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Corresponding author: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Plasma cyclophilin A (CyPA) levels were significantly elevated in chronic thromboembolic pulmonary hypertension.
•
CyPA levels were linearly correlated with mean pulmonary arterial pressure and pulmonary vascular resistance.
•
Balloon pulmonary angioplasty (BPA) reduced CyPA regardless of brain natriuretic peptide (BNP) at baseline.
•
BPA decreased CyPA irrespective of the body mass index (BMI) at baseline.
•
BPA did not lower BNP in patients with normal BNP or high BMI at baseline.
Abstract
Background
Although cardiac troponin and natriuretic peptide have been shown to decrease after balloon pulmonary angioplasty (BPA) with improved right ventricular afterload in chronic thromboembolic pulmonary hypertension (CTEPH), biomarkers to evaluate the effects of BPA independently of heart failure status remain to be developed.
Methods
In 39 consecutive CTEPH patients including 31 who underwent BPA, we measured plasma levels of cyclophilin A (CyPA), which we demonstrated is secreted from pulmonary vascular smooth muscle cells in response to mechanical stretch and hypoxia.
Results
CyPA levels were elevated in CTEPH patients (12.7, IQR: 7.6-16.0) compared with 8 thromboembolic controls with a history of venous thromboembolism (4.9, IQR: 2.4-11.2) or 18 healthy controls (4.1, IQR: 2.4-6.8) (both p < 0.05) and were linearly correlated with mean pulmonary arterial pressure (r = 0.50, p = 0.0003) and pulmonary vascular resistance (r = 0.32, p = 0.026). BPA reduced CyPA levels and tended to lower brain-type natriuretic peptide (BNP) levels (p < 0.01 and p = 0.07). When comparing the changes in CyPA before and after BPA in the two subgroups with higher (≥35 pg/mL) and normal (<35 pg/mL) BNP at baseline, CyPA decreased both in patients with higher BNP and those with normal BNP (both p < 0.05). In contrast, BNP decreased only in patients with higher BNP (p < 0.05). Also, CyPA decreased both in patients with lower (<25 kg/m2) and higher (≥25 kg/m2) body mass index (BMI) at baseline (both p < 0.05), whereas BPA tended to reduce BNP in patients with lower BMI (p = 0.12) but not in those with higher BMI (p = 0.55).
Conclusions
CyPA could be a useful biomarker to evaluate the effects of BPA even in patients with normal BNP or high BMI.
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the persistence of stenosis and obstruction of the pulmonary arteries as organized thrombi and fibrous tissue with resultant pulmonary hypertension [
]. We and others have recently demonstrated the beneficial effects of balloon pulmonary angioplasty (BPA) for CTEPH patients, including the beneficial hemodynamic and prognostic effects for inoperable CTEPH patients more than those which were previously reported [
Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.
Pulmonary edema predictive scoring index (PEPSI), a new index to predict risk of reperfusion pulmonary edema and improvement of hemodynamics in percutaneous transluminal pulmonary angioplasty.
Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.
Pulmonary edema predictive scoring index (PEPSI), a new index to predict risk of reperfusion pulmonary edema and improvement of hemodynamics in percutaneous transluminal pulmonary angioplasty.
], we still need an invasive examination by right heart catheterization to evaluate the effectiveness of BPA. Kriechbaum et al. reported that cardiac troponin and N-terminal pro-B-type natriuretic peptide decreased after BPA indicating that reducing right ventricular afterload has led to lessening right ventricular wall stress and myocardial damage [
]. Intracellular CyPA plays essential roles in protein folding and trafficking of extracellular signal-regulated kinase 1/2 and apoptosis-inducing factor [
Cyclophilin A is required for CXCR4-mediated nuclear export of heterogeneous nuclear ribonucleoprotein A2, activation and nuclear translocation of ERK1/2, and chemotactic cell migration.
