Direct intra-cardiomuscular transfer of β2-adrenergic receptor gene augments cardiac output in cardiomyopathic hamsters

In chronic heart failure, down-regulation of beta -adrenergic receptor (beta -AR) occurs in cardiomyocytes, resulting in low catecholamine response and impaired cardiac function. To correct the irregularity in the beta -AR system, beta -AR gene was transduced in vivo into failing cardiomyocytes. The Epstein-Barr virus (EBV)-based plasmid vector carrying human beta (2)-AR gene was injected into the left ventricular muscle of Bio14.6 cardiomyopathic hamsters whose beta -AR is downregulated in the cardiomyocytes. The echocardiographic examinations revealed that stroke volume (SV) and cardiac output (CO) were significantly elevated at 2 to 4 days after the beta (2)-AR gene transfer. Systemic loading of isoproterenol increased the cardiac parameters more significantly on day 2 to day 7, indicating that the adrenergic response was augmented by the genetic transduction. The same procedure did not affect the cardiac function of normal hamsters. Immunohistochemical examinations demonstrated human beta (2)-AR expression in failing cardiomyocytes transduced with the gene. RT-PCR analysis detected mRNA for the transgene in the heart but not in the liver, spleen, or kidney. The procedures may provide a feasible strategy for gene Therapy of severe heart failure.