Ischemia-induced Ventricular Fibrillation Research Articles

Abstract 13503: Assessment of Automatic Measurement of Short-Term Variability of Repolarization for Arrhythmic Risk Monitoring in a Porcine Model of Ischemic Ventricular Fibrillation

Background: Short-term variability of repolarization derived from the QT-interval (STV-QT) has previously been demonstrated to increase prior to arrhythmias in both humans and animals. To continuously monitor the arrhythmic risk by a cardiovascular implantable electronic device (CIED), a fully automatic method to determine STV on intracardiac electrograms (STV-EGM auto ) has been developed. This method demonstrated high effectiveness in monitoring and predicting Torsade de Pointes arrhythmias in the CAVB dog model. However, this technique has not been evaluated in arrhythmias related to ischemia yet. Purpose: To assess the novel automatic method of arrhythmic risk monitoring by CIEDs through STV-EGM auto measurements in a porcine model of ischemia-induced ventricular fibrillation (VF). Methods: Myocardial infarction was induced in 8 anesthetized pigs by balloon occlusion of the left anterior descending coronary artery for 75 minutes, followed by reperfusion. Monitoring included a 12-lead ECG and a duodecapolar EGM catheter in the right ventricle. STV-EGM auto and STV-QT, our gold standard calculated by the method of fiducial segment averaging, were assessed at baseline, occlusion, one minute before VF and just before VF. The STV values and the percentual changes from baseline to the successive three timepoints were compared between STV-EGM auto and STV-QT. Results: VF occurred 21±8.8 minutes after occlusion. Both STV-EGM auto and STV-QT increased significantly from baseline to VF (1.1±0.8 ms vs 2.4±1.5 ms, p<0.05; 1.0±0.5 ms vs 2.2±0.9 ms, p<0.05, respectively). The percentual change in STV-EGM auto from baseline to occlusion, one minute before VF and VF showed an excellent correlation with the changes in STV-QT from baseline to the successive timepoints (r 2 = 0.94; p<0.001). Bland-Altman analysis of the values showed a small bias of 0.26 ms and 95% limits of agreement between -1.1 and 1.6 ms. Conclusion: The STV values derived from the fully-automatic method for continuous STV measurements on intracardiac EGM signals (STV-EGM auto ) show values and trends similar to the clinically validated STV-QT in a porcine model of ischemia-related VF. Future integration of this technique in CIEDs can furnish continuous monitoring of arrhythmic risk.

No evidence of association between habitual physical activity and ECG traits: Insights from the electronic Framingham Heart Study

No evidence of association between habitual physical activity and ECG traits: Insights from the electronic Framingham Heart Study

Cardiac sympathectomy and spinal cord stimulation attenuate reflex-mediated norepinephrine release during ischemia preventing ventricular fibrillation.

The purpose of this study was to define the mechanism by which cardiac neuraxial decentralization or spinal cord stimulation (SCS) reduces ischemia-induced ventricular fibrillation (VF). Direct measurements of norepinephrine (NE) levels in the left ventricular interstitial fluid (ISF) by microdialysis, in response to transient (15-minute) coronary artery occlusion (CAO), were performed in anesthetized canines. Responses were studied in animals with intact neuraxes and were compared with those in which the intrathoracic component of the cardiac neuraxes (stellate ganglia) or the intrinsic cardiac neuronal (ICN) system was surgically delinked from the central nervous system and those with intact neuraxes with preemptive SCS (T1-T3). With intact neuraxes, animals with exaggerated NE release due to CAO were at increased risk for VF. During CAO, there was a 152% increase in NE when the neuraxes were intact compared with 114% following stellate decentralization and 16% following ICN decentralization. During SCS, CAO NE levels increased by 59%. Risk for CAO-induced VF was 38% in controls, 8% following decentralization, and 11% following SCS. These data indicate that ischemia-related afferent neuronal transmission differentially engages central and intrathoracic sympathetic reflexes and amplifies sympathoexcitation. Differences in regional ventricular NE release are associated with increased risk for VF. Surgical decentralization or SCS reduced NE release and VF.

