Cardiovascular & Haematological Disorders - Drug Targets - Volume 6, Issue 4, 2006

Atherosclerosis is considered to be a chronic inflammatory disease. Vascular inflammation occurs in response to injury induced by various stimuli, such as oxidative stress, shear stress, infection, and so on. This concept is supported by the recent clinical findings that C-reactive protein (CRP) is an independent risk factor for coronary heart disease. CRP, which was originally identified as a protein that could precipitate the C-polysaccharide of pneumococcal cell walls, has been widely used as a clinical marker of the state of inflammation, since its production by hepatocytes increases during the acute phase of the inflammatory response. Recent investigations have provided two new concepts for the research field of CRP, namely, its extra-hepatic production and its potent biological activities such as the induction of adhesion molecules and chemokines. Recently, we demonstrated that smooth muscle cells and macrophages in coronary arteries expressed CRP protein and mRNA, as evaluated using coronary specimens of coronary artery disease (CAD) patients obtained by atherectomy. The expression of vascular CRP was closely associated with NAD(P)H oxidase, an important enzymatic origin of reactive oxygen species (ROS) in vessel walls. Furthermore, CRP directly up-regulated NAD(P)H oxidase p22phox and enhanced ROS generation in cultured coronary artery smooth muscle cells. Thus, vascular CRP is likely to be a direct participant in vascular inflammation and lesion formation via its potent biological effects. Since lysophosphatidylcholine, a major atherogenic lipid of oxidized LDL, was reported to activate vascular NAD(P)H oxidase, we speculate that there is a vicious circle consisting of vascular NAD(P)H oxidase, ROS and oxidized LDL. Since phagocytic NAD(P)H oxidase is at the first line of the host defense system, it is important to selectively suppress vascular NAD(P)H oxidase in the localized inflammatory lesions in therapeutic strategies for CAD. In this review, we will discuss the roles of vascular CRP and NAD(P)H oxidase in the pathogenesis of CAD from the viewpoint of oxidative stress.

Atrial fibrillation (AF) is the most common clinically encountered arrhythmia affecting 0.4% of the general population. Its prevalence increases with age, affecting more than 6% of people over 80 years of age. The annual risk of ischemic stroke in patients with lone AF is approximately 1.3%. This annual risk increases up to 10% -12% in patients with a prior stroke or transient ischemic attack. Randomized clinical trials (RCT) comparing adjusted-dose oral anticoagulation and placebo showed a risk reduction of 61% (95% CI 47% to 71%). The absolute risk reduction for stroke with oral anticoagulants is about 3% per year. Aspirin has been shown in meta-analyses to have on average a 20-25% relative risk reduction, and is inferior to oral anticoagulants. In high risk patients with AF warfarin is a class I ACC/AHA indication unless there is a contraindication for anticoagulation. Unfortunately, this therapy requires frequent monitoring with blood samples and the interaction with food and several medications makes its use difficult and sometimes unreliable. It requires strict patient compliance and its use is also linked to potentially serious bleeding complications. In clinical practice, less than 60% of patients who do not have contraindications to oral anticoagulation are actually receiving them. Additionally, of those that receive oral anticoagulation, less than 50% are consistently within therapeutic targets. As such, the “real world” efficacy of a strategy towards prescribing oral anticoagulants is likely significantly lower than that demonstrated in clinical trials. As such, the need to discover other methods of anticoagulation with oral bioavailability, predictable pharmacokinetics, and minimal interactions with diet and other pharmacological agents is imperative. In high risk patients with AF warfarin is a class I ACC/AHA indication unless there is a contraindication for anticoagulation. Unfortunately, this therapy requires frequent monitoring with blood samples and the interaction with food and several medications makes its use difficult and sometimes unreliable. It requires strict patient compliance and its use is also linked to potentially serious bleeding complications. In clinical practice, less than 60% of patients who do not have contraindications to oral anticoagulation are actually receiving them. Additionally, of those that receive oral anticoagulation, less than 50% are consistently within therapeutic targets. As such, the “real world” efficacy of a strategy towards prescribing oral anticoagulants is likely significantly lower than that demonstrated in clinical trials. As such, the need to discover other methods of anticoagulation with oral bioavailability, predictable pharmacokinetics, and minimal interactions with diet and other pharmacological agents is imperative. Low molecular weight heparin has a more predictable bioavailability and a longer half-life, but its subcutaneous mode of administration and long-term risks, in particular, osteoporosis makes the chronic use of this medication non-feasible. An-tiplatelet agents such as clopidogrel have proven efficacy and superiority compared to aspirin to prevent systemic vascular events in at-risk patient populations, but currently they do not play an important role in the prevention of AF related thromboembolic events. The ACTIVE study is a randomized trial comparing the combination of clopidogrel and aspirin therapy to oral anticoagulation with warfarin in patients with AF, and was unfortunately terminated prematurely by the data safety and monitoring board because of increased events in the antiplatelet arm. Direct thrombin inhibitors, such as ximelagatran, may be as effective as warfarin for stroke-risk reduction in patients with AF. No anticoagulation monitoring is needed and it has excellent bioavailability, with a twice-daily oral dose. Elevation of liver enzymes was an initial concern regarding the use of this new drug, which is not available for general use. Ongoing pharmacological research and future clinical trials may one day leave the “warfarin days” behind. Unfortunately, the new therapies that are being tested seem to be at least several years away from being available on a widespread basis. In this review, we discuss the underlying pathophysiology of AF and stroke. We also provide a comprehensive discussion regarding various available therapies to treat AF.

The introduction of stents to clinical practice was the major breakthrough in the field of percutaneous coronary intervention. The introduction of stents was associated with two serious complications, the first was increase in subacute thrombosis within the first 30 days of stent implantation later controlled with the use of high pressure inflation and dual antiplatelet therapy, the second was the phenomenon of in-stent restenosis that was primarily caused by smooth muscle proliferation. While coronary stenting eliminates elastic recoil, it is unable to inhibit excessive neointimal formation. Stents were associated with an increase of neointimal formation compared to balloon angioplasty as a result of excessive injury to the vessel wall and the inflammatory process from interaction of metal with vessel wall. Local delivery of the potential agents for inhibition of neointimal formation to the site of the lesion was considered the desired approach. Several compounds have been tested for stent coating, primarily with the aim of the inhibition of SMC proliferation. Recently, new stents have emerged which are loaded with anti-inflammatory, anti-migratory, anti-proliferative or pro-healing drugs. In this review article the results of clinical studies investigating drug-eluting stents are discussed from pharmacological and clinical points of view, reviewing the current literature and the future prospective.

Beta-blockers have been used to treat ischemic heart disease, due to negative chronotropic and inotropic properties, thus inducing a decrease in myocardial consumption of oxygen and nutrients, allowing a better balance between nutritional needs and the supply provided by the coronary blood flow. Recent developments in cell biology allowed us to understand that not all beta-blockers are equal, as their intracellular mechanisms of action can be very different. This paper will focus on carvedilol, a non-selective beta-blocker with alfa-blocker properties, currently used to treat hypertension, heart failure and coronary artery disease. Effects of carvedilol on cardiac mitochondria, their relation to its antioxidant properties, and how these can improve cardiomyocyte resistance to aggression and cardiac function will be discussed. We will begin by depicting the effect of carvedilol on mitochondrial parameters, namely oxidative phosphorylation, calcium homeostasis and energy production. Then we will focus on the mitochondrial permeability transition (MPT) and how the antioxidant properties of carvedilol can be used to minimize oxidative stress, a powerful inducer of MPT. Carvedilol will also be highlighted as an enzyme modulator, focusing on its importance to prevent doxorubicin (DOX) cardiotoxicity. The mitochondrial-related mechanism of cardioprotection involving carvedilol will also be addressed, as we will discuss some clinical pieces of evidence showing the importance of mechanisms previously depicted. In conclusion, based upon its molecular mechanisms of action, carvedilol seems to be a unique beta-blocker. These unique characteristics can help us understand the positive impact of carvedilol on the prognosis of patients with heart disease.

