Índice apo B/apo A-I e predição de risco cardiovascular
Universidade Federal de Minas Gerais - Belo Horizonte, MG - Brasil
As apolipoproteínas são proteínas que estão em associação com lípides nas partículas de lipoproteínas e desempenham funções importantes no metabolismo lipoprotéico, como transporte dessas moléculas hidrofóbicas no meio aquoso plasmático, ligação aos receptores específicos na superfície celular para direcionar corretamente os lípides para os órgãos-alvo e tecidos do organismo, e ativação ou inibição de enzimas envolvidas no metabolismo lipídico1. A apolipoproteína A-I (apo A-I) é o maior componente da partícula de lipoproteína de alta densidade (HDL), representando cerca de 45% de sua massa molecular2 , e atua como cofator para a enzima lecitina colesterol acil transferase, e também como mediador na transferência do colesterol das células para as partículas de HDL, processos importantes para o transporte reverso do colesterol para o fígado2. A apolipoproteína B (apo B) está presente nos quilomícrons como apo B-48 e nas lipoproteínas de densidade muito baixa (VLDL), lipoproteína de densidade intermediária (IDL), e lipoproteína de baixa densidade (LDL) como apo B-100, que é responsável pela ligação da lipoproteína ao seu receptor tecidual específico3. A apo B é a principal proteína funcional para o transporte de colesterol para as células periféricas4. Cerca de 90% da proteína na LDL se constitui de apo B5.
As partículas de LDL, IDL e VLDL apresentam uma molécula de apo B em sua estrutura3, e, dessa forma, a concentração plasmática de apo B indica o número total de partículas potencialmente aterogênicas, correlacionando-se como nível decolesterol não-HDL6. A concentração plasmática de apo A-I é fortemente associada com HDLc, e a expressão de apo A-I pode ser responsável pela determinação dos níveis plasmáticos de HDLc6. Assim, o índice apo B/apo A-I representa o balanço entre as partículas de colesterol potencialmente aterogênicas ricas em apo B e as partículas de colesterol antiaterogênicas ricas em apo A-I.
As pesquisas envolvendo o valor preditivo das apolipoproteínas A-I e B nas doenças ateroscleróticas surgiram há aproximadamente duas décadas, inicialmente m estudos do tipo caso-controle7-9 e, posteriormente, em estudos prospectivos10-12. Atualmente, os níveis plasmáticos das apolipoproteínas A-I e B têm sido descritos como melhores preditores de doenças ateroscleróticas do que as concentrações de lípides e lipoproteínas6,13, e tem sido sugerido que o índice apo B/apo A-I representa um parâmetro superior para predição de risco cardiovascular do que outros índices lipídicos, como colesterol total/HDLc, LDLc/HDLc e colesterol não-HDL/HDLc14,15.
As dosagens das apolipoproteínas apresentam algumas vantagens metodológicas quando comparadas com a quantificação de LDLc. Na maioria das vezes, o LDLc é quantificado usando-se a equação de Friedewald16, a qual fornece uma estimativa dos valores de LDLc, e depende das dosagens de colesterol total, triglicérides e HDLc17. Dessa forma, a estimativa pode incorporar os possíveis erros analíticos desses três parâmetros utilizados para o cálculo do LDLc6, aumentando assim a probabilidade de erros, com potencial impacto nas decisões clínicas18. Essa equação apresenta, ainda, várias limitações, e a estimativa do LDLc não pode ser ampliada para amostras apresentando níveis de triglicérides superiores a 400 mg/dl, amostras contendo quilomícrons e para pacientes portadores de disbetalipoproteinemia19 . Além disso, os estudos têm demonstrado que o método homogêneo para a dosagem de LDLc e a estimativa desses valores pela equação de Friedewald não apresentam resultados semelhantes20-22 .
