Exercise Pathophysiology in Patients With Primary Pulmonary Hypertension
Background Patients with primary pulmonary hypertension (PPH) have a pulmonary vasculopathy that leads to exercise intolerance due to dyspnea and fatigue. To better understand the basis of the exercise limitation in patients with PPH, cardiopulmonary exercise testing (CPET) with gas exchange measurements, New York Heart Association (NYHA) symptom class, and resting pulmonary hemodynamics were studied.
Methods and Results We retrospectively evaluated 53 PPH patients who had right heart catheterization and cycle ergometer CPET studies to maximum tolerance as part of their clinical workups. No adverse events occurred during CPET. Reductions in peak O2 uptake (V̇o2), anaerobic threshold, peak O2 pulse, rate of increase in V̇o2, and ventilatory efficiency were consistently found. NYHA class correlated well with the above parameters of aerobic function and ventilatory efficiency but less well with resting pulmonary hemodynamics.
Conclusions Patients with PPH can safely undergo noninvasive cycle ergometer CPET to their maximal tolerance. The CPET abnormalities were consistent and characteristic and correlated well with NYHA class.
Received March 16, 2001; revision received May 11, 2001; accepted May 14, 2001.
Primary pulmonary hypertension (PPH) is a progressive and usually fatal disease of unknown etiology1–3 that leads to increased pulmonary vascular resistance and loss of the pulmonary vasodilator response to exercise. Because of inefficient lung gas exchange and the inability of the right ventricle to adequately increase pulmonary blood flow (cardiac output [CO]) for the O2 exercise demand, dyspnea and/or fatigue ensues. The increased right ventricular work eventually causes pulmonary hypertension at rest, at which time cardiac catheterization and/or echocardiography is used to establish the diagnosis and to grade the severity.
Cardiopulmonary exercise testing (CPET) with gas exchange has the potential of noninvasively grading the severity of exercise limitation, quantifying the hypoperfusion of the lung and systemic circulation, and assessing responses to therapy4,5 before overt right ventricular failure and pulmonary hypertension are evident at rest.
The objective of the present study was to quantify the exercise abnormalities in aerobic function and ventilatory efficiency in PPH patients and to relate them to traditional measurements, such as resting hemodynamics and New York Heart Association (NYHA) symptom class.
Patients and Normal Control Subjects
The medical records of 53 patients with PPH who systematically underwent echocardiography, right heart catheterization, and CPET for clinical evaluation were retrospectively studied. The diagnosis of PPH was based on clinical and laboratory data, which included right heart catheterization to satisfy diagnostic criteria described by a National Institutes of Health registry of PPH and by the World Health Organization.3,6 Patients with other disorders were excluded. For comparison purposes, the CPET findings of 20 normal subjects of similar age, sex, and body size were also analyzed. The institution’s Human Subjects Committee approved the project.
Right heart catheterization with standard hemodynamic measurements was performed within 1 month of each patient’s CPET study. Just before their CPET studies, patients had standard pulmonary function tests.
Each patient performed a physician-supervised, standard, progressively increasing work rate (WR) CPET to maximum tolerance on an electromagnetically braked cycle ergometer. Gas exchange measurements (Cardiopulmonary Metabolic Cart, Medical Graphics) were made during 3 minutes of rest, 3 minutes of unloaded leg cycling at 60 rpm followed by a progressively increasing WR exercise of 5 to 15 (10±3) W · min−1 to maximum tolerance, and 2 minutes of recovery.7 Pulse oximetry (Spo2), heart rate (HR), 12-lead ECG, and cuff blood pressure were monitored and recorded.
Minute ventilation (V̇e, BTPS), O2 uptake (V̇o2, STPD), CO2 output (V̇co2, STPD), and other exercise variables were computer-calculated breath by breath, interpolated second by second, and averaged over 10-second intervals.7,8 The anaerobic threshold (AT), ratio of O2 uptake to WR increase (ΔV̇o2/ΔWR), and oxygen pulse (O2 pulse) were determined as previously described.7 Ventilatory efficiency during exercise was expressed as the ratio of ventilation to CO2 output at AT (V̇e/V̇co2@AT)7 and the slope of V̇e versus V̇co2 over the linear component of the plot of V̇e versus V̇co2.9 The rate of V̇o2 increase during unloaded cycling was expressed as the mean response time (MRT) for a monoexponential curve fit to the second-by-second V̇o2 measurements during the 3 minutes of unloaded cycling.10 If the first breath V̇o2 equaled the 3-minute V̇o2, the MRT was considered equal to the duration of the first breath.
