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Sumario Vol. 42 - Nº 2 Abril - Junio 2013

Folic Acid and Endothelial Function in Patients
with Diagnosis of Hypertension

Roberto Miguel Miatello

Facultad de Ciencias Médicas, Universidad Nacional de Cuyo.
Parque General San Martín. (5500) Mendoza, Argentina.
Correo electrónico

The author declares not having a conflict of interest.
Rev Fed Arg Cardiol. 2013; 42(2): 85-87
 


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The study carried out by Raymid García Fernández et al [1], from the Instituto de Cardiología y Cirugía Cardiovascular from Cuba, is based on prior evidence that shows the effect of the administration of folic acid on endothelial function. It conveniently quotes studies made on individuals with different pathological conditions that have in common, their capacity of causing an increase in global cardiovascular risk. They also discuss the variability of the previous results existing on the basis of folic acid doses used in these studies, contributing references about meta-analysis that have interpreted these differences.

Since the main objective is evaluating the effect of the administration of folic acid, it is necessary to remember some concepts related to the metabolism of this substance and its participation in vascular function.

Folic acid or folate is a hydrosoluble vitamin of the B group. It is considered an essential nutrient, which means that human beings are not capable of synthesizing it. The only sources of folates are diet and the synthesis from some intestinal bacteria. Although the daily requirement is low (approximately 400 micrograms) and is covered with varied food, its deficit is frequent and the main causes are an inappropriate consumption, absorption problems or interferences produced by medication. Another relevant cause is pregnancy, since the fetus in development consumes rapidly the maternal deposits of folic acid. This has led to the sanitary authorities recommending the strengthening of flours with this nutrient to prevent congenital malformations.

Although folic acid has been traditionally associated to the development of macrocytic anemia, it is known currently that marginal deficiencies or alterations of its metabolism are associated to other frequent pathologies, such as cardiovascular diseases. Folates have mainly two significant physiological effects: they are a cofactor for enzymes that synthesize DNA and RNA, and are necessary to convert homocysteine into methionine. It has been proved that folic acid, as well as vitamins B12 and B6 are determinant for the plasma levels of homocysteine, because of their direct participation in the metabolism of this amino acid. Epidemiological studies have shown consistently that high levels of plasma homocysteine constitute a cardiovascular risk factor.

The exact mechanism by which homocysteine constitutes a cardiovascular risk factor is not clear; however, it is known that an alteration occurs in the antithrombotic mechanisms and the vasodilator capacity, dependent on the endothelium, is altered. The existing evidence suggests that hyperhomocysteinemia produces endothelial dysfunction mediated by free radicals generated during homocysteine oxidation. Moreover, this amino acid stimulates the proliferation of vascular smooth muscle cells, and inhibits the growth of endothelial cells. Also, the high levels of homocysteine promote thrombosis through an increase in the generation of thrombin. Other possible mechanisms of atherogenic damage by homocysteine have been described. See the paper published.

The authors decided to evaluate variables directly linked to endothelial function, such as vasodilation mediated by blood flow in the brachial artery, as well as indirect markers but clearly associated, as the levels of C reactive protein, marker of active inflammatory state; microalbuminuria, indicator of glomerular function and the levels of systolic, diastolic and average blood pressure, considering hypertension as a pathology clearly associated to endothelial dysfunction and under the assumption that the improvement of endothelial function contributes to the figures of systemic blood pressure.

They decided to perform a study with the goal of evaluating the effect of the administration of folic acid in doses of 5 mg/day, in patients with essential hypertension and its repercussion on the control of the blood pressure figures, as well as in the other mentioned variables. This dose is extremely larger than the daily requirements of folates as a vitamin, an aspect that the authors discuss partially, comparing the dose used in their study with those applied in others.

In regard to the methodology used, they selected standardized measurement variables, relatively easy to access. The quantification of the degree of vasodilation mediated by blood flow of the brachial artery constitutes a non-invasive ultrasonographic technique, easily available, economic, simple, reproducible and validated, that allows knowing the health state and vascular endothelium functioning. It is a response dependent on endothelial nitric oxide and when decreased, it expresses an alteration of the normal endothelial functioning. The vasodilation measured by this method is reduced in patients with vascular risk factors and constitute an independent predictor of cardiovascular events with the capacity to detect the degree of endothelial dysfunction degree.

