INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

PATIENTS AFFECTED BY chronic heart failure (CHF) often exhibit excessive ventilation for a given workload during exercise (4, 8, 11, 14, 21, 33, 34), mostly sustained by an increase in breathing frequency rather than in tidal volume (VT) (4, 8, 14, 33). Several mechanisms have been proposed to explain the increased ventilatory response to exercise in CHF, including ventilation-perfusion abnormalities, altered control of breathing, impaired central and peripheral hemodynamics, early onset of anaerobic metabolism, and respiratory and skeletal muscle fatigue (6). The reasons and the mechanisms causing exercise hyperpnea to be achieved by increasing breathing frequency more than VT in CHF are unknown and represent the object of this study.

The most prominent pulmonary abnormality in CHF is an increased lung stiffness (9, 14, 21, 24, 26, 34, 35). This may result from a number of mechanisms, including vascular congestion, interstitial edema and fibrosis, increased alveolar surface tension, ventilation inhomogeneities, and activation of contractile elements. An increased lung stiffness may contribute to alter the pattern of breathing during exercise by different mechanisms. First, vascular congestion and interstitial edema, either preexisting or developing during exercise, may trigger rapid and shallow breathing by direct stimulation of irritant or J receptors (8, 25). Second, an increase in breathing frequency may be necessary from the beginning of exercise because the increase in VT is limited by mechanical constraints. These are represented by 1) an excessive elastic work of breathing, which limits the increase of end-inspiratory lung volume, and 2) premature occurrence of expiratory flow limitation (EFL) (15), which prevents the physiological decrease of functional residual capacity (FRC) during exercise.

This study was undertaken to investigate whether differences in ventilation during an incremental exercise test between CHF and normal subjects are related to differences in lung stiffness, EFL, or both. Both static and dynamic lung compliance were measured at rest and during exercise in an attempt to separate the effects of various determinants of increased lung stiffness. The occurrence of EFL was inferred from the reduction of the expiratory flow reserve (EFR), i.e., the difference between tidal and forced expiratory flows in the range of tidal breathing.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Subjects

Lung Function Measurements

Lung mechanics before and during exercise were measured by using a Direc/NEP 200A recording system (Raytech, Vancouver, BC). Flow was measured by a screen-type pneumotachograph placed between mouthpiece and mass flow sensor and connected to a differential pressure transducer (±5 cmH₂O). Transpulmonary pressure (Ptp) was estimated from the difference between esophageal and mouth pressures. Esophageal pressure was measured by positioning a 10-cm-long thin latex balloon in the esophagus, 38-42 cm from the nostrils. Volume and pressure channels were calibrated before each study according to the recommendations of the manufacturer by using a 3-liter syringe and a water-filled manometer, respectively. The balloon was connected to a pressure transducer (±100 cmH₂O) and filled with 0.8 ml of air. Its positioning was considered correct if Ptp remained constant while mouth pressure increased during a gentle effort against a small orifice (20). Mouth pressure was measured by a pressure transducer (±100 cmH₂O). Care was taken to avoid thermal drift by zeroing the flow and volume signals immediately before recording tidal breathing necessary to compute dynamic compliance (CL_dyn) and before recording quasi-static pressure-volume (PV) curves. The latter were measured by intermittent manual occlusion of the expiratory port of the pneumotachograph with the patient slowly expiring from TLC. Quasi-static lung compliance (CL_st) was measured only at rest and within 2 min from the end of maximum exercise, whereas CL_dyn was measured at rest and at each step of the incremental exercise test. The frequency responses of flow- and Ptp-measuring systems had been determined to be flat up to 10 Hz. All signals were recorded at a frequency of 100 Hz and digitized by a computer for subsequent analysis.

During exercise, minute ventilation (E), oxygen consumption (O₂), and carbon dioxide output (CO₂) were measured breath by breath (Vmax, SensorMedics). Sets of simple and very reproducible maneuvers consisting of four to six regular tidal breaths immediately followed by a forced expiration from end-tidal inspiration to near RV (partial forced expiration) and a forced inspiration to TLC were performed in triplicate at rest and once over the last 20 s at the end of each step to estimate the changes in FRC, end-inspiratory lung volume (EILV), EFR, partial forced expiratory flow at 50% of FVC (part₅₀), and maximal inspiratory flow at 50% of FVC. Specifically, changes in FRC and EILV during exercise were defined as the changes in dynamically determined lung volumes at end-tidal expiration and inspiration, respectively. Both FRC and EILV were related to TLC, which was assumed to remain constant during exercise. This assumption was verified by measuring Ptp at TLC. EFR was determined at each step of the test from the difference between partial and tidal expiratory flows near FRC (27). In the case that FRC tended to increase when tidal expiratory flow near FRC impinged on partial flow at some level of ventilation, EFR was computed as the difference between the tidal expiratory flow near the increased lung volume and the partial flow measured at the level of the lowest FRC attained during the test. Thus EFR becomes negative if FRC increases.

