René Cardinal

Epicardial and endocardial mapping of ventricular tachycardia in patients with myocardial infarction. Is the origin of the tachycardia always subendocardially localized

BackgroundLeft ventricular endocardial reentry is the conventional concept underlying surgery for ventricular tachycardia (VT). We assessed the incidences of patterns showing complete reentry circuits at either the subendocardial or subepicardial level and of patterns in which left ventricular endocardial mapping could only in part account for a reentrant mechanism. Methods and ResultsWe retrospectively analyzed epicardial and left ventricular endocardial isochronal maps of 47 VTs induced in 28 patients with chronic myocardial infarction (inferior, 14 patients; anteroseptal, 14 patients). Electrograms were recorded intraoperatively from 128 sites with epicardial sock and transatrial left ventricular endocardial balloon electrode arrays. Given the methodology used in this study, the mapping characteristics of the tachycardias suggested five types of activation patterns: 1) complete (90% or more ofVT cycle length) subendocardial reentry circuits in seven VTs (15%) and seven patients (25%), 2) complete subepicardial reentry circuits in fourVTs (9%o) and four patients (14%), 3) incompletely mapped circuits with a left ventricular endocardial breakthrough preceding the epicardial breakthrough in 25 VTs (53%) and 21 patients (75%), 4) incompletely mapped circuits with a left ventricular epicardial breakthrough preceding the endocardial breakthrough in three VTs (6%) and three patients (11%), and 5) a right ventricular epicardial breakthrough preceding the left ventricular endocardial breakthrough in eight VTs (17%) and seven patients (25%). After surgery, one type 3 VT and three type 5 VTs were reinducible. Thus, left ventricular endocardial reentry substrates (types 1 and 3) accounted for 68% of VTs, but substrates involving subepicardial (types 2 and 4) and deep septal layers (type 5) accounted for 32% of VTs. ConclusionsIn a substantial number of VTs, a substrate localization that is at variance with the conventional concept can be detected by simultaneous epicardial and endocardial mapping and may require modification of the surgical approach conventionally aimed at endocardial layers.

Domperidone Should Not Be Considered a No-Risk Alternative to Cisapride in the Treatment of Gastrointestinal Motility Disorders

BackgroundSeveral cases of QT prolongation and ventricular tachyarrhythmia have been reported with domperidone, a gastrokinetic and antiemetic agent available worldwide but still under investigation in the United States. Although electrolyte disturbances such as hypokalemia could account for some of these events, we hypothesized that domperidone may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. Methods and ResultsStudies were undertaken in 9 isolated guinea pig hearts, which demonstrated reverse use–dependent prolongation of cardiac repolarization by 100 nmol/L domperidone. Action potential duration increased 27% from baseline with domperidone (from 114±3 to 145±2 ms) during pacing at a cycle length of 250 ms, and a 9% increase (from 97±2 to 106±3 ms) was seen with pacing at a cycle length of 150 ms. Experiments in human ether-a-go-go–related gene (HERG)-transfected Chinese hamster ovary cells (n=32) demonstrated a concentration-dependent block of the rapid component (IKr) of the delayed rectifier potassium current. The tail current decreased by 50% at 162 nmol/L domperidone. ConclusionsDomperidone possesses cardiac electrophysiological effects similar to those of cisapride and class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations of the drug. Therefore, domperidone should not be considered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market.

Sildenafil (Viagra) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.

Markedly different effects on ventricular remodelling result in a decrease in inducibility of ventricular arrhythmias