Sudden cardiac arrest due to coronary vasospasm in a patient with Wolff-Parkinson-White syndrome during brain surgery: a case report

BackgroundWolff-Parkinson-White (WPW) syndrome has the risk of sudden cardiac death. Without appropriate treatment, coronary vasospasm is also a potentially fatal condition due to ischemia-induced ventricular fibrillation. A rare case of cardiac arrest due to coronary vasospasm during general anesthesia in a patient with pre-existing WPW syndrome is presented.Case presentationA 55-year-old man was scheduled for brain surgery under general anesthesia. During surgery, the ECG monitor showed ST segment elevation followed by sustained ventricular tachycardia and the patient’s blood pressure was unmeasurable. Since pseudo-VT with WPW syndrome was suspected, pilsicainide was administered. A few weeks later, a spasm provocation test with acetylcholine was performed, which showed complete spastic occlusion of the right coronary artery.ConclusionsA rare case of cardiac arrest during surgery in a patient with WPW syndrome, possibly caused by coronary vasospasm, was described.

Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF.

Ventricular fibrillation (VF) is an important cause of sudden cardiac arrest following myocardial infarction. Following resuscitation from VF, decreased cardiac contractile function is a common problem. During and following myocardial ischemia, decreased glucose oxidation, increased anaerobic glycolysis for cardiac energy production are harmful and energetically expensive. The objective of the present study is to determine the effects of dichloroacetate (DCA), a glucose oxidation stimulator, on cardiac contractile dysfunction following ischemia-induced VF. Male Sprague-Dawley rat hearts were Langendorff perfused in Tyrode's buffer. Once stabilized, hearts were subjected to 15 min of global ischemia and 5 min of aerobic reperfusion in the presence or absence of DCA. At the 6th min of reperfusion, VF was induced electrically, and terminated. Left ventricular (LV) pressure was measured using a balloon. Pretreatment with DCA significantly improved post-VF left ventricular developed pressure (LVDP) and dp/dtmax. In DCA-pretreated hearts, post-VF lactate production and pyruvate dehydrogenase (PDH) phosphorylation were significantly reduced, indicative of stimulated glucose oxidation, and inhibited anaerobic glycolysis by activation of PDH. Epicardial NADH fluorescence was increased during global ischemia above preischemic levels, but decreased below preischemia levels following VF, with no differences between nontreated controls and DCA-pretreated hearts, whereas DCA pretreatment increased NADH production in nonischemic hearts. With exogenous fatty acids (FA) added to the perfusion solution, DCA pretreatment also resulted in improvements in post-VF LVDP and dp/dtmax, indicating that the presence of exogenous FA did not affect the beneficial actions of DCA. In conclusion, enhancement of PDH activation by DCA mitigates cardiac contractile dysfunction following ischemia-induced VF.

The Effect of Inhibition of Glycolysis on Susceptibility to Ischemia‐Induced Ventricular Fibrillation in the Isolated Rat Heart

Ventricular fibrillation (VF) is a major cause of sudden cardiac death but the triggers of VF in myocardial ischemia are poorly understood. We have previously proposed that ATP depletion may be the major trigger for development of VF in myocardial ischemia due to the consequent ionic and electrical dysfunction that creates an arrhythmogenic substrate. In the present study we determined the importance of ATP supplied by glycolysis to development of ischemia-induced VF by examining the effect of inhibition of glycolysis on the incidence and onset of VF. Isolated rat hearts (n=12 per group) were perfused in the Langendorff mode with modified Krebs solution, and then switched in randomized and blinded manner to one of three test solutions: Glucose Control (Krebs containing glucose + vehicle), Pyruvate Control (Krebs containing pyruvate + vehicle) or Pyrvuate + IAA (Krebs containing pyruvate + 100μM sodium iodoacetate, an irreversible inhibitor of glycolysis). After 15 min of perfusion with test solution, regional ischemia was induced by coronary occlusion and maintained for 30 minutes. Arrhythmias were determined from the ECG. The incidence of VF was 83%, 42% and 67% in the glucose control, pyruvate control and pyruvate + IAA groups respectively (P=NS). The mean time to onset of VF was 832±67 s, 823±76 s, and 671±67 s in the glucose control, pyruvate control and pyruvate + IAA groups respectively (P=NS). Thus, inhibition of glycolysis with pyruvate + IAA increased VF incidence and shortened the time to VF as a trend. We are increasing group size in order to avoid a Type II error when evaluating the effect of glycolytic inhibition on VF susceptibility. Supported by a Scientist Development Grant from the American Heart Association.