Predicted values are from Quanjer et al. (29) for lung function tests and from Jones (16) for the exercise test.

Study Protocol

Screening day. All subjects attended the laboratory for clinical history and physical examination, electrocardiogram, and lung function measurements. CHF subjects also underwent an echocardiography. All subjects were taught how to perform reproducibly the partial forced expiratory maneuvers required for the study and underwent an incremental cardiopulmonary exercise test to have their maximum exercise capacity determined.

Study day. The subjects attended the laboratory in the midafternoon after a light meal. Partial and full forced expiratory flow-volume curves were recorded in triplicate through the mass flow sensor. Blood pressure and heart rate were measured. All CHF and six normal subjects accepted to have an esophageal balloon positioned after topical anesthesia of the nose and throat. Before starting the exercise test, at least three quasi-static PV curves, two sets of CL_dyn, and several regular breaths followed by three sets of reproducible tidal, partial, and maximal flow-volume curves were obtained.

Data Analysis

Only representative breaths recorded during the exercise test before the partial forced expiratory maneuver were used for analysis of breathing pattern. VT and inspiratory and expiratory times (TI and TE, respectively) were calculated breath by breath and averaged over several breaths, thus allowing minute ventilation (E), breathing frequency, and ratio of inspiratory time to total respiratory cycle duration (TI/Ttot) to be computed.

To allow comparison between subjects with different respiratory volumes, VT and E were normalized to TLC, which is the most representative index of lung volumes in CHF, and were referred to as adjusted VT (VT_adj) and adjusted E (E_adj), respectively. Differences in breathing pattern during exercise between groups were assessed by regressing breathing frequency, TI, TE, TI/Ttot, VT_adj, Ptp_EILV, CL_dyn, part₅₀, O₂, and EFR against CO₂, rather than considering their single values at maximum exercise as conventionally done. Such an analysis is expected to give an accurate estimate of the changes in breathing pattern during exercise, because it takes into account all the values recorded during the test and minimizes the high variability of a single value. The reason for regressing the variables against CO₂ rather than the more conventional E or E_adj relies on the fact that, for a given CO₂, E is much higher in CHF than in normal subjects. Thus using E instead of CO₂ would have led to a systematic overestimation of the relationship of the relevant variables with the respiratory stimulus in the normal subjects and possibly blurred the mechanisms causing tachypnea in the CHF.

The regression of EFR against CO₂ was taken as an index of EFL during exercise on the basis of the following reasoning. When ventilation increases, EFR tends to decrease because tidal expiratory flow increases and FRC decreases. When EFR is reduced to zero, flow is limited and greater ventilation can be achieved only by increasing FRC. Thus a lower intercept and/or a greater slope of the regression of EFR vs. CO₂ in CHF compared with normal individuals would suggest occurrence of premature EFL and/or worsening of it with the increase in ventilatory stimulus, or both.

Statistics

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Pulmonary Function Tests at Rest

1

1

1

1

1

1

Maximum Exercise Test

Analysis of the most important variables of breathing pattern during exercise (Fig. 1) revealed that exertional hyperpnea was achieved by proportionally more rapid breathing in CHF than in normal subjects, as documented by a significantly greater slope of breathing frequency vs. CO₂ (10.9 ± 5.5 in CHF and 5.7 ± 2.6 in normal subjects, P < 0.01) and a similar slope of VT_adj vs. CO₂. In the CHF group, the slope of breathing frequency vs. CO₂ was inversely correlated with resting CL_dyn (r = 0.61, P < 0.05) (Fig. 2), FEV₁ %predicted (r = 0.58, P < 0.05), FVC %predicted (r = 0.67, P < 0.01), TLC %predicted (r = 0.74, P < 0.01), and FRC %predicted (r = 0.56, P < 0.05). In contrast, the slope of breathing frequency vs. CO₂ did not correlate with baseline CL_st, change in CL_st at end exercise, slope of CL_dyn vs. CO₂, and regression parameters of EFR vs. CO₂. Thus exercise tachypnea mostly occurred in those subjects who had restrictive abnormalities and/or reduced CL_dyn at baseline.

