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Effect of calcium channel blockers evaluated by cardiopulmonary exercise testing in idiopathic pulmonary arterial hypertension responding to acute pulmonary vasoreactivity testing
Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
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Effect of calcium channel blockers evaluated by cardiopulmonary exercise testing in idiopathic pulmonary arterial hypertension responding to acute pulmonary vasoreactivity testing Yi Tang a, Lei Yao b, Zhihong Liu a, *, Xiuping Ma a, Qin Luo a, Zhihui Zhao a, Zhiwei Huang a, Laura Tu c, Liu Gao a, Qi Jin a, Xinhai Ni a, Changming Xiong a a
Center for Pulmonary Vascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Department of Cardiology, People's Hospital of Shouguang City, Shandong, China c Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 June 2016 Received in revised form 21 January 2017 Accepted 28 January 2017 Available online 1 February 2017
Background: The baseline exercise capacity evaluated by cardiopulmonary exercise testing (CPET) and the change after administration of calcium channel blockers (CCB) therapy in patients with vasodilatorresponsive idiopathic pulmonary arterial hypertension (VR-IPAH)are unknown. Methods: 25 patients with newly diagnosed VR-IPAH from 1 January 2012 to 16 November 2015 were prospectively enrolled, and 28 age, sex and pulmonary vascular resistance matched newly diagnosed patients with vasodilator-nonresponsive idiopathic pulmonary arterial hypertension (VNR-IPAH) were enrolled. CPET was performed before and after 3.5 ± 0.8 months of CCB or sildenafil therapy. Results: Ventilatory efficiency at rest, anaerobic threshold (AT), and peak were significantly higher (lower _ _ VCO _ in VE/ 2@AT and higher in PETCO2@AT) in VR-IPAH group than that in VNR-IPAH group. Peak VO2 (13.9 ± 2.9 mL kg1$min1 vs 16.4 ± 4.1 mL kg1$min1, p ¼ 0.001), peak O2 pulse _ VCO _ (5.5 ± 0.8 mL min1$beat1 vs 6.9 ± 1.3 mL min1$beat1, p ¼ 0.001), VE/ 2@AT (34.2 ± 5.0 vs 31.6 ± 3.1, p ¼ 0.02) and PETCO2@AT (33.1 ± 4.0 mmHg vs 35.3 ± 3.2 mmHg, p ¼ 0.02) were significantly improved after high dose of CCB therapy, along with improvement of WHO functional class, 6-min walking distance, NT-proBNP and tricuspid regurgitation pressure gradient. Conclusions: Ventilatory efficiency in patients with VR-IPAH is better than that in patients with VNRIPAH. CCB can improve aerobic capacity and ventilatory efficiency during exercise in patients with VRIPAH. Clinical trial registration number: ClinicalTrials.gov:NCT02061787. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Idiopathic pulmonary arterial hypertension Cardiopulmonary exercise testing Vasoreactivity testing Calcium channel blockers Chemical compounds studied in this article: Diltiazem (PubChem CID: 39186) Diltiazem (PubChem CID: 2162) Sildenafil (PubChem CID: 5212)
1. Introduction Pulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary vascular resistance that
leads to right heart failure and death. The REVEAL registry of pulmonary arterial hypertension study showed that the 5-year survival rate for newly diagnosed group 1 PAH was 61.2% [1]. However, a subset of idiopathic pulmonary arterial hypertension (IPAH)
Abbreviations: AT, anaerobic threshold; CCB, calcium channel blockers; CI, Cardiac index; CPET, cardiopulmonary exercise testing; DBP, diastolic blood pressure; HR, heart rate; LVED, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal of the prohormone brain natriuretic peptide; PCWP, pulmonary capillary wedge pressure; PETCO2@AT, endtidal partial pressure of carbon dioxide at anaerobic threshold; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RER, respiratory exchange ratio; RHC, right heart catheterization; RVED, right ventricular end-diastolic diameter; RVEDP, right ventricular end-diastolic pressure; SBP, systolic blood pressure; SPO2, arterial oxygen saturation; SvO2, mixed venous oxygen saturation; TRPG, ricuspid regurgitation pressure _ ventilation; VE/ _ VCO _ _ gradient; VE, 2@AT, ratio of ventilation to carbon dioxide output at anaerobic threshold; VO2, oxygen consumption; VR-IPAH, vasodilator-responsive idiopathic pulmonary arterial hypertension; VNR-IPAH, vasodilator-nonresponsive idiopathic pulmonary arterial hypertension; WHO-FC, World Health Organization Functional Class; 6WMD, 6 min walk distance; 6MWT, 6 min walk test. * Corresponding author. Center for Pulmonary Vascular Diseases, Fuwai Hospital, 167 BeiLiShi Rd, Xicheng District, Beijing 100037, China. E-mail address: [email protected] (Z. Liu). http://dx.doi.org/10.1016/j.pupt.2017.01.012 1094-5539/© 2017 Elsevier Ltd. All rights reserved.
Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
characterized by acute vasodilator responsiveness for vasodilator agents (VR-IPAH), who has excellent survival time under the treatment of calcium channel blockers (CCB), has a 5-year survival rate of 98% [2]. The effects of CCB in patients with VR-IPAH is mainly evaluated by right heart catheterization (RHC), 6 min walking distance (6WMD),NT-proBNP, electrocardiogram and WHO function class [2,3]. Recently, cardiopulmonary exercise testing (CPET) has been widely used in patients with PAH, as it can accurately quantify cardiorespiratory fitness and formulate function-based prognostic _ 2 rather than stratification [4]. Study also showed that peak VO resting hemodynamic parameters obtained from RHC is an independent and strong predictor of survival in patients with IPAH [5].The effects of sildenafil on exercise capacity in patients with PAH have already been evaluated by CPET [6].However, the characteristics of CPET in patients with VR-IPAH and the change after CCB therapy have not been previously studied. The main aim of our study was to investigate the characteristics of CPET before and after the treatment of high doses of CCB in patients with VR-IPAH. 2. Material and methods 2.1. Study sample Patients aged over 18 years old with newly diagnosed IPAH who demonstrated a significant acute response to aerosolised iloprost at Fuwai Hospital from 1 January 2012 to 16 November 2015 were prospectively enrolled, meanwhile, patients aged over 18 years old with newly diagnosed IPAH who did not demonstrate a significant acute response to aerosolised iloprost (VNR-IPAH) and treated with sildenafil from 1 January 2012 to 1 January 2014 were also prospectively enrolled. IPAH was defined according to 2009ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension [7]. Patients with the following conditions were excluded: (1) other types of pulmonary hypertension; (2) hemodynamic instability; (3) NYHA class IV; (4) restrictive or obstructive pulmonary disease. The study complies with the Declaration of Helsinki and was approved by the Ethics Committee of Fuwai Hospital (No. 2011e331). All written informed consents were obtained from participants. 2.2. Cardiopulmonary exercise testing Symptom-limited CPET was performed on all recruited patients with VR-IPAH and patients with VNR-IPAH at baseline. Gas exchange measurements (Cosmed, Italy) were performed continuously during the 3 min of resting time, 3 min of unloaded pedaling at 60 rpm followed by a progressively increasing work rate exercise of 5e20 W/min to maximum tolerance, and then 5 min of recovery. _ 2), carbon dioxide output (VCO _ Oxygen consumption (VO 2) and _ were computer-calculated breath by breath minute ventilation (VE) and averaged over 10s intervals. AT (anaerobic threshold) was detected by a combination of the V-slope method and ventilatory _ 2 equivalents for oxygen.O2 pulse was calculated by dividing the VO by heart rate (HR). Pulmonary gas exchange was assessed by _ measuring the ratio of ventilation to carbon dioxide output (VE/ _ VCO 2) and end tidal partial pressure of carbon dioxide (PETCO2). Pulse oximetry (SpO2), HR, 12-lead ECG and blood pressure were monitored and recorded. The equipment was calibrated in a standard procedure using reference gases prior to each test.
