Ann Thorac Surg 2002;74:2076-2081
© 2002 The Society of Thoracic Surgeons
Original article: general thoracic
Holter changes resulting from right-sided and bilateral infrastellate upper thoracic sympathectomy
Pierre Abraham, MD, PhDc*,
Jean Berthelot, MDa,
Jacques Victor, MDb,
Jean-Louis Saumet, MD, PhDc,
Jean Picquet, MDc,
Bernard Enon, MDa
a department of Cardiovascular and Thoracic Surgery, University Hospital, Angers, France
b department of Cardiology, University Hospital, Angers, France
c department of Vascular Investigation and Sports Medicine, University Hospital, Angers, France
Accepted for publication July 22, 2002.
* Address reprint requests to Dr Abraham, Laboratory for Vascular Investigation and Sports Medicine, Angers University Hospital, 4 rue Larrey, 49033 Angers Cedex 01, France.
e-mail: piabraham{at}chu-angers.fr
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Abstract
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BACKGROUND: We tested the hypothesis that no right-sided dominance exists after infrastellate surgical upper-thoracic sympathectomy. We aimed to confirm whether a significant bradycardia was constant and only dependent on the right side.
METHODS: We performed 24-hour Holter electrocardiographic recordings in 12 patients referred for bilateral sympathectomy. Surgery was performed at two distinct times allowing for the study of the consequences of unilateral right and bilateral sympathectomy.
RESULTS: Heart rate was 77 ± 8 beats per minute before surgery on the 24-hour recording and significantly decreased after bilateral (67.8 ± 6.5 beats per minute; p < 0.05) but not after unilateral right sympathectomy. Consistently spectral analysis variables significantly changed after bilateral surgery but showed no right-sided dominance. Little effect of sympathectomy was found on the QT interval, which tended to decrease after bilateral sympathectomy.
CONCLUSIONS: Patients should be informed of the bradycardia resulting from sympathectomy. No right-sided dominance can be found consistently with the random distribution of substellate cardiac fibers reported in anatomic studies.
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Introduction
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The main cardiac sympathetic neural control is devoted to the cervical sympathetic fibers but in numerous anatomic studies "accessory" fibers are reported coming from the substellar thoracic chain to the heart [1]. Little is known about the prevalence and distribution of those fibers in the population. Schwartz and colleagues [2–3] have suggested that stellectomy in dogs may have different effects on ventricular arrhythmia and QT duration depending on the operated side. In humans several reports suggest a decreased risk of ventricular arrhythmia after left stellectomy in congenital long QT syndrome [3–5] despite inconstant decrease of the QT value.
Sympathetic control of the microcirculation of the upper limb is issued from the first sympathetic thoracic nerves. Thereby surgical thoracic sympathectomy is widely used as an efficient technique in the surgical treatment of vascular disorders in the upper limb (such as severe Raynaud’s syndromes) or in primary palmar hyperhydrosis. In order to limit the risk of complications [6–9] and specifically that of Horner’s syndrome sympathectomy is usually limited to the substellate thoracic sympathetic chain. Although rarely reported in recent reviews [7] of surgical complications of infrastellate-endoscopic thoracic sympathectomy (IS-ETS) a significant relative bradycardia seems to be frequently observed in the subjects undergoing infrastellate sympathectomy both at rest and during exercise [10, 11]. Previous reports have shown a decrease of heart rate (HR), an increased HR variability after bilateral IS-ETS performed during a single surgical time but the potential effect of unilateral right sympathectomy was not evaluated. As a result little is known about the effect of unilateral and bilateral IS-ETS on ventricular arrhythmia, QT duration, HR, and HR variability in the same subjects.
We performed a prospective analysis of repeated 24-hour electrocardiographic (ECG) Holter recordings in subjects undergoing bilateral IS-ETS at two distinct surgical times, enabling the study of the consequences of unilateral and then bilateral infrastellate sympathectomy in the same subjects. The effect of IS-ETS on sinus node and ventricular repolarization was approached using HR variability and automated QT analysis, respectively.