View larger version (31K): [in this window] [in a new window]   Fig. 1.   Mean regression lines of some of the respiratory variables plotted against CO2 production (CO2) during exercise in chronic heart failure patients (CHF; solid lines) and in the control group (dashed lines). A: tidal volume (VTadj). B: breathing frequency (f). C and D: inspiratory and expiratory times (TI and TE, respectively). E: respiratory duty cycle (TI/Ttot). F: partial forced expiratory flow at 50% of control forced vital capacity (part50). G: expiratory flow reserve (EFR). H: lung dynamic compliance (CLdyn). Significant differences of intercept (Int) and slopes (Sl) are reported.

View larger version (12K): [in this window] [in a new window]   Fig. 2.   Slope of the linear regression of f vs. CO2 during exercise plotted against CLdyn at control in the CHF group (r = 0.61, P < 0.05).

The rate of decrease of TI with CO₂ was not significantly different between groups, whereas the rate of decrease of TE with CO₂ was much faster in CHF than in normal subjects (0.9 ± 0.3 vs. 0.4 ± 0.2, P < 0.001). Thus the slope of TI/Ttot vs. CO₂ was significantly greater in CHF than in normal subjects (3.3 ± 3.9 vs. 0.1 ± 4.5, P < 0.05). The slope of the regression of part₅₀ vs. CO₂ was significantly less in CHF than in normal subjects (0.2 ± 0.4 vs. 0.6 ± 0.4, P < 0.02) and not significantly different from zero, thus suggesting absence of bronchodilatation with exercise in the former. In the normal subjects, part₅₀ tended to increase by ~50% from rest to end exercise. The intercept, but not the slope, of the regression of EFR vs. CO₂ was significantly less in CHF than in normal subjects (0.74 ± 0.33 vs. 1.70 ± 1.13, P < 0.01), suggesting that EFR zeroed at lower CO₂ in the former. The intercept of the regression of CL_dyn vs. CO₂ was less in CHF than in the normal subjects (0.16 ± 0.08 vs. 0.28 ± 0.09, P < 0.02). No significant differences were observed between groups for the relationship of Ptp_FRC vs. CO₂ .

Although the increase in VT with CO₂ was similar between groups, it was achieved with an earlier increase of FRC in CHF (Table 3). In this group, after a transient initial decrease FRC tended to reach the resting value at the end of the test. Without the increase in FRC, impingement of tidal expiratory flow on partial forced flow would have been remarkable (Fig. 3, left). In three subjects, however, FRC decreased from the beginning of exercise and then remained low through the end of the test. EFR never zeroed. In contrast, in the normal group FRC decreased from the beginning of exercise and then remained significantly less than the resting value (Fig. 3, right). Because of an initial high EFR in normal subjects, tidal expiratory flow never impinged on forced expiratory flow, except in two overweight individuals and two former smokers, in whom FRC tended to increase progressively from the beginning of exercise because of a small resting EFR.

View larger version (24K): [in this window] [in a new window]   Fig. 3.   Composite tidal flow-volume and transpulmonary pressure (Ptp)-volume loops at rest (dashed lines), at ~40% of maximal ventilation (thin solid lines), and at maximum exercise (thick solid lines) in typical CHF (left) and normal (right) subjects. The 2 oblique lines on flow-volume loops are partial forced expiratory flows recorded at rest (dotted line) and at maximum exercise (dashed line). Total lung capacity is at the interception of x- and y-axes on the flow-volume loops. CHF subject: at rest, EFR, i.e., the difference in flow between near end tidal expiration and forced flow at the same absolute volume, is much less than in the normal individual because of the lower functional residual capacity (FRC). At the beginning of exercise, FRC decreases and Ptp (PtpFRC) becomes slightly negative. Tidal expiratory flow near FRC encroaches on forced expiratory flow, thus suggesting initial occurrence of expiratory flow limitation (EFL). Then, FRC tends to increase above resting value at the end of exercise whereas PtpFRC becomes more negative. The increase in PtpFRC is not associated with increase in flow, thus suggesting further EFL. Forced expiratory flow at maximum exercise (dashed oblique line) is similar to resting conditions (dotted oblique line), which is consistent with lack of bronchodilatation. Normal subject: FRC decreases early during exercise and remains low through the end of exercise. PtpFRC becomes slightly negative over the second half of tidal expiration. EFL would have likely occurred at maximum exercise if forced expiratory flow had not increased.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The major findings of this study are that exercise tachypnea in CHF was 1) inversely correlated with resting dynamic compliance but not with quasi-static compliance, either at rest or at maximum exercise, 2) not correlated with the occurrence of EFL, and 3) characterized by a greater rate of decrease in expiratory time than in the normal subjects.

