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Role of Endothelial Dysfunction in the Progression from Hypertension to Heart Failure

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Hypertension and Heart Failure

Part of the book series: Updates in Hypertension and Cardiovascular Protection ((UHCP))

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Abstract

In the microcirculatory system, endothelial cells mediate the dialogue between the bloodstream and the tissue. They play an essential role in the adaptive response to any stimuli. The large number of physiologic processes in which they are involved is defined as endothelial function and is dependent on nitric oxide bioavailability. In hypertension, several factors concur to increase the level of reactive oxygen species, reducing nitric oxide bioavailability. In this chapter, we will first describe the physiologic role of endothelial cells. Then, we will move to which are the major factors responsible for endothelial dysfunction in the patient with arterial hypertension. We will explore microvascular inflammation, cyclo-oxygenase 2, mineralocorticoid receptors and the role of the sphingolipid metabolisms. We will provide mechanistic insight on how these factors induce microvascular dysfunction and how this latter became the major propellent for a vicious cycle that leads to the progressive onset of heart failure. In this regard, we will focus on heart failure with a preserved ejection fraction, a metabolic phenotype of heart failure embodied in the cardiometabolic spectrum of disease to which arterial hypertension also belongs and on which the role of endothelial dysfunction is crucial.

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References

  1. Rizzoni D, Mengozzi A, Masi S, Agabiti Rosei C, De Ciuceis C, Virdis A. New noninvasive methods to evaluate microvascular structure and function. Hypertension. 2022;79:874–86.

    Article  CAS  Google Scholar 

  2. Mengozzi A, Pugliese NR, Taddei S, Masi S, Virdis A. Microvascular inflammation and cardiovascular prevention: the role of microcirculation as earlier determinant of cardiovascular risk. High Blood Press Cardiovasc Prev. 2021;29:41–8.

    Article  Google Scholar 

  3. Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease—a 30th anniversary update. Acta Physiol. 2017;219:22–96.

    Article  CAS  Google Scholar 

  4. Mengozzi A, Pugliese NR, Chiriaco M, Masi S, Virdis A, Taddei S. Microvascular ageing links metabolic disease to age-related disorders: the role of oxidative stress and inflammation in promoting microvascular dysfunction. J Cardiovasc Pharmacol. 2021;78:S78–87.

    Article  CAS  Google Scholar 

  5. Cooke J. Endotheliopathy of obesity. Circulation. 2020;142:380–3.

    Article  Google Scholar 

  6. Masi S, Colucci R, Duranti E, Nannipieri M, Anselmino M, Ippolito C, et al. Aging modulates the influence of arginase on endothelial dysfunction in obesity. Arterioscler Thromb Vasc Biol. 2018;38:2474–83.

    Article  CAS  Google Scholar 

  7. Barrett EJ, Liu Z, Khamaisi M, King GL, Klein R, Klein BEK, et al. Diabetic microvascular disease: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2017;102:4343–410.

    Article  Google Scholar 

  8. Kim M, Kim M, Yoo HJ, Lee SY, Lee SH, Lee JH. Age-specific determinants of pulse wave velocity among metabolic syndrome components, inflammatory markers, and oxidative stress. J Atheroscler Thromb. 2018;25:178–85.

    Article  CAS  Google Scholar 

  9. Park S, Lee J, Kim B, Lee S, Chang H, Choi D, et al. Lack of association between arterial stiffness and genetic variants by genome-wide association scan. Blood Press. 2015;24:258–61.

    Article  CAS  Google Scholar 

  10. Shah SJ, Kitzman DW, Borlaug BA, van Heerebeek L, Zile MR, Kass DA, et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation. 2016;134:73–90.

    Article  Google Scholar 

  11. Paneni F, Volpe M, Lüscher TF, Cosentino F. SIRT1, p66(Shc), and Set7/9 in vascular hyperglycemic memory: bringing all the strands together. Diabetes. 2013;62:1800–7.

    Article  CAS  Google Scholar 

  12. Messerli FH, Rimoldi SF, Bangalore S. The transition from hypertension to heart failure: contemporary update. JACC Heart Fail. 2017;5:543–51.

    Article  Google Scholar 

  13. Fan L, Pan JA, Lin H, Wang CQ, Zhang JF, Gu J. Optimal management of blood glucose, blood pressure and atrial fibrillation to reduce the risk of heart failure with preserved ejection fraction. Intern Med J. 2022;52:301–9.

    Article  CAS  Google Scholar 

  14. Myhre PL, Selvaraj S, Solomon SD. Management of hypertension in heart failure with preserved ejection fraction: is there a blood pressure goal? Curr Opin Cardiol. 2021;36:413–9.

