1. Voorgestelde werkingsmechanismen - state of the art -
Ronald P. Mensink
Maastricht University, Department of Human Biology
School of Nutrition, Toxicology, and Metabolism (NUTRIM) 1

2. Fact
Dairy consumption lowers blood pressure 2

3. 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? 3

4. Why the metabolic syndrome
Abdominal
obesity
Pro-
thrombotic
state
Atherogenic
dyslipidemia
Diabetes Mellitus
CVD
Elevated
blood pressure
Pro-
inflammatory
state
Insulin
resistance 4

5. Measurements Blood sampling: Week 0, 4, 7, 8 Blood pressure
Abdominal
obesity
Blood sampling:
Week 0, 4, 7, 8
Blood pressure
Body weight
Pro-
thrombotic
state
Atherogenic
dyslipidemia
Elevated
blood pressure
Pro-
inflammatory
state
Insulin
resistance 5

6. Subjects Baseline 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 6

7. Study design 40 overweight or obese subjects         A
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 A
Low-fat dairy
Control B
        T 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 8

9. Decrease in 1,25-(OH)2-Vitamin D3 (calcitriol) Confirmed Compliance
Calcium intake depresses calcitriol levels
Used as compliance marker
 = 8.7 pmol/L
Control
Low-fat dairy
pmol/L *
* P < 0.05 9

10. Low-fat Dairy Decreased Systolic, but not Diastolic, Blood Pressure
= 2.9 mm Hg
p=0.027
= 1.6 mm Hg
p=0.090
mm Hg
mm Hg
Control
Low-fat dairy 10

11. Results when 10 Subjects on Anti-Hypertensive Medication are Excluded
Systolic
Diastolic
= 4.2 mm Hg
p=0.010
= 1.8 mm Hg
p=0.055
mm Hg
mm Hg
Control
Low-fat dairy 11

12. Conclusion
Consumption of low-fat dairy for 8 weeks does lower systolic blood pressure in overweight subjects

13. What is the Active Component in Dairy?
Dairy is an important source of:
Protein
Calcium
Fat

14. Does Dietary Fat Affect Blood Pressure?

15. Changes in Systolic BP After 1 Yr of Follow-up are Related to Low-Fat, but Not to High-Fat Dairy, Consumption
(mm Hg) * *
P for trend, Low-Fat: 0.01
High-fat: 0.84
Low-fat Dairy High-Fat Dairy
Toledo E et al. Br J Nutr, 2008

16. Changes in Diastolic BP After 1 Yr of Follow-up are Related to Low-Fat, but Not to High-Fat Dairy, Consumption
(mm Hg) *
P for trend, Low-Fat: 0.09
High-fat: 0.61
Low-fat Dairy High-Fat Dairy
Toledo E et al. Br J Nutr, 2008

17. Flow-Mediated Dilatation is Impaired by Saturated Fatty Acids
Keogh JN et al. ATVB, 2005

18. 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

19. Total Fat Intake Has No Effect on Systolic and Diastolic BP
(mm Hg)
+ Low-carb
6 mo 12 mo 6 mo 12 mo
Systolic Diastolic
Nordmann AJ et al. Arch Intern Med, 2006

20. Is there a role for CLA?

21. CLA and Vaccenic Acid Have No Effect on Blood Pressure
mm Hg
CLA Vaccenic acid Control
Raft M et al. J Nutr, 2006

22. CLA and Vaccenic Acid Have No Effect on Arterial Function
Arterial compliance did not change
Raft M et al. J Nutr, 2006

23. Conclusion - Fat -
The amount or composition of fat in dairy products cannot be responsible for the relationship between dairy consumption and blood pressure

24. Does Animal Protein Affect Blood Pressure?

25. A Mixture of Animal and Vegetable Protein Lowers BP Compared with Carbohydrates
(mm Hg)
All Pre-HT HT All Pre-HT HT
Systolic Diastolic
Protein Unsaturated Fat
Appel LJ et al. JAMA, 2005

26. Peptides from Milk Proteins May Have ACE-Inhibiting Properties
Val-Pro-Pro
Valine-Proline-Proline
Ile-Pro-Pro
Isoleucine-Proline-Proline
Isoleucine
Valine
Proline

27. The Role of ACE (Angiotensin Converting Enzyme) in Blood Pressure Regulation
Angiotensinogen in plasma
Renin
ANG I in plasma
ACE
ANG II in plasma
Blood pressure

28. In Vitro and Animal Studies Have Shown that Tripeptides Lower ACE-activity
Control
Tripeptide
Fermented milk
Lactobacillus
helveticus
Sipola M. J Physiol Pharmacol, 2001

29. 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

30. A Fermented Milk High in Peptides Lowers Human Blood Pressure
Systolic Diastolic
(mm Hg)
P=0.059
P=0.030
Intervention Control
Seppo L et al. Am J Clin Nutr, 2003

31. A Fermented Milk High in Peptides Lowers Human Blood Pressure
Seppo L et al. Am J Clin Nutr, 2003

32. 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

33. The Four Treatments Control Fermented lactotripeptides
Enzymatic lactotripeptides
Synthetic lactotripeptides
Engberink MF et al. Hypertension, 2008

34. Lactotripeptides Show No Effect on Human Blood Pressure
Engberink MF et al. Hypertension, 2008

35. Lactotripeptides Did not Change ACE-activity and Angiotensin II
U/L
pmol/L
Control
Fermented
LTP
Enzymatic
LTP
Syntethic
LTP
Engberink MF et al. Hypertension 2008

36. 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

37. Does Dietary Calcium Affect Blood Pressure?

38. 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?

39. Why does dietary calcium lower BP - Zemel Hypothesis -
1,25-(OH)2-D
Vascular
resistance
Calcium influx
Intracellular
calcium
Blood pressure

40. 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

41. 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

42. 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

43. Why is Plasma 1,25-(OH)2-D Negatively Related to Blood Pressure?
Angiotensinogen in plasma
Renin
ANG I in plasma
ACE
Hypothesis:
1,25-(OH)2-D lowers renin
expression and activity
ANG II in plasma
Blood pressure

44. Conclusion - Calcium - Calcium is a likely candidate
There is not much support for the Zemel-hypothesis

45. 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