Arterial Stiffness: Pathophysiological and Genetic Aspects

Rafael de Oliveira Alvim Paulo Caleb Junior Lima Santos Luiz Aparecido Bortolotto José Geraldo Mill Alexandre da Costa Pereira About the authors

Abstract

Cardiovascular diseases (CVD) are the main cause of mortality and it represents a significant percentage of hospitalizations. In the scenario of minimization of costs of the health system, methods that identify subclinical CVD would be important. Some guidelines include the measures of aortic stiffness and intima-media thickness of the carotid artery as methods to identify subclinical CVD in hypertensive patients. The pulse wave velocity (PWV) is the gold standard for the evaluation of arterial stiffness. In this review, we report the pathophysiology, the determinants of arterial stiffness, and justify its inclusion in the assessment of hypertensive patient due its direct association with cardiovascular risk, as show in the I Diretriz Brasileira de Prevenção Cardiovascular. In addition, we raised the main genetic studies of this phenotype, due to its complexity, can be modulated by dozens of genes. However, a better understanding of the relationship genetic-arterial stiffness and, even an intervention based on genotypes, should be achieved in future studies.

Keywords
Vascular stiffness; polymorphism; heritability; pathophysiology.

Resumo

As doenças cardiovasculares (DCV) são a principal causa de morte e representam uma percentagem significativa das internações. No cenário de minimização dos custos ao sistema de saúde, métodos que identifiquem DCV subclínica seriam importantes. Algumas diretrizes incluem a medida da rigidez aórtica e da espessura íntima-média da artéria carótida como métodos para identificação de DCV subclínica em hipertensos. A velocidade de onda de pulso (VOP) é considerada padrão-ouro para avaliar a rigidez arterial. Nesta revisão, abordamos a fisiopatologia e os determinantes da rigidez arterial e justificamos sua inclusão na avaliação do paciente hipertenso dada a associação direta com o risco cardiovascular, como estabelecido na I Diretriz Brasileira de Prevenção Cardiovascular. Apresentamos ainda os principais estudos genéticos deste fenótipo que, dada sua complexidade, pode ser modulado por dezenas de genes. No entanto, um melhor entendimento da relação genética-rigidez arterial, e até mesmo uma intervenção baseada em genótipos, devem ser investigadas em estudos futuros.

Palavras-chave
Doenças Cardiovasculares; Envelhecimento; Fatores de Risco; Aterosclerose; Rigidez Vascular / Fisiopatologia; Polimorfismo Genético

Introduction

Circulation, "Cardiovascular Health in Brazil - Trends and Perspectives", addressed an issue of aging and an increasing prevalence of obesity, hypertension and diabetes in the Brazilian population. Despite the 24% reduction in mortality rates for CVD, on the period from 2000 to 2011, since CVD is a major public health problem in the country, it is a leading cause of death and represents a significant percentage of expenditures on health with hospital admissions.11 Ribeiro AL, Duncan BB, Brant LC, Lotufo PA, Mill JG, Barreto SM. Cardiovascular health in Brazil: trends and perspectives. Circulation. 2016;133(4):422-33.

The VII Brazilian Guideline of Hypertension includes the measurement of arterial stiffness and the intima-media thickness of the carotid artery as methods to assess the additional risk in the hypertensive patient. The PWV measurement constitutes the gold standard for the evaluation of arterial stiffness, due to the reproducibility and reliability of the method, as well as the demonstration of its association with cardiovascular risk in different populations.22 Tolezani EC, Costa-Hong V, Correia G, Mansur AJ, Drager LF, Bortolotto LA. Determinants of functional and structural properties of large arteries in healthy individuals. Arq Bras Cardiol. 2014;103(5):426-32.,33 Sociedade Brasileira de Cardiologia; Sociedade Brasileira de Hipertensão, Sociedade Brasileira de Nefrologia. VII Diretrizes Brasileiras de hipertensão. Arq Bras Cardiol. 2016;107(1 supl.3):1-82.

In this narrative review, we address the pathophysiology and determinants of arterial stiffness. Still, we raised the main genetic studies for this phenotype.

