Ventricular Fibrillation In Pigs Research Articles

Reperfusion injury protection during Basic Life Support improves circulation and survival outcomes in a porcine model of prolonged cardiac arrest

ObjectiveIschemic postconditioning (PC) using three intentional pauses at the start of cardiopulmonary resuscitation (CPR) improves outcomes after cardiac arrest in pigs when epinephrine (epi) is used before defibrillation. We hypothesized PC, performed during basic life support (BLS) in the absence of epinephrine, would reduce reperfusion injury and enhance 24h functional recovery. DesignProspective animal investigation. SettingAnimal laboratory SubjectsFemale farm pigs (n=46, 39±1kg). InterventionsProtocol A: After 12min of ventricular fibrillation (VF), 28 pigs were randomized to four groups: (A) Standard CPR (SCPR), (B) active compression-decompression CPR with an impedance threshold device (ACD-ITD), (C) SCPR+PC (SCPR+PC) and (D) ACD-ITD CPR+PC. Protocol B: After 15min of VF, 18 pigs were randomized to ACD-ITD CPR or ACD-ITD+PC. The BLS duration was 2.75min in Protocol A and 5min in Protocol B. Following BLS, up to three shocks were delivered. Without return of spontaneous circulation (ROSC), CPR was resumed and epi (0.5mg) and defibrillation delivered. The primary end point was survival without major adverse events. Hemodynamic parameters and left ventricular ejection fraction (LVEF) were also measured. Data are presented as mean±SEM. Measurements and Main ResultsProtocol A: ACD-ITD+PC (group D) improved coronary perfusion pressure after 3min of BLS versus the three other groups (28±6, 35±7, 23±5 and 47±7 for groups A, B, C, D respectively, p=0.05). There were no significant differences in 24h survival between groups. Protocol BLVEF 4h post ROSC was significantly higher with ACD-ITD+PC vs ACD-ITD alone (52.5±3% vs. 37.5±6.6%, p=0.045). Survival rates were significantly higher with ACD-ITD+PC vs. ACD-ITD alone (p=0.027). ConclusionsBLS using ACD-ITD+PC reduced post resuscitation cardiac dysfunction and improved functional recovery after prolonged untreated VF in pigs. Protocol number12-11.

Abstract 14109: Basic Life Support With Reperfusion Injury Protection Improves 24 Hour Survival Outcomes in a Porcine Model of Prolonged Cardiac Arrest

Introduction: Ischemic postconditioning (PC) using 3 intentional short pauses at the start of cardiopulmonary resuscitation (CPR) improves outcomes after cardiac arrest in pigs when epinephrine (epi) is used before defibrillation. Hypothesis: Basic life support (BLS) with PC will protect against reperfusion injury and enhance 24 hour functional recovery in the absence of epi. Methods: Female pigs (n=46; wt ~ 40 kg) were anesthetized (isoflurane). PC was delivered using 3 cycles alternating between automated CPR for 20 sec and no CPR for 20 sec at the start of each protocol. Protocol A: After 12 minutes of ventricular fibrillation (VF), 28 pigs were randomized in 4 groups: A/ Standard CPR (SCPR), B/ active compression-decompression with an impedance threshold device (ACD-ITD), C/ SCPR+PC (SCPR+PC) and D/ ACD-ITD+PC. Protocol B: After 15 min of VF, 18 pigs were randomized to ACD-ITD CPR or ACD-ITD + PC. The BLS duration was 2.75 min in Protocol A and 5 min in Protocol B. Following BLS up to 3 shocks were delivered. Without return of spontaneous circulation (ROSC) CPR was resumed and epi (0.5 mg) and defibrillation delivered. The primary end point was the incidence of major adverse outcomes at 24 h (defined as death or coma, refractory seizures and cardio-respiratory distress leading to euthanasia). Hemodynamic parameters and left ventricular ejection fraction (LVEF) were also measured. Data are presented as mean ± standard error of mean. Results: Protocol A: ACD-ITD CPR + PC (group D) provided the highest coronary perfusion pressure after 3 min of BLS compared with the 3 other groups (28 ± 6, 35 ± 7, 23 ± 5 and 47 ± 7 for groups A, B, C, D respectively, p= 0.05 by ANOVA). ROSC with BLS was achieved in 0, 3, 0, and 3 pigs in groups A, B, C and D, respectively (p=0.22) with no significant differences in 24-hour survival between groups. Protocol B: Four hours post ROSC, LVEF was significantly higher with ACD-ITD+IPC vs ACD-ITD alone (52.5 ± 3% vs. 37.5 ± 6.6%, p = 0.045). There was a significantly lower incidence of major adverse outcomes 24 hr after ROSC with ACD-ITD+PC compared with ACD-ITD alone (Log-rank comparison, p=0.027). Conclusion: BLS using ACD-ITD + PC mitigates post resuscitation cardiac dysfunction and facilitates neurological recovery after prolonged untreated VF in pigs.

