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Circulation. 1996;93:1114-1122

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(Circulation. 1996;93:1114-1122.)
© 1996 American Heart Association, Inc.

Articles

Patency of Infarct-Related Artery

Effect of Restoration of Anterograde Flow on Vagal Reflexes

Andrea Mortara, MD; Giuseppe Specchia, MD; Maria Teresa La Rovere, MD; J. Thomas Bigger, Jr, MD; Frank I. Marcus, MD; John A. Camm, MD; Stefan H. Hohnloser, MD; Ryuji Nohara, MD; Peter J. Schwartz, MD; on Behalf of the ATRAMI Investigators

From the Divisione di Cardiologia, Centro Medico di Montescano, Fondazione Clinica del Lavoro, IRCCS (A.M., M.T.L.R.) and the Cattedra di Cardiologia, Dipartimento di Medicina Interna, University of Pavia (Italy), Policlinico S. Matteo, IRCCS (G.S., P.J.S.); the Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY (J.T.B.Jr); the Department of Medicine, University Medical Center, University of Arizona, Tucson (F.I.M.); the Department of Cardiological Sciences, St George Hospital, Medical School, London, UK (J.A.C.); the Department of Cardiology, University Hospital Freiburg (Germany) (S.H.H.); the Third Division of Internal Medicine, Kyoto (Japan) University Hospital, Sakyoku (R.N.); and the Centro di Fisiologia Clinica ed Ipertensione, Istituto di Clinica Medica Generale e Terapia Medica, University of Milan (Italy) (P.J.S.).

Correspondence to Andrea Mortara, MD, Divisione di Cardiologia, Centro Medico di Montescano, 27040 Montescano (Pavia), Italy.


*    Abstract
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 *Abstract
down arrowIntroduction
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down arrowResults
down arrowDiscussion
down arrowAppendix
down arrowReferences
 
Background In post–myocardial infarction (MI) patients, the restoration of anterograde flow in the infarct-related artery (IRA) significantly improves survival. Limitation of infarct size and increased electrical stability of the myocardium are likely operating mechanisms for this beneficial effect. We tested the hypothesis that patency of the IRA may enhance vagal reflexes, a factor known to affect electrical stability of the infarcted myocardium.

Methods and Results Analysis of angiographic data was performed in 359 of 1284 post-MI patients enrolled in a multicenter prospective study within 8 weeks after the index MI. All the patients underwent baroreflex sensitivity (BRS) assessment by the phenylephrine method. The BRS of the entire population averaged 8.2±5.5 ms/mm Hg and was significantly related to age but not to ejection fraction (EF). One-, two-, and three-vessel disease was present in 138, 96, and 99 patients, respectively, while no coronary stenosis was observed in 26. IRA patency was documented in 234 patients (65%), while in the remaining 125 (35%), the artery remained occluded. Patients with occluded IRAs had more extensive coronary disease (2 to 3 vessels, 71% versus 46%, P<.01) and more depressed left ventricular (LV) function (LVEF, 48±13% versus 53±12%, P<.001). Patency of the IRA was associated with higher BRS values (BRS, 8.9±5.8 versus 7.1±4.7 ms/mm Hg, P<.005) and with a lower incidence (9% versus 18%, P<.02) of markedly depressed BRS (<3 ms/mm Hg), a condition suggested by preliminary studies to be associated with an increased risk of post-MI mortality. The association between IRA patency and BRS was more evident in anterior than in inferior MI. Multivariate regression analysis showed that age of the patient and patency of the IRA were the major independent determinants of BRS, while LVEF was weakly related to BRS and only when analyzed as a categorized variable.

Conclusions The presence of an open IRA is associated with a higher baroreflex sensitivity, and this effect is largely independent of limitation of infarct size by IRA patency. These data offer new insights into the mechanisms by which coronary artery patency may affect cardiac electrical stability and survival.