Aspects of arterial stiffness

Pathophysiology

Increased arterial stiffness is a complex phenomenon characterized by decreased complacency (distensibility) of the large arteries. The phenomenon occurs with aging44 Zhang Y, Agnoletti D, Xu Y, Wang JG, Blacher J, Safar ME. Carotid-femoral pulse wave velocity in the elderly. J Hypertens. 2014;32(8):1572-6. and in the presence of diseases associated with the cardiovascular system, such as: diabetes55 de Oliveira Alvim R, Santos PC, Musso MM, de Sa Cunha R, Krieger JE, Mill JG, et al. Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population. Diabetol Metab Syndr. 2013;5(1):45., atherosclerosis66 Tarnoki A, Tarnoki DL, Godor E, Littvay L, Horvath T, Jermendy A, et al. 2d.05: Relationship of coronary atherosclerosis with arterial stiffness and central systolic blood pressure. J Hypertens. 2015;33(Suppl 1):e29. and chronic kidney disease77 Chue CD, Townend JN, Steeds RP, Ferro CJ. Arterial stiffness in chronic kidney disease: causes and consequences. Heart. 2010;96(11):817-23.. Clinically, increased arterial stiffness may be manifested by increased pulse pressure (PP) and isolated systolic hypertension.88 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72.,99 Dart AM, Kingwell BA. Pulse pressure--a review of mechanisms and clinical relevance. J Am Coll Cardiol. 2001;37(4):975-84. Aortic stiffening results in elevated systolic blood pressure (SBP) and decreased diastolic blood pressure (DBP). Thus, arterial stiffness is associated with increased post-load of the left ventricle and decrease in mean coronary perfusion pressure1010 Nichols WW, O' Rourke MF, Vlachopoulos C. McDonald's blood flow in arteries: theoretical, experimental and clinical principles. 6.ed. Boca Raton (FL): Taylor & Francis Group; 2011., which occurs mainly in the diastole. These changes result in hypertrophy of the left ventricle1111 Yucel C, Demir S, Demir M, Tufenk M, Nas K, Molnar F, et al. Left ventricular hypertrophy and arterial stiffness in essential hypertension. Bratisl Lek Listy. 2015;116(12):714-8., worsening of coronary ischemia1212 Leung MC, Meredith IT, Cameron JD. Aortic stiffness affects the coronary blood flow response to percutaneous coronary intervention. Am J Physiol Heart Circ Physiol. 2006;290(2):H624-30. and increased stress in the vascular wall1313 O'Rourke MF. Basic concepts for the understanding of large arteries in hypertension. J Cardiovasc Pharmacol. 1985;7(Suppl 2):S14-21. which, in turn, may facilitate the rupture of atherosclerotic plaques.1414 Van Bortel L. Focus on small artery stiffness. J Hypertens. 2002;20(9):1707-9.

Arterial stiffening occurs through a complex interaction between dynamic and stable adaptations involving cellular elements and the extracellular matrix of the vascular wall. These changes are influenced by hemodynamic forces1515 Wolinsky H, Glagov S. Structural basis for the static mechanical properties of the aortic media. Circ Res. 1964;14(5):400-13.,1616 Tedla YG, Yano Y, Carnethon M, Greenland P. Association between long-term blood pressure variability and 10-year progression in arterial stiffness: the multiethnic study of atherosclerosis. Hypertension. 2017;69(1):118-27. and extrinsic factors, such as hormones1717 Aroor AR, Demarco VG, Jia G, Sun Z, Nistala R, Meininger GA, et al. The role of tissue renin-angiotensin-aldosterone system in the development of endothelial dysfunction and arterial stiffness. Front Endocrinol (Lausanne). 2013;4:161. and inflammatory mediators1818 Labat C, Temmar M, Nagy E, Bean K, Brink C, Benetos A, et al. Inflammatory mediators in saliva associated with arterial stiffness and subclinical atherosclerosis. J Hypertens. 2013;31(11):2251-8., which may be related to sodium and glucose balance.1919 Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932-43. Arterial rigidity is modulated by means of a fine balance between production and degradation of elastin and collagen. The loss or disorganization of elastin and its replacement by collagen determines the increase in wall stiffness. Therefore, imbalance of this system, which may be caused by pro-inflammatory substances, alterations in the inhibition or activation of metalloproteinases and pressure overload may lead to collagen overproduction and/or reduction of elastin, thus contributing to a decrease in vascular distensibility,2020 Johnson CP, Baugh R, Wilson CA, Burns J. Age related changes in the tunica media of the vertebral artery: implications for the assessment of vessels injured by trauma. J Clin Pathol. 2001;54(2):139-45. as shown in Figure 1.

Figure 1
Diagram of the main effectors involved in the regulation of arterial stiffness.

Evaluation of arterial stiffness and cardiometabolic phenotypes

The evaluation of arterial stiffness can be performed by invasive and non-invasive methods. In the clinic, non-invasive methods are increasingly applicable and three techniques can be used: assessment of distensibility (given by simultaneous measurement of intravascular volume and pressure),2121 Gepner AD, Tedla Y, Colangelo LA, Tattersall MC, Korcarz CE, Kaufman JD, et al. Progression of carotid arterial stiffness with treatment of hypertension over 10 years: the Multi-Ethnic Study of Atherosclerosis. Hypertension. 2017;69(1):87-95. arterial pulse waveform analysis (arterial tonometry),2222 Chester RC, Gornbein JA, Hundley WG, Srikanthan P, Watson KE, Horwich T. Reflection magnitude, a measure of arterial stiffness, predicts incident heart failure in men but not women: Multi-Ethnic Study of Atherosclerosis (MESA). J Card Fail. 2017;(16).3024-6. and measurement of PWV. The latter, according to consensus, is the gold standard method for measuring arterial stiffness.2323 Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol. 2003;23(4):554-66.

