Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65173910.31857/S0869813924100149VPZISZEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleRapid adaptive regulation of systemic circulation is suppressed in pulmonaryБыстрая адаптивная регуляция системного кровообращения подавлена при легочной артериальной гипертензии в результате дисфункции барорефлекторного контроля сердечного ритмаAbramovА. А.АбрамовА. А.
Russian Federation
ferk_88@list.ruLakomkinV. L.ЛакомкинВ. Л.
Russian Federation
ferk_88@list.ruLukoshkovaЕ. V.ЛукошковаЕ. В.
Russian Federation
ferk_88@list.ruProsvirninА. V.ПросвирнинА. В.
Russian Federation
ferk_88@list.ruKapelkoV. I.КапелькоВ. И.
Russian Federation
ferk_88@list.ruKuzminV. S.КузьминВ. С.
Russian Federation
ferk_88@list.ruNational Medical Research Centre of Cardiology named after Academician E. I. Chazov of the Ministry of Health of the Russian FederationНациональный медицинский исследовательский центр кардиологии им. академика Е. И. ЧазоваLomonosov Moscow State UniversityМосковский государственный университет имени М. В. Ломоносова15102024110101777179802022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/651739

Pulmonary arterial hypertension (PAH) is characterized by an increase of a pressure in the pulmonary circulation; PAH is accompanied by activation of the sympathetic (SNS) and the renin-angiotensin-aldosterone system (RAAS). However, PAH-associated changes in baroreceptor regulation of systemic circulation, which is tightly interwoven with SNS and RAAS, have not been studied. The baroreceptor response (BRR) was studied in a chronic monocrotaline (MCT) model of PAH in rats (Wistar, 290 ± 30 g, 2–4 months). Phenylephrine as an agonist of α1-adrenergic receptor and sodium nitroprusside as NO donor were gradually administered to chronically catheterized, non-anesthetized control animals and animals with PAH (4 weeks after MCT administration) to induce vasomotor responses. Mean arterial pressure and heart rate (HR) were recorded under the action of vasoactive compounds alone or under the action of vasoactive compounds in presence of angiotensin-II (ATII), atropine. The parameters characterizing baroreceptor change in HR including maximal and minimal heart rate (HRmax, HRmin), reflex tachycardia (TBRR) and bradycardia (BBRR), range (ABBR) and the baroreceptor response sensitivity index (SIBRR) were calculated. A significant decrease in HRmax, TBRR, ABBR (but not BBRR), as well as the sensitivity index of BRR was observed in rats with PAH. ATII induces significant and different changes in the BRR parameters in control rats and in rats with PAH if administered 4 weeks after the start of the experiment. In rats with PAH, ATII causes less pronounced changes in HRmax, TBRR, and BBRR than in control animals. ATII insignificantly affects parasympathetic component of the baroreceptor reflex in rats with PAH. Thus, at least in the MCT-mediated model in rats, PAH significantly deteriorates the baroreceptor regulation of HR. This effect manifests in a decrease in the range and sensitivity of the baroreceptor response. Also, PAH unequally affects the sympathetic and parasympathetic control of the baroreceptor regulation of HR. On the other hand, ATII exhibits weak ability to alter BRR in rats with HAP. In conclusion, PAH leads to a disfunction of immediate, reflex mechanisms HR and systemic circulation control.

