Background
Acute pulmonary vasodilator testing is important for patients with pulmonary arterial hypertension, but little is known about the predictors of response to such testing.
Methods
Forty-eight patients (mean age, 41.3 ± 11.6 years; 91.7% women) with pulmonary arterial hypertension associated with connective tissue diseases who underwent right-heart catheterization and acute pulmonary vasodilator testing were prospectively recruited. Echocardiography was performed before and immediately after testing.
Results
There were 14 responders (29.2%) to acute pulmonary vasodilator testing. Responders had lower pulmonary vascular resistance, higher peak systolic velocity of the lateral tricuspid valve annulus (right ventricular [RV] S′) and tricuspid annular plane systolic excursion, and smaller RV end-diastolic area. After vasodilator testing, mean pulmonary artery pressure and pulmonary vascular resistance decreased significantly in both groups, cardiac index increased significantly in responders, and RV function improved significantly in nonresponders. Receiver operating characteristic curve analysis identified an optimal cutoff value for RV S′ of ≥10.5 cm/sec to predict response, with sensitivity of 71% and specificity of 71%. There were more responders among patients with RV S′ ≥ 10.5 cm/sec (45.5% vs 15.4%, P = .02). On multivariate logistic regression analysis, RV S′ ≥ 10.5cm/sec emerged as an independent predictor of response (odds ratio, 4.58; 95% confidence interval, 1.18–17.79; P = .02).
Conclusions
Right-heart function is better in responders to acute pulmonary vasodilator testing than in nonresponders among patients with pulmonary arterial hypertension associated with connective tissue diseases, and pulmonary vasodilators may improve RV function in nonresponders and cardiac index in responders. RV S′ is a simple and clinically useful tool for predicting the results of pulmonary vasodilator testing.
Acute pulmonary vasodilator testing is important for patients with pulmonary arterial hypertension (PAH) to identify those who may benefit from long-term therapy with calcium channel blockers, and it is recommended in both idiopathic PAH and PAH associated with connective tissue diseases (CTDs) such as systemic sclerosis (SSC) and systemic lupus erythematosus (SLE).
To our knowledge, there is no established predictor of acute response to pulmonary vasodilator testing. Acute responders have a better prognosis, and right-heart function is also an important determinant of prognosis in patients with PAH. We hypothesized that right-heart function may reflect pulmonary vasoreactivity, and better right-heart function may predict positive results on acute pulmonary vasodilator testing.
Methods
Patients
Between February 2010 and February 2011, patients who underwent right-heart catheterization for PAH associated with CTDs (mainly SLE and SSC) were enrolled in this study. PAH was defined as mean pulmonary artery pressure (mPAP) > 25 mm Hg with a pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg and pulmonary vascular resistance (PVR) > 3 Wood units on right-heart catheterization. SLE was diagnosed according to the 1982 revised American Rheumatism Association criteria, and SSC was diagnosed according to the 1980 American Rheumatism Association definition.
The study protocol was reviewed and approved by the ethics committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (Beijing, China), and all patients provided written informed consent.
Hemodynamic Measurements and Acute Pulmonary Vasodilator Testing
Right-heart catheterization hemodynamic assessments were obtained before and after acute pulmonary vasodilator testing. A 8.5-Fr introducer sheet was placed in the right internal jugular vein or the right subclavian vein, and a six-lumen 8-Fr Swan-Ganz catheter (Edwards Lifesciences, Irvine, CA) was advanced into the pulmonary artery. Systemic blood pressure, mean right atrial pressure, mPAP, and PCWP were measured at baseline and after vasodilator drug administration. Cardiac output was measured in triplicate using the thermodilution technique (Edwards Lifesciences). The cardiac index (CI) was calculated as cardiac output indexed to body surface area. PVR was calculated using standard hemodynamic formulas.
After baseline measurement of hemodynamic parameters, iloprost 20 μg (Ventavis; Bayer-Schering Pharma, Berlin, Germany) was delivered by a PARI LC STAR nebulizer (PARI GmbH, Starnberg, Germany) driven by a PARI TurboBOY-N compressor (PARI GmbH) for 10 to 15 min. Another complete set of hemodynamic parameters was obtained at the end of inhalation.
