Molecular mechanisms of right ventricular failure

Circulation

Volumn 132, Issue 18, 2015, Pages 1734-1742

  Reddy, Sushma ^a   Bernstein, Daniel ^a  

^a STANFORD UNIVERSITY   (United States)

Author keywords

Angiogenesis; Heart defects, congenital; Heart failure; Hypertrophy; Oxidative stress

Indexed keywords

ADRENERGIC RECEPTOR; ANTIOXIDANT; MICRORNA; REACTIVE OXYGEN METABOLITE;

ANGIOGENESIS; ARTICLE; CONGENITAL HEART DISEASE; CORONARY ARTERY BLOOD FLOW; DISEASE ASSOCIATION; HEART AFTERLOAD; HEART HEMODYNAMICS; HEART LEFT VENTRICLE FAILURE; HEART RIGHT VENTRICLE FAILURE; HEART RIGHT VENTRICLE HYPERTROPHY; HEART RIGHT VENTRICLE OUTFLOW TRACT; HEART RIGHT VENTRICLE OVERLOAD; HEART RIGHT VENTRICLE VOLUME; HEART STRESS; HEART VENTRICLE REMODELING; HEMODYNAMIC STRESS; HUMAN; HYPOXIA; METABOLISM; MOLECULAR PATHOLOGY; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; ADAPTATION; ANIMAL; CARDIAC MUSCLE; CELL HYPOXIA; DISEASE MODEL; GENE EXPRESSION REGULATION; GENETICS; HEART FAILURE; HEART MITOCHONDRION; HEART MUSCLE ISCHEMIA; HEART VENTRICLE; HEMODYNAMICS; PATHOPHYSIOLOGY; PHYSIOLOGY;

ADAPTATION, PHYSIOLOGICAL; ANIMALS; CELL HYPOXIA; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION; HEART FAILURE; HEART VENTRICLES; HEMODYNAMICS; HUMANS; MICRORNAS; MITOCHONDRIA, HEART; MYOCARDIAL ISCHEMIA; MYOCARDIUM; NEOVASCULARIZATION, PHYSIOLOGIC; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES; RENIN-ANGIOTENSIN SYSTEM;

EID: 84947104414     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.114.012975     Document Type: Article

References (77)

