Advertisement

The Role of Statins in the Management of Heart Failure with Preserved Ejection Fraction

  • Stelina AlkagietEmail author
  • George Giannakoulas
  • Apostolos I. Hatzitolios
  • Konstantinos Tziomalos
Cardiovascular Pharmacology (J Ndisang, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Cardiovascular Pharmacology

Abstract

Purpose of Review

To discuss the current evidence regarding the role of statins in heart failure with preserved ejection fraction (HFpEF).

Recent Findings

HFpEF is a heterogeneous clinical syndrome with numerous contributors to its pathophysiology, including inflammation, arterial stiffness, and dysfunction of the autonomic nervous system. The management of HFpEF is currently symptomatic whereas agents that improve the survival of patients with HF with reduced ejection fraction, including beta-blockers, inhibitors of renin angiotensin system, and aldosterone antagonists have showed no effect on the outcome of HFpEF. On the other hand, preliminary data suggest that statins might reduce the risk of hospitalization and improve the survival of patients with HFpEF. The pleiotropic actions of these agents, particularly their effects on left ventricular function and structure and their antiinflammatory and vasoprotective actions, appear to be implicated in the improved survival of patients with HFpEF treated with statins.

Summary

Given the rising prevalence of HFpEF and the lack of treatments that affect the cardiovascular morbidity and mortality of this population, these apparent benefits of statins have potentially important clinical implication. However, randomized controlled trials are clearly needed to establish the role of statins in the management of HFpEF.

Keywords

Statins Heart failure with preserved ejection fraction Mortality Pleiotropic actions Left ventricular remodeling 

