Current Medicinal Chemistry – Cardiovascular & Hematological Agents, Vol. 3, No. 3, 2005
Contents
Glycoprotein IIb/IIIa
Inhibitors in Patients Undergoing Percutaneous Mechanical Intervention for
Acute Myocardial Infarction Pp.173-179
David Antoniucci
The Pharmacologic
Approach to the Prevention of Preeclampsia: From Antiplatelet, Antithrombosis
and Antioxidant Therapy to Anticonvulsants Pp.181-185
J. Bar, A.
Ben-Haroush, D. Feldberg and M. Hod
Risk Stratification of
Dyslipidemia: Insights from the Framingham Study Pp.187-193
W.B. Kannel
Pleiotropic Effects of
3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors: Candidate
Mechanisms for Anti-Lipid Deposition in Blood Vessels Pp.195-201
T. Kumai, N.
Matsumoto, Y. Koitabashi, Y. Takeba, S. Oonuma, S. Sekine, M. Tadokoro and S.
Kobayashi
Aspirin and
Clopidogrel: A Sweeping Combination in Cardiology Pp.203-219
Antonis S. Manolis,
Stylianos Tzeis, George Andrikopoulos, Spyros Koulouris and Helen Melita
Stent-Based Delivered
Anti-Proliferative Drugs in the Prevention of Coronary Stent Restenosis
Pp.221-229
Raúl Moreno and Carlos
Macaya
Cardiac
Adrenomedullin: Its Role in Cardiac Hypertrophy and Heart Failure
Pp.231-242
Toshio Nishikimi and
Hiroaki Matsuoka
Anti-Inflammatory and
Anti-Apoptotic Effects of Levosimendan in Decompensated Heart Failure: A Novel
Mechanism of Drug-Induced Improvement in Contractile Performance of the Failing
Heart Pp.243-247
Ioannis A.
Paraskevaidis, John T. Parissis and Dimitios Th Kremastinos
Snake Venom
Metalloproteinase Containing a Disintegrin-like Domain, its Structure-activity
Relationships at Interacting with Integrins Pp.249-260
X. Lu, D. Lu, M.F. Scully and V.V. Kakkar
Role of Cardiovascular
Aldosterone in Hypertension Pp.261-266
Yoshiyu Takeda
Influence of Impaired Liver
Methionine Metabolism on the Development of Vascular Disease and Inflammation
Pp.267-281
M.A. Avila, C. Berasain, J. Prieto, J.M. Mato, E.R. Garcia-Trevijano and F.J. Corrales
Abstracts
[Back
to top] Glycoprotein IIb/IIIa Inhibitors in Patients
Undergoing Percutaneous Mechanical Intervention for Acute Myocardial Infarction
David Antoniucci
Limitations in study designs and adoption of rigid criteria for randomization in clinical trials on acute myocardial infarction (AMI) may result in the enrolment of artificial populations, and subsequent trial results may be misleading in many ways rendering problematic the generalization of the trial results to a “real world population” of AMI. Furthermore, the “frequentist” approach in study designs with inclusion of thousands of low-risk patients and high statistical inference have produced inconclusive or negative results despite the high potential for a strong impact on outcome of the study drug, or device, or strategy.
The investigative approaches to the use of IIb/IIIa inhibitors as adjunctive treatment to primary coronary intervention (PCI) for AMI are a clear instance of this crucial problem in the evidence-based medicine era. Five concluded randomized trials comparing abciximab with placebo in patients undergoing primary PCI for AMI have produced different and conflicting results with a broad spectrum of possibilities. No benefit of the drug in patients receiving infarct artery stenting, benefit of the drug only in patients undergoing conventional balloon angioplasty with provisional stenting and limited to the early phase, and mainly driven by the decrease in the need for urgent target vessel revascularization, benefit in terms of decreased mortality, reinfarction and target vessel revascularization at 1-month but not maintained at 6 months, long-term benefit in the composite of death, reinfarction and target vessel revascularization, improved early and late outcome including long-term survival. This review of the trials of abciximab and other IIb/IIIa inhibitors in patients undergoing PCI for AMI tries to put the studies and their results into a proper perspective for the correct use of adjunctive IIb/IIIa inhibitor use in patients with AMI.