1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890-1900.
2. Belmont JW. Recent progress in the molecular genetics of congenital heart defects. Clin Genet. 1998;54:11-19.
3. Lund O, Kristensen LH, Baandrup U, Hansen OK, Nielsen TT, Emmertsen K, Jensen FT, Flø C, Rasmussen BS, Pilegaard HK. Myocardial structure as a determinant of pre-and postoperative ventricular function and long-term prognosis after valve replacement for aortic stenosis. Eur Heart J. 1998;19:1099-1108.
4. Douglas PS, Reichek N, Hackney K, Ioli A, Sutton MG. Contribution of afterload, hypertrophy and geometry to left ventricular ejection fraction in aortic valve stenosis, pure aortic regurgitation and idiopathic dilated cardiomyopathy. Am J Cardiol. 1987;59:1398-1404.
5. Kaufman BD, Desai M, Reddy S, Osorio JC, Chen JM, Mosca RS, Ferrante AW, Mital S. Genomic profling of left and right ventricular hypertrophy in congenital heart disease. J Card Fail. 2008;14:760-767. doi: 10.1016/j.cardfail.2008.06.002.
6. Buermans HP, Redout EM, Schiel AE, Musters RJ, Zuidwijk M, Eijk PP, van Hardeveld C, Kasanmoentalib S, Visser FC, Ylstra B, Simonides WS. Microarray analysis reveals pivotal divergent mRNA expression profles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics. 2005;21:314-323. doi: 10.1152/physiolgenomics.00185.2004.
7. Gomez-Arroyo J, Sakagami M, Syed AA, Farkas L, Van Tassell B, Kraskauskas D, Mizuno S, Abbate A, Bogaard HJ, Byron PR, Voelkel NF. Iloprost reverses established fbrosis in experimental right ventricular failure. Eur Respir J. 2015;45:449-462. doi: 10.1183/09031936.00188013.
8. Hopkins WE, Ochoa LL, Richardson GW, Trulock EP. Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant. 1996;15(1 pt 1):100-105.
9. Hopkins WE. The remarkable right ventricle of patients with Eisenmenger syndrome. Coron Artery Dis. 2005;16:19-25.
10. Friedberg MK, Redington AN. Right versus left ventricular failure: differences, similarities, and interactions. Circulation. 2014;129:1033-1044. doi: 10.1161/CIRCULATIONAHA.113.001375.
11. Winter MM, Bouma BJ, Groenink M, Konings TC, Tijssen JG, van Veldhuisen DJ, Mulder BJ. Latest insights in therapeutic options for systemic right ventricular failure: a comparison with left ventricular failure. Heart. 2009;95:960-963. doi: 10.1136/hrt.2008.156265.
12. Szymañski P, Klisiewicz A, Hoffman P. Therapeutic options for systemic right ventricular failure. Heart. 2009;95:1950-1951; author reply 1951. doi: 10.1136/hrt.2009.179952.
13. Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, Rosenthal DN, Burr J, LaSalle B, Holubkov R, Lukas MA, Tani LY; Pediatric Carvedilol Study Group. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007;298:1171-1179. doi: 10.1001/jama.298.10.1171.
14. Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, Barker PC, Ravishankar C, McCrindle BW, Williams RV, Altmann K, Ghanayem NS, Margossian R, Chung WK, Border WL, Pearson GD, Stylianou MP, Mital S; Pediatric Heart Network Investigators. Enalapril in infants with single ventricle: results of a multicenter randomized trial. Circulation. 2010;122:333-340. doi: 10.1161/CIRCULATIONAHA.109.927988.
15. Gentles TL, Mayer JE Jr, Gauvreau K, Newburger JW, Lock JE, Kupferschmid JP, Burnett J, Jonas RA, Castañeda AR, Wernovsky G. Fontan operation in fve hundred consecutive patients: factors infuencing early and late outcome. J Thorac Cardiovasc Surg. 1997;114:376-391.
16. Buckberg GD; RESTORE Group. The ventricular septum: the lion of right ventricular function, and its impact on right ventricular restoration. Eur J Cardiothorac Surg. 2006;29 Suppl 1:S272-S278. doi: 10.1016/j. ejcts.2006.02.011.
