Moon Hyoung Lee

Nerve Sprouting and Sudden Cardiac Death

The factors that contribute to the occurrence of sudden cardiac death (SCD) in patients with chronic myocardial infarction (MI) are not entirely clear. The present study tests the hypothesis that augmented sympathetic nerve regeneration (nerve sprouting) increases the probability of ventricular tachycardia (VT), ventricular fibrillation (VF), and SCD in chronic MI. In dogs with MI and complete atrioventricular (AV) block, we induced cardiac sympathetic nerve sprouting by infusing nerve growth factor (NGF) to the left stellate ganglion (experimental group, n=9). Another 6 dogs with MI and complete AV block but without NGF infusion served as controls (n=6). Immunocytochemical staining revealed a greater magnitude of sympathetic nerve sprouting in the experimental group than in the control group. After MI, all dogs showed spontaneous VT that persisted for 5.8+/-2.0 days (phase 1 VT). Spontaneous VT reappeared 13.1+/-6.0 days after surgery (phase 2 VT). The frequency of phase 2 VT was 10-fold higher in the experimental group (2.0+/-2.0/d) than in the control group (0.2+/-0.2/d, P<0.05). Four dogs in the experimental group but none in the control group died suddenly of spontaneous VF. We conclude that MI results in sympathetic nerve sprouting. NGF infusion to the left stellate ganglion in dogs with chronic MI and AV block augments sympathetic nerve sprouting and creates a high-yield model of spontaneous VT, VF, and SCD. The magnitude of sympathetic nerve sprouting may be an important determinant of SCD in chronic MI.

Nerve Sprouting and Sympathetic Hyperinnervation in a Canine Model of Atrial Fibrillation Produced by Prolonged Right Atrial Pacing

Background—Long-term rapid atrial pacing may result in atrial fibrillation (AF) in dogs. Whether there is histological evidence for neural remodeling is unclear. Method and Results—We performed rapid right atrial pacing in 6 dogs for 111±76 days to induce sustained AF. Tissues from 6 healthy dogs were used as controls. Immunocytochemical staining of cardiac nerves was performed using anti–growth-associated protein 43 (GAP43) and anti–tyrosine hydroxylase (TH) antibodies. In dogs with AF, the density of GAP43-positive and TH-positive nerves in the right atrium was 470±406 and 231±126 per mm2, respectively, which was significantly (P <0.001) higher than the nerve density in control tissues (25±32 and 88±40 per mm2, respectively). The density of GAP43-positive and TH-positive nerves in the atrial septum was 317±36 and 155±85 per mm2, respectively, and was significantly (P <0.001) higher than the nerve density in control tissues (9±13 and 30±7 per mm2, respectively). Similarly, the density of GAP43-positive and TH-positive nerves in the left atrium of dogs with AF was 119±61 and 91±40 per mm2, respectively, which was significantly (P <0.001) higher than the nerve density in control tissues (10±15 and 38±39 per mm2, respectively). Furthermore, in dogs with AF, the right atrium had a significantly higher nerve density than the left atrium. Microscopic examinations revealed an inhomogeneous distribution of cardiac nerves within each sampling site. Conclusions—Significant nerve sprouting and sympathetic hyperinnervation are present in a canine model of sustained AF produced by prolonged right atrial pacing. The magnitude of nerve sprouting and hyperinnervation was higher in the right atrium than in the left atrium.

Role of Papillary Muscle in the Generation and Maintenance of Reentry During Ventricular Tachycardia and Fibrillation in Isolated Swine Right Ventricle

BACKGROUND The role of papillary muscle (PM) in the generation and maintenance of reentry is unclear. METHODS AND RESULTS Computerized mapping (477 bipolar electrodes, 1.6-mm resolution) was performed in fibrillating right ventricles (RVs) of swine in vitro. During ventricular fibrillation (VF), reentrant wave fronts often transiently anchored to the PM. Tissue mass reduction was then performed in 10 RVs until VF converted to ventricular tachycardia (VT). In an additional 6 RVs, procainamide infusion converted VF to VT. Maps showed that 77% (34 of 44) of all VT episodes were associated with a single reentrant wave front anchored to the PM. Purkinje fiber potentials preceded the local myocardial activation, and these potentials were recorded mostly around the PM. When PM was trimmed to the level of endocardium (n = 4), sustained VT was no longer inducible. Transmembrane potential recordings (n = 5) at the PM revealed full action potential during pacing, without evidence of ischemia. Computer simulation studies confirmed the role of PM as a spiral wave anchoring site that stabilized wave conduction. CONCLUSIONS We conclude that PM is important in the generation and maintenance of reentry during VT and VF.

