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(Chest. 2006;130:841-846.)
© 2006 American College of Chest Physicians

Chronic Thromboembolic and Pulmonary Arterial Hypertension Share Acute Vasoreactivity Properties*

Silvia Ulrich, MD; Manuel Fischler, MD; Rudolf Speich, MD, FCCP; Vladimir Popov, MD and Marco Maggiorini, MD, FCCP

* From the Department of Internal Medicine (Drs. Ulrich, Fischler, Speich, and Maggiorini), Divisions of Respiratory and Critical Care Medicine, University Hospital Zurich, Zurich, Switzerland; and Clinic of Pulmonary Medicine and Rehabilitation (Dr. Popov), Barmelweid, Switzerland.

Correspondence to: Silvia Ulrich, MD, Department of Internal Medicine, University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland; e-mail: ulris{at}bluewin.ch

Abstract

Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the major classes of pulmonary hypertensive disorders according to the World Health Organization; both lead to right heart failure and death. A better understanding of disease mechanisms has led to the suggestion that the thromboembolic and nonthromboembolic types of pulmonary hypertension may share pathophysiologic features. We therefore compared acute vasoreactivity and proximal pulmonary artery compliance in patients with PAH and CTEPH during the initial diagnostic heart catheterization.

Methods: Right heart catheterization using a flow-directed Swan-Ganz catheter was performed in patients with CTEPH (n = 22) and PAH (n = 35). Pulmonary hemodynamics were assessed at baseline, during the inhalation of 40 ppm of nitric oxide, and 30 min after the inhalation of 10 µg of iloprost. To assess the proximal pulmonary artery compliance, the pulse pressure (PP) [systolic – diastolic pressure] and the fractional PP (PPf) [divided by the mean pressure] were calculated.

Results: Both vasodilators produced similar hemodynamic improvement, and the difference between CTEPH and PAH was not significant. The baseline PP and PPf did not vary between the two groups.

Conclusion: Patients with PAH and CTEPH show similar acute vasoreactivity to inhaled nitric oxide and iloprost, and have similar pulmonary artery compliance. These findings support the presence of some shared pathophysiologic pathways in both disorders and may lead to therapeutic implications in patients with inoperable CTEPH.

Key Words: chronic thromboembolic pulmonary hypertension • pulmonary arterial hypertension • pulmonary hemodynamics • pulmonary vascular compliance • vasoreactivity testing

Structural and functional changes in the vascular wall and thrombus formation are the main factors responsible for increased pulmonary vascular resistance (PVR) in patients with pulmonary hypertension (PH).12 The contribution of each of these factors is thought to be different among the variables underlying the causes of PH, thereby accounting for the varying responses to treatment with vasodilatative and antiproliferative agents in patients with PH of different etiology.3 Accordingly, pulmonary vasodilator agents have been used primarily for the treatment of patients with pulmonary arterial hypertension (PAH) and to a lesser extent in those patients with chronic thromboembolic PH (CTEPH) because of the notion that the fibrous organization of thrombotic material in the proximal vessel wall would block the vasodilator effect.

Nakayama and coworkers4 suggested the use of pulsatility indexes to distinguish between proximal and distal pulmonary arterial involvement. They showed that patients with CTEPH have higher pulmonary artery pulse pressures (PPs) [systolic – diastolic pressure] and lower mean pulmonary artery pressures (MPAPs) compared to patients with PAH, suggesting decreased proximal pulmonary arterial compliance and a less pronounced distal vessel involvement.4 However, these hemodynamic differences could not be confirmed in a 2002 cohort.5 Castelain et al5 explained their results by a secondary increase in vascular resistance at the level of small pulmonary arteries in patients with end-stage CTEPH, and suggested a common pathophysiologic mechanism between end-stage CTEPH and end-stage PAH. This new theory is supported by the histologic examination of small pulmonary vessels in CTEPH patients,6 which has indicated that the morphology of the vessels not affected by thrombotic occlusion is similar to that in PAH patients, as well as by other clinical trials,789 which have shown a favorable effect of vasodilator treatment not only in patients with PAH but also in those with CTEPH. To test this new concept, we conducted acute vasoreactivity testing using inhaled nitric oxide (iNO) and inhaled iloprost (iILO) in patients with PAH and CTEPH (World Health Organization [WHO] functional class III to IV) during their initial diagnostic right heart catheterization.