Standard equations were used to predict actual and percent predicted (%Pred) values for maximal voluntary ventilation and CPET parameters.7,11 The predicted value for V̇e/V̇co2@AT was calculated as 24.71−4.04×sex (female=0, male=1)+0.115×age (data from 41 normal subjects). Resting CPET values were compared with their predicted values by using paired 2-tailed t tests. A significant change was defined as an α level of P<0.05. Correlation and regression analyses were performed by ANOVA. Simple individual linear regression analyses were performed by the Pearson correlation coefficient (r) between individual variables and each of the other variables. Multicolinearity analyses were performed to predict NYHA class by using stepwise regression with an α level of P=0.05 for tolerance level.12,13
Pulmonary Hemodynamics and Cardiopulmonary Exercise Analyses
Most of the 53 PPH patients were middle-aged women (Table 1) of NYHA class 3. Their symptoms were dyspnea (87%), fatigue (42%), lower extremity edema (21%), syncope (13%), light-headedness (11%), chest pain or tightness (8%), and palpitations (6%).
At cardiac catheterization, all patients had resting pulmonary hypertension (mean pulmonary artery pressure 64±18 mm Hg), increased mean right atrial pressure and pulmonary vascular resistance, reduced CO and cardiac index, and normal left ventricular ejection fraction (Table 1). On echocardiography, all patients had an enlarged right ventricle and/or right atrium, 89% had tricuspid valve regurgitation, and approximately one third had a patent foramen ovale.
All patients completed CPET without incident. Two patients completed only 2 to 3 minutes of unloaded pedaling; the duration of exercise in all others averaged 8±2 (range 3.5 to 14) minutes. All subjects exercised above their ATs; this finding and their high end-exercise respiratory exchange ratio (1.23±0.11) indicate that they had developed a significant metabolic acidosis and had exercised to a heavy, if not maximal, work intensity. The dominant symptoms described for stopping cycle exercise were leg fatigue (49%), dyspnea (43%), palpitations (4%), and light-headedness (2%).
Pattern of Exercise Gas Exchange
The parameters of exercise gas exchange were systematically abnormal in the PPH patients (Table 1). Peak V̇o2, peak WR, peak O2 pulse or V̇o2/HR, the ratio of V̇o2 increase to WR increase (ΔV̇o2/ΔWR), AT, and MRT were all moderately to severely reduced. There was a marked increase in the slope of V̇e versus V̇co2 and a moderate decrease in peak HR in all patients. Compared with the control group, the differences between actual and predicted values for all of these variables were significant (P<0.0001) (Table 1). The typical abnormal pattern of CPET findings for 2 PPH patients, 1 with moderate and 1 with severe exercise limitation, and a normal control subject are shown in Figure 1. The exercise pathophysiology is reflected in the reduced peak V̇o2, AT, ΔV̇o2/ΔWR, and peak O2 pulse and high V̇e/V̇co2.
Table 2 summarizes multiple correlations between CPET and other variables. NYHA class was significantly correlated with exercise parameters of aerobic function and ventilatory efficiency and better with %Pred values than either per kilogram or absolute values. NYHA class was significantly, but weakly, correlated with resting CO and pulmonary vascular resistance but not with pulmonary artery pressure. Peak WR, AT, and O2 pulse (V̇o2/HR), slope of V̇e versus V̇co2, and V̇e/V̇co2@AT were also significantly correlated with NYHA class ( P<0.01 to P<0.0001 for all) (Table 2).