The consolidation of the PWV measure in the evaluation of arterial stiffness led several studies to demonstrate the association of this phenotype with several pathological conditions. Blacher et al.2424 Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension. 1999;33(5):1111-7., studying individuals with atherosclerosis, showed that PWV is associated not only with the presence but also with the extension of the atherosclerotic process. In another study, London et al.2525 London GM, Marchais SJ, Safar ME, Genest AF, Guerin AP, Metivier F, et al. Aortic and large artery compliance in end-stage renal failure. Kidney Int. 1990;37(1):137-42. showed higher PWV values ​​in patients with chronic kidney disease compared to healthy controls. Toto-Moukouo et al.2626 Toto-Moukouo JJ, Achimastos A, Asmar RG, Hugues CJ, Safar ME. Pulse wave velocity in patients with obesity and hypertension. Am Heart J. 1986;112(1):136-40., evaluating the properties of large arteries of obese and non-obese individuals with essential hypertension, observed that PWV was higher in obese subjects. In addition, epidemiological studies have reported the role of arterial stiffness in predicting morbidity and mortality, independently of other cardiovascular risk factors. Recently, Vlachopoulos et al.2727 Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55(13):1318-27., in a meta-analysis with 17 studies, reported that elevated PWV (≥ 12 m / s) predicted a 102% increase in the risk of mortality from cardiovascular events. In addition, they showed that the 1 m/s increase in PWV corresponded to a 15% increase in cardiovascular risk. These data led to the inclusion of carotid-femoral PWV as part of the evaluation of cardiovascular risk in primary and secondary care.

Determinants of arterial stiffness

The main biological factor associated with increased arterial stiffness is the progression of age.44 Zhang Y, Agnoletti D, Xu Y, Wang JG, Blacher J, Safar ME. Carotid-femoral pulse wave velocity in the elderly. J Hypertens. 2014;32(8):1572-6. Hypertension,2828 Benetos A, Laurent S, Hoeks AP, Boutouyrie PH, Safar ME. Arterial alterations with aging and high blood pressure. A noninvasive study of carotid and femoral arteries. Arterioscler Thromb. 1993;13(1):90-7. diabetes,55 de Oliveira Alvim R, Santos PC, Musso MM, de Sa Cunha R, Krieger JE, Mill JG, et al. Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population. Diabetol Metab Syndr. 2013;5(1):45. dyslipidemia2929 Wilkinson IB, Prasad K, Hall IR, Thomas A, MacCallum H, Webb DJ, et al. Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia. J Am Coll Cardiol. 2002;39(6):1005-11. and obesity3030 Strasser B, Arvandi M, Pasha EP, Haley AP, Stanforth P, Tanaka H. Abdominal obesity is associated with arterial stiffness in middle-aged adults. Nutr Metab Cardiovasc Dis. 2015;25(5):495-502. are pointed out as potential promoters of increased arterial stiffness. Some studies have argued that African ancestry would be associated with greater arterial stiffness.3131 Santos PC, Alvim Rde O, Ferreira NE, de Sa Cunha R, Krieger JE, Mill JG, et al. Ethnicity and arterial stiffness in Brazil. Am J Hypertens. 2011;24(3):278-84. Of all the above factors, age and high blood pressure are the most relevant.3232 Hae Guen S, Eung Ju K, Hong Seog S, Seong Hwan K, Chang Gyu P, Seong Woo H, et al. Relative contributions of different cardiovascular risk factors to significant arterial stiffness. Int J Cardiol. 2010;139(3):263-8.

Data from the Framingham Heart Study show that, up to 50 years of age, the proportion of individuals with high PWV (≥ 12 m / s) is relatively low (only 5-10%). This proportion increases rapidly from this age, so that, in the age group over 70 years, the prevalence is greater than 60%.3333 Mitchell GF, Wang N, Palmisano JN, Larson MG, Hamburg NM, Vita JA, et al. Hemodynamic correlates of blood pressure across the adult age spectrum: noninvasive evaluation in the Framingham Heart Study. Circulation. 2010;122(14):1379-86. In recent years, studies have shown that the increase in PWV with aging is not uniform throughout the aorta.3434 Hickson SS, Butlin M, Graves M, Taviani V, Avolio AP, McEniery CM, et al. The relationship of age with regional aortic stiffness and diameter. JACC Cardiovasc Imaging. 2010;3(12):1247-55.,3535 Taviani V, Hickson SS, Hardy CJ, McEniery CM, Patterson AJ, Gillard JH, et al. Age-related changes of regional pulse wave velocity in the descending aorta using Fourier velocity encoded M-mode. Magn Reson Med. 2011;65(1):261-8. Hickson et al.3434 Hickson SS, Butlin M, Graves M, Taviani V, Avolio AP, McEniery CM, et al. The relationship of age with regional aortic stiffness and diameter. JACC Cardiovasc Imaging. 2010;3(12):1247-55. reported that much of the vascular stiffening occurs in the abdominal aorta and presents an increase rate of 0.9 m/s per decade. Recent studies have shown that increased arterial stiffness associated with aging is closely related to increased sympathetic nerve activity3636 Barnes JN, Hart EC, Curry TB, Nicholson WT, Eisenach JH, Wallin BG, et al. Aging enhances autonomic support of blood pressure in women. Hypertension. 2014;63(2):303-8. and, consequently, exacerbation of the inflammatory process.3737 Zubcevic J, Jun JY, Kim S, Perez PD, Afzal A, Shan Z, et al. Altered inflammatory response is associated with an impaired autonomic input to the bone marrow in the spontaneously hypertensive rat. Hypertension. 2014;63(3):542-50. It is important to note that the chronic diseases most associated with increased PWV (diabetes, hypertension and obesity itself) have an underlying inflammatory component. Thus, the PWV measurement could represent the clinical sentinel monitoring the chronic inflammatory process in these conditions.

