*5.1. Astaxanthin of Marine Origin*

Astaxanthin used in nutritional supplements is usually a mixture of configurational isomers produced by *Haematococcus pluvialis*, a unicellular microalga [50]. Astaxanthin can be produced in its natural forms on a large scale [51]. The initial production of astaxanthin from *Haematococcus pluvialis* uses closed culture systems followed by a 5–7 day, "reddening" cycle, conducted in open culture ponds. At each production stage, the cultures are closely monitored by microscopic examination to ensure they remain free of contamination. After the reddening cycle, *Haematococcus pluvialis* cultures are harvested, washed and dried. The final step for the production of astaxanthin is extraction of dried *Haematococcus pluvialis* biomass using supercritical carbon dioxide to produce a purified oleoresin, which is free of any contamination. Other sources used for the commercial production of astaxanthin include cultures of *Euphausia pacifica* (Pacific krill), *Euphausia superba* (Antarctic krill), *Pandalus borealis* (shrimp) and *Xanthophyllomyces dendrorhous*, formerly *Phaffia rhodozyma* (yeast). Astaxanthin from natural sources varies considerably from one organism to another. For instance, the astaxanthin found in seafood will depend on the stereoisomer ingested. Astaxanthin produced by *haematococcus pluvialis*, consists of the (3-*S*,3<sup>ȝ</sup>-*S*) stereoisomer which is most commonly used in aquaculture. It is therefore the form most commonly consumed by humans. 

## *5.2. Synthetic Astaxanthin*

There are three stereoisomers of astaxanthin; (3- *R*,3<sup>ȝ</sup>-*R*), (3- *R*,3<sup>ȝ</sup>-*S*) and (3-*S*,3<sup>ȝ</sup>-*S*). Disodium disuccinate astaxanthin (DDA) is a synthetic astaxanthin containing a mixture of all three stereoisomers, in the proportions 1:2:1*.* DDA was manufactured by Cardax Pharmaceuticals and used in animal studies investigating the myocardial ischemia-reperfusion injury models [34–36,52–54]. This form of astaxanthin was touted to have better aqueous solubility, unlike other carotenoids, and this enabled both oral and intravenous administration. DDA is no longer available but the same company now produces a second synthetic astaxanthin compound; Heptax/XanCor, CDX-085. The company claims that it is developed for thrombotic protection, triglyceride reduction, metabolic syndrome, and inflammatory liver disease. In addition, it has increased water dispersibility and enhanced bioavailability compared to natural astaxanthin and DDA. The synthetic forms are metabolized via hydrolysis in the intestine yielding free astaxanthin for intestinal absorption. CDX-085 has been used in one study, discussed below [55]. 

It is not yet clear which form of astaxanthin should be administered in clinical studies, the natural form from the marine environment or a synthetic form. As the proportions of stereoisomers, vary between these different forms of astaxanthin they may not be therapeutically equivalent [56]. Thus synthetic astaxanthin could result in different outcomes when assessed clinically [57]. 

## **6. Astaxanthin-Experimental Studies**

Experimental studies undertaken with astaxanthin specifically relevant to the cardiovascular system are summarised in Table 1. Astaxanthin attenuates mediators of oxidative stress and inflammation and has shown beneficial effects in non-cardiovascular models of disease [58–69]. In addition, astaxanthin has decreased markers of lipid peroxidation [70], inflammation [61,62,67,68] and thrombosis [55]. 


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