ORIGINAL RESEARCH published: 03 May 2021 doi: 10.3389/fphys.2021.631326 Pulmonary Arterial Remodeling Is Related to the Risk Stratification and Right Ventricular-Pulmonary Arterial Coupling in Patients With Pulmonary Arterial Hypertension Juan C. Grignola 1* † , Enric Domingo 2,3† , Manuel López-Meseguer 4,5 , Pedro Trujillo 6 , Edited by: Jian Wang, Carlos Bravo 4,5 , Santiago Pérez-Hoyos 7 and Antonio Roman 4,5 Guangzhou Medical University, China 1 Pathophysiology Department, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Reviewed by: Uruguay, 2 Area del Cor, Hospital Vall d’Hebron, Barcelona, Spain, 3 Physiology Department, School of Medicine, Universitat Normand Leblanc, Autonoma, Barcelona, Spain, 4 Department of Pneumology, Hospital Vall d’Hebron, Barcelona, Spain, 5 Ciberes, IS Carlos III, University of Nevada, Reno, Madrid, Spain, 6 Centro Cardiovascular Universitario, Hospital de Clínicas, Facultad de Medicina, Universidad de la United States República, Montevideo, Uruguay, 7 Unidad de Estadística, Vall d’Hebron Institut de Recerca, Barcelona, Spain Changming Xiong, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Background: Pulmonary arterial (PA) stiffness has an essential contribution to the Union Medical College, China right ventricular (RV) failure pathogenesis. A comprehensive and multiparameter Ziying Lin, Guangzhou Medical University, China risk assessment allows predicting mortality and guiding treatment decisions in PA *Correspondence: hypertension (PAH). We characterize PA remodeling with intravascular ultrasound (IVUS) Juan C. Grignola in prevalent and stable patients with PAH according to the ESC/ERS risk table and jgrig@fmed.edu.uy analyze the RV-PA coupling consequences. † These authors have contributed equally to this work and share first Methods: Ten control subjects and 20 prevalent PAH adult patients underwent right authorship heart catheterization (RHC) with simultaneous IVUS study. We estimated cardiac index Specialty section: (CI), pulmonary vascular resistance, and compliance (PVR, PAC) by standard formulas. This article was submitted to From IVUS and RHC data, PA diameter, wall thickness/luminal diameter ratio, and Vascular Physiology, a section of the journal indexes of stiffness (pulsatility, compliance, distensibility, incremental elastic modulus Frontiers in Physiology - Einc-, and the stiffness index β) were measured. We evaluated RV-PA coupling by Received: 19 November 2020 the ratio of tricuspid annular plane systolic excursion to systolic pulmonary arterial Accepted: 08 April 2021 pressure (TAPSE/sPAP). The individual average risk was calculated by assigning a score Published: 03 May 2021 of 1 (low-risk -LR-), 2 (intermediate-risk -IR-), and 3 (high-risk -HR-) for each of seven Citation: Grignola JC, Domingo E, variables (functional class, six-minute walking test, brain natriuretic peptide, right atrial López-Meseguer M, Trujillo P, area and pressure, CI, and PA oxygen saturation) and rounding the average value to the Bravo C, Pérez-Hoyos S and Roman A (2021) Pulmonary Arterial nearest integer. Remodeling Is Related to the Risk Results: All PA segments interrogated showed increased vessel diameter, wall cross- Stratification and Right Ventricular-Pulmonary Arterial sectional area (WCSA), and stiffness in patients with PAH compared to control subjects. Coupling in Patients With Pulmonary 45% corresponded to LR, and 55% corresponded to IR PAH patients. The different Arterial Hypertension. Front. Physiol. 12:631326. measurements of PA stiffness showed significant correlations with TAPSE/sPAP (r = 0.6 doi: 10.3389/fphys.2021.631326 to 0.76) in PAH patients. The IR group had higher PA stiffness and lower relative WCSA Frontiers in Physiology | www.frontiersin.org 1 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification than LR patients (P < 0.05), and it is associated with a lower PAC and TAPSE/sPAP (P < 0.05). Conclusion: In prevalent PAH patients, the severity of proximal PA remodeling is related to the risk stratification and associated with PAC and RV-PA coupling impairment beyond the indirect effect of the mean PA pressure. The concomitant assessment of IVUS and hemodynamic parameters at diagnosis and follow-up of PAH patients could be a feasible and safe tool for risk stratification and treatment response of the PA vasculopathy during serial hemodynamic measurements. Keywords: pulmonary arterial stiffness, right ventricular-arterial coupling, pulmonary arterial hypertension, intravascular ultrasound, risk stratification INTRODUCTION stiffness parameters (Rodes-Cabau et al., 2003; Sanz et al., 2009; Lau et al., 2012; Shen et al., 2016). Emerging evidence supports the idea that vascular stiffening The prognosis of PAH patients is determined mainly by in the pulmonary arterial bed can precede the development RV adaptation to increased afterload. Accurate risk assessment of pulmonary hypertension (PH) as an early disease marker is essential in PAH to optimize treatment decisions aiming and promotes pulmonary vascular remodeling that ultimately to slow disease progression and improve outcomes (Galie leads to right ventricular (RV) failure (Sanz et al., 2009; Wang et al., 2018). Nowadays, achieving a low-risk status has and Chesler, 2011; Lammers et al., 2012). Measurements of been proposed as a potential surrogate outcome in PAH pulmonary vascular stiffness are considered to be superior clinical trials (Weatherald et al., 2018). There are different to other hemodynamic parameters in predicting mortality approaches to assessing risk in PAH by using different (Mahapatra et al., 2006). However, the exact role of vascular baseline and follow-up parameters, including