Легочная артериальная гипертензия (ЛАГ) сопровождается подъемом давления в малом круге кровообращения; для ЛАГ характерна активация симпатического отдела вегетативной нервной системы и ренин-ангиотензин-альдостероновой систем (РААС). Изменение барорецепторной регуляции системного кровообращения, тесно переплетенной с СНС и РААС, при ЛАГ не исследовано. В работе изучали барорецепторную реакцию (БРР) в хронической монокроталиновой (МКТ) модели ЛАГ у крыс (Wistar, 290 ± 30 г, 2–4 месяца). Для индукции вазомоторных ответов хронически катетеризованным, бодрствующим контрольным животным и животным с ЛАГ (4 недели после инъекции МКТ) градуально, последовательно вводили агонист α1-адренорецепторов (фенилэфрин) и донор NO (нитропруссид натрия). Среднее артериальное давление и ЧСС регистрировали только при действии вазоактивных соединений, при действии вазоактивных соединений на фоне ангиотензина-II (АТII), атропина. Рассчитывали параметры, характеризующие барорецепторное изменение ЧСС: наибольшую и наименьшую достижимую ЧСС (ЧССmax, ЧССmin), рефлекторную тахикардию (ТКБРР) и брадикардию (БКБРР), диапазон (АБРР) и индекс чувствительности (ИЧБРР) барорецепторной реакции (БРР). У крыс c ЛАГ наблюдали значимое снижение ЧССmax, ТКБРР , АБРР , а также индекса чувствительности БРР, но не БКБРР . При введении через 4 недели после начала эксперимента АТII приводит к заметным, но различным изменениям параметров БРР у контрольных крыс и у крыс с ЛАГ. У крыс с ЛАГ АТII вызывает менее значимые изменения ЧССmax и ТКБРР , чем у животных контрольной группы. АТII незначительно влияет на парасимпатический компонент барорецепторного рефлекса у крыс с ЛАГ. Таким образом, в условиях МКТ модели у крыс ЛАГ оказывает существенное влияние на барорецепторную регуляцию. Это влияние манифестирует в уменьшении диапазона и чувствительности БРР. ЛАГ не одинаково влияет на симпатический и парасимпатический компоненты барорецепторной регуляции ЧСС. В модели ЛАГ влияние АТII на БРР оказывается снижен. В заключение – ЛАГ приводит к нарушению немедленных, рефлекторных механизмов регуляции ЧСС и кровообращения в большом круге.

pulmonary arterial hypertensionheart rhythmsystemic circulationbaroreceptor reflexbaroreceptor regulationparasympathetic controlheart rhythmangiotensin IIлегочная артериальная гипертензияритм сердцасистемное кровообращениебарорецепторная реакцияпарасимпатическая регуляция ЧССангиотензин IIРоссийский научный фондRussian Science Foundation22-15-00189Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F (2011) Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 8: 443–455. https://doi.org/10.1038/nrcardio.2011.87Hassoun PM (2021) Pulmonary Arterial Hypertension. N Engl J Med 385: 2361–2376. https://doi.org/10.1056/NEJMra2000348Абрамов АА, Лакомкин ВЛ, Лукошкова ЕВ, Просвирнин АВ, Капелько ВИ, Кузьмин ВС (2023) ЛЕГОЧНАЯ АРТЕРИАЛЬНАЯ ГИПЕРТЕНЗИЯ ОСЛАБЛЯЕТ ВАЗОКОНСТРИКТОРНЫЕ РЕАКЦИИ, ВЫЗВАННЫЕ АКТИВАЦИЕЙ АЛЬФА-1-АДРЕНОРЕЦЕПТОРОВ В БОЛЬШОМ КРУГЕ КРОВООБРАЩЕНИЯ. Рос физиол журн им ИМ Сеченова 109: 1498–1514. [Abramov AA, Lakomkin VL, Lukoshkova EV, Prosvirnin AV, Kapelko VI, Kuzmin VS (2023) PULMONARY ARTERIAL HYPERTENSION WEAKENS VASOCONSTRICTOR REACTIONS CAUSED BY ACTIVATION OF ALPHA-1-ADRENERGIC RECEPTORS IN THE LARGE CIRCULATORY CIRCLE. Russ J Physiol 109: 