Optical Mapping of Ventricular Defibrillation in Isolated Swine Right Ventricles Demonstration of a Postshock Isoelectric Window After Near-Threshold Defibrillation Shocks

Background—Investigators who studied ventricular defibrillation by use of optical mapping techniques failed to observe an initial defibrillation event (isoelectric window or quiescent period) shown by electrode mapping studies. This discrepancy has important implications for the mechanisms of defibrillation. The purpose of the present study was to demonstrate an optical equivalent of an isoelectric window after a near-threshold defibrillation shock. Methods and Results—We studied 10 isolated, perfused swine right ventricles. Upper limit of vulnerability was determined by shocks on T waves. A 50% probability of successful defibrillation (DFT50) was determined with an up-down algorithm. Immediately after unsuccessful defibrillation shock, new wavefronts were generated. When the shock strength was low, immediate reinitiation of reentry and ventricular fibrillation might occur without a postshock isoelectric window. However, if the shock strength was within 50 V of DFT50 (near-threshold), a synchronized activation occurred, followed by organized repolarization that ended 64±18 ms after shock. After a period of quiescence (18±24 ms), activation recurred 83±33 ms after shock and reinitiated ventricular fibrillation. Similar patterns of activation, including a quiescent period, were observed after shock was applied on the T wave of the paced beat that induced ventricular fibrillation. Upper limit of vulnerability correlated well with DFT50. Conclusions—In isolated swine right ventricles, an optical equivalent of an isoelectric window exists after near-threshold defibrillation shocks. These findings support the idea that a near-threshold defibrillation shock terminates all activation wavefronts but fails to halt ventricular fibrillation because the same shock reinitiates ventricular fibrillation after an isoelectric window.

Increased Wave Break During Ventricular Fibrillation in the Epicardial Border Zone of Hearts With Healed Myocardial Infarction

Background —The action potential duration (APD) restitution hypothesis of wave break during ventricular fibrillation (VF) in the epicardial border zone (EBZ) of hearts with chronic myocardial infarction is unknown. Methods and Results —VF was induced by rapid pacing, and the EBZ with the two adjoining sites (right ventricle and lateral left ventricle) were sequentially mapped in random order in 7 open-chest anes the tized dogs 6 to 8 weeks after left anterior descending artery occlusion and in 4 control dogs. At each site, 3 seconds of VF was mapped with 477 bipolar electrodes 1.6 mm apart. The number of wave fronts and approximate entropy were significantly (P <0.01) higher in the EBZ than all other sites in both groups independent of the rate of invasion of new wave fronts and epicardial breakthroughs. The higher wavelet density in the EBZ was caused by increased (P <0.01) incidence of spontaneous wave breaks. There was no difference between the two groups in either reentry period (80 episodes) or VF cycle length. Reentry in the EBZ had a smaller core perimeter, slower rotational speed, and a small or no excitable gap (P <0.01), often causing termination after one rotation. The dynamic monophasic action potential duration restitution curve in the EBZ had longer (P <0.01) di a stol ic intervals, over which the slope was >1. Connexin43-positive staining was significantly (P <0.01) and selectively reduced in the EBZ. Conclusions —A selective increase in wave break and alteration of reentry occur in the EBZ during VF in hearts with healed myocardial infarction. Increased wave break in the EBZ is compatible with the action potential duration restitution hypothesis.

Mechanisms of Ventricular Fibrillation Induction by 60-Hz Alternating Current in Isolated Swine Right Ventricle

BackgroundThe mechanisms by which 60-Hz alternating current (AC) can induce ventricular fibrillation (VF) are unknown. Methods and ResultsWe studied 7 isolated perfused swine right ventricles in vitro. The action potential duration restitution curve was determined. Optical mapping techniques were used to determine the patterns of activation on the epicardium during 5-second 60-Hz AC stimulation (10 to 999 &mgr;A). AC captured the right ventricles at 100±65 &mgr;A, which is significantly lower than the direct current pacing threshold (0.77±0.45 mA, P <0.05). AC induced ventricular tachycardia or VF at 477±266 &mgr;A, when the stimulated responses to AC had (1) short activation CLs (128±14 ms), (2) short diastolic intervals (16±9 ms), and (3) short diastolic intervals associated with a steep action potential duration restitution curve. Optical mapping studies showed that during rapid ventricular stimulation by AC, a wave front might encounter the refractory tail of an earlier wave front, resulting in the formation of a wave break and VF. Computer simulations reproduced these results. ConclusionsAC at strengths less than the regular pacing threshold can capture the ventricle at fast rates. Accidental AC leak to the ventricles could precipitate VF and sudden death if AC results in a fast ventricular rate coupled with a steep restitution curve and a nonuniform recovery of excitability of the myocardium.

