Interactions of medication, physical exerciseand folic acid supplementation on reductions

of blood pressure and/or plasma homocysteinein hypertensive subjects

Avany F. Pereira, Fábio L. Orsatti, Franz H. P. Burini, Maria Dorotéia Borges-Santos, Roberto C. Burini*

UNESP Medical School (Botucatu- SP) Brasil

www.cemenutri.fmb.unesp.brcemenutri@fmb.unesp.br

ABSTRACTHyperhomocysteine (HyHcy) and hypertensive states share the role of being risk factors for cardiovascular diseases. Chronic-aerobic exercise and/or reduction of body fat as well as medication are the options to lower blood pressure (BP whereas folic acid (FA) supplement is na efficient way to lower HyHcy. Thiazine a common diuretic used for high BP treatment is related to lower folic availability to the body.PURPOSE: To investigate the interactions of these BP lowering agents were investigated.METHODS: 69 hypertensive patients (HT): 141 15 mmHg/86 10 mmHg, 57 10 yrs old, 22 males and 47 females matched by sex, age and body composition with 50 normotensive subjects (NT): 130 10 mmHg (SBP) and 80 mmHg (DBP) all volunters for the study. After na initial (M0) assessment for medical, anthropometric, dietetic, blood chemists and V02max variables they started a 6 mo. Program of supervised physical exercise (SPE) composed by 80 min-session (60-70% V02max), 3-5 days/wk. The HT group (under BP medication) was divided in subgroups receiving ( HTT, n=32) or not (HTC,n=37) the thiazidic drug.Both HT subgroups were given orally 500 g/d of FA capsules, during 2 mo. In a crossover design with placebo (lactose),interpolated with a 2 mo. washout period. The assessments of BP (24 hours ambulatory BP measurements),food intake, body composition,blood chemists (including Hcy,folic acid and vitamin B12) were repeated every two-month (M0,M1 and M2).RESULTS:At M0 HT showed higher BP and Hcy (14 3 X 10,4 1,8 mol/L) than NT. Subgroups HTT and HTC were similar for all variables. Besides medicated 62% of HT showed uncontrolled BP. Six mo. of SPE downgraded the hypertensive status of HT patients without affecting significantly their body composition or blood chemistry,including Hcy. Folic acid supplementation (2 mo.) increased plasma folate and decreased HyHcy prevalence in HT from 11% (HTT) to 19% (HTC). However Hcy normalization occured only in HT that became normotensive. The remaining HT showed HyHcy downgraded to a borderline levels. The grater response of Hcy occurred with the higher plasma folate,both in the absence of thiazidic (HyHcy decreasing: HTC 71% > HTT 42%).CONCLUSIONS:The normalization of BP by SPE, FA supplementation and drugs was not followed neither by body-weight or general blood changes except by plasma Hcy normalization. SPE alone had no effect on Hcy. The presenceof thiazidic boostered the BP normalization but reduced the HyHcy. Supported by FAPESP and CNPq

INTRODUCTION

TREATMENTS RISK FACTORS

DISEASE

Physical Exercise

Essential Hypertensio

nAtheroscleroti

cCardiovascular

DiseaseHigh plasma Homocystein

e

Drugs

Folate Suppl.

Thiazidic

Body storage-folic acid

(-)

(-)

(-)

(-)

INTRODUCTION

- Hypertension and hyperhomocysteinemia (HyHcy) are risk factorsfor cardiovascular diseases, with potential interrelationship betweenboth factors.

- Physical exercises, reduction of body fat and drugs are the options to lower blood pressure (BP) whereas folic acid (FA) supplementationis the best way to reducing plasma homocysteine.

- Thiazidic has potential anti-folic acid bioavailability actions.

OBJECTIVE

To investigate the interactions of medication, physical exercise and folic acid supplementation as BP loweringagents in hypertensive subjects.

SUBJECTS

G1- Normotensives: 130 ± 10 mmHg (n=50) 20M 30F (55 ± 8 yrs old)

G2 – Hypertensives: 141 ± 15 mmHg (n=69) 22M 47F (57 ± 8 yrs old)

Informed Consent was obtained from all patients

and the study was approved by the Research Ethics Committee of Botucatu Medical School

- UNESP

METHODS Blood hypertension diagnosis: - Clinical (digital OMRON, mod. HEM-413C) - 24 hours Ambulatory BP measurements (Spacelabs-Inc, mod.90207- 50)Anthropometry: - Body-weight and height (150 kg plataform scale -100g precision);- Body Mass Index (BMI) = kg/m2 (standards - WHO,2002)- Electrical Bioimpedance: fat-free mass (Segal et al,1988)- Waist circunference: inelastic tape (0,1cm).Standards: men<102 cm, women < 88 cm.

