Triple protection for your arteries

Triple protection

for your arteries

Today’s modern lifestyle works against cardiovascular

health, with many risk factors (abnormal blood lipid levels,

hypertension, diabetes, obesity) associated with coronary

heart disease and stroke

_.

Some of these factors, such as family history or aging,

cannot be modified, while others, like physical inactivity,

a poor diet or smoking, can be modified with lifestyle changes.

The combination of at least three of these risk factors

is known as Metabolic Syndrom. Metabolic Syndrome

is a perfect storm for your health, and multiplying the risk

of developing cardiovascular disease.

Cardiose maintains

arterial flexibility

Flow Mediated Dilation (FMD)

Flow-mediated dilation (FMD) is an accepted technique to quantify endothelial function, showing a predictive value for cardiovascular disease. To measure FMD, shear stress is induced by occluding the upper-arm for five minutes, followed by cuff release. Changes in blood flow cause an endothelial response that is assessed measuring artery diameter with ultrasound3_.

Cardiose’s led to a significant improvement in FMD:

In individuals with metabolic syndrome after supplementation of 500 mg/day Cardiose® for three weeks8_.

11 8 7 6 5 4 3 Placebo Placebo Baseline Baseline Final Final FMD (%) Inflam at ory m ak er s (mg/L) CRP SAA CRP SAA Cardiose® Cardiose® 10 9 8

Laser Doppler Flowmetry and Iontophoresis

Laser Doppler Flowmetry uses laser light to measure red blood cell velocity and concentration, and therefore, to evaluate blood flux in microvasculature. The endothelium function in these micro-vessels is assessed by administering vasodilator agonists through the skin using small electrical currents (iontophoresis).

Cardiose® consumption causes a significant improvement in microvascular reactivity

In healthy, moderately overweight men, after acute consumption. The increase in blood flow was significantly correlated with the concentrations of hesperidin metabolites in blood plasma10_.

Cardiose® also reduces the levels of systemic inflammation markers.

After the intake of a high-fat meal in overweight individuals supplemented with Cardiose® (500 mg/day) for a period of six weeks.

*Adapted from Rizza et al.8

*Adapted from Rizza et al.8

Cardiose reduces

plaque formation

Endothelial adhesion molecules are key components

for the normal function of the cardiovascular system.

However, endothelial adhesion molecules like E-selectin, VCAM-1 and ICAM-1 are potent adhesion molecules that trigger platelets and white blood cells to stick to arterial walls.

After four weeks of Cardiose® consumption (600 mg/day) E-selectin concentration decreased in patients suffering from myocardial infarction12_{. In the same way, the three-week}

Cardiose® supplementation (500 mg/day) led to a reduction of the circulating

concentrations of soluble E-Selectin in individuals with Metabolic Syndrome8_.

Elevated serum concentrations of these cell adhesion molecules are related to cardiovascular disease (CVD)11_{. High}

levels of these molecules induce thrombus formation, and promote plaque formation, leading to atherosclerosis3_.

Six weeks of Cardiose® supplementation brought about a significant down-regulation of circulating soluble VCAM-1 and ICAM-1 molecules in an overweight population.

Cardiose® may modulate the altered concentration of these molecules:

Adhesion molecule reduction following supplementation

Placebo Cardiose® * * (Δng mL -1 ) 20 0 -20 -40 sVCAM-1sICAM-1

Cardiose minimizes

cardiovascular risk factors

Elevated levels of cholesterol and fats put us at risk of experiencing serious cardiovascular events.

Impact on cholesterol levels

A three week treatment with Cardiose® (500 mg/day) in individuals with

Metabolic Syndrome caused a significant8_:

Total cholesterol.

High-density lipoprotein (HDL). Apolipoprotein B, the main proteic component of LDL. Supplementation with Cardiose®

(600 mg/day) in post-infarction subjects significantly increased HDL levels

and decreased LDL levels12_.

REF 1

Risk factors - World Heart Federation, (n.d.). https://www.world-heart-federation.org/ resources/risk-factors/ (accessed February 6, 2018).

REF 2

N. Lipovetzky, H. Hod, A. Roth, Y. Kishon, S. Sclarovsky, M.S. Green, Heavy meals as a trigger for a first event of the acute coronary syndrome: A case-cros-sover study, Isr. Med. Assoc. J. 6 (2004) 728–731.

REF 3

H.A.R. Hadi, C.S. Carr, J. Al Suwaidi, Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome., Vasc. Health Risk Manag. 1 (2005) 183–98.

REF 4

C. Tsioufis, E. Mantzouranis, T. Kalos, D. Konstantinidis, D. Tousoulis, Risk Factors of Atherosclerosis, Coron. Artery Dis. (2018) 43–66.

High blood pressure values are considered a major risk factor for cardiovascular diseases. The development of CVD can be prevented by lowering one’s blood pressure.

Impact on blood pressure

A four-week consumption of Cardiose® significantly lowered diastolic, but not systolic, blood pressure in moderately overweight healthy men10_.

Similarly, a trend towards lower systolic and diastolic blood pressure was also observed after six weeks of Cardiose® supplementation in overweight individuals9_.

*Adapted from Haidari et al.12 _{*Adapted from Morant et al.}10

REF 5

T. Strisciuglio, S. De Luca, E. Capuano, R. Luciano, T. Niglio, B. Trimarco, et al., Endothelial Dysfunction: Its Clinical Value and Methods of Assessment, Curr. Atheroscler. Rep. 16 (2014) 417.