Myocardial electrotonic response to submaximal exercise in dogs with healed myocardial infarctions: evidence for β-adrenoceptor mediated enhanced coupling during exercise testing.

Introduction: Autonomic neural activation during cardiac stress testing is an established risk-stratification tool in post-myocardial infarction (MI) patients. However, autonomic activation can also modulate myocardial electrotonic coupling, a known factor to contribute to the genesis of arrhythmias. The present study tested the hypothesis that exercise-induced autonomic neural activation modulates electrotonic coupling (as measured by myocardial electrical impedance, MEI) in post-MI animals shown to be susceptible or resistant to ventricular fibrillation (VF).Methods: Dogs (n = 25) with healed MI instrumented for MEI measurements were trained to run on a treadmill and classified based on their susceptibility to VF (12 susceptible, 9 resistant). MEI and ECGs were recorded during 6-stage exercise tests (18 min/test; peak: 6.4 km/h @ 16%) performed under control conditions, and following complete β-adrenoceptor (β-AR) blockade (propranolol); MEI was also measured at rest during escalating β-AR stimulation (isoproterenol) or overdrive-pacing.Results: Exercise progressively increased heart rate (HR) and reduced heart rate variability (HRV). In parallel, MEI decreased gradually (enhanced electrotonic coupling) with exercise; at peak exercise, MEI was reduced by 5.3 ± 0.4% (or -23 ± 1.8Ω, P < 0.001). Notably, exercise-mediated electrotonic changes were linearly predicted by the degree of autonomic activation, as indicated by changes in either HR or in HRV (P < 0.001). Indeed, β-AR blockade attenuated the MEI response to exercise while direct β-AR stimulation (at rest) triggered MEI decreases comparable to those observed during exercise; ventricular pacing had no significant effects on MEI. Finally, animals prone to VF had a significantly larger MEI response to exercise.Conclusions: These data suggest that β-AR activation during exercise can acutely enhance electrotonic coupling in the myocardium, particularly in dogs susceptible to ischemia-induced VF.

Coxsackie and Adenovirus Receptor Is a Modifier of Cardiac Conduction and Arrhythmia Vulnerability in the Setting of Myocardial Ischemia

The aim of this study was to investigate the modulatory effect of the coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. A heritable component in the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the CAR, a cell adhesion molecule predominantly located at the intercalated disks of the cardiomyocyte. The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed using CAR haploinsufficient (CAR⁺/⁻) mice. In human left ventricular samples, the risk allele at the chr21q21 genome-wide association study locus was associated with lower CXADR messenger ribonucleic acid levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced ventricular fibrillation. Hearts from CAR⁺/⁻ mice displayed slowing of ventricular conduction in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia after ligation of the left anterior descending artery. Expression and distribution of connexin 43 were unaffected, but CAR⁺/⁻ hearts displayed increased arrhythmia susceptibility on pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR⁺/⁻ myocytes showed reduced sodium current magnitude specifically at the intercalated disk. Moreover, CAR coprecipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5. CAR is a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease.

Abstract 214: Therapeutic Hypothermia Promotes Arrhythmogenic Calcium-Mediated Delayed Afterdepolarizations During Sympathetic Stimulation

Introduction: Most patients who undergo therapeutic hypothermia (TH) suffer cardiac arrest due to ischemia-induced ventricular fibrillation (VF). Ischemia and hypothermia both cause cellular calcium (Ca) overload, a substrate for Ca-mediated triggered arrhythmias. Previously, we showed that under non-ischemic conditions, TH suppresses Ca-mediated arrhythmias. However, the mechanistic relationship between hypothermia-induced Ca dysregulation and arrhythmias during ischemia, the most common clinical scenario, is unknown. We hypothesized that TH and ischemia would synergistically promote spontaneous Ca release and subsequent arrhythmogenic delayed afterdepolarizations (DADs). We examined this relationship during sympathetic stimulation, as occurs when epinephrine is given during resuscitation from VF. Methods and Results: Dual optical mapping of Ca transients and action potentials was performed in canine left ventricular wedge preparations during 10 minutes of no flow ischemia during normothermia (NT, 36°C, n=5) and TH (32°C, n=7) with and without beta-sympathetic stimulation (isoproterenol, 0.2uM, each n=5). Multicellular spontaneous Ca release events (mSCRs) and resultant DADs were induced by rapid pacing. During ischemia, TH increased mSCR amplitude (44±3%) vs. NT (26±4%, p&lt;0.04). In contrast, the slope (amplitude/rise time) of mSCRs, an important determinant of triggered activity (TA), and DAD amplitudes were similar in TH and NT (24±6 and 21%±2% respectively, both p=NS). Importantly, when sympathetic stimulation was present during ischemia, TH increased the amplitude mSCRs compared to NT (61±5 vs. 31±7%, respectively p&lt;.01) and the slope of mSCRs was 2-fold greater (p&lt;.01), resulting in greater amplitude of DADs (50±9 vs. 28±7%, p=.08) and TA was observed. Conclusions: During ischemia, TH is not arrhythmogenic unless sympathetic stimulation is introduced, where it promotes spontaneous Ca release and DADs. Moreover, these data suggest that when TH is initiated during ischemia, as in intra-arrest cooling, sympathetic stimulation during cardiac arrest may be proarrhythmic by increasing susceptibility to Ca-mediated triggered arrhythmias.