Materials and Methods

Patient Population
Thirty-five patients with PAH and 22 patients with CTEPH were included in the study after obtaining written informed consent. The study was approved by the local ethics committee. PAH was diagnosed as idiopathic (n = 25) if the evaluation performed before catheterization did not reveal any other causes of elevated pulmonary pressure and was associated with other conditions such as congenital heart disease (n = 6), connective tissue disease (n = 2), and HIV (n = 2) that were diagnosed by medical history, echocardiography, antibody screening, rheumatologic examination, blood analyses, and additional tests if required according to best clinical practice (eg, pulmonary function tests, blood gas assessment, thoracic CT scan, and coronary angiography). CTEPH was diagnosed if both the radioisotope ventilation-perfusion scan showed more than two areas with perfusion defects and pulmonary angiography showed clear evidence of chronic major-vessel thromboembolic disease with disruption or changes in vessel caliber, arterial wall irregularities, transversal bands tethering the arterial lumen, and/or the absence of segmental or lobar arterial branches. None of our patients had medical conditions that would pose a relative contraindication to vasodilator testing due to the possibility of systemic vasodilatation such as that occurring in severe coronary heart or cerebrovascular disease, preexisting systemic hypotension, or other life-threatening illnesses. Patients receiving regular vasodilatative medication were excluded from the study; other medication regimens were kept unchanged. Basic demographics, the 6-min walking distance (6MWD), and the Borg dyspnea scale were assessed according to standard protocols before right heart catheterization and at 3 and 12 months after catheterization; during this time, the patients were treated with either oral or inhaled pulmonary vasodilators.

Hemodynamic Assessment
All patients were investigated in the ICU. An 8F introducer sheath was placed in the right jugular or left subclavian vein, through which a triple-lumen 7.5F flow-directed Swan-Ganz catheter (Baxter/Edwards; Deerfield, IL) was placed in the pulmonary artery, which was confirmed by radioscopy. The transducers for continuous hemodynamic monitoring were positioned at the mid-axillary line and zeroed to atmospheric pressure. A 4F plastic (Teflon; Dupont; Wilmington, DE) catheter was inserted into the radial or femoral artery for continuous monitoring of systemic BP and arterial blood sampling. Pulmonary and systemic arterial pressures and the right atrial pressure (RAP) were continuously recorded, and the pulmonary artery occlusion pressure (PAOP) was recorded intermittently. The cardiac output (CO) was assessed by thermodilution (Cardiac Output Computer; Baxter/Edwards). The cardiac index (CI) was calculated as CO divided by the body surface area. PVR and systemic vascular resistance (SVR) were calculated according to the following standard formulas: PVR = (MPAP – PAOP) x 80/CO); and SVR = (MAP – RAP) x 80/CO). The PP was calculated as the difference between systolic and diastolic pressure, and the fractional PP was calculated by dividing PP by MPAP.410 Arterial and mixed-venous blood samples were drawn simultaneously and were analyzed for arterial oxygen saturation (SaO2) with a blood gas analyzer (model 865; Chiron; Emeryville, CA) that was automatically calibrated every hour.

Testing Protocol
After insertion of the catheter, the hemodynamics were measured until stable baseline values were obtained (ie, < 10% variation within measurements for at least 15 min). Thereafter, patients were instructed to inhale iNO at a dose of 40 ppm via a tightly fitting facial mask without additional oxygen. Complete hemodynamic measures were obtained after 10 min while the patient kept inhaling.1112 After an iNO washout period of at least 15 min and the return of hemodynamic values to baseline (< 10% variation to baseline), the patients inhaled 10 µg of iloprost (Ilomedin; Schering AG; Berlin, Germany) using an inhaler (Optineb; Nebu-Tec; Elsenfeld, Germany), and complete hemodynamic measures obtained 30 min later.

Statistical Analysis
All results are expressed as the median and interquartile range. A statistical software package (SPSS, version 12.0.1; SPSS; Chicago, IL) was used for the statistical analyses. For comparisons between patients groups and within single patients the Mann-Whitney U test and the Wilcoxon matched pair test were used as appropriate. To compare vasoreactivity test responders with nonresponders, the Pearson {chi}2 test was used. For correlations between responses to iNO and iILO, the Pearson correlation coefficient was calculated. A p value of < 0.05 was considered to be statistical significant.

Results

Patient Characteristics
A total of 57 patients, 35 with PAH and 22 with CTEPH, were included in the study. Patient characteristics are presented in Table 1 . Patients with CTEPH were on average older than those with PAH, and had lower CI, SaO2, and mixed venous saturation (SvO2). Other parameters did not vary significantly between the two groups.


