Search

Ranolazine (RAN) has previously been shown to lower the onset of cholinergic atrial fibrillation in intact animals; however, its efficacy in the setting of atrial tachycardia (AT) is unknown. The purpose of this study was to investigate the effects of RAN alone or in combination with amiodarone (AMIO) on rapid pacing-evoked right AT in rabbit hearts. Right atrial monophasic action potentials (MAPs) were recorded in 11 anesthetized rabbits, using combination MAP pacing catheters. Vulnerability to AT was tested by employing consecutive trains of rapid burst pacing prior to and after 2.4 mg/kg of RAN alone delivered intravenously and then in combination with 3 mg/kg of AMIO as a 15-minute infusion. Primary endpoints were postdrug AT reproducibility as well as cycle length (CL) and tachycardia duration. MAP duration at 75% repolarization and the effective refractory period (ERP) were assessed during programmed pacing to calculate the atrial postrepolarization refractoriness (aPRR = ERP – MAPD75%). AT was elicited in eight out of 11 rabbits; only these animals were included for further investigation. RAN did not abolish the inducibility of AT in any experiment; however, it prolonged its CL (baseline vs. RAN: 120 ± 16 ms vs. 138 ± 18 ms; p = 0.053). Supplemental AMIO further increased the AT CL (baseline vs. RAN + AMIO: 120 ± 16 ms vs. 152 ± 23 ms; p = 0.006), without affecting arrhythmia reinducibility. Slowing of the tachycardia after RAN or RAN + AMIO was associated with spontaneous termination of the arrhythmia. RAN prolonged the aPRR significantly, while AMIO in addition to RAN potentiated this effect. Neither RAN alone nor its combination with AMIO abolished the elicitation of AT in this model. However, both agents synergistically prolonged the aPRR, resulting in the slowing of AT and promoting spontaneous termination of the arrhythmia.

Background Endurance physical training plays a protective role in against ventricular fibrillation (VF), but the exact underlying mechanisms are not completely understood. It is well-known that modifications in myocardial ventricular properties such as refractoriness, conduction velocity and wavelength are key in the initiation and maintenance of VF; furthermore, vagus nerve stimulation has prophylactic effects on malignant arrhythmias and VF. On the other hand, parasympathetic nervous system activity is increased in trained individuals, which in turn affects different ventricular electrophysiological properties. We hypothesized that physical training increases conduction velocity and wavelength, and that these changes are mediated by myocardial cholinergic neurons. Methods To test this hypothesis, ten rabbits were submitted to a six-week endurance training protocol and twenty controls were not trained (divided in control group, n=10 and sham group n=10). After training, rabbits were euthanized and their hearts excised, isolated and perfused in a Langendorff system. A pacing electrode and a plaque with 240 recoding electrodes acquiring at 1 KHz were positioned on the left ventricle (LV). Extraestimulus test using four different pacing cycle lengths (90% basal cycle length, 250, 200 and 150 ms) was performed before and after atropine (1μM, control and trained groups) or vehicle (tyrode, sham group) infusion. We studied 1) LV effective refractory period (ERP), 2) LV functional refractory period (FRP), 3) LV conduction velocity (CV), and 4) LV wavelength, determined as LV FRP x CV. Factorial ANOVA (mixed model) was used for statistical analysis (p Results Before parasympathetic blockade, LV FRP increased in trained animals (Figure, B) whereas no difference was found in LV CV between trained and control animals at any pacing cycle length (Figure, A). In consequence, LV wavelength increased in trained animals (Figure, C). There were no changes in LV ERP, FRP, CV and wavelength when comparisons were made within groups before and after atropine infusion. In sham animals, vehicle infusion or time-course of the experiment did not modify LV FRP, ERP, CV and wavelength. Conclusion Physical training increases LV wavelength, which can be one electrophysiological mechanism by which endurance training could protect against VF. Since modifications of ventricular refractoriness and wavelength do not seem dependent of intrinsic parasympathetic nervous system activity, other intrinsic mechanisms could be implied and warrant further research. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Generalitat Valenciana

Objective. Dibornol-HES, a water-soluble drug based on the derivative of 2,6-diisobornyl-4-methylphenol Dibornol conjugated with hydroxyethyl starch, can reduce the occurrence and severity of arrhythmias by preventive intravenous administration, but it is unknown whether the drug could reduce the myocardial arrhythmogenicity once ischemia has developed at the developed ischemia.Materials and methods. In the model of acute ischemia / reperfusion of the rabbit heart, the effect of Dibornol-HEC (80 mg/kg body weight of the animal) on the electrophysiological indices characterizing myocardial arrhythmogenicity (global and border dispersion of repolarization) was studied during the restoration of blood flow. In the model of acute ischemia / reperfusion with 64 unipolar epicardial leads, the activation-recovery intervals were measured and global and border dispersion of repolarization in the native rabbits (control group, n = 9) and in the rabbits treated by Dibornol-HES (on the 25th minute of occlusion, the experimental group, n = 6).Results. The introduction of Dibornol-HES did not lead to a change in the electrocardiographic parameters of rabbits. By the 30th minute of the coronary occlusion on the ECG in the animals of the control and the experimental groups, the intervals RR, QT, QTc were shortened (p < 0.05). In the animals of both groups by the 30th minute of coronary occlusion, the global dispersion of repolarization increased (p < 0.05), the boundary dispersion of repolarization also increased (p < 0.05), due to the decrease in the duration of the activation-recovery intervals in the ischemic zone (p < 0.05). During the 30-minute reperfusion the magnitude of the global dispersion of repolarization did not change in animals of the both groups, and the magnitude of the border dispersion of repolarization in the control rabbits decreased (p < 0.05), while in the rabbits treated by Dibornol-HES the border dispersion of repolarization did not changed.Conclusion. In rabbits of the experimental group, the values of the global and border dispersions of repolarization did not differ from those of the animals in the control group. Therefore, the administration to Dibornol-HES just prior to reperfusion does not lead to the decrease in the dispersion of repolarization increased as a result of acute ischemic myocardial damage.

Previous clinical studies have shown that ranolazine (RAN) added to amiodarone (AMIO) might accelerate the termination of recent-onset atrial fibrillation. This study was undertaken to delineate possible mechanisms that contribute to the enhancement of the antiarrhythmic efficacy of RAN-AMIO coadministration. Ten rabbits were anesthetized and two monophasic action potential (MAP) catheters were sequentially inserted into the right atrium. One MAP electrode was used to pace and record; the other electrode was used only for recording MAP from an adjacent atrial region. Intraatrial conduction time (IACT), 2:1 intraatrial conduction block (IACB), and atrial post-repolarization refractoriness (aPRR) were consecutively determined by high-rate atrial burst pacing and programmed stimulation, respectively. All parameters were evaluated during baseline and following AMIO (3 mg/kg iv) or AMIO+RAN (2.4 mg/kg iv bolus +0.134 mg/kg/min maintenance infusion). The IACT remained unchanged post AMIO compared with baseline (37.6 ± 3.8 vs 36.4 ± 2.4 ms), whereas the addition of RAN to AMIO significantly prolonged IACT (50.4 ± 3.6 ms, p < .001). The pacing cycle length producing 2:1 IACB was 101.2 ± 21.7 ms at baseline , 117.5 ± 15 ms after AMIO (p = 0.265), and 150 ± 14 ms after AMIO+RAN (p < .001). Baseline aPRR was longer following AMIO treatment (35 ± 5 vs 50 ± 9 ms, p < .01) but remarkably prolonged with RAN supplementation (105 ± 11 ms, p < .001). RAN significantly prolonged the propagation time of rapid atrial depolarizations and potentiated the AMIO-induced moderate increases in aPRR. These mechanisms possibly contribute to the earlier termination of atrial fibrillation when RAN is co-administered with AMIO.

