ijcs International Journal of Cardiovascular Sciences Int. J. Cardiovasc. Sci. 2359-4802 2359-5647 Sociedade Brasileira de Cardiologia 3ZGGMcbk6vb5gHCj6rH5GhC S2359-56472017000500433 10.5935/2359-4802.20170053 Review Articles Arterial Stiffness: Pathophysiological and Genetic Aspects Alvim Rafael de Oliveira 1 2 Santos Paulo Caleb Junior Lima 1 3 Bortolotto Luiz Aparecido 1 Mill José Geraldo 2 Pereira Alexandre da Costa 1 Universidade de São Paulo Faculdade de Medicina Instituto do Coração SP Brazil Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, SP Universidade de São Paulo Universidade Federal do Espírito Santo Departamento de Saúde Coletiva Vitória ES Brazil Departamento de Saúde Coletiva, Universidade Federal do Espírito Santo, Vitória, ES Universidade Federal do Espírito Santo Universidade Federal de São Paulo Departamento de Farmacologia SP Brazil Departamento de Farmacologia, Universidade Federal de São Paulo (EPM-UNIFESP), SP - Brazil Universidade Federal de São Paulo Mailing Address: Rafael de Oliveira Alvim, Rua Alaor de Queiroz Araujo, 135/202. Postal Code: 29050-245, Enseada do Suá, Vitória, ES - Brazil. E-mail: r.alvim@hotmail.com; alvimfaefid@ig.com.br

Author contributions

Conception and design of the research: Alvim RO, Santos PCJL. Acquisition of data: Alvim RO, Santos PCJL. Analysis and interpretation of the data: Alvim RO. Writing of the manuscript: Alvim RO, Santos PCJL, Mill JG, Pereira AC. Critical revision of the manuscript for intellectual content: Alvim RO, Bortolotto LA, Mill JG, Pereira AC.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 Sep-Oct 2017 30 05 433 441 20 09 2016 24 01 2017 11 04 2017 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 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.1

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.2,3

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 aging4 and in the presence of diseases associated with the cardiovascular system, such as: diabetes5, atherosclerosis6 and chronic kidney disease7. Clinically, increased arterial stiffness may be manifested by increased pulse pressure (PP) and isolated systolic hypertension.8,9 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 pressure10, which occurs mainly in the diastole. These changes result in hypertrophy of the left ventricle11, worsening of coronary ischemia12 and increased stress in the vascular wall13 which, in turn, may facilitate the rupture of atherosclerotic plaques.14

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 forces15,16 and extrinsic factors, such as hormones17 and inflammatory mediators18, which may be related to sodium and glucose balance.19 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,20 as shown in Figure 1.

Diagram of the main effectors involved in the regulation of arterial stiffness. NaCl: sodium chloride; VSMC: vascular smooth muscle cell; AGE's: advanced glycation end product; MMP: matrix metalloproteinases; I-CAM: intercellular adhesion molecule; TGF-β: transforming growth factor-beta.

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),21 arterial pulse waveform analysis (arterial tonometry),22 and measurement of PWV. The latter, according to consensus, is the gold standard method for measuring arterial stiffness.23

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.24, 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.25 showed higher PWV values ​​in patients with chronic kidney disease compared to healthy controls. Toto-Moukouo et al.26, 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.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.4 Hypertension,28 diabetes,5 dyslipidemia29 and obesity30 are pointed out as potential promoters of increased arterial stiffness. Some studies have argued that African ancestry would be associated with greater arterial stiffness.31 Of all the above factors, age and high blood pressure are the most relevant.32