27
study. Aerosolised iloprost was used when subjects underwent acute pulmonary vasodilator testing according to the methods reported previously [8]. After baseline hemodynamic parameters and blood gases have been obtained, 20 mg iloprost (Bayer-Schering Pharma) was delivered by a PARI LC STAR nebulizer (PARI GmbH) driven by a PARI TurboBOY-N compressor (PARI GmbH) for 10e15min. Following that, another set of hemodynamic measurements and blood gases was obtained. Blood gas analysis was performed using a blood gas analyzer (Nova Biomedical). A positive acute response was defined as a decrease of mean pulmonary arterial pressure (mPAP) by more than 10 mmHg to below 40 mmHg with an increased or preserved cardiac output (CO). CO was calculated by Fick's method and cardiac index (CI) was calculated by dividing cardiac output by body surface area. Pulmonary vascular resistance (PVR) was calculated as dividing (mPAPePCWP) by pulmonary blood flow. Spirometry and body plethysmography were performed with the use of a constant volume body plethysmograph (Cosmed, Italy) to exclude underlying restrictive or obstructive pulmonary disease. Anthropometry data, blood pressure, 6 min walk test (6MWT), electrocardiograms, echocardiograms, routine blood examinations, N-terminal pro-brain natriuretic peptide (NT-proBNP) were also evaluated at baseline. 2.4. Calcium channel blockers or sildenafil therapy and follow -up Oral CCB therapy was initiated in patients with newly diagnosed VR-IPAH. Diltiazem or amlodipine was used, which depended on the patient's heart rate at rest (diltiazem for heart rate 100 bpm, amlodipine for heart rate <100 bpm) [3]. Patients were recommended to add 1.25 mg or 2.5 mg of amlodipine (once a day), 7.5 mg or15 mg of diltiazem (three times a day) every three or five days on the basis of previous drug doses until they exhibited side effects such as hypotension or bradycardia after they were discharged. Patients with newly diagnosed VNR-IPAH received sildenafil, which was given at a dose of 20 mg three times a day. For both groups, warfarin was prescribed to patients if they did not have any contradiction or adverse effects. Diuretics and digoxin were prescribed to patients based on physician's judgement of patient's condition. Patients were followed up 3e6 months after treatment with CCB or sildenafil. CPET, 6MWT, WHO function class, NT-proBNP, echocardiography were performed again except RHC. In addition, cardiovascular events, the dose of the CCB, the side effects, blood pressure, heart rate, routine blood examinations, chest X-ray electrocardiograms were also performed. 2.5. Statistical analysis Continuous variables with normal distribution were expressed as mean ± SD and as median and interquartile range with nonnormal distribution, while categorical variables were presented as percentages or absolute numbers. Comparisons between VR-IPAH group and control group were made using chi-square tests for categorical variables, independent-samples Student's t tests for normally distributed continuous variables, and ManneWhitney U tests for non-normally continuous distributed variables. A paired Student's t tests was used to compare variables between baseline and follow-up. All testing was 2 tailed at a significance level of 0.05. All statistical analyses were performed using SPSS version 19.0(SPSS, Inc., Chicago, IL, USA).
2.3. Right heart catheterization 3. Results Diagnostic RHC with standard hemodynamic measurements was performed at baseline within 5 days of each patient's CPET
Twenty-five patients met the criteria of IPAH who also
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Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
demonstrated a significant acute response to iloprost, and Twentyeight age, sex and PVR matched patients with VNR-IPAH were enrolled. The mean follow-up time was 3.5 ± 0.8 months (3e6 months). No serious adverse events such as severe hypotension, right heart failure, or death were observed during the follow up in both groups, the mean daily dose of diltiazem (n ¼ 18) was 320 ± 90 mg (range, 180e540 mg), that of amlodipine (n ¼ 7) was 12±5 mg (range, 7.5e15 mg).Four patients had mild headache after treatment with sildenafil and well tolerated in VNR-IPAH group. Baseline characteristics of patients with VR-IPAH and VNR-IPAH are present in Table 1. The mean age, gender, height, weight and body surface area (BSA) did not differ between the two groups. There were no significant differences in the 6-min walk distance, tricuspid regurgitation pressure gradient (TRPG), NT-proBNP, PVR, cardiac index and background therapy between patients with VRPAH and VNR-PAH, but the mPAP was significantly higher in the VNR-PAH group than in the VR-PAH group (p ¼ 0.006). Baseline CPET characteristics of patients with VR-IPAH and VNRIPAH are present in Table 2. There were no accidents during CPET in both groups. All subjects exercised above their ATs. Ventilatory efficiency at rest, anaerobic threshold (AT), and peak were signifi_ VCO _ cantly lower (higher in VE/ 2@ AT and lower in PETCO2@ AT) in VNR-IPAH group than in VR-IPAH group, other CPET parameters at _ 2 and O2 pulse, were not rest, AT and peak, including work rate, VO significantly different between the VNR-IPAH and VR-IPAH group. The CPET parameters at rest, AT (anaerobic threshold) and peak at the baseline and after therapy are shown in Tables 3 and 4. In the _ VCO _ VNR-PAH group, the O2 pulse, PETCO2, VE/ 2 at rest, AT and peak
_ 2 at rest was were significantly improved after sildenafil therapy. VO _ 2 at AT tended to increase not significantly increased (p ¼ 0.19), VO _ 2 at peak was significantly increased (p ¼ 0.01). (p ¼ 0.08) and VO DBP at rest tended to decrease (p ¼ 0.06) and HR at rest was significantly decreased (p ¼ 0.02). In the VR-PAH group, the O2 pulse, PETCO2 at rest, anaerobic threshold and peak were significantly improved after CCB therapy. _ VCO _ _ Work rate, VE/ 2, VO2 at AT and peak were significantly _ _ _ 2 at rest were not significantly increased, but VE/VCO2, VO improved. DBP at rest was significantly decreased (p ¼ 0.005). HR at rest tended to decrease (p ¼ 0.08) and HR at peak was significantly decreased (p ¼ 0.02), however, in the VNR-PAH group, Work rate at AT and peak as well as HR at peak did not significant change _ VCO _ (p ¼ 0.17.0.20 respectively), VE/ 2 at rest was significantly improved (p ¼ 0.03). The parameters of WHO function class, 6MWD, NT-proBNP, uric acid, creatinine and echocardiograms at baseline and after therapy are shown in Table 5. In the VNR-PAH group, 6MWD, NT-proBNP significantly decreased after treatment with sildenafil, LVED tended to increase and TRPG tended to decrease (p ¼ 0.08, 0.08 respectively). Whereas, in the VR-PAH group, the 6MWD, NT-proBNP, uric acid, RVED and TRPG significantly decreased after treatment with CCB. The increase in LVED was borderline significant (p ¼ 0.05). 4. Discussion To our knowledge, for the first time, we report the baseline and the change of exercise capacity evaluated by CPET after CCB therapy
Table 1 Baseline characteristics of studied patients. Variable
VR-IPAH (n ¼ 25)
VNR-IPAH (n ¼ 28)
P
Age, year Male,% Height, cm Weight, kg BSA,m2 WHO-FC I/II, n III/IV, n Six-minute walk distance, m Echocardiographic measurements LVED,mm LVEF,% RVED,mm TRPG, mmHg Laboratory tests NT-proBNP, pg/ml Uric acid, mmol/L Creatinine, mmol/L Baseline hemodynamics Mean RAP, mmHg RVEDP, mmHg Mean PAP, mmHg Mean PCWP, mmHg PVR, woods CI, L$min1 m2 SVO2,% Medications Warfarin, n (%) Digoxin, n (%) Diuretics, n (%) Diltiazem, n (%) Amlodipine, n (%) Sildenafil, n (%)
33 ± 11 24.0 163.5 ± 6.8 59.7 ± 10.6 1.6 ± 0.2
35 ± 9 32.1 164.0 ± 8.4 66.2 ± 12.9 1.7 ± 0.2
0.61 0.55 0.86 0.14 0.17 0.10
15 10 455.6 ± 48.7
10 18 425.8 ± 57.8
0.13
± ± ± ±
0.34 0.18 0.35 0.15
38.4 63.5 30.6 89.6
± ± ± ±
6.3 3.7 4.4 30.3
36.3 65.1 32.2 75.5
5.1 6.1 7.7 20.2
852.4 (336.2,1079.5) 373.9 ± 115.4 68.5 ± 12.1
922.6 (583.5,1792.5) 456.9 ± 215.6 74.6 ± 16.9
0.24 0.19 0.27
4.1 ± 3.2 7.0 ± 4.6 43.8 ± 8.2 5.8 ± 2.6 7.9 ± 2.6 3.2 ± 0.9 73.3 ± 5.1
5.5 ± 5.4 9.6 ± 4.8 51.5 ± 5.4 5.8 ± 2.7 9.8 ± 3.5 3.0 ± 1.1 72.2 ± 6.9
0.40 0.14 0.006 0.96 0.12 0.66 0.61
22 (88.0) 19 (76.0) 18 (72.0) 18 (72.0) 7 (28.0) e
24 (85.7) 24 (85.7) 26 (92.8)
1.0 0.48 0.06 e e e
100 (100)
Data are expressed as mean ± SD or number of patients or percent (%). CI: Cardiac index; LVED: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; NT-proBNP: N-terminal of the prohormone brain natriuretic peptide; PAP: pulmonary artery pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure; RVED: right ventricular end-diastolic diameter; RVEDP: right ventricular end-diastolic pressure; SvO2: mixed venous oxygen saturation. TRPG: tricuspid regurgitation pressure gradient; VR-IPAH: vasodilator-responsive idiopathic pulmonary arterial hypertension; VNRIPAH: vasodilator-nonresponsive idiopathic pulmonary arterial hypertension; WHO-FC: World Health Organization Functional Class.
Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
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Table 2 Baseline cardiopulmonary exercise testing characteristics of studied patients. Variable
Rest
P value
VNR-IPAH
VR-IPAH
Work rate, W _ 2,mL$kg1$min1 VO RER O2 pulse, mL$min1$beat1 SBP, mmHg DBP, mmHg _ L$ min1 VE,
0 4.5 ± 1.1
0 4.5 ± 0.7
0.85 ± 0.13 3.3 ± 0.8 106 ± 9 76 ± 8 10.4 ± 2.3
PETCO2, mm Hg _ VCO _ VE/ 2 HR, min1 SPO2, %
AT
P value
VNR-IPAH
VR-IPAH
e 1.0
45.7 ± 11.7 9.8 ± 2.6
42.6 ± 11.6 10.3 ± 1.9
0.88 ± 0.08 3.1 ± 0.5 101 ± 11 76 ± 8 8.7 ± 2.1
0.98 0.32 0.22 0.92 0.91
0.91 ± 0.07 5.5 ± 1.3 138 ± 45 91 ± 36 23.9 ± 8.3
27.9 ± 4.2 43.3 ± 6.5
32.2 ± 3.3 36.6 ± 3.7
0.004 0.002
86 ± 14 95.8 ± 2.2
86 ± 9 96.5 ± 2.6
0.97 0.44
Peak
P value
VNR-IPAH
VR-IPAH sildenafil
0.90 0.87
81.8 ± 23.3 12.5 ± 3.4
73.7 ± 12.1 13.9 ± 2.9
0.85 0.89
0.92 ± 0.06 5.2 ± 1.0 121 ± 35 83 ± 13 19.1 ± 3.1
0.99 0.40 0.26 0.43 0.96
1.11 ± 0.14 5.7 ± 1.5 158 ± 46 97 ± 35 40.4 ± 10.7
1.11 ± 0.06 5.5 ± 0.8 146 ± 38 97 ± 20 33.7 ± 7.3
0.95 0.65 0.42 0.96 0.91
28.0 ± 6.6 42.7 ± 11.3
33.1 ± 4.0 34.2 ± 5.0
0.01 0.01
24.6 ± 6.0 47.6 ± 12.4
30.3 ± 6.0 38.0 ± 8.1
0.01 0.01
112 ± 14 94.9 ± 2.2
117 ± 14 96.1 ± 3.5
0.35 0.27
143 ± 24 92.1 ± 6.3
147 ± 17 93.6 ± 5.2
0.63 0.51
Data are expressed as mean ± SD. DBP: diastolic blood pressure; HR: heart rate; PETCO2@AT:endtidal partial pressure of carbon dioxide at anaerobic threshold; RER: res_ ventilation; VE/ _ VCO _ piratory exchange ratio; SBP: systolic blood pressure; SPO2: arterial oxygen saturation; VE: 2@AT: ratio of ventilation to carbon dioxide output at anaerobic _ 2: oxygen consumption; VR-IPAH: vasodilator-responsive idiopathic pulmonary arterial hypertension; VNR-IPAH: vasodilator-nonresponsive idiopathic pulthreshold; VO monary arterial hypertension.
Table 3 Parameters during CPET at rest, AT and peak for VNR-IPAH patients. Variable
Rest
P value
AT
Baseline
After sildenafil
Work rate, W _ 2,mL$kg1$min1 VO
0 4.5 ± 1.1
RER O2 pulse, mL$min1$beat1 SBP, mmHg DBP, mmHg _ L$ min1 VE, PETCO2, mm Hg _ VCO _ VE/ 2 HR, min1 SPO2, %
P value
Peak
Baseline
After sildenafil
0 4.7 ± 0.8
e 0.19
45.7 ± 11.7 9.8 ± 2.6
0.85 ± 0.13 3.3 ± 0.8 106 ± 9 76 ± 8 10.4 ± 2.3
0.82 ± 0.06 3.8 ± 0.9 105 ± 9 70 ± 8 9.7 ± 2.4
0.41 0.002 0.69 0.06 0.26
27.9 ± 4.2 43.3 ± 6.5
31.2 ± 4.4 39.2 ± 5.9
86 ± 14 95.8 ± 2.2
80 ± 9 95.5 ± 2.1
P value
Baseline
After sildenafil
51.7 ± 13.6 11.4 ± 2.7
0.17 0.08
81.8 ± 23.3 12.5 ± 3.4
89.5 ± 20.2 15.5 ± 3.9
0.20 0.01
0.91 ± 0.07 5.5 ± 1.3 138 ± 45 91 ± 36 23.9 ± 8.3
0.89 ± 0.04 6.4 ± 1.6 125 ± 26 83 ± 13 23.1 ± 5.2
0.67 0.02 0.30 0.40 0.70
1.11 ± 0.14 5.7 ± 1.5 158 ± 46 97 ± 35 40.4 ± 10.7
1.11 ± 0.11 6.8 ± 1.8 138 ± 37 91 ± 24 44.4 ± 11.2
0.86 0.006 0.22 0.59 0.21
0.01 0.03
28.0 ± 6.6 42.7 ± 11.3
32.2 ± 6.2 36.4 ± 8.6
0.003 0.01
24.6 ± 6.0 47.6 ± 12.4
27.8 ± 6.4 41.5 ± 11.0
0.01 0.01
0.02 0.64
112 ± 14 94.9 ± 2.2
116 ± 19 94.0 ± 3.1
0.49 0.30
143 ± 24 92.1 ± 6.3
148 ± 25 90.7 ± 5.8
0.44 0.40
Data are expressed as mean ± SD. AT: anaerobic threshold; CPET: cardiopulmonary exercise testing; DBP: diastolic blood pressure; HR: heart rate; PETCO2@AT:endtidal partial _ _ pressure of carbon dioxide at anaerobic threshold; RER: respiratory exchange ratio; SBP: systolic blood pressure; SPO2: arterial oxygen saturation; VE: ventilation; VE/ _ _ VCO 2@AT: ratio of ventilation to carbon dioxide output at anaerobic threshold; VO2: oxygen consumption, VNR-IPAH: vasodilator-nonresponsive idiopathic pulmonary arterial hypertension.
Table 4 Parameters during CPET at rest, AT and peak for VR-IPAH patients. Variable
Rest
P value
Baseline
After CCB
Work rate, W _ 2,mL$kg1$min1 VO RER O2 pulse, mL$min1beat1 SBP, mmHg DBP, mmHg _ L$min1 VE,
0 4.5 ± 0.7
0 4.6 ± 0.8
0.88 ± 0.08 3.1 ± 0.5 101 ± 11 76 ± 8 8.7 ± 2.1
PETCO2, mm Hg VE/VCO2 HR, min1 SPO2, %
32.2 ± 3.3 36.6 ± 3.7 86 ± 9 96.5 ± 2.6
AT
P value
Baseline
After CCB
e 0.44
42.6 ± 11.6 10.3 ± 1.9
52.1 ± 11.9 11.8 ± 2.4
0.84 ± 0.02 3.4 ± 0.7 105 ± 6 68 ± 7 8.1 ± 1.4
0.13 0.03 0.17 0.005 0.18
0.92 ± 0.06 5.2 ± 1.0 121 ± 35 87 ± 21 19.1 ± 3.1
33.9 ± 1.4 35.0 ± 1.6 80 ± 11 96.9 ± 1.5
0.03 0.15 0.08 0.47
33.1 ± 4.0 34.2 ± 5.0 117 ± 14 96.1 ± 3.5
Peak
P value
Baseline
After CCB
0.005 0.01
73.7 ± 12.1 13.9 ± 2.9
85.7 ± 18.6 16.4 ± 4.1
0.001 0.001
0.92 ± 0.02 6.3 ± 1.2 131 ± 25 83 ± 13 20.5 ± 3.5
1.0 0.005 0.42 0.57 0.14
1.11 ± 0.06 5.5 ± 0.8 146 ± 38 97 ± 20 33.7 ± 7.3
1.12 ± 0.05 6.9 ± 1.3 152 ± 36 92 ± 19 37.3 ± 8.9
0.56 0.001 0.67 0.50 0.05
35.3 ± 3.2 31.6 ± 3.1 111 ± 14 95.6 ± 2.8
0.02 0.02 0.11 0.61
30.3 ± 6.0 38.0 ± 8.1 147 ± 17 93.6 ± 5.2
32.8 ± 4.8 34.1 ± 5.2 140 ± 17 94.1 ± 5.1
0.03 0.01 0.02 0.73
Data are expressed as mean ± SD. AT: anaerobic threshold; CCB: calcium channel blockers; CPET: cardiopulmonary exercise testing; DBP: diastolic blood pressure; HR: heart rate; PETCO2@AT:endtidal partial pressure of carbon dioxide at anaerobic threshold; RER: respiratory exchange ratio; SBP: systolic blood pressure; SPO2: arterial oxygen _ ventilation; VE/ _ VCO _ _ saturation; VE: 2@AT: ratio of ventilation to carbon dioxide output at anaerobic threshold; VO2: oxygen consumption; VR-IPAH: vasodilator-responsive idiopathic pulmonary arterial hypertension.
