ijcs International Journal of Cardiovascular Sciences Int. J. Cardiovasc. Sci. 2359-5647 2359-4802 Sociedade Brasileira de Cardiologia 4XXySVvfRpLzjbFxjbDVZMy S2359-56472017000400354 10.5935/2359-4802.20170051 VIEWPOINT Detailing Peripheral Arterial Tonometry in Heart Failure. An Endothelial Function Evaluation Tavares Aline Cristina 1 2 3 Bocchi Edimar Alcides 1 Guimarães Guilherme Veiga 1 Universidade de São Paulo Faculdade de Medicina Hospital das Clínicas Brazil Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) Universidade de São Paulo Instituto do Câncer do Estado de São Paulo Brazil Instituto do Câncer do Estado de São Paulo Hospital Sírio-Libanês São Paulo SP Brazil Hospital Sírio-Libanês São Paulo, SP - Brazil Hospital Sírio-Libanês Mailing Address: Aline Cristina Tavares, Rua Londrina, 658. Postal Code: 09181-160, Vila Linda, Santo André, São Paulo, SP - Brazil. E-mail: alinet84@gmail.com

Author contributions

Conception and design of the research: Tavares AC, Guimarães GV. Acquisition of data: Tavares AC, Guimarães GV. Analysis and interpretation of the data: Tavares AC, Bocchi EA. Writing of the manuscript: Tavares AC, Guimarães GV. Critical revision of the manuscript for intellectual content: Tavares AC, Bocchi EA, Guimarães GV. Making of Figures: Tavares AC.

Potential Conflict of Interest

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

 Jul-Aug 2017 30 4 354 358 17 06 2016 15 08 2016 24 02 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. Keywords Endothelium/physiopathology Heart Failure Stroke Volume Nitric Oxide Introduction

Endothelium regulates cardiac function and vasomotor tone, adjusts vascular permeability, preserves blood fluidity, playing an important role in cardiovascular homeostasis.1,2 In adults with heart failure (HF), endothelial dysfunction severity is related to diastolic dysfunction,1,2 increase in cardiovascular risk,1-10 heart failure,11,12 exercise incapacity,13 severity of cardiovascular symptoms,6,7,10,14,15 cardiovascular events,16 cardiac transplant and death.17,18

Although endothelium is at the interface between circulating cardiovascular factors and underlying organ tissues, cardiovascular and endothelial peripheral dysfunctions are not totally linked so far.18-20 Evaluation of endothelial function appears as a tempting adjunct for cardiovascular risk stratification,16 and understanding this matter may help having a faster approach and better screening in the cardiomyopathy field in everyday clinical practice, which brings the importance of this paper.

The objective of this study was to perform an interpretation of endothelial function development in HF patients.

 Methods

Different databases (PubMed e Medline) were searched to identify the characteristics about endothelial function evaluation in both coronary and peripheral circulation, as a way to better explain the interface between endothelial dysfunction and heart failure.

 Results

Heart failure represents the heart incapacity of performing sufficient cardiac output to satisfy all body demands3, 20,11 either with preserved ejection fraction or not.8,16

There are several potential mechanisms by which endothelial dysfunction may contribute to disease progression in patients with heart failure (HF). Adult patients with HF, in New York Heart Association (NYHA) functional class II-III and more severe endothelial dysfunction would have a higher incidence of hospitalization due to decompensation of HF, cardiac transplantation, or cardiac-causing death in a 1-year follow-up than those with relatively preserved endothelium-dependent relaxation.17

Nonetheless, it may be a cycle dysfunction and it is not known whether endothelial dysfunction is the cause or the consequence of heart failure (Figure 1).7-44

Cycle dysfunction representation between heart failure and endothelial dysfunction ↑ increase; ↓ decrease; ACE: angiotensin converting enzyme; O2- O2-radical; NO: nitric oxide.

Impaired availability of endothelium-derived nitric oxide (NO) contributes to this abnormal vasodilator response to physiological stimuli7,17,20 in heart failure, both in the coronary and peripheral circulation.13,14,23-28

Regarding this, it is interesting to note also that a common polymorphism of endothelial NO-synthase (eNOS) shows increased vasoconstrictive response,14,24,29 which may be associated with decreased NO-synthase (NOS) activity. This polymorphism is associated with poorer event-free survival and clinical endpoints reflecting progression of the disease in patients with heart failure.30-32

Therefore, endothelial dysfunction may contribute to the sympathetic tone systemically,33-37 which contributes to exercise intolerance,14,26,40 reduced capillary density in cardiac muscle,28 impaired myocardial perfusion,14,39 inhibited myocardial contractility,30 impaired myocardial oxygen consumption,40 impaired left ventricular relaxation in pressure-overload hypertrophy,41 enhanced cardiac afterload,14,22,25-27 left ventricular remodeling in HF,14,29,31,42,43 and further increase in myocardial damage.14,25,27,28,31,38,43,44

Experimental and clinical studies have provided new data about the mechanisms of specific aspects of endothelial function, therefore a potential mechanism of endothelial dysfunction is alteration of the signaling mechanisms involved in eNOS activation.45