… Histamine can stimulate the heart by directly interacting with cardiac histaminereceptors. In the present study we have investigated the H2 receptor activity in isolated rabbitheart. Cimetidine, a specific H2 receptor antagonist was used. The isolated heart was mountedin langendroff apparatus. The heart was perfused at a constant pressure with oxygenatedRinger‘s Locke solution. H2 receptor antagonist produces negative inotropic effect in thepresence of histamine. This indicates that H2 receptors are present in rabbit heart, and plays arole in mediation of positive inotropic effect produced through CAMP by histamine.

Mitochondrial membrane potential (ΔΨm) depolarization has been implicated in the loss of excitability (asystole) during global ischemia, which is relevant for the success of defibrillation and resuscitation after cardiac arrest. However, the relationship between ΔΨm depolarization and asystole during no-flow ischemia remains unknown. We applied spatial Fourier analysis to confocally recorded fluorescence emitted by ΔΨm-sensitive dye tetramethylrhodamine methyl ester. The time of ischemic ΔΨm depolarization ( tmito_depol) was defined as the time of 50% decrease in the magnitude of spectral peaks reflecting ΔΨm. The time of asystole ( tasys) was determined as the time when spontaneous and induced ventricular activity ceased to exist. Interventions included tachypacing (150 ms), myosin II ATPase inhibitor blebbistatin (heart immobilizer), and the combination of blebbistatin and the inhibitor of glycolysis iodoacetate. In the absence of blebbistatin, confocal images were obtained during brief perfusion with hyperkalemic solution and after the contraction failed between 7 and 15 min of ischemia. In control, tmito_depol and tasys were 24.4 ± 6.0 and 26.0 ± 5.0 min, respectively. Tachypacing did not significantly affect either parameter. Blebbistatin dramatically delayed tmito_depol and tasys (51.4 ± 8.6 and 45.7 ± 5.3 min, respectively; both P < 0.0001 vs. control). Iodoacetate combined with blebbistatin accelerated both events ( tmito_depol, 12.7 ± 1.8 min; and tasys, 6.5 ± 1.1 min; both P < 0.03 vs. control). In all groups pooled together, tasys was strongly correlated with tmito_depol ( R2 = 0.845; P < 0.0001). These data may indicate a causal relationship between ΔΨm depolarization and asystole or a similar dependence of the two events on energy depletion during ischemia. Our results urge caution against the use of blebbistatin in studies addressing pathophysiology of myocardial ischemia.

An α2A-adrenergic agonist guanfacine improves autonomic imbalance in attention-deficit hyperactivity disorder, suggesting that it may be useful to correct autonomic imbalance in chronic heart failure (CHF) patients. To investigate the effects of guanfacine on cardiac autonomic nerve activities, a microdialysis technique was applied to anesthetized rabbit heart. Acetylcholine (ACh) and norepinephrine (NE) concentrations in atrial dialysates were measured as indices of cardiac autonomic nerve activities. Guanfacine at a dose of 100 μg/kg significantly decreased heart rate and increased dialysate ACh concentration without decreasing sympathetic NE release. Guanfacine may be useful for vagal activation therapy in CHF patients.

Background. Myocardial ischaemia occurs due to inadequate supply of oxygen to fulfill the myocardial tissue oxygen demand. This leads to angina pectoris or referred pain, whichhappens because of the inability of the brain to distinguish the visceral afferent inputs from the somatic afferent inputs since they run along a common pathway via the dorsal root ganglia. Aims. This study aims to distinguish specific areas of the rabbit heart that are projected to specific dorsal root ganglia, which then associates to its specific dermatomes. Methods. A double-retrograde neurotracing method was used, with True Blue and Nuclear Yellow as the neurotracers. Rabbits were divided into 3 groups, which the first and second groups were ligated at the left anterior descending artery and at the left circumflex artery, respectively.The third group acted as the control group, without ligation.True blue was injected at ischaemic sites following ligation. Nuclear yellowwas injected at the skin, dermatomes T1-T4. Dorsal root ganglia levels T1-T4 were then examined for both neurotracers at 3 days post injection. Results. There is significant association between the site of ligation to the projection of the neurotracers at specific dorsal root ganglia (p

[EN] Panoramic optical mapping is the primary method for imaging electrophysiological activity from the entire outer surface of Langendorff-perfused hearts. To date, it is the only method of simultaneously measuring multiple key electrophysiological parameters, such as transmembrane voltage and intracellular free calcium, at high spatial and temporal resolution. Despite the impact it has already had on the fields of cardiac arrhythmias and whole-heart computational modeling, present-day system designs precludes its adoption by the broader cardiovascular research community because of their high costs. Taking advantage of recent technological advances, we developed and validated low-cost optical mapping systems for panoramic imaging using Langendorff-perfused pig hearts, a clinically-relevant model in basic research and bioengineering. By significantly lowering financial thresholds, this powerful cardiac electrophysiology imaging modality may gain wider use in research and, even, teaching laboratories, which we substantiated using the lower-cost Langendorff-perfused rabbit heart model., The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). This work was also partially supported by the following sources: Spanish Society of Cardiology (D.F.R.); Jesus Serra Foundation (D.F.R.); Carlos III Health Institute/European Regional Development Fund (ERDF) Grants: CB16/11/00458 (D.F.R., J.G.Q.), FIS PI12/00993 (C.J.C., J.M.), FIS PI15/00748 (C.J.C., J.M.) and FIS PI15/01408 (F.J.C); Generalitat Valenciana Grants GV/2015/019 (C.J.C.) and PROMETEO/2014/037 (C.J.C., F.J.C., J.M.). We thank Daniel Garcia-Leon for his assistance during the Langendorff-perfused heart experiments

Repolarization heterogeneity (RH) has been shown to increase with ventricular premature beats (VPBs). Moreover, several differences between left ventricle (Lv) and right ventricle (Rv), such as fibrillation threshold and anatomic properties have been presented. Nevertheless, few results exist regarding the influence of the origin site of VPBs on modulation of ventricular RH, as well as the optimal electrode location to assess the origin of VPBs. We studied electrocardiographic indices as a function of the coupling interval and the site of VPBs, in an isolated rabbit heart preparation (n = 18) using ECG multi-lead (5 rows \(\times \) 8 columns) system. In both ventricles, results have shown significant increases in ventricular depolarization duration. Also, we have observed that when the VPBs were applied to the Lv, a significant decrease of the total repolarization duration was detected, while in the Rv premature stimulation we have not found significant changes of total repolarization duration. Also, we compared twenty machine learning classification techniques with the aim to find the optimal electrode placement (row4–column4 to Lv stimulation and row5–column3 to Rv stimulation) and interpret the site of origin of VPBs. It was observed that the Random Forest classifier has shown the best performance among all the techniques studied. Finally, we found differences in the overall duration of repolarization associated to transmural RH.

