Biomedical subjects

R De Maria

Publications and source records attributed to R De Maria.

At least 55 records · Page 3Linked to original sources

PubMed1997

Requirement for GD3 ganglioside in CD95- and ceramide-induced apoptosis.

Gangliosides participate in development and tissue differentiation. Cross-linking of the apoptosis-inducing CD95 protein (also called Fas or APO-1) in lymphoid and myeloid tumor cells triggered GD3 ganglioside synthesis and transient accumulation. CD95-induced GD3 accumulation depended on integral receptor "death domains" and on activation of a family of cysteine proteases called caspases. Cell-permeating ceramides, which are potent inducers of apoptosis, also triggered GD3 synthesis. GD3 disrupted mitochondrial transmembrane potential (DeltaPsim), and induced apoptosis, in a caspase-independent fashion. Transient overexpression of the GD3 synthase gene directly triggered apoptosis. Pharmacological inhibition of GD3 synthesis and exposure to GD3 synthase antisense oligodeoxynucleotides prevented CD95-induced apoptosis. Thus, GD3 ganglioside mediates the propagation of CD95-generated apoptotic signals in hematopoietic cells.

Apoptosis↗

PubMed1997

Fas-induced changes in cdc2 and cdk2 kinase activity are not sufficient for triggering apoptosis in HUT-78 cells.

Recent evidence suggested a role for the cell cycle dependent kinases cdc2 and cdk2 in apoptosis. An important mechanism by which many cell types could undergo apoptosis is through the activation of the Fas molecule on the cell membrane. To investigate whether Fas-induced cell death activated cdc2 and cdk2 kinases inappropriately, the human T lymphoma cells HUT-78, which express a high copy number of Fas, and two other previously characterized subclones of the same cell line which express mutant, cell death-deficient dominant-negative forms of Fas, were Fas-challenged and the changes in cdc2 and cdk2 kinase activity monitored. In both wild-type and Fas-mutated HUT-78 cells, apoptosis was associated simultaneously with decreased cdc2 and increased cdk2 activity. This association suggested that changes in cdc2 and cdk2 kinase activity are secondary events in cell death mediated by Fas.

Apoptosis↗

PubMed1997

Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis.

The mechanisms responsible for thyrocyte destruction in Hashimoto's thyroiditis (HT) are poorly understood. Thyrocytes from HT glands, but not from nonautoimmune thyroids, expressed Fas. Interleukin-1beta (IL-1beta), abundantly produced in HT glands, induced Fas expression in normal thyrocytes, and cross-linking of Fas resulted in massive thyrocyte apoptosis. The ligand for Fas (FasL) was shown to be constitutively expressed both in normal and HT thyrocytes and was able to kill Fas-sensitive targets. Exposure to IL-1beta induced thyrocyte apoptosis, which was prevented by antibodies that block Fas, suggesting that IL-1beta-induced Fas expression serves as a limiting factor for thyrocyte destruction. Thus, Fas-FasL interactions among HT thyrocytes may contribute to clinical hypothyroidism.

Antibodies, Monoclonal↗

PubMed1997

Defective expression of CD95 (FAS/APO-1) molecule suggests apoptosis impairment of T and B cells in HLA-B8, DR3-positive individuals.

Activation-induced apoptosis is one of the primary control mechanisms for the negative selection of an immune response, leading to maintenance of immune homeostasis and selective T cell deletion. The interaction between the surface molecule Fas and its ligand (FasL) has been proposed as a primary mechanism initiating T cell apoptosis. The T cell receptor modulates the expression and function of these molecules. Defects in the Fas/FasL apoptosis pathway have been shown to result in autoimmune disease in humans and in murine models. Because subjects carrying the HLA-B8, DR3 haplotype show a number of immune dysfunctions, including membrano-proliferative glomerulonephritis, systemic lupus erythematosus, Graves' disease, and others, we investigated Fas expression on T and B cells, and sensitivity to Fas-mediated apoptosis of activated T cells, to determine whether abnormalities of the Fas pathway might be associated with the development of autoimmune diseases in this group of individuals. Our findings show that B cells and resting T cells from HLA-B8+, DR3+ subjects express markedly reduced levels of Fas compared with those isolated from HLA-B8-, DR3+ individuals. Reduced levels of Fas were also evident on the surface of T cells from HLA-B8+, DR3+ subjects activated in vitro by stimulation with OKT3 and phytohemoagglutinin. Cycling T cells from these subjects, evaluated for apoptotic nuclei by flow cytometry after incubation with a cytolytic anti-Fas mAb, showed a significantly lower percentage of Fas-mediated apoptosis than did those from HLA-B8-, DR3- individuals. Normal levels of apoptosis were restored after exposure to a synthetic ceramide analog (C2). Further elucidation of the interaction of these molecules in autoimmune diseases may lead to better understanding of the pathogenesis of these disorders.