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Material and methods
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Twelve patients (7 females, 5 males) aged 31 ± 11 years (range: 19 to 48) were included in this study. All patients had the right side operated on first. Mean weight was 61 ± 15 kg and height was 166 ± 6 cm. All patients were referred for bilateral infrastellate thoracic sympathectomy for palmar hyperhydrosis. No patient was taking medication at the time of the study. After complete explanation of the proposed protocol the subjects were asked to give written informed consent to the study that had been approved by the local ethics committee and administration in June 1999.
Bilateral sympathectomy was performed at two distinct operative times, separated by at least 2 weeks (mean 72 days, range 15 to 145). Minimal invasive video-assisted procedures with excluded lung by Carlens tube were performed under general anesthesia. Three incisions performed on the fourth and fifth intercostal spaces permitted the excision of the second to the fourth thoracic sympathetic ganglions using electrocoagulation. The first thoracic sympathetic ganglion is disconnected from the last cervical one forming the stellate ganglia in 80% of cases according to Ellison and colleagues [1]. This first thoracic ganglion was always respected to avoid Horner’s syndrome. One chest drain was routinely left in place for about 48 hours at the end of surgery.
Study protocol
For the study of surgical collateral effects each subject was submitted to three different investigations including interrogation searching for any cardiac complaints and for the importance and localization of hyperhidrosis, clinical examination, and Holter recordings. Recordings were performed preoperatively during the week preceding the first sympathectomy, interoperatively at least 2 days before the second surgical procedure and at least 10 days after the first surgery, and postoperatively 3 months after the second sympathectomy.
Holter recordings
A seven-lead 24-hour-ECG Holter recording was performed with Synesis (ELA Medical, Le Plessis Robinson, France). Recordings started systematically at 1:30 PM after lunch. Subjects were asked not to perform intense exercise and to have routine daily activity during the recording. The recordings were analyzed using the Elatec V3.03 software (ELA Medical, France) which classified all beats as sinusal, ventricular, or artifacts and allowed manual verification of the automatic classification. Variability analysis was performed with HR variability module V2.00 (ELATEC, France). For the QT analysis the digitized two-channel ECG signals were processed by ELATEC QT and morphology analysis module V1 to 11-A (ELA Medical, France). Each variable was analyzed off line for three periods as follows: diurnal values from 9 AM to 9 PM, nocturnal values from 11 PM to 6 AM, and for 24 hours.
Analysis of heart rate variability
Cycles in which beats had normal morphologic characteristics and that were within 25% of the preceding cycle length were automatically selected for calculation of HR variability. The software automatically detects normal (nonventricular premature) beats (N) and calculates the beat to beat intervals (NN). For the variability analysis, recorded variables included the following: (1) in the time domain: mean HR, root mean square of successive interval differences (rMSSD), percentage of successive interval differences exceeding 50 ms (pNN50), average of the standard deviation of normal beat to beat intervals (NN) in all 5-minute periods (ASDNN5), standard deviation (SD) of average NN in all 5-minute periods (SDANN), and SD of all NN intervals (SDNN); and (2) in the frequency domain using fast Fourrier transform on 128 points: total frequency power (Ptot) on the 0.00 to 0.40 Hz interval, low frequency power (LF 0.04 to 0.15 Hz), high frequency power (HF 0.15 to 0.40 Hz), from which we calculated their derived variables LF/HF, and normalized values (LF/Ptot, HF/Ptot).
QT analysis
The QT analysis software converted the 24-hour-recording into 2,880 templates obtained at 30-second intervals. To improve the signal-to-noise ratio, one median complex was computed every 6 seconds from the consecutive sinus beats, then the five median beats within each 30-second template were averaged in order to obtain a single representative PQRST complex for each of the 2,880 templates. For each template the algorithm automatically measured the mean and SD of the QT apex (QTa), the QT end (QTe), and the RR interval (in ms). The T-wave apex was determined by fitting a parabola through the peak of the T wave whereas the T-wave end was determined by the intersection of the tangent to the downslope of the T-wave with the isoelectric baseline. In each template, the QTa measurement was performed only if the amplitude of the T wave was greater than 0.15 mV. For each template the mean QTe and QTa values were then plotted against the mean cycle length of the 30-second interval. The program automatically computed both linear regressions (QTe/RR and QTa/RR) for the entire 24 hours on the diurnal and nocturnal periods and provided the slope, the intersect, and the correlation coefficient of the linear regressions. The program also provided the values of QTe and QTa at fixed cycle lengths (25 ms stepwise) and the 24-hour mean and SD of RR intervals and of QTe corrected for HR according to Bazett’s formula (QTc). The origins and slope of the QT to RR relationship are referred to as oQTa and pQTa for QT apex and oQTe and pQTe for the QTend.
