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Am J Physiol Heart Circ Physiol 287: H2899-H2905, 2004. First published July 29, 2004; doi:10.1152/ajpheart.00455.2004
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Exercise hyperventilation, dyspnea sensation, and ergoreflex activation in lone atrial fibrillation

Marco Guazzi,1 Sebastiano Belletti,1 Gabriele Tumminello,1 Cesare Fiorentini,1 and Maurizio D. Guazzi2

1Cardiopulmonary Laboratory, Cardiology Division, University of Milano, San Paolo Hospital, and 2Institute of Cardiology, University of Milan, 20144 Milan, Italy

Submitted 14 May 2004 ; accepted in final form 21 July 2004


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Lone atrial fibrillation may be associated with daily life disability and exercise limitation. The extracardiac pathophysiology of these effects is poorly explored. In 35 subjects with lone atrial fibrillation (mean age 67 ± 7 yr), we investigated pulmonary function, symptom-limited cardiopulmonary exercise performance, muscle ergoreflex (handgrip exercise) contribution to ventilation, and brachial artery flow-mediated dilation (as a measure of endothelial function) before and after (average interval 20 ± 5 days) restoring sinus rhythm with external cardioversion. Respiratory volumes and lung diffusing capacity at rest were within normal limits during both atrial fibrillation and after restoring sinus rhythm. Cardioversion was associated with the following changes: a decrease of the slope of exercise ventilation vs. CO2 production (from 35 ± 5 to 29 ± 3; P < 0.01) and of dyspnea sensation (Borg score from 4 to 2) and an increase of peak oxygen uptake (O2; from 16 ± 4 to 20 ± 5 ml·min–1·kg–1; P < 0.01), O2 at anaerobic threshold (from 11 ± 2 to 13 ± 2 ml·min–1·kg–1; P < 0.05), and O2 pulse (from 8 ± 3 to 11 ± 3 ml/beat; P < 0.01). After cardioversion, the observed improvement in ventilatory efficiency was accompanied by a significant peak end-tidal CO2 increase (from 33 ± 2 to 37 ± 2 mmHg; P < 0.01) and no changes in dead space-to-tidal volume ratio (from 0.23 ± 0.03 to 0.23 ± 0.02; P = not significant). In addition, the ergoreflex contribution to ventilation was remarkably attenuated, and the brachial artery flow-mediated dilatation was significantly augmented (from 0.32 ± 0.07 to 0.42 ± 0.08 mm; P < 0.01). Ten patients had atrial fibrillation relapse and, compared with values after restoration of regular sinus rhythm, invariably showed worsening of endothelial function, exercise ventilatory efficiency, and muscle ergoreflex contribution to ventilation. In subjects with lone atrial fibrillation, an impairment in ventilatory efficiency appears to be involved in the pathophysiology of exercise limitation, and to be primarily related with a demodulated peripheral control of ventilation.

lone atrial fibrillation; exercise; ventilation; dyspnea

LONE ATRIAL FIBRILLATION is the most common sustained arrhythmia encountered in clinical practice (11, 39). A reduced maximal exercise oxygen uptake (O2; see Refs. 12, 21, and 23) is a frequent finding, and exercise intolerance is not an uncommon daily life disability factor (19, 22). As to the pathophysiological bases of physical limitation, previous studies have extensively investigated the putative role of hemodynamic abnormalities associated with atrial fibrillation (3, 8, 10, 36). Exercise performance, however, not only depends on the cardiovascular system function but on any organ system involved in O2 transport, including the respiratory system, skeletal muscles, hormonal and neural feedback control system for breathing, cardiac output, blood pressure, and blood volume. A contribution of peripheral changes resulting from this arrhythmia to the pathogenesis of exercise intolerance is undefined, although there are good reasons to believe that this is a possibility. In fact, the intermittent peripheral blood flow dynamics might affect the shear stress flow-mediated vascular control, impair the blood flow redestribution to exercising muscles (13, 35), and sustain changes in muscle myofibrillar energetics (25). An irregular ventricular activity as induced by atrial fibrillation leads to a significant increase of the sympathetic outflow, which is responsible for an abnormal reflexogenic cardiovascular control and neural imbalance (37). Both an inadequate muscle perfusion (stimulation of group IV afferents sensitive to metabolic by-products) and an increased sympathetic activity (hyperkinetic cardiovascular response to exercise that limits tolerance to physical activity) may affect the ventilatory response to exercise. In addition, the lack of the atrial contribution to ventricular filling may in cases of diastolic dysfunction facilitate subclinical interstitial lung edema.