1498–1514. (In Russ)]. https://doi.org/10.31857/S0869813923100023Peled N, Shitrit D, Fox BD, Shlomi D, Amital A, Bendayan D, Kramer MR (2009) Peripheral arterial stiffness and endothelial dysfunction in idiopathic and scleroderma associated pulmonary arterial hypertension. J Rheumatol 36: 970–975. https://doi.org/10.3899/jrheum.081088Malenfant S, Brassard P, Paquette M, Le Blanc O, Chouinard A, Nadeau V, Allan PD, Tzeng Y-C, Simard S, Bonnet S, Provencher S (2017) Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension. J Am Heart Assoc 6: e006126. https://doi.org/10.1161/JAHA.117.006126Nickel NP, O’Leary JM, Brittain EL, Fessel JP, Zamanian RT, West JD, Austin ED (2017) Kidney dysfunction in patients with pulmonary arterial hypertension. Pulm Circ 7: 38–54. https://doi.org/10.1086/690018Nickel NP, Yuan K, Dorfmuller P, Provencher S, Lai Y-C, Bonnet S, Austin ED, Koch CD, Morris A, Perros F, Montani D, Zamanian RT, de Jesus Perez VA (2020) Beyond the Lungs: Systemic Manifestations of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 201: 148–157. https://doi.org/10.1164/rccm.201903-0656CIHumbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43: 13S–24S. https://doi.org/10.1016/j.jacc.2004.02.029Vaillancourt M, Chia P, Sarji S, Nguyen J, Hoftman N, Ruffenach G, Eghbali M, Mahajan A, Umar S (2017) Autonomic nervous system involvement in pulmonary arterial hypertension. Respir Res 18. https://doi.org/10.1186/s12931-017-0679-6Wensel R, Jilek C, Dörr M, Francis DP, Stadler H, Lange T, Blumberg F, Opitz C, Pfeifer M, Ewert R (2009) Impaired cardiac autonomic control relates to disease severity in pulmonary hypertension. Eur Respir J 34: 895–901. https://doi.org/10.1183/09031936.00145708Velez-Roa S, Ciarka A, Najem B, Vachiery J-L, Naeije R, van de Borne P (2004) Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 110: 1308–1312. https://doi.org/10.1161/01.CIR.0000140724.90898.D3Samavat S, Ahmadpoor P, Samadian F (2011) Aldosterone, hypertension, and beyond. Iran J Kidney Dis (2): 71–76.Dimopoulos S, Anastasiou-Nana M, Katsaros F, Papazachou O, Tzanis G, Gerovasili V, Pozios H, Roussos C, Nanas J, Nanas S (2009) Impairment of Autonomic Nervous System Activity in Patients with Pulmonary Arterial Hypertension: A Case Control Study. J Card Failure 15: 882–889. https://doi.org/10.1016/j.cardfail.2009.06.001Andersen MØ, Diederichsen SZ, Svendsen JH, Carlsen J (2023) Continuous long-term heart rate variability and risk assessment in pulmonary hypertension. Open Heart 10: e002302. https://doi.org/10.1136/openhrt-2023-002302Ramos RP, Arakaki JSO, Barbosa P, Treptow E, Valois FM, Ferreira EVM, Nery LE, Neder JA (2012) Heart rate recovery in pulmonary arterial hypertension: relationship with exercise capacity and prognosis. Am Heart J 163: 580–588. https://doi.org/10.1016/j.ahj.2012.01.023Minai OA, Gudavalli R, Mummadi S, Liu X, McCarthy K, Dweik RA (2012) Heart rate recovery predicts clinical worsening in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 185: 400–408. https://doi.org/10.1164/rccm.201105-0848OCMar PL, Nwazue V, Black BK, Biaggioni I, Diedrich A, Paranjape SY, Loyd JE, Hemnes AR, Robbins IM, Robertson D, Raj SR, Austin ED (2016) Valsalva Maneuver in Pulmonary Arterial Hypertension: Susceptibility to Syncope and Autonomic