Faculty Bibliography

Testosterone replacement therapy is recommended for men with clinical androgen deficiency with decades of evidence supporting its use for treatment of sexual, physical, and psychological consequences of male hypogonadism. In this updated review, the authors discuss the implications of testosterone deficiency and conflicting evidence regarding testosterone replacement therapy and its effects on the cardiovascular system. Based on mounting evidence, the authors conclude that testosterone therapy can be safely considered in men with appropriately diagnosed clinical androgen deficiency and concurrent cardiovascular risk factors and even manifest cardiovascular disease after a thorough discussion of potential risks and with guideline-recommended safety monitoring.

BACKGROUND: Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events. STUDY DESIGN: EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur. CONCLUSIONS: The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

BACKGROUND: Preoperative anemia is a well-established risk factor for short-term mortality in patients undergoing non-cardiac surgery, but appropriate thresholds for transfusion remain uncertain. The objective of this study was to determine long-term outcomes associated with anemia, hemorrhage and red blood cell transfusion in patients undergoing non-cardiac surgery. METHODS: We performed a long-term follow-up study of consecutive subjects undergoing hip, knee, and spine surgery between November 1, 2008 and December 31, 2009. Clinical data were obtained from administrative and laboratory databases, and retrospective record review. Pre-operative anemia was defined as baseline hemoglobin <13 g/dL for men and <12 g/dL for women. Hemorrhage was defined by ICD-9 coding. Data on long-term survival were queried from the Social Security Death Index (SSDI) database. Logistic regression models were used to identify factors associated with long-term mortality. RESULTS: 3,050 subjects underwent orthopedic surgery. Pre-operative anemia was present in 17.6% (537) of subjects, hemorrhage occurred in 33 (1%), and 766 (25%) received >/=1 red blood cell transfusion. Over 9,015 patient-years of follow up, 111 deaths occurred. Anemia (HR 3.91, CI 2.49 - 6.15) and hemorrhage (HR 5.28, CI 2.20 - 12.67) were independently associated with long-term mortality after multivariable adjustment. Red blood cell transfusion during the surgical hospitalization was associated with long-term mortality (HR 3.96, CI 2.47 - 6.34), which was attenuated by severity of anemia (no anemia [HR 4.39], mild anemia [HR 2.27], and moderate/severe anemia [HR 0.81], P for trend 0.0015). CONCLUSIONS: Preoperative anemia, perioperative bleeding and red blood cell transfusion are associated with increased mortality at long-term follow up after non-cardiac surgery. Strategies to minimize anemia and bleeding should be considered for all patients and restrictive transfusion strategies may be advisable. Further investigation into mechanisms of these adverse events is warranted.

The cardioprotective mechanisms of colchicine in patients with stable ischemic heart disease remain uncertain. We tested varying concentrations of colchicine on platelet activity in vitro and a clinically relevant 1.8-mg oral loading dose administered over 1 h in 10 healthy subjects. Data are shown as median [interquartile range]. Colchicine addition in vitro decreased light transmission platelet aggregation only at supratherapeutic concentrations but decreased monocyte- (MPA) and neutrophil-platelet aggregation (NPA) at therapeutic concentrations. Administration of 1.8 mg colchicine to healthy subjects had no significant effect on light transmission platelet aggregation but decreased the extent of MPA (28 % [22-57] to 22 % [19-31], p = 0.05) and NPA (19 % [16-59] to 15 % [11-30], p = 0.01), platelet surface expression of PAC-1 (370 mean fluorescence intensity (MFI) [328-555] to 333 MFI [232-407], p = 0.02) and P-selectin (351 MFI [269-492] to 279 [226-364], p = 0.03), and platelet adhesion to collagen (10.2 % [2.5-32.6] to 2.0 % [0.2-9.5], p = 0.09) 2 h post-administration. Thus, in clinically relevant concentrations, colchicine decreases expression of surface markers of platelet activity and inhibits leukocyte-platelet aggregation but does not inhibit homotypic platelet aggregation.

Regulation of integrins is critical for lymphocyte adhesion to endothelium and trafficking through secondary lymphoid organs. Inside-out signaling to integrins is mediated by the small GTPase Rap1. Two effectors of Rap1 regulate integrins, RapL and Rap1 interacting adaptor molecule (Riam). Using mice conditionally deficient in both Rap1a and Rap1b and mice null for Riam we show that the Rap1/Riam module is not required for T or B cell development but is essential for efficient adhesion to ICAM-1 and VCAM-1 and for proper trafficking of lymphocytes to secondary lymphoid organs. Interestingly, in Riam deficient mice, whereas peripheral lymph nodes (pLNs) were depleted of both B and T cells and recirculating B cells were diminished in the bone barrow (BM), the spleen was hypercellular, albeit with a relative deficiency of marginal zone B cells. The abnormality in lympyhocyte trafficking was accompanied by defective humoral immunity to T cell-dependent antigens. Platelet function was intact in Riam deficient animals. These in vivo results confirm a role for Riam in the regulation of some, but not all, leukocyte integrins and suggest that Riam-regulated integrin activation is required for trafficking of lymphocytes from blood into pLNs and BM where relatively high shear forces exist in high endothelial venules and sinusoids, respectively.