[Back
to top] The Pharmacologic Approach to the Prevention
of Preeclampsia: From Antiplatelet, Antithrombosis and Antioxidant Therapy to Anticonvulsants
J.
Bar, A. Ben-Haroush, D. Feldberg and M. Hod
Preeclampsia has been suggested to be a two-stage disorder of an alteration in placental perfusion (stage 1) leading to generalized vascular endothelial damage (stage 2). Because the mechanism linking the two stages remains unclear, effective primary prevention is still impossible. However, advances made in our understanding of the pathophysiology of preeclampsia have paved the way for secondary and tertiary prevention approaches.
Platelets are known to be activated in early pregnancy. They also play a pivotal role in the process of inflammation, as demonstrated by the finding that CD40 ligand is shed from activated platelets to directly initiate inflammation of the vessel wall. According to the Cochrane Library Update summarizing data from over 30,000 women, secondary prevention with antiplatelet drugs is associated with a 19% decrease in the risk of preeclampsia.
Additional randomized controlled trials are needed to establish the association between preeclampsia and thrombophilia. The effect of the antithrombotic agent heparin on pregnancy outcome in preeclampsia and its potential preventive action in high-risk patients need to be elucidated.
One of the several hypotheses of the pathogenesis of preeclampsia focuses on the oxidative stress caused by the imbalance in prooxidant and antioxidant forces. Preliminary findings on vitamin E and vitamin C supplementation in preeclamptic women are encouraging, and suggest a rationale for larger clinical trials.
Although there is currently no explanation for the positive effect of magnesium sulfate on eclamptic seizures, studies have provided enough evidence to encourage its worldwide use as the primary anticonvulsant of choice in the tertiary prevention of maternal and perinatal death in severe preeclampsia/eclampsia.
In conclusion, secondary and tertiary prevention of preeclampsia is possible when targeted at reducing maternal and neonatal morbidity and mortality.
[Back
to top] Risk Stratification of Dyslipidemia: Insights
from the Framingham Study
W.B. Kannel
Dyslipidemia, fundamental to the atherosclerotic process, is now a readily correctable risk factor with established efficacy of treatment for reducing risk of CHD and strokes. The current focus on LDL-cholesterol for risk assessment needs to be broadened to accommodate the two-way traffic of cholesterol entering and leaving the arterial intima reflected by the LDL/HDL ratio or the Total/HDL ratio. The choice of lipid therapy should be individualized to take into account the presence of the metabolic syndrome and the lipid profile of the patient. The intensity of therapy and goals should be linked to multivariable risk, particularly in those with modest lipid values. Cardiovascular risk factor clustering is pronounced for each lipid, is promoted by adiposity and greatly influences its CHD hazard. Global risk assessment taking clustering into account is essential for efficient preventive management of lipids. More attention needs to be afforded the absolute risk reduction attainable and must recognize that the number needed to treat to prevent one event increases the lower the lipid value, the lower global risk and the healthier the subject.
[Back
to top] Pleiotropic Effects of
3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors: Candidate
Mechanisms for Anti-Lipid Deposition in Blood Vessels
T.
Kumai, N. Matsumoto, Y. Koitabashi, Y. Takeba, S. Oonuma, S. Sekine, M.
Tadokoro and S. Kobayashi
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are considered first-line therapeutic agents for the prevention of coronary heart disease and atherosclerotic disorders related to hypercholesterolemia. Statins inhibit lipid deposition in the aortic endothelium. Although it has been accepted that the statins are potent inhibitors of cholesterol biosynthesis in the liver and that they lower circulating cholesterol levels, several cholesterol-independent (pleiotropic) effects have been reported. The cholesterol-independent effects of statins involve normalization of the nitric oxide (NO)-NO synthase system, anti-inflammatory effects through the inhibition of cytokine/chemokine production, inhibition of vascular smooth muscle cell proliferation and migration, and inhibition of platelet thrombus formation/reduction of the thrombotic response. Some pleiotropic effects of statins may depend on the inhibition of the biosynthesis of farnesyl- and geranylgeranyl-nonsterol compounds from mevalonate in the cells. The Rho/Rho kinase pathway and the phospatidylinositol-3 kinase/Akt pathway mediate the pleiotropic effects of statins. As variations occur in absorption, metabolism, and excretion mechanisms due to the characteristics of specific statins including their hydrophilicity and lipophilicity, there are differences in the transfer mechanisms of statins into tissues. However, the pleiotropic effects occur regardless of statin hydrophilicity and lipophilicity. This review summarizes the pleiotropic effects of statins on lipid deposition in blood vessels.