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  		Table 1.. Baseline Characteristics*

 
Acute Vasoreactivity Testing
iNO and iILO significantly decreased MPAP and PVR in both PAH and CTEPH patients, and to a comparable extent. The response to iNO and iILO, as well as the response between patients with PAH and those with CTEPH, were not statistically significant (Table 2 , Fig 1 ). Pooling all patients, the correlation coefficient between iNO and iILO for the change in MPAP and PVR was 0.37 (p < 0.01) and 0.46 (p < 0.01), respectively. iILO but not iNO increased CI significantly in both the PAH (p = 0.008) and the CTEPH patients (p = 0.001). However, the difference between the two groups was not statistically significant (p = 0.57). Both vasodilators increased SvO2 significantly in both PAH and CTEPH patients (Fig 1). In both groups, the effect of both iNO and iILO on SaO2 was small and of questionable clinical relevance.


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  		Table 2.. Changes in Different Hemodynamic Variables Associated With Acute Vasoreactivity Testing*

 

Figure 1
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  		Figure 1.. Values are given as medians and interquartile ranges. * = p < 0.05 compared to baseline; t = p < 0.01 compared to baseline.

 
Based on the criterion of a MPAP or PVR reduction of ≥ 20%, more patients could be classified as pressure responders (p = 0.006) or resistance responders (p = 0.03) to iILO than to iNO (Table 3 ). Using the proposed positive response criteria13 with an absolute MPAP decrease of at least 10 mm Hg and < 40 mm Hg along with stable CI, the incidence of iNO responders remained nearly unchanged (5% vs 7%, respectively), whereas the number of iILO responders decreased from 21 to 12% (p = <0.001), the difference between iNO and iILO responders was still significant (p = 0.003) [Table 3]. In the pooled groups of patients, a positive response to iILO was associated with a concurrent positive response to iNO in 75% of the patients. Conversely, a positive response to iNO was present only in 25% of the patients with a positive response to iILO. The effect of both vasodilators was similar in the patients with PAH and those with CTEPH (Table 3).


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  		Table 3.. Responders to Vasoreactivity Testing According to Different Definition Criteria*

 
Follow-up of Patients After This Initial Hemodynamic Evaluation
After this diagnostic hemodynamic baseline examination, patients with PAH were treated with regular iILO (n = 18), bosentan (n = 16), and/or sildenafil (n = 2). The initial treatment of patients with CTEPH was with iILO (n = 20) and/or bosentan (n = 3). Five patients with CTEPH underwent successful pulmonary thrombendarterectomy after the initial vasoreactivity testing, nine patients declined the operation, major surgery was contraindicated in seven patients, and one patient underwent successful lung transplantation 2 years later. Therefore, the initial acute vasodilator response to iNO and/or iILO at the diagnostic baseline evaluation was not related to an improvement in WHO functional class or 6MWD. Again, there was no difference between the PAH and CTEPH patients.

Discussion

We found that the inhalation of iNO and/or iILO during the initial diagnostic right heart catheterization decreased MPAP and increased CI in patients with CTEPH and PAH who were in WHO functional classes III to IV, with the magnitude of the response as well as the number of responders being not different between CTEPH and PAH patients. Patients with PAH and CTEPH also had similar indexes of proximal pulmonary arterial compliance. These results suggest that CTEPH and PAH may share some pathophysiologic characteristics, which probably involve both the proximal and the distal precapillary pulmonary arteries.

Previous studies13141516 in patients with PAH have shown that iNO and iILO decrease MPAP by 9% on average, increase CO by 5 to 8%, and decrease PVR by 18%. We found a similar extent of vasodilator effect of these agents in our patients. However, despite a similar effect on MPAP and CI, in our study more patients could be identified as responders to iILO compared with iNO, independently of the criterion that we used to distinguish between vasoreactivity testing results in responders and nonresponders. The inhalation of iILO predicted a positive response to iNO in 75% of the patients; conversely, the inhalation of iNO identified only 25% of iILO responders. Whether this difference between iNO and iILO is of clinical relevance for the small number of responders in our study and other studies11141718 remains to be established. Until then, vasoreactivity testing with either agent singly is considered to be sufficient in the baseline evaluation of patients with PH.18

