Publications

Heart failure (HF) and atrial fibrillation (AF) commonly coexist and adversely affect mortality when found together. AF begets HF and HF begets AF. Rhythm restoration with antiarrhythmic drugs failed to show a mortality benefit but can be effective in improving symptoms. Nonpharmacologic treatment of AF may be of value in the HF population.

Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel-Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.

BACKGROUND

Atrial fibrillation (AF) risk has been associated with leaky ryanodine receptor 2 (RyR2) Ca release channels. Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca-binding protein calsequestrin 2 (Casq2) display an increased risk for AF. Here, we examine the underlying mechanisms of AF associated with loss of Casq2 and test mechanism-based drug therapy.

METHODS AND RESULTS

Compared with wild-type Casq2+/+ mice, atrial burst pacing consistently induced atrial flutter or AF in Casq2-/- mice and in isolated Casq2-/- hearts. Atrial optical voltage maps obtained from isolated hearts revealed multiple independent activation sites arising predominantly from the pulmonary vein region. Ca and voltage mapping demonstrated diastolic subthreshold spontaneous Ca elevations (SCaEs) and delayed afterdepolarizations whenever the pacing train failed to induce AF. The dual RyR2 and Na channel inhibitor R-propafenone (3 μmol/L) significantly reduced frequency and amplitude of SCaEs and delayed afterdepolarizations in atrial myocytes and intact atria and prevented induction of AF. In contrast, the S-enantiomer of propafenone, an equipotent Na channel blocker but much weaker RyR2 inhibitor, did not reduce SCaEs and delayed afterdepolarizations and failed to prevent AF.

CONCLUSIONS

Loss of Casq2 increases risk of AF by promoting regional SCaEs and delayed afterdepolarizations in atrial tissue, which can be prevented by RyR2 inhibition with R-propafenone. Targeting AF caused by leaky RyR2 Ca channels with R-propafenone may be a more mechanism-based approach to treating this common arrhythmia.

Injection drug use is an ongoing urban health crisis in China and one of the largest drivers of the transmission of HIV/AIDS. Sentinel surveillance sites in Yunnan province show upwards of 20% of injection drug users (IDUs) are HIV positive. Though the Ministry of Health has scaled-up needle exchange programs (NEPs), they have not received official government recognition nor have they been extensively evaluated to explore factors influencing their acceptability and feasibility. Using in-depth qualitative interviews conducted from February to July 2008 with 35 participants consisting of IDUs and other key stakeholders, we explored facilitators and barriers to accessing needle exchange programs in Kunming, the capital of Yunnan province. Content analysis was conducted to identify themes including attitudes toward NEPs and harm reduction, barriers to access, and suggestions for improvement. Themes that emerged included fears of breached confidentiality and police interference at the exchange sites and tensions between the public health and law enforcement perspective. Low levels of NEP-related knowledge and awareness were uniformly reported among interviewees. Suggestions to facilitate an increase in NEP acceptance included raising awareness of harm reduction and HIV more generally, offering services such as psychological counseling, job training and behavioral therapy at NEPs, and increasing communication between police, government, and public health officials. High rates of HIV infection among injection drug users in China have prompted rapid scale up of NEPs. Additional adaptations are necessary, however, to increase needle exchange use among injection drug users. This study finds that an urgent need to raise awareness of NEPs among policy makers and IDUs and act upon identified steps for developing social-structural interventions to create enabling environments that facilitate increased access to NEPs among injection drug users in Kunming.

Summary Due to the shared risk factors for viral transmission, coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common. This study examined the seroprevalence of HCV among HIV-infected patients in inpatient and outpatient settings. A retrospective chart review of 256 HIV-infected patients was conducted in Prince George's Hospital Center (inpatients from 1 September 2011 to 1 March 2012) and Glenridge Medical Center (outpatients from 1 January 2011 to 31 December 2012). The mean age of the population was 46 ± 12 and 44 ± 11 for inpatients and outpatients, respectively. HIV-infected men comprised 61.9% inpatients and 64.8% outpatients. The overall prevalence of HCV infection in HIV/AIDS patients was 12.5% (32/256), with a higher prevalence in the inpatient group than that in the outpatient group (24.6% vs 11.2%, p < 0.01). The percentages of drug abuse (43.8% vs 16.5%, p < 0.01) and alcoholism (25.0% and 14.3%, p < 0.05) in HCV/HIV-coinfected patients were higher than those in HIV-monoinfected patients. In addition, only 64.9% of HIV-infected and 50.0% of HCV/HIV-coinfected inpatients were followed up with outside care after discharge. To our knowledge, this study, for the first time, revealed that HCV/HIV coinfection was significantly higher in inpatients compared to outpatients. Considering the high prevalence and comorbidities associated with HCV/HIV coinfection, it is recommended that evaluation of hepatic damage, especially fibrosis, should be initiated during hospitalization as well as outpatient care.

While global health (GH) opportunities have expanded at schools of medicine, nursing, and public health, few examples of interprofessional approaches to GH education have been described. The elective GH program at our university serves as an important opportunity for high-quality interprofessional education. We undertook a qualitative study to examine the experience of student, faculty and administrative leaders of the program. We used content analysis to code responses and analyze data. Among the leadership, key themes fell within the categories of interprofessional education, student-faculty collaboration, professional development, and practical considerations for the development of such programs. The principles described could be considered by institutions seeking to develop meaningful partnerships in an effort to develop or refine interprofessional global health education programs.