], and is secreted from vascular smooth muscle cells (VSMCs) in response to several stimuli including mechanical stretch, hypoxia, and oxidative stress [
]. We found that intracellular and extracellular CyPA promotes intimal thickening, abdominal aortic aneurysms, atherosclerosis, and cardiac hypertrophy in mice [
]. Additionally, we have demonstrated that plasma levels of CyPA are significantly higher in patients with coronary artery disease in proportion to the severity of the disorder [
]. Notably, Zuern et al. reported that CyPA expression in myocardial biopsy samples is an independent predictor of clinical outcome in patients with heart failure [
]. A previous study showed that CyPA expression increased in a time-dependent manner in the pulmonary microvascular walls in hypoxia-induced pulmonary hypertension (PH) in wild-type mice [
]. Also, CyPA was also demonstrated to be strongly expressed in the remodeled pulmonary microvasculature in patients with pulmonary arterial hypertension (PAH) undergoing lung transplantation [
]. Importantly, plasma CyPA levels in patients with PAH were increased parallel to the severity of pulmonary vascular resistance (PVR), and high plasma CyPA levels in those patients were associated with poor outcomes including death and lung transplantation [
In the present study, we thus aimed to evaluate plasma CyPA levels also in CTEPH patients and to examine the change of CyPA before and after BPA for determining whether CyPA could be useful to assess the effect of BPA.
Methods
Study population
The ethical review board of Tohoku University approved the study protocol, and written informed consent was obtained from all patients (No. 2008-470, 2015-1-191). We enrolled a total of 39 CTEPH patients including 31 patients who underwent BPA in our hospital from January 2010 to April 2017. They were diagnosed as having inoperable CTEPH based on the standard criteria [
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
]. CTEPH patients were compared with 8 thromboembolic controls and 18 healthy controls. Thromboembolism controls were patients who had a history of venous thromboembolism (VTE) with findings of PH on echocardiography or with residual thrombi on scintigraphy or contrast-enhanced computed tomography but had mean pulmonary arterial pressure (mPAP) <25 mmHg on right heart catheterization. Healthy controls were patients who underwent coronary arteriography for examination of chest pain. In all the CTEPH patients and thromboembolic controls, we examined hemodynamic parameters by right heart catheterization with measurements of plasma levels of CyPA and brain natriuretic peptide (BNP). In 31 CTEPH patients treated with BPA, we also compared the data before and after the BPA procedure.
BPA
We performed BPA via the right femoral vein to treat pulmonary arterial branches [
Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.
]. We selected targeted vessels based on comprehensive findings, including webs, bands, abrupt narrowing, and complete obstructions, obtained by pulmonary angiography, 3D-reconstructed computed tomography, and intravascular imaging modalities including optical computed tomography [
Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.
]. The procedures were repeated more than 4 weeks apart in all patients, and additional BPA was repeated until mPAP decreased below 30 mmHg or no more treatable lesions were found [
Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.
]. Treating physicians were not aware of the CyPA level while making management decisions.
Measurement of plasma CyPA levels
In CTEPH patients, fasting blood samples for the measurement of CyPA were drawn from the sheath immediately after being inserted into a vein in both timings of diagnostic catheterization and BPA session. The blood samples were also drawn at the beginning of the catheterization from the sheath in VTE controls and a peripheral vein in healthy controls. Plasma samples were collected using EDTA and centrifuged for 10 min at 2,500 g within 30 min of collection, and aliquots were stored at −80 °C. CyPA was measured with the use of an immunoassay based on the sandwich technique according to the protocol (Human Cyclophilin A ELISA Kit, CSB-E09920 h, Cusabio, Wuhan, China) [
Continuous variables are expressed as the mean ± SD or median (interquartile range), and categorical variables as the number (%). Means, medians, and percentages were compared using paired t-test, Wilcoxon signed-rank test, and χ2 or Fisher exact test, as appropriate. Values of p < 0.05 were considered to be statistically significant for all analyses. All analyses were performed with JMP Pro 12.2.0 (Japanese version, SAS Institute Inc., Tokyo, Japan).
Results
Patient characteristics
Baseline characteristics and hemodynamic profile of the CTEPH patients, VTE controls, and healthy controls are shown in Table 1. The mean age of CTEPH patients was 63 ± 12 years, and 87% were female. The proportion of females was higher in the CTEPH cohort than in the other two groups. Of the patients with CTEPH, 46% had hypertension, 23% diabetes mellitus, and 38% dyslipidemia, frequencies that were comparable to the other two controls. Mean PAP, cardiac index, and the median value of PVR in CTEPH patients were 34 ± 8 mmHg, 2.5 ± 0.7 L/min/m2, and 528 [inter-quartile range (IQR), 398-688] dynes/sec/cm5, respectively, which were worse than VTE controls. CTEPH patients underwent a median of 2 sessions of BPA per patient (IQR, 1–3), and the median follow-up period before and after BPA was 1.8 years. Their characteristics and medications before and after BPA are shown in Table 2. The use of PH-specific medications was comparable before and after BPA.
