Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 11, Issue 1, 2013

The prognostic importance of large artery structure and function in relation to cardiovascular morbidity and mortality, together with the identification of new genetic risk factors have been two major areas of investigation in recent years. Carotid intima-media thickness (CIMT), as measured by B-mode ultrasound, is a surrogate marker for atherosclerosis and can be used to detect an accelerated disease process as well as subclinical disease. However, the genetic basis for CIMT variation is almost unknown. Cardiovascular genetics has led to numerous clinical studies generally focused on only one candidate gene and were frequently conducted in subjects with cardiovascular diseases and/or taking drugs that could affect CIMT. Pharmacogenetics is the study of the effect of a medication as it relates to single or defined sets of genes. An important goal of pharmacogenetics in cardiovascular disorders is to integrate the two (drugs plus genes) so that true personalized therapy can be delivered. In this paper, we will discuss the interaction between genes involved in lipid metabolism and statin therapy that affects intermediate phenotype (plasma lipid levels) and CIMT in patients with type 2 diabetes.

Atrial fibrillation (AF) is the most common arrhythmia and one of the major causes of morbidity and hospitalization. It is an important risk factor for thromboembolic complications and cerebrovascular disease. In AF, extensive electrical and structural remodeling of atrial tissue takes place with the main underlying mechanisms being inflammation and fibrosis. In recent years it has been shown, that beside conventional antiarrhythmic therapies, modalities aiming at reversal of atrial tissue derangement could be of some benefit in the treatment of AF. In this respect, the main focus was oriented towards drugs such as angiotensin convertase (ACE) inhibitors, angiotensin receptor blockers (ARBs), polyunsaturated fatty acids and statins. Data about the potential beneficial role of statins for AF treatment is continuously growing. It is now evident that statins act on AF mainly through their pleiotropic and not their lipid lowering properties. Several retrospective trials have shown that statins exert antiarrhythmic effects in patients with AF, while data from prospective studies are still conflicting. Thus, the definitive confirmation and explanation of statin's role in AF treatment is still missing. Herein, the current patophysiological concepts providing rationale for the use of statins in AF treatment as well as up-to-date data from retrospective and prospective clinical studies are reviewed and discussed. Particular attention is paid to various clinical settings such as primary prevention, secondary prevention (post-cardioversion) and postoperative setting. We also present our own data regarding the role of statins in prevention of the recurrence of AF after successful cardioversion.

We present a promising in silico paradigm called literature-based discovery (LBD) and describe its potential to identify novel pharmacologic approaches to treating diseases. The goal of LBD is to generate novel hypotheses by analyzing the vast biomedical literature. Additional knowledge resources, such as ontologies and specialized databases, are often used to supplement the published literature. MEDLINE, the largest and most important biomedical bibliographic database, is the most common source for exploiting LBD. There are two variants of LBD, open discovery and closed discovery. With open discovery we can, for example, try to find a novel therapeutic approach for a given disease, or find new therapeutic applications for an existing drug. With closed discovery we can find an explanation for a relationship between two concepts. For example, if we already have a hypothesis that a particular drug is useful for a particular disease, with closed discovery we can identify the mechanisms through which the drug could have a therapeutic effect on the disease. We briefly describe the methodology behind LBD and then discuss in more detail currently available LBD tools; we also mention in passing some of those no longer available. Next we present several examples in which LBD has been exploited for identifying novel therapeutic approaches. In conclusion, LBD is a powerful paradigm with considerable potential to complement more traditional drug discovery methods, especially for drug target discovery and for existing drug relabeling.

Metabolic syndrome (MS) is an obesity-associated collection of disorders, each of which contributes to cardiovascular risk. For patients with MS, it is difficult to follow a diet/exercise regime that would improve their symptoms. Therefore, the investigation of agents that may deal with its more serious aspects is an important medical field for research. Numerous experimental studies have confirmed the important role of medicinal plants or their active components in the prevention and treatment, and in lowering risk factors of MS. As oxidative stress and inflammation are involved in the association between obesity, insulin resistance (IR) and hypertension, antioxidant and anti-inflammatory plant components like polyphenols might be useful as a treatment for MS. The aqueous extract of Hibiscus Sabdariffa L (HSE), rich in several polyphenols, is commonly and effectively used in native medicines against hypertension, diabetes and liver disorders. HSE has also shown therapeutic promise in the prevention of MS in patients, probably due to its polyphenol content. Curcumins, derived from the spice turmeric, and resveratrol, polyphenols found in grapes and red wine respectively, in addition to their antioxidant and anti-inflammatory properties, inhibit preadipocyte proliferation, de novo lipogenesis and fat accumulation in liver. Thus, due to their efficacy in the regulation of multiple targets, polyphenols have received considerable interest as potential therapeutic agents for the prevention and treatment of MS. This review discusses the therapeutic use of HSE, as well as curcumin and resveratrol, in the context of obesity as an initiator of insulin resistance and hypertension, the two main features of MS, together with the underlying mechanisms of action.