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%.33 In recent years, studies have shown that the increase in PWV with aging is not uniform throughout the aorta.34,35 Hickson et al.34 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 activity36 and, consequently, exacerbation of the inflammatory process.37 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.38 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,39,40 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.41,42 Alvim et al.,5 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.43,44 Despite the data presented, the association between diabetes and increased arterial stiffness has been contested. A systematic review, published in the journal Hypertension,45 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.46,47 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.48,49 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.50,51 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.52 In addition, obesity is known to significantly increase CVD mortality.53 Recently, it has been suggested that vascular dysfunction, Including increased arterial stiffness, may be the link between obesity and CVD.54 Some studies have shown that adults55,56 and obese children57 have increased arterial stiffness compared to their eutrophic pairs. However, inverse association,58 or absence of association after adjustment for blood pressure59 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,60 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,61 regular physical exercise,62 elimination of smoking63 and reduction of alcohol consumption,64 use of fish oils65, and consumption of foods rich in isoflavonoids66. There are controversies about the contribution of drugs in reducing arterial stiffness. Some studies have identified positive results using antihypertensives67,68 and hypolipidemic agents.69,70 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.71,72 Concomitantly, numerous investigations with families have shown moderate heritability (21-66%) for traits associated with arterial stiffness.73,74

In a study of 1480 individuals belonging to 817 nuclei of the Framingham Study Offspring Cohort, Mitchell et al.75 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.76 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.77) 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.78 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.75,79 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).

Genetic variants associated with arterial stiffness
Gene Polymorphism Association with arterial stiffness phenotypes
Angiotensin converting enzyme (ECA), chromosome 17; Location 17q23.3 rs4340: I/D (Instron insertion 16) Allele I: increase of PWV73
Angiotensinogen (AGT), chromosome 1: location 1q42-q43 rs699: c.704T>C (Exon 2, p.Met235Thr) Allele T: reduction of carotid distensibility74
Endothelial nitric oxide synthase (eNOS), chromosome 7; Location 7q36 rs1799983: c.894G>T (exon 7, p.Glu298Asp) Genotype GG: high central PP76
Endothelin β receptor (ETBR), chromosome 13; Location 12q22 rs5351: c.831A>G (exon 5, p.Leu277Leu) Allele G: increase in PWV, only in women77
P22phox subunit of NADPH oxidase (p22phox or CYBA), chromosome 16; Location 16p2 rs4673: c.242C>T(exon 3, p.Tyr72His) TT genotype: increased PWV, increased risk of increased arterial stiffness79
Thioredoxin interacting protein (TXNIP), chromosome 1; Location 1p13 rs7212: 1035C>G3'UTR (Untranslated region) Allele G: increase of PWV78
Tumor necrosis factor alpha (TNF-α), chromosome 6; Location 6p21.3 rs1800629: -308A>G (Promoter region) Allele A: increased carotid stiffness index in patients with Kawasaki disease81
C-reactive protein (CRP), chromosome 1; Location 1q22-q25 rs1130864: 1444C>T 3'UTR (Untranslated region) T allele: increased carotid stiffness index in patients with Kawasaki disease81
Vascular cell adhesion molecule (VCAM-1), chromosome 1; Location 1p32-p31 rs3176878: c.2079T>C (exon 9, p.Asp693Asp) CC genotype: increase in PWV82
Metalloproteinase 9 from the matrix (MMP-9), chromosome 20; Location 20q11.2-q13.1 rs17576: c.855A>G (exon 6, p.Arg279Gln) Allele G: increase in PWV84
Elastin (ELN),Chromosome 7; Location 7q11.23 3'UTR - / A (untranslated region) Allele A: increase in PWV83

PWV: pulse wave velocity.

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.,80 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.,81 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.82 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.,83 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.,84 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.85,86 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.86 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.85

