Impairments in reinforcement learning do not explain enhanced habit formation in cocaine use disorder.

RATIONALE: Drug addiction has been suggested to develop through drug-induced changes in learning and memory processes. Whilst the initiation of drug use is typically goal-directed and hedonically motivated, over time, drug-taking may develop into a stimulus-driven habit, characterised by persistent use of the drug irrespective of the consequences. Converging lines of evidence suggest that stimulant drugs facilitate the transition of goal-directed into habitual drug-taking, but their contribution to goal-directed learning is less clear. Computational modelling may provide an elegant means for elucidating changes during instrumental learning that may explain enhanced habit formation. OBJECTIVES: We used formal reinforcement learning algorithms to deconstruct the process of appetitive instrumental learning and to explore potential associations between goal-directed and habitual actions in patients with cocaine use disorder (CUD). METHODS: We re-analysed appetitive instrumental learning data in 55 healthy control volunteers and 70 CUD patients by applying a reinforcement learning model within a hierarchical Bayesian framework. We used a regression model to determine the influence of learning parameters and variations in brain structure on subsequent habit formation. RESULTS: Poor instrumental learning performance in CUD patients was largely determined by difficulties with learning from feedback, as reflected by a significantly reduced learning rate. Subsequent formation of habitual response patterns was partly explained by group status and individual variation in reinforcement sensitivity. White matter integrity within goal-directed networks was only associated with performance parameters in controls but not in CUD patients. CONCLUSIONS: Our data indicate that impairments in reinforcement learning are insufficient to account for enhanced habitual responding in CUD.

Impulsivity in borderline personality disorder.

BACKGROUND: Impulsivity is a core feature of borderline personality disorder (BPD) and is most frequently measured using self-rating scales. There is a need to find objective, valid and reliable measures of impulsivity. This study aimed to examine performance of participants with BPD compared with healthy controls on delay and probabilistic discounting tasks and the stop-signal task (SST), which are objective measures of choice and motor impulsivity, respectively. METHOD: A total of 20 participants with BPD and 21 healthy control participants completed delay and probabilistic discounting tasks and the SST. They also completed the Barratt Impulsiveness Scale (BIS), a self-rating measure of impulsivity. RESULTS: Participants with BPD showed significantly greater delay discounting than controls, manifest as a greater tendency to accept the immediately available lesser reward rather than waiting longer for a greater reward. Similarly they showed significantly greater discounting of rewards by the probability of payout, which correlated with past childhood trauma. Participants with BPD were found to choose the more certain and/or immediate rewards, irrespective of the value. On the SST the BPD and control groups did not differ significantly, demonstrating no difference in motor impulsivity. There was no significant difference between groups on self-reported impulsivity as measured by the BIS. CONCLUSIONS: Measures of impulsivity show that while motor impulsivity was not significantly different in participants with BPD compared with controls, choice or reward-related impulsivity was significantly affected in those with BPD. This suggests that choice impulsivity but not motor impulsivity is a core feature of BPD.

Orbitofrontal dopamine depletion upregulates caudate dopamine and alters behavior via changes in reinforcement sensitivity.

Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia.

Reduction of apoptosis in the amygdala by an A2A adenosine receptor agonist following myocardial infarction.

It has been observed that a cytokine synthesis inhibitor, pentoxifylline, prevents the apoptotic processes taking place in the amygdala following myocardial infarction. However, it is unknown if the cardioprotective effect of A(2A) adenosine receptor agonist, CGS21680, which reduces cytokine synthesis, would lead to such amygdala apoptosis regression. Thus, this study was designed to investigate whether cardioprotective A(2A) adenosine receptor activation reduces apoptosis in the amygdala following myocardial infarction. Anesthetized rats were subjected to left anterior descending coronary artery occlusion for 40 min, followed by 72 h of reperfusion. The A(2A) agonist CGS21680 (0.2 mug/kg/min i.v.) was administered continuously for 120 min, starting (1) five minutes prior to instituting reperfusion (Early) or (2) five minutes after the beginning of reperfusion (Late). After reperfusion, myocardial infarct size was determined and the amygdala was dissected from the brain. Infarct size was reduced significantly in the Early compared to the Control group (34.6 +/- 1.8% and 52.3 +/- 2.8% respectively; p < 0.05), with no difference compared to the Late group (40.1 +/- 6.1%). Apoptosis regression was documented in the amygdala of the Early group by an enhanced phosphatidylinositol 3-kinase-Akt pathway activation and Bcl-2 expression concurrently to a caspase-3 activation limitation and reduction in TUNEL-positive cells staining. On the other hand, amygdala TUNEL-positive cell numbers were not reduced in the Late group. Moreover, TNFalpha was significantly reduced in the amygdala of the Early group compared to the Control and Late groups. These results indicate that A(2A) adenosine receptor stimulation is associated with apoptosis regression in the amygdala following myocardial infarction.

