Voorgestelde werkingsmechanismen

- state of the art -

Ronald P. Mensink

Maastricht University, Department of Human Biology

School of Nutrition, Toxicology, and Metabolism (NUTRIM)

Fact

• Dairy consumption lowers blood pressure

Some considerations

• Most studies are observational

• Intervention studies on low-fat

dairy are scarce

• Main research question:

What are the effects of low-fat dairy products

on metabolic risk markers in subjects at

increased risk of metabolic disorders?

Why the metabolic syndrome

Abdominal obesity

Insulinresistance

Elevated blood pressure

Pro-inflammatory

state

Atherogenicdyslipidemia

Pro-thrombotic

state

CVDDiabetes Mellitus

Measurements

• Blood sampling:

Week 0, 4, 7, 8

• Blood pressure

• Body weight

Abdominal obesity

Insulinresistance

Elevated blood pressure

Pro-inflammatory

state

Atherogenicdyslipidemia

Pro-thrombotic

state

SubjectsBaseline characteristics

Men / women 10 / 25

Age (y) 49.5 ± 13.2

BMI (kg/m2) 32.0 ± 3.8

Systolic BP (mmHg) 135 ± 19.9

Diastolic BP (mmHg) 88 ± 13.2

Total cholesterol (mmol/L) 6.06 ± 1.0

HDL cholesterol (mmol/L) 1.40 ± 0.4

LDL cholesterol (mmol/L) 4.04 ± 1.0

Triglycerides (mmol/L) 1.36 ± 0.5

Glucose (mmol/L) 5.68 ± 0.6

Study design

40 overweight or obese subjects• BMI > 27 kg/m2 and/or waist > 102 cm (men) or 88 cm (women)

• Low dairy intake (< 500 g)

Group Period 1

(8 wk)

Wash out

(2 wk)

Period 2

(8 wk)

A Low-fat dairy Control

B Control Low-fat dairy

T0 4 7 8 0 4 7 8

Dietary intervention

Dairy

500 mL low-fat milk

150 g low-fat yogurt

375 kcal

24.4 g

43.6 g

9.8 g

800 mg

Control

600 mL fruit juice

3 fruit biscuits

400 kcal

2.4 g

89.6 g

3.9 g

-

Energy

Protein

Carbohydrates

Fat

Calcium

110

120

130

Decrease in 1,25-(OH)2-Vitamin D3 (calcitriol) Confirmed Compliance

• Calcium intake depresses calcitriol levels• Used as compliance marker

*

* P < 0.05

pm

ol/L

Control

Low-fat dairy

= 8.7 pmol/L

120

125

130

135

80

85

90

Low-fat Dairy Decreased Systolic, but not Diastolic, Blood Pressure

mm

Hg

Control

= 2.9 mm Hgp=0.027

mm

Hg

Low-fat dairy

Systolic

= 1.6 mm Hgp=0.090

Diastolic

80

85

90

Results when 10 Subjects on Anti-Hypertensive Medication are Excluded

120

125

130

135

mm

Hg

Control

mm

Hg

Low-fat dairy

= 4.2 mm Hgp=0.010

Systolic

= 1.8 mm Hgp=0.055

Diastolic

Conclusion

Consumption of low-fat dairy for 8 weeks does lower systolic blood pressure in

overweight subjects

What is the Active Component in Dairy?

Dairy is an important source of:• Protein• Calcium

• Fat

Does Dietary Fat Affect Blood Pressure?

-6

-4

-2

0

2

Q 1 Q 2 Q 3 Q 4 Q 5

(m

m H

g)

Changes in Systolic BP After 1 Yr of Changes in Systolic BP After 1 Yr of Follow-up are Related to Low-Fat, but Follow-up are Related to Low-Fat, but Not to High-Fat Dairy, ConsumptionNot to High-Fat Dairy, Consumption

Low-fat Dairy High-Fat DairyToledo E et al. Br J Nutr, 2008

P for trend, Low-Fat: 0.01High-fat: 0.84

*

*

-6

-4

-2

0

2

Q 1 Q 2 Q 3 Q 4 Q 5

(mm

Hg)

Changes in Diastolic BP After 1 Yr of Changes in Diastolic BP After 1 Yr of Follow-up are Related to Low-Fat, but Follow-up are Related to Low-Fat, but Not to High-Fat Dairy, ConsumptionNot to High-Fat Dairy, Consumption

Low-fat Dairy High-Fat DairyToledo E et al. Br J Nutr, 2008

P for trend, Low-Fat: 0.09High-fat: 0.61

*

Flow-Mediated Dilatation is Flow-Mediated Dilatation is Impaired by Saturated Fatty AcidsImpaired by Saturated Fatty Acids

Keogh JN et al. ATVB, 2005

But ...

• Effects of low-fat vs. high-fat dairy products are not consistent

• Many studies have shown that total or saturated fat intake is not a determinant of blood pressure

Total Fat Intake Has No Effect on Total Fat Intake Has No Effect on Systolic and Diastolic BPSystolic and Diastolic BP

-6

-4

-2

0

2

0 1 2 3 4 5 6

6 mo 12 mo 6 mo 12 moSystolic Diastolic

(m

m H

g)

+ Low-carb

Nordmann AJ et al. Arch Intern Med, 2006

Is there a role for CLA?

