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The role of arterial hypertension in development heart failure with preserved ejection fraction: just a risk factor or something more?

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Abstract

Heart failure with preserved ejection fraction (HFpEF) is an entity that still raises many questions. The agreement about definition, pathophysiology, and therapeutic approach is still missing. Arterial hypertension is present in majority of patients with HFpEF, and it is still not clear if it represent a risk factor or “sine qua non” condition for HFpEF development. The underlying mechanisms of hypertension and HFpEF involve the same biohumoral systems: renin-angiotensin-aldosterone, sympathetic nervous system, and oxidative stress. However, not all hypertensive patients have HFpEF. The predisposition of some hypertensive patients to develop HFpEF needs to be resolved. Large randomized controlled trials did not prove the usefulness of renin–angiotensin–aldosterone inhibitors, diuretics, calcium channel blockers, and beta-blockers in HFpEF patients. The majority of studies did not succeed to demonstrate the reduction of cardiovascular and all-cause mortality in HFpEF individuals. One of the major limitations in these investigations was the inconsistency of HFpEF definition, which mainly refers to left ventricular ejection fraction (LVEF) cut-off that ranged from 40 to 50% in different studies. This review article provides the available data about pathophysiology and mechanisms that connect hypertension and HFpEF, investigations and therapy used in both conditions.

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References

  1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-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) Authors/Task Force Members. 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 Heart J 37(27):2129–2200

    Article  PubMed  Google Scholar 

  2. Dunlay SM, Roger VL, Redfield MM (2017) Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 14:591–602

    Article  PubMed  Google Scholar 

  3. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, Nodari S, Lam CSP, Sato N, Shah AN, Gheorghiade M (2014) The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 63(12):1123–1133

    Article  PubMed  Google Scholar 

  4. Lam CSP, Gamble GD, Ling LH, Sim D, Leong KTG, Yeo PSD, Ong HY, Jaufeerally F, Ng TP, Cameron VA, Poppe K, Lund M, Devlin G, Troughton R, Richards AM, Doughty RN. Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study. Eur Heart J. 2018 Jan 29. doi: https://doi.org/10.1093/eurheartj/ehy005.

  5. McMurray JJ, Carson PE, Komajda M, McKelvie R, Zile MR, Ptaszynska A, Staiger C, Donovan JM, Massie BM (2008) Heart failure with preserved ejection fraction: clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial. Eur J Heart Fail 10(2):149–156

    Article  PubMed  Google Scholar 

  6. Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM (2006) NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 8(5–6):691–728

    Article  PubMed  CAS  Google Scholar 

  7. Negi SI, Jeong EM, Shukrullah I, Veleder E, Jones DP, Fan TH, Varadarajan S, Danilov SM, Fukai T, Dudley SC Jr (2015) Renin-angiotensin activation and oxidative stress in early heart failure with preserved ejection fraction. Biomed Res Int 2015:825027

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Khan MS, Fonarow GC, Khan H, Greene SJ, Anker SD, Gheorghiade M, Butler J (2017) Renin-angiotensin blockade in heart failure with preserved ejection fraction: a systematic review and meta-analysis. ESC Heart Fail. 4(4):402–408

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fukuta H, Goto T, Wakami K, Ohte N (2017) Effect of renin-angiotensin system inhibitors on mortality in heart failure with preserved ejection fraction: a meta-analysis of observational cohort and randomized controlled studies. Heart Fail Rev 22(6):775–782

    Article  PubMed  CAS  Google Scholar 

  10. Beldhuis IE, Streng KW, Ter Maaten JM, Voors AA, van der Meer P, Rossignol P, McMurray JJ, Damman K (2017) Renin-angiotensin system inhibition, worsening renal function, and outcome in heart failure patients with reduced and preserved ejection fraction: a meta-analysis of published study data. Circ Heart Fail. 10(2):e003588

    Article  PubMed  CAS  Google Scholar 

  11. Clarke C, Flores-Muñoz M, McKinney CA, Milligan G, Nicklin SA (2013) Regulation of cardiovascular remodeling by the counter-regulatory axis of the renin-angiotensinsystem. Futur Cardiol 9(1):23–38

    Article  CAS  Google Scholar 

  12. Catena C, Colussi G, Brosolo G, Novello M, Sechi LA (2015) Aldosterone and left ventricular remodeling. Horm Metab Res 47(13):981–986

    Article  PubMed  CAS  Google Scholar 

  13. Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AH (2015) Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res 116(6):960–975