clinical, functional, stiffening in the development and progression of PH is exercise, noninvasive and invasive variables combined in lacking due to insufficient understanding of the spatiotemporal formulas or calculators (Benza et al., 2012, 2018; Hoeper development of pulmonary vascular stiffness (Dabral and et al., 2018). The 2015 European Society of Cardiology Pullamsetti, 2017). It has been proposed that the crosstalk (ESC)/European Respiratory Society (ERS) PH guidelines between the proximal-elastic and distal-muscular pulmonary propose a comprehensive and multidimensional risk strategy arteries (PAs) play a role in the PH progression. Stiffer using several modifiable risk factors based on expert opinion proximal large PA will enhance transmission of flow and and validated by three independent contemporary European pressure pulsatility (shear and barotrauma) to the distal low PAH cohorts recently (Boucly et al., 2017; Hoeper et al., 2017; impedance (high compliance/low resistance) PAs, causing its Kylhammar et al., 2018). muscularization and remodeling (Dieffenbach et al., 2018). PA stiffness is an important factor governing the RV Muscularization of distal PAs promotes increased mean arterial afterload and the RV-PA coupling. The increased PA stiffness pressures, resulting in extensive vessel wall remodeling, stiffening leading to higher RV pulsatile workload reduced contractile the large PAs in a positive feedback cycle of pathologic vascular performance and impaired RV-PA coupling. Guazzi et al. remodeling. Finally, vascular stiffening may promote local (2013) first proposed tricuspid annular plane systolic excursion remodeling through alterations in gene expression and cellular normalized by pulmonary artery systolic pressure (TAPSE/sPAP) behaviors in response to the local mechanical microenvironment as a noninvasive measurement RV-PA coupling and an (“mechanobiological feedback”) (Bertero et al., 2015). Arterial independent predictor of survival in patients with heart failure stiffness can be obtained by assessing the relation between with and without PH. In the last few years, Tello et al. changes in arterial pressure (“stress”) and changes in arterial (2019b) proposed TAPSE/sPAP ratio as a surrogate of the volume, cross-sectional area, or diameter (“strain”). Both cardiac gold standard measure of RV-PA coupling (invasive pressure- magnetic resonance and intravascular ultrasound (IVUS) are volume loop-derived end-systolic/arterial elastance [Ees/Ea] increasingly used to evaluate PA dimensions and different arterial ratio) in PAH patients. They also showed that TAPSE/sPAP was associated with hemodynamics, functional class, and outcome Abbreviations: BNP, brain natriuretic peptide; dPAP, diastolic pulmonary artery in patients with PAH, proposing the possible added value of pressure; Einc, incremental elastic modulus; Ep: strain-pressure elastic modulus; TAPSE/sPAP in current risk assessment strategies for PAH h/D: wall thickness/luminal diameter ratio; IVUS: intravascular ultrasound; LCSA: (Tello et al., 2018). lumen cross-sectional area; mPAP, mean pulmonary artery pressure; 6MWT, six- minute walking test; PA, pulmonary artery; PAC, pulmonary arterial capacitance; The present study aimed to characterize PA remodeling with PAH, pulmonary arterial hypertension; PAOP, pulmonary arterial occlusion IVUS in prevalent patients with PAH according to the disease pressure; PH, pulmonary hypertension; pPAP, pulmonary artery pulse pressure; severity assessed by a multiparametric risk stratification approach PVR, pulmonary vascular resistance; PWV, pulse wave velocity; RHC, right heart and analyze the RV-PA coupling consequences. We hypothesized catheterization; RV, right ventricular; sPAP, systolic pulmonary artery pressure; TAPSE/sPAP, ratio of tricuspid annular plane systolic excursion to systolic that the pulmonary arterial remodeling (structural and functional pulmonary arterial pressure. wall properties) is related to the estimated risk score (ESC/ERS Frontiers in Physiology | www.frontiersin.org 2 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification FIGURE 1 | (A) Intravascular ultrasound probe positioning with X-Ray control. (B) Measurements of maximum systolic area, minimum diastolic area, and wall cross-sectional area in a pulmonary arterial hypertension patient (Diameter: 2.8 mm; pulsatility 31%; WCSA: 4.6 mm2 ; relative WCSA: 18%). risk table) and is associated with the RV-PA impairment coupling Hemodynamic and IVUS Examination in prevalent PAH patients. All PAH patients underwent right heart catheterization (RHC) in the supine position after 12 h of fasting and breathing room air. A 7F Swan-Ganz catheter (Edwards Lifesciences, MATERIALS AND METHODS United States) was inserted into a brachial or femoral vein, and a 5F end-hole catheter was inserted into a radial artery. Catheters Study Population were connected to fluid-filled transducers and zeroed at the The study was conducted according to the principles expressed atmospheric pressure. Hemodynamic measurements included in the Declaration of Helsinki. The local institutional ethics right atrial pressure, systolic (sPAP), diastolic (dPAP), mean committee approved the study, and all patients provided written (mPAP), and pulse PA pressure (pPAP), PA occlusion pressure informed consent. (PAOP), cardiac output and cardiac index (Fick method), Twenty prevalent PAH patients clinically stable in NYHA pulmonary vascular resistance (PVR, calculated as mPAP minus functional class I-III were recruited between April 2016 and PAOP divided by the cardiac output), PA oxygen saturation, and October 2017. Selection patients were consecutive patients pulmonary arterial compliance (PAC, estimated as stroke volume attending the Pulmonary Hypertension Unit outpatient of divided by pPAP). Hospital Universitari Vall d’Hebron that were stable and accepted After the hemodynamic study was completed, a guiding the protocol. A stable patient was defined by no clinical status catheter (Boston Scientific MPA Convey 7F) was advanced changes and PAH-specific medication in the previous 6 months. into different pulmonary arterial tree locations for IVUS image The only exclusion criteria were refusal to participate in the study acquisition, as seen in Figure 1. IVUS examination of the PAs or having PAH in functional class IV. PH was defined as mPAP was performed using a 40 MHz catheter (Opticross, Boston greater or equal than 25 mmHg. Scientific, United States) advanced over a 0,014” guidewire The same physician performed clinical assessment of patients with a 10–15 mm scan area and axial resolution of 43 mm. who categorized functional class and certified clinical stability. Selective pulmonary angiography was performed to determine We compared the RV afterload (PVR and PAC) and PA the anatomical position of the most distal, least-branching remodeling indices of PAH patients with a historical control segment of the PA with good image quality (defined as the group of subjects (n = 10) referred for cardiac catheterization complete circumferential demarcation of the intima and wall to due to clinically suspected PH and in whom PH and adventitia boundaries) (Figure 1). We attempted to image at least other respiratory and cardiovascular diseases were discarded four different pulmonary locations across the lungs, including (Domingo et al., 2017). upper and lower lobes of indistinct lungs. The images were Frontiers in Physiology | www.frontiersin.org 3 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification TABLE 1 | Indices of local pulmonary arterial stiffness. Parameter Formula Notes (sLCSA−dLCSA) Pulsatility, % dLCSA × 100 Relative change in lumen area during cardiac cycle (sLCSA−dLCSA) Compliance Coefficient, mm2 /mmHg pPAP Absolute change in lumen area for a given change in pressure (sLCSA−dLCSA) Distensibility Coefficient, %/mmHg dLCSA×pPAP × 100 Relative change in lumen area for a given change in pressure LCSA Incremental elastic modulus (Einc), kPa 3 × (1 + WCSA ) × EP Elastic modulus defined over a particular stress or strain range q EP Local Pulse Wave Velocity (PWV), m/s ρ Pulse generated by the ejecting heart propagates through the arterial wall with a given speed, the pulse wave velocity* sPAP Ln( dPAP ) Stiffness index β (sLCSA−dLCSA)/dLCSA Slope of the function between distending arterial pressure and arterial distension dLCSA and sLCSA: diastolic and systolic lumen cross-sectional area, respectively; sPAP, dPAP, and pPAP: systolic, diastolic and pulse pulmonary arterial pressure, respectively; EP : pressure-strain modulus; ρ: blood density (1.055 g/cm3 ) (*, according to Bramwell-Hill equation for a uniform tube) (Bramwell and Hill, 1922). TABLE 2 | Summary of demographic, humoral, echocardiographic, and hemodynamic data. Total (n = 20) Low-Risk (n = 9) Intermediate-Risk (n = 11) P-value Age (years) 50 ± 10 45 ± 10 53 ± 10 0.091 Sex (n M / F) 1 / 19 0/9 1 / 10 1.000 BMI (kg/m2 ) 23.9 ± 4.9 21.9 ± 2.4 25.6 ± 5.8 0.085 BSA (m2 ) 1.66 ± 0.18 1.68 ± 0.19 1.64 ± 0.19 0.663 FC (n I-II / III) 18 / 2 9/0 9/2 0.479 6MWT (meters) 417 ± 100 471 ± 106 365 ± 76 0.049 BNP (ng/L) 47 (32–75) 35 (20–46) 60 (47–250) 0.016 RA area (cm2 ) 19 (16–22) 18 (16–20) 20 (18–24) 0.278 TAPSE (mm) 18.5 ± 3.0 18.3 ± 2.7 18.7 ± 3.3 1.000 TAPSE/sPAP (mm/mmHg) 0.25 ± 0.08 0.30 ± 0.08 0.21 ± 0.06 0.023 mPAP (mmHg) 48 ± 15 43 ± 10 53 ± 18 0.194 pPAP (mmHg) 44 ± 16 39 ± 11 49 ± 18 0.186 CI (L/min/m2 ) 2.0 ± 0.4 2.2 ± 0.3 1.9 ± 0.5 0.162 HR (bpm) 68 ± 10 67 ± 9 70 ± 11 0.569 SVI (mL/m2 ) 28 ± 5 33 ± 6 26 ± 4 0.033 RA pressure (mmHg) 8.9 ± 4.0 7.0 ± 3.2 11 ± 4.5 0.103 PAOP (mmHg) 11.2 ± 3.2 11.8 ± 2.9 10.4 ± 3.7 0.562 PVR (Wood unit) 11 ± 5.6 9.7 ± 4.7 13.0 ± 5.3 0.167 PAC (mL/mmHg) 1.1 (0.7–1.4) 1.3 (1.0–2.0) 0.8 (0.7–1.1) 0.045 RC time (sec) 0.66 ± 0.14 0.68 ± 0.16 0.64 ± 0.14 0.556 PA oxygen saturation (%) 68 (63–70) 70 (68–74) 64 (60–68) 0.001 Data are presented as mean ± SD or median (interquartile range). BMI, body mass index; BNP, brain natriuretic peptide; BSA, body surface area; CI, cardiac index; FC, NYHA functional class; HR, heart rate; mPAP and pPAP, mean and pulse pulmonary arterial pressure, respectively; PAC, pulmonary arterial compliance; PAOP, pulmonary arterial occlusion pressure; PVR, pulmonary vascular resistance; RA, right atrial; SVI, stroke volume index; 6MWT, six-minute walking test; TAPSE/sPAP, tricuspid annular plane systolic excursion normalized by pulmonary artery systolic pressure. obtained and stored in digital format. Both diastolic and systolic defined as the total vessel area minus luminal cross-sectional area cross-sectional areas and the diameter of the studied segment (LCSA) during diastole; and %WCSA as WCSA divided by total were analyzed post-procedure by two independent observers vessel area × 100 (Gussenhoven et al., 1989). The mean vessel unaware of clinical and hemodynamic findings. diameter of the segments was obtained from the LCSA. Intra and interobserver validation of IVUS-derived We estimated the wall thickness/lumen diameter ratio (h/D) measurements of total PA area, luminal area, and diameter from the equations of Bramwell-Hill and Moens-Korteweg that have previously been reported (Rodes-Cabau et al., 2003; provide the link between the local PWV and the distensibility Grignola et al., 2013). All pressure measurements and IVUS (corresponding to the inverse of the pressure-strain modulus, images were acquired