Background: Decaying stem juice ofMusa acuminata ◊ balbisianais commonly used by local communities and traditional herbalist in Central Uganda in the management of cardiovascular conditions like hypertension. Aims: The study investigated the ionotropic and chronotropic effect of fresh and decaying stem juice ofMusa acuminata ◊ balbisianaon the isolated perfused rabbit heart. Materials andMethods :Methods. Study Design: An experimental study.

BackgroundIsoprenaline (ISO) acts through β-adrenergic receptors to increase the intracellular Ca2+, which has effects on action potential duration (APD) restitution and arrhythmogenesis. Thus, we investigated the effect of chronic stimulation with isoprenaline on APD restitution and ventricular tachyarrhythmias (VA) in the rabbit heart.Methods and resultsRabbits were randomly selected to receive an injection of isoprenaline (ISO group) or an equal volume of 0.9% saline (CTL group). The S1–S2 protocol (n=15) and S1 dynamic pacing (n=15) were performed to construct APD restitution and to induce APD alternans or arrhythmia in 10 sites of Langendorff-perfused hearts. Compared with the same sites in the control group, long-term ISO administration (7 days) shortened the APD90 and the effective refractory period (ERP), and greatly increased the spatial dispersion of APD and ERP (p

Supplemental Digital Content is available in the text., Background— External chest impacts (commotio cordis) can cause mechanically induced premature ventricular excitation (PVEM) and, rarely, ventricular fibrillation (VF). Because block of stretch-sensitive ATP-inactivated potassium channels curtailed VF occurrence in a porcine model of commotio cordis, VF has been suggested to arise from abnormal repolarization caused by stretch activation of potassium channels. Alternatively, VF could result from abnormal excitation by PVEM, overlapping with normal repolarization-related electric heterogeneity. Here, we investigate mechanisms and determinants of PVEM induction and its potential role in commotio cordis–induced VF. Methods and Results— Subcontusional mechanical stimuli were applied to isolated rabbit hearts during optical voltage mapping, combined with pharmacological block of ATP-inactivated potassium or stretch-activated cation-nonselective channels. We demonstrate that local mechanical stimulation reliably triggers PVEM at the contact site, with inducibility predicted by local tissue indentation. PVEM induction is diminished by pharmacological block of stretch-activated cation-nonselective channels. In hearts where electrocardiogram T waves involve a well-defined repolarization edge traversing the epicardium, PVEM can reliably provoke VF if, and only if, the mechanical stimulation site overlaps the repolarization wave edge. In contrast, application of short-lived intraventricular pressure surges neither triggers PVEM nor changes repolarization. ATP-inactivated potassium channel block has no effect on PVEM inducibility per se, but shifts it to later time points by delaying repolarization and prolonging refractoriness. Conclusions— Local mechanical tissue deformation determines PVEM induction via stretch-activation of cation-nonselective channels, with VF induction requiring PVEM overlap with the trailing edge of a normal repolarization wave. This defines a narrow, subject-specific vulnerable window for commotio cordis–induced VF that exists both in time and in space.

AIMS: Cardiac histo-anatomical organization is a major determinant of function. Changes in tissue structure are a relevant factor in normal and disease development, and form targets of therapeutic interventions. The purpose of this study was to test tools aimed to allow quantitative assessment of cell-type distribution from large histology and magnetic resonance imaging- (MRI) based datasets. METHODS AND RESULTS: Rabbit heart fixation during cardioplegic arrest and MRI were followed by serial sectioning of the whole heart and light-microscopic imaging of trichrome-stained tissue. Segmentation techniques developed specifically for this project were applied to segment myocardial tissue in the MRI and histology datasets. In addition, histology slices were segmented into myocytes, connective tissue, and undefined. A bounding surface, containing the whole heart, was established for both MRI and histology. Volumes contained in the bounding surface (called 'anatomical volume'), as well as that identified as containing any of the above tissue categories (called 'morphological volume'), were calculated. The anatomical volume was 7.8 cm(3) in MRI, and this reduced to 4.9 cm(3) after histological processing, representing an 'anatomical' shrinkage by 37.2%. The morphological volume decreased by 48% between MRI and histology, highlighting the presence of additional tissue-level shrinkage (e.g. an increase in interstitial cleft space). The ratio of pixels classified as containing myocytes to pixels identified as non-myocytes was roughly 6:1 (61.6 vs. 9.8%; the remaining fraction of 28.6% was 'undefined'). CONCLUSION: Qualitative and quantitative differentiation between myocytes and connective tissue, using state-of-the-art high-resolution serial histology techniques, allows identification of cell-type distribution in whole-heart datasets. Comparison with MRI illustrates a pronounced reduction in anatomical and morphological volumes during histology processing.

Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates the principle ion channels mediating cardiac excitability and conduction, but how this regulation translates to the normal and ischemic heart remains unknown. Diverging results on CaMKII regulation of Na+ channels further prevent predicting how CaMKII activity regulates excitability and conduction in the intact heart. To address this deficiency, we tested the effects of the CaMKII blocker KN93 (1 and 2.75 μM) and its inactive analog KN92 (2.75 μM) on conduction and excitability in the left (LV) and right (RV) ventricles of rabbit hearts during normal perfusion and global ischemia. We used optical mapping to determine local conduction delays and the optical action potential (OAP) upstroke velocity (d V/d tmax). At baseline, local conduction delays were similar between RV and LV, whereas the OAP d V/d tmax was lower in RV than in LV. At 2.75 μM, KN93 heterogeneously slowed conduction and reduced d V/d tmax, with the largest effect in the RV outflow tract (RVOT). This effect was further exacerbated by ischemia, leading to recurrent conduction block in the RVOT and early ventricular fibrillation (at 6.7 ± 0.9 vs. 18.2 ± 0.8 min of ischemia in control, P < 0.0001). Neither KN92 nor 1 μM KN93 depressed OAP d V/d tmax or conduction. Rabbit cardiomyocytes isolated from RVOT exhibited a significantly lower d V/d tmax than those isolated from the LV. KN93 (2.75 μM) significantly reduced d V/d tmax in cells from both locations. This led to frequency-dependent intermittent activation failure occurring predominantly in RVOT cells. Thus CaMKII blockade exacerbates intrinsically lower excitability in the RVOT, which is proarrhythmic during ischemia. NEW & NOTEWORTHY We show that calcium/calmodulin-dependent protein kinase II (CaMKII) blockade exacerbates intrinsically lower excitability in the right ventricular outflow tract, which causes highly nonuniform chamber-specific slowing of conduction and facilitates ventricular fibrillation during ischemia. Constitutive CaMKII activity is necessary for uniform and safe ventricular conduction, and CaMKII block is potentially proarrhythmic.