As apolipoproteínas, por sua vez, podem ser medidas diretamente no plasma, por métodos exatos e precisos, padronizados internacionalmente23,24, utilizando-se material de referência comum para apo A-I e apo B, o qual não está disponível para as medidas de HDLc e LDLc, e sem a interferência significativa de níveis elevados de triglicérides18. Os níveis plasmáticos das apolipoproteínas sofrem pouca influência de variáveis biológicas, enquanto os lípides apresentam flutuação dos níveis plasmáticos em resposta aos vários estímulos do controle metabólico4. Dessa forma, as variáveis pré-analíticas exercem menor influência nas dosagens das apolipoproteínas A-I e B, que podem ser quantificadas mesmo sem a necessidade de jejum prévio do paciente11,12,25.
No Brasil, os custos operacionais relacionados com as determinações das apolipoproteínas reduziram consideravelmente nos últimos anos, com a introdução no mercado brasileiro de conjuntos de reagentes nacionais com padronização internacional. Esse fato propiciou a realização das determinações das apolipoproteínas A-I e B por um maior número de laboratórios clínicos, por um custo mais acessível aos pacientes e com cobertura desses pela maioria dos convênios de saúde do país.
O valor preditivo das apolipoproteínas A-I e B para DAC está bem estabelecido e documentado na literatura. Níveis elevados de apo B, diminuição dos níveis de apo A-I e aumento do índice apo B/apo A-I têm sido consistentemente associados ao risco de DAC26-29.
Quatro estudos prospectivos recentes destacam importantes evidências para a associação entre as apolipoproteínas A-I e B e a DAC. O
Na avaliação de cerca de 170 mil indivíduos suecos, o estudo AMORIS (
Já o estudo INTERHEART31 avaliou cerca de 30 mil indivíduos de 52 países e demonstrou que o índice apo B/apo A-I se mostrou mais fortemente associado com a predição de IAM do que vários fatores de risco convencionais, entre esses tabagismo, hipertensão, diabetes, estresse e obesidade abdominal, independentemente de sexo, idade e origem étnica. No estudo MONICA/KORA32, 1.414 homens e 1.436 mulheres sem história prévia de IAM foram avaliados durante 13 anos. O principal resultado desse estudo foi a observação da forte associação entre níveis aumentados de apo B e risco aumentado para IAM, e a elevação dos níveis de apo A-I não foi significativamente associada ao baixo risco de IAM. Entretanto, a análise multivariada demonstrou que o índice apo B/apo A-I se associou fortemente ao risco de IAM, mesmo após ajustes para idade, índice de massa corporal, tabagismo, diabetes e hipertensão.
Contrariamente, o
Enquanto alguns estudos demonstraram a utilidade de níveis elevados de apo B como preditores de risco cardíaco32,34, outros atribuíram esse risco à diminuição dos níveis de apo A-I35. Entretanto, prevalece um consenso na literatura de que o balanço entre as partículas aterogênicas e antiaterogênicas, refletido pelo índice apo B/apo A-I, representa um parâmetro adicional e importante para predição do risco cardiovascular, sendo atualmente considerado superior aos lípides, lipoproteínas e índices lipídicos convencionais14,36.
Ao contrário da vasta literatura disponível para o risco de DAC, a associação entre aterosclerose periférica como índice apo B/apo A-I ainda não está bem consolidada, sendo essa correlação descrita em poucos estudos. Em 1984, McConathy e cols.37 demonstraram que as apolipoproteínas A-I e B foram importantes para diferenciar indivíduos com doença arterial obstrutiva periférica (DAOP) de indivíduos hígidos em um grupo de mulheres, quando os dados foram analisados em conjunto com as dosagens de colesterol total e triglicérides. Por sua vez, no estudo prospectivo de Schmidt e cols.38, envolvendo 391 homens adultos, acompanhados durante 6,6 anos, observou-se que o índice apo B/apo A-I apresentou associação com aterosclerose na artéria femoral e com risco aumentado para doenças cardiovasculares, comportando-se como um marcador de risco superior ao LDLc. Dois estudos de coorte transversal conduzidos em nosso laboratório (dados não-publicados) mostraram resultados controversos em relação aoí ndice apo B/apo A-I e ateroscleroseperiférica. No primeiro estudo, o índice apo B/apo A-I se apresentou significativamente elevado em pacientes jovens com aterosclerose periférica em diferentes sítios anatômicos (membros superiores, inferiores e retina), quando comparados com indivíduos hígidos. Contrariamente, outro estudo avaliando pacientes idosos apresentando doença arterial periférica apenas em membros inferiores, o índice apo B/apo A-I não apresentou contribuição adicional quando os pacientes foram comparados com indivíduos hígidos. Apesar de as diferenças na composição dos grupos terem sido significativas (idade, fatores de risco, sítios anatômicos comprometidos etc), esses dados reforçam a idéia da necessidade de estudos adicionais envolvendo o índice apo B/apo A-I e doenças ateroscleróticas periféricas.