in patients with VR-IPAH and also in patients with VNR-IPAH treated with sildenafil. Ventilatory efficiency at rest, AT, and peak _ VCO _ were significantly higher (lower in VE/ 2@AT and higher in PETCO2@AT) in VR-IPAH group than that in VNR-IPAH group. In _ 2 and peak O2 pulse) and both groups, Aerobic capacity (peak VO _ VCO _ ventilatory efficiency (VE/ 2@AT and PETCO2@AT) were
significantly improved after therapy, along with improvement of NYHA functional class, 6MWD, NT-proBNP and TRPG. VR-IPAH is an infrequent subphenotype of IPAH which is characterized by reversible vasoconstriction rather than cellular obstruction [9,10]. Previous studies showed that high-dose CCB could improve right ventricular hypertrophy, 6WMD, and also
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Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
Table 5 Parameters of WHO-FC, 6WMD, laboratory tests and echocardiograms at baseline and after treatment. Variable
WHO-FC I/II, n III/IV,n 6WMD, m Laboratory tests NT-proBNP, pg/ml Uric acid, mmol/L Creatinine, mmol/L Echocardiography LVED, mm LVEF,% RVED,mm TRPG, mmHg
VNR-IPAH
P value
Baseline
After sildenafil
10 18 425.8 ± 57.8
22 6 501.0 ± 64.7
922.6 (583.5,1792.5) 456.9 ± 215.6 74.6 ± 16.9
456.9 (89.6,1428.3) 446.7 ± 121.7 72.7 ± 10.8
VR-IPAH
P value
Baseline
After CCB
0.0001
15 10 455.6 ± 48.7
25 0 502.5 ± 53.1
0.0001
0.02 0.84 0.64
852.4 (336.2,1079.5) 373.9 ± 115.4 68.5 ± 12.1
141.5 (58.1392.2) 316.3 ± 92.1 68.4 ± 11.5
0.002 0.01 0.97
0.08 0.96 0.39 0.08
38.4 63.5 30.6 89.6
0.003
36.3 65.1 32.2 75.5
± ± ± ±
5.1 6.1 7.7 20.2
38.7 65.9 30.7 65.2
± ± ± ±
6.7 6.0 9.4 23.9
0.001
± ± ± ±
6.3 3.7 4.4 30.3
41.1 67.2 27.1 70.1
± ± ± ±
4.2 8.1 5.2 17.9
0.05 0.13 0.03 0.01
Data are expressed as mean ± SD or number of patients. CPET: cardiopulmonary exercise testing; CCB: calcium channel blockers; LVED: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; NT-proBNP: N-terminal of the prohormone brain natriuretic peptide; RVED: right ventricular end-diastolic diameter; TRPG: tricuspid regurgitation pressure gradient, 6WMD: 6 min walk distance, WHO-FC: World Health Organization Functional Class; VR-IPAH: vasodilator-responsive idiopathic pulmonary arterial hypertension; VNR-IPAH: vasodilator-nonresponsive idiopathic pulmonary arterial hypertension.
reduce pulmonary arterial pressure and pulmonary vascular resistance in patients with VR-IPAH [2,3]. Our study showed that the improvement of NYHA functional class, 6MWD, NT-proBNP, RVED and TRPG after 3e6 months of CCB therapy, which was in agreement with previous studies. Increased pulmonary vascular resistance (PVR) in patients with VR-IPAH could decrease blood flow to the left side of the heart and shift the ventricular septum leftward, leading to a decrease in CO, _ 2 and which eventually cause a decrease in peak work rate, peak VO peak O2 pulse. In addition, increased PVR could also increase physiologic dead space, which was reflected by decreased ventila_ VCO _ tory efficiency (elevated VE/ 2@AT and diminished PETCO2@AT) [11]. Our study showed that Ventilatory efficiency in VNR-IPAH group were lower compared with VR-IPAH group even PVR, peak _ 2 and peak O2 pulse were similar between two groups, which VO may be due to that increased PVR was based on vascular tone rather than intimal proliferation leading to greater recruit underperfused microvasculature and downstream capillary surface area under the condition of exercise in patients with VR-IPAH [12,13]. Hoeper et al. demonstrated significant improvements in peak _ 2 after 2e3 months of sildenafil therapy in 9 patients with PAH VO [14]. Ronald J. Oudiz, et al. reported that improvement of ventilatory efficiency, peak O2 pulse, peak work rate after 4 ± 2 months of treatment with sildenafil in 14 patients with PAH [6]. In the present _ 2, peak O2 pulse, VE/ _ VCO _ study, we demonstrated that peak VO 2 @AT and PETCO2 @AT improved significantly after 3e6 months of sildenafil therapy in patients with VNR-IPAH. For patients with VR_ 2, peak O2 pulse, VE/ _ VCO _ IPAH, peak work rate, peak VO 2@AT and PETCO2 @AT also improved significantly with 3e6 months of high dose of CCB therapy, which indicate that CCB can also work on vascular smooth muscle in patients with VR-IPAH as sildenafil vasodilate the pulmonary vascular bed in patients with VNR-IPAH [10]. In addition, our study showed that diastolic blood pressure at rest in both groups decreased after treatment, which can be explained that both of them, sildenafil and CCB, can decrease peripheral vascular resistance via promoting relaxation of vascular smooth-muscle cells in peripheral arteries, and heart rate at peak was decreased in VR-IPAH group, which may due to that CCB itself, especially diltiazem, can slow down heart rate [10,15]. There was no blinding to exclude a placebo effect. Nonetheless it was not ethical for vasodilator-responsive IPAH patients to not receive CCB treatment. In addition, the resting haemodynamic parameters were not studied to further support evidences of improvement as repeat catheterization was not clinically indicated
after 3e6 months of therapy. Finally, a small number of patients may have certain influence to the results. A multi-center trial with large samples and long term follow-up is required. 5. Conclusions In conclusion, Ventilatory efficiency in patients with VR-IPAH is better than that in patients with VNR-IPAH. CCB improves peak _ 2, peak O2 pulse PETCO2@AT, VE/ _ VCO _ VO 2@AT during exercise, as well as NYHA functional class, 6MWD, NT-proBNP and TRPG in patients with VR-IPAH, and these parameters are also improved in patients with VNR-IPAH after sildenafil therapy. Our study demonstrates that CPET can be a non-invasive and useful tool to assess and monitor the therapeutic effects in patients with VNR-IPAH under the treatment of CCB. Funding This work was supported by Central Public Interest Scientific Institution Basal Research Fund for Young Researchers (No. 2010F11). Conflict of interest The authors have no conflicts of interest to disclose. References [1] H.W. Farber, D.P. Miller, A.D. Poms, D.B. Badesch, A.E. Frost, E. Muros-Le Rouzic, A.J. Romero, W.W. Benton, C.G. Elliott, M.D. McGoon, R.L. Benza, FiveYear outcomes of patients enrolled in the REVEAL registry, Chest 148 (2015) 1043e1054. [2] O. Sitbon, M. Humbert, X. Jais, V. Ioos, A.M. Hamid, S. Provencher, G. Garcia, F. Parent, P. Herve, G. Simonneau, Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension, Circulation 111 (2005) 3105e3111. [3] S. Rich, E. Kaufmann, P.S. Levy, The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension, N. Engl. J. Med. 327 (1992) 76e81. [4] M. Guazzi, V. Adams, V. Conraads, M. Halle, A. Mezzani, L. Vanhees, R. Arena, G.F. Fletcher, D.E. Forman, D.W. Kitzman, C.J. Lavie, J. Myers, EACPR/AHA Joint Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations, Euro. Heart J. 33 (2012) 2917e2927. [5] R. Wensel, C.F. Opitz, S.D. Anker, J. Winkler, G. Hoffken, F.X. Kleber, R. Sharma, M. Hummel, R. Hetzer, R. Ewert, Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise
Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31 testing, Circulation 106 (2002) 319e324. [6] R.J. Oudiz, G. Roveran, J.E. Hansen, X.G. Sun, K. Wasserman, Effect of sildenafil on ventilatory efficiency and exercise tolerance in pulmonary hypertension, Eur. J. heart Fail. 9 (2007) 917e921. [7] N. Galie, M.M. Hoeper, M. Humbert, A. Torbicki, J.L. Vachiery, J.A. Barbera, M. Beghetti, P. Corris, S. Gaine, J.S. Gibbs, M.A. Gomez-Sanchez, G. Jondeau, W. Klepetko, C. Opitz, A. Peacock, L. Rubin, M. Zellweger, G. Simonneau, Guidelines for the diagnosis and treatment of pulmonary hypertension: the task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS), endorsed by the international society of heart and lung transplantation (ishlt), Eur. heart J. 30 (2009) 2493e2537. [8] H.L. Zhang, Z.H. Liu, Y. Wang, C.M. Xiong, X.H. Ni, J.G. He, Q. Luo, Z.H. Zhao, Q. Zhao, X.G. Sun, Acute responses to inhalation of Iloprost in patients with pulmonary hypertension, Chin. Med. J. 125 (2012) 2826e2831. [9] A.R. Hemnes, A.W. Trammell, S.L. Archer, S. Rich, C. Yu, H. Nian, N. Penner, M. Funke, L. Wheeler, I.M. Robbins, E.D. Austin, J.H. Newman, J. West, Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension, Circulation 131 (2015) 401e409. [10] B.I. Medarov, M.A. Judson, The role of calcium channel blockers for the