50

70

90

110

130

Systolic Diastolic

mm

Hg

CLA and Vaccenic Acid Have No Effect CLA and Vaccenic Acid Have No Effect on Blood Pressureon Blood Pressure

CLA Vaccenic acid ControlRaft M et al. J Nutr, 2006

CLA and Vaccenic Acid Have No Effect CLA and Vaccenic Acid Have No Effect on Arterial Functionon Arterial Function

Raft M et al. J Nutr, 2006

• Arterial compliance did not change

Conclusion- Fat -

• The amount or composition of fat in dairy products cannot be responsible for the relationship between dairy consumption and blood pressure

Does Animal Protein Affect Blood Pressure?

A Mixture of Animal and Vegetable Protein A Mixture of Animal and Vegetable Protein Lowers BP Compared with CarbohydratesLowers BP Compared with Carbohydrates

-4

-2

0

All Pre-HT HT All Pre-HT HTSystolic Diastolic

(m

m H

g)

Appel LJ et al. JAMA, 2005 Protein Unsaturated Fat

Peptides from Milk Proteins May Have ACE-Inhibiting Properties

• Val-Pro-Pro

Valine-Proline-Proline

• Ile-Pro-Pro

Isoleucine-Proline-Proline

Isoleucine Valine Proline

The Role of ACE (Angiotensin Converting Enzyme) in Blood Pressure Regulation

Angiotensinogen in plasma

ANG I in plasma

ANG II in plasma

Renin

ACE

Blood pressure

In Vitro and Animal Studies Have Shown that Tripeptides Lower ACE-activity

Sipola M. J Physiol Pharmacol, 2001

Control

Tripeptide

Fermented milkLactobacillushelveticus

Design

• Parallel-design with two groups• 39 hypertensive subjects• 21 weeks• 2.0 mg Val-Pro-Pro per 100 g• 1.5 mg Ile-Pro-Pro per 100 g• Daily intake: 150 mL fermented milk• Measurement taken at home by the subject

Seppo L et al. Am J Clin Nutr, 2003

Seppo L et al. Am J Clin Nutr, 2003

A Fermented Milk High in Peptides Lowers Human Blood Pressure

-20

-15

-10

-5

0

(mm

Hg)

Intervention Control

P=0.059

P=0.030

Systolic Diastolic

Seppo L et al. Am J Clin Nutr, 2003

A Fermented Milk High in Peptides Lowers Human Blood Pressure

Design

• Parallel-design with four groups• 134 subjects with elevated SBP• 8 weeks• 2.0 mg Val-Pro-Pro per 100 g• 2.6 mg Ile-Pro-Pro per 100 g• Daily intake: 200 mL yogurt• Measurements taken at home by the subject

Engberink MF et al. Hypertension, 2008

The Four Treatments

• Control• Fermented lactotripeptides• Enzymatic lactotripeptides• Synthetic lactotripeptides

Engberink MF et al. Hypertension, 2008

Engberink MF et al. Hypertension, 2008

Lactotripeptides Show No Effect on Human Blood Pressure

Engberink MF et al. Hypertension 2008

Lactotripeptides Did not Change ACE-activity and Angiotensin II

-0,4

-0,2

0,0

0,2

0,4

-4

-2

0

U/L

Control

pm

ol/L

FermentedLTP

ACE-activity Angiotensin II

EnzymaticLTP

SyntethicLTP

Conclusion- Protein / Bioactive peptides -

• Protein may lower blood pressure compared with carbohydrates

• There is no unequivocal evidence that tripeptides (Ile-Pro-Pro or Val-Pro-Pro) lower human blood pressure

Does Dietary Calcium Affect Blood Pressure?

Calcium may lower blood pressure

• Several meta-analyses have suggested an effect of dietary calcium on in particular systolic blood pressure

• This effect may diminish at higher intakes and depend on genetic background

• Is the effect of dietary sources stronger than that of supplements?

Why does dietary calcium lower BP- Zemel Hypothesis -

Dietary calcium

Intracellularcalcium

1,25-(OH)2-D

Vascularresistance

Blood pressure

Calcium influx

Some Important Implications of the Zemel Hypothesis

• Dietary calcium lowers plasma 1,25-(OH)2-D concentrations

• Dietary calcium lowers intracellular calcium concentrations

• Plasma 1,25-(OH)2-D concentrations are positively related to blood pressure

Some Important Implications of the Zemel Hypothesis

• Dietary calcium lowers plasma 1,25-(OH)2-D concentrations

• Dietary calcium lowers intracellular calcium concentrations

• Plasma 1,25-(OH)2-D concentrations are positively related to blood pressure

Plasma 1,25-(OH)2-D levels are NOT positively related to blood pressure

• An inverse relationship exists between plasma 1,25-(OH)2-D and blood pressure

• Vitamin D treatment lowers blood pressure

• Ultraviolet light may lower blood pressure

• Blood pressure tends to be higher in winter than in summer

• Studies in transgenic animals

Why is Plasma 1,25-(OH)2-D Negatively Related to Blood Pressure?

Hypothesis:

1,25-(OH)2-D lowers renin

expression and activity

Angiotensinogen in plasma

ANG I in plasma

ANG II in plasma

Renin

ACE

Blood pressure

Conclusion- Calcium -

• Calcium is a likely candidate• There is not much support for the Zemel-

hypothesis

Conclusions

• There is consistent evidence that a diet rich in low-fat dairy products lower blood pressure

• This effect may be related to the increased protein and calcium intakes on such diets

• Despite several hypotheses, the underlying mechanisms are not clear