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Cardiology Research

Original Article

Volume 15, Number 2, April 2024, pages 117-124

Insights Into Differences in Pulmonary Hemodynamics in Hispanic Patients With Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a vascular remodeling syndrome that results in increased right ventricular (RV) afterload and ultimately leads to right heart failure. Adaptation of the RV to an increasing afterload is a crucial determinant of outcomes in PAH [1, 2]. Recently, various PAH vascular phenotypes have been identified, with variations in hemodynamic profiles and differences in the contribution of left heart and lung disease [3]. Additionally, RV structure and function are known to vary by age, sex, and ethnicity [4, 5]. Studies have shown that Hispanics free of known cardiovascular disease have a higher RV mass and RV end-diastolic volume at baseline than other ethnicities [6]. Moreover, Hispanic patients with PAH appear to have a survival benefit compared to other PAH ethnicities [7, 8]. However, the extent, validity, and potential reasons for this survival advantage remain unclear. There is a scarcity of detailed studies on right heart hemodynamics in Hispanic patients. One study found that Hispanic patients had higher mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) than African-American and non-Hispanic white patients [7]. Conversely, another study involving 98 Hispanic and 585 non-Hispanic patients did not find significant differences in right heart hemodynamics, although Hispanic patients exhibited improved unadjusted survival rates [9].

The purpose of the current study was to examine potential baseline hemodynamic differences in treatment-naive Hispanic and non-Hispanic patients with PAH in a single-center patient cohort and to assess whether these differences have any implications on mortality.

This was a single-center retrospective study conducted in a large referral center, University Medical Center (UMC) at the American-Mexican border with access to all advanced PAH-targeted therapies. Of 226 total patients with PAH, 138 Hispanic PAH patients who met the inclusion criteria and were consecutively managed at the University Center between January 2012 and December 2022 were included. Patients were enrolled in this registry as inpatients with outpatient follow-up or as outpatients only. We chose only patients who met the following criteria based on previous and most recent guidelines [10]: 1) treatment-naive with newly diagnosed PAH; 2) initiation of PAH-targeted therapies within 6 months after diagnosis; 3) mPAP > 25 mm Hg (> 20 mm Hg after 2019), pulmonary artery wedge pressure < 15 and pulmonary vascular resistance (PVR) > 3 Wood Units (PVR > 2 after 2019); and 4) exclusion of World Health Organization (WHO)-group 2, 3, and 4 pulmonary hypertension (PH) based on past medical history, echocardiography, high-resolution chest imaging, pulmonary function testing, and ventilation perfusion scans. PAH-targeted therapies were reported within 3 months after diagnosis of PAH. Ethnicity was self-reported and extracted from patients’ medical records.

Pressure measurements were recorded at end-expiration at rest. Cardiac output (CO) was measured by thermodilution. Pulmonary pressures, pulmonary capillary wedge pressure (PCWP), CO, cardiac index (CI), and PVR were extracted from medical records after the catheterization report was completed. Stroke volume (SV) index was calculated based on heart rate, CO and body surface area (BSA). Pulmonary arterial compliance (PAc) was calculated as SV divided by pulmonary artery pulse pressure. Resistance-compliance (RC) time (s) was calculated as the product of PVR (mm Hg × s/mL) and PAc (mL/mm Hg).

Data are presented as absolute numbers, percentage, mean (standard deviation), or median (interquartile range). Differences in baseline variables were assessed using Spearman rank correlation, Chi-square, or t-test. All statistical analyses were performed using SPSS 29 and GraphPad Prism 8.0 software. Kaplan-Meier survival analysis was used to assess the 5-year survival rates in both patient populations, while adjusting for age, gender, and WHO functional classification (WHO-FC).

Written informed consent was not required for this study and it was performed in accordance with Texas Tech University Institutional Review Board.