Antigens, CD19↗

PubMed1997

Lipomatous metaplasia in left ventricular scar.

BACKGROUND AND OBJECTIVE: Substitution of interstitial tissue by fat may be observed in the right ventricle of hearts but is less common in the left ventricle. Fat was noted in myocardial scars of patients undergoing heart transplantation, prompting this retrospective study to determine the frequency of left ventricular myocardial scar being replaced by fat and its significance METHODS AND RESULTS: The left and right ventricles and coronary arteries were sampled systematically and lesions quantified histologically in 97 normal subjects dying accidentally; 116 consecutive failing hearts excised at transplantation from patients with ischemic heart disease, idiopathic dilated cardiomyopathy or chronic valvulopathy; and 34 autopsy hearts of apparently normal subjects with "silent' Chagas' heart disease who died suddenly and unexpectedly. Twenty-two left ventricular aneurysmectomy specimens from ischemic patients with heart failure were also studied. Among excised hearts lipomatous metaplasia of myocardial scar was observed in 68% of ischemic heart disease, in 37% of chronic valvulopathy and in 26% of idiopathic dilated cardiomyopathy patients; it was seen in 15% of Chagasic patients and in 55% of aneurysm walls. CONCLUSIONS: Lipomatous metaplasia of scar is often associated with severe heart failure and is more frequent and extensive in ischemic heart disease. Transformation of a compact scar into compressible and "sliding' adipose tissue may worsen ventricular wall function, thus facilitating and/or aggravating aneurysm formation. This phenomenon must be considered in the evaluation of myocardial repair, cardiac imaging of viable myocardium, quantitative morphology of autopsy specimens, and qualitative and quantitative biochemical analysis of myocardial tissue.

Adipose Tissue↗

PubMed1996

Ceramide inhibits antigen uptake and presentation by dendritic cells.

Ceramides are intramembrane diffusible mediators involved in transducing signals originated from a variety of cell surface receptors. Different adaptive and differentiative cellular responses, including apoptotic cell death, use ceramide-mediated pathways as an essential part of the program. Here, we show that human dendritic cells respond to CD40 ligand, as well as to tumor necrosis factor-alpha and IL-1 beta, with intracellular ceramide accumulation, as they are induced to differentiate. Dendritic cells down-modulate their capacity to take up soluble antigens in response to exogenously added or endogenously produced ceramides. This is followed by an impairment in presenting soluble antigens to specific T cell clones, while cell viability and the capacity to stimulate allogeneic responses or to present immunogenic peptides is fully preserved. Thus, ceramide-mediated pathways initiated by different cytokines can actively modulate professional antigen-presenting cell function and antigen-specific immune responses.

Antigen-Presenting Cells↗

PubMed1996

Determination of PAH in airborne particulate: comparison between off-line sampling techniques and an automatic analyser based on a photoelectric aerosol sensor.

The automatic analyser is based on a photoelectric aerosol sensor, with continuous sampling and an on-line detection system. Traditional sampling monitoring systems consist of collecting airborne particulate on filters; the sample is then extracted, purified and analysed. It is possible to identify each compound and to determine its relative abundance in the total particulate matter, on the other hand, this method requires great complexity of analysis. Continuous monitoring systems allow getting quicker results to compare with threshold levels. It is also possible to obtain an easier correlation with factors such as traffic flows or meteorological conditions. However, such systems cannot quantify single compounds, and data are expressed as total PAH. The comparison between the results shows a satisfactory linearity between the data obtained with the two methods. The difference of about one order of magnitude between the data obtained with photoelectric aerosol sensor (PAS) system and the sum of the concentrations of selected PAHs determined with off-line methods can be explained with the different selectivity of the two methods employed. This work has been developed in Aosta, the administrative centre of the Aosta Valley district.

Aerosols↗

PubMed1996

Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. A potential role for the acidic sphingomyelinase pathway in normal immunoregulation.