The association between arterial hypertension and increased arterial stiffness is well established. Increased pressure causes increased pulsatile stress in the vascular wall resulting in more rapid degradation of elastin fibers.3838 McEniery CM, Spratt M, Munnery M, Yarnell J, Lowe GD, Rumley A, et al. An analysis of prospective risk factors for aortic stiffness in men: 20-year follow-up from the Caerphilly prospective study. Hypertension. 2010;56(1):36-43. However, the cause/effect relationship between hypertension and elevated arterial stiffness has been much discussed in the last decade. Studies indicate that high blood stiffness in normotensive individuals is associated with the progression of blood pressure levels and an increased risk of hypertension,3939 Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012;308(9):875-81.,4040 O'Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE. Clinical applications of arterial stiffness; definitions and reference values. Am J Hypertens. 2002;15(5):426-44. suggesting that stiffness could also be a cause and not a consequence of pressure increase. The most probable is the existence of a biunivocal relationship between these two variables. Only long-term longitudinal studies can delimit the contribution of pressure increase to increase stiffness or, conversely, increase stiffness (which raises the afterload) by determining adaptive pressure rise response.

Increased arterial stiffness associated with diabetes has been widely reported in recent years.4141 Lukich E, Matas Z, Boaz M, Shargorodsky M. Increasing derangement of glucose homeostasis is associated with increased arterial stiffness in patients with diabetes, impaired fasting glucose and normal controls. Diabetes Metab Res Rev. 2010;26(5):365-70.,4242 Vyssoulis G, Pietri P, Vlachopoulos C, Alexopoulos N, Kyvelou SM, Terentes-Printzios D, et al. Early adverse effect of abnormal glucose metabolism on arterial stiffness in drug naive hypertensive patients. Diab Vasc Dis Res. 2012;9(1):18-24. Alvim et al.,55 de Oliveira Alvim R, Santos PC, Musso MM, de Sa Cunha R, Krieger JE, Mill JG, et al. Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population. Diabetol Metab Syndr. 2013;5(1):45. studying individuals from the Brazilian general population, showed that diabetics had higher PWV values ​​compared to non-diabetics. The presence of diabetes represented a 127% greater risk for increased arterial stiffness when compared to the group of individuals without diabetes. Experimental studies have demonstrated that elevated glycemic levels may intensify the inflammatory process, increase advanced glycation products, and reduce NO bioavailability in vessels.4343 Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens. 2003;21(1):3-12.,4444 Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet. 2008;371(9626):1800-9. Despite the data presented, the association between diabetes and increased arterial stiffness has been contested. A systematic review, published in the journal Hypertension,4545 Cecelja M, Chowienczyk P. Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review. Hypertension. 2009;54(6):1328-36. indicated that only 52% of the studies suggested an association between these variables.

The inadequate lipid profile is recognized as an important cardiovascular risk factor. In the last decades, numerous studies have demonstrated the relationship between LDL-c, HDL-c, triglycerides and total cholesterol concentrations and the progression of atherosclerotic disease.4646 Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-97.,4747 de Freitas EV, Brandao AA, Pozzan R, Magalhaes ME, Fonseca F, Pizzi O, et al. Importance of high-density lipoprotein-cholesterol (HDL-C) levels to the incidence of cardiovascular disease (CVD) in the elderly. Arch Gerontol Geriatr. 2011;52(2):217-22. Part of these results can be explained by the vascular dysfunction generated by the inflammatory process increase, increase of the oxidative process, and oxidation of the particles of LDL-c.4848 Aviram M. Hyperlipidaemia and cardiovascular disease: inflammation and oxidative stress in diabetic patients. Curr Opin Lipidol. 2009;20(3):258-9.,4949 Parthasarathy S, Raghavamenon A, Garelnabi MO, Santanam N. Oxidized low-density lipoprotein. Methods Mol Biol. 2010;610:403-17. However, despite the strong correlation between atherosclerosis and vascular dysfunction, the results of the studies associating the lipid profile with arterial stiffness phenotypes are controversial.5050 Homma S, Kato K, Hayashi J, Yamamoto M. Negative associations between arterial stiffness parameter evaluated by cardio-ankle vascular index and serum low-density lipoprotein cholesterol concentration in early-stage atherosclerosis. Angiology. 2015;66(2):143-9.,5151 Wang F, Ye P, Luo L, Xiao W, Qi L, Bian S, et al. Association of serum lipids with arterial stiffness in a population-based study in Beijing. Eur J Clin Invest. 2011;41(9):929-36. Part of these contradictions can be justified, however, or by the differences between the populations investigated or by the different methods used in the determination of arterial stiffness.