Cardiac restitution is the shortening of the action potential duration with an increase in the heart rate. A shorter action potential duration enables a longer diastolic interval which ensures that the heart gets adequate time to refill with blood. At higher rates however, restitution becomes steep and thus, can lead to unstable electrical activity (alternans) in the heart, leading to fatal cardiac rhythms. It has been proposed that maintaining a shallow slope of cardiac restitution could have potentially anti-arrhythmic effects. Previous studies involved the control of action potential duration (APD) or diastolic interval (DI) in isolated tissue samples based on the feedback from single microelectrode recordings. This limited the spatial resolution of the feedback system. Here, we aimed to develop a real time feedback control system that enabled the detection of APDs from various single pixels based on optical mapping recordings. Stimuli were applied after a predefined fixed DI after detection of an APD. We validated our algorithm using optical mapping movies from an ex-vivo rabbit heart. Thus, we provide an optical mapping based approach for the control of cardiac restitution and a potential means to validate its anti-arrhythmic effects.

Oxytocin (OXT) pretreatment protects the heart during ischemia-reperfusion injury by activating ATP-dependent potassium (K(ATP)) channels. The aim of the current study was to elucidate the roles of nitric oxide synthaseNOS and myocardial biochemistry in the cardioprotective effects of OXT and ischemic preconditioning (IPC).Male New Zealand White anesthetized rabbits (13 groups) were subjected to 30 min of occlusion of the left coronary artery and 120 min of reperfusion with or without IPC.IPC (1 cycle), OXT (0.03 μg/kg, i.p.) or IPC + OXT yield significant infarct size reductions (21.8±1.5%, 20.5±1.2% and 19.4±1.4%, respectively, versus 38.9±3.5% in the S-CONT group; P0.01) and antiarrhythmic effects, including VF (0%, 0% and 0%, versus 50% in S-CONT group; P0.05) sustained VT (13%, 13% and 13%, versus 100% in S-CONT group; P0.005) and other arrhythmias (25%, 13% and 25%, versus 100% in S-CONT group; P0.005, P0.01 and P0.005, respectively). Atosiban (ATO, a selective OXT receptor antagonist), 5-HD and L-NAME (a nonspecific NOS inhibitor) abolished the beneficial effects of IPC and OXT, suggesting that the benefits are achieved via selective activation of OXT receptors, mitochondrial K(ATP) channels and NO. An iNOS inhibitor (1400 W) blocked the beneficial effects of IPC but not OXT. The IPC, OXT, IPC + OXT and 1400 W + OXT interventions significantly preserved ATP levels in the heart.This study demonstrates similarities between acute OXT pretreatment and IPC in terms of infarct size reduction, antiarrhythmic activity, and metabolic status.

Cardiac electrophysiological heterogeneity related to the washout of acetylcholine (ACh) remains incompletely characterized. The aim of this study was to examine whether positive cardiac inotropic action is associated with electrophysiological heterogeneity between the atrium and the ventricle after ACh perfusion and washout. Epicardial monophasic action potentials (MAPs) from the right ventricle and right atrium, as well as cardiac contractility, were recorded from isolated Langendorff-perfused rabbit hearts using MAP electrodes and a force transducer. The results indicated that rebound positive inotropic actions were induced by ACh washout with adrenaline preconditioning. This effect was accompanied by an increase in MAP amplitude (MAPA) in the right ventricle but not the right atrium. These findings indicate that cholinergic muscarinic stimulation may lead to positive cardiac inotropic action followed by changes in regional electrophysiological heterogeneity between the atrial and ventricular myocardium. Therefore, we hypothesize that electrophysiological heterogeneity is an underlying cause of arrhythmogenesis as well as hemodynamic disturbance elicited by sudden termination of vagus stimulation.

Summary The effects of tetracycline and oxytetracycline on cardiac contractility and heart rate were tested on the isolated rabbit heart. The tetracyclines exerted a dose-dependent, inhibiting effect on the amplitude of the heart beat, similar to that of EDTA and this effect was diminished by simultaneous administration of CaCl2. There was no effect on heart rate. In the anaesthetized rabbit intravenous injection of therapeutic doses of the tetracyclines caused a marked reduction in heart rate, but had only a limited effect on arterial blood pressure, which in most cases went up a little. The effect on the heart rate was dose-dependent, but also depended on the rate of injection. A dose which caused a pronounced fall in heart rate when injected over a period of 3, 10 or 20 seconds, had little if any effect when injected slowly over a period of 60 seconds. Zusammenfassung Die Wirkung von Tetrazyklinen auf das Kaninchenherz Am isolierten Kaninchenherz wurden die Wirkungen von Tetrazyklin (TZ) und Oxytetrazyklin auf die Kontraktilitat und Herzschlagfrequenz untersucht. TZ reduzierte die Amplitude der Herzschlage in ahnlicher Weise wie EDTA. Dieser Effekt verkleinerte sich bei simultaner Applikation von CaCl2. Ein Einfluβ auf die Herzschlagfrequenz wurde nicht festgestellt. Eine i. v. Injektion von therapeutischen TZ-Dosen bewirkte bei narkotisierten Kaninchen eine erhebliche Verminderung der Herzfrequenz, hingegen hatte sie einen nur geringen Effekt auf den arteriellen Blutdruck, welcher sich meistens ein bischen erhohte. Der Effekt auf die Herzfrequenz war sowohl dosenabhangig als auch abhangig von der Injektionsgeschwindigkeit. Eine Dosis, welche bei einer Injektionsdauer von 3, 10 oder 20 sec die Herzfrequenz deutlich senkte, hatte bei einer Injektionsdauer von 60 sec nur einen geringen oder gar keinen Effekt. Resume Action des tetracyclines sur le coeur du lapin On a examine les actions de la tetracycline et de l'oxytetracycline sur la contractibilite et la frequence cardiaque du coeur isole de lapin. La tetracycline diminue l'amplitude des battements cardiaques de la meme maniere que l'EDTA. Cet effet a ete diminue par l'application simultanee de CaCl2. On n'a pas constate d'influence sur la frequence cardiaque. Une injection i/v de doses therapeutiques de tetracycline chez des lapins sous narcose a provoque une nette diminution de la frequence cardiaque mais n'a eu qu'un faible effet sur la pression arterielle faiblement augmentee. L'effet sur la frequence cardiaque dependait aussi bien de la dose que de la rapidite de l'injection. Une dose qui abaissait nettement la frequence cardiaque lors d'une duree d'injection de 3,10 ou 20 secondes n'a eu qu'un tres faible effet ou pas du tout lors d'une duree d'injection de 60 secondes. Resumen La accion de tetraciclinas sobre el corazon de conejo En el corazon aislado de conejo se estudiaron las acciones de la tetraciclina (TC) y oxitetraciclina sobre la contractilidad y la frecuencia de latidos cardiacos. TC reducia la amplitud de los latidos cardiacos de manera similar a EDTA. Se disminuia este efecto aplicando simultaneamente Cl2Ca. No se comprobo ningun influjo sobre la frecuencia de latidos cardiacos. La inyeccion iv. de dosis terapeuticas de TC ocasionaba en conejos narcotizados una reduccion considerable de la frecuencia cardiaca, mientras que no ejercia mas que un efecto escaso sobre la tension sanguinea arterial, la cual solia aumentar un poco. El efecto sobre la frecuencia cardiaca dependia tanto de la dosis como de la velocidad de inyeccion. Una dosis que con una duracion de inyeccion de 3, 10 o 20 sec disminuia de forma pronunciada la frecuencia cardiaca, no promovia mas que un efecto escaso o este era nulo cuando se inyectaba lentamente durante un periodo superior a 60 sec.