Statistical analysis
Results are presented as mean ± SD in the text and tables and mean ± SEM in the figures. The comparisons between preoperative, interoperative, and postoperative results within each group were determined with paired t tests. For each test a p value less than 0.05 is considered to indicate statistical significance.
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Results
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No apparent complication was noted in the operated patients during and immediately after surgery and specifically no Horner’s syndrome occurred. Symptoms of palmar hyperhidrosis disappeared completely immediately after the operation in all patients on the operated side. A compensatory hyperhidrosis was noted in 3 patients. Before and after surgery, the patients reported no episode of dyspnea and no palpitations, orthostatic intolerance, or syncope.
After bilateral IS-ETS, mean HR and none of the time domain variables significantly changed during the diurnal period in the whole group. A significant decrease of mean HR occurred both on 24-hour analysis from 76.9 ± 8.4 to 67.8 ± 6.5 (p < 0.05) and during the night from 68.1 ± 9.3 to 59.6 ± 11.4 (p < 0.05) as shown in Table 1.
Mean HR decreased in a larger proportion after the second (left) sympathectomy than after the right unilateral sympathectomy as shown in Figure 1.
The other time domain measured indices of cardiac variability and showed few if any changes (Table 1).
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Table 1. Time Domain Analysis of Holter Results Before and After Bilateral Infrastellate Endoscopic Thoracic Sympathectomy (IS-ETS) in 12 Subjects
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Fig 1. Histogram (mean ± SEM) of the heart rate before (T1, solid bars), after right-side (T2, hatched bars), and after bilateral (T3, open bars) infrastellate sympathectomy. For T3 p< 0.05 from T1 and T2 on the 24-hour and night analysis.
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In the frequency domain HF tended to increase whereas LF was unchanged resulting in a significant decrease of the LF/HF ratio on the diurnal, nocturnal, and 24-hour analyses, respectively (Table 2).
As presented in Figure 2,
LF/HF ratios significantly decreased but only after bilateral surgery. The decrease was proportional after each surgery for both variables in the different periods of analysis.
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Table 2. Frequency Domain Analysis of Holter Results Before and After Bilateral Infrastellate Endoscopic Thoracic Sympathectomy (IS-ETS) in 12 Subjects
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Fig 2. Histogram of the frequency domain low frequency to high frequency ratio (LF/HF) before (T1, solid bars), after right-side (T2, hatched bars), and after bilateral (T3, open bars) infrastellate sympathectomy. For T3 p< 0.05 T1 on the 24 hours, day and night analysis and p< 0.05 from T2 for the day analysis only.
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None of the different variables of QT variability studied significantly decreased after surgery for the diurnal period and on 24-hour analysis (Table 3).
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Comment
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Upper thoracic sympathectomy is expected to result in a permanent and powerful vasodilation in the upper limb associated with a significant decrease of sweat production in the area of denervation and has thereby largely been used in the treatment of upper limb hyperhidrosis or ischemic vascular disease. Stellectomy has also been proposed in cardiac diseases such as angina pectoris or in long QT syndrome to reduce the sympathetic influence to the heart [12, 13]. ß-Blockers have dramatically changed the therapeutic approach of cardiac diseases and stellectomy has been progressively abandoned because of the significant morbidity and mortality of this surgery [12, 13], particularly that of Horner’s syndrome. With video-assisted approaches and with surgery limited to the infrastellate fibers the risk of complications has led to a renewed interest and development of surgical sympathectomy in the vascular diseases of the upper limb. Owing to the presence of infrastellate fibers to the heart [1, 14] IS-ETS provides a unique model of partial cardiac denervation in patients free of underlying cardiac anomalies. Although several recent studies have focused on the different complications of infrastellate sympathectomy the effect on HR is rarely reported and when estimated, the effect of unilateral surgery is not studied [11, 12, 15] .