The increased incidence of diabetes, metabolic syndrome and systemic arterial hypertension is strongly related to the obesity epidemic.5252 Leopold JA. Cellular and molecular mechanisms of arterial stiffness associated with obesity. Hypertension. 2013;62(6):1003-4. In addition, obesity is known to significantly increase CVD mortality.5353 Lewis CE, McTigue KM, Burke LE, Poirier P, Eckel RH, Howard BV, et al. Mortality, health outcomes, and body mass index in the overweight range: a science advisory from the American Heart Association. Circulation. 2009;119(25):3263-71. Recently, it has been suggested that vascular dysfunction, Including increased arterial stiffness, may be the link between obesity and CVD.5454 Bastien M, Poirier P, Lemieux I, Despres JP. Overview of epidemiology and contribution of obesity to cardiovascular disease. Prog Cardiovasc Dis. 2014;56(4):369-81. Some studies have shown that adults5555 Sutton-Tyrrell K, Newman A, Simonsick EM, Havlik R, Pahor M, Lakatta E, et al. Aortic stiffness is associated with visceral adiposity in older adults enrolled in the study of health, aging, and body composition. Hypertension. 2001;38(3):429-33.,5656 Wildman RP, Mackey RH, Bostom A, Thompson T, Sutton-Tyrrell K. Measures of obesity are associated with vascular stiffness in young and older adults. Hypertension. 2003;42(4):468-73. and obese children5757 Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, et al. Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet. 2001;358(9291):1400-4. have increased arterial stiffness compared to their eutrophic pairs. However, inverse association,5858 Ferreira I, Snijder MB, Twisk JW, van Mechelen W, Kemper HC, Seidell JC, et al. Central fat mass versus peripheral fat and lean mass: opposite (adverse versus favorable) associations with arterial stiffness? The Amsterdam Growth and Health Longitudinal Study. J Clin Endocrinol Metab. 2004;89(6):2632-9. or absence of association after adjustment for blood pressure5959 Rodrigues SL, Baldo MP, Lani L, Nogueira L, Mill JG, Sa Cunha R. Body mass index is not independently associated with increased aortic stiffness in a Brazilian population. Am J Hypertens. 2012;25(10):1064-9. between PWV and visceral obesity were also reported in other studies, indicating the need for additional investigations to detect the causal link between these phenotypes.

The more robust studies show that age and blood pressure are the main determinants of arterial stiffness. However, it is possible that other variables, such as diabetes, dyslipidemias and obesity, are important actors in this complex scenario.

