Aceite de oliva composicion y salud hecho por medicos barcelona 2006

EFFECT OF OLIVE OIL AND ITS PHENOLIC

COMPOUNDS ON REDUCTION OF HEART

DISEASE RISK FACTORS AND OXIDATIVE

DAMAGE

M.I. CovasLipids and Cardiovascular Epidemiology UnitInstitut Municipal d´Investigació Mèdica (IMIM). Barcelona. Spain

Sessions dels Groups i Unitats d´Epidemiologia. IMIM. Maig 2006

Background

The benefits of olive oil consumption are becoming increasingly recognized.

Recently, the FDA permitted a claim on olive oil labels concerning:

“the benefits on the risk of coronary heart disease (CHD) of eating about 2 tablespoons (23 grams) of olive oil daily, due to the monounsaturated fat

(MUFA) in olive oil”.

However, if the effect of olive oil can be attributed solely to is MUFA content, any type of olive oil, rapeseed oil, or or MUFA-rich food would provide the same

health benefits.

Olive oil is the main source of fat in the Mediterranean Diet

Thus, Public Health implications exist as to whether a specific type of MUFA fat or olive oil should be recomended as individualized eating strategies for oxidative stress

associated diseases prevention

OLIVE OIL COMPONENTS

• Major components: Fatty acids– Saturated (8-14%)– Monounsaturated (oleic acid 55-83%)– Poliunsaturated (4-20%)

• Minor components:– Squalene, Sterols, triterpenes– Vitamin E, Beta-carotene– Phenolic compounds (tyrosol, hydroxytyrosol,

oleuropeine, lignanes).

EUROPEAN OLIVE OIL MEDICAL INFORMATION LIBRARY

TYPES OF OLIVE OILOLIVES

LEAF REMOVAL

WASHING

CRUSHING-MILLING

PASTE MALAXATION

PRESSURE OR CENTRIFUGATION

VIRGIN OLIVE OILOLIVE POMACE

Refination

Orujo de oliva

Refination Refined olive oil

Mixture

Low phenolic content

(10-30 mg/Kg)

High phenolic content

(150-400 mg/Kg)

Low phenolic content

(10-70 mg/Kg)

Phenolic content (0-5 mg/kg)

Pomace olive oil Common olive oil

The phenolic content of an olive oil varies, depending on the cultivar, climate, ripeness of the olives at harvesting, and the processing system for the type of olive oil:

Background

Olive oil phenolic compounds show:•strong antioxidant properties against free radical generation and LDL oxidation in experimental studies• delayed the progression of atherosclerosis in animal models.

Oleate-rich LDL is less susceptible against oxidative modification than linoleate-rich LDL.

There is increasing evidence that dietary phenolic compounds can modulate lipid and lipoprotein metabolism.

Oxidative damage of deoxyribonucleic acid (DNA) is linked pathogenically to a variety of diseases such as cancer and also to ageing Low density lipoprotein (LDL) oxidation is a hallmark for atherosclerosis development.

Olive oil phenolic compounds are bioavailable in humans

Data regarding the benefits of olive oil phenolic compounds in humans from real-life daily doses of olive oil are controversial and scarce

The protective effects on lipid oxidation in these trials being better displayed in oxidative stress conditions

Carefully controlled studies in appropriate populations (i.e. oxidative stress conditions, or with a large sample size (in the case of healthy volunteers), are required to definitively establish the health properties of olive oil phenolic

compounds in humans.

Consensus report. Expert Panel

International Conference of Olive Oil and Health. Jaen, Spain October 2004

Expert Panel. Pérez-Jiménez, Coordinator, et al, Eur J Clin Invest 2005;35:421-4

THE EFFECT OF OLIVE OIL CONSUMPTION ON OXIDATIVE DAMAGE IN EUROPEAN

POPULATIONS. The EUROLIVE Study (QRLT-2001-00287)

Covas MI, Poulsen HE, Nyyssönen K, Zunft HFJ, Kiesewetter H, Gaddi A, López-Sabater C,

Kaikkonen J, on behalf of the EUROLIVE Investigators

IMIM

UBGL

KEPKA

DIfE

RHK

UKU

EUC

UB

JLB

UBER

Objective

To assess the effect of three similar types

of olive oil, but with differences in their

phenolic content, on blood lipids, and the

oxidative/antioxidative status in healthy

human volunteers.

