. 11.3 6 0.5 ml/kg/min, p 5 0.03). CONCLUSIONS In DCM patients who were poor responders to chronic metoprolol, carvedilol treatment was associated with favorable effects on LV systolic function and remodeling as well as on ventricular arrhythmias, whereas it had a negative effect on peak oxygen consumption. (J Am Coll Cardiol 1999;33:1926 ‐34)

Evidence from family studies for autoimmunity in dilated cardiomyopathy

Organ-specific antibodies are found in patients with autoimmune disease and their symptom-free relatives many years before clinical onset. Organ-specific cardiac antibodies can be found in patients with dilated cardiomyopathy (DCM) and their relatives, which supports the idea that DCM is an autoimmune disease. We did non-invasive cardiological assessment and antibody screening in 342 symptom-free relatives (170 male, 172 female, mean [SD] age 31 [16] years). 177 relatives were from 33 families with more than 1 affected individual (familial DCM) and 165 relatives from 31 families with only 1 affected member (non-familial DCM). The frequency of cardiac antibodies was higher among relatives of DCM patients than in controls (20% vs 3.5%, p = 0.0001). In 37 (58%) of the families studied, cardiac antibodies were found in the proband and/or in at least 1 family member and were more common in familial than in non-familial DCM (24% vs 15%, p = 0.036). Antibody-positive relatives were younger (26 [15] vs 33 [17] years, p = 0.01) and had a larger mean echocardiographic left ventricular end-systolic dimension (35 [6] vs 32 [6], p = 0.01 mm) and reduced percentage fractional shortening compared with antibody-negative relatives (31 [6] vs 34 [6], p = 0.008). Presence of cardiac-specific autoantibodies in symptom-free DCM relatives provides evidence of autoimmunity in a subset of our patients (58%), including familial and non-familial forms of DCM. These antibodies are associated with mild left ventricular systolic dysfunction on echocardiography and may be early markers for relatives at risk of DCM.

Primary pulmonary hypertension: effects of nifedipine.

The results of the medical treatment of primary pulmonary hypertension are usually very poor. A case of severe primary pulmonary hypertension in chronic heart failure was treated with the calcium antagonist nifedipine, a powerful vasodilator which acts directly on vascular smooth muscle. Nifedipine, administered in a dose of 20 mg sublingually, caused a pronounced fall in pulmonary and systemic vascular resistances (54 and 49%, respectively) and a rise in cardiac output (90.3%). Improvement was maintained over a three-month period. These data suggest that nifedipine can be used in the treatment of this condition.

Ventricular arrhythmias in dilated cardiomyopathy as an independent prognostic hallmark

Prevalence and characteristics of ventricular arrhythmias (VA) on Holter monitoring were evaluated in 218 patients with invasively documented idiopathic dilated cardiomyopathy to clarify their relation to pump dysfunction, and their prognostic role. VA were observed in 205 patients (94%) and were high grade (ventricular pairs or tachycardia) in 130 (60%). No simple or multiform ventricular premature complexes were present in 88 patients (group 1; 41%), ventricular pairs in 63 (group 2; 32%), and ventricular tachycardia in 67 (group 3; 27%). Only echocardiographic right ventricular dimensions (p less than 0.05) and prevalence of VA during effort (8% in group 1, 15% in group 2, and 14% in group 3; p = 0.0005) differed significantly between groups. VA severity, and number of ventricular premature beats and tachycardia episodes were not correlated to right/left ventricular dimensions and pump function indexes. During a mean follow-up of 29 +/- 16 months, 27 patients died from cardiac events, and 16 received transplants. Three-year survival probability was lower in groups 2 (0.82) and 3 (0.81) than in group 1 (0.94). By Cox multivariate analysis, VA severity (p less than 0.01) was a major independent predictor of prognosis after markers of ventricular dysfunction such as left ventricular ejection fraction (p less than 0.001) and stroke work index (p less than 0.001).