Nucleus accumbens dopamine depletion impairs both acquisition and performance of appetitive Pavlovian approach behaviour: implications for mesoaccumbens dopamine function.

The involvement of mesoaccumbens dopamine in adaptive learning and behaviour is unclear. For example, dopamine may act as a teaching signal to enable learning, or more generally modulate the behavioural expression, or selection, of an already-learned response. The present study investigated the involvement of the mesoaccumbens dopamine system in a fundamental form of learning: Pavlovian conditioning. In this case, the temporal association of a previously neutral visual stimulus and a biologically significant unconditioned stimulus (US), subsequently led to the production of the conditioned response (CR) of discriminated approach behaviour directed toward the conditioned stimulus (CS+), relative to a control (CS-) stimulus. 6-hydroxydopamine lesions of the nucleus accumbens (NAcc), leading to approximately 80% reductions in tissue dopamine, were made at varying time points in four experimental groups of rats, either before or subsequent to the acquisition of the CR. NAcc dopamine depletion produced long-term neuroadaptations in dopamine function 2 months after surgery, and profoundly impaired discriminated Pavlovian approach regardless of when the lesion was made. Thus, NAcc dopamine not only plays a role in conditioned behavioural activation, but also in making the appropriate discriminated response i.e. the direction of response. Further, acquisition lesions produced a far greater impact on discriminated approach than performance lesions. This difference in lesion-induced impairment implies that mesoaccumbens dopamine may play differential roles in the learning and performance of preparatory Pavlovian conditioning.

Differential involvement of NMDA, AMPA/kainate, and dopamine receptors in the nucleus accumbens core in the acquisition and performance of pavlovian approach behavior.

Stimuli paired with primary rewards can acquire emotional valence and the ability to elicit automatic, Pavlovian approach responses that have been shown to be mediated by the nucleus accumbens. The present experiment investigated the effects of infusions of glutamatergic or dopaminergic receptor antagonists into the core of the nucleus accumbens on the acquisition and performance of Pavlovian discriminated approach to an appetitive conditioned stimulus. Rats were trained on an autoshaping task in which a conditioned stimulus (CS+; a lever) was inserted into the operant chamber for 10 sec, after which a food pellet was delivered. Presentation of another lever (CS-) was never followed by food. Subjects developed a conditioned response of approaching and contacting the CS+ selectively, although food delivery was not in any way contingent on the animals' response. A triple dissociation in the effects of AP-5, LY293558 [(3SR, 4aRS, 6RS, 8aRS)-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid], and alpha-flupenthixol infused into the nucleus accumbens core on the acquisition and performance of this conditioned response was observed. The AMPA/kainate receptor antagonist LY293558 disrupted discriminated approach performance but not acquisition, as evidenced by increased approaches to the CS-. In contrast, the NMDA receptor antagonist AP-5 impaired only the acquisition, but not performance, of autoshaping whereas the dopamine D1/D2 receptor antagonist alpha-flupenthixol decreased approaches to the CS+ during both acquisition and performance. The data are discussed with reference to dissociable interactions of these receptor types with limbic cortical and dopaminergic afferents to the nucleus accumbens core during the acquisition and expression of Pavlovian conditioned approach.

Pimozide (Orap) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current in native cardiac myocytes.