3.1.1 Characteristics of the olive oils

Determination of phenolic content in several virgin olive oils (HPC)Virgin olive oil

Picual from Jaen (Andalucia, Spain, 366 ppm of PC)

Measurement of fatty acid profile and vitamin E

Determination of fatty acid profile and vitamin E of several refined virgin olive oils from similar cultivar and soil

(VLPC) Refined olive oil (similar characteristics to the virgin one)

Mixture (MPC) Common olive oil

3.1 Protocol of management for Olive Oils

Characteristics of the Olive Oils Administered

Type of olive oil

750 430 580

Free acidity (% oleic acid) 0.03 0.08 0.18

Peroxide value (mEq O2/kg) 4.12 5.89 11.28

Fatty acids (%)

C14:0 0.01 0.01 0.01

C16:0 10.63 10.50 10.63

C16:1 0.88 0.86 0.88

C17:0 0.05 0.05 0.04

C17:1 0.09 0.09 0.09

C18:0 3.27 3.13 2.84

C18:1 79.08 79.80 80.60

C18:2 4.64 4.21 3.35

C20:0 0.39 0.39 0.35

C18:3 0.58 0.58 0.58

C20:1 0.26 0.25 0.25

C22:0 0.11 0.10 0.10

C24:0 0.01 0.02 0.02

-Tocopherol (ppm) 229 228 228

Phenolic compounds (mg/Kg) 2.7 164 366

Squalene (mg/g) 3.0 3.2 3.4

-sitosterol (mg/g) 1.4 1.5 1.5

The EUROLIVE Study

Study population: 200 healthy non-smoker males recruited between December 2002 and July 2003 in 6 Centers of 5 European Countries (Denmark, Finland, Germany (2 Centres), Italy, and Spain).

The EUROLIVE Study. Methods

Eligibility criteria: to be healthy on the basis of clinical exanimation and laboratory analyses; willingness to provide written, informed consent; and to agree to the adherence to the protocol

Exclusion criteria: -smoking -intake of antioxidant supplements

- diabetes - hypertension

-Hyperlipidaemia - any condition limiting mobility

-obesity (body mass index >30 kg/m2)

-aspirin, or drugs with established antioxidant properties

-celiac or other intestinal disease, life-threatening diseases, or any other disease or condition that would impair compliance.

Persons invited to be screenedn = 344

144 ineligible 98 Did Not Met Protocol criteria 46 Unwilling to Participate

68 Assigned to Order 2,(MPC, LPC, HPC)

200 Randomized

67 Assigned to Order 1,(HPC, MPC, LPC)

65 Assigned to Order 3(LPC, HPC, MPC)

6 Out of Follow-up 3 Unable to adhere 2 Moved away 1 Collateral event

5 Out of Follow-up 2 Unable to adhere 2 Moved away 1 Collateral event

7 Out of Follow-up 4 Unable to adhere 1 Moved away 2 Collateral events

61 Included in the Analysis 63 Included in the Analysis 58 Included in the Analysis

Flow-chart describing progress of participants through the EUROLIVE Study

LPC, MPC, and HPC, olive oils with low, medium and high phenolic content, respectively.


Latin Square for three treatments in the cross-over clinical trial

Examination Number: 1 2 3 4 5 6 7 Blood collection Anthropometric measures

Order 1

HPC WO MPC WO LPC

Order 2

WO MPC WO LPC WO HPC

Order 3 WO LPC WO HPC WO MPC

LPC, MPC, and HPC: olive oils with low, medium, and high phenolic contentWO: wash-out period, (2 weeks) .Intervention periods 3 weeks (25 mL/day olive oil ingestionExamination number (general measurements and/or blood collection): 1, baseline; 2, post-first washout; 3, post-first intervention; 4, post-second washout; 5, post-second intervention; 6, post-third washout; 7, post-third intervention .

3DDR 3DDR 3DDR 3DDR

FHD/PA PA


WO

Outcome measurements in the Clinical Trials

Urinary tyrosol and hydroxytyrosol, the major olive oil phenolic compounds, as markers of compliance

Oxidative markers

Lipid oxidation

F2 isoprostanes (pl)

OH-Fatty acids (pl)

Conjugated dienes (LDL)

Oxidized LDL (pl)

Antibodies against oxidized LDL (s))

DNA and RNA oxidation

8-oxo-dGuo (u)

8-oxo-Guo(u)

8-oxo-Gua (u)

Antioxidative markers

Endogenous

SOD (b)

GSH-Px (pl)

GR (pl)

GSH/GSSG (b)

Enterolactone (s)

PON (s)

Exogenous

AA (pl)

Tocopherol (pl)

-carotene (pl)

Lycopene (pl)

Lipid status: Fatty acids in LDL; Serum Cholesterol, LDL, HDL


3-O-methyl-hydroxytyrosol in urine as a marker of the individual bioavailability and metabolic capacity of the hydroxytyrosol ingested.

No differences at baseline were observed among the three groups of olive oil administration order:

•For energy, macronutrients, or for the main antioxidant (vit E, beta-carotene...) or pro-oxidant intake (iron).

•For the evaluated end-points, with the exception of low levels of Ab-oxLDL in order 1 group and 8-dGuo in order 3 group (P<0.05).

The EUROLIVE Study. Results

No carryover effect, examined through the interaction treatment by period in the models, was observed for any outcome.

No changes in daily energy expenditure in leisure time physical activity were observed from the beginning to the end of the study (mean values, 282 vs 275 kcal/day).

Diet was similar in the three groups during each type of olive oil administration.

