Right heart dysfunction and failure in heart failure with preserved ejection fraction: mechanisms and management. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology

European Journal of Heart Failure

Volumn 20, Issue 1, 2018, Pages 16-37

  Gorter, Thomas M ^a   van Veldhuisen, Dirk J ^a   Bauersachs, Johann ^b   Borlaug, Barry A ^c   Celutkiene, Jelena ^d   Coats, Andrew J S ^e,f   Crespo Leiro, Marisa G ^g   Guazzi, Marco ^h   Harjola, Veli Pekka ⁱ   Heymans, Stephane ^j   Hill, Loreena ^k   Lainscak, Mitja ^l   Lam, Carolyn S P ^m   Lund, Lars H ⁿ   Lyon, Alexander R ^o   Mebazaa, Alexandre ^p   Mueller, Christian ^q   Paulus, Walter J ^r   Pieske, Burkert ^s,ab   Piepoli, Massimo F ^t   Ruschitzka, Frank ^u   Rutten, Frans H ^v   Seferovic, Petar M ^w   Solomon, Scott D ^x   Shah, Sanjiv J ^y   Triposkiadis, Filippos ^z   Wachter, Rolf ^aa   Tschöpe, Carsten ^s,ab   de Boer, Rudolf A ^a   more..

^a UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^b HANNOVER MEDICAL SCHOOL   (Germany)

^c MAYO CLINIC   (United States)

^d VILNIUS UNIVERSITY   (Lithuania)

^e MONASH UNIVERSITY   (Australia)

^f UNIVERSITY OF WARWICK   (United Kingdom)

^g UNIVERSITY OF A CORUÑA   (Spain)

^h UNIVERSITY OF MILAN   (Italy)

ⁱ UNIVERSITY OF HELSINKI   (Finland)

^j MAASTRICHT UNIVERSITY   (Netherlands)

^k QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

^l General Hospital Murska Sobota   (Slovenia)

^m DEPARTMENT OF CARDIOLOGY   (Singapore)

ⁿ KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^o NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^p ASSISTANCE PUBLIQUE HÔPITAUX DE PARIS   (France)

^q UNIVERSITY HOSPITAL BASEL   (Switzerland)

^r VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^s CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^t GUGLIELMO DA SALICETO HOSPITAL   (Italy)

^u UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^v UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^w CLINICAL CENTER OF SERBIA   (Serbia)

^x BRIGHAM AND WOMEN S HOSPITAL   (United States)

^y NORTHWESTERN UNIVERSITY   (United States)

^z UNIVERSITY HOSPITAL OF LARISSA   (Greece)

^aa UNIVERSITY HOSPITAL LEIPZIG   (Germany)

^ab BERLIN INSTITUTE OF HEALTH   (Germany)

more..

Author keywords

Biomarkers; Heart failure; Heart failure with preserved ejection fraction; Pulmonary hypertension; Right ventricular function

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; APELIN; BOSENTAN; CALCIUM CHANNEL BLOCKING AGENT; CARVEDILOL; CYCLIC GMP; DIGOXIN; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENDOTHELIN; ENKEPHALINASE INHIBITOR; ILOPROST; MACITENTAN; MILRINONE; NEBIVOLOL; NITRIC OXIDE; PDE9A; PHOSPHODIESTERASE V; PROSTACYCLIN; RANOLAZINE; RIOCIGUAT; SALBUTAMOL; SILDENAFIL; SPIRONOLACTONE; TREPROSTINIL; VERICIGUAT;

AEROBIC EXERCISE; ANTICOAGULANT THERAPY; ARTICLE; ATRIAL FIBRILLATION; CARDIOVASCULAR MAGNETIC RESONANCE; COMORBIDITY; CORONARY ARTERY DISEASE; ECHOCARDIOGRAPHY; EXERCISE TEST; HEART DISEASE; HEART FAILURE WITH PRESERVED EJECTION FRACTION; HEART VENTRICLE FUNCTION; HUMAN; PATHOGENESIS; PREVALENCE; PRIORITY JOURNAL; PROGNOSIS; PULMONARY HYPERTENSION; SIGNAL TRANSDUCTION; CARDIOLOGY; COMPLICATION; ETIOLOGY; EUROPE; HEART FAILURE; HEART RIGHT VENTRICLE FUNCTION; HEART STROKE VOLUME; MEDICAL SOCIETY; PATHOPHYSIOLOGY; PHYSIOLOGY; PRACTICE GUIDELINE;

CARDIOLOGY; EUROPE; HEART FAILURE; HUMANS; PRACTICE GUIDELINES AS TOPIC; SOCIETIES, MEDICAL; STROKE VOLUME; VENTRICULAR DYSFUNCTION, RIGHT;

EID: 85041471654     PISSN: 13889842     EISSN: 18790844     Source Type: Journal    
DOI: 10.1002/ejhf.1029     Document Type: Article

References (176)

1. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183–188.
2. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation 2008;117:1717–1731.
3. Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right heart dysfunction in heart failure with preserved ejection fraction. Eur Heart J 2014;35:3452–3462.
4. Mohammed SF, Hussain I, Abou Ezzeddine OF, Takahama H, Kwon SH, Forfia P, Roger VL, Redfield MM. Right ventricular function in heart failure with preserved ejection fraction: a community-based study. Circulation 2014;130:2310–2320.
5. Gorter TM, Hoendermis ES, van Veldhuisen DJ, Voors AA, Lam CS, Geelhoed B, Willems TP, van Melle JP. Right ventricular dysfunction in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Eur J Heart Fail 2016;18:1472–1487.
6. Puwanant S, Priester TC, Mookadam F, Bruce CJ, Redfield MM, Chandrasekaran K. Right ventricular function in patients with preserved and reduced ejection fraction heart failure. Eur J Echocardiogr 2009;10:733–737.
7. Morris DA, Gailani M, Vaz Perez A, Blaschke F, Dietz R, Haverkamp W, Ozcelik C. Right ventricular myocardial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction. J Am Soc Echocardiogr 2011;24:886–897.
8. Aschauer S, Kammerlander AA, Zotter-Tufaro C, Ristl R, Pfaffenberger S, Bachmann A, Duca F, Marzluf BA, Bonderman D, Mascherbauer J. The right heart in heart failure with preserved ejection fraction: insights from cardiac magnetic resonance imaging and invasive haemodynamics. Eur J Heart Fail 2016;18:71–80.
9. Ghio S, Guazzi M, Scardovi AB, Klersy C, Clemenza F, Carluccio E, Temporelli PL, Rossi A, Faggiano P, Traversi E, Vriz O, Dini FL; all investigators. Different correlates but similar prognostic implications for right ventricular dysfunction in heart failure patients with reduced or preserved ejection fraction. Eur J Heart Fail 2017;19:873–879.
10. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ; Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–1463.
11. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39.e14.
12. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–270.
13. Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ. Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology. Eur J Heart Fail 2009;11:130–139.
14. Opitz CF, Hoeper MM, Gibbs JS, Kaemmerer H, Pepke-Zaba J, Coghlan JG, Scelsi L, D'Alto M, Olsson KM, Ulrich S, Scholtz W, Schulz U, Grunig E, Vizza CD, Staehler G, Bruch L, Huscher D, Pittrow D, Rosenkranz S. Pre-capillary, combined, and post-capillary pulmonary hypertension: a pathophysiological continuum. J Am Coll Cardiol 2016;68:368–378.
15. Unger ED, Dubin RF, Deo R, Daruwalla V, Friedman JL, Medina C, Beussink L, Freed BH, Shah SJ. Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 2016;18:103–112.
16. Chan MM, Lam CS. How do patients with heart failure with preserved ejection fraction die? Eur J Heart Fail 2013;15:604–613.
17. Aschauer S, Zotter-Tufaro C, Duca F, Kammerlander A, Dalos D, Mascherbauer J, Bonderman D. Modes of death in patients with heart failure and preserved ejection fraction. Int J Cardiol 2017;228:422–426.
18. Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, Vallakati A, Shroff P, Rich S. Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail 2011;4:257–265.
19. Kind T, Mauritz GJ, Marcus JT, van de Veerdonk M, Westerhof N, Vonk-Noordegraaf A. Right ventricular ejection fraction is better reflected by transverse rather than longitudinal wall motion in pulmonary hypertension. J Cardiovasc Magn Reson 2010;12:35.
20. Pica S, Ghio S, Tonti G, Camporotondo R, Turco A, Pazzano AS, Scelsi L, Raineri C, Oltrona Visconti L. Analyses of longitudinal and of transverse right ventricular function provide different clinical information in patients with pulmonary hypertension. Ultrasound Med Biol 2014;40:1096–1103.
21. Ghio S, Temporelli PL, Klersy C, Simioniuc A, Girardi B, Scelsi L, Rossi A, Cicoira M, Tarro Genta F, Dini FL. Prognostic relevance of a non-invasive evaluation of right ventricular function and pulmonary artery pressure in patients with chronic heart failure. Eur J Heart Fail 2013;15:408–414.
22. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB; National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure. Circulation 2006;114:1883–1891.
23. Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, O'Meara E, Desai AS, Heitner JF, Li G, Fang J, Rouleau J, Zile MR, Markov V, Ryabov V, Reis G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD. Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial. Circ Heart Fail 2014;7:740–751.
24. Burke MA, Katz DH, Beussink L, Selvaraj S, Gupta DK, Fox J, Chakrabarti S, Sauer AJ, Rich JD, Freed BH, Shah SJ. Prognostic importance of pathophysiologic markers in patients with heart failure and preserved ejection fraction. Circ Heart Fail 2014;7:288–299.
25. Pellicori P, Kallvikbacka-Bennett A, Khaleva O, Carubelli V, Costanzo P, Castiello T, Wong K, Zhang J, Cleland JG, Clark AL. Global longitudinal strain in patients with suspected heart failure and a normal ejection fraction: does it improve diagnosis and risk stratification? Int J Cardiovasc Imaging 2014;30:69–79.
26. Freed BH, Daruwalla V, Cheng JY, Aguilar FG, Beussink L, Choi A, Klein DA, Dixon D, Baldridge A, Rasmussen-Torvik LJ, Maganti K, Shah SJ. Prognostic utility and clinical significance of cardiac mechanics in heart failure with preserved ejection fraction: importance of left atrial strain. Circ Cardiovasc Imaging 2016;9:e003754.