BACKGROUND: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent neuroleptic useful in the management of motor and phonic tics associated with Tourette syndrome. To further elucidate the mechanism underlying these clinical observations, the effects of pimozide on monophasic action potential duration (MAPD(90)) and on potassium currents involved in the repolarization of native isolated ventricular myocytes were examined. METHODS AND RESULTS: Studies were undertaken in eight isolated guinea pig hearts that demonstrated reverse rate-dependent prolongation of cardiac repolarization by pimozide 100 nmol/L. Action potential duration increased 24% from baseline 115 +/- 2 to 142 +/- 4 msec with pimozide 100 nmol/L during pacing at 250 msec cycle length, while a 10% increase from 97 +/- 2 to 107 +/- 3 msec was seen with pacing at a cycle length of 150 msec. Experiments in native isolated ventricular myocytes (n = 20) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: tail current was decreased by 50% at 15 nmol/L. CONCLUSIONS: Pimozide possesses cardiac electrophysiological effects similar to those of class III antiarrhythmic drugs. These effects are concentration-dependent and observed at recommended dosages of the drug. Since pimozide is strongly metabolized by CYP3A4, special care should be taken to avoid potential pharmacokinetic interactions leading to high plasma levels of pimozide and proarrhythmia.

Negative inotropic and chronotropic effects of oxytocin.

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 5x10(-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.

Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task.

Optimization of cognitive processing may depend on specific and distinct functions of the cortical cholinergic and noradrenergic systems. This investigation dissociates functions of cortical acetylcholine (ACh) and noradrenaline (NA) in arousal and visual attention by simultaneously measuring ACh and NA efflux in the rat prefrontal cortex during sustained attentional performance. The five-choice serial reaction time task was used to provide a continuous assessment of visuospatial attention. Previous studies using this task have established a critical role for the cortical cholinergic system in the detection of visual targets. However, selective lesions of the locus coeruleus noradrenergic system impair performance only when additional attentional demands are placed on the subject by distractors or temporally unpredictable targets. To test the hypothesis that the cortical noradrenergic system is particularly sensitive to novel task contingencies, we also assessed NA and ACh efflux in rats that been trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished. Cortical ACh efflux showed a robust and task-related increase during established contingent performance. This response was significantly attenuated in noncontingent subjects, although it still exceeded pretask values. In contrast, NA efflux only increased transiently in contingent subjects after task onset but showed sustained elevations in noncontingent subjects on the first day when contingencies were changed. These data also implicate cortical ACh in aspects of attentional functioning but highlight a specific involvement of the cortical noradrenergic system in detecting shifts in the predictive relationship between instrumental action and reinforcement.

Decision making and neuropsychiatry.

Abnormal decision making is a central feature of neuropsychiatric disorders. Recent investigations of the neural substrates underlying decision making have involved qualitative assessment of the cognition of decision making in clinical lesion studies (in patients with frontal lobe dementia) and neuropsychiatric disorders such as mania, substance abuse and personality disorders. A neural network involving the orbitofrontal cortex, ventral striatum and modulatory ascending neurotransmitter systems has been identified as having a fundamental role in decision making and in the neural basis of neuropsychiatric diseases. This network accounts for the dissociations among decision-making deficits in different clinical populations. Ultimately, a more refined and sophisticated characterization of such deficits might guide the early diagnosis and cognitive and therapeutic rehabilitation of these patients.

Impulsive choice induced in rats by lesions of the nucleus accumbens core.

Impulsive choice is exemplified by choosing a small or poor reward that is available immediately, in preference to a larger but delayed reward. Impulsive choice contributes to drug addiction, attention-deficit/hyperactivity disorder, mania, and personality disorders, but its neuroanatomical basis is unclear. Here, we show that selective lesions of the nucleus accumbens core induce persistent impulsive choice in rats. In contrast, damage to two of its afferents, the anterior cingulate cortex and medial prefrontal cortex, had no effect on this capacity. Thus, dysfunction of the nucleus accumbens core may be a key element in the neuropathology of impulsivity.

Functional desensitization to isoproterenol without reducing cAMP production in canine failing cardiocytes.