Dysfunction. CHEST 149: 1252–1260. https://doi.org/10.1016/j.chest.2015.11.015Yi H-T, Hsieh Y-C, Wu T-J, Huang J-L, Lin W-W, Liang K-W, Su C-S, Tsai W-J, Wang K-Y (2014) Heart rate variability parameters and ventricular arrhythmia correlate with pulmonary arterial pressure in adult patients with idiopathic pulmonary arterial hypertension. Heart Lung 43: 534–540. https://doi.org/10.1016/j.hrtlng.2014.05.010Paula-Ribeiro M, Ribeiro IC, Aranda LC, Silva TM, Costa CM, Ramos RP, Ota-Arakaki J, Cravo SL, Nery LE, Stickland MK, Silva BM (2021) Cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension at rest and during orthostatic stress: role of the peripheral chemoreflex. J Appl Physiol (1985) 131: 794–807. https://doi.org/10.1152/japplphysiol.00152.2021Vittorio TJ, Fudim M, Wagman G, Kosmas CE (2014) Alpha-1 adrenoceptor-angiotensin II type 1 receptor cross-talk and its relevance in clinical medicine. Cardiol Rev 22: 51–55. https://doi.org/10.1097/CRD.0b013e31829ce723Head GA, McCarty R (1987) Vagal and sympathetic components of the heart rate range and gain of the baroreceptor-heart rate reflex in conscious rats. J Auton Nerv Syst 21: 203–213. https://doi.org/10.1016/0165-1838(87)90023-3An H, Landis JT, Bailey AG, Marron JS, Dittmer DP (2019) dr4pl: A Stable Convergence Algorithm for the 4 Parameter Logistic Model. R Journal 11: 171–190. https://doi.org/10.32614/RJ-2019-003Ritz C, Baty F, Streibig JC, Gerhard D (2015) Dose-Response Analysis Using R. PLoS One 10: e0146021. https://doi.org/10.1371/journal.pone.0146021R Core Team (2020) R: A Language and Environment for Statistical Computing.Wickham H, Averick M, Bryan J, Chang W, McGowan LD, François R, Grolemund G, Hayes A, Henry L, Hester J, Kuhn M, Pedersen TL, Miller E, Bache SM, Müller K, Ooms J, Robinson D, Seidel DP, Spinu V, Takahashi K, Vaughan D, Wilke C, Woo K, Yutani H (2019) Welcome to the tidyverse. J Open Source Software 4: 1686. https://doi.org/10.21105/joss.01686Pinheiro J, Bates D (2000) Mixed-Effects Models in S and S-PLUS. Springer-Verlag. New York. https://doi.org/10.1007/b98882Pinheiro J, Bates D, R Core Team (2024) nlme: Linear and Nonlinear Mixed Effects Models. https://doi.org/10.32614/CRAN.package.nlmeMiguez F, Archontoulis S, Dokoohaki H (2018) Nonlinear Regression Models and Applications. In: Glaz B, Yeater KM (eds) Applied Statistics in Agricultural, Biological, and Environmental Sciences. Wiley. 401–447. https://doi.org/10.2134/appliedstatistics.2016.0003.c15Oddi FJ, Miguez FE, Ghermandi L, Bianchi LO, Garibaldi LA (2019) A nonlinear mixed-effects modeling approach for ecological data: Using temporal dynamics of vegetation moisture as an example. Ecol and Evolut 9: 10225–10240. https://doi.org/10.1002/ece3.5543Bates D, Mächler M, Bolker B, Walker S (2015) Fitting Linear Mixed-Effects Models Using lme4. J Stat Software 67: 1–48. https://doi.org/10.18637/jss.v067.i01Lenth RV (2024) Emmeans: Estimated Marginal Means, aka Least-Squares Means. https://doi.org/10.32614/CRAN.package.emmeansPustejovsky J (2024) clubSandwich: Cluster-Robust (Sandwich) Variance Estimators with Small-Sample Corrections. https://doi.org/10.32614/CRAN.package.clubSandwichPustejovsky JE, Tipton E (2018) Small-Sample Methods for Cluster-Robust Variance Estimation and Hypothesis Testing in Fixed Effects