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.

Clinical response with adaptive CRT algorithm compared with CRT with echocardiography-optimized atrioventricular delay: a retrospective analysis of multicentre trials.

AIMS: Adaptive cardiac resynchronization therapy (aCRT) is a novel algorithm for CRT pacing that provides automatic ambulatory selection between synchronized left ventricular (LV) or bi-ventricular (BiV) pacing and optimization of atrioventricular (AV) and inter-ventricular (VV) delays based on periodic measurement of intrinsic conduction. We aimed to compare the clinical response between aCRT and standard CRT in historical trials. METHODS AND RESULTS: The treatment arm of the aCRT trial was compared with a pooled historical control (HC) derived from the CRT arms of four clinical trials (MIRACLE, MIRACLE ICD, PROSPECT, and InSync III Marquis) with respect to the proportion of patients who had an improved clinical composite score (CCS) at the 6-month follow-up. Patients in the HC underwent echocardiography-guided AV optimization after the implant. A propensity score model was used to adjust for 22 potential baseline confounders of the effect of CRT. Patients were stratified into quintiles according to the propensity score and the adjusted absolute treatment effect was obtained by averaging estimates across these quintiles. The propensity score model included 751 patients (aCRT: 266, historical trials: 485). The adjusted absolute difference in percent improved in CCS between the aCRT and HC arms was 11.9% [95% confidence interval (CI): 2.7-19.2%] favouring aCRT. The patients in the aCRT group were significantly more likely to have an improved CCS than the patients in the HC (odds ratio = 1.65, 95% CI: 1.1-2.5). CONCLUSION: The aCRT algorithm may be associated with additional improvement in clinical response compared with historical CRT with echocardiographic AV optimization.

Interatrial conduction correlates with optimal atrioventricular timing in cardiac resynchronization therapy devices.

BACKGROUND: Echocardiographic optimization of the atrioventricular delay (AV) may result in improvement in cardiac resynchronization therapy (CRT) outcome. Optimal AV has been shown to correlate with interatrial conduction time (IACT) during right atrial pacing. This study aimed to prospectively validate the correlation at different paced heart rates and examine it during sinus rhythm (Sinus). METHODS: An electrophysiology catheter was placed in the coronary sinus (CS) during CRT implant (n = 33). IACT was measured during Sinus and atrial pacing at 5 beats per minute (bpm) and 20 bpm above the sinus rate as the interval from atrial sensing or pacing to the beginning of the left atrial activation in the CS electrogram. P-wave duration (PWd) was measured from 12-lead surface electrocardiogram, and the interval from the right atrial to intrinsic right ventricular activation (RA-RV) was measured from device electrograms. Within 3 weeks after the implant patients underwent echocardiographic optimization of the sensed and paced AVs by the mitral inflow method. RESULTS: Optimal sensed and paced AVs were 129 ± 19 ms and 175 ± 24 ms, respectively, and correlated with IACT during Sinus (R = 0.76, P < 0.0001) and atrial pacing (R = 0.75, P < 0.0001), respectively. They also moderately correlated with PWd (R = 0.60, P = 0.0003 during Sinus and R = 0.66, P < 0.0001 during atrial pacing) and RA-RV interval (R = 0.47, P = 0.009 during Sinus and R = 0.66, P < 0.0001 during atrial pacing). The electrical intervals were prolonged by the increased atrial pacing rate. CONCLUSION: IACT is a critical determinant of the optimal AV for CRT programming. Heart rate-dependent AV shortening may not be appropriate for CRT patients during atrial pacing.

Interatrial conduction measured during biventricular pacemaker implantation accurately predicts optimal paced atrioventricular intervals.

BACKGROUND: Optimizing atrioventricular (AV) delay during biventricular (BiV) pacemaker implantation can require substantial resources. Hence, a simpler method is desirable. We hypothesized that interatrial conduction time (IACT), measured at the time of BiV device implant, could be a surrogate value for the optimal AV delay. OBJECTIVE: This study determined the relationship between paced IACT and the optimal paced AV delay (PAV), as determined by echocardiography. METHODS: Consecutive subjects (N = 25; age = 66 +/- 10 years; M/F: 17/8) undergoing BiV pacemaker implantation and in sinus rhythm were included. Cannulation of the coronary sinus (CS) was at the operator's discretion. A quadripolar electrophysiology catheter was inserted via the guiding sheath into the inferiolateral CS to measure left atrial depolarization. The IACT was calculated as the interval between right atrial stimulation artifact and earliest deflection on the coronary sinus catheter electrogram. Subsequently, during atrial pacing the PAV was determined using transmitral pulsed wave Doppler echocardiography (iterative method). The relationship between paced IACT and PAV was then determined. RESULTS: The mean +/- SD paced IACT and PAV were 126 +/- 25 msec and 157 +/- 23 msec, respectively. There was a strong positive correlation between the paced IACT and PAV (r = 0.73, P < 0.001). The equation describing the relationship was PAV = 0.68 * (IACT + 104) msec. CONCLUSIONS: The paced IACT has a strong correlation with the echo derived optimal PAV. This method may be used to program PAV intervals without need for echocardiography in patients undergoing BiV pacemaker implantation.

