Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study

Idiopathic dilated cardiomyopathy (DCM) is associated with reduced myocardial vascular density and increased collagen deposition with subsequent myocardial fibrosis and heart failure. The urokinase plasminogen activator (uPA)/plasminogen activator inhibitor (PAI) system plays an important role in extracellular matrix homeostasis as well as in preserving the integrity of the vascular endothelial cell (EC) intimal layer and EC regeneration, proliferation and motility. However, the involvement of the uPA/PAI system in DCM and graft remodeling following cardiac transplantation remains unclear. Gene expression of uPA, the uPA receptor uPAR and PAI-1 was examined in left ventricular (LV) biopsies of explanted hearts in 24 ischemic cardiomyopathy (ICM) and 60 DCM patients and 12 controls by real time RT-PCR and Western blotting. Vascular endothelial growth factor (VEGF) and uPA/PAI interplay was examined in stimulated DCM and ICM myocardium in vitro. Expression of uPA and PAI-1 mRNA was evaluated in endomyocardial biopsies (EMB) at 1, 2, 3, 4, 7, 12, 24 and 52 weeks post-transplant. The mRNA levels of uPA and uPAR were unchanged in both ICM and DCM patients compared to controls. PAI-1 mRNA and protein were up-regulated in DCM compared to ICM and controls (p<0.01). Active and inactive uPA protein was down-regulated in DCM and ICM compared to controls (p<0.05). VEGF stimulation in vitro did not affect uPA, uPAR or PAI-1 expression. Following transplantation, PAI-1 expression returned to baseline control levels in EMB from both patient groups, although PAI-1 expression increased at 24 and 52 weeks post-transplant in DCM patients (p<0.01 compared to post-transplant weeks 6 and 12). These data indicate a significant PAI-1 up-regulation associated with uPA down-regulation in DCM, independent of VEGF, which was temporarily corrected by cardiac transplantation. However, recurring up-regulation of myocardial PAI-1 levels at 6 and 12 months post-transplant suggest a persistent PAI-1-related molecular pathology in DCM. We have previously shown increased endothelin-1 expression and collagen deposition in grafts of DCM patients at 1 year post-transplant. The present data point to a previously unknown role of PAI-1 in mediating graft sclerosis.

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Anaemia is a predictor of early death or cardiac transplantation in children with idiopathic dilated cardiomyopathy

Cardiology in the Young ◽

10.1017/s1047951111001442 ◽

2011 ◽

Vol 22 (3) ◽

pp. 293-300 ◽

Cited By ~ 6

Author(s):

Issam Kammache ◽

Giovanni Parrinello ◽

Davide Marini ◽

Damien Bonnet ◽

Gabriella Agnoletti

Keyword(s):

Confidence Interval ◽

Dilated Cardiomyopathy ◽

Cardiac Transplantation ◽

Cox Model ◽

Early Death ◽

Hazard Ratio ◽

Idiopathic Dilated Cardiomyopathy ◽

C Reactive Protein ◽

Reactive Protein ◽

First Diagnosis

AbstractIntroductionThe aim of our study was to establish the prevalence and the prognostic value of haematological abnormalities in children with cardiac failure.Patients and methodsA series of 218 consecutive children with a first diagnosis of idiopathic dilated cardiomyopathy were retrospectively examined. Haematological evaluation was performed at first diagnosis. Death or cardiac transplantation was the main outcome measure.ResultsThe median age was 0.6 years, ranging from 1 day to 15.8 years and median follow-up was 2.65 years, ranging from 0 to 17.2 years. After a median interval of 0.2 years, ranging from 0 to 8.7 years, 56 patients died and 25 were transplanted. Event-free survival at 1 and 5 years was 68% (95% confidence interval, 63–75%) and 62% (95% confidence interval, 56–69%). Blood levels of haemoglobin less than 10 grams per decilitre, urea over 8 millimoles per litre, and C-reactive protein over 10 milligrams per litre were found in 24%, 20%, and 24% of patients, respectively. The log-rank test showed that haemoglobin (p = 0.000) and C-reactive protein (p = 0.021) were predictors of death or transplantation. In the multivariate Cox model, haemoglobin (hazard ratio = 0.735; confidence interval = 0.636–0.849; p = 0.000) and urea (hazard ratio = 1.083; confidence interval = 1:002–1:171; p = 0.045) were predictive of poor outcome. Cubic spline functions showed that the positive role of haemoglobin on survival was linear for values less than 12 grams per decilitre and null for values more than 12 grams per decilitre. Adaptive index models for risk stratification and Classification and Regression Tree analysis allowed to identify the cut-off values for haemoglobin (less than 10.2 grams per decilitre) and urea (more than 8.8 millimoles per litre), as well as to derive a predictor model.ConclusionsIn children with idiopathic dilated cardiomyopathy, anaemia is the strongest independent prognostic factor of early death or transplantation.

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