The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
권호 표지
DOI QR코드

DOI QR Code

Breakthrough in heart failure with preserved ejection fraction: are we there yet?

  • Received : 2015.09.04
  • Accepted : 2015.10.13
  • Published : 2016.01.01
⟨ Previous Next ⟩

Abstract

Heart failure with preserved ejection fraction (HFPEF) is a global health problem of considerable socioeconomic burden. It is projected to worsen with the aging population worldwide. The lack of effective therapies underscores our incomplete understanding of this complex heterogeneous syndrome. A novel paradigm has recently emerged, in which central roles are ascribed to systemic inflammation and generalized endothelial dysfunction in the pathophysiology of HFPEF. In this review, we discuss the role of the endothelium in cardiovascular homeostasis and how deranged endothelial-related signaling pathways contribute to the development of HFPEF. We also review the novel therapies in various stages of research and development that target different components of this signaling pathway.

Keywords

References

  1. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787-1847. https://doi.org/10.1093/eurheartj/ehs104
  2. Yancy CW, Jessup M, Bozkurt B, 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. J Am Coll Cardiol 2013;62:e147-e239. https://doi.org/10.1016/j.jacc.2013.05.019
  3. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-2467. https://doi.org/10.1056/NEJMoa0805450
  4. Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338-2345. https://doi.org/10.1093/eurheartj/ehl250
  5. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777-781. https://doi.org/10.1016/S0140-6736(03)14285-7
  6. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383-1392. https://doi.org/10.1056/NEJMoa1313731
  7. Oktay AA, Rich JD, Shah SJ. The emerging epidemic of heart failure with preserved ejection fraction. Curr Heart Fail Rep 2013;10:401-410. https://doi.org/10.1007/s11897-013-0155-7
  8. van Heerebeek L, Borbely A, Niessen HW, et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 2006;113:1966-1973. https://doi.org/10.1161/CIRCULATIONAHA.105.587519
  9. van Heerebeek L, Hamdani N, Falcao-Pires I, et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 2012;126:830-839. https://doi.org/10.1161/CIRCULATIONAHA.111.076075
  10. Westermann D, Lindner D, Kasner M, et al. Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail 2011;4:44-52. https://doi.org/10.1161/CIRCHEARTFAILURE.109.931451
  11. Borbely A, van der Velden J, Papp Z, et al. Cardiomyocyte stiffness in diastolic heart failure. Circulation 2005;111:774-781. https://doi.org/10.1161/01.CIR.0000155257.33485.6D
  12. Chaturvedi RR, Herron T, Simmons R, et al. Passive stiffness of myocardium from congenital heart disease and implications for diastole. Circulation 2010;121:979-988. https://doi.org/10.1161/CIRCULATIONAHA.109.850677
  13. Campbell RT, Jhund PS, Castagno D, Hawkins NM, Petrie MC, McMurray JJ. What have we learned about patients with heart failure and preserved ejection fraction from DIG-PEF, CHARM-preserved, and I-PRESERVE? J Am Coll Cardiol 2012;60:2349-2356. https://doi.org/10.1016/j.jacc.2012.04.064
  14. Mohammed SF, Borlaug BA, Roger VL, et al. Comorbidity and ventricular and vascular structure and function in heart failure with preserved ejection fraction: a community-based study. Circ Heart Fail 2012;5:710-719. https://doi.org/10.1161/CIRCHEARTFAILURE.112.968594
  15. 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. https://doi.org/10.1016/j.jacc.2013.02.092
  16. Lim SL, Lam CS, Segers VF, Brutsaert DL, De Keulenaer GW. Cardiac endothelium-myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J 2015;36:2050-2060. https://doi.org/10.1093/eurheartj/ehv132
  17. Brutsaert DL. Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Physiol Rev 2003;83:59-115. https://doi.org/10.1152/physrev.00017.2002
  18. Castro LR, Verde I, Cooper DM, Fischmeister R. Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation 2006;113:2221-2228. https://doi.org/10.1161/CIRCULATIONAHA.105.599241
  19. Takimoto E, Belardi D, Tocchetti CG, et al. Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation 2007;115:2159-2167. https://doi.org/10.1161/CIRCULATIONAHA.106.643536
