Lung Function and Exercise Gas Exchange in Chronic Heart Failure
Background The ventilatory response to exercise in patients with chronic heart failure (HF) is greater than normal for a given metabolic rate. The objective of the present study was to determine the mechanism(s) for the high ventilatory output in patients with chronic HF.
Methods and Results Centers in Germany, Italy, Japan, and the United States participated in this study. Each center contributed studies on patients and normal subjects of similar age and sex. One hundred thirty patients with chronic HF and 52 healthy subjects participated. Spirometric and breath-by-breath gas exchange measurements were made during rest and increasing cycle exercise. Arterial blood was sampled for measurement of pH, Paco2, Pao2, and lactate during exercise in 85 patients. Resting forced expiratory volume in 1 second (FEV1) and vital capacity (VC) were proportionately reduced at all levels of impairment. Patients with more severe HF had greater tachypnea and a smaller tidal volume (Vt) at a given exercise expired volume per unit time (V̇e). This was associated with an expiratory flow pattern characteristic of lung restriction. V̇e and V̇co2 as a function of V̇o2 were increased during exercise in HF patients. The increases were greater the lower the peak V̇o2 per kilogram of body weight. The ratio of Vd (physiological dead space) to Vt and the difference between arterial and end tidal Pco2 at peak V̇o2 also increased inversely with peak V̇o2/kg. In contrast, the difference between alveolar and arterial Po2 and PaCO2 were both normal, on average, at peak V̇o2 regardless of the level of impairment. The more severe the exercise limitation, the higher the lactate and the lower the HCO3− at a given V̇o2, although pH was tightly regulated.
Conclusions The increase in V̇e in chronic HF patients is caused by an increase in Vd/Vt due to high ventilation/perfusion mismatching, an increase in V̇co2 relative to V̇o2 resulting from HCO3− buffering of lactic acid, and a decrease in Paco2 due to tight regulation of arterial pH. With regard to the excessive V̇e in HF patients, the increases in Vd/Vt and V̇co2 relative to V̇o2 are more important as the patient becomes more exercise limited. Regional hypoperfusion but not hypoventilation typifies lung gas exchange in HF. This and other mechanisms might account for the restrictive changes leading to exercise tachypnea in HF patients.
The ventilatory response to exercise in patients with chronic HF is known to be abnormally high.1 2 3 4 5 6 7 8 Three physical factors determine the ventilatory response to exercise. These are the CO2 production, the arterial CO2 tension (Paco2) or set point, and Vd/Vt. By analyzing each factor in quantitative terms, it is possible to determine the role of each in the high ventilatory response observed in HF patients during exercise.
V̇a can be simply quantified from measurement of CO2 output (V̇co2) and the “ideal” alveolar CO2 concentration estimated from the arterial CO2 tension (Paco2) as shown in the following equation: where 863 is a constant that combines the sea level barometric pressure and correction factor to express V̇a as body temperature, pressure, saturate with H2O (BTPS) and V̇co2 as standard temperature (0°C), pressure (760 mm Hg), dry (0% water vapor) (STPD). Because the physiological dead space must also be ventilated, our interest must be in the minute ventilation (V̇e), ie, V̇a plus the physiological dead space ventilation, as shown in Equation 2: By combining Equations 1, and 2, we can express V̇e as shown in the following useful equation: Experimentally, V̇e was found to increase linearly and uniformly with V̇co2 when the work was performed without lactic acidosis in normal subjects.9 The relatively consistent values for Paco2 and Vd/Vt obtained for normal subjects account for the similar ventilatory responses to exercise observed below the lactate threshold.9 This contrasts with the variable ventilatory responses in patient populations with diseases involving the heart, lungs, and pulmonary circulation.10
Sullivan et al7 and Kobayashi et al,4 using arterial Paco2 to calculate Vd, found that exercise Vd/Vt was increased in HF patients. CO2 production should also be increased at a given rate of aerobic respiration (V̇o2) in HF patients compared with that observed in normal subjects because additional CO2 is released by the cell at a relatively low WR when intracellular HCO3− buffers lactic acid.9 11 Also, the ventilatory response relative to the increase in V̇o2 may be more steep in HF patients than in normal subjects when the CO2 set point (Paco2) is reduced (Equation 3), because as the exercise-induced lactic acidosis develops, H+ stimulates the carotid bodies.12 Thus, the inappropriately large ventilatory response (V̇e) in HF patients may be caused in part or entirely by all three variables shown in Equation 3. The present study was conducted to investigate the role of each variable in the ventilatory response to exercise in patients with HF and how each changes in relation to the severity of cardiac dysfunction.
