Dobutamine stress echocardiography for detection and assessment of coronary artery disease

AbstractStress echocardiography with dobutamine infusion for detection of coronary artery disease is a potential alternative to exercise stress testing with some theoretic advantages. Fifty patients who were not receiving cardioactive medication were prospectively studied with two-dimensional echocardiography and 12-lead electrocardiography (ECG) during incremental dobutamine infusion (5, 10, 15 and 20 μg/kg body weight per min, each dose for 8 min). Images were analyzed by using an 11-segment left ventricular model. All patients underwent correlative exercise ECG and coronary angiography, which revealed normal coronary arteries in 14 and significant disease (≥70% diameter stenosis) in 36.Peak rate-pressure product during dobutamine infusion was 18,845 ± 4,156 versus 23,740 ± 6,158 mm Hg/min on exercise (p < 0.01). Interobserver concordance for wall motion analysis was good (kappa coefficient = 0.77). The use of baseline (n = 14) or reversible (n = 24) regional asynergy to define an abnormal dobutamine echocardiogram resulted in a sensitivity for detecting coronary artery disease of 78% and a specificity of 93%. Corresponding data for the dobutamine ECG were 47% and 71% and for the exercise ECG were 72% and 71%, respectively. The development of new mitral regurgitation on Doppler color flow imaging (n = 4) improved sensitivity to 81% without loss of specificity.Inducible asynergy or new mitral regurgitation was observed in 6 (50%) of 12 patients with single-, 6 (60%) of 10 with double-and 12 (86%) of 14 with triple-vessel disease. The site of transient asynergy provided additional localizing information. Exercise duration and time to diagnostic ST segment shift were shorter in patients with coronary artery disease with versus those without echocardiographic evidence of ischemia (both p < 0.05). Side effects during dobutamine infusion were mild and short-lived.Dobutamine stress echocardiography is well tolerated, is useful for detection and assessment of coronary artery disease and is applicable to patients unable to exercise

Innate Immunity and Resistance to Tolerogenesis in Allotransplantation

The development of immunosuppressive drugs to control adaptive immune responses has led to the success of transplantation as a therapy for end-stage organ failure. However, these agents are largely ineffective in suppressing components of the innate immune system. This distinction has gained in clinical significance as mounting evidence now indicates that innate immune responses play important roles in the acute and chronic rejection of whole organ allografts. For instance, whereas clinical interest in natural killer (NK) cells was once largely confined to the field of bone marrow transplantation, recent findings suggest that these cells can also participate in the acute rejection of cardiac allografts and prevent tolerance induction. Stimulation of Toll-like receptors (TLRs), another important component of innate immunity, by endogenous ligands released in response to ischemia/reperfusion is now known to cause an inflammatory milieu favorable to graft rejection and abrogation of tolerance. Emerging data suggest that activation of complement is linked to acute rejection and interferes with tolerance. In summary, the conventional wisdom that the innate immune system is of little importance in whole organ transplantation is no longer tenable. The addition of strategies that target TLRs, NK cells, complement, and other components of the innate immune system will be necessary to eventually achieve long-term tolerance to human allograft recipients

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade–mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8(+) T cells (CD44(hi)CD62L(hi)CCR7(+)). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts. Intravital 2-photon imaging revealed that CCR7 expression on CD8(+) T cells was critical for formation of stable synapses with antigen-presenting cells, resulting in IFN-γ production, which induced NO and downregulated alloimmune responses. Thus, we describe a critical role for CD8(+) central memory T cells in lung allograft acceptance and highlight the need for tailored approaches for tolerance induction in the lung

Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It.

MHC alloantigen is recognized by two pathways: "directly," intact on donor cells, or "indirectly," as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.This work was supported by a British Heart Foundation project grant, the National Institute of Health Research Cambridge Biomedical Research Centre, and the National Institute of Health Research Blood and Transplant Research Unit. J.M.A. was supported by a Wellcome Trust Clinical Research Training Fellowship and Raymond and Beverly Sackler Scholarships. K.S.-P. was supported by an Academy of Medical Sciences/Wellcome Trust starter grant

Update on Dendritic Cell-Induced Immunological and Clinical Tolerance.

Dendritic cells (DCs) as highly efficient antigen-presenting cells are at the interface of innate and adaptive immunity. As such, they are key mediators of immunity and antigen-specific immune tolerance. Due to their functional specialization, research efforts have focused on the characterization of DCs subsets involved in the initiation of immunogenic responses and in the maintenance of tissue homeostasis. Tolerogenic DCs (tolDCs)-based therapies have been designed as promising strategies to prevent and control autoimmune diseases as well as allograft rejection after solid organ transplantation (SOT). Despite successful experimental studies and ongoing phase I/II clinical trials using autologous tolDCs in patients with type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and in SOT recipients, additional basic research will be required to determine the optimal DC subset(s) and conditioning regimens for tolDCs-based treatments in vivo. In this review, we discuss the characteristics of human DCs and recent advances in their classification, as well as the role of DCs in immune regulation and their susceptibility to in vitro or in vivo manipulation for the development of tolerogenic therapies, with a focus on the potential of tolDCs for the treatment of autoimmune diseases and the prevention of allograft rejection after SOT