Trapped Platelets Activated in Ischemia Initiate Ventricular Fibrillation

We tested the hypothesis that ischemia-induced ventricular fibrillation (VF) is facilitated by platelets, trapped regionally in the ischemic zone and activated to release arrhythmogenic secretome. In a randomized study in blood-free, buffer-perfused isolated rat hearts, ischemic zone territory (34±1% of left ventricle) was selected so that ischemia evoked VF in only 42% of controls. VF incidence was increased to 91% (P<0.05) by coronary ligation-induced trapping of freshly prepared autologous platelets (infused before and during coronary ligation, with trapping confirmed by 111In-labeled platelet autoradiographic imaging). Trapping of platelet secretome prepared ex vivo, or platelet-sized fluorospheres, did not increase ischemia-induced VF incidence. Secretome alone did, however, evoke VF in 2 sham coronary-ligated hearts. Perfusion did not activate infused platelets in sham coronary-ligated hearts, whereas ligation activated trapped platelets (assessed by thromboxane release). In a separate study, trapping whole-heparinized blood mimicked the ability of trapped platelets to increase VF incidence. This effect was not prevented by >5 days oral pretreatment in vivo with clopidogrel (10 mg/kg per day) or indomethacin (2.4 mg/kg per day). Platelets facilitate VF during acute ischemia independently of their ability to participate in occlusive thrombosis. Moreover, the effect is unresponsive to antiplatelet drugs commonly used. Labile secretome constituents appear to be responsible. This opens a novel avenue for antiarrhythmic drug research.

Susceptibility to ischemia-induced ventricular fibrillation in isolated female rat hearts varies moderately with estrous cycle stage

IntroductionThe vast majority of studies employing the isolated perfused rat heart model to study ischemic arrhythmias have used male rats only. The objective of this study was to determine the susceptibility to ischemia-induced ventricular fibrillation (VF) in isolated female rat hearts in each stage of the estrous cycle that corresponds with a different endogenous reproductive hormonal environment. MethodsHearts were isolated from female rats under pentobarbital anesthesia and perfused with modified Krebs solution containing 3mM K+. Experiments were grouped according to estrous cycle stage that was determined by prior vaginal lavage (n=10–13 per group). A group of male rat hearts was used as the control. Regional ischemia was induced by coronary ligation and maintained for 30min. The incidence of VF was determined from the ECG. ResultsThe incidence of VF in male hearts was 100%, while the incidence of VF in female hearts was also high but varied moderately with stage of the estrous cycle (diestrus 70%, metestrus 100%, proestrus 90%, estrus 69%; P>0.05). Compared to male hearts, the onset of VF was similar in all groups except for hearts excised from rats in proestrus, in which it was delayed. There was no difference between groups in an arrhythmia score, ischemic zone size, or baseline electrocardiographic or hemodynamic variables. DiscussionIn conclusion, the susceptibility of isolated female rat hearts to ischemic VF is comparable to that of male rat hearts, meaning that isolated female rat hearts can be used as controls in studies to assess antiarrhythmic drug efficacy. Since female rats can be used for isolated heart studies of ischemic VF, the need to cull female rats is reduced. However, the variation in VF susceptibility in female rat hearts that is associated with the different stages of the estrous cycle may affect statistical power that could potentially lead to Type II statistical errors. This problem can be prevented with careful randomization.

