James A. Coles

Opioid preconditioning: myocardial function and energy metabolism.

BACKGROUND Opioid receptor agonists are involved in ischemic preconditioning and natural hibernation. The aim of this study was to determine whether pretreatment with D-Ala2-Leu5-enkephalin or morphine confers cardioprotection in large mammalian hearts. We assessed myocardial functional recovery and global energy metabolism after ischemic cold storage. METHODS After pretreatment with D-Ala2-Leu5-enkephalin, morphine sulfate, or saline (n = 6 each), swine hearts were excised and stored for 75 minutes at 4 degrees C, then reperfused in a four-chamber isolated working heart apparatus. Serial myocardial biopsies were performed to assess cellular energy metabolism. RESULTS Improved systolic (cardiac output, contractility) and diastolic (tau) left ventricular functions were observed in hearts pretreated with D-Ala2-Leu5-enkephalin or morphine. These benefits were not correlated with changes in high-energy phosphate levels. Cardiac enzyme leakage (creatine kinase, troponin-I) was similar among treated and control groups. Lactate efflux increased significantly in controls, but not in opioid-pretreated hearts (p < 0.01) at 75 minutes of reperfusion. CONCLUSIONS D-Ala2-Leu5-enkephalin and morphine pretreatments improve postischemic function after cold storage of swine hearts. Postischemic lactate reduction, but not high-energy phosphate levels, may account for the observed cardioprotective effects.

Hibernation induction trigger reduces hypoxic damage of swine skeletal muscle

A link between the cardioprotective benefits of pharmacological preconditioning and natural mammalian hibernation is considered to involve the cellular activation of opioid receptors and subsequent opening of KATP channels. In previous studies, we have demonstrated the protective effects of specific δ‐opioid agonists against porcine cardiac ischemia/reperfusion injury. We hypothesize here that preincubation with hibernation induction trigger (HIT) should confer a similar protection in skeletal muscles. Therefore, muscle bundles from swine were pretreated with plasma from hibernating woodchucks (HWP) for 30 min, then exposed to hypoxia for 90 min and reoxygenation for 120 min. Stimulated twitch forces were assessed. The functional effects of pretreatment with nonhibernation (summer) woodchuck plasma, a KATP blocker, or opioid antagonist were also studied. During the reoxygenation period, significantly greater force recoveries were observed only for bundles pretreated with HWP; this response was blocked by naloxone (P < 0.05). We conclude that HIT pretreatment could be used to confer protection against hypoxia/reperfusion injury of skeletal muscles of nonhibernators; it could potentially be utilized to prevent injury during surgical procedures requiring ischemia.

Images of the human coronary sinus ostium obtained from isolated working hearts

Due to increasing interest in using the coronary venous system for placement of intracardiac devices, the functional anatomy of the coronary sinus ostium is clinically important. Using Plegisol cardioplegia and stan-dard cardiac surgery procedures, six human hearts deemed not viable for transplant were explanted to an isolated heart apparatus. A modified Krebs-Henseleit buffer was used as a blood substitute to sustain the hearts, allowing for visualization of internal structures of the functioning hearts. Video footage of the coronary sinus ostia was obtained using a 6-mm diameter flexible videoscope inserted into the hearts through the superior vena cava or the right atrial appendage. A wide range of coronary sinus morphologies was observed including remnant Thebesian valves covering approximately 50% of the coronary sinus ostium and a large fenestrated Thebesian valve covering greater than 50% of the coronary sinus ostium. These images demonstrate why difficulties are sometimes encountered while cannulating the coronary sinus during surgical procedures. Figure 1 shows still images of the coronary sinus ostia of six human hearts. Each image represents a single frame captured from beta video recordings. In each image, the ostium of the coronary sinus is marked “O” and the Thebesian valve is marked “v.” Images in Figures 1A , 1B, and 1D show well-developed Thebesian valves covering large portions of the coronary sinus ostium. Images in Figures 1C, 1E, and 1F show remnant Thebesian valves. Figure 2 illustrates serial images showing the movement of Thebesian valves that cover the coronary sinus ostia in three hearts. Consecutive frames in images in Figures 2A and 2B are 0.033 seconds apart and frames in images in Figure 2C are 0.067 seconds apart. The image in Figure 2A is a different view of the Thebesian valve shown in Figure 1A. The Thebesian valves in images in Figures 2A and 2B completely cover the coronary sinus ostium during systole, except for the small fenestrations in both valves. The Thebesian valve image in Figure 2C, although large enough to cover the entire coronary sinus ostium, never actually completely covers the ostium.