Plasma Assays:

- Homocysteine (Hcy) - HPLC method (Ubbink et al,1991)

- Folic Acid (FA) and B12 vitamin - Fluorimetric method

(Immulite-DPC,2000)

- Glucose, triglycerides, total and HDL-cholesterol

(Dry chemistry- Johnson & Johnson 750/950)

METHODS (cont.) Folate Supplementation (FS):

- 500 g of folic acid during 2 months, crossed over with lactose as placebo and 2 mo. of washout.

Supervised Physical Exercise Program (SPE):- Daily sessions of 80 min exercises: 10 min warm up, 40 min brisk walk (60-80% max HR/age), 20 min flexibility, 10 min relaxing; Statistical Analysis:

- Association among variables: x2 test corrected by Fisher exact test;

- Mean comparison between groups (Student t test for independent

variables);

- Mean comparison among intragroup moments (Student t test for

dependent variables);

- Significance level 5%

EXPERIMENTAL DESIGN M4washout

** **

G1 NTN=50

**

HTC (n=37)

M0 M2 M6 months

G2 HTN=69

HTT (n=32)

***

FAS

Placebo

Physical ExerciseG1 =control - normotensivesG2 HT= Hypertensive groupHTC= Hypertensive without taking thiazidicHTT= Hypertensive taking thiazidicFAS: Folate supplementation (500g/d)Placebo: lactose * Clinical and Ambulatory BP measurement** BP registry, anthropometric and biochemical assessments

RESULTS- Hypertensives (G2- HT) differed of normotensives (G1- NT) by their higher blood pressure (SBP and DBP) and higher plasma homocysteine levels(Table 1).

- At baseline (M0) 62% of hypertensives (HT) showed uncontrolled blood pressure (BP), mostly females (Fig. 1).

- Hypertensive subjects receiving (HTT) or not (HTC) thiazidic diuretic (TZN) as treatment differed only in plasma Hcy, being higher in HTT (Tables 2a and 2b).

- Physical exercise protocol (2 mo) decreased the prevalence of moderate (6%) and mild (9%) and increased the borderline (16%) hypertension degree (Fig.2)

RESULTS (cont.)

- Physical exercise protocol (2 mo) did not change significantly (M0/M1) neither body composition, blood pressure or plasma Hcy (Table 3).

- Folate supplements (FS) boostered the BP normalization by physical exercises (Table 4).

-The normalization of plasma homocysteine occurred only in normotyensives. On the other hand, the moderated homocysteinemia increases in the borderline (2/6) and mild (10/12) hypertensive patients and decrease in moderated hypertensive (Table 5).

- Folate supplements (FS) increased significantly the plasma folic acid in both thiazidic treated (HTT) and non-treated (HTC) hypertensives (Table 6).

- Folate supplements (FS) decreased the plasma Hcy mainly in hypertensive not receiving thiazidic (HTC) (Table 7).

RESULTS

14 3

86 10

141 15

57 10

Hypertensives (G2,n=69)

10.4 1,8

80 9

130 10

55 8

Normotensives (G1,n=50)

p < 0.001

p < 0.001

p < 0.001

p =0.245

t test significance

Homocysteine (mol/L)

DBP (mmHg)

SBP (mmHg)

Age (yrs)

Variables

SBP- sistolic blood pressure; DBP- diastolic blood pressure

Table 1 . Comparisons between normotensive and hypertensive groups

RESULTS

45

55

34

66

0

10

20

30

40

50

60

70

Male Female

Controled HBP

Uncontrolled HBP

% S

ub

jects

HBP- High Blood Pressure

Figure 1 – Percent of controlled and uncontrolled hypertensive subjects according to ambulatory BP measurement 

RESULTS

159 74160 65Triglycerides (mg/dL)

0.9 0.21.1 0.3Serum Creatinine (mg/dL)

136 31139 35LDL-cholesterol (mg/dL)

47 1249 14HDL-cholesterol (mg/dL)

215 35220 42Cholesterol (mg/dL)

103 39105 37Glucose (mg/dL)

26 827 9Vo2 max (ml/kg/min)

86 1287 9DBP (mmHg)

141 17142 14SBP (mmHg)

57 858 10Age (yrs)