Susceptibility of the isolated female rat heart to ischemia‐induced ventricular fibrillation varies with estrous cycle stage

The vast majority of studies employing the isolated perfused rat heart model to study ischemic arrhythmias have used male rats only. The objective of this study was to determine the variation in susceptibility to ischemia‐induced ventricular fibrillation (VF) in isolated female rat hearts with the changing endogenous reproductive hormonal environment associated with the estrous cycle.Hearts were isolated from female rats under anesthesia and perfused with 3 mM K+ Krebs solution. Experiments were grouped according to estrous cycle stage that was determined by prior vaginal lavage (n=9–13 per group). A group of male rats was used as the control. Regional ischemia was induced by coronary ligation and maintained for 30 min. The incidence of VF was determined from the ECG.The incidence of VF in male hearts was 100%, while the incidence of VF in female hearts was also high but varied with stage of the estrous cycle (proestrus 89%, diestrus 78%, metestrus 100%, estrus 69%; p&gt;0.05). There was no difference between groups in time to onset of VF or ischemic zone size (range 40–44% of total ventricular weight).In conclusion, the susceptibility of isolated female rat hearts to ischemic VF is comparable to that of male rat hearts. However, the variation in VF susceptibility in female rat hearts associated with the different stages of the estrous cycle may affect the statistical power of a study.Supported by a WVSOM intramural grant.

Eicosapentaenoic acid reduces ischemic ventricular fibrillation via altering monophasic action potential in pigs

Although high intake of n-3 fatty acids is associated with reduced mortality of patients with ischemic heart disease, especially reduction in sudden cardiac death (SCD), the detailed mechanisms remain to be elucidated. Thus, the present study was designed to examine whether long-term treatment with eicosapentaenoic acid (EPA), a major component of n-3 fatty acids, reduces ischemia-induced ventricular fibrillation (VF) in pigs in vivo, and if so, what molecular mechanisms are involved. Male pigs were treated with either a control chow (control group) or a control chow plus EPA (600 mg/kg/day, PO, EPA group) for 3 weeks and were subjected to myocardial ischemia for 90 min (n = 8 each) with measurement of the monophasic action potential (MAP), as a marker of ventricular electrophysiological activities. The EPA treatment significantly attenuated the occurrence of VF (control 5.1 ± 1.7 vs. EPA 1.5 ± 0.8 times/animal, P < 0.05) and markedly reduced the mortality (control 50% vs. EPA 0%, P < 0.05), with the attenuation of MAP duration shortening during ischemia (control − 28.1 ± 3.0% vs. EPA − 18.2 ± 1.4%, P < 0.05). These beneficial effects of EPA were abolished by pre-treatment with cromakalim, a K ATP channel opener (0.3 μg/kg/min, IC). Furthermore, EPA significantly inhibited the mRNA and protein expression of Kir6.2, a major component of sarcolemmal K ATP channels, in both the ischemic region and non-ischemic regions. These results indicate that long-term treatment with EPA reduces ischemia-induced VF and SCD in pigs in vivo, for which attenuation of MAP duration shortening may be involved.

253 Effects of the selective heart rate-reducing agent ivabradine on the risk of onset of ventricular fibrillation during myocardial ischemia in pigs: involved mechanisms

A major risk of myocardial ischemia (MI) is the onset of ventricular fibrillation (VF). Our study evaluated the effect of heart rate reduction (HRR) induce by ivabradine (IVA), the first selective inhibitor of the pacemaker current If, on the risk of onset of VF, and study the possible mechanisms involved. MI was induced in pigs by total occlusion of the anterior interventricular artery until onset of VF, which was assessed by the VF threshold (VFT; protocol 1) or the time to onset of VF (TOF; protocol 2), with or without IVA (0.25 mg/kg, i.v.). Electrophysiological, hemodynamic parameters and ischemic area were assessed in these two protocols. The impact of IVA was evaluated on: i) ultrastructure of mitochondria (by electron microscopy) in protocol 1; ii) myocardial energetic status compared with a β-blocker, propranolol (PROP) in protocol 2; iii) regional myocardial blood flow (RMBF) after 1 min-ischemia followed (without VF) by reperfusion by positrons emission tomography in protocol 3. IVA induced a significant HRR (∼25%), increased the VFT and the TOF. When compare to control, IVA prevented the apparition of mitochondrial alterations due to repetitive sequences of MI/VF and reperfusion. IVA improved the RMBF during reperfusion (after 1 min-occlusion). Also, the myocardial energetic status evaluated by the concentrations of high energy phosphates, was in part preserved with IVA. All of these changes were correlated with IVA-induced HRR and were not associated with modifications in the dP/dtmax. Our results showed that IVA decreases the risk of the onset of ischemia-induced VF. This effect can be explained by a preservation of ultrastructure of mitochondria, an improvement in the RMBF and a better conservation of myocardial energetic status. Although further work is needed to determine the mechanisms underlying these effects, this might give a place of choice to IVA in the prevention of ischemia-induced VF.

