ISSN 0326-646X





Sumario Vol. 42 - Nº 2 Abril - Junio 2013

Folic Acid and Endothelial Function in Patients
with Diagnosis of Hypertension

Raymid García Fernández, Marcos Dopazo Alonso,
Jesús Sánchez García, Flor Heres Álvarez, Juan Valiente Mustelier, Mireya Amoedo Mon, David García Barreto

Instituto de Cardiología y Cirugía Cardiovascular de Cuba.
Calle 17 Nº 702, entre paseo y A. La Habana, Cuba.
Teléfono: 5532245844.
Correo electrónico

The authors declare not having a conflict of interest.

Print version Imprimir sólo la columna central



Introduction: The altered endothelial function is related with the physiopathogenesis of systemic arterial hypertension.
Objective: To determine if 5 mg of folic acid daily improves the endothelial function and reduces the artery pressure values.
Method: A controlled placebo clinical trial was undertaken including 60 patients with high blood pressure diagnosis. The patients came from the Institute of Cardiology during a period extending from February 2009 to April 2010. Cross-over design. Two treatment groups were assigned: group A: placebo, group B: Folic acid (5mg daily). Both received atenolol and/or hydrochlorothiazide. The pressure values were controlled and the endothelial function was studied at the beginning, and at 6, 12, 18, and 24 weeks of treatment. At 12 weeks the groups were interchanged. The microalbuminuria values at the beginning, and 12 and 24 weeks were determined. For each variable mean and variance were estimated. P = 0.05 was considered significant throughout the work.
Results: At 6 and 12 weeks, there was a significant increase in flow mediated dilation in group B while in group A there wasn't (p=0.0016, p=2.722064E-05 respectively). After the crossover there was a decrease of the flow mediated dilation in Group B and it kept increasing in Group A. There was a significant decrease of the microalbuminuria values without difference between groups.
Conclusions: It is concluded that 5 mg of folic acid daily improves flow mediated dilation without significant changes in the pressure values.

Key words: Flow mediated dilation. Endothelial dysfunction.High blood pressure.Folic acid.
Rev Fed Arg Cardiol. 2013; 42(2): 127-134



Systemic hypertension has been considered the health disorder most widespread throughout the world [1]. It is also one of the greatest risk factors of cardiovascular diseases so, a timely diagnosis and a proper treatment contribute to prevent the effect caused on the target organs.

Atherosclerosis constitutes the main cause of mortality in the world, but if detecte timely, it can be delayed, halted or even reversed [2].

The vascular endothelium acts not only as a mechanical barrier between the blood and the vessel, but also as an autocrine, paracrine and endocrine gland. This organ of flat cells is capable of regulating arterial tone, the proliferation of the smooth muscle, platelet aggregation, the adhesion of monocytes, hemostasis, thrombolysis, inflammation, some immune responses and the production of free radicals [3].

Vasodilator substances secreted by the endothelium are: nitric oxide (NO), prostacyclin, bradykinin, and the hyperpolarizing factor; while vasoconstrictive substances of endothelial origin are: endothelin 1, thromboxane, and angiotensin II activated by the converting enzyme that is expressed in the endothelial cell. The predominantly vasodilator hormone is NO that acts by releasing cyclic guanosine monophosphate in the smooth muscle cell [4].

Endothelial dysfunction is the basis for the development of the atherosclerotic process [3]. Psychic stress and the habit of smoking negatively influence the endothelial function, at least transitorily [5-7]. Altered endothelial function relates in part, to the physiopathogenesis of essential hypertension and associated complications [8].

Microalbuminuria, a well known risk marker of early renal impairment, is considered an independent predictor of adverse cardiovascular events in several populations [9]. On the other hand, C-reactive protein (CRP), an acknowledged marker of inflammation has also emerged as a risk biomarker of atherosclerotic cardiovascular disease. Levels of CRP <1, 1-3 and >3 mg/L, have been considered as low, medium and high cardiovascular risk, respectively [10]. The association between high levels of CRP or microalbuminuria and hypertension has been reported. The elevation of CRP levels (determined by high sensibility methods) reflects vascular inflammation in a low degree, characteristic of atherosclerosis [11]; while microalbuminuria seems to be a marker of widespread endothelial impairment in the vascular tree, including the glomerulus [12]. Both markers reflect closely related components of the atherosclerotic process.

