No abstract

BACKGROUND Relatively limited epidemiological data are available regarding the prognosis of congestive heart failure (CHF) and temporal changes in survival after its onset in a population-based setting. METHODS AND RESULTS Proportional hazards models were used to evaluate the effects of selected clinical variables on survival after the onset of CHF among 652 members of the Framingham Heart Study (51% men; mean age, 70.0 +/- 10.8 years) who developed CHF between 1948 and 1988. Subjects were older at the diagnosis of heart failure in the later decades of this study (mean age at heart failure diagnosis, 57.3 +/- 7.6 years in the 1950s, 65.9 +/- 7.9 years in the 1960s, 71.6 +/- 9.4 years in the 1970s, and 76.4 +/- 10.0 years in the 1980s; p < 0.001). Median survival after the onset of heart failure was 1.7 years in men and 3.2 years in women. Overall, 1-year and 5-year survival rates were 57% and 25% in men and 64% and 38% in women, respectively. Survival was better in women than in men (age-adjusted hazards ratio for mortality, 0.64; 95% CI, 0.54-0.77). Mortality increased with advancing age in both sexes (hazards ratio for men, 1.27 per decade of age; 95% CI, 1.09-1.47; hazards ratio for women, 1.61 per decade of age; 95% CI, 1.37-1.90). Adjusting for age, there was no significant temporal change in the prognosis of CHF during the 40 years of observation (hazards ratio for men for mortality, 1.08 per calendar decade; 95% CI, 0.92-1.27; hazards ratio for women for mortality, 1.02 per calendar decade; 95% CI, 0.83-1.26). CONCLUSIONS CHF remains highly lethal, with better prognosis in women and in younger individuals. Advances in the treatment of hypertension, myocardial ischemia, and valvular heart disease during the four decades of observation did not translate into appreciable improvements in overall survival after the onset of CHF in this large, unselected population.

Cytotoxic T lymphocytes and natural killer cells use the perforin/granzyme pathway to kill virally infected cells and tumor cells. Mutations in genes important for this pathway are associated with several human diseases. CD4(+) T regulatory (Treg) cells have emerged as important in the control of immunopathological processes. We have previously shown that human adaptive Treg cells preferentially express granzyme B and can kill allogeneic target cells in a perforin-dependent manner. Here, we demonstrate that activated human CD4(+)CD25(+) natural Treg cells express granzyme A but very little granzyme B. Furthermore, both Treg subtypes display perforin-dependent cytotoxicity against autologous target cells, including activated CD4(+) and CD8(+) T cells, CD14(+) monocytes, and both immature and mature dendritic cells. This cytotoxicity is dependent on CD18 adhesive interactions but is independent of Fas/FasL. Our findings suggest that the perforin/granzyme pathway is one of the mechanisms that Treg cells can use to control immune responses.

ClinicalTrials.gov identifier: NCT01375842.

IntroductionThe innate and adaptive immune systems include cytotoxic lymphocytes (natural killer [NK] and cytotoxic T lymphocyte [CTL] cells) that are important for responses to intracellular pathogens and tumor cells. Although there are several mechanisms by which these cells kill (eg, Fas/Fas ligand, tumor necrosis factor [TNF]/TNF receptor, and Toll receptors), the major mechanism is that of the perforin/granzyme (granule exocytosis) pathway. [1][2][3][4] This pathway is critical for host mechanisms of defense, including viral clearance and tumor cell killing. Dysregulation of this pathway is associated with a number of human diseases, such as hemophagocytic lymphohistiocytosis, Griscelli syndrome, and X-linked lymphoproliferative disease. 1,[5][6][7] The granzymes are serine proteases that are packaged into the specialized cytotoxic granules of CTL and NK cells. It is believed that individual cells are armed with both perforin and granzymes, and that expression is limited to CD8 ϩ T lymphocytes and NK cells. 8 Although human CD4 ϩ T lymphocyte clones have been shown to express perforin and granzymes, the functional significance of the granule exocytosis pathway in these cells has not yet been clearly established. [9][10][11][12][13][14] Recent data from Kelso et al have suggested that individual cells may express different combinations of granzymes, implying an additional level of control in the process of cellular cytotoxicity. 15 Most studies of granzyme expression have relied on Northern blots, RNA protection assays, and/or reverse-transcriptionpolymerase chain reaction (RT-PCR) analysis to define cellular expression patterns. In addition, the majority of these studies have analyzed bulk cell populations. 8 There are 2 prior studies that have reported single-cell expression of either granzyme A or granzyme B in human CD8 ϩ T-cell subsets using intracellular flow cytometry. 16,17 In this report, we examine the dual expression patterns of both granzymes A and B using granzyme-specific monoclonal antibodies in an intracellular flow cytometry assay. We used this assay to characterize the expression patterns of granzymes A and B in resting and activated human peripheral blood mononuclear cells (PBMCs). Most CD56 ϩ 8 Ϫ NK cells, nearly all CD56 ϩ 8 ϩ NKT cells, and approximately half of the circulating CD8 ϩ T lymphocytes were found to coexpress both granzymes A and B. While few resting CD4 ϩ T lymphocytes expressed granzyme A or B, activation of CD4 ϩ T lymphocytes with concanavalin A (ConA)/ interleukin-2 (IL-2), or with antibodies directed against CD3/CD28 or CD3/CD46, induced high levels of granzyme B expression, but not granzyme A. Naive CD4 ϩ CD45RA ϩ T cells stimulated with antibodies to CD3/CD46 to generate adaptive Tr cells strongly expressed granzyme B, while stimulation with antibodies to CD3/CD28 was ineffective at driving granzyme B expression. In contrast, memory CD4 ϩ CD45RO ϩ T cells were found to express granzyme B with both modes of stimulation. Finally, we show that these activated granzyme ...