REF 6

C. Steyers, F. Miller, Endothelial Dysfunction in Chronic Inflammatory Diseases, Int. J. Mol. Sci. 15 (2014) 11324–11349.

REF 7

R.T. Ras, M.T. Streppel, R. Draijer, P.L. Zock, Flow-mediated dilation and cardiovascular risk prediction: A systematic review with metaa-nalysis, Int. J. Cardiol. 168 (2013) 344–351.

REF 8

S. Rizza, R. Muniyappa, M. Iantorno, J.A. Kim, H. Chen, P. Pullikotil, et al., Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome, J. Clin. Endocrinol. Metab. 96 (2011) 782–792.

REF 9

B.N. Salden, F.J. Troost, E. de Groot, Y.R. Stevens, M. Garces-Rimon, S. Possemiers, et al., Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals., Am. J. Clin. Nutr. (2016).

REF 10

C. Morand, C. Dubray, D. Milenkovic, D. Lioger, J.F. Martin, A. Scalbert, et al., Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers, Am. J. Clin. Nutr. 93 (2011) 73–80.

REF 11

E. Demerath, B. Towne, J. Blangero, R.M. Siervogel, The relationship of soluble ICAM-1, VCAM-1, P-selectin and E-selectin to cardiovascular disease risk factors in healthy men and women, Ann.Hum.Biol. 28 (2001) 664–678.

REF 12

F. Haidari, H. Heybar, M.T. Jalali, K. Ahmadi Engali, B. Helli, E. Shirbeigi, Hesperidin Supplementation Modulates Inflammatory Responses Following Myocardial Infarction, J. Am. Coll. Nutr. 34 (2015) 205–211.

REF 13

D. Milenkovic, C. Deval, C. Dubray, A. Mazur, C. Morand, Hesperidin displays relevant role in the nutrigenomic effect of orange juice on blood leukocytes in human volunteers: a randomized controlled cross-over study, PLoS One. 6 (2011) e26669

REF 14

D. Ettehad, C.A. Emdin, A. Kiran, S.G. Anderson, T. Callender, J. Emberson, et al., Blood pressure lowering for prevention of cardiovascular disease and death: A systematic review and metaanalysis, Lancet. 387 (2016) 957–967. Δ (% ) Blood pr essur e (mm Hg) 20 140 40 0 120 -20 90 -40 80

Placebo Cardiose® Systolic Diastolic

*

*

*

HDL Placebo

The endothelium

The entire circulatory system is lined with an ultra-thin layer of cells called endothelial cells, or the endothelium. The endothelium is an active organ that plays an indispensable role in arterial contraction and expansion, and facilitates proper blood flow.

The endothelium is the production site of the signaling molecule nitric oxide (NO), which is responsible for dilating blood vessels, increasing blood supply, and lowering blood pressure when it is too high. Additionally, NO has anti-inflammatory properties that protect against atherosclerosis

by regulating the endothelium’s anti-adhesive, anti-inflammatory and vasodilator properties. Endothelial dysfunction is caused by a diminished production/availability of NO4_{, induced}

by cardiovascular risk factors. Its alteration leads to a systemic disorder, being implicated in the development of several diseases5_.

Cardiovascular risk factors Hypertension, diabetes, smoking, obesity Endothelial dysfunction NO reduction Cardiovascular disease

Peripheral and coronary atherosclerosis

Endothelial dysfunction represents

a key early step in the development

of atherosclerosis. Some of the clinical signs of endothelial dysfunction, such as impaired blood flow or increased adhesion molecules, are also present in cardiovascular disease4_.

Endothelial dysfunction may be especially relevant if there is a history of coronary heart disease5_{. Additionally endothelial dysfunction}

has also been related with some chronic inflammatory diseases, such as rheumatoid arthritis or inflammatory bowel disease6_.

Standard hesperidin consists of

a mixture of S-and R-isomers. In nature the 2S-hesperidin is dominant.

Cardiose® has an S:R ratio that is closer to the natural form.

The regulations governing food, food additives, dietary supplements and cosmetics do vary between countries, and the use of some products may be restricted in some places. Therefore, customers are requested to observe the appropriate regulations when using these products. While the information provided in this document is presented in good faith and believed to be accurate, it does not bind HTBA (HealthTech Bio Actives, S.L.U.) under any legal obligations. It is presented only for your guidance. Any information in this document may change without prior notice.

7day wash out

Cardiovascular health

Cardiose has a 50% higher bioavailability than standard hesperidin 1 day

N = 10 healthy adults (18-65 years)

STANDARD

HESPERIDIN HESPERIDINSTANDARD

500mg CARDIOSE

Per day 500mg CARDIOSEPer day

CHOLESTEROL Beta, glucans and other fibers

Triple protection of arteries

CHOLESTEROL

Stanols and sterols CHOLESTEROLRed yeast extract,

Statins

CHOLESTEROL

Fish oil , Omega 3 BLOOD PRESURECoQ10

ANALYSIS OF METABOLITES

(BLOOD AND PLASMA SAMPLES AT REGULAR INTERVALS)

Area under the curve

Standard hesperidin Cardiose

Total main metabolite in blood plasma (in mg) in 0-10h

1 day 0 50 100 150 200 250 300 350 +50 400 Better bioavailability

Distinctive positioning Key features

100% natural

Mediterranean origin