Com relação à aterosclerose em artérias cerebrais, as evidências são recentes e escassas. No estudo de Bhatia e cols.39, envolvendo 261 pacientes com isquemia transitória prévia, acompanhados por 10 anos, o índice apo B/apo A-I apresentou-se como o melhor preditor independente para AVC isquêmico nesse grupo de pacientes, seguido pela apo B, quando os dados foram analisados em conjunto com lípides, lipoproteínas e índices lipídicos tradicionais. Essa observação foi confirmada pelo estudo AMORIS40, o qual demonstrou uma forte associação entre o índice apo B/apo A-I e o risco de desenvolvimento de acidente vascularcerebral (AVC), isquêmico ou não, sugerindo que essa associação seria semelhante à observada para DAC. A análise multivariada deste último estudo também demonstrou que o índice apo B/apo A-I foi melhor preditor de risco do que os índices convencionais colesterol total/HDLc e LDLc/HDLc, constituindo-se em um melhor marcador de eventos isquêmicos.
Estudos envolvendo o índice apo B/apo A-I têm demonstrado que os agentes hipolipemiantes, sobretudo as estatinas, exercem efeitos relevantes no perfil apolipoprotéico, algumas com significativa redução nos níveis de apo B41,outras com aumento nos níveis de apo A-I e outras ainda atuando nas duas apolipoproteínas6,42,43. Dessa forma, o tratamento com esses agentes pode apresentar um grande potencial em corrigir o balanço anormal entre lipoproteínas aterogênicas e antiaterogênicas que está intimamente associado com o risco cardiovascular.
O uso das apolipoproteínas A-I e B, assim como o índice apo B/apo A-I, como meta terapêutica para agentes hipolipemiantes, no entanto, ainda não está completamente consolidado pela literatura. A inclusão desses parâmetros nos consensos americano e europeu para prevenção de doenças cardiovasculares tem sido alvo de controvérsia e discussão entre os pesquisadores da área44 . O maior problema destacado seria o fato de que, uma vez definida a meta terapêutica para o índice apo B/apo A-I, seria melhor diminuir os valores do numerador (apo B) ou aumentar os valores do denominador (apo A-I)? As evidências a favor da diminuição dos níveis de apo B são muito fortes45,46, mas o aumento dos níveis de apo A-I também é importante para diminuir o risco cardíaco28. O mérito dos benefícios dos agentes hipolipemiantes no perfil apolipoprotéico não está sendo questionado [ver ref. 44], mas um bom marcador de risco cardio vascular não necessariamente precisa indicar uma meta para terapia. Dessa forma, a elevação do índice apo B/apo A-I pode perfeitamente ser usada apenas como um marcador de risco aumentado. e não necessariamente como alvo para terapia com agentes hipolipemiantes.
Em 2004, Walldius e cols.6 sugeriram pontos de corte para o índice apo B/apo A-I de 0,9 e 0,8 para homens e mulheres, respectivamente, demonstrando que valores superiores a esses representariam risco aumentado para doenças cardiovasculares. Esses valores têm sido confirmados por outras pesquisas37,47,48 e os resultados dos estudos AMORIS5 e INTERHEART31 estabeleceram faixas de risco para infarto agudo do miocárdio, mostrados na
Com base nas recentes evidências das vantagens do uso das apolipoproteínas A-I e B como marcadores de risco cardiovascular, o índice apo B/apo A-I emerge como importante parâmetro complementar para avaliação desse risco, especialmente em indivíduos normolipêmicos, com potencial importância para aplicação na monitoração de pacientes de alto risco em terapia com agentes hipolipemiantes no futuro.