Mean daily energy consumption (SD) and selected nutrient intake (SD) according olive oil intervention

Olive Oil

Nutrient Low phenolics Medium phenolics

High phenolics

Energy (kcal)

2212

(690.6)

2228

(741.4)

2245

(650.0)

Carbohydrate (%)* 48.4 (27.6) 46.2 (9.5) 46.3 (9.3)

Protein (%)* 15.3 (3.3) 15.6 (3.7) 15.4 (3.6)

Total Fat (%)* 36.2 (8.1) 36.2 (8.1) 36.1 (8.2)

Saturated fat (%)* 12.6 (3.5) 12.6 (3.5) 12.8 (3.6)

Monounsaturated fat (%)* 14.6 (4.4) 14.7 (4.7) 14.7 (4.6)

Polyunsaturated fat (%)* 4.9 (2.0) 4.9 (1.9) 4.8 (1.9)

Vitamin C (mg) 102 (71.4) 104 (73.2) 115 (96.5)

Vitamin E (mg) 9.2 (4.8) 9.2 (5.6) 8.9 (4.9)

ß-carotene (mg) 2.4 (2.6) 2.6 (3.0) 2.2 (2.3)

*Expressed in percentage of total energy intake


Changes in total fat after intervention periods

Post-HPCPost-MPCPost-LPCBaseline

Tota

l fat

(g)

110

100

90

80

* * *

* P < 0.001, Tukey´s test



Changes in carbohydrate intake after intervention periods


Post-HPCPost-MPCPost-LPCBaseline

Car

bohy

drat

e in

take

(g/d

ay)

290

280

270

260

250

240

*

*P < 0.001, Tukey, t test


P < 0.001 for linear trend; * P< 0.05 versus LPC, † P< 0.001 versus MPC

2000

Cha

nge

(%)

3000

2500

2000

1500

1000

500

0

Hydroxytyrosol * †

*

Type of olive oil administered

HPCMPCLPC

Cha

nge

(%) 1500

1000

500

0

Tyrosol * †

*

The EUROLIVE Study. Results-Urinary tyrosol and hydroxytyrosol as markers of Compliance


LPC

Olive oil intervention

MPC

HPC

Post-int Change Post-int Change Post-int Ghange

Body mass index (kg/m 2) 24.1 (2.8) 0.03 (0.31) 24.1 (2.8) 0.05 (0.33)) 24.0 (0.21) 0.01 (0.30)

SBP(mmHg) 123 (0.88) 122 (0.95) 123 (0.89) 123 (0.85) 123 (0.82) 123 (0.93)

DBP (mmHg) 75 (0.65) 76 (0.64) 76 (0.68) 76 (0.60) 76 (0.62) 76 (0.65)

Glucose (mg/dL) 86 (6.6) -0.29 (0.8) 86 (7.2) -0.29 (8.5) 86 (5.9) -0.08 (11.2)

Cholesterol (mg/dL)

Total 182 (37) 0.21 (21) 181 (36) 0.51 (24) 183 (37) 0.50 (17)

LDL 115 (34) 0.55 (19) 113 (33) -0.88 (21) 2115 (34) -0.41 (18)

HDL 49.2 (10.8) 0.99 (6.1) * 49.6 (10.3) 1.23 (6.5)* 50.4 (11.1) 1.76 (5.3)‡

Triglycerides (mg/dL) 91 (37) -6.1 (37) * 92 (37) -5.0 (41) 91 (32)

1.76 (5.3)‡1.23 (6.5)*0.99 (6.1)*

-6.1 (37)* -5.0 (41)

The EUROLIVE Study. ResultsThe EUROLIVE Study. Results

P for linear trend2

0.55

0.12

0.78

0.27

0.31

0.68

0.90-4.7 (32)*-4.7 (32)*

0.018

Total Cholesterol/HDL 3.88 (1.11) -0.09 (0.58) 3.81 (1.06) -0.10 (0.55) 3.81 (1.07) -0.12 (0.50) 0.005

LDL/HDL ratio 2.46 (0.95) -0.05 (0.49) 2.38 (0.88) -0.07 (0.49) 2.41 (0.93) -0-09 (0.45) 0.052 -0-09 (0.45) †

-0.10 (0.55) † -0.012 (0.50)*

-0.07 (0.49)*

0.018

0.005

0.052

Changes1 in Body Weight, Systolic and Diastolic Blood pressure, Glucose, and Blood Lipids after intervention with olive oil with high (HPC), medium (MPC), and low ( LPC) phenolic content (mean (SD).

1 General linear model, * P < 0.05; P<0.01, ‡ P < 0.001 versus the corresponding baseline, Tukey´s test. 2 General linear model with post-intervention values adjusted by baseline values.