This was a multicenter study consisting of HF patients from Harbor–UCLA Medical Center, Torrance, Calif; Tokyo Medical and Dental University, Tokyo, Japan; the Department of Cardiology and Pneumonology, Ludwigshafen, Germany; Istituto di Cardiologia, Milan, Italy; and Ospedale Cardiologico, Ancona, Italy. A total of 130 patients with chronic HF and 52 healthy subjects of similar age and sex were studied during a progressively increasing cycle ergometer exercise test. The age and sex characteristics and the average peak V̇o2 and LAT of the patients from each center are shown in Table 1⇓. The average age of the healthy subjects was 52.1±1 years (mean±SE) (30 men, 22 women). The averages and SDs of the peak V̇o2 and LAT for the normal subjects were 24.8±7.1 and 15.2±5.2, respectively. Diagnoses, NYHA functional class, ejection fraction, and treatment at the time of study for the HF patient groups are shown in Table 2⇓. Data from the 18 patients with COPD shown in Fig 1⇓ were obtained from Harbor–UCLA Medical Center. These patients were not studied during exercise.
The patients were divided into three groups according to exercise limitation, similar to the approach of Weber13 in which cardiac function is classified according to peak V̇o2 per kilogram of body weight. In the present study, group 1 had peak V̇o2 >16 mL · min−1 · kg−1 (least severe), group 2 had peak V̇o2 of 12 to 16 mL · min−1 · kg−1 (moderately severe), and group 3 had peak V̇o2 <12 mL · min−1 · kg−1 (most severe). The mean±SE of the LAT/peak V̇o2 ratios was 0.68±0.013, 0.71±0.016, and 0.72±0.030 for groups 1, 2, and 3, respectively. These values were significantly higher than for the normal group (0.56±0.016). Informed consent was obtained from each patient. The study was approved by each institution’s human subjects committee.
The rate of the WR increase was between 10 and 15 W/min. The subjects reached the point of fatigue in 5 to 12 minutes of the incremental period of exercise. Gas exchange was measured breath by breath at all institutions. At Harbor-UCLA and Ludwigshafen, a Medical Graphics CPX Metabolic Cart was used. In Ancona and Milan, Italy, a SensorMedics Metabolic Cart was used. In Tokyo, Japan, a Minato Metabolic Cart was used. The LAT was measured by the v-slope method14 15 in which V̇co2 is plotted as a function of V̇o2, breath by breath or over several breaths. The breakpoint at which V̇co2 increases more rapidly than V̇o2 is taken as the LAT, on the basis of previous research.14 Arterial blood was sampled during exercise in 85 HF patients from a percutaneously placed catheter in the radial or brachial artery. Arterial blood gases, pH, and lactate were measured with electrodes by standard methods.
Unless otherwise described, values are expressed as mean±SE. Student’s t tests were used to compare differences between control and HF patients. Multiple comparison ANOVA tests were used to compare differences among the three groups of HF patients. Simple linear regression analysis was used to examine relationships between P(A−a)O2, P(a−et)CO2, and Vd/Vt as functions of peak V̇O2. P<.05 was considered significant.
Resting Lung Function
Fig 1⇑ shows the FEV1 and VC expressed as percent of predicted16 for the HF and COPD patients and normal control subjects. FEV1 and VC are either normal or proportionately reduced in HF. This contrasts with COPD patients, in whom FEV1 is reduced to a greater degree than VC. The control population had results for both FEV1 and VC that were very similar to those predicted.
Exercise Minute Ventilation as Related to Exercise Limitation
The increase in exercise ventilation as related to V̇o2 in patients with HF is shown in Fig 2⇓. Those patients with the more impaired exercise capacity, expressed as peak V̇o2/kg, have a higher ventilatory requirement. V̇e at the peak V̇o2 of the most limited group was almost twice normal.
Breathing Pattern in Chronic HF
Fig 3⇓ shows the Vt normalized to body height as a function of exercise V̇e for work performed up to peak V̇o2 in normal subjects and patients with HF. The lower the peak V̇o2, the smaller the height-adjusted Vt and the faster the breathing frequency at a given V̇e.