It has been reported for years that bilateral stellectomy in dogs induces a significant HR decrease [16]. Consistently in bilateral surgery of T2-T4 sympathectomy in hyperhidrosis Drott and colleagues [10] showed a significant decrease of HR. The decrease of HR after surgery in hyperhidrosis might be due to an abnormal presurgical increased HR compared with control subjects [17]. Nevertheless a comparable result was found on 24-hour Holter recordings in patients who had severe nonsurgical angina pectoris [18, 19] after bilateral sympathectomy. Although resting HR did not significantly change in the study of Tedoriya and colleagues [15] response to stress test was altered after surgery.
Studies in the 1980s showed no or few effects of left stellectomy on resting HR in dogs [16] as well as in long QT syndrome patients [2, 5]. Consistently chemical unilateral left stellate blockade and contralateral right stellate stimulation induce no change of HR in humans with long QT syndrome [4]. On the other hand, using perioperative recordings of resting HR in patients undergoing bilateral upper thoracic sympathectomy limited to infrastellate fibers, Papa and colleagues [11] advocate for a unilateral right-side effect of sympathectomy on HR. In the present study the decrease in HR does not seem only dependent on the right-sided surgery. Few studies have been performed on time domain analyses but recently Tygesen and colleagues [20] have found a significant prolonged increase of rMSSD and an increase of SDANN but only 2 years after surgery. The absence of changes found in the present experiment is likely a result of the small number of patients studied in comparison with the study of Tygesen and colleagues [20].
As for the studies of HR, frequency domain indices of HR variability are also impaired by sympathectomy both in hyperhidrosis and cardiac disease patients [15, 18–20]. Fujiki and colleagues studying 20 young healthy volunteers found that these changes are influenced by right rather that left sympathectomy [21], also suggesting a right dominant effect of sympathetic influence on HR variability. This difference does not appear in the 12 patients operated on first on the right side in the present study and on average changes in our group seem almost comparable after right and left surgery as presented in Figure 1.
Significance of the various frequency domain variables issued from Holter recording is debated. Vagal afferents are generally assumed to be related to HF power variables through respiratory influences [22–24]. Interpretation of LF value is more controversial [24]. It has been proposed that normalized LF values (LF/Ptot) would be a quantitative marker of sympathetic modulation [23]. Other authors recommend the use of LF/HF, that would reflect sympathovagal balance to the heart [25–28]. LF/HF and LF/Ptot decreased after bilateral IS-ETS in our study but the difference reached significance only after left-side surgery and was not found significant in any of the frequency domain variables after unilateral right-side surgery.
Several publications have shown a rhythmic protective effect of left stellectomy or enlarged left cervicothoracic procedures in long QT syndrome in humans [4, 5, 29] although QT duration is not normalized at rest [4]. Consistently studies during exercise [4, 5, 30, 31] have shown comparable QT decrease without normalization of the QT value. In human studies of long QT syndrome as well as in animal studies left stellate blockade or right stimulation tend to decrease QT and vice versa [2, 4, 32]. In normal subjects or in cases of hyperhidrosis no significant change of QT has been observed [10, 15] after surgery or chemical blockade of infrastellate fibers, although Papa and colleagues [11] showed a decrease of QTc from 399 to 389 ms (p < 0.05) in hyperhidrosis after bilateral T2-T3 sympathectomy. None of the QT variables studied in the present experiments except QTe duration significantly changed either after unilateral or bilateral IS-ETS. Noradrenaline myocardial concentration has been shown to decrease from the apex to the base of the myocardium, suggesting that sympathetic innervation is lower in ventricles than in auricles [33]. In addition to the small number of subjects studied, the absence of significant sympathetic fibers coming from the substellate chain to the ventricle could appear as an explanation of the lack of apparent effect on QT variables compared with sinusal variability in the present study.