27. Andersen MJ, Hwang SJ, Kane GC, Melenovsky V, Olson TP, Fetterly K, Borlaug BA. Enhanced pulmonary vasodilator reserve and abnormal right ventricular: pulmonary artery coupling in heart failure with preserved ejection fraction. Circ Heart Fail 2015;8:542–550.
28. Donal E, Lund LH, Oger E, Hage C, Persson H, Reynaud A, Ennezat PV, Bauer F, Drouet E, Linde C, Daubert C; KaRen Investigators. New echocardiographic predictors of clinical outcome in patients presenting with heart failure and a preserved left ventricular ejection fraction: a subanalysis of the Ka (Karolinska) Ren (Rennes) Study. Eur J Heart Fail 2015;17:680–688.
29. Morris DA, Krisper M, Nakatani S, Kohncke C, Otsuji Y, Belyavskiy E, Radha Krishnan AK, Kropf M, Osmanoglou E, Boldt LH, Blaschke F, Edelmann F, Haverkamp W, Tschope C, Pieske-Kraigher E, Pieske B, Takeuchi M. Normal range and usefulness of right ventricular systolic strain to detect subtle right ventricular systolic abnormalities in patients with heart failure: a multicentre study. Eur Heart J Cardiovasc Imaging 2017;18:212–223.
30. Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right ventricular function in cardiovascular disease, part I: Anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation 2008;117:1436–1448.
31. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685–713.
32. Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular–pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J 2016;37:3293–3302.
33. McLaughlin VV, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol 2015;65:1976–1997.
34. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975.
35. Goliasch G, Zotter-Tufaro C, Aschauer S, Duca F, Koell B, Kammerlander AA, Ristl R, Lang IM, Maurer G, Mascherbauer J, Bonderman D. Outcome in heart failure with preserved ejection fraction: the role of myocardial structure and right ventricular performance. PLoS One 2015;10:e0134479.
36. Focardi M, Cameli M, Carbone SF, Massoni A, De Vito R, Lisi M, Mondillo S. Traditional and innovative echocardiographic parameters for the analysis of right ventricular performance in comparison with cardiac magnetic resonance. Eur Heart J Cardiovasc Imaging 2015;16:47–52.
37. Karakus G, Kammerlander AA, Aschauer S, Marzluf BA, Zotter-Tufaro C, Bachmann A, Degirmencioglu A, Duca F, Babayev J, Pfaffenberger S, Bonderman D, Mascherbauer J. Pulmonary artery to aorta ratio for the detection of pulmonary hypertension: cardiovascular magnetic resonance and invasive hemodynamics in heart failure with preserved ejection fraction. J Cardiovasc Magn Reson 2015;17:79.
38. Mascherbauer J, Marzluf BA, Tufaro C, Pfaffenberger S, Graf A, Wexberg P, Panzenbock A, Jakowitsch J, Bangert C, Laimer D, Schreiber C, Karakus G, Hulsmann M, Pacher R, Lang IM, Maurer G, Bonderman D. Cardiac magnetic resonance postcontrast T1 time is associated with outcome in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging 2013;6:1056–1065.
39. Freed BH, Gomberg-Maitland M, Chandra S, Mor-Avi V, Rich S, Archer SL, Jamison EB Jr, Lang RM, Patel AR. Late gadolinium enhancement cardiovascular magnetic resonance predicts clinical worsening in patients with pulmonary hypertension. J Cardiovasc Magn Reson 2012;14:11.
40. Chan RH, Maron BJ, Olivotto I, Assenza GE, Haas TS, Lesser JR, Gruner C, Crean AM, Rakowski H, Rowin E, Udelson J, Lombardi M, Tomberli B, Spirito P, Formisano F, Marra MP, Biagini E, Autore C, Manning WJ, Appelbaum E, Roberts WC, Basso C, Maron MS. Significance of late gadolinium enhancement at right ventricular attachment to ventricular septum in patients with hypertrophic cardiomyopathy. Am J Cardiol 2015;116:436–441.
41. Freed BH, Collins JD, Francois CJ, Barker AJ, Cuttica MJ, Chesler NC, Markl M, Shah SJ. MR and CT imaging for the evaluation of pulmonary hypertension. JACC Cardiovasc Imaging 2016;9:715–732.
42. Vonk Noordegraaf A, Westerhof BE, Westerhof N. The relationship between the right ventricle and its load in pulmonary hypertension. J Am Coll Cardiol 2017;69:236–243.
43. Kuehne T, Yilmaz S, Steendijk P, Moore P, Groenink M, Saaed M, Weber O, Higgins CB, Ewert P, Fleck E, Nagel E, Schulze-Neick I, Lange P. Magnetic resonance imaging analysis of right ventricular pressure–volume loops: in vivo validation and clinical application in patients with pulmonary hypertension. Circulation 2004;110:2010–2016.
44. Sanz J, Garcia-Alvarez A, Fernandez-Friera L, Nair A, Mirelis JG, Sawit ST, Pinney S, Fuster V. Right ventriculo–arterial coupling in pulmonary hypertension: a magnetic resonance study. Heart 2012;98:238–243.
45. Vanderpool RR, Pinsky MR, Naeije R, Deible C, Kosaraju V, Bunner C, Mathier MA, Lacomis J, Champion HC, Simon MA. RV–pulmonary arterial coupling predicts outcome in patients referred for pulmonary hypertension. Heart 2015;101:37–43.
46. Guazzi M, Bandera F, Pelissero G, Castelvecchio S, Menicanti L, Ghio S, Temporelli PL, Arena R. Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis. Am J Physiol Heart Circ Physiol 2013;305:H1373–H1381.
47. Gerges M, Gerges C, Pistritto AM, Lang MB, Trip P, Jakowitsch J, Binder T, Lang IM. Pulmonary hypertension in heart failure. Epidemiology, right ventricular function, and survival. Am J Respir Crit Care Med 2015;192:1234–1246.
48. Gorter TM, van Veldhuisen DJ, Voors AA, Hummel YM, Lam CS, Berger RM, van Melle JP, Hoendermis ES. Right ventricular–vascular coupling in heart failure with preserved ejection fraction and pre- vs. post-capillary pulmonary hypertension. Eur Heart J Cardiovasc Imaging 2017 May 22. https://doi.org/10.1093/ehjci/jex133 [Epub ahead of print].