Increase in V̇o2 and V̇co2 as Related to Exercise Limitation
The rate at which V̇o2 and V̇co2 increased per watt of work was calculated for the progressively increasing exercise period beginning 1 minute after the WR started to increase. The delay of 1 minute after the start of the increase in WR was used to take into account the time constant for V̇o2 to respond to the increasing WR (≈35 seconds for normal subjects17 ). The mean±SD for ΔV̇o2/ΔWR is 10.3±1.0 mL · min−1 · W−1 for a normal population.18 Data for the HF subjects are shown in Table 3⇓. The ratio of ΔV̇o2/ΔWR progressively decreased the lower the peak V̇o2, being significant for the <12 mL · min−1 · kg−1 functional group. In contrast ΔV̇co2/ΔWR did not change significantly as related to the degree of cardiac impairment, reflecting additional CO2 produced during HCO3− buffering of accumulating lactic acid19 when ATP is regenerated anaerobically. The slower rise in V̇o2 as WR increases indicates that there is less ATP regenerated aerobically in the more severely limited patients.
Arterial Blood Gases, pH, and Vd/Vt as Related to Exercise Limitation
Fig 4⇓ shows the changes in PaCO2, PetCO2, and P(a−et)CO2 at peak V̇o2 for 83 of the 85 patients with arterial blood gases (data of 2 subjects were deleted for this plot because the investigator believed that these subjects stopped exercise without making a maximum effort). PaCO2 was not affected by the degree of impairment. However, PetCO2 decreased as peak V̇o2 decreased. Thus, although P(a−et)CO2 is negative by ≈4 mm Hg on average in normal subjects,20 P(a−et)CO2 became more positive the more severe the exercise limitation.
Exercise PaO2, PaO2, and P(A−a)O2 as a function of peak V̇o2 are shown in Fig 5⇓ for the 83 subjects. PaO2, PaO2, and P(A−a)O2 were normal at peak V̇o2 without a systematic change as related to exercise limitation, in contrast to CO2 exchange.
The Vd/Vt at peak V̇o2 was calculated from the Bohr equation, ie, Vd/Vt=(PaCO2−PeCO2)/PaCO2 where PaCO2 is assumed to be the ideal alveolar Pco2 and PeCO2 is the mixed expired Pco2. The breathing-valve dead space is subtracted from Vd and Vt. The Vd/Vt is high in almost all patients with HF and is elevated above normal to a greater degree the more severe the exercise limitation (Fig 6⇓).
Exercise Lactate and Acid-Base Changes as Related to Cardiac Dysfunction
At any given V̇o2, the lactate increase and HCO3− decrease are greater the more severe the exercise impairment (Fig 7⇓). Arterial pH is well controlled at the low metabolic rates of the more exercise-limited HF patients but decreases as V̇o2 increases in a similar pattern to that for normal subjects.21
Gas exchange measurements have been used to grade severity of heart disease in the selection of patients for heart transplantation.22 23 V̇e is notably high in HF patients. The greater the dysfunction, the greater the increase in V̇e.1 2 3 6 24 Therefore, we classified the degree of cardiac dysfunction in each HF patient by their peak V̇o2 per kilogram of body weight, believing this to be more quantitative than the NYHA grading. Nevertheless, 50% of NYHA functional class III patients were in the group with peak V̇o2 <12 mL · min−1 · kg−1 whereas only 24% of this class were in the >16 mL · min−1 · kg−1 group. The anaerobic threshold has also been a useful measure of cardiac dysfunction.13 25 Had we graded function by the anaerobic threshold or the percent of predicted peak V̇o2, such as reported by Stelken et al,26 it is unlikely that we would have reached substantially different conclusions.
How worsening cardiac function brings about an increase in ventilation should be addressed within the framework of the three factors that determine the magnitude of the ventilatory response to a given level of exercise and the physiological mechanisms controlling each. The magnitude of the ventilatory response is inversely related to the arterial Pco2 (CO2 set point) and directly related to the CO2 production and Vd/Vt (Equation 3). Thus, to understand the pathophysiological mechanisms leading to the increased ventilatory response and its relationship to the degree of exercise impairment, each of the three physical factors that determine the response were investigated.
As shown in Table 3⇑ and as previously reported,8 CO2 production is increased relative to V̇o2 in HF patients at WRs that are regarded to be mild or moderate for normal subjects. Because the skeletal muscle respiratory quotient is close to 1.0, the total body respiratory quotient normally increases as WR increases. However, the slope of increase in V̇co2 relative to V̇o2 of the exercising muscle cannot be >1.0 unless lactic acid is accumulating in the cells and its H+ is simultaneously buffered by bicarbonate. As shown in Table 3⇑, the slope of ΔV̇o2/ΔWR is decreased the lower the peak V̇o2. In contrast, ΔV̇co2/ΔWR is not significantly changed. This demonstrates the increasing importance of CO2 from buffering of lactic acid by HCO3− as a source of ventilatory drive relative to that from CO2 derived from aerobic metabolism as exercise limitation from heart failure becomes more marked.