Cardiopulmonary exercise testing (CPET) has the potential of grading the severity of exercise limitation and detecting the organ system involved in the reduced exercise performance (2, 14). An analysis of the effects that an irregular ventricular activity produces on the cardiorespiratory performance may expand our knowledge concerning the etiology of exercise intolerance in atrial fibrillation.

We hypothesized that peripheral extracardiac factors may be relevant to the overall exercise performance. To this end, resting pulmonary function, CPET, brachial artery flow-mediated dilation (as an index of the conduit arteries endothelial function) tests, and the ergoreflex test (for exploring the influence of reflexes of muscular origin on the ventilatory control) were performed before and after conversion to sinus rhythm in patients with lone atrial fibrillation. Those who had arrhythmia relapse after cardioversion served as controls.


   METHODS
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 METHODS
RESULTS
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Study population. Thirty-five patients (30 men and 5 women) with known lone atrial fibrillation for 10 to 12 mo were prospectively investigated. Lone atrial fibrillation was defined as electrocardiographic (ECG) evidence of atrial fibrillation in the least two consecutive follow-up visits separated by an interval of 3 mo. Exclusion criteria were the following: 1) history of high blood pressure; 2) significant valvular heart diseases; 3) previous myocardial infarction; 4) New York Heart Association class III to IV heart failure; 5) angina, chronic obstructive lung disease, claudication, or any other abnormality potentially interfering with maximal exercise testing performance; 6) thyroid dysfunction; and 7) abnormal lung function. In all patients, anticoagulant therapy was such as to maintain prothrombin time within a target range of 1.5–2.0 x control for at least 4 wk before external cardioversion. Fifty percent of patients were taking digoxin, and 34% was taking verapamil. None was receiving {beta}-blockers. Treatment with cardioactive agents was withheld for at least five half-lives before CPET. Before entering the study, all subjects gave informed written consent. The study was approved by the local Ethical Committee.

Study design. From 8 to 10 days before cardioversion, patients underwent pulmonary function tests and a maximal CPET for familiarization with the procedure. CPET was then repeated 5 days before cardioversion and was taken as representative of patients' maximal exercise capacity. Before restoration of sinus rhythm (3 days), patients were subjected to vascular assessments and a handgrip exercise test for evaluating ergoreflex. After an interval of 18 ± 5 days after external cardioversion, patients repeated CPET and, in the next 48 h, an ergoreflex test and vascular studies. Investigators who read the exercise results were blind to the study design and purpose.

Echocardiography. Two-dimensional and Doppler cardiac ultrasounds were performed by current methods. Pulmonary artery systolic pressure, left atrial dimensions, left ventricular end-systolic and end-diastolic chamber dimensions, and left ventricular volumes, by the area-length method (to measure ejection fraction), were quantitated by standard techniques.

Pulmonary function tests. Spirometry was performed with equipment that met the American Thoracic Society performance criteria (1). To adjust for height, age, and sex, we used published prediction equations for forced expiratory volume in 1 s and forced vital capacity (FVC; see Ref. 17). Diffusing lung capacity for carbon monoxide (DLco) was determined two times with washout intervals of at least 4 min (the average was taken as the final result) with a standard single-breath technique. DLco subcomponents, i.e., the alveolar-capillary membrane diffusion capacity (DM) and the capillary pulmonary blood volume available for gas exchange (VC), were determined according to the method of Roughton and Forster (30). This method partitions diffusing capacity into its component resistances: the diffusive resistance of the alveolar-capillary membrane (1/DM) and the reactive resistance resulting from capillary blood (1/{theta}Vc, where {theta} = the rate of reaction of CO with Hb) according to the following equation, which assumes that the red blood cell membrane has a negligible resistance to gas exchange:

where Hb is the subject's Hb concentration (g/dl) and PaO2 is the alveolar O2 partial pressure. Measuring DLco at different fraction of inspired O2 (20, 40, and 60%), a plot of 1/DLco against 1/{theta} will yield a straight line with a y-intercept of 1/DM and a gradient of 1/Vc.

