Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
Circulation Research. 2000;86:816-821

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Methods
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cao, J.-M.
Right arrow Articles by Chen, P.-S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cao, J.-M.
Right arrow Articles by Chen, P.-S.
Right arrowPubmed/NCBI databases
*Substance via MeSH
Medline Plus Health Information
*Cardiac Arrest
*Heart Attack
Related Collections
Right arrow Structure
Right arrow Coronary circulation
Right arrow Animal models of human disease
Right arrow Arrythmias-basic studies
Right arrow Physiological and pathological control of gene expression
(Circulation Research. 2000;86:816.)
© 2000 American Heart Association, Inc.


Integrative Physiology

Nerve Sprouting and Sudden Cardiac Death

Ji-Min Cao, Lan S. Chen, Bruce H. KenKnight, Toshihiko Ohara, Moon-Hyoung Lee, Jerome Tsai, William W. Lai, Hrayr S. Karagueuzian, Paul L. Wolf, Michael C. Fishbein, Peng-Sheng Chen

From the Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center (J.-M.C., T.O., M.-H.L., J. T, W.W.L., H.S.K., P.-S.C.), and the Department of Neurology, Childrens Hospital and University of Southern California (L.S.C.), Los Angeles, Calif; Guidant Corp, St Paul, Minn (B.H.K.); the Department of Pathology, VA Medical Center and UCSD, San Diego, Calif (P.L.W.); and the Department of Pathology and Anatomy, UCLA School of Medicine, Los Angeles, Calif (M.C.F.).

Correspondence to Peng-Sheng Chen, MD, Room 5342, CSMC, 8700 Beverly Blvd, Los Angeles, CA 90048-1865. E-mail chenp{at}csmc.edu


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMaterials and Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Abstract—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.


Key Words: cardiac innervation • myocardial infarction • nerve growth factor • ventricular tachycardia • ventricular fibrillation


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMaterials and Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Sudden cardiac death (SCD) remains a major and unresolved public health problem, claiming 300 000 lives a year in the United States alone. Previous myocardial infarction (MI) can be identified in 75% of SCD victims.1 In most cases, the direct cause of SCD is ventricular fibrillation (VF), which is usually preceded by ventricular tachycardia (VT). The interaction between VT (the "trigger") and the diseased myocardium (the "substrate") results in the transition of VT to VF2 and subsequent SCD. There are a number of experimental models3 4 5 6 7 8 9 in which ventricular tachyarrhythmias have been provoked in the presence or absence of structural alterations imposed on the myocardium. However, the investigators induced ischemia or provided artificial triggers, such as electrical stimulation or drugs, to induce VT or VF. The only SCD model in which VT occurs spontaneously10 was in dogs with inherited ventricular arrhythmia. This latter model may not be applicable to the vast majority of patients whose vulnerability to SCD develops after they have suffered an MI. To date, no high-yield animal model exists in which SCD caused by VF occurs spontaneously in chronic MI. Recently, Vos et al11 reported that complete atrioventricular (AV) block may result in electrical remodeling and enhance the susceptibility to acquired torsade de pointes. It is also known that sympathetic activity is important in the generation of spontaneous ventricular ectopy and SCD after MI12 13 and that stimulating the left stellate ganglion enhances cardiac arrhythmogenesis.4 6 14 15 16 17 On the basis of these findings, we hypothesize that induction of increased sympathetic nerve sprouting by nerve growth factor (NGF) infusion to the left stellate ganglion in dogs with complete AV block11 18 and MI may increase the frequency of ventricular arrhythmia. A combination of this trigger and the diseased myocardium (the substrate) may result in a high-yield animal model of spontaneous SCD. The purpose of the present study was to test these hypotheses.


*    Materials and Methods
up arrowTop
up arrowAbstract
up arrowIntroduction
*Materials and Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Induction of Cardiac Nerve Sprouting by NGF Infusion
We first developed a method to induce cardiac nerve sprouting and hyperinnervation. The method was tested in 3 dogs. NGF 7S was infused into the left stellate ganglion via an osmotic pump. One month later, the hearts were removed for immunocytochemical studies of myocardial innervation.