49. Frea S, Pidello S, Bovolo V, Iacovino C, Franco E, Pinneri F, Galluzzo A, Volpe A, Visconti M, Peirone A, Morello M, Bergerone S, Gaita F. Prognostic incremental role of right ventricular function in acute decompensation of advanced chronic heart failure. Eur J Heart Fail 2016;18:564–572.
50. Kusunose K, Yamada H, Nishio S, Ishii A, Hirata Y, Seno H, Saijo Y, Ise T, Yamaguchi K, Yagi S, Soeki T, Wakatsuki T, Sata M. RV myocardial strain during pre-load augmentation is associated with exercise capacity in patients with chronic HF. JACC Cardiovasc Imaging 2017;10(10 Pt B):1240–1249.
51. Guazzi M, Villani S, Generati G, Ferraro OE, Pellegrino M, Alfonzetti E, Labate V, Gaeta M, Sugimoto T, Bandera F. Right ventricular contractile reserve and pulmonary circulation uncoupling during exercise challenge in heart failure: pathophysiology and clinical phenotypes. JACC Heart Fail 2016;4:625–635.
52. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Aboyans V, Vaz Carneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Paolo Badano L, Albert Barbera J, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol C, Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GY, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel MP, Rigau D, Rosenkranz S, Voller H, Luis Zamorano J. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67–119.
53. Bandera F, Generati G, Pellegrino M, Donghi V, Alfonzetti E, Gaeta M, Villani S, Guazzi M. Role of right ventricle and dynamic pulmonary hypertension on determining DeltaVO2/DeltaWork Rate flattening: insights from cardiopulmonary exercise test combined with exercise echocardiography. Circ Heart Fail 2014;7:782–790.
54. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010;3:588–595.
55. Sugimoto T, Bandera F, Generati G, Alfonzetti E, Bussadori C, Guazzi M. Left atrial function dynamics during exercise in heart failure: pathophysiological implications on the right heart and exercise ventilation inefficiency. JACC Cardiovasc Imaging 2017;10(10 Pt B):1253–1264.
56. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH, Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation 2012;125:289–297.
57. Malhotra R, Dhakal BP, Eisman AS, Pappagianopoulos PP, Dress A, Weiner RB, Baggish AL, Semigran MJ, Lewis GD. Pulmonary vascular distensibility predicts pulmonary hypertension severity, exercise capacity, and survival in heart failure. Circ Heart Fail 2016;9:e003011.
58. Obokata M, Reddy Y, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 2017;136:6–19.
59. Vachiery JL, Adir Y, Barbera JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galie N, Ghio S, Gibbs JS, Martinez F, Semigran M, Simonneau G, Wells A, Seeger W. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 2013;62(25 Suppl):D100–D108.
60. Hoeper MM, Barbera JA, Channick RN, Hassoun PM, Lang IM, Manes A, Martinez FJ, Naeije R, Olschewski H, Pepke-Zaba J, Redfield MM, Robbins IM, Souza R, Torbicki A, McGoon M. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl):S85–S96.
61. Rosenkranz S, Gibbs JS, Wachter R, De Marco T, Vonk-Noordegraaf A, Vachiery JL. Left ventricular heart failure and pulmonary hypertensiondagger. Eur Heart J 2016;37:942–954.
62. Hoeper MM, Lam CS, Vachiery JL, Bauersachs J, Gerges C, Lang IM, Bonderman D, Olsson KM, Gibbs JS, Dorfmuller P, Guazzi M, Galie N, Manes A, Handoko ML, Vonk-Noordegraaf A, Lankeit M, Konstantinides S, Wachter R, Opitz C, Rosenkranz S. Pulmonary hypertension in heart failure with preserved ejection fraction: a plea for proper phenotyping and further research. Eur Heart J 2017;38:2869–2873.
63. Dixon DD, Trivedi A, Shah SJ. Combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction. Heart Fail Rev 2016;21:285–297.
64. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009;53:1119–1126.
65. Shah AM, Shah SJ, Anand IS, Sweitzer NK, O'Meara E, Heitner JF, Sopko G, Li G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD; TOPCAT Investigators. Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. Circ Heart Fail 2014;7:104–115.
66. Obokata M, Borlaug BA. Right ventricular dysfunction and pulmonary hypertension in heart failure with preserved ejection fraction. Eur J Heart Fail 2016;18:1488–1490.
67. Kraigher-Krainer E, Shah AM, Gupta DK, Santos A, Claggett B, Pieske B, Zile MR, Voors AA, Lefkowitz MP, Packer M, McMurray JJ, Solomon SD; PARAMOUNT Investigators. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014;63:447–456.
68. Dauterman K, Pak PH, Maughan WL, Nussbacher A, Arie S, Liu CP, Kass DA. Contribution of external forces to left ventricular diastolic pressure. Implications for the clinical use of the Starling law. Ann Intern Med 1995;122:737–742.
69. Kasner M, Westermann D, Steendijk P, Drose S, Poller W, Schultheiss HP, Tschope C. Left ventricular dysfunction induced by nonsevere idiopathic pulmonary arterial hypertension: a pressure–volume relationship study. Am J Respir Crit Care Med 2012;186:181–189.
70. Kasner M, Westermann D, Schultheiss HP, Tschope C. Diastolic heart failure and LV dyssynchrony. Curr Pharm Biotechnol 2012;13:2539–2544.
71. Kotecha D, Lam CSP, van Veldhuisen DJ, van Gelder IC, Voors AA, Rienstra M. Heart failure with preserved ejection fraction and atrial fibrillation: vicious twins. J Am Coll Cardiol 2016;68:2217–2228.
72. Lam CS, Rienstra M, Tay WT, Liu LC, Hummel YM, van der Meer P, de Boer RA, Van Gelder IC, van Veldhuisen DJ, Voors AA, Hoendermis ES. Atrial fibrillation in heart failure with preserved ejection fraction: association with exercise capacity, left ventricular filling pressures, natriuretic peptides, and left atrial volume. JACC Heart Fail 2017;5:92–98.
