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

Fact Dairy consumption lowers blood pressure 2

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

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

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

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

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         T0 4 7 8 0 4 7 8 7

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

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

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

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

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?

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

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

Flow-Mediated Dilatation is Impaired 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 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

Is there a role for CLA?

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

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

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 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

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 Renin ANG I in plasma ACE ANG II in plasma Blood pressure

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

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

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

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

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

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

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

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 - 1,25-(OH)2-D Vascular resistance Calcium influx Intracellular calcium 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

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? 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

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