    Article  Google Scholar 

  15. 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.

    Article  Google Scholar 

  16. Taddei S, Virdis A, Mattei P, Ghiadoni L, Fasolo CB, Sudano I, et al. Hypertension causes premature aging of endothelial function in humans. Hypertension. 1997;29:736.

    Article  CAS  Google Scholar 

  17. Taddei S, Virdis A, Ghiadoni L, Salvetti G, Bernini G, Magagna A, et al. Age-related reduction of NO availability and oxidative stress in humans. Hypertension. 2001;38:274–9.

    Article  CAS  Google Scholar 

  18. Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Fasolo CB, et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation. 1995;91:1981–7.

    Article  CAS  Google Scholar 

  19. Weerts J, Mourmans SGJ, Barandiarán Aizpurua A, Schroen BLM, Knackstedt C, Eringa E, et al. The role of systemic microvascular dysfunction in heart failure with preserved ejection fraction. Biomolecules. 2022;12:278.

    Article  CAS  Google Scholar 

  20. Carrick D, Haig C, Maznyczka AM, Carberry J, Mangion K, Ahmed N, et al. Hypertension, microvascular pathology, and prognosis after an acute myocardial infarction. Hypertension. 2018;72:720–30.

    Article  CAS  Google Scholar 

  21. Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation. 1998;97:2222–9.

    Article  CAS  Google Scholar 

  22. Virdis A, Duranti E, Colucci R, Ippolito C, Tirotta E, Lorenzini G, et al. Ghrelin restores nitric oxide availability in resistance circulation of essential hypertensive patients: role of NAD(P)H oxidase. Eur Heart J. 2015;36:3023–30.

    CAS  Google Scholar 

  23. Virdis A. Endothelial dysfunction in obesity: role of inflammation. High Blood Press Cardiovasc Prev. 2016;23:83–5.

    Article  CAS  Google Scholar 

  24. Lam CSP, Voors AA, de Boer RA, Solomon SD, van Veldhuisen DJ. Heart failure with preserved ejection fraction: from mechanisms to therapies. Eur Heart J. 2018;39:2780–92.

    Article  CAS  Google Scholar 

  25. Lu X, Crowley SD. Inflammation in salt-sensitive hypertension and renal damage. Curr Hypertens Rep. 2018;20:103.

    Article  Google Scholar 

  26. Guzik TJ, Touyz RM. Oxidative stress, inflammation, and vascular aging in hypertension. Hypertension. 2017;70:660–7.

    Article  CAS  Google Scholar 

  27. Targoński R, Sadowski J, Price S, Targoński R. Sodium-induced inflammation-an invisible player in resistant hypertension. Hypertens Res. 2020;43:629–33.

    Article  Google Scholar 

  28. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. 2017;127:1–4.

    Article  Google Scholar 

  29. Virdis A, Santini F, Colucci R, Duranti E, Salvetti G, Rugani I, et al. Vascular generation of tumor necrosis factor-alpha reduces nitric oxide availability in small arteries from visceral fat of obese patients. J Am Coll Cardiol. 2011;58:238–47.

    Article  CAS  Google Scholar 

  30. Virdis A, Duranti E, Rossi C, Dell'Agnello U, Santini E, Anselmino M, et al. Tumour necrosis factor-alpha participates on the endothelin-1/nitric oxide imbalance in small arteries from obese patients: role of perivascular adipose tissue. Eur Heart J. 2015;36:784–94.

    Article  CAS  Google Scholar 

  31. Madhur MS, Elijovich F, Alexander MR, Pitzer A, Ishimwe J, Van Beusecum JP, et al. Hypertension: do inflammation and immunity hold the key to solving this epidemic? Circ Res. 2021;128:908–33.

    Article  CAS  Google Scholar 

  32. Virdis A, Bacca A, Colucci R, Duranti E, Fornai M, Materazzi G, et al. Endothelial dysfunction in small arteries of essential hypertensive patients: role of cyclooxygenase-2 in oxidative stress generation. Hypertension. 2013;62:337–44.

    Article  CAS  Google Scholar 

  33. Verma S, Raj SR, Shewchuk L, Mather KJ, Anderson TJ. Cyclooxygenase-2 blockade does not impair endothelial vasodilator function in healthy volunteers: randomized evaluation of rofecoxib versus naproxen on endothelium-dependent vasodilatation. Circulation. 2001;104:2879–82.

    Article  CAS  Google Scholar 

  34. Muñoz M, Sánchez A, Pilar Martínez M, Benedito S, López-Oliva ME, García-Sacristán A, et al. COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats. Free Radic Biol Med. 2015;84:77–90.

