Heart Failure Reviews

, Volume 24, Issue 4, pp 421–437 | Cite as

Cardiorenal syndrome in heart failure with preserved ejection fraction—an under-recognized clinical entity

  • Akanksha AgrawalEmail author
  • Mario Naranjo
  • Napatt Kanjanahattakij
  • Janani Rangaswami
  • Shuchita Gupta


Cardiorenal syndrome (CRS) results from the complex and bidirectional interaction between the failing heart and the kidneys. Limited information exists about the pathophysiology and treatment options for worsening kidney function in the setting of heart failure with preserved ejection fraction (HFpEF). This review summarizes the salient pathophysiological pathways in CRS in patients with HFpEF, with emphasis on type 1 and type 2 phenotypes, and outlines diagnostic and therapeutic strategies that are applicable in this population. Elevated central venous and intra-abdominal pressure, left ventricular hypertrophy, LV strain, RAAS activation, oxidative injury, pulmonary hypertension, and RV dysfunction play key roles in the pathogenesis of CRS in the backdrop of HFpEF. The availability of biomarkers of renal and cardiac injury offer a new dimension in accurately diagnosing and quantifying end organ damage in CRS and will improve the accuracy of goal-directed therapies in this population. Novel targeted therapies such as the development of angiotensin/neprilysin inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer new territory in realizing potential benefits in reduction of cardio-renal adverse outcomes in this population. Future studies focusing exclusively on renal outcomes in patients with HFpEF are crucial in delivering optimal therapies in this subset of patients.


Heart failure with preserved ejection fraction Cardiorenal syndrome Worsening renal function Kidney 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ronco C, MCullough P, Anker SD et al (2010) Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 31(6):703–711Google Scholar
  2. 2.
    McCullough PA (2003) Why is chronic kidney disease the “spoiler” for cardiovascular outcomes? J Am Coll Cardiol 41(5):725–728Google Scholar
  3. 3.
    NHLBI Working Group. Cardio-renal connections in heart failure and cardiovascular disease. National Heart, Lung, and Blood Institute Web site. Accessed 20 October 2017
  4. 4.
    Roger VL (2013) Epidemiology of heart failure. Circ Res 113(6):646–659Google Scholar
  5. 5.
    Dunlay SM, Roger VL, Redfield MM (2017) Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 14:591–602Google Scholar
  6. 6.
    Bock JS, Gottlieb SS (2010) Cardiorenal syndrome: new perspectives. Circulation 121:2592–2600Google Scholar
  7. 7.
    Forman DE, Butler J, Wang Y, Abraham WT, O’Connor CM, Gottlieb SS, Loh E, Massie BM, Rich MW, Stevenson LW, Young JB, Krumholz HM (2004) Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 43:61–67Google Scholar
  8. 8.
    Khwaja A (2012) KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 120(4):c179–c184Google Scholar
  9. 9.
    Testani JM, McCauley BD, Chen J, Shumski M, Shannon RP (2010a) Worsening renal function defined as an absolute increase in serum creatinine is a biased metric for the study of cardio-renal interactions. Cardiology 116:206–212Google Scholar
  10. 10.
    Adams KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP (2005) Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 149(2):209–216Google Scholar
  11. 11.
    Damman K, Tang WH, Testani JM, McMurray JJ (2014a) Terminology and definition of changes renal function in heart failure. Eur Heart J 35(48):3413–3416Google Scholar
  12. 12.
    Fischer M, Baessler A, Hense HW, Hengstenberg C, Muscholl M, Holmer S, Döring A, Broeckel U, Riegger G, Schunkert H (2003) Prevalence of left ventricular diastolic dysfunction in the community: results from a Doppler echocardiographic-based survey of a population sample. Eur Heart J 24(4):320–328Google Scholar
  13. 13.
    Kawaguchi M, Hay I, Fetics B, Kass DA (2003) Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation 107(5):714–720Google Scholar
  14. 14.