-0.09 (0.58)†

LPC


MPC

HPC

Post-int Change Post-int Change Post-int Change

F2-isoprostanes ( g/L) 28 (4.9) 0.15 (4.9) 28 (4.3) -0.31 (5.4) 28 (6.4) 0.08 (5.3)

Uninduced dienes (mol/mol chol)

2.60 (0.96) -0.03 (0.83)

2.57 (0.92) -0.20 (0.91) ‡

2.50 (0.91) 0.18 (0.78) †

Hydroxyfatty acids (mol/L)

1.26 (0.18) -0.03 (0.51)

1.25 (0.18) -0.06 (0.49)

1.21 (0.17) 1.22 (0.026)*

8-oxo-deoxyguanosine (nmol/24h-urine)

18.6 (0.63) -2.3 (0.75) ‡

17.9 (0.53) -2.9 (0.50) ‡

18.1 (0.57) -2.1 (0.55) †

8-oxo-guanosine (nmol/24h-urine)

21.6 (0.74) 0.9(0.76)

21.0 (0.72) 0.4 (0.71)

21.5 (0.74) 0.3 (0.81)

8-oxo-guanine (nmol/24h-urine)

121 (6.5) 28 (13)

160 (14.9) 25 (7.8)

152 (9.6) 24 (14.3)

-

-2.9 (0.50)‡

-0.20 (0.91) † -0.18 (0.78) †

-0.08 (0.49) †

-2.3 (0.75)‡ -2.1 (0.55)†


P for linear Trend2

0.23

Antibodies against 3

oxidized LDL (U/L) 590 (234;1397)

-0.20 (-80 ; 85)

636 (228;1416)

9.8 (-61; 153)

557 (240;1403)

8.3 (-67 ;116)

0.60

0.001

0.004

0.16

0.23

0.39

Oxidized LDL (U/L) 47 (18) 0.94 (17) 46 (16) -1.85 (14) 45 (16) 45.7 (1.8)*

-3.5 (15) † 0.0140.014

0.001

0.004

1 General linear model, ‡ P<0.01, ‡ P < 0.001 versus the corresponding baseline, Tukey´s test. 2 General linear model with post-intervention values adjusted by baseline values. 3 median (25th-75th percentile)

Changes1 in oxidative stress biomarkers after intervention of olive oil with high (HPC), medium (MPC), and low (LPC) phenolic content (mean (SD)

LPC


MPC

HPC

Post-int Change Post-int Change Post-int Change

Endogenous

Paraoxonase (U/L) 165 (113) 0.27 (33) 164 (109) 0.13 (28) 165 (113) -2.46 (25)

.

Superoxide dismutase (U/L) 142 (20) -0.47 (14) 141 (20) -1.50 (13) 142 (20) 0.12 (14)

Glutathione peroxidase (U/L) 708 (152) -2.3 (119) 704 (134) -1.1 (106) 714 (162) -3.7 (126)

Glutathione reductase (U/L) 62 (10) -1.9 (18) 63 (10) -1.6 (19) 63 (11) 0.78 (20)

Reduced glutathione (mol/L) 5.85 (0.64) 0.31 (0.40) ‡ 5.85 (0.67) 0.28 (0.32)‡ 5.87 (0.56) 0.33 (0.38)‡

Oxidized glutathione (mol/L) 0.84 (0.18) -0.12 (0.17) ‡ 0.82 (0.19) -0.14 (0.16) ‡ 0.83 (0.17) -0.12 (0.18) ‡

Red/Ox glutathione ratio 7.9 (2.2) 1.74 (2.9) ‡ 8.2 (2.6) 2.0 (3.4) ‡ 8.1 (1.6) 1.5 (3.7) ‡

-0.14 (0.16)‡

0.31 (0.40)‡ 0.28 (0.32)‡ 0.33 (0.38)‡

-0.12 (0.17)‡ -0.12 (0.18)‡

1.5 (3.7)‡2.0 (3.4)‡1.74 (2.9)‡


P for linear trend2

0.77

0.53

0.31

0.02

0.70

0.69

0.77

No changes in plasma exogenous antioxidants (vit C,vit E, -carot, Lycopene).

Changes1 in antioxidative biomarkers after intervention of olive oil with high (HPC), medium (MPC), and low (LPC) phenolic content (mean (SD)

1 General linear model, ‡ P < 0.001 versus the corresponding baseline, Tukey´s test. 2 General linear model with post-intervention values adjusted by baseline values, order and centre.

Paired comparisons among values after olive oils interventions

Mean of Differences (SEM)

Variable HPC vs LPC p MPC vs LPC p HPC vs MPC p

HDL Cholesterol (mg/dL) 1.93 (0.77) 0.012 0.71 (0.66) 0.283 1.22 (0.64) 0.045

Uninduced dienes (mol/L) -0.060 (0.02) 0.013 -0.036 (0.02) 0.084 -0.024 (0.02) 0.218

Oxidized LDL (U/L) -4.48 (1.73) 0.010-2.96 (1.48) 0.046 -1.52 (1.43) 0.288


0.012 0.045

0.013

0.010 0.046

GLMM adjusted by basal values for each intervention period, olive oil administration order,center, and age

Results improved when difference of fat and carbohidrate from baseline are added to the model.