It is remarkable that in our cohort the acute vasodilator response between patients with major-vessel CTEPH and PAH was not different. The acute responses to various vasodilators have been widely investigated in patients with PAH,11112141619202122 but not in patients with CTEPH. Comparable acute hemodynamic responses have been reported for different PAH subclasses23 and were attributed to qualitatively similar histopathologic vascular characteristics between subclasses,24 which were mainly located in the distal pulmonary vascular bed, with a higher capacity to vasodilate. In recent years, a better understanding of the mechanisms responsible for elevated pulmonary arterial pressure and vascular resistance in the different types of PH has led to the suggestion that the thromboembolic and nonthromboembolic types of PH may share common pathophysiologic features.25 This concept is supported by data indicating that the mechanisms leading to PH in patients who have experienced repeated pulmonary thromboembolic events are not only mechanistic (ie, nonrecanalized thrombotic vessel occlusion),2627 but possibly also are related to vascular remodeling that is located distal to the occluded artery28 and in noninvolved adjacent pulmonary vessels,6 possibly leading to endothelial dysfunction. The vascular lesions in these noninvolved vessel segments were histologically indistinguishable from those in PAH patients.6 In line with this concept are observations that almost half of the patients with CTEPH did not have a history suggestive of acute pulmonary thromboembolism and that only 45% of patients have findings that are suggestive of previous venous thrombosis on lower extremity duplex ultrasound.29 In addition, the incidence of hereditary thrombophilia seems not to be increased in patients with CTEPH.3031 Central pulmonary artery thrombi have been shown to occur also in patients with PAH.32 In line with the results of studies reporting an active vascular remodeling process in CTEPH patients are also studies reporting789 the successful use of oral and inhaled vasodilators in patients with CTEPH. Thus, our results indicating a similar acute vasodilator response in patients with CTEPH and PAH support this new concept and encourage future vasodilator trials also in selected patients with CTEPH who are waiting for thrombendarterectomy, or who are not operable, or who have a major contraindication for surgery, many of whom were experiencing a very restricted quality of life with dismal prognosis.

The primary objective of acute vasodilator testing in patients with PAH is to identify the subset of patients who might be treated effectively with oral calcium-channel blockers. However, this drug class will probably never be a valuable therapeutic option in patients with CTEPH due to its capacity to increase ventilation-perfusion mismatch and thus intrapulmonary shunting.1333343536 In patients with PAH, a pronounced response to short-acting pulmonary vasodilators has been shown3738 to be associated with a better prognosis, at least in some patients. However, vasoreactivity testing has not been recommended for the assessment of long-term prognosis because of great interindividual variability. This view might be strengthened by our study results, which failed to show an association between acute vasodilatation response and change in functional class or 6MWD 3 and 12 months after the initiation of long-term vasodilator therapy in both CTEPH and PAH patients. Our findings also indicate that neither a structural difference between CTEPH and PAH nor the baseline vasodilator reserve are indicators of long-term treatment response. Thus, there is no rationale for performing vasoreactivity testing at the baseline evaluation in CTEPH patients as well. But these findings have to be interpreted with caution, as the present study was not designed to answer question concerning the relationship between acute vasoreactivity and the long-term response to vasodilatative treatment, as individual treatment strategies after the acute assessment differed considerably, not allowing a formal correlation study. Further, the results of the present study have to be interpreted with caution, as, for logistical reasons, the design was not randomized placebo-controlled, and investigators were not blinded concerning the patient’s medical records and history. This study, however, provides a rationale for future studies that would be sufficiently powered and designed to answer these clinically important questions.

In summary, in the present study we could show that, despite obvious differences between CTEPH and PAH, both entities share similar acute vasoreactivity properties and vessel compliance, indicating some common pathogenetic pathways, thus also providing a rationale for long-term vasodilator and antiproliferative treatment strategies in patients with inoperable CTEPH.

Footnotes

Abbreviations: CI = cardiac index; CO = cardiac output; CTEPH = chronic thromboembolic pulmonary hypertension; iNO = inhaled nitric oxide; iILO = inhaled iloprost; MPAP = mean pulmonary artery pressure; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; PP = pulse pressure; PPf = fractional pulse pressure; PVR = pulmonary vascular resistance; SaO2 = arterial oxygen saturation; 6MWD = 6-min walking distance; SvO2 = mixed venous saturation; SPAP = systolic pulmonary artery pressure

Drs. Ulrich, Fischler, Speich, Popov, and Maggiorini have been supported in attending research meetings by Actelion/Switzerland and Schering/Switzerland. Dr. Popov worked for 6 months (2002) at Actelion/Switzerland. Dr. Speich has received educational grants from Roche/Switzerland, Actelion/Switzerland, and Schering/Switzerland, and receives financial support for a study nurse from Actelion/Switzerland and Schering/Switzerland.

Received for publication January 8, 2006. Accepted for publication March 6, 2006.

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