Understanding the association between endothelial dysfunction and left ventricle diastolic dysfunction in development of coronary artery disease and heart failure

Main Article Content

Livija Sušić https://orcid.org/0000-0001-7271-4449
Lana Maričić http://orcid.org/0000-0001-6035-6760
Josip Vincelj http://orcid.org/0000-0003-0064-9128
Milena Vadoci http://orcid.org/0000-0002-5288-3103
Tihomir Sušić http://orcid.org/0000-0002-8264-5384


amino terminal pro brain natriuretic peptide, biomarkers, coronary artery disease, heart failure, endothelium, microcirculation, risk assessment


Cardiovascular diseases (CVDs)  have been the most common cause of death worldwide for decades. Until recently the most affected patients were middle-aged and elderly, predominantly men, with more frequent ST elevation myocardial infarction  (STEMI) caused by obstructive coronary artery disease (CAD). However, in the last two decades we have noticed an increased incidence of ischemia with non-obstructive coronary arteries (INOCA), which includes myocardial infarction with non-obstructive coronary arteries (MINOCA) and non-myocardial infarction syndromes, such as microvascular and vasospastic angina, conditions that have been particularly pronounced in women and young adults - the population we considered low-risky till than. Therefore, it has become apparent that for this group of patients conventional methods of assessing the risk of future cardiovascular (CV) events are no longer specific and sensitive enough. Heart failure with preserved ejection fraction (HFpEF) is another disease, the incidence of which has been rising rapidly during last two decades, and predominantly affects elderly population. Although the etiology and pathophysiology of INOCA and HFpEF are complex and not fully understood, there is no doubt that the underlying cause of both conditions is endothelial dysfunction (ED) which further promotes the development of left ventricular diastolic dysfunction (LVDD). Plasma biomarkers of ED, as well as natriuretic peptides (NPs), have been intensively investigated recently, and some of them have great potential for early detection and better assessment of CV risk in the future.


