Frontiers in Cardiovascular Drug Discovery

Platelet represents the cornerstone of both physiologic hemostasis and thrombosis acting via different pathways. Adenosine diphosphate (ADP) plays a crucial role in platelet activation and thrombus formation through its interaction with platelet P2Y12 receptor, making therefore this receptor an interesting therapeutic target for anti-thrombotic agents.

Around the world, millions of people affected by coronary artery disease are treated with anti-platelet agents. Indeed, dual anti-platelet therapy, consisting of a combination of aspirin and a P2Y12 receptor antagonist, is the recommended strategy in patients with acute coronary syndrome and those who underwent percutaneous coronary intervention with stent implantation. Furthermore, the introduction of different generations of P2Y12 receptor antagonists has immensely improved the clinical outcome, as well established through literature.

Although the concept to replace “one size fits all” paradigm to a more individualized approach in anti-platelet therapy seems to be rational, in the area of based evidence medicine, a clear prognostic impact of such a strategy is not yet clearly demonstrated.

In the current chapter, we tried to summarize the mechanisms of P2Y12 receptor antagonists anti-platelet action, to report clinical proofs regarding the efficacy/safety of new generations of this class of drugs, and to discuss the place of a tailored strategy and its impact on improving clinical outcome.

Heart Failure is a chronic disease with increasing prevalence around the world. It is associated with significant mortality, morbidity, and healthcare costs. Over the past 2-3 decades, major advances in drug development have contributed significantly in decreasing mortality among those with chronic systolic heart failure. However, similar advances are missing in patients experiencing acute heart failure and heart failure with preserved ejection fraction. In the current chapter, we will review the historical development of pharmacotherapy in heart failure medical management. A comparative review of contribution of each class towards reducing mortality will be performed. More importantly, drugs which failed to succeed or impact significantly will be reviewed and an insight on why they may have failed will be provided. Development of new drugs is limited by regulatory requirements as well as disease heterogeneity. New agents under development will be summarized and mode of their action will be detailed. This chapter aims to serve as a comprehensive resource on strategies both past and current as well as provide discussion regarding potential future developments in heart failure pharmacotherapy.

Arginine vasopressin or antidiuretic hormone has got name “vasopressin” due to its vasoconstrictor properties. Vasopressin is a posterior pituitary hormone which is essential for the cardiovascular homeostasis. In normal physiological conditions, it helps in regulation of plasma osmolality and volume via its action on the kidney. Other important actions of vasopressin include regulation of vascular smooth muscle tone, control of circadian rhythm, thermoregulation, and adrenocorticotropic hormone release (ACTH).

In recent years, vasopressin has emerged as an important therapeutic option in the treatment of various shock states. Vasopressin has increasingly been used in both pediatric and adult critical care units for the management of central diabetes insipidus, bleeding abnormalities, oesophageal variceal haemorrhage, asystolic cardiac arrest, and various shock states e.g. shock due to ventricular fibrillation, hypovolaemia, sepsis and cardiopulmonary bypass.

Ongoing researches helped in increasing understanding of the endocrine response to shock and importance of vasopressin in their management. Prolonged vasodilatory shock is characterised by relative deficiency of endogenous vasopressin and marked vasopressor effects of the exogenously administered hormone. Sepsis and post cardiopulmonary bypass conditions are the most common causes of vasodilatory shock; however, vasodilation can be a common final pathway of any type of shock. Unlike other vasoconstrictors, vasopressin also exerts some vasodilatory properties which can be due to its action on various receptors, namely V1 vascular, V2 renal, V3 pituitary and oxytocin receptors, and the P2 purinergic receptors producing variable and seemingly contradictory responses.

To better understand the variable responses on the vascular system, which vasopressin exerts, it is prudent to acquire the knowledge of the physiology and action of the different vasopressin receptors. In this chapter, vascular actions of vasopressin along with distribution of the classic vasopressin receptors and signalling pathways will be explored.

The term cerebral small vessel disease (CSVD) or microangiopathy includes several pathological processes of different aetiologies which cause an increase of wall thickness (basically the basement membrane), a narrowing of the lumen, and a weakening of walls in arterioles, capillaries and venules. These vascular modifications cause a loss of proteins towards the interstice and a slowness of blood flow, increasing the risk of ischemia and tissue bleeding.

The CSVD may be aetiopathogenically classified in 6 types. The CSVD type 1, called arteriolosclerosis, is the most prevalent form and has a 6 to 10 times higher prevalence than stroke. It is related to aging and classical vascular risk factors, like arterial hypertension and diabetes mellitus. This review will focus on type 1 CSVD.