The expression and function of Fas (CD95/APO-1), a cell surface receptor directly responsible for triggering cell death by apoptosis, was investigated on human T lymphocytes resident within the intestinal lamina propria, a major site of antigen challenge and persistent lymphocyte activation. Three color immunofluorescence and FACS analysis indicated that virtually all freshly isolated human gut lamina propria T lymphocytes (T-LPL) express Fas, together with the marker of progress activation CD45R0. A discrete fraction of freshly isolated T-LPL also constitutively expressed Fas ligand (FasL), perhaps as a result of recent in vivo activation. Importantly, whereas Fas cross-linking did not result in apoptosis induction in peripheral blood T lymphocytes (T-PBL), Fas was found to be fully effective in generating the apoptotic signal in T-LPL. This was associated with the activation of an acidic sphingomyelinase and with ceramide generation, early events known to be involved in Fas-mediated apoptotic signaling. By contrast, acidic sphingomyelinase activation and ceramide production were not detectable in T-PBL after Fas cross-linking. However C2-ceramide, a cell permeant synthetic analog of ceramide, could efficiently induce apoptosis in T-LPL and T-PBL when added exogenously. These data indicate that T-LPL constitutively express both Fas and FasL and that Fas cross-linking generates signals resulting in sphingomyelin hydrolysis and apoptosis, outlining a potential mechanism involved in intestinal tolerance. Moreover, they provide the first evidence of a role for ceramide-mediated pathways in normal immunoregulation.

Apoptosis↗

PubMed1996

Fas/Apo-1 (CD95) receptor lacking the intracytoplasmic signaling domain protects tumor cells from Fas-mediated apoptosis.

FAS/Apo-1 (CD95) is an apoptosis-signaling cell surface receptor belonging to the TNF receptor family. Tumor cells resistant to Fas-mediated apoptosis have been described, but to date, the mechanisms responsible for this resistance are not well understood. We found that a series of apoptosis-resistant clones from human HUT78 lymphoma cells express a splicing variant coding for a truncated Fas molecule that lacks the intracellular death-signaling domain. The mutation responsible for the FasExo8Del expression was identified as a deletion-insertion in the intron 7/exon 8 region of the Fas gene. Moreover this mutation affects the phenotype in a dominant negative fashion, i.e., even in the presence of the normal receptor.

Adult↗

PubMed1996

Morphological bases for thallium-201 uptake in cardiac imaging and correlates with myocardial blood flow distribution.

To determine the morphological bases of thallium-201 myocardial distribution in chronic cardiac dysfunction and their relation to myocardial blood flow, myocardial slices from ten excised hearts of five chronic ischaemic heart disease patients and five idiopathic dilated cardiomyopathy patients, were imaged on a gamma camera to quantitate the uptake of thallium-201, injected 4 h before surgery, and myocardial blood flow from distribution of technetium-99m-labelled human albumin microspheres injected during surgery. Tracer distribution was correlated with histologically assessed myocardial fibrosis and myocytolysis. Thallium-201 uptake was inversely related to fibrosis (r = -0.73, in ischaemic heart disease, r = -0.65 in idiopathic dilated cardiomyopathy). In ischaemic heart disease, myocardial blood flow was related neither to thallium-201 uptake (r = 0.41) nor to the extent of fibrosis (r = -0.48). In this group, segments with normal or mildly reduced thallium-201 uptake showed significantly lower fibrosis than those with moderate or severe uptake defects (5 +/- 7% and 7 +/- 11% vs 33 +/- 14% and 42 +/- 12%, respectively, P < 0.0001. In a clinical model of chronic ischaemic dysfunction, despite severely depressed myocardial blood flow, extensive areas of myocardium devoid of significant structural impairment are present. Thallium-201 uptake effectively discriminates regions with preserved viability from those with relevant myocardial damage.

Adult↗

PubMed1996

Prognostic determinants of six-month morbidity and mortality in heart transplant recipients. The Italian Study Group on Infection in Heart Transplantation.