Models. J Busin & Econom Statist 36: 672–683. https://doi.org/10.1080/07350015.2016.1247004Bretz F, Hothorn T, Westfall P (2016) Multiple Comparisons Using R. CRC Press.Wickham H (2016) ggplot2: Elegant Graphics for Data Analysis. Springer Int Publ.Tiedemann F (2020) gghalves: Compose Half-Half Plots Using Your Favourite Geoms.Kay M (2024) ggdist: Visualizations of Distributions and Uncertainty in the Grammar of Graphics. IEEE Transact Visual Comput Graphics 30: 414–424. https://doi.org/10.1109/TVCG.2023.3327195Pedersen TL (2024) patchwork: The Composer of Plots. https://doi.org/10.32614/CRAN.package.patchworkKumagai H, Oshima N, Matsuura T, Iigaya K, Imai M, Onimaru H, Sakata K, Osaka M, Onami T, Takimoto C, Kamayachi T, Itoh H, Saruta T (2012) Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure. Hypertens Res 35: 132–141. https://doi.org/10.1038/hr.2011.208Charles CJ, Jardine DL, Nicholls MG, Richards AM (2005) Adrenomedullin increases cardiac sympathetic nerve activity in normal conscious sheep. J Endocrinol 187: 275–281 https://doi.org/10.1677/joe.1.06337Fujita M, Kuwaki T, Ando K, Fujita T (2005) Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in the brain. Hypertension 45: 1165–1172. https://doi.org/10.1161/01.HYP.0000165690.85505.37Xu Y, Krukoff TL (2006) Adrenomedullin in the rostral ventrolateral medulla inhibits baroreflex control of heart rate: a role for protein kinase A. Br J Pharmacol 148: 70–77. https://doi.org/10.1038/sj.bjp.0706698Bouzina H, Rådegran G (2020) Plasma adrenomedullin peptides and precursor levels in pulmonary arterial hypertension disease severity and risk stratification. Pulm Circ 10: 2045894020931317. https://doi.org/10.1177/2045894020931317Hartopo AB, Anggrahini DW, Dinarti LK, Schäfer A-K, Bergmann A, Fachiroh J, Somma SD (2023) Prognostic Value for Mortality of Plasma Bioactive Adrenomedullin in Patients with Pulmonary Arterial Hypertension: A Sub Analysis of the Biomarker Study in the COHARD-PH Registry. Medicina (Kaunas) 59: 748. https://doi.org/10.3390/medicina59040748Shinoda M, Saku K, Oga Y, Tohyama T, Nishikawa T, Abe K, Yoshida K, Kuwabara Y, Fujii K, Ishikawa T, Kishi T, Sunagawa K, Tsutsui H (2019) Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension. Exp Physiol 104: 1164–1178. https://doi.org/10.1113/EP087253Zaloga GP, Chernow B, Fletcher JR, Hughes P, Rainey TG, Lake CR (1984) Increased circulating plasma norepinephrine concentrations in noncardiac causes of pulmonary hypertension. Crit Care Med 12: 85–89. https://doi.org/10.1097/00003246-198402000-00001Mak JC, Haddad EB, Buckley NJ, Barnes PJ (1993) Visualization of muscarinic m4 mRNA and M4 receptor subtype in rabbit lung. Life Sci 53: 1501–1508. https://doi.org/10.1016/0024-3205(93)90624-cMorice AH, Pepke-Zaba J, Brown MJ, Thomas PS, Higenbottam TW (1990) Atrial natriuretic peptide in primary pulmonary hypertension. Eur Respir J 3: 910–913.Suga S, Nakao K, Hosoda K, Mukoyama M, Ogawa Y, Shirakami G, Arai H, Saito Y, Kambayashi Y, Inouye K (1992) Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology 130: 229–239. https://doi.org/10.1210/endo.130.1.1309330Birkenfeld AL, Boschmann M, Moro C, Adams F, Heusser K, Tank J, Diedrich A, Schroeder C, Franke G, Berlan M, Luft FC, Lafontan M, Jordan J (2006) Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and metabolic regulation. J Clin Endocrinol Metab 91: 5069–5075. https://doi.org/10.1210/jc.2006-1084Luchner A, Schunkert H (2004) Interactions between the sympathetic nervous system and the cardiac natriuretic peptide system. Cardiovasc Res 63: 443–449. https://doi.org/10.1016/j.cardiores.2004.05.004Conde SV, Sacramento JF, Melo BF, Fonseca-Pinto R, Romero-Ortega MI, Guarino MP (2021) Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation. Front Neurosci 15: 725751. https://doi.org/10.3389/fnins.2021.725751Wallbach M, Koziolek MJ (2018) Baroreceptors in the carotid and hypertension-systematic review and meta-analysis of the effects of baroreflex activation therapy on blood pressure. Nephrol Dial Transplant 33: 1485–1493. https://doi.org/10.1093/ndt/gfx279Kougias P, Weakley SM, Yao Q, Lin PH, Chen C (2010) Arterial baroreceptors in the management of systemic hypertension. Med Sci Monit 16: RA1–RA8.Mancia G, Ferrari A, Gregorini L, Parati G, Ferrari MC, Pomidossi G, Zanchetti A (1979) Control of blood pressure by carotid sinus baroreceptors in human beings. Am J Cardiol 44: 895–902. https://doi.org/10.1016/0002-9149(79)90220-0Yokoyama T, Settai K, Nakamuta N, Yamamoto Y (2019) Distribution and morphology of baroreceptors in the rat carotid sinus as revealed by immunohistochemistry for P2X3 purinoceptors. Histochem Cell Biol 151: 161–173. https://doi.org/10.1007/s00418-018-1734-1Wang J, Chen J, Shu L, Zhang R, Dai M, Fang X, Hu Z, Xiao L, Xi Z, Zhang J, Bao M (2024) Carotid Baroreceptor Stimulation Improves Pulmonary Arterial Remodeling and Right Ventricular Dysfunction in Pulmonary Arterial Hypertension. JACC Basic Transl Sci 9: 475–492. https://doi.org/10.1016/j.jacbts.2024.01.012Heusser K, Tank J, Luft FC, Jordan J (2005) Baroreflex failure. Hypertension 45: 834–839. https://doi.org/10.1161/01.HYP.0000160355.93303.72Biaggioni I, Shibao CA, Diedrich A, Muldowney JAS, Laffer CL, Jordan J (2019) Blood Pressure Management in Afferent Baroreflex Failure: JACC Review Topic of the Week. J Am Coll Cardiol 74: 2939–2947. https://doi.org/10.1016/j.jacc.2019.10.027Kummer W (2011) Pulmonary vascular innervation and its role in responses to hypoxia: size matters! Proc Am Thorac Soc 8: 471–476. https://doi.org/10.1513/pats.201101-013MWDa Silva Gonçalves Bos D, Happé C, Schalij I, Pijacka W, Paton JFR, Guignabert C, Tu L, Thuillet R, Bogaard H-J, van Rossum AC, Vonk-Noordegraaf A, de Man FS, Handoko ML (2017) Renal Denervation Reduces Pulmonary Vascular Remodeling and Right Ventricular Diastolic Stiffness in Experimental Pulmonary Hypertension. JACC Basic Transl Sci 2: 22–35. https://doi.org/10.1016/j.jacbts.2016.09.007Ntiloudi D, Qanud K, Tomaio J-N, Giannakoulas G, Al-Abed Y, Zanos S (2019) Pulmonary arterial hypertension: the case for a bioelectronic treatment. Bioelectron Med 5. https://doi.org/10.1186/s42234-019-0036-9Karpov AA, Vachrushev NS, Shilenko LA, Smirnov SS, Bunenkov NS, Butskih MG, Chervaev A-KA, Vaulina DD, Ivkin DY, Moiseeva OM, Galagudza MM (2023) Sympathetic Denervation and Pharmacological Stimulation of Parasympathetic Nervous System Prevent Pulmonary Vascular Bed Remodeling in Rat Model of Chronic Thromboembolic Pulmonary Hypertension. J Cardiovasc Dev Dis 10: 40. https://doi.org/10.3390/jcdd10020040