Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 7, Issue 3, 2009

The no-reflow phenomenon is a poorly understood complication of percutaneous coronary intervention in which diminished blood flow to distal microvascular beds persists despite the successful treatment of the occlusive lesion from the epicardial coronary artery or arteries. In this contemporary review we endeavour to discuss the pathophysiology of coronary no-reflow, understand the predictors and describe current pharmacological and mechanical strategies to prevent and treat coronary no-reflow.

The decision to anti-coagulate patients with heart failure (HF) is a difficult one, with limited data available to support clinical judgment. Thromboembolic complications, both arterial (stroke) and venous (deep vein thrombosis and pulmonary embolism), remain a significant cause of mortality and morbidity in this population. The pathophysiology of thrombogenesis in HF may be contextualized in the classic triad of stasis, endothelial dysfunction and hypercoagulability. Dilated cardiac chambers, reduced systolic function, and left ventricular aneurysm or thrombus have been suggested as potential contributing factors. HF is associated with activation of inflammatory and neuroendocrine pathways, leading to endothelial dysfunction and a prothrombotic state with dysregulated platelets and activation of the coagulation cascade. The epidemiology of thromboembolic events in HF is poorly defined. Most studies are retrospective and include patients with concurrent atrial fibrillation. The current body of health outcomes research is reviewed to identify the specific etiological factors, prevalence, and impact of thromboembolic events in this patient population. Conflicting analyses exist regarding the risks and benefits of prophylaxis in HF. The data surrounding several classes of therapeutic agents are synthesized. Recent clinical trials on anticoagulation and HF are reviewed, including WATCH, WASH, and WARCEF. The absence of compelling clinical trial data leaves many unanswered questions regarding systemic anticoagulation in patients with HF.

Epidemiological studies suggest a strong association between hypertension and ischemic heart disease (IHD), and hypertension is a major independent risk factor for the development of cardiovascular disease (CVD) including myocardial infarction (MI) and stroke. The primary objective of the management of hypertension in patients with IHD is modification of the balance between myocardial oxygen supply and demand to improve symptoms and reduce future cardiovascular adverse events. Patients with hypertension and heart failure constitute another important cohort in this high risk group. While several classes of antihypertensive agents have been shown to be beneficial in treating these patients, there are also several classes of drugs that should be avoided when treating hypertension in patients with IHD and heart failure. This review discusses which antihypertensive drugs should be used in patients who have established IHD with angina pectoris, in those with acute coronary syndromes and MI, and in those with heart failure. These recommendations are based on current guidelines. Finally, although there may be some differences in cardiovascular risk reduction among antihypertensive agents, the most important objective in hypertension management is to adequately control blood pressure irrespective of the agent used.

Cyclic adenosine 3'5'-monophosphate (cAMP) and cyclic guanosine 3'5'-monophosphate (cGMP) are critical intracellular messengers involved in transduction of signals generated by a wide variety of extracellular stimuli, including growth factors, cytokines, peptide hormones, light and neurotransmitters. These messengers modulate many fundamental biological processes, including myocardial contractility, platelet aggregation, vascular smooth muscle relaxation, proliferation and apoptosis, etc. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, and are important in regulating intracellular concentrations and biological actions of these signal-transducing molecules. These enzymes contain at least 11 highly regulated and structurally related gene families (PDE1-11). In this review, we will discuss some general information of PDEs and then focus on PDE3 gene family, including the molecular biology, structure, function and potential as therapeutic targets. Furthermore, we show the possibilities of PDE3 as therapeutic targets in malignant tumor cells and salivary gland.

Endothelial dysfunction is characterized by an impairment of endothelium-dependent vasodilatation. It has been linked to each of the known atherogenic risk factors, including diabetes mellitus, hypertension, dyslipidaemia, cigarette smoking, menopause, etc. A number of recent studies have shown that the severity of endothelial dysfunction correlates with the development of coronary artery disease and predicts future cardiovascular events. Therefore, these findings strengthen the hypothesis that endothelial dysfunction may be an early stage of coronary atherosclerosis. This phenomenon primarily reflects an imbalance between the vasodilating (nitric oxide) and vasoconstrictor agents (endothelin- 1). Several invasive (intracoronary or intrabrachial infusions of vasoacting agents) and non-invasive techniques (assessment of flow mediated vasodilatation in the brachial artery by ultrasound) have been developed during the last few years to evaluate endothelial function in the coronary and peripheral circulation. This new methodology has allowed assessing the severity of the abnormalities in vascular function and their regression by several pharmacological and nonpharmacological interventions. It is likely that restoration of endothelial function can regress the atherosclerotic disease process and prevent future cardiovascular events. Most pharmacological interventions attempting to improve endothelial dysfunction targeted the risk factors linked to endothelial dysfunction: hypertension (ACE-inhibitors, calcium antagonists), dyslipidaemia (lipid-lowering agents) and menopause (estrogens). Nevertheless, several pharmacological agents have been suggested to achieve vascular protection through different mechanisms beyond their primary therapeutic actions: ACE-inhibitors, statins, third generation of beta-blockers (nebivolol), endothelium-derived nitric oxide synthesis (tetrahydrobiopterin, BH4) and antioxidants agents. In this review we will focus on the current pharmacological management of the endothelial dysfunction.

