ISSN 0326-646X
 

 
 
 
 
 
 
 
 

 
 

1024x768

 
 
 
 
 
 

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

 

SUMMARY

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

 

 

INTRODUCTION
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.


MATERIAL AND METHODS
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.


RESULTS
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

Variables

Group A

Group B

Significance
P <0,05

Age (years)

47.7 ±5.4

47.6±5.6

n/s

Gender

M: 13    F:18

M:12  F: 16

n/s

BMI (kg/m2)

26.7 ±3.23

27.3 ±4.65

n/s

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).


DISCUSSION
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.


CONCLUSIONS
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.

 

 

REFERENCES

  1. Mancia G, De Backer G, Dominizack A, et al. Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension and the European Society Cardiology. J Hypertens 2007; 25: 1105-1187.
  2. García Barreto D, García Fernández R, García Perez-Velazco EJ, et al. Diagnóstico pre-clínico de ateroesclerosis: Función endotelial. Rev Cubana Med 2003; 42 (1): 58-63.
  3. Vogel RA. Coronary risk factors, endothelial function and atherosclerosis. A review. Clin Cardiol 1997; 20: 426-432.
  4. Ceballos Reyes G, Ramirez Sánchez I, Calzada Mendoza C, et al. Disfunción endotelial y estrés oxidativo. Rev Endocrinol Nutr 2006; 14 (4): 233-236.
  5. García Fernández R, García Pérez-Velasco EJ, Milián AC, et al. Disfunción Endotelial tras 24 horas de guardia en Cardiólogos. Rev Esp Cardiol 2002; 55 (11): 1202-1204.
  6. Toda N, Nakanishi-Toda M. How mental stress affects endothelial function. Pflügers Archiv Eur J Physiol 2011; 462: 779-794.
  7. García Fernández R, García Pérez Velasco EJ, Milián AC, et al. Estrogen does not prevent endothelial dysfunction caused by cigarette smoking. Clin Cardiol 2004; 27: 71-73.
  8.  Veedrabhadrappa P, Diaz KM, Feairheller DL,. Endothelial dependent flow-mediated dilation in African American with masked-hypertesion. Am J Hypertens. 2011; 24 (10): 1102-1107.
  9. de Zeeuw D, Parving HH, Henning RH. Microalbuminuria as an early marker for cardiovascular disease. J Am Soc Nephrol 2006; 17: 2100-2105.
  10. Stefanadi E, Tousoulis D, Androulakis ES, et al. Review inflammatory markers in essential hypertension potential clinical implications. Curr Vasc Pharmacol 2010; 8 (4): 509-5116.
  11. Ridker P M. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk moving an inflammatory hypothesis toward consensus J Am Coll Cardiol 2007; 49: 2129-2138.
  12. Ochodnicky P, Henning RH, van Dokkum RP, et al. Microalbuminuria and endothelial dysfunction: emerging targets for primary prevention of end-organ damage. J Cardiovasc Pharmacol2006; 47 Suppl 2: S151–S162; S172–S176.
  13. Unzo A, Rossi R, Grazia M. Endothelial dysfunction in postmenopausal women and hypertension. Circulation 2007; 3: 515-518.
  14. Bots ML, Remme WJ, Luscher TF, et al. ACE inhibition and endothelial function: Main findings of PERFECT, a sub-study of the EUROPA Trial. Cardiovasc Drugs Ther 2007; 4: 269-279.
  15. Higashi Y, Chayama K, Yoshizumi M. Angiotensin II type I receptor blocker and endothelial function in humans: role of nitric oxide and oxidative stress. J Hypertens 2006; 24 (1): 95-102.
  16. Milián AC, García Fernández R, García Pérez-Velasco EJ, et al. Regresión electrocardiográfica de los signos de Hipertrofia Ventricular Izquierda. Rev Cubana Med 2003; 42 (6).
  17. Rodrigo R, Passalacqua W, Araya J, et al. Homocysteine and essential hypertension. J Clin Pharmacol 2003; 43: 1299-1306.
  18.  Title LM, Ur E, Giddens K, et al. Folic acid improves endothelial dysfunction in type II diabetes an effect independent of homocystein-lowering. Vasc Med 2006; 11 (2): 101-109.
  19.  Doshi SN, McDowell IF, Moat SJ, et al. Folic Acid improves endothelial functions in coronary artery diseases via mechanisms largely independent of homocystein lowering. Circulation 2002; 105: 22-26.
  20. Bechir M, Enseleit F, Chenevard R, et al. Folic acid improves baroreceptor sensitivity in hypertension. J Cardiosvasc Pharmacol 2005; 45: 44-48.
  21. Taddei S, Virdis A, Ghiadoni L, et al. Effects of antihypertensive drugs on endotelial dysfunction: clinical implications. Drugs 2002; 62: 265-284.
  22. Witte Dr, Westering J, de Koning EJ, et al. Is the association between flow-mediated dilatation and cardiovascular risk limited to low risk population? J Am Coll Cardiol 2005; 45 (12): 1987-1993.
  23. Bazzano LA, Reynolds K, Holder KN. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006; 296 (22): 2720-2726.