AIMS: Left atrial (LA) stretch-associated electrophysiological changes in patients with mitral stenosis (MS) predispose to atrial fibrillation. We hypothesized that the normalization of the pressure gradient by percutaneous transvenous mitral balloon valvotomy (PTMV) affects LA but not right atrial (RA) conduction, depending on the site of stimulation. Because direction-dependent (asymmetric) changes of conduction may contribute to arrhythmogenesis, we assessed conduction symmetry in MS patients and tested whether it is restored by PTMV. METHODS AND RESULTS: In nine patients with MS, atrial effective refractory period and local activation times (ATs) were determined during stimulation before and after PTMV, with up to four decapolar catheters (LA and RA). Eight patients with ventricular pre-excitation served as controls. ATs at basic cycle length were similar before and after PTMV. With stimulation from either atrium, they were about 45 ms in the ipsilateral atrium and about 115 ms in the contralateral atrium. With premature stimulation, ATs increased dramatically. The shortest ATs were found in the RA with RA stimulation (78 +/- 9 and 80 +/- 6 ns, before and after PTMV). PTMV caused a shortening in LA-ATs (following LA stimulation) from 118 +/- 14 to 82 +/- 5 ms (before and after; P

In a group of 20 unmodified rabbit recipients receiving a cardiac allograft 7 rabbits formed lymphocytotoxic antibodies. The histological features of rejection were identical in all cases, independent of antibody formation. Thirteen rabbits were presensitized against the prospective heart donor by means of skin grafts and spleen cell injections, and the majority of these recipients were transplanted in the presence of donorreactive cytotoxic antibodies. Accellerated rejection took place in every recipient but the rapidity, of the reaction and the histological picture did not correlate well with the presence and potency of preexisting antibodies. Histological findings varied considerably including infiltration of mononuclear cells and polymorphonuclear leucocytes, extensive oedema and interstitial haemorrhage, and early degeneration of myofibres. Only one case of “hyperacute” clinical rejection was observed, in which the transplant was rejected within 2 1/2 hrs. Heavy deposits of gamma-globulins were demonstrated by the fluorescent antibody method to be localized in the vessel walls of this transplant.

BACKGROUND The effects of dyssynchrony on global left ventricular (LV) mechanics have been well documented; however, its impact on LV energetics has received less attention. OBJECTIVE To assess the effects of LV contraction dyssynchrony on global LV mechano-energetic function in a pacing-induced acute model of dyssynchrony. METHODS Using blood-perfused isolated rabbit heart preparations (n = 11), LV pressure, coronary flow, and arteriovenous oxygen content difference were recorded for isovolumic contractions under right atrial (RA) pacing (control) and simultaneous RA and right ventricular outflow tract (RVOT) pacing (dyssynchrony). LV mechanical function was quantified by the end-systolic pressure-volume relationship (ESPVR). Myocardial oxygen consumption-pressure-volume area (MVO(2)-PVA) relationship quantified LV energetic function. Internal PVA for MVO(2 RVOT) was calculated based on the MVO(2)-PVA relationship for RA pacing. Thus, lost PVA (internal PVA-PVA(RVOT)) represents the mechanical energy not observable at the global level. RESULTS Compared to RA pacing, RVOT pacing depressed LV mechanics as indicated by a rightward shift of ESPVR (i.e., increase in V(d) from 0.58 +/- 0.10 to 0.67 +/- 0.10 mL, P < 0.05). Despite depressed mechanics, RVOT pacing was associated with greater MVO(2) such that the MVO(2)-PVA relationship intercept was markedly increased from 0.025 +/- 0.003 to 0.029 +/- 0.003 mL*O(2)/beat/100gLV (P < 0.05). Excess MVO(2) (i.e., MVO(2 RVOT)- MVO(2 RA)) significantly correlated with lost PVA (R(2)= 0.54, P < 0.001). CONCLUSION A potential mechanism explaining the observed increase in MVO(2) with dyssynchrony may be that the measured PVA at the global level underestimates the internal PVA at the cellular level, which is likely to be the true determinant of MVO(2).

We compared the negative chronotropic and inotropic effects of landiolol and esmolol, two clinically available short-acting beta1-blockers with high beta1-selectivity, using whole isolated rabbit heart preparations.Tachycardia was induced by continuous perfusion of 10(-7) M isoproterenol, and we used concentrations of landiolol or esmolol in ascending steps (1 . 10(-6), 3 . 10(-6), 1 . 10(-5), 3 . 10(-5), and 1 x 10(-4) M). Heart rate (HR), left ventricular developed pressure (LVDP), the maximal rates of left ventricular force development (LVdP/dt(max)), and myocardial oxygen consumption (MVO2) were measured and compared.Both landiolol and esmolol produced dosedependent decreases in HR, LVDP, LVdP/dt(max), and MVO2. The HR lowering effects of the two agents were comparable. At concentrations of 3 . 10(-5) and 1 . 10(-4) M, esmolol produced more profound depression of LVDP (47 +/- 26 and 12 +/- 11 mmHg, respectively; mean +/- SD) and reduction of LVdP/dt(max) (650 +/- 287 and 120 +/- 103 mmHg x s(-1)) than landiolol (68 +/- 20 and 64 +/- 20 mmHg, and 897 +/- 236 and 852 +/- 240 mmHg.s(-1), respectively). At the same concentrations, esmolol caused more profound reduction in MVO(2) (40 +/- 11 and 35 +/- 10 microl x min(-1) x g(-1)) than landiolol (50 +/- 8 and 48 +/- 8 microl x min(-1) x g(-1)), respectively.Our results indicate that in the isolated rabbit heart, landiolol and esmolol had equipotent negative chronotropic effects, however, landiolol had a less potent negative inotropic effect than esmolol.

To analyse the kinetic changes of uptake, washout and retention of Tc-sestamibi in order to evaluate the protective effects and possible mechanism of ischaemic preconditioning and adenosine preconditioning on myocardium injured by ischaemia/reperfusion.Isolated ischaemia/reperfusion rabbit heart models, as established by Langendorff, were used. Eighteen rabbit hearts perfused in Krebs-Henseleit (KH) buffer were randomly assigned to three groups: ischaemia/reperfusion (I/R, n=6), adenosine preconditioning (AD, n=6), and ischaemic preconditioning (IPC, n=6). Tc-sestamibi (55.5 MBq) in KH was perfused for 40 min and washed out for 40 min. The kinetic changes of Tc-sestamibi within myocardial tissue was monitored during the uptake and washout phases. Cardiac haemodynamic parameters, creatine kinase and lactate dehydrogenase leakage in coronary effluent, and myocardial infarct size were measured to assess myocardial injuries in rabbit hearts.In the early phases of uptake, there were no significantly different uptake rates of Tc-sestamibi between AD (before 20 min), IPC (before 15 min) and I/R myocardium (all P0.05). Uptake rates of Tc-sestamibi in myocardium of the three groups all tended to increase, with the uptake time increasing. In the late phases of uptake, AD and IPC were significantly higher than I/R (all P0.05). In the washout phases, the retention fractions of Tc-sestamibi in myocardium of the three groups all showed a descending tendency with washout time increasing. The retention fractions in AD and IPC were all higher than I/R (all P0.05). There were no statistical differences in uptake rates and retention fractions of Tc-sestamibi between AD and IPC (all P0.05). Cardiac haemodynamic parameters, creatine kinase and lactate dehydrogenase leakage, and myocardial infarct size demonstrated there is lighter injury in AD and IPC myocardium than in I/R (all P0.05). The retention of Tc-sestamibi and myocardial infarction weight were significantly negatively correlated (r=-0.8384, P0.001).Adenosine preconditioning has similar myocardial protective effects on ischaemia/reperfusion myocardium as does ischaemic preconditioning. Tc-sestamibi may be a sensitive and reliable measure for evaluating the importance and mechanism of ischaemic preconditioning and adenosine preconditioning.