To corroborate alterations in the functional responses to beta-adrenergic receptor (beta-AR) stimulation with changes in beta-AR signaling in failing cardiomyocytes, contractile and L-type Ca(2+) current responses to isoproterenol along with stimulated cAMP generation were compared among cardiomyocytes isolated from canines with tachycardia-induced heart failure or healthy hearts. The magnitude of shortening of failing cardiomyocytes was significantly depressed (by 22 +/- 4.4%) under basal conditions, and the maximal response to isoproterenol was significantly reduced (by 45 +/- 18%). Similar results were obtained when the responses in the rate of contraction and rate of relaxation to isoproterenol were considered. The L-type Ca(2+) current amplitude measured in failing cardiomyocytes under basal conditions was unchanged, but the responses to isoproterenol were significantly reduced compared with healthy cells. Isoproterenol-stimulated cAMP generation was similar in sarcolemmal membranes derived from the homogenates of failing (45 +/- 6.8) and healthy cardiomyocytes (52 +/- 8.5 pmol cAMP. mg protein(-1). min(-1)). However, stimulated cAMP generation was found to be significantly reduced when the membranes were derived from the homogenates of whole tissue (failing: 67 +/- 8.1 vs. healthy: 140 +/- 27.8 pmol cAMP. mg protein(-1). min(-1)). Total beta-AR density was not reduced in membranes derived from either whole tissue or isolated cardiomyocyte homogenates, but the beta(1)/beta(2) ratio was significantly reduced in the former (failing: 45/55 vs. healthy: 72/28) without being altered in the latter (failing: 72/28, healthy: 77/23). We thus conclude that, in tachycardia-induced heart failure, reduction in the functional responses of isolated cardiomyocytes to beta-AR stimulation may be attributed to alterations in the excitation-contraction machinery rather than to limitation of cAMP generation.

Onset dynamics of reentrant tachycardia and rate-dependent conduction changes in canine ventricular muscle: effects of Na+ and Ca2+ channel blockade.

To show that cycle-length (CL) prolongation occurring at the onset of reentrant tachycardias may be associated with an increase in conduction time (CT), and to investigate the involvement of Na+ and Ca2+ channel activity, reentrant activity was induced by programmed stimulation in thin ventricular muscle slices with a central cryothermal lesion, as documented with 7 to 12 bipolar recordings. We studied the course of the CL measured in successive tachycardia beats, as well as the course of conduction times after abrupt transition from a pacing CL of 1,000 to 400 ms (pacing paradigm). The majority of the tachycardias displayed a dynamic behavior in which CL increased progressively, with an exponential rate constant of 37 +/- 35 beats (mean +/- SD), stabilizing at 325 +/- 67 ms after a total increase of 17 +/- 17 ms. In the pacing paradigm, CT was prolonged from 68 +/- 21 ms to 79 +/- 24 ms according to a biphasic course consisting of an abrupt increase in the first response to 400 ms, followed up by an exponential increase, stabilizing with a rate constant of 18 +/- 23 beats. Lidocaine 5 x 10(-5) mol/L induced an increase in steady-state CT, which was not further modified by adding verapamil 10(-5) mol/L. However, verapamil prolonged the rate constant of the exponential course by 60 +/- 40 beats. Thus, the onset dynamics of reentrant tachycardias share common features with the dynamic behavior of CT in the pacing paradigm, in which both Na+ channel activity and Ca2+-modulated cellular coupling appear to be involved.

Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders.

BACKGROUND: Several 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 RESULTS: Studies 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 (I(Kr)) of the delayed rectifier potassium current. The tail current decreased by 50% at 162 nmol/L domperidone. CONCLUSIONS: Domperidone 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.

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.

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.

Spontaneous changes in ventricular tachycardia cycle length and their relation to earliest sites of epicardial activation in a canine model.

BACKGROUND: The purpose of this study was to examine the spontaneous changes in cycle length during episodes of sustained monomorphic (MVT) and polymorphic (PVT) ventricular tachycardias and to relate these changes with the earliest epicardial activation site of the beat. METHODS: Isochronal activation maps were obtained from 127 unipolar electrograms recorded from the surface of both ventricles with a sock electrode array in 24 open chest anesthetized dogs. After atrioventricular block, the left anterior descending coronary artery was occluded for 60 min under ventricular pacing (140/min), followed by reperfusion. In 7 dogs the left stellate ganglion was stimulated 5 min after reperfusion. RESULTS: In 7 MVTs (reperfusion) and 4 PVTs (sympathetic stimulation), cycle length changes showed an initial acceleration, reaching a minimum cycle length and then decelerating before termination. Isochronal maps showed radial spread from earliest activation, without conduction block. Cycle length (481 +/- 80 msec) in MVT had beat to beat variations of 15 +/- 17 msec corresponding to small shifts in sites of the earliest activation, clustered along the border of the ischemic myocardium. In PVTs the cycle length (352 +/- 90 msec, p < 0.01) had a variability of 62 +/- 23 msec, corresponding to wide changes in the sites of earliest activation in right and left ventricles. Linear regression analysis showed a strong and significant correlation between cycle length variability and the number of electrodes with the earliest activation (r = 0.77, p < 0.0001). CONCLUSION: In these models of monomorphic and polymorphic ventricular tachycardias, cycle length variability showed a significant correlation with the number of electrodes with the earliest activation. MVTs showed concentrated origins with regular cycle length, whereas PVTs showed dispersed origins with irregular cycle length. These results suggest that the earliest epicardial activation site of the beat could be a factor in determining the dynamics in the cycle length.