17. Kondo RP, Dederko DA, Teutsch C, Chrast J, Catalucci D, Chien KR, Giles WR. Comparison of contraction and calcium handling between right and left ventricular myocytes from adult mouse heart: a role for repo-larization waveform. J Physiol. 2006;571(pt 1):131-146. doi: 10.1113/jphysiol.2005.101428.
18. Piao L, Marsboom G, Archer SL. Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure. J Mol Med (Berl). 2010;88:1011-1020. doi: 10.1007/s00109-010-0679-1.
19. Urashima T, Zhao M, Wagner R, Fajardo G, Farahani S, Quertermous T, Bernstein D. Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis. Am J Physiol Heart Circ Physiol. 2008;295:H1351-H1368. doi: 10.1152/ajpheart.91526.2007.
20. Tedford RJ. Determinants of right ventricular afterload (2013 Grover Conference series). Pulm Circ. 2014;4:211-219. doi: 10.1086/676020.
21. Zong P, Tune JD, Downey HF. Mechanisms of oxygen demand/supply balance in the right ventricle. Exp Biol Med (Maywood). 2005;230:507-519.
22. Kusachi S, Nishiyama O, Yasuhara K, Saito D, Haraoka S, Nagashima H. Right and left ventricular oxygen metabolism in open-chest dogs. Am J Physiol. 1982;243:H761-H766.
23. Phillips D, Aponte AM, Covian R, Neufeld E, Yu ZX, Balaban RS. Homogenous protein programming in the mammalian left and right ventricle free walls. Physiol Genomics. 2011;43:1198-1206. doi: 10.1152/physiolgenomics.00121.2011.
24. Do E, Baudet S, Verdys M, Touzeau C, Bailly F, Lucas-Héron B, Sagniez M, Rossi A, Noireaud J. Energy metabolism in normal and hypertrophied right ventricle of the ferret heart. J Mol Cell Cardiol. 1997;29:1903-1913. doi: 10.1006/jmcc.1997.0429.
25. Gunes Y, Guntekin U, Tuncer M, Sahin M. Improved left and right ventricular functions with trimetazidine in patients with heart failure: a tissue Doppler study. Heart Vessels. 2009;24:277-282. doi: 10.1007/s00380-008-1118-x.
26. Gu Q, Chen XT, Xiao YB, Chen L, Wang XF, Fang J, Chen BC, Hao J. Identifcation of differently expressed genes and small molecule drugs for Tetralogy of Fallot by bioinformatics strategy. Pediatr Cardiol. 2014;35:863-869. doi: 10.1007/s00246-014-0868-8.
27. Rastogi S, Sharov VG, Mishra S, Gupta RC, Blackburn B, Belardinelli L, Stanley WC, Sabbah HN. Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am J Physiol Heart Circ Physiol. 2008;295:H2149-H2155. doi: 10.1152/ajpheart.00728.2008.
28. Phan TT, Shivu GN, Choudhury A, Abozguia K, Davies C, Naidoo U, Ahmed I, Yousef Z, Horowitz J, Frenneaux M. Multi-centre experience on the use of perhexiline in chronic heart failure and refractory angina: old drug, new hope. Eur J Heart Fail. 2009;11:881-886. doi: 10.1093/eurjhf/hfp106.
29. Halbirk M, Nørrelund H, Møller N, Schmitz O, Gøtzsche L, Nielsen R, Nielsen-Kudsk JE, Nielsen SS, Nielsen TT, Eiskjær H, Bøtker HE, Wiggers H. Suppression of circulating free fatty acids with acipi-mox in chronic heart failure patients changes whole body metabolism but does not affect cardiac function. Am J Physiol Heart Circ Physiol. 2010;299:H1220-H1225. doi: 10.1152/ajpheart.00475.2010.
30. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, Shannon RP. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962-965. doi: 10.1161/01. CIR.0000120505.91348.58.
31. O'Connor RD, Xu J, Ewald GA, Ackerman JJ, Peterson LR, Gropler RJ, Bashir A. Intramyocardial triglyceride quantifcation by magnetic resonance spectroscopy: In vivo and ex vivo correlation in human subjects. Magn Reson Med. 2011;65:1234-1238. doi: 10.1002/mrm.22734.