  20. Cornwell TL, Pryzwansky KB, Wyatt TA, Lincoln TM. Regulation of sarcoplasmic reticulum protein phosphorylation by localized cyclic GMP-dependent protein kinase in vascular smooth muscle cells. Mol Pharmacol 1991;40:923-931.
  21. Schlossmann J, Ammendola A, Ashman K, et al. Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature 2000;404:197-201. https://doi.org/10.1038/35004606
  22. Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 1994;368:850-853. https://doi.org/10.1038/368850a0
  23. Horowitz A, Menice CB, Laporte R, Morgan KG. Mechanisms of smooth muscle contraction. Physiol Rev 1996;76:967-1003. https://doi.org/10.1152/physrev.1996.76.4.967
  24. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109-142.
  25. Radomski M, Moncada S. The biological and pharmacological role of nitric oxide in platelet function. In: Authi KS, Watson SP, Kakkar VV, eds. Mechanisms of Platelet Activation and Control. New York: Plenum Press, 1993:251-264.
  26. De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60-68. https://doi.org/10.1172/JCI118074
  27. McNamara DB, Bedi B, Aurora H, et al. L-arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem Biophys Res Commun 1993;193:291-296. https://doi.org/10.1006/bbrc.1993.1622
  28. Mohan P, Brutsaert DL, Paulus WJ, Sys SU. Myocardial contractile response to nitric oxide and cGMP. Circulation 1996;93:1223-1229. https://doi.org/10.1161/01.CIR.93.6.1223
  29. Rastaldo R, Pagliaro P, Cappello S, et al. Nitric oxide and cardiac function. Life Sci 2007;81:779-793. https://doi.org/10.1016/j.lfs.2007.07.019
  30. Vila-Petroff MG, Younes A, Egan J, Lakatta EG, Sollott SJ. Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes. Circ Res 1999;84:1020-1031. https://doi.org/10.1161/01.RES.84.9.1020
  31. Layland J, Li JM, Shah AM. Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes. J Physiol 2002;540(Pt 2):457-467. https://doi.org/10.1113/jphysiol.2001.014126
  32. LeWinter MM, Granzier H. Cardiac titin: a multifunctional giant. Circulation 2010;121:2137-2145. https://doi.org/10.1161/CIRCULATIONAHA.109.860171
  33. Paulus WJ, Bronzwaer JG. Nitric oxide's role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol 2004;287:H8-H13. https://doi.org/10.1152/ajpheart.01147.2003
  34. Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012;59:998-1005. https://doi.org/10.1016/j.jacc.2011.11.040
  35. Kalogeropoulos A, Georgiopoulou V, Psaty BM, et al. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol 2010;55:2129-2137. https://doi.org/10.1016/j.jacc.2009.12.045
  36. Matsubara J, Sugiyama S, Nozaki T, et al. Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol 2011;57:861-869. https://doi.org/10.1016/j.jacc.2010.10.018
  37. Shah KB, Kop WJ, Christenson RH, et al. Prognostic utility of ST2 in patients with acute dyspnea and preserved left ventricular ejection fraction. Clin Chem 2011;57:874-882. https://doi.org/10.1373/clinchem.2010.159277
  38. Matsubara BB, Matsubara LS, Zornoff LA, Franco M, Janicki JS. Left ventricular adaptation to chronic pressure overload induced by inhibition of nitric oxide synthase in rats. Basic Res Cardiol 1998;93:173-181. https://doi.org/10.1007/s003950050084
  39. Calderone A, Thaik CM, Takahashi N, Chang DL, Colucci WS. Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest 1998;101:812-818. https://doi.org/10.1172/JCI119883
  40. Giannetta E, Isidori AM, Galea N, et al. Chronic inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation 2012;125:2323-2333. https://doi.org/10.1161/CIRCULATIONAHA.111.063412
  41. Kasner M, Westermann D, Lopez B, et al. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol 2011;57:977-985. https://doi.org/10.1016/j.jacc.2010.10.024
  42. Zannad F, Radauceanu A. Effect of MR blockade on collagen formation and cardiovascular disease with a specific emphasis on heart failure. Heart Fail Rev 2005;10:71-78. https://doi.org/10.1007/s10741-005-2351-3
  43. 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. https://doi.org/10.1016/j.jacc.2008.11.051