Animal Model of Spontaneous SCD After MI
The experimental (NGF) group underwent survival surgery in which AV block was created by catheter ablation. An implantable cardioverter-defibrillator (ICD, Guidant model 1762 or 1810) was implanted. The ICD was programmed to the monitor-only mode with a back-up pacing rate of 40 bpm. During follow-up, the ICD declared VT episodes once the ventricular rate exceeded 100 bpm for 8 of 10 beats. An osmotic pump was implanted to infuse NGF to the left stellate ganglion. The left anterior descending coronary artery (LAD) was ligated below the first diagonal branch to create MI. The dog was allowed to recover for up to 3 months. The control group underwent the same procedures to create AV block and MI. However, we did not infuse NGF in the control group.

Immunocytochemical Studies
Left ventricular tissues from the edge of the posterior papillary muscle, the anterior papillary muscle, and the interventricular septum of the middle sections were used for immunocytochemical studies. We also sectioned the tissues in the AV nodal region for immunocytochemical studies. The nerve markers tyrosine hydroxylase (TH), synaptophysin (SYN), and growth-associated protein 43 (GAP43) were stained.

Statistical Analysis
Student’s t tests were used to compare the means between 2 groups. To quantify the periodic structure of the frequency of occurrence of VT, single and double harmonic regression models were fitted to the data.19 The null hypothesis was rejected at a value of P<=0.05.

An expanded Materials and Methods section is available online at http://www.circresaha.org.


*    Results
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMaterials and Methods
*Results
down arrowDiscussion
down arrowReferences
 
NGF-Induced Nerve Sprouting and Hyperinnervation in Normal Dogs
In normal canine hearts without NGF infusion, the numbers of nerves per mm2 that stained positive for TH and SYN were 14.9±2.0 and 22.9±1.7, respectively. The GAP43 stains were negative in these tissues, indicating the absence of nerve sprouting in normal dogs. In comparison, the densities (numbers of nerve fibers/mm2) of nerves that stained positive for TH, SYN, and GAP43 (Figure 1ADown through 1C) were 24.7±1.6, 37.7±2.3, and 18.4±7.3, respectively, in normal dogs that received NGF infusion to the left stellate ganglion (P<0.01 for all comparisons). These results indicate that NGF infusion to the left stellate ganglion induced significant cardiac nerve sprouting in normal dogs.



View larger version (84K):
[in this window]
[in a new window]
 
Figure 1. Examples of immunocytochemical staining of cardiac nerves (arrows). First, second, and third columns show TH, SYN, and GAP43 stains, respectively. A through C, Myocardial hyperinnervation of a normal dog that received NGF infusion to the left stellate ganglion. D through F, Results of the experimental group, which has higher concentration of nerve fibers than the control group (examples in G through I).

NGF-Induced Nerve Sprouting and Hyperinnervation in Dogs With MI and AV Block
There was significantly greater ventricular sympathetic nerve density (TableDown) in the experimental (NGF-treated) group (examples in Figure 1DUp through 1F) than in the control group (examples in Figure 1GUp through 1I). The presence of GAP43-positive nerves in the control group suggests that a certain degree of nerve sprouting occurs after MI even without NGF infusion.


View this table:
[in this window]
[in a new window]
 
Table 1. Nerve Density

In all dogs, abundant sympathetic nerves were observed in the region of the AV node. These nerves stained positive for TH, SYN, and GAP43 (Figure 2Down). These findings indicate that radiofrequency ablation of the AV node did not destroy sympathetic fibers passing through that area.



View larger version (139K):
[in this window]
[in a new window]
 
Figure 2. Immunocytochemical staining of cardiac nerves around AV node. This example was taken from dog 9 in the experimental group. A, Low-power (x12) view of the AV nodal region. Dark purple area shows calcification (Ca) after radiofrequency ablation of AV node. Arrows point to nerves stained positive for TH in the perivascular area. Endocardium (En) is at right upper corner. B through D, High-power (x66) view of the AV nodal artery region (near left arrow in A) with nerves stained positive for TH, SYN, and GAP43, respectively. Arrows point to nerve fibers.

Spontaneous VT, VF, and SCD After MI
A total of 15 dogs (9 in experimental group and 6 in control group) survived the first surgery. The ventricular escape rate after a successful AV junction ablation was between 38 and 65 bpm in all dogs studied. The dogs were followed for 43±25 days (experimental group) and 68±25 days (control group) before SCD or a second surgery for tissue harvesting. Four (44%) of the 9 dogs in the experimental group died suddenly of VF at days 11, 17, 60, and 25 (Figure 3Down). In comparison, none in the control group died during follow-up. All dogs developed spontaneous VT after surgery. These episodes persisted for 5.8±2.0 days (phase 1 VT) before subsiding. Spontaneous VT reappeared 13.1±6.0 days after surgery (phase 2 VT) (Figure 4Down and Figure 1Up online; see http://www.circresaha.org). On average, there was an arrhythmia-free period of 7.3±5.8 days (range, 2 to 20 days) between VT phases 1 and 2. The average number of phase 2 VT episodes within 60 days after first surgery was 10-fold greater in the experimental group (2.0±2.0 per day) than in the control group (0.2±0.2 per day, P<0.05).



