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Interactions of medication, physical exercise and folic acid supplementation on reductions

Interactions of medication, physical exercise and folic acid supplementation on reductions of blood pressure and/or plasma homocysteine in hypertensive subjects. Avany F. Pereira, Fábio L. Orsatti, Franz H. P. Burini, Maria Dorotéia Borges-Santos, Roberto C. Burini*.

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Interactions of medication, physical exercise and folic acid supplementation on reductions

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  1. Interactions of medication, physical exercise and folic acid supplementation on reductions of blood pressure and/or plasma homocysteine in 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

  2. ABSTRACT Hyperhomocysteine (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

  3. INTRODUCTION RISK FACTORS DISEASE TREATMENTS Atherosclerotic Cardiovascular Disease (-) Physical Exercise Essential Hypertension (-) High plasma Homocysteine Drugs Folate Suppl. (-) Body storage-folic acid (-) Thiazidic

  4. INTRODUCTION • Hypertension and hyperhomocysteinemia (HyHcy) are risk factors • for cardiovascular diseases, with potential interrelationship between • both factors. • Physical exercises, reduction of body fat and drugs are the options • to lower blood pressure (BP) whereas folic acid (FA) supplementation • is the best way to reducing plasma homocysteine. • Thiazidic has potential anti-folic acid bioavailability actions.

  5. OBJECTIVE To investigate the interactions of medication, physical exercise and folic acid supplementation as BP lowering agents in hypertensive subjects.

  6. 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

  7. 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)

  8. 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%

  9. EXPERIMENTAL DESIGN washout M4 M0 M2 M6 months ** * ** ** ** G1 NT N=50 FAS HTC (n=37) G2 HT N=69 Placebo HTT (n=32) Physical Exercise G1 =control - normotensives G2 HT= Hypertensive group HTC= Hypertensive without taking thiazidic HTT= Hypertensive taking thiazidic FAS: Folate supplementation (500g/d) Placebo: lactose * Clinical and Ambulatory BP measurement ** BP registry, anthropometric and biochemical assessments

  10. 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)

  11. 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).

  12. RESULTS Table 1 . Comparisons between normotensive and hypertensive groups Variables Normotensives (G1,n=50) Hypertensives (G2,n=69) t test significance Age (yrs) 55  8 57  10 p =0.245 SBP (mmHg) 130  10 141  15 p < 0.001 DBP (mmHg) 80  9 86  10 p < 0.001 Homocysteine (mol/L) 10.4  1,8 14  3 p < 0.001 SBP- sistolic blood pressure; DBP- diastolic blood pressure

  13. RESULTS Figure 1 – Percent of controlled and uncontrolled hypertensive subjects according to ambulatory BP measurement  % Subjects HBP- High Blood Pressure

  14. RESULTS Table 2a – Comparisons between hypertensives receiving (HTT) or not (HTC) thiazidic treatment Variables HTC (n=32) HTT (n=37) Age (yrs) 58  10 57  8 SBP (mmHg) 142  14 141  17 DBP (mmHg) 87  9 86  12 Vo2 max (ml/kg/min) 27  9 26  8 Glucose (mg/dL) 105  37 103  39 Cholesterol (mg/dL) 220  42 215  35 HDL-cholesterol (mg/dL) 49  14 47  12 LDL-cholesterol (mg/dL) 139  35 136  31 Triglycerides (mg/dL) 160  65 159  74 1.1  0.3 0.9  0.2 Serum Creatinine (mg/dL) SBP- sistolic blood pressure; DBP- diastolic blood pressure. * p <0.05

  15. RESULTS Table 2b – Comparisons between hypertensives receiving (HTT) or not (HTC) thiazidic treatment HTC (n=32) HTT (n=37) Variables Plasma Homocysteine (mol/L) 14.9  3.3* 13.1  2.2* Serum Folate (ng/mL) 8.1  3.5 8.6  3.8 Serum B12 Vitamin (pg/mL) 476  200 480  135 BMI (kg/m2) 31  4 34  9 Waist Circunference (cm) 100  12 98  13 Body fat (%) 33  8 34  9 Folate dietetic ingestion (g/dia) 175  70 170  60 B12 vitamin dietetic ingestion (g/dia) 4.2  1.6 3.6  1.8 Methionine dietetic ingestion (mg/kg/dia) 15  4 13  2 BMI – body mass index * statistical significance ( p < 0,05)

  16. RESULTS Figure 2. Effect of physical exercise protocol (2 mo) on the prevalence of hypertension in male and female adults 60 51 50 42 40 33 Mo 30 M1(2 mo.) 19 19 % Subjects 17 20 12 6 10 0 Nt Bl Mild Mod Nt- normotensives Mod-moderated M1- Bimestral evaluation Bl- borderline M0- first evaluation

  17. RESULTS 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 Hcy (mol/L) Without Physical Exercise With Physical Exercise G2 (Placebo) G1 (FS) G2 (Placebo) G1 (FS) BMI (kg/m2) 29  4.8/29.4  4.8 29  4.6/29.2  4.5 30.8  4.6/30..3  4.6 29  4.7/29.,3  4.6 33.2  8.8/33.3  8,8 33.6  8.3/33.8  8.7 33,5  8,5/33,8  8,8 33,3  8,5/33,5  8,8 % Body fat Waist circunference (cm) 96  12.3/96.4  12.3 96  11.7/96.7  11,8 97  12/97.4  12 96  11,9/96.5 , 12 14.6  3.6/13.9  2.8 14.9  3.40/15.7  3.0 14.8  3.2/14.2  2.5 14.4  3/15.3  2.9 Hcy (mol/L) Sistolic blood pressure (mmHg) 139  13.5/141.5  16.4 137.6  13.4/140  14.8 138.5  13/140  15 139  13/141  16 Diastolic blood pressure (mmHg) 83  9.6/86  10.4 83.8  9.6/86.7  10.3 8 4 9.4/86  10.6 83  9.1/86.3  10.4 * P< 0.05 (M1/M0);BMI-body mass index, Hcy- homocysteine; FS- folate supplementation

  18. RESULTS Table 4. – Effect of folate supplementation (FS) for 2 months on the frequency of hypertension degrees (M1/M0) Hypertensive Groups FS HT degrees Placebo Normotensive 5/8 8/5 Borderline 14/6 9/6 Mild 15/18 14/17 Moderate 3/5 1/4 HT-hypertensive; FS-folate supplementation

  19. Table 5 – Associations of hypertension degrees and plasma homocysteine estratification Hypertension degrees Plasma Homocysteine (mmol/L) 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

  20. RESULTS 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 HTC HTT Placebo FS Placebo FS 14,3  2,1/ 14,4  2,7 13,2 2,4 /14,9  3,3* 15,5  3,8/ 13,3  2,2* 14  2,4/ 17,3  4,3 Hcy (mol/L) 7,2  2,5 /9,2  2,8* 12,4  4,7/ 7,4  2,8* 12,7  5 /8,1  3,5* Folic acid 7,0  2,5/ 8,6  3,8 * statistical significance ( p < 0,05)

  21. RESULTS 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) Hypertensive Groups Hcy levels (mol/L) HTT HTC < 10 1/1 4/0 10-15 29/8 21/20 > 15 7/28 7/12 Hcy-- homocysteine

  22. 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,

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