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.87 Thus, researchers investigated the possible impact of genetic polymorphisms on proinflammatory genes on arterial stiffness phenotypes. Cheung et al.,88 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.89 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.20 Iwai et al.,90 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.,91 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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Levy D Larson MG Benjamin EJ Newton-Cheh C Wang TJ Hwang SJ Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness BMC Med Genet 2007 8 Suppl 1 S3 S3 75 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. Mitchell GF DeStefano AL Larson MG Benjamin EJ Chen MH Vasan RS Heritability and a genome-wide linkage scan for arterial stiffness, wave reflection, and mean arterial pressure: the Framingham Heart Study Circulation 2005 112 2 194 199 76 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. 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Iwai N Kajimoto K Kokubo Y Tomoike H Extensive genetic analysis of 10 candidate genes for hypertension in Japanese Hypertension 2006 48 5 901 907 91 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. Yasmin McEniery CM O'Shaughnessy KM Harnett P Arshad A Wallace S Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals Arterioscler Thromb Vasc Biol 2006 26 8 1799 1805 Artigos de Revisão Rigidez Arterial: Aspectos Fisiopatológicos e Genéticos Alvim Rafael de Oliveira 1 2 Santos Paulo Caleb Junior Lima 1 3 Bortolotto Luiz Aparecido 1 Mill José Geraldo 2 Pereira Alexandre da Costa 1 Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, SP Departamento de Saúde Coletiva, Universidade Federal do Espírito Santo, Vitória, ES Departamento de Farmacologia, Universidade Federal de São Paulo (EPM-UNIFESP), SP - Brasil Correspondência: Rafael de Oliveira Alvim, Rua Alaor de Queiroz Araujo, 135/202. CEP: 29050-245, Enseada do Suá, Vitória, ES - Brasil. E-mail: r.alvim@hotmail.com; alvimfaefid@ig.com.br

Contribuição dos autores

Concepção e desenho da pesquisa: Alvim RO, Santos PCJL. Obtenção de dados: Alvim RO, Santos PCJL. Análise e interpretação dos dados: Alvim RO. Redação do manuscrito: Alvim RO, Santos PCJL, Mill JG, Pereira AC. Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Alvim RO, Bortolotto LA, Mill JG, Pereira AC.

Potencial Conflito de Interesse

Declaro não haver conflito de interesses pertinentes.

 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 Introdução

Um artigo recente publicado no periódico Circulation, "Cardiovascular Health in Brazil - Trendsand Perspectives", abordou a questão do envelhecimento e a prevalência crescente de obesidade, hipertensão e diabetes na população brasileira. Apesar da redução de 24% nas taxas de mortalidade para DCV, ajustadas por idade, no período de 2000 a 2011, as DCV ainda constituem grande problema de saúde pública no país, pois são a principal causa de morte e representam uma percentagem significativa dos gastos em saúde com internações hospitalares.1

A VII Diretriz Brasileira de Hipertensão inclui a medida de rigidez arterial e da espessura íntima-média da artéria carótida como métodos para avaliação do risco adicional no paciente hipertenso. A medida da VOP constitui o padrão-ouro para a avaliação da rigidez arterial, por conta da reprodutibilidade e confiabilidade do método, além da demonstração de sua associação com o risco cardiovascular em diferentes populações.2,3

Nesta revisão narrativa, abordamos a fisiopatologia e os determinantes da rigidez arterial. Ainda, levantamos os principais estudos genéticos para este fenótipo.

 Aspectos da rigidez arterial Fisiopatologia

O aumento da rigidez arterial é um fenômeno complexo caracterizado pela diminuição da complacência (distensibilidade) das grandes artérias. O fenômeno ocorre com o envelhecimento4 e em presença de doenças associadas ao sistema cardiovascular, tais como: diabetes,5 aterosclerose6 e doença renal crônica.7 Clinicamente, a rigidez arterial aumentada pode se manifestar por meio do aumento da pressão de pulso (PP) e da hipertensão sistólica isolada.8,9 O enrijecimento da aorta resulta na elevação da pressão arterial sistólica (PAS) e na diminuição da pressão arterial diastólica (PAD). Assim, o enrijecimento arterial associa-se ao aumento da pós-carga do ventrículo esquerdo e à diminuição da pressão média de perfusão coronariana10 que ocorre, principalmente, na diástole. Essas mudanças resultam em hipertrofia do ventrículo esquerdo,11, agravamento da isquemia coronária12 e aumento do estresse na parede vascular13 que, por sua vez, podem facilitar a ruptura de placas ateroscleróticas.14