in end-expiration. EP ), the wall thickness (h), and lumen diameter (D) of the artery (Bramwell and Hill, 1922). Data Analysis s Total vessel area was defined by the area circumscribed by EP (Bramwell−Hill) PWV = the bright elastic lamina; wall cross-sectional area (WCSA) was ρ Frontiers in Physiology | www.frontiersin.org 4 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification s  h × Einc Moens − Korteweg PWV = D×ρ h EP = D Einc where Einc corresponds to the incremental elastic modulus, and ρ corresponds to blood density (Table 1). Vessel diameter, h/D ratio, WCSA, and %WCSA were used to characterize structural PA remodeling. Table 1 defines various indices used to assess local functional PA stiffness obtained from the invasive pressure and ultrasound measurements. We assumed that the cross-section of the artery is circular, with isotropic and incompressible wall (Laurent et al., 2006). Risk Stratification Based on the ESC/ERS PH recommendation about the multidimensional risk stratification of PAH patients, we used a risk model of seven modifiable variables: functional class, six-minute walking test (6MWT), brain natriuretic peptide (BNP), right atrial area and pressure, cardiac index and PA oxygen saturation (Galie et al., 2016). The individual global risk was calculated by assigning a score of 1, 2, and 3 for each variable (1 = low-risk, 2 = intermediate-risk, and 3 = high-risk). Dividing the sum of all grades by the number of variables rendered a mean grade. The mean grade was rounded to the nearest integer, which was used to define the patient’s risk (Hoeper et al., 2017; Kylhammar et al., 2018). We obtained the right atrial area and the ratio of TAPSE/sPAP by a transthoracic echocardiogram performed following the recommendations of the European Association of Echocardiography (Galderisi et al., 2011). 6MWT, plasma sample to dose BNP, and transthoracic FIGURE 2 | (A) Inverse relationship of PVR-PAC relationship and (B) Log PVR-log PAC plot for all patients (n = 9 low-risk patients; n = 11 echocardiography were taken on the same day of the RHC; intermediate-risk patients) (The PVR and PAC values of control patients are therefore, all the seven variables included in the risk score were expressed by mean ± SD, n = 10). PAC, pulmonary arterial compliance; PVR, obtained concomitantly. pulmonary vascular resistance). In order to carry out a more in-depth analysis of risk stratification, we took into account the number of parameters at low-risk grade (French approach in low-risk patients) for The association between structural (vessel diameter and WCSA) the low-risk group and the advanced risk stratification strategy and functional vascular remodeling (Einc) and between PA described by Yogeswaran et al. for the intermediate-risk group stiffness indices and TAPSE/sPAP ratio were explored using who distinguished low-intermediate and high-intermediate linear regression analysis (Pearson coefficient). All tests were risk according to TAPSE/sPAP ratio (TAPSE/sPAP ≥ 2-tailed, and a P value of 0.05 was considered statistically 0.24 mm/mmHg and TAPSE/sPAP < 0.24 mm/mmHg, significant. Statistical analyses were performed with the statistical respectively) (Boucly et al., 2017; Yogeswaran et al., 2020). package SPSS for Windows (version 21.0, SPSS Inc., Chicago, IL, United States). Statistical Analysis Data are expressed as mean ± SD. If continuous variables were found not to follow a normal distribution (Shapiro-Wilk RESULTS test), they were expressed as median with the interquartile range (IQR) and were compared using unpaired Mann-Whitney Demographic, Clinical, Hemodynamic, U-test. Fischer’s exact test or Chi-squared test was used to and Risk Profile compare categorical variables, expressed as the absolute number All patients belonged to group I and were idiopathic PAH. At or percentage. Significant differences between control subjects the time of the inclusion, eight patients received monotherapy and PAH risk groups were analyzed using one-way ANOVA. (40%), and twelve patients received combined therapy (60%) Frontiers in Physiology | www.frontiersin.org 5 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification (eight patients with dual therapy and four with triple therapy) IVUS Measurements: PA Remodeling without significant differences between risk groups. The According to the Global Risk pulmonary vasodilator drugs used were distributed as follows: ambrisentan (8), bosentan (3), diltiazem (3), epoprostenol (4), Assessment inhaled iloprost (1), macitentan (2), sildenafil (8), tadalafil As shown in Table 3, PA structural dimensions and stiffness (6), selexipag (1). indexes were higher in the patients with PAH than the control Patients’ demographic, humoral, echocardiographic, and group (P < 0.05). hemodynamic data are summarized in Table 2. The age A total of 85 PA segments were studied in PAH patients (4.2 and body mass index of PAH subjects (50 ± 10 years; seg/patient) with a median luminal diameter of 4.4 mm (IQR 23.9 ± 4.9 kg/m2 ) and control subjects (51 ± 6 years; 3.4–5.9). Thirty-seven PA segments corresponded to low-risk 23.6 ± 3.8 kg/m2 ) were well matched. Women predominate patients [3.7 (3.2–4.9) mm] and forty-eight to intermediate-risk in the PAH group compared to control subjects (95 versus patients [4.9 (3.8–7.1) mm]. All PA segments interrogated in 60%, P < 0.05). 