Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Some Actions of Prostaglandins on the Heart

Note:The role of prostaglandins (PGs) in influencing myocardial and coronary performance was studied in isolated hearts. PGE2 and PGF2a induced rhythm instabilities in isolated rat hearts at low concentrations while at higher levels the dysrhythmic activity declined. These effects were prevented by either copper or chloroquine. Comparative effects of PGE2, PGD2, PGFla and PGF2a were studied on rat hearts. PGF2a had potent inotropic and coronary constricting actions. PGD2 was also a potent coronary constrictor but had no inotropic effects. PGE2 had slight inotropic actions and constricted the coronaries at low concentrations and dilated them at high ones. All PGs studied decreased the heart rate. It was also found in these studies that the cardiac effects of PGs can be influenced by the sex of the animal or by gonadectomy. […]Le rôle des prostaglandines (PGs) dans des coeurs isolés de rats a été étudié en ce qui a trait à leur influence sur la performance du myocarde et des artères coronaires. La PGE2 et la PGF2a à faible concentration dans des coeurs de rats isolés produisaient des irrégularités rythmiques tandis que à concentrations plus élevées l'activité dysrythmique était diminuée. Ces effets étaient empêches soit par le cuivre ou la chloroquine. Nous avons comparé les effets de la PGE2, la PGD2, la PGFla et la PGF2a dans le coeur des rats. La PGF2a avait de puissantes actions inotropiques et constrictait les vaisseaux coronaires. La PGD2 était aussi un puissant constricteur mais n'avait aucun effet inotropique.La PGE2 avait une légère action inotropique et constrictait à faibles concentrations les coronaires et les dilatait à concentrations élevées. Les PGs étudiées diminuaient les battements cardiaques. Ces études ont démontré que les effets cardiaques peuvent être influences par le sexe de l'animal ou par la gonadectomie. […

Cardioprotection by Ginseng: Experimental and Clinical Evidence and Underlying Mechanisms

Protection of the ischemic and reperfused myocardium represents a major therapeutic challenge. Translating results from animal studies to the clinical setting has been disappointing, yet the need for effective intervention particularly to limit heart damage following infarction or surgical procedures such as coronary artery bypass grafting is substantial. Among the many compounds touted as cardioprotective agents is ginseng, a medicinal herb belonging to the genus Panax which has been used as a medicinal agent for thousands of years, particularly in Asian societies. The biological actions of ginseng are very complex and reflect composition of many bioactive components although many of the biological and therapeutic effects of ginseng have been attributed to the presence of steroid-like saponins termed ginsenosides. Both ginseng as well as many ginsenosides have been shown to exert cardioprotective properties in experimental models. There is also clinical evidence that traditional Chinese medications containing ginseng exert cardioprotective properties although such clinical evidence is less robust primarily owing to the paucity of large scale clinical trials. Here, we discuss the experimental and clinical evidence for ginseng, ginsenosides and ginseng-containing formulations as cardioprotective agents against ischemic and reperfusion injury. We further discuss potential mechanisms, particularly as these relate to antioxidant properties.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Treatment of the cardiac hypertrophic response and heart failure with ginseng, ginsenosides and ginseng-related products

Heart failure is a major medical as well as economic burden throughout the world. Although various treatment options are available to treat heart failure, death rates in both men and women remain high. Potential adjunctive therapies may lie with use of herbal medications many of which possess potent pharmacological properties. Among the most widely studied is ginseng, a member of the genus Panax which is grown in many parts of the world and which has been used as a medical treatment for a variety of conditions for thousands of years, particularly in Asian societies. There are a number of ginseng species each possessing distinct pharmacological effects due primarily to differences in their bioactive components including saponin ginsenosides and polysaccharides. While experimental evidence for salutary effects of ginseng on heart failure is robust clinical evidence is less so primary due to a paucity of large scale well controlled clinical trials. However, there is evidence from small trials that ginseng-containing Chinese medications such as Shenmai can offer benefit when administered as adjunctive therapy to heart failure patients. Substantial additional studies are required, particularly in the clinical arena, to provide evidence for a favourable effect of ginseng in heart failure patients.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Ginseng for the Treatment of Diabetes and Diabetes-related Cardiovascular Complications. A Discussion of the Evidence

Diabetes mellitus is a chronic metabolic disorder associated with elevated blood glucose levels due either to insufficient insulin production (Type 1 diabetes) or to insulin resistance (Type 2 diabetes). The incidence of diabetes around the world continues to rise dramatically with more than 400 million cases reported today. Among the most serious consequences of chronic diabetes include cardiovascular complications which can result in both cardiac and vascular deleterious effects. Although numerous treatment options are available for treating diabetes, both pharmacological and non- pharmacological, there is substantial emerging interest in the use of traditional medicines for the treatment of this condition and its complications. Among these is ginseng, a medicinal herb which belongs to the genus Panax and which has been used for thousands of years as a medicinal agent especially in Asian cultures. There is emerging evidence from both animal and clinical studies that ginseng, ginseng constituents including ginsenosides and ginseng-containing formulations can produce beneficial effects in terms of normalization of blood glucose levels and attenuation of cardiovascular complications through a multiplicity of mechanisms. Although more research is required, ginseng may offer a useful therapy for the treatment of diabetes as well as its complications.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Inhibition of Myocardial Remodeling and Heart Failure by Traditional Herbal Medications: Evidence from Ginseng and ginkgo biloba

Herbal-based medications have been used as therapeutic agents for thousands of years, particularly in Asian cultures. It is now well established that these herbal medications contain potent bioactive phytochemicals which exert a plethora of beneficial effects such as those seen on the cardiovascular system. Among the most widely studied of these herbal agents is ginseng, a member of the genus Panax, which has been shown to produce beneficial effects in terms of reducing cardiac pathology, at least in experimental studies. The beneficial effects of ginseng observed in such studies are likely attributable to their constituent ginsenosides, which are steroid-like saponins of which there are at least 100 and which vary according to ginseng species. Many ginseng species such as Panax ginseng (also known as Asian ginseng) and P quinquefolius (North American ginseng) as well as specific ginsenosides have been shown to attenuate hypertrophy as well as other indices of myocardial remodeling in a wide variety of experimental models. Ginkgo biloba on the other hand has been much less studied although the leaf extract of the ancient ginkgo tree has similarly consistently been shown to produce anti-remodeling effects. Ginkgo’s primary bioactive constituents are thought to be terpene trilactones called ginkgolides, of which there are currently seven known types. Ginkgo and ginkgolides have also been shown to produce anti-remodeling effects as have been shown for ginseng in a variety of experimental models, in some cases via similar mechanisms. Although a common single mechanism for the salutary effects of these compounds is unlikely, there are a number of examples of shared effects including antioxidant and antiapoptotic effects as well as inhibition of pro-hypertrophic intracellular signaling such as that involving the calcineurin pathway which results in the upregulation of pro-hypertrophic genes. Robust clinical evidence represented by large scale phase 3 trials is lacking although there is limited supporting evidence from small trials at least with respect to ginseng. Taken together, both ginseng and ginkgo as well as their bioactive components offer potential as adjuvant therapy for the treatment of myocardial remodeling and heart failure