O enrijecimento arterial acontece por uma complexa interação entre adaptações dinâmicas e estáveis envolvendo elementos celulares e a matriz extracelular da parede vascular. Essas alterações são influenciadas por forças hemodinâmicas15,16 e fatores extrínsecos, tais como: hormônios17 e mediadores inflamatórios,18 que podem estar vinculados ao balanço do sódio e da glicose.19 A rigidez arterial é modulada por meio de um fino balanço entre a produção e a degradação de elastina e de colágeno. A perda ou a desorganização da elastina e sua substituição por colágeno determina o aumento da rigidez da parede. Portanto, o desequilíbrio desse sistema, que pode ser causado por substâncias pró-inflamatórias, alterações na inibição ou na ativação de metaloproteinases e sobrecarga de pressão pode acarretar na superprodução de colágeno e/ou redução da elastina, contribuindo assim para a diminuição da distensibilidade vascular,20 conforme esquema apresentado na Figura 1.

Esquema dos principais efetores envolvidos na regulação da rigidez arterial. NaCl: cloreto de sódio; CMLV: célula muscular lisa vascular; AGE's: produto final de glicação avançada; MMP: metaloproteinases da matriz; I-CAM: molécula de adesão intercelular; TGF-β: fator de crescimento transformador-beta.

Avaliação da rigidez arterial e fenótipos cardiometabólicos

A avaliação da rigidez arterial pode ser realizada por métodos invasivos e não invasivos. Na clínica, os métodos não invasivos encontram aplicabilidade crescente e três técnicas podem ser utilizadas: avaliação da distensibilidade (dado pela medida simultânea do volume e da pressão intravascular),21 análise do formato da onda de pulso arterial (tonometria arterial)22 e medida da VOP. Este último, segundo consensos, o método padrão-ouro para medir a rigidez arterial.23

A consolidação da medida da VOP na avaliação da rigidez arterial levou diversos estudos a demonstrarem a associação deste fenótipo com diversas condições patológicas. Blacher et al.,24 estudando indivíduos portadores de aterosclerose, mostraram que a VOP está associada não só com a presença, mas também com a extensão do processo aterosclerótico. Em outro estudo, London et al.,25 mostraram maiores valores de VOP em pacientes com doença renal crônica, comparados a controles saudáveis. Toto-Moukouo et al.,26 avaliando as propriedades das grandes artérias de obesos e de não obesos com hipertensão essencial, observaram que a VOP era maior em obesos. Além disso, estudos epidemiológicos reportaram o papel da rigidez arterial na predição de morbidade e mortalidade, independentemente de outros fatores de risco cardiovascular. Recentemente, Vlachopoulos et al.,27 em uma metanálise com 17 estudos, reportaram que valores elevados de VOP (≥ 12 m/s) prediziam aumento de 102% no risco de mortalidade decorrentes de eventos cardiovasculares. Além disso, mostraram que o aumento de 1 m/s na VOP correspondeu ao incremento de 15% no risco cardiovascular. Tais dados levaram à inclusão da VOP carotídeo-femoral como parte da avaliação do risco cardiovascular na atenção primária e secundária.

 Determinantes da rigidez arterial

O principal fator biológico associado ao aumento da rigidez arterial é a progressão da idade.4 A hipertensão arterial,28 o diabetes,5 a dislipidemia29 e a obesidade30 são apontados como promotores potenciais do incremento da rigidez arterial. Alguns estudos sustentam que a ancestralidade africana estaria associada a maior rigidez arterial.31 Dentre todos os fatores supracitados, a idade e a pressão arterial elevada demonstram ser os mais relevantes.32