Notes

Compliance with ethical standards

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Kapur NK, Musunuru K. Clinical efficacy and safety of statins in managing cardiovascular risk. Vasc Health Risk Manag. 2008;4:341–53.CrossRefGoogle Scholar
  2. 2.
    Sirtori CR, Mombelli G, Triolo M, Laaksonen R. Clinical response to statins: mechanism(s) of variable activity and adverse effects. Ann Med. 2012;44:419–32.CrossRefGoogle Scholar
  3. 3.
    Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci U S A. 1983;80:4124–8.CrossRefGoogle Scholar
  4. 4.
    Medina MW, Theusch E, Naidoo D, Bauzon F, Stevens K, Mangravite LM, et al. Rhoa is a modulator of the cholesterol-lowering effects of statin. PLoS Genet. 2012;8:e1003058.CrossRefGoogle Scholar
  5. 5.
    MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:7–22.Google Scholar
  6. 6.
    Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504.CrossRefGoogle Scholar
  7. 7.
    Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;287:3215–22.CrossRefGoogle Scholar
  8. 8.
    Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–8.CrossRefGoogle Scholar
  9. 9.
    Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TEXCAPS. JAMA. 1998;279:1615–22.CrossRefGoogle Scholar
  10. 10.
    Scandinavian Simvastatin Survival Study G. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet. 1994;344:1383–9.Google Scholar
  11. 11.
    Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–9.CrossRefGoogle Scholar
  12. 12.
    Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The long-term intervention with pravastatin in ischaemic disease (LIPID) study group. N Engl J Med. 1998;339:1349–57.CrossRefGoogle Scholar
  13. 13.
    Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118.CrossRefGoogle Scholar
  14. 14.
    Vidt DG, Cressman MD, Harris S, Pears JS, Hutchinson HG. Rosuvastatin-induced arrest in progression of renal disease. Cardiology. 2004;102:52–60.CrossRefGoogle Scholar
  15. 15.
    Erichsen R, Froslev T, Lash TL, Pedersen L, Sorensen HT. Long-term statin use and the risk of gallstone disease: a population-based case-control study. Am J Epidemiol. 2011;173:162–70.CrossRefGoogle Scholar
  16. 16.
    McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, et al. Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomised placebo- controlled trial. Lancet. 2004;363:2015–21.CrossRefGoogle Scholar
  17. 17.
    Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851–61.CrossRefGoogle Scholar
  18. 18.
    Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol. 2003;14:1605–13.CrossRefGoogle Scholar
  19. 19.
    Krum H, Jelinek MV, Stewart S, Sindone A, Atherton JJ, National Heart Foundation of Australia; Cardiac Society of Australia and New Zealand. 2011 update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Med J Aust. 2011;194:405–9.Google Scholar
  20. 20.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 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. Circulation. 2013;128:e240–327.Google Scholar
  21. 21.
    National Vasc Dis Prev Alliance. Guidelines for the management of absolute cardiovascular disease risk. 2012.Google Scholar
  22. 22.
    Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol. 2014;63:2889–934.CrossRefGoogle Scholar
  23. 23.
    Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–39.CrossRefGoogle Scholar
  24. 24.
    European Association for Cardiovascular P, Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, et al. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818.CrossRefGoogle Scholar
  25. 25.
    Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–9.CrossRefGoogle Scholar
  26. 26.
    Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta- analysis. Eur Heart J. 2012;33:1750–7.CrossRefGoogle Scholar
  27. 27.
    Heinzel FR, Hohendanner F, Jin G, Sedej S, Edelmann F. Myocardial hypertrophy and its role in heart failure with preserved ejection fraction. J Appl Physiol (1985). 2015;119:1233–42.CrossRefGoogle Scholar
  28. 28.
    Paulus WJ, Tschöpe 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;62:263–71.CrossRefGoogle Scholar
  29. 29.
    Røe ÅT, Sjaastad I, Louch WE. Heart failure with preserved ejection fraction. Tidsskr Nor Legeforen. 2017;137(18).Google Scholar
  30. 30.
    • Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 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;37:2129–200 The most recent European guidelines for the management of patients with heart failure. CrossRefGoogle Scholar
  31. 31.
    Paulus JW, Ballegoij MJ. Treatment of heart failure with normal ejection fraction: an inconvenient truth. J Am Coll Cardiol. 2010;55:526–37.CrossRefGoogle Scholar
  32. 32.
    Lipinski MJ, Cauthen CA, Biondi-Zoccai GGL, Abbate A, Vrtovec B, Khan BV, et al. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol. 2009;104:1708–16.CrossRefGoogle Scholar
  33. 33.
    Fukuta H, Goto T, Wakami K, Ohte N. The effect of statins on mortality in heart failure with preserved ejection fraction: a meta-analysis of propensity score analyses. Int J Cardiol. 2016;214:301–6.CrossRefGoogle Scholar
  34. 34.