View larger version (74K):
[in this window]
[in a new window]
 
Figure 3. Examples of spontaneous VF episodes in experimental group. All VF episodes were initiated by a premature ventricular contraction that occurred before the end of the T wave (R on T). Bottom tracing shows an episode of nonsustained VF or polymorphic VT in dog 6 at 2 days before SCD.



View larger version (46K):
[in this window]
[in a new window]
 
Figure 4. Number of spontaneous VT and VF episodes after surgery. So that the phase 2 VT episodes can be displayed more clearly, the phase 1 VT episodes (open columns) that exceeded 20/d were clipped. The phase 2 VT is shown in solid columns. NGF (+) indicates experimental group; NGF (-) indicates control group.

The average heart and body weights in the experimental group (259±37 g and 25±3 kg) were not significantly different from those in the control group (226±25 g and 23±2 kg, P=0.09 and P=0.14, respectively). Among the dogs in the experimental group, the heart weight of dogs that died of SCD (249±48 g) was not statistically different from that of the dogs that did not die of SCD (269±25 g). There were no significant differences between the infarct size in the experimental group (17±4%) and the control group (14±4%).

Evidence for Increased Sympathetic Activity During the Initiation of VT and SCD
The phase 2 VTs may have been triggered by increased sympathetic activity. When the dogs were at rest, the ventricular rate was 60±10 bpm (61±10 bpm for the experimental group and 59±12 bpm for the control group, P=NS). In comparison, immediately before the onset of VT, the ventricular rate was 75±14 bpm (P<0.01). In 10 animals, atrial activation rate could be determined by visual inspection of the electrogram stored by ICD. The atrial rate immediately before the VT averaged 192±24 bpm. After the VT spontaneously stopped, there was a transient but remarkable reduction of the atrial rate to 132±37 bpm (P<0.01) (Figure 5Down), suggesting vagal activation and/or sympathetic withdrawal before VT termination.



View larger version (59K):
[in this window]
[in a new window]
 
Figure 5. Atrial rates immediately before and after phase 2 VT episodes. A, Summary of 47 episodes of VT. B, Example of actual recordings. P indicates the far-field P wave recorded by an ICD lead. F indicates fusion between the P wave and the QRS complex. The atrial rate was faster before the onset of VT than immediately after the termination of VT.

The phase 2 VT occurred throughout the day (Figure 6Down), with the maximum frequency occurring in the morning. In the experimental group, the single harmonic fit to the data was statistically significant (P<0.05), indicating a periodic nature of VT. For this model, the estimated coefficient for the sine term was significantly different from zero (P=0.0285), whereas the coefficient of the cosine term was statistically indistinguishable from zero. The R2 for this model was 0.30. The single-harmonic equation for the frequency of VT was as follows: VT per hour=11.6-5.1 cos (2{pi}t/24)+6.4 sin (2{pi}t/24), where t is the time of day in hours. The same analyses for the control group showed no statistically significant periodicity in the occurrence of phase 2 VT.



View larger version (20K):
[in this window]
[in a new window]
 
Figure 6. Phase 2 VT episodes within 60 days of the first surgery in the experimental group (A) and the control group (B). These episodes were totaled across days and animals. The data were then plotted according to the time of occurrence throughout the 24-hour period.

SCD in 4 dogs of the experimental group occurred at 10:22 AM, 12:33 PM, 1:42 PM, and 5:30 AM. Two SCD episodes were witnessed by technicians in the room. These 2 dogs were not exercising or feeding at the time of death. The other 2 SCD episodes were not witnessed, and the dog’s activities at the time of death were unknown.