    Article  CAS  Google Scholar 

  14. Pacurari M, Kafoury R, Tchounwou PB, Ndebele K (2014) The renin-angiotensin-aldosterone system in vascular inflammation and remodeling. Int J Inflam 2014:689360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Bahramali E, Firouzabadi N, Rajabi M, Manafi A, Zarghami M, Mousavi SM, Jamshidi J (2017) Association of renin-angiotensin-aldosterone system gene polymorphisms with left ventricular hypertrophy in patients with heart failure with preserved ejection fraction: a case-control study. Clin Exp Hypertens 39(4):371–376

    Article  PubMed  CAS  Google Scholar 

  16. Verloop WL, Beeftink MM, Santema BT, Bots ML, Blankestijn PJ, Cramer MJ, Doevendans PA, Voskuil M (2015) A systematic review concerning the relation between the sympathetic nervous system and heart failure with preserved left ventricular ejection fraction. PLoS One 10(2):e0117332

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Grassi G, Seravalle G, Quarti-Trevano F, Dell'Oro R, Arenare F, Spaziani D, Mancia G (2009) Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 53(2):205–209

    Article  PubMed  CAS  Google Scholar 

  18. Piccirillo G, Germanò G, Vitarelli A, Ragazzo M, di Carlo S, De Laurentis T, Torrini A, Matera S, Magnanti M, Marchitto N, Bonanni L, Magrì D (2006) Autonomic cardiovascular control and diastolic dysfunction in hypertensive subjects. Int J Cardiol 110(2):160–166

    Article  PubMed  Google Scholar 

  19. de Souza SB1, Rocha JA, Cuoco MA, Guerra GM, Ferreira-Filho JC, Borile S, Krieger EM, Bortolotto LA, Consolim-Colombo FM. High muscle sympathetic nerve activity is associated with left ventricular dysfunction in treated hypertensive patients. Am J Hypertens 2013 Jul;26(7):912–917

  20. Rosendorff C (2009) The chicken and the egg: sympathetic nervous system activity and left ventricular diastolic dysfunction. Hypertension 53(2):108–109

    Article  PubMed  CAS  Google Scholar 

  21. Mancia G, Dell'Oro R, Quarti-Trevano F, Scopelliti F, Grassi G (2006) Angiotensin-sympathetic system interactions in cardiovascular and metabolic disease. J Hypertens Suppl 24(1):S51–S56

    Article  PubMed  CAS  Google Scholar 

  22. Szelényi Z, Fazakas Á, Szénási G, Kiss M, Tegze N, Fekete BC, Nagy E, Bodó I, Nagy B, Molvarec A, Patócs A, Pepó L, Prohászka Z, Vereckei A (2015) Inflammation and oxidative stress caused by nitric oxide synthase uncoupling might lead to left ventricular diastolic and systolic dysfunction in patients with hypertension. J Geriatr Cardiol 12(1):1–10

    PubMed  PubMed Central  Google Scholar 

  23. Heinzel FR, Hohendanner F, Jin G3, Sedej S, Edelmann F (2015) Myocardial hypertrophy and its role in heart failure with preserved ejection fraction. J Appl Physiol (1985) 119(10):1233–1242

    Article  CAS  Google Scholar 

  24. Tadic M, Pieske-Kraigher E, Cuspidi C, Genger M, Morris DA, Zhang K, Walther NA, Pieske B (2017) Left ventricular strain and twisting in heart failure with preserved ejection fraction: an updated review. Heart Fail Rev 22(3):371–379

    Article  PubMed  Google Scholar 

  25. Tadic M, Cuspidi C, Backovic S, Kleut M, Ivanovic B, Scepanovic R, Iracek O, Celic V (2014) High-normal blood pressure, functional capacity and left heart mechanics: is there any connection? Blood Press 23(5):315–321

    Article  PubMed  Google Scholar 

  26. Saito M, Khan F, Stoklosa T, Iannaccone A, Negishi K, Marwick TH (2016) Prognostic implications of LV strain risk score in asymptomatic patients with hypertensive heart disease. JACC Cardiovasc Imaging 9(8):911–921

    Article  PubMed  Google Scholar 

  27. Buggey J, Alenezi F, Yoon HJ, Phelan M, DeVore AD, Khouri MG, Schulte PJ, Velazquez EJ (2017) Left ventricular global longitudinal strain in patients with heart failure with preserved ejection fraction: outcomes following an acute heart failure hospitalization. ESC Heart Fail. 4(4):432–439

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pandey A, Khan H, Newman AB, Lakatta EG, Forman DE, Butler J, Berry JD (2017) Arterial stiffness and risk of overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced ejection fraction: the health ABC study (health, aging, and body composition). Hypertension 69(2):267–274

    Article  PubMed  CAS  Google Scholar 

  29. Koh AS, Tay WT, Teng THK, Vedin O, Benson L, Dahlstrom U, Savarese G, Lam CSP, Lund LH (2017) A comprehensive population-based characterization of heart failure with mid-range ejection fraction. Eur J Heart Fail 19:1624–1634