45% of patients corresponded to low low-risk patients were from inferior lobes (59% left lung and risk and 55% to intermediate risk. None were at high 41% right lung). Among the forty-eight segments corresponding risk. Compared with intermediate-risk, low-risk patients from intermediate-risk patients, thirty-six were interrogated showed higher walking distance, stroke volume index, PAC from the inferior lobes, and twelve were interrogated from non- and PA oxygen saturation, and a lower BNP concentration inferior lobes (62% left lung and 38% right lung). No significant (P < 0.05). differences were found in the diameter [5.5 (3.8–7.2) vs. 4.6 (3.7– Figure 2A displays the hyperbolic relationship of PVR and 6.5) mm], absolute WCSA [(6.1 (5.2–7.3) vs. 5.2 (4.9–6.9) mm2 ], PAC of all patients, showing that low-risk subjects are at the and relative WCSA (13.1 ± 4.6 vs. 11.9 ± 5.6 %) of the vessels upper and left end of the curve due to the higher PAC. PAH from the lower lobes versus the middle/upper lobes. However, the patients showed greater PVR (11 ± 5.6 versus 2.8 ± 0.74 Wu) Einc of the PA segments from inferior lobes were lower than from and lower PAC (1.0 ± 0.4 versus 6.2 ± 1.1 mL/mmHg) the non-inferior lobes (567 ± 370 vs. 913 ± 580 kPa; P < 0.05). compared to control group (P < 0.05). The logarithmically Figure 3 shows the distribution of the vessel diameters studied transformed PVR-PAC plot showed that linear regression slope in the entire cohort and both risk groups. The segments of was −0.91, indicating that PVR and PAC are tightly and inversely the low-risk patients are concentrated on smaller diameters coupled (Figure 2B). than the segments of intermediate-risk patients distributed more Based on the French low-risk approach, the number of homogeneously and extensively, reaching values greater than variables in low-risk grade among low-risk patients showed 5.5 mm in up to 44% compared to 11% in the low-risk group. the following distribution: nobody had all variables in low- Despite similar PAP, PVR, and h/D ratio, intermediate-risk risk grade, one patient had six variables, five patients had five subjects had lower PAC, higher diameter, absolute WCSA, and parameters, and three patients showed only four parameters PA stiffness (except compliance coefficient) than patients with in low-risk grade. low-risk subjects (Table 3). Intermediate-risk patients had a reduced TAPSE/sPAP ratio All PA stiffness indices were significantly correlated with than low-risk patients because a concomitant increase in TAPSE/sPAP ratio (Figure 4). contractility did not accompany the increase in afterload with From the pooled data of all segments, there was a significant the disease severity. Based on the advanced risk stratification correlation between Einc and relative WCSA (r = −0.538; proposed by Yogeswaran et al., five patients were in low- P < 0.05) and between Einc and vessel diameter (r =−0.534; intermediate risk, and six patients were in high-intermediate risk. P < 0.05) (Figures 5A,B). We estimated the median values TABLE 3 | Pulmonary arterial geometric (structural) and stiffness (functional) data. Total (n = 20) Low-Risk (n = 9) Intermediate- Risk (n = 11) Control (n = 10) P1−2 P2−3 P1−3 Diameter (mm) 4.4 (3.4–5.9) 3.7 (3.2–4.9) 4.9 (3.8–7.1) 3.8 (3.5–3.9) 0.002 0.009 0.385 h/D × 10−2 5.8 ± 0.9 5.9 ± 0.8 5.8 ± 1.1 2.4 ± 0.3 0.896 0.000 0.000 WCSA (mm2 ) 5.3 (4.7–6.5) 5.0 (4.4–5.5) 5.9 (5.1–7.1) 1.0 (0.8–1.2) 0.001 0.000 0.000 Relative WCSA (%) 15 ± 3 17 ± 2 13 ± 3 1.4 ± 1.3 0.000 0.000 0.000 Pulsatility (%) 30 ± 10 35 ± 11 25 ± 8 52 ± 8 0.031 0.000 0.001 CC (mm2 /mmHg) 0.08 (0.06–0.1) 0.09 (0.06–0.12) 0.08 (0.06–0.1) 0.56 (0.37–0.69) 0.760 0.000 0.000 DC (%/mmHg) 0.52 (0.35–0.66) 0.61 (0.49–1.2) 0.35 (0.32–0.57) 4.54 (3.8–6.2) 0.020 0.000 0.000 PWV (m/s) 4.9 ± 1.2 4.2 ± 1.0 5.4 ± 1.1 1.6 ± 0.3 0.017 0.000 0.000 Einc (kPa)◦ 519 ± 292 344 ± 146 662 ± 325 116 ± 23 0.039 0.000 0.000 Stiffness index β 5.5 ± 2.9 3.6 ± 2.3 6.1 ± 2.8 1.4 ± 0.5 0.038 0.000 0.017 Data are presented as the mean ± SD or median (interquartile range). CC, cross-sectional compliance coefficient; DC, cross-sectional distensibility coefficient; Einc, incremental elastic modulus; h/D, wall thickness/lumen diameter ratio; PWV, local pulse wave velocity. (◦ , 1 kPa = 7.5 mmHg) (P1−2 , low-risk versus intermediate-risk; P 2−3 , intermediate-risk versus control; P 1−3 , low-risk versus control). Frontiers in Physiology | www.frontiersin.org 6 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification FIGURE 3 | Histograms of the pulmonary artery segments from all patients (n = 85), low-risk (n = 37) and intermediate-risk patients (n = 48). of the Einc PA segments and mPAP of each risk group. Einc to the estimated risk derived from the ESC/ERS risk assessment values below and above the median values showed an upward table, leading to the RV-PA coupling impairment. displacement from low-risk patients to intermediate-risk patients Risk stratification is dependent on several patient factors, beyond mPAP (P < 0.05) (Figure 5C). including non-modifiable demographic factors (e.g., age, gender, and PAH etiology) and modifiable factors (functional capacity, RV function, and hemodynamic variables). We applied the DISCUSSION ESC/ERS risk assessment tool employing seven modifiable variables largely influenced by RV adaptation to increased The present study results reveal that in prevalent PAH patients, afterload (Galie et al., 2018). Each patient risk profile was proximal PA has a significantly different remodeling according obtained by grading each variable according to the risk categories Frontiers in Physiology | www.frontiersin.org 7 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification FIGURE 4 | Scatter plots between pulmonary arterial stiffness indices and the ratio of tricuspid annular plane systolic excursion to systolic pulmonary artery pressure (TAPSE/sPAP) (Einc, incremental elastic modulus; PWV, local pulse wave velocity). (n = 9 low-risk patients; n = 11 intermediate-risk patients). and calculating a mean