Our study will need confirmation in a larger number of subjects but our results suggest, similar to previous reports, that the sympathetic cardiac innervation is not only due to cervical afferences. A decrease of the Holter variables reflecting sympathetic influence to the heart can be observed after IS-ETS in hyperhidrosis. Contrary to previous reports we have found no dominance of right-side infrastellate sympathectomy on HR or HR variability. This observation is consistent with the random distribution of infrastellate sympathetic fibers to the heart described in anatomical studies and with our previous report during exercise [34]. Moreover no significant changes of QT variables after unilateral and bilateral sympathectomy have been observed in our population. Thereby a significant effect on sinusal activity was found whereas no apparent repolarization changes were observed in contrast with what is reported after stellectomy. Patients treated for hyperhidrosis are generally informed of severe but rare complications. They should also be informed of the ß-blocker–like effect resulting from IS-ETS. When IS-ETS is proposed as an alternative or compassionate approach in the treatment of cardiac disorders (eg, angina pectoris, adrenergic supraventricular arrhythmias) it is likely that unilateral right surgery should not be recommended.
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Acknowledgments
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This work was promoted by Center Hospitalier Universitaire d’Angers and supported in part by Projet Hospitalier de Recherche Clinique no.99/001.
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References
|
|---|
- Ellison J., Williams T. Sympathetic nerve pathways to the human heart, and their variations. Am J Anat 1969;124:149-162.[Medline]
- Schwartz P.J., Locati E.H., Moss A.J., Crampton R.S., Trazzi R., Ruberti U. Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome. A worldwide report. Circulation 1991;2:503-511.
- Schwartz P.J., Stone H.L. Left stellectomy in the prevention of ventricular fibrillation caused by acute myocardial ischemia in conscious dogs with anterior myocardial infarction. Circulation 1980;62:1256-1265.[Abstract/Free Full Text]
- Crampton R. Preeminence of the left stellate ganglion in the long QT syndrome. Circulation 1979;59:769-779.[Abstract/Free Full Text]
- Bhandari A.K., Scheinman M.M., Morady F., Svinarich J., Mason J., Winkle R. Efficacy of left cardiac sympathectomy in the treatment of patients with the long QT syndrome. Circulation 1984;70:1018-1023.[Abstract/Free Full Text]
- Gothberg G., Drott C., Claes G. Thoracoscopic sympathicotomy for hyperhidrosis—surgical technique, complications and side effects. Eur J Surg 1994;572:51-53.
- Lee D.Y., Yoon Y.H., Shin H.K., Kim HK Hong Y.J. Needle thoracic sympathectomy for essential hyperhidrosis: intermediate-term follow-up. Ann Thorac Surg 2000;69:251-253.[Abstract/Free Full Text]
- Fox A.D., Hands L., Collin J. The results of thoracoscopic sympathetic trunk transection for palmar hyperhidrosis and sympathetic ganglionectomy for axillary hyperhidrosis. Eur J Vasc Endovasc Surg 1999;17:343-346.[Medline]
- Sung S.W., Kim Y.T., Kim J.H. Ultra-thin needle thoracoscopic surgery for hyperhidrosis with excellent cosmetic effects. Eur J Cardiothorac Surg 2000;17:691-696.[Abstract/Free Full Text]
- Drott C., Claes G., Gothberg G., Paszkowski P. Cardiac effects of endoscopic electrocautery of the upper thoracic sympathetic chain. Eur J Surg 1994;160:65-70.
- Papa M.Z., Schneiderman J., Tucker E., Bass A., Drori Y., Adar R. Cardiovascular changes after bilateral upper dorsal sympathectomy: short and long term effects. Ann Surg 1986;204:715-718.[Medline]
- Drott C. The history of cervicothoracic sympathectomy. Eur J Surg 1994;572:5-8.