Key Words: myocardial infarction • reperfusion • angiography • nervous system, autonomic


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowAppendix
down arrowReferences
 
Thrombolysis and patency of the IRA may be beneficial in improving survival independently of their effect on preservation of left ventricular function.1 2 3 4 Among the mechanisms involved, it has been proposed that an occluded IRA may increase sudden death by reducing the electrical stability of the myocardium.3 5 6 The favorable effect of patency of the IRA on the electrophysiological substrate for ventricular arrhythmias is manifested by a decreased incidence of late potentials on the signal-averaged ECG7 8 9 and by a reduction in QT-interval dispersion.10 Whether IRA patency also has a clear effect on the autonomic modulators of arrhythmogenesis, such as the sympathovagal balance and particularly vagal tone, is uncertain.

In the postinfarction period, a depressed BRS, a marker of depressed vagal reflexes, is associated with an increased risk of serious ventricular arrhythmias and subsequent sudden death.11 12 13 Thrombolytic therapy seems to affect baroreceptive reflexes.14 15 However, given the early rate of patency after thrombolysis ranging between 50% and 80%16 and the >=10% occurrence of reocclusion in the first month,17 it is unwarranted to draw an inference about the relation between IRA patency and BRS in the absence of angiographic data. At this time, no data are available on the influence of the patency of the IRA on BRS.

In 1991, a prospective multicenter study, ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction), was designed to assess the prognostic implications of heart rate variability and of BRS after a recent MI.18 The trial, conducted in 25 centers in Europe, North America, and Japan (see "Appendix"), enrolled 1284 patients and is near conclusion.

The purpose of the present study was to examine, in a large population of patients who had survived an MI, whether a relation exists between patency of the IRA, left ventricular function, and BRS. The underlying hypothesis was that an open IRA would be associated with improved baroreflex control of heart rate.

Preliminary data have been presented.19


*    Methods
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 up arrowAbstract
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 *Methods
down arrowResults
down arrowDiscussion
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Study Population
Of 1284 patients with a recent MI enrolled into the ATRAMI multicenter trial between May 1991 and February 1994, 574 patients had coronary angiography. The present analysis was performed on the first 413 sets of data received at the coordinating center. The diagnosis of acute MI was confirmed by serial ECGs and serum enzyme changes in all patients. For the present analysis, coronary angiography, measurement of LVEF, and BRS assessment were required.

Patients were excluded from ATRAMI if they were >80 years old and had at least one of the following criteria: coexisting significant valvular disease or cardiomyopathy, arterial blood pressure of >160/90 mm Hg, insulin-dependent diabetes, unstable angina, atrial fibrillation, or abnormal sinus node function.

Among the patients who underwent angiography, 54 were excluded from the analysis either because angiography was performed more than 8 weeks after MI (n=40) or because the IRA was not detectable (n=14). The final study population consisted of 359 patients. They all gave informed consent, and the study was approved by the local ethical committee of each center.

Coronary Angiography
Cardiac catheterization was performed according to the policy and the usual procedure of each center. Clinical data from the patients who did and who did not undergo coronary angiography are reported in Table 1Down. This table shows that no significant difference exists between the patients who did and who did not undergo angiography, with the exception of a slightly lower LVEF (49% versus 51%) among the patients who did not receive angiography. This argues against the possibility of a selection bias in the population examined here, a factor that would have prevented the extrapolation of the results to the general post-MI population. A significant coronary artery stenosis was defined as a >=70% decrease in luminal diameter in one, two, or three of the major coronary branches. A closed IRA was defined as a complete occlusion; a patent IRA was defined as one with stenosis but not complete occlusion. The IRA was identified by assessment of the ECGs, the ventriculographic location of contractile abnormality, and the presence of obstruction in the corresponding artery.16 The status of the infarct-related vessels was determined by two investigators (A.M. and G.S.) without knowledge of the BRS values of the individual patients. LVEF was calculated from the 30° right anterior oblique ventriculogram by a standard area-length method; in the patients without angiography, it was calculated by echocardiography.