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Contents lists available at ScienceDirect
Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Effect of calcium channel blockers evaluated by cardiopulmonary exercise testing in idiopathic pulmonary arterial hypertension responding to acute pulmonary vasoreactivity testing Yi Tang a, Lei Yao b, Zhihong Liu a, *, Xiuping Ma a, Qin Luo a, Zhihui Zhao a, Zhiwei Huang a, Laura Tu c, Liu Gao a, Qi Jin a, Xinhai Ni a, Changming Xiong a a
Center for Pulmonary Vascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Department of Cardiology, People's Hospital of Shouguang City, Shandong, China c Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 18 June 2016 Received in revised form 21 January 2017 Accepted 28 January 2017 Available online 1 February 2017
Background: The baseline exercise capacity evaluated by cardiopulmonary exercise testing (CPET) and the change after administration of calcium channel blockers (CCB) therapy in patients with vasodilatorresponsive idiopathic pulmonary arterial hypertension (VR-IPAH)are unknown. Methods: 25 patients with newly diagnosed VR-IPAH from 1 January 2012 to 16 November 2015 were prospectively enrolled, and 28 age, sex and pulmonary vascular resistance matched newly diagnosed patients with vasodilator-nonresponsive idiopathic pulmonary arterial hypertension (VNR-IPAH) were enrolled. CPET was performed before and after 3.5 ± 0.8 months of CCB or sildenafil therapy. Results: Ventilatory efficiency at rest, anaerobic threshold (AT), and peak were significantly higher (lower _ _ VCO _ in VE/ 2@AT and higher in PETCO2@AT) in VR-IPAH group than that in VNR-IPAH group. Peak VO2 (13.9 ± 2.9 mL kg1$min1 vs 16.4 ± 4.1 mL kg1$min1, p ¼ 0.001), peak O2 pulse _ VCO _ (5.5 ± 0.8 mL min1$beat1 vs 6.9 ± 1.3 mL min1$beat1, p ¼ 0.001), VE/ 2@AT (34.2 ± 5.0 vs 31.6 ± 3.1, p ¼ 0.02) and PETCO2@AT (33.1 ± 4.0 mmHg vs 35.3 ± 3.2 mmHg, p ¼ 0.02) were significantly improved after high dose of CCB therapy, along with improvement of WHO functional class, 6-min walking distance, NT-proBNP and tricuspid regurgitation pressure gradient. Conclusions: Ventilatory efficiency in patients with VR-IPAH is better than that in patients with VNRIPAH. CCB can improve aerobic capacity and ventilatory efficiency during exercise in patients with VRIPAH. Clinical trial registration number: ClinicalTrials.gov:NCT02061787. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Idiopathic pulmonary arterial hypertension Cardiopulmonary exercise testing Vasoreactivity testing Calcium channel blockers Chemical compounds studied in this article: Diltiazem (PubChem CID: 39186) Diltiazem (PubChem CID: 2162) Sildenafil (PubChem CID: 5212)
1. Introduction Pulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary vascular resistance that
leads to right heart failure and death. The REVEAL registry of pulmonary arterial hypertension study showed that the 5-year survival rate for newly diagnosed group 1 PAH was 61.2% [1]. However, a subset of idiopathic pulmonary arterial hypertension (IPAH)
Abbreviations: AT, anaerobic threshold; CCB, calcium channel blockers; CI, Cardiac index; CPET, cardiopulmonary exercise testing; DBP, diastolic blood pressure; HR, heart rate; LVED, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal of the prohormone brain natriuretic peptide; PCWP, pulmonary capillary wedge pressure; PETCO2@AT, endtidal partial pressure of carbon dioxide at anaerobic threshold; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RER, respiratory exchange ratio; RHC, right heart catheterization; RVED, right ventricular end-diastolic diameter; RVEDP, right ventricular end-diastolic pressure; SBP, systolic blood pressure; SPO2, arterial oxygen saturation; SvO2, mixed venous oxygen saturation; TRPG, ricuspid regurgitation pressure _ ventilation; VE/ _ VCO _ _ gradient; VE, 2@AT, ratio of ventilation to carbon dioxide output at anaerobic threshold; VO2, oxygen consumption; VR-IPAH, vasodilator-responsive idiopathic pulmonary arterial hypertension; VNR-IPAH, vasodilator-nonresponsive idiopathic pulmonary arterial hypertension; WHO-FC, World Health Organization Functional Class; 6WMD, 6 min walk distance; 6MWT, 6 min walk test. * Corresponding author. Center for Pulmonary Vascular Diseases, Fuwai Hospital, 167 BeiLiShi Rd, Xicheng District, Beijing 100037, China. E-mail address: [email protected] (Z. Liu). http://dx.doi.org/10.1016/j.pupt.2017.01.012 1094-5539/© 2017 Elsevier Ltd. All rights reserved.
Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
characterized by acute vasodilator responsiveness for vasodilator agents (VR-IPAH), who has excellent survival time under the treatment of calcium channel blockers (CCB), has a 5-year survival rate of 98% [2]. The effects of CCB in patients with VR-IPAH is mainly evaluated by right heart catheterization (RHC), 6 min walking distance (6WMD),NT-proBNP, electrocardiogram and WHO function class [2,3]. Recently, cardiopulmonary exercise testing (CPET) has been widely used in patients with PAH, as it can accurately quantify cardiorespiratory fitness and formulate function-based prognostic _ 2 rather than stratification [4]. Study also showed that peak VO resting hemodynamic parameters obtained from RHC is an independent and strong predictor of survival in patients with IPAH [5].The effects of sildenafil on exercise capacity in patients with PAH have already been evaluated by CPET [6].However, the characteristics of CPET in patients with VR-IPAH and the change after CCB therapy have not been previously studied. The main aim of our study was to investigate the characteristics of CPET before and after the treatment of high doses of CCB in patients with VR-IPAH. 2. Material and methods 2.1. Study sample Patients aged over 18 years old with newly diagnosed IPAH who demonstrated a significant acute response to aerosolised iloprost at Fuwai Hospital from 1 January 2012 to 16 November 2015 were prospectively enrolled, meanwhile, patients aged over 18 years old with newly diagnosed IPAH who did not demonstrate a significant acute response to aerosolised iloprost (VNR-IPAH) and treated with sildenafil from 1 January 2012 to 1 January 2014 were also prospectively enrolled. IPAH was defined according to 2009ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension [7]. Patients with the following conditions were excluded: (1) other types of pulmonary hypertension; (2) hemodynamic instability; (3) NYHA class IV; (4) restrictive or obstructive pulmonary disease. The study complies with the Declaration of Helsinki and was approved by the Ethics Committee of Fuwai Hospital (No. 2011e331). All written informed consents were obtained from participants. 2.2. Cardiopulmonary exercise testing Symptom-limited CPET was performed on all recruited patients with VR-IPAH and patients with VNR-IPAH at baseline. Gas exchange measurements (Cosmed, Italy) were performed continuously during the 3 min of resting time, 3 min of unloaded pedaling at 60 rpm followed by a progressively increasing work rate exercise of 5e20 W/min to maximum tolerance, and then 5 min of recovery. _ 2), carbon dioxide output (VCO _ Oxygen consumption (VO 2) and _ were computer-calculated breath by breath minute ventilation (VE) and averaged over 10s intervals. AT (anaerobic threshold) was detected by a combination of the V-slope method and ventilatory _ 2 equivalents for oxygen.O2 pulse was calculated by dividing the VO by heart rate (HR). Pulmonary gas exchange was assessed by _ measuring the ratio of ventilation to carbon dioxide output (VE/ _ VCO 2) and end tidal partial pressure of carbon dioxide (PETCO2). Pulse oximetry (SpO2), HR, 12-lead ECG and blood pressure were monitored and recorded. The equipment was calibrated in a standard procedure using reference gases prior to each test.