After assessing eligibility criteria, a total of 226 patients with PAH, 138 Hispanic patients and 88 non-Hispanic patients, were included in this study, between 2012 and 2022. The study cohort consisted predominantly of females (74.3%) with a mean age of 56.3 years. The baseline characteristics, including WHO-FC, body mass index (BMI), 6-min walking distance (6MWD), and hemodynamic variables are shown in Table 1. Hispanic patients had a higher 6MWD (352 ± 121 vs. 320 ± 109, P = 0.047), but similar WHO-FC (3.0 ± 0.5 vs. 3.0 ± 0.4, P = 0.506). Compared to the non-Hispanic cohort, mPAP (43.2 ± 11.8 vs. 50.6 ± 12.1, P = 0.001), systolic pulmonary artery pressure (SPAP) (71.5 ± 18.7 vs. 81.7 ± 21.0, P = 0.004), PVR (9.9 ± 6.8 vs. 11.7 ± 5.2, P = 0.024), and pulse pressure (PP) (42.6 ± 13.0 vs. 58.6 ± 14.3, P = 0.001) were significantly lower in Hispanic patients. However, there were no significant differences in diastolic pulmonary artery pressure (DPAP), PCWP, SV, and CI between the two groups. Notably, PAc was significantly higher in Hispanic patients (1.36 ± 0.64 vs. 1.0 ± 0.48, P = 0.020) as shown in Table 1 and Figure 1. The RC time for the entire cohort was 0.66 s and longer in Hispanic patients (0.7 s) compared to non-Hispanic patients (0.61 s, P = 0.004). These differences remained in a subgroup analysis excluding patients with congenital heart disease (CHD)-PAH (Supplementary Material 1, www.cardiologyres.org). Hispanic patients had a significantly higher adjusted 5-year survival rate compared to the non-Hispanic cohort (Fig. 2). This survival benefit remained after removing patients with CHD-PAH from the cohort (Supplementary Material 2, www.cardiologyres.org). A reduced PAc was associated with poor outcomes in both cohorts. Hispanic patients with a PAc below the mean for the Hispanic cohort (1.36 mL/mm Hg) had a significantly higher 5-year mortality (estimated median survival 4.6 versus 4.0 years, P < 0.001, Fig. 2b). Non-Hispanic patients with a PAc below the mean for the non-Hispanic cohort (1.0 mL/mm Hg) had a significantly higher 5-year mortality (estimate mean survival 4.6 versus 4.5 years, P < 0.001, Fig. 2c). There were no significant differences in the intensity of PAH-targeted therapies (mono- double- or triple therapy) in Hispanic and non-Hispanic patients (Supplementary Material 1, www.cardiologyres.org) at the end of the study.

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Table 1. Baseline Characteristics of All Cohort

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Figure 1. Relationship of baseline hemodynamic profiles between Hispanic and non-Hispanic patients, with mean pulmonary artery pressure (mPAP), pulmonary arterial pulse pressure (PAPP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), stroke volume (SV), peripheral vascular resistance (PVR), pulmonary arterial compliance (PAc), and resistance-compliance (RC) time significantly different between both groups. All values are recorded as mean ± standard deviation.

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Figure 2. Kaplan-Meier survival estimate: 5-year survival in (a) Hispanic and non-Hispanic patients; (b) Hispanic patients with pulmonary arterial compliance (PAc) of 1.36 mL/mm Hg; c) non-Hispanic patients with PAc of 1.0 mL/mm Hg.

This study has three main findings. 1) Despite similar age, gender, and WHO-FC, Hispanic patients present with a favorable hemodynamic profile at baseline, characterized by lower PAPs, PVR, and higher PAc. 2) Hispanic patients have a higher baseline functional capacity. 3) Hispanic patients have improved 5-year survival rates compared to non-Hispanic patients.