Declaro não haver conflitos de interesses pertinentes.
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Marinez Oliveira Sousa Av. Antônio Carlos, 6627 - UFMG - Faculdade de Farmácia 31270-901 - Belo Horizonte, MG - Brasil E-mail:
Artigo recebido em 26/06/06; revisado recebido em 17/11/06; aceito em 17/11/06.
Apo B/apo A-I ratio and cardiovascular risk prediction
Universidade Federal de Minas Gerais - Belo Horizonte, MG - Brazil
Apolipoproteins are proteins associated with lipids in lipoprotein particles. They play important roles in lipoprotein metabolism, such as transport of these hydrophobic molecules in plasma aqueous medium, binding to specific receptors in cell surface to correctly direct lipids to target organs and body tissues, and activation or inhibition of enzymes involved in lipid metabolism1. Apolipoprotein A-I (apo A-I) is the largest component of the high density lipoprotein (HDL) particle, representing approximately 45% of its molecular mass2. Moreover, it acts as a co-factor for the enzyme lecithin cholesterol acyl transferase and as a mediator in transfer of cholesterol from cells to HDL particles, which are important processes for the reverse transport of cholesterol to the liver2. Apolipoprotein B (apo B) is present in chylomicrons, such as apo B-48, and in very low density lipoproteins (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), such as apo B-100, which is responsible for binding the lipoprotein to its specific tissue receptor3. Apo B is the main functional protein for transporting cholesterol to peripheral cells4. About 90% of protein in LDL is composed of apo B5.
LDL, IDL and VLDL particles present an apo B molecule in their structure3; therefore, the plasma concentration of apo B indicates the total number of potentially atherogenic particles, correlating with the non-HDL cholesterol levels6. The plasma concentration of apo A-I is strongly associated with HDLc, and the expression of apo A-I may be responsible for determining HDLc plasma levels6. Hence, the apo B/apo A-I ratio represents the balance between apo-B-rich potentially atherogenic cholesterol particles and apo-A-I-rich antiatherogenic cholesterol particles.
Researches involving the predictive value of apolipoproteins A-I and B in atherosclerotic diseases emerged approximately two decades ago, initially as case-control studies7-9 and, later, in prospective studies10-12. At present, plasma apolipoprotein A-I and B levels have been described as better predictors of atherosclerotic diseases than lipid and lipoprotein concentrations6,13; it has also been suggested that the apo B/apo A-I ratio represents a superior parameter for predicting cardiovascular risk as compared with other lipid ratios, such as total cholesterol/HDLc, LDLc/HDLc and non-HDL cholesterol/HDLc14,15.
Apolipoprotein measurements present some methodological advantages when compared with LDLc quantification. In most cases, LDL cisquantified by the Friedewald equation16, which provides an estimate of the LDLc values and depends on total cholesterol, triglyceride and HDLc levels17. In this manner,the estimate may include the possible analytical errors of these three parameters used for calculating LDLc6, thus increasing the likelihood of errors and of potential impact in clinical decisions18. This equation also presents several limitations and the LDLc estimate can not be extended to samples presenting triglyceride levels higher than 400mg/dl, samples containing chylomicrons and to patients with dysbetalipoproteinemia19. In addition, some studies have shown that the homogeneous method for measuring LDLc and the estimate of these values by the Friedewald equation do not show similar results20-22.
On the other hand, apolipoproteins may be measured directly in plasma throug haccurate and precise internationally standardized methods23,24, by using a common reference material for apo A-I and apo B which is not available for measurements of HDL cand LDLc, and without the significant interference of high triglyceride levels18. Plasma apolipoprotein levels are slightly influenced by biological variables, whereas plasma lipid levels fluctuate in response to various metabolic control stimulus4. Therefore preanalytical variables have less influence in the measurements of apolipoproteins A-I and B, which can be dosed with no need of prior fasting11,12,25.