CPET measurements. Each patient performed a supervised, standard, progressively increasing (personalized ramp protocol) work rate (WR) CPET to maximum tolerance on an elctromagnetically braked cycle ergometer. Gas exchange measurements (Cardiopulmonary Metabolic Cart, Sensormedics Vmax Spectra) were obtained at rest (3 min) and during 2 min of unloaded cycling at 60 rpm, followed by a progressively increasing WR exercise and 3 min of recovery. Heart rate (HR), 12-lead ECG, and cuff blood pressure were monitored and recorded.

HR reserve was calculated as the difference between resting and peak exercise HR. Minute ventilation (E), O2 uptake (O2), CO2 output (CO2), respiratory exchange ratio (RER), dead space-to-tidal volume ratio (VD/VT), and other exercise variables were computer-calculated breath by breath, interpolated second by second, and averaged at 10-s intervals (38).

The V-slope analysis method was used to measure the anaerobic threshold (4). The ratio of O2 uptake to WR increase ({Delta}O2/{Delta}WR) and oxygen pulse (O2 pulse) were determined as previously described (14). Ventilation efficiency during exercise was expressed as the slope of E vs. CO2 over the linear component of E vs. CO2 (34). O2 arterial saturation was monitored with an ear oxymeter (Sensormedics). PaCO2 was estimated from the end-tidal partial pressure of CO2 (PETCO2), as gauged from the formula of Jones et al. (18). Peak exercise O2 uptake (peak O2) was the highest O2 achieved during exercise. Age-, gender-, and weight-adjusted predicted O2 values were also determined (2). Exercise dyspnea sensation was graded by the Borg (5) scale. Dyspnea and breathlessness are used interchangeably and refer to an uncomfortable or unpleasant respiratory-related sensation that normally develops during exercise. Symptoms were related to E by plotting the Borg score against E and calculating the slope of this relationship for each test (E vs. Borg score slope).

Vascular studies. Vascular assessments were performed according to guidelines of the International Brachial Artery Reactivity Task Force (9). Imaging studies of the brachial artery were performed with a high-resolution ultrasound Hewlett-Packard 11-MHz linear-array transducer, based on the technique described by Celermajer et al. (6). Measurements included brachial diameter and flow velocity assessed by pulsed Doppler with the range gate (1.5 mm) in the center of the artery. The system permitted a direct evaluation of the angle between blood stream and the intersecting ultrasound beam, which was then used to calculate blood flow velocity. Ultrasound images were obtained by the same investigator throughout the study. Blood flow-mediated vasodilation was assessed by measurement of the change in diameter of the brachial artery during reactive hyperemia created by release of a cuff inflated (50 mmHg above systolic pressure for 5 min) on the forearm. Arterial diameter was measured in millimeters from the artery-blood interface on both the anterior and posterior walls, coincident with the R waves on the ECG, at two sites along the artery for five cardiac cycles, with these 10 measurements averaged. The image analysis and measurement of the vasodilator response from repeated studies were performed by an individual who was blinded to the sequence.

We calculated blood flow by multiplying the velocity-time integral of the Doppler flow signal by the cross-sectional area of the vessel and HR. The brachial artery flow-mediated dilatation was calculated as absolute maximal increase in diameter compared with baseline. Reactive hyperemia was calculated as absolute maximal change in flow during hyperemia compared with baseline.

Ergoreflex evaluation. A maximal voluntary handgrip test was measured as the greatest of the peak forces produced by three brief maximal handgrip contractions preliminarily performed before the ergoreflex test. Ergoreceptor stimulation consisted of a 3-min ventilation recording during rest followed by a handgrip session that was performed two times (4-h interval) in a random order according to the following protocols: 1) a 5-min session of rhythmic handgrip achieved by squeezing the balloon of a sphygmomanometer (30 squeezes/min) at 50% of the predetermined maximal capacity followed by 3-min control recovery and 2) the same protocol followed immediately after cessation of exercise by 3 min of blood flow stasis on the exercise arm by inflating an upper arm biceps tourniquet to 30 mmHg above systolic pressure at the beginning of recovery (27). The ergoreflex contribution to ventilation was computed as the difference of the changes in ventilation between the mean value at rest and the average of the 2nd- and 3rd-min recovery with and without posthandgrip circulatory occlusion (31).