Respiratory syncytial virus (RSV) is a very important pathogen worldwide. It occurs and recurs naturally throughout life. Both short and long term morbidity, and mortality are particularly significant for infants, especially those infants with underlying conditions and risk factors. Current treatment strategies for these patients (e.g Ribavirin) are limited but several new interventions (e.g. RSV604, BTA9881, ALN-RSV01) are under investigation. Several preventive agents and strategies have been developed (e.g. RSV-IGIV, palivizumab) and others are in the pipeline (e.g. motavizumab) and under development (e,g, Medi-557). In this article, we review the RSV clinical condition with a focus on the highest risk populations. In addition we review prevention and treatment strategies of the past, present and future for these high-risk patients. This review should provide a single valuable source of information to clinicians and investigators.

The plasma kallikrein-kinin system (KKS) plays a critical role in human physiology. The KKS encompasses coagulation factor XII (FXII), the complex of prekallikrein (PK) and high molecular weight kininogen (HK). The conversion of plasma prekallikrein to kallikrein by the activated FXII and in response to numerous different stimuli leads to the generation of bradykinin (BK) and activated HK (HKa, an antiangiogenic peptide). BK is a proinflammatory peptide, a pain mediator and potent vasodilator, leading to robust accumulation of fluid in the interstitium. Systemic production of BK, HKa with the interplay between BK bound-BK receptors and the soluble form of HKa are key to angiogenesis and hemodynamics. KKS has been implicated in the pathogenesis of inflammation, hypertension, endotoxemia, and coagulopathy. In all these cases increased BK levels is the hallmark. In some cases, the persistent production of BK due to the deficiency of the blood protein C1-inhibitor, which controls FXII, is detrimental to the survival of the patients with hereditary angioedema (HAE). In others, the inability of angiotensin converting enzyme (ACE) to degrade BK leads to elevated BK levels and edema in patients on ACE inhibitors. Thus, the mechanisms that interfere with BK liberation or degradation would lead to blood pressure dysfunction. In contrast, anti-kallikrein treatment could have adverse effects in hemodynamic changes induced by vasoconstrictor agents. Genetic models of kallikrein deficiency are needed to evaluate the quantitative role of kallikrein and to validate whether strategies designed to activate or inhibit kallikrein may be important for regulating whole-body BK sensitivity.

Single nucleotide polymorphisms (SNP) in the CYBA gene encoding p22phox have been associated with respiratory burst and cardiovascular phenotypes. We previously reported a reduced phagocytic respiratory burst activity in healthy adults with the C242T SNP, but found no correlation between CYBA SNPs and coronary artery disease (CAD) phenotype. Using lymphoblastoid cells, we hypothesized that CYBA SNPs affect enzyme activity in patients with cardiovascular disease (CVD), but would not be associated with angiographic severity of CAD due to confounding by risk factors. We established lymphoblastoid cell lines from patients with CVD and genotyped the study cohort for CYBA SNPs and phenotyped each subject's coronary angiogram for CAD severity. As quantified by electron spin resonance, superoxide production in picomoles per 106 resting lymphoblastoid cells per minute for the CC, CT, and TT genotypes of the C242T SNP were 16.2±1.4, n=70, 11.9±0.7, n=87, and 11.9±1.5, n=28, respectively (P=0.002). The -930A/G and A640G SNPs did not affect superoxide production (P>0.2). Expression of p22phox was not affected as determined by real-time RT-PCR and Western blot analysis. The C242T CYBA SNP is associated with altered NADPH oxidase activity in lymphoblastoid cells of patients with CVD. By reducing the influence of confounding environmental factors, lymphoblastoid cell lines could serve as a tool to assess direct genotype/phenotype interactions of candidate genes known to affect atherosclerosis.