Abstract 5061: Long-Term Treatment with Eicosapentaenoic Acid Suppresses Ischemia-Induced Ventricular Fibrillation: Potential Involvement of ATP-Sensitive Potassium (KATP) Channel

Although epidemiologic studies demonstrated that eicosapentaenoic acid (EPA) reduces sudden cardiac death in patients with coronary artery disease, the mechanisms remain to be examined. It was reported that during early myocardial ischemia, activated KATP channels could cause fatal ventricular arrhythmia. We thus hypothesized that long-term treatment with EPA suppresses ischemia-induced ventricular fibrillation (VF) by inhibiting myocardial KATP channels. Male pigs were treated with either a control chow or EPA (600 mg/kg/day, PO) for 3 weeks (n=8 each). They were subjected to myocardial ischemia (90 min) by occlusion of the left circumflex coronary artery and monophasic action potential (MAP) that reflects electrical activity of the LV in vivo was measured. In the EPA group, EPA content in red blood cells was increased to 4.5±0.3 mol%, a comparable level in the clinical studies (~5.8 mol%). The EPA treatment significantly reduced the occurrence of VF and the need for DC cardioversion, with a resultant marked improvement in mortality (EPA 0% vs. control 50%, P&lt;0.05). Furthermore, the EPA treatment significantly inhibited ischemia-induced shortening of MAP duration (measured at 90% repolarization) (EPA −19.5±3.0% vs. control −27.6±8.1%, P&lt;0.05). Importantly, the beneficial effect of EPA on MAP was abolished by pre-treatment with diazoxide, a KATP channel opener (5 mg/kg/min for 20 min, IC) (EPA+diazoxide −27.9±6.4%, P&lt;0.05 vs. EPA) ( Figure ). These results indicate that long-term treatment with EPA stabilizes ventricular electrical property during myocardial ischemia partly through suppression of KATP channels in vivo. Representative Recordings of Monophasic Action Potential(MAP) in Pigs

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.

Pravastatin Inhibits Arrhythmias Induced by Coronary Artery Ischemia in Anesthetized Rats

We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats without lowering the serum cholesterol level. The present study was undertaken to evaluate whether pravastatin prevents ischemia-induced lethal VF, simultaneously examining myeloperoxidase (MPO) activity in ischemic myocardial tissues. Anesthetized rats were subjected to 30-min ischemia and 60-min reperfusion after chronic administration of pravastatin (0.02, 0.2, and 2mg/kg), fluvastatin (2 and 4 mg/kg), or vehicle for 22 days, orally, once daily. ECG and blood pressure were continually recorded, and MPO was measured by a spectrophotometer. Pravastatin and fluvastatin significantly (P<0.05) decreased MPO activities, but only pravastatin decreased the incidence of ischemia-induced lethal VF. Both statins had no significant effects on body weight, blood pressure, heart rate, and QT interval as we reported earlier. Our results prove further that pravastatin has benefits to decrease cardiovascular mortality beyond its cholesterol-lowering effect. Pravastatin is more potent than fluvastatin in prevention of arrhythmias. A decrease in the neutrophil infiltration may be partly involved in the inhibitory effect of pravastatin on the ischemia-induced VF.

Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis.