Recreating an artificial biological pacemaker: insights from a theoretical model.

BACKGROUND: Normal cardiac rhythm is critically dependent on the sinoatrial (SA) node, the natural biological pacemaker. Although recent studies have focused on the development of "artificial" biological pacemakers using gene transfer, less is known about the functional consequences of such interventions. OBJECTIVE: The purpose of this study was to investigate the electrophysiological consequences of two approaches used to create a biological pacemaker: overexpression of the hyperpolarization-activated cyclic nucleotide gated channel (HCN "pacemaker" channels) and suppression of the inward-rectifier potassium current, I(K1). METHODS: We used a linear multicellular Luo-Rudy (LRd) AP model consisting of 130 ventricular cells connected by resistive gap junctions. To induce automaticity, I(K1) current was reduced or I(f) (HCN) current was introduced in endocardial and midmyocardial (M) cells. RESULTS: Similar to the previously published results for a single LRd model, myocyte I(K1) suppression induced automaticity in the fiber. While introduction of I(f) also resulted in automaticity, the main differences between I(K1) suppression and I(f) expression were (1) a relatively more gradual phase 4 depolarization with HCN expression, (2) stabilization of cycle lengths during I(K1) suppression, but not during HCN expression, and (3) responsiveness to beta-adrenergic stimulation during HCN expression, but not during I(K1) suppression. Upon further investigation, we found that cycle length instability during HCN expression was primarily due to a gradual reduction of intracellular potassium ([K(+)](i)) from its baseline value of 142 mM to 120 mM in 600 beats and subsequent alteration of potassium-dependent ionic currents. A twofold increase in HCN expression also led to a similar behavior. We attribute this decrease in [K(+)](i) to a large I(K1) during phase 4 depolarization. When intracellular [K(+)](i) loss was minimized, cycle lengths stabilized during HCN expression. CONCLUSIONS: Our results help to further understand the electrophysiologic consequences as well as some of the challenges associated with the creation of biological pacemakers using HCN and I(K1) gene transfer strategies.

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.

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 microg/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.

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 K(ATP) channels. In previous studies, we have demonstrated the protective effects of specific delta-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 K(ATP) 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.

The potential benefits of 1.5% hetastarch as a cardioplegia additive.

INTRODUCTION: Myocardial edema is a clinically relevant problem found in post-ischemic reperfused hearts. The objective of this study was to understand the effects of hetastarch-supplemented cardioplegia on post-ischemic edema and cardiac function. MATERIALS AND METHODS: Swine hearts were arrested with either St. Thomas Hospital cardioplegia with (n=6) or without (n=7) 1.5% hetastarch. Following hypothermic global ischemia, hearts were crystalloid reperfused in a four-chamber isolated working mode. RESULTS: Hetastarch decreased myocardial water content gains after three hours of reperfusion (control versus hetastarch, hour 0: 67+/-5% versus 67+/-3%, NS; hour 3: 82+/-2% versus 78+/-1%, p=0.1). Post-ischemic control group left ventricular end-diastolic pressures were elevated after 1h (in mm Hg, hour 0: 13+/-2, hour 1: 19+/-3, hour 2: 19+/-3, hour 3: 20+/-2) but remained stable (<16 mm Hg) in the hetastarch group. Post-reperfusion creatine phosphokinase perfusate levels in the hetastarch treated hearts were decreased (control: 1.6 IU/l/g versus hetastarch: 0.6 IU/l/g, p=0.15). DISCUSSION/CONCLUSIONS: Hetastarch treatment delayed myocardial edema development and attenuated myocardial creatine kinase efflux, thereby preserving diastolic function.

In vitro studies of human hearts.

