Adults in the United States spent $33.9 billion out-of-pocket on complementary and alternative medicines (CAMs) in 2007, nearly half of which went toward purchasing nonvitamin, nonmineral natural products (NVNMNPs) .
One of the most common uses of NVNMNPs is for the management of blood cholesterol (CH) levels. Despite a poor understanding of the efficacy and effects of these treatments consumers can find dozens of over-the-counter plant-based CH remedies at local grocery stores or pharmacies. Not surprisingly, practitioners of Western medicine frequently dismiss phytomedical options due to the lack of experimentally derived data on their effects and modes of action. One reason for this empirical deficit is that each plant has numerous potential effects and for any prescribed ailment there are many candidate plant-based treatments. Further complicating the matter, the effects of these treatments may be subtler than those of purified Western pharmaceuticals, all of which necessitates testing large numbers of organisms. Mammalian model systems offer a potential solution to this problem however, while offering the benefit of a close phylogenetic proximity to humans, they are expensive to house and to maintain. Alternatively, cell culture-based models of disease offer the advantage of significantly higher-throughput testing at substantially lower cost. Unfortunately, in vitro experiments can recapitulate neither the biological complexity nor the physiochemical connectivity of an intact vertebrate system. As a result, the extent to which these data represent the patterns and processes in the actual human disease condition is somewhat limited.
The high-fecundity, rapid development, low husbandry costs and optical clarity of their larvae have contributed to the zebrafish's emergence as a premier vertebrate model in biomedicine . Several studies have demonstrated that zebrafish digestive physiology and lipid metabolism are very similar to that of humans and that treatment of zebrafish with antihyperlipidemic drugs elicits similar responses to their mammalian counterparts [3–6]. Recent work has also shown that zebrafish exhibit similarities to human lipid-related pathologies including increased vascular permeability and thickening, increased levels of total CH, LDL and oxidized cholesteryl esters [5, 7]. Further, blood serum lipid levels in adult zebrafish can be reduced by treatment with herbal extracts of laurel, turmeric, cinnamon and clove [8, 9]. These data are promising, and combined with the observation that the cardiodynamic response of embryonic zebrafish to many pharmacological agents is similar to those observed in mammals [10–15] makes it a potentially powerful nontraditional model for studying the physiological effects of a high cholesterol diet (HCD) and its treatment through diet-based phytomedical interventions.
Western pharmaceutical medicine is largely based on a reductionist paradigm of both disease and its treatment where an emphasis is placed upon the molecular mechanics of single purified/synthesized molecules and their influence on specific body receptors. A more holistic view of disease and its treatment, where whole plant products are administered, may allow for treatment of not only one characteristic of the disease but potentially several of its peripheral aspects as well [16, 17]. In contrast to the inherent complexity involved in analyzing the molecular interactions and specific physiological effects of each potentially active component in a phytotherapy, we propose to initially focus only on holistically relevant bioprocesses. In this study we measure both CH and cardiac output (CO) as indicators of overall cardiovascular health under conditions of diet-induced hypercholesterolemia. We suggest that the ability of any treatment (CAM or traditional) to positively alter these metrics indicates a potent therapeutic potential.
The hawthorn (Crataegus sp.) plant has been utilized for thousands of years to treat a variety of illnesses. In Eastern Traditional medical systems, hawthorn is commonly used to alleviate digestive ailments and poor circulation. In Western medicine, particularly in Europe, the hawthorn plant is utilized to treat cardiovascular maladies such as cardiac failure for which it is certified to treat New York Heart Association Type II heart failure . Its purported cardiotonic properties include inotropic, chronotropic  and vasodilatory effects , but the evidence for these effects comes largely from isolated organ and cell culture-based studies where the overall whole-animal physiological impact cannot readily be assessed. Hawthorn is also purported to possess antihypercholesterolemic properties. A recent study by Dalli et al. revealed that leaf and flower extracts of Crataegus laevigata (HLF) appeared to lower LDL CH levels in diabetic patients with coronary heart disease, although their results were not statistically significant. Similarly, studies in both rats and rabbits have demonstrated hypolipidemic effects of hawthorn berries (HB) [22, 23]. Potential antihypercholesterolemic effects and cardiotonic activity suggests hawthorn may have substantial utility as a treatment for the multi-faceted pathophysiology of lipid-based diseases.
Here we present data demonstrating the utility of the zebrafish model in empirically assessing the therapeutic potential of CAMs by testing whole plant treatments on animals with diet-induced hypercholesterolemia. This holistic approach to treatment recognizes that putative synergistic actions of components of the plant may have benefits different from those conferred by each individual molecule [16, 17]. We begin by experimentally identifying the best optical marker for quantifying diet-induced hypercholesterolemia in the larval zebrafish. We then use our animal model system to assess the effects of hawthorn on the cardiovascular pathophysiology of hypercholesterolemia and finally, we test the ability of a commonly used CAM, hawthorn, to influence CO in both healthy and diseased animals.