Cycle length dynamics at the onset of postinfarction ventricular tachycardias induced in canines: dependence on interval-dependent excitation properties of the reentrant substrate.

INTRODUCTION: Postinfarction monomorphic ventricular tachycardias induced by programmed stimulation may display initial cycle length (CL) variations before stabilizing. METHODS AND RESULTS: To show that tachycardia onset dynamics depend on rate-dependent electrical properties of the reentrant substrate, we extracted activation times and maximum negative slopes of local activation complexes (-dV/dt(max)) from 191 unipolar electrograms recorded in the anterior left ventricular wall of anesthetized, 3-day-old infarct canine preparations. Measurements were made of the responses to programmed stimulation, as well as in early and later beats of tachycardias, which displayed either a constant trend in CL (group A, n = 5 preparations) or one in which CL prolongation occurred according to an exponential course before stabilizing (group B, n = 9). Stimulation protocols inducing the tachycardias were more aggressive and their CL was significantly shorter (CL = 159 +/- 24 msec) in group A than in group B (stabilized CL = 206 +/- 34 msec). Reentrant activity occurred in subepicardial areas in which the absolute value of -dV/dt(max) (absolute value(-dV/dtmax)) was heterogeneously depressed (<2 mV/msec). Absolute value(-dV/dtmax) was reduced and activation delay increased in the successive responses to extrastimuli. Further reductions in absolute value(-dV/dtmax) (10% to 23%) were shown to occur between early and later beats in 5 of the 9 tachycardias in group B (no change in the 4 others), and they were associated with localized prolongation of conduction times in reentrant pathways. In contrast, absolute value(-dV/dtmax) improved in all group A tachycardias (7% to 25%). CONCLUSION: This study provides evidence that the onset dynamics of postinfarction ventricular tachycardias are determined by interval-dependent electrical changes occurring in the reentrant substrate.

Vitamin K modulates cardiac action potential by blocking sodium and potassium ion channels.

BACKGROUND: Cardiovascular collapses, syncopes, and sudden deaths have been observed following the rapid administration of intravenous vitamin K. Our objectives were to characterize the effects of vitamin K on cardiac action potentials and to evaluate effects of vitamin K on sodium and potassium currents, namely I(Na), I(Kr), and I(Ks). METHODS AND RESULTS: Guinea pig hearts (n = 21) were paced at a cycle length of 250 msec and exposed to vitamin K at 1.15-4.6 micromol/L (2.5-10 mg/L). Monophasic action potential duration measured at 90% repolarization (MAPD(90)) was not significantly reduced (-1.6 +/- 0.3 msec; P >.05; N.S.) at 1.15 micromol/L, but increased by 6.5 +/- 0.4 msec (P <.05) at 2.3 micromol/L. MAPD(90) was not measurable at 4.6 micromol/L, as a result of inexcitability. Patch-clamp experiments in ventricular myocytes demonstrated a approximately 50% reduction in I(Na) by 10 micromol/L vitamin K and a concentration-dependent reduction of the K(+) current elicited by short depolarizations (250 msec; I(K250)). Estimated IC(50) for I(K250), mostly representing I(Kr), was 2.3 micromol/L. Vitamin K was less potent to block the K(+) current elicited by long depolarizations (5,000 msec; I(K5000)), mostly representing I(Ks), with an estimated IC(50) over 100 micromol/L. CONCLUSIONS: Therapeutic concentrations ( approximately 1.5 micromol/L) of intravenous vitamin K modulate cardiac action potential by blocking ionic currents involved in cardiac depolarization and repolarization.