Comparison of Cerebral Metabolism between Pig Ventricular Fibrillation and Asphyxial Cardiac Arrest Models

Background:Morbidity and mortality after resuscitation largely depend on the recovery of brain function. Ventricular fibrillation cardiac arrest (VFCA) and asphyxial cardiac arrest (ACA) are the two most prevalent causes of sudden cardiac death. Up to now, most studies have focused on VFCA. However, results from the two models have been largely variable. So, it is necessary to characterize the features of postresuscitation cerebral metabolism of both models.Methods:Forty-four Wuzhishan miniature inbred pigs were randomly divided into three groups: 18 for VFCA group, ACA group, respectively, and other 8 for sham-operated group (SHAM). VFCA was induced by programmed electric stimulation, and ACA was induced by endotracheal tube clamping. After 8 min without treatment, standard cardiopulmonary resuscitation (CPR) was initiated. Following neurological deficit scores (NDS) were evaluated at 24 h after achievement of spontaneous circulation, cerebral metabolism showed as the maximum standardized uptake value (SUVmax) was measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Levels of serum markers of brain injury, neuron specific enolase (NSE), and S100β were quantified with an enzyme-linked immunosorbent assay.Results:Compared with VFCA group, fewer ACA animals achieved restoration of spontaneous circulation (61.1% vs. 94.4%, P < 0.01) and survived 24-h after resuscitation (38.9% vs. 77.8%, P < 0.01) with worse neurological outcome (NDS: 244.3 ± 15.3 vs. 168.8 ± 9.71, P < 0.01). The CPR duration of ACA group was longer than that of VFCA group (8.1 ± 1.2 min vs. 4.5 ± 1.1 min, P < 0.01). Cerebral energy metabolism showed as SUVmax in ACA was lower than in VFCA (P < 0.05 or P < 0.01). Higher serum biomarkers of brain damage (NSE, S100β) were found in ACA than VFCA after resuscitation (P < 0.01).Conclusions:Compared with VFCA, ACA causes more severe cerebral metabolism injuries with less successful resuscitation and worse neurological outcome.

Abstract 249: Sodium Nitroprusside Combined with Intrathoracic Pressure Regulation Increases Neurologically Favorable 24-Hour Survival in a Porcine Model of Prolonged Ventricular Fibrillation