73. Triposkiadis F, Harbas C, Kelepeshis G, Sitafidis G, Skoularigis J, Demopoulos V, Tsilimingas N. Left atrial remodeling in patients younger than 70 years with diastolic and systolic heart failure. J Am Soc Echocardiogr 2007;20:177–185.
74. Melenovsky V, Hwang SJ, Redfield MM, Zakeri R, Lin G, Borlaug BA. Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction. Circ Heart Fail 2015;8:295–303.
75. Shinbane JS, Wood MA, Jensen DN, Ellenbogen KA, Fitzpatrick AP, Scheinman MM. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol 1997;29:709–715.
76. Alam M, Samad BA, Hedman A, Frick M, Nordlander R. Cardioversion of atrial fibrillation and its effect on right ventricular function as assessed by tricuspid annular motion. Am J Cardiol 1999;84:1256–1258, A8.
77. Aziz EF, Kukin M, Javed F, Musat D, Nader A, Pratap B, Shah A, Enciso JS, Chaudhry FA, Herzog E. Right ventricular dysfunction is a strong predictor of developing atrial fibrillation in acutely decompensated heart failure patients, ACAP-HF data analysis. J Card Fail 2010;16:827–834.
78. Olsson KM, Nickel NP, Tongers J, Hoeper MM. Atrial flutter and fibrillation in patients with pulmonary hypertension. Int J Cardiol 2013;167:2300–2305.
79. Rottlaender D, Motloch LJ, Schmidt D, Reda S, Larbig R, Wolny M, Dumitrescu D, Rosenkranz S, Erdmann E, Hoppe UC. Clinical impact of atrial fibrillation in patients with pulmonary hypertension. PLoS One 2012;7:e33902.
80. Doesch C, Lossnitzer D, Rudic B, Tueluemen E, Budjan J, Haubenreisser H, Henzler T, Schoenberg SO, Borggrefe M, Papavassiliu T. Right ventricular and right atrial involvement can predict atrial fibrillation in patients with hypertrophic cardiomyopathy? Int J Med Sci 2016;13:1–7.
81. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disease in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014;63:2817–2827.
82. Gorter TM, Lexis CP, Hummel YM, Lipsic E, Nijveldt R, Willems TP, van der Horst IC, van der Harst P, van Melle JP, van Veldhuisen DJ. Right ventricular function after acute myocardial infarction treated with primary percutaneous coronary intervention (from the Glycometabolic Intervention as Adjunct to Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction III Trial). Am J Cardiol 2016;118:338–344.
83. Andersen HR, Falk E, Nielsen D. Right ventricular infarction: frequency, size and topography in coronary heart disease: a prospective study comprising 107 consecutive autopsies from a coronary care unit. J Am Coll Cardiol 1987;10:1223–1232.
84. Alam M, Hedman A, Nordlander R, Samad B. Right ventricular function before and after an uncomplicated coronary artery bypass graft as assessed by pulsed wave Doppler tissue imaging of the tricuspid annulus. Am Heart J 2003;146:520–526.
85. Schuuring MJ, Bolmers PP, Mulder BJ, de Bruin-Bon RA, Koolbergen DR, Hazekamp MG, Lagrand WK, De Hert SG, de Beaumont EM, Bouma BJ. Right ventricular function declines after cardiac surgery in adult patients with congenital heart disease. Int J Cardiovasc Imaging 2012;28:755–762.
86. Srivaratharajah K, Coutinho T, deKemp R, Liu P, Haddad H, Stadnick E, Davies RA, Chih S, Dwivedi G, Guo A, Wells GA, Bernick J, Beanlands R, Mielniczuk LM. Reduced myocardial flow in heart failure patients with preserved ejection fraction. Circ Heart Fail 2016;9:e002562.
87. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263–271.
88. Chahal H, McClelland RL, Tandri H, Jain A, Turkbey EB, Hundley WG, Barr RG, Kizer J, Lima JA, Bluemke DA, Kawut SM. Obesity and right ventricular structure and function: the MESA-Right Ventricle Study. Chest 2012;141:388–395.
89. Wong CY, O'Moore-Sullivan T, Leano R, Hukins C, Jenkins C, Marwick TH. Association of subclinical right ventricular dysfunction with obesity. J Am Coll Cardiol 2006;47:611–616.
90. Farrero M, Blanco I, Batlle M, Santiago E, Cardona M, Vidal B, Castel MA, Sitges M, Barbera JA, Perez-Villa F. Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction. Circ Heart Fail 2014;7:791–798.
91. Hilde JM, Skjorten I, Grotta OJ, Hansteen V, Melsom MN, Hisdal J, Humerfelt S, Steine K. Right ventricular dysfunction and remodeling in chronic obstructive pulmonary disease without pulmonary hypertension. J Am Coll Cardiol 2013;62:1103–1111.
92. Gottdiener JS, Gay JA, Maron BJ, Fletcher RD. Increased right ventricular wall thickness in left ventricular pressure overload: echocardiographic determination of hypertrophic response of the “nonstressed” ventricle. J Am Coll Cardiol 1985;6:550–555.
93. Pedrinelli R, Canale ML, Giannini C, Talini E, Dell'Omo G, Di Bello V. Abnormal right ventricular mechanics in early systemic hypertension: a two-dimensional strain imaging study. Eur J Echocardiogr 2010;11:738–742.
94. Cuspidi C, Valerio C, Sala C, Negri F, Esposito A, Masaidi M, Giudici V, Zanchetti A, Mancia G. Metabolic syndrome and biventricular hypertrophy in essential hypertension. J Hum Hypertens 2009;23:168–175.
95. Masaidi M, Cuspidi C, Negri F, Giudici V, Sala C, Zanchetti A, Mancia G. Left and right ventricular structural changes in obese hypertensives. Blood Press 2009;18:23–29.
96. Karamitsos TD, Karvounis HI, Dalamanga EG, Papadopoulos CE, Didangellos TP, Karamitsos DT, Parharidis GE, Louridas GE. Early diastolic impairment of diabetic heart: the significance of right ventricle. Int J Cardiol 2007;114:218–223.
97. Ter Maaten JM, Damman K, Verhaar MC, Paulus WJ, Duncker DJ, Cheng C, van Heerebeek L, Hillege HL, Lam CS, Navis G, Voors AA. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur J Heart Fail 2016;18:588–598.
98. Dini FL, Demmer RT, Simioniuc A, Morrone D, Donati F, Guarini G, Orsini E, Caravelli P, Marzilli M, Colombo PC. Right ventricular dysfunction is associated with chronic kidney disease and predicts survival in patients with chronic systolic heart failure. Eur J Heart Fail 2012;14:287–294.