Table 1Patient characteristics.
CTEPH
VTE controls
Healthy controls
p-Value CTEPH vs VTE controls
p-Value CTEPH vs Healthy controls
N
39
8
18
Age (years)
63 ± 12
62 ± 10
56 ± 13
0.83
0.06
Female (%)
34 (87)
2 (25)
10 (56)
0.001
0.02
Body mass index
23 ± 4
24 ± 2
24 ± 3
0.64
0.63
eGFR (mL/min/1.73 m2)
63 ± 16
67 ± 30
71 ± 15
0.69
0.07
D-dimer (μg/mL)
0.5 (0.5–0.7)
1.1 (0.5–1.8)
0.6 (0.5–0.9)
0.02
0.12
BNP (pg/mL)
36 (14–50)
25 (8–55)
19 (6–40)
0.44
0.11
WHO FC III or IV (%)
5 (13)
1 (13)
0
1.00
0.17
Medical history
Hypertension
18 (46)
5 (63)
11 (61)
0.46
0.40
Diabetes
9 (23)
3 (38)
7 (39)
0.40
0.34
Dyslipidemia
15 (38)
2 (25)
11 (61)
0.69
0.15
Hemodynamics
mPAP (mmHg)
34 ± 8
15 ± 3
NA
<0.0001
NA
PAWP (mmHg)
9 ± 3
8 ± 4
NA
0.47
NA
RAP (mmHg)
5 ± 3
5 ± 2
NA
0.81
NA
CI (L/min/m2)
2.5 ± 0.7
3.0 ± 0.6
NA
0.03
NA
PVR (dynes/sec/cm5)
528 (398–688)
114 (111–140)
NA
<0.0001
NA
Heart rate (bpm)
70 ± 11
72 ± 9
NA
0.62
NA
SaO2 (%)
92 ± 5
96 ± 4
NA
0.10
NA
SvO2 (%)
67 ± 6
70 ± 10
NA
0.11
NA
Data are presented as n (%), mean ± SD or median (interquartile range), unless otherwise stated. BNP, brain natriuretic peptide; CI, cardiac index; CTEPH, chronic thromboembolic pulmonary hypertension; eGFR, estimated glomerular filtration rate; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SaO2, arterial oxygen saturation; SvO2, mixed venous oxygen saturation; VTE, venous thromboembolism; WHO FC, World Health Organization functional class.
BPA significantly improved the hemodynamic status, including mPAP (34 ± 7 to 26 ± 5 mmHg) and PVR (562 ± 252 to 354 ± 124 dynes/sec/cm5), and heart rate (72 ± 10 to 67 ± 9 bpm) (Fig. 1). Before and after BPA, no significant change was noted in right atrial pressure, cardiac index, or mixed venous oxygen saturation.
Fig. 1Hemodynamic parameters before and after balloon pulmonary angioplasty (BPA) in chronic thromboembolic pulmonary hypertension patients (n = 31). (A) Mean pulmonary arterial pressure (mPAP). (B) Right atrial pressure (RAP). (C) Cardiac index. (D) Pulmonary vascular resistance (PVR). (E) Heart rate (HR). (F) Mixed venous oxygen saturation (SvO2).
Plasma CyPA levels were elevated in CTEPH patients (12.7, IQR: 7.6–16.0) compared with thromboembolic controls (4.9, IQR: 2.4-11.2, p = 0.04) and with healthy controls (4.1, IQR: 2.4-6.8, p < 0.001) (Fig. 2A). There was no significant difference between thromboembolic controls and healthy controls. In 31 CTEPH patients who underwent BPA, the procedure reduced plasma CyPA
Fig. 2Plasma cyclophilin A (CyPA) Levels. (A) Plasma CyPA levels were significantly elevated in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared with patients with a history of venous thromboembolism (VTE) without pulmonary hypertension or healthy controls. (B and C) Balloon pulmonary angioplasty (BPA) markedly reduced CyPA (B), but only tended to reduce brain natriuretic peptide (BNP) (C) (n = 31).
levels (12.0, IQR: 8.4-15.8 to 4.7, IQR: 0.8-8.4, p < 0.0001) (Fig. 2B), and tended to reduce plasma BNP levels (26, IQR: 13-47 to 19, IQR: 9-36, p = 0.07) (Fig. 2C). In CTEPH patients before BPA and VTE controls at baseline, plasma CyPA levels were linearly correlated with mPAP (r = 0.50, p = 0.0003) and PVR (r = 0.32, p = 0.026) (Fig. 3A, B). Similarly, plasma BNP levels were correlated with mPAP (r = 0.40, p = 0.006) and PVR (r = 0.57, p < 0.0001) (Fig. 3C, D).