Among 148 episodes of phase 2 VT or VF in which the stored electrograms were available, the patterns of onset were premature ventricular contraction on the T wave with long-short coupling interval (type 1) in 46 (31%), premature ventricular contraction without long-short coupling (type 2) in 51 (34.5%), and acceleration of ventricular escape rhythm into the VT zone (type 3) in 51 (34.5%). The mean rates (bpm) were 217±98, 141±28, and 119±22 for VT types 1, 2, and 3, respectively (P<0.01 for all comparisons). Figure 3Up shows that 3 VF episodes had type I onset (dogs 2, 6, and 9), and 1 was preceded by type 2 onset (dog 4).


*    Discussion
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMaterials and Methods
up arrowResults
*Discussion
down arrowReferences
 
In this study, we have developed a high-yield animal model of spontaneous VT, VF, and SCD after chronic MI. Because the only difference between the experimental group and the control group was the presence of increased nerve sprouting in the former, these results also suggest a direct relationship between sympathetic nerve sprouting and SCD in this model.

Mechanisms of SCD
The initiation of spontaneous VT, VF, and SCD depends on the presence of both substrate(s) and trigger(s). The anatomic and functional20 heterogeneities induced by MI or AV block may serve as the substrates for SCD. However, the presence of MI or AV block alone does not lead to a high incidence of SCD. Hunt and Ross21 reported a 3% incidence of SCD in 97 dogs that were subjected to LAD ligation. Vos et al9 11 reported a low incidence of spontaneous SCD (1 of 7) in dogs with AV block. These findings suggest that MI and AV block created a substrate for SCD. However, because of the absence of the spontaneous triggers, these dogs had a low incidence of SCD.

Functional studies by other investigators showed that increased sympathetic tone may provoke ventricular arrhythmia both in the animal models and in human patients.6 13 14 22 23 In our study, dogs in the experimental group had significantly more frequent VT episodes than dogs in the control group. When VT occurs with either type I or type II onset, the fast rates of these VT episodes may induce spatiotemporal heterogeneity of action potential duration and refractoriness, resulting in VT to VF transition.2 24 We conclude that a combination of the spontaneous ventricular arrhythmia (trigger) and the underlying anatomic and electrophysiological abnormalities (substrate) account for a high incidence of spontaneous VT, VF, and SCD in this animal model.

Nerve Sprouting and SCD Syndrome in Humans
It is known that MI results in cardiac nerve injury.23 25 Because peripheral nerve injury is often followed by nerve sprouting,26 it is possible that nerve sprouting occurs after MI. Compatible with that hypothesis, Nori et al27 demonstrated in a rat model that necrotic myocardial injury resulted in denervation followed by sympathetic regeneration. Also compatible with that hypothesis, abnormal patterns of neurilemma proliferation have been documented in infarcted human hearts28 and that sympathetic scintigraphy demonstrated both denervation and reinnervation after MI.23 Others reported that the nerve fibers in human hearts were usually TH-positive.29

To demonstrate a relationship between ventricular arrhythmia and nerve sprouting in humans, we recently completed a study30 using the pathological specimens collected from 53 native hearts of cardiac transplant recipients. We also reviewed the history to determine whether or not there were ventricular arrhythmias. Results showed that the density of nerve fibers in patients with arrhythmia was significantly higher than that in patients without arrhythmia (19.6±11.2/mm2 versus 13.5±6.1/mm2, P<0.05). The nerve density in patients with arrhythmia overlaps with the nerve density in the experimental group of the present study (TableUp). For example, dogs 1, 2, 7, and 8 in the experimental group have sympathetic nerve densities within 1 SD from the mean nerve density in human patients with ventricular arrhythmia. These results suggest that cardiac nerve sprouting may occur after MI even without exogenous NGF. Infusion of NGF accelerated and intensified the development of nerve sprouting, resulting in a high incidence of SCD. Depending on the quantity and timing of nerve sprouting, ventricular arrhythmia and SCD may occur at different times after the MI. This sequence of events is similar to that observed in injury-related epilepsy, which is associated with abnormal nerve sprouting in the central nervous system after brain injury.31

Clinical Implications
The results of our study may explain the efficacy of ß-blockers in the prevention of SCD.32 33 It may also explain the finding that sotalol, a drug with ß-blocking effects, is an effective antiarrhythmic agent in patients with chronic MI.34 In contrast, d-sotalol, a drug without significant ß-blocking activity, increased mortality in patients with MI.35 One clinical implication of this study is that future development of antiarrhythmic interventions should target not only the electrical remodeling but also the neural remodeling (sympathetic nerve sprouting and hyperinnervation) after MI.