    Article  Google Scholar 

  35. Hernanz R, Briones AM, Salaices M, Alonso MJ. New roles for old pathways? A circuitous relationship between reactive oxygen species and cyclo-oxygenase in hypertension. Clin Sci (Lond). 2014;126:111–21.

    Article  CAS  Google Scholar 

  36. de Oliveira HT, Couto GK, Davel AP, Xavier FE, Rossoni LV. Chronic cyclooxygenase-2 inhibition prevents the worsening of hypertension and endothelial dysfunction induced by ouabain in resistance arteries of spontaneously hypertensive rats. Vascul Pharmacol. 2021;139:106880.

    Article  Google Scholar 

  37. Virdis A, Colucci R, Fornai M, Blandizzi C, Duranti E, Pinto S, et al. Cyclooxygenase-2 inhibition improves vascular endothelial dysfunction in a rat model of endotoxic shock: role of inducible nitric-oxide synthase and oxidative stress. J Pharmacol Exp Ther. 2005;312:945–053.

    Article  CAS  Google Scholar 

  38. Title LM, Giddens K, McInerney MM, McQueen MJ, Nassar BA. Effect of cyclooxygenase-2 inhibition with rofecoxib on endothelial dysfunction and inflammatory markers in patients with coronary artery disease. J Am Coll Cardiol. 2003;42:1747–53.

    Article  CAS  Google Scholar 

  39. Bogaty P, Brophy JM, Noel M, Boyer L, Simard S, Bertrand F, et al. Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study. Circulation. 2004;110:934–9.

    Article  CAS  Google Scholar 

  40. Schjerning AM, McGettigan P, Gislason G. Cardiovascular effects and safety of (non-aspirin) NSAIDs. Nat Rev Cardiol. 2020;17:574–84.

    Article  CAS  Google Scholar 

  41. Lu J, Wang L, Bennamoun M, Ward I, An S, Sohel F, et al. Machine learning risk prediction model for acute coronary syndrome and death from use of non-steroidal anti-inflammatory drugs in administrative data. Sci Rep. 2021;11:18314.

    Article  CAS  Google Scholar 

  42. Chen W, Zhong Y, Feng N, Guo Z, Wang S, Xing D. New horizons in the roles and associations of COX-2 and novel natural inhibitors in cardiovascular diseases. Mol Med. 2021;27:123.

    Article  CAS  Google Scholar 

  43. Davel AP, Anwar IJ, Jaffe IZ. The endothelial mineralocorticoid receptor: mediator of the switch from vascular health to disease. Curr Opin Nephrol Hypertens. 2017;26:97–104.

    CAS  Google Scholar 

  44. Chen L, Ding ML, Wu F, He W, Li J, Zhang XY, et al. Impaired endothelial repair capacity of early endothelial progenitor cells in hypertensive patients with primary hyperaldosteronemia: role of 5,6,7,8-tetrahydrobiopterin oxidation and endothelial nitric oxide synthase uncoupling. Hypertension. 2016;67:430–9.

    Article  CAS  Google Scholar 

  45. Silva MA, Bruder-Nascimento T, Cau SB, Lopes RA, Mestriner FL, Fais RS, et al. Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling. Front Physiol. 2015;6:269.

    Article  Google Scholar 

  46. Davel AP, Lu Q, Moss ME, Rao S, Anwar IJ, DuPont JJ, et al. Sex-specific mechanisms of resistance vessel endothelial dysfunction induced by cardiometabolic risk factors. J Am Heart Assoc. 2018;7:e007675.

    Article  Google Scholar 

  47. Biwer LA, Carvajal BV, Lu Q, Man JJ, Jaffe IZ. Mineralocorticoid and estrogen receptors in endothelial cells coordinately regulate microvascular function in obese female mice. Hypertension. 2021;77:2117–26.

    Article  CAS  Google Scholar 

  48. Józefczuk E, Nosalski R, Saju B, Crespo E, Szczepaniak P, Guzik TJ, et al. Cardiovascular effects of pharmacological targeting of sphingosine kinase 1. Hypertension. 2020;75:383–92.

    Article  Google Scholar 

  49. Jozefczuk E, Guzik TJ, Siedlinski M. Significance of sphingosine-1-phosphate in cardiovascular physiology and pathology. Pharmacol Res. 2020;156:104793.

    Article  CAS  Google Scholar 

  50. Di Pietro P, Carrizzo A, Sommella E, Oliveti M, Iacoviello L, Di Castelnuovo A, et al. Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension. J Clin Invest. 2022;132:e146343.