RV failure is a complex process that is incompletely understood and not all aspects of RV function and dysfunction are captured by right heart catheterization. However, the adaptation of the RV to an increasing afterload from pulmonary vascular remodeling is a major determinant of outcomes in PAH and a drop in afterload can improve survival [11, 12]. Favorable hemodynamics at baseline in Hispanic patients are therefore likely related to improved 5-year survival in this cohort. The afterload of the RV is characterized by a static component (PVR) and a pulsatile component (PAc). A striking difference in our cohort was the higher PAc in Hispanic patients with a longer RC-time, compared to non-Hispanic patients. There is debate if both parameters reflect the same functional and anatomic vascular bed and truly provide independent prognostic information beyond other hemodynamic variables, especially PVR [13-22]. However, more recently, PAc has been shown to be an independent predictor of survival and a predictor of RV functional recovery [23-26].

Our study confirms the well-established inverse hyperbolic relation of PAc and PVR with a relative maximum of pulmonary artery stiffness at higher resistance values (Supplementary Materials 1-4, www.cardiologyres.org) [21]. The understanding of the pathophysiologic relationship between increasing PVR and decreasing compliance in PAH has evolved over time [27]. With a stable CO and PCWP, an increase in mPAP will lead to an increase in PVR and a decrease in PAc due to the non-linear compliance of the PA [13, 14, 28]. A compliant pulmonary vascular bed accumulates blood during systole and releases this volume during diastole, resulting in a continuous peripheral flow during the complete cardiac cycle. The product of PVR and PAc is expressed as the RC time which characterizes the decay of DPAP. In this study, both cohorts had similar heart rates, PCWP, and patients with non-WHO 1 PH were excluded. Therefore, the RC time was narrowly constraint in both cohorts (0.73 ± 0.21, 0.61 ± 0.18), similar to previous reports [21, 22]. However, this finding is not supported by other studies [29, 30]. Differences in data acquisition and analysis, variations heart rate, elevation in left atrial pressure in different PAH subtypes might be potential contributors for RC time scatter [22, 31].

Due to its inverse hyperbolic relationship, at high PVR, a significant decrease of such is needed (> 7 WU) to improve compliance [22, 32]. Hispanic patients had a slower diastolic pressure decay, shown by an increased RC time, compared to non-Hispanic patients despite similar CO, SV and PCWP resulting in a steeper RC time curve (Supplementary Materials 1-4, www.cardiologyres.org). A steeper RC time curve in Hispanic patients could imply more improvement of PAc for each unit the PVR is lowered, potentially translating into a favorable response to PAH-targeted therapies and survival.

Several alternative explanations may account for the relationship between improved baseline hemodynamics in PAH and better survival outcomes. A lower PAP and PVR and increased PAc can be associated with a decrease in RV pulsatile workload, leading to decreased wall-stress, oxygen consumption, and a lower risk for RV-PA uncoupling [33, 34]. However, it should be noted that our study does not provide data on RV anatomy and therefore any comments on RV adaptation in these cohorts remain speculative. Nonetheless, our findings are in line with previous studies showing that PAc is a strong predictor of mortality in different patient cohorts with various forms of PH [23, 35-38].

The higher pulmonary compliance observed in Hispanic patients may provide insights into the phenomenon known as the “Hispanic paradox” [17]. This phenomenon suggests that Hispanic patients exhibit better survival after cardiovascular events despite having worse comorbidities and cardiovascular risk factors. While the precise mechanisms behind this paradox remain elusive, our findings align with the hypothesis that inherently higher vascular compliance in Hispanic patients may be related to a favorable survival, despite the presence of other risk factors and comorbidities. A prominent feature of pulmonary vascular remodeling in PAH is the thickening of the smooth muscles cell layer in the pulmonary artery, leading to an increase in PVR [39]. In addition, vascular remolding of the adventitia with a decrease in elastin content and an increase in collagen, fibronectin, glycosaminoglycans, and tenascin-C deposition is linked to a decrease in PAc. It is interesting to note that in preclinical PH models, extracellular matrix changes in the pulmonary artery precede pulmonary artery smooth muscle cell hypertrophy [40-46]. Similarly in humans, patients with exercise-induced PH can have normal mPAP and a decrease in PAc [13, 14], indicating that low PAc could contribute to the progression of PAH. Furthermore, there is cumulating evidence that the majority of PAc is located in distal arteries, indicating that resistance vessels are the same as compliance vessels [20, 27, 47]. It is possible that Hispanic patients may have a different pulmonary vascular or RV genotype that leads to an altered molecular and cellular response to pulmonary vascular remodeling, associated with less pulmonary vascular stiffening, leading to advantageous baseline hemodynamics, a possible favorable response to PAH-targeted therapies, and potentially better clinical outcomes. Combination PAH-targeted therapies can improve outcomes [48, 49]; however, in our cohort, we did not detect differences in the use of combination therapy. Given that this was a single-center retrospective analysis, patients received fairly homogenous care and it is therefore less likely that differences in PAH therapy contributed to differences in outcomes.