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  		Table 1. Clinical Characteristics of ATRAMI Patients Who Did or Did Not Undergo Coronary Angiography

BRS Assessment
Arterial baroreceptor function was evaluated by the administration of a vasoactive drug, phenylephrine, according to the method proposed by Smyth et al.20 BRS studies were performed with the same technique in all ATRAMI centers and were centrally analyzed in Montescano by two independent and experienced observers (M.T.L.R. and A.M.), as previously described.12 Briefly, one ECG lead and systolic arterial pressure obtained either directly from the radial/brachial artery or noninvasively by Finapres (Ohmeda) were continuously recorded and digitally converted in a personal computer system. The invasive and noninvasive methods provide highly correlated (r=.92) BRS values.21 When heart rate and blood pressure were stable, an intravenous bolus of phenylephrine HCl (Neo-Synephrine, Winthrop Laboratories, 2 µg/kg) was given to raise the systolic arterial pressure by 15 to 40 mm Hg. If blood pressure did not increase as desired, additional injections were made, increasing the dosage of phenylephrine by increments of 25 to 50 µg. The bolus injection was repeated at least three times at the dosage found to induce the required blood pressure increase and at not less than 10-minute intervals. The RR intervals were plotted against the preceding arterial pulse, and a linear regression analysis was performed for those points included between the beginning and the end of the first significant increase in systolic arterial pressure. Only regression lines with a statistically significant correlation coefficient (P<.05) were accepted for analysis. A final slope was usually obtained by calculating the mean value of at least three determinations. This value was then considered as representing BRS (ms/mm Hg).

BRS was assessed at a mean of 17±7 days (range, 5 to 35 days) after MI. As previously suggested,12 we considered a BRS value <3.0 ms/mm Hg to be a markedly depressed BRS.

Statistical Analysis
Results are expressed as mean±SD. Statistical significance was defined at a value of P<.05. One-way ANOVA for continuous measures and the {chi}2 test for categorical variables were used to assess the correlation with patent or occluded IRA. Because of the skewed distribution of BRS, Wilcoxon signed-rank test and Kruskal-Wallis ANOVA were used when appropriate, and Spearman's rank correlation procedure was used to determine the correlation of BRS with other clinical variables. Stepwise regression analysis was performed with the natural logarithm of BRS slope as a dependent variable to determine the most important predictors of differences in BRS.


*    Results
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*Results
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down arrowAppendix
down arrowReferences
 
Patient Characteristics
The mean age of the final study group (n=359) was 56±11 years (range, 21 to 79 years); 89% were men. Thrombolytic therapy, either streptokinase or tissue-type plasminogen activator, was administered to 206 patients (57%); of the entire population, 24% were on ß-blockers. The site of infarction was anterior in 191 patients (53%) and inferior in 168 (47%), while 21% had non–Q-wave MI. The mean LVEF was 51±12% (range, 20% to 79%).

Baroreflex Sensitivity
No adverse effects were observed during or after the phenylephrine injections. The BRS of the entire population was 8.2±5.5 ms/mm Hg (range, 0.1 to 37.5 ms/mm Hg; median, 7.3 ms/mm Hg); no relation was found between BRS and the time elapsed between MI and BRS determination (r=-.10) (Fig 1Down). As previously reported,12 22 BRS was significantly related to age (r=-.52, P<.001) (Fig 2Down) but not to ejection fraction (r=.16) (Fig 3ADown) or to left ventricular end-systolic volume (r=.10), even though patients with the lowest ejection fraction (<=30%) had a more depressed BRS (Fig 3BDown). Patients with non–Q-wave MI had a higher BRS than those with Q-wave MI (9.0±5.6 versus 7.9±5.8 ms/mm Hg, P<.05).



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  		Figure 1. Scatterplot showing the relation between BRS slope (ms/mm Hg) and time elapsed between MI and BRS study. There is no difference between BRS determined early vs late after MI.



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  		Figure 2. Scatterplot showing the relation between age and BRS slope (ms/mm Hg). A significant negative relation is present.




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  		Figure 3. BRS slope and LVEF. A, Scatterplot showing a nonsignificant linear relation between the two variables. B, Bar graph illustrating the same relation after categorization of LVEF into four classes. BRS slope is significantly more depressed only in the patients with the lowest LVEF. *P<.03 vs other groups.

Coronary Angiography
Coronary angiography was performed a mean of 26±35 days (range, 0 to 60 days) after MI. Clinical characteristics of patients who had early (0 to 7 days) versus late (8 to 60 days) coronary angiography were not significantly different (Table 2Down).