    Article  PubMed  Google Scholar 

  30. Teng TK, Tay WT, Dahlstrom U, Benson L, Lam CSP, Lund LH (2018) Different relationships between pulse pressure and mortality in heart failure with reduced, mid-range and preserved ejection fraction. Int J Cardiol 254:203–209

    Article  PubMed  Google Scholar 

  31. Sartipy U, Dahlström U, Fu M, Lund LH (2017) Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 5(8):565–574

    Article  PubMed  Google Scholar 

  32. Tsimploulis A, Lam PH, Arundel C, Singh SN, Morgan CJ, Faselis C, Deedwania P, Butler J, Aronow WS, Yancy CW, Fonarow GC, Ahmed A (2018) Systolic blood pressure and outcomes in patients with heart failure with preserved ejection fraction. JAMA Cardiol. https://doi.org/10.1001/jamacardio.2017.5365 [Epub ahead of print]

  33. Gu J, Fan YQ, Zhang HL, Zhang JF, Wang CQ (2018) Serum uric acid is associated with incidence of heart failure with preserved ejection fraction and cardiovascular events in patients with arterial hypertension. J Clin Hypertens (Greenwich) 20:560–567. https://doi.org/10.1111/jch.13210. [Epub ahead of print]

    Article  CAS  Google Scholar 

  34. Okura H, Kataoka T, Yoshida K (2016) Comparison of left ventricular relaxation and left atrial function in patients with heart failure and preserved ejection fraction versus patients with systemic hypertension and healthy subjects. Am J Cardiol 118(7):1019–1023

    Article  PubMed  Google Scholar 

  35. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, PEP-CHF Investigators (2006) The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 27(19):2338–2345

    Article  PubMed  CAS  Google Scholar 

  36. Kitzman DW, Hundley WG, Brubaker PH, Morgan TM, Moore JB, Stewart KP, Little WC (2010) A randomized double-blind trial of enalapril in older patients with heart failure and preserved ejection fraction: effects on exercise tolerance and arterial distensibility. Circ Heart Fail 3(4):477–485

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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 ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362(9386):777–781

  38. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A, Investigators I-PRESERVE (2008) Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359(23):2456–2467

    Article  PubMed  CAS  Google Scholar 

  39. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejectionfraction: a phase 2 double-blind randomised controlled trial. 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. Lancet. 2012;380(9851):1387–95

  40. 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, Investigators TOPCAT (2014) Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370(15):1383–1392

    Article  PubMed  CAS  Google Scholar 

  41. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, Duvinage A, Stahrenberg R, Durstewitz K, Löffler M, Düngen HD, Tschöpe C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B, Investigators A-DHF (2013) 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 309(8):781–791

    Article  PubMed  CAS  Google Scholar 

  42. Yamamoto K, Origasa H, Hori M, Investigators J-DHF (2013) Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail 15(1):110–118

    Article  PubMed  CAS  Google Scholar 

  43. van Veldhuisen DJ, Cohen-Solal A, Böhm M, Anker SD, Babalis D, Roughton M, Coats AJ, Poole-Wilson PA, Flather MD, Investigators SENIORS (2009) 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 53(23):2150–2158

    Article  PubMed  CAS  Google Scholar 

  44. Mittal N, Shafiq N, Reddy S, Malhotra S, Kumari S, Varma S (2017) Evaluation of efficacy of metoprolol in patients having heart failure with preserved ejection fraction: a randomized, double-blind, placebo-controlled pilot trial. Perspect Clin Res 8(3):124–131

    PubMed  PubMed Central  Google Scholar 

  45. Patel K, Fonarow GC, Ahmed M, Morgan C, Kilgore M, Love TE, Deedwania P, Aronow WS, Anker SD, Ahmed A (2014) Calcium channel blockers and outcomes in older patients with heart failure and preserved ejection fraction. Circ Heart Fail 7(6):945–952

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Kiuchi S, Hisatake S, Kabuki T, Oka T, Dobashi S, Fujii T, Ikeda T (2017) Azelnidipine is a useful medication for the treatment of heart failure preserved ejection fraction. Clin Exp Hypertens 39(4):350–354

    Article  PubMed  CAS  Google Scholar 

  47. Kanorskii SG, Sereda AF (2016) Comparison of verapamil and amlodipine for treatment of chronic heart failure with preserved left ventricular ejection fraction in patients with hypertensive disease. Kardiologiia 56(12):27–32