Table 4. Changes after olive oil interventions by centre

Variable Centre 1(Barcelona)

(n =30)

Centre 2(Copenhagen)

(n =28)

Centre 3(Kuopio)

(n =30)

Center 4(Bologna)

(n = 25)

Center 5(Postdam)

(n = 38)

Center 6(Berlin)

(n =32)

HDL cholesterol, mg/dLLow PC olive oil

Medium PC olive oil

High PC olive oil

0.92 (-1.1 to 2.9)

1.38 (-0.08 to 2.8)

2.20 (0.58 to 3.8)

1.50 (-1.3 to 4.2)

3.63 (-0.7 to 7.9)

1.49 (-1.1 to 4.1)

0.93 (-1.1 to 2.9)

0.38 (-1.9 to 2.5)

1.73 (-0.2 to 3.7)

0.54 (-1.4 to 2.5)

0.11 (-2.2 to 2.4)

2.62 (0.2 to 5.0)

1.28(-1.1 to 3.7)

1.38 (-0.6 to 3.3)

2.58 (0.6 to 4.5)

0.20 (-1.3 to 1.7)

0.52 (-1.3 to 2.3)

0.58 (-1.8 to 2.9)

Oxidized LDL, U/LLow PC olive oil

Medium PC olive oil

High PC olive oil

3.38

(-2.6 to 9.4)-1.62

(-6.2 to 3.0)-3.10

(-6.9 to 0.8)

2.7

(-6.7 to 12)-2.87

(-10.3to 4.6)0.40

(-7.2 to 8.0)

-0.49

(-4.2 to 3.3)-1.93

(-5.9 to 2.1)-1.64

(-4.9 to 1.6)

2.30

(-4.6 to 8.7)-0.84

(-10.0to 9.8)-8.69

(-15.8 to-2.2)

-5.53

(-11.8 to 0.7)-2.12

(-6.6 to 2.4)-8.75

(-14.0 to –2.9)

2.26

(-2.7 to 7.2)-2.0

(-5.7 to 1.6)-2.28

(-5.7 to0.48)

Hydroxy fatty

acids,* nmol/L Low PC olive oil

Medium PC olive oil

High PC olive oil

10 (109 to 106)

-3 (-127 to 134)

-22 (-116 to 71)

40 (-86 to 166)

-13 (-124to 150)

-114 (-247 to 19)

33 (-75 to 141)

-19 (-130 to 93)

-65 (-195 to 65)

-45 (-222to 132)

-165 (-299 to -31)

-109 (-223 to -9)

-66 (-167 to 35)

14 (-87 to 114)

-14 (-85 to 56)

-130 (-273 to 13)

-69 (-189 to 30)

-76 (-174 to -4)

Consumption of 25 mL daily doses of all types of olive oil, as source of raw fat, reduced lipid cardiovascular risk factors, improved the

glutathione antioxidant status, and decreased oxidative DNA damage

Consumption of the olive oil with the high phenolic content (virgin) provided the highest benefits by increasing HDL cholesterol levels and

reducing the oxidative damage on lipids

Daily consumption of olive oils with medium and high phenolic content decreased oxidative damage on lipids.

The EUROLIVE Study. ResultsThe EUROLIVE Study. Comments

Changes in biomarkers were modest, as was expected for the administration of real-life doses of a single food, during three weeks.

Our results supports the body of research concerning that a rich-MUFA diet can help to reduce triglycerides and raise HDL cholesterol, in

accordance with current cardiovascular guidelines.

The EUROLIVE Study. Comments

Our finding suggest an independent effect of olive oil phenolics increasing HDL-cholesterol levels.

The enhancement of HDL-cholesterol related with the phenolic content of the olive oil is in line with the results obtained after phenolic-rich

food conssumption in other human studies.


Type of olive oil

HPCMPCLPC

Diff

eren

ce in

HD

L (m

mm

ol/L

)

0.065

0.052

0.039

0.026

0.01

0.00

Threshold

A 0.026 mmol/L increase in circulating HDL cholesterol levels is associated with a decrease from 1 to 3.6% in cardiovascular mortality, and with a 3.7% reduction of the risk to develop acute myocardial infarction (Stampfer MJ et al. JAMA 1996; 276: 882-8).

Projected reduction in CHD risk associated with 25 mL olive oil per day versus non olive oil consumption (%)

Type of olive oil

Biomarker Relative risk (95% CI)1 LPC MPC HPC

HDL-C 0.69 (0.47 to 0.99 per 10 mg/dL) 3.60 4.45 6.30

Triglycerides 1.33 (1.05 to 1.68 per 100 mg/dL) 1.72 1.41 1.33

1 From Jacobs DR et al. Am J Epidemiol 1990; 131: 32-47 and Stampfer MJ et al. JAMA 1996; 276: 882-888.

LPC, MPC, and HPC, olive oils with low (14.7 mg/Kg), medium (164 mg/Kg), and high (366 mg/Kg) phenolic content, respectively.

These risk decrements were based upon data from cohort

studies. Whether a HDL or triglycerides reduction due to

olive oil and its phenolic consumption would lead to these

decreases in CHD risk has not been established.

Oxidative damage to lipids decreased in a linear form with the phenolic content of olive oil, particularly in those markers directly associated with LDL oxidation.

Oxidation of the lipids present in LDL (measured by conjugated dienes and hydroxy fatty acids) or direct oxidation of the LDL protein led to a change into the lipoprotein conformation (measured by the levels of oxidized LDL) by which the LDL is more able to enter in the monocyte/macrophage system, inside the arterial wall, and promote the atherosclerotic process.