  24. Pullin CH, Ashfield-Wat PA, Burr ML. Optimization of dietary folate or low-dose folic acid supplements lower homocysteine but do not enhance endothelial function healthy adults irrespective of the methylenetetrahydrofolate reductase genotype. J Am Coll Cardiol 2001; 38 (7): 1799-805.
  25. Olthof MR, Bots ML, Katan MB, et al. Effect of folic acid and betaine supplementation on flow mediated-dilatation: a randomized controlled study in healthy volunteers. PLoS Clin Trials 2006; 1 (2): e10.
  26. Marc PM. High dose folic acid supplementation effects on endothelial function and blood pressure in hypertensive patients: a meta-analysis of randomized controlled clinical trials. J Chiropract Med 2009; 8: 15-24.
  27. Verhaar MC, Wever RM, Kastelein JJ, et al. Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation 1999;100 (4): 335-338.
  28. Stroes ES, van Faassen EE, Yo M, Martasek P, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 2000; 86 (11): 1129-1134.
  29. Van Dijk RA, Rauwerda MS, Twisk JW, et al. Long-term homocysteine-lowering treatment with acid folic plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilatation or carotid artery stiffness: 2-year, randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol 2001; 21: 2072-2079.
  30. Van Etten RW, Koning EJ, Verhaar MC, et al. Impaired NO-dependent vasodilatation in patients with Type II 8non-insulin-dependt) diabetes mellitus is restored by acute administration of folate. Diabetologia 2002; 45: 1004-1010.
  31. Moens L, Clayes MJ, Wuyts FL, et al. Effect of Folic Acid on endothelial function following acute myocardial infarction. Am J Cardiol 2007; 99 (4): 476-81.
  32. Woo KS, Chook P, Lolin YI, et al. Folic acid improves endothelial function in adults with hyperhomocystinemia. J Am Coll 1999; 34: 2002-2006.
  33.  Hoch AZ, Papanek P, Szabo A, et al. Folic acid supplementation improves vascular function in professional dancers with endothelial dysfunction. PMYR. 2011; 3 (11): 1005-12.
  34. Forman JP, Rimm EB, Stampfer MJ, Curhan GC. Folate intake and the risk of incident hypertension among US women. JAMA 2005; 293 (3): 320-329.
  35. Stehouwer CD, van Guldener C. Does homocysteine cause hypertension?. Clin Chem Lab Med 2003; 41 (11): 1408-1411.
  36. Usui M, Matsuoka H, Miyazaki H, et al Endothelial dysfunction by acute hyperhomocysteinaemia: restoration by folic acid. Clin Csi 1999; 96 (3): 235-239.
  37. Mc Dowell IF, lango D. Homocysteine and endothelial dysfunction: a link with cardiovascular disease. J Nutr 2000; 130: 369-372.
  38. Doshi SN, McDowell IF, Moat SJ, et al. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol 2001; 21 (7): 1196-1202.
  39. Verhaar MC, Stroes E, Rabelink TJ. Folates and cardiovascular disease. Arterioscler Thromb Vas Biol 2002; 22 (1): 6-13.
  40. Moens AL, Vrints CJ, Claeys MJ, et al. Mechanism and potential therapeutic targets for folic acid in cardiovascular disease. Am J Physiol Heart Cir Physiol 2008; 294 (5): 1971-1977.
  41. Moat SJ, Clarke ZL, Madhavan AK, et al. Folic acid reverses endothelial dysfunction induces by inhibition of tetrahydrobiopterin biosynthesis. Eur J Pharmacol 2006; 530 (3): 250-258.
  42. Versari D, Daghini E, Virdis A, et al. Endothelial dysfunction as a target for prevention for cardiovascular disease. Diabetes Care 2009; 32 (Suppl.2): 314-321.
  43. Ochodnicky P, Henning RH, van Dokkurn RP, et al. Microalbuminuria and endothelial dysfunction: emerging targets for primary prevention of end-organ damage. J Cardiovasc Pharmacol 2006; 47 (Suppl. 2): 5151-5162.
  44. Savoia C, Schiffrin EL. Reduction of C-reactive protein and the use of anti-hypertensives. Vasc Health Risk Manag 2007; 3 (6): 975-983.
  45. Tsioufis C, Dimitriadis K, Andrikou E, et al. ADMA, C-reactive protein, and albuminuria in untreated essential hypertension: A cross-sectional study. Am J Kidney Dis 2010; 55: 1050-1059.
  46. Sabanayagam C, Lee J, Shankar A, et al. C-reactive protein and microalbuminuria in a multi-ethnic Asian population. Nephrol Dial Transplant. 2010; 25: 1167-1172.
  47. Kshirsagar AV, Bomback AS, Bang H, et al. Association of C-Reactive Protein and Microalbuminuria (from the National Health and Nutrition Examination Surveys, 1999 to 2004). Am J Cardiol 2008; 101: 401–406.
  48. Reriani MK, Lerman LO, Lerman A. Endothelial function as a functional expression of cardiovascular risk factors. Biomark Med 2010; 4 (3): 351-360.
  49. Kitta Y, Obata JE, Nakamura T. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol 2009; 53 (4): 323-30.

 

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
 

 
Búsquedas
Revista de FAC

gogbut

Contenidos Científicos
y Académicos

gogbut

 

 
Accesos rapidos