Statistical analysis. Values are expressed as means ± SD. CPET differences between pre- and postcardioversion were analyzed by paired t-test as well as average changes in E vs. CO2 slope, E vs. O2 slope, and E vs. Borg score slope. An ANOVA multiple-comparison test was used for testing differences between pre- and postcardioversion ergoreflex tests and when comparing differences in the group of patients who presented with atrial fibrillation relapse. A P value of <0.05 was considered to be significant. Statistical analyses were performed by means of Stata 7.0 package.


   RESULTS
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Thyroid hormone levels, plasma electrolytes, left ventricular dimensions, and ejection fraction (average of 5 consecutive beats) were within normal limits in each subject, and some showed significant atrial enlargement. All CPET were completed without adverse events.

Table 1 summarizes the demographic and ecocardiographic data at study entry.


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  		Table 1. Demographic and echocardiographic data

 
Pulmonary function test and CPET. All patients exhibited normal lung function (Table 2), and no changes occurred after external cardioversion. The finding that all patients exercised above their anaerobic thresholds and the achievement of a high peak RER (1.07 ± 0.4 precardioversion vs. 1.14 ± 0.4 postcardioversion; P = not significant) indicate that patients had developed a significant metabolic acidosis and had exercised at a high, if not maximal, work intensity. Before cardioversion, the symptoms reported for stopping exercise were leg fatigue in 30%, breathlessness in 60%, and palpitations in 10%. Interestingly, 20% of subjects who, while on atrial fibrillation had stopped exercise because of dyspnea or palpitations, after restoration of sinus rhythm reported leg fatigue as the limiting symptom.


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  		Table 2. Pulmonary function tests, CPET data, and results of vascular studies pre- and postcardioversion

 
Exercise gas exchange analysis. As shown in Table 2 and Fig. 1, cardioversion was associated with significant (all P < 0.01) increases in peak O2, O2 at the anaerobic threshold, O2 pulse, {Delta}O2/{Delta}WR, and PETCO2 and decreases in the E vs. CO2 slope, E vs. O2 slope, E vs. Borg score slope, and of HR at rest and peak exercise. No changes in O2 saturation, peak E, peak RER, and VD/VT were observed. Interestingly, after cardioversion, a significant increase in PETCO2 for any matched exercise time postcardioversion was observed despite no differences in VD/VT (Fig. 2).



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  		Fig. 1. Average values of E vs. CO2 slope (A), E vs. O2 slope (B), and dyspnea sensation (E vs. Borg score slope) (C) plotted over each minute of ramp incremental exercise.

 


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  		Fig. 2. Average values of dead space-to-tidal volume ratio (VD/VT) and end-tidal partial pressure of CO2 (PETCO2) plotted at 2-min intervals at rest (3 min) during unloaded cycling (2 min), ramp incremental exercise to peak exercise (broken lines before peak exercise indicate different exercise duration pre- and postcardioversion), and recovery (3 min). *P < 0.05 vs. precardioversion; **P < 0.01 vs. precardioversion.

 
Vascular analysis. Brachial artery flow-mediated dilatation and reactive hyperemia to distal circulatory arrest were significantly improved by external cardioversion (Table 2). An example of improvement in hyperemic response is reported in Fig. 3.



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  		Fig. 3. Example of brachial artery Doppler flow in a patient before and after cardioversion in the control state and during reactive hyperemia.

 
Ergoreflex test. Figure 4 depicts the ventilatory responses to handgrip preceding and after restoration of sinus rhythm, without and with blood flow stasis by cuff occlusion. A significant difference in ventilation between the recovery with posthandgrip circulatory occlusion and the recovery without reflects the ergoreflex component to the ventilatory response to exercise.



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  		Fig. 4. Mean values of ventilation at rest (2 min), on exercise (5 min), and in the recovery period (3 min) of ergoreflex test pre- and postcardioversion. *P < 0.01 vs. no occlusion.

 
Atrial fibrillation relapse. Ten subjects had atrial fibrillation relapse after restoration of sinus rhythm. Interestingly, in this group, CPET variables, endothelial function, and the ergoreflex component to the ventilatory response to handgrip all reverted to precardioversion levels after fibrillation relapse (Table 3).