99. Harjola VP, Mebazaa A, Celutkiene J, Bettex D, Bueno H, Chioncel O, Crespo-Leiro MG, Falk V, Filippatos G, Gibbs S, Leite-Moreira A, Lassus J, Masip J, Mueller C, Mullens W, Naeije R, Nordegraaf AV, Parissis J, Riley JP, Ristic A, Rosano G, Rudiger A, Ruschitzka F, Seferovic P, Sztrymf B, Vieillard-Baron A, Yilmaz MB, Konstantinides S. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016;18:226–241.
100. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 2015;36:2585–2594.
101. van der Feen DE, Bartelds B, de Boer RA, Berger RM. Pulmonary arterial hypertension in congenital heart disease: translational opportunities to study the reversibility of pulmonary vascular disease. Eur Heart J 2017;38:2034–2041.
102. Salzberg SP, Lachat ML, von Harbou K, Zund G, Turina MI. Normalization of high pulmonary vascular resistance with LVAD support in heart transplantation candidates. Eur J Cardiothorac Surg 2005;27:222–225.
103. Farha S, Lundgrin EL, Erzurum SC. Novel therapeutic approaches to preserve the right ventricle. Curr Heart Fail Rep 2013;10:12–17.
104. Ueno M, Miyauchi T, Sakai S, Kobayashi T, Goto K, Yamaguchi I. Effects of physiological or pathological pressure load in vivo on myocardial expression of ET-1 and receptors. Am J Physiol 1999;277(5 Pt 2):R1321–R1330.
105. Fan TH, Liang CS, Kawashima S, Banerjee SP. Alterations in cardiac beta-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs. Eur J Pharmacol 1987;140:123–132.
106. Hoeper MM, Meyer K, Rademacher J, Fuge J, Welte T, Olsson KM. Diffusion capacity and mortality in patients with pulmonary hypertension due to heart failure with preserved ejection fraction. JACC Heart Fail 2016;4:441–449.
107. Olson TP, Johnson BD, Borlaug BA. Impaired pulmonary diffusion in heart failure with preserved ejection fraction. JACC Heart Fail 2016;4:490–498.
108. Koller B, Steringer-Mascherbauer R, Ebner CH, Weber T, Ammer M, Eichinger J, Pretsch I, Herold M, Schwaiger J, Ulmer H, Grander W. Pilot Study of Endothelin Receptor Blockade in Heart Failure with Diastolic Dysfunction and Pulmonary Hypertension (BADDHY-Trial). Heart Lung Circ 2017;26:433–441.
109. Van Aelst LN, Celutkiene J, Mebazaa A. Advanced heart failure: look right to prognosticate right! Eur J Heart Fail 2016;18:573–575.
110. ter Maaten JM, Valente MA, Damman K, Hillege HL, Navis G, Voors AA. Diuretic response in acute heart failure—pathophysiology, evaluation, and therapy. Nat Rev Cardiol 2015;12:184–192.
111. Kitzman DW, Brubaker P, Morgan T, Haykowsky M, Hundley G, Kraus WE, Eggebeen J, Nicklas BJ. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2016;315:36–46.
112. Zhang M, Kass DA. Phosphodiesterases and cardiac cGMP: evolving roles and controversies. Trends Pharmacol Sci 2011;32:360–365.
113. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 2011;124:164–174.
114. Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E; RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013;309:1268–1277.
115. Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, van Veldhuisen DJ, Voors AA. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur Heart J 2015;36:2565–2573.
116. Liu LC, Hummel YM, van der Meer P, Berger RM, Damman K, van Veldhuisen DJ, Voors AA, Hoendermis ES. Effects of sildenafil on cardiac structure and function, cardiopulmonary exercise testing and health-related quality of life measures in heart failure patients with preserved ejection fraction and pulmonary hypertension. Eur J Heart Fail 2017;19:116–125.
117. Hussain I, Mohammed SF, Forfia PR, Lewis GD, Borlaug BA, Gallup DS, Redfield MM. Impaired right ventricular–pulmonary arterial coupling and effect of sildenafil in heart failure with preserved ejection fraction: an ancillary analysis from the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial. Circ Heart Fail 2016;9:e002729.
118. Matyas C, Nemeth BT, Olah A, Torok M, Ruppert M, Kellermayer D, Barta BA, Szabo G, Kokeny G, Horvath EM, Bodi B, Papp Z, Merkely B, Radovits T. Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase-5A inhibitor vardenafil in rats with type 2 diabetes. Eur J Heart Fail 2017;19:326–336.
119. Guazzi M, van Heerebeek L, Paulus WJ. Phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction: trading therapy for prevention. Eur J Heart Fail 2017;19:337–339.
120. Lee DI, Zhu G, Sasaki T, Cho GS, Hamdani N, Holewinski R, Jo SH, Danner T, Zhang M, Rainer PP, Bedja D, Kirk JA, Ranek MJ, Dostmann WR, Kwon C, Margulies KB, Van Eyk JE, Paulus WJ, Takimoto E, Kass DA. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 2015;519:472–476.
121. Bonderman D, Pretsch I, Steringer-Mascherbauer R, Jansa P, Rosenkranz S, Tufaro C, Bojic A, Lam CS, Frey R, Ochan Kilama M, Unger S, Roessig L, Lang IM. Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study. Chest 2014;146:1274–1285.
122. Pieske B, Maggioni AP, Lam CS, Pieske-Kraigher E, Filippatos G, Butler J, Ponikowski P, Shah SJ, Solomon SD, Scalise AV, Mueller K, Roessig L, Gheorghiade M. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J 2017;38:1119–1127.
123. Lim SL, Benson L, Dahlstrom U, Lam CS, Lund LH. Association between use of long-acting nitrates and outcomes in heart failure with preserved ejection fraction. Circ Heart Fail 2017;10:e003534.
124. Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, LeWinter MM, Joseph SM, Shah SJ, Semigran MJ, Felker GM, Cole RT, Reeves GR, Tedford RJ, Tang WH, McNulty SE, Velazquez EJ, Shah MR, Braunwald E; NHLBI Heart Failure Clinical Research Network. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 2015;373:2314–2324.