27
study. Aerosolised iloprost was used when subjects underwent acute pulmonary vasodilator testing according to the methods reported previously [8]. After baseline hemodynamic parameters and blood gases have been obtained, 20 mg iloprost (Bayer-Schering Pharma) was delivered by a PARI LC STAR nebulizer (PARI GmbH) driven by a PARI TurboBOY-N compressor (PARI GmbH) for 10e15min. Following that, another set of hemodynamic measurements and blood gases was obtained. Blood gas analysis was performed using a blood gas analyzer (Nova Biomedical). A positive acute response was defined as a decrease of mean pulmonary arterial pressure (mPAP) by more than 10 mmHg to below 40 mmHg with an increased or preserved cardiac output (CO). CO was calculated by Fick's method and cardiac index (CI) was calculated by dividing cardiac output by body surface area. Pulmonary vascular resistance (PVR) was calculated as dividing (mPAPePCWP) by pulmonary blood flow. Spirometry and body plethysmography were performed with the use of a constant volume body plethysmograph (Cosmed, Italy) to exclude underlying restrictive or obstructive pulmonary disease. Anthropometry data, blood pressure, 6 min walk test (6MWT), electrocardiograms, echocardiograms, routine blood examinations, N-terminal pro-brain natriuretic peptide (NT-proBNP) were also evaluated at baseline. 2.4. Calcium channel blockers or sildenafil therapy and follow -up Oral CCB therapy was initiated in patients with newly diagnosed VR-IPAH. Diltiazem or amlodipine was used, which depended on the patient's heart rate at rest (diltiazem for heart rate 100 bpm, amlodipine for heart rate <100 bpm) [3]. Patients were recommended to add 1.25 mg or 2.5 mg of amlodipine (once a day), 7.5 mg or15 mg of diltiazem (three times a day) every three or five days on the basis of previous drug doses until they exhibited side effects such as hypotension or bradycardia after they were discharged. Patients with newly diagnosed VNR-IPAH received sildenafil, which was given at a dose of 20 mg three times a day. For both groups, warfarin was prescribed to patients if they did not have any contradiction or adverse effects. Diuretics and digoxin were prescribed to patients based on physician's judgement of patient's condition. Patients were followed up 3e6 months after treatment with CCB or sildenafil. CPET, 6MWT, WHO function class, NT-proBNP, echocardiography were performed again except RHC. In addition, cardiovascular events, the dose of the CCB, the side effects, blood pressure, heart rate, routine blood examinations, chest X-ray electrocardiograms were also performed. 2.5. Statistical analysis Continuous variables with normal distribution were expressed as mean ± SD and as median and interquartile range with nonnormal distribution, while categorical variables were presented as percentages or absolute numbers. Comparisons between VR-IPAH group and control group were made using chi-square tests for categorical variables, independent-samples Student's t tests for normally distributed continuous variables, and ManneWhitney U tests for non-normally continuous distributed variables. A paired Student's t tests was used to compare variables between baseline and follow-up. All testing was 2 tailed at a significance level of 0.05. All statistical analyses were performed using SPSS version 19.0(SPSS, Inc., Chicago, IL, USA).
2.3. Right heart catheterization 3. Results Diagnostic RHC with standard hemodynamic measurements was performed at baseline within 5 days of each patient's CPET
Twenty-five patients met the criteria of IPAH who also
28
Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
demonstrated a significant acute response to iloprost, and Twentyeight age, sex and PVR matched patients with VNR-IPAH were enrolled. The mean follow-up time was 3.5 ± 0.8 months (3e6 months). No serious adverse events such as severe hypotension, right heart failure, or death were observed during the follow up in both groups, the mean daily dose of diltiazem (n ¼ 18) was 320 ± 90 mg (range, 180e540 mg), that of amlodipine (n ¼ 7) was 12±5 mg (range, 7.5e15 mg).Four patients had mild headache after treatment with sildenafil and well tolerated in VNR-IPAH group. Baseline characteristics of patients with VR-IPAH and VNR-IPAH are present in Table 1. The mean age, gender, height, weight and body surface area (BSA) did not differ between the two groups. There were no significant differences in the 6-min walk distance, tricuspid regurgitation pressure gradient (TRPG), NT-proBNP, PVR, cardiac index and background therapy between patients with VRPAH and VNR-PAH, but the mPAP was significantly higher in the VNR-PAH group than in the VR-PAH group (p ¼ 0.006). Baseline CPET characteristics of patients with VR-IPAH and VNRIPAH are present in Table 2. There were no accidents during CPET in both groups. All subjects exercised above their ATs. Ventilatory efficiency at rest, anaerobic threshold (AT), and peak were signifi_ VCO _ cantly lower (higher in VE/ 2@ AT and lower in PETCO2@ AT) in VNR-IPAH group than in VR-IPAH group, other CPET parameters at _ 2 and O2 pulse, were not rest, AT and peak, including work rate, VO significantly different between the VNR-IPAH and VR-IPAH group. The CPET parameters at rest, AT (anaerobic threshold) and peak at the baseline and after therapy are shown in Tables 3 and 4. In the _ VCO _ VNR-PAH group, the O2 pulse, PETCO2, VE/ 2 at rest, AT and peak
_ 2 at rest was were significantly improved after sildenafil therapy. VO _ 2 at AT tended to increase not significantly increased (p ¼ 0.19), VO _ 2 at peak was significantly increased (p ¼ 0.01). (p ¼ 0.08) and VO DBP at rest tended to decrease (p ¼ 0.06) and HR at rest was significantly decreased (p ¼ 0.02). In the VR-PAH group, the O2 pulse, PETCO2 at rest, anaerobic threshold and peak were significantly improved after CCB therapy. _ VCO _ _ Work rate, VE/ 2, VO2 at AT and peak were significantly _ _ _ 2 at rest were not significantly increased, but VE/VCO2, VO improved. DBP at rest was significantly decreased (p ¼ 0.005). HR at rest tended to decrease (p ¼ 0.08) and HR at peak was significantly decreased (p ¼ 0.02), however, in the VNR-PAH group, Work rate at AT and peak as well as HR at peak did not significant change _ VCO _ (p ¼ 0.17.0.20 respectively), VE/ 2 at rest was significantly improved (p ¼ 0.03). The parameters of WHO function class, 6MWD, NT-proBNP, uric acid, creatinine and echocardiograms at baseline and after therapy are shown in Table 5. In the VNR-PAH group, 6MWD, NT-proBNP significantly decreased after treatment with sildenafil, LVED tended to increase and TRPG tended to decrease (p ¼ 0.08, 0.08 respectively). Whereas, in the VR-PAH group, the 6MWD, NT-proBNP, uric acid, RVED and TRPG significantly decreased after treatment with CCB. The increase in LVED was borderline significant (p ¼ 0.05). 4. Discussion To our knowledge, for the first time, we report the baseline and the change of exercise capacity evaluated by CPET after CCB therapy
Table 1 Baseline characteristics of studied patients. Variable
VR-IPAH (n ¼ 25)
VNR-IPAH (n ¼ 28)
P
Age, year Male,% Height, cm Weight, kg BSA,m2 WHO-FC I/II, n III/IV, n Six-minute walk distance, m Echocardiographic measurements LVED,mm LVEF,% RVED,mm TRPG, mmHg Laboratory tests NT-proBNP, pg/ml Uric acid, mmol/L Creatinine, mmol/L Baseline hemodynamics Mean RAP, mmHg RVEDP, mmHg Mean PAP, mmHg Mean PCWP, mmHg PVR, woods CI, L$min1 m2 SVO2,% Medications Warfarin, n (%) Digoxin, n (%) Diuretics, n (%) Diltiazem, n (%) Amlodipine, n (%) Sildenafil, n (%)
33 ± 11 24.0 163.5 ± 6.8 59.7 ± 10.6 1.6 ± 0.2
35 ± 9 32.1 164.0 ± 8.4 66.2 ± 12.9 1.7 ± 0.2
0.61 0.55 0.86 0.14 0.17 0.10
15 10 455.6 ± 48.7
10 18 425.8 ± 57.8
0.13
± ± ± ±
0.34 0.18 0.35 0.15
38.4 63.5 30.6 89.6
± ± ± ±
6.3 3.7 4.4 30.3
36.3 65.1 32.2 75.5
5.1 6.1 7.7 20.2
852.4 (336.2,1079.5) 373.9 ± 115.4 68.5 ± 12.1
922.6 (583.5,1792.5) 456.9 ± 215.6 74.6 ± 16.9
0.24 0.19 0.27
4.1 ± 3.2 7.0 ± 4.6 43.8 ± 8.2 5.8 ± 2.6 7.9 ± 2.6 3.2 ± 0.9 73.3 ± 5.1
5.5 ± 5.4 9.6 ± 4.8 51.5 ± 5.4 5.8 ± 2.7 9.8 ± 3.5 3.0 ± 1.1 72.2 ± 6.9
0.40 0.14 0.006 0.96 0.12 0.66 0.61
22 (88.0) 19 (76.0) 18 (72.0) 18 (72.0) 7 (28.0) e
24 (85.7) 24 (85.7) 26 (92.8)
1.0 0.48 0.06 e e e
100 (100)
Data are expressed as mean ± SD or number of patients or percent (%). CI: Cardiac index; LVED: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; NT-proBNP: N-terminal of the prohormone brain natriuretic peptide; PAP: pulmonary artery pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure; RVED: right ventricular end-diastolic diameter; RVEDP: right ventricular end-diastolic pressure; SvO2: mixed venous oxygen saturation. TRPG: tricuspid regurgitation pressure gradient; VR-IPAH: vasodilator-responsive idiopathic pulmonary arterial hypertension; VNRIPAH: vasodilator-nonresponsive idiopathic pulmonary arterial hypertension; WHO-FC: World Health Organization Functional Class.
Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
29
Table 2 Baseline cardiopulmonary exercise testing characteristics of studied patients. Variable
Rest
P value
VNR-IPAH
VR-IPAH
Work rate, W _ 2,mL$kg1$min1 VO RER O2 pulse, mL$min1$beat1 SBP, mmHg DBP, mmHg _ L$ min1 VE,
0 4.5 ± 1.1
0 4.5 ± 0.7
0.85 ± 0.13 3.3 ± 0.8 106 ± 9 76 ± 8 10.4 ± 2.3
PETCO2, mm Hg _ VCO _ VE/ 2 HR, min1 SPO2, %
AT
P value
VNR-IPAH
VR-IPAH
e 1.0
45.7 ± 11.7 9.8 ± 2.6
42.6 ± 11.6 10.3 ± 1.9
0.88 ± 0.08 3.1 ± 0.5 101 ± 11 76 ± 8 8.7 ± 2.1
0.98 0.32 0.22 0.92 0.91
0.91 ± 0.07 5.5 ± 1.3 138 ± 45 91 ± 36 23.9 ± 8.3
27.9 ± 4.2 43.3 ± 6.5
32.2 ± 3.3 36.6 ± 3.7
0.004 0.002
86 ± 14 95.8 ± 2.2
86 ± 9 96.5 ± 2.6
0.97 0.44
Peak
P value
VNR-IPAH
VR-IPAH sildenafil
0.90 0.87
81.8 ± 23.3 12.5 ± 3.4
73.7 ± 12.1 13.9 ± 2.9
0.85 0.89
0.92 ± 0.06 5.2 ± 1.0 121 ± 35 83 ± 13 19.1 ± 3.1
0.99 0.40 0.26 0.43 0.96
1.11 ± 0.14 5.7 ± 1.5 158 ± 46 97 ± 35 40.4 ± 10.7
1.11 ± 0.06 5.5 ± 0.8 146 ± 38 97 ± 20 33.7 ± 7.3
0.95 0.65 0.42 0.96 0.91
28.0 ± 6.6 42.7 ± 11.3
33.1 ± 4.0 34.2 ± 5.0
0.01 0.01
24.6 ± 6.0 47.6 ± 12.4
30.3 ± 6.0 38.0 ± 8.1
0.01 0.01
112 ± 14 94.9 ± 2.2
117 ± 14 96.1 ± 3.5
0.35 0.27
143 ± 24 92.1 ± 6.3
147 ± 17 93.6 ± 5.2
0.63 0.51
Data are expressed as mean ± SD. DBP: diastolic blood pressure; HR: heart rate; PETCO2@AT:endtidal partial pressure of carbon dioxide at anaerobic threshold; RER: res_ ventilation; VE/ _ VCO _ piratory exchange ratio; SBP: systolic blood pressure; SPO2: arterial oxygen saturation; VE: 2@AT: ratio of ventilation to carbon dioxide output at anaerobic _ 2: oxygen consumption; VR-IPAH: vasodilator-responsive idiopathic pulmonary arterial hypertension; VNR-IPAH: vasodilator-nonresponsive idiopathic pulthreshold; VO monary arterial hypertension.
Table 3 Parameters during CPET at rest, AT and peak for VNR-IPAH patients. Variable
Rest
P value
AT
Baseline
After sildenafil
Work rate, W _ 2,mL$kg1$min1 VO
0 4.5 ± 1.1
RER O2 pulse, mL$min1$beat1 SBP, mmHg DBP, mmHg _ L$ min1 VE, PETCO2, mm Hg _ VCO _ VE/ 2 HR, min1 SPO2, %
P value
Peak
Baseline
After sildenafil
0 4.7 ± 0.8
e 0.19
45.7 ± 11.7 9.8 ± 2.6
0.85 ± 0.13 3.3 ± 0.8 106 ± 9 76 ± 8 10.4 ± 2.3
0.82 ± 0.06 3.8 ± 0.9 105 ± 9 70 ± 8 9.7 ± 2.4
0.41 0.002 0.69 0.06 0.26
27.9 ± 4.2 43.3 ± 6.5
31.2 ± 4.4 39.2 ± 5.9
86 ± 14 95.8 ± 2.2
80 ± 9 95.5 ± 2.1
P value
Baseline
After sildenafil
51.7 ± 13.6 11.4 ± 2.7
0.17 0.08
81.8 ± 23.3 12.5 ± 3.4
89.5 ± 20.2 15.5 ± 3.9
0.20 0.01
0.91 ± 0.07 5.5 ± 1.3 138 ± 45 91 ± 36 23.9 ± 8.3
0.89 ± 0.04 6.4 ± 1.6 125 ± 26 83 ± 13 23.1 ± 5.2
0.67 0.02 0.30 0.40 0.70
1.11 ± 0.14 5.7 ± 1.5 158 ± 46 97 ± 35 40.4 ± 10.7
1.11 ± 0.11 6.8 ± 1.8 138 ± 37 91 ± 24 44.4 ± 11.2
0.86 0.006 0.22 0.59 0.21
0.01 0.03
28.0 ± 6.6 42.7 ± 11.3
32.2 ± 6.2 36.4 ± 8.6
0.003 0.01
24.6 ± 6.0 47.6 ± 12.4
27.8 ± 6.4 41.5 ± 11.0
0.01 0.01
0.02 0.64
112 ± 14 94.9 ± 2.2
116 ± 19 94.0 ± 3.1
0.49 0.30
143 ± 24 92.1 ± 6.3
148 ± 25 90.7 ± 5.8
0.44 0.40
Data are expressed as mean ± SD. AT: anaerobic threshold; CPET: cardiopulmonary exercise testing; DBP: diastolic blood pressure; HR: heart rate; PETCO2@AT:endtidal partial _ _ pressure of carbon dioxide at anaerobic threshold; RER: respiratory exchange ratio; SBP: systolic blood pressure; SPO2: arterial oxygen saturation; VE: ventilation; VE/ _ _ VCO 2@AT: ratio of ventilation to carbon dioxide output at anaerobic threshold; VO2: oxygen consumption, VNR-IPAH: vasodilator-nonresponsive idiopathic pulmonary arterial hypertension.
Table 4 Parameters during CPET at rest, AT and peak for VR-IPAH patients. Variable
Rest
P value
Baseline
After CCB
Work rate, W _ 2,mL$kg1$min1 VO RER O2 pulse, mL$min1beat1 SBP, mmHg DBP, mmHg _ L$min1 VE,
0 4.5 ± 0.7
0 4.6 ± 0.8
0.88 ± 0.08 3.1 ± 0.5 101 ± 11 76 ± 8 8.7 ± 2.1
PETCO2, mm Hg VE/VCO2 HR, min1 SPO2, %
32.2 ± 3.3 36.6 ± 3.7 86 ± 9 96.5 ± 2.6
AT
P value
Baseline
After CCB
e 0.44
42.6 ± 11.6 10.3 ± 1.9
52.1 ± 11.9 11.8 ± 2.4
0.84 ± 0.02 3.4 ± 0.7 105 ± 6 68 ± 7 8.1 ± 1.4
0.13 0.03 0.17 0.005 0.18
0.92 ± 0.06 5.2 ± 1.0 121 ± 35 87 ± 21 19.1 ± 3.1
33.9 ± 1.4 35.0 ± 1.6 80 ± 11 96.9 ± 1.5
0.03 0.15 0.08 0.47
33.1 ± 4.0 34.2 ± 5.0 117 ± 14 96.1 ± 3.5
Peak
P value
Baseline
After CCB
0.005 0.01
73.7 ± 12.1 13.9 ± 2.9
85.7 ± 18.6 16.4 ± 4.1
0.001 0.001
0.92 ± 0.02 6.3 ± 1.2 131 ± 25 83 ± 13 20.5 ± 3.5
1.0 0.005 0.42 0.57 0.14
1.11 ± 0.06 5.5 ± 0.8 146 ± 38 97 ± 20 33.7 ± 7.3
1.12 ± 0.05 6.9 ± 1.3 152 ± 36 92 ± 19 37.3 ± 8.9
0.56 0.001 0.67 0.50 0.05
35.3 ± 3.2 31.6 ± 3.1 111 ± 14 95.6 ± 2.8
0.02 0.02 0.11 0.61
30.3 ± 6.0 38.0 ± 8.1 147 ± 17 93.6 ± 5.2
32.8 ± 4.8 34.1 ± 5.2 140 ± 17 94.1 ± 5.1
0.03 0.01 0.02 0.73
Data are expressed as mean ± SD. AT: anaerobic threshold; CCB: calcium channel blockers; CPET: cardiopulmonary exercise testing; DBP: diastolic blood pressure; HR: heart rate; PETCO2@AT:endtidal partial pressure of carbon dioxide at anaerobic threshold; RER: respiratory exchange ratio; SBP: systolic blood pressure; SPO2: arterial oxygen _ ventilation; VE/ _ VCO _ _ saturation; VE: 2@AT: ratio of ventilation to carbon dioxide output at anaerobic threshold; VO2: oxygen consumption; VR-IPAH: vasodilator-responsive idiopathic pulmonary arterial hypertension.