[Back
to top] Aspirin and Clopidogrel: A Sweeping
Combination in Cardiology
Antonis
S. Manolis, Stylianos Tzeis, George Andrikopoulos, Spyros Koulouris and Helen
Melita
Platelets play a pivotal role in the pathogenesis of atherothrombosis, believed to be integrally involved in both the development and progression of atherosclerotic heart disease, as well as in its acute thrombotic complications. Antiplatelet therapy constitutes the cornerstone in the management of patients with acute coronary syndromes and generally high-risk patients with atherothrombosis. Until recently, long-term antiplatelet therapy for the treatment and prevention of the complications of atherothrombotic disease was traditionally limited to aspirin. The availability of the thienopyridines, in particular clopidogrel, represents an important addition to the physician's armamentarium. Clopidogrel is currently one of the most widely prescribed drugs for the treatment of symptomatic coronary artery disease. Aspirin and clopidogrel interfere with platelet activation in complementary, but separate pathways. Aspirin irreversibly inhibits cyclooxygenase, thus preventing the production of thromboxane A2, which is a prothrombotic and vasoconstrictive substance. Clopidogrel, a newer thienopyridine which has largely supplanted ticlopidine due to a more favorable safety profile, irreversibly prevents platelet activation by blocking one of the three known adenosine 5'-diphosphate (ADP) receptors (the P2Y12 receptor) on the platelet surface, thus interfering with platelet activation, degranulation and aggregation. Both these antiplatelet agents have a potent protective effect against adverse vascular events, but the combination of these two agents has an even stronger antiplatelet effect translating into superior antithrombotic protection in coronary, cerebral or peripheral arterial disease, without an inordinate increase in bleeding complications.
A number of seminal clinical trials have demonstrated and confirmed the incremental benefit and efficacy of the combination of clopidogrel and aspirin therapy above and beyond that of aspirin alone, with multiple other important large-scale clinical trials currently ongoing. Newer data are being accumulated from studies where indications for the use of clopidogrel and aspirin continue to expand into other patient groups, rendering this dual antiplatelet drug therapy a sweeping combination in Cardiology. However, important issues remain to be further and more thoroughly explored about the benefit of this antiplatelet drug combination in these other patient groups, such as in patients with heart failure, where preliminary data indicate a favorable effect on thrombotic vascular events, in patients with atrial fibrillation, where there is hope that this combination may replace or be an alternative treatment modality to coumadin in certain subpopulations, in patients undergoing demanding catheter ablation procedures, where data point to a protective effect from thromboembolic events. Another pertaining issue to be further investigated is the occurrence of drug-resistance observed in some patients for both these antithrombotic agents. This article is a comprehensive review of all these data and the landmark trials on the two antiplatelet agents, the issues involved and the current recommendations for their use in patients with atherosclerotic heart disease and other cardiovascular disorders and procedures.
[Back
to top] Stent-Based Delivered Anti-Proliferative Drugs
in the Prevention of Coronary Stent Restenosis
Raúl Moreno and Carlos Macaya
Coronary stents are currently used in most percutaneous coronary interventions, since they have demonstrated to reduce restenosis and allow to solve threatened closure after balloon angioplasty. Despite these beneficial effects, restenosis remains as the main limitation of percutane ous coronary interventions even with the use of coronary stents. In the last 3 years, some coronary stents eluting anti-proliferative drugs have demonstrated to dramatically reduce the risk of restenosis. By November 2004, two different types of antiproliferative drugs eluted by coronary stents are commercially available: sirolimus (rapamycin) and paclitaxel. The mechanisms, clinical evidence, as well as the remaining limitations of these drug-eluting stents are reviewed. The current knowledge of other anti-proliferative drugs that are currently under investigation is also reviewed.