Focal Pharmacological Modulation of Atrioventricular Nodal Conduction via Implantable Catheter A Novel Therapy for Atrial Fibrillation

Background— Pharmacological ventricular rate control is an acceptable atrial fibrillation (AF) therapy limited by systemic toxicity. We postulate that focal catheter-based drug delivery into the atrioventricular nodal (AVN) region may effectively control ventricular rate during AF without systemic toxicity. This study evaluated the effects of focally administered acetylcholine on AVN conduction and refractoriness during sinus rhythm and AF. Methods and Results— Canines (n=7) were anesthetized and instrumented to assess cardiac electrophysiology and blood pressure. A custom drug delivery catheter was implanted in the AVN region. Incremental doses of acetylcholine starting at 10 &mgr;g/min were infused until complete AV block was achieved. Acetylcholine induced dose-dependent AV block. AF induction and electrophysiology measurements were performed during baseline and acetylcholine-induced first-degree and third-degree AV block. During AF, infusion of acetylcholine decreased ventricular rates from 182±32 to 77±28 and 28±8 bpm (first-degree and third-degree AV block, respectively; P<0.05). At the first-degree AV block dose, AVN effective refractory period increased from 186±37 to 282±33 ms, and Wenckebach cycle length increased from 271±29 to 378±58 ms (P<0.05). The first-degree AV block dose prolonged AV and AH intervals by 26% and 23% (P<0.05), whereas AA intervals and blood pressure remained unchanged, demonstrating a local effect. All effects were reversed 20 minutes after infusion was stopped. Conclusions— Focal acetylcholine delivery into the AVN increased AVN refractoriness and significantly decreased ventricular rate response during induced AF in a dose-related, reversible manner without systemic side effects. This may represent a novel therapy for AF whereby ventricular rate is controlled with the use of an implantable drug delivery system.

Featured Article: Pharmacological postconditioning with delta opioid attenuates myocardial reperfusion injury in isolated porcine hearts:

Ischemic preconditioning has been utilized to protect the heart from ischemia prior to ischemia onset, whereas postconditioning is employed to minimize the consequences of ischemia at the onset of reperfusion. The underlying mechanisms and pathways of ischemic pre- and postconditioning continue to be investigated as therapeutic targets. We evaluated the administration of a delta opioid agonist or cariporide on various parameters associated with myocardial reperfusion injury upon reperfusion of isolated porcine hearts. The hearts were reperfused in vitro with a Krebs buffer containing either: (1) 1 µM Deltorphin D (delta opioid specific agonist, n = 6); (2) 3 µM cariporide (sodium–hydrogen exchange inhibitor, n = 4); or (3) no treatment (control, n = 6). Subsequently, postischemic hemodynamic performance, arrhythmia burden, relative tissue perfusion, and development of necrosis were assessed over a 2 h reperfusion period. Postconditioning with Deltorphin D significantly improved diastolic relaxation (Tau, P < 0.05 versus controls) and decreased the incidence of ventricular arrhythmias during early reperfusion. Additionally, these treated hearts demonstrated increased tissue perfusion after 2 h (P < 0.05 versus controls), suggesting improved microvascular function. Delta opioid agonists elicited the potential to attenuate reperfusion injury, suggesting a postconditioning effect of these agents. We hypothesize that the induced benefits of delta opioids, in part, are associated with decreased calcium influx on reperfusion, independent of sodium–hydrogen exchange inhibition. Such agents may have a potential role in minimizing reperfusion injury associated with coronary stenting, bypass surgery, myocardial infarction, cardiac transplantation, or with the utilization of heart preservation systems. Impact statement In this study, we found that postconditioning with Deltorphin D significantly improved diastolic relaxation and decreased the incidence of ventricular arrhythmias during early reperfusion. Furthermore, these treated hearts demonstrated increased tissue perfusion after 2 h, suggesting improved microvascular function. Delta opioid agonists attenuated reperfusion injury, suggestive of a postconditioning effect. Such agents may have a potential role in minimizing reperfusion injury associated with coronary stenting, bypass surgery, myocardial infarction, cardiac transplantation, or with the utilization of heart preservation systems.

Reversible and Irreversible Damage of the Myocardium: Ischemia/Reperfusion Injury and Cardioprotection

Ischemia and reperfusion injuries can lead to major compromises in cardiac function. While the intent of many of the past cardioprotective therapies was to protect the myocardium from ischemic necrosis, it may be that reperfusion injury following ischemia may occur despite such preventative attempts. There are continued efforts to identify improvements in myocardial protective strategies (pre- and postconditioning), and their ultimate goals are to minimize the risk of cellular injuries to all types of patients undergoing cardiovascular therapies, treatments, or surgeries.

VDD Lead‐Lead Interaction and Atrial Oversensing: An Acute Animal Study

Limited data exist on the utilization of a transvenous A‐sense; V‐pace/sense (VDD) pacing system with a chronically retained nonfunctioning endocardial V‐sense/pace (VVI) pacing lead. In an acute canine model, no atrial oversensing was observed with lead‐lead interaction between the VDD lead and the pseudo‐retained VVI lead. Undersensing occurred <10% of all beats observed.

Reversible and irreversible damage of the myocardium new ischemic syndromes, ischemia/reperfusion injury, and cardioprotection

Ischemia and reperfusion injuries can lead to major compromises in cardiac function. While the intent of many of the past cardioprotective therapies was to protect the myocardium from ischemic necrosis, it may be that reperfusion injury following ischemia may occur despite such preventative attempts. There are continued efforts to identify improvements in myocardial protective strategies, and their ultimate goals are to minimize the risk of cellular injuries to all types of patients undergoing cardiovascular therapies, treatments, or surgeries. The goal of this chapter is to provide the reader with a general review of the physiology and pathophysiology of “myocardial ischemia.”