Dados do Framingham Heart Study apontam que, até os 50 anos de idade, a proporção de indivíduos com VOP alta (≥ 12 m/s) é relativamente baixa (apenas 5-10%). Essa proporção cresce rapidamente a partir desta idade, de modo que, na faixa etária superior a 70 anos, a prevalência é maior que 60%.33 Nos últimos anos, estudos mostraram que o aumento da VOP com o envelhecimento não é uniforme ao longo da aorta.34,35 Hickson et al.34 reportaram que grande parte do enrijecimento vascular ocorre na aorta abdominal e apresenta taxa de incremento de 0,9 m/s por década. Estudos recentes têm demonstrado que o aumento da rigidez arterial associado ao envelhecimento está intimamente relacionado à elevação da atividade nervosa simpática36 e, consequentemente, da exacerbação do processo inflamatório.37 Importante notar que as doenças crônicas mais associadas ao aumento da VOP (diabetes, hipertensão e a própria obesidade) têm um componente inflamatório subjacente. Assim, a medida da VOP poderia representar a sentinela clínica de monitoramento do processo inflamatório crônico nestas condições.

A associação entre hipertensão arterial e incremento da rigidez arterial está bem estabelecida. O aumento da pressão gera aumento do estresse pulsátil na parede vascular resultando em degradação mais rápida das fibras de elastina.38 Entretanto, a relação de causa/efeito entre hipertensão e rigidez arterial elevada tem sido muito discutida na última década. Estudos apontam que a rigidez arterial elevada, em indivíduos normotensos, está associada à progressão dos níveis de pressão arterial e aumento do risco de hipertensão,39,40 sugerindo que a rigidez poderia ser também causa e não consequência do incremento pressórico. O mais provável é a existência de relação biunívoca entre estas duas variáveis. Apenas estudos longitudinais de longo prazo poderão delimitar a contribuição do aumento pressórico para o aumento da rigidez ou, inversamente, o aumento da rigidez (que eleva a pós-carga) determinando resposta adaptativa de elevação da pressão.

O aumento da rigidez arterial associado ao diabetes tem sido amplamente retratado nos últimos anos.41,42 Alvim et al.,5 estudando indivíduos da população geral brasileira, demonstraram que os diabéticos possuíam maiores valores da VOP, comparados aos não diabéticos. A presença do diabetes representou um risco 127% maior para rigidez arterial aumentada quando comparado ao grupo de indivíduos sem diabetes. Estudos experimentais demonstraram que níveis glicêmicos elevados podem intensificar o processo inflamatório, aumentar os produtos de glicação avançada e reduzir a biodisponibilidade de NO nos vasos.43,44 Apesar dos dados apresentados, a associação entre diabetes e rigidez arterial aumentada tem sido contestada. Uma revisão sistemática, publicada no periódico Hypertension,45 indicou que somente 52% dos estudos sugeriram a associação entre estas variáveis.

O perfil lipídico inadequado é reconhecidamente um importante fator de risco cardiovascular. Nas últimas décadas, inúmeros estudos têm demonstrado a relação entre as concentrações de LDL-c, HDL-c, triglicérides e colesterol total e a progressão da doença aterosclerótica.46,47 Parte desses resultados pode ser explicada pela disfunção vascular gerada pelo incremento do processo inflamatório, aumento do estresse oxidativo e oxidação das partículas de LDL-c.48,49 Contudo, apesar da forte correlação entre aterosclerose e disfunção vascular, os resultados dos estudos associando o perfil lipídico com fenótipos de rigidez arterial são controversos.50,51 Parte dessas contradições pode ser justificada, entretanto, ou pelas diferenças entre as populações investigadas ou pelos distintos métodos utilizados na determinação da rigidez arterial.

O aumento da incidência de diabetes, síndrome metabólica e hipertensão arterial sistêmica está fortemente relacionada à epidemia da obesidade.52 Além disso, sabe-se que a obesidade aumenta significativamente a mortalidade decorrente das DCV.53 Recentemente, tem sido sugerido que a disfunção vascular, incluindo a rigidez arterial aumentada, pode ser o link entre a obesidade e as DCV.54 Alguns estudos mostraram que adultos55,56 e crianças57 obesos apresentam rigidez arterial aumentada, comparados aos seus pares eutróficos. Entretanto, associação inversa,58 ou ausência de associação após ajuste pela pressão arterial59 entre VOP e obesidade visceral foram também relatadas em outros estudos, indicando a necessidade de investigações adicionais para se detectar o elo causal entre estes fenótipos.

