Bruno Pinamonti

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.

Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks. Methods and Results— All 312 titin exons known to be expressed in human cardiac titin and the complete 3′ untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%). Conclusions— Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks.

Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment.

OBJECTIVES The purpose of this study was to determine the prevalence and prognostic role of left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (IDCM). BACKGROUND Tailored medical therapy can lead to LVRR in IDCM. The prevalence and prognostic impact of LVRR remain unclear. METHODS We consecutively enrolled 361 IDCM patients. LVRR was defined as a left ventricular ejection fraction increase of ≥10 U or a left ventricular ejection fraction of ≥50% and a decrease in indexed left ventricular end-diastolic diameter of ≥10% or indexed left ventricular end-diastolic diameter of ≥33 mm/m(2) at 24 months (range 9 to 36 months). Follow-up echocardiographic data were available for 242 patients (67%), 34 (9%) died/underwent heart transplantation (HTx) before re-evaluation, and 85 (24%) did not have a complete re-evaluation. After re-evaluation, the surviving patients were followed for 110 ± 53 months; there were 55 deaths (23%) and 32 HTx (13%). RESULTS LVRR was found in 89 of 242 patients (37%). Baseline predictors of LVRR were higher systolic blood pressure (p = 0.047) and the absence of left bundle branch block (p = 0.009). When added to a prognostic baseline model including male sex, heart failure duration, New York Heart Association functional classes III to IV, LVEF, significant mitral regurgitation, and beta-blockers, LVRR, New York Heart Association functional classes III to IV, and significant mitral regurgitation after 24 months emerged as independent predictors of death/HTx and heart failure death/HTx. The model including follow-up variables showed additional prognostic power with respect to baseline model (for death/HTx, area under the curve: 0.80 vs. 0.70, respectively, p = 0.004). Furthermore, only LVRR was significantly associated with sudden death/major ventricular arrhythmia in the long-term. CONCLUSIONS LVRR characterized approximately one-third of IDCM patients surviving 2 years while receiving optimal medical therapy and allowed a more accurate long-term prognostic stratification of the disease.

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)

Right ventricle in pulmonary arterial hypertension: haemodynamics, structural changes, imaging, and proposal of a study protocol aimed to assess remodelling and treatment effects.

Although right ventricular (RV) failure is the main cause of death in patients with pulmonary arterial hypertension (PAH), there is insufficient data about the effects of PAH treatment on RV geometry and function mainly because the RV assessment has been hampered by its complex crescentic shape, large infundibulum, and its trabecular nature. Echocardiography is a widely available imaging technique particularly suitable for follow-up studies, because of its non-invasive nature, low cost, and lack of ionizing radiation or radioactive agent. Real-time three-dimensional echocardiography (RT3DE) has been shown to be accurate in assessing RV and left ventricular (LV) volumes, stroke volumes, and ejection fractions in comparison with cardiac magnetic resonance imaging. In this review, we describe RV structural and functional changes which occur in patients with PAH and strengths and weaknesses of current non-invasive imaging techniques to assess them. Finally, we describe an ongoing multicentre, prospective observational study involving seven centres expert in treating patients with PAH from four different countries. Investigators will use conventional and advanced echo parameters from RT3DE and speckle-tracking echocardiography to assess the extent of LV and RV remodelling before symptom onset and during pharmacological treatment in patients with PAH. Seventy patients who will survive for at least 1 year will be recruited. All the participating institutions will perform comprehensive standard 2D and Doppler as well as RT3DE examinations with a pre-defined imaging protocol. Measurements will be performed at the core echocardiography laboratory by experienced observers who will be unaware of each patients treatment assignment and whether the examination was a baseline or a follow-up study. Enrolment duration is expected to be 1 year.

Long-term prognostic impact of therapeutic strategies in patients with idiopathic dilated cardiomyopathy: changing mortality over the last 30 years

ACE‐inhibitors, β‐blockers, implantable cardioverter–defibrillator (ICD) and cardiac resynchronization therapy (CRT) improved prognosis of heart failure. We sought to analyse the long‐term prognostic impact of evidence‐based integrated therapeutic strategies in patients with idiopathic dilated cardiomyopathy (IDCM).

Quantitative texture analysis in two-dimensional echocardiography : application to the diagnosis of myocardial amyloidosis.

Qualitative and subjective analysis of two-dimensional echocardiographic images of the myocardial wall allows one to identify amyloid heart disease; the quantitative analysis of regional image texture might be an accurate method to differentiate normal from amyloid myocardial structures. To test this hypothesis, two-dimensional echocardiograms of nine normal subjects and six patients with histologically documented amyloid heart disease were evaluated. Quantitative texture measurements of the first order (mean gray level, skewness, kurtosis, energy and entropy) overlapped between the two groups. Among the second order statistics variables, entropy was significantly and consistently higher in amyloid versus normal patient data (septum in parasternal long-axis view: 6.3 +/- 0.3 versus 5.9 +/- 0.4; septum in apical four chamber view: 6.2 +/- 0.2 versus 5.8 +/- 0.3). Therefore, amyloid-involved myocardial walls show ultrasound image texture alterations that may be quantified with digital image analysis techniques.