Frontiers in Cardiovascular Drug Discovery

The validity of the lipid hypothesis has been debated recently in both, the media and the medical press. In this chapter we review the relevant evidence to evaluate whether it is still applicable in cardiovascular prevention. After a brief description of developments leading to the lipid hypothesis we consider prospective epidemiological studies, paying particular attention to the Framingham Heart Study as it was conceived at a time when lipid lowering therapy was unavailable. We also present the predictive factors of the other commonly used cardiovascular risk scoring models. All the algorithms show cholesterol (total or low density lipoprotein – cholesterol) and high density lipoproteins to predict cardiovascular disease. Our own data from the Whickham Study where subjects were recruited in the pre-statin era also show total cholesterol to be significantly associated with coronary heart disease. We then discuss intervention randomised controlled studies using agents that lower low density lipoprotein – cholesterol (resins, statins, ezetimibe and Proprotein convertase subtilisin/kexin type 9 inhibitors) paying particular attention to studies not demonstrating reduction in cardiovascular outcomes. Apart from patients with heart failure and possibly on dialysis the lipid hypothesis appears to be true. This is reinforced by a meta-analysis carried out by the Cholesterol Treatment Trialists’ Collaboration. We do not feel that outcomes from cohort studies consisting of patients subject to multiple guideline driven treatments can be used as good quality evidence against the lipid hypothesis. We do acknowledge that more research is required regarding heterogeneity and describe a non-invasive way in which atherogenesis of the individual may be measured. We would like future randomised controlled trials to incorporate study of disease mechanism(s) within the study design.

Diabetes mellitus (DM) is an important independent risk factor for incident heart failure (HF). DM is also a prominent prognostic factor for major cardiovascular (CV) adverse events in patients with established HF with reduced (HFrEF) or preserved ejection fraction (HFpEF). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are recently approved drugs for DM treatment. SGLT2i lead to natriuresis and glycosuria with subsequent reductions in blood glucose, intravascular volume, and blood pressure. SGLT2i demonstrated a remarkable relative risk reduction in hospitalization for heart failure in large CV outcome trials of patients with DM. In addition, there was a more modest but also a relevant reduction in CV mortality with empagliflozin. SGLT2i reduce recurrent myocardial infarctions in patients with prior myocardial infarction. SGLT2i were subsequently evaluated in patients with HFrEF, including those without DM. Dapagliflozin was associated with reductions in the primary composite endpoint of worsening heart failure or CV death and each component separately. Considering their remarkable CV benefits and nephroprotection, SGLT2i represent invaluable therapy for the primary and secondary prevention of heart diseases in patients with DM or HFrEF. Ongoing trials may confirm the potential impact of SGTL2i in patients with HFpEF and acutely decompensating HF.

Pathologies associated with hypercoagulable states, including myocardial infarction, deep vein thrombosis, and pulmonary embolism, are one of the most important causes of morbidity and mortality worldwide. Despite the approval of several new synthetic (including orally active) antithrombotic agents in recent years for treating such diseases, mainly direct thrombin, and factor Xa inhibitors, concerns still exist for side-effects, especially bleeding. There is still a therapeutic demand for safe and effective anticoagulant agents that present fewer side effects than the currently available drugs. Natural products and semi-synthetic molecules, as well as molecules inspired by natural scaffolds, have been an important source of drugs in the past decades. This chapter covers reports published in the last ten years concerning natural (or semi-synthetic) products that have been reported as in vitro and/or in vivo antithrombotic agents.

Transient receptor potential (TRP) channels are ubiquitously expressed cellular sensors that respond to changes in the cellular environment. They act in nociception, taste perception, thermosensation, mechanosensing, osmolarity sensing, and signal transduction. Mammalian TRP channels comprise 28 members divided into six subfamilies: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin) and TRPV (vanilloid). TRP mutations that result in either gain or loss of function have been linked to several human diseases, among them hypertension, cardiac hypertrophy, obesity, and diabetes. In the myocardium, TRP channels modulate Ca+2 handling and are differentially expressed in models of cardiac remodeling and dysfunction. TRP channels are also involved in insulin release from pancreatic beta-cells and glucose tolerance in rodent models of type 2 diabetes. Some of these channels promote thermogenesis and thus prevent diet-induced obesity. How TRP channels are modulated in vivo is still unknown since few endogenous ligands were identified so far. However, a wide range of natural products with therapeutic potential activates TRP channels and might serve as models for new drug discovery and development to prevent cardiometabolic morbidity and mortality. Studies with TRP channels show promising results, but the translation to preventive or therapeutic strategies against cardiometabolic diseases is challenging since they are found in multiple tissues and enrolled in several physiological actions, which increases the risk of adverse effects.