Acute response was defined according to the international consensus statement as a decrease in mPAP of ≥10 mm Hg to reach an absolute value <40 mm Hg, with increased or unchanged cardiac output.
Echocardiography
All subjects underwent echocardiographic examination before and immediately after acute pulmonary vasodilator testing using commercially available equipment (Vivid I; GE Vingmed Ultrasound AS, Horten, Norway). All studies were performed and reviewed by cardiologists with advanced training in echocardiography.
Right atrial area, inferior vena cava, end-diastolic right ventricular (RV) wall thickness, and tricuspid annular plane systolic excursion (TAPSE) were measured according to the American Society of Echocardiography’s guidelines. RV end-diastolic area (RVEDA), RV end-systolic area, and RV fractional area change were assessed in the apical four-chamber view. Left ventricular (LV) end-diastolic volume, LV end-systolic volume, and LV ejection fraction were assessed using the modified biplane Simpson equation in the apical four-chamber and two-chamber views.
Doppler tissue imaging was performed in the apical four-chamber view for the long-axis motion of the heart. The pulsed Doppler sample volume was placed at the lateral tricuspid valve (TV) annulus to obtain the systolic (RV S′), and early diastolic (RV E′) velocities ( Figure 1 ). TV closure opening time and ejection time were measured using pulsed Doppler tissue imaging. The RV index of myocardial performance (RMPI) was calculated according the following formula: RMPI = (TV closure opening time − ejection time)/ejection time.
Tricuspid inflow was assessed using pulsed-wave Doppler echocardiography from the apical four-chamber view. The Doppler beam was aligned parallel to the direction of flow, and a 1-mm to 2-mm sample volume was placed between the tips of tricuspid leaflets during diastole. From the inflow profile, the E-wave and A-wave velocities of the TV were obtained. The E/E′ and E/A ratios from the TV were calculated.
During echocardiography, at least three consecutive beats were stored, and the images were analyzed offline using EchoPAC version 6.3.6 (GE Vingmed Ultrasound AS).
The right ventricle was assessed by right atrial area, RV wall thickness, RV outflow tract, RVEDA, RV fractional area change, RV S′,TAPSE, RMPI, TV E/A ratio, and RV E/E′ ratio. At least three consecutive beats were measured, and the average value was taken.
Statistical Analysis
Differences in mean values between the two groups were examined using independent or paired t tests, and categorical variables were analyzed using χ 2 or Fisher’s exact tests. Multivariate logistic regression analysis was performed to investigate the independent effect of various covariates on acute response to pulmonary vasodilator testing in a stepwise forward conditional manner, with entry and retention in the model set at a significance level of .05. SPSS version 13.0 (SPSS, Inc., Chicago, IL) was used for calculations. All data are expressed as mean ± SD. P values < .05 were considered statistically significant.
Results
A total of 48 patients (mean age, 41.3 ± 11.6 years; 91.7% women) were enrolled in the study. There were 14 responders (29.2%) to acute pulmonary vasodilator testing. Patients were divided into groups of responders and nonresponders. Baseline clinical characteristics, hemodynamic parameters, echocardiographic data, and the results of vasodilator testing are listed in Tables 1 and 2 .