Os estudos mais robustos mostram que a idade e a pressão arterial são os principais determinantes da rigidez arterial. No entanto, há a possibilidade de que outras variáveis, como o diabetes, as dislipidemias e a obesidade serem importantes atores neste cenário complexo.

 Tratamento

Devido ao comprovado impacto da rigidez arterial aumentada no risco de morbidade e mortalidade cardiovascular, uma questão que se coloca é a possibilidade de tratamento. Levando em consideração que a degeneração estrutural dos componentes elásticos das grandes artérias é pouco reversível com as terapias farmacológicas atuais,60 é de extrema importância avaliar o impacto de intervenções preventivas, isto é, que diminuíssem o impacto do envelhecimento no aumento da rigidez. Os fatores até aqui propostos incluem a restrição de sódio na alimentação,61 a realização de exercício físico regular,62 a eliminação do tabagismo63 e a redução do consumo de álcool,64 a utilização de óleos derivados de peixe65 e o consumo de alimentos ricos em isoflavonoides.66 Existem controvérsias sobre a contribuição dos fármacos na redução da rigidez arterial. Alguns estudos identificaram resultados positivos mediante a utilização de anti-hipertensivos67,68 e de hipolipemiantes.69,70 O efeito dos anti-hipertensivos, entretanto, decorre da redução da pressão arterial. Desta forma, o tratamento farmacológico para outras doenças, associado às medidas citadas acima, que podem atenuar a perda de fibras elásticas nas artérias, pode ter um efeito adicional no controle da rigidez arterial.

 Aspectos genéticos da rigidez arterial Herdabilidade da rigidez arterial

Diversos estudos mostraram a influência de fatores genéticos na modulação de fenótipos relacionados à rigidez arterial.71,72 Concomitantemente, inúmeras investigações com famílias demonstraram herdabilidade moderada (21-66%) para traços associados à rigidez arterial.73,74

Em estudo com 1480 indivíduos pertencentes a 817 núcleos familiares do Framingham Study Offspring Cohort, Mitchell et al.75 demonstraram que a herdabilidade da VOP foi de 40%. Em outro estudo envolvendo pares de gêmeos dizigóticos e monozigóticos residentes na Hungria e nos Estados Unidos, Tarnoki et al.76 observaram 51%, ajustada para idade, sexo e país de origem. Sayed-Tabatabaei et al.,77 estudando 930 indivíduos pertencentes ao grupo familiar do Erasmus Rucphen Family Study, identificaram que a herdabilidade da VOP foi de 26%, ajustada para diversos fatores de risco (sexo, idade, pressão arterial média, LDL-c, frequência cardíaca e glicemia de jejum). Alvim et al.,78 estudando 1675 indivíduos de uma população brasileira (Baependi Heart Study), observaram uma herdabilidade da VOP moderada (26%), após ajustes para diversos fatores de confusão.

Assim, estes estudos indicam haver uma significativa variação nos valores da herdabilidade da VOP. Grande parte dessa discrepância poderia ser explicada por diferenças relacionadas ao desenho do estudo (gêmeos ou núcleos familiares), diferenças populacionais (etnia) e tipos de ajustes utilizados nas análises estatísticas.

 Marcadores genéticos e rigidez arterial

O número de estudos genéticos envolvendo fenótipos vasculares cresceu exponencialmente nos últimos anos. Investigações utilizando métodos de varredura de genoma apontou que o fenótipo de rigidez arterial pode ser modulado por diferentes regiões cromossômicas.75,79 A despeito do crescente investimento em métodos mais sofisticados de avaliação genética, os estudos de associação com genes candidatos continuam sendo os mais abundantes na literatura. Tendo em vista o fenótipo de rigidez arterial, os polimorfismos mais investigados são provenientes de sistemas que, de forma direta ou indireta, interagem na fisiopatologia do enrijecimento vascular, tais como os integrantes do sistema renina-angiotensina-aldosterona (SRAA), proteínas da estrutura vascular, efetores relacionados à função endotelial e agentes pró-inflamatórios (Tabela 1).