Treatment

Due to the proven impact of increased arterial stiffness on the risk of cardiovascular morbidity and mortality, one issue that arises is the possibility of treatment. Considering that the structural degeneration of the elastic components of the great arteries is little reversible with current pharmacological therapies,6060 Sakuragi S, Abhayaratna WP. Arterial stiffness: methods of measurement, physiologic determinants and prediction of cardiovascular outcomes. Int J Cardiol. 2010;138(2):112-8. it is extremely important to evaluate the impact of preventive interventions, that is, to reduce the impact of aging on increasing stiffness. The factors proposed so far include sodium restriction in diet,6161 Gates PE, Tanaka H, Hiatt WR, Seals DR. Dietary sodium restriction rapidly improves large elastic artery compliance in older adults with systolic hypertension. Hypertension. 2004;44(1):35-41. regular physical exercise,6262 Endes S, Schaffner E, Caviezel S, Dratva J, Autenrieth CS, Wanner M, et al. Physical activity is associated with lower arterial stiffness in older adults: results of the SAPALDIA 3 Cohort Study. Eur J Epidemiol. 2016;31(3):275-85. elimination of smoking6363 Jatoi NA, Jerrard-Dunne P, Feely J, Mahmud A. Impact of smoking and smoking cessation on arterial stiffness and aortic wave reflection in hypertension. Hypertension. 2007;49(5):981-5. and reduction of alcohol consumption,6464 Sierksma A, Lebrun CE, van der Schouw YT, Grobbee DE, Lamberts SW, Hendriks HF, et al. Alcohol consumption in relation to aortic stiffness and aortic wave reflections: a cross-sectional study in healthy postmenopausal women. Arterioscler Thromb Vasc Biol. 2004;24(2):342-8. use of fish oils6565 Nestel P, Shige H, Pomeroy S, Cehun M, Abbey M, Raederstorff D. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr. 2002;76(2):326-30., and consumption of foods rich in isoflavonoids6666 Teede HJ, McGrath BP, DeSilva L, Cehun M, Fassoulakis A, Nestel PJ. Isoflavones reduce arterial stiffness: a placebo-controlled study in men and postmenopausal women. Arterioscler Thromb Vasc Biol. 2003;23(6):1066-71.. There are controversies about the contribution of drugs in reducing arterial stiffness. Some studies have identified positive results using antihypertensives6767 Kim JH, Oh SJ, Lee JM, Hong EG, Yu JM, Han KA, et al. The effect of an Angiotensin receptor blocker on arterial stiffness in type 2 diabetes mellitus patients with hypertension. Diabetes Metab J. 2011;35(3):236-42.,6868 Mahmud A, Feely J. Antihypertensive drugs and arterial stiffness. Expert Rev Cardiovasc Ther. 2003;1(1):65-78. and hypolipidemic agents.6969 Davenport C, Ashley DT, O'Sullivan EP, McHenry CM, Agha A, Thompson CJ, et al. The Effects of Atorvastatin on Arterial Stiffness in Male Patients with Type 2 Diabetes. J Diabetes Res. 2015;2015:846807.,7070 Kanaki AI, Sarafidis PA, Georgianos PI, Kanavos K, Tziolas IM, Zebekakis PE, et al. Effects of low-dose atorvastatin on arterial stiffness and central aortic pressure augmentation in patients with hypertension and hypercholesterolemia. Am J Hypertens. 2013;26(5):608-16. The effect of antihypertensives, however, is due to the reduction of blood pressure. Thus, pharmacological treatment for other diseases, associated with the measures mentioned above, which may attenuate the loss of elastic fibers in the arteries, may have an additional effect on the control of arterial stiffness.

Genetic aspects of arterial stiffness

Heritability of arterial stiffness

Several studies have shown the influence of genetic factors in the modulation of phenotypes related to arterial stiffness.7171 Camp NJ, Hopkins PN, Hasstedt SJ, Coon H, Malhotra A, Cawthon RM, et al. Genome-wide multipoint parametric linkage analysis of pulse pressure in large, extended utah pedigrees. Hypertension. 2003;42(3):322-8.,7272 DeStefano AL, Larson MG, Mitchell GF, Benjamin EJ, Vasan RS, Li J, et al. Genome-wide scan for pulse pressure in the National Heart, Lung and Blood Institute's Framingham Heart Study. Hypertension. 2004;44(2):152-5. Concomitantly, numerous investigations with families have shown moderate heritability (21-66%) for traits associated with arterial stiffness.7373 Atwood LD, Samollow PB, Hixson JE, Stern MP, MacCluer JW. Genome-wide linkage analysis of pulse pressure in Mexican Americans. Hypertension. 2001;37(2 Pt 2):425-8.,7474 Levy D, Larson MG, Benjamin EJ, Newton-Cheh C, Wang TJ, Hwang SJ, et al. Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness. BMC Med Genet. 2007;8 Suppl 1:S3.

In a study of 1480 individuals belonging to 817 nuclei of the Framingham Study Offspring Cohort, Mitchell et al.7575 Mitchell GF, DeStefano AL, Larson MG, Benjamin EJ, Chen MH, Vasan RS, et al. Heritability and a genome-wide linkage scan for arterial stiffness, wave reflection, and mean arterial pressure: the Framingham Heart Study. Circulation. 2005;112(2):194-9. demonstrated that the heritability of PWV was 40%. In another study involving pairs of dizygotic and monozygotic twins living in Hungary and the United States, Tarnoki et al.7676 Tarnoki AD, Tarnoki DL, Stazi MA, Medda E, Cotichini R, Nistico L, et al. Heritability of central blood pressure and arterial stiffness: a twin study. J Hypertens. 2012;30(8):1564-71. observed 51%, adjusted for age, gender and country of origin. A study of 930 individuals in the family of the Erasmus Rucphen Family Study (Sayed-Tabatabaei et al.7777 Sayed-Tabatabaei FA, van Rijn MJ, Schut AF, Aulchenko YS, Croes EA, Zillikens MC, et al. Heritability of the function and structure of the arterial wall: findings of the Erasmus Rucphen Family (ERF) study. Stroke. 2005;36(11):2351-6.) found that the heritability of PWV was 26%, adjusted for several risk factors (gender, age, mean arterial pressure, LDL-c , heart rate, and fasting glycemia). Alvim et al.7878 Alvim RO, Horimoto AR, Oliveira CM, Bortolotto LA, Krieger JE, Pereira AC. Heritability of arterial stiffness in a Brazilian population: Baependi Heart Study. J Hypertens. 2017;35(1):105-10. studying 1675 individuals from a Brazilian population (Baependi Heart Study), observed a moderate heritability of PWV (26%), after adjusting for several confounding factors.