125. Borlaug BA, Koepp KE, Melenovsky V. Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J Am Coll Cardiol 2015;66:1672–1682.
126. Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res 2016;119:880–886.
127. Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, Gorcsan J,3rd, Parsley EL, Gladwin MT. Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight 2016;1:e89620.
128. Valero-Munoz M, Li S, Wilson RM, Boldbaatar B, Iglarz M, Sam F. Dual endothelin-A/endothelin-B receptor blockade and cardiac remodeling in heart failure with preserved ejection fraction. Circ Heart Fail 2016;9:e003381.
129. Lindman BR, Davila-Roman VG, Mann DL, McNulty S, Semigran MJ, Lewis GD, de las Fuentes L, Joseph SM, Vader J, Hernandez AF, Redfield MM. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol 2014;64:541–549.
130. Vachiery J, Delcroix M, Al-Hiti H, Efficace M, Hutyra M, Lack G, Papadakis K, Rubin L. MELODY-1: a pilot study of macitentan in pulmonary hypertension due to left ventricular dysfunction. J Am Coll Cardiol 2017;69(11 Suppl): 1880 [abstract].
131. Califf RM, Adams KF, McKenna WJ, Gheorghiade M, Uretsky BF, McNulty SE, Darius H, Schulman K, Zannad F, Handberg-Thurmond E, Harrell FE Jr, Wheeler W, Soler-Soler J, Swedberg K. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart J 1997;134:44–54.
132. Grossman NL, Fiack CA, Weinberg JM, Rybin DV, Farber HW. Pulmonary hypertension associated with heart failure with preserved ejection fraction: acute hemodynamic effects of inhaled iloprost. Pulm Circ 2015;5:198–203.
133. Van Veldhuisen DJ, Cohen-Solal A, Bohm M, Anker SD, Babalis D, Roughton M, Coats AJ, Poole-Wilson PA, Flather MD; SENIORS Investigators. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol 2009;53:2150–2158.
134. Lund LH, Benson L, Dahlstrom U, Edner M, Friberg L. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA 2014;312:2008–2018.
135. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J, Vardas PE, Bohm M, Dei Cas L. Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail 2012;14:219–225.
136. Ameri P, Bertero E, Meliota G, Cheli M, Canepa M, Brunelli C, Balbi M. Neurohormonal activation and pharmacological inhibition in pulmonary arterial hypertension and related right ventricular failure. Heart Fail Rev 2016;21:539–547.
137. Bergstrom A, Andersson B, Edner M, Nylander E, Persson H, Dahlstrom U. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail 2004;6:453–461.
138. Quaife RA, Christian PE, Gilbert EM, Datz FL, Volkman K, Bristow MR. Effects of carvedilol on right ventricular function in chronic heart failure. Am J Cardiol 1998;81:247–250.
139. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J; PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338–2345.
140. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777–781.
141. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A; I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456–2467.
142. Lund LH, Benson L, Dahlstrom U, Edner M. Association between use of renin–angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. JAMA 2012;308:2108–2117.
143. Borgdorff MA, Bartelds B, Dickinson MG, Steendijk P, Berger RM. A cornerstone of heart failure treatment is not effective in experimental right ventricular failure. Int J Cardiol 2013;169:183–189.
144. de Man FS, Tu L, Handoko ML, Rain S, Ruiter G, Francois C, Schalij I, Dorfmuller P, Simonneau G, Fadel E, Perros F, Boonstra A, Postmus PE, van der Velden J, Vonk-Noordegraaf A, Humbert M, Eddahibi S, Guignabert C. Dysregulated renin–angiotensin–aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186:780–789.
145. Massie B, Kramer BL, Topic N, Henderson SG. Hemodynamic and radionuclide effects of acute captopril therapy for heart failure: changes in left and right ventricular volumes and function at rest and during exercise. Circulation 1982;65:1374–1381.
146. Pechlivanidis G, Mantziari L, Giannakoulas G, Dimitroula H, Styliadis H, Karvounis H, Styliadis IH, Parharidis G. Effects of renin–angiotensin system inhibition on right ventricular function in patients with mild essential hypertension. J Renin Angiotensin Aldosterone Syst 2011;12:358–364.
147. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–1392.
148. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, Duvinage A, Stahrenberg R, Durstewitz K, Loffler M, Dungen HD, Tschope C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B; Aldo-DHF Investigators. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA 2013;309:781–791.
149. Maron BA, Zhang YY, White K, Chan SY, Handy DE, Mahoney CE, Loscalzo J, Leopold JA. Aldosterone inactivates the endothelin-B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension. Circulation 2012;126:963–974.
150. Shah AM, Claggett B, Sweitzer NK, Shah SJ, Deswal A, Anand IS, Fleg JL, Pitt B, Pfeffer MA, Solomon SD. Prognostic importance of changes in cardiac structure and function in heart failure with preserved ejection fraction and the impact of spironolactone. Circ Heart Fail 2015;8:1052–1058.
151. Khan SS, Cuttica MJ, Beussink-Nelson L, Kozyleva A, Sanchez C, Mkrdichian H, Selvaraj S, Dematte JE, Lee DC, Shah SJ. Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study. Pulm Circ 2015;5:547–556.
152. Finch KT, Stratton EA, Farber HW. Ranolazine for the treatment of pulmonary hypertension associated with heart failure with preserved ejection fraction: a pilot study. J Heart Lung Transplant 2016;35:1370–1373.