BACKGROUND: Knowledge of time course and risk factors for morbidity and mortality may allow better cardiac graft allocation, surveillance timing, and planning of immunosuppressive strategies. METHODS: Six-month morbidity and mortality were retrospectively analyzed in a multiinstitutional series of 645 heart transplant recipients. RESULTS: During a 3432 patient-months follow-up, 87 patients died of infection (n = 11), rejection (n = 11), multiorgan failure (n = 9) and other transplant-related causes (n = 56); six-month survival rate was 86%. Three hundred thirty-seven recipients had 967 treated rejection episodes (2.87 episodes/patient with rejection, lethality 3.2%); 223 major infectious episodes occurred in 162 patients (1.38 episodes/infected patient, lethality 7%). Six-month rejection and infection-free survival rates were 44% and 73%. Total mortality and cause-specific morbidity sharply declined after the first month; 160 patients (25%) had no events during follow-up. At multivariable analysis, significant risk factors for mortality were postoperative acute kidney failure, prolonged cardiopulmonary bypass time, and previous cardiac surgery. Rejection was associated with steroid-free and globulin-free immunosuppression and infection was associated with steroid immunosuppression, cytolytic treatment, venous lines placement greater than 7 days, and mechanical ventilation time. No single or combination of variables was able to discriminate patients with an event-free course. CONCLUSIONS: Morbidity and mortality have the highest incidence during the early posttransplantation phase. Preoperative variables are of limited value with respect to immunosuppressive treatment in predicting outcome. Infection is far less frequent than rejection but, in view of the higher lethality rate, deserves a vigorous effort for prevention, which is best addressed by appropriate modulation of immunosuppressive strategies.

Adult↗

PubMed1995

Multiple pathways originate at the Fas/APO-1 (CD95) receptor: sequential involvement of phosphatidylcholine-specific phospholipase C and acidic sphingomyelinase in the propagation of the apoptotic signal.

The early signals generated following cross-linking of Fas/APO-1, a transmembrane receptor whose engagement by ligand results in apoptosis induction, were investigated in human HuT78 lymphoma cells. Fas/APO-1 cross-linking by mAbs resulted in membrane sphingomyelin hydrolysis and ceramide generation by the action of both neutral and acidic sphingomyelinases. Activation of a phosphatidylcholine-specific phospholipase C (PC-PLC) was also detected which appeared to be a requirement for subsequent acidic sphingomyelinase (aSMase) activation, since PC-PLC inhibitor D609 blocked Fas/APO-1-induced aSMase activation, but not Fas/APO-1-induced neutral sphingomyelinase (nSMase) activation. Fas/APO-1 cross-linking resulted also in ERK-2 activation and in phospholipase A2 (PLA2) induction, independently of the PC-PLC/aSMase pathway. Evidence for the existence of a pathway directly involved in apoptosis was obtained by selecting HuT78 mutant clones spontaneously expressing a newly identified death domain-defective Fas/APO-1 splice isoform which blocks Fas/APO-1 apoptotic signalling in a dominant negative fashion. Fas/APO-1 cross-linking in these clones fails to activate PC-PLC and aSMase, while nSMase, ERK-2 and PLA2 activates are induced. These results strongly suggest that a PC-PLC/aSMase pathway contributes directly to the propagation of Fas/APO-1-generated apoptotic signal in lymphoid cells.

Antibodies, Monoclonal↗

PubMed1995

Cross-linking of alpha 4 beta 1 and alpha 5 beta 1 fibronectin receptors enhances natural killer cell cytotoxic activity.

Cell/extracellular matrix interactions mediated by integrins regulate differentiation, migration, and effector functions of immune system components. Human NK cells express alpha 4 beta 1 and alpha 5 beta 1 integrins, which mediate their binding to fibronectin (FN). We have investigated the ability of FN and its beta 1 integrin receptors to modulate NK cytotoxicity. Our data show that the presence of immobilized FN significantly augments the spontaneous cytotoxic activity of in vitro cultured human NK cells against several NK-susceptible, but not NK-resistant, target cells; Ab-dependent cytotoxicity against Ab-coated P815 target cells and the redirected lysis of anti-CD16 hybridomas are also enhanced in the presence of FN. Solid-phase-bound anti-human beta 1, or its F(ab')2 fragment, anti-alpha 4 and anti-alpha 5 mAbs, all consistently enhance Ab-dependent cytotoxicity against Ab-coated murine target cells. The 120-kDa (alpha 5 beta 1-binding), but not the 40-kDa (alpha 4 beta 1-binding), FN fragment fully reproduced the enhancing effect observed with the entire molecule. Our data also demonstrate that alpha 4 beta 1 and alpha 5 beta 1 cross-linking on NK cells induces an increase of intracellular Ca2+ concentration that is abrogated by EGTA, thus suggesting that the capacity to mobilize Ca2+ is involved in the coactivating role of alpha 4 beta 1 and alpha 5 beta 1 FN receptors in the cytotoxic functions of NK cells.

