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

Microfocal X-Ray Computed Tomography Post-Processing Operations for Optimizing Reconstruction Volumes of Stented Arteries During 3D Computational Fluid Dynamics Modeling

Restenosis caused by neointimal hyperplasia (NH) remains an important clinical problem after stent implantation. Restenosis varies with stent geometry, and idealized computational fluid dynamics (CFD) models have indicated that geometric properties of the implanted stent may differentially influence NH. However, 3D studies capturing the in vivo flow domain within stented vessels have not been conducted at a resolution sufficient to detect subtle alterations in vascular geometry caused by the stent and the subsequent temporal development of NH. We present the details and limitations of a series of post-processing operations used in conjunction with microfocal X-ray CT imaging and reconstruction to generate geometrically accurate flow domains within the localized region of a stent several weeks after implantation. Microfocal X-ray CT reconstruction volumes were subjected to an automated program to perform arterial thresholding, spatial orientation, and surface smoothing of stented and unstented rabbit iliac arteries several weeks after antegrade implantation. A transfer function was obtained for the current post-processing methodology containing reconstructed 16 mm stents implanted into rabbit iliac arteries for up to 21 days after implantation and resolved at circumferential and axial resolutions of 32 and 50 μm, respectively. The results indicate that the techniques presented are sufficient to resolve distributions of WSS with 80% accuracy in segments containing 16 surface perturbations over a 16 mm stented region. These methods will be used to test the hypothesis that reductions in normalized wall shear stress (WSS) and increases in the spatial disparity of WSS immediately after stent implantation may spatially correlate with the temporal development of NH within the stented region

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

Adenosine Type 1 (A ) Receptors Mediate Protection Against Myocardial 1 Infarction Produced by Chronic, Intermittent Ingestion of Ethanol in Dogs

Background: Chronic consumption of small amounts of ethanol protects myocardium from ischemic injury. We tested the hypothesis that adenosine type 1 (A1) receptors mediate these beneficial effects. Methods: Dogs (n=37) were fed with ethanol (1.5 g/kg) or water mixed with dry food twice per day for 12 weeks, fasted overnight before experimentation, and instrumented for measurement of hemodynamics. Dogs received intravenous drug vehicle (50% polyethylene glycol in 0.1 N sodium hydroxide and 0.9% saline over 15 min) or the selective A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.8 mg/kg over 15 min) and were subjected to a 60 min coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size and transmural coronary collateral blood flow were measured with triphenyltetrazolium chloride staining and radioactive microspheres, respectively. Results: The area at risk (AAR) for infarction was similar between groups. Pretreatment with ethanol significantly reduced infarct size to 13±2% (n=7) of the AAR as compared to control experiments (26±2%; n=7). DPCPX abolished the protective effects of ethanol pretreatment (30±3%; n=7) but had no effect in dogs that did not receive ethanol (25±2%; n=7). No differences in transmural coronary collateral blood flow were observed between groups. Conclusions: The present findings indicate that chronic ingestion of small amounts of ethanol produces myocardial protection that persists after the discontinuation of ethanol. The results indicate that A1 receptors mediate ethanol-induced preconditioning in dogs independent of alterations in systemic hemodynamics or coronary collateral blood flow

Influence of Isoflurane on Left Atrial Function in Dogs With Pacing-Induced Cardiomyopathy: Evaluation With Pressure-Volume Relationships

Objective The actions of volatile anesthetics on left ventricular (LV) function in normal and failing hearts have been previously evaluated, but the effects of these agents on left atrial (LA) function in the presence of LV dysfunction are unknown. The hypothesis was tested that isoflurane alters LA mechanics evaluated with pressure-volume relations. Design Prospective. Setting Laboratory. Participants Barbiturate-anesthetized dogs (n = 8) were instrumented for measurement of aortic, LA, and LV pressures (micromanometers), and LA volume (epicardial orthogonal sonomicrometers) after 3 weeks of rapid ventricular pacing (220 beats/min). Interventions LA myocardial contractility (Ees) was assessed with end-systolic pressure-volume relations. LA stroke work and reservoir function were assessed by A and V loop area, respectively, from the steady-state pressure-volume diagram. LA-LV coupling was determined by the ratio of Ees to LV elastance (ELV). Dogs received 0.6, 0.9, and 1.2 minimum alveolar concentration isoflurane in a random manner, and LA function was determined after a 20-minute equilibration at each dose. Measurements and main results Isoflurane significantly (p \u3c 0.05) decreased heart rate, mean arterial pressure, LV end-systolic pressure, and LV +dP/dtmax. Isoflurane produced dose-related reductions in Ees and Ees/ELV. Declines in LA stroke work, emptying fraction, reservoir volume, V loop area, and the active LA contribution to LV filling also occurred. Conclusions The results indicate that isoflurane depresses LA myocardial contractility, impairs LA-LV coupling, and reduces active LA contribution to LV filling in dogs with pacing-induced cardiomyopathy. The impact of isoflurane on LA function in the presence of LV dysfunction has profound effects on cardiac performance

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