Introduction: Use of epinephrine and standard (S) CPR has not been shown to improve neurologically-sound survival after cardiac arrest. Treatment with the potent vasodilator sodium nitroprusside (SNP) improves neurologically intact survival rates in animals when combined with abdominal compression, active compression decompression (ACD) CPR, and an impedance threshold device (ITD). We recently observed that SNP combined with ACD-CPR and a new intrathoracic pressure regulator (IPR), which provides continuous negative intrathoracic pressure after each positive pressure ventilation, increases blood flow to the heart and brain in the absence of epinephrine or abdominal compression. We hypothesized that this combination of SNP plus ACD CPR plus IPR (S-A-I) would improve 24h survival with favorable neurologic function compared with S-CPR. Method: After 12 minutes of untreated ventricular fibrillation (VF), 14 pigs received 3 minutes of S-CPR and were then randomized to a) a bolus of epinephrine (0.05mcg/kg), 2 more minutes of S-CPR and up to 3 defibrillation shocks or b) S-A-I and up to 3 shocks 2 minutes later. All resuscitated animals received therapeutic hypothermia for 4 hours. The primary endpoint was favorable neurologic outcome 24h after resuscitation defined by a Cerebral Performance Category score ≤ 2 (CPC with 1 for no deficit and 5 as dead or unable to resuscitate) as determined by a blinded veterinarian. Hemodynamic parameters and left ventricular ejection fraction were recorded. Data are presented as mean±SEM. Results: At 24 hours, 0/7 pigs in the S-CPR group vs. 5/7 pigs in S-A-I had favorable outcome (p=0.02). One pig survived 24 hours in the S-CPR group with a CPC of 4 vs. 5 in the S-A-I group with a CPC of 1.4±0.2. Carotid blood flow and ETCO2 were higher with S-A-I_vs. S-CPR and epinephrine (127±32 vs. 22±4 ml/min, p=0.005, and 46±5 vs. 22±3 mmHg, respectively, p=0.001). Conclusion: After prolonged VF in pigs, treatment with the combination of ACD CPR, an intrathoracic pressure regulator and SNP, in the absence of epinephrine, significantly increased carotid flow, ETCO2 levels, and neurologically-favorable 24 hour survival rates compared with S-CPR and epinephrine. This novel and promising approach should be considered for a Phase 1 human trial.

Verapamil reduces incidence of reentry during ventricular fibrillation in pigs.

The characteristics of reentrant circuits during short duration ventricular fibrillation (SDVF; 20 s in duration) and the role of Ca(++) and rapid-activating delayed rectifier potassium currents during long duration ventricular fibrillation (LDVF; up to 10 min in duration) were investigated using verapamil and sotalol. Activation mapping of the LV epicardium with a 21 × 24 electrode plaque was performed in 12 open-chest pigs. Pigs were given either verapamil (0.136 mg/kg) or sotalol (1.5 mg/kg) and verapamil. Reentry patterns were quantified for SDVF, and, for LDVF, activation patterns were compared with our previously reported control LDVF data. Verapamil significantly increased conduction velocity around the reentrant core by 10% and reduced the reentrant cycle length by 15%, with a net reduction in reentry incidence of 70%. Sotolol had an opposite effect of decreasing the conduction velocity around the core by 6% but increasing the reentrant cycle length by 13%, with a net reduction of reentry incidence of 50%. After 200 s of VF, verapamil significantly slowed wavefront conduction velocity and activation rate compared with control data. Verapamil decreased the incidence of reentry in SDVF by accelerating conduction velocity to increase the likelihood of conduction block, possibly through increased sympathetic tone. The drug slowed activation rate and conduction velocity after 200 s of VF, suggesting that L-type Ca(++) channels remain active and may be important in the maintenance of LDVF. Sotalol in addition to verapamil caused no additional antiarrhythmic effect.

Application of Positron Emission Tomography in the Detection of Myocardial Metabolism in Pig Ventricular Fibrillation and Asphyxiation Cardiac Arrest Models after Resuscitation

ObjectiveTo study the application of positron emission tomography (PET) in detection of myocardial metabolism in pig ventricular fibrillation and asphyxiation cardiac arrest models after resuscitation. MethodsThirty-two healthy miniature pigs were randomized into a ventricular fibrillation cardiac arrest (VFCA) group (n=16) and an asphyxiation cardiac arrest (ACA) group (n=16). Cardiac arrest (CA) was induced by programmed electric stimulation or endotracheal tube clamping followed by cardiopulmonary resuscitation (CPR) and defibrillation. At four hours and 24 h after spontaneous circulation was achieved, myocardial metabolism was assessed by PET. 18F-FDG myocardial uptake in PET was analyzed and the maximum standardized uptake value (SUVmax) was measured. ResultsSpontaneous circulation was 100% and 62.5% in VFCA group and ACA group, respectively. PET demonstrated that the myocardial metabolism injuries was more severe and widespread after ACA than after VFCA. The SUVmax was higher in VFCA group than in ACA group (P<0.01). In VFCA group, SUVmax at 24 h after spontaneous circulation increased to the level of baseline. ConclusionACA causes more severe cardiac metabolism injuries than VFCA. Myocardial dysfunction is associated with less successful resuscitation. Myocardial stunning does occur with VFCA but not with ACA.

Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs.

Supplemental digital content is available in the text. The aim of this experimental study was to compare survival and hemodynamic effects of a low-dose amiodarone and vasopressin compared with vasopressin in hypovolemic cardiac arrest model in piglets. Eighteen anesthetized male piglets (with a weight of 25.3 [1.8] kg) were bled approximately 30% of the total blood volume via the femoral artery to a mean arterial blood pressure of 35 mm Hg in a 15-minute period. Afterward, the piglets were subjected to 4 minutes of untreated ventricular fibrillation followed by 11 minutes of open-chest cardiopulmonary resuscitation. At 5 minutes, circulatory arrest amiodarone 1 mg/kg was intravenously administered in the amiodarone group (n = 9), while the control group received the same amount of saline (n = 9). At the same time, all piglets received vasopressin 0.4 U/kg intravenously administered and hypertonic-hyperoncotic solution 3-mL/kg infusion for 20 minutes. Internal defibrillation was attempted from 7 minutes of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 hours after resuscitation. Three-hour survival was greater in the amiodarone group (p = 0.02). After the successful resuscitation, the amiodarone group piglets had significantly lower heart rate as well as greater systolic, diastolic, and mean arterial pressure. Troponin I plasma concentrations were lower and urine output was greater in the amiodarone group. Combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters, and smaller myocardial injury compared with resuscitation with vasopressin only.

Hemodynamic and Catecholamine Changes after Recurrent Ventricular Fibrillation

BackgroundPatients with recurrent ventricular fibrillation (VF) have a high mortality rate, which may be partly due to hemodynamic instability. ObjectivesThe aim of this study was to simulate spontaneous recurrent VF by repeated induction of VF in pigs, and to evaluate the subsequent changes in heart rate (HR), blood pressure (BP), and serum catecholamine levels. MethodsVF was induced four times in each of eight female pigs. Defibrillation was first attempted at 30 s after induction of each episode of VF. Circulation was allowed to stabilize for 30 min after return of spontaneous circulation (ROSC) before induction of the next episode of VF. HR and BP were measured before each induction of VF and at 1 min after each ROSC, and venous blood was drawn at the same times to measure serum catecholamine levels. ResultsVF was induced a total of 32 times. Serum epinephrine (EPI) and norepinephrine (NE) levels decreased (p all < 0.05) and dopamine (DA) levels gradually increased (p < 0.05) with repeated episodes of VF. Compared with baseline values before each episode of VF, BP increased significantly at 1 min after ROSC (p all < 0.05) and then gradually returned to baseline values. HR increased significantly after the first ROSC and stayed elevated. No significant correlations were found between catecholamine levels and HR or BP. ConclusionWith repeated episodes of VF, BP increased transiently and then gradually returned to baseline values, but HR stayed elevated. Serum DA levels increased, EPI and NE levels gradually decreased.

Thiazolidinedione Drugs Promote Onset, Alter Characteristics, and Increase Mortality of Ischemic Ventricular Fibrillation in Pigs