There are hypotensive medications that due to their mechanism of action improve endothelial function, among other reasons by increasing the synthesis of Nitric Oxide, such is the case of angiotensin converting enzyme inhibitors and angiotensin receptor antagonists II [13-15]. Although there is no consensus that by controlling blood pressure figures, endothelial function may be improved, it is indeed true that left ventricular hypertrophy reverts, among other reasons for hemodynamic control [16]. It is known that folic acid causes an improvement in endothelial function regardless of the figures of homocysteine in blood [17]. In type II diabetic patients, 10 mg of folic acid administered for two weeks improved endothelial function regardless of homocysteine levels; however, there was no modification in inflammation markers as C-reactive protein [18]. There is evidence that 5 mg of folic acid improve endothelial function in patients with chronic ischemic heart disease after six weeks of treatment [19], as well as the sensibility of baroreceptors in hypertensive patients with autonomic dysregulation [20]. Supposedly, the endothelial function improvement contributes to decrease the figures of systemic blood pressure.

With the aim of evaluating the influence of 5 mg of folic acid on endothelial function of patients with essential hypertension and its repercussion on the control of blood pressure figures, we decided to conduct this study.

A randomized, cross-sectional, controlled with placebo and double blind study was made, which included 60 patients with diagnosis of uncomplicated systemic hypertension, received at the Instituto de Cardiología y Cirugía Cardiovascular (ICCCV), with ages ranging from 40 to 60 years, in the term between February 2009 and April 2010. The follow-up was 24 weeks from the inclusion. Every patient was his/her own control.

The population was constituted by all hypertensive patients coming to the cardiology offices in the term of the study.

The estimation of the size of the sample, considering a difference in blood pressure of 5% and also an improvement of 5% in endothelial function, with a type 1 error of 0.5 and a power of 80% is 60 patients.

To control the biases in the design, the patients were randomized according to a table of random numbers, controlled by placebo and double blind.

Inclusion criteria.
Those patients with figures greater or equal to 140 mmHg of systolic pressure and 90 mmHg of diastolic pressure, with a recent diagnosis and who were not taking medications, and those who in spite of taking antihypertensive medications were not controlled, were included. Likewise, the controlled patients that were taking atenolol and/or hydrochlorothiazide were also included. The patients that were treated with angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor antagonists (ARA II), calcium antagonists, were proposed to suspend these medications to be included in the investigation.

Exclusion criteria.
The patients with the following conditions were excluded from the study: bronchial asthma, diabetes mellitus, 2nd degree atrioventricular block or higher, hypertension complicated by left ventricular hypertrophy (defined as echocardiography by left ventricular mass index and relative parietal thickness), CAD, secondary hypertension, dementia, alcoholism and/or addiction to drugs, epileptic patients, those with treatment with HMG CoA reductase inhibitors, vitamin C, vitamin B complex, and the patients with microalbuminuria.

The patients were assigned randomly to two groups of treatment according to a table of randomized numbers: one group received placebo and atenolol and/or hydrochlorothiazide (group A) and another group received 5 mg of folic acid per day plus atenolol and/or hydrochlorothiazide (group B). The initial dose of atenolol was 50 mg per day and when there was no control it was increased to 100 mg, while the initial dose of hydrochlorothiazide was 12.5 mg per day with a chance of increasing it to 25 mg if necessary. If there was no control of blood pressure after 6 weeks of treatment with the previous scheme, a third drug was added, which if it was ACEI, ARA II or a calcium antagonist made the patient be excluded from the investigation, though continuing with the intention-to-treat consultation. Once the investigation was over, the patients continued with their care in a visit to the ICCCV.