Circulating ox-LDL levels show a positive relationship with the severity of acute coronary syndromes and are biomarkers for CHD risk.


Mechanisms involved could be the own antioxidant activity of the phenolic compounds and the combined protective effect of both the phenolic and the

MUFA content of the olive oil

Phenolic compounds in LDL

Levels of oleic acid and antioxidants in LDL after sustained (1 week, 25ml/day) doses of virgin olive oil

8.5ng

/mg

prot

ein

7.0

5.5 4.0

Baseline Post-intervention

†10

8.5

g/m

g pr

otei

n

7.0

5.5

4.0Vit E in LDL

†10

*

Oleic acid in LDL

2220

1816

14

Gimeno et al. Eur J Clin Nutr 2002; 56:114-120

12

% o

f Tot

al fa

t

22

The susceptibility of LDL to oxidation depends not only on its fatty content, but also

of the LDL content of antioxidants, such as vitamin E and phenolic compounds (Fuller CJ, Jialal I. Am J Clin Nutr.

1994; 60:1010-3).

B

a


HPCMPCLPC

60

40

20

0

-20

-40

Cha

nge

(%) f

rom

bas

elin

e 80

60

40

20

0

-20

-40

A

a

HPCMPCLPC


Changes in the total phenolic content of the LDL are modulated by olive oil phenolic compounds

at 1h (A), and after 4 days (B) of 25 mL/day consumption of olive oils with high (HPC, 360 mg/Kg), medium (164 mg/Kg), and low (2.7 mg/Kg) phenolic content

P = 0.032 for linear trend P = 0.042 for linear trend

a P< 0.05 versus LPC

Covas MI et al. Free Rad Biol Med 2006

Hydroxytyrosol in plasma (g/L)403020100C

hang

e (%

) of P

C in

LD

L

200

100

0

-100

R = 0.780, P = 0.009A

Tyrosol in plasma (g/L)181614121086

Cha

nge

(%) o

f PC

in

LD

L

300

200

100

0

-100

R = 608, P = 0.036B

R = 0.699, P = 0.011

Tyrosol in plasma (g/L)2220181614121086

Cha

nge

(%) o

f PC

in L

DL

400

300

200

100

0

-100

C

Relationship between tyrosol and hydroxytyrosol in plasma and changes in the LDL phenolic content

Covas MI et al. Free Rad Biol Med 2006

Projected reduction in CHD risk associated with 25 mL olive

oil per day versus non olive oil consumption

After HPC olive oil a mean decrease of –3.2 U/L in oxidized

LDL was observed

Although several studies reported a direct relationship between oxidized

LDL and CHD risk, the attributable CHD risk associated with a 1U/L

change of oxidized LDL is, at present, unknown.

In a recent study, the mean difference, in circulating oxidized LDL values

between CHD patients and healthy controls, measured using the same

antibody and method as in the present study, was 17 U/L.

Limitations of the study


Inability to determine whether an interaction between olive oil components and others from diet could account for the changes in cardiovascular risk factors observed, which might affect the generalizability of the results due to dietary differences among countries.

The overall inter-country consistency of the results, however, contributes to the generalizability of the message.

Our design, did not allow modeling the first- and second-order possible carryover effects. The measurements of dietary intake relied on self-reporting and were therefore subjective.

Although the trial was blinded, some participants might have identified the low phenolic olive oil (LPC) or the high phenolic content (HPC) by their color and taste and, not liking them, masking a lack of full compliance despite a good overall compliance.

Consumption of all types of olive oil provide benefits on the cardiovascular risk profile, antioxidant endogenous defences (GSH), and oxidative DNA damage, without modifying levels of antioxidant endogenous enzymes.

The results of the study show that olive oil is more than a MUFA fat.

The phenolic content of an olive oil can account for greater benefits on blood lipids and oxidative damage than those provided by the MUFA content of the olive oil.

The results of the EUROLIVE study provide evidence to recommend the use of olive oil rich in phenolic compounds as a source of fat in order to achieve additional benefits against cardiovascular risk factors.

The EUROLIVE Study. ConclusionsThe EUROLIVE Study. Conclusions

Recommendations which stem from the EUROLIVE study are:

• Among the olive oils with a taste that better suits personal preferences, the best choice is that with the highest phenolic content.

• For health policy makers, the phenolic content of an olive oil should be present in the olive oil labels.

The EUROLIVE Study. ConclusionsThe EUROLIVE Study. Recommendations

Olive oils with high phenolic content are stronger, and, in general more bitter and greener than those with low phenolic content.

Olive oil must not be taken as a medicine.

Daily consumption of high phenolic olive oil did not compromise the endogenous antioxidant enzymes. In some studies, polyphenol-rich food and antioxidant supplementation led to a decrease in these enzymes, presumably due to a lack of activation of their production by the decrease in free radicals.

This decrease has been considered a negative effect in situations of free radical production, such as exercise, in which the role of the antioxidant enzymes is crucial in counteracting oxidative damage

The absence of changes in plasma antioxidant vitamins suggests an

independent effect of phenolic compounds from olive oil on oxidative

damage.