Despite favorable metabolic and vascular effects, thiazolidinedione (TZD) drugs have not convincingly reduced cardiovascular mortality in clinical trials, raising the possibility of countervailing, off-target effects. We previously showed that TZDs block cardiac ATP-sensitive potassium (K(ATP)) channels in pigs. In this study, we investigated whether TZDs affect onset, spectral characteristics, and mortality of ischemic ventricular fibrillation (VF) and whether such effects are recapitulated by a non-selective K(ATP) blocker (glyburide) or a mitochondrial K(ATP) blocker (5-hydroxydecanoate). A total of 121 anesthetized pigs were pre-treated with TZD (pioglitazone or rosiglitazone, 1 mg/kg IV, resulting in clinically relevant plasma concentrations), glyburide (1 mg/kg IV), 5-hydroxydecanoate (5 mg/kg IV) or inert vehicle. Ischemia was produced by occlusion of the left anterior descending coronary artery. In a subset of pigs treated with rosiglitazone or vehicle, ischemic preconditioning was performed. VF developed in all but 6 pigs. In non-preconditioned pigs, onset of VF occurred sooner with pioglitazone (11±3 min, p<0.05) or rosiglitazone (14±3 min, p=0.06) than with vehicle (20±2 min). Defibrillation of VF was successful in 44% of pigs treated with vehicle, compared with 0% with pioglitazone (p=0.057) and 33% with rosiglitazone (NS). After ischemic preconditioning, defibrillation was successful in 62% of pigs treated with vehicle, compared with 26% treated with rosiglitazone (p=0.03). TZDs attenuated slowing of conduction due to ischemia and shifted ECG power spectra during VF toward higher frequencies. All effects of TZDs were recapitulated by glyburide, but not by 5-hydroxydecanoate, supporting an interaction of TZDs with the sarcolemmal K(ATP) channel. In a porcine model, TZDs promote onset and increase mortality of ischemic VF, associated with alterations of conduction and VF spectral characteristics. Similar effects in a clinical setting might adversely impact cardiovascular mortality.

Evolution of activation patterns during long-duration ventricular fibrillation in pigs

Quantitative analysis has demonstrated five temporal stages of activation during the first 10 min of ventricular fibrillation (VF) in dogs. To determine whether these stages exist in another species, we applied the same analysis to the first 10 min of VF recorded in vivo from two 504-electrode arrays, one each on left anterior and posterior ventricular epicardium in six anesthetized pigs. The following descriptors were continuously quantified: 1) number of wavefronts, 2) wavefront fractionations, 3) wavefront collisions, 4) repeatability, 5) multiplicity index, 6) wavefront conduction velocity, 7) activation rate, 8) mean area activated by the wavefronts, 9) negative peak rate of voltage change, 10) incidence of breakthrough/foci, 11) incidence of block, and 12) incidence of reentry. Cluster analysis of these descriptors divided VF into four stages (stages i-iv). The values of most descriptors increased during stage i (1-22 s after VF induction), changed quickly to values indicating greater organization during stage ii (23-39 s), decreased steadily during stage iii (40-187 s), and remained relatively unchanged during stage iv (188-600 s). The epicardium still activated during stage iv instead of becoming silent as in dogs. In conclusion, during the first 10 min, VF activation can be divided into four stages in pigs instead of five stages as in dogs. Following a 16-s period during the first minute of VF when activation became more organized, all parameters exhibited progressive decreased organization. Further studies are warranted to determine whether these changes, particularly the increased organization of stage ii, have clinical consequences, such as alteration in defibrillation efficacy.

The Persistent Sodium Current Blocker Riluzole Is Antiarrhythmic and Anti-Ischaemic in a Pig Model of Acute Myocardial Infarction

BackgroundThe potential of the cardiac persistent sodium current as a target for protection of the myocardium from ischaemia and reperfusion injury is gaining increasing interest. We have investigated the anti-ischaemic and antiarrhythmic effects of riluzole, a selective INaP blocker, in an open chest pig model of infarction.Methods and Principal FindingsThe left anterior descending coronary artery (LAD) was ligated in 27 anesthetised pigs (landrace or large white, either sex, 20–35 kg) which had received riluzole (8 mg/kg IP; n = 6), lidocaine (2.5–12 mg/kg bolus plus 0.05–0.24 mg/kg/min; n = 11) or vehicle (n = 10) 50 min prior. Arrhythmias could be delineated into phase 1a (0 to 20 min), phase 1b (20 to 50 min) and phase 2 (from 50 min to termination at 180 min) and were classified as premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) (spontaneously reverting within 15 s) or sustained VT or VF (ie. requiring cardioversion at 15 s). Riluzole reduced the average number of all arrhythmias in Phase 2 (PVCs from 484+/−119 to 32+/−13; non sustained arrhythmias from 8.9+/−4.4 to 0.7+/−0.5; sustained arrhythmias from 3.9+/−2.2 to 0.5+/−0.4); lidocaine reduced the average number of non-sustained and sustained arrhythmias (to 0.4+/−0.3 and 0.4+/−0.3 respectively) but not PVCs (to 390+/−234). Riluzole and lidocaine reduced the average number of sustained arrhythmias in phase 1b (from 1.8+/−0.4 to 0.17+/−0.13 (p<0.02) and to 0.55+/−0.26 (p = ns) respectively). Neither lidocaine or riluzole changed the ECG intervals: there was no statistical significance between groups at time zero (just before ligation) for any ECG measure. During the course of the 3 hour period of the ischaemia R-R, and P-R intervals shortened slightly in control and riluzole groups (not significantly different from each other) but not in the lidocaine group (significantly different from control). QRS and QTc did not change appreciably in any group Riluzole reduced the degree of histopathological tissue damage across the infarct zone considerably more than did lidocaine.ConclusionsAt the doses used, riluzole was at least as effective as lidocaine at reducing the number of episodes of ischaemic VT or VF in pigs, and much more effective at reducing the number of PVCs. We propose that this is related to the ability of riluzole to block cardiac persistent sodium current.