Left stellectomy is effective in the prevention of SCD after MI both in animal models and in humans.36 37 38 The present study provides mechanistic insights into the efficacy of left stellectomy in the prevention of SCD.

Summary
The present study reports a high-yield model of spontaneous VT, VF, and SCD in dogs with AV block and chronic MI. The physiological and pathological evidence supports a causal relationship between enhanced sympathetic nerve sprouting and occurrence of SCD. This model may also be useful in future investigations of the mechanisms of SCD and in testing novel methods for prediction and prevention of SCD syndrome.


*    Acknowledgments
 
This study was supported by fellowship grants from the American Heart Association (AHA) (J.-M.C.) and Yonsei University, Seoul, Korea (M.-H.L.); a Cedars-Sinai ECHO Foundation Award (H.S.K.); a Piansky endowment (M.C.F.); and a Pauline and Harold Price Endowment (P.-S.C.) and was supported in part by Guidant Corp; an NIH SCOR Grant in Sudden Death (P50-HL-52319); AHA National Center Grants-in-Aid (9750623N, 9950464N); UC-TRDRP 6RT-0020; and the Ralph M. Parsons Foundation, Los Angeles, Calif. We thank Pei-Li Yan, Jen Rollins, Angela C. Lai, Masaaki Yashima, Tsu-Juey Wu, Young-Hoon Kim, Ali Hamzei, Douglas J. Lang, Babak Armin, Avile McCullen, Meiling Yuan, Nina Wang, Shengmei Zhou, and Elaine Lebowitz for assistance.

Received December 15, 1999; accepted December 20, 1999.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMaterials and Methods
up arrowResults
up arrowDiscussion
*References
 