    PubMed  CAS  Google Scholar 

  48. Kosmala W, Holland DJ, Rojek A, Wright L, Przewlocka-Kosmala M, Marwick TH (2013) Effect of If-channel inhibition on hemodynamic status and exercise tolerance in heart failure with preserved ejection fraction: a randomized trial. J Am Coll Cardiol 62(15):1330–1338

    Article  PubMed  CAS  Google Scholar 

  49. Pal N, Sivaswamy N, Mahmod M, Yavari A, Rudd A, Singh S, Dawson DK, Francis JM, Dwight JS, Watkins H, Neubauer S, Frenneaux M, Ashrafian H (2015) Effect of selective heart rate slowing in heart failure with preserved ejection fraction. Circulation 132(18):1719–1725

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Komajda M, Isnard R, Cohen-Solal A, Metra M, Pieske B, Ponikowski P, Voors AA, Dominjon F, Henon-Goburdhun C, Pannaux M, Böhm M (2017) prEserveD left ventricular ejectIon fraction chronic heart failure with ivabradine studY (EDIFY) Investigators. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur J Heart Fail 19(11):1495–1503

    Article  PubMed  CAS  Google Scholar 

  51. Zheng SL, Chan FT, Nabeebaccus AA, Shah AM, McDonagh T, Okonko DO, Ayis S (2018) Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart 104(5):407–415

    Article  PubMed  Google Scholar 

  52. De Vecchis R, Ariano C (2017) Differential efficacy profile of aldosterone receptor antagonists, depending on the type of chronic heart failure, whether with reduced or preserved left ventricular ejection fraction-results of a meta-analysis of randomized controlled trials. Cardiovasc Diagn Ther 7(3):272–287

    Article  PubMed  PubMed Central  Google Scholar 

  53. Fukuta H, Goto T, Wakami K, Ohte N (2017) The effect of beta-blockers on mortality in heart failure with preserved ejection fraction: a meta-analysis of observational cohort and randomized controlled studies. Int J Cardiol 228:4–10

    Article  PubMed  Google Scholar 

  54. Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, Yip T, Lau ST, Lau CP, Tang MO, Yu CM, Sanderson JE (2008) The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart 94(5):573–580

    Article  PubMed  CAS  Google Scholar 

  55. Lam CS, Carson PE, Anand IS, Rector TS, Kuskowski M, Komajda M, McKelvie RS, McMurray JJ, Zile MR, Massie BM, Kitzman DW (2012) Sex differences in clinical characteristics and outcomes in elderly patients with heart failure and preserved ejection fraction: the Irbesartan in heart failure with preserved ejection fraction (I-PRESERVE) trial. Circ Heart Fail. 5(5):571–578

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. 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):1179–1188

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Deswal A, Richardson P, Bozkurt B, Mann DL (2011) Results of the randomized aldosterone antagonism in heart failure with preserved ejection fraction trial (RAAM-PEF). J Card Fail 17(8):634–642

    Article  PubMed  Google Scholar 

  58. Jhund PS, Claggett B, Packer M, Zile MR, Voors AA, Pieske B, Lefkowitz M, Shi V, Bransford T, McMurray JJ, Solomon SD (2014) Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fraction: an analysis of the PARAMOUNT trial. Eur J Heart Fail 16(6):671–677

    Article  PubMed  CAS  Google Scholar 

  59. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen DJ, von Lueder TG, Böhm M, Andersson B, Kjekshus J, Packer M, Rigby AS, Rosano G, Wedel H, Hjalmarson Å, Wikstrand J, Kotecha D; Beta-blockers in Heart Failure Collaborative Group. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018;39(1):26–35

  60. Ruiz G, Andrey JL, Puerto JL, Escobar MA, Romero SP, Aranda R, Pedrosa MJ, Gomez F (2016) Prognosis of heart failure with preserved ejection fraction treated with β-blockers: a propensity matched study in the community. Int J Cardiol 222:594–602

    Article  PubMed  Google Scholar 

  61. Gu J, Fan YQ, Bian L, Zhang HL, Xu ZJ, Zhang Y, Chen QZ, Yin ZF, Xie YS, Wang CQ (2016 Sep) Long-term prescription of beta-blocker delays the progression of heart failure with preserved ejection fraction in patients with hypertension: a retrospective observational cohort study. Eur J Prev Cardiol 23(13):1421–1428

    Article  PubMed  Google Scholar 

  62. Lund LH, Benson L, Dahlström U, Edner M, Friberg L (2014) Association between use of β-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA 312(19):2008–2018

    Article  PubMed  CAS  Google Scholar 

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Tadic, M., Cuspidi, C., Frydas, A. et al. The role of arterial hypertension in development heart failure with preserved ejection fraction: just a risk factor or something more?. Heart Fail Rev 23, 631–639 (2018). https://doi.org/10.1007/s10741-018-9698-8

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