The adaptation of the RV to an increase in afterload is different in different forms of PAH. For instance, patients with post-tricuspid ventricular defects have a more favorable RV adaptation to the same afterload, and improved survival, compared to patients with idiopathic PAH (IPAH) or systemic sclerosis-associated PAH (SSc-PAH) [50, 51]. It is important to note that 18% of the Hispanic patients carried a diagnosis of CHD, compared to 5.7% of the non-Hispanic cohort. In subgroup analyses, excluding patients with CHD-PAH, we could not find significant differences in baseline hemodynamics or adjusted 5-year survival. It is therefore less likely that the survival benefit observed in this study is explained by a favorable RV phenotype from CHD-PAH patients [52].

This study has several limitations, mainly based on its single-center cohort, retrospective design, and lack of hemodynamic follow-up. The methodology of PAc and RC time measurements represents simplified equations to calculate resistance, compliance, and the RC time, which may not reflect true physiologic values [29, 47]. All variables investigated here are mathematically coupled and accurate interpretation of the functional relationship necessitates caution. Furthermore, this study lacks insight into RV performance measured by volumetric assessment or derived pressure volume loops. Therefore, the results of this study need to be interpreted critically and larger, more sophisticated studies are needed to confirm our results and expand on these findings. It is important to note that even though we recruited patients from one predominantly Hispanic region, such groups are potentially genetically diverse, carrying varying degrees of different ancestries [9].

In conclusion, our study presents compelling evidence supporting a favorable hemodynamic profile in Hispanic patients with PAH compared to non-Hispanic patients, which appears to be linked to improved clinical outcomes independent of PAH-targeted therapies or PAH subgroups. Our findings indicate that Hispanic PAH patients demonstrate significantly lower mPAP, PVR, and higher PAc in comparison to non-Hispanic patients, potentially contributing to enhanced RV function. However, further investigation is necessary to understand the specific factors driving this difference in PAc and RV adaptation to elucidate the underlying pathobiological mechanisms. Prospective studies incorporating larger sample sizes, a more detailed anatomic and functional assessment of the RV, and diverse populations are crucial to validate our findings and explore the potential implications of PAc as a predictor of mortality outcomes in PAH. Of note, Hispanics are not a homogeneous ethnic group, as there is great genetic diversity and socioeconomic, educational, and demographic variation among them and future studies with disaggregated data may provide even greater insight into PAH pathophysiology in different ethnic groups. By uncovering the mechanisms and factors influencing variations in pulmonary vascular compliance among different ethnicities, novel therapeutic interventions and strategies to improve patient outcomes in PAH may be identified.

Suppl 1. PAH-Targeted Medications.

Suppl 2. Kaplan-Meier curves without CHD-PAH.

Suppl 3. Patient Cohorts Without CHD-PAH.

Suppl 4. Scatterplot with nonlinear regression line delineating the relationship between pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAc).

Acknowledgments

None to declare.

Financial Disclosure

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of Interest

The authors declare no conflict of interest.

Informed Consent

Written informed consent was not required for this study.