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  		Table 2. Clinical Characteristics of the Study Population According to Early (0 to 7 Days) or Late (8 to 60 Days) Coronary Angiography

One-vessel disease was present in 138 patients (38%), two-vessel disease in 96 (27%), and three-vessel disease in 99 (28%); no significant coronary stenosis was observed in 26 patients (7%). The extent of coronary disease was not related to age; indeed, when age was divided into four percentiles, the incidence of two- and three-vessel disease was found to be similar in all four groups (<=49 years, 23%; 50 to 57 years, 32%; 58 to 64 years, 25%; and >65 years, 28%). At the time of coronary angiography, 234 patients (65%) had a patent IRA and 125 (35%) a closed IRA. Comparison of clinical and angiographic data between patients with patent and occluded IRAs is reported in Table 3Down. Thrombolysis had been used more frequently in patients with a patent IRA, but despite therapy, 66 (30%) of the patients who received thrombolysis showed an occluded vessel, whereas 65 (47%) who did not receive thrombolysis had an open IRA. As expected, patency of the IRA was associated with less extensive severity of coronary disease (see Table 3Down). These results were not influenced by the sequence or time elapsed between the BRS study and cardiac catheterization (the most common temporal sequence), which was similar in patients with patent and closed IRAs (5.6±24 versus 6.7±27 days, P=.7).


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  		Table 3. Clinical Characteristics of the Study Population According to the Presence of Patent or Occluded IRA

Relation Between BRS, Arterial Patency, and Left Ventricular Function
BRS was not significantly different in patients who had early versus late cardiac catheterization (Table 2Up). There is a trend toward a more depressed BRS in patients with multivessel disease. Patients with occluded IRAs had a more depressed ventricular function (LVEF, 48±13% versus 53±12%, P<.001) and a lower BRS (7.1±4.7 versus 8.9±5.8 ms/mm Hg, P<.005) compared with patients with patent IRAs (Table 3Up). This relation between BRS and patency of the IRA persists also when the number of stenotic vessels (Fig 4Down) and the severity of ventricular dysfunction are considered, with the exception of the group with the most depressed LVEF (Fig 5Down).



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  		Figure 4. Bar graph illustrating relation between patency of IRA and BRS slope (ms/mm Hg) according to number of stenotic coronary vessels. BRS slope is only slightly reduced in patients with multivessel disease, but despite the number of vessels involved, a significant difference in BRS slope is present between patients with patent or occluded IRAs.



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  		Figure 5. Bar graph showing the relation between patency of IRA and BRS slope (ms/mm Hg) according to severity of ventricular dysfunction. Patency of the IRA is associated with higher BRS values in all groups with the exception of patients with the most depressed LVEF.

There was no correlation between BRS and the location of the vessel involved, ie, right or left coronary artery. However, patency of the IRA was associated with a higher BRS in anterior than in inferior MI (anterior MI: open artery, 9.3±5 versus closed artery, 6.2±3 ms/mm Hg, P=.001; inferior MI: open artery, 8.9±6 versus closed artery, 7.9±5 ms/mm Hg, P=.03). This site-dependent differential effect of IRA patency on BRS was not evident on LVEF, which was higher to a similar degree in all patients with patent IRAs independently of the location of MI (Table 4Down).


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  		Table 4. Relationship Among BRS, LVEF, and Site of MI in Patients With Patent or Occluded IRA

The distribution of patients with BRS <3 ms/mm Hg was calculated according to patent or occluded IRA because this cutoff value had previously been found to be associated with higher mortality.12 13 Fig 6Down documents the significantly lower incidence of markedly depressed BRS in patients with patent IRAs (9.4% versus 17.6%, {chi}2=5.3, P<.02).



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  		Figure 6. Bar graph illustrating the significantly lower incidence of markedly depressed BRS slope (<=3 ms/mm Hg) in patients with patent IRA compared with patients with occluded IRA.

Six clinical and angiographic variables, including age, LVEF (analyzed both as a continuous variable and also as categorized into four classes: <=30%, 31% to 40%, 41% to 50%, and >50%), extent of coronary artery disease, site of MI, time between MI and BRS determination, and patency of the IRA, were entered into a stepwise multiple regression analysis with BRS as a dependent variable. Age of the patient and patency of the IRA emerged as significant independent predictors of BRS (Table 5Down). LVEF was significantly associated with BRS only when it was entered into the regression analysis as a categorized variable but not when it was analyzed as a continuous variable (Table 5Down), which indicates a weak association.