Fig. 3Relationship between cyclophilin A (CyPA) or brain-type natriuretic peptide (BNP) levels and hemodynamic parameters at baseline. In chronic thromboembolic pulmonary hypertension (CTEPH) patients and those with a history of venous thromboembolism (VTE) without pulmonary hypertension, plasma CyPA levels linearly correlated with (A) baseline mean pulmonary arterial pressure (mPAP) and (B) pulmonary vascular resistance (PVR). BNP also correlated with (C) baseline mPAP and (D) PVR.
We further compared the changes in plasma CyPA levels before and after BPA in the two subgroups with higher (≥35 pg/ml, n = 12) and normal (<35 pg/ml, n = 19) levels of BNP at baseline according to the upper limit of normal in heart failure [
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
]. Patients with higher BNP and those with normal BNP at baseline both showed decreased plasma levels of CyPA after BPA (10.7, IQR: 8.2-15.7 to 3.3, IQR: 0.8-8.2, p = 0.0005; 12.8, IQR: 8.4-15.8 to 4.7, IQR: 0.8-10.8, p = 0.013, respectively) (Fig. 4A). In contrast, patients with higher BNP at baseline showed decreased plasma levels of BNP (54, IQR: 39-104 to 36, IQR: 9-46, p = 0.016) but not in those with normal BNP at baseline (14, IQR: 9-25 to 15, IQR: 9-21, p = 0.87) (Fig. 4B). Additionally, we compared the changes in plasma CyPA levels before and after BPA in the two subgroups with lower (<25 kg/m2, n = 22) and higher (≥25 kg/m2, n = 9) levels of body mass index (BMI) at baseline. BPA reduced CyPA both in patients with lower BMI and those with higher BMI (12.2, IQR: 8.2-15.6 to 4.6, IQR: 0.8-8.6, p = 0.0005; 12.0, IQR: 8.0-16.5 to 5.9, IQR: 1.4-9.3, p = 0.039, respectively) (Fig. 4C). On the other hand, BPA tended to reduce BNP in patients with lower BMI (29, IQR: 12-58 to 21, IQR: 10-36, p = 0.12) but not in those with higher BMI (25, IQR: 11-36 to 12, IQR: 8-32, p = 0.55) (Fig. 4D). The changes in hemodynamics between 2 groups according to BNP or BMI at baseline were comparable before and after BPA (Table 3).
Fig. 4Differences as a biomarker between brain-type natriuretic peptide (BNP) and cyclophilin A (CyPA) in chronic thromboembolic pulmonary hypertension by BNP or by body mass index (BMI) at baseline. (A) Patients with both higher (≥35 pg/mL) and normal (<35 pg/mL) levels of BNP at baseline showed a significant decrease in plasma levels of CyPA after balloon pulmonary angioplasty (BPA). (B) Patients with higher BNP at baseline showed a significant reduction in plasma levels of BNP but not in those with normal BNP after BPA. (C) In patients with both lower (<25 kg/m2) and higher (≥25 kg/m2) BMI, BPA significantly reduced CyPA. (D) In patients with lower BMI at baseline, BPA tended to decrease plasma BNP levels but not in those with higher BMI.
The novel findings of this study are as follows: 1) plasma CyPA levels were significantly elevated in CTEPH patients compared with VTE controls and healthy controls, 2) CyPA levels were correlated with mPAP and PVR, 3) BPA reduced CyPA regardless of the levels of BNP at baseline, whereas there was no significant change in BNP levels in patients with normal BNP levels at baseline, and 4) BPA reduced CyPA regardless of BMI at baseline, whereas there was no apparent change in BNP in patients with high BMI at baseline. To the best of our knowledge, this is the first study that demonstrates that plasma levels of CyPA in CTEPH patients could be a useful biomarker to evaluate the effects of BPA even in patients with normal BNP levels or high BMI.
