Meihua Gao

Prospects for gene transfer for clinical heart failure

Congestive heart failure is an inexorable disease associated with unacceptably high morbidity and mortality. Preclinical results indicate that gene transfer using various proteins is a safe and effective approach for increasing function of the failing heart. In the current review, we provide a summary of cardiac gene transfer in general and summarize findings using adenylyl cyclase 6 as therapeutic gene in the failing heart. We also discuss the potential usefulness of a new treatment for congestive heart failure, paracrine-based gene transfer.

Dissociation between regional dysfunction and β-adrenergic receptor signaling in heart failure

We have previously shown that left ventricular (LV) pacing-induced heart failure is associated with preserved wall thickening in the interventricular septum (IVS) compared with the posterolateral wall (PLW). The current study focuses on the relationship between regional myocardial function and altered β-adrenergic receptor (β-AR) signaling. We studied 15 pigs: 6 controls and 9 paced from the left ventricle (225 beats/min, 26 ± 3 days). Heart failure was documented by decreased LV fractional shortening ( P < 0.0001) and increased left atrial pressure ( P < 0.0001). In heart failure, despite marked differences in basal regional function (percent wall thickening: IVS, 33 ± 10% vs. PLW, 13 ± 7%; P = 0.0003), there were no differences between the two regions in β-AR responsiveness, measured by regional wall thickening in response to dobutamine infusion and any measurement of adrenergic signaling. Adenylyl cyclase activity, β-AR number, and β-AR/Gscoupling were markedly reduced in failing LV without regional differences. In animals with heart failure, LV G protein receptor kinase (GRK) isoform 2 content was unchanged and GRK5, the other major GRK isoform, was increased more than threefold (IVS, 0.51 ± 0.20 vs. 0.12 ± 0.12 arbitrary densitometric units, P = 0.01; PLW, 0.47 ± 0.15 vs. 0.13 ± 0.09 arbitrary densitometric units, P = 0.03), but again, there were no regional differences. These data indicate that systemic rather than regional factors govern LV adrenergic signaling and that regional adrenergic signaling abnormalities poorly predict wall thickening in the same regions.