OBJECTIVES The purpose of this study was to determine whether the type and extent of ventricular remodeling after infarction influence inducibility of ventricular arrhythmias after infarction. BACKGROUND Although serious ventricular arrhythmias after infarction are related to ventricular dysfunction, the relation between inducibility of ventricular arrhythmias and ventricular remodeling remains incompletely understood. METHODS Rats that survived ligation of the left anterior descending coronary artery (n = 218) were randomized to receive placebo (saline solution) or captopril or propranolol therapy and were followed up for 5 weeks. Hemodynamic and neurohumoral blood measurements were obtained, and therapy was stopped. Two days later, susceptibility to ventricular arrhythmias was assessed by programmed electrical stimulation, and hearts were prepared for pathologic studies. RESULTS Placebo-treated rats with a large myocardial infarction had ventricular dysfunction, marked neurohumoral activation, ventricular enlargement (endocardial circumference 16 +/- 3 [mean +/- SD] to 20 +/- 4 mm, p < 0.05) and increased cardiac fibrosis (volume density of collagen 2.3 +/- 0.8% to 5.6 +/- 2.4%, p < 0.05). In many rats this resulted in easily inducible ventricular arrhythmias (inducibility quotient 4.9 +/- 2.2). Captopril attenuated the development of ventricular dysfunction, neurohumoral activation, ventricular hypertrophy and dilation (endocardial circumference 18 +/- 3 mm) and cardiac fibrosis (3.1 +/- 0.8%, p < 0.05). These modifications were accompanied by decreased inducibility of ventricular arrhythmias (inducibility quotient 1.1 +/- 2.0, p < 0.05). Propranolol did not prevent ventricular dysfunction, had variable effects on neurohumoral activation and led to increased ventricular dilation (endocardial circumference 25 +/- 4 mm, p < 0.05) and cardiac fibrosis (7.7 +/- 1.2%, p < 0.05). Nevertheless, these morphologic changes led to decreased inducibility of ventricular arrhythmias (inducibility quotient 2.2 +/- 2.5%, p < 0.05). CONCLUSIONS This study indicates that the inducibility of ventricular arrhythmias can be reduced as a result of markedly different effects on ventricular remodeling, indicating that the relation between ventricular remodeling, arrhythmias and survival is more complex than previously thought.

Negative Inotropic and Chronotropic Effects of Oxytocin

Abstract—We have previously shown that oxytocin receptors are present in the heart and that perfusion of isolated rat hearts with oxytocin results in decreased cardiac flow rate and bradycardia. The mechanisms involved in the negative inotropic and chronotropic effects of oxytocin were investigated in isolated dog right atria in the absence of central mechanisms. Perfusion of atria through the sinus node artery with 10−6 mol/L oxytocin over 5 minutes (8 mL/min) significantly decreased both beating rate (−14.7±4.9% of basal levels, n=5, P <0.004) and force of contraction (−52.4±9.1% of basal levels, n=5, P <0.001). Co-perfusion with 10−6 mol/L oxytocin receptor antagonist (n=3) completely inhibited the effects of oxytocin on frequency (P <0.04) and force of contraction (P <0.004), indicating receptor specificity. The effects of oxytocin were also totally inhibited by co-perfusion with 5×10−8 mol/L tetrodotoxin (P <0.02) or 10−6 mol/L atropine (P <0.03) but not by 10−6 mol/L hexamethonium, which implies that these effects are neurally mediated, primarily by intrinsic parasympathetic postganglionic neurons. Co-perfusion with 10−6 mol/L NO synthase inhibitor (L-NAME) significantly inhibited oxytocin effects on both beating rate (−1.85±1.27% versus −14.7±4.9% in oxytocin alone, P <0.05) and force of contraction (−24.9±4.4% versus −52.4±9.1% in oxytocin alone, n=4, P <0.04). The effect of oxytocin on contractility was further inhibited by L-NAME at 10−4 mol/L (−8.1±1.8%, P <0.01). These studies imply that the negative inotropic and chronotropic effects of oxytocin are mediated by cardiac oxytocin receptors and that intrinsic cardiac cholinergic neurons and NO are involved in these actions.

Anisotropic conduction and functional dissociation of ischemic tissue during reentrant ventricular tachycardia in canine myocardial infarction.