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  		Table 3. CPET data, results of vascular studies, and ergoreflex activity in 10 patients who presented an atrial fibrillation relapse after successful cardioversion

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study provides, for the first time, the evidence that patients with lone atrial fibrillation peculiarly exhibit a high ventilatory activity for CO2 production and an abnormally increased dyspnea sensation during incremental exercise. Remarkably, restoration of sinus rhythm abolished the ventilatory abnormalities, mitigated the dyspnea sensation, and promoted a significant improvement in peak O2. Activation of muscle ergoreflex and changes in PETCO2 set point, rather than abnormalities in lung function and ventilation/perfusion matching, account for the observed abnormal ventilatory pattern and are of pathophysiological relevance to the reduced maximal exercise capacity.

How and whether atrial fibrillation and an irregular ventricular contraction may affect exercise physiology has been matter of investigation since several years (2, 8, 10, 12, 21, 23, 36). Physiology-based studies have, however, primarily focused on the hemodynamic bases for exercise intolerance. Exercise gas exchange analysis by means of CPET has been employed in several previous studies, but information available is limited to peak O2 and to an analysis of cardiac factors involved in its changes (2, 8, 10, 12, 21, 23, 36). We aimed at targeting additional mechanisms that are potentially involved in exercise in patients with lone atrial fibrillation.

Exercise performance in lone atrial fibrillation. An intuitive mechanism for a reduced exercise performance in atrial fibrillation is an inadequate increase of cardiac output limitation. This arrhythmia may affect cardiac output in several ways, including loss of atrial contribution to left ventricular filling, atrioventricular valve regurgitation, increased ventricular rate and reduced diastolic time, and irregular R-R interval. It is controversial whether, at least as concerns atrial fibrillation, a higher HR at rest may limit chronotropic competence by reducing the HR reserve. Some reports (3, 36) suggest that patients with lone atrial fibrillation, despite a high resting HR, exhibit a maximum attainable HR at peak exercise higher than observed after sinus rhythm conversion, which accounts for the minor differences in peak O2 between the two conditions (3, 36). Conversely, others studies (12, 23) demonstrated that sinus rhythm restoration, compared with simple rate control, translates into a significant improvement in peak O2 and submaximal O2 kinetics (O2 deficit) irrespective of the underlying cardiac disease. In the present study, peak exercise HR was significantly higher during atrial fibrillation, compensating for a higher resting HR. HR reserve pre- and postcardioversion was similar. Sinus rhythm conversion promoted a 25% rise in peak O2, a 37% increase in O2 pulse, and a 30% enhancement of {Delta}O2/{Delta}WR, suggesting an improvement in stroke volume, peripheral blood flow distribution, and aerobic efficiency. These changes imply that: 1) the augmented HR response to exercise during atrial fibrillation may not invariably compensate for the loss of atrial contribution to ventricular filling and/or 2) extracardiac factors may be involved in the overall exercise limitation.

Exercise gas exchange and ventilation pre- and postcardioversion. CPET is the gold standard technique for noninvasively assessing gas exchange and ventilatory response during exercise (1, 14, 38). Under this respect, the major finding of the study is that patients, while having lone atrial fibrillation, exhibited an impaired ventilatory efficiency, as revealed by steeper E vs. O2 and E vs. CO2 slopes, along with a lower PETCO2, for any matched exercise time, compared with sinus rhythm. Two isolated studies by Lundstrom and Karlsson (24) and by Schimpf et al. (33) reported an improved ventilatory response to maximal and submaximal exercise, respectively, after conversion of chronic atrial fibrillation to sinus rhythm. However, most patients presented with an underlying heart disease, and no mechanistic implications were reported.

