Heart Toxicity Related to Herbs and Dietary Supplements: Online Table of Case Reports. Part 4 of 5.

BACKGROUND: The purpose of this review was to create an online research summary table of heart toxicity case reports related to dietary supplements (DS; includes herbs). METHODS: Documented PubMed case reports of DS appearing to contribute to heart-related problems were used to create a "Toxic Table" that summarized the research (1966 to April, 2016, and cross-referencing). Keywords included "herb," "dietary supplement," and cardiac terms. Case reports were excluded if they were herb combinations (some exceptions), Chinese herb mixtures, teas of mixed herb contents, mushrooms, poisonous plants, self-harm (e.g. suicide), excess dose (except vitamins/minerals), drugs or illegal drugs, drug-herbal interactions, and confounders of drugs or diseases. The spectrum of heart toxicities included hypertension, hypotension, hypokalemia, bradycardia, tachycardia, arrhythmia, ventricular fibrillation, heart attack, cardiac arrest, heart failure, and death. RESULTS: Heart related problems were associated with approximately seven herbs: Four traditional Chinese medicine herbs - Don quai (Angelica sinensis), Jin bu huan (Lycopodium serratum), Thundergod vine or lei gong teng (Tripterygium wilfordii Hook F), and Ting kung teng (Erycibe henryi prain); one an Ayruvedic herb - Aswagandha, (Withania somnifera); and two North American herbs - blue cohosh (Caulophyllum thalictroides), and Yohimbe (Pausinystalia johimbe). Aconitum and Ephedra species are no longer sold in the United States. The DS included, but are not limited to five DS - bitter orange, caffeine, certain energy drinks, nitric oxide products, and a calming product. Six additional DS are no longer sold. Licorice was the food related to heart problems. CONCLUSION: The online "Toxic Table" forewarns clinicians, consumers and the DS industry by listing DS with case reports related to heart toxicity. It may also contribute to Phase IV post marketing surveillance to diminish adverse events that Government officials use to regulate DS.

Primary constituents of blue cohosh: quantification in dietary supplements and potential for toxicity.

Dietary supplements containing dried roots or extracts of the roots and/or rhizomes of blue cohosh (Caulophyllum thalictroides) are widely available. This botanical has a long history of use by Native Americans and its use continues to the present day. The primary constituents of blue cohosh are its alkaloids and saponins. The structures of the alkaloids magnoflorine, baptifoline, anagyrine, and N-methylcytisine have been known for many years. The last 10 years have seen a great increase in isolation and identification of the large number of saponins present in blue cohosh. Important developments in nuclear magnetic resonance techniques have contributed substantially to the increase in elucidation of the structures of the complex saponins. Several authors have described quantitative methods for both the alkaloids and saponins in blue cohosh. Such methods have made it possible to quantify these constituents in dietary supplements containing this botanical ingredient. Concentrations of both alkaloids and saponins vary substantially in dietary supplements of blue cohosh. The nicotinic alkaloid, N-methylcytisine, a potent toxicant, has been found in all dietary supplements of blue cohosh analyzed. The teratogenic alkaloid anagyrine has been found in some but not all dietary supplements.

Teratogenic effects of blue cohosh (Caulophyllum thalictroides) in Japanese medaka (Oryzias latipes) are probably mediated through GATA2/EDN1 signaling pathway.

Blue cohosh (Caulophyllum thalictroides) (BC) has been used widely to induce labor and to treat other uterine conditions. However, the safety and effectiveness of this herbal product has not yet been evaluated by the US Food and Drug Administration (FDA). Several conflicting reports indicated that the root extract of BC is a teratogen and, by some unknown mechanisms, is able to induce cardiovascular malfunctions in new-born babies. To understand the mechanism, we have used Japanese medaka (Oryzias latipes) embryo-larval development as the experimental model and the methanolic extract of BC root as the teratogen. The embryo mortality, hatching efficiency, and morphological abnormalities in craniofacial and cardiovascular systems are considered for the evaluation of BC toxicity. Our results indicate that BC is able to disrupt cardiovascular and craniofacial cartilage development in medaka embryo in a dose and developmental stage-specific manner. Moreover, embryos in precirculation are to some extent more resistant to BC than ones with circulation. By using subtractive hybridization, we have observed that gata2 mRNA was differentially expressed in the circulating embryos after BC treatment. As GATA-binding sequences are required for the expression of the endothelin1 (edn1) gene and edn1 expressed in blood vessels and craniofacial cartilages, we have extended our investigations to edn1 gene expression regulation by BC. We found that edn1, furin1, and endothelin receptor A (ednrA) genes are developmentally regulated; endothelin converting enzyme mRNA (ece1) maintained a steady-state level throughout development. Circulating medaka embryos (3 days post fertilization, dpf) exposed to BC (10 microg/mL) for 48 h have increased levels of gata2, ece1, and preproenodthelin (preproedn1) mRNA contents; however, other mRNAs (furin and ednrA) remained unaltered. Therefore, the enhanced expression of gata2 mRNA followed by ece1 and preproedn1 mRNA by BC might be able to induce vasoconstriction and cardiovascular defects and disrupt craniofacial cartilages in medaka embryos. We conclude that cardiovascular and craniofacial defects in medaka embryogenesis by BC are probably mediated through a GATA2-EDN1 signaling pathway.