Peak V̇o2 and V̇e/V̇co2@AT correlated well with NYHA class (P<0.0001) (Figure 2). Peak V̇o2 and V̇o2/HR also correlated well with AT (P<0.0001, Figure 2), showing that the latter can be used as a submaximal parameter for grading aerobic function. The good correlation between peak V̇o2/HR and AT suggests that the latter is highly influenced by stroke volume (SV).
The MRT of V̇o2 for PPH patients during unloaded cycling exercise averaged 48±17 seconds versus 14±9 seconds for the control subjects (P<0.0001) (Figure 3). MRT was positively correlated with NYHA class and negatively correlated with peak V̇o2, AT, and peak O2 pulse (all P<0.001).
By use of stepwise regression analysis of multiple factors, NYHA class could be estimated from peak V̇o2 (%Pred) and the slope of V̇e versus V̇co2 (%Pred) (R=0.64, P<0.0001).
Physiological Severity of PPH
The physiological responses to exercise were abnormal in all patients. Table 3 categorizes the PPH patients into 4 groups on the basis of the severity of reduction in their %Pred peak V̇o2 rather than the less discriminating gradations in NYHA class or pulmonary hemodynamic data. By use of this method of grading disease severity, there is virtually no overlap in any of the key parameters of aerobic function (peak V̇o2, AT, ΔV̇o2/ΔWR, peak O2 pulse, and MRT of V̇o2) or ventilatory efficiency (V̇e/V̇co2@AT and slope of V̇e versus V̇co2) when the control subjects and the PPH patients of mildest severity are compared. Peak V̇e became a lesser fraction of the actual maximal voluntary ventilation as disease severity increased.
Basis for CPET Abnormalities in PPH
The breathlessness of PPH patients during exercise can be related to the relative hypoperfusion of their well-ventilated alveoli (increased “dead space”). In normal subjects, the ventilatory response (V̇e) to exercise is tightly related to CO2 output (V̇co2).9,11,14,15 In PPH, the ventilation of underperfused alveoli causes an increase in dead space ventilation, manifested by a hyperbolic increase in V̇e relative to the V̇co2 increase during exercise. In addition, the lactic acidosis at low WRs and hypoxemia can act as additional stimuli to breathing7 and contribute to the sensation of dyspnea in PPH patients, even though their peak V̇e was well below their maximal voluntary ventilation. Concurrently, the inability to adequately increase pulmonary (and therefore systemic) blood flow during exercise results in the failure to meet the exercise O2 requirement.
A brief description of 5 parameters of aerobic function (peak V̇o2, peak O2 pulse, AT, ΔV̇o2/ΔWR, and MRT) that reflect the inability of pulmonary blood flow to increase adequately in PPH patients follows.
Peak V̇o2 assesses the subject’s maximal work ability and the maximal ability of the circulatory system to increase CO. In PPH, this relates to the pulmonary vasculopathy, which limits blood flow through the lung (and thus through the body).
Peak O2 Pulse
From the Fick principle, V̇o2 equals CO×C(a−)O2. C(a−)O2 denotes content difference between arterial and mixed venous blood. Because CO is the product of HR and SV, dividing both sides of the Fick equation by HR discloses that the O2 pulse (V̇o2/HR) at any given time equals SV×C(a−)O2. As noted previously,16–18 a low peak O2 pulse usually indicates a low peak SV.
The AT, which describes the highest V̇o2 that the patient can sustain without developing a lactic acidosis, appears to be an independent marker of PPH severity.
ΔV̇o2/ΔWR also characterizes PPH severity7 (Table 3). Values progressively lower than 10 mL/min per watt disclose a higher than normal dependence on anaerobic metabolism and, therefore, a decreased ability to aerobically satisfy high-energy phosphate requirements.
Mean Response Time
The MRT of V̇o2 for constant WR exercise depends on the rate of increase of pulmonary blood flow at the start of exercise.10 Because our patients were so exercise limited, the kinetics, even for unloaded cycling, were markedly slower than that for our normal subjects, with the latter achieving steady-state V̇o2 values within 15 seconds on average (Figure 3).
Abnormalities in Exercise Physiology in PPH Patients and Basis of Symptoms
On the basis of our CPET findings, the mechanisms that might account for the most common symptoms in PPH patients (dyspnea and/or fatigue with exercise) can be better understood (Figure 4).