| Variable | Acute responders ( n = 14) | Nonresponders ( n = 34) | P |
|---|---|---|---|
| Age (y) | 43.3 ± 8.6 | 40.5 ± 12.6 | .46 |
| Women | 14 (100%) | 30 (88.2%) | .31 |
| Diagnosis | |||
| SLE | 10 | 24 | |
| SSC | 4 | 10 | .95 |
| Blood pressure (mm Hg) | |||
| Systolic | 115.3 ± 18.6 | 121.9 ± 25.1 | .38 |
| Diastolic | 71.6 ± 8.3 | 78.3 ± 13.1 | .08 |
| RV S′ (cm/sec) | 11.9 ± 2.2 | 9.7 ± 1.9 | <.01 |
| RVFAC | 0.3 ± 0.1 | 0.3 ± 0.1 | .93 |
| TAPSE (mm) | 19.7 ± 2.6 | 17.8 ± 2.4 | .02 |
| RMPI | 0.5 ± 0.1 | 0.5 ± 0.2 | .59 |
| RV E/E′ ratio | 5.5 ± 1.6 | 6.3 ± 2.7 | .78 |
| TV E/A ratio | 0.82 ± 0.35 | 0.82 ± 0.28 | .95 |
| RA area (cm 2 ) | 14.3 ± 2.8 | 15.3 ± 3.6 | .32 |
| RVEDA (cm 2 ) | 16.4 ± 1.3 | 19.5 ± 5.7 | <.01 |
| RVWT (mm) | 5.4 ± 0.8 | 5.1 ± 1.0 | .23 |
| IVC (mm) | 12.1 ± 3.0 | 12 ± 3.2 | .89 |
| LVEDV (mL) | 49.9 ± 9.7 | 46.9 ± 11.4 | .40 |
| LVEF (%) | 65.1 ± 7.1 | 63.1 ± 7.7 | .40 |
| mRAP (mm Hg) | 3.3 ± 2.6 | 4.5 ± 3.3 | .18 |
| mPAP (mm Hg) | 39.9 ± 6.9 | 44.1 ± 11.3 | .12 |
| PCWP (mm Hg) | 6.4 ± 4.1 | 6.1 ± 3.2 | .74 |
| CI (L/min/m 2 ) | 2.7 ± 0.6 | 2.5 ± 0.8 | .43 |
| PVR (Wood units) | 7.8 ± 3.6 | 11.7 ± 7.9 | .02 |
| Variable | Responders ( n = 14) | P | Nonresponders ( n = 34) | P | ||
|---|---|---|---|---|---|---|
| Before testing | After testing | Before testing | After testing | |||
| Blood pressure (mm Hg) | ||||||
| Systolic | 115.3 ± 18.6 | 105.7 ± 10.7 | .01 | 121.9 ± 25.1 | 117.4 ± 29 | .01 |
| Diastolic | 71.6 ± 8.3 | 66.9 ± 8.1 | .02 | 78.3 ± 13.1 | 69.7 ± 13.9 | <.01 |
| mPAP (mm Hg) | 39.9 ± 6.9 | 28.1 ± 6.6 | <.01 | 44.1 ± 11.3 | 38.2 ± 13.1 | <.01 |
| PCWP (mm Hg) | 6.4 ± 4.1 | 6.7 ± 2.3 | .78 | 6.1 ± 3.2 | 6.7 ± 3.3 | .08 |
| CI (L/min/m 2 ) | 2.7 ± 0.6 | 3.0 ± 0.6 | <.01 | 2.5 ± 0.8 | 2.6 ± 0.7 | .91 |
| PVR (Wood units) | 7.8 ± 3.6 | 4.6 ± 2.2 | <.01 | 11.7 ± 7.9 | 9.6 ± 7.0 | <.01 |
| RV S′ (cm/sec) | 11.9 ± 2.2 | 12.1 ± 2.9 | .57 | 9.7 ± 1.9 | 11.1 ± 2.1 | <.01 |
| RVFAC | 0.3 ± 0.1 | 0.4 ± 0.1 | .39 | 0.3 ± 0.1 | 0.3 ± 0.1 | .10 |
| TAPSE (mm) | 19.7 ± 2.6 | 20.7 ± 3.5 | .17 | 17.8 ± 2.4 | 18.7 ± 2.2 | .21 |
| RMPI | 0.5 ± 0.1 | 0.5 ± 0.2 | .20 | 0.5 ± 0.2 | 0.6 ± 0.3 | .34 |
| RV E/E′ ratio | 5.5 ± 1.6 | 5.6 ± 1.3 | .81 | 6.3 ± 2.7 | 5.8 ± 2.7 | .04 |
| TV E/A ratio | 0.82 ± 0.35 | 0.81 ± 0.36 | .33 | 0.82 ± 0.28 | 0.77 ± 0.20 | .11 |
| LVEDV (mL) | 49.9 ± 9.7 | 49.0 ± 11.0 | .64 | 46.9 ± 11.4 | 48.8 ± 8.6 | .07 |
| LVEF (%) | 65.1 ± 7.1 | 63.6 ± 4.2 | .44 | 63.1 ± 7.7 | 63.1 ± 5.6 | .95 |
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