Download data is not yet available.
Abstract 963 | PDF Downloads 291


1. World Health Organization (WHO) Report of Cardiovascular diseases (CVDs) 17 May 2017. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
2. Garcia MM, Rodrigues MG, Reis Neto JA, Correia LC. Influence of subclinical atherosclerosis on diastolic function in individuals free of cardiovascular disease. Arq Bras Cardiol 2010; 95: 473-8
3. Zeiher AM, Drexler H, Wollschläger H, Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991; 83: 391-401.
4. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med 2010; 362: 2155-65
5. Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and no obstructive coronary artery disease (INOCA). Developing evidence – based therapies and research agenda for the next decade. Circulation 2010; 135: 1075-92
6. Owan TE, Hodge DO, Herges RM, Jaconsen SJ, Roger VJ, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Eng J Med 2006; 355: 251-9
7. Taqueti VR, Solomon SD, Shah AM, et al. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. Eur Heart J 2018; 39: 840-9
8. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010; 362: 886-95
9. Rozanski A, Gransar H, Hayes SW, et al. Temporal trends in the frequency of inducible myocardial ischemia during cardiac stress testing:1991 to 2009. J Am Coll Cardiol 2013; 61: 1054-65
10. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24: 987-1003
11. D´Agostino RB, Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008; 117: 743-53
12. Kane GC, Karon BL, Mahoney DW et al. Progression of left ventricular diastolic dysfunction and risk of heart failure. JAMA 2011; 306 (8): 856-863
13. Puntmann VO, Taylor PC, Mayr M. Coupling vascular and myocardial inflammatory injury into a common phenotype of cardiovascular dysfunction: systematic inflammation and aging – A mini review. Gerontology 2011; 57: 295-303
14. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87: 840-844
15. Luscher TF, Vanhoutte PM. The Endothelium: modulator of cardiovascular function. Boca Raton, FL, CRC Press 1990
16. Taddei S, Ghiadoni L, Virdis A, Versari D, Salvetti A. Mechanisms of endothelial dysfunction: clinical significance and preventive non-pharmacological therapeutic strategies. Curr Pharm Des 2003; 9: 2385–402
17. Esper RJ, Nordaby RA, Vilariňo JO, Paragano A, Cacharrón JL, Machado RA. Endothelial dysfunction: a comprehensive appraisal. Cardiovascular Diabetology 2006; 5: 4: P1-18
18. Giannitsi S , Maria B , Bechlioulis A, Naka K. Endothelial dysfunction and heart failure: A review of the existing bibliography with emphasis on flow mediated dilation. JRSM Cardiovascular Disease 2019; 8: 1–7
19. Dias RG, Negrão CE, Krieger MH. Ơxido nítrico y sistema cardiovascular: activación celular, reactividad vascular y variante genética. Arq Bras Cardiol 2011; 96(1): 68-75
20. Corretti MC, Todd J, Anderson AJ et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilatation of the brachial artery. J Am Coll Cardiol 2002; 39: 257-65
21. Corretti MC, Plotnik GD, Vogel RA. Technical aspects of evaluating brachial artery vasodilatation using high-frequency ultrasound. Am J Physiol 1995; 268: H1397-H1404
22. Anderson TJ, Gerhard MD, Meredith IT, et al. Systemic nature of endothelial dysfunction in atherosclerosis. Am J Cardiol 1995; 75: 71B-74B
23. Sengupta PP, Khandheria BK, Narula J. Twist and untwist mechanics of the left ventricle. Heart Fail Clin 2008; 4(3): 315-24
24. Mesquita ET, Jorge AJ. Insuficiêntia cardíaca com fraçăo de ejaçăo normal – novos critérios diagnósticos e avanços fisipatológicos. Arq Bras Cardiol 2009; 93(2): 180-7
25. Tsujino T, Kawasaki D, Masuyama T. Left ventricular diastolic dysfunction in diabetic patients: pathophysiology and therapeutic implications. Am J Cardiovasc Drugs 2006; 6(4): 219-30
26. Kloch- Badelek M, Kuznetsova T, Sakiewicz W et al. Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds. Cardiovascular Ultrasound 2012; 10:10. http://www.cardiovascularultrasound.com/content/10/1/10
27. Mesquita ET, Lagoeiro Jorge AJ. Understanding asymptomatic diastolic dysfunction in clinical practice. Arq Bras Cardiol 2013; 100(1): 94-101
28. Kuznetsova T, Herbots L, López B et al. Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail 2009; 2: 105-112
29. Nagueh SF, Smiseth OA, Appleton CP et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016; 29: 277-314
30. Ponikowski P, Voors AA, Anker SD 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. European Heart Journal 2016; 37: 2129-200
31. Wan SH, Vogel MW, Chen HH. Pre-clinical diastolic dysfunction. J Am Coll Cardiol 2014; 63: 407-16
32. Yeboah J, Folsom AR, Burke GL,et al. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: The Multi-Ethnic Study of Atherosclerosis. Circulation 2009; 120(6): 502-9
33. Witte DR, Westerink J, de Koning E, van dr Graaf Y, Grobbee DE, Bots ML. Is the association between flow-mediated dilatation and cardiovascular risk limited to low-risk population? J Am Coll Cardiol 2005; 45: 1987-93