The ventilatory response also depends on how tightly pH and PaCO2 are regulated as WR is increased. However, there appears to be nothing unusual about the control mechanisms that regulate pH and PaCO2 in HF patients during exercise (Figs 4⇑ and 7⇑). The end-exercise PaCO2 is only slightly reduced from that at rest. The three patient groups did not differ with respect to regulation of arterial pH as V̇o2 increased. Patients with the lowest peak V̇o2 values had the least end-exercise arterial metabolic acidosis, although the lactate increase was greater for the WR performed (Fig 7⇑). Despite the relatively small arterial lactic acidosis at peak V̇o2 in the group with the lowest peak V̇o2, metabolic acid buffering takes place at a high rate relative to V̇o2 in the muscles (Table 3⇑). The increasing proportion of V̇o2 derived from HCO3− buffering relative to that coming from aerobic metabolism accounts for a relatively steep ventilatory response to exercise above the lactate threshold when ventilation is plotted as a function of V̇o2.
As shown in Fig 2⇑, the patients in group 3 (peak V̇o2 <12 mL · min−1 · kg−1), at their average peak V̇o2 (782.5 mL/min), had an average V̇e and increase in V̇e in response to exercise of 169% and 203% of the normal group, respectively. When Equation 3 is applied, using the data in Table 3⇑ and Figs 4⇑ and 6⇑, it can be estimated that the increase in ventilatory response observed in the HF patients at their peak V̇o2 could be attributed to all three factors in the equation. The reduction in PaCO2 (from 38 to 35 mm Hg), the increase in V̇co2, (743.4 to 1093 mL/min), and the increase in Vd/Vt (0.25 to 0.48) account for 8%, 47% and 45% of the increase in ventilatory response, respectively.
The increase in Vd/Vt (Fig 6⇑) and P(a−ET)CO2 (Fig 4⇑) in proportion to the degree of exercise limitation without the development of arterial hypoxemia or increased P(A−a)O2 (Fig 5⇑) is an observation of great importance in understanding why patients with more severe cardiac dysfunction have a greater ventilatory requirement at any given WR. These observations suggest that pathologically high ventilation/perfusion ratio mismatching occurs in HF patients without significant (from the point of view of gas exchange) low ventilation/perfusion ratio mismatching. This places the abnormality on the pulmonary circulation rather than the airway side of the gas exchange unit, ie, perfusion is reduced or absent in the well-ventilated lung. If pulmonary edema developed during maximal exercise, we might have expected arterial hypoxia and cough to develop. However, P(A−a)O2 was usually normal at maximal exercise, and a cough after the exercise was uncommon in the HF patients studied.
Perhaps the decrease in pulmonary perfusion relative to alveolar ventilation results from uneven elevations in pulmonary venous pressure, with greater reduction in perfusion to lung units with higher venous pressures. Alternatively, because of chronic pulmonary stasis, pulmonary blood vessels might have become thrombosed. A third mechanism accounting for the increase in Vd/Vt might be a change in paracrine secretion regulating pulmonary vasomotor tone. Relative stasis and decreased shear stress in the pulmonary blood vessels might reduce nitric oxide production and increase endothelin-1 production, both of which would promote pulmonary vasoconstriction.27 A reduction in nitric oxide production has been described in the pulmonary artery of an animal model of chronic HF.28 The pulmonary vasoconstriction resulting from the reduction in vasodilator paracrines and the increase in vasoconstrictor paracrines in the pulmonary circulation should increase Vd/Vt. This vasoconstrictor mechanism would protect the lungs from high-pressure fluid transudation from the capillary bed (pulmonary edema). This hypothesis is supported by the report of Bocchi et al,29 which showed that administration of exogenous nitric oxide to the lungs of cardiac patients promotes pulmonary edema in HF but not other cardiac patients.
It is not likely that the increased Vd/Vt is due to the breathing pattern of patients with HF, although this breathing pattern may contribute to the increase. During exercise, the Vt values are above the resting levels, whereas Vd/Vt values are higher than normal resting values (Fig 6⇑).