    Messerli FH, Rimoldi SF, Bangalore S (2017) The transition from hypertension to heart failure: contemporary update. JACC Heart Fail. 5(8):543–551Google Scholar
  15. 15.
    Winton FR (1931) The influence of venous pressure on the isolated mammalian kidney. J Physiol 72:49–61Google Scholar
  16. 16.
    Doty JM, Saggi BH, Sugerman HJ, Blocher CR, Pin R, Fakhry I, Gehr TWB, Sica DA (1999) Effect of increased renal venous pressure on renal function. J Trauma 47(6):1000–1003Google Scholar
  17. 17.
    Damman K, Testani JM (2015) The kidney in heart failure: an update. Eur Heart J 36(23):1437–1444Google Scholar
  18. 18.
    Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, Young JB, Tang WH (2009) Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 53(7):589–596Google Scholar
  19. 19.
    Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL (2009) Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 53(7):582–588Google Scholar
  20. 20.
    Binanay C, Califf RM, Hasselblad V, O’Connor CM, Shah MR, Sopko G, Stevenson LW, Francis GS, Leier CV, Miller LW, ESCAPE Investigators and ESCAPE Study Coordinators (2005) Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 294(13):1625–1633Google Scholar
  21. 21.
    Iida N, Seo Y, Sai S, Machino-Ohtsuka T, Yamamoto M, Ishizu T, Kawakami Y, Aonuma K (2016) Clinical implications of intrarenal hemodynamic evaluation by Doppler ultrasonography in heart failure. JACC Heart Failure 4(8):674–682Google Scholar
  22. 22.
    Nijst P, Martens P, Dupont M, Tang WHW, Mullens W (2017) Intrarenal flow alterations during transition from euvolemia to intravascular volume expansion in heart failure patients. JACC Heart Fail. 5(9):672–681Google Scholar
  23. 23.
    Verbrugge FH, Dupont M, Steels P, Grieten L, Malbrain M, Tang WHW, Mullens W (2013) Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol 62(6):485–495Google Scholar
  24. 24.
    Mullens W, Abrahams Z, Skouri HN, Francis GS, Taylor DO, Starling RC, Paganini E, Tang WHW (2008a) Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 51(3):300–306Google Scholar
  25. 25.
    Mullens W, Abrahams Z, Francis GS, Taylor DO, Starling RC, Tang WHW (2008b) Prompt reduction in intra-abdominal pressure following large-volume mechanical fluid removal improves renal insufficiency in refractory decompensated heart failure. J Card Fail 14(6):508–514Google Scholar
  26. 26.
    Lam CSP, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM (2009) Pulmonary hypertension in heart failure with preserved ejection fraction: a community- based study. J Am Coll Cardiol 53(13):1119–1126Google Scholar
  27. 27.
    Thenappan T, Shah SJ, Gomberg-Maitland M, Collander B, Vallakati A, Shroff P, Rich S (2011) Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail 4(3):257–265Google Scholar
  28. 28.
    Ghio S, Campana C, Inserra C et al (2001) Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 37:183–188Google Scholar
  29. 29.
    Mielniczuk LM, Chandy G, Stewart D, Dominguez VC, Haddad H, Pugliese C, Davies RA (2012) Worsening renal function and prognosis in pulmonary hypertension patients hospitalized for right heart failure. Congestive Heart Failure 18(3):151–157Google Scholar
  30. 30.
    Mukherjee M, Sharma K, Madrazo JA, Tedford RJ, Russell SD, Hays AG (2017) Right-sided cardiac dysfunction in heart failure with preserved ejection fraction and worsening renal function. Am J Cardiol 120(2):274–278Google Scholar
  31. 31.
    Nickel NP, O’Leary JM, Brittain EL (2017) Kidney dysfunction in patients with pulmonary arterial hypertension. Pulmonary Circulation 7(1):38–54Google Scholar
  32. 32.