Downregulation of immunodetectable atrial Connexin40 in a canine model of chronic left ventricular myocardial infarction: Implications to atrial fibrillation

Background: The substrate(s) for atrial fibrillation associated with chronic left ventricular myocardial infarction remain poorly defined. Since atrial connexin40 has a rapid turnover rate and may cause atrial fibrillation, we hypothesized that chronic left ventricular myocardial infarction downregulates atrial Connexin40 and increases atrial fibrillation vulnerability. Methods and Results: The left anterior descending coronary artery was occluded distal to the first diagonal branch in five dogs and studied 7 weeks later. Five dogs with no left anterior descending coronary artery occlusion served as control. Vulnerability to atrial fibrillation was tested by burst atrial stimulation (50 milliseconds for 3 seconds). Atrial fibrillation was induced in all myocardial infarction dogs, lasting from 20 seconds to several minutes. In contrast, only rapid repetitive activity and short-lasting atrial fibrillation (< 5 seconds) could be induced in control dogs. The mean refractory periods of epicardial RA and LA appendages were not significantly different in the two groups. Mean left ventricular myocardial infarction size was 17 ± 4% of the left ventricle. Histologic analyses showed no signs of atrial ischemic injury or interstitial fibrosis in either group. Atrial myocyte diameter measured at the level of the nuclei of longitudinally sectioned myocytes was not significantly different in the two groups (10.1 ± 1.2 pm vs. 10.2 ± 1.2 pm; P = 0.3). Atrial Connexin40 (both left and right atria) in the left ventricular myocardial infarction group was highly heterogeneous and had significantly smaller total area stained than in the control (0.48 ± 0.09% vs. 0.82 ± 0.13%; P < 0.01). Conclusions: Chronic left ventricular myocardial infarction downregulates immunodetectable atrial Connexin40, a property that might contribute to the increased atrial fibrillation vulnerability in this model.

The role of approximate entropy in predicting ventricular defibrillation threshold.

Background: The role of myocardial tissue mass on ventricular defibrillation threshold (DFT) is unclear. We hypothesized that changes in tissue mass modulate DFT by changing ventricular fibrillation (VF) wavefront regularity (entropy). Methods and Results: The right ventricles (RV) of seven farm pigs were isolated, superfused and perfused through the right coronary artery with oxygenated Tyrodes solution at 37 The epicardial surface was stained with the voltage sensitive dye, di-4-ANEPPS, and activation wavefront numbers (AWN) during VF were determined from the optical maps using a CCD camera (96 x 96 pixels over a 3.5 x 3.5 cm area). The RV mass was progressively reduced by sequential cutting of 1 to 2 g of tissue (approximately 12 cuts in total) distal to the perfusion site. After each cut, VF was reinduced, optical maps obtained, and the 50% probability of successful DFT50 determined using an up-down algorithm. After each cut, the approximate entropy (ApEn) was also computed using 5 seconds of VF data obtained with a bipolar electrode and a pseudo-electrocardiogram. Tissue mass reduction of up to one third of the RV mass (ie, from 48.4 ± 4.25 g to 34 ± 4.7 g) caused little or no change in the DFT, ApEn or AWN. However, further progressive reduction of the RV mass near the critical mass of VF resulted in a significant (P < 0.05) progressive decrease in all three measured parameters. DFT energy was reduced by 27% (1.47 ± 0.34 J vs. 1.02 ± 0.14 J). There was a significant (P < 0.01) correlation between the DFT and ApEn, which significantly further increased (P < 0.001) near the critical mass. In a separate series of 6 isolated RVs, the ApEn correlated well with the Kolmogorov-Sinai (K-S) entropy, the standard method of calculating entropy. Conclusion: Tissue mass reduction significantly reduces DFT when the mass reduction increases VF wavefront regularity.

Clinical significance of changes in the corrected QT interval in stress-induced cardiomyopathy

Background/Aims: Although transient changes in the electrocardiogram (ECG) of patients with stress-induced cardiomyopathy (SCMP) are common, there are little data about ECG changes in patients with SCMP and the clinical implications of these variations. Methods: We investigated a total of 128 patients (age, 63.2 ± 15.4 years; female, 60.9%) diagnosed with SCMP. We compared the ECGs taken after SCMP diagnosis and during the recovery phase to those taken before SCMP diagnosis under baseline conditions. All patients were divided into two groups according to corrected QT (QTc) interval changes: recovered QTc group (QTc in SCMP > QTc in recovery phase, n = 77) and nonrecovered QTc group (QTc in SCMP ≤ QTc in recovery phase, n = 51). Results: In comparison of baseline, SCMP, and recovery phase, we found the mean heart rate (81.5 ± 18.7, 96.8 ± 25.3, and 83.0 ± 19.4/min, respectively; p < 0.001), frequencies of ST segment elevation (0.0%, 8.6%, and 1.6%, p = 0.004), ST segment depression (0.0%, 6.3%, and 1.6%, p = 0.007), T wave inversion (4.4 %, 43.8%, and 61.7%, p < 0.001), and QTc (447.4 ± 35.3, 488.9 ± 67.1, and 468.0 ± 49.5, p < 0.001) showed significant changes. In-hospital mortality (9.1% vs. 25.5%, p = 0.012) and critical care (54.5% vs. 72.5%, p = 0.040) occurred more frequently in the nonrecovered QTc group than in recovered QTc group. Conclusions: The QTc can be prolonged in patients with SCMP. Short-term mortality was increased in patients where the QTc did not recover.