Cardiovascular disease on the rise


Cardiovascular disease (CVD) is a major global health problem that substantially contributes to morbidity, mortality, and escalating health care costs. The American Heart Association estimates the prevalence of CVD is 48% in all adults and increased with advancing age1. Heart diseases ranked first as the leading cause of death1.

Although treatment advances and preventive measures caused a decline in age-adjusted mortality rates of CVD in high-income countries2, recent increases in the incidence of deaths from coronary heart disease and stroke offset the gains made in other disorders because of the aging society and the increased prevalence of diabetes and obesity3.


How the Mediterranean diet can support heart health

Population studies revealed lower rates of chronic diseases and differences in mortality statistics in Mediterranean populations compared to other parts of the world4.

A high adherence to the Mediterranean diet during midlife was associated with a 39% lower coronary mortality risk and a 29% lower cardiovascular mortality risk in middle-aged and elderly5. Review papers confirm the Mediterranean diet could have a protective effect on CVD6,7.

These effects are usually ascribed to the Mediterranean diet’s abundance of antioxidants and anti-inflammatory actives, their impact on cell membrane viability, and even their ability to modify the microbiome.

Olive oil polyphenols such as oleuropein and hydroxytyrosol have been studied extensively for their antioxidant and anti-inflammatory effects and vasodilatory properties 8,10. Today, experts recognize that hydroxytyrosol-rich olive oil decreases the oxidation of LDL cholesterol, an important atherogenic factor. Consequently, the European Food Safety Authority (EFSA) approved a health claim that “olive oil polyphenols contribute to the protection of blood lipids from oxidative stress”9.

Alongside olives, citrus fruits are typically consumed in the Mediterranean diet. They are notably rich in a different type of polyphenols: flavonoids. Many of the citrus compounds improve vascular health and have biologic activities on lipid metabolism, oxidative stress and inflammation11.

Maintaining a healthy blood pressure

Hypertension or raised blood pressure affects around 40% of adults. Because of population growth and aging, the global number of people with high blood pressure or uncontrolled hypertension rose to nearly 1 billion in 2008 (GHO data). An increase in blood pressure is mostly caused by aging-related arterial stiffening, and can be accelerated by the presence of metabolic syndrome14.

Fortunately, there is evidence that arterial stiffening causing elevated blood pressure can be counteracted by the consumption of olive polyphenols15.

Benolea® (EFLA®934) is an olive leaf extract manufactured from carefully selected Mediterranean-grown olive leaves (Olea europaea L.).

An in vivo trial in rats showed that supplementation with Benolea® leads to a normalization of blood pressure in rats with established hypertension as well as prevented the experimentally induced rise in blood pressure16.

These blood pressure-modulating effects have also been confirmed in an open, randomized, controlled clinical trial comparing the effect of lifestyle changes to the daily consumption of 500 mg Benolea® in twenty monozygotic twin pairs with slightly elevated blood pressure. Benolea® significantly reduced blood pressure after six weeks, with a maximal difference between treatment and control of up to 6 mmHg systolic and 5 mmHg diastolic pressure, respectively. A dose increase to 1000 mg Benolea® enhanced the effect to a difference of up to 13 mmHg systolic and 5 mmHg diastolic pressure17.

In a double-blind, controlled study the anti-hypertensive effect of Benolea® was compared to captopril, a standard therapy for individuals with stage 1 hypertension18. 232 patients with elevated blood pressure were randomized to 500 mg Benolea® twice daily for 8 weeks or to an increasing dose of captopril that was adapted to the patient’s response. After 8 weeks, both groups experienced a significant decrease in systolic and diastolic blood pressure with a comparable effect (Figure 1).

Figure 1: Decrease of systolic blood pressure from baseline (*p<0.05, significant differences between groups based on statistical analysis).

In addition to the anti-hypertensive effect, a significant reduction of LDL-cholesterol (LDL-C) was observed in the groups consuming Benolea® (Figure 2). Such effects were not observed with captopril.

Figure 2: Reduction of mean LDL-C concentration compared to baseline, after 4 and 8 weeks of intervention, respectively. Data represent means ± SEM of LDL-C differences within twin pairs of group 1 (500 mg Benolea vs. control) and group 2 (500 vs 1000 mg Benolea) (* p<0.05, significant difference

These results have prompted the scientific team to design a blend of Mediterranean ingredients that has a supportive effect on even more aspects of cardiovascular health.