Some novel approaches in patients with polymorphisms or mutations of genes that might play a pathogenic role in endothelial dysfunction investigate the relationship between genetic factors associated with endothelial function and the development of cardiac alterations.45-48

The ecNOS gene a/b polymorphism and the β-Nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase p22phox gene C242T polymorphism are found to be significantly associated with the development of CAD.45,46 Regarding this topic, the following reduce NO bioavailability: polymorphisms in the eNOS gene,47 upregulation of matrix metalloproteinase-2,49 and elevated levels of dimethylarginine, which is a competitive antagonist of endothelial nitric oxide synthase (eNOS). Some studies also found microRNA 217 upregulation, an NAD-dependent deacetylase, as responsible for endothelial alteration and eNOS activity decrease.46-50

Other factors that may also worsen endothelial function, such as activation of the endoplasmic reticulum(ER) stress response,41 high pro-inflammatory status, inflammatory cytokines, such as E-selectin and P-selectin,52-55 over expression of tumor necrosis factor α, interleukin, high levels of plasminogen-activator inhibitor 1 (PAI-1),56 increased adipose tissue mass, lower adropin levels4 and lower tissue 5-methyltetrahydrofolate (5- MTHF)56-57 levels, are correlated with endothelium-dependent vasodilation impairment.

Therefore, endothelial cycle dysfunction is influenced by several correlated mechanisms, which promote better the understanding of the topic and also improve its contribution in the cardiovascular field (Figure 2).

Representation of cycle dysfunction between heart failure and endothelial dysfunction with genetic and other influences ↑ increase; ↓ decrease; 5- MTHF: 5-methyltetrahydrofolate; ACE: angiotensin converting enzyme; O2 - O2-radical; eNOS: endothelial nitric oxide synthase; ER: endoplasmic reticulum; IL-6: interleukin 6; NO: nitric oxide; PAI-1: plasminogen-activator inhibitor 1; TNF-∞: tumor necrosis factor α; VEGFR2: vascular endothelial growth factor receptor-2

Conclusion

Low endothelial response to blood flow contributes to cardiac dysfunction. The other way around is also accurate, which involves cardiac dysfunction as a start for endothelial change. Therefore, a cycling dysfunction may be involved in both central and peripheral alterations.

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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Contribuição dos autores

Concepção e desenho da pesquisa: Tavares AC, Guimarães GV. Obtenção de dados: Tavares AC, Guimarães GV. Análise e interpretação dos dados: Tavares AC, Bocchi EA. Redação do manuscrito: Tavares AC, Guimarães GV. Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Tavares AC, Bocchi EA, Guimarães GV. Confecção de Figuras: Tavares AC.

Potencial Conflito de Interesse

Declaro não haver conflito de interesses pertinentes.

 Palavras-chave Endotélio/fisiopatologia Insuficiência Cardíaca Volume Sistólico Óxido Nítrico Introdução

O endotélio regula a função cardíaca e o tônus vasomotor, ajusta a permeabilidade vascular, preserva a fluidez sanguínea, desempenhando um papel importante na homeostase cardiovascular.1,2 Em adultos com insuficiência cardíaca (IC), a severidade da disfunção endotelial está relacionada à disfunção diastólica,3,4 aumento do risco cardiovascular,5-10 insuficiência cardíaca,11,12 incapacidade de praticar exercícios,13 gravidade dos sintomas cardiovasculares,6,7,10,14,15 eventos cardiovasculares,16 transplante cardíaco e óbito.17,18

Embora o endotélio encontre-se na interface entre os fatores cardiovasculares circundantes e os tecidos dos órgãos subjacentes, as disfunções cardiovasculares e endoteliais periféricas não se encontram totalmente relacionadas até o momento.18-20 A avaliação da função endotelial aparece como um fator coadjuvante tentador para a estratificação do risco cardiovascular16 e a compreensão desse assunto pode ajudar a promover uma abordagem mais ágil e melhorar a triagem no campo das cardiomiopatias na prática clínica diária, o que justifica a importância deste artigo.

O objetivo deste estudo foi realizar uma interpretação do desenvolvimento da função endotelial em pacientes com IC.

 Métodos

Diferentes bases de dados (PubMed e Medline) foram pesquisadas ​​para identificar as características sobre a avaliação da função endotelial nas circulações coronária e periférica como uma forma de explicar melhor a relação entre a disfunção endotelial e a insuficiência cardíaca.

 Resultados

A insuficiência cardíaca representa a incapacidade do coração de realizar débito cardíaco suficiente para satisfazer todas as demandas,3,20,21 seja com fração de ejeção preservada ou não.8,16

Há diversos possíveis mecanismos pelos quais a disfunção endotelial pode contribuir para a progressão da doença em pacientes com insuficiência cardíaca (IC). Pacientes adultos com IC enquadrados na classe funcional II-III da New York Heart Association (NYHA) e com disfunção endotelial mais grave teriam maior incidência de hospitalização devido à descompensação da IC, transplante cardíaco ou óbito, devido a causas cardíacas em seguimento de um ano em comparação com aqueles com relaxamento dependente do endotélio relativamente preservado.17

No entanto, pode ser uma disfunção de ciclo e não se sabe se a disfunção endotelial é a causa ou a consequência da insuficiência cardíaca (Figura 1).7-44

Representação do ciclo de disfunção entre a insuficiência cardíaca e a disfunção endotelial ↑ aumento; ↓ diminuição; ECA: enzima conversora da angiotensina; O<sub>2</sub> - O2-radical; NOS: enzima óxido nítrico-sintase; ON: óxido nítrico.