BACKGROUND: Isolated mammalian hearts have been used in numerous studies that have led to many important discoveries in cardiac physiology, pharmacology, and surgery. Multiple methods of perfusion have been described including retrograde and/or antegrade flows and crystalloid or blood perfusates. Furthermore, multiple species have been utilized for such studies including the following: rat, rabbit, guinea pig, canine, and swine. The objective of this study was to describe a unique isolated heart preparation, utilizing human hearts not viable for transplant, which allows for physiologic perfusion and endocardial imaging. METHODS: Utilizing standard cardiac transplantation procedures, 12 human hearts deemed not viable for transplant were explanted to an isolated heart apparatus. A clear, modified Krebs-Henseleit buffer was used as a blood substitute, which allowed for endocardial imaging utilizing 6.0 mm endoscopic video cameras inserted into the cardiac chambers. The hearts were perfused in Langendorff (retrograde) and/or working (physiologic) mode. RESULTS: Eleven of 12 hearts achieved the following performance in working mode: peak left ventricular pressure of 21.5 to 75.8 mm Hg, with an average of 42.7 +/- 19.9 mm Hg. Intracardiac anatomical imaging was possible in all hearts, providing unique views of normal and pathological endocardial anatomy as well as biomedical device-heart interactions. CONCLUSIONS: We have described a unique isolated heart preparation with which we have successfully reanimated 11 human hearts deemed not viable for transplant, perfused them by working mode, and performed intracardiac anatomical imaging. This approach provides a novel means for obtaining images of functional human cardiac anatomy and various types of unique biomedical assessments.

Role of kappa-opioid receptor activation in pharmacological preconditioning of swine.

Pharmacological preconditioning with kappa-opioid receptor agonists is proarrhythmic and exerts antipreconditioning effects in rats. In swine, it is unknown whether kappa-opioid receptor stimulation plays a role in pharmacological preconditioning. Swine were preconditioned with 1) saline (controls), 2) [d-Ala(2),d-Leu(5)]enkephalin (DADLE), 3) morphine, 4) pentazocine, 5) norbinaltorphimine (nor-BNI), 6) DADLE + nor-BNI, 7) morphine + nor-BNI, or 8) pentazocine + nor-BNI before occlusion (45 min) and reperfusion (180 min) of the left anterior descending coronary artery. Infarct size to area at risk (IS), regional (systolic shortening) and global (pressures and flows) myocardial function, and arrhythmia occurrence were assessed. Only DADLE + nor-BNI preconditioning significantly decreased infarct size compared with controls (47 +/- 13 vs. 65 +/- 5%, P < 0.05); morphine preconditioning was not cardioprotective with or without kappa-opioid receptor blockade (nor-BNI). DADLE preconditioning significantly increased ischemia-induced arrhythmias relative to controls, whereas pentazocine-preconditioned animals (n = 2) experienced intractable ventricular fibrillation during ischemia. kappa-Opioid receptor blockade with DADLE or pentazocine preconditioning alleviated proarrhythmic effects. These results suggest that kappa-opioid receptor activation during pharmacological preconditioning is proarrhythmic in swine.

Role of delta-opioid receptor agonists on infarct size reduction in swine.

Opioids are involved in cardiac ischemic preconditioning. Important species differences in cellular signaling mechanisms, antiarrhythmic, and antistunning effects have been described. The role of the delta-opioid receptor activation in swine remains unknown. Forty minutes before a 45-min occlusion and 180-min reperfusion of the left anterior descending coronary artery, open-chest, pentobarbital-anesthetized swine received either 1) saline (controls); 2) [D-Ala(2),D-Leu(5)]enkephalin (DADLE); 3) [D-Pen(2,5)]enkephalin (DPDPE); 4) deltorphin-D, a novel delta(2)-opioid agonist; or 5) ischemic preconditioning (IP). Assessed were 1) infarct size to area at risk (IS, triphenyltetrazolium staining), 2) regional and global myocardial function (sonomicrometry, ventricular pressure catheters), and 3) arrhythmias (electrocardiogram analyses). It was found that DPDPE and deltorphin-D pretreatment reduced IS from 64.7 +/- 5 to 36.5 +/- 6% and 27.4 +/- 11% (P < 0.01), respectively, whereas DADLE had no effect (66.8 +/- 3%). Both IP and DADLE had a proarrhythmic effect (P < 0.01). However, no differences in global or regional myocardial function or arrhythmia scores were observed between groups. This suggests that delta-receptor-specific opioids provide cardioprotection in swine.