Introduction Rate-dependent AV nodal function is often assessed with premature protocols. Conduction curves generated from nodal responses differ with the selected recovery index (atrial-atrial, AA, or His-atrial interval, HA). We propose that these differences arise from changes in pretest conduction time that affect nodal recovery time assessment. Methods and results We varied the basic (S(1)S(1)), pretest (S(1)S(2)), and test (S(2)S(3)) cycle length with S(1)S(2)S(3) protocols, and analyzed nodal responses as AA (A(3)H(3) vs A(2)A(3)) and HA (A(3)H(3) vs H(2)A(3)) curves in six rabbit heart preparations. Any A(2)H(2) (pretest conduction time) prolongation bodily shifted AA curve rightward and HA curve leftward, regardless of prevailing basic cycle length. A prolonged A(2)H(2) caused all A(3)H(3) to occur at longer A(2)A(3) and shorter H(2)A(3,) as compared with control. When corrected for these shifts, AA and HA curves displayed similar recovery and fatigue properties. To further investigate the possibility that nodal recovery time varies beyond that imposed by pacing interval, six additional preparations were subjected to 5-minute frequency step protocols during which a long cycle was introduced after every 30th short cycle. After each long cycle, nodal conduction time increased progressively despite the constant short cycle length and fatigue level. Conclusions Increases in the pretest conduction time play a pivotal role in apparent recovery-index-dependent differences in rate-dependent AV nodal function by shifting AA and HA curves in opposite directions along the x-axis. When corrected for pretest effects, AA and HA curves display similar rate-dependent AV nodal function with recovery and fatigue as main properties.

Optical signal is the image created from the propagating electrical signal. Due to optical features (absorption, scattering, etc.) of the heart tissue the coincidence between optical and electrical action potentials (APs) is moderate. Having electrical action potentials recorded transmurally, we aimed to evaluate contribution of the electrical and the optical features on OAP upstroke formation using blue-green and near-infrared (NIR) lights. Here we introduce a new approach in analysis of the electrical activity from the optical mapping (OM) studies by recording transmural-APs with glass-microelectrodes and comparing them with the OAP, obtained using blue-green (di-4-ANEPPS) and NIR (di-4-ANBDQBS) dyes in Langendorff-perfused rabbit heart under atrial/endo-/epicardial pacing. We used averaged upstroke of transmural-APs for isolation of electrical and optical (of dye/tissue) impacts influencing formation of OAP upstroke shape, and this had helped to split the OAP upstroke into components (depth-weighted and lateral-scattering). These components separately reflect the transmural and the parallel to the epicardium electrical propagating wave. In addition, to calculate depth-weighted component, we used the probing-depth constant for fluorescence measurement that was detected directly during the OM experiment, but not from separate measurements of the excitation and the emission light penetration. The detected probing-depth constant (k) for the NIR dye was ∼2 mm, while that magnitude was about twice smaller for the blue-green dye. The results of the study open a new opportunity for the future investigations of the electrical impulse propagation in the heart.This research was funded by the European Social Fund under the Global Grant measure.

Introduction and objectives. The analysis of frequency variability during ventricular fibrillation has yielded inconsistent results. We used an experimental model of ventricular fibrillation, with a short timescale, to analyze variations in frequency and their associated spatial distribution. Methods. Epicardial recordings of ventricular fibrillation were made in 10 perfused isolated rabbit heart preparations using a multiple electrode system (i.e., 240 unipolar electrodes). Both spectral and time-frequency analysis were used to derive the dominant frequency in the anterolateral wall of the left ventricle. Results. Linear regression analysis showed that there was a good correlation between the dominant frequency obtained using the two signal analysis methods: frequency (spectral analysis) = 1.01 × frequency (time-frequency analysis) ‐ 0.4 (r=0.9; P

Background— The basis for the unique effectiveness of long-term amiodarone treatment on cardiac arrhythmias is incompletely understood. The present study investigated the pharmacogenomic profile of amiodarone on genes encoding ion-channel subunits. Methods and Results— Adult male mice were treated for 6 weeks with vehicle or oral amiodarone at 30, 90, or 180 mg · kg −1 · d −1 . Plasma and myocardial levels of amiodarone and N -desethylamiodarone increased dose-dependently, reaching therapeutic ranges observed in human. Plasma triiodothyronine levels decreased, whereas reverse triiodothyronine levels increased in amiodarone-treated animals. In ECG recordings, amiodarone dose-dependently prolonged the RR, PR, QRS, and corrected QT intervals. Specific microarrays containing probes for the complete ion-channel repertoire (IonChips) and real-time reverse transcription–polymerase chain reaction experiments demonstrated that amiodarone induced a dose-dependent remodeling in multiple ion-channel subunits. Genes encoding Na + (SCN4A, SCN5A, SCN1B), connexin (GJA1), Ca 2+ (CaCNA1C), and K + channels (KCNA5, KCNB1, KCND2) were downregulated. In patch-clamp experiments, lower expression of K + and Na + channel genes was associated with decreased I to,f , I K,slow , and I Na currents. Inversely, other K + channel α- and β-subunits, such as KCNA4, KCNK1, KCNAB1, and KCNE3, were upregulated. Conclusions— Long-term amiodarone treatment induces a dose-dependent remodeling of ion-channel expression that is correlated with the cardiac electrophysiologic effects of the drug. This profile cannot be attributed solely to the amiodarone-induced cardiac hypothyroidism syndrome. Thus, in addition to the direct effect of the drug on membrane proteins, part of the therapeutic action of long-term amiodarone treatment is likely related to its effect on ion-channel transcripts.