In Brazil, the operational costs related to apolipoprotein measures have considerably decreased in the past years with the introduction in the market of kits containing international-standard reagents made in the country. This fact enabled apolipoprotein A-I and B measuring by a larger number of clinical laboratories, at a more affordable cost to patients and payment by most health insurance plans.
The predictive value of apolipoproteins A-I and B in CAD is well established and documented in the medical literature. High apo B levels, decreased apo A-I levels and increased apo B/apo A-I ratios have been consistently associated with risk of CAD26-29.
Four recent prospective studies emphasized important evidence in the association between apolipoproteins A-I and B and CAD. The Quebec Cardiovascular Study10 assessed 2155 Canadian men and it was the first prospective study to show that apo B was superior to the conventional lipid ratios to predict cardiovascular risk. In the same study, after a 13-year follow-up30, increased plasma levels of apo B remained as an independent risk factor for prediction of ischemic coronary events and the authors concluded that this association is higher in men with desirable levels of LDLc.
In an evaluation of 170 thousand Swedish individuals, the AMORIS (Apolipoprotein-related Mortality Risk)11 study showed that apo B was a better marker of cardiovascular risk than LDLc, especially in individuals with desirable levels of LDLc, regardless of sex. The apo B/apo A-I ratio was identified in this study as the single variable that was more strongly associated with increased risk of fatal myocardial infarction (MI), particularly when lipid levels were within the range of desirable values. Other data obtained in this study15 showed that the total cholesterol/HDLc ratio considerably underestimates the cardiovascular risk, and the apo B/apo A-I ratio was the best variable related to lipids to quantify coronary risk as compared with total cholesterol/HDLc, LDLc/HDLc and non-HDL cholesterol/HDLc ratios14.
However, the INTERHEART31 study evaluated about 30 thousand individuals in 52 countries and demonstrated that the apo B/apo A-I ratio was more strongly associated with MI prediction than several conventional risk factors, such as smoking, hypertension, diabetes, stress and abdominal obesity, regardless of sex, age and ethnicicity. In the MONICA/KORA32 study, 1414 men and 1436 women with no past history of MI were evaluated for 13 years. The main result of this study was the strong association between raised apo B levels and increased risk of MI, whereas increased apo A-I levels were not significantly associated with low risk of MI. However, the multivariate analysis showed that the apo B/apo A-I ratio was strongly associated with the risk of MI even after adjustments to age, body mass index, smoking, diabetes mellitus and hypertension.
Contrary to this study, the Women's Health Study33 , which evaluated 15000 women aged over 45 years for 10 years, revealed that the non-HDL cholesterol and the total cholesterol/HDLc ratio were as efficient asapolipoproteins A-I and B and the apo B/apo A-I ratio to predict cardiovascular risk. Nonetheless, apo B was the best single parameter to predict future cardiovascular events in women.
While some studies show the usefulness of increased apo B levels as predictors of cardiac risk32,34, other shave attributed this risk to diminished apo A-I levels35. But the consensus in the literature is still that the balance between atherogenic and antiatherogenic particles, reflected by the apo B/apo A-I ratio, represents an additional and important parameter for cardiovascular risk prediction, and nowadays it is considered a better marker when compared to lipids, lipoproteins and conventional lipid ratios14,36.
As opposed to the extensive literature available for CAD risk, the association between peripheral atherosclerosis and apo B/apo A-I ratio is not well established and this correlation has been described in few studies. In 1984, McConathy et al37 showed that apolipoproteins A-I and B were important to differentiate individuals with peripheral occlusive arterial disease (POAD) from healthy individuals in a group of women, when the data were analyzed in conjunction with the measurement of total cholesterol and triglycerides. On the other hand, in a prospective study carried out by Schmidt et al38 comprising 391 adult males who were followed up for 6.6 years, it was noted that the apo B/apo A-I ratio showed an association with atherosclerosis in the femoral artery and increased risk of cardiovascular diseases; this ratio behaved as a risk marker better than LDLc levels.