    Article  Google Scholar 

  51. Packer M, Lam CSP, Lund LH, Maurer MS, Borlaug BA. Characterization of the inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction: a hypothesis to explain influence of sex on the evolution and potential treatment of the disease. Eur J Heart Fail. 2020;22:1551–67.

    Article  Google Scholar 

  52. Cohen JB, Schrauben SJ, Zhao L, Basso MD, Cvijic ME, Li Z, et al. Clinical phenogroups in heart failure with preserved ejection fraction: detailed phenotypes, prognosis, and response to spironolactone. JACC Heart Fail. 2020;8:172–84.

    Article  Google Scholar 

  53. Pugliese NR, Paneni F, Mazzola M, De Biase N, Del Punta L, Gargani L, et al. Impact of epicardial adipose tissue on cardiovascular hemodynamics, metabolic profile and prognosis in heart failure. Eur J Heart Fail. 2021;23:1858–71.

    Article  CAS  Google Scholar 

  54. D'Amario D, Migliaro S, Borovac JA, Restivo A, Vergallo R, Galli M, et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol. 2019;10:1347.

    Article  Google Scholar 

  55. Bayes-Genis A, Bisbal F, Núñez J, Santas E, Lupón J, Rossignol P, et al. Transitioning from preclinical to clinical heart failure with preserved ejection fraction: a mechanistic approach. J Clin Med. 2020;9:1110.

    Article  Google Scholar 

  56. Ekström M, Hellman A, Hasselström J, Hage C, Kahan T, Ugander M, et al. The transition from hypertension to hypertensive heart disease and heart failure: the PREFERS Hypertension study. ESC Heart Fail. 2020;7:737–46.

    Article  Google Scholar 

  57. Masi S, Rizzoni D, Taddei S, Widmer RJ, Montezano AC, Lüscher TF, et al. Assessment and pathophysiology of microvascular disease: recent progress and clinical implications. Eur Heart J. 2021;42:2590–604.

    Article  CAS  Google Scholar 

  58. Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, et al. The assessment of endothelial function: from research into clinical practice. Circulation. 2012;126:753–67.

    Article  Google Scholar 

  59. Shah SJ, Lam CSP, Svedlund S, Saraste A, Hage C, Tan RS, et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. Eur Heart J. 2018;39:3439–50.

    Article  CAS  Google Scholar 

  60. Pugliese NR, De Biase N, Conte L, Gargani L, Mazzola M, Fabiani I, et al. Cardiac reserve and exercise capacity: insights from combined cardiopulmonary and exercise echocardiography stress testing. J Am Soc Echocardiogr. 2021;34:38–50.

    Article  Google Scholar 

  61. Shafiq A, Brawner CA, Aldred HA, Lewis B, Williams CT, Tita C, et al. Prognostic value of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. The Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX) project. Am Heart J. 2016;174:167–72.

    Article  Google Scholar 

  62. Theuerle JD, Al-Fiadh AH, Amirul Islam FM, Patel SK, Burrell LM, Wong TY, et al. Impaired retinal microvascular function predicts long-term adverse events in patients with cardiovascular disease. Cardiovasc Res. 2021;117:1949–57.

    Article  CAS  Google Scholar 

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Acknowledgments

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Alessandro Mengozzi

  2. Health Science Interdisciplinary Center, Sant’Anna School of Advanced Studies, Pisa, Italy

    Alessandro Mengozzi

  3. Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of Zürich, Schlieren, Switzerland

    Alessandro Mengozzi

  4. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Stefano Taddei & Agostino Virdis

Authors
  1. Alessandro Mengozzi
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  2. Stefano Taddei
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  3. Agostino Virdis
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Correspondence to Agostino Virdis .

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Editors and Affiliations

  1. Carol Davila University of Medicine and Pharmacy, Bucharest, Bucuresti, Romania

    Maria Dorobantu

  2. Department of Pharmacology, Toxicology and Clinical Psychopharmacology Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

    Victor Voicu

  3. University of Milano-Bicocca, Milano, Italy

    Guido Grassi

  4. Dept of Clinical and Experimental Sci, University of Brescia, Brescia, Italy

    Enrico Agabiti-Rosei

  5. University of Milano-Bicocca, Milano, Italy

    Giuseppe Mancia

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Mengozzi, A., Taddei, S., Virdis, A. (2023). Role of Endothelial Dysfunction in the Progression from Hypertension to Heart Failure. In: Dorobantu, M., Voicu, V., Grassi, G., Agabiti-Rosei, E., Mancia, G. (eds) Hypertension and Heart Failure. Updates in Hypertension and Cardiovascular Protection. Springer, Cham. https://doi.org/10.1007/978-3-031-39315-0_12

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  • DOI: https://doi.org/10.1007/978-3-031-39315-0_12

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