After 12 weeks of treatment, the patients were crossed in the following manner: those patients that were assigned to the treatment with folic acid received placebo, while the patients that were assigned to the placebo group received folic acid.

A control was made of blood pressure figures and the endothelial function was studied at the beginning, at 6, 12, 18 and 24 weeks of treatment.

The results were delivered to an independent observer, away from the execution stage, while such results were being obtained. If 6 weeks after crossing the patients there were no results or these were evident, the observer could consider the study finished. It is worth mentioning that there was no need to exclude any patient for these causes.

The main variables to be used were: endothelial function and systemic blood pressure.

Endothelial function was evaluated by dilatation mediated by brachial artery flow. To determine this variable, the Celermajer procedure was followed by our group of previous studies [2,5-7].

A value of dilatation dependent from the endothelium was considered normal when equal or higher to 5%. The patients had to be in a fasting condition and not having smoked for at least 8 hours.

The measures of blood pressure were taken in the right arm with the patient in a sitting position and 2 takes were made with an interval of 2 minutes between them. Blood pressure was considered high when the figures were greater or equal to 140/90 mmHg.

The determination of microalbuminuria was made in urine samples (obtained in the initial consultation, at 12 and 24 weeks), using a method of agglutination with latex particles. Microalbuminuria was defined as concentrations of albumin in urine between 0.02 and 0.2 g/L.

The concentrations of CRP were determined in serum samples (obtained in the initial consultation) by an immunoturbidimetric method of high sensibility: CRPHS (Tina-quant Cardiac C-reactive Protein (Latex) High Sensitive) from the commercial trademark Roche Diagnostics. The concentrations of CRP were expressed in mg/L.

Statistical analysis
A comparison was made of the variables of gender, age, and body mass index (BMI: weight in kg/square of height) by groups to determine the homogeneity between them. Here we used the Mann-Whitney test.

For each variable, the average and the variance were estimated. These values are presented in tables and figures.

The results of the cross-sectional design were analyzed by the corresponding variance analysis. For every measurement time, a comparison was made between the groups studied. The Mann-Whitney test was used for this.

A Student’s t-test was made for the variables dependent on the ultrasound study. A p≤0.05 was considered significant.

A: Placebo plus atenolol and/or hydrochlorothiazide.
B: Folic acid plus atenolol and/or hydrochlorothiazide.


Ethical procedures
The patients participating in the study had to give their informed consent at the time of being included. The study was approved by the Committee of Ethics of the Institution.

The average age of both groups was similar, and there were no significant differences between them. Female gender represented 57.6% of the sample of the study. There were no differences as to the gender or body mass index. So, the groups were homogeneous as to age, gender and body mass index (Table 1).

Table 1. General variables in both groups according to age, gender and body mass index


Group A

Group B

P <0,05

Age (years)

47.7 ±5.4




M: 13    F:18

M:12  F: 16


BMI (kg/m2)

26.7 ±3.23

27.3 ±4.65


BMI: body mass index


In the initial consultation, the average of systolic blood pressure (SBP), diastolic blood pressure (DBP) and median blood pressure (MBP) were similar in both groups, displaying mild figures of hypertension (group A: SBP 141.1±5.4 mmHg, DBP 91.9±6.4 mmHg, MBP 108±4.5 mmHg; group B: SBP 140.4±7.8 mmHg, DBP 92.8±5.5 mmHg, MBP 108.4±4.8 mmHg) (Figure 1).

Figure 1. Behavior of systolic, diastolic and medianblood pressure in both groups of hypertensive patients. Group A: Onset with placebo plus
atenolol and hydrochlorothiazide. Group B: started with folic acid plus atenolol and hydrochlorothiazide. T1: initial visit; T2: 6 weeks; T3: visit at 12 weeks, when the crossing is made between the groups; T4: week 18; and T5: week 24. There were no significant differences between the groups.


