Effect of renin-angiotensin system inhibition on cardiac structure and function and exercise capacity in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials

Abstract

Targeting the renin-angiotensin system (RAS) pathways has been considered a logical intervention for patients with heart failure with preserved ejection fraction (HFpEF), due to its hypothesized link to left ventricular (LV) remodeling. Although the effects of RAS inhibitors including angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and direct renin inhibitors (DRIs) on LV structure and function and exercise capacity in HFpEF patients have been examined in multiple randomized controlled trials (RCTs), results are inconsistent due partly to limited power. We conducted a meta-analysis of RCTs on the effects of RAS inhibitors on LV structure and function as well as exercise capacity in HFpEF patients. The search of electronic databases identified 7 trials including 569 patients; 4 trials were on ACE-Is; 2 on ARBs; and 1 on DRIs. Follow-up duration ranged across trials from 12 to 52 weeks. The pooled analysis showed that RAS inhibitors significantly increased EF compared with control (weighted mean difference [95% CI] = 2.182 [0.462, 3.901] %). In contrast, RAS inhibitors did not significantly change the ratio of peak early to late diastolic mitral inflow velocities (weighted mean difference [95% CI] = 0.046 [− 0.012, 0.105]), early diastolic mitral annular velocity (0.327 [− 0.07, 0.725] cm/s), the ratio of early diastolic mitral inflow to annular velocities (0.291 [− 0.937, 1.518]), LV mass (− 6.254 [− 15.165, 2.656] g), or 6-min walk distance (1.972 [− 14.22, 18.163] m) compared with control. The present meta-analysis suggests that RAS inhibitors may increase LVEF in HFpEF patients.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D (1999) Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol. 33:1948–1955

    CAS  Article  Google Scholar 

  2. 2.

    Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259

    CAS  Article  Google Scholar 

  3. 3.

    Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, Yokota T, Goto D, Yokoshiki H, Kato N, Takeshita A, Tsutsui H (2009) Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry Of Heart Failure in Cardiology (JCARE-CARD). Circ J. 73:1893–1900

    Article  Google Scholar 

  4. 4.

    Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 362:777–781

    CAS  Article  Google Scholar 

  5. 5.

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

    CAS  Article  Google Scholar 

  6. 6.

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

    CAS  Article  Google Scholar 

  7. 7.

    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 370:1383–1392

    CAS  Article  Google Scholar 

  8. 8.

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

    CAS  Article  Google Scholar 

  9. 9.

    Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, Marburger CT, Brosnihan B, Morgan TM, Stewart KP (2002) Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 288:2144–2150

    Article  Google Scholar 

  10. 10.

    Bhella PS, Prasad A, Heinicke K, Hastings JL, Arbab-Zadeh A, Adams-Huet B, Pacini EL, Shibata S, Palmer MD, Newcomer BR, Levine BD (2011) Abnormal haemodynamic response to exercise in heart failure with preserved ejection fraction. Eur J Heart Fail 13:1296–1304

    Article  Google Scholar 

  11. 11.

    Hogg K, McMurray J (2005) Neurohumoral pathways in heart failure with preserved systolic function. Prog Cardiovasc Dis. 47:357–366

    CAS  Article  Google Scholar 

  12. 12.

    Wright JW, Mizutani S, Harding JW (2008) Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies. Heart Fail Rev 13:367–375

    CAS  Article  Google Scholar 

  13. 13.

    Aronow WS, Kronzon I (1993) Effect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol. 71:602–604

    CAS  Article  Google Scholar 

  14. 14.

    Zi M, Carmichael N, Lye M (2003) The effect of quinapril on functional status of elderly patients with diastolic heart failure. Cardiovasc Drugs Ther 17:133–139

    CAS  Article  Google Scholar 

  15. 15.

    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 94:573–580

    CAS  Article  Google Scholar 

  16. 16.

    Parthasarathy HK, Pieske B, Weisskopf M, Andrews CD, Brunel P, Struthers AD, MacDonald TM (2009) A randomized, double-blind, placebo-controlled study to determine the effects of valsartan on exercise time in patients with symptomatic heart failure with preserved ejection fraction. Eur J Heart Fail 11:980–989

    CAS  Article  Google Scholar 

  17. 17.

    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 3:477–485

    Article  Google Scholar 

  18. 18.

    Upadhya B, Brubaker PH, Morgan TM, Eggebeen JD, Jao GT, Stewart KP, Kitzman DW (2018) The effect of Aliskiren on exercise capacity in older patients with heart failure and preserved ejection fraction: a randomized, placebo-controlled, double-blind trial. Am Heart J 201:164–167

    CAS  Article  Google Scholar 

  19. 19.

    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 151:264–269 W64

    Article  Google Scholar 

  20. 20.

    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  Google Scholar 

  21. 21.

    Follmann D, Elliott P, Suh I, Cutler J (1992) Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol. 45:769–773

    CAS  Article  Google Scholar 

  22. 22.

    Shah RV, Desai AS, Givertz MM (2010) The effect of renin-angiotensin system inhibitors on mortality and heart failure hospitalization in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis. J Card Fail 16:260–267

    CAS  Article  Google Scholar 

  23. 23.

    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 4:402–408

    Article  Google Scholar 

  24. 24.