It is well accepted that lung parenchyma is commonly involved in CHF for a series of reasons. Pulmonary congestion and hypertension, edema, increased perivascular pressure, vascular thrombosis, increased heart size, and neurohumoral mechanisms may increase lung stiffness both at rest and during exercise (9, 14, 21, 24, 26, 34, 35). In addition, regional hypoperfusion may result in pneumoconstriction with local decrease in lung compliance (22). Altogether these mechanisms are deemed to decrease lung compliance, thus causing a restrictive lung abnormality (34). In the present study, lung restriction was present only in two patients, as documented by a TLC <80% of predicted, whereas the average lung function of the other subjects was unexpectedly maintained within the normal range. This finding may be explained by the fact that average CL_st in CHF was similar to that of normal subjects and is in line with similar values reported by others for CHF patients with similar NYHA class (2, 8, 34).

If the range of operational lung volume is restricted, VT may not be able to increase sufficiently to meet the ventilatory demands during exercise and the required E may be achieved mostly by increasing breathing frequency. A given increase in E attained with increase in frequency rather than in VT would result in an increase in dead space, thus requiring a greater E for a given power output. Moreover, if we accept that breathing pattern is regulated in a way to minimize the work of breathing (19), then we could speculate that the increase in frequency for a given E is more advantageous in CHF than an increase in VT.

In the present study, the rate of increase of breathing frequency with CO₂ was inversely correlated with resting CL_dyn but not with CL_st. Although these findings seem to be discrepant at a first sight, it may be speculated that exercise tachypnea is related to increase in lung parenchyma hysteresis rather than to lung stiffness itself. A decrease in CL_dyn is known to reflect an involvement of lung parenchyma as a result of exaggerated growth of inextensible fibrotic tissue, vascular congestion and edema, altered alveolar surface tension, activation of contractile elements, recruitment/derecruitment of alveolar units, and ventilation inhomogeneities (12). Whether tachypnea was prevalently triggered by one or more of the above factors cannot be inferred from the present data, although vascular congestion, alteration in surface tension together with large differences between opening and closing pressures, and parenchymal and airways contractile elements appear to be the most plausible ones. Indeed, exaggerated growth of fibrotic tissue, which is known to decrease CL_st in addition to CL_dyn, is unlikely to have occurred in the subjects of the present study given that baseline CL_st was similar between groups and did not correlate with the increase in breathing frequency vs. CO₂. Also ventilation inhomogeneities, which are known to cause decrease in CL_dyn with increase in frequency, were likely of little importance in the present study, because CL_dyn increased with CO₂ similarly in CHF and normal subjects. Therefore, these data would substantiate at least in part the accepted notion that exercise tachypnea in CHF may be either the most economic breathing adaptation to the high elastic load due to the primary cardiovascular disease (14) or the consequence of neural reflexes evoked by stimulation of the irritant and/or J receptors because of chronic excess of extravascular fluid in the lungs (25). That perturbed breathing frequency during exercise is linked to involvement of the lungs in CHF is also supported by two additional observations. First, the rate of increase of breathing frequency with CO₂ correlated with most of the lung function parameters measured at rest. Second, the relationship between the rate of increase in breathing frequency and resting CL_dyn remained significant when the former was expressed as a function of E (r = 0.53, P < 0.05).

At variance with a previous study (8), the significant decrement in CL_st recorded in CHF at maximum exercise did not correlate with an increase of ventilation and especially of breathing frequency. Presumably, such a decrease was due to pulmonary congestion, likely because of high intravascular hydrostatic pressures developed at high ventilation (30). If this is the case, then one would wonder why exercise-induced increase in lung stiffness did not evoke tachypnea as much as preexisting involvement of lung parenchyma. One possible reason is that the tachypnoic response to exercise occurs with a certain time delay and becomes more visible in the recovery phase (8).