The EUROLIVE Study

THE EFFECT OF OLIVE OIL CONSUMPTION ON OXIDATIVE DAMAGE IN EUROPEAN

POPULATIONS. The EUROLIVE Study

IMIM

UBGL

KEPKA

DIfE

RHK

UKU

EUC

UB

JLB

UBER

EUROLIVE Investigators: Institut Municipal d´Investigació Mèdica (IMIM), Barcelona, Spain:

Lipids and Cardiovascular Epidemiology Research Unit: Covas MI (Study Coordinator), Marrugat J, Fitó M, Elosua R, Schröder H, Vila J. Cladellas M.

Pharmacology Research Unit, de la Torre R, Farré-Albaladejo M.

Department of Clinical Pharmacology, Rigshospitalet, University Hospital Copenhagen, Denmark: Poulsen H E (Centre Coordinator), Weimann A.

Research Institute of Public Health, University of Kuopio, Finland: Salonen JT (Centre Coordinator), Konttinen A, Nyyssönen K Mursu J; Rissanen T, Tuomainen T-P, Valkonen V-P, Virtanen J.

Centro per lo Studio dell'Arteriosclerosi e delle Malattie Dismetaboliche"GC Descovich". Dipartimento di Medicina Clinica e Biotecnologia Applicata.Policlinico S. Orsola-Malpighi, Bologna, Italy: Gaddi A (Centre Coordinator), D’Addato S, Fiorito A, Grandi E, Linarello S, Nascetti S, Sangiorgi Z

German Institute of Human Nutrition Potsdam-Rehbruecke, Germany: Zunft, H-J F (Centre Coordinator), Koebnick C, Machowetz A

Institute of Transfusion Medicine, Charité-University Medicine of Berlin, Germany: Kiesewetter H (Centre Coordinator), Bäumler H

Department of Nutrition and Bromatology. University of Barcelona, Spain: López-Sabater C, Lamuela-Raventós R, de la Torre K,Castellote AI

Oy Jurilab, Kuopio, Finland:

Kaikkonen J

oxldl post- MPC intervention interven (U/L)

120100806040200

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oxLD

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st-M

PC

inte

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(U/L

)

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0

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oxldl post- LPC intervention (U/L)

140120100806040200

Ab-

oxLD

L po

st- L

PC

inte

rven

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(U/L

)

7000

6000

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0

-1000

oxLDL at baseline (U/L)

120100806040200

Ab-

oxLD

L at

bas

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e (U

/L) 6000

5000

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0

-1000

oxLDL post- HPC intervention (U/L)

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oxld

l pos

t- H

PC

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tion

(U/L

)

6000

5000

4000

3000

2000

1000

0

-1000

R = -0.264, P < 0.001

R = -0.210, P =0.005

R = -0.201, P =0.007

R = -0.213, P =0.004


Antioxidative Biomarkers after HPC, MPC, and LPC intervention periods

Exogenous

Ascorbic acid (mol/L) 62 (1.6) 62 (1.6) 61 (1.7) 59 (1.6) 61 (1.7) 61 (1.5)

-tocopherol (mol/L) 25 (0.48) 25 (0.47) 25 (0.49) 25 (0.48) 25 (0.48) 25 (0.48)

-carotene (mol/L) 0.41 (0.024) 0.38 (0.020) 0.40 (0.021) 0.41 (0.026) 0.42 (0.027) 0.40 (0.023)

Lycopene (mol/L) 0.45 (0.017) 0.44 (0.017) 0.43 (0.016) 0.45 (0.017) 0.45 (0.017) 0.44 (0.015)

Enterolactone (mol/L) 17 (1.6) 20 (1.9) 17 (1.5) 21 (2.3)* 17 (1.5) 18 (1.4)

Enterodiol (mol/L) 3.3 (1.2) 3.7 (0.89) 2.2 (0.50) 5.9 (1.9)* 2.7 (0.72) 2.8 (0.73)

Values are mean (SEM), except for antibodies against oxidized LDL which are expressed in median (25th -75th percentile).

Models adjusted by order of administration of olive oil and tyrosol post -intervention values.

*P < 0.05 versus the corresponding baseline, Tukey´s test

Pre-int Post-int Pre-int Post-int Pre-int Post-int

LPC MPC HPC


5.9 (1.9)*

21 (2.3)*


*80 6040200

-20-40

*

A

Olive oil interventionHighPCMedium PCLow PC

Cha

nge

(ng/

g FA

) fr

om b

asel

ine

60

40

20

0

-20

-40

B

Changes in the phenolic content of the LDL after a single dose of 40 mL (A) and after sustained doses (25 mL/day, 4 days) of similar olive oils but with differences in their phenolic content (PC)

Basal characteristics, glucose, lipid profile, and oxidative stress biomarkers at the beginning of the study by subgroups of order of olive oil administration according to an intent-to treat analyis.