- Kadowaki M.H., Levett J.M. Sympathectomy in the treatment of angina and arrhythmias. Ann Thorac Surg 1986;41:572-578.[Abstract/Free Full Text]
- Gray H. The peripheral nervous system. In: Clemente C, ed. Anatomy of the human body. 30th American ed. Philadelphia: Lea & Febiger, 1995:1247–63
- Tedoriya T., Sakagami S., Ueyama T., Thompson L., Hetzer R. Influences of bilateral endoscopic transthoracic sympathicotomy on cardiac autonomic nervous activity. Eur J Cardiothorac Surg 1999;15:194-198.[Abstract/Free Full Text]
- Schwartz P.J., Verrier R.L., Lown B. Effect of stellectomy and vagotomy on ventricular refractoriness in dogs. Circ Res 1977;40:536-540.[Abstract/Free Full Text]
- Noppen M., Dendale P., Hagers Y., Herregodts P., Vincken W., D’Haens J. Changes in cardiocirculatory function after thoracoscopic upper dorsal sympathicolysis for essential hyperhidrosis. J Autonom Nerv Syst 1996;60:115-120.[Medline]
- Tygesen H., Claes G., Drott C., et al. Effect of endoscopic transthoracic sympathicotomy on heart rate variability in severe angina pectoris. Am J Cardiol 1997;79:1447-1452.[Medline]
- Wettervik C., Claes G., Drott C., et al. Endoscopic transthoracic sympathicotomy for severe angina. Lancet 1995;345:97-98.[Medline]
- Tygesen H., Wettervik C., Claes G., et al. Long-term effect of endoscopic transthoracic sympathicotomy on heart rate variability and QT dispersion in severe angina pectoris. Int J Cardiol 1999;31:283-292.
- Fujiki A., Masuda A., Inoue H. Effects of unilateral stellate ganglion block on the spectral characteristics of heart rate variability. Jpn Circ J 1999;63:854-858.[Medline]
- Eckberg D.L. Sympathovagal balance. A critical appraisal. Circulation 1997;96:3224-3232.[Free Full Text]
- Malliani A., Pagani M., Lombardi F., Cerruti S. Cardiovascular neural regulation explored in the frequency domain. Circulation 1991;84:482-492.[Abstract/Free Full Text]
- Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiogy. Heart rate variability. Standard of measurements, physiological interpretation, and clinical use. Circulation 1996;93:1043-1065.[Free Full Text]
- Coumel P., Leenhardt A., Leclercq J.F. Autonomic influences on ventricular arrhythmias in myocardial hypertrophy and heart failure. Circulation 1993;87:VII-84-VII-91.
- Malliani A. Association of heart rate variability components with physiological regulatory mechanisms. In: Malik M., Camm A.J., eds. Heart rate variability. Armonk, NY: Futura, 1995:173-188.
- Montano N., Ruscone T.G., Porta A., Lombardi F., Pagani M., Malliani A. Power spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt. Circulation 1994;90:1826-1831.[Abstract/Free Full Text]
- Pagani M., Lombardi F., Guzzetti S., et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 1986;59:178-193.[Abstract/Free Full Text]
- Moss A.J., McDonald J. Unilateral cervicothoracic sympathetic ganglionectomy for the treatment of long QT interval syndrome. N Eng J Med 1971;16:903-904.
- Austoni P., Rosati R., Gregorini L. Effects of stellectomy on exercise-induced QT changes in man. Circulation 1977;55:710.
- Austoni P., Rosati R., Gregorini L., Bianchi E., Bortolani E., Schwartz P.J. Stellectomy and exercise in man. Am J Cardiol 1979;43:399.
- Yanowitz B.A., Preston J.B., Abildskov J.A. 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;18:416-438.[Abstract/Free Full Text]
- Randall W.C., Kaye M.P., Hageman G.R., Jacobs H.K., Euler D.E., Wehrmacher W. Cardiac dysrythmias in the conscious dog after surgically induced autonomic imbalance. Am J Cardiol 1976;38:178-183.[Medline]
- Abraham P., Picquet J., Bickert S., et al. Infrastellate thoracic sympathectomy results in a relative bradycardia during exercise, irrespective of the operated side. Eur J Cardio-thorac Surg 2001;20:1095-1100.[Abstract/Free Full Text]
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Abstract
Introduction
