transforming-growth-factor-beta and Death--Sudden--Cardiac

In patients with sudden unexpected cardiac death, there is a relationship between the interstitial fibrosis of the myocardium and matrix molecules with a role in global remodeling of the cardiac stroma. Tissue samples of left ventricular myocardium from 17 middle-aged patients with sudden cardiac death, following acute or chronic ischemic cardio(myo)pathies, were analyzed using standard HE stain and the indirect tristadial ABC peroxidase immunohistochemical method for a panel of four antibodies involved in the dynamic remodeling of extracellular matrix: matrix metalloproteinase 9 (MMP9), tenascin X (Tn-X), TGF-b, CD54 (ICAM-1), together with simultaneously assessment of troponin in myocardic fibers. The most sensitive reaction was noticed for ICAM-1 in 71% of cases, followed by MMP9 in 59% of cases and TGF-b in 47% of cases (with great specificity for capillary vessels), in the extracellular matrix of the residual cardiomyocytes. A direct correlation, statistically significant was recorded between troponin and MMP9 (r = 0.65, p = 0.01), troponin and ICAM-1 (r = 0.31, p = 0.02), respectively ICAM-1 and tenascin (r = 0.72, p = 0.01). The extensive expression of ICAM-1 in the extracellular matrix from the perilesional area probably plays a role in the stimulation of new developing adhesion substrates between residual cells and adjacent stroma, while the over expression of troponin in the residual cardiomyocytes is accompanied by a high expression of MMP9 in the myocardic interstitium, with heterogeneous remodeling of the ventricular stroma. The simultaneous IHC expression of tenascin and ICAM-1 suggests a colocalization required for the nerve sprouting in the residual myocardium and for developing new focal cell-matrix adhesion contacts.

Topics: Adult; Antigens, CD; Death, Sudden, Cardiac; Extracellular Matrix Proteins; Female; Humans; Immunophenotyping; Intercellular Adhesion Molecule-1; Male; Matrix Metalloproteinase 9; Middle Aged; Myocardium; Tenascin; Transforming Growth Factor beta; Troponin

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous disorder characterized by fibro-fatty replacement of the right ventricular myocardium, associated with high risk of sudden death. The objective of this study is to identify the gene involved in ARVD1, which has been elusive ever since its locus was mapped to chromosome 14q24.3.. Mutation screening of the promoter and untranslated regions (UTRs) of the transforming growth factor-beta3 (TGFbeta3) gene was performed by direct sequencing of genomic DNA of one index case belonging to an ARVD1 family including 38 members in four generations. We detected a nucleotide substitution (c.-36G>A) in 5' UTR of TGFbeta3 gene, invariably associated with the typical ARVC clinical phenotype in the affected family members, according to the established diagnostic criteria. Investigation extended to 30 unrelated ARVC patients, performed by denaturing high-performance liquid chromatography (DHPLC), led to the identification of an additional mutation (c.1723C>T) in the 3' UTR of one proband. Neither nucleotide change was found in 300 control subjects. In vitro expression assays with constructs containing the mutations showed that mutated UTRs were twofold more active than wild-types.. We identified TGFbeta3 as the disease gene involved in ARVD1. The identification of a novel ARVC gene will increase the power of the genetic screening for early diagnosis of asymptomatic carriers among relatives of ARVC patients.

Topics: 3' Untranslated Regions; 5' Untranslated Regions; Animals; Arrhythmogenic Right Ventricular Dysplasia; Case-Control Studies; Cells, Cultured; Child; Chromatography, High Pressure Liquid; Death, Sudden, Cardiac; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Male; Mice; Myocytes, Cardiac; Pedigree; Transforming Growth Factor beta; Transforming Growth Factor beta3

Characterization of a distinct, and as yet unexplained phenotype of sudden cardiac death (SCD).. In a subgroup of patients with SCD, postmortem findings are limited to isolated idiopathic myocardial fibrosis (IMF). The absence of confounding factors may facilitate evaluation of the relationship between myocardial fibrosis and ventricular arrhythmogenesis.. Six patients with IMF were identified from a postmortem, consecutive 13-year series of 270 subjects presenting with SCD. Ventricular interstitial remodeling was assessed quantitatively and qualitatively and comparisons made with 6 age- and sex-matched control subjects who suffered noncardiac death. Myocardial collagen volume fraction and perivascular fibrosis ratio were determined and evidence for inflammatory response and apoptotic cell death was sought. The potential role of transforming growth factor beta 1 (TGF-beta(1)) in the pathogenesis of IMF was evaluated.. Overall myocardial collagen volume fraction was 1.6-fold higher in IMF (mean age 34 +/- 4 yrs) vs. controls (mean age 34 +/- 4 yrs, .022 +/- .001 vs .013 +/- .001; P < .001). Collagen volume fraction increase was diffuse but disproportionately so in the LV inferior wall (3.4-fold increase; .035 +/- .005 vs .012 +/- .018; P < .001). Perivascular fibrosis ratio was also increased (.770 +/- .014 vs .723 +/- .010; P = .007). There was no evidence of either myocardial inflammatory response or myocyte apoptosis in cases or controls. Expression of TGF-beta(1) was significantly increased in IMF vs controls.. IMF involves diffuse and heterogeneous remodeling of the ventricular interstitium, with a predilection for the LV inferior wall. TGF-beta(1) is a potential mediator of interstitial remodeling in IMF and SCD.

Topics: Adult; Analysis of Variance; Apoptosis; Cadaver; Case-Control Studies; Collagen; Death, Sudden, Cardiac; Endomyocardial Fibrosis; Female; Humans; Male; Phenotype; Statistics, Nonparametric; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling