The Effects of Astaxanthin - Cardiovascular Health

 

 

 

Atherosclerosis: 

A Silent Cardiovascular Condition that Kills 1 Person Every 3 Seconds

High blood pressure, high levels of triglycerides, oxidation of Low Density Lipoprotein (LDL) cholesterol and lowering levels of High Density Lipoprotein (HDL) cholesterol are the primary cause that leads to oxidative stress and chronic inflammation in the vessels. This condition emerges at early age and gradually compromises vascular integrity leading to atherosclerosis at a later stage of a person lifespan. Atherosclerosis is a cardiovascular condition in which fat deposits and become oxidized along the inner lining of the artery walls. This silent yet deadly build up progressively thickens, hardens and eventually blocks the arteries leading to sudden and severe circulatory complications including vascular ischemia, stroke or heart attack. Cardiovascular and circulatory deaths related to atherosclerosis accounts for 29% of all deaths globally; the primary cause of death in EU (42%), Eastern Europe (48%), UK (39%), North America (49%), China (34%), South America (31%); Middle East (31%) and India (29%) – World Health Report, 2010.

Salmon Consumption and Lower Incidence of Cardiovascular Diseases Among Japanese. Just a Coincidence?

The cardiovascular and circulatory benefits of natural astaxanthin are evident among Japanese who are the uppermost consumers of food containing astaxanthin (AX) in the world and have the lowest incidences of heart diseases amongst developed countries. As the French paradox of cardiovascular health is connected to “sipping red-wine” and Italians longevity to “olive oil dressed” salads, Japanese cardiovascular resilience can be associated with consumption of “astaxanthin-soaked” salmon. In fact, a growing number of scientific evidence points to a robust link between natural astaxanthin and cardiovascular health – 30 cardiovascular specific research publications including 10 clinical studies. Research suggests that oral supplementation of astaxanthin may reduce the risks of cardiovascular diseases by reducing hypertension while enhancing blood rheology, capillary circulation and vascular resilience.

The Effects of Astaxanthin on Atherosclerosis Prevention and Development

Astaxanthin Increase HDL Cholesterol and Decrease Serum Triglycerides

For every 1 mg/dl increase in good cholesterol HDL, the risk of cardiovascular diseases drops by 3%. In fact, baby boomers with low-HDL (> 40mg/dL) increase their chances of experiencing coronary events by 50%. Recent studies suggest that individuals with low HDL cholesterol who also have high triglycerides levels are 11 times more likely to develop cardiovascular diseases. Achieving a significant increase of HDL is notoriously hard because it requires drastic lifestyle changes, so often ending with modest results or sudden relapses.
Recent research suggests that astaxanthin supplementation can support lifestyle changers by synergizing HDL increasing effect with decreased level of serum triglycerides. Two recent studies demonstrated that astaxanthin consumption can steadily increase HDL cholesterol in both healthy and less healthy individuals -both as preventive and therapeutic use. Yoshida et al., (2009) conducted the first ever randomized, placebo-controlled human study to evaluate astaxanthin effect on dyslipidemia and metabolic syndrome. Sixty-one hyper-triglyceride subjects between 42-47 years old (BMI 24 mg/kg), received 0 (placebo), 6 mg, 12mg, 18mg of astaxanthin daily for 12 weeks. While the placebo group did not change their existing condition, the astaxanthin groups increased their HDL cholesterol by 11%, 15% and 7% respectively and decreased their serum triglycerides level by 17%, 25% and 24% respectively (figure 1).

Figure 1. Astaxanthin increase HDL cholesterol and decrease Serum Triglycerides (STR). Subjects with lower levels of HDL and higher levels of STR are 11 times more likely to develop cardiovascular diseases (Yoshida et al., 2009) 61 hyper- triglyceride subjects between 42-47 yo; (BMI 24 mg/kg), received 0 (placebo), 6 mg, 12mg, 18mg of astaxanthin per day for 12 weeks

In a recent clinical study, 73 subjects between 20-60 years of age who received 4mg of natural astaxanthin per day for 4 weeks had their serum triglycerides level decreased by 25 %(Satoh et al., 2009). In another study conducted in Japan, 15 healthy adults increased their HDL by 6% after ingesting 9mg/daily of astaxanthin for 8 weeks (Matsumaya et al., 2010). In 2007, Hussein et al., has shown that astaxanthin reduced the size of fat cells in rats, which lead to a lower risk of cardiovascular complications and chronic inflammation (figure 2).

Figure 2. Astaxanthin reduced the size of fat cells. Large cells usually indicate higher risk of fat-oxidation chronic inflammation and oxidative stress, which are the leading causes of cardiovascular diseases (x10) (Hussein et al., 2006)

Astaxanthin Decrease Red Blood Cells Oxidation and Lipid-Peroxidation

High levels of triglycerides and low levels of HDL also increase the likelihood of fat-oxidation in vessels and formation of "wounds" in the inner lining of artery walls (endothelium) leading to chronic inflammation and oxidative stress; this situation causes degradation, narrowing and thickening of arteries. Three recent clinical studies have robustly pointed to astaxanthin ability to reduce fat peroxidation in blood plasma. In a randomized-double-blind placebo study, 33 overweight subjects received 5mg or 20mg astaxanthin daily for 3 weeks. Their lipid peroxidation markers plasma MDA Level (mmol) and plasma ISP (ng/mL) decreased by 30% and 60% in average (Choi et al., 2011).
In another randomized double blind placebo controlled study, 30 subjects between 50 and 69 years of age received 0 (placebo), 6 or 12mg astaxanthin daily for 12 weeks (Nakagawa et al., 2011). The amount of oxidized red blood cells (PLOOH um0l/ml) decreased by 17% and 24% respectively(figure 3).

Figure 3. Astaxanthin reduces red blood cells oxidation (RBCO) in senior subjects. RBCO cells has high correlation with neuro-degenerative (eg. dementia) and cardiovascular diseases (eg. heart attack) (Nakagawa et al., 2011) 30 subjects (15 F and 15 M) between 50 and 69 years of age , BMI 27·5 kg/m² received 0 (placebo), 6 or 12mg astaxanthin per day for 12 weeks

In 2007, Karppi et al., conducted a randomized double blind conducted placebo controlled study with 40 non-smoking subjects between 19-33 years of age who received 0 (placebo) or 8mg of astaxanthin daily for 12 weeks. Their lipid peroxidation markers -plasma-15-hydroxy fatty acidsdecreased by 60% and plasma-12-hydroxy fatty acids by 36%. In 2000, Iwamoto et al., has also shown that astaxanthin inhibited LDL oxidation in human subjects. Professor Aoi from Kyoto Prefectural University, has shown that astaxanthin limits exercise-induced cardiac oxidation damage in mice.

Astaxanthin Enhance Biomarkers of Anti-oxidant Healthiness in the Blood Plasma

Low antioxidant activity in the blood correlates with high incidences of stroke, neurological impairment in stroke patients and cardiovascular diseases. Therefore, it is crucial to monitor the biomarkers of antioxidant capacity in the blood when assessing the efficacy of an active ingredient. In a randomized double blind study, 33 overweight subjects received 5mg or 20mg astaxanthin daily for 3 weeks. Their plasma Superoxide Dismutase Level (SOD) (U/mL) and Plasma Total Antioxidant Capacity (TAC) Level (mmol) increased 45% and 19% respectively. (Choi et al., 2011) (figure 4).
Other studies have produced similar results using different assessment methods. In an open label clinical study, 35 postmenopausal women were treated with astaxanthin daily dose of 12 mg for 8 weeks (Yonei et al., 2009). Astaxanthin supplementation increased biological antioxidant potential in the blood plasma by 5% in 8 weeks. In addition, Camera et al., suggested that astaxanthin protects and synergize with our endogenous antioxidant systems (superoxide dismutase, catalase and glutathione) from early degradation when subjected to oxidative stress (Camera et al., 2008).

Figure 4. Astaxanthin increases Plasma SOD Level and Plasma TAC level. Low levels of SOD and TAC correlates with higher incidences of stroke, neurological impairment and cardiovascular diseases (Choi et al., 2011) 33 subjects received 5mg or 20mg astaxanthin x day for 3 weeks; BMI (25.0 -30.0 kg/m²) - aged 25.Normal Body Subjects – 10 non-intervention subjects (20.0 < BMI≤24.9 kg/m²) age 26

Astaxanthin Decrease Chronic Inflammation that comprise Blood Vessels Integrity

In the presence of oxidized cells in the endothelial lesions, macrophages white blood cells infiltrate in affected areas to clear away pathogens and dead cells. Yet, in the attempt to clean up the oxidized areas, macrophages may get overweighed with excessive lipoproteins and unable to leave the artery walls. This peculiar but common situation triggers a cascade of chronic inflammatory responses and pro-oxidant activities that degraded the structural integrity of the vessels. Therefore, up-regulated activity of oxidized LDL via macrophage induced inflammation is central to the initiation and progression of atherosclerosis. They are closely associated with plaque development, aggravation and ruptures.
A recent study shows that astaxanthin decreased macrophage occupied lesion areas and therefore inflammation in the vessels of rabbits by 40% compared to control group (figure 5). Furthermore, rabbits that ingested 4mg astaxanthin everyday for 24 weeks decreased programmed cell death (apoptosis) by 42% and cell death (necrosis) by 17% in the aorta (Li et al., 2004).

Figure 5. Astaxanthin decrease chronic inflammation and cell death in the inner lining of the vessels. Chronic inflammation and apoptosis in the endothelium dramatically accelerates vascular degradation and atherosclerotic plaque formation. (Li et al., 2004) Rabbits ingested 4mg of placebo, Vitamin E or astaxanthin everyday for 24 weeks.

In-vitro study provides further evidences that astaxanthin (5-10uM) decreases macrophages related activation (SR-A and CD36) by 48% and 58% respectively (Kishimoto et al., 2009). A recent animal studies show that astaxanthin could ameliorate endothelial dysfunction by significantly improving the level of substances important for the regulation of vascular integrity. In more details, treatment with astaxanthin for 42 days decreased serum oxidized LDL cholesterol, aortic MDA levels, attenuated endothelium-dependent vasodilatory to acetylcholine, up-regulate eNOS expression and decreased LDL cholesterol receptor expression (figure 6).

Figure 6. Astaxanthin treatment improved markers of endothelial dysfunction by reducing oxidation of LDL cholesterol and MDA. Higher levels of LDL oxidation and MDA expression highly correlates with structural damages in blood vessels and impairment of blood flow. (Zhao et al., 2011) Diabetic rats were treated with 10 mg/kg of astaxanthin or olive oil for 42 days.

Animal studies have also shown that astaxanthin ameliorated structural changes in the blood vessels - reduction in wall thickness by 47% and improved vascular tone by 36% in spontaneously hypertensive rats (Hussein et al., 2006). Such structural changes was observed in the reduction of the number of branched elastin bands and improved vessel wall to lumen thickness ratio.
In another study, 24 weeks supplementation of natural astaxanthin reduced levels of MMP3 expression in the aorta of rabbits - a crucial factor that lead to a degradation of elastin and collagen structures which determines the mechanical properties of connective tissues in the vessels (figure 7). In the experiment, astaxanthin enhanced plaque stability leading to a significant reduction of plaque ruptures (Li et al., 2004).

Figure 7. Astaxanthin inhibit MMP over-expression in the thoracic aorta. Over-expression of MMP is a crucial factor that leads to the degradation of vascular integrity and escalation of atherosclerotic plaque ruptures (Li et al., 2004) Animal Study – Rabbits ingested AX 4mg/ Kg of body weight daily x 24weeks

Astaxanthin Improving Vascular Resilience and Capillary Blood Flow

Good circulation, quality of blood and resilient vessels are the key features required to fight development and progression of atherosclerosis. Blood rich in antioxidants bring nutrients and oxygen to organs while removing waste through a smooth vascular resilience and capillary flow.
Recent human studies suggest that 6mg daily of astaxanthin can enhance blood flow by 10% in terms of capillary transit time -how fast the blood runs through the vessels (Miyawaki et al., 2008). Another complementary study showed that astaxanthin decreased lower limb vascular resistance by 17% - the degree to which the blood vessels impede the flow of blood (Iwabayashi et al., 2009).(figure 8) High resistance causes an increase in blood pressure, which increases the workload of the heart. In 2005, Nagaki et al., conducted another randomized double-blind study in which 36 subjects who received oral astaxanthin, 6mg/day for 4 weeks experienced a 4% improvement in capillary blood flow (Nagaki et al., 2005).

Figure 8. astaxanthin decreased lower limb vascular resistance (LLVR) – the degree to which the vessels impede the flow of blood. LLVR increase blood pressure and circulatory complications that lead to peripheral vascular diseases, venous thrombosis and painful claudication (Yonei et al., 2009) 35 healthy postmenopausal women (BMI 22.1) were included in the study, treated with astaxanthin daily dose of 12 mg for 8 weeks.

Astaxanthin Reduces Hypertension

A series of human studies suggest that astaxanthin decreases blood pressure by improving blood flow and vascular tone. In a recent clinical study, 73 subjects, between 20-60 years of age, who received 4mg of astaxanthin for day for 4 weeks showed a significant decrease in systolic blood pressure (Satoh et al., 2009). In another study, 15 healthy subjects, between 27-50 of age, who received 9mg/day of astaxanthin for 12 weeks had their diastolic blood pressure decreased significantly (Matsuyama et al., 2010).
A series of animal studies have largely replicated the effects of astaxanthin found in human studies (e.g. Ruiz et al., 2010; Preuss, 2011).

