Citations

Abstract Studies have shown that the immune system can recognize self-antigens under conditions (eg, cell injury) in which the self-tissue might elaborate immune-activating endogenous danger signals. Uric acid (UA) is an endogenous danger signal recently identified to be released from dying cells. Prior work has shown that UA activates immune effectors of both the innate and adaptive immune system, including neutrophils and cytotoxic T-cell immunity. However, it was unclear whether UA could enhance antibody immunity, which was examined in this study. When added to dying tumor cells or with whole protein antigen, UA increased IgG1-based humoral immunity. Further, UA blocked growth of tumor in subsequent tumor challenge experiments, which depended on CD4, but not CD8, T cells. Sera derived from UA-treated animals enhanced tumor growth, suggesting it had little role in the antitumor response. UA did not signal for T-cell expansion or altered tumor-infiltrating leukocyte populations. Consistent with the lack of T-cell expansion, when applied to dendritic cells, UA suppressed T-cell growth factors but up-regulated B cell–activating cytokines. Understanding the nature of endogenous danger signals released from dying cells may aid in a better understanding of mechanisms of immune recognition of self.

Background— Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease. Methods and Results— We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (<17 μg/mg for men and <25 μg/mg for women). Independent of the estimated glomerular filtration rate and other baseline covariates, a higher ACR, even within the normal range, was associated with increased risks for all-cause mortality ( P <0.001) and cardiovascular death ( P =0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 μg/mg, P =0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82). Conclusions— Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Background— Diastolic dysfunction is a major pathophysiological abnormality in hypertrophic cardiomyopathy (HCM). Doppler echocardiographic parameters correlate with left ventricular (LV) filling pressures in other diseases, but it is unclear whether these findings apply to patients with HCM, who have multiple complex interrelated events leading to diastolic dysfunction. This study compares Doppler echocardiographic estimates of filling pressures to direct measurements of left atrial pressure (LAP) via catheterization in 100 patients with HCM. Methods and Results— One hundred patients who were symptomatic with HCM (New York Heart Association class III/IV, 82%) underwent measurement of early diastolic transmitral flow velocity (E) and mitral annular velocities (e′) with the use of transthoracic echocardiography within 48 hours of cardiac catheterization with direct measurement of LAP. In a subset of 42 patients, echocardiographic and catheterization measurements were performed simultaneously. Mean LAP directly correlated with medial E-e′ ratio in the overall population ( r =0.44, P <0.0001) and also in the subgroup of patients who had simultaneous echocardiographic and catheterization studies ( r =0.28, P =0.07). However, scatter was present. A calculated mean LV filling pressure was derived from the E-e′ ratio with the use of a previously described regression equation, and the 95% confidence limits of agreement with measured mean LAP exceeded ±18 mm Hg both for the overall group and for the subgroup who had simultaneous studies. Similar results were obtained with the lateral E-e′ ratio. Only 1 patient had a previously defined “normal” E-e′ ratio of <8. Conclusions— In symptomatic patients with HCM, Doppler echocardiographic estimates of LV filling pressure with the use of transmitral flows and mitral annular velocities correlate modestly with direct measurement of LAP. Given the complex nature of diastolic dysfunction in HCM, precise characterization of LV filling pressure in an individual patient cannot be determined with the use of these noninvasive parameters.

Background— We investigated the potential of conversion to sirolimus (SRL) as a primary immunosuppressant in attenuating cardiac allograft vasculopathy progression. Methods and Results— Twenty-nine cardiac transplant recipients were converted to SRL 3.8±3.4 years after transplantation with complete calcineurin inhibitor (CNI) withdrawal. Secondary immunosuppressants (azathioprine or mycophenolate) and steroids remained unchanged. Forty patients (controls) 4.8±4.0 years from transplantation were maintained on CNIs. Three-dimensional intravascular ultrasound studies were performed at baseline and 12.1±2.6 months later. Mean plaque (media and intima) volume (PV) and plaque index (PI) (PV/vessel volume percent) increased significantly in the CNI group (1.28±2.86 mm 3 /mm, P =0.004; and 6±8%, P =0.0001) but not in the SRL group (0.1±1.13 mm 3 /mm, P =0.63; and 0.1±8%, P =0.94). In patients enrolled within 2 years after transplantation, the increases in PV (0.06±1.06 versus 1.77±1.65 mm 3 /mm; P =0.0081) and PI (0±9% versus 10±8%; P =0.0145) were smaller in the SRL group (n=11) than in the CNI (n=12) group. In patients enrolled ≥2 years after transplantation, the increase in PI was less in the SRL group compared with the CNI group (0.1±6.5% versus 5±8%; P =0.033), but changes in PV did not differ significantly. Treatment with azathioprine or mycophenolate did not affect PV or PI in either the SRL group (PV: 0.22±0.66 versus 0.05±1.45 mm 3 /mm, P =0.46; PI: 1.5±6% versus −1.6±8.5%, P =0.29) or the CNI group (PV: 1.42±1.39 versus 1.06±2.28 mm 3 /mm, P =0.49; PI: 7.8±8.7% versus 4.8±7.3%, P =0.23). Conclusions— Substituting CNI with SRL as primary immunosuppression attenuates cardiac allograft vasculopathy progression.