Regional imbalanced activation of the calcineurin/BAD apoptotic pathway and the PI3K/Akt survival pathway after myocardial infarction.

BACKGROUND: The underlying molecular mechanisms of the remodeling after myocardial infarction (MI) remain unclear. The purpose of this study was to investigate the role of a survival pathway (PI3K/Akt) and an apoptosis pathway (calcineurin/BAD) in the remodeling after MI in a large animal model. METHODS: Ten Dorset hybrid sheep underwent 25% MI in the left ventricle (LV, n=10). Five sheep were used as sham control. The regional strain was calculated from sonomicrometry. Apoptosis and the activation of the PI3K/Akt and calcineurin/BAD pathways were evaluated in the non-ischemic adjacent zone and the remote zone relative to infarct by immunoblotting, immunoprecipitation, and immunofluorescence staining. RESULTS: Dilation and dysfunction of LV were present at 12 weeks after MI. The regional strain in the adjacent zone was significantly higher than in the remote zone at 12 weeks (36.6 ± 4.0% vs 9.5 ± 3.6%, p<0.05). Apoptosis was more severe in the adjacent zone than in the remote zone. The PI3K/Akt and calcineurin/BAD pathways were activated in the adjacent zone. Dephosphorylation and translocation of BAD were evident in the adjacent zone. Regional correlation between the strain and the expression of calcineurin/BAD indicated that the activation was strain-related (R(2)=0.46, 0.48, 0.39 for calcineurin, BAD, mitochondrial BAD, respectively, p<0.05). CONCLUSIONS: The PI3K/Akt survival and calcineurin/BAD apoptotic pathways were concomitantly activated in the non-ischemic adjacent zone after MI. The calcineurin/BAD pathway is strain related and its imbalanced activation may be one of the causes of progressive remodeling after MI.

Functional and biocompatibility performances of an integrated Maglev pump-oxygenator.

To provide respiratory support for patients with lung failure, a novel compact integrated pump-oxygenator is being developed. The functional and biocompatibility performances of this device are presented. The pump-oxygenator is designed by combining a magnetically levitated pump/rotor with a uniquely configured hollow fiber membrane bundle to create an assembly free, ultracompact, all-in-one system. The hemodynamics, gas transfer and biocompatibility performances of this novel device were investigated both in vitro in a circulatory flow loop and in vivo in an ovine animal model. The in vitro results showed that the device was able to pump blood flow from 2 to 8 L/min against a wide range of pressures and to deliver an oxygen transfer rate more than 300 mL/min at a blood flow of 6 L/min. Blood damage tests demonstrated low hemolysis (normalized index of hemolysis [NIH] approximately 0.04) at a flow rate of 5 L/min against a 100-mm Hg afterload. The data from five animal experiments (4 h to 7 days) demonstrated that the device could bring the venous blood to near fully oxygen-saturated condition (98.6% +/- 1.3%). The highest oxygen transfer rate reached 386 mL/min. The gas transfer performance was stable over the study duration for three 7-day animals. There was no indication of blood damage. The plasma free hemoglobin and platelet count were within the normal ranges. No gross thrombus is found on the explanted pump components and fiber surfaces. Both in vitro and in vivo results demonstrated that the newly developed pump-oxygenator can achieve sufficient blood flow and oxygen transfer with excellent biocompatibility.

Early in vivo experience with the pediatric Jarvik 2000 heart.

The need for smaller, more efficient ventricular assist devices that can be used in a more chronic setting have led to exploration of mechanical circulatory support in the pediatric population. The pediatric Jarvik 2000 heart (child size), under development, was implanted in six juvenile sheep and studied for both acute fit and chronic performance evaluation. Daily hemodynamic measurements of cardiac output and pump output at varying pump speeds were taken. In addition, plasma free hemoglobin, lactic acid dehydrogenase, and platelet activation from blood samples were determined at baseline, after implantation, and twice a week thereafter. The measured flow through the outflow graft at increasing speeds from 10,000 rpm to 14,000 rpm with an increment of 1,000 rpm were 1.47 +/- 0.43, 1.89 +/- 0.52, 2.36 +/- 0.61, 2.80 +/- 0.73, and 3.11 +/- 0.86 (L/min). The baseline plasma free hemoglobin was 11.95 +/- 4.76 (mg/dL), with subsequent mean values being <30 mg/dL at postimplantation and weekly postimplantation measurements. Both lactic acid dehydrogenase and platelet activation showed an acute increase within the first week after implantation with subsequent return to baseline by 2 weeks after surgery. Our initial animal in vivo experience with the pediatric Jarvik 2000 heart shows that a small axial flow pump can provide partial to nearly complete circulatory support with minimal adverse effects on blood components.