    Martin N, Manoharan K, Thomas J, Davies C, Lumbers RT (2018) Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction. Cochrane Database Syst Rev. 6:CD012721

    PubMed  Google Scholar 

  25. 25.

    Pfeffer JM, Pfeffer MA (1988) Angiotensin converting enzyme inhibition and ventricular remodeling in heart failure. Am J Med. 84:37–44

    CAS  Article  Google Scholar 

  26. 26.

    Boluyt MO, Bing OH, Lakatta EG (1995) The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. Eur Heart J 16(Suppl N):19–30

    CAS  Article  Google Scholar 

  27. 27.

    Sutton MG, Sharpe N (2000) Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 101:2981–2988

    CAS  Article  Google Scholar 

  28. 28.

    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 JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (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. 2013(62):e147–e239

    Article  Google Scholar 

  29. 29.

    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 Heart J 2016(37):2129–2200

    Article  Google Scholar 

  30. 30.

    Little WC, Braunwald E (1997) Assessment of cardiac function. In: Braunwald (ed) Heart disease: A text book of cardiovascular medicine, 5th edn. W.B.Saunders Company, Philadelphia, pp 421–444

    Google Scholar 

  31. 31.

    Zile MR, Kjellstrom B, Bennett T, Cho Y, Baicu CF, Aaron MF, Abraham WT, Bourge RC, Kueffer FJ (2013) Effects of exercise on left ventricular systolic and diastolic properties in patients with heart failure and a preserved ejection fraction versus heart failure and a reduced ejection fraction. Circ Heart Fail. 6:508–516

    CAS  Article  Google Scholar 

  32. 32.

    Haykowsky MJ, Tomczak CR, Scott JM, Paterson DI, Kitzman DW (2015) Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction. J Appl Physiol (1985) 119:739–744

    CAS  Article  Google Scholar 

  33. 33.

    Pandey A, Parashar A, Kumbhani DJ, Agarwal S, Garg J, Kitzman D, Levine BD, Drazner M, Berry JD (2015) Exercise training in patients with heart failure and preserved ejection fraction: meta-analysis of randomized control trials. Circ Heart Fail 8:33–40

    Article  Google Scholar 

  34. 34.

    Dunlay SM, Roger VL, Weston SA, Jiang R, Redfield MM (2012) Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction. Circ Heart Fail 5:720–726

    Article  Google Scholar 

  35. 35.

    Kalogeropoulos AP, Kim S, Rawal S, Jadonath A, Tangutoori R, Georgiopoulou V (2019) Serial changes in left ventricular ejection fraction and outcomes in outpatients with heart failure and preserved ejection fraction. Am J Cardiol 124:729–735

    Article  Google Scholar 

  36. 36.

    Park JJ, Park CS, Mebazaa A, Oh IY, Park HA, Cho HJ, Lee HY, Kim KH, Yoo BS, Kang SM, Baek SH, Jeon ES, Kim JJ, Cho MC, Chae SC, Oh BH, Choi DJ (2020) Characteristics and outcomes of HFpEF with declining ejection fraction. Clin Res Cardiol 109:225–234

    CAS  Article  Google Scholar 

  37. 37.

    Simon CB, Lee-McMullen B, Phelan D, Gilkes J, Carter CS, Buford TW (2015) The renin-angiotensin system and prevention of age-related functional decline: where are we now? Age (Dordr) 37:9753

    Article  Google Scholar 

  38. 38.

    Sakata Y, Yamamoto K, Mano T, Nishikawa N, Yoshida J, Nakayama H, Otsu K, Suzuki K, Tada M, Hori M, Miwa T, Masuyama T (2003) Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of ca(2+) regulatory proteins and extracellular matrix. J Hypertens 21:1737–1745

    CAS  Article  Google Scholar 

  39. 39.

    Yamamoto K, Mano T, Yoshida J, Sakata Y, Nishikawa N, Nishio M, Ohtani T, Hori M, Miwa T, Masuyama T (2005) ACE inhibitor and angiotensin II type 1 receptor blocker differently regulate ventricular fibrosis in hypertensive diastolic heart failure. J Hypertens 23:393–400

    CAS  Article  Google Scholar 

  40. 40.

    Vaduganathan M, Michel A, Hall K, Mulligan C, Nodari S, Shah SJ, Senni M, Triggiani M, Butler J, Gheorghiade M (2016) Spectrum of epidemiological and clinical findings in patients with heart failure with preserved ejection fraction stratified by study design: a systematic review. Eur J Heart Fail 18:54–65

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hidekatsu Fukuta.

Ethics declarations

Conflict of interest

Dr. Ohte has received lecture fees from Daiichi Sankyo Co. and grant support from Takeda Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. Dr. Kamiya has received lecture fees from Astellas Pharma Inc. and Mochida Pharmaceutical Co., Ltd.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Supplemental Table 1

(DOCX 69 kb).

Supplemental Table 2

(DOCX 67 kb).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fukuta, H., Goto, T., Wakami, K. et al. Effect of renin-angiotensin system inhibition on cardiac structure and function and exercise capacity in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials. Heart Fail Rev (2020). https://doi.org/10.1007/s10741-020-09969-1

Download citation

Keywords

  • Heart failure
  • Meta-analysis
  • Randomized controlled trial
  • Pharmacotherapy
  • Renin angiotensin system