grade, rounded to the nearest integer. that PAs of PAH subjects could show an outward hypertrophic To our knowledge, this is the first study that links the estimated remodeling given by significant enlargement of vessel diameter, risk grade with PA structural and functional remodeling and RV- increased h/D ratio, and WCSA. Intermediate-risk patients had PA coupling. higher WCSA and lowered relative WCSA than low-risk subjects, The arterial wall responds to prolonged transmural pressure maintaining the same h/D ratio, which allows a continuum and/or flow through geometrical, structural, and functional in the remodeling process of the proximal PAs as the risk adaptation. The arterial remodeling tends to be vessel specific increases (Figure 6). and takes place in order to restore stresses and strain to control An interesting finding in this investigation is that the large levels. There are two major types of arterial structural remodeling PAs’ stiffening increases with the estimated risk. Stiffness is depending on the change in vascular diameter and wall: inward or a mechanical behavior that describes the amount of force outward (decrease or increase in the diameter, respectively) and required to achieve a given deformation. The mechanical hypertrophic, eutrophic, and hypotrophic (increase, no change behavior of a vessel depends on the geometry and the wall or decrease in the amount of wall components, respectively) viscoelastic properties. Since arteries are non-linear elastic (Mulvany, 1999). Compared with controls, we may speculate materials, the increase in stiffness measured clinically may be Frontiers in Physiology | www.frontiersin.org 8 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification due to the elevation in blood pressure, which increases vessel wall stretch and/or chronic remodeling-induced changes in extracellular matrix content (loss of elastin and increase in collagen content) and arterial geometry (Wang et al., 2017). We assessed local PA stiffness by different indices (Laurent et al., 2006). The intermediate-risk patients showed PA stiffness values similar to those published by Sanz et al. (2009). The arterial pulsatility, cross-sectional compliance coefficient, cross- sectional distensibility coefficient, and local PWV evaluated the elastic properties of the PA as a hollow structure and have more dependency on vessel geometry and intravascular pressure (extrinsic properties). The Einc and stiffness index β assess the inherent elastic properties of the arterial wall material and depend predominantly on the wall viscoelastic properties (intrinsic properties, mPAP independent) (Townsend et al., 2015; Chirinos et al., 2019). Although we cannot rule out an effect of stress/strain (extrinsic mechanism, mPAP dependent) on increased arterial stiffness in intermediate-risk compared to low-risk patients, wall remodeling-induced stiffening (intrinsic mechanism) plays a critical role. As it is widely known, the stiffness index β was proposed as the stiffness parameter, which does not depend upon blood pressures at the time of measurement due to the logarithmic transformation of the luminal distending pressure (Segers, 2017). Thus, the increase in stiffness index β observed in PAH patients, and the different values between low versus intermediate-risk subjects support an intrinsic change in PAs’ elastic properties. The significant upward shifted of the Einc values below and above the median values of the intermediate- risk group compared with low-risk patients would also be confirming the stiffer wall material of proximal elastic PAs beyond the indirect effect of raising the mPAP. Accordingly, there is growing evidence that suggests the association between the increase of vascular stiffness with an accumulation of collagen and loss of elastin in the proximal PAs during wall remodeling, making the vascular extracellular matrix an attractive potential therapeutic target not only for the treatment but also for the prevention of PAH (Thenappan et al., 2018). Lastly, the PAs Einc of our whole PAH cohort showed similar values of the normal systemic arteries at a pressure of 100 mmHg (∼500 kPa, 5 × 106 dyn/cm2 ) (Westerhof et al., 2019). By contrast to Bressollette et al. (2001) we found no differences in structural alterations between non-inferior and inferior pulmonary lobes in intermediate-risk patients. The use of a higher IVUS frequency probe could explain these anatomical differences. The worse functional remodeling in the segments of the non-inferior than inferior lobes with the same anatomical features could be explained by an increase in the collagen/elastin ratio of the arterial wall. The significantly higher PA stiffness in the intermediate-risk group than low-risk PAH subjects was associated with a lower FIGURE 5 | Scatter plot between the incremental elastic modulus (Einc) and PAC. PAC depicts the pulsatile afterload in normal pulmonary the relative wall cross-sectional wall (WCSA) (A), the vessel diameter (B), and circulation and contributes to approximately 25% of the total the mean pulmonary arterial pressure (mPAP) (C) of all PA segments RV afterload (Saouti et al., 2010). The PAC values of our cohort interrogated (n = 37 low-risk patient segments; n = 48 intermediate-risk showed similar values to the second (1.26–2.0 mL/mmHg; low- patient segments). (*P < 0.05 differences between low-risk and risk) and third quartiles (0.82–1.25 mL/mmHg, intermediate- intermediate-risk patients of the Einc and mPAP below and above the median values, respectively). risk) of the cohort studied by Mahapatra et al. (2006) who had 4-year mortality between 5 and 15%. Frontiers in Physiology | www.frontiersin.org 9 