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  		Table 5. Results of Multiple Regression Analysis Testing the Major Determinants of BRS Slope


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowAppendix
down arrowReferences
 
The present results indicate that, largely independently of ventricular function, restoration of anterograde flow in the infarct-related vessel is associated with a higher BRS, a marker of vagal activity that appears to have prognostic value for post-MI patients.18 These data also suggest that sustained patency of the IRA is beneficial not only by limiting infarct size but also by improving cardiac electrical stability through a specific autonomic modulation.

BRS and MI
Electrical stability of the myocardium is largely influenced by the balance between the sympathetic and parasympathetic components of the autonomic nervous system.23 24 Vagal activation, largely through the sympathetic-parasympathetic antagonism,25 opposes most of the arrhythmogenic influences mediated by the release of catecholamines.26 Moreover, there is now strong evidence for an antifibrillatory effect of vagal activation produced either by direct electrical stimulation,27 by pharmacological activation of muscarinic receptors,28 or by exercise training.29 30 MI can modify the autonomic balance by decreasing vagal tone and reflexes,11 as shown by the depression in heart rate variability and in BRS so often observed after an MI.31 32 Experimental11 and clinical12 13 studies have shown that a depressed BRS in the post-MI period represents a marker of increased risk for life-threatening arrhythmias and for sudden death.

The mechanism by which BRS is reduced after MI remains speculative. BRS decreases whenever the autonomic balance shifts toward a sympathetic dominance. MI, by impairing myocardial contractility and stroke volume, may produce changes both in arterial pressure and in the rate of ejection, which are sensed by baroreceptors and thus influence autonomic responses.33 Another possible mechanism involves the changes in the geometry of a beating heart secondary to the presence of necrotic and noncontracting segments, which may increase the firing of sympathetic afferent fibers beyond normal by mechanical distortion of their sensory endings.34 This excitation of cardiac sympathetic afferent fibers impairs the baroreceptor reflex and has an inhibitory effect on vagal activity directed to the heart.35 36 37 In addition, experimental and clinical data indicate that an MI alters both afferent and efferent cardiac innervation, thus disrupting or modifying the afferent activity originating from ventricular mechanoreceptors.38

Since the derangement in neural activity of cardiac origin is likely to be a major cause of increased sympathetic activity after MI, it would be logical to assume that the larger the infarct size, the lower the baroreflex function. As a matter of fact, data exist to support this concept. In the animal model for sudden death that demonstrated the relation between depressed BRS and risk of ventricular fibrillation during an ischemic episode,11 an analysis was performed on the relation between infarct size (in percentage of the left ventricle), BRS, and survival. It was found that large infarcts were more frequently associated with very depressed BRS and that only in the presence of this association did the risk of sudden death increase sharply, which suggests that autonomic triggers acquire special relevance in the presence of an arrhythmogenic substrate.39 This is consistent with our present finding of more depressed BRS in patients with more severe ventricular dysfunction. Nevertheless, BRS should not be considered merely an index of the status of ventricular function, as demonstrated by the fact that no linear correlation has been found between LVEF and BRS slope in several studies,12 13 including the present one. Admittedly, LVEF could be an imperfect measure of ventricular performance because it is load-dependent; however, similar results have also been obtained by use of different indexes of ventricular function, such as peak positive dP/dt, dP/dt/P, end-diastolic pressure, and mean systolic ejection rate.40 Finally, no correlation was found in the present study between BRS and left ventricular end-systolic volume.

Coronary Artery Patency, BRS, and Cardiac Electrical Stability
Reperfusion of the IRA significantly and independently increases survival. This effect, documented in small angiographic studies41 42 and in large trials with thrombolytic agents,16 43 44 seems to be independent of the limitation in infarct size.1 2 3 43 It has been suggested that other mechanisms, such as a more favorable left ventricular remodeling,45 a "scaffolding effect" by the blood-filled coronary vascular bed perfusing the necrotic myocardium,3 and/or a reduction in the incidence of malignant arrhythmias,5 6 may be involved.