Thus, these studies indicate a significant variation in the heritability values of PWV. Much of this discrepancy could be explained by differences related to the study design (twins or family nuclei), population differences (ethnicity), and types of adjustments used in statistical analyzes.

Genetic markers and arterial stiffness

The number of genetic studies involving vascular phenotypes has grown exponentially in recent years. Investigations using genome scanning methods have pointed out that the arterial stiffness phenotype can be modulated by different chromosomal regions.7575 Mitchell GF, DeStefano AL, Larson MG, Benjamin EJ, Chen MH, Vasan RS, et al. Heritability and a genome-wide linkage scan for arterial stiffness, wave reflection, and mean arterial pressure: the Framingham Heart Study. Circulation. 2005;112(2):194-9.,7979 Turner ST, Fornage M, Jack CR, Jr., Mosley TH, Kardia SL, Boerwinkle E, et al. Genomic susceptibility loci for brain atrophy in hypertensive sibships from the GENOA study. Hypertension. 2005;45(4):793-8. Despite the increasing investment in more sophisticated methods of genetic evaluation, the association studies with candidate genes remain the most abundant in literature. Considering the arterial stiffness phenotype, the most investigated polymorphisms come from systems that directly or indirectly interact in the vascular enhancer pathophysiology, such as the renin-angiotensin-aldosterone system (RAAS), proteins of the structure Vascular, effectors related to endothelial function and pro-inflammatory agents (Table 1).

Table 1
Genetic variants associated with arterial stiffness

RAAS, in addition to its important function in the regulation of blood pressure, is prominent in the vascular remodeling process. Therefore, it is evident that genetic variants capable of affecting the activity of its effectors (angiotensin, angiotensin-converting enzyme, angiotensinogen and renin) could significantly influence vascular pathophysiology. In this sense, several studies have observed an association between some polymorphisms in RAAS genes with arterial stiffness phenotypes. Benetos et al.,8080 Benetos A, Gautier S, Ricard S, Topouchian J, Asmar R, Poirier O, et al. Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation. 1996;94(4):698-703. studying healthy and hypertensive individuals, demonstrated that the presence of the I allele I/D polymorphism of angiotensin-converting enzyme (ACE) was associated with increased arterial stiffness in both groups. Bozec et al.,8181 Bozec E, Lacolley P, Bergaya S, Boutouyrie P, Meneton P, Herisse-Legrand M, et al. Arterial stiffness and angiotensinogen gene in hypertensive patients and mutant mice. J Hypertens. 2004;22(7):1299-307. studying hypertensive patients, demonstrated that the presence of the TT genotype of the p.Met235Thr polymorphism of angiotensinogen (AGT) was associated with lower compliance and greater carotid artery wall stiffness.

Endothelium, which also plays a key role in vascular physiology, mainly acts in the control of vascular tone and flow through the release of nitric oxide and other vasoactive peptides.8282 Trepels T, Zeiher AM, Fichtlscherer S. The endothelium and inflammation. Endothelium. 2006;13(6):423-9. The importance of endothelial integrity and function in vascular function is proven. Evaluated the impact of genetic variants linked to endothelial physiology with arterial stiffness phenotypes. Mitchell et al.,8383 Mitchell GF, Guo CY, Kathiresan S, Vasan RS, Larson MG, Vita JA, et al. Vascular stiffness and genetic variation at the endothelial nitric oxide synthase locus: the Framingham Heart study. Hypertension. 2007;49(6):1285-90. studying the Framingham Heart Study population, demonstrated that the GG genotype of the endothelial nitric oxide synthase (eNOS) enzyme p.Glu298Asp polymorphism was associated with high central PP, especially in women. However, the data were not reproduced, as expected, for VWP. Lajemi et al.,8484 Lajemi M, Gautier S, Poirier O, Baguet JP, Mimran A, Gosse P, et al. Endothelin gene variants and aortic and cardiac structure in never-treated hypertensives. Am J Hypertens. 2001;14(8 Pt 1):755-60. studying untreated hypertensive patients, demonstrated the association of the G allele of the c-30G> A polymorphism of the endothelin β receptor (ETBR) with higher levels of PWV in women. In addition, two studies with the Brazilian general population observed associations of polymorphisms in the p22phox and TXNIP genes with PWV.8585 Alvim RO, Santos PC, Ferreira NE, Mill JG, Krieger JE, Pereira AC. Thioredoxin interacting protein (TXNIP) rs7212 polymorphism is associated with arterial stiffness in the Brazilian general population. J Hum Hypertens. 2012;26(5):340-2.,8686 de Oliveira Alvim R, Santos PC, Dias RG, Rodrigues MV, de Sa Cunha R, Mill JG, et al. Association between the C242T polymorphism in the p22phox gene with arterial stiffness in the Brazilian population. Physiol Genomics. 2012;44(10):587-92. The first showed that individuals with TT genotype for p22phox c.242C>T polymorphism had a higher mean of PWV and greater risk for increased arterial stiffness compared to individuals with CC or CT genotypes.8686 de Oliveira Alvim R, Santos PC, Dias RG, Rodrigues MV, de Sa Cunha R, Mill JG, et al. Association between the C242T polymorphism in the p22phox gene with arterial stiffness in the Brazilian population. Physiol Genomics. 2012;44(10):587-92. The second one identified individuals with CG or GG genotypes for the TXNIP rs7212 polymorphism had a higher mean of PWV, compared to individuals with genotype CC.8585 Alvim RO, Santos PC, Ferreira NE, Mill JG, Krieger JE, Pereira AC. Thioredoxin interacting protein (TXNIP) rs7212 polymorphism is associated with arterial stiffness in the Brazilian general population. J Hum Hypertens. 2012;26(5):340-2.