Author Contributions

Kedzie Arrington, Seyed Khalafi, Michael Brockman, and Kahtan Fadah collected data for this project; Kahtan Fadah and Nils P. Nickel wrote the original manuscript; Debabrata Mukherjee, Haider Alkhateeb, and Hernando Garcia revised the manuscript and provided key feedback and insights. Kahtan Fadah and Nils P. Nickel analyzed and created figures, tables, and supporting information. Nils P. Nickel supervised the project.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

1. Lahm T, Douglas IS, Archer SL, Bogaard HJ, Chesler NC, Haddad F, Hemnes AR, et al. Assessment of right ventricular function in the research setting: knowledge gaps and pathways forward. an official American Thoracic Society Research Statement. Am J Respir Crit Care Med. 2018;198(4):e15-e43.
   doi pubmed pmc
2. Leopold JA, Kawut SM, Aldred MA, Archer SL, Benza RL, Bristow MR, Brittain EL, et al. Diagnosis and treatment of right heart failure in pulmonary vascular diseases: a national heart, lung, and blood institute workshop. Circ Heart Fail. 2021;14(6):e007975.
   doi pubmed pmc
3. Hoeper MM, Apitz C, Grunig E, Halank M, Ewert R, Kaemmerer H, Kabitz HJ, et al. Targeted therapy of pulmonary arterial hypertension: Updated recommendations from the Cologne Consensus Conference 2018. Int J Cardiol. 2018;272S:37-45.
   doi pubmed
4. Henein M, Waldenstrom A, Morner S, Lindqvist P. The normal impact of age and gender on right heart structure and function. Echocardiography. 2014;31(1):5-11.
   doi pubmed
5. Leary PJ, Kaufman JD, Barr RG, Bluemke DA, Curl CL, Hough CL, Lima JA, et al. Traffic-related air pollution and the right ventricle. The multi-ethnic study of atherosclerosis. Am J Respir Crit Care Med. 2014;189(9):1093-1100.
   doi pubmed pmc
6. Kawut SM, Lima JA, Barr RG, Chahal H, Jain A, Tandri H, Praestgaard A, et al. Sex and race differences in right ventricular structure and function: the multi-ethnic study of atherosclerosis-right ventricle study. Circulation. 2011;123(22):2542-2551.
   doi pubmed pmc
7. Karnes JH, Wiener HW, Schwantes-An TH, Natarajan B, Sweatt AJ, Chaturvedi A, Arora A, et al. Genetic admixture and survival in diverse populations with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2020;201(11):1407-1415.
   doi pubmed pmc
8. Fadah K, Cruz Rodriguez JB, Alkhateeb H, Mukherjee D, Garcia H, Schuller D, Mohammad KO, et al. Prognosis in Hispanic patient population with pulmonary arterial hypertension: An application of common risk stratification models. Pulm Circ. 2023;13(2):e12209.
   doi pubmed pmc
9. Bernardo RJ, Lu D, Ramirez RL, 3rd, Hedlin H, Kawut SM, Bull T, De Marco T, et al. Hispanic ethnicity and social determinants of health in pulmonary arterial hypertension: the Pulmonary Hypertension Association Registry. Ann Am Thorac Soc. 2022;19(9):1459-1468.
   doi pubmed
10. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731.
    doi pubmed
11. van de Veerdonk MC, Huis In TVAE, Marcus JT, Westerhof N, Heymans MW, Bogaard HJ, Vonk-Noordegraaf A. Upfront combination therapy reduces right ventricular volumes in pulmonary arterial hypertension. Eur Respir J. 2017;49(6):1700007.
    doi pubmed
12. Badagliacca R, Poscia R, Pezzuto B, Papa S, Reali M, Pesce F, Manzi G, et al. Prognostic relevance of right heart reverse remodeling in idiopathic pulmonary arterial hypertension. J Heart Lung Transplant. 2018;37(2):195-205.
    doi pubmed
13. Lau EMT, Chemla D, Godinas L, Zhu K, Sitbon O, Savale L, Montani D, et al. Loss of vascular distensibility during exercise is an early hemodynamic marker of pulmonary vascular disease. Chest. 2016;149(2):353-361.