    Paulus WJ, Tschöpe C (2013) 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 62(4):263–271Google Scholar
  33. 33.
    Damkjær M, Vafaee M, Møller ML, Braad PE, Petersen H, Høilund-Carlsen PF, Bie P (2010) Renal cortical and medullary blood flow responses to altered NO availability in humans. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 299(6):R1449–R1455Google Scholar
  34. 34.
    Satoh N, Nakamura M, Suzuki A, Tsukada H et al (2017) Effects of nitric oxide on renal proximal tubular Na+ transport. Biomed Res Int 2017:6871081Google Scholar
  35. 35.
    Shah SJ, Lam CSP, Svedlund S, Saraste A, Hage C, Tan RS, Beussink-Nelson L, Ljung Faxén U, Fermer ML, Broberg MA, Gan LM, Lund LH (2018) Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. Eur Heart J 39:3439–3450Google Scholar
  36. 36.
    Paolillo S, Filardi PP (2015) Cardio-renal protection through renin-angiotensin-aldosterone system inhibition: current knowledge and new perspectives. European Heart Journal-Cardiovascular Pharmacotherapy 1:132–133Google Scholar
  37. 37.
    The Heart Outcomes Prevention Evaluation Study Investigators (2000) Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342:145–153Google Scholar
  38. 38.
    Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362(9386):782–788Google Scholar
  39. 39.
    The PEACE Trial Investigators (2004) Angiotensin-converting–enzyme inhibition in stable coronary artery disease. N Engl J Med 351:2058–2068Google Scholar
  40. 40.
    Tojo A, Onozato ML, Kobayashi N, Goto A, Matsuoka H, Fujita T (2002) Angiotensin II and oxidative stress in Dahl salt-sensitive rat with heart failure. Hypertension 40:834–839Google Scholar
  41. 41.
    Ravera M, Noberasco G, Signori A, Re M, Filippi A, Cannavo R, Weiss U, Cricelli C, Deferrari G, Paoletti E (2013) Left-ventricular hypertrophy and renal outcome in hypertensive patients in primary-care. Am J Hypertens 26(5):700–707Google Scholar
  42. 42.
    Zelnick LR, Katz R, Young BA, Correa A, Kestenbaum BR, de Boer IH, Bansal N (2017) Echocardiographic measures and estimated GFR decline among African Americans: the Jackson Heart Study. Am J Kidney Dis 70(2):199–206Google Scholar
  43. 43.
    Cameli M, Mondillo S, Righini FM, Lisi M, Dokollari A, Lindqvist P, Maccherini M, Henein M (2016) Left ventricular deformation and myocardial fibrosis in patients with advanced heart failure requiring transplantation. J Card Fail 22:901–907Google Scholar
  44. 44.
    Kraigher-Krainer E, Shah AM, Gupta DK, Santos A, Claggett B, Pieske B, Zile MR, Voors AA, Lefkowitz MP, Packer M, McMurray JJV, Solomon SD (2014) Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol 63(5):447–456Google Scholar
  45. 45.
    Natali A, Nesti L, Fabiani I, Calogero E, Di Bello V (2017) Impact of empagliflozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: rationale and design of the EMPA-HEART trial. Cardiovasc Diabetol 16(1):130Google Scholar
  46. 46.
    González-López E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ et al (2015) Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 36(38):2585–2594Google Scholar
  47. 47.
    Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, Kass DA (2006) Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 114(20):2138–2147Google Scholar
  48. 48.
    Klein DA, Katz DH, Beussink-Nelson L, Sanchez CL, Strzelczyk TA, Shah SJ (2015) Association of chronic kidney disease with chronotropic incompetence in heart failure with preserved ejection fraction. Am J Cardiol 116(7):1093–1100Google Scholar
  49. 49.
    DiBona GF, Kopp UC (1997) Neural control of renal function. Physiol Rev 77:75–197Google Scholar
  50. 50.
