Publications

BACKGROUND

Tissue engineering approaches involving the direct transplantation of cardiac patches have received significant attention as alternative methods for the treatment of damaged hearts. In contrast, we used cardiomyocyte sheets harvested from temperature-responsive culture dishes to create pulsatile myocardial tubes and examined their in vivo function and survival.

METHODS AND RESULTS

Neonatal rat cardiomyocyte sheets were sequentially wrapped around a resected adult rat thoracic aorta and transplanted in place of the abdominal aorta of athymic rats (n=17). Four weeks after transplantation, the myocardial tubes demonstrated spontaneous and synchronous pulsations independent of the host heartbeat. Independent graft pressures with a magnitude of 5.9+/-1.7 mm Hg due to their independent pulsations were also observed (n=4). Additionally, histological examination and transmission electron microscopy indicated that the beating tubes were composed of cardiac tissues that resemble the native heart. Finally, when myocardial tubes used for aortic replacement were compared with grafts implanted in the abdominal cavity (n=7), we observed significantly increased tissue thickness, as well as expression of brain natriuretic peptide, myosin heavy chain-alpha, and myosin heavy chain-beta.

CONCLUSIONS

Functional myocardial tubes that have the potential for circulatory support can be created with cell sheet engineering. These results also suggest that pulsation due to host blood flow within the lumen of the myocardial tubes has a profound effect on stimulating cardiomyocyte hypertrophy and growth. These results demonstrate a novel approach for the future development of engineered cardiac tissues with the ability for independent cardiac assistance.

BACKGROUND

Altered conduction is associated with increased atrial fibrillation (AF) vulnerability in canine models of chronic mitral regurgitation (MR) and heart failure (HF). Rotigaptide (ZP123) augments gap junction conductance, improving cell-to-cell coupling. We studied the effects of rotigaptide on atrial conduction and AF vulnerability in the canine MR and HF models.

METHODS AND RESULTS

Twenty-one dogs in 3 groups were studied: control (n=7), chronic MR induced by mitral avulsion (n=7), and HF induced by ventricular tachypacing (n=7). Epicardial mapping of both atria was performed with a 512-electrode array at baseline and at increasing rotigaptide doses (10, 50, and 200 nmol/L). Conduction velocity increased in both atria in control animals and MR animals (maximum percentage increase: 24+/-5%, 38+/-6% [P<0.001, <0.001] in the left atrium and 19+/-9%, 18+/-3% [P<0.001, <0.001] in the right atrium). Conduction velocity did not change in the left atrium of the HF group and increased minimally in the right atrium (3+/-3%, 17+/-5% [P=NS, P=0.001]). AF duration was increased at baseline in MR and HF animals (control: 16+/-25 seconds, MR: 786+/-764 seconds, HF: 883+/-684 seconds; P=0.013). At 50 nmol/L of rotigaptide, duration of AF markedly decreased in the MR animals (96% reduction, P<0.001), reducing AF duration to that of control animals (control: 9+/-11 seconds, MR: 14+/-16 seconds, HF: 1622+/-355 seconds; P=0.04).

CONCLUSIONS

Gap junction modulation with rotigaptide reduces AF vulnerability in a canine MR model of AF to a level similar to control animals but does not affect AF vulnerability in the canine HF model. This may be a novel therapeutic target in some forms of AF.

A 15-year-old girl with perinatal HIV-1 infection has remained asymptomatic with undetectable plasma HIV-1 viremia for more than 5 years after discontinuing all antiretroviral therapy. Viral sequence analysis of proviral HIV-1 DNA revealed no evident fitness-attenuating deletions or mutations. This subject exhibited an unusually robust HIV-specific T-cell response, with an intact CD4+ T cell-proliferative response to HIV-1 antigens. In addition, the subject was found to be heterozygous for the 32-bp deletion in the CCR5 gene, which encodes the primary coreceptor for HIV-1 entry into cells. This mutation mediates profound resistance to HIV infection in homozygotes and has been associated with delayed disease progression in heterozygotes after both horizontal and vertical HIV-1 infection. Although adults with long-term nonprogressive HIV disease have been studied at length, there is no prior description in the literature of a perinatally HIV-infected child whose plasma HIV-1 viremia is controlled to undetectable levels in the absence of antiretroviral therapy.

SETTING

Few studies have examined strategies for optimizing adherence to latent tuberculosis infection (LTBI) treatment programs in homeless populations.

OBJECTIVES

1) To compare the effectiveness of an intervention program employing nurse case management and incentives (NCMI) vs. a control program with standard care and incentives on completion of LTBI treatment; and 2) to compare the impact of the two programs on tuberculosis (TB) knowledge among participants.

DESIGN

A prospective, two-group site-randomized design conducted among 520 homeless adults residing in the Skid Row region of Los Angeles from 1998 to 2003, assessing completion rates of a 6-month isoniazid (INH) treatment program and change in TB knowledge.

RESULTS

Using intent-to-treat analysis, 62% of participants in the intervention program, compared with 39% of controls, completed the full 6-month course of LTBI treatment with INH. Logistic regression modeling revealed that intervention participants had three times greater odds of completing INH treatment than controls. TB knowledge improved in both programs, but the increase was greater among the intervention participants (P < 0.001).

CONCLUSIONS

Nurse case management combined with education, incentives, and tracking dramatically improves both adherence to LTBI treatment and TB knowledge in homeless persons compared to a standard approach of outreach and incentives.