Variantes genéticas associadas à rigidez arterial
Gene Polimorfismo Associação com fenótipos de rigidez arterial
Enzima conversora de angiotensina (ECA), cromossomo 17; localização 17q23.3 rs4340: I/D (inserção no íntron 16) Alelo I: aumento do VOP73
Angiotensinogênio (AGT), cromossomo 1: localização 1q42-q43 rs699: c.704T>C (éxon 2, p.Met235Thr) Alelo T: redução da distensibilidade carotídea74
Óxido nítrico sintase endotelial (eNOS), cromossomo 7; localização 7q36 rs1799983: c.894G>T (éxon 7, p.Glu298Asp) Genótipo GG: PP central elevada76
Receptor β de endotelina (ETBR), cromossomo 13; localização 12q22 rs5351: c.831A>G (éxon 5, p.Leu277Leu) Alelo G: aumento da VOP, somente em mulheres77
Subunidade p22phox da NADPH oxidase (p22phox ou CYBA), cromossomo 16; localização 16p2 rs4673: c.242C>T (éxon 3, p.Tyr72His) Genótipo TT: aumento da VOP, maior risco de rigidez arterial aumentada79
Proteína que interage com tioredoxina (TXNIP), cromossomo 1; localização 1p13 rs7212: 1035C>G3'UTR (região não traduzida) Alelo G: aumento da VOP78
Fator de necrose tumoral alfa (TNF-α), cromossomo 6; localização 6p21.3 rs1800629: -308A>G (região promotora) Alelo A: aumento do índice de rigidez da carótida em pacientes com doença de Kawasaki81
Proteína C-reativa (PCR), cromossomo 1; localização 1q22-q25 rs1130864: 1444C>T 3'UTR (região não traduzida) Alelo T: aumento do índice de rigidez da carótida em pacientes com doença de Kawasaki81
Molécula de adesão de célula vascular (VCAM-1), cromossomo 1; localização 1p32-p31 rs3176878: c.2079T>C (éxon 9, p.Asp693Asp) Genótipo CC: aumento da VOP82
Metaloproteinase 9 da matriz (MMP-9), cromossomo 20; localização 20q11.2-q13.1 rs17576: c.855A>G (éxon 6, p.Arg279Gln) Alelo G: aumento da VOP84
Elastina (ELN), cromossomo 7; localização 7q11.23 3'UTR -/A (região não traduzida) Alelo A: aumento da VOP83

VOP: velocidade de onda de pulso.

O SRAA, além de sua importante função na regulação da pressão arterial, exerce destaque no processo de remodelamento vascular. Portanto, torna-se evidente que variantes genéticas capazes de afetar a atividade de seus efetores (angiotensina, enzima conversora de angiotensina, angiotensinogênio e renina), poderiam influenciar significativamente a fisiopatologia vascular. Neste sentido, diversos estudos observaram associação entre alguns polimorfismos em genes do SRAA com fenótipos de rigidez arterial. Benetos et al.,80 estudando indivíduos saudáveis e hipertensos, demonstraram que a presença do alelo I do polimorfismo I/D da enzima conversora de angiotensina (ECA) estava associada ao aumento da rigidez arterial em ambos os grupos. Bozec et al.,81 estudando pacientes hipertensos, demonstraram que a presença do genótipo TT do polimorfismo p.Met235Thr do angiotensinogênio (AGT) foi associado a menor distensibilidade e maior rigidez de parede da artéria carótida.