  44. Farrero M, Blanco I, Batlle M, et al. Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction. Circ Heart Fail 2014;7:791-798. https://doi.org/10.1161/CIRCHEARTFAILURE.113.000942
  45. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation 2000;102:1718-1723. https://doi.org/10.1161/01.CIR.102.14.1718
  46. Kalk P, Godes M, Relle K, et al. NO-independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy. Br J Pharmacol 2006;148:853-859.
  47. Boerrigter G, Costello-Boerrigter LC, Cataliotti A, et al. Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41-2272 in experimental congestive heart failure. Circulation 2003;107:686-689. https://doi.org/10.1161/01.CIR.0000055737.15443.F8
  48. Borlaug BA, Olson TP, Lam CS, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010;56:845-854. https://doi.org/10.1016/j.jacc.2010.03.077
  49. Kitzman DW, Nicklas B, Kraus WE, et al. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol 2014;306:H1364-H1370. https://doi.org/10.1152/ajpheart.00004.2014
  50. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 2015;131:550-559. https://doi.org/10.1161/CIRCULATIONAHA.114.009625
  51. Akiyama E, Sugiyama S, Matsuzawa Y, et al. Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejecion fraction. J Am Coll Cardiol 2012;60:1778-1786. https://doi.org/10.1016/j.jacc.2012.07.036
  52. Matsue Y, Suzuki M, Nagahori W, et al. Endothelial dysfunction measured by peripheral arterial tonometry predicts prognosis in patients with heart failure with preserved ejection fraction. Int J Cardiol 2013;168:36-40. https://doi.org/10.1016/j.ijcard.2012.09.021
  53. van Heerebeek L, Hamdani N, Handoko ML, et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation 2008;117:43-51. https://doi.org/10.1161/CIRCULATIONAHA.107.728550
  54. Kawaguchi M, Techigawara M, Ishihata T, et al. A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessels 1997;12:267-274. https://doi.org/10.1007/BF02766802
  55. Lam CS. Diabetic cardiomyopathy: an expression of stage B heart failure with preserved ejection fraction. Diab Vasc Dis Res 2015;12:234-238. https://doi.org/10.1177/1479164115579006
  56. Jonk AM, Houben AJ, de Jongh RT, Serne EH, Schaper NC, Stehouwer CD. Microvascular dysfunction in obesity: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension. Physiology (Bethesda) 2007;22:252-260. https://doi.org/10.1152/physiol.00012.2007
  57. Wallis MG, Wheatley CM, Rattigan S, Barrett EJ, Clark AD, Clark MG. Insulin-mediated hemodynamic changes are impaired in muscle of Zucker obese rats. Diabetes 2002;51:3492-3498. https://doi.org/10.2337/diabetes.51.12.3492
  58. Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes 2006;55:1436-1442. https://doi.org/10.2337/db05-1373
  59. de Jongh RT, Serne EH, IJzerman RG, de Vries G, Stehouwer CD. Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation 2004;109:2529-2535. https://doi.org/10.1161/01.CIR.0000129772.26647.6F
  60. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest 1996;97:2601-2610. https://doi.org/10.1172/JCI118709
  61. De Filippis E, Cusi K, Ocampo G, et al. Exercise-induced improvement in vasodilatory function accompanies increased insulin sensitivity in obesity and type 2 diabetes mellitus. J Clin Endocrinol Metab 2006;91:4903-4910. https://doi.org/10.1210/jc.2006-1142
  62. McMurray JJ, Carson PE, Komajda M, et al. Heart failure with preserved ejection fraction: clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial. Eur J Heart Fail 2008;10:149-156. https://doi.org/10.1016/j.ejheart.2007.12.010
  63. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355:260-269. https://doi.org/10.1056/NEJMoa051530
  64. Fischer M, Baessler A, Hense HW, et al. Prevalence of left ventricular diastolic dysfunction in the community: results from a Doppler echocardiographic-based survey of a population sample. Eur Heart J 2003;24:320-328.
  65. Melchiorre K, Sutherland GR, Liberati M, Thilaganathan B. Preeclampsia is associated with persistent postpartum cardiovascular impairment. Hypertension 2011;58:709-715. https://doi.org/10.1161/HYPERTENSIONAHA.111.176537
  66. Cohen RA, Tong X. Vascular oxidative stress: the common link in hypertensive and diabetic vascular disease. J Cardiovasc Pharmacol 2010;55:308-316. https://doi.org/10.1097/FJC.0b013e3181d89670