Sex differences in cardiac injury after severe haemorrhage and ventricular fibrillation in pigs

Aim of the study Experimental studies have shown sex differences in haemodynamic response and outcome after trauma and haemorrhagic shock. We recently reported that female sex protects against cerebral injury after exsanguination cardiac arrest (CA), independent of sexual effects of hormones. The current study examines if female sex is also cardioprotective. Methods In this study 21 sexually immature piglets (12 males and 9 females) were subjected to 5 min of haemorrhagic shock followed by 2 min of ventricular fibrillation and 8 min of cardiopulmonary resuscitation (CPR). Volume resuscitation was started during CPR with intravenous administration of 3 ml kg −1 hypertonic saline-dextran (HSD) solution for 20 min. Sexually immature animals were used to differentiate innate sex differences from the effects of sexual hormones. Sex differences in haemodynamics, myocardial injury (troponin I), and short-term survival (3-h) were evaluated. Results After resuscitation female animals had a higher blood pressure, lower heart rate, lower troponin I concentrations, and higher survival rate (100% and 63% in 3 h) despite comparable sex hormone levels. Conclusions After resuscitation from haemorrhage and circulatory arrest, haemodynamic parameters are better preserved and myocardial injury is smaller in female piglets. This difference in outcome is independent of sexual hormones.

Sex differences in cerebral injury after severe haemorrhage and ventricular fibrillation in pigs

Experimental studies of haemorrhagic shock have documented a superior haemodynamic response and a better outcome in female animals as compared with male controls. Such sexual dimorphism has, nevertheless, not been reported after circulatory arrest that follows exsanguination and shock. We aimed to study differences in cerebral injury markers after exsanguination cardiac arrest in pre-pubertal piglets. The hypothesis was that cerebral injury is less extensive in female animals, and that this difference is independent of sexual hormones or choice of resuscitative fluid. Thirty-two sexually immature piglets (14 males and 18 females) were subjected to 5 min of haemorrhagic shock followed by 2 min of ventricular fibrillation and 8 min of cardiopulmonary resuscitation, using three resuscitation fluid regimens (whole blood, hypertonic saline and dextran, or acetated Ringers' solution plus whole blood and methylene blue). Haemodynamic values, cellular markers of brain injury and brain histology were studied. After successful resuscitation, female piglets had significantly greater cerebral cortical blood flow, tended to have lower S-100beta values and a lower cerebral oxygen extraction ratio. Besides, in female animals, systemic and cerebral venous acidosis were mitigated. Female piglets exhibited a significantly smaller increase in neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) expression in their cerebral cortex, smaller blood-brain-barrier (BBB) disruption and significantly smaller neuronal injury. After resuscitation from haemorrhagic circulatory arrest, cerebral reperfusion is greater, and BBB permeability and neuronal injury is smaller in female piglets. An increased cerebral cortical iNOS and nNOS expression in males implies a mechanistic relationship with post-resuscitation neuronal injury and warrants further investigation.

