Is There a Role for Genetics in the Prevention of Sudden Cardiac Death?

The identification of patients at risk for sudden cardiac death (SCD) is fundamental for both acquired cardiovascular diseases (such as coronary artery diseases, CAD) and inherited arrhythmia syndromes (such as the long‐QT syndrome, LQTS). Genetics may play a role in both situations, although the potential to exploit this information to reduce the burden of SCD varies among these two groups. Concerning acquired cardiovascular diseases, which affect most of the general population, preliminary data suggest an association between genetics and the risk of dying suddenly. The maximal utility, instead, is reached in inherited arrhythmia syndromes, where the discovery of monogenic diseases such as LQTS tracked the way for the first genotype‐phenotype correlations. The aim of this review is to provide a general overview focusing on the current genetic knowledge and on the present and future applicability for prevention in these two populations at risk for SCD.     

CELLULAR KINETIC AND PHENOTYPIC HETEROGENEITY IN AND AMONG BURKITT'S AND BURKITT-LIKE LYMPHOMAS

This study asks whether the known genotypic heterogeneity within and between endemic or sporadic Burkitt's lymphomas (eBLs and sBLs, n=10 each), and Burkitt-like lymphomas (BLLs, n-12), is reflected in divergent cytokinetics and related immunophenotypes. There was strong evidence that eBL and BLL grow markedly faster than sBL, as shown by differences in mitotic and apoptotic indices. Furthermore, in BLL, the median percentage of neoplastic cells immunoreactive for the bcl-2 protein was much higher than that observed in eBL and sBL. The reverse was true for the median fraction of cells containing c-myc protein. In eBL and sBL, the median fraction of bcl-6 protein-positive cells reached values above 50 per cent, while cells of 8/12 BLLs did not contain detectable amounts of this protein. This observation indicates that in this respect, eBL and sBL resemble normal germinal centres of lymphatic tissue much more than do BLL. Evidence for infection of neoplastic cells by the Epstein-Barr virus (EBV) was observed in 9/10 cases of eBL and in 3/10 of sBL, but not in BLL. EBV-positive lymphomas were associated with distinctly lower apoptotic indices and smaller median percentages of bcl-6-positive cells than EBV-negative tumours. © 1997 John Wiley & Sons, Ltd.     

INTERLEUKIN 6 GENE-TRANSFECTED MOUSE MAMMARY ADENOCARCINOMA: TUMOUR CELL GROWTH AND METASTATIC POTENTIAL

Cells from the spontaneous metastatic TSA mammary adenocarcinoma of BALB/C mouse were transfected with the murine (interleukin-6) IL6 gene. The clone (TSA-IL6) secreting the largest amount of IL6 displayed an in vitro increased growth rate compared with that of TSA cells transfected with the neomycin resistance gene only (TSA-neo). TSA-IL6 cell colonies consisted mainly of fusiform cells and TSA-neo colonies of polygonal cells. When subcutaneously (s.c.) injected in syngeneic mice, TSA-IL6 cells gave rise to tumours that grew significantly slower than TSA-neo cell tumours. Microscopically, TSA-IL6 tumours displayed a fascicular pattern of growth, associated with a very scanty macrophage infiltrate. S.c. TSA-IL6 tumours were significantly less metastatic than TSA-neo tumours. By contrast, following intravenous (i.v.) challenge, TSA-IL6 cells produced 5–7 times more lung metastases than TSA-neo cells. The i.v. TSA-IL6 cell lung metastases showed a marked macrophage infiltrate and a rich vascularization. The high in vitro TSA-IL6 cell growth rate is attributable to the IL6-induced production of growth factors, some of which possess heparin-binding properties, such as amphiregulin. The differences in vascularization and macrophage infiltrate may underlie the observed differences between s.c. TSA-IL6 tumour growth with low spontaneous metastatic potential and the widespread growth of i.v. metastasis. © 1997 John Wiley & Sons, Ltd.