  1. Myerburg RJ, Castellanos A. Cardiac arrest and sudden cardiac death. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Philadelphia, Pa: WB Saunders; 1992:756–789.
  2. Garfinkel A, Chen P-S, Walter DO, Karagueuzian HS, Kogan B, Evans SJ, Karpoukhin M, Hwang C, Uchida T, Gotoh M, Nwasokwa O, Sager P, Weiss JN. Quasiperiodicity and chaos in cardiac fibrillation. J Clin Invest. 1997;99:305–314.[Medline] [Order article via Infotrieve]
  3. Schwartz PJ. Do animal models have clinical value? Am J Cardiol. 1998;81:14D–20D.[Medline] [Order article via Infotrieve]
  4. Schwartz PJ, Vanoli E, Zaza A, Zuanetti G. The effect of antiarrhythmic drugs on life-threatening arrhythmias induced by the interaction between acute myocardial ischemia and sympathetic hyperactivity. Am Heart J. 1985;109:937–948.[Medline] [Order article via Infotrieve]
  5. Karagueuzian HS, Fenoglio JJ, Weiss MB Jr, Wit AL. Protracted ventricular tachycardia induced by premature stimulation of the canine heart after coronary artery occlusion and reperfusion. Circ Res. 1979;44:833–846.[Abstract/Free Full Text]
  6. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death: new insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation. 1998;78:969–979.[Abstract/Free Full Text]
  7. Echt DS, Griffin JC, Ford AJ, Knutti JW, Feldman RC, Mason JW. Nature of inducible ventricular tachyarrhythmias in a canine chronic myocardial infarction model. Am J Cardiol. 1983;52:1127–1132.[Medline] [Order article via Infotrieve]
  8. Pak PH, Nuss HB, Tunin RS, Kaab S, Tomaselli GF, Marban E, Kass DA. Repolarization abnormalities, arrhythmia and sudden death in canine tachycardia-induced cardiomyopathy. J Am Coll Cardiol. 1997;30:576–584.[Abstract]
  9. Vos MA, Verduyn SC, Gorgels AP, Lipcsei GC, Wellens HJ. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation. 1995;91:864–872.[Abstract/Free Full Text]
  10. Moise NS, Meyers-Wallen V, Flahive WJ, Valentine BA, Scarlett JM, Brown CA, Chavkin MJ, Dugger DA, Renaud-Farrell S, Kornreich B, Schoenborn WC, Sparks JR, Gilmour RF Jr. Inherited ventricular arrhythmias and sudden death in German shepherd dogs. J Am Coll Cardiol. 1994;24:233–243.[Abstract]
  11. Vos MA, de Groot SH, Verduyn SC, van der Zande J, Leunissen HD, Cleutjens JP, van Bilsen M, Daemen MJ, Schreuder JJ, Allessie MA, Wellens HJ. Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation. 1998;98:1125–1135.[Abstract/Free Full Text]
  12. Lown B, Tykocinski M, Garfein A, Brooks P. Sleep and ventricular premature beats. Circulation. 1973;48:691–701.[Abstract/Free Full Text]
  13. Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death: experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation. 1992;85(suppl I):I-77–I-91.
  14. Schwartz PJ, Priori SG. Sympathetic nervous system and cardiac arrhythmias. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia, Pa: WB Saunders Co; 1990:330–343.
  15. Yanowitz F, Preston JB, Abildskov JA. Functional distribution of right and left stellate innervation to the ventricles: production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone. Circ Res. 1966;18:416–428.[Abstract/Free Full Text]
  16. Janse MJ, Schwartz PJ, Wilms-Schopman F, Peters RJ, Durrer D. Effects of unilateral stellate ganglion stimulation and ablation on electrophysiologic changes induced by acute myocardial ischemia in dogs. Circulation. 1985;72:585–595.[Abstract/Free Full Text]
  17. Verrier RL, Thompson PL, Lown B. Ventricular vulnerability during sympathetic stimulation: role of heart rate and blood pressure. Cardiovasc Res. 1974;8:602–610.[Medline] [Order article via Infotrieve]
  18. Volders PG, Sipido KR, Vos MA, Kulcsar A, Verduyn SC, Wellens HJ. Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation. 1998;98:1136–1147.[Abstract/Free Full Text]
  19. Muller JE, Ludmer PL, Willich SN, Tofler GH, Aylmer G, Klangos I, Stone PH. Circadian variation in the frequency of sudden cardiac death. Circulation. 1987;75:131–138.[Abstract/Free Full Text]
  20. Wit AL, Janse MJ. Experimental models of ventricular tachycardia and fibrillation caused by ischemia and infarction. Circulation. 1992;85(suppl I):I-32–I-42.
  21. Hunt GB, Ross DL. Influence of infarct age on reproducibility of ventricular tachycardia induction in a canine model. J Am Coll Cardiol. 1989;14:765–773.[Abstract]
  22. Lown B, Verrier R, Corbalan R. Psychologic stress and threshold for repetitive ventricular response. Science. 1973;182:834–836.[Abstract/Free Full Text]
  23. Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of heart. Circulation. 1990;82:1095–1104.[Free Full Text]
  24. Cao J-M, Qu Z, Kim YH, Wu TJ, Garfinkel A, Weiss JN, Karagueuzian HS, Chen PS. Spatiotemporal heterogeneity in the induction of ventricular fibrillation by rapid pacing: importance of cardiac restitution properties. Circ Res. 1999;84:1318–1331.[Abstract/Free Full Text]
  25. Barber MJ, Mueller TM, Henry D, Felten SY, Zipes DP. Transmural myocardial infarction in the dog produces sympathectomy in non-infarcted myocardium. Circulation. 1983;67:787–796.[Free Full Text]
  26. Guth L. Regeneration in the mammalian peripheral nervous system. Physiol Rev. 1956;36:441–478.[Free Full Text]
  27. Nori SL, Gaudino M, Alessandrini F, Bronzetti E, Santarelli P. Immunohistochemical evidence for sympathetic denervation and reinnervation after necrotic injury in rat myocardium. Cell Mol Biol. 1995;41:799–807.[Medline] [Order article via Infotrieve]
  28. Vracko R, Thorning D, Frederickson RG. Nerve fibers in human myocardial scars. Hum Pathol. 1991;22:138–146.[Medline] [Order article via Infotrieve]
  29. Marron K, Wharton J, Sheppard MN, Fagan D, Royston D, Kuhn DM, de Leval MR, Whitehead BF, Anderson RH, Polak JM. Distribution, morphology, and neurochemistry of endocardial and epicardial nerve terminal arborizations in the human heart. Circulation. 1995;92:2343–2351.[Abstract/Free Full Text]
  30. Cao J-M, Fishbein MC, Han JB, Lai WW, Wu T-J, Czer L, Wolf PL, Denton TA, Shintaku IP, Chen P-S, Chen LS. Relationship between regional ventricular hyperinnervation and ventricular arrhythmia. Circulation In press.
  31. Sutula T, He X-X, Cavazos J, Grayson S. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science. 1988;239:1147–1150.[Abstract/Free Full Text]
  32. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304:801–807.[Abstract]
  33. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318:1730–1737.[Abstract/Free Full Text]
  34. Mason JW, Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias. N Engl J Med. 1993;329:445–451.[Abstract/Free Full Text]
  35. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP, The SWORD Investigators (Survival With Oral d-Sotalol). Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet. 1996;348:7–12.[Medline] [Order article via Infotrieve]
  36. Schwartz PJ, Motolese M, Pollavini G, Lotto A, Ruberti U, Trazzi R, Bartorelli C, Zanchetti A, Italian Sudden Death Prevention Group. Prevention of sudden cardiac death after a first myocardial infarction by pharmacologic or surgical antiadrenergic interventions. J Cardiovasc Electrophysiol. 1992;3:2–16.
  37. Schwartz PJ. The rationale and the role of left stellectomy for the prevention of malignant arrhythmias. Ann N Y Acad Sci. 1984;427:199–221.[Medline] [Order article via Infotrieve]
  38. Nelson SD, Lynch JJ, Sanders D, Montgomery DG, Lucchesi BR. Electrophysiologic actions and antifibrillatory efficacy of subacute left stellectomy in a conscious, post-infarction canine model of ischemic ventricular fibrillation. Int J Cardiol. 1989;22:365–376.[Medline] [Order article via Infotrieve]