  67. Preston RA, Ledford M, Materson BJ, Baltodano NM, Memon A, Alonso A. Effects of severe, uncontrolled hypertension on endothelial activation: soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and von Willebrand factor. J Hypertens 2002;20:871-877. https://doi.org/10.1097/00004872-200205000-00021
  68. Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation 2001;104:735-740. https://doi.org/10.1161/hc3101.091158
  69. Houben AJ, Canoy MC, Paling HA, Derhaag PJ, de Leeuw PW. Quantitative analysis of retinal vascular changes in essential and renovascular hypertension. J Hypertens 1995;13(12 Pt 2):1729-1733.
  70. West R, Liang L, Fonarow GC, et al. Characterization of heart failure patients with preserved ejection fraction: a comparison between ADHERE-US registry and ADHERE- International registry. Eur J Heart Fail 2011;13:945-952. https://doi.org/10.1093/eurjhf/hfr064
  71. Petrofsky JS, Laymon M, Lee H, et al. CoQ10 and endothelial function in Asians from Korea compared to Asians born in the United States and US born Caucasians. Med Sci Monit 2013;19:339-346. https://doi.org/10.12659/MSM.883902
  72. Shantsila E, Wrigley B, Shantsila A, et al. Ethnic differences in macrovascular and microvascular function in systolic heart failure. Circ Heart Fail 2011;4:754-762. https://doi.org/10.1161/CIRCHEARTFAILURE.111.962365
  73. Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol 2000;36:845-851. https://doi.org/10.1016/S0735-1097(00)00790-7
  74. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ Heart Fail 2011;4:8-17. https://doi.org/10.1161/CIRCHEARTFAILURE.110.944694
  75. Redfield MM, Chen HH, Borlaug BA, et al. 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. https://doi.org/10.1001/jama.2013.2024
  76. Blanco-Rivero J, Cachofeiro V, Lahera V, et al. Participation of prostacyclin in endothelial dysfunction induced by aldosterone in normotensive and hypertensive rats. Hypertension 2005;46:107-112. https://doi.org/10.1161/01.HYP.0000171479.36880.17
  77. Farquharson CA, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond) 2002;103:425-431. https://doi.org/10.1042/cs1030425
  78. Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, Schiffrin EL. Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension 2002;40:504-510. https://doi.org/10.1161/01.HYP.0000034738.79310.06
  79. Sanz-Rosa D, Oubina MP, Cediel E, et al. Eplerenone reduces oxidative stress and enhances eNOS in SHR: vascular functional and structural consequences. Antioxid Redox Signal 2005;7(9-10):1294-1301. https://doi.org/10.1089/ars.2005.7.1294
  80. Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 2000;101:594-597. https://doi.org/10.1161/01.CIR.101.6.594
  81. Deswal A, Richardson P, Bozkurt B, Mann DL. Results of the Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction trial (RAAM-PEF). J Card Fail 2011;17:634-642. https://doi.org/10.1016/j.cardfail.2011.04.007
  82. Edelmann F, Wachter R, Schmidt AG, et al. 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. https://doi.org/10.1001/jama.2013.905
  83. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation 2015;131:34-42. https://doi.org/10.1161/CIRCULATIONAHA.114.013255
  84. Shah AM, Spurgeon HA, Sollott SJ, Talo A, Lakatta EG. 8-bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. Circ Res 1994;74:970-978. https://doi.org/10.1161/01.RES.74.5.970
  85. Paulus WJ, Vantrimpont PJ, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans: assessment by bicoronary sodium nitroprusside infusion. Circulation 1994;89:2070-2078. https://doi.org/10.1161/01.CIR.89.5.2070
  86. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-1552. https://doi.org/10.1056/NEJM198606123142404
  87. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-2057. https://doi.org/10.1056/NEJMoa042934
  88. Zamani P, Rawat D, Shiva-Kumar P, et al. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation 2015;131:371-380. https://doi.org/10.1161/CIRCULATIONAHA.114.012957
  89. Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 2006;5:755-768. https://doi.org/10.1038/nrd2038
