The neurotrophin brain-derived neurotrophic factor (BDNF) is required for the maintenance of cardiac vessel wall stability during embryonic development through direct angiogenic actions on endothelial cells expressing the tropomysin receptor kinase B (TrkB). However, the role of BDNF and a related neurotrophin ligand, neurotrophin-4 (NT-4), in the regulation of revascularization of the adult tissues is unknown. To study the potential angiogenic capacity of BDNF in mediating the neovascularization of ischemic and non-ischemic adult mouse tissues, we utilized a hindlimb ischemia and a subcutaneous Matrigel model. Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A. The introduction of BDNF into non-ischemic ears or ischemic limbs induced neoangiogenesis, with a 2-fold increase in the capillary density. Remarkably, treatment with BDNF progressively increased blood flow in the ischemic limb over 21 days, similar to treatment with VEGF-A. The mechanism by which BDNF enhances capillary formation is mediated in part through local activation of the TrkB receptor and also by recruitment of Sca-1 + CD11b + pro-angiogenic hematopoietic cells. BDNF induces a potent direct chemokinetic action on subsets of marrow-derived Sca-1 + hematopoietic cells co-expressing TrkB. These studies suggest that local regional delivery of BDNF may provide a novel mechanism for inducing neoangiogenesis through both direct actions on local TrkB-expressing endothelial cells in skeletal muscle and recruitment of specific subsets of TrkB + bone marrow-derived hematopoietic cells to provide peri-endothelial support for the newly formed vessels.

The neurotrophin brain-derived neurotrophic factor (BDNF) is required for the maintenance of cardiac vessel wall stability during embryonic development through direct angiogenic actions on endothelial cells expressing the tropomysin receptor kinase B (TrkB). However, the role of BDNF and a related neurotrophin ligand, neurotrophin-4 (NT-4), in the regulation of revascularization of the adult tissues is unknown. To study the potential angiogenic capacity of BDNF in mediating the neovascularization of ischemic and non-ischemic adult mouse tissues, we utilized a hindlimb ischemia and a subcutaneous Matrigel model. Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A. The introduction of BDNF into non-ischemic ears or ischemic limbs induced neoangiogenesis, with a 2-fold increase in the capillary density. Remarkably, treatment with BDNF progressively increased blood flow in the ischemic limb over 21 days, similar to treatment with VEGF-A. The mechanism by which BDNF enhances capillary formation is mediated in part through local activation of the TrkB receptor and also by recruitment of Sca-1+CD11b+ pro-angiogenic hematopoietic cells. BDNF induces a potent direct chemokinetic action on subsets of marrow-derived Sca-1+ hematopoietic cells co-expressing TrkB. These studies suggest that local regional delivery of BDNF may provide a novel mechanism for inducing neoangiogenesis through both direct actions on local TrkB-expressing endothelial cells in skeletal muscle and recruitment of specific subsets of TrkB+ bone marrow-derived hematopoietic cells to provide peri-endothelial support for the newly formed vessels.

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Key Points Carfilzomib 56 mg/m2 provided a high overall response rate with a remarkable duration of response in patients with R/RMM. Nonhematologic grade 3/4 AEs likely related to carfilzomib treatment included hypertension and heart failure.

Postoperative hemodynamic instability after pericardial window portends a grave prognosis. Evidence of tamponade, larger effusion volumes, and positive cytologic findings may predict a higher risk of paradoxical hemodynamic instability and anticipate a need for invasive monitoring and intensive care postoperatively.

Prior studies report 9–27% of persons receiving a hematopoietic cell transplant develop arrhythmias, but the effect on outcomes is largely unknown. We reviewed data from 1177 consecutive patients {greater than or equal to}40 years old receiving a hematopoietic cell transplant at one center during 1999–2009. Transplant indication was predominately leukemia, lymphoma and multiple myeloma. Overall, 104 patients were found to have clinically significant arrhythmia: 43 prior to and 61 following transplant. Post-transplant arrhythmias were most frequently atrial fibrillation(N=30), atrial flutter(N=7) and supraventricular tachycardia(N=11). Subjects with an arrhythmia post-transplant were more likely to have longer median hospital stays (32 days vs 23, P=<.001,) a greater probability of an ICU admission (52% vs 7%; P<.001), more inhospital deaths (28% vs 3%, P<0.001), and more deaths within one year of transplant (41% vs 15%; P<0.001) than patients without arrhythmia at any time. In a multivariate model including age at transplant, diagnosis, history of pre-transplant arrhythmia, and transplant-related variables, post-transplant arrhythmia was associated with a greater risk of death within a year of transplant (OR 3.5, 95% CI: 2.1, 5.9; P < 0.001). Our data suggest arrhythmias after transplants are associated with significant morbidity and mortality. A prospective study of arrhythmia in the transplant setting is warranted.

The introduction of cisplatin-based chemotherapy has transformed germ cell tumors (GCTs), the most common malignancy to affect young adult men, into a highly curable cancer, even in the setting of advanced disease. However, over the past decade, the success of these chemotherapy regimens in curing GCTs has been temporized by an increasing recognition of their important late toxicities, such as cardiovascular disease. The relative risk of coronary artery disease in this population is particularly elevated within the first 10 years of follow-up, when patients are still in their 30s and 40s, which are age groups often considered too young to experience cardiovascular events. Two hypotheses have been proposed to explain the association between chemotherapy and cardiovascular disease in this population. The direct hypothesis asserts that chemotherapy causes diffuse endothelial damage, including in the coronary arteries, gradually leading to cardiovascular disease. In contrast, the indirect hypothesis proposes that chemotherapy leads to an increased incidence of cardiovascular disease risk factors, such as hypertension, hyperlipidemia, and the metabolic syndrome, which in turn enhance the risk of cardiovascular disease. This article summarizes the data on the association between chemotherapy (predominantly cisplatin-based) and the development of cardiovascular disease among GCT survivors, and reviews the evidence supporting both mechanistic hypotheses. In addition, recommendations are provided for the management of GCT survivors who received cisplatin-based chemotherapy and are therefore at risk for cardiovascular toxicity.

Background. The purpose of this study was to investigate the prognostic importance of functional capacity in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for hematological malignancies. Patients and Methods. Using a retrospective design, 407 patients completed a 6-minute walk distance (6MWD) test to assess functional capacity before HCT; 193 (47%) completed a 6MWD test after hospital discharge. Cox proportional hazards regression was used to estimate the risk of nonrelapse mortality (NRM) and overall survival (OS) according to the 6MWD category (,400 m vs. $400 m) and the change in 6MWD (before HCT to discharge) with or without adjustment for Karnofsky performance status (KPS), age, and other prognostic markers. Results. Compared with ,400 m, the unadjusted hazard ratio for NRM was 0.65 (95% confidence interval, 0.44-0.96)