In the same figure it is possible to see a decrease in blood pressure figures to normal values of 10.3% of SBP, 8.1% of DBP and 9.9% of MBP in group A, as well as 11.3% of SBP, 12.4% of DBP and 11.9% of MBP in group B. This decrease was maintained uniformly until the end of the study, even without taking the folic acid. In no case there were significant differences between both groups (p 0.29, 0.19 and 0.25 for SBP, DBP and MBP respectively).

There were no significant differences between the basal diameter of the brachial artery between groups A and B (p = 0.13) (Figure 2). There was a decrease, although not significant, of the basal diameter of the brachial artery when measured at the beginning and the end of the study in both groups (group A: 3.57 mm±0.7 mm; 3.54 mm±0.7 mm, p=0.054; group B: 3.44 mm±0.6 mm; 3.39 mm±0.6 mm, p=0.083).

Figure 2. Basal diameter of the brachial artery in both groups in the different weeks of follow-up. BBL: Basal brachial lumen. A: group that started with placebo; B: group that started with folic acid. T1: initial visit; T2: 6 weeks; T3: 12 weeks; T4: week 18; and T5: week 24. There were no significant differences between the groups (p=0.13). Basal diameter of brachial artery when measured at the onset and the end of the study in both groups (group A: 3.57 mm±0.7 mm; 3.54 mm±0.7 mm; p=0.054; group B: 3.44 mm±0.6 mm; 3.39 mm±0.6 mm; p=0.083).


After 6 weeks of treatment, group B that started with folic acid had an average of brachial dilatation of 6.84%; while group A had an average of 4.52% of dilatation dependent from flow (p=0.0016). Both groups had an increase of the average of brachial dilatation in regard to the baseline taken in week 1, not being significant in group A (p=0.22) and being significant in group B (p=0.00036) (Figure 3).

Figure 3. Percentage of dilatation of the brachial artery dependent on flow in both groups during all the study. Group A: vascular dilatation at 6 weeks (T2): 4.52%; p=0.22. Group B: vascular dilatation at 6 weeks (T2): 6.84%; p=0.00036. T3: 12 weeks: (group A: 5.11% vs. group B: 7.92%; p=2.72064E-05). T4: week 18; and T5: week 24: there were no significant differences between both groups with a tendency to an increase in group A.


At week 12 of the follow-up, before crossing the groups, the difference was still maintained. The group that took folic acid had a percentage of greater dilatation than the group that did not initially (7.92% vs. 5.11%, p=2.72064E-05). Figure 3.

At week 18, after crossing the groups, group B started the treatment with placebo plus antihypertensive therapy and group A started the treatment with folic acid plus antihypertensive therapy. Although in group B the vasodilator effect dependent on the flow was maintained after hyperemia, this decreased by 16.6% in regard to the basal percentage of the initial consultation. In group A, there was an increase of the percentage of dilatation mediated by flow of 26.6% in regard to week 12. There were no significant differences between both groups in week 10 (p=0.75).

Since this date and until week 24 of the treatment there was an increase, although not significant, of the percentage of dilatation mediated by flow in group A and a tendency to decrease in group B (group A: 6.88%; group B: 6.66%, p=0.59).

There were no significant differences between both groups when the figures of microalbuminuria were compared in the initial consultation, at weeks 12 and 24 (p=0.35, p=0.11 and p=0.07 respectively). However, when comparing the average figures of microalbuminuria at the onset (group A: 0.029±0.025; group B: 0.022±0.007), there was a statistically significant decrease in the results of group A (p=0.01) and in group B (p=0.04) (Figure 4). The median of CRP concentrations in the samples obtained at the onset of the study, was 2.033 (1.101-3.32) mg/L.

Figure 4. Behavior of the figures of microalbuminuria at the onset, at 12 and 24 weeks. There were no significant differences between both groups (p=0.35; p=0.11 and p=0.07 respectively). There was a significant decrease when comparing the average figures of microalbuminuria at the onset and the end of the study: group A: 0.077±0.10 vs. 0.029±0.025; p=0.01 and group B: 0.054±0.08 vs. 0.22±0.007; p=0.04.