Alterações na disponibilidade de óxido nítrico (ON) derivado do endotélio contribuem para essa resposta vasodilatadora anormal a estímulos fisiológicos7,17,20 na insuficiência cardíaca, tanto na circulação coronária quanto na periférica.13,14,23-28

Sobre essa questão, é interessante observar também que um polimorfismo comum da sintase endotelial de óxido nítrico (eNOS) mostra aumento da resposta vasoconstritora,14,24,29 que pode estar associada à diminuição da atividade da sintase de óxido nítrico (NOS). Esse polimorfismo está associado à piora da sobrevida livre de eventos e desfechos clínicos que refletem a progressão da doença em pacientes com insuficiência cardíaca.30-32

Portanto, a disfunção endotelial pode contribuir sistemicamente para o tônus simpático,33-37 o que contribui para a intolerância ao exercício,14,26,40 redução da densidade capilar do músculo cardíaco,38 alteração da perfusão miocárdica,14,39 inibição da contratilidade miocárdica,40 alteração do consumo de oxigênio pelo miocárdio,40 alteração do relaxamento ventricular esquerdo na hipertrofia de sobrecarga de pressão,41 pós-carga cardíaca aumentada,14,22,25-27 remodelação ventricular esquerda na IC,14,29,31,42,43 e elevação adicional do dano miocárdico.14,25,27,28,31,38,43,44

Estudos experimentais e clínicos têm fornecido novos dados sobre os mecanismos de aspectos específicos da função endotelial. Portanto, um possível mecanismo da disfunção endotelial é a alteração dos mecanismos de sinalização envolvidos na ativação da eNOS.45

Algumas abordagens inovadoras em pacientes com polimorfismos ou mutações genéticas que podem desempenhar um papel patogênico na disfunção endotelial investigam a relação entre fatores genéticos associados à função endotelial e o desenvolvimento de alterações cardíacas.45-48

O polimorfismo do gene ecNOS a/b e o polimorfismo C242T p22phox do dinucleótido de β-nicotinamida e adenina/fosfato de dinucleótido de β-nicotinamida e adenina (NADH/NADPH) oxidase estão significativamente associados ao desenvolvimento de DAC.45,46 No que diz respeito a esse assunto, os seguintes fatores reduzem a biodisponibilidade de ON: polimorfismos genéticos da eNOS,47 regulação positiva da matriz metaloproteinase-2,49 e níveis elevados de dimetilarginina, que é um antagonista competitivo da sintase endotelial de óxido nítrico (eNOS). Alguns estudos também reportam a regulação positiva do microRNA 217, deacetilase NAD-dependente, como sendo responsável pela alteração endotelial e diminuição da atividade da eNOS.46-50

Outros fatores que também podem prejudicar a função endotelial, como a ativação da resposta ao estresse do retículo endoplasmático (RE).51 alto estado pró-inflamatório, citocinas inflamatórias, tais como a E-selectina e P-selectina,52-55 sobre-expressão do fator α de necrose tumoral, interleucina,6 altos níveis de inibidor do ativador do plasminogênio 1 (PAI-1),56 aumento da massa de tecido adiposo, redução dos níveis de adropina e redução dos níveis teciduais de 5-metiltetraidrofolato (5-MTHF)56-57, estão correlacionados com insuficiência na vasodilatação endotélio-dependente.

Portanto, a disfunção endotelial é influenciada por diversos mecanismos correlatos, que promovem uma melhor compreensão do tema e também melhoram sua contribuição no campo cardiovascular (Figura 2).

Representação da disfunção do ciclo entre insuficiência cardíaca e disfunção endotelial com influências genéticas e outras influências ↑ aumento; ↓ redução; 5-MTHF: 5-metiltetrahidrofolato; ECA: enzima conversora da angiotensina; O<sub>2</sub> - O2-radical; eNOS: sintase endotelial de óxido nítrico; RE: retículo endoplasmático; IL-6: interleucina 6; ON: óxido nítrico; PAI-1: inibidor do ativador de plasminogênio 1; TNF-∞: fator de necrose tumoral α; VEGFR2: receptor-2 do fator de crescimento endotelial vascular; NOS: enzima óxido nítrico-sintase; NADPH: fosfato de dinucleótido de β-nicotinamida eadenina.

Conclusão

Baixa resposta endotelial ao fluxo sanguíneo contribui para a disfunção cardíaca. O contrário também ocorre, envolvendo a disfunção cardíaca como início da alteração endotelial. Portanto, pode-se ter o envolvimento de uma disfunção de ciclo tanto nas alterações centrais quanto nas periféricas.

Fontes de Financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação Acadêmica

Não há vinculação deste estudo a programas de pós-graduação