34. Gökce N, Keaney JF Jr., Hunter LM, Watkins MT, Menzoian JO, Vita JA. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation 2002; 105: 1567–72
35. Meyer B, Mörtl D, Strecker K et al. Flow-mediated vasodilation predicts outcome in patients with chronic heart failure comparison with B-type natriuretic peptide. J Am Coll Cardiol 2005; 46: 1011– 8
36. Shah A, Gkaliagkousi E, Ritter JM, Ferro A. Endothelial function and arterial compliance are not impaired in subjects with heart failure of non-ischemic origin. J Cardiac Fail 2010; 16: 114-20
37. Kishimoto S, Kajikawa M, Maruhashi T et al. Endothelial dysfunction and abnormal vascular structure are simultaneously present in patients with heart failure with preserved ejection fraction. Int J Cardiol 2017; 231:181-7
38. Shah SJ, Lam CSP, Svedlund S et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF, European Heart Journal 2018; 39: 3439–50
39. Alderete JF, Torales JM, Garcia LB, Centurion OA. Myocardial infarction and non-obstructive coronary arteries (MINOCA) associated to diastolic dysfunction of the left ventricle. J Cardiol Curr Resi 2018; 11(4): 161-4
40. Gallagher J, Watson C, Campbell P, Ledwidge M, McDonald K. Natriuretic peptide-based screening and prevention of heart failure. Cardiac Failure Review 2017; 3(2): 83–5
41. Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. Eur Heart J 2014; 35: 1101-11
42. 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
43. Gurusamy N, Das DK. Autophagy, redox signalling, and ventricular remodeling. Antioxid Redox Signal 2009; 11: 1975–88.
44. Hare JM. Oxidative stress and apoptosis in heart failure progression. Circ Res 2001; 89: 198–200.
45. Penn MS. The role of leukocyte-generated oxidants in left ventricular remodeling. Am J Cardiol 2008; 101: 30D–3D
46. Taqueti VR, Di Carli MF. Coronary microvascular disease pathogenic mechanisms and therapeutic options. JACC State-of-the-Art Review. J Am Coll Cardiol 2018; 72: 2625-41
47. Ong P, Camici PG, Beltrame JF, et al. International standardization of diagnostic criteria for microvascular angina. Int J Cardiol 2018; 250: 16-20
48. Sato Y, Fujiwara H, Takatsu Y. Biochemical markers in heart failure. Journal of Cardiology 2012; 59: 1-7
49. Ledwidge M, Gallagher J, Conlon C et al. Natriuretic peptide–based screening and collaborative care for heart failure The STOP-HF Randomized Trial. JAMA 2013; 310(1): 66-74.
50. Huelsmann M, Neuhold S, Resl M et al. PONTIAC (NT-proBNP selected PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease) A prospective randomized controlled trial. J Am Coll Cardiol 2013; 62: 1365–72
51. Natriuretic Peptides Studies Collaboration. Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis. Lancet Diabetes Endocrinol 2016; 4: 840–49
52. Neves JA, Neves JA , de Cássia Meneses Oliveira R . Biomarkers of endothelial function in cardiovascular diseases: hypertension. J Vasc Bras 2016; 15(3): 224-33
53. Willeit P, Freitag DF, Laukkanen JA,et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. J Am Heart Assoc 2015; 4(6): e001833 doi/10.1161/JAHA.115.001833. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599532/
54. Pan W, Lian B, Lu H, Liao P, Guo L, Zhang M. Prognostic value of asymmetric dimethylarginine in patients with heart failure: A systematic review and meta-analysis. Hindawi BioMed Research International 2020; Article ID 6960107, 9 pages. https://doi.org/10.1155/2020/6960107
55. Gao S, Liu J. Association between circulating oxidized low-density lipoprotein and atherosclerotic cardiovascular disease. Chronic Diseases and Translational Medicine 2017; 3: 89-94
56. Berezin AE. Endothelial derived micro particles: biomarkers for heart failure diagnosis and management. J Clin Trial Cardiol 2015; 2(3): 1-3
57. Tushuizen ME, Diamant M, Sturk A, Nieuwland R. Cell-derived microparticles in the pathogenesis of cardiovascular disease. Friend or foe? Arterioscler Thromb Vasc Biol 2011; 31: 4-9.
58. Qiu Y, Zhang C, Zhang G, Tao J. Endothelial progenitor cells in cardiovascular diseases. Aging Med 2018; 1: 204–8
59. Kim YH, Nijst P, Kiefer K, Tang WHW. Endothelial glycocalyx as biomarker for cardiovascular diseases: mechanistic and clinical implications. Curr Heart Fail Rep 2017; 14(2): 117–26
60. Poreba R, Gac P, Poreba M, et al. Left ventricle diastolic dysfunction and plasma assymetric dimethylarginine concentration in persons with essential hypertension. Arch Med Sci 2015; 11(3): 521-9
61. Razaei SS, Weisshaar S, Litschauer B, Gouya G, Ohrenberger G, Woltz M. ADMA and NT pro BNP are associated with overall mortality in elderly. Eur J Clin Invest 2018; 0:e 13041. https://doi.org/10.1111/eci.13041
62. Bork NI and Nikolaev VO. Signaling in the cardiovascular system – the role of compartmentation and its live cell imaging. Int J Mol Sci 2018; 19,801. doi: 10.3390/ijms 19030801