An estimated 11% of the U.S. population has chronic kidney disease (CKD). Cardiovascular morbidity and mortality remain high among individuals with CKD and the higher mortality from cardiovascular disease persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. This has led to the current understanding that the pathophysiology of cardiovascular disease in CKD involves a complex interplay of both the traditional as well as nontraditional, uremia-related risk factors. Given the high cardiovascular morbidity and mortality, patients with CKD should be a target for aggressive cardiovascular risk reduction.

Bivalirudin, a direct thrombin inhibitor, is an anticoagulant commonly used in invasive cardiology procedures. It has evolved from relative obscurity, as an anticoagulation option only utilized in rare instances of allergy or resistance to heparin products, to the now preferred antithrombotic anticoagulant in the cardiac catheterization laboratory. On the way to displacing unfractionated heparin as the preferred anticoagulant for percutaneous coronary intervention, multiple studies comparing bivalirudin with heparin have consistently shown equivalent ischemic efficacy endpoints (i.e. cardiovascular death, myocardial infarction, etc.), with significant reductions in bleeding. Bleeding has been directly linked to worse hospital outcomes in cardiac patient's undergoing invasive coronary artery revascularization procedures. More recent bivalirudin studies now demonstrate reductions in mortality, which has led to a paradigm shift to bivalirudin as the anticoagulant choice both in elective and emergent coronary procedures. We present the major studies that have brought bivalirudin to the forefront of coronary artery disease, specifically coronary interventional procedures.

Blood platelets play a key role in normal hemostasis but also in atherothrombosis due to their ability of thrombus formation at site of a ruptured atherosclerotic plaque. Platelets are also involved in vascular inflammation due to interactions with endothelial cells, leukocytes, and smooth muscle cells that may result in an excessive fibroproliferative response after vessel dilatation. This review article describes both, the current status of standard anti-platelet drug therapy using acetylsalicylic acid, adenosine diphosphate or glycoprotein IIb-IIIa receptor antagonists in the prevention of cardiovascular events as well as drawbacks like non-responsiveness or increased bleeding rates leading to enhanced reintervention and transfusion rates, both responsible for adverse clinical outcomes after coronary interventions.

With improved and highly active antiretroviral therapy (HAART) the average life span of HIV infected individuals has increased tremendously. HIV infections can now be managed with HAART for years making it a chronic disease much in line with others like diabetes or high blood pressure. However the increasing use of HAART therapy for HIV management has also revealed a growing concern for the side effects associated with this treatment regimen. The two groups of drugs currently at the forefront of HAART therapy namely Nucleoside Reverse Transcriptase inhibitors (NRTI) and Protease inhibitors (PI) are known to induce toxicities that lead to cardiovascular complications. While NRTIs are known to directly affect cardiac cells via their effect on mitochondria; the PIs have more indirect effects through alteration of lipid metabolism leading to dyslipidemia, a predisposing factor for atherosclerosis and heart disease. In this review, we provide a summary of the mechanism of cardiovascular complications that are associated with HIV infection as well as long term treatment with HAART.

Background: membranous glomerulopathy (MG) is an immunomediated disorder which accounts for the most common cause of nephrotic syndrome (NS) following allogeneic hematopoietic stem cell transplantation (HSCT). Objective and Methods: to provide an update on the issue by reviewing pertinent literature on the MEDLINE database. Results: sixty-nine post allogenic HSCT patients (42 male) with MG were identified. The median age was 43 (5 to 68) years. Time interval from allogenic HSCT to MG diagnosis ranged from 3 to 134 months (median 17). Most MG patients had a history of acute (70%) or chronic (84%) graft versus host disease (GVHD). Corticosteroids and cyclosporine were the most common therapeutic agents used in this setting; alternative therapies, including rituximab, were given to a lower number of patients. Outcome data were available in 64 out of 69 MG patients; 38 (59%) and 18 (28%) patients achieved a complete and a partial response respectively, whereas treatment failure was recorded in the remaining 8 (13%). Conclusion: MG after allogenic HSCT appears to be associated with a sub clinical or overt cGVHD, which follows the discontinuation of immunosuppressive prophylaxis. Although a standard therapeutic approach has not been established, the application of available measures can induce favorable response in more than 80% of affected patients, but treatmentfailure and progressive deterioration of the renal function may occur in about one fifth of cases.

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of progression of arterial hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD). Previous studies suggested that a direct renin inhibitor, aliskiren, may be effective for blood pressure lowering, renoprotection and cardiovascular protection. This review focuses on the effects of aliskiren for arterial hypertension, CKD and CVD.