Prevention of Ventricular Arrhythmias With Sarcoplasmic Reticulum Ca 2+ ATPase Pump Overexpression in a Porcine Model of Ischemia Reperfusion

Ventricular arrhythmias are life-threatening complications of heart failure and myocardial ischemia. Increased diastolic Ca2+ overload occurring in ischemia leads to afterdepolarizations and aftercontractions that are responsible for cellular electric instability. We inquired whether sarcoplasmic reticulum Ca2+ ATPase pump (SERCA2a) overexpression could reduce ischemic ventricular arrhythmias by modulating Ca2+ overload. SERCA2a overexpression in pig hearts was achieved by intracoronary gene delivery of adenovirus in the 3 main coronary arteries. Homogeneous distribution of the gene was obtained through the left ventricle. After gene delivery, the left anterior descending coronary artery was occluded for 30 minutes to induce myocardial ischemia followed by reperfusion. We compared this model with a model of permanent coronary artery occlusion. Twenty-four-hour ECG Holter recordings showed that SERCA2a overexpression significantly reduced the number of episodes of ventricular tachycardia after reperfusion, whereas no significant difference was found in the occurrence of sustained or nonsustained ventricular tachycardia and ventricular fibrillation in pigs undergoing permanent occlusion. We show that Ca2+ cycling modulation using SERCA2a overexpression reduces ventricular arrhythmias after ischemia-reperfusion. Strategies that modulate postischemic Ca2+ overload may have clinical promise for the treatment of ventricular arrhythmias.

The Long and the Short of Long and Short Duration Ventricular Fibrillation

See related article, pages 1256–1264 The mechanisms behind the complex activation sequences during ventricular fibrillation (VF) have been the topic of intense research over many years. Experimental studies in animal models of VF, as well as clinical studies of human VF,1–8 have provided a wealth of data on the nature of electric activity in the fibrillating heart. Supplemented by computer simulations and a theoretical framework of wave propagation in excitable media,9,10 our community has amassed significant insights into the mechanisms that lead to the degradation of electric activity into VF and of VF maintenance. However, the majority of these studies have been devoted to VF mechanisms in the short time period after VF onset (short-duration VF, lasting less than 1 minute). In an episode of cardiac arrest outside of the hospital, the median time to delivery of the first defibrillation shock is 4.4 minutes,11 with VF episodes often lasting as long as 10 minutes (long-duration VF); over this period, the heart becomes ischemic while being subjected to excessively high excitation rates. Changes in the electrophysiological properties of the myocardium take place over these long-duration VF episodes. This is reflected in the altered outcome of a defibrillation shock, with survival rates decreasing rapidly with the increase in minutes spent in VF.12 Similarly, the guidelines for optimal resuscitation therapy differ depending on VF duration: immediate defibrillation is prescribed if time from VF onset is less than 4 or …

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs.

Opening of ATP-sensitive potassium (K(ATP)) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K(ATP) channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K(ATP) channels in vivo. Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K(ATP) channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K(ATP) blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion. With vehicle, epicardial MAP shortened by 44+/-9 ms during ischaemia. This effect was attenuated to 12+/-8 ms with troglitazone and 6+/-6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K(ATP) blockade. Intracoronary levcromakalim shortened MAP by 38+/-10 ms, an effect attenuated to 12+/-8, 13+/-4 and 9+/-5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K(ATP) blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K(ATP) blockade promotes ischaemic ventricular fibrillation in this model. Thiazolidinedione drugs block cardiac K(ATP) channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.

Trimetazidine Protective Effect Against Ischemia-Induced Susceptibility to Ventricular Fibrillation in Pigs