Cardiac ischemia causes beat-to-beat fluctuation in action potential duration (APD) alternans, which leads to T wave alternans and arrhythmias. Occurrence of APD alternans that is out of phase at two sites is especially important, but most APD alternans studies have involved rapid pacing of normal myocardium rather than ischemia. To determine the spatial features of APD alternans during ischemia, blood-perfused rabbit hearts were stained with 4-{β-[2(di- n-butylamino)-6-napthyl]vinyl}pyridinium (di-4-ANEPPS) and imaged with a high-resolution camera. Hearts were perfused with oxygenated Tyrode solution at 37°C for staining and then switched to a 50:50% blood/Tyrode mixture. Hearts were paced from the right ventricle at 3/s, and made ischemic by stopping flow for 6 min. Images of 10,000 pixels were obtained at 300 frames/s. Motion artifact was controlled by immobilization and by manual selection of undistorted single-pixel records. Upstroke propagation and conduction isochrones were displayed by computerized image processing. APD alternans was demonstrated in six of seven hearts, and was out of phase in different regions of the image in three hearts. The largest spatial variation in the onset of depolarization to 50% repolarization (APD50) was 155%. This caused beat-to-beat reversal of repolarization. An alternans map could be constructed for well-immobilized portions of the image. There were discrete regions of APD alternans separated by a boundary, as occurs with intracellular Ca2+ concentration alternans. Pixels as close together as 1.1 mm showed an APD alternans that was out of phase. The out-of-phase APD alternans was not due to conduction alternans, as shown by upstroke intervals and conduction isochrones. This contrasts with rapid pacing, where a causal relationship appears to exist. These new observations suggest distinct mechanisms for the genesis of arrhythmias during ischemia.

The adenosine A(1)/A(2) receptor agonist AMP 579 has been reported to protect the heart against infarction even when administered after the onset of ischemia. The present study explored both the timing and the duration of treatment required to limit infarct size in in situ rabbit hearts subjected to 30 min of regional ischemia and 3 hours of reperfusion. In groups 1 and 2, AMP 579 was infused from 10 min before reperfusion and continued for either 30 or 40 min. In group 3, AMP 579 was begun at the onset of reperfusion and continued for 70 min. In group 4, AMP 579 was also infused for 70 min but begun 10 min after reperfusion. In untreated hearts 36.4 +/- 3.1% of the risk zone infarcted. Protection was observed only in hearts having a 70-minute infusion of AMP 579 starting at reperfusion (13.0 +/- 1.9%, P < 0.05). Therefore, AMP 579 must be present at the moment of reperfusion and have a continued presence of more than 30 min thereafter to protect. Importantly, because AMP 579 can protect when administered up to the time of reperfusion, it likely prevents a reperfusion injury, and, therefore, has impressive clinical potential.

Mapping techniques are used to study the significance of the morphological patterns of the electrograms (EGMs) obtained during VF in an experimental model. In 24 isolated rabbit heart preparations recordings were made of activation during VF using a multiple electrode (121 unipolar electrodes) positioned on the lateral wall of the left ventricle. Three types of activation maps were selected: (A) with functional block of an activation front; (B) with epicardial breakthrough; and (C) with a single broad wavefront without block lines. The EGMs were classified as negative (Q), positive-negative with a predominance of the negative (rS) or positive wave (Rs), and positive (R). In 60 type A maps the morphology in the zone limiting the block line corresponded to an R wave in 55 (92%) cases and to Rs in 5 (8%) cases. In 67 type B maps, the EGM in the earliest activation zone most often showed Q wave morphology (48 [72%] cases), followed by rS (18 [27%] cases), and Rs morphology (1 [1%] case); in no case was R wave morphology seen. Finally, in 78 type C maps the morphology corresponded to a Q wave in 15 (19%) cases, rS in 38 (49%), Rs in 24 (31%), and R in a 1 (1%) case. The differences between the three types of maps were significant (P < 0.0001). Q wave EGM sensitivity for indicating the existence of an epicardial breakthrough pattern was 72%, with a specificity of 89%, and positive and negative predictive values of 76% and 87%, respectively. R wave EGM sensitivity for indicating the existence of conduction block was 92%, with a specificity of 99%, and positive and negative predictive values of 98% and 97%, respectively. R wave morphology is highly sensitive and specific for indicating conduction block. EGM recordings with initial positivity predominance are infrequent in the earliest activation zones of epicardial breakthrough during VF. The recording of the EGM with Q wave morphology indicates centrifugal activation from the explored zone.

It has been hypothesised that activation of matrix metalloproteinase-2 (MMP-2) contributes to reversible myocardial dysfunction (stunning) following short-term ischaemia and reperfusion. Gelatin zymography was used to measure release of both pro-MMP-2 (72 kDa) and MMP-2 (62 kDa), into the coronary effluent from isolated, perfused rabbit hearts during 90 min aerobic perfusion (control), or low-flow ischaemia (15 or 60 min at 1 mL/min), followed by 60 min reperfusion. In controls, pro-MMP-2 was detected in the coronary effluent throughout the first 30 min of aerobic perfusion, but MMP-2 was not detected. In contrast, MMP-2 was detected in the coronary effluent during reperfusion after both 15 and 60 min ischaemia. However, while left ventricular systolic function was impaired after both 15 min and 60 min ischaemia, a significant increase in the release of MMP-2 was only detected in hearts following 60 min ischaemia. The dissociation between mechanical function and MMP-2 levels suggest that MMP-2 does not contribute to myocardial stunning in this model, but may contribute to myocardial dysfunction following prolonged ischaemia.

Introduction and objectives. The aim of this study was to analyze the effects of myocardial stretching on excitation frequencies, as determined by spectral analysis, during ventricular fibrillation. Methods. In 12 isolated rabbit heart preparations, ventricular activation during ventricular fibrillation was recorded with multiple electrodes. Recordings were obtained before, during and after ventricular dilatation produced with an intraventricular balloon. The dominant frequency of the signals obtained with each of the electrodes was determined by spectral analysis. Results. During the control phase, the mean, minimum and maximum dominant frequencies were, respectively, 14.3 ± 1.7, 12.5 ± 1.7, and 16.2 ± 1.4 Hz, and the average difference between the maximum and minimum frequencies was 3.6 ± 2.1 Hz. This difference was over 4 Hz in four cases, and in no case did it exceed 8 Hz. During ventricular stretching, the mean dominant frequency increased significantly (21.1 ± 6.1 Hz; p < 0.0001), as did the minimum values (14 ± 2.6 Hz; p < 0.05) and especially the maximum values (26.6 ± 7.7 Hz; p < 0.0001). The difference between the maximum and minimum frequencies (12.6 ± 6.4 Hz; p < 0.001) was over 4 Hz in all cases except one, and over 8 Hz in 9 cases. The maximum values were distributed heterogeneously during ventricular stretching. Upon suppressing ventricular stretching, the dominant frequency did not differ from controls. Conclusions. Myocardial frequency maps during ventricular fibrillation show limited variations in the dominant frequency of the signals recorded in the lateral wall of the left ventricle. During stretching, the patterns were heterogeneous, due mainly to the marked increase in the maximum dominant frequency. In the experimental model used, the effects of stretching remitted after suppressing ventricular dilatation.