The remodeling of the vascular wall results from the interaction of several mechanisms, among them, the inflammatory process. Numerous studies have demonstrated the role of inflammatory agents in endothelial dysfunction and atherosclerosis.8787 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135-43. Thus, researchers investigated the possible impact of genetic polymorphisms on proinflammatory genes on arterial stiffness phenotypes. Cheung et al.,8888 Cheung YF, Huang GY, Chen SB, Liu XQ, Xi L, Liang XC, et al. Inflammatory gene polymorphisms and susceptibility to kawasaki disease and its arterial sequelae. Pediatrics. 2008;122(3):e608-14. studying patients with a history of Kawasaki disease, demonstrated the synergistic effect of the A-allele's 308 A> G polymorphism of tumor necrosis factor alpha (TNF-α) and the T allele of the 1444 C> T polymorphism Of the C-reactive protein (CRP) with the high arterial stiffness index in the carotid artery. Moreover, considering the pathophysiological role of adhesion molecules, Zhu et al.8989 Zhu H, Yan W, Tan Y, Li K, Kapuku G, Treiber FA, et al. Adhesion molecule polymorphisms and pulse wave velocity in American youth. Twin Res Hum Genet. 2008;11(5):517-23. demonstrated in young and healthy individuals the association of the CC genotype of the p.Asp693Asp polymorphism in the VCAM-1 gene (vascular cell adhesion molecules) with higher levels of PWV.

In addition to the endocrine, inflammatory and vasoactive endothelium-derived components, the structural components of the vessel wall are also protagonists in the vascular stiffening process, since imbalance in the synthesis of collagen and/or elastin contributes to the decrease of vascular distensibility.2020 Johnson CP, Baugh R, Wilson CA, Burns J. Age related changes in the tunica media of the vertebral artery: implications for the assessment of vessels injured by trauma. J Clin Pathol. 2001;54(2):139-45. Iwai et al.,9090 Iwai N, Kajimoto K, Kokubo Y, Tomoike H. Extensive genetic analysis of 10 candidate genes for hypertension in Japanese. Hypertension. 2006;48(5):901-7. evaluating individuals from the Japanese population, demonstrated the association of allele A of the 3'-UTR elastin polymorphism (ELN) with higher values ​​of PWV. The influence of polymorphisms on genes of some metalloproteinases was also investigated. Yasmin et al.,9191 Yasmin, McEniery CM, O'Shaughnessy KM, Harnett P, Arshad A, Wallace S, et al. Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals. Arterioscler Thromb Vasc Biol. 2006;26(8):1799-805. studying healthy subjects, demonstrated the association of the G-allele of the c.855A> G polymorphism of matrix metalloproteinase-9 (MMP-9) with increased values of PWV.

The above studies reinforce the hypothesis that genetic variants, located in different genes, contribute to the modulation of the arterial stiffness phenotype. Within this theme, larger studies that evaluate the use of genetic markers in the prevention, diagnosis, treatment and prognosis of the patient are still necessary.

Conclusion

Knowing the physiopathological aspects, as well as the determinants of arterial stiffness, it is plausible that PWV is included as one of the components in CVD prevention efforts, at least in hypertensive patients, as indicated in the VII Brazilian Hypertension Guideline and in the I Brazilian Guideline on Cardiovascular Prevention. The assessment of arterial stiffness can be done by the measurement of PWV or other previously validated methods. Genetic data indicate that dozens of genes can modulate this complex phenotype. However, a better understanding of the genetic-arterial rigidity relationship, and even a genotype-based intervention, should constitute goals to be achieved in future studies.

  • Sources of Funding
    There were no external funding sources for this study.
  • Study Association
    This study is not associated with any thesis or dissertation work.

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Publication Dates

  • Publication in this collection
    Sep-Oct 2017

History

  • Received
    20 Sept 2016
  • Reviewed
    24 Jan 2017
  • Accepted
    11 Apr 2017
Sociedade Brasileira de Cardiologia Avenida Marechal Câmara, 160, sala: 330, Centro, CEP: 20020-907, (21) 3478-2700 - Rio de Janeiro - RJ - Brazil
E-mail: sbc@cardiol.br