In the study a significant correlation was found between the values of the median blood pressure and the values of microalbuminuria and the average of the percentage of dilatation mediated by flow of the brachial artery (r=0.52 and r=0.36 respectively). There was significant correlation between CRP values and microalbuminuria obtained in the initial consultation (r=0.48; p<0.05).

Endothelial dysfunction has been described as an early marker in the development of hypertension and has become a target for prevention and treatment of vascular impairment and the atherosclerosis associated to hypertension and other pathological states [8].

The results of the study showed a significant increase of the percentage of dilatation of the brachial artery dependent on the flow when 5 mg of folic acid were administered to a group of hypertensive patients compared to those treated with placebo. This dilating effect decreased when the drug was suspended at 12 weeks, but was maintained above  the basal percentage at the onset of the study. In the group that initially took placebo, a non-significant increase occurred in regard to the basal one, suggesting that the treatment with beta blockers and diuretics have little effect on vascular dilatation dependent on the endothelium. A similar result is shown by Taddei et al, who report that these drugs cause little to no improvement on endothelial function [21].

In the patients of our study, there was a significant reduction of the figures of blood pressure below 140/90 mmHg after 6 weeks of treatment; however, there were no significant differences between the patients that took folic acid or placebo. It is likely that because these are patients with slightly high figures of blood pressure, with no evidence of lesion in the target organ, the effect of the folic acid on blood pressure may not be the expected one or the dose of folic acid was not enough.

Although there was no significant decrease in blood pressure between the patients with antihypertensive treatment plus folic acid and the placebo group, the fact of improving endothelial function should contribute in a significant manner to decrease the risk of future cardiovascular events, if we take into account that endothelial dysfunction is the basis for the development of the process of atherosclerosis. Witte et al, mention that a significant increase in the percentage of vascular dilatation dependent on flow corresponds to a 5% decrease in CAD risk [22]. This result is in contrast with those of a meta-analysis of 12 studies that gathered 16,958 participants that showed that the supplement of folic acid did not reduce cardiovascular risk; however, in more than half of the participants, the dose of the drug was less than 5 mg per day [23].

The effect on endothelial function seems to be linked to the dose of the drug, since several studies point out that low doses (400-800 mcg per day) do not improve vascular dilatation mediated by flow [24,25].

In a meta-analysis it was shown that folic acid supplements, of 5 or 10 mg per day for 6 weeks caused an increase in the dilatation mediated by flow of the brachial artery and mild decreases of systolic blood pressures. From the 8 studies included in the meta-analysis, 5 of them showed a tendency to decrease the figures of systolic blood pressure, but only 1 had significant differences compared to the control group [26]. As to diastolic pressure, in 3 studies there was a tendency to a decrease in the group of folic acid but without significant differences in comparison to the control group.

Several studies have shown that the supplement of folic acid improves endothelial function in several conditions, including hypercholesterolemia [27,28], hypertension [29], diabetes mellitus [30], CAD [31], states in which there is hyperhomocysteinemia [32], and even independent from homocysteine [19], suggesting the protective vascular effect of ingesting high doses of this drug.

In a study where 10 mg per day of folic acid was administered to female dancers with endothelial dysfunction (the average of dilatation mediated by flow of brachial artery of 2.9%±1.5%) for 4 weeks, a significant increase of dilatation mediated by flow was found [33].

Epidemiological evidence suggest that a deficiency of folic acid could cause hypertension and a negative association has been reported with the figures of BP [34]. Epidemiological observations point out the inverse relation between the levels of folates in the organism, the figures of systolic blood pressure and the percentage of vascular dilatation mediated by flow, which justifies the supplement of folic acid [35].