This article has been cited by other articles:


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
A. Y. Tan, S. Zhou, B. C. Jung, M. Ogawa, L. S. Chen, M. C. Fishbein, and P.-S. Chen
Ectopic atrial arrhythmias arising from canine thoracic veins during in vivo stellate ganglia stimulation
Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H691 - H698.
[Abstract] [Full Text] [PDF]


Home page
RadiologyHome page
V. R. S. Fernandes, K. C. Wu, B. D. Rosen, A. Schmidt, A. C. Lardo, N. Osman, H. R. Halperin, G. Tomaselli, R. Berger, D. A. Bluemke, et al.
Enhanced Infarct Border Zone Function and Altered Mechanical Activation Predict Inducibility of Monomorphic Ventricular Tachycardia in Patients with Ischemic Cardiomyopathy
Radiology, December 1, 2007; 245(3): 712 - 719.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart J SupplHome page
E. Vanoli and P. B. Adamson
What does the future hold for the management of chronic heart failure?
Eur. Heart J. Suppl., June 1, 2006; 8(suppl_C): C51 - C57.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
M. M. Kreusser, M. Haass, S. J. Buss, S. E. Hardt, S. H. Gerber, R. Kinscherf, H. A. Katus, and J. Backs
Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts
Hypertension, February 1, 2006; 47(2): 209 - 215.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
M. Esler and D. Kaye
Sympathetic Nervous System Neuroplasticity
Hypertension, February 1, 2006; 47(2): 143 - 144.
[Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. A. Fallavollita, B. J. Riegel, G. Suzuki, U. Valeti, and J. M. Canty Jr.
Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy
Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2688 - H2696.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
M. Swissa, S. Zhou, O. Paz, M. C. Fishbein, L. S. Chen, and P.-S. Chen
Canine model of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia
Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1851 - H1857.
[Abstract] [Full Text] [PDF]


Home page
J CARDIOVASC PHARMACOL THERHome page
S. H. Hohnloser
Ventricular Arrhythmias: Antiadrenergic Therapy for the Patient with Coronary Artery Disease
Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4_suppl): S23 - S31.
[Abstract] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
V. Ovchinnikov, G. Suzuki, J. M. Canty Jr., and J. A. Fallavollita
Blunted functional responses to pre- and postjunctional sympathetic stimulation in hibernating myocardium
Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1719 - H1728.
[Abstract] [Full Text] [PDF]


Home page
JNMHome page
A. J. Luisi Jr., G. Suzuki, R. deKemp, M. S. Haka, S. A. Toorongian, J. M. Canty Jr., and J. A. Fallavollita
Regional 11C-Hydroxyephedrine Retention in Hibernating Myocardium: Chronic Inhomogeneity of Sympathetic Innervation in the Absence of Infarction
J. Nucl. Med., August 1, 2005; 46(8): 1368 - 1374.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
G. F. Tomaselli and D. P. Zipes
What Causes Sudden Death in Heart Failure?
Circ. Res., October 15, 2004; 95(8): 754 - 763.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
R. L. Verrier and K. F. Kwaku
Frayed Nerves in Myocardial Infarction: The Importance of Rewiring
Circ. Res., July 9, 2004; 95(1): 5 - 6.
[Full Text] [PDF]