As to the relation between an open IRA and cardiac electrical stability, there is evidence that thrombolytic therapy reduces the incidence of ventricular fibrillation,46 inducible ventricular tachycardia,47 48 and arrhythmic events.49 Life-threatening arrhythmias in post-MI patients are facilitated by the interaction between an abnormal substrate and an autonomic imbalance characterized by either decreased vagal or increased sympathetic activity.18 Reperfusion has a favorable effect on the incidence of late potentials,7 8 9 49 thus reducing one substrate for ventricular reentry. At variance with the growing knowledge on the relation between a patent IRA and the anatomic substrates for cardiac arrhythmias, very little is known about the potential relation between a patent IRA and the autonomic nervous system, particularly in reference to vagal reflexes. The present data show that IRA patency is closely related to BRS, a marker of the capability of reflexly increasing vagal activity. Of special clinical relevance is the fact that IRA patency seems to significantly increase the mean BRS value and to reduce the incidence of patients with markedly depressed BRS, who are at higher risk of arrhythmic events.

The effect of IRA patency on BRS seems to be largely independent of LVEF. Several arguments militate in favor of this concept. The first is the very weak correlation between BRS and LVEF. The second and major one is that multivariate analysis identified age and patency of the IRA as major independent determinants of BRS but not LVEF, with the exception of when it was analyzed as a categorized variable. Finally, even in the last case, patency of the IRA maintained its high independent value as a determinant of BRS.

The present study contributes to clarification of the question of a presumed relation between BRS and infarct site. In the first clinical study published,12 based on 78 patients, it was reported that BRS was lower in patients with an inferior MI. Not surprisingly, the finding was confirmed in a subset of the same population.50 Subsequently, in a population of 122 patients, no difference was found between anterior and inferior MI.13 The present data, based on 359 patients, indicate no significant difference. Overall, it seems that the initial findings were probably dependent on the small size of the population under study.

When the IRA was patent, the greatest effect on BRS was observed in the patients with an anterior MI. If the hypothesis is correct that a patent-IRA–dependent improvement in BRS may favorably affect cardiac electrical stability, then one would expect improved survival particularly in the group of patients with patent IRA and anterior MI. This seems indeed to be the case, according to a report that IRA patency markedly influences long-term survival, especially in patients with the left anterior descending or the left circumflex coronary artery as culprit vessel.41

Even though the study was not designed to investigate the mechanisms underlying the relation between IRA patency and BRS, a few tenable hypotheses exist. Namely, IRA patency may affect BRS (1) by causing a more favorable remodeling in the ventricular walls3 45 and producing both a "scaffolding" effect, which supports the surrounding necrotic myocardium, and areas of hibernating myocardium, which limit ventricular dilatation and aneurysm formation3 6 51 ; (2) by improving ventricular function, which stimulates baroreceptors via an increased stroke volume; and (3) at neurohormonal levels, by reducing plasma concentration of norepinephrine and especially of angiotensin II,52 which affects BRS directly in the vasomotor and cardiac centers in the brain.53 However, it is likely that more than one of these mechanisms may be operant in the same patient.

As to the relation between successful reperfusion and autonomic activity, the present data are in agreement with previous reports based on the analysis of heart rate variability.54 55 Hermosillo et al54 observed an increase of all components of the heart rate variability power spectrum in patients with patent IRAs, particularly in the high-frequency band, which largely reflects vagal tone. Similarly, Odemuyiwa et al,55 using another index of heart rate variability, found that the status of the IRA favorably influenced the autonomic balance. Our own results provide novel information because BRS and heart rate variability, even if they are probably interrelated,56 are very different measures of vagal activity and are not redundant.50 57

In conclusion, we suggest that sustained anterograde flow in the IRA attenuates the detrimental effect of MI on vagal reflexes, thus probably contributing to increased cardiac electrical stability.


*    Selected Abbreviations and Acronyms
 
BRS = baroreflex sensitivity
IRA = infarct-related artery
LVEF = left ventricular ejection fraction
MI = myocardial infarction


*    Acknowledgments
 
The authors are especially grateful for the technical support, throughout the study, by GianDomenico Pinna, BME, and Giovanni Corsico, BMT, of the Biomedical Engineering Department of the Centro Medico di Montescano.