in patients with VR-IPAH and also in patients with VNR-IPAH treated with sildenafil. Ventilatory efficiency at rest, AT, and peak _ VCO _ were significantly higher (lower in VE/ 2@AT and higher in PETCO2@AT) in VR-IPAH group than that in VNR-IPAH group. In _ 2 and peak O2 pulse) and both groups, Aerobic capacity (peak VO _ VCO _ ventilatory efficiency (VE/ 2@AT and PETCO2@AT) were
significantly improved after therapy, along with improvement of NYHA functional class, 6MWD, NT-proBNP and TRPG. VR-IPAH is an infrequent subphenotype of IPAH which is characterized by reversible vasoconstriction rather than cellular obstruction [9,10]. Previous studies showed that high-dose CCB could improve right ventricular hypertrophy, 6WMD, and also
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Y. Tang et al. / Pulmonary Pharmacology & Therapeutics 43 (2017) 26e31
Table 5 Parameters of WHO-FC, 6WMD, laboratory tests and echocardiograms at baseline and after treatment. Variable
WHO-FC I/II, n III/IV,n 6WMD, m Laboratory tests NT-proBNP, pg/ml Uric acid, mmol/L Creatinine, mmol/L Echocardiography LVED, mm LVEF,% RVED,mm TRPG, mmHg
VNR-IPAH
P value
Baseline
After sildenafil
10 18 425.8 ± 57.8
22 6 501.0 ± 64.7
922.6 (583.5,1792.5) 456.9 ± 215.6 74.6 ± 16.9
456.9 (89.6,1428.3) 446.7 ± 121.7 72.7 ± 10.8
VR-IPAH
P value
Baseline
After CCB
0.0001
15 10 455.6 ± 48.7
25 0 502.5 ± 53.1
0.0001
0.02 0.84 0.64
852.4 (336.2,1079.5) 373.9 ± 115.4 68.5 ± 12.1
141.5 (58.1392.2) 316.3 ± 92.1 68.4 ± 11.5
0.002 0.01 0.97
0.08 0.96 0.39 0.08
38.4 63.5 30.6 89.6
0.003
36.3 65.1 32.2 75.5
± ± ± ±
5.1 6.1 7.7 20.2
38.7 65.9 30.7 65.2
± ± ± ±
6.7 6.0 9.4 23.9
0.001
± ± ± ±
6.3 3.7 4.4 30.3
41.1 67.2 27.1 70.1
± ± ± ±
4.2 8.1 5.2 17.9
0.05 0.13 0.03 0.01
Data are expressed as mean ± SD or number of patients. CPET: cardiopulmonary exercise testing; CCB: calcium channel blockers; LVED: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; NT-proBNP: N-terminal of the prohormone brain natriuretic peptide; RVED: right ventricular end-diastolic diameter; TRPG: tricuspid regurgitation pressure gradient, 6WMD: 6 min walk distance, WHO-FC: World Health Organization Functional Class; VR-IPAH: vasodilator-responsive idiopathic pulmonary arterial hypertension; VNR-IPAH: vasodilator-nonresponsive idiopathic pulmonary arterial hypertension.
reduce pulmonary arterial pressure and pulmonary vascular resistance in patients with VR-IPAH [2,3]. Our study showed that the improvement of NYHA functional class, 6MWD, NT-proBNP, RVED and TRPG after 3e6 months of CCB therapy, which was in agreement with previous studies. Increased pulmonary vascular resistance (PVR) in patients with VR-IPAH could decrease blood flow to the left side of the heart and shift the ventricular septum leftward, leading to a decrease in CO, _ 2 and which eventually cause a decrease in peak work rate, peak VO peak O2 pulse. In addition, increased PVR could also increase physiologic dead space, which was reflected by decreased ventila_ VCO _ tory efficiency (elevated VE/ 2@AT and diminished PETCO2@AT) [11]. Our study showed that Ventilatory efficiency in VNR-IPAH group were lower compared with VR-IPAH group even PVR, peak _ 2 and peak O2 pulse were similar between two groups, which VO may be due to that increased PVR was based on vascular tone rather than intimal proliferation leading to greater recruit underperfused microvasculature and downstream capillary surface area under the condition of exercise in patients with VR-IPAH [12,13]. Hoeper et al. demonstrated significant improvements in peak _ 2 after 2e3 months of sildenafil therapy in 9 patients with PAH VO [14]. Ronald J. Oudiz, et al. reported that improvement of ventilatory efficiency, peak O2 pulse, peak work rate after 4 ± 2 months of treatment with sildenafil in 14 patients with PAH [6]. In the present _ 2, peak O2 pulse, VE/ _ VCO _ study, we demonstrated that peak VO 2 @AT and PETCO2 @AT improved significantly after 3e6 months of sildenafil therapy in patients with VNR-IPAH. For patients with VR_ 2, peak O2 pulse, VE/ _ VCO _ IPAH, peak work rate, peak VO 2@AT and PETCO2 @AT also improved significantly with 3e6 months of high dose of CCB therapy, which indicate that CCB can also work on vascular smooth muscle in patients with VR-IPAH as sildenafil vasodilate the pulmonary vascular bed in patients with VNR-IPAH [10]. In addition, our study showed that diastolic blood pressure at rest in both groups decreased after treatment, which can be explained that both of them, sildenafil and CCB, can decrease peripheral vascular resistance via promoting relaxation of vascular smooth-muscle cells in peripheral arteries, and heart rate at peak was decreased in VR-IPAH group, which may due to that CCB itself, especially diltiazem, can slow down heart rate [10,15]. There was no blinding to exclude a placebo effect. Nonetheless it was not ethical for vasodilator-responsive IPAH patients to not receive CCB treatment. In addition, the resting haemodynamic parameters were not studied to further support evidences of improvement as repeat catheterization was not clinically indicated
after 3e6 months of therapy. Finally, a small number of patients may have certain influence to the results. A multi-center trial with large samples and long term follow-up is required. 5. Conclusions In conclusion, Ventilatory efficiency in patients with VR-IPAH is better than that in patients with VNR-IPAH. CCB improves peak _ 2, peak O2 pulse PETCO2@AT, VE/ _ VCO _ VO 2@AT during exercise, as well as NYHA functional class, 6MWD, NT-proBNP and TRPG in patients with VR-IPAH, and these parameters are also improved in patients with VNR-IPAH after sildenafil therapy. Our study demonstrates that CPET can be a non-invasive and useful tool to assess and monitor the therapeutic effects in patients with VNR-IPAH under the treatment of CCB. Funding This work was supported by Central Public Interest Scientific Institution Basal Research Fund for Young Researchers (No. 2010F11). Conflict of interest The authors have no conflicts of interest to disclose. References [1] H.W. Farber, D.P. Miller, A.D. Poms, D.B. Badesch, A.E. Frost, E. Muros-Le Rouzic, A.J. Romero, W.W. Benton, C.G. Elliott, M.D. McGoon, R.L. Benza, FiveYear outcomes of patients enrolled in the REVEAL registry, Chest 148 (2015) 1043e1054. [2] O. Sitbon, M. Humbert, X. Jais, V. Ioos, A.M. Hamid, S. Provencher, G. Garcia, F. Parent, P. Herve, G. Simonneau, Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension, Circulation 111 (2005) 3105e3111. [3] S. Rich, E. Kaufmann, P.S. Levy, The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension, N. Engl. J. Med. 327 (1992) 76e81. [4] M. Guazzi, V. Adams, V. Conraads, M. Halle, A. Mezzani, L. Vanhees, R. Arena, G.F. Fletcher, D.E. Forman, D.W. Kitzman, C.J. Lavie, J. Myers, EACPR/AHA Joint Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations, Euro. Heart J. 33 (2012) 2917e2927. [5] R. Wensel, C.F. Opitz, S.D. Anker, J. Winkler, G. Hoffken, F.X. Kleber, R. Sharma, M. Hummel, R. Hetzer, R. Ewert, Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise
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