    •• Liu G, Zheng XX, Xu YL, Ru J, Hui RT, Huang XH. Meta-analysis of the effect of statins on mortality in patients with preserved ejection fraction. Am J Cardiol. 2014;113:1198–204 A recent meta-analysis of the effect of statins on mortality in patients with preserved ejection fraction. CrossRefGoogle Scholar
  35. 35.
    Tsujimoto T, Kajio H. Favorable effects of statins in the treatment of heart failure with preserved ejection fraction in patients without ischemic heart disease. Int J Cardiol. 2018;255:111–7.CrossRefGoogle Scholar
  36. 36.
    Ouzounian M, Tu VJ, Austin CP, Chong A, Liu PP, Lee DS. Statin therapy and clinical outcomes in heart failure: a propensity-matched analysis. J Card Fail. 2009;15:241–8.CrossRefGoogle Scholar
  37. 37.
    Patel R, Nagueh SF, Tsybouleva N, Abdellatif M, Lutucuta S, Kopelen HA, et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation. 2001;104:317–24.CrossRefGoogle Scholar
  38. 38.
    Hayashidani S, Tsutsui H, Shiomi T, Suematsu N, Kinugawa S, Ide T, et al. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2002;105:868–73.CrossRefGoogle Scholar
  39. 39.
    Ichihara S, Noda A, Nagata K, Obata K, Xu J, Ichihara G, et al. Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure. Cardiovasc Res. 2006;69:726–35.CrossRefGoogle Scholar
  40. 40.
    Bauersachs J, Galuppo P, Fraccarollo D, Christ M, Ertl G. Improvement of left ventricular remodeling and function by hydroxymethylglutaryl co-enzyme A reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction. Circulation. 2001;104:982–5.CrossRefGoogle Scholar
  41. 41.
    Athyros VG, Kakafika AI, Tziomalos K, Karagiannis A, Mikhailidis DP. Pleiotropic effects of statins--clinical evidence. Curr Pharm Des. 2009;15:479–89.CrossRefGoogle Scholar
  42. 42.
    Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol. 2008;51:415–26.CrossRefGoogle Scholar
  43. 43.
    Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Nishizawa T, et al. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol. 2006;47:770–9.CrossRefGoogle Scholar
  44. 44.
    Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation. 2005;111:2356–63.CrossRefGoogle Scholar
  45. 45.
    Corti R, Fuster V, Fayad ZA, Worthley SG, Helft G, Smith D, et al. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years’ follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation. 2002;106:2884–7.CrossRefGoogle Scholar
  46. 46.
    Okura H, Asawa K, Kubo T. Impact of statin therapy on systemic inflammation, left ventricular systolic and diastolic function and prognosis in low risk ischemic heart disease patients without history of congestive heart failure. Intern Med. 2007;46:1337–43.CrossRefGoogle Scholar
  47. 47.
    Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556–65.CrossRefGoogle Scholar
  48. 48.
    Nochioka K, Sakata Y, Miyata S, Miura M, Takada T, Tadaki S, et al. CHART-2 investigators. Prognostic impact of statin use in patients with heart failure and preserved ejection fraction. Circ J. 2015;79:574–82.CrossRefGoogle Scholar
  49. 49.
    Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, et al. Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation. 2005;111:1841–6.CrossRefGoogle Scholar
  50. 50.
    Novack V, Eisinger M, Frenkel A, Terblanche M, Adhikari NK, Douvdevani A, et al. The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial. Intensive Care Med. 2009;35:1255–60.CrossRefGoogle Scholar
  51. 51.
    Deo SH, Fisher JP, Vianna LC, Kim A, Chockalingam A, Zimmerman MC, et al. Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart failure. Am J Physiol Heart Circ Physiol. 2012;303:377–85.CrossRefGoogle Scholar
  52. 52.
    Tokuhisa H, Murai H, Okabe Y, Hamaoka T, Sugimoto H, Mukai Y, et al. Differential effects of lipophilic and hydrophilic statins on muscle sympathetic nerve activity in heart failure with preserved left ventricular ejection fraction. Auton Neurosci. 2018;213:8–14.CrossRefGoogle Scholar
  53. 53.
    Verloop WL, Beeftink MMA, Santema BT, Bots ML, Blankestijn PJ, Cramer MJ, et al. A systematic review concerning the relation between the sympathetic nervous system and heart failure with preserved left ventricular ejection fraction. PLoS One. 2015;10:1–14.Google Scholar
  54. 54.
    Grassi G, Seravalle G, Quarti-Trevano F, Dell'Oro R, Arenare F, Spaziani D, et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension. 2009;53:205–9.CrossRefGoogle Scholar
  55. 55.
    Gomes ME, Lenders JWM, Bellersen L, Verheugt FWA, Smits P, Tack CJ. Sympathoinhibitory effect of statins in chronic heart failure. Clin Auton Res. 2010;20:73–8.CrossRefGoogle Scholar
  56. 56.
    Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, et al. Simvastatin therapy normalizes sympathetic neural control in experimental heart failure: roles of angiotensin II type 1 receptors and NAD(P)H oxidase. Circulation. 2005;112:1763–70.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.First Propedeutic Department of Internal Medicine, Medical SchoolAristotle University of Thessaloniki, AHEPA HospitalThessalonikiGreece
  2. 2.Department of Cardiology, Medical SchoolAristotle University of Thessaloniki, AHEPA HospitalThessalonikiGreece

Personalised recommendations