There is a growing interest in the pathophysiological relevance attributable to E vs. CO2 slope in a variety of cardiac disorders, because this variable is a powerful indicator of clinical course and prognosis in patients with left ventricular dysfunction (7, 15, 28, 29). Traditionally, a steep exercise E vs. CO2 slope has been considered to be a distinctive feature of severe heart failure (7, 28); current evidence, however, suggests that E vs. CO2 slope may be increased even in normal subjects or in patients with preserved left ventricular function (15, 28). Although this makes more acceptable the novel concept that lone atrial fibrillation is associated with an abnormal exercise ventilatory efficiency, the basic question concerning the pathophysiological substrate remains to be answered. Different factors may account for an excessive ventilatory response to exercise. Mathematically, the E vs. CO2 slope is determined by the following three variables: the amount of CO2 produced, the physiological VD/VT, and the arterial CO2 partial pressure. Thus, for a given CO2, an increased E vs. CO2 slope may be the result of either an abnormally high dead space fraction (increased VD/VT), a low PaCO2, or both. A low PaCO2 derives from an augmented central or peripheral command to ventilation, which drives the PaCO2 below the physiological range, and/or from the occurrence of early metabolic acidosis, which demands ventilatory compensation. It follows that measurement of PaCO2 and calculation of VD/VT are required to quantify ventilatory efficiency. The loss of atrial contraction may, especially in the presence of ventricular diastolic dysfunction, produce an increase in pulmonary venous pressure, leading to clinical or subclinical interstitial pulmonary edema, subsequent impairment of the alveolar-capillary diffusing capacity, and/or to ventilation/perfusion mismatching. These possibilities, however, are ruled out in our patients by the fact that alveolar-capillary membrane diffusing capacity and exercise VD/VT were within normal limits and were unchanged after external cardioversion. Conversely, the finding that PETCO2, was significantly reduced over the entire duration of exercise and increased to normal after restoration of sinus rhythm is in favor of a primary involvement of extrapulmonary factors.

Dyspnea sensation and ergoreflex activation. Interestingly, lone atrial fibrillation was associated with an increase in breathlessness at any matched level of ventilation that is not attributable to an augmented dead space ventilation and ventilation/perfusion mismatching on exertion. Lack of variations in arterial oxygen saturation with cardioversion does not support a role for uneven pulmonary capillary recruitment and consequent hypoxemia in the presence of atrial fibrillation, and does not explain the higher dyspnea sensation. In chronic heart failure, group IV afferents, which are primarily sensitive to metabolic by-products (26, 31), have been hypothesized to play a key role in the genesis of symptoms and in the progress of the disease (27, 28, 31). The present study documents a significant activation of the metaboreflex contribution to ventilation in the presence of atrial fibrillation and not while on sinus rhythm. This pattern is paralleled by a blunted conduit artery flow-mediated vasodilatation that is considerably improved with restoration of regular sinus rhythm, which suggests that peripheral blood flow fluctuations in atrial fibrillation may induce exercise muscle underperfusion, impair the endothelial responsiveness to vascular shear stress, and contribute to a peripheral reflex increase in ventilation.

Furthermore, during atrial fibrillation, anaerobic threshold occurred at a O2 significantly lower (–18%) than after cardioversion along with an increased CO2. Both CO2 and H+ are two powerful stimuli to ventilation (38) and well explain hyperventilation and breathlessness sensation for any matched workload. It is also remarkable that, in the ergoreflex activation, a primary role of high-H+ concentration in cases of premature anaereobiosis and lactic acid production has recently been demonstrated (32). All these considerations are in favor of the occurrence of premature WR lactic acidosis or an increase in the sensitivity to the same levels of metabolites.

Study limitations. Lack of a direct measure of changes in PaCO2 during incremental exercise may represent a limitation to this study. However, in view of a normal DLco (98% of predicted normal value) with a normal alveolar-capillary membrane component, making the estimation of PaCO2 by PETCO2, highly reliable, we decided to avoid repeated invasive measures. The same reasoning applies to VD/VT calculation. Further investigation to assess lactic acidosis and chemoreflex responsiveness is warranted. The average age of our patient population was somewhat higher than that reported in previous similar studies. However, age as a cause of a steeper E vs. CO2 slope is contradicted by the evidence that atrial fibrillation reoccurrence led to a new-onset significant impairment in ventilatory efficiency and a parallel reduction in exercise performance.

Conclusions. Our findings provide additional insights into the origin of exercise limitation in patients with lone atrial fibrillation and prospect the possibility that extracardiac factors may be at work. An impaired ventilatory efficiency seems to play a significant pathophysiological role and to be related with a disordered reflexogenic control of ventilation by changes in skeletal muscle perfusion and metabolism.


   GRANTS
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REFERENCES
 
This work was supported by a grant from the Ministry of Health, Rome, Italy.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Guazzi, Cardiopulmonary Laboratory, Cardiology Division, Univ. of Milano, San Paolo Hospital, Via A. di Rudinì, 8 20144 Milano, Italy (E-mail: Marco.Guazzi{at}unimi.it)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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