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification FIGURE 6 | Proposed progression of the pulmonary arterial remodeling according to the stratification risk on prevalent PAH patients. Compared with controls, we may speculate that pulmonary arteries of PAH subjects could show an outward hypertrophic remodeling given by significant enlargement of vessel diameter, increased h/D ratio, and WCSA. The possibility of pathways with different trajectories is highlighted (h/D, wall thickness/lumen diameter ratio; PAH, pulmonary arterial hypertension; WCSA, wall cross-sectional area). Although the proximal elastic PAs account for only 15– reserve from normal values of 1.5–2 to 0.8, being able to detect 20% of the total PAC, they play a critical role in buffering the onset of RV failure (defined by excessive volume increase) in pulsatile RV ejection and RV-PA coupling (Thenappan et al., patients with PH (Tello et al., 2019a). By multivariate analysis, 2016). The greater stiffness of PAs in the intermediate-risk group Tello et al. reported that TAPSE/sPAP is independently related led to RV-PA uncoupling. All PA stiffness indices correlated to invasively measured Ees/Ea in severe PAH patients. Using with TAPSE/sPAP ratio. Therefore, the vascular stiffening of PA receiver operating characteristic analyses and the Youden index, a bed could be the main responsible for the RV-PA decoupling, TAPSE/sPAP cut-off value of 0.31 mm/mmHg identified patients either by an extrinsic mechanism (PA stress/strain stiffening, with RV-arterial uncoupling defined by an Ees/Ea ratio < 0.805. mPAP dependent) or intrinsic mechanism (wall remodeling- Patients with TAPSE/sPAP < 0.31 mm/mmHg were at increased induced stiffening, mPAP independent). However, the possibility risk for clinical worsening and had an increase in mortality. They to differentiate between strain- and remodeling-induced PA suggested the possible added value of TAPSE/sPAP in current stiffening in clinical settings by using different stiffness indices risk assessment strategies for PAH (Tello et al., 2018). We could may lead to tailored treatments for PA stiffening in PH patients. argue that low-risk patients with four subjects TAPSE/sPAP ratio Accordingly, whereas vasodilator therapy should reduce PA below 0.3 mm/mmHg, had a RV-PA coupling reserve exhausted, stiffness in PH patients with only strain-induced destiffening illustrating the deleterious effect of arterial stiffening on the RV- (extrinsic mechanism), inhibiting collagen accumulation or PA coupling. Besides, TAPSE/sPAP of low-risk and intermediate- promoting collagen degradation would be more effective risk groups showed similar values to middle and low terciles of therapies in PH patients with both strain- and chronic wall Tello et al. (2018) data, respectively. remodeling-induced PA destiffening (extrinsic and intrinsic The French low-risk approach analyzed the association mechanism, respectively) (Golob et al., 2017). between the number of low-risk criteria at baseline or achieved The adaptation of RV function to loading is defined by a within 1 year of diagnosis and long-term prognosis using an ratio of end-systolic to arterial elastances and has considerable abbreviated risk assessment tool. In our cohort, no patient Frontiers in Physiology | www.frontiersin.org 10 May 2021 | Volume 12 | Article 631326 Grignola et al. PA Remodeling According to PAH Risk Stratification had all variables in low-risk grade. The majority had five of Probably, as the risk increase, the loss of elastin and the increase seven variables in low-risk grade with arterial remodeling similar in the collagen content of the PA wall could explain the greater to patients with PH associated with interstitial lung disease stiffness with less relative WCSA despite preserving h/D ratio. candidates for lung transplantation (Domingo et al., 2017). From a clinical perspective, it would be very interesting to explore Among the intermediate-risk subjects, six of eleven were in high- the impact of therapy on the PA remodeling, RV-PA coupling, intermediate risk. Our findings strengthen the inappropriateness and risk grade of incident/naive PAH patients on their follow-up. of the term “stable,” even for patients in the low-risk category who may have a significant PA remodeling with a RV-PA coupling reserve exhausted (Boucly et al., 2017; Hoeper et al., 2017; DATA AVAILABILITY STATEMENT Kylhammar et al., 2018), and also supports not only low-risk profile as a pursue treatment goal but a novel candidate surrogate The raw data supporting the conclusions of this article will be outcome in future clinical trials designs (Weatherald et al., 2018). made available by the authors, without undue reservation. There are several limitations to this study. Although it is a small study cohort, the characterization of the PA remodeling of more than four segments per patient, obtaining the seven ETHICS STATEMENT risk variables simultaneously, and the inclusion of prevalent and stable patients would overcome the low number of patients The studies involving human participants were reviewed and in interpreting the results. Several tools are currently available approved by all procedures were approved by the Institutional for assessing risk in PAH. Although the 2015 ESC/ERS PH Ethics Committee of the Hospital Universitari Vall d’Hebron risk table is based on expert opinion, do not include non- (Barcelona). The patients/participants provided their written modifiable variables, do not use a weighting of variables, and informed consent to participate in this study. do not work in all forms of PAH, a retrospective analysis of three major registries provided an independent validation of this approach and