Lymphocyte levels of GRK2 (betaARK1) mirror changes in the LVAD-supported failing human heart: lower GRK2 associated with improved beta-adrenergic signaling after mechanical unloading.

Background: In human heart failure, increased expression of G protein-coupled receptor kinases (GRKs) causes the loss of beta-adrenergic receptor (betaAR) signaling and function. Mechanical unloading with a left ventricular assist device (LVAD) promotes reverse remodeling, which includes restoration of betaAR responsiveness. We tested the hypothesis that LVAD support of the failing human heart alters the expression and activity of GRKs and we sought to determine whether changes in myocardial GRKs could be tracked in lymphocytes.

A Gbetagamma inhibitor reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

Objective: Approximately 50% of aortocoronary saphenous vein grafts are occluded 10 years after coronary revascularization surgery. Intimal hyperplasia, a critical component in saphenous vein graft failure, is defined by vascular smooth muscle cell proliferation, which is mediated in part by betagamma subunits of heterotrimeric G proteins (G(betagamma)) and downstream effectors such as mitogen-activated protein kinases. A peptide consisting of the carboxyl-terminus of the beta-adrenergic receptor kinase (betaARKct) binds G(betagamma), thereby inhibiting G(betagamma) signaling.

Modulation of phosphatidylinositol 3-kinase signaling reduces intimal hyperplasia in aortocoronary saphenous vein grafts.

Objectives: Fifty percent of human aortocoronary saphenous vein grafts are occluded after 10 years. Intimal hyperplasia is an initial step in graft occlusion and consists of vascular smooth muscle cell proliferation. Phosphatidylinositol 3-kinase and its downstream regulator, the inositol 3-phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), are important regulators of vascular smooth muscle cell proliferation, migration, and cell death.

Catheter-mediated subselective intracoronary gene delivery to the rabbit heart: introduction of a novel method.

Background: Recent studies suggest that gene therapy using replication-deficient adenoviruses will benefit treatment of cardiovascular diseases including heart failure. A persistent hurdle is the effective and reproducible delivery of a transgene to the myocardium with minimal iatrogenic morbidity. In this study, we sought to design a relatively non-invasive percutaneous gene delivery system that would maximize cardiac transgene expression and minimize mortality after intracoronary adenovirus injection.

beta2 adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery.

Objective: Heart surgery is associated with impairment of the myocardial beta-adrenoceptor (betaAR) system. Effective therapies for post-operative ventricular dysfunction are limited. Prolonged inotrope exposure is associated with further betaAR down-regulation.

Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts.

Erythropoietin has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia. In this study, we evaluated the in vivo protective potential of erythropoietin in the reperfused rabbit heart following ventricular ischemia. We show that "preconditioning" with erythropoietin activates cell survival pathways in myocardial tissue in vivo and adult rabbit cardiac fibroblasts in vitro.

Gene delivery to aortocoronary saphenous vein grafts in a large animal model of intimal hyperplasia.

Objective: More than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is an initial, critical step in the progression toward occlusion. To date, no clinically relevant large animal models of aortocoronary saphenous vein graft intimal hyperplasia have been fully characterized.

A novel protective effect of erythropoietin in the infarcted heart.

Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury.

The beta-adrenergic receptor kinase in heart failure.

Heart failure (HF) remains a significant and increasing cause of worldwide morbidity and mortality. HF is less a disease than a common clinical endpoint resulting from diverse, but often co-existing etiologies-including hypertension, coronary artery disease, and viral cardiomyopathy. Regardless of the pathologic trigger, HF can be characterized by a series of specific, molecular changes in the diseased myocardium.

BVS5000 support after cardiac transplantation.

Objective: This study examines short-term mechanical assist device support for cardiac transplant patients and compares their outcomes with nontransplant patients requiring similar support.

Methods: Of 350 cardiac transplant patients at our institution, 7 patients required mechanical ventricular assistance with the Abiomed BVS5000 assist device (Abiomed, Inc, Danvers, Mass) after transplant secondary to severe acute rejection with cardiogenic shock (n = 4) or primary graft failure (n = 3). Recovery of ventricular function, survival to discharge, and complications were determined for the transplant group and compared with a second group comprising all other patients supported with the BVS5000 at our institution (n = 15).

Mechanical ventricular support lowers pulmonary vascular resistance in a patient with congential heart disease.

Severely elevated pulmonary vascular resistance (PVR) is a relative contraindication to orthotopic heart transplantation. A potential novel strategy to reverse elevated PVR may be implantation of a chronic left ventricular assist device with subsequent left ventricular unloading. We present a patient with elevated PVR secondary to congenital heart disease who was listed for heart-lung transplant.