In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.

BACKGROUND: Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo beta-adrenergic receptor kinase (betaARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI). METHODS AND RESULTS: Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5x10(11) viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of betaARK1 (Adeno-betaARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-betaARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the betaARKct. Baseline in vivo LV systolic performance was improved in Adeno-betaARKct-treated animals compared with their individual pre-gene delivery values and compared with EV-treated rabbits. Total beta-AR density and betaARK1 levels were unchanged between treatment groups; however, beta-AR-stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-betaARKct-treated rabbits compared with EV-treated animals. CONCLUSIONS: In vivo delivery of Adeno-betaARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of betaARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of betaARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.

Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart : prospects for molecular ventricular assistance.

BACKGROUND: Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human beta(2)AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. METHODS AND RESULTS: Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-betaGal) or the beta(2)AR (Adeno-beta(2)AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-beta(2)AR resulted in approximately 10-fold overexpression in a chamber-specific manner. Delivery of Adeno-betaGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of beta(2)ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. CONCLUSIONS: Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the beta(2)AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.

Investing in the Homeland: Foreign Assets and Patterns of Immigrant Economic Incorporation

This dissertation consists of three separate studies that examine patterns of immigrant incorporation in the United States. The first study tests competing hypotheses derived from conflicting theoretical frameworks−transnational perspective and cross-national framework− to determine whether transnational engagement and incorporation are concurrent processes among Chinese, Indian, and Mexican immigrants. This study measures transnational engagement and incorporation as home and home country asset ownership using multi-panel, nationally representative data from the New Immigrant Survey (NIS) collected in 2003 and 2007. Results support a cross-border framework and indicate that transnational asset ownership decreases among all immigrant groups, while U.S. asset ownership increases. Findings from this study also indicate that due to disadvantaged pre-migration SES and low human capital, Mexican immigrants are less likely than other immigrants to own home country assets during the year after receiving their green card.

The second study examines the doubly disadvantaged position of elderly immigrants in the U.S. wealth distribution by applying the life course perspective to the dominance-differentiation theory of immigrant wealth stratification. I analyze elderly immigrant wealth in respect to U.S.-born seniors and younger immigrant cohorts using two data sets: the Survey of Income and Program Participation (SIPP) and the New Immigrant Survey (NIS). The Survey of Income and Program Participation (2001 to 2005) is a nationally representative survey of U.S. households. The first series of analyses reveals a significant wealth gap between U.S.- and foreign-born seniors which is most pronounced among the wealthiest households in my sample; however, U.S. tenure explains much of this difference. The second series of analyses suggests that elderly immigrants experience greater barriers to incorporation compared to their younger counterparts.

In the third study, I apply a transnational lens to the forms-of-capital and opportunity structure models of entrepreneurship in order to analyze the role of foreign resources in immigrant business start-ups. I propose that home country property use represents financial, social, and class resources that facilitate immigrant entrepreneurship. I test my hypotheses using survey data on Latin American immigrants from the Comparative Immigrant Entrepreneurship Project. Findings from these analyses suggest that home country asset ownership provides financial and social capital that is related to an increased likelihood of immigrant entrepreneurship.