showed a clear difference in 5-year survival AUTHOR CONTRIBUTIONS or transplantation-free survival, depending on risk stratification JG conceptualized the study objectives, performed the category at both baseline and first follow-up (Galie et al., 2018). quantitative data analysis, interpreted data, and drafted the We quantified the arterial stiffness in a pressure-independent manuscript. ED participated in the study design, contributed to way by the so-called stiffness index β. However, Spronck et al. study coordination and data acquisition and preparation of the (2017) have demonstrated that the common practice of using manuscript, and supervised the data collection. PT contributed to diastolic blood pressure and diameter values as a surrogate for the data analysis and preparation of the manuscript. CB and ML-M values at a reference pressure introduces pressure dependencies contributed to data analysis. SP-H contributed to statistical in the derived stiffness index β, questioning an intrinsic change analysis of data. AR conceptualized the study objectives, obtained in the arterial wall in patients with intermediate-risk. The upward funding, and contributed to the study design, interpretation of shift of Einc values in function of the mPAP of intermediate- data, and manuscript preparation. All authors contributed to the risk patients allows us to assume a real change in the viscoelastic article and approved the submitted version. properties of the arterial wall compared to low-risk subjects. Although the main PA stiffness indices can be assessed non- invasively by cardiac magnetic resonance, the advantage of IVUS ACKNOWLEDGMENTS is that it is performed concomitantly with RHC, and it provides data on vessel wall dimensions (WCSA and h/D). The authors declare that this study received funding from GSK (GlaxoSmithKline), London, United Kingdom. The funder paid for the IVUS catheters used in the study. The funder was not CONCLUSION involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it In prevalent PAH patients, the proximal PA stiffening impairs for publication. Preliminary data of this study were presented RV-PA coupling and is related to the simplified risk stratification. in part in the Annual Scientific Session of the American Despite a small sample size, our results show that proximal PA Heart Association (AHA), November 16–18, 2019. Philadelphia, remodeling (intrinsic mechanism) is worse in intermediate-risk United States. Circulation 2019; 140 (Suppl_1): A9949. JG is a than in low-risk PAH patients, leading to RV-PA uncoupling, member (Researcher Level II) of ANII (Agencia Nacional de beyond the indirect effect of the mPAP (extrinsic mechanism). Investigación e Innovación). REFERENCES arterial hypertension. Chest 141, 354–362. doi: 10.1378/chest.11- 0676 Benza, R. L., Gomberg-Maitland, M., Miller, D. P., Frost, A., Frantz, Benza, R. L., Lohmueller, L. C., Kraisangka, J., and Kanwar, M. (2018). Risk R. P., Foreman, A. J., et al. (2012). The REVEAL registry risk assessment in pulmonary arterial hypertension patients: the long and short of score calculator in patients newly diagnosed with pulmonary it. Adv. Pulm. Hypertens. 16, 125–135. doi: 10.21693/1933-088x-16.3.125 Frontiers in Physiology | www.frontiersin.org 11 May 2021 | Volume 12 | Article 631326 Grignola et al. 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Pulmonary vascular wall stiffness: an Yogeswaran, A., Richter, M. J., Sommer, N., Ghofrani, H. A., Seeger, W., important contributor to the increased right ventricular afterload with Tello, K., et al. (2020). Advanced risk stratification of intermediate risk pulmonary hypertension. Pulm Circ. 1, 212–223. doi: 10.4103/2045-8932. group in pulmonary arterial hypertension. Pulm Circ. 10, 1–5. doi: 10.1177/ 83453 2045894020961739 Wang, Z., Schreier, D. A., Abid, H., Hacker, T. A., and Chesler, N. C. (2017). Pulmonary vascular collagen content, not cross-linking, contributes Conflict of Interest: The authors declare that this study received funding from to right ventricular pulsatile afterload and overload in early pulmonary GSK (GlaxoSmithKline), London, United Kingdom. The funder paid for the IVUS hypertension. J. Appl. Physiol. 122, 253–263. doi: 10.1152/japplphysiol.00325. catheters used in the study. The funder was not involved in the study design, 2016 collection, analysis, interpretation of data, the writing of this article, or the decision Weatherald, J., Boucly, A., Sahay, S., Humbert, M., and Sitbon, O. (2018). The to submit it for publication. low-risk profile in pulmonary arterial hypertension: time for a paradigm shift to goal-oriented clinical trial endpoints? Am. J. Respir. Crit. Care Med. 197, Copyright © 2021 Grignola, Domingo, López-Meseguer, Trujillo, Bravo, Pérez-Hoyos 860–868. doi: 10.1164/rccm.201709-1840PP and Roman. This is an open-access article distributed under the terms of the Creative Westerhof, N., Stergiopulos, N., Noble, M. I. M., and Westerhof, B. E. (2019). Commons Attribution License (CC BY). The use, distribution or reproduction in “Elasticity,” in Snapshots of Hemodynamics: An Aid for Clinical Research and other forums is permitted, provided the original author(s) and the copyright owner(s) Graduate Education, Vol. 3rd, eds N. Westerhof, N. Stergiopulos, M. I. M. are credited and that the original publication in this journal is cited, in accordance Noble, and B. E. Westerhof (New York, NY: Springer International Publishing with accepted academic practice. No use, distribution or reproduction is permitted AG), 57–64. doi: 10.1007/978-3-319-91932-4_10 which does not comply with these terms. Frontiers in Physiology | www.frontiersin.org 13 May 2021 | Volume 12 | Article 631326