In the brain, the main pathological findings are loss of smooth muscle cells in the media, accumulation of fibrohyaline material, fibrinoid necrosis, and development of microatheromas and Charcot-Bouchard microaneurysms. The parenchymatous consequences of these vessel modifications are both ischemic (white matter lesions, lacunes) and haemorrhagic (microhaemorrhages, intracerebral haemorrhages). The clinical manifestations of arteriolosclerosis include cognitive deterioration, dementia, mood disorders, gait and motor disturbances, lacunar strokes, and disability. In vivo, the diagnosis of CSVD is supported by neuroimaging findings (lacunes, leukoaraiosis, white matter lesions, microhaemorrhages), especially by use of magnetic resonance techniques. The role of other biomarkers (plasma and cerebrospinal fluid biochemical parameters, resistance indexes in transcranial Doppler study) is not completely defined.

In patients with diagnosis of microangiopathy there are three main therapeutic considerations. First, there are specific risks in these patients during standard clinical management of acute ischemic stroke. Several studies showed an increased risk of intracranial bleeding related to thrombolytic therapy for acute stroke and anticoagulant treatment for secondary prevention. Indeed, the presence of leukoaraiosis raised the probability of peri-operative stroke or death in patients who underwent carotid endarterectomy. Second, the symptomatic management of patients with cognitive impairment related to CSVD, which is currently based on memantine and acetylcholinesterase inhibitors used in Alzheimer's disease. Third, the specific therapy directed to vessel pathology and parenchymatous consequences (secondary prevention). Available data support the use of antiaggregant drugs to reduce the risk of recurrence of lacunar strokes. Aspirin, ticlopidine, aspirin plus clopidogrel, dipiridamol plus aspirin, and cilostazol showed efficacy in this subtype of stroke. The optimal control of arterial pressure and cholesterol level also reduces the risk of stroke, independently if mechanism of disease was macro or microvascular. However, the specific drugs and the optimal goals are not defined and ongoing trials are trying to evaluate different drugs and preventive strategies (cilostazol plus aspirin, aggressive versus standard blood pressure control). Considering the specific treatment of vascular pathology, there are few available data. Experimental studies showed that relaxin may increase the arterial distensibility. In humans, one ongoing trial is investigating the efficacy and safety of an anti-amyloid beta monoclonal antibody in patients with probable cerebral amyloid angiopathy (CSVD type 2).

Despite huge improvements in clinical diagnosis as well as numerous options in patient care and treatment, the incidence of cardiovascular disease (CVD) has been on the rise in the last decade potentially due to hitherto deteriorating lifestyle. As a chronic inflammatory response of the arterial vessel wall, atherosclerosis and its clinical sequelae such as coronary heart disease, cerebrovascular disease and peripheral artery disease continue to be the leading causes of morbidity and mortality worldwide. This makes it necessary to explore novel therapeutic strategies to control and manipulate the mediators of atherosclerosis and cardiac repair processes in order to help combat cardiovascular events. The complement system, an important part of the innate immune response, constitutes a complex network of plasma proteins and membrane cofactors which act in concert with other immunological systems of the body for a rapid defense against foreign intrusions and infections. Activation of the complement cascade in CVD is well established. Numerous well-conducted studies on targeting specific components of the complement cascade in CVD have opened avenues for targeted pharmacological inhibition of the complement system at different levels of complement activation. The use of gene targeting and neutralizing antibodies as well as small molecule inhibitors in animal models of human CVD has provided a clear beneficial role for blocking complement C5, C5a, C5a receptor (C5aR1, CD88) and the soluble complement receptor 1 (sCR1) and different regulators at C3 convertase level. Moreover, the discovery of the second receptor for C5a, the C5aR2 (C5L2, C5a receptor-like 2) and recent studies on the functional role in atherosclerosis has raised the intriguing possibility of the use of this receptor as a novel antiinflammatory strategy. Though work is still in progress to determine whether there is a global effect of this receptor in pathogenesis of cardiovascular disease, there is no doubt that complement blocking strategies is an emerging field in medical pharmacology.

The most important adverse effect of antiplatelet and anticoagulant therapy is the occurrence of bleeding. Gastroenterologists, cardiologists, and primary care physicians often find themselves balancing the benefits of antiplatelet and anticoagulant therapy with the risk of bleeding, namely gastrointestinal bleeding. While aspirin and warfarin have long been the mainstay of oral antiplatelet and anticoagulant therapy, respectively, recent discoveries of more precise targets for therapy have come to market in order to reduce the risk of cardiovascular events and overcome the wellknown limitations that plague warfarin therapy (e.g. narrow therapeutic index, variable individual metabolic response, and numerous food and drug interactions). Despite the fact that these novel agents may increase the risk of gastrointestinal bleeding [1], their ease of use makes them more attractive than conventional agents. This review will provide an overview of the pharmacology of available antiplatelet agents and anticoagulants, outline risks that clinicians should be cognizant of when considering prophylactic therapy in order to reduce the risk of gastrointestinal toxicity, and provide up to date data on reversal agents that are currently available as well as those that are in the pipeline.