One of the main roles of vascular endothelial cells is to maintain a normal vascular function and regulate blood pressure. Improper endothelium-dependent vasodilation can be an early sign of cardiovascular diseases, even preceding common markers such as elevated blood pressure. Research indicates that aging and increased oxidative stress reduces the availability and activity of two important vasodilators; NO (nitric oxide) which is released by the endothelium 19 and prostacyclin (PGI2)20.

Increased oxidative stress contributes to an accumulation of oxidized low-density lipoproteins (oxLDL). Oxidized LDL plays an important role in atherogenesis by promoting an inflammatory environment and lipid deposition in the arterial wall, impairing endothelial function, and it is increasingly used as a marker for cardiovascular risk20.

CitrOliveTM was developed as a unique synergistic blend of citrus and olive extracts; the combination of the key olive polyphenols oleuropein and hydroxytyrosol with citrus flavonoids such as naringin and neohesperidin gives CitrOliveTM a robust antioxidant and anti-inflammatory effect.

In animal trials, CitrOliveTM has been shown to reduce postprandial triglyceride levels after an oral fat load22.

A double-blind, controlled pilot trial in humans, supplementing 500 mg/d CitrOliveTM for three months, showed this sustained triglyceride-lowering of about 15%23. Elevated levels of fasting and postprandial triglyceride levels are linked to a higher cardiovascular risk24.

Additionally, CitrOliveTM has vasodilatory effects and induces endothelium-dependent vascular relaxation in methoxamine pre-contracted aortic rings. The vasodilatory activity is attributed, at least partly, to an increased NO release and to a modulation of prostacyclin formation25. Finally, the citrus and olive extract blend successfully decreased oxidized LDL (low-density lipoprotein) by 38% (p<0.05) in subjects with elevated cholesterol (Figure 3)23.

Figure 3: Change in LDL-C oxidation after 3 months of supplementation of placebo or CitrOlive

After the promising results of the first blend, IFF Health developed a triple Mediterranean blend, designed to support even more aspects of cardiovascular health. CitroVen™ has clinically proven beneficial effects on LDL-cholesterol oxidation, blood pressure regulation, inflammation, blood clotting and endothelial function.

Endothelial function has increasingly been recognized as an important prognostic marker for cardiovascular disease, and markers for endothelial dysfunction can point to an early stage of atherosclerosis.

A randomized, double-blind controlled trial was conducted to assess the efficacy of a combination of this blend for eight weeks (n = 51) versus placebo (n = 45) on reduction of cardiovascular risk in healthy volunteers26.

Statistically significant improvements were seen after 8 weeks compared to baseline in flow-mediated vasodilation, systolic and diastolic blood pressure, total cholesterol, LDL-C, LDL-oxidase, oxidation ratio, and IL-6, an inflammatory marker.


FIGURE 4: Change in LDL-c oxidation after 8 weeks of supplementation of placebo or CitroVen

FIGURE 5: Change in endothelium-dependent vasodilatation after 8 weeks of supplementation of placebo or CitroVen

These results are underlining the previous results of Benolea and the CitrOlive blend, while delivering additional benefits on antioxidation potential and endothelial function. These findings, taken together, support a beneficial effect of supplementation with CitroVen underlying mechanisms that may interact each other to decrease the cardiovascular risk in healthy people.


Supporting cardiovascular health by unlocking the potential of the Mediterranean diet

Sticking to the Mediterranean diet style can help slow down aging as recently found in the EU funded project NU-AGE27. However, when it is not possible or desirable to follow this healthy eating pattern strictly, dietary supplements and functional foods enriched with the scientifically backed ingredients of the Mediterranean area a convenient alternative. Inspired by the Mediterranean diet, Benolea®, CitrOliveTM, and CitroVen® are ingredients based on sound scientific data and high quality standards. These ingredients will help manufacturers to create innovative cardiovascular product concepts that target not only people with increased risk of CVD but also people interested in prevention and wellbeing.

This content sponsored and provided by IFF Health.