The reduced FEV1 in proportion to VC (Fig 1⇑) suggests that patients with stable HF may develop lung restriction. In agreement with this was the finding that the expiratory flow pattern at maximal exercise was normal or characteristic of a restrictive lung defect in which peak flow occurs toward the middle of expiration (1/2 sine-wave pattern) during spontaneous breathing in a subset of six HF patients from the Harbor-UCLA laboratory. This contrasts with the expiratory flow pattern of patients with obstructive lung disease. In the latter, the peak expiratory flow occurs very early in expiration, and the expiratory flow pattern is trapezoidal in appearance.30
It is tempting to link the decrease in pulmonary blood flow to ventilated lung, evident from the finding of increased Vd/Vt and P(a−et)CO2 but normal P(A−a)O2, to the changes in lung mechanics observed in HF. Regional hypoperfusion reduces alveolar Pco2. This has been described as an operational mechanism for the restrictive changes that occur in the lung in animals31 32 and humans33 when lung perfusion is decreased. Lung restriction takes place by contraction of alveolar duct smooth muscle, resulting in reduced lung compliance (increased lung stiffness) without increased airway resistance. Colebatch et al31 and Nadel et al32 showed that gas was expelled from the lungs and lung compliance decreased immediately after the intravenous injection of substances that reduce pulmonary blood flow in experimental dogs and cats. Histological studies showed a simultaneous reduction in acinar volume. It was concluded that smooth muscle contraction can take place in the peripheral regions of the lungs, reducing lung compliance without increasing airway resistance (pneumoconstriction).
Pneumoconstriction was also observed by Swenson et al33 in humans during unilateral pulmonary artery occlusion. This decreased the ventilation of the nonperfused lung by reducing its distensibility. PaCO2 remained unchanged because ventilation shifted to the lung with perfusion and greater distensibility. The lung with reduced blood flow, of course, had reduced CO2 in its alveoli. The reduction in alveolar Pco2 was suggested as the mechanism for pneumoconstriction because the reduced lung distensibility was reversed when the nonperfused lung was ventilated with 6% CO2.33
Another mechanism accounting for the restrictive changes might be the cardiomegaly that was likely present in some of these patients. A large heart volume would displace lung gas. Hosenpud et al34 reported that “almost” 70% of the increase in vital capacity measured after heart transplantation could be accounted for by the change in heart volume. Although there was no evidence of pulmonary congestion at rest, an engorged lung might become relatively rigid from the high pressure in pulmonary blood vessels. However, neither the cardiomegaly nor the lung plethora mechanism would explain the increase in Vd/Vt and P(a-et)CO2 observed in the HF patients in the present study.
Finally, pulmonary fibrosis secondary to long-standing pulmonary edema or thrombosis might account for restrictive changes. However, lung restriction secondary to pulmonary fibrosis would not be expected to reverse. Hosenpud et al,34 Agostoni et al,35 and Kleber et al5 all observed improvement in the restrictive changes in the lungs of HF patients after different forms of treatment (heart transplantation, ultrafiltration, and afterload reducing and diuretic therapy, respectively). Further studies are needed to document the extent of reversibility of the restrictive changes and high ventilation/perfusion mismatching observed in HF patients.
We conclude that the high ventilatory response to exercise relative to V̇o2 in HF patients is due primarily to two mechanisms: the increase in V̇co2 relative to V̇o2 due to HCO3− buffering of the accumulating lactic acid and the increase in Vd/Vt due to reduced perfusion of ventilated lung. These mechanisms are of increasing importance as the HF patient becomes more dysfunctional. The lung of HF patients also undergoes restrictive changes. The restrictive changes may be linked to the high ventilation/perfusion mismatching that takes place in the lungs of HF patients.
Selected Abbreviations and Acronyms
|COPD||=||chronic obstructive pulmonary disease|
|FEV1||=||forced expiratory volume in 1 second|
|LAT||=||lactic acidosis threshold|
|NYHA||=||New York Heart Association|
|P(A−a)O2||=||difference between alveolar and arterial Po2|
|P(a−ET)CO2||=||difference between arterial and end tidal Pco2|
|V̇ a||=||alveolar ventilation|
|Vd||=||physiological dead space|
|Vd/Vt||=||ratio of physiological dead space to tidal volume|
|V̇ e||=||minute ventilation|
- Received March 17, 1997.
- Revision received May 21, 1997.
- Accepted May 28, 1997.
- Copyright © 1997 by American Heart Association
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