  90. Jones ES, Kemp-Harper BK, Stasch JP, Schmidt HH, Widdop RE. Cardioprotective effects in aged spontaneously hypertensive rats due to chronic stimulation/activation of sGC without hypotension. BMC Pharmacol 2009;9(Suppl 1):P29.
  91. Masuyama H, Tsuruda T, Sekita Y, et al. Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart. Hypertens Res 2009;32:597-603. https://doi.org/10.1038/hr.2009.64
  92. Schindler U, Strobel H, Schonafinger K, et al. Biochemistry and pharmacology of novel anthranilic acid derivatives activating heme-oxidized soluble guanylyl cyclase. Mol Pharmacol 2006;69:1260-1268. https://doi.org/10.1124/mol.105.018747
  93. Stasch JP, Becker EM, Alonso-Alija C, et al. NO-independent regulatory site on soluble guanylate cyclase. Nature 2001;410:212-215. https://doi.org/10.1038/35065611
  94. Bonderman D, Pretsch I, Steringer-Mascherbauer R, et al. 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. https://doi.org/10.1378/chest.14-0106
  95. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010;50:401-414. https://doi.org/10.1177/0091270009343932
  96. Solomon SD, Zile M, Pieske B, et al. 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. https://doi.org/10.1016/S0140-6736(12)61227-6
  97. 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;113:1198-1204. https://doi.org/10.1016/j.amjcard.2013.12.023
  98. Borbely A, Papp Z, Edes I, Paulus WJ. Molecular determinants of heart failure with normal left ventricular ejection fraction. Pharmacol Rep 2009;61:139-145. https://doi.org/10.1016/S1734-1140(09)70016-7
  99. Willemsen S, Hartog JW, van Veldhuisen DJ, et al. The role of advanced glycation end-products and their receptor on outcome in heart failure patients with preserved and reduced ejection fraction. Am Heart J 2012;164:742.e3-749.e3. https://doi.org/10.1016/j.ahj.2012.07.027
  100. Little WC, Zile MR, Kitzman DW, Hundley WG, O’Brien TX, Degroof RC. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11:191-195. https://doi.org/10.1016/j.cardfail.2004.09.010
  101. Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996;93:210-214. https://doi.org/10.1161/01.CIR.93.2.210
  102. Edelmann F, Gelbrich G, Dungen HD, et al. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 2011;58:1780-1791. https://doi.org/10.1016/j.jacc.2011.06.054
  103. Kitzman DW, Brubaker PH, Morgan TM, Stewart KP, Little WC. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circ Heart Fail 2010;3:659-667. https://doi.org/10.1161/CIRCHEARTFAILURE.110.958785
  104. Kitzman DW, Brubaker PH, Herrington DM, et al. Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. J Am Coll Cardiol 2013;62:584-592. https://doi.org/10.1016/j.jacc.2013.04.033
  105. Heilbronn LK, Noakes M, Clifton PM. Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women. Arterioscler Thromb Vasc Biol 2001;21:968-970. https://doi.org/10.1161/01.ATV.21.6.968
  106. Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804-809. https://doi.org/10.1161/hc0702.104279
  107. Romero-Corral A, Sert-Kuniyoshi FH, Sierra-Johnson J, et al. Modest visceral fat gain causes endothelial dysfunction in healthy humans. J Am Coll Cardiol 2010;56:662-666. https://doi.org/10.1016/j.jacc.2010.03.063
  108. Leichman JG, Wilson EB, Scarborough T, et al. Dramatic reversal of derangements in muscle metabolism and left ventricular function after bariatric surgery. Am J Med 2008;121:966-973. https://doi.org/10.1016/j.amjmed.2008.06.033
  109. Wong CY, Byrne NM, O’Moore-Sullivan T, Hills AP, Prins JB, Marwick TH. Effect of weight loss due to lifestyle intervention on subclinical cardiovascular dysfunction in obesity (body mass index >30 kg/m2). Am J Cardiol 2006;98:1593-1598. https://doi.org/10.1016/j.amjcard.2006.07.037
  110. de las Fuentes L, Waggoner AD, Mohammed BS, et al. Effect of moderate diet-induced weight loss and weight regain on cardiovascular structure and function. J Am Coll Cardiol 2009;54:2376-2381. https://doi.org/10.1016/j.jacc.2009.07.054

Cited by

  1. Commentary: Heart Failure with Preserved Ejection Fraction Induces Beiging in Adipose Tissue vol.7, pp.None, 2016, https://doi.org/10.3389/fphys.2016.00085
  2. Attitudes toward advance directives and prognosis in patients with heart failure: a pilot study vol.35, pp.1, 2016, https://doi.org/10.3904/kjim.2018.158