[Back
to top] Cardiac Adrenomedullin: Its Role in Cardiac
Hypertrophy and Heart Failure
Toshio
Nishikimi and Hiroaki Matsuoka
Co-localization of adrenomedullin (AM) and its receptor components such as calcitonin receptor like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in peripheral tissues, including the heart, kidney, and vasculature, suggests an important role for the peptide as a regulator of cardiovascular function. Indeed, we previously reported that AM gene expression and / or immunoreactivity are increased in the ventricles of cardiac hypertrophy and heart failure. Recently, we also found that not only levels of AM peptide and AM gene expression, but also mRNA levels of CRLR, RAMP2 and RAMP3 are increased in cardiac hypertrophy and failing heart. Cardiac myocytes and fibroblast produce and secrete two molecular forms of AM and express CRLR, RAMP2 and RAMP3, and AM is known to have inhibitory effect of collagen synthesis and antiproliferative effect in cardiac fibroblasts. Stimulation by IL-1ß significantly increased gene expression of AM and its receptor components in cardiac fibroblasts. Preincubated IL-1ß elevated the intracellular cAMP response to exogenous administered AM. AM antisense oligodeoxynucleotide treatment significantly lowered AM levels in cultured medium. IL-1ß significantly increased 3H-proline incorporation and AM antisense oligodeoxynucleotide treatment further increased 3H-proline incorporation. Collectively, these results support a protective role for increased AM in the cardiac hypertrophy and heart failure. Then, we tested the effects of acute administration of AM in experimental and human heart failure, because AM has hemodynamic effects including vasodilation, increases in cardiac contractility, cardiac output, diuresis, and natriuresis. We observed profound and sustained cardiovascular, hormonal and renal effects. These effects may incorporate many of the therapeutic goals of heart failure management.
[Back
to top] Anti-Inflammatory and Anti-Apoptotic Effects
of Levosimendan in Decompensated Heart Failure: A Novel Mechanism of
Drug-Induced Improvement in Contractile Performance of the Failing Heart
Ioannis A. Paraskevaidis, John T. Parissis and Dimitios Th Kremastinos
Recent experimental and clinical observations indicate that over-expression of pro-inflammatory cytokines is actively implicated to chronic heart failure progression through their cytotoxic and negative inotropic effects. Calcium-sensitizing agents, such as levosimendan, promotes inotropy by stabilizing troponin C in a configuration that enhances the calcium sensitivity of cardiac myofilaments, preserving also diastolic relaxation. Levosimendan also opens ATP-dependent potassium channels in peripheral vessels, leading to vasodilatation. Large scale randomized clinical trials have shown that levosimendan administration in patients with severe heart failure due to left ventricular systolic dysfunction results in favorable hemodynamic changes, symptomatic benefit, and a reduction in short-term morbidity and mortality. This review describes current knowledge about novel cellular mechanisms associated with beneficial effects of levosimendan on cardiac contractile performance, focusing mainly on its immunomodulatory and anti-apoptotic properties. Levosimendan-induced improvement in contractile reserve and clinical status of severe heart failure patients, seems to be related with the reduction of major pro-inflammatory cytokines (TNF-a, IL-6) and soluble apoptosis signaling molecules Fas/Fas Ligand. Modulation of pro-inflammatory and pro-apoptotic pathways into the failing heart by levosimendan may be an additional pathophysiologic mechanism that prevents further clinical and hemodynamic consequences of abnormal immune responses in decompensated heart failure and beneficially affects the progression of the syndrome.
[Back
to top] Snake Venom Metalloproteinase Containing a Disintegrin-like Domain,
its Structure-activity Relationships at Interacting with Integrins
X. Lu, D. Lu, M.F. Scully and V.V. Kakkar
Snake venom disintegrins represent a family of RGD (Arg-Gly-Asp) or KGD (Lys-Gly-Asp)-containing proteins which have been reported to be unique and potentially useful tools not only for investigating integrin-ligand interactions, but also for the development of anti-thrombotic agents in terms of their anti-platelet activities. Snake venom proteins containing a disintegrin-like domain represent another super-family of proteins