**1. Introduction**

Astaxanthin is a xanthophyll carotenoid of predominantly marine origin, with potent antioxidant and anti-inflammatory effects demonstrated in both experimental and human studies. Oxidative stress and inflammation are common pathophysiological features of atherosclerotic cardiovascular disease hence astaxanthin may have a potential therapeutic role in this condition. This review will summarise the available evidence suggesting astaxanthin may be of therapeutic value in cardiovascular disease. 

## **2. Oxidative Stress and Inflammation**

Oxidative stress and inflammation are established non-traditional risk factors for atherosclerosis associated cardiovascular morbidity and mortality [1]. Dietary antioxidants can reduce the oxidation of lipids and proteins and have the potential to protect from the development of arterial stiffening and atherosclerosis [2–4]. Cross-sectional and prospective observational studies have demonstrated an association between the intake of dietary antioxidants and/or their plasma levels and a reduction of cardiovascular events [5–10]. This supports the theory that oxidative stress is a pathophysiological process involved in atherosclerotic vascular damage. Also, a reduced dietary antioxidant intake is associated with oxidative stress and inflammation [11]. Newer more potent dietary antioxidants such as astaxanthin have yet to be studied in this setting. Studies that have assessed the intake of βcarotene or dietary β-carotene supplementation have shown higher β-carotene consumption is associated with a reduction in cardiovascular disease [6,12–17]. Other than a few studies [18– 20], cardiovascular intervention trials using antioxidants have not demonstrated benefits [21– 23]. This may be because study participants did not have oxidative stress and/or the antioxidants used were insufficiently potent. In addition, it is becoming recognized that there is communication between oxidative stress and inflammatory processes leading to the additional hypothesis that antioxidants may be able to modify both deleterious events. Further research is needed studying antioxidants with different biological actions in patients with demonstrated oxidative stress. 

## **3. Carotenoids**

Carotenoids are ubiquitous, and found in high concentrations in plants, algae and microorganisms. Humans and other animals cannot synthesize them and therefore are required to source them in their diet [24]. Carotenoids are classified, according to their chemical structure, into carotenes and xanthophylls. The carotene carotenoids include βcarotene and lycopene and the xanthophyll carotenoids include lutein, canthaxanthin, zeaxanthin, violaxanthin, capsorubin and astaxanthin [25,26]. 

The effects of carotenoids vary dependent on how they interact with cell membranes [25]. The effects of astaxanthin, zeaxanthin, lutein, β-carotene and lycopene on lipid peroxidation have been assessed using a polyunsaturated fatty acid enriched membrane model [25,27]. Nonpolar carotene carotenoids such as lycopene and β-carotene caused membrane disorder and lipid peroxidation in contrast to the polar xanthophyll carotenoid astaxanthin, which  preserved membrane structure [27]. Contrasting effects of different carotenoids may be responsible for the differing biological effects seen in clinical studies. For instance, in some studies the non-polar carotenoid, β-carotene has been shown to have no benefit on cardiovascular disease [28–32] and in fact it may be pro-oxidant at high doses [33]. In contrast, the polar carotenoid astaxanthin has protective effects on the cardiovascular system demonstrated in animal studies. However, this has not been studied in human clinical trials [34–36]. β-carotene at physiological levels may act in differing ways when ultraviolet A light A (UVA) acts on keratinocytes including vitamin A-independent pathways [37]. Astaxanthin, canthaxanthin and β-carotene had differential effects on UVA-induced oxidative damage [38]. In addition, carotenoids may also alter the immune response [39] and transcription [40]. 

## **4. Astaxanthin**

Astaxanthin contains two oxygenated groups on each ring structure (see Figure 1), which is responsible for its enhanced antioxidant features [41]. It is found in living organisms particularly in the marine environment where it is present in microalgae, plankton, krill and seafood. It gives salmon, trout, and crustaceans such as shrimp and lobster their distinctive reddish coloration [42]. It is also present in yeast, fungi, complex plants and the feathers of some birds including flamingos and quail [42]. In 1987, the United States Food and Drug Administration approved astaxanthin as a feed additive for use in the aquaculture industry and in 1999 it was approved for use as a dietary supplement (nutraceutical) [41]. The microalgae *Haematococcus pluvialis* produces the astaxanthin isomer (3*S*, 3*S*<sup>ȝ</sup>), which is the same as the form found in wild salmon. Synthesis of astaxanthin is not possible in humans and it cannot be converted to vitamin A, which means excess intake will not cause hypervitaminosis A toxicity [43,44]. Astaxanthin and canthaxanthin are scavengers of free radicals, chainbreaking antioxidants and potent quenchers of reactive oxygen and nitrogen species including singlet oxygen, single and two electron oxidants [45–47]. They (astaxanthin and canthaxanthin) have terminal carbonyl groups that are conjugated to a polyene backbone [26] and are more potent antioxidants and scavengers of free radicals than carotene carotenoids such as βcarotene [47,48]. For these reasons dietary supplementation with astaxanthin has the potential to provide antioxidant protection of cells and from atherosclerotic cardiovascular disease [49]. 

## **5. Astaxanthin Formulations**