Sudden cardiac death forms a major cause of mortality. Myocardial ischemia-induced ventricular fibrillation (VF) is frequently the underlying mechanism. Ventricular arrhythmias arise in two distinct phases during the first hour of ischemia. The first, the 1A phase, has been extensively studied, and few studies relate to the 1B phase. The latter is associated with intercellular electrical uncoupling, mediated by decreased conductance of gap junction channels. Although the relation between gap junctional uncoupling and decreased conduction velocity appears clear under normoxic conditions, additional factors contribute to conduction slowing during ischemia, and VF occurs preferentially at moderate levels of uncoupling. A potential mechanism of arrhythmias depends on temporary electrotonic depression of intrinsically viable tissue by the large bulk of the ischemic zone. This causes conduction slowing and conduction block in the surviving layers, leading to arrhythmias. These arrhythmias then resolve with progression of uncoupling. It is unknown whether either accelerated uncoupling or maintenance of gap junctional communication is antiarrhythmic. Ischemic preconditioning postpones both gap junctional uncoupling and occurrence of VF. Given the burden of sudden death and the large number of casualties in the low-risk population, there is, even in the era of implantable cardiac defibrillators, need for further understanding the mechanism of ischemia-induced VF.

Tracking cardiac electrical instability by computing interlead heterogeneity of T-wave morphology.

Oscillations in T-wave morphology, particularly T-wave alternans (TWA), have been fundamentally linked to increased susceptibility to ventricular fibrillation (VF). We investigated whether the escalation in complexity of T-wave oscillations before VF is attributable to increased spatial heterogeneity of repolarization. Peak interlead T-wave heterogeneity (TWH) was measured by second central moment analysis of T-wave morphology in epicardial electrograms in dogs during left anterior descending coronary artery occlusion. TWH differentiated cases in which myocardial ischemia provoked VF from those without VF (563 +/- 56 vs. 139 +/- 36 microV, P < 0.01). In the former group, progressive, significant increases in TWH above preocclusion baseline (70 +/- 8 microV) began at 2.25 min after the start of occlusion and were associated successively with TWA (at 155 +/- 19 microV), T-wave multupling (at 386 +/- 100 microV), complex oscillatory T-wave forms (at 560 +/- 76 microV), discordant TWA (at 572 +/- 98 microV), and VF at 4.36 +/- 0.14 min. TWH in precordial ECGs in 12 pigs during angioplasty-balloon-induced myocardial ischemia also discriminated animals that experienced VF (from 90 +/- 14 at baseline to 382 +/- 39 microV, P < 0.05) from those without VF (from 96 +/- 17 at baseline to 199 +/- 61 microV, NS). Ischemia-induced changes in ST segment and T-wave amplitude did not predict VF. Heightened spatial heterogeneity of repolarization, as assessed by second central moment analysis of TWH, underlies TWA and increased risk for ischemia-induced VF. Monitoring spatial TWH from precordial leads could prove useful in stratifying risk for life-threatening arrhythmias.

Progressive increases in complexity of T-wave oscillations herald ischemia-induced ventricular fibrillation.

T-wave alternans (TWA), an ABAB oscillation, has been postulated as the initial pattern in a stepwise progression to higher-order oscillations, culminating in sudden arrhythmic death. The present study is the first to provide experimental evidence to support this intriguing concept. Epicardial and endocardial ECGs from 12 dogs were monitored during 8-minute left anterior descending coronary artery occlusion with right atrial pacing at 150 bpm. TWA magnitude was measured by modified moving average beat analysis, and the complexity of T-wave oscillations was assessed by complex demodulation. In 6 animals with subsequent ventricular fibrillation (VF), TWA achieved a threshold of 5.00+/-1.30 mV in epicardial ischemic-zone electrograms, which then exhibited a stepwise increase in T-wave oscillation complexity to quadrupling (ABCDABCD, 3 cases) or tripling (ABCABC, 2 cases) and to more complex forms (5 cases) preceding VF (6 cases). In dogs without VF, peak TWA levels did not increase from baseline, measuring a maximum of 0.35+/-0.10 mV (P=NS), or only 7% the value of those with VF, and T-wave multupling was not observed (0 of 6 versus 5 of 6, P<0.005). Discordant TWA episodes, with T waves alternating out of phase, were associated with increased T-wave complexity and fibrillation in 4 of 6 dogs with VF but in none of the 6 dogs without VF (P<0.025). TWA appears to be the first step in an orderly progression of T-wave complexity, episodes of discordant TWA, and VF. This demonstrated increase in T-wave complexity points to a fundamental mechanistic link underlying the ability of TWA to predict lethal arrhythmias.