KATP channels are present in sarcolemmal and mitochondrial membranes. This study tests the hypothesis that opening mitochondrial KATP channels with Diazoxide (DZ) improves tolerance to cardioplegic ischemia during surgery. Twenty-two rabbit hearts were perfused with Krebs−Henseleit buffer (KHB) on a Langendorff apparatus and underwent 50 min of 37°C global ischemia with St Thomas' cardioplegia (STCP). Hearts were divided into three groups. Ten (control) received no pretreatment. Seven (DZ) received 10 min of 30 μM DZ, a selective mitochondrial KATP opener, in KHB before arrest with STCP containing 30 μM DZ. Five (5-HD + DZ) received 10 min of 100 μM sodium 5-hydroxydecanoate (5-HD), a selective mitochondrial KATP channel blocker, followed by 10 min of 30 μM DZ and 100 μM 5-HD in KHB before arrest with STCP + 30 μM DZ + 100 μM 5-HD. LV developed pressure (LVDP), dP/dt and coronary flow (CF) were measured after 60 min of reperfusion. Diazoxide pretreatment significantly improved the recovery of LV function and coronary flow compared to control (LVDP: 49 ± 5* vs. 31 ± 4; +dP/dtmax 927 ± 93 vs. 507 ± 85 mmHg/sec*; CF 33 ± 4 vs. 22 ± 2 ml/min, *p < 0.05). Mitochondria KATP channel blockade with 5-HD prevented DZ's salutary effect on the recovery of LV and vascular function. Diazoxide pretreatment protects the rabbit heart during cardioplegic ischemia by opening mitochondrial KATP channels. Opening mitochondrial KATP channels may be a new strategy for improving myocardial protection during cardiac surgery.

A previous study in dogs indicated that preconditioning (PC) of a specific myocardial region not only evoked a local cardioprotective effect but also rendered remote myocardium resistant to infarction. In the present study we devised a method to test for remote PC in the rabbit which it is not possible to ligate two separate coronary branches on the same heart. In situ hearts were subjected to PC with two cycles of 5-min regional ischemia/5-min reperfusion. Following this in vivo PC protocol, the hearts were removed and perfused on a Langendorff apparatus with crystalloid buffer. They then underwent 30 min of global ischemia with the entire left ventricle at risk followed by 2 h of reperfusion. At the end of the experiment the myocardium previously subjected to the in vivo PC protocol (preconditioned region) was identified as the tissue without fluorescence after fluorescent particles had been injected into the aortic root following reocclusion of the snared branch of the left coronary artery. Infarcted myocardium was identified by triphenyltetrazolium chloride staining. Tissue salvage was observed only in the preconditioned region where 13.2 +/- 3.6% of the myocardium infarcted as opposed to 44.6 +/- 1.3% in the remaining non-preconditioned left ventricular tissue (p0.05, n = 6). In sham-operated hearts (snare but no PC), infarction was similar in both the snared vessel's perfusion territory and the rest of the left ventricular myocardium (49.2 +/- 6.5% vs. 43.7 +/- 3.7%, n = 5). Hence PC of one myocardial region does not necessarily confer PC protection to all regions of the heart. Because remote PC could not be demonstrated in rabbits, this phenomenon may be species or protocol-specific, and should not be assumed to occur in man.

The general anesthetic propofol protects the adult heart against ischemia and reperfusion injury; however, its efficacy has not been investigated in the immature heart. This work, for the first time, investigates the cardioprotective efficacy of propofol at clinically relevant concentrations in the immature heart. Langendorff perfused rabbit hearts (7–12 days old) were exposed to 30 minutes’ global normothermic ischemia followed by 40 minutes’ reperfusion. Left ventricular developed pressure (LVDP) and coronary flow were monitored throughout. Lactate release into coronary effluent was measured during reperfusion. Microscopic examinations of the myocardium were monitored at the end of reperfusion. Hearts were perfused with different propofol concentrations (1, 2, 4, and 10 μg/mL) or with cyclosporine A, prior to ischemic arrest and for 20 minutes during reperfusion. Propofol at 4 and 10 μg/mL caused a significant depression in LVDP prior to ischemia. Propofol at 2 μg/mL conferred significant and maximal protection with no protection at 10 μg/mL. This protection was associated with improved recovery in coronary flow, reduced lactate release, and preservation of cardiomyocyte ultrastructure. The efficacy of propofol at 2 μg/mL was similar to the effect of cyclosporine A. In conclusion, propofol at a clinically relevant concentration is cardioprotective in the immature heart.

VirtualElectrodePolarization. Introduction: Our previous article examined cardiac vulnerability to reentry in the near e eld within the framework of the virtual electrode polarization (VEP) concept. The present study extends this examination to the far e eld and compares its predictions to the critical point hypothesis. Methods and Results: We simulate the electrical behavior of a sheet of myocardium using a twodimensional bidomain model. The e ber e eld is extrapolated from a set of rabbit heart e ber directions obtained experimentally. An S1 stimulus is applied along the top or left border. An extracellular line electrode on the top delivers a cathodal or anodal S2 stimulus. A VEP pattern matching that seen experimentally is observed and covers the entire sheet, thus constituting a far-e eld effect. Reentry arises from break excitation, make excitation, or a combination of both, and subsequent propagation through deexcited and recovered areas. Reentry occurs in cross-e eld, parallel-e eld, and uniform refractoriness protocols. For long coupling intervals (CIs) above CI min make (dee ned as the shortest CI at which make excitation can take place), rotors move away from the cathodal electrode and the S1 site for increases in S2 strength and CI, respectively. For cathodal S2 stimuli, e ndings are consistent with the critical point hypothesis. For CIs below CI min make , reentry is initiated by break excitation only, and the resulting reentrant patterns are no longer consistent with those predicted by the critical point hypothesis. Conclusion: Shock-induced VEP can explain vulnerability in the far e eld. The VEP theory of vulnerability encompasses the critical point hypothesis for cathodal S2 shocks at long CIs. (J Cardiovasc

Background —Atrial fibrillation (AF) is frequently associated with atrial dilatation caused by pressure or volume overload. Stretch-activated channels (SACs) have been found in myocardial cells and may promote AF in dilated atria. To prove this hypothesis, we investigated the effect of the SAC blocker gadolinium (Gd 3+ ) on AF propensity in the isolated rabbit heart during atrial stretch. Methods and Results —In 16 isolated Langendorff-perfused rabbit hearts, the interatrial septum was perforated to equalize biatrial pressures. Caval and pulmonary veins were occluded. Intra-atrial pressure (IAP) was increased in steps of 2 to 3 cm H 2 O by increasing the pulmonary outflow fluid column. Vulnerability to AF was evaluated by 15-second burst pacing at each IAP level. At baseline, IAP needed to be raised to 8.8±0.2 cm H 2 O (mean±SEM) to induce AF. A dose-dependent decrease in AF vulnerability was observed after Gd 3+ 12.5, 25, and 50 μmol/L was added. AF threshold increased to 19.0±0.5 cm H 2 O with Gd 3+ 50 μmol/L ( P 2 O at baseline but never during Gd 3+ . Atrial effective refractory period shortened progressively from 78±3 ms at 0.5 cm H 2 O to 52±3 ms at 20 cm H 2 O ( P 3+ 50 μmol/L had no significant effect on effective refractory period. Conclusions —Acute atrial stretch significantly enhances the vulnerability to AF. Gd 3+ reduces the stretch-induced vulnerability to AF in a dose-dependent manner. Block of SAC might represent a novel antiarrhythmic approach to AF under conditions of elevated atrial pressure or volume.