HTT (n=37)HTC (n=32)Variables

Table 2a – Comparisons between hypertensives receiving (HTT) or not (HTC) thiazidic treatment

SBP- sistolic blood pressure; DBP- diastolic blood pressure. * p <0.05

RESULTS

13.1 2.2*14.9 3.3*Plasma Homocysteine (mol/L)

13 215 4Methionine dietetic ingestion (mg/kg/dia)

3.6 1.84.2 1.6 B12 vitamin dietetic ingestion (g/dia)

170 60175 70Folate dietetic ingestion (g/dia)

34 933 8Body fat (%)

98 13100 12Waist Circunference (cm)

34 931 4BMI (kg/m2)

480 135476 200Serum B12 Vitamin (pg/mL)

8.6 3.88.1 3.5Serum Folate (ng/mL)

HTT (n=37)HTC (n=32)Variables

* statistical significance ( p < 0,05)BMI – body mass index

Table 2b – Comparisons between hypertensives receiving (HTT) or not (HTC) thiazidic treatment

Nt- normotensives Mod-moderated M1- Bimestral evaluationBl- borderline M0- first evaluation

19 1917

33

51

42

126

0

10

20

30

40

50

60

Nt Bl Mild Mod

Mo

M1(2 mo.)

% S

ub

jectsRESULTSFigure 2. Effect of physical exercise protocol (2 mo) on the prevalence

of hypertension in male and female adults

RESULTS

Hcy (mol/L)

Sistolicblood pressure (mmHg)

Diastolic blood pressure

(mmHg)

Waistcircunference (cm)

% Body fat

BMI (kg/m2)

Without Physical Exercise With Physical Exercise G2 (Placebo) G1 (FS) G2 (Placebo) G1 (FS)

Hcy(mol/L)

29 4.8/29.4 4.8

33,3 8,5/33,5 8,8

96 12.3/96.4 12.3

14.6 3.6/13.9 2.8

139 13.5/141.5 16.4

83 9.6/86 10.4

29 4.6/29.2 4.5

33,5 8,5/33,8 8,8

96 11.7/96.7 11,8

14.9 3.40/15.7 3.0

137.6 13.4/140 14.8

83.8 9.6/86.7 10.3

30.8 4.6/30..3 4.6

33.2 8.8/33.3 8,8

97 12/97.4 12

14.8 3.2/14.2 2.5

138.5 13/140 15

8 4 9.4/86 10.6

96 11,9/96.5 , 12

14.4 3/15.3 2.9

33.6 8.3/33.8 8.7

29 4.7/29.,3 4.6

83 9.1/86.3 10.4

139 13/141 16

* P< 0.05 (M1/M0);BMI-body mass index, Hcy- homocysteine; FS- folate supplementation

Table 3. – Effect of physical exercise (PE) on the body composition, blood pressure and plasma Hcy levels of placebo and folic acid supplemented (FS) hypertensive subjects

RESULTS

8/55/8Normotensive

1/43/5Moderate

14/1715/18Mild

9/614/6Borderline

FSHT degrees Placebo

Hypertensive Groups

HT-hypertensive; FS-folate supplementation

Table 4. – Effect of folate supplementation (FS) for 2 months on the frequency of hypertension degrees (M1/M0)

Table 5 – Associations of hypertension degrees and plasma homocysteine estratification

PlasmaHomocysteine (mol/L)

Hypertension degrees

NT BD MILD MOD

Pré Pós Pré Pós Pré Pós Pré Pós

< 10 1 4 1 1 0 0 2 1

10 – 15 10 7 9 16 25 17 5 2

> 15 2 2 2 6 10 12 2 1

All 13 13 12 23 35 29 9 4

NT=normotensive; BD=borderline, MOD=moderate

RESULTS

7,2 2,5/9,2 2,8*

Folic acid

Hcy (mol/L)

HTC HTT

Placebo FS Placebo FS

15,5 3,8/13,3 2,2*

14,3 2,1/14,4 2,7

12,4 4,7/7,4 2,8*

7,0 2,5/ 8,6 3,8

14 2,4/17,3 4,3

13,2 2,4/14,9 3,3*

12,7 5/8,1 3,5*

* statistical significance ( p < 0,05)

Table 6. - Effect of folate supplementation (FS) for 2 months (M1/M0) on plasma homocysteine (Hcy) and folic acid of groups treated (HTT) or not (HTC) with thiazidic diuretic

RESULTS

4/01/1< 10

7/127/28> 15

21/2029/810-15

Hcy levels (mol/L)

Hypertensive Groups

HTT HTC

Hcy-- homocysteine

Table 7. – Effect of folate supplementation (FS) for 2 months (M1/M0) on the plasma homocysteine (Hcy) distribution in the presence (HTT) and absence of thiazidic (HTC)

CONCLUSIONS- The physical exercises downgraded the

hypertension severity by 31% without significant effects on plasma homocysteine,however blood pressure normalization occurred only in the presence of normal plasma homocysteine values.