    doi pubmed
14. Sanz J, Kariisa M, Dellegrottaglie S, Prat-Gonzalez S, Garcia MJ, Fuster V, Rajagopalan S. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance. JACC Cardiovasc Imaging. 2009;2(3):286-295.
    doi pubmed
15. Newman JH, Brittain EL, Robbins IM, Hemnes AR. Effect of acute arteriolar vasodilation on capacitance and resistance in pulmonary arterial hypertension. Chest. 2015;147(4):1080-1085.
    doi pubmed pmc
16. Reeves JT, Linehan JH, Stenmark KR. Distensibility of the normal human lung circulation during exercise. Am J Physiol Lung Cell Mol Physiol. 2005;288(3):L419-425.
    doi pubmed
17. Krenz GS, Dawson CA. Flow and pressure distributions in vascular networks consisting of distensible vessels. Am J Physiol Heart Circ Physiol. 2003;284(6):H2192-2203.
    doi pubmed
18. Engelberg J, Dubois AB. Mechanics of pulmonary circulation in isolated rabbit lungs. Am J Physiol. 1959;196(2):401-414.
    doi pubmed
19. Wiener F, Morkin E, Skalak R, Fishman AP. Wave propagation in the pulmonary circulation. Circ Res. 1966;19(4):834-850.
    doi pubmed
20. Saouti N, Westerhof N, Helderman F, Marcus JT, Stergiopulos N, Westerhof BE, Boonstra A, et al. RC time constant of single lung equals that of both lungs together: a study in chronic thromboembolic pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2009;297(6):H2154-2160.
    doi pubmed
21. Lankhaar JW, Westerhof N, Faes TJ, Gan CT, Marques KM, Boonstra A, van den Berg FG, et al. Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension. Eur Heart J. 2008;29(13):1688-1695.
    doi pubmed
22. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH, et al. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation. 2012;125(2):289-297.
    doi pubmed pmc
23. Gan CT, Lankhaar JW, Westerhof N, Marcus JT, Becker A, Twisk JW, Boonstra A, et al. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest. 2007;132(6):1906-1912.
    doi pubmed
24. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol. 2006;47(4):799-803.
    doi pubmed
25. Dupont M, Mullens W, Skouri HN, Abrahams Z, Wu Y, Taylor DO, Starling RC, et al. Prognostic role of pulmonary arterial capacitance in advanced heart failure. Circ Heart Fail. 2012;5(6):778-785.
    doi pubmed pmc
26. Rischard FP, Bernardo RJ, Vanderpool RR, Kwon DH, Acharya T, Park MM, Katrynuik A, et al. Classification and predictors of right ventricular functional recovery in pulmonary arterial hypertension. Circ Heart Fail. 2023;16(10):e010555.
    doi pubmed pmc
27. Thenappan T, Prins KW, Pritzker MR, Scandurra J, Volmers K, Weir EK. The critical role of pulmonary arterial compliance in pulmonary hypertension. Ann Am Thorac Soc. 2016;13(2):276-284.
    doi pubmed pmc
28. Reuben SR. Compliance of the human pulmonary arterial system in disease. Circ Res. 1971;29(1):40-50.
    doi pubmed
29. Chemla D, Lau EM, Papelier Y, Attal P, Herve P. Pulmonary vascular resistance and compliance relationship in pulmonary hypertension. Eur Respir J. 2015;46(4):1178-1189.
    doi pubmed
30. Hadinnapola C, Li Q, Su L, Pepke-Zaba J, Toshner M. The resistance-compliance product of the pulmonary circulation varies in health and pulmonary vascular disease. Physiol Rep. 2015;3(4):e12363.
    doi pubmed pmc
31. Metkus TS, Mullin CJ, Grandin EW, Rame JE, Tampakakis E, Hsu S, Kolb TM, et al. Heart rate dependence of the pulmonary resistance x compliance (RC) time and impact on right ventricular load. PLoS One. 2016;11(11):e0166463.
    doi pubmed pmc