We measured the conduction characteristics at the epicardial surface of the left anterior ventricular wall in the in situ canine heart before and 3 to 5 days (n = 9 dogs) after permanent occlusion of the left anterior descending coronary artery (LAD). During ventricular stimulation generating wavefronts conducted along the longitudinal or the transverse fiber direction, 61 unipolar electrograms were recorded with a fine-meshed plaque electrode. Before occlusion, the fastest conduction velocity was consistently found in a direction perpendicular to the nearby LAD segment (longitudinal direction), and the slowest velocity in a direction parallel to the LAD segment (transverse fiber direction). In 3- to 5-day-old infarct preparations, a layer of subepicardial muscle with 1 to 3 mm thickness survived over necrotic tissue. The velocities and directions of fast and of slow conduction measured in ischemic subepicardial muscle were not significantly different from preocclusion values during stimulation at a basic rate, but excitability was found to be depressed in response to premature stimuli. Premature impulses initiated in nonischemic myocardium and conducted into ischemic tissue in the longitudinal or in the transverse directions induced sustained (greater than 100 beats) monomorphic tachycardias during which figure-eight activation patterns were mapped with sock-array electrodes. During these tachycardias, the direction of the common reentrant wavefront of the figure-eight pattern was preferentially oriented along the longitudinal fiber direction, independently of the direction of the initiating impulse. When polymorphic beats were induced, tachycardia terminated spontaneously within 20 beats, or changed to a monomorphic pattern, as described above. In conclusion, the anisotropic organization of surviving subepicardial muscle overlying an infarct provides a spatial constraint that determines a preferential direction of reentrant propagation and may contribute to sustaining monomorphic tachycardia.

The heart reinnervates after transplantation

BACKGROUND Whether cardiac reinnervation occurs after transplantation remains controversial. If reinnervation does occur, how sympathetic and parasympathetic efferent neurons do this remains unknown. METHODS Power spectral analysis of heart rate variability was assessed for 1 year after cardiac autotransplantation in 9 dogs. After induction of anesthesia 13 months after transplantation, cardiac and intrinsic cardiac neuronal responses elicited by both electrical stimulation of parasympathetic or sympathetic efferent neurons and systemic or local coronary artery administration of nicotine (5 microg/kg), angiotensin II (0.75 microg/kg), and tyramine (1.2 microg/kg) were studied. The transmembrane electrical properties of intrinsic cardiac neurons were studied in vitro. Ventricular tissue catecholamine content, alpha-tubulin expression, and beta-adrenergic receptor density and affinity were studied. The presence of axons crossing suture lines was sought histologically. RESULTS Nerves were identified crossing suture lines. Electrical or chemical (ie, nicotine or angiotensin II) activation of sympathetic efferent neurons enhanced cardiodynamics, as did tyramine. Stimulating vagal efferent preganglionic axons induced bradycardia in half of the dogs. Functional reinnervation did not correlate with specific power spectra derived from rate variability in the conscious state. Responding to nicotine and angiotensin II in situ, transplanted intrinsic cardiac neurons generated spontaneous activity. These neurons displayed nicotine-dependent synaptic inputs in vitro. Ventricular tissue had normal beta-adrenergic receptor affinity and density but reduced catecholamine and alpha-tubulin contents. CONCLUSIONS The intrinsic cardiac nervous system receives reduced input from extracardiac sympathetic efferent neurons after transplantation and inconsistent input from parasympathetic efferent preganglionic neurons. These heterogeneous neuronal inputs are not reflected in heart rate variability or ventricular beta-adrenergic receptor function. Transplanted angiotensin II-sensitive intrinsic cardiac neurons exert greater cardiac control than do nicotine-sensitive ones. The intrinsic cardiac nervous system remodels itself after cardiac transplantation, and this indicates that direct assessment of extracardiac and intrinsic cardiac neuronal behavior is required to fully understand cardiac control after transplantation.

Post-ischemic cardioprotection by A2A adenosine receptors: dependent of phosphatidylinositol 3-kinase pathway.