32. Reddy S, Zhao M, Hu DQ, Fajardo G, Katznelson E, Punn R, Spin JM, Chan FP, Bernstein D. Physiologic and molecular characterization of a murine model of right ventricular volume overload. Am J Physiol Heart Circ Physiol. 2013;304:H1314-H1327. doi: 10.1152/ajpheart.00776.2012.
33. Nagendran J, Gurtu V, Fu DZ, Dyck JR, Haromy A, Ross DB, Rebeyka IM, Michelakis ED. A dynamic and chamber-specifc mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted. J Thorac Cardiovasc Surg. 2008;136:168-78, 178.e1. doi: 10.1016/j. jtcvs.2008.01.040.
34. Gomez-Arroyo J, Mizuno S, Szczepanek K, Van Tassell B, Natarajan R, dos Remedios CG, Drake JI, Farkas L, Kraskauskas D, Wijesinghe DS, Chalfant CE, Bigbee J, Abbate A, Lesnefsky EJ, Bogaard HJ, Voelkel NF. Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension. Circ Heart Fail. 2013;6:136-144. doi: 10.1161/CIRCHEARTFAILURE.111.966127.
35. Tsutsui H, Ide T, Hayashidani S, Suematsu N, Utsumi H, Nakamura R, Egashira K, Takeshita A. Greater susceptibility of failing cardiac myocytes to oxygen free radical-mediated injury. Cardiovasc Res. 2001;49:103-109.
36. Ecarnot-Laubriet A, Rochette L, Vergely C, Sicard P, Teyssier JR. The activation pattern of the antioxidant enzymes in the right ventricle of rat in response to pressure overload is of heart failure type. Heart Dis. 2003;5:308-312. doi: 10.1097/01.hdx.0000089836.03515.a9.
37. Redout EM, van der Toorn A, Zuidwijk MJ, van de Kolk CW, van Echteld CJ, Musters RJ, van Hardeveld C, Paulus WJ, Simonides WS. Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure. Am J Physiol Heart Circ Physiol. 2010;298:H1038-H1047. doi: 10.1152/ajpheart.00097.2009.
38. Redout EM, Wagner MJ, Zuidwijk MJ, Boer C, Musters RJ, van Hardeveld C, Paulus WJ, Simonides WS. Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species. Cardiovasc Res. 2007;75:770-781. doi: 10.1016/j. cardiores.2007.05.012.
39. Karamanlidis G, Bautista-Hernandez V, Fynn-Thompson F, Del Nido P, Tian R. Impaired mitochondrial biogenesis precedes heart failure in right ventricular hypertrophy in congenital heart disease. Circ Heart Fail. 2011;4:707-713. doi: 10.1161/CIRCHEARTFAILURE.111.961474.
40. Saito D, Tani H, Kusachi S, Uchida S, Ohbayashi N, Marutani M, Maekawa K, Tsuji T, Haraoka S. Oxygen metabolism of the hypertrophic right ventricle in open chest dogs. Cardiovasc Res. 1991;25:731-739.
41. Ohuchi H, Beighley PE, Dong Y, Zamir M, Ritman EL. Microvascular development in porcine right and left ventricular walls. Pediatr Res. 2007;61:676-680. doi: 10.1203/pdr.0b013e31805365a6.
42. Zamir M. The Physics of Coronary Blood Flow. New York, NY: Springer; 2005.
43. Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y, Akazawa H, Tateno K, Kayama Y, Harada M, Shimizu I, Asahara T, Hamada H, Tomita S, Molkentin JD, Zou Y, Komuro I. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 2007;446:444-448. doi: 10.1038/nature05602.
44. Choi YH, Cowan DB, Nathan M, Poutias D, Stamm C, del Nido PJ, McGowan FX Jr. Myocardial hypertrophy overrides the angiogenic response to hypoxia. PLoS One. 2008;3:e4042. doi: 10.1371/journal. pone.0004042.
45. Zhao M, Fajardo G, Urashima T, Spin JM, Poorfarahani S, Rajagopalan V, Huynh D, Connolly A, Quertermous T, Bernstein D. Cardiac pressure overload hypertrophy is differentially regulated by β-adrenergic receptor subtypes. Am J Physiol Heart Circ Physiol. 2011;301:H1461-H1470. doi: 10.1152/ajpheart.00453.2010.
46. Partovian C, Adnot S, Eddahibi S, Teiger E, Levame M, Dreyfus P, Raffestin B, Frelin C. Heart and lung VEGF mRNA expression in rats with monocrotaline-or hypoxia-induced pulmonary hypertension. Am J Physiol. 1998;275(6 pt 2):H1948-H1956.
47. Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, Ockaili R, McCord JM, Voelkel NF. Chronic pulmonary artery pressure elevation is insuffcient to explain right heart failure. Circulation. 2009;120:1951-1960. doi: 10.1161/CIRCULATIONAHA.109.883843.
48. Bian X, Williams AG Jr, Gwirtz PA, Downey HF. Right coronary auto-regulation in conscious, chronically instrumented dogs. Am J Physiol. 1998;275(1 pt 2):H169-H175.
49. Gómez A, Bialostozky D, Zajarias A, Santos E, Palomar A, Martínez ML, Sandoval J. Right ventricular ischemia in patients with primary pulmonary hypertension. J Am Coll Cardiol. 2001;38:1137-1142.
50. Setty S, Tune JD, Downey HF. Nitric oxide contributes to oxygen demand-supply balance in hypoperfused right ventricle. Cardiovasc Res. 2004;64:431-436. doi: 10.1016/j.cardiores.2004.07.021.
51. Tune JD, Richmond KN, Gorman MW, Feigl EO. Role of nitric oxide and adenosine in control of coronary blood fow in exercising dogs. Circulation. 2000;101:2942-2948.
52. Piao L, Fang YH, Parikh KS, Ryan JJ, D'Souza KM, Theccanat T, Toth PT, Pogoriler J, Paul J, Blaxall BC, Akhter SA, Archer SL. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation. 2012;126:2859-2869. doi: 10.1161/CIRCULATIONAHA.112.109868.
53. Norozi K, Bahlmann J, Raab B, Alpers V, Arnhold JO, Kuehne T, Klimes K, Zoege M, Geyer S, Wessel A, Buchhorn R. A prospective, randomized, double-blind, placebo controlled trial of beta-blockade in patients who have undergone surgical correction of tetralogy of Fallot. Cardiol Young. 2007;17:372-379. doi: 10.1017/S1047951107000844.
54. Doughan AR, McConnell ME, Book WM. Effect of beta blockers (carvedilol or metoprolol XL) in patients with transposition of great arteries and dysfunction of the systemic right ventricle. Am J Cardiol. 2007;99:704-706. doi: 10.1016/j.amjcard.2006.10.025.
55. Sun LS, Du F, Quaegebeur JM. Right ventricular infundibular beta-adre-noceptor complex in tetralogy of Fallot patients. Pediatr Res. 1997;42:12-16. doi: 10.1203/00006450-199707000-00003.
56. Molenaar P, Bartel S, Cochrane A, Vetter D, Jalali H, Pohlner P, Burrell K, Karczewski P, Krause EG, Kaumann A. Both beta(2)-and beta(1)-adren-ergic receptors mediate hastened relaxation and phosphorylation of phos-pholamban and troponin I in ventricular myocardium of Fallot infants, consistent with selective coupling of beta(2)-adrenergic receptors to G(s)-protein. Circulation. 2000;102:1814-1821.
57. Wang GY, McCloskey DT, Turcato S, Swigart PM, Simpson PC, Baker AJ. Contrasting inotropic responses to alpha1-adrenergic receptor stimulation in left versus right ventricular myocardium. Am J Physiol Heart Circ Physiol. 2006;291:H2013-H2017. doi: 10.1152/ajpheart.00167.2006.
58. Wang GY, Yeh CC, Jensen BC, Mann MJ, Simpson PC, Baker AJ. Heart failure switches the RV alpha1-adrenergic inotropic response from negative to positive. Am J Physiol Heart Circ Physiol. 2010;298:H913-H920. doi: 10.1152/ajpheart.00259.2009.
59. Anand IS, Chandrashekhar Y, Ferrari R, Sarma R, Guleria R, Jindal SK, Wahi PL, Poole-Wilson PA, Harris P. Pathogenesis of congestive state in chronic obstructive pulmonary disease. Studies of body water and sodium, renal function, hemodynamics, and plasma hormones during edema and after recovery. Circulation. 1992;86:12-21.
60. Farber MO, Roberts LR, Weinberger MH, Robertson GL, Fineberg NS, Manfredi F. Abnormalities of sodium and H2O handling in chronic obstructive lung disease. Arch Intern Med. 1982;142:1326-1330.