C reactive protein circulates in blood as a response to inflammation, so it is considered a marker of the existence of inflammatory phenomena and, in this regard, also a clear marker of cardiovascular risk. Epidemiological studies suggest that chronic vascular inflammation is a phenomenon that precedes harsh events such as acute CAD or strokes.

C reactive protein is produced by the liver and by adipocytes. It is one of the positive acute phase reagents, which increase their levels during inflammatory processes. Their increase is extremely high in a situation of acute inflammation, as in infections. Since its half life is constant, its level is mainly determined by the rate of production. In hypertensive disease, the vascular wall presents a chronic state of mild inflammation, which leads to a barely increased production, but significant, of the plasma levels of this reagent. Its elevation may predict a greater risk of acute cardiovascular symptoms. In this paper, the authors quote the reference values used universally to establish limits of low, moderate and severe risk, according to cardiovascular diseases and use a lab methodology sensitive enough for evaluation in the patients of their study.

on of albumin in the patients with hypertension, represents an early state of renal function impairment and relates to a greater morbi-mortality by cardiovascular events. Besides, it has been proven that several factors favor the production of microalbuminuria in patients with hypertension. In brief, microalbuminuria, a sign transmitted through the kidneys, indicates that vasculature in general does not work well, so to conclude, it is an index of endothelial dysfunction. The authors of this article determined microalbuminuria in urine samples, obtained in the initial consultation, at 12 and 24 weeks. The method used, agglutination with latex particles, has been little described, the conditions of urine sample extraction are not mentioned and it does not seem to be very sensitive, although they define microalbuminuria in these conditions as concentrations of albumin in urine between 0.02 and 0.2 g/L.

The protocol design includes clear definitions for the inclusion and exclusion of patients. The fact smokers were included stands out, with the only restriction of not having smoked in the 8 hours previous to each study, when in the introduction they emphasize smoking as a cause for endothelial dysfunction.

The time design of the observations and the crossing between the placebo and treated groups halfway through the registry is interesting, although the statistical methodology used is confusing. The authors stated that “the follow-up was 24 weeks since the inclusion. Every patient was his/her own control.” This analytical choice would have originated the application of the ANOVA test of repeated measurements in each group, but the results of this type of analysis are not reported.

About the presentation of their results, the authors state that they are presented, in the case of quantitative variables, as mean ± variance. It is not usual in biomedical literature, to use variance as a measurefor dispersion, since standard deviation is more useful to understand the results, and in the case of analysis, standard error of the mean.

The levels of vasodilatation are expressed as percent variation, with this information not being accompanied by the corresponding dispersion, information that would help the reader to get a clearer view of the phenomenon occurred. The median of C reactive protein concentrations is not accompanied by eloquent dispersion measures either.

At the end of the Results section, there is a reference to correlation studies between variables, indicating the coefficients obtained but not their statistical significance or the size of the sample intervening in the estimation. The magnitudes of those coefficients are relatively low and should not allow the authors to mention them. It is not clear at what time of the protocol the values originating the correlation coefficients were recorded, but it is remarkable that between the “blood pressure” and “percent variation of vasodilation” variables there is a positive correlation. This result would indicate that the greater the vasodilation, the greater the blood pressure.

The graphs lack dispersion indications, as well as symbols indicating the statistical significance in successive protocol stages, which makes their interpretation difficult.

In the Discussion section the authors make a thorough review of studies and meta-analysis devoted to interpret the effects of the administration of folates in variable doses. The conclusions drawn from their own results are mainly supported by the correlation analyses, which as mentioned before, do not provide enough information to validate them.

In brief, the study by Dr. Raymid García Fernández et al, represents an important attempt to understand the effect of the administration of folates on endothelial function. Their results are interesting, especially those related to the measurement of vasodilatation mediated by brachial artery blood flow. More accuracy in the analysis methodology would have allowed a better validation of results and the conclusions drawn from them. It is important to highlight that the authors propose that these non-invasive techniques could be used to predict cardiovascular risk, but suggest that for this the study should be extended to hypertensive patients in more severe stages of their pathology.

 

 

REFERENCES

  1. Garcia Fernández R, Dopazo Alonso M, Sánchez García J, et al. Acido fólico y función endotelial en pacientes con diagnóstico de hipertensión arterial. Rev Fed Arg Cardiol 2013; 42 (2): __-__.

 

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Publication: June 2013

 
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