Antibodies, Monoclonal↗

PubMed1995

Epstein-Barr virus DNA is present both in CD10/CD77 positive and negative subsets of human tonsillar lymphocytes.

We report the fractionation of freshly isolated subsets of tonsillar lymphocytes according to cell density and double sorting for the differential expression of CD10 and CD77, and their analysis for the presence of Epstein Barr virus genome by nested PCR. All the subsets of tonsillar lymphocytes gave unequivocal evidence for the presence of EBV DNA, when obtained from EBV seropositive individuals. Confirmation of all cases examined demonstrates that B lymphocytes from the germinal centers of tonsils are also involved in carrying the EBV infection in vivo.

Adolescent↗

PubMed1995

Low bcl-2 expression and increased spontaneous apoptosis in T-lymphocytes from newly-diagnosed IDDM patients.

The bcl-2 gene product has been shown to regulate apoptotic cell death, and its dysregulation has been shown to induce several abnormalities in the immune system. No data exist regarding bcl-2 expression in autoimmune diseases, such as human insulin-dependent diabetes mellitus (IDDM). We investigated bcl-2 protein expression by testing T lymphocytes from 15 newly-diagnosed (< 3 weeks) IDDM patients in comparison to 10 age-matched control subjects. The expression of bcl-2 on CD3+ lymphocyte subsets was investigated after membrane permeabilization by two- or three-colour immunofluorescence. When the percentage and mean fluorescence intensity (MFI) of bcl-2+/CD3+ cells from normal individuals and patients were compared, we found that bcl-2 expression within the CD3+ and CD4+ CD45R0+ T-cell populations was reduced significantly in IDDM patients (46.8 +/- 15.4 vs 79.6 +/- 11.7; 25.7 +/- 3.8 vs 47.15 +/- 5.7, respectively; p < 0.001). To establish whether low bcl-2 expression in T cells from newly-diagnosed patients reflects their susceptibility to death by an apoptotic process, we also evaluated DNA staining with propidium iodide in CD3+ lymphocyte suspension after a (24-72 h) culture period (spontaneous apoptosis). We found that IDDM patients have higher levels of spontaneous apoptosis (mean +/- SEM: 24 h = 4.6 +/- 0.8; 48 h = 9.9 +/- 1; 72 h = 12.8 +/- 1.1) than control subjects (24 h = 1.8 +/- 0.4; 48 h = 4.6 +/- 0.4; 72 h = 5.7 +/- 0.3; p < 0.02-0.001). Our study suggests that recent onset IDDM is characterised by reduced bcl-2 expression, which in turn may be associated with the increased spontaneous apoptosis we observed.

Adolescent↗

PubMed1995

Defective expression of the apoptosis-inducing CD95 (Fas/APO-1) molecule on T and B cells in IDDM.

Triggering of CD95 (Fas/APO-1) cell surface receptors regulates the elimination of autoreactive T and B lymphocytes through a mechanism of cell suicide called apoptosis. Three different mutations involving CD95 or its ligand are responsible for induction of autoimmunity in susceptible mouse strains. To determine whether a defect involving the CD95 receptor is associated with human insulin-dependent diabetes mellitus (IDDM), we have studied the expression of CD95 on peripheral blood mononuclear cells from IDDM patients at different stages of the disease. Three-colour flow cytometry and mean fluorescence analysis showed that T and B lymphocytes from newly diagnosed IDDM and patients with long-standing disease, and subjects at high risk of developing the disease were highly defective in CD95 expression (p < 0.001), whereas monocytes from all the groups studied expressed normal amounts of CD95 molecules on their cell surface. T-cell subset analysis showed that the impairment of CD95 expression in IDDM patients and high-risk subjects involved both CD3+ CD4+ (p < 0.001) and CD3+ CD8+ cells (p range: < 0.01-0.001), suggesting that this alteration concerns both helper and cytotoxic T cells. Moreover, after activation in vitro with anti-CD3 monoclonal antibody, T cells from newly diagnosed IDDM patients maintained a reduced CD95 expression during the entire cell culture period (24-72 h) in comparison to the control population (p < 0.001). In conclusion, we found a reduced expression of the apoptosis-inducing CD95 receptor on T and B lymphocytes of individuals with clinical and preclinical IDDM. We hypothesize that this defective expression may impair the capacity of autoreactive lymphocytes to undergo CD95-mediated apoptosis, contributing to the lack of control on beta-cell specific B- and T-cell clones.