61. Schrier RW, Bansal S. Pulmonary hypertension, right ventricular failure, and kidney: different from left ventricular failure? Clin J Am Soc Nephrol. 2008;3:1232-1237. doi: 10.2215/CJN.01960408.
62. Maron BA, Leopold JA. The role of the renin-angiotensin-aldosterone system in the pathobiology of pulmonary arterial hypertension (2013 Grover Conference series). Pulm Circ. 2014;4:200-210. doi: 10.1086/675984.
63. van der Bom T, Winter MM, Bouma BJ, Groenink M, Vliegen HW, Pieper PG, van Dijk AP, Sieswerda GT, Roos-Hesselink JW, Zwinderman AH, Mulder BJ. Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot trial. Circulation. 2013;127:322-330. doi: 10.1161/CIRCULATIONAHA.112.135392.
64. Dore A, Houde C, Chan KL, Ducharme A, Khairy P, Juneau M, Marcotte F, Mercier LA. Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical trial. Circulation. 2005;112:2411-2416. doi: 10.1161/CIRCULATIONAHA.105.543470.
65. Robinson B, Heise CT, Moore JW, Anella J, Sokoloski M, Eshaghpour E. Afterload reduction therapy in patients following intraatrial baffe operation for transposition of the great arteries. Pediatr Cardiol. 2002;23:618-623. doi: 10.1007/s00246-002-0046-2.
66. Cordes KR, Srivastava D. MicroRNA regulation of cardiovascular development. Circ Res. 2009;104:724-732. doi: 10.1161/CIRCRESAHA.108.192872.
67. Callis TE, Wang DZ. Taking microRNAs to heart. Trends Mol Med. 2008;14:254-260. doi: 10.1016/j.molmed.2008.03.006.
68. El-Armouche A, Schwoerer AP, Neuber C, Emons J, Emmons J, Biermann D, Christalla T, Grundhoff A, Eschenhagen T, Zimmermann WH, Ehmke H. Common microRNA signatures in cardiac hypertrophic and atro-phic remodeling induced by changes in hemodynamic load. PLoS One. 2010;5:e14263. doi: 10.1371/journal.pone.0014263.
69. Yang M, Yao Y, Eades G, Zhang Y, Zhou Q. MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism. Breast Cancer Res Treat. 2011;129:983-991. doi: 10.1007/s10549-011-1604-1.
70. Smith-Vikos T, Slack FJ. MicroRNAs and their roles in aging. J Cell Sci. 2012;125(Pt 1):7-17. doi: 10.1242/jcs.099200.
71. Yu J, Li Q, Xu Q, Liu L, Jiang B. MiR-148a inhibits angiogenesis by targeting ERBB3. J Biomed Res. 2011;25:170-177. doi: 10.1016/S1674-8301(11)60022-5.
72. Reddy S, Zhao M, Hu DQ, Fajardo G, Hu S, Ghosh Z, Rajagopalan V, Wu JC, Bernstein D. Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics. 2012;44:562-575. doi: 10.1152/physiolgenomics.00163.2011.
73. Tabuchi T, Satoh M, Itoh T, Nakamura M. MicroRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression. Clin Sci (Lond). 2012;123:161-171. doi: 10.1042/CS20110563.
74. Potus F, Malenfant S, Graydon C, Mainguy V, Tremblay È, Breuils-Bonnet S, Ribeiro F, Porlier A, Maltais F, Bonnet S, Provencher S. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014;190:318-328. doi: 10.1164/rccm.201402-0383OC.
75. Thum T, Batkai S. MicroRNAs in right ventricular (dys)function (2013 Grover Conference series). Pulm Circ. 2014;4:185-190. doi: 10.1086/675981.
76. Paulin R, Sutendra G, Gurtu V, Dromparis P, Haromy A, Provencher S, Bonnet S, Michelakis ED. A miR-208-Mef2 axis drives the decompensation of right ventricular function in pulmonary hypertension. Circ Res. 2015;116:56-69. doi: 10.1161/CIRCRESAHA.115.303910.
77. Rain S, Handoko ML, Trip P, Gan CT, Westerhof N, Stienen GJ, Paulus WJ, Ottenheijm CA, Marcus JT, Dorfmüller P, Guignabert C, Humbert M, Macdonald P, Dos Remedios C, Postmus PE, Saripalli C, Hidalgo CG, Granzier HL, Vonk-Noordegraaf A, van der Velden J, de Man FS. Right ventricular diastolic impairment in patients with pulmonary arterial hypertension. Circulation. 2013;128:2016-25, 1. doi: 10.1161/CIRCULATIONAHA.113.001873.