Although EFL occurred fairly soon with exercise in CHF, as suggested by a significantly lower intercept of EFR vs. CO₂ than in the control group, there was no relationship between this and exercise tachypnea. Studies in chronic obstructive pulmonary disease during exercise demonstrate that, when EFR occurs, FRC is accommodated to higher lung volume to allow greater ventilation (18, 23, 27). This adaptation entails a mechanical constraint of VT with exercise, so that for a given ventilation breathing frequency has to increase. The fact that in our CHF patients none of the indexes of EFL were associated with rapid shallow breathing does not rule out that EFL may contribute to tachypnea. Other triggers, such as lung stiffness, could have been more predominant in this respect. Alternatively, comparison of tidal and maximal flow measured at the mouth is not sensitive enough to detect the occurrence of regional EFL, as suggested by a recent study (28).

We observed that the rate of increase of TI/Ttot with CO₂ in the CHF was abnormally higher than in the normal subjects. TI decreased with CO₂ similarly in CHF and normal group, but TE decreased as twice as fast in the former. Thus the increase in TI/Ttot was mostly due to excessive shortening of TE with constant decrease in TI. Although we do not have a clear explanation for this finding, we speculate that the greater decrease in TE with exercise may reflect a complex respiratory adaptation tending to limit or contrast functional events specifically arising late on expiration, such as dynamic compression of the airways, which occurred in most of the CHF patients. Under these conditions, increased TI/Ttot could have limited the dangerous effects on the cardiovascular system (10), even though such a strategy may burden the inspiratory muscles. Certainly, any decrease in TE should increase breathing frequency, unless compensated by a change in TI. Thus it is not unreasonable to suspect that what caused the rate of TI/Ttot with CO₂ to increase more in CHF than in the control group also contributed to tachypnea, had TI not blurred the effect.

Dynamic lung hyperinflation is almost mandatory when EFL occurs but has several side effects. Increasing FRC would necessarily decrease VT, unless EILV mutually increased by the same magnitude. In the present study, EILV at maximum load was significantly less in CHF than in normal subjects, thus preventing VT_adj from further increase. One reason for this could be that the decrement in CL_st recorded at end exercise in CHF, possibly due to regional hypoperfusion and consequent pneumoconstriction (22, 35) or engorged pulmonary vascular bed (1), was such as to impose an extra end-inspiratory load intolerable to the inspiratory muscles, thus prematurely terminating inspiration. Dynamic lung hyperinflation could put the inspiratory muscles in an unfavorable condition to generate force (32); edema formation as a result of increased pulmonary vascular pressure could stimulate lung parenchyma receptors, thus prematurely interrupting ventilation; and, finally, respiratory muscle deoxygenation (17) could lead to inability to sustain lung expansion over an adequate period of time. Alternatively, external factors such as leg fatigue could have contributed to interrupt exercise prematurely and prevented EILV in CHF from increasing as much as in normal subjects.

Although most of the differences in lung function at rest between CHF and normal subjects were quantitatively trivial, EFR was <50% compared with the control group. Its decrement was not likely due to airway narrowing, because forced expiratory flows were similar between groups. More likely, it was the small increase in lung stiffness that caused FRC to accommodate at a lower lung volume at which EFR is necessarily low, as suggested by a significant relationship between FRC as percent of predicted and CL_dyn. A still-positive EFR at rest in the CHF patients would explain why VT increased similarly to that of the normal subjects at the beginning of exercise, because it was not such to prevent EILV and FRC from expanding adequately. However, with EFR becoming zero at lower CO₂ than in the normal subjects, breathing pattern had to adapt with a gradual increase in FRC to achieve greater expiratory flow and with a decrease in VT and increase in breathing frequency.

Normal individuals tend to increase maximal flows during exercise (15, 27), likely because of an increase in airway caliber. Catecholamines, decreased vagal tone with exercise, and tidal stretching of airway smooth muscle could be responsible for the phenomenon. If catecholamines in exercising CHF subjects are assumed to increase at least as much as in healthy subjects (1, 7), a lack of increment in forced expiratory flow in CHF would suggest that vagal tone persists in CHF (5) and/or that tidal stretching is ineffective to distend the airways, or that airway walls are inextensible with lung expansion. Whatever the underlying mechanisms, the inability to increase flow during exercise heavily weighted on the choice of breathing adaptation.

In conclusion, the present data are consistent with the notion that lung stiffness may lead to a mainly tachypnoic response to exercise in CHF. This pattern of response seems to be attributable to longstanding decrease in CL_dyn, reflecting chronic perivascular and alveolar edema, surface phenomena, and recruitment/derecruitment. According to the present data, dynamic compression of the airways during expiration is not directly involved in tachypnea, although it may contribute to alter breathing pattern.