Home page
Circ. Res.Home page
S. Zhou, L. S. Chen, Y. Miyauchi, M. Miyauchi, S. Kar, S. Kangavari, M. C. Fishbein, B. Sharifi, and P.-S. Chen
Mechanisms of Cardiac Nerve Sprouting After Myocardial Infarction in Dogs
Circ. Res., July 9, 2004; 95(1): 76 - 83.
[Abstract] [Full Text] [PDF]


Home page
ANN INTERN MEDHome page
M. S. Lee and R. R. Makkar
Stem-Cell Transplantation in Myocardial Infarction: A Status Report
Ann Intern Med, May 4, 2004; 140(9): 729 - 737.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
J. M. Canty Jr, G. Suzuki, M. D. Banas, F. Verheyen, M. Borgers, and J. A. Fallavollita
Hibernating Myocardium: Chronically Adapted to Ischemia but Vulnerable to Sudden Death
Circ. Res., April 30, 2004; 94(8): 1142 - 1149.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
P. J. Schwartz, S. G. Priori, M. Cerrone, C. Spazzolini, A. Odero, C. Napolitano, R. Bloise, G. M. De Ferrari, C. Klersy, A. J. Moss, et al.
Left Cardiac Sympathetic Denervation in the Management of High-Risk Patients Affected by the Long-QT Syndrome
Circulation, April 20, 2004; 109(15): 1826 - 1833.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
M. Swissa, S. Zhou, I. Gonzalez-Gomez, C.-M. Chang, A. C. Lai, A. W. Cates, M. C. Fishbein, H. S. Karagueuzian, P.-S. Chen, and L. S. Chen
Long-term subthreshold electrical stimulation of the left stellate ganglion and a canine model of sudden cardiac death
J. Am. Coll. Cardiol., March 3, 2004; 43(5): 858 - 864.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
R. R. Makkar, M. Lill, and P.-S. Chen
Stem cell therapy for myocardial repair: Is it arrhythmogenic?
J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2070 - 2072.
[Full Text] [PDF]


Home page
CirculationHome page
Y. Miyauchi, S. Zhou, Y. Okuyama, M. Miyauchi, H. Hayashi, A. Hamabe, M. C. Fishbein, W. J. Mandel, L. S. Chen, P.-S. Chen, et al.
Altered Atrial Electrical Restitution and Heterogeneous Sympathetic Hyperinnervation in Hearts With Chronic Left Ventricular Myocardial Infarction: Implications for Atrial Fibrillation
Circulation, July 22, 2003; 108(3): 360 - 366.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
I. R. Efimov
Fibrillation or Neurillation: Back to the Future in Our Concepts of Sudden Cardiac Death?
Circ. Res., May 30, 2003; 92(10): 1062 - 1064.
[Full Text] [PDF]


Home page
Circ. Res.Home page
Y.-B. Liu, C.-C. Wu, L.-S. Lu, M.-J. Su, C.-W. Lin, S.-F. Lin, L. S. Chen, M. C. Fishbein, P.-S. Chen, and Y.-T. Lee
Sympathetic Nerve Sprouting, Electrical Remodeling, and Increased Vulnerability to Ventricular Fibrillation in Hypercholesterolemic Rabbits
Circ. Res., May 30, 2003; 92(10): 1145 - 1152.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
A. Hamabe, Y. Okuyama, Y. Miyauchi, S. Zhou, H.-N. Pak, H. S. Karagueuzian, M. C. Fishbein, and P.-S. Chen
Correlation Between Anatomy and Electrical Activation in Canine Pulmonary Veins
Circulation, March 25, 2003; 107(11): 1550 - 1555.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. Zhou, C.-M. Chang, T.-J. Wu, Y. Miyauchi, Y. Okuyama, A. M. Park, A. Hamabe, C. Omichi, H. Hayashi, L. A. Brodsky, et al.
Nonreentrant focal activations in pulmonary veins in canine model of sustained atrial fibrillation
Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1244 - H1252.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
A. J. Luisi Jr, J. A. Fallavollita, G. Suzuki, and J. M. Canty Jr
Spatial Inhomogeneity of Sympathetic Nerve Function in Hibernating Myocardium
Circulation, August 13, 2002; 106(7): 779 - 781.
[Abstract] [Full Text] [PDF]