Frye, Robert L.

Coronary artery disease (CAD) accounts for a large fraction of the morbidity, mortality, and cost of diabetes. Recognizing this, nearly 10 years ago the American Diabetes Association published a consensus recommendation that clinicians consider a risk factor–guided screening approach to early diagnosis of CAD in both symptomatic and asymptomatic patients. Subsequent clinical trial results have not supported those recommendations. Since the prior consensus statement, newer imaging methods, such as coronary artery calcium scoring and noninvasive angiography with computed tomography (CT) techniques, have come into use. These technologies, which allow quantitation of atherosclerotic burden and can predict risk of cardiac events, might provide an approach to more widespread coronary atherosclerosis screening. However, over this same time interval, there has been recognition of diabetes as a cardiovascular disease (CVD) equivalent, clear demonstration that medical interventions should provide primary and secondary CVD risk reduction in diabetic populations, and suggestive evidence that percutaneous coronary revascularization may not provide additive survival benefit to intensive medical management in patients with stable CAD. This additional evidence raises the question of whether documenting asymptomatic atherosclerosis or ischemia in people with diabetes is warranted. More data addressing this issue will be forthcoming from the BARI 2-D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. Until then, for patients with type 2 diabetes who are asymptomatic for CAD, we recommend that testing for atherosclerosis or ischemia, perhaps with cardiac CT as the initial test, be reserved for those in whom medical treatment goals cannot be met and for selected individuals in whom there is strong clinical suspicion of very-high-risk CAD. Better approaches to identify such individuals based on readily obtained clinical variables are sorely needed.

Background— Although age-adjusted cardiovascular disease (CVD) mortality has declined over the past decades, controversies remain about whether this trend was similar across locations of death and disease categories and about the existence of age and sex disparities. Methods and Results— We examined CVD mortality trends in Olmsted County, Minnesota, between 1979 and 2003 using the categories defined by the American Heart Association, including coronary heart disease (CHD), non-CHD diseases of the heart, and noncardiac circulatory diseases. Data on demographics, cause, and location of death of all 6378 residents who died of CVD were analyzed. Although decreases in the age-adjusted rates occurred in all groups, the magnitude of the decline varied widely. Lesser annual declines were noted in out-of-hospital than in-hospital deaths (1.8% versus 4.8%; P <0.001), in older than in younger persons (1.5% at age ≥85 years versus 3.9% for those ≤74 years of age; P <0.001), and in women relative to men (2.5% versus 3.3%; P =0.007). Furthermore, although CHD showed a marked annual decrease (3.3%), more modest decrements were found for non-CHD diseases of the heart (2.1%) and noncardiac circulatory diseases (2.4%) ( P =0.02 and P =0.04 for the comparison with CHD decline, respectively). Conclusions— Over the past 25 years, CVD mortality declined markedly in the community, but there were large disparities in the magnitude of the decline, resulting in a shift in the distribution toward out-of-hospital and non-CHD deaths. Further reduction in CVD mortality will require strategies directed at elderly persons and women, in whom out-of-hospital rates have improved only minimally.

CD4 T cells, through the release of cytokines as well as direct effector functions, have been implicated in promoting inflammation of the atherosclerotic plaque. Plaque-infiltrating CD4 T cells include a specialized subset of CD4 + CD28 − T cells that express a unique profile of regulatory receptors and are responsive to novel microenvironmental cues. Here we report that CD4 + CD28 − T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. CD4 + CD28 − IL-12R + cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of CD4 + CD28 − T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of CD4 + CD28 − T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated CD4 + CD28 − T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, CD4 + CD28 − T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12–inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions.

Acute coronary syndromes (ACS) are precipitated by a rupture of the atherosclerotic plaque, often at the site of T cell and macrophage infiltration. Here, we show that plaque-infiltrating CD4 T cells effectively kill vascular smooth muscle cells (VSMC). VSMCs sensitive to T cell–mediated killing express the death receptor DR5 (TNF-related apoptosis-inducing ligand [TRAIL] receptor 2), and anti-TRAIL and anti-DR5 antibodies block T cell–mediated apoptosis. CD4 T cells that express TRAIL upon stimulation are expanded in patients with ACS and more effectively induce VSMC apoptosis. Adoptive transfer of plaque-derived CD4 T cells into immunodeficient mice that are engrafted with human atherosclerotic plaque results in apoptosis of VSMCs, which was prevented by coadministration of anti-TRAIL antibody. These data identify that the death pathway is triggered by TRAIL-producing CD4 T cells as a direct mechanism of VSMC apoptosis, a process which may lead to plaque destabilization.

Background— The primary aim and central hypothesis of the study are that a designated syncope unit in the emergency department improves diagnostic yield and reduces hospital admission for patients with syncope who are at intermediate risk for an adverse cardiovascular outcome. Methods and Results— In this prospective, randomized, single-center study, patients were randomly allocated to 2 treatment arms: syncope unit evaluation and standard care. The 2 groups were compared with χ 2 test for independence of categorical variables. Wilcoxon rank sum test was used for continuous variables. Survival was estimated with the Kaplan-Meier method. One hundred three consecutive patients (53 women; mean age 64±17 years) entered the study. Fifty-one patients were randomized to the syncope unit. For the syncope unit and standard care patients, the presumptive diagnosis was established in 34 (67%) and 5 (10%) patients ( P <0.001), respectively, hospital admission was required for 22 (43%) and 51 (98%) patients ( P <0.001), and total patient-hospital days were reduced from 140 to 64. Actuarial survival was 97% and 90% ( P =0.30), and survival free from recurrent syncope was 88% and 89% ( P =0.72) at 2 years for the syncope unit and standard care groups, respectively. Conclusions— The novel syncope unit designed for this study significantly improved diagnostic yield in the emergency department and reduced hospital admission and total length of hospital stay without affecting recurrent syncope and all-cause mortality among intermediate-risk patients. Observations from the present study provide benchmark data for improving patient care and effectively utilizing healthcare resources.

The inflammatory infiltrate in atherosclerotic plaque is composed of T cells and macrophages. CD4 + T cells with a unique phenotype, CD4 + CD28 null , are preferentially recruited into culprit lesions. These T cells are distinct from classic CD4 + CD28 + T cells in gene expression and function, including their ability to mediate cytolysis. In this study, we have investigated the regulation of CD4 + CD28 null T-cell cytolytic function. In patients with acute coronary syndromes (ACS), CD4 + CD28 null T cells express killer immunoglobulin-like receptors (KIRs). KIRs encompass a polymorphic family of receptors that recognize HLA class I molecules and have been implicated in self-tolerance. CD4 + CD28 null T-cell clones from patients with ACS and age-matched controls were compared for their KIR-expression profile. T-cell clones derived from the patients expressed a broader spectrum of KIRs ( P <0.001) with preference for the stimulatory variant, CD158j. Additionally, CD4 + T-cell clones from patients but not those from controls acquired de novo expression of the DAP12 molecule, an adapter chain that transmits CD158j-derived signals. Cumulative expression of CD158j and DAP12 endowed cytolytic competence on CD4 + CD28 null T cells, allowing them to kill in the absence of T-cell receptor triggering. Our data demonstrate that CD4 + CD28 null T cells in ACS are characterized by a unique gene expression profile. Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance.