Lung function and stress echocardiography in pulmonary arterial hypertension: a cross-sectional study

ABSTRACT BACKGROUND: The mechanism of exercise limitation in idiopathic pulmonary arterial hypertension (IPAH) is not fully understood. The role of hemodynamic alterations is well recognized, but mechanical, ventilatory and gasometric factors may also contribute to reduction of exercise capacity in these individuals. OBJECTIVE: To investigate whether there is an association between ventilatory pattern and stress Doppler echocardiography (SDE) variables in IPAH patients. DESIGN AND SETTING: Single-center prospective study conducted in a Brazilian university hospital. METHODS: We included 14 stable IPAH patients and 14 age and sex-matched controls. Volumetric capnography (VCap), spirometry, six-minute walk test and SDE were performed on both the patients and the control subjects. Arterial blood gases were collected only from the patients. The IPAH patients and control subjects were compared with regard to the abovementioned variables. RESULTS: The mean age of the patients was 38.4 years, and 78.6% were women. The patients showed hypocapnia, and in spirometry 42.9% presented forced vital capacity (FVC) below the lower limit of normality. In VCap, IPAH patients had higher respiratory rates (RR) and lower elimination of CO2 in each breath. There was a significant correlation between reduced FVC and the magnitude of increases in tricuspid regurgitation velocity (TRV). In IPAH patients, VCap showed similar tidal volumes and a higher RR, which at least partially explained the hypocapnia. CONCLUSIONS: The patients with IPAH showed hypocapnia, probably related to their higher respiratory rate with preserved tidal volumes; FVC was reduced and this reduction was positively correlated with cardiac output.


INTRODUCTION
Pulmonary arterial hypertension (PAH) is a rare disease characterized by increased pulmonary arterial pressure as a consequence of remodeling of arterial pulmonary microcirculation. Idiopathic pulmonary arterial hypertension (IPAH) is diagnosed after ruling out pulmonary hypertension associated with left heart disease, hypoxic lung diseases, chronic pulmonary thromboembolic disease and some other conditions of PAH. 1 Clinically, IPAH produces severe and progressive limitation on physical exercise and activities of daily living. The exercise limitation is usually explained by the progressive reduction in cardiac output (CO), but there are still many gaps in the understanding of the interrelationships between hemodynamic abnormalities and respiratory mechanics. Volumetric capnography (VCap), spirometry and blood gas analysis can reveal aspects of ventilatory patterns that are not routinely investigated. We hypothesized that some of these resting variables could have correlations with hemodynamic variables collected during stress Doppler echocardiography (SDE).

OBJECTIVE
In order to investigate this hypothesis, we sought to assess the resting breathing pattern among patients with IPAH, by means of VCap, arterial blood gases and spirometry. Patients were also evaluated during exercise by means of the six-minute walk test (6MWT) and SDE. We then sought to identify whether the variables obtained at rest would correlate with those collected during exercise.

METHODS
This was a single-center prospective observational study conducted at the Department of Pulmonology of a Brazilian university hospital. We considered for inclusion all patients with IPAH, of both sexes and over 18   The variations between rest (r) and stress (s) were calculated for TRV, SPAP, PVR and CO and were designated as ∆TRV = TRV s -TRV r ; ∆SPAP = SPAP s -SPAP r ; ∆PVR = PVR s -PVR r ; and ∆CO = CO s -CO r , respectively. Echocardiographic assessments were performed in accordance with current guidelines. 8

Data analysis
Exploratory data analysis was performed using summary measurements (mean, standard deviation, minimum, median, maximum, frequency and percentage). The groups were compared using the Mann-Whitney test or Fisher's exact test, as appropriate. The factors for ΔTRV and ΔCO were evaluated by means of linear regression, after transformation of the variables into ranks.
Probability values of less than 0.05 were considered to be statistically significant. The analysis were performed using the SAS System for Windows (Statistical Analysis System, version 9.4; SAS Institute Inc., Cary, North Carolina, United States).

RESULTS
We evaluated the medical records of 99 patients with a previous diagnosis of IPAH who were being followed at our outpatient clinic. Of these, 24 met the inclusion criteria, but 10 declined to participate, leaving 14 patients who completed all the proposed tests. Fourteen control subjects who were matched for age and sex with the group of patients were also enrolled. The clinical data are shown in Table 1, and there were no differences between the groups regarding age, sex or BMI. None of the subjects in the control group had any respiratory symptoms.
Data on lung function and functional capacity (6MWT) are shown in Table 2. In spirometry, the IPAH patients had lower FVC and lower FEV 1 than the control subjects.
In the VCap evaluation, the IPAH patients had lower values than the control group, in relation to VCO 2 /br, Ti and Te. In addition, the respiratory rate was higher than in the control group. In blood gas analysis, all the IPAH patients presented hypocapnia at rest (PaCO 2 = 29.5 ± 4.6 mmHg).
In the 6MWT, the IPAH patients had significantly higher Borg index values before and at the end of the test, compared with the control group. They also walked shorter distances than the control group.
The stress Doppler echocardiography (SDE) results are shown in Table 3. All the IPAH patients discontinued the SDE test due to physical exhaustion, but all had a HR above 85% of maximal HR (220 beats per minute minus the patient's age). In the control group, the test was halted when submaximal HR was reached (above 80% of maximal HR).
The IPAH patients presented higher values for TRV than the control patients at rest (TRVr) and at exercise peak (TRVs). In addition, ΔTRV was higher in the patient group. Also, higher values for pulmonary vascular resistance and SPAP were observed in the IPAH group, compared with the control subjects. The two groups presented similar CO values at rest, but CO under stress and the difference between stress and rest (ΔCO) were significantly lower in the patient group than in the control group.  Values expressed as mean ± standard deviation. FVC = forced vital capacity; FEV 1 = forced expiratory volume in one second; LLN = lower limit of normality; RR = respiratory rate during VCap; Vd/Vt aw = ratio of tidal volume to anatomical dead space; VCO 2 = excretion of carbon dioxide; Ve = expiratory volume; Ti = inspiratory time; Te = expiratory time; EtCO 2 = end-tidal CO 2 ; VCO 2 /br = excretion of CO 2 per respiratory cycle; Slp3/Ve = slope 3 normalized according to expired volume; PaCO 2 = partial pressure of carbon dioxide in the arterial blood; Borg = scale for evaluation of the degree of respiratory discomfort before (at rest) and at the end of 6MWT test; HR = heart rate; SpO 2 = oxygen saturation of hemoglobin; ∆SpO 2 = SpO 2 in the sixth minute minus initial SpO 2 ; 6MWT = six-minute walk test.
In the correlation analysis, there were positive correlations between ΔTRV and FVC, pulmonary vascular resistance under stress (PVRs) and the variation in PVR during SDE (ΔPVR).
Thus, the higher the values of ΔTRV were, the higher the values of PVR, ΔPVR and FVC also were. We also found positive correlations between ΔCO and the values for BMI and PaCO 2 ; and a negative correlation between ΔCO and Vd/Vt aw. ( Table 4)

DISCUSSION
The patients presented hypocapnia at rest and, in comparison with the control subjects, had lower FVC. A higher proportion of the patients had FVC below the lower limit of normality (42.9% versus 0%), even with FEV 1 /FVC ratio > 0.8. In VCap, the IPAH patients presented a higher respiratory rate than the control subjects, with similar tidal volumes (Vi and Ve). Also, the VCO 2 eliminated at each expiration was lower in the patients. Taken together, these findings suggest a respiratory pattern at rest indicative of restrictive disorder and tachypnea.
The low PaCO 2 and higher respiratory rates measured in VCap suggested that the IPAH patients were hyperventilating even during rest, which could explain the hypocapnia. In fact, there is evidence that patients with PAH seem to hyperventilate during exercise, at rest and even during sleep. 9 Some authors found hypocapnia (PaCO 2 < 35 mmHg) in patients with pulmonary hypertension 10,11 and Hoeper et al. also showed that in IPAH patients, hypocapnia seemed to be an independent marker for mortality, whereas PaO 2 had no significant prognostic value. 10 Patients with left heart failure and pulmonary hypertension   evaluated lung function in patients with pulmonary hypertension (PH), compared with controls, and they identified signs of peripheral airway obstruction, seen as reductions in FVC and FEV 1 /FVC, and increases in residual volume and the residual volume/total lung capacity ratio. 14 These authors postulated that there was evidence of premature airway closure, leading to reduction in FVC, perhaps due to impairment of lung elastic recoil.
In our study, we also found a positive correlation between ΔTRV (difference in tricuspid regurgitation velocity between rest and peak effort) and FVC (P = 0.029). Richter et al. described a negative correlation between the change in inspiratory capacity (IC) during exercise and the pulmonary vascular resistance. Moreover, they observed that the reduction in IC seemed to be related to a decrease in aerobic exercise capacity. 11 The same authors suggested that IC might have prognostic value among patients with PH: patients with better IC at rest (> 89% of predicted values) have significantly better survival rates than those with IC ≤ 89%. 15 Laveneziana et al. 16 also identified signs of dynamic hyperinflation (DH) and reduction of IC as factors involved in exercise limitation among PAH patients.
Meyer et al. reported that residual volumes and the residual volume/total lung capacity ratios were significantly higher in PH patients than in controls, but that airway resistance was similar in the two groups. Those patients showed airflow limitation that could be explained by loss of elastic recoil. 14 Considering that the reduction in FVC may be related to the reduction in resting inspiratory capacity, it can be speculated that this reduction of FVC may have some prognostic significance. The positive correlation between ΔTRV and FVC that we found in our study gives strength to this hypothesis, since exercise-induced increases in TRV and PSAP may be considered to be measurements of right ventricular contractile reserve. Using stress Doppler echocardiography, Grünig et al. demonstrated that exercise-induced increases in PSAP had clinical and prognostic relevance in PH patients, such that the lower the pressure increase was, the worse the prognosis also was. 17 VCap evaluation showed that the IPAH patients had increased respiratory rates even at rest, without changes in expired volumes.
Interestingly, they eliminated less CO 2 per breath (P = 0.012) and had lower EtCO 2 , although this difference was not statistically significant (P = 0.069). Some investigators have shown that patients with PAH have low EtCO 2 , and that they present a further decrease from baseline in cardiopulmonary exercise testing. [18][19][20] As discussed above, the patients in this study had hypocapnia at rest, a condition that explains their low CO 2 values per breath (VCO 2 /br) and low EtCO 2 . There was no significant difference in the elimination of CO 2 per minute between the cases and controls, given that the patients had higher respiratory rates.
It is also noteworthy that CO 2 elimination is related to CO, and that VCap has been used to monitor the efficiency of cardiac resuscitation procedures. However, this relationship may not be linear. Smaller reductions in CO than those observed in cardiac arrest are probably not detected through VCap.
Although our results are tentative, they suggest that there is a characteristic ventilatory pattern in patients with IPAH. The reduction in FVC, the hypocapnia and the VCap findings might be associated with reduction in pulmonary perfusion and low right ventricular contractile reserve.

Limitations and strengths
One of the strengths of our study is that it searched for noninvasive methods for assessing patients with PH, such as VCap.
Lung function has been poorly studied in patients with PH, and findings such as reduced vital capacity or hypocapnia may have clinical relevance as biomarkers. Considering the small number of patients studied here, the findings cannot be generalized to all patients with pulmonary hypertension. The unavailability of lung compliance and elastance analysis prevented confirmation of the hypothesis raised in this study. Our findings are tentative and need further investigation. Nevertheless, the idea is appealing and, from our perspective, deserves consideration.