    Drechsler C, Delgado G, Wanner C, Blouin K, Pilz S, Tomaschitz A, Kleber ME, Dressel A, Willmes C, Krane V, Kramer BK, Marz W, Ritz E, van Gilst WH, van der Harst P, de Boer RA (2015) Galectin-3, renal function, and clinical outcomes: results from the LURIC and 4D studies. J Am Soc Nephrol 26(9):2213–2221Google Scholar
  51. 51.
    Wagener G, Minhaz M, Mattis FA, Kim M, Emond JC, Lee HT (2011) Urinary neutrophil gelatinase-associated lipocalin as a marker of acute kidney injury after orthotopic liver transplantation. Nephrol Dial Transplant 26(5):1717–1723Google Scholar
  52. 52.
    Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A (2009) Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation 54(6):1012–1024Google Scholar
  53. 53.
    Ahmad T, Jackson K, Rao VS, Tang WHW, Brisco-Bacik MA, Chen HH, Felker GM, Hernandez AF, O’Connor CM, Sabbisetti VS, Bonventre JV, Wilson FP, Coca SG, Testani JM (2018) Worsening renal function in acute heart failure patients undergoing aggressive diuresis is not associated with tubular injury. Circulation 137:2016–2028. Google Scholar
  54. 54.
    Miller WL, Mullan BP (2016) Volume overload profiles in patients with preserved and reduced ejection fraction chronic heart failure: are there differences? A pilot study. JACC: Heart Failure 4(6):453–459Google Scholar
  55. 55.
    Takei M, Kohsaka S, Shiraishi Y, Goda A, Izumi Y, Yagawa M, Mizuno A, Sawano M, Inohara T, Kohno T, Fukuda K, Yoshikawa T (2015) Effect of estimated plasma volume reduction on renal function for acute heart failure differs between patients with preserved and reduced ejection fraction. Circ Heart Fail. 8(3):527–532Google Scholar
  56. 56.
    Sharma K, Vaishnav J, Kalathiya R, Hu JR, Miller J, Shah N, Hill T, Sharp M, Tsao A, Alexander KM, Gupta R, Montemayor K, Kovell L, Chasler JE, Lee YJ, Fine DM, Kass DA, Weiss RG, Thiemann DR, Ndumele CE, Schulman SP, Russell SD (2018) Randomized evaluation of heart failure with preserved ejection fraction patients with acute heart failure and dopamine: the ROPA-DOP Trial. JACC Heart Fail 6(10):859–870Google Scholar
  57. 57.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 62(16):e147–e239Google Scholar
  58. 58.
    Brisco-Bacik MA, ter Maaten JM, Houser SR, Vedage NA et al (2018) Outcomes associated with a strategy of adjuvant metolazone or high-dose loop diuretics in acute decompensated heart failure: a propensity analysis. J Am Heart Assoc 7:e009149Google Scholar
  59. 59.
    Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP (2010b) Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 122(3):265–272Google Scholar
  60. 60.
    Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM (2011) Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 364(9):797–805Google Scholar
  61. 61.
    Bart BA, Boyle A, Bank AJ, Anand I, Olivari MT, Kraemer M, Mackedanz S, Sobotka PA, Schollmeyer M, Goldsmith SR (2005) Ultrafiltration versus usual care for hospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients with Decompensated Congestive Heart Failure (RAPID-CHF) trial. J Am Coll Cardiol 46(11):2043–2046Google Scholar
  62. 62.
    Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerlink JR, Jaski BE, Fang JC, Feller ED, Haas GJ, Anderson AS, Schollmeyer MP, Sobotka PA (2007) Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 49(6):675–683Google Scholar
  63. 63.
    Bart BA, Goldsmith SR, Lee KL, Givertz MM, O'Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E (2012) Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 367:2296–2304Google Scholar
  64. 64.
    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 (2008) Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359:2456–2467Google Scholar
  65. 65.