The finding of an increased ventilatory response to exercise appears to be a uniform finding in PPH patients (Table 3). Their dyspnea can be attributed to at least 3 mechanisms that increase ventilatory drive relative to metabolism (Figure 4, left branch).
The first is ventilation/perfusion mismatching, resulting in an increased ratio of dead space volume to tidal volume that is due to hypoperfusion of ventilated alveoli.1,15,19 The second mechanism is the increased hydrogen ion (H+) stimulus to ventilation resulting from a low WR lactic acidosis (low AT). This stimulates V̇e, not only from the increase in H+ that is due to the decrease in HCO3− but also from the increase in V̇co2 that is due to the dissociation of a large amount of HCO3− as it buffers the newly formed lactic acid. The third mechanism, present in many of our patients, is arterial hypoxemia, which is due to a reduced pulmonary capillary bed with shortened red blood cell transit times or to a right to left shunt through a patent foramen ovale. The hypoxemic (shunted) blood entering the systemic arterial circulation stimulates ventilation profoundly because it has not only a low Po2 but also a high Pco2 and high H+ concentration.
In PPH, aerobic regeneration of ATP is impaired, with more work being done anaerobically at relatively low WRs, as reflected by the reduced peak V̇o2, AT, and ΔV̇o2/ΔWR in our patients (Figure 4, right branch). Because the mechanism of anaerobic ATP regeneration stimulates anaerobic glycolysis, a prominent lactic acidosis results. Probably the most important mechanism leading to muscle fatigue in PPH is the reduction in the rate of aerobic regeneration of ATP.
The light-headedness with exercise that some PPH patients experience is probably related to their inability to adequately maintain CO and systemic blood pressure with exercise and/or sudden arterial hypoxemia via a patent foramen ovale.
Resting Pulmonary Hemodynamics in PPH Patients
There were significant but modest correlations between resting CO and pulmonary vascular resistance with NYHA class and several of the CPET measures of aerobic function (Table 2). Cardiac catheterization is invasive and carries a significant risk of morbidity and mortality in PPH,3,4,20 although it is essential in making the diagnosis. In contrast, CPET measures of aerobic function and gas exchange efficiency might be better for determining disease severity and tracking the clinical course, especially in view of the better correlations of these measures with NYHA symptom class.
Grading of Physiological Impairment in PPH
All of the CPET parameters of aerobic function and gas exchange efficiency in our patients correlated well with their NYHA symptom class. Because NYHA class correlated best with %Pred peak V̇o2, we chose the latter parameter to physiologically grade the impairment in PPH (Table 3), as did Weber et al18 for chronic heart failure. The absence of overlap in the predicted peak V̇o2 of our PPH patients (18 to 75 %Pred) and our 20 control subjects (82 to 132 %Pred) (Table 3) indicates the discriminating power of CPET even in “mild” PPH. Two thirds of our PPH patients had peak V̇o2 levels of <50% predicated value, a level associated with a 60% 2-year mortality in patients with chronic left heart failure.21
Peak O2 pulse and AT decreased in parallel fashion within the grading established by the peak V̇o2 in our patients (Table 3). Because O2 pulse equals SV×C(a−)O2, the progressively decreasing peak O2 pulse likely reflects a progressive reduction in peak SV paralleling disease severity. The AT becomes a higher fraction of peak V̇o2 as disease severity (peak V̇o2) worsens, suggesting a decrease in cardiovascular reserve as PPH worsens (Table 3).
The pathophysiological CPET findings that we have described in PPH appear to be consistent and characteristic. CPET is of great potential value for evaluating patients with dyspnea and fatigue safely, reproducibly, and noninvasively.8,22,23 It may become as useful in assessing the prognosis of PPH patients as it has been in patients with chronic heart failure,11,23 or it may be used for the purpose of prioritizing patients for lung transplantation and for evaluating drug therapy.4,5 The need to categorize disease severity accurately and noninvasively in PPH patients makes it desirable that physicians responsible for diagnosis and management of these patients become familiar with CPET and the information that can be derived from it.
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