Zatebradine, a specific bradycardic agent, enhances the positive inotropic actions of dobutamine in ischemic myocardium

AbstractObjectives. This investigation determined whether attenuation of the tachycardia produced by dobutamine administration would improve perfusion and function distal to a severe coronary artery stenosis.Background. Tachycardia adversely affects perfusion and function distal to a coronary artery stenosis. It is not known whether a specific bradycardic agent can improve blood flow and function in an ischemic zone during administration of dobutamine.Methods. The effects of dobutamine (2, 5 and 10 μg/kg body weight per min) alone and in combination with zatebradine (0.5 mg/kg), a specific bradycardic agent, on hemodynamic status, segment shortening (ultrasound length transducers) and myocardial perfusion (microspheres) were studied in anesthetized dogs with severe left circumflex coronary artery stenosis.Results. A 50% reduction in left circumflex coronary artery blood flow (58 ± 4 to 29 ± 2 ml/min [mean value ± SEM]) produced a decrease in systolic shortening in the ischemic zone. Only a dose of dobutamine that did not elevate heart rate (2 μg/kg per min) produced an increase in segment shortening in the ischemic zone. High doses of dobutamine (10 μ/kg per min) caused an increase in heart rate without improvement in function and a reduction in the subendocardial/subepicardial flow ratio (0.74 ± 0.06 to 0.48 ± 0.05). Zatebradine administered in the presence of dobutamine caused a decrease in heart rate, an increase in subendocardial/subepicardial blood flow ratio (0.48 ± 0.05 to 0.78 ± 0.09) and allowed an increase in ischemic zone segment shortening. When normalized for changes in heart rate, ischemic zone subendocardial flow increased by 123 ± 41% (0.39 ± 0.09 to 0.71 ± 0.12 ml/100 g per beat). Atrial pacing abolished the effects of zatebradine.Conclusions. The present data suggest that the perfusion-contraction matching that accompanies a decrease in heart rate results in enhancement of inotropic stimulation of an ischemic zone. The actions of zatebradine are related to an increase in subendocardial blood flow per beat that allows improvement of regional contractile function

Mechanisms of Volatile Anesthetic-Induced Myocardial Protection

Volatile anesthetics protect myocardium against reversible and irreversible ischemic injury. Experimental evidence from several in vitro and in vivo animal models demonstrates that volatile agents enhance the recovery of stunned myocardium and reduce the size of myocardial infarction after brief or prolonged coronary artery occlusion and reperfusion, respectively. This protective effect persists after the anesthetic has been discontinued, a phenomenon known as anesthetic-induced preconditioning (APC). Recent clinical data also demonstrates evidence of APC in patients during cardiac surgery. Thus, administration of volatile anesthetics may represent a novel therapeutic approach that reduces morbidity and mortality associated with perioperative myocardial ischemia and infarction. The mechanisms responsible for APC appear to be similar to those implicated in ischemic preconditioning, but nonetheless have subtle differences. Accumulating evidence indicates that APC is characterized by complex signal transduction pathways that may include adenosine receptors, G proteins, protein kinase C, reactive oxygen species, and sarcolemmal or mitochondrial KATP channels. Opioid analgesics may further enhance APC as well. This article will review recent advances in the understanding of mechanisms responsible for volatile anesthetic-induced myocardial protection

Cardioprotection by Glucose-Insulin-Potassium: Dependence on K\u3csub\u3eATP\u3c/sub\u3e Channel Opening and Blood Glucose Concentration Before Ischemia

We tested the hypothesis that glucose-insulin-potassium (GIK)-induced protection against myocardial infarction depends on ATP-dependent K+ (KATP) channel activation and is abolished by hyperglycemia before the ischemia. Dogs were subjected to a 60-min coronary artery occlusion and 3-h reperfusion in the absence or presence of GIK (25% dextrose; 50 IU insulin/l; 80 mM/l KCl infused at 1.5 ml·kg−1·h−1) beginning 75 min before coronary artery occlusion or 5 min before reperfusion. The role of KATP channels was evaluated by pretreatment with glyburide (0.1 mg/kg). The efficacy of GIK was investigated with increases in blood glucose (BG) concentrations to 300 or 600 mg/dl or experimental diabetes (alloxan/streptozotocin). Infarct size (IS) was 29 ± 2% of the area at risk in control experiments. GIK decreased (P \u3c 0.05) IS when administered beginning 5 min before reperfusion. This protective action was independent of BG (13 ± 2 and 12 ± 2% of area at risk; BG = 80 or 600 mg/dl, respectively) but was abolished in dogs receiving glyburide (30 ± 4%), hyperglycemia before ischemia (27 ± 4%), or diabetes (25 ± 3%). IS was unchanged by GIK when administered before ischemia independent of BG (31 ± 3, 27 ± 2, and 35 ± 3%; BG = 80, 300, and 600 mg/dl, respectively). The insulin component of GIK promotes cardioprotection by KATP channel activation. However, glucose decreases KATP channel activity, and this effect predominates when hyperglycemia is present before ischemia