Lipoprotein(a) (Lp(a)) is of interest to both basic researchers who endeavour to understand the mechanism of action of this unique lipoprotein, as well as to clinicians who are interested in the contribution of Lp(a) to cardiovascular risk profiles. The Lp(a) particle contains a moiety that is indistinguishable from circulating LDL, covalently linked to the unique glycoprotein component apolipoprotein(a) (apo(a)). Since the 1970s, epidemiological data have been accumulated that, on balance, indicate that elevated plasma Lp(a) concentrations are an independent risk factor for vascular diseases. Apo(a) is highly homologous to the fibrinolytic proenzyme plasminogen, containing many tandemly-repeated kringle motifs similar to several of those found in the plasminogen molecule; the size of the kringle domain in apo(a) gives rise to Lp(a) isoform size heterogeneity which is a hallmark of this lipoprotein. The similarity between Lp(a) and plasminogen led to speculation of a bridging role for Lp(a) in atherothrombotic disease based on the duality of the structure of this lipoprotein. In this scenario, LDL would contribute to the proatherosclerotic properties of the particle, while apo(a) would interfere with the normal fibrinolytic functions of plasminogen, thereby inhibiting the breakdown of thrombi formed in the vasculature. Many in vitro and in vivo studies have suggested a prothrombotic role for Lp(a) which is attributable to the apo(a) component of the particle. However, there are a number of unique properties that apo(a) confers to Lp(a) which are independent of its similarity to plasminogen. These include the ability of apo(a)/Lp(a) to affect platelet function, to contribute to endothelial dysfunction, and to inhibit the clearance of chylomicron remnant particles in a transgenic mouse model. Very recent data have revealed a potential role for Lp(a) in the preferential binding of oxidized phospholipid adducts through one of the kringle motifs in apo(a). Many questions remain to be answered regarding the role of Lp(a) in atherothrombotic disease. This article will review the relevant literature concerning the contribution of Lp(a) to risk for both atherosclerotic and purely thrombotic disorders, as well as the proposed mechanisms of Lp(a) pathogenicity related to the structure of this lipoprotein. Emerging areas of interest in the field including the role of apo(a) isoform size as a risk factor for CHD - independent of Lp(a) levels - will also be discussed, as will speculation as to the possible physiological role of Lp(a). Future directions in the field as well as recommendations for the use of Lp(a) in clinical contexts will also be addressed.

Atherosclerosis is a chronic inflammatory process. The adhesion of leukocytes to the vascular endothelium, mediated by endothelial cell adhesion molecules including vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin, is the pivotal early event in atherogenesis. Inflammatory cytokines could activate redox-sensitive transcription factors and induce endothelial expression of adhesion molecules, which could be inhibited to various degrees by different antioxidants suggesting the potential role of endogenous reactive oxygen species (ROS) in atherogenesis. Many clinical drugs that against cardiovascular diseases have exhibited antioxidant effects; these drugs simultaneously inhibit endothelial adhesion molecule expression, such as aspirin, probucol, HMG-CoA reductase inhibitors, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, peroxisome proliferator-activated receptor α and γ ligands, calcium channel blockers, β-adrenergic blockers, etc. In addition, we have previously demonstrated that Ginkgo biloba extract, a Chinese herb with antioxidant activity, could significantly suppress inflammatory cytokine-stimulated endothelial adhesiveness to human monocytic cells by attenuating intracellular ROS formation, redox-senstive transcription factor activation, and VCAM-1 as well as ICAM-1 expression in human aortic endothelial cells. The similar anti-atherosclerosis effects have been also shown in other Chinese herbs or dietary supplements with antioxidant activity such as magnolol and salvianolic acid B either in vitro or in vivo. Thus, oxidative stress is critical to endothelial adhesiveness in atherogenesis. The inhibition of endothelial adhesion molecule expression by drugs/agents with antioxidant activity may serve as a potential therapeutic strategy for clinical atherosclerosis.