- The folic acid supplementation (FAS) increased the plasma folate and reduced the hyperhomocysteine prevalence among hypertensives.

- The presence of thiazidic (HTT) lead to a lower response to folic acid supplementation (FAS),suggesting increased needs of FAS in the presence of this drug,

REFERENCES1) 7º JNC. JAMA, V. 289, n.19, p.2560-71, 2003.

2) Ali et al. The American Journal of Cardiology, v.82, p.1543-45, 1998.3) Araki et al. Atherosclerosis, v.79, p.139-46, 1989. 4) Bates et al. European Journal of Clinical Nutrition, v. 51, p.691-97, 1997.5) Boushey et al. JAMA, v.274, n.13, p.1049-57,1995.6) Brattstrom. European Journal of Clinical Investigation, v.22, p.214-21, 992.7) Brouwer et al. Annals of Nutrition & Metabolism, v. 44, p.194-97, 2000.8) Chait et al. American Journal of Clinical Nutrition, v. 70, p.881-70, 1999.9) Clarke et al. The New England Journal Medicine v.324, p. 1149-55, 1991.10) Cohn. Journal of Hypertension, v.16, p.2117-24, 1998.11) De Bree et al. American Journal of Clinical Nutrition, v. 73, p.1027-33, 2001.12) Dengel et al. Metabolism, v.47, p.1075-82, 1998. 13) Forrest et al. Medicine and Science in Sports and Exercise, v.33,

n.9,p.1598-04,2001. 14) Genest et al. Journal of the American College Cardiology, v. 16, p.1114-19,

199015) Jacques et al. American Journal of Clinical Nutrition, v. 73, p.613-21, 2001.16) Knauf et al. Journal of Cardiovascular Pharmacology, v.22, suppl.6, p. S1-

S7, 1993.17) Kesaniemi. Medicine & Science in Sports & Exercise, v.33, n.6, p. S351-

S358, 2001.18) Lin & Cassano. American Journal of Epidemiology, v.156,p.1105-13,2002.19) Lip et al. American Journal of Hypertension, v.14, p.627-31,2001.20) Malinow et al. Circulation, v.87, p.1107-1111, 1993 21) Malinow et al. Atherosclerosis, v.114, p.175-83, 1995.22) Mendes et al. Journal of Internal Medical Research, v. 27,n. 1, p.38-44,

1999.

23) Montenero et al. Acta Victaminology Enzymology, v.2, p.27-45,1980. 24) Nutwin -Departamento de Informática em Saúde –DIS.Universidade Federal de São Paulo –UNIFESP, 2002.25) Nygard et al. JAMA, v.274, p. 1526-33,199526) Nygard et al. American Journal of Clinical Nutrition, v.67, p. 263-70, 1998.27) Rasmussen et al. American Journal of Clinical Nutrition, v. 72, p. 1156-63, 2000.28) Refsun et al. Annual Review Medicine, v.49, p. 31-62, 1998.29) Schorah et al. European Journal of Clinical Nutrition, v.52, p.401-411, 1998.30) Segal et al. American Journal of Clinical Nutrition, v.47, p.7-14, 1988.31) Stanger et al. Clinical Chemistry Lab Med, v. 41, n.11, p.1392-1403, 2003. 32) Strandberg et al. Journal of Hypertension, v.19, p.35-9, 2001.33) Sundstrom et al. Hypertension, v.42, p.1100-05,2003. 34) Tavares et al. Revista da Sociedade de Cardiologia do Estado de São Paulo, v.10, n.6,p.712-22, 2000.35) Vandenhoogen et al. Journal of Internal Medicine, v. 245, p. 175-83,1999. 36) Verhoef. Arteriosclerosis Thrombosis and Vascular Biology, v.17, p. 989-95, 1997.37) Ubbink et al.Journal of Nutrition, v.124, p.1927-3, 1994. 38) WHO-2002, Expert Consultation on diet, nutrition and prevention of chronic diseases), 2002.39) Wright et al. The Journal of Sports Medicine and Physical Fitness, v.38, n.3, p.262-265, 1998.

REFERENCES (cont.)