153. Haglund NA, Burdorf A, Jones T, Shostrom V, Um J, Ryan T, Shillcutt S, Fischer P, Cox ZL, Raichlin E, Anderson DR, Lowes BD, Dumitru I. Inhaled milrinone after left ventricular assist device implantation. J Card Fail 2015;21:792–797.
154. Hyldebrandt JA, Siven E, Agger P, Frederiksen CA, Heiberg J, Wemmelund KB, Ravn HB. Effects of milrinone and epinephrine or dopamine on biventricular function and hemodynamics in an animal model with right ventricular failure after pulmonary artery banding. Am J Physiol Heart Circ Physiol 2015;309:H206–H212.
155. James AT, Corcoran JD, McNamara PJ, Franklin O, El-Khuffash AF. The effect of milrinone on right and left ventricular function when used as a rescue therapy for term infants with pulmonary hypertension. Cardiol Young 2016;26:90–99.
156. Kaye DM, Nanayakkara S, Vizi D, Byrne M, Mariani JA. Effects of milrinone on rest and exercise hemodynamics in heart failure with preserved ejection fraction. J Am Coll Cardiol 2016;67:2554–2556.
157. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.
158. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ; Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380:1387–1395.
159. Setaro JF, Zaret BL, Schulman DS, Black HR, Soufer R. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981–986.
160. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, Love TE, Aronow WS, Adams KF Jr, Gheorghiade M. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary Digitalis Investigation Group trial. Circulation 2006;114:397–403.
161. Rich S, Seidlitz M, Dodin E, Osimani D, Judd D, Genthner D, McLaughlin V, Francis G. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest 1998;114:787–792.
162. Kleinz MJ, Skepper JN, Davenport AP. Immunocytochemical localisation of the apelin receptor, APJ, to human cardiomyocytes, vascular smooth muscle and endothelial cells. Regul Pept 2005;126:233–240.
163. Japp AG, Cruden NL, Barnes G, van Gemeren N, Mathews J, Adamson J, Johnston NR, Denvir MA, Megson IL, Flapan AD, Newby DE. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 2010;121:1818–1827.
164. Brash L, Barnes G, Brewis M, Church C, Gibbs S, Howard L, Johnson M, McGlinchey N, Simpson J, Stirrat C, Thomson S, Watson G, Welsh D, Wilkins M, Newby D, Peacock A. Apelin improves cardiac output in patients with pulmonary arterial hypertension. Eur Respir J 2015;46(Suppl 59):PA2107 [abstract].
165. Barnes GD, Alam S, Carter G, Pedersen CM, Lee KM, Hubbard TJ, Veitch S, Jeong H, White A, Cruden NL, Huson L, Japp AG, Newby DE. Sustained cardiovascular actions of APJ agonism during renin–angiotensin system activation and in patients with heart failure. Circ Heart Fail 2013;6:482–491.
166. Hasenfuss G, Hayward C, Burkhoff D, Silvestry FE, McKenzie S, Gustafsson F, Malek F, Van der Heyden J, Lang I, Petrie MC, Cleland JG, Leon M, Kaye DM; REDUCE LAP-HF Study Investigators. A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet 2016;387:1298–1304.
167. Feldman T, Komtebedde J, Burkhoff D, Massaro J, Maurer MS, Leon MB, Kaye D, Silvestry FE, Cleland JG, Kitzman D, Kubo SH, Van Veldhuisen DJ, Kleber F, Trochu JN, Auricchio A, Gustafsson F, Hasenfubeta G, Ponikowski P, Filippatos G, Mauri L, Shah SJ. Transcatheter interatrial shunt device for the treatment of heart failure: rationale and design of the randomized trial to REDUCE Elevated Left Atrial Pressure in Heart Failure (REDUCE LAP-HF I). Circ Heart Fail 2016;9:e003025.
168. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, Strickland W, Neelagaru S, Raval N, Krueger S, Weiner S, Shavelle D, Jeffries B, Yadav JS; CHAMPION Trial Study Group. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–666.
169. Heywood JT, Jermyn R, Shavelle D, Abraham WT, Bhimaraj A, Bhatt K, Sheikh F, Eichorn E, Lamba S, Bharmi R, Agarwal R, Kumar C, Stevenson LW. Impact of practice based management of PA pressures in 2000 patients implanted with the CardioMEMS Sensor. Circulation 2017;135:1509–1517.
170. Gorter TM, Rienstra M, van Veldhuisen DJ. Measuring pulmonary artery pressures in heart failure: A new useful diagnostic tool? Circulation 2017;135:1518–1521.
171. Desai AS, Bhimaraj A, Bharmi R, Jermyn R, Bhatt K, Shavelle D, Redfield MM, Hull R, Pelzel JA, Davis K, Dalal N, Adamson PB, Heywood JT. Ambulatory hemodynamic monitoring reduces heart failure hospitalizations in ‘real-world’ clinical practice. J Am Coll Cardiol 2017;69:2357–2365.
172. Adamson PB, Abraham WT, Bourge RC, Costanzo MR, Hasan A, Yadav C, Henderson J, Cowart P, Stevenson LW. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ Heart Fail 2014;7:935–944.
173. Ghio S, Serio A, Mangiavacchi M, Kjellstrom B, Valsecchi S, Vicini I, Campana C, Gasparini M, Gronda E, Tavazzi L. Hemodynamic changes before acute heart failure episodes in patients with advanced systolic left ventricular dysfunction. J Cardiovasc Med (Hagerstown) 2008;9:799–804.
174. Chen SL, Zhang FF, Xu J, Xie DJ, Zhou L, Nguyen T, Stone GW. Pulmonary artery denervation to treat pulmonary arterial hypertension: the single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension). J Am Coll Cardiol 2013;62:1092–1100.
175. Hoeper MM, Galiè N. Letter by Hoeper and Galiè Regarding Article, “Hemodynamic, functional, and clinical responses to pulmonary artery denervation in patients with pulmonary arterial hypertension of different causes: phase II results from the Pulmonary Artery Denervation-1 Study”. Circ Cardiovasc Interv 2016;9:e003422.
176. Zhang H, Zhang J, Xie DJ, Jiang X, Zhang FF, Chen SL. Pulmonary artery denervation for treatment of a patient with pulmonary hypertension secondary to left heart disease. Pulm Circ 2016;6:240–243.