Raynaud’s phenomenon (RP) represents a clinical expression of recurrent vasospasm of the small arteries and arterioles of the acral parts (most commonly fingers and toes) provoked by cold exposure and emotional stress. Here, the therapeutic strategies in primary and secondary RP in systemic sclerosis (SSc) are discussed that are based on the evolving knowledge about different pathogenic pathways of the peripheral vascular syndrome. The vasospasm in primary RP is reversible while the secondary SSc-related RP is associated with endothelial injury and subsequent structural abnormalities that lead to tissue damage. The disbalance between vasodilators (nitric oxide - NO, prostacycline) and vasoconstrictors (endothelin-1, angiotensin) is the major consequence of the endothelial injury in secondary SScrelated RP. Therapeutic options in primary RP patients include administration of oral, well-tolerated drugs such as herbal extracts from Ginkgo biloba, pentoxifyllin, or calcium channel blockers. European League Against Rheumatism recommends standardised therapeutic approach for management of SSc-related RP that includes administration of dihydropyridine-type calcium channel blockers, fluoxetine, phosphodiesterase type 5 inhibitors and intravenous iloprost. Other approaches have been also studied such as inhibition of renin-angiotensin system, statins, botulinum toxin but currently there is not enough evidence for their use. Scientific knowledge about mechanisms of action of different drugs corresponding to the underlying pathogenesis are discussed as well as available experience in RP regarding efficacy and safety profile. Individualization of therapy with using complex approach and drug combinations in resistant cases of severe RP and digital ulcers are presented.

Cardiovascular diseases continue being the major cause of death worldwide, despite the constant and consistent efforts made towards the management and control of coronary artery diseases. These diseases are resulted by the metabolic imbalance involving elevated energy requirements and deficient oxygen supply to the cardiac myocytes, ultimately leading to myocardial necrosis. These diseases are closely associated with several changes in metabolic and signaling pathways that involve increased oxidative stress, excessive cytoplasmic and mitochondrial calcification, elevated lipid peroxidation, disturbed antioxidant homeostasis, dynamic cellular metabolism, irreversible DNA damage, and other pathophysiological alterations. The mechanism of pharmacological action demonstrated by modern western medicines usually adopt the lock-and-key model that involves the action of a principle therapeutic agent onto a specific and selective target to regulate a prime metabolic and signaling pathway, therefore becoming unsuitable to treat the disorders mediated by multiple molecular pathways. The side-effects associated with the use of such synthetic drugs are also an alarming health concern. The traditional system of medicine applies multiple natural ingredients that contain several active metabolites, therefore imparting a holistic pharmacological effect on multiple targets that orchestrate multiple pathways, without eliciting significant side-effects. This book chapter reviews various Indian and Chinese polyherbal formulations designed and developed according to the traditional system of medicine, which have been appropriately formulated and adequately characterized in-vitro, in-vivo, and in-silico following the stipulated scientific standards and medical regulations. Significant emphasis is also laid to review the informatic branches and cellular models available to evaluate and assess the pharmacology and toxicology of such polyherbal formulations.

In the post-genomic era, the main challenge is to extract meaningful and valuable information from a large pool of data generated by high throughput techniques like microarray and deep sequencing techniques. Systems biology is an emerging discipline that aids in interpreting a large amount of biological data in a meaningful way. It helps to draw significant inference from a large amount of data about the interactions of genes or proteins, by developing quantitative mathematical models. Due to its complex nature, cardiovascular diseases can be better understood using the systems biology concept. Different components of the disease like heart failure and coronary artery disease can be comprehended in a modular fashion, wherein each module consists of multiple genes and their nonlinear interactions. Another approach is population genetics or Genome-Wide Association Studies (GWAS), which has identified over two hundred chromosomal loci that modulate the risk of cardiovascular diseases. These GWAS variation data can be integrated with multi-omics data and gene network data to identify the susceptible pathways, modules and genotyping cause behind it. Identification of a hub gene in a network is one of the main approaches of research in systems biology of cardiovascular diseases. This hub gene can serve as a biomarker for early detection or therapeutic targets. Comorbidities are another cause of increased risk leading to further complications in patients with cardiovascular diseases. Analysis of association of the comorbidities, using a system biology approach, focuses on the prevention of severe vascular events. The most common comorbidities include diabetes, kidney disease, peripheral arterial disease, etc. Systems biology can aid in identifying special biomarkers for early diagnosis of cardiovascular comorbidities and the following careful management might lead to prolonged survival of the patient.