*    Appendix
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 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*Appendix
down arrowReferences
 
The following centers and investigators participated in the ATRAMI study. The principal investigators are denoted by an asterisk. Numbers in parentheses are the number of enrolled patients for each center.

Italy: Centro Medico di Montescano, Pavia (M.T. La Rovere,* A. Mortara, P. Pantaleo) (101); Università di Milano, Istituto di Clinica Medica II (P.J. Schwartz,* E. Vanoli) and Policlinico di Milano (A. Lotto,* G. De Ferrari) (64); Centro Medico di Tradate, Varese (R. Tramarin,* R. Pedretti, E. Colombo) (86); Ospedale di S. Donato, Milano (L. de Ambroggi,* A. Caporotondi) (54); Ospedale Maggiore di Milano (C. de Vita,* G. Cataldo, M. Tavanelli) (24); Ospedale "V. Cervello," Palermo (E. Geraci,* S. Grasso, A. Canonico) (88); Istituto di Fisiologia Clinica CNR, Pisa (A. L'Abbate,* C. Carpeggiani) (31); Centro Medico di Veruno, Novara (G. Mazzuero,* P. Lanfranchi) (65); Policlinico "S. Matteo," Pavia (G. Specchia,* A. Mussini) (48); Ospedale "Careggi," Firenze (P.F. Fazzini,* G.M. Santoro, P.G. Buonamici) (62); Ospedale Civile "Umberto I," Venezia-Mestre (E. Piccolo,* A. Raviele, L. Corò) (11); Ospedale Consorziale-Policlinico di Bari (P. Rizzon,* A. Bortone, N. Di Venere) and Centro Medico di Cassano Murge, Bari (F. Mastropasqua) (53); Ospedale Maggiore di Lodi (M. Orlandi,* S. Belletti, G.F. Galloni) (28); Ospedale Civile di Alessandria (P.A. Ravazzi,* F. Provera, M.C. Ferrara) (11); Ospedale Maggiore, Varese (G. Binaghi,* F. Forgione, E. Castaldo) (9); Ospedale di Rovereto, Trento (M. Disertori,* M.T. Della Mea, M. DelGreco) (31).

France: Hôpital Central, Nancy (E. Aliot,* N. Sadoul, P. Simon, C. De Chillou) (41).

Germany: Westfälische Wilhelms-Universität Münster (G. Breithardt,* M. Block, T. Fetsch, D. Bocker) (23); Albert Ludwigs University Hospital, Freiburg (S. Hohnloser,* M. Zabel) (150).

United Kingdom: St Georges Hospital, London (J. Camm,* M. Malik, A. Staunton) (150).

United States: College of Physicians and Surgeons, Columbia University, New York, NY (J.T. Bigger, Jr,* D. Bloomfield) (19); Health Sciences Center, University of Arizona, Tucson (F.I. Marcus,* C. Furman, K. Gear) (13); Memorial Hospital, Oklahoma City, Oklahoma (R. Lazzara,* S. Harris, T.L. Deaton) (11); Strong Memorial Hospital, University of Rochester, Rochester, NY (Chang sen Liang,* J. Delehanty) (5).

Japan: Kyoto University Hospital, Sakyoku, Kyoto City (R. Nohara) (106).

Steering Committee: P.J. Schwartz, Pavia, Italy (Chairman); J.T. Bigger, Jr, New York, NY; M.T. La Rovere, Montescano, Pavia, Italy; F.I. Marcus, Tucson, Ariz.

Events Committee: F.I. Marcus, Tucson, Ariz (Chairman); S. Hohnloser, Freiburg, Germany; G. Specchia, Pavia, Italy.

Data Coordinating Center: Centro Medico di Montescano, Pavia, Italy: M.T. La Rovere, A. Mortara.

Technical Support: G.D. Pinna (Coordinator); G. Corsico, Department of Biomedical Engineering, Centro Medico di Montescano, Pavia, Italy.

Administrative Coordination: Fondazione Clinica del Lavoro, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro Medico di Montescano, Pavia, Italy.

Received July 24, 1995; revision received October 16, 1995; accepted October 18, 1995.


*    References
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 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
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*References
 

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