Antegrade Iliac Artery Stent Implantation for the Temporal and Spatial Examination of Stent-Induced Neointimal Hyperplasia and Alterations in Regional Fluid Dynamics

Neointimal hyperplasia remains an important problem after stent implantation. Previous investigations examining vascular responses to stent implantation and effects of drugs have used a retrograde deployment approach that may inadvertently alter the local fluid dynamics surrounding the stent. We present a model of antegrade iliac artery stent implantation that facilitates the analysis of stent-induced alterations in neointimal hyperplasia and wall shear stress in vivo.Methods: Stent delivery catheters were inserted through the left carotid artery in anesthetized rabbits (n=37). Catheters were advanced under fluoroscopic guidance to the distal iliac arteries, where the stent was deployed. Hemotoxylin and eosin (H&E) staining of unstented and stented vascular sections was performed 21 days after implantation. Results: Selective unilateral stent implantation was successful in 32 of 37 rabbits. No histological abnormalities were observed in the aorta, contralateral unstented iliac, or distal femoral arteries. Neointimal hyperplasia was localized to the stented region.Discussion: The model of stent implantation was relatively easy to perform and produced selective neointimal hyperplasia within the stented region without evidence of damage, cellular proliferation, or flow disruption in the surrounding normal arterial vessels. The model will allow detailed examination of the influence of stent implantation on indices of wall shear stress, neointimal hyperplasia, the mechanisms of cellular proliferation in vivo, and their modification by drugs

An Automated Coronary Artery Occlusion Device for Stimulating Collateral Development in Vivo

Introduction: Repetitive, brief coronary artery occlusions produce collateral development in experimental animals. This model causes coronary collateralization in a highly reproducible fashion, but the process is very labor intensive. We report the design and use of a fully automated hydraulic coronary occlusion device capable of producing repetitive coronary occlusions and enhancement of coronary collateral development in dogs. Methods: The device consists of analog electronics that allow adjustment of occlusion number, frequency, pressure and duration, and mechanical components responsible for the coronary occlusion. The motor and piston of the device are coupled to a chronically implanted hydraulic vascular occluder placed around the left anterior descending coronary artery (LAD) of dogs instrumented for measurement of systemic and coronary hemodynamics. One group of dogs (n=6) underwent brief (2 min) LAD occlusions once per hour, eight times per day, 5 days/week for 3 weeks to stimulate collateral development (measured using radioactive microspheres). Another group of dogs (n=6) that did not receive repetitive occlusions served as controls. Results: The device reproducibly produced repetitive LAD occlusions for the duration, frequency, and time interval initially programmed. A time-dependent increase in transmural collateral blood flow was observed in dogs undergoing repetitive occlusions using the device. Collateral blood flow was unchanged in dogs that did not undergo occlusions. Discussion: The automated occluder device reliably produces repetitive coronary occlusions and may facilitate further study of coronary collateral development in response to chronic myocardial ischemia

A History of Alcohol Dependence Increases the Incidence and Severity of Postoperative Cognitive Dysfunction in Cardiac Surgical Patients

Postoperative cognitive dysfunction (POCD) commonly occurs after cardiac surgery. We tested the hypothesis that a history of alcohol dependence is associated with an increased incidence and severity of POCD in male patients undergoing cardiac surgery using cardiopulmonary bypass. Recent verbal and nonverbal memory and executive functions were assessed before and one week after surgery in patients with or without a history of alcohol dependence. Cognitive function was significantly reduced after cardiac surgery in patients with versus without a history of alcohol dependence. The results suggest that a history of alcohol dependence increases the incidence and severity of POCD after cardiac surgery

Circumferential Vascular Deformation after Stent Implantation Alters Wall Shear Stress Evaluated with Time-Dependent 3D Computational Fluid Dynamics Models

The success of vascular stents in the restoration of blood flow is limited by restenosis. Recent data generated from computational fluid dynamics (CFD) models suggest that stent geometry may cause local alterations in wall shear stress (WSS) that have been associated with neointimal hyperplasia and subsequent restenosis. However, previous CFD studies have ignored histological evidence of vascular straightening between circumferential stent struts. We tested the hypothesis that consideration of stent-induced vascular deformation may more accurately predict alterations in indexes of WSS that may subsequently account for histological findings after stenting. We further tested the hypothesis that the severity of these alterations in WSS varies with the degree of vascular deformation after implantation. Steady-state and time-dependent simulations of three-dimensional CFD arteries based on canine coronary artery measurements of diameter and blood flow were conducted, and WSS and WSS gradients were calculated. Circumferential straightening introduced areas of high WSS between stent struts that were absent in stented vessels of circular cross section. The area of vessel exposed to low WSS was dependent on the degree of circumferential vascular deformation and axial location within the stent. Stents with four vs. eight struts increased the intrastrut area of low WSS in vessels, regardless of cross-sectional geometry. Elevated WSS gradients were also observed between struts in vessels with polygonal cross sections. The results obtained using three-dimensional CFD models suggest that changes in vascular geometry after stent implantation are important determinants of WSS distributions that may be associated with subsequent neointimal hyperplasia

Mechanism of Preconditioning by Isoflurane in Rabbits: A Direct Role for Reactive Oxygen Species

LARGE quantities of reactive oxygen species (ROS) released during reperfusion after coronary artery occlusion damage proteins responsible for intracellular homeostasis, produce tissue injury, depress contractile function, and increase myocardial infarct size. In contrast, small quantities of ROS may exert beneficial effects during ischemia and reperfusion when released before a prolonged ischemic event. ROS derived from mitochondria during a brief ischemic episode produce preconditioning. Free radical scavengers administered during ischemic preconditioning (IPC) markedly attenuate the protective effect of the preconditioning stimulus on infarct size. These data suggest that IPC is mediated in part by small quantities of ROS released during preconditioning. Volatile anesthetics protect myocardium against infarction through a signal transduction pathway that includes adenosine type 1 receptors, protein kinase C, inhibitory guanine regulatory proteins, and mitochondrial and sarcolemmal adenosine triphosphate-regulated potassium (KATP) channels. A recent investigation by Müllenheim et al . provides compelling evidence that ROS also mediate myocardial protection produced by volatile anesthetics. We sought to confirm and extend these important results by examining the hypothesis that ROS scavengers inhibit isoflurane-induced protection against irreversible ischemic injury. We further tested the hypothesis that isoflurane directly generates ROS in rabbit ventricular myocardium in vivo using a confocal microscopic technique combined with the superoxide anion-specific fluorescent probe dihydroethidium

Stent Design Properties and Deployment Ratio Influence Indexes of Wall Shear Stress: a Three-Dimensional Computational Fluid Dynamics Investigation within a Normal Artery

Restenosis limits the effectiveness of stents, but the mechanisms responsible for this phenomenon remain incompletely described. Stent geometry and expansion during deployment produce alterations in vascular anatomy that may adversely affect wall shear stress (WSS) and correlate with neointimal hyperplasia. These considerations have been neglected in previous computational fluid dynamics models of stent hemodynamics. Thus we tested the hypothesis that deployment diameter and stent strut properties (e.g., number, width, and thickness) influence indexes of WSS predicted with three-dimensional computational fluid dynamics. Simulations were based on canine coronary artery diameter measurements. Stent-to-artery ratios of 1.1 or 1.2:1 were modeled, and computational vessels containing four or eight struts of two widths (0.197 or 0.329 mm) and two thicknesses (0.096 or 0.056 mm) subjected to an inlet velocity of 0.105 m/s were examined. WSS and spatial WSS gradients were calculated and expressed as a percentage of the stent and vessel area. Reducing strut thickness caused regions subjected to low WSS (/cm2) to decrease by ∼87%. Increasing the number of struts produced a 2.75-fold increase in exposure to low WSS. Reducing strut width also caused a modest increase in the area of the vessel experiencing low WSS. Use of a 1.2:1 deployment ratio increased exposure to low WSS by 12-fold compared with stents implanted in a 1.1:1 stent-to-vessel ratio. Thinner struts caused a modest reduction in the area of the vessel subjected to elevated WSS gradients, but values were similar for the other simulations. The results suggest that stent designs that reduce strut number and thickness are less likely to subject the vessel to distributions of WSS associated with neointimal hyperplasia