Outlook

Clinical studies suggests that oral supplementation of natural astaxanthin (4mg-12mg) may reduce the risk cardiovascular complications by enhancing blood rheology, lipid-metabolism, capillary circulation, vascular resilience and the endogenous antioxidant defense. Other clinical studies have also shown that astaxanthin reduce lipid-peroxidation, LDL cholesterol, blood pressure and DNA damage. Mechanism of action includes inhibition of macrophage-induced inflammation in the endothelium, oxidative stress-induced apoptosis and MPP-induced-structural degradation of the vessels. Furthermore, recent studies have also outlined that astaxanthin ameliorates nitric oxide dependent vessels dilation and reduce sensitivity to the angiotensin.

References

1. Aoi et al., (2003). Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. Antioxidants & Redox Signaling. 5(1):139-44.
2. Hussein et al., (2005b). Antihypertensive potential and mechanism of action of astaxanthin II. Vascular reactivity and hemorheology in spontaneously hypertensive rats. Biol. Pharm. Bull., 28(6):967-971.
3. Hussein et al., (2006b). Antihypertensive potential and mechanism of action of astaxanthin: III. Antioxidant and histopathological effects in spontaneously hypertensive rats. Biol. Pharm. Bull., 29(4):684-688.
4. Hussein et al., (2005a). Antihypertensive and Neuroprotective Effects of Astaxanthin in Experimental Animals. Biol. Pharm. Bull., 28(1): 47-52.
5. Iwabayashi et al., (2009). Efficacy and safety of eight-week treatment with astaxanthin in individuals screened for increased oxidative stress burden. Journal of Anti-Aging Medicine., 6(4):15-21
6. Iwamoto et al., (2000). Inhibition of low-density lipoprotein oxidation by astaxanthin. Journal of Atherosclerosis Thrombosis. 7(4):216-22.
7. Karppi et al., (2007). Effects of astaxanthin supplementation on lipid eroxidation. Int J Vitam Nutr Jan; 77 (1): 3-11.
8. Kishimoto et al., (2009). Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages. European Journal of Nutrition., 49(2):17-26
9. Li et al., (2004). Alpha-tocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits. Journal of Molecular and Cellular Cardiology., 37:969-978.
10. Matsuyama et al., (2010) A Safety Study on the Long-Term Consumption of Astaxanthin in Healthy Human Volunteer. Japanese Journal of Complementary and Alternative Medicine., (7):43-50. (Translated from Japanese)
11. Miyawaki et al., (2005). Effects of Astaxanthin on Human Blood Rheology. Journal of Clinical Therapeutics and Medicines., 21(4):421-429.7.
12. Murillo (1992). Hypercholesterolemic effect of canthaxanthin and astaxanthin in rats. Arch. Latinoam Nutr., 42(4):409-413.
13. Preuss et al., (2009). Astaxanthin lowers blood pressure and lessens the activity of the eroxi-angiotensin system in Zucker Fatty Rats., Journal of Functional Foods., I:13-22
14. Yoshida et al., (2010). Administration of natural astaxanthin increases serum HDL-cholesterol and adiponectin in subjects with mild hyperlipidemia., 209 (2): 520-3.
15. Nakagawa et al., (2011). Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes British Journal of Nutrition., (31):1-9
16. Choi et al., (2011). Effects of Astaxanthin on Oxidative Stress in Overweight and Obese Adults Phytother. Research (in-press).
17. Satoh et al., (2009).Preliminary Clinical Evaluation of Toxicity and Efficacy of a New Astaxanthin-rich Hameotoccus Pluvialis. J. Clin. Biochem. Nutr., 44: 280–284.
18. Hussein et al., (2007). Astaxanthin ameliorates features of metabolic syndrome in SHR/NDmcr-cp. Life Sci., 16;80(6):522-9.
19. Preuss, et al., (2011). High Dose Astaxanthin Lowers Blood Pressure and Increases Insulin Sensi-tivity in Rats: Are These Effects Interdependent?., 8(2):126-138.
20. Ruiz et al., (2010). Astaxanthin-enriched-diet reduces blood pressure and improves cardiovascular parameters in spontaneously hypertensive rats. Pharmacological Research., 63(1):44-50
21. Zhao et al., (2011). Ameliorative effect of astaxanthin on endothelial dysfunction in streptozotocin-induced diabetes in male rats. Arzneimittelforschung., 61(4): 239-246.

 CCRES special thanks to 
Mr. Mitsunori Nishida, 
President of Corporate Fuji Chemical Industry Co., Ltd.

Croatian Center of Renewable Energy Sources (CCRES)