Activation of myocardial A2A adenosine receptors during reperfusion has been shown to be cardioprotective. The intracellular mechanisms underlying this protection remain unknown. To understand the beneficial effects of activated A2A adenosine receptors in such a state, we investigated whether the enzymes phosphatidylinositol 3-kinase (PI3K) and caspase-3 can account for this post-ischemic cardioprotective effect in an anesthetized rabbit model of myocardial infarction (30 minutes ischemia; 5 hours reperfusion). Administration of the A2A agonist CGS21680 (0.2 &mgr;g/kg/min) 5 minutes before reperfusion began (Early) reduced infarct size expressed as a percentage of the area at risk (25.7 ± 5.3% versus 46.5 ± 5.3% for the control group; * P < 0.05). Treatment with the A2A agonist 5 minutes after the onset of reperfusion (Late) had no effect on infarct size (38.2 ± 6.2%). In the presence of a selective inhibitor of PI3K (LY294002), the beneficial effects of CGS21680 on infarct size was no longer observed (43.9 ± 7.9%). After 5 hours of reperfusion, higher PI3K activity in the ischemic region was observed in the Early group compared with the other experimental groups. Caspase-3 activity was not observed in these different groups. In another set of experiments, PI3K activity was significantly higher during the first 15 minutes of reperfusion in the Early group as compared with the Control group. Caspase-3 activity increased rapidly during the first 15 minutes of reperfusion in the Control group and remained stable in the Early group. These results indicated that post-ischemic cardioprotection afforded by A2A adenosine receptor activation is PI3K-dependent and modulate rapidly other signaling pathways such as caspase-3.

An Integrated System for Intraoperative Cardiac Activation Mapping

This paper describes an electrophysiological data acquisition and processing system which is programmed to rapidly generate cardiac activation maps for experimental studies and antiarrhythmia surgery. The basic system consists of a PDP-11/23+ minicomputer (DEC) with 1.5 Mbit memory and a 10 Mbit hard disk, a 64-channel data acquisition unit controlled by a specially designed interface card, and a modified video terminal. The data acquisition unit includes 64 instrumentation amplifiers with programmable gain and bandwidth. Signals are sampled and digitized at a maximum rate of 1000 samples/s/channel (10 bits) and transferred to the interface card by an optically isolated data bus. The operator controls the system by pointing to function boxes and signals appearing on the graphic terminal with a light pen. The software is based on a general-purpose data acquisition program with a command language interpreter. This program includes a setup section to define the systems parameters (gains, bandwidths, sampling rate) and an acquisition section to initiate data recording into a ring buffer, display the signals simultaneously on the screen, select heartbeats, and store or retrieve data on disk. The data processing procedures (in this case, mapping) can be easily interchanged to accommodate future signal processing needs. Current mapping procedures include an automatic detection section and an editor to manually define the local activation times on any electrogram. Another section displays the activation sequence as a map of isochronal lines. Typical processing time from the selection of a heartbeat to the visualization of the corresponding isochrone map is 2 min.

Dorsal spinal cord stimulation obtunds the capacity of intrathoracic extracardiac neurons to transduce myocardial ischemia

Populations of intrathoracic extracardiac neurons transduce myocardial ischemia, thereby contributing to sympathetic control of regional cardiac indices during such pathology. Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) modulates such local reflex control. In 10 anesthetized canines, middle cervical ganglion neurons were identified that transduce the ventricular milieu. Their capacity to transduce a global (rapid ventricular pacing) vs. regional (transient regional ischemia) ventricular stress was tested before and during SCS (50 Hz, 0.2 ms duration at 90% MT) applied to the dorsal aspect of the T1 to T4 spinal cord. Rapid ventricular pacing and transient myocardial ischemia both activated cardiac-related middle cervical ganglion neurons. SCS obtunded their capacity to reflexly respond to the regional ventricular ischemia, but not rapid ventricular pacing. In conclusion, spinal cord inputs to the intrathoracic extracardiac nervous system obtund the latters capacity to transduce regional ventricular ischemia, but not global cardiac stress. Given the substantial body of literature indicating the adverse consequences of excessive adrenergic neuronal excitation on cardiac function, these data delineate the intrathoracic extracardiac nervous system as a potential target for neuromodulation therapy in minimizing such effects.