Ventricular fibrillation (VF) is a possible consequence of brief myocardial ischemia. Such a short ischemia does not provoke cell damage, but induces changes in intracellular cardiac metabolism due to diminished oxygen supply to the heart. Trimetazidine (TMZ) is a drug able to restore the metabolic balance between fatty acid and glucose oxidation in ischemic myocardial cells. The aim of this double-blind study was to investigate TMZ effect on VF in pigs during short-term ischemia. Ischemia was induced after thoracotomy by complete, but brief (1 min) occlusion of the left anterior descending coronary artery under electrical stimulation. The ventricular fibrillation threshold (VFT), heart rate (HR), various hemodynamic parameters and malondialdehyde (MDA) blood levels were measured before and during ischemia in two groups of eight anesthetized pigs. The mass of ischemic myocardial tissue was also evaluated. No effects on either the HR or the hemodynamic parameters were observed during myocardial ischemia, whereas TMZ increased the VFT and decreased both MDA blood levels (an index of lipid peroxidation) and the ischemic area. TMZ limited ischemia-induced electrical dysfunction leading to cardiac susceptibility to VF by decreasing lipid peroxidation and maintaining ionic homeostasis. TMZ could therefore provide protection against ischemia-induced VF.

Abstract 1358: Reentry within the Working Myocardium is not the Sole Mechanisms by which Ventricular Fibrillation is Maintained

Background: For well over 50 years, it has been assumed that ventricular fibrillation (VF) is maintained solely by reentry in the working myocardium. This hypothesis has never been tested by recording VF with electrodes spaced sufficiently close together to map activation sequences in 3-dimensions. Methods and Results: We recorded for 10 min during VF from the region of insertion of the anterior papillary muscle in the left ventricle of 4 open-chest pigs. A 3-D transmural unipolar electrode array consisting of a 9×9 array of needles with 2-mm spacing and 6 electrodes 2 mm apart on each needle was used to record from the working myocardium. The numbers of wavefronts, foci and reentrant circuits per sec were counted. A focus was identified when a wavefront appeared de novo within the central portion of the mapped region, insuring that it did not arise from another wavefront nor propagate into the mapped region from outside it. While intramural reentry was present early but not late during VF in the mapped region, foci were numerous and increased as VF continued (Figure ). Conclusion: Intramural foci are present during VF in pigs and, as VF continues, increase in incidence while the incidence of reentry in working myocardium decreases. These results suggest that, particularly after the first 2 min of VF, mechanisms other than reentry in the working myocardium maintain VF. It remains to be determined if these mechanisms consist of abnormal automaticity, afterdepolarizations, or reentry in which Purkinje fibers form all or part of the circuit.

External cardiac defibrillation during wet-surface cooling in pigs

Objective During surface cooling with ice-cold water, safety and effectiveness of transthoracic defibrillation was assessed. Methods In a pig ventricular fibrillation cardiac arrest model, once (n = 6), defibrillation was done first in a dry and then in a wet condition using the ThermoSuit System (Life Recovery Systems, HD, LLC, Kinnelon, NJ), which circulates a thin layer of ice-cold water (≈4°C) over the skin surface. Another time (n = 6), defibrillation was done first in a wet and then in a dry condition. Success of defibrillation was defined as restoration of spontaneous circulation, and the current and voltage of the defibrillation signal was measured. Results There was a tendency toward less number of shocks needed for achieving restoration of spontaneous circulation in the wet condition as compared with the number of shocks needed in the dry condition. The energy delivered in both dry and wet conditions was 144 ± 3 J. Discussion Transthoracic defibrillation is safe and effective in a wet condition after cooling with ice-cold water.

Taser Dart-to-Heart Distance That Causes Ventricular Fibrillation in Pigs

Electromuscular incapacitating devices (EMDs), such as Tasers, deliver high current, short duration pulses that cause muscular contractions and temporarily incapacitate the human subject. Some reports suggest that EMDs can kill. To help answer the question, "Can the EMD directly cause ventricular fibrillation (VF)?", ten tests were conducted to measure the dart-to-heart distance that causes VF in anesthetized pigs [mass = 64 kg +/- 6.67 standard deviation (SD)] for the most common X26 Taser. The dart-to-heart distance that caused VF was 17 mm +/- 6.48 (SD) for the first VF event and 13.7 mm +/- 6.79 (SD) for the average of the successive VF events. The result shows that when the stimulation dart is close enough to the heart, X26 Taser current will directly trigger VF in pigs. Echocardiography of erect humans shows skin-to-heart distances from 10 to 57 mm (dart-to-heart distances of 1-48 mm). These results suggest that the probability of a dart on the body landing in 1 cm2 over the ventricle and causing VF is 0.000172.