Two cross-section cohort studies conducted in our laboratory (unpublished data) showed controversial results in terms of the apo B/apo A-Iratio and peripheral atherosclerosis. In the first study, the apo B/apo A-I ratio was significantly increased in young patients with peripheral atherosclerosis at different anatomical sites (upper and lower limbs and retina) when compared with healthy individuals. On the contrary, in another study that evaluated elderly patients with peripheral arterial disease in lower limbs, the apo B/apo A-I ratio did not show any additional contribution when patients were compared with healthy individuals. In spite of the significant differences in the group composition (age, risk factors, affected anatomical sites, etc), these data reinforce the need of further studies involving the apo B/apo A-I ratio and peripheral atherosclerotic diseases.
As to atherosclerosis in cerebral arteries, evidence is recent and scarce. In a study by Bhatia et al39 with 261 patients with previous transient ischemia and followed up for 10 years, the apo B/apo A-I ratio was the best independent predictor for ischemic stroke in this group of patients, followed by apo B, when the data were analyzed along with lipids, lipoproteins and traditional lipid ratios. This observation was confirmed by the AMORIS study40 that showed a strong association between apo B/apo A-I ratio and risk of stroke, ischemic or not, suggesting that this association would be similar to that reported for CAD. The multivariate analysis of this latest study also established that the apo B/apo A-I ratio was a better risk predictor than the conventional ratios of total cholesterol/ HDLc and LDLc/HDLc, thus representing a better marker of ischemic events.
Some studies involving the apo B/apo A-Iratio revealed that lipid-lowering drugs, especially statins, have relevant effects on the apolipoprotein profile, some leading to significant reduction in apo B levels41, others to increased apo A-I levels, and still other statinsacting in both apolipoproteins6,42,43. Hence treatment with these drugs may present a great potential to correct the abnormal balance between atherogenic and antiatherogenic lipoproteins, which is closely associated with cardiovascular risk.
However, the use of apolipoproteins A-I and B and apo B/apo A-I ratio as treatment target for lipid-lowering drugs has not been completely established in the literature. The inclusion of these parameters in the North American and European consensus for the prevention of cardiovascular diseases has been the object of controversy and debate among researchers in this area44. The greatest problem would be that, once the treatment goal for the apo B/apo A-I ratio is established, would it be better to decrease the numerator values (apo B) or increase the denominator values (apo A-I)? Evidences favoring the decrease of apo B levels are very strong45,46, but the increase of apo A-I levels is also important to decrease the cardiac risk28. The benefits of lipid-lowering drugs in the apolipoprotein profile are not under discussion [see Ref 44], but a good cardiovascular risk marker does not necessarily have to indicate a treatment goal. Thus, increased apo B/apo A-I ratio can perfectly be used only as marker of increased risk and not necessarily as a target for therapy with lipid-lowering drugs.
In 2004, Walldius et al6 suggested cut-off points for the apo B/apo A-I ratio of 0.9 and 0.8 for men and women, respectively, showing that higher values would represent an increased risk of cardiovascular disease. These values have been confirmed by other researches37,47,48 and the results of the AMORIS11 and INTERHEART31 studies established risk ranges for MI, which are shown in
Based on recent evidence of the advantages of using apolipoproteins A-I and B as markers of cardiovascular risk, apo B/apo A-Iratio emerges as an important complementary parameter for the evaluation of this risk, especially in normolipidemic individuals, and it has potential importance in the future monitoring of high-risk patients receiving lipid-lowering drugs.
No potential conflict of interest relevant to this article was reported.
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Marinez Oliveira Sousa Av. Antônio Carlos, 6627 - UFMG - Faculdade de Farmácia 31270-901 - Belo Horizonte, MG - Brazil E-mail:
Manuscript received June 26, 2006; revised received November 17, 2006; accepted November 17, 2006.
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