Jeffrey Burdick

Apelin Has In Vivo Inotropic Effects on Normal and Failing Hearts

Background—Apelin has been shown ex vivo to be a potent cardiac inotrope. This study was undertaken to evaluate the in vivo effects of apelin on cardiac function in native and ischemic cardiomyopathic rat hearts using a novel combination of a perivascular flow probe and a conductance catheter. Methods and Results—Native rats (n =32) and rats in heart failure 6 weeks after left anterior descending coronary artery ligation (n =22) underwent median sternotomy with placement of a perivascular flow probe around the ascending aorta and a pressure volume conductance catheter into the left ventricle. Compared with sham-operated rats, the ligated rats had significantly decreased baseline Pmax and max dP/dt. Continuous infusion of apelin at a rate of 0.01 &mgr;g/min for 20 minutes significantly increased Pmax and max dP/dt compared with infusion of vehicle alone in both native and failing hearts. Apelin infusion increased cardiac contractility, indicated by a significant increase in stroke volume (SV) without a change in left ventricular end diastolic volume (102±16% change from initial SV versus 26±20% for native animals, and 110±30% versus 26±11% for ligated animals), as well as an increase in preload recruitable stroke work (180±24 mm Hg versus 107±9 mm Hg for native animals). Conclusions—The present study is the first to show that apelin has positive inotropic effects in vivo in both normal rat hearts and rat hearts in failure after myocardial infarction. Apelin may have use as an acute inotropic agent in patients with ischemic heart failure.

Gene Transfer of Hepatocyte Growth Factor Attenuates Postinfarction Heart Failure

Background—Despite advances in surgical and percutaneous coronary revascularization, ongoing ischemia that is not amenable to standard revascularization techniques is a major cause of morbidity and mortality. Hepatocyte Growth Factor (HGF) has potent angiogenic and anti-apoptotic activities, and this study evaluated the functional and biochemical effects of HGF gene transfer in a rat model of postinfarction heart failure. Methods and Results—Lewis rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient recombinant adenovirus encoding HGF (n=10) or empty null virus as control (n=9), and animals were analyzed after six weeks. Pressure-volume conductance catheter measurements demonstrated significantly preserved contractile function in the HGF group compared with Null control animals as measured by maximum developed LV pressure (79±5 versus 56±4 mm Hg, P <0.001) and maximum dP/dt (2890±326 versus 1622±159 mm Hg/sec, P <0.01). Significant preservation of LV geometry was associated with HGF treatment (LV Diameter HGF 13.1±0.54 versus Null 14.4±0.15 mm P <0.01; LV wall thickness 1.73±0.10 versus 1.28±0.07 mm P <0.01). Angiogenesis was significantly enhanced in HGF treated animals as measured by both Von Willebrand’s Factor immunohistochemical staining and a microsphere assay. TUNEL analysis revealed a significant reduction in apoptosis in the HGF group (3.42±0.83% versus 8.36±1.16%, P <0.01), which correlated with increased Bcl-2 and Bcl-xL expression in the HGF animals. Conclusions—Hepatocyte Growth Factor gene transfer following a large myocardial infarction results in significantly preserved myocardial function and geometry, and is associated with significant angiogenesis and a reduction in apoptosis. This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure.

Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy

Background—Enhanced activity of matrix metalloproteinases (MMPs) has been associated with extracellular matrix degradation and ischemic heart failure in animal models and human patients. This study evaluated the effects of MMP inhibition by gene transfer of TIMP-1 in a rat model of ischemic cardiomyopathy. Methods and Results—Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient adenovirus encoding TIMP-1 (n=8) or null virus as control vector (n=8), and animals were analyzed after 6 weeks. Both systolic and diastolic cardiac function was significantly preserved in the TIMP-1 group compared with control animals (maximum left ventricular [LV] pressure: TIMP-1 70±10 versus control 56±12 mmHg, P<0.05; maximum dP/dt 2697±842 versus 1622±527 mmHg/sec, P<0.01; minimum dP/dt −2900±917 versus −1195±593, P<0.001). Ventricular geometry was significantly preserved in the TIMP-1 group (LV diameter 13.0±0.7 versus control 14.4±0.4 mm, P<0.001; border-zone wall thickness 1.59±0.11 versus control 1.28±0.19 mm, P<0.05), and this was associated with a reduction in myocardial fibrosis (2.36±0.87 versus control 3.89±1.79 &mgr;g hydroxyproline/mg tissue, P<0.05). MMP activity was reduced in the TIMP-1 animals (1.5±0.9 versus control 43.1±14.9 ng of MMP-1 activity, P<0.05). Conclusions—TIMP-1 gene transfer inhibits MMP activity and preserves cardiac function and geometry in ischemic cardiomyopathy. The reduction in myocardial fibrosis may be primarily responsible for the improved diastolic function in treated animals. TIMP-1 overexpression is a promising therapeutic target for continued investigation.

A novel technique for light delivery through branched or bent anatomic structures

OBJECTIVE Photodynamic therapy is an effective cancer treatment, but light delivery constraints currently limit its application to superficial, easily visualized tumors. The goal of this study was to determine whether it would be possible to manipulate the optical properties of irregularly shaped anatomic structures for the purpose of light delivery. Such a technique could potentially expand the role of photodynamic therapy to treat tumors currently viewed as inaccessible to visible light. METHODS Ex vivo sheep tracheas and lungs were filled with substances of varying refractive indices. The effects on transmission of visible light of a known wavelength introduced into the proximal lumen of the organs were studied. Data were collected with naked-eye observation, standard photography, charge-coupled device imaging, and direct light measurement. RESULTS Filling a lung or trachea with a liquid possessing a refractive index higher than that of tissue dramatically increases the ability to deliver light around bends and through a branched network. CONCLUSION It is possible to manipulate the optical properties of an ex vivo organ for the purpose of enhanced light delivery.