Adult↗

PubMed1995

T-cell activation in HLA-B8, DR3-positive individuals. Early antigen expression defect in vitro.

The HLA-B8, DR3 haplotype is overrepresented in several autoimmune diseases, implying that genes predisposing to these disorders are linked to this haplotype. In the patients affected by these diseases, as well as in healthy HLA-B8, DR3 individuals, various dysfunctions reflecting an impairment of T-cell activation have been found. To better characterize T-cell impairment of HLA-B8, DR3-positive healthy individuals, we analyzed the surface expression of early (CD69) and late (CD71) activation phenotypes. MNC cultures were stimulated with PHA and used for T-cell phenotyping by flow cytometry analysis. The results showed that the percentage of CD69+ T cells was significantly decreased in MNC from HLA-B8, DR3+ subjects. This defect was detected in cell cultures from all subjects studied, but it attained significance only in females in the early hours after stimulation. The difference in CD69 expression between HLA-B8, DR3-positive individuals and -negative ones was not due to differences in CD4 and CD8 ratios in the HLA-B8, DR3 cells that underwent activation, as following activation the pattern of CD4 and CD8 antigen expression was the same in both groups of subjects. Concerning the late antigen CD71, no significant difference in percentage was observed between T lymphocytes from HLA-B8, DR3+ and HLA-B8, DR3- subjects at all the times studied. The analysis of the requirements for CD69 expression has suggested that sustained PKC activation and an increase of intracellular CA2+ could be responsible for TCR/CD3-mediated CD69 induction. Thus, present data suggest a defect in the signal transduction pathway of the TCR/CD3 complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

[Dilated cardiomyopathy: a new natural history? The experience of the Italian Multicenter Cardiomyopathy Study (SPIC)].

BACKGROUND: The natural history of idiopathic dilated cardiomyopathy (IDC), once a disease with a dire prognosis, is thought to be changing. Aim of this study was to describe the clinical characteristics, long term course and prognostic factors of IDC patients followed up prospectively since the late eighties. METHODS: Patients with a diagnosis of IDC confirmed by normal coronary angiography, non specific endomyocardial biopsy findings and a left ventricular ejection fraction below 50% were consecutively enrolled in a multicenter registry and followed up at 6-months intervals. RESULTS: From January 1986 till January 1994, 441 IDC patients with a mean age of 43 +/- 13 years (range 8-68) entered the registry. Thirty per cent of patients were women and 8% had familial dilated cardiomyopathy. NYHA class was I-II in 77% and 35% of patients were asymptomatic at the time of diagnosis. Treatment included digitalis in 235 patients (53%), diuretics in 239 (54%), angiotensin converting enzyme inhibitors in 269 (61%), betablockers in 108 (24%). Chronic atrial fibrillation was detected in 10% of patients and left bundle branch block in 24%. Mean cardiothoracic ratio was 0.54 +/- 0.06. Mean left ventricular end diastolic dimension was 38 +/- 6 mm/m2; 48% of patients had minimal or mild left ventricular dilatation. Mean left ventricular ejection fraction was 30 +/- 10%. At Holter monitoring 67% of cases had complex ventricular arrhythmias, 37% had ventricular tachycardia and 4% had advanced atrioventricular block. Mean exercise stress test duration was 9 +/- 4 minutes. After a mean follow up of 31 +/- 24 months, 337 patients were alive without transplantation and 5 were lost to follow up; 60 patients (14%) had died of cardiac causes, namely heart failure (6%), sudden death (7%) and pulmonary embolism (< 1%) and 30 had been transplanted (7%), while 4 had died of unclear causes. Survival and transplant-free survival were 94% and 90% at 2 years and 82 and 76% at 5 years, respectively. At multivariate analysis pulmonary capillary wedge pressure (p = 0.0001, odds ratio, for values > 15 mm Hg, 2.05) and betablocker treatment (p = 0.002, odds ratio 0.26) were independent predictors of survival. CONCLUSIONS: In this large, multicenter prospective study, prognosis of IDC in the eighties appears to be improved. Early diagnosis, together with improved medical treatment, probably bears a causal relation to these changes.

Adolescent↗