The role of CyPA in the pathophysiology of CTEPH
The organized thrombi in CTEPH patients were considered to be originated from acute pulmonary thromboembolism [
]. Several reports of a series of CTEPH patients who underwent pulmonary endarterectomy showed the presence of inflammation in resected pulmonary artery tissue, such as neointima, angiogenesis, increased cellularity within thrombi around newly formed recanalizing vessels, and atherosclerotic lesions containing macrophage-derived foam cells with lipid droplets [
]. Indeed, inflammatory markers including C-reactive protein, interleukin-10, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, and matrix metalloproteinase-9 have been reported to be increased in CTEPH patients compared with healthy controls [
Additionally, we have recently demonstrated that the thrombin-activatable fibrinolysis inhibitor plays a crucial role in the development of CTEPH and promotes the secretion of inflammatory cytokines [
], and stimulates VSMCs through basigin, which is an extracellular receptor for CyPA. Extracellular CyPA promotes cell proliferation and inflammation and induces inflammatory cell migration [
]. In the present study, plasma CyPA levels were significantly correlated with mPAP and PVR. Here, vascular reactive oxygen species (ROS) formation can be stimulated by mechanical stretch, pressure, shear stress, hypoxia, and growth factors, all of which activate the Rho-kinase system [
Extracellular cyclophilin A, especially acetylated, causes pulmonary hypertension by stimulating endothelial apoptosis, redox stress, and inflammation.
]. Interestingly, the antibody-based blockade of extracellular CyPA inhibited thrombosis and thrombi-related inflammation without affecting blood homeostasis in vitro and in vivo [
]. These findings highlight the potential role of CyPA through inflammation and ROS in the development of CTEPH.
The effects of BPA on the secretion of CyPA
The present results provide the mechanistic insights into the CyPA-mediated hemodynamic assessment and effectiveness after BPA. According to a report of measuring pulmonary artery flow by phase contrast magnetic resonance imaging after BPA in one lung, PVR and mPAP were decreased in both lungs after BPA [
Balloon pulmonary angioplasty relieves haemodynamic stress towards untreated-side pulmonary vasculature and improves its resistance in patients with chronic thromboembolic pulmonary hypertension.
]. In contrast, pulmonary artery flow was increased only in the treatment side and was reduced in the non-treatment side, suggesting that the decrease in PVR on the non-treatment side was the indirect effect exerted by hemodynamic unloading and reducing inflammation which could regress the progression of the small-vessel arteriopathy in non-treatment side vasculature [
Balloon pulmonary angioplasty relieves haemodynamic stress towards untreated-side pulmonary vasculature and improves its resistance in patients with chronic thromboembolic pulmonary hypertension.
]. Moreover, lumen diameter and blood flow were improved even more after 3 months than immediately after BPA, although no additional procedure was performed at the lesion [
Spontaneous enlargement of pulmonary artery after successful balloon pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension.
]. An autopsy of a PAH patient at 9 years after single-lung transplantation gives support to those findings of BPA-mediated reverse remodeling of the pulmonary vasculature in CTEPH [
]. The case with severe PAH has shown that single-lung transplantation shifted the pulmonary arterial flow from the native diseased lung into the lung allograft soon after transplantation, which gradually normalized over the years [
]. Furthermore, an autopsy revealed the amelioration of the small-vessel arteriopathy including vessel occlusion and plexiform lesion in the native diseased lung compared to the lung resected 9 years previously [
]. These findings may indicate that pulmonary unloading by BPA reduces shear stress and improves oxygenation, and soothing inflammation in the process of pulmonary vascular reverse remodeling, resulting in less ROS production and CyPA secretion.
Next, it must be noticed that right heart function is closely linked to the prognosis of CTEPH patients [
]. The increase in pressure overload leads to an increase in wall stress, causing right ventricular hypertrophy, and eventually cardiac contractile force decreases, resulting in right ventricular dilation, for which maladaptive neurohumoral signaling, oxidative stress, and inflammatory responses may be involved [
Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure.
]. Although no significant change was noted in right atrial pressure or cardiac index after BPA at rest, recent studies have shown the amelioration of exercise tolerance [
Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.
Echocardiographic evidence of right ventricular functional improvement after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.
] after BPA. Here, CyPA has a direct hypertrophic effect on cardiac myocytes and stimulates the proliferation of cardiac fibroblasts, which also secrete CyPA, in response to angiotensin II [
]. Remarkably, basigin, a receptor for CyPA, is upregulated in pressure-overloaded heart and augments
inflammation and oxidative stress and mediates mechanical stretch- and angiotensin II-induced activation of cardiac fibroblasts and inflammatory cytokine secretion [
]. Importantly, treatment with celastrol which downregulates the expressions of CyPA and basigin in the heart and the lung ameliorated cardiac dysfunction and postcapillary PH [
]. Thus, BPA-mediated reduction in plasma CyPA levels could have been caused by lowering CyPA production from cardiac fibroblasts in the right ventricle due to reduced pressure-overload.
Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial.
Comparison of brain natriuretic peptide levels to simultaneously obtained right heart hemodynamics in stable outpatients with pulmonary arterial hypertension.
], in contrast, CyPA had a linear correlation with mPAP and PVR, suggesting the potential as a more sensitive biomarker to detect the slight loading on pulmonary VSMCs and right ventricles. Since actively lowering mPAP has been demonstrated to be quite successful for improving prognosis in PAH patients [
], the characteristics of CyPA may be useful for treating CTEPH.
In this study, BPA reduced plasma CyPA levels regardless of BMI before BPA, whereas there was no significant change in BNP levels in patients with high BMI. Large-scale epidemiological studies demonstrated that natriuretic peptide levels are influenced by obesity, which is called “natriuretic handicap” [
]. This paradoxical phenomenon is explained by increased clearance of natriuretic peptides in adipose tissue in obese subjects, the secretion of bioactive substances by adipose tissue that affects natriuretic peptide production in the heart, alterations in sex hormone production and activity, and insulin resistance [
]. An experimental study demonstrated that glucocorticoids increased, and free fatty acids, insulin-like growth factor-1, and insulin decreased the expression of the growth hormone stimulatory receptors, growth hormone-releasing hormone receptor, and ghrelin-receptor, without significantly altering CyPA mRNA levels [
]. It is tempting to speculate that plasma CyPA may not be suppressed by obese-related hormones, however, this hypothesis needs scrutiny.
Study limitations
Several limitations should be mentioned in the present study. First, the period of follow-up and the number of BPA procedures differed among patients. Second, evaluation of right ventricular function, pulmonary vascular function, and inflammatory state with modality other than right heart catheterization may result in a more detailed estimation of the source of plasma CyPA. Finally, since CyPA has been shown to have a close relationship with several cardiovascular diseases [
], it can be influenced by other comorbidities before and after BPA. In this study, there were 5 patients with hepatic disorders, including cholelithiasis in 3, alcoholic liver disease in 1, and unknown bile duct dilatation in 1. However, no significant change was noted in the hepatobiliary enzymes before and after BPA. The usefulness of CyPA as a biomarker for liver disease needs to be validated in another study.
Conclusions
In the present study, we were able to demonstrate that plasma levels of CyPA could be a useful biomarker to evaluate the effects of BPA even in patients with normal BNP levels or high BMI.
Sources of Funding
This work was supported in part by the grants-in-aid for Scientific Research (15H02535, 15H04816, and 15K15046) from the Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan, the grants-in-aid for Scientific Research from the Ministry of Health, Labour, and Welfare, Tokyo, Japan (10102895), and the grants-in-aid for Scientific Research from the Japan Agency for Medical Research and Development, Tokyo, Japan (15ak0101035h0001, 16ek0109176h0001, 17ek0109227h0001).
Disclosure
The authors declare that there is no conflict of interest.
Acknowledgments
We are grateful to the laboratory members in the Department of Cardiovascular Medicine of the Tohoku University for valuable technical assistance, especially to Yumi Watanabe, Ai Nishihara, and Hiromi Yamashita.
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Vascular and right ventricular remodelling in chronic thromboembolic pulmonary hypertension.
Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications.
Pulmonary edema predictive scoring index (PEPSI), a new index to predict risk of reperfusion pulmonary edema and improvement of hemodynamics in percutaneous transluminal pulmonary angioplasty.
Cyclophilin A is required for CXCR4-mediated nuclear export of heterogeneous nuclear ribonucleoprotein A2, activation and nuclear translocation of ERK1/2, and chemotactic cell migration.
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
Extracellular cyclophilin A, especially acetylated, causes pulmonary hypertension by stimulating endothelial apoptosis, redox stress, and inflammation.
Balloon pulmonary angioplasty relieves haemodynamic stress towards untreated-side pulmonary vasculature and improves its resistance in patients with chronic thromboembolic pulmonary hypertension.
Spontaneous enlargement of pulmonary artery after successful balloon pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension.
Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure.
Echocardiographic evidence of right ventricular functional improvement after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.
Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial.
Comparison of brain natriuretic peptide levels to simultaneously obtained right heart hemodynamics in stable outpatients with pulmonary arterial hypertension.
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