Beating heart direct left atrial access balloon cryoablation: safety and efficacy of pulmonary vein isolation in an ovine model.

OBJECTIVE: : Clinical experience with endocardial cryoablation for the surgical treatment of atrial fibrillation has demonstrated safety and efficacy. Direct access to the left atrium via a thoracoscopic or pericardial approach with a balloon-tipped cryoablation catheter might facilitate endocardial cryoablation on the beating heart. We investigated the ability of a novel cryoballoon to produce endocardial pulmonary vein ostial cryolesions on the beating heart in a large-animal model. METHODS: : Six sheep underwent small left thoracotomy. A 10.5F catheter with a 23-mm cryoballoon was inserted directly into the left atrium under fluoroscopic and intracardiac echo (ICE) guidance. Cryoablation of the pulmonary vein ostia was performed. Animals were killed at 14 days. Pulmonary venous electrical isolation was assessed immediately before the animals were killed. RESULTS: : All animals survived balloon cryoablation with no periprocedural complications. Balloon occlusion was well tolerated hemodynamically, with minimal change in blood pressure (-4 ± 6 mm Hg systolic BP) and no change in heart rate. ICE demonstrated an absence of intracardiac air or ice embolization during ablation. Mean balloon temperature was -67 ± 8°C. All animals were neurologically intact after the procedure. Five of 6 (83%) veins exhibited circumferential exit block. Phrenic nerve function was intact in all animals. On gross inspection, all lesions were circumferential and continuous without evidence of endocardial thrombus. Pathology confirmed circumferential transmurality in all treated veins. CONCLUSIONS: : Direct left atrial access cryoballoon ablation was effective for isolating pulmonary veins. This technology may be an important component of a minimally invasive beating heart CryoMaze procedure for the treatment of atrial fibrillation.

Strain-related regional alterations of calcium-handling proteins in myocardial remodeling.

BACKGROUND: Cardiac remodeling has been shown to have deleterious effects at both the global and local levels. The objective of this study is to investigate the role of strain in the initiation of structural and functional changes of myocardial tissue and its relation to alteration of calcium-handling proteins during cardiac remodeling after myocardial infarction. METHODS: Sixteen sonomicrometry transducers were placed in the left ventricular free wall of 9 sheep to measure the regional strain in the infarct, adjacent, and remote myocardial regions. Hemodynamic, echocardiographic, and sonomicrometry data were collected before myocardial infarction, after infarction, and 2, 6, and 8 weeks after infarction. Regional myocardial tissues were collected for calcium-handling proteins at the end study. RESULTS: At time of termination, end-systolic strains in 3 regionally distinct zones (remote, adjacent, and infarct) of myocardium were measured to be -14.65 +/- 1.13, -5.11 +/- 0.60 (P < or = .05), and 0.92 +/- 0.56 (P < or = .05), respectively. The regional end-systolic strain correlated strongly with the abundance of 2 major calcium-handling proteins: sarcoplasmic reticulum Ca2+ adenosine triphosphatase subtype 2a (r2 = 0.68, P < or = .05) and phospholamban (r2 = 0.50, P < or = .05). A lesser degree of correlation was observed between the systolic strain and the abundance of sodium/calcium exchanger type 1 protein (r2 = 0.17, P < or = .05). CONCLUSIONS: Regional strain differences can be defined in the different myocardial regions during postinfarction cardiac remodeling. These differences in regional strain drive regionally distinct alterations in calcium-handling protein expression.