Frontiers in Cardiovascular Drug Discovery

Cardiovascular disease describes a wide range of heart and blood vessel diseases and includes conditions such as congenial heart defects, coronary artery disease, arrhythmias and more. Cardiovascular disease is the number 1 killer of men and women in the United States and in other countries as well. Natural products play an important role as nutritional supplements and provide potential health benefits in cardiovascular diseases such as hypertension, atherosclerosis, dyslipidemia, arrhythmias, and heart failure. Traditional Chinese medicine is one of the world’s oldest forms of medicine, with a history of more than 2,500 years. Chinese herbs and basic principles regarding Chinese traditional medicine such as “yin and yang” balance as well as disease were interpreted in this chapter. Compiling data from experimental, epidemiological and clinical studies indicates that dietary nutrients have profound cardioprotective effects in the primary as well as secondary prevention of coronary heart disease. The mechanism of cardioprotection produced by herbs and dietary nutritional supplements such as tea, omega-3 (ω-3) fatty acids (fish oil and fish-based products), and garlic in the prevention and treatment of cardiovascular disorders have been discussed in this chapter, with the emphasis of epidemiological and clinical studies. Based on the intriguing results of various studies, prophylactic and therapeutic potential of natural products have been suggested. The supplementation of natural products needs to be considered in all populations who have high prevalence of cardiovascular disorders.

Based on the existing knowledge of the cellular mechanisms that govern in atherosclerosis development, several sites of action for the agents capable of preventing atherogenesis or promoting the regression of atherosclerotic manifestations can be suggested. The main manifestation of plaque development relates to the formation of foam cells in the arterial intima. It is reasonable to consider that any drug which would not prevent directly the transformation of normal intimal cell into an “atherosclerotic” one (namely, foam cell) should be regarded as an indirect anti-atherogenic action drug. Only that drug which would exhibit its preventive activity focally, at the arterial wall level, is a direct anti-atherogenic drug. At the arterial cell level, a drug with a direct anti-atherosclerotic action should be capable to induce the diminishing of the major cellular manifestations of atherosclerosis, i.e. reduce the intracellular lipid content, suppress cell proliferation or inhibit the extracellular matrix production.

In our current work we examine the effects of various agents (drugs) on atherosclerosisrelated features of cultured arterial human cells. In these experiments, cells are isolated from the subendothelial portion of the human aortic intima, i.e. from the part of the aorta which is located between the endothelial lining and the tunica media. The intima of the adult human aorta has a distinctive structure allowing us the identification of its different layers. Using collagenase and elastase, cells are isolated from the subendothelial layer of the intima of both normal and atherosclerotic parts of the aorta. This approach makes it possible to study a direct anti-atherosclerotic action of various drugs at the vascular cell level. An important advantage of this approach is that human material is used and thus, the examinations which we carry out are relevant to human atherosclerosis.

Cells of the subendothelial intima isolated from atherosclerotic lesions have been proved to retain all major characteristics of atherosclerotic cells in primary cell culture. Cells cultures obtained from fatty streaks and fatty infiltration zones have an enhanced proliferative activity. A large proportion of cells cultured from atherosclerotic lesions are foam cells containing numerous inclusions that fill the most space of the cytoplasm; these inclusions represent lipid droplets. The excess lipids in foam cells are cholesterol and cholesteryl esters. It should be noted that the content and composition of lipids in cultured cells remain unchanged within the first 10-12 days of the cultivation and retain the properties of the freshly isolated cells. Cultivated cells that obtained from the intima are capable of synthesizing collagen, proteoglycans and other components of the extracellular matrix. Thus, cells isolated from an atherosclerotic lesion of the human aorta retain in culture all main properties, typical to atherosclerotic lesion cells. They exhibit an enhanced proliferative activity, contain excess cholesterol in the form of intracellular inclusions and synthesize the extracellular matrix. This allows one to regard primary culture of atherosclerotic cells as a convenient model for the investigation of effects of various agents on atherosclerotic manifestations. Therefore, the in vitro investigations are carried out directly on exactly the same cells which would “face” with a therapeutic action in vivo.

Using such cell model, we have examined the effects of different drugs and chemicals. Many substances have been already tested. Some of the tested drugs elicited antiatherosclerotic effects in cell culture, others have been proved to be ineffective against cellular atherosclerotic manifestations; some tested substances have been found to.... stimulate the development of atherosclerotic features.

Stroke prevention in atrial fibrillation (AF) has been challenging over decades, mostly due to a number of difficulties associated with oral vitamin K antagonists (VKAs), which were the most effective stroke prevention treatment and the only available drugs for oral anticoagulation for a long time. The oral direct thrombin inhibitors and oral direct inhibitors of factor Xa have recently emerged as a viable alternative to VKAs for stroke prevention in AF. These drugs act rapidly and have a predictable, dose-related anticoagulant effect with a few clinically relevant interactions with other drugs. The novel oral anticoagulants are used in fixed doses with no need for a regular laboratory monitoring of anticoagulation intensity.

Several phase III randomized trials with novel oral anticoagulants for stroke prevention in AF have been completed recently: the RE-LY trial with dabigatran, the ROCKET-AF with rivaroxaban and the ARISTOTLE trial with apixaban, and all 3 trials compared the novel drug with warfarin. The AVERROES trial, which included AF patients who have failed or were unsuitable for warfarin, compared apixaban versus aspirin for stroke prevention in AF. Altogether, the novel oral anticoagulants showed impressive performance in these trials and have already been implemented into clinical practice worldwide. In addition, many more novel anticoagulants are at various stages of clinical investigation.

In this chapter, we present a brief summary of clinical trials with oral vitamin K antagonists for stroke prevention in AF and the caveats regarding these trials. We further present a detailed overview of the recently completed phase III randomized trials on the novel oral anticoagulants along with clinical implications of the results and summarize the current knowledge on the investigational oral anticoagulants which are under development.

Hypertension is a prevalent condition leading to cardiovascular adverse events and mortality. Despite the pharmacologic treatments available, persistently elevated blood pressure can be observed in a significant number of patients. Dysfunction of the sympathetic nervous system plays an important role in hypertension. Radiofrequency ablation can disrupt the sympathetic innervation localized in the adventitia of the renal arteries, thus modulating the sympathetic nervous system. In this chapter sympathetic nerve modulation will be discussed, including physiopathological considerations, technical aspects and experience arising from animal and clinical studies.