O endotélio, que também tem papel fundamental na fisiologia vascular, atua principalmente no controle do tono e do fluxo vascular, por meio da liberação de óxido nítrico e de outros peptídeos vasoativos.82 Comprovada a importância da integridade e funcionalidade endotelial na função vascular, estudos avaliaram o impacto de variantes genéticas ligadas à fisiologia endotelial com fenótipos de rigidez arterial. Mitchell et al.,83 estudando a população do Framingham Heart Study, demonstraram que o genótipo GG do polimorfismo p.Glu298Asp da enzima óxido nítrico sintase endotelial (eNOS) foi associado com elevada PP central, principalmente em mulheres. Contudo, os dados não foram reproduzidos, como se esperava, para a VOP. Lajemi et al.,84 estudando pacientes hipertensos não tratados, demonstraram a associação do alelo G do polimorfismo c.30G>A do receptor β da endotelina (ETBR) com maiores níveis da VOP em mulheres. Além destes, dois estudos com a população geral brasileira observaram associações de polimorfismos nos genes p22phox e TXNIP com a VOP.85,86 O primeiro mostrou que indivíduos com genótipo TT para o polimorfismo p22phox c.242C>T apresentaram maior média da VOP e maior risco para rigidez arterial aumentada, comparados aos indivíduos com genótipos CC ou CT.86 Já o segundo, identificou que indivíduos com genótipos CG ou GG para o polimorfismo TXNIP rs7212 apresentaram maior média da VOP, comparados aos indivíduos com genótipo CC.85

O remodelamento da parede vascular resulta da interação de diversos mecanismos, dentre eles, o processo inflamatório. Inúmeros estudos vêm demonstrando o papel de agentes inflamatórios na disfunção endotelial e na aterosclerose.87 Assim, pesquisadores investigaram o possível impacto de polimorfismos genéticos em genes pró-inflamatórios nos fenótipos de rigidez arterial. Cheung et al.,88 estudando pacientes com histórico de doença de Kawasaki, demonstraram o efeito sinérgico do alelo A do polimorfismo -308 A>G do fator de necrose tumoral alfa (TNF-α) e o alelo T do polimorfismo 1444 C>T da proteína C-reativa (PCR) com o elevado índice de rigidez arterial em artéria carótida. Além disso, considerando o papel fisiopatológico das moléculas de adesão, Zhu et al.89 demonstraram em indivíduos jovens e saudáveis, a associação do genótipo CC do polimorfismo p.Asp693Asp no gene VCAM-1 (moléculas de adesão de células vasculares) com maiores níveis da VOP.

Além dos fatores endócrinos, inflamatórios e vasoativos derivados do endotélio, os componentes estruturais da parede do vaso também são protagonistas no processo de enrijecimento vascular, visto que o desequilíbrio na síntese de colágeno e/ou elastina contribui para a diminuição da distensibilidade vascular.20 Iwai et al.,90 avaliando indivíduos da população japonesa, demonstraram a associação do alelo A do polimorfismo 3'-UTR da elastina(ELN) com maiores valores da VOP. A influência de polimorfismos em genes de algumas metaloproteinases também foi investigada. Yasmin et al.,91 estudando indivíduos saudáveis, demonstraram a associação do alelo G do polimorfismo c.855A > G da metaloproteinase-9 da matriz (MMP-9) com valores aumentados da VOP.

Os estudos acima reforçam a hipótese de que variantes genéticas, localizadas em diferentes genes, contribuam para a modulação do fenótipo da rigidez arterial. Dentro desta temática, estudos mais amplos e que avaliem a utilização de marcadores genéticos na prevenção, no diagnóstico, no tratamento e no prognóstico do paciente são ainda necessários.

 Conclusão

Conhecendo os aspectos fisiopatológicos, assim como os determinantes da rigidez arterial, é plausível que a VOP seja incluída como um dos componentes nos esforços de prevenção das DCV, pelo menos em hipertensos, como indicado na VII Diretriz Brasileira de Hipertensão e na I Diretriz Brasileira de Prevenção Cardiovascular. A avaliação da rigidez arterial pode ser feita pela medida da VOP ou por outros métodos previamente validados. Já os dados genéticos indicam que dezenas de genes podem modular este fenótipo complexo. No entanto, um melhor entendimento da relação genética-rigidez arterial e, até mesmo uma intervenção baseada em genótipos, devem constituir metas a serem alcançadas em estudos futuros.

Fontes de Financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação Acadêmica

Não há vinculação deste estudo a programas de pós-graduação.