32. Vanderpool RR, Hunter KS, Insel M, Garcia JGN, Bedrick EJ, Tedford RJ, Rischard FP. The right ventricular-pulmonary arterial coupling and diastolic function response to therapy in pulmonary arterial hypertension. Chest. 2022;161(4):1048-1059.
    doi pubmed pmc
33. Wang Z, Chesler NC. Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension. Pulm Circ. 2011;1(2):212-223.
    doi pubmed pmc
34. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, et al. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62(25 Suppl):D22-33.
    doi pubmed
35. Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart Fail. 2013;1(4):290-299.
    doi pubmed
36. Douwes JM, Roofthooft MT, Bartelds B, Talsma MD, Hillege HL, Berger RM. Pulsatile haemodynamic parameters are predictors of survival in paediatric pulmonary arterial hypertension. Int J Cardiol. 2013;168(2):1370-1377.
    doi pubmed
37. Mahapatra S, Nishimura RA, Oh JK, McGoon MD. The prognostic value of pulmonary vascular capacitance determined by Doppler echocardiography in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr. 2006;19(8):1045-1050.
    doi pubmed
38. Dragu R, Rispler S, Habib M, Sholy H, Hammerman H, Galie N, Aronson D. Pulmonary arterial capacitance in patients with heart failure and reactive pulmonary hypertension. Eur J Heart Fail. 2015;17(1):74-80.
    doi pubmed
39. Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol. 1995;146(2):389-397.
    pubmed pmc
40. Jones PL, Cowan KN, Rabinovitch M. Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol. 1997;150(4):1349-1360.
    pubmed pmc
41. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2012;122(12):4306-4313.
    doi pubmed pmc
42. Dodson RB, Morgan MR, Galambos C, Hunter KS, Abman SH. Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep. Am J Physiol Lung Cell Mol Physiol. 2014;307(11):L822-828.
    doi pubmed pmc
43. Le VP, Stoka KV, Yanagisawa H, Wagenseil JE. Fibulin-5 null mice with decreased arterial compliance maintain normal systolic left ventricular function, but not diastolic function during maturation. Physiol Rep. 2014;2(3):e00257.
    doi pubmed pmc
44. Kobs RW, Muvarak NE, Eickhoff JC, Chesler NC. Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia-induced hypertension. Am J Physiol Heart Circ Physiol. 2005;288(3):H1209-1217.
    doi pubmed
45. Ooi CY, Wang Z, Tabima DM, Eickhoff JC, Chesler NC. The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2010;299(6):H1823-1831.
    doi pubmed pmc
46. Todorovich-Hunter L, Dodo H, Ye C, McCready L, Keeley FW, Rabinovitch M. Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Respir Dis. 1992;146(1):213-223.
    doi pubmed
47. Ghio S, Schirinzi S, Pica S. Pulmonary arterial compliance: how and why should we measure it? Glob Cardiol Sci Pract. 2015;2015(4):58.
    doi pubmed pmc
48. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142(2):448-456.
    doi pubmed
49. Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394-403.
    doi pubmed pmc
50. Hurdman J, Condliffe R, Elliot CA, Davies C, Hill C, Wild JM, Capener D, et al. ASPIRE registry: assessing the spectrum of pulmonary hypertension identified at a REferral centre. Eur Respir J. 2012;39(4):945-955.
    doi pubmed
51. van der Bruggen CEE, Tedford RJ, Handoko ML, van der Velden J, de Man FS. RV pressure overload: from hypertrophy to failure. Cardiovasc Res. 2017;113(12):1423-1432.
    doi pubmed
52. Hopkins WE. The remarkable right ventricle of patients with Eisenmenger syndrome. Coron Artery Dis. 2005;16(1):19-25.
    doi pubmed

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