    Damman K, Perez AC, Anand IS, Komajda M, McKelvie RS, Zile MR, Massie B, Carson PE, McMurray JJV (2014b) Worsening renal function and outcome in heart failure patients with preserved ejection fraction and the impact of angiotensin receptor blocker treatment. J Am Coll Cardiol 64(11):1106–1113Google Scholar
  66. 66.
    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 (2014) Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370:1383–1392Google Scholar
  67. 67.
    Beldhuis IE, Streng KW, Maaten JMT et al (2017) Renin-angiotensin system inhibition, worsening renal function, and outcome in heart failure patients with reduced and preserved ejection fraction. Circ Heart Fail 10:e003588Google Scholar
  68. 68.
    Schwartzenberg S, Redfield MM, From AM, Sorajja P, Nishimura RA, Borlaug BA. Effects of vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct pathophysiologies on response to therapy. J Am Coll Cardiol 2012; 59:442–451, Effects of Vasodilation in Heart Failure With Preserved or Reduced Ejection FractionGoogle Scholar
  69. 69.
    Philbin EF, Rocco TA Jr, Lindenmuth NW, Ulrich K, Jenkins PL (2000) Systolic versus diastolic heart failure in community practice: clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors. Am J Med 109(8):605–613Google Scholar
  70. 70.
    Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ et al (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet (London, England) 362(9386):777–781Google Scholar
  71. 71.
    Tribouilloy C, Rusinaru D, Leborgne L, Peltier M, Massy Z, Slama M (2008) Prognostic impact of angiotensin-converting enzyme inhibitor therapy in diastolic heart failure. Am J Cardiol 101(5):639–644Google Scholar
  72. 72.
    Lund LH, Benson L, Dahlstrom U, Edner M (2012) Association between use of renin-angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. JAMA 308(20):2108–2117Google Scholar
  73. 73.
    Patel K, Fonarow GC, Kitzman DW, Aban IB, Love TE, Allman RM, Gheorghiade M, Ahmed A (2012) Angiotensin receptor blockers and outcomes in real-world older patients with heart failure and preserved ejection fraction: a propensity-matched inception cohort clinical effectiveness study. Eur J Heart Fail 14(10):1179–1188Google Scholar
  74. 74.
    Damman K, Solomon SD, Pfeffer MA, Swedberg K, Yusuf S, Young JB, Rouleau JL, Granger CB, McMurray JJV (2016) Worsening renal function and outcome in heart failure patients with reduced and preserved ejection fraction and the impact of angiotensin receptor blocker treatment: data from the CHARM-study programme. Eur J Heart Fail 18(12):1508–1517Google Scholar
  75. 75.
    Voors AA, Gori M, Liu LC, Claggett B et al (2015) Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 17(5):510–517Google Scholar
  76. 76.
    McMurray JJV, 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 (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993–1004Google Scholar
  77. 77.
    Solomon SD, Rizkala AR, Gong J, Wang W, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Shi VC, Lefkowitz MP, McMurray JJV (2017) Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF Trial. JACC Heart Fail. 5(7):471–482Google Scholar
  78. 78.
    Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI (2017) Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Send to Circulation 136(17):1643–1658Google Scholar
  79. 79.
    Abdul-Ghani M, Prato SD, Chilton R, RA DF (2016) SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME Study. Diabetes Care 39(5):717–725Google Scholar
  80. 80.
    Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377(7):644–657Google Scholar
  81. 81.
    Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, Woerle HJ, Broedl UC, von Eynatten M, Zinman B (2018) Empagiflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation 137(2):119–129Google Scholar
  82. 82.
    Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB (2016a) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322Google Scholar
  83. 83.
    Verma S, Leiter LA, Meizer CD, et al (2018) Liraglutide reduces cardiovascular events and mortality in type 2 diabetes mellitus independently of baseline low-density lipoprotein cholesterol levels and statin use: results from the LEADER trial. Circulation 138(15):1605–1607Google Scholar
  84. 84.
    Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T (2016b) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375:1834–1844Google Scholar
  85. 85.
    Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, Chan JC, Choi J, Gustavson SM, Iqbal N, Maggioni AP, Marso SP, Öhman P, Pagidipati NJ, Poulter N, Ramachandran A, Zinman B, Hernandez AF (2017) Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 377:1228–1239Google Scholar
  86. 86.
    Esposito G, Cappetta D, Russo R, Rivellino A, Ciuffreda LP, Roviezzo F, Piegari E, Berrino L, Rossi F, De Angelis A, Urbanek K (2017) Sitagliptan reduces inflammation, fibrosis and preserves diastolic function in a rat model of heart failure with preserved ejection fraction. Br J Pharmacol 174(22):4070–4086Google Scholar
  87. 87.
    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 (2011) Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 377(9766):658–666Google Scholar
  88. 88.
    Ghosh RK, Banerjee K, Tummala R, Ball S, Ravakhah K, Gupta A (2017) Serelaxin in acute heart failure: most recent update on clinical and preclinical evidence. Cardiovasc Ther 35(1):55–63Google Scholar
  89. 89.
    Filippatos G, Teerlink JR, Farmakis D, Cotter G, Davison BA, Felker GM, Greenberg BH, Hua T, Ponikowski P, Severin T, Unemori E, Voors AA, Metra M (2014) Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial. Eur Heart J 35(16):1041–1050Google Scholar
  90. 90.
    Reddy YNV, Lewis GD, Shah SJ, LeWinter M, Semigran M, Davila-Roman VG, Anstrom K, Hernandez A, Braunwald E, Redfield MM, Borlaug BA (2017) INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction): rationale and design. Circ Heart Fail 10:e003862Google Scholar
  91. 91.
    Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC, Chirinos JA (2015) Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation 131(4):371–380Google Scholar
  92. 92.
    Borlaug BA 2018 INDIE-HFpEF: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF. A randomized clinical trial. Paper Presented to The American College of Cardiology (ACC) Annual Scientific Session Orlando, 2018Google Scholar
  93. 93.
    Breitenstein S, Roessig L, Sander P, Lewis KS (2017) Novel sGC stimulators and sGC activators for the treatment of heart failure. Handb Exp Pharmacol 243:225–247Google Scholar
  94. 94.
    Pieske B, Maggioni AP, Lam CSP, Pieske-Kraigher E, Filippatos G, Butler J, Ponikowski P, Shah SJ, Solomon SD, Scalise AV, Mueller K, Roessig L, Gheorghiade M (2017) 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 38(15):1119–1127Google Scholar
  95. 95.
    Mascherbauer J, Grünig E, Halank M, Hohenforst-Schmidt W, Kammerlander AA, Pretsch I, Steringer-Mascherbauer R, Ulrich S, Lang IM, Wargenau M, Frey R, Bonderman D (2016) Evaluation of the pharmacodynamic effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction: study protocol for a randomized controlled trial. Wien Klin Wochenschr 128(23–24):882–889Google Scholar
  96. 96.
    Feldman T, Mauri L, Kahwash R, Litwin S, Ricciardi MJ, van der Harst P, Penicka M, Fail PS, Kaye DM, Petrie MC, Basuray A, Hummel SL, Forde-McLean R, Nielsen CD, Lilly S, Massaro JM, Burkhoff D, Shah SJ (2018) Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure with Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With heart Failure]). A phase 2, randomized, sham-controlled trial. Circulation 137:364–375Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Internal MedicineAlbert Einstein Medical CenterPhiladelphiaUSA
  2. 2.Department of NephrologyAlbert Einstein Medical CenterPhiladelphiaUSA
  3. 3.Department of CardiologyAlbert Einstein Medical CenterPhiladelphiaUSA

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