The mechanism primarily proposed to explain the effect of the folic acid on the endothelial function was by the reduction of the plasma concentrations of homocysteine, through remethylation and conversion to methionine [36]. Homocysteine increases oxidative stress by increase in the production of superoxide anion, which results in a decrease in the levels of NO, a condition that is associated to HTN [37]. However, there are other mechanisms that do not depend on the action of the folic acid on homocysteine. For example, antioxidative properties are proposed which in a direct way may decrease the concentrations of superoxide anions capable of destroying the endothelial enzyme nitric oxide synthase (NOS), its co-factor tetrahydrobiopterin (BH4), and its product NO [38]; on the other hand it determines an increase in BH4 concentrations which increases the production of NO [39,40] and finally, folic acid may directly improve the production of NO by increase in the enzymatic activity of NOS, since it contains a pteridine ring, which is similar to the structural sequence found in co-factor BH4. This sequence allows folic acid to join to NOS, and so miming the co-factor BH4, it results in an increase of NO synthesis [41].

The present study showed a significant decrease of the figures of microalbuminuria in each group, when the initial figures were compared to those at weeks 12 and 24, suggesting that by controlling the figures of blood pressure, it is possible to decrease renal impairment. However, there were no differences between the groups, whether they took folic acid or not. Microalbuminuria constitutes a subclinical marker of organic impairment in diabetes mellitus and in hypertension [42].

Both microalbuminuria and the altered dilatation mediated by flow are the expression of endothelial impairment [42]. In our study there was no correlation between these two variables, similar to the results from other authors [43,44]. The data suggest that there is no connection between them or endothelial dysfunction preceding glomerular impairment. It is necessary to indicate that the average figures of microalbuminuria at the onset, in both groups, were slightly high,which could influence the lack of correlation.

The basal concentrations of CRP found are an evidence of inflammation in a low degree present in patients with HTN, and they correspond to values of medium cardiovascular risk, characteristic of patients with a few factors of risk as those included in the present study [10]. Other authors have reported high concentrationsof CRP in patients with hypertension and the role of inflammation in the development of hypertension was considered [45].

The results of the present study coincide with those of other authors that report that high levels of CRP are associated with microalbuminuria, regardless of diabetes, hypertension and other potential confounders [46]. These findings suggest that vascular inflammation, evaluated by CRP levels, may contribute to early renal and cardiac disease and reinforce the hypothesis that vascular inflammation may be a determinant of microalbuminuria [46,47]. Also, it is possible that endothelial function induced by hypertension, could be related to the increase of these two markers, but given the design of the investigation, it is not possible to make inferences of causality.

The traditional risk factors as those defined in the Framingham study, have shown results not consistent when predicting cardiovascular events when applied to different populations and predict the development of CAD in 25 to 50% of the cases [48]. Kitta et al, in a recent study, showed that the persistence of endothelial function deterioration in patients with CAD, constitute a strong predictor of cardiovascular events [49].

It would be important to know if treating patients with endothelial dysfunction by administering 5 mg per day of folic acid, would decrease cardiovascular risk, mainly when dealing with hypertensive patients with mild figures of blood pressure. The inflammatory processes and oxidative stress induce endothelial dysfunction, constituting a significant premise for the development of atherosclerosis and hypertension. For this reason, the treatment of this disease should not be approached just by reducing the figures of blood pressure. The management of endothelial dysfunction could be key in the treatment of hypertension.

In patients with diagnosis of mild hypertension, 5 mg per day of folic acid does not cause significant decrease in the figures of blood pressure when compared to placebo. However, the group of patients that were given folic acid, had a dilatation mediated by flow of the brachial artery in response to hyperemia, significantly greater than the group that did not receive it. There was a significant correlation between the figures of average blood pressure, the figures of microalbuminuria and the percentage of vascular dilatation mediated by flow. C reactive protein was effectively correlated to microalbuminuria.

To establish the prediction of cardiovascular risk of this noninvasive procedure, it is necessary to extend the study to hypertensive patients with greater figures of blood pressure.




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Publication: June 2013

Editorial Electrónica
de FAC

8vo. Congreso Virtual de Cardiología

1º Setiembre al
30 Noviembre, 2013

XXXI Congreso Nacional de Cardiología

30-31 Mayo,
1º Junio, 2013
Organiza: Región Patagónica

Revista de FAC


Contenidos Científicos
y Académicos



Accesos rapidos