  1. Benjamin, E.J.; Muntner, P.; Alonso, A.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Chang, A.R.; Cheng, S.; Das, S.R.; et al. Heart Disease and Stroke Statistics—2019 Update: A Report From the American Heart Association. Circulation2019139, e56–e528.
  2. Lopez, A.D.; Adair, T. Is the long-term decline in cardiovascular-disease mortality in high-income countries over? Evidence from national vital statistics.  J. Epidemiol.201948, 1815–1823.
  3. Mc Namara, K.; Alzubaidi, H.; Jackson, J.K. Cardiovascular disease as a leading cause of death: How are pharmacists getting involved?  Pharm. Res. Pract.20198, 1–11.
  4. Kiefte-de Jong JC et al. Nutrition and healthy aging: the key ingredients. Proc Nutr Soc 2014; 73: 249-259
  5. Knoops KTB et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004 Sep 22;292(12):1433-9. doi: 10.1001/jama.292.12.1433.
  6. Rosato V et al. Mediterranean diet and cardiovascular disease: a systematic review and meta-analysis of observational studies Eur J Nutr. 2019 Feb;58(1):173-191. doi: 10.1007/s00394-017-1582-0.
  7. Fito M and Konstantinidou V. Nutritional genomics and the Mediterranean Diet´s effect on human cardiovascular health. Nutrients 2016; 8(4): 218
  8. Reboredo-Rodriguez et al. State of the art on functional virgin olive oils enriched with bioactive compounds and their properties. Int J Mol Sci 2017; 18(3): 668
  9. EFSA 2012: Commission Regulation (EU) No. 432/2012 of 16 May 2012 Establishing a List of Permitted Health Claims Made on Foods, Other than Those Referring to the Reduction of Disease Risk and to Children’s Development and Health. Commission Regulation (EU); London, UK: 2012.
  10. Barbaro B et al. Effects of the oil-derived polyphenol oleuropein on human health. Int J Mol Sci 2014; 15(10): 18508-24
  11. Alam MA et al. Effect of citrus flavonoids, naringin and naringenin, on metabolis syndrome and their mechanism of action. Adv Nutr 2014; 5:404-417
  12. Ramadon BK et al. Hypogylcemic and pancreatic protective effects of Portulaca oleracea extract in alloxan induced diabetic rats. BMC Compl Alt Med 2017; 17:37
  13. Iranshanhy M et al. A review of traditional uses, phytochemistry and pharmacology of Portulaca oleracea L. J Ethnopharmacol 2017; 205: 158-172
  14. Sun Z. Aging, arterial stiffness and hypertension. Hypertension 2015; 65:252-256
  15. Moreno-Luna R et al. Olive oil polyphenols decrease blood pressure and improve endothelial function in young women with mild hypertension. Am J Hypertens 2012; 25(12): 1299-304
  16. Khayyal MT, et al., Blood pressure lowering effect of an olive leaf extract (olea europaea) in l-NAME-induced hypertension in rats, Arzneimittelforschung 2002, 52(11), 797-80
  17. Perrinjaquet-Moccetti P et al. Food supplementation with an olive (Olea euopaea L.) leaf extract reduces blood pressure in borderline hypertensive monocygotic twins, Phytotherapy Research 2008, 22: 1239-1242.
  18. Susalit E et al. Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: comparison with Captopril, Phytomedicine 2011, 18: 251-258
  19. Seals DR et al. Aging and vascular endothelial function in humans. Clin Sci 2011; 120(9): 357-375
  20. Nicolson WT et al. Aging is associated with reduced prostacyclin-mediated dilation in the human forearm. Hypertension 2009; 53(6): 973-978
  21. Trpkovic A et al. Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases ref Crit Rev Clin Lab Sci. 2015;52(2):70-85.
  22. proprietary internal data by Frutarom
  23. proprietary internal data by Frutarom
  24. Enkhmaa B et al. Postprandial lipoproteins and cardiovascular disease risk in diabetes mellitus. Curr Diab Rep 2010; 10(1): 61-69
  25. López-Carreras N et al. Endothelium-dependent vascular relaxing effects of different citrus and olive extracts in aorta rings from spontaneously hypertensive rats. Food Res Int 2015; 77: 484-490
  26. Sánchez Macarro M et al. Effect of a Combination of Citrus Flavones and Flavanones and Olive Polyphenols for the Reduction of Cardiovascular Disease Risk: An Exploratory Randomized, Double-Blind, Placebo-Controlled Study in Healthy Subjects. Nutrients 2020, 12(5), 1475;
  27. Science Daily: Mediterranean diet style might slow down aging, reduce bone loss. ; accessed 06.07.2017


Please enter your comment!
Please enter your name here