Order 1(n=67)

Order 2(n=68)

Order 3(n=65)

Age (years) 33.4 (11.2) 34.3 (11.0) 31.9 (10.8)

BMI (Kg/m2) 23.7 (2.8) 23.8 (2.5) 24.0 (3.2)

Physical activity (kcal/day) 312 (250) 294 (248) 288 (207)

Systolic blood pressure (mmHg) 125 (14.4) 125 (11.1) 123 (12.7)

Diastolic blood pressure 77 (7.6) 78 (8.2) 76 (8.5)

Total cholesterol (mmol/L) 4.84 (0.96) 4.77 (1.06) 4.61 (1.09)

LDL cholesterol (mmol/L) 3.11(0.93) 3.08 (0.93) 2.95 (0.98)

HDL cholesterol (mmol/L) 46.9 (11.3) 46.4 (10.3) 48.5 (11.9)

Triglycerides (mmol/L) 102 (53) 1.2 (0.4) 1.0 (0.5)

Glucose (mmolL) 85 (9.4) 86 (10.4) 86 (9.4)

Oxidized LDL (U/L) 51 (26) 49 (20) 48 (22)

Antibodies against oxidized LDL (U/L) * 787 (120)* 1104 (153) 1092 (149)

Hydroxyfatty acids (mol/L) 1.3 (0.33) 1.35 (0.46) 1.30 (0.57)

F2-isoprostanes (g/L) 30.6 (5.8) 29.1 (5.9) 31.6 (7.6)

Uninduced dienes (mol/L) 11.3 (3.6) 11.4 (3.0) 12.1 (3.7)

8-oxo-deoxyguanosine (nmol/24h) 22.4 (8.2) 20.9 (8.0) 17.6 (6.6)*

8-oxo-guanosine (nmol/24h) 23.1 (9.5) 22.5 (8.4) 20.0 (8.6)

8-oxo-guanine (nmol/24h) 158 (100) 137 (84) 123 (92)

Values are men (SD). Order 1, High, medium , and low phenolic content olive oil; Order 2, medium, low, and high phenolic content olive oil; Order 3,low, high, and medium phenolic content olive oil.. *P < 0.05 versus order 1 group.


Antioxidant status at the beginning of the study by subgroups of subjects depending on the order of olive oil administration according to an intent-to treat analysis

Order 1(n=61)

Order 2(n=63)

Order 3(n=58)

Endogenous

Superoxide dismutase (U/L) 142 (21) 144 (22) 140 (19)

Glutathione peroxidase (U/L) 719 (183) 686 (133) 692 (184)

Glutathione reductase (U/L) 64 (17) 64 (16) 64(16)

Reduced glutathione (GSH) (mol/L) 4.71 (0.59) 4.53 (0.57) 4.61 (0.72)

Oxidized glutathione (GSSG) (mol/L) 1.24 (0.12) 1.26 (0.12) 1.24 (0.12)

GSH/GSSG ratio 3.85 (0.62) 3.61 (0.57) 3.74 (0.71)

Paraoxonase 150 (95) 150 (90) 198 (142)

Exogenous

Ascorbic acid 61 (26) 60 (23) 62 (23)

-tocopherol (mol/L) 25.6 (5.7) 24.6 (6.3) 24.2 (6.8)

-carotene (mol/L) 0.45 (0.39) 0.40 (0.28) 0.35 (0.25)

Lycopene (mol/L) 0.46 (0.23) 0.42 (0.20) 0.43 (0.22)

Enterolactone (nmol/L) 16.8 (18.1) 22.6 (24.9)* 21.8 (36.6)

Enterodiol (nmol/L) 1.51 (5.30) 1.54 (4.13) 2.60 (9.6)

Order 1, high, medium , and low phenolic content olive oil; Order 2, medium, low, and high phenolic content olive oil; Order 3,low, high, and medium phenolic content olive oil.


Hydroxytyrosol (ug in 24h urine)

500040003000200010000-1000

F2 is

opro

stan

es (

ng/L

) 50

45

40

35

30

25

20

15

R =- 0.200, P < 0.01

Inverse relationship between plasma F2-isoprostanes and hydroxytyrosol in urine after high phenolic content olive oil (HPC) intervention period. Spearman´s correlation

Statistical analyses •Normality of continuous variables was assessed by normal probability plots.

•One-factor ANOVA and Kruskal-Wallis test were used to determine differences in basal characteristics and nutrient intake among the three olive oil interventions.

•A general linear model for repeated measurements was used, with multiple paired comparisons corrected by Tukey´s method, in order to assess differences among post-intervention values adjusted by baseline values.•The paired comparison of target concentrations post-intervention was carried out by a General Linear Mixed Model (GLMM) with :

•Random effect: individual level of test subjects •Fixed factor: the olive oil phenolic dose (high, medium, low) administered•Covariates: basal values for each intervention period , olive oil administration order, age, difference of fat and carbohydrate intake from baseline. •An additional model with adjustment for 3-O-methyl, hydroxytyrosol levels was also fitted


Statistical significance was defined as P < 0.05 for a two-sided test. Analyses were performed using the SAS System for Windows release 8.02.

Paradoxes of Southern Europe

Mediterranean Paradox Protective factors Candidates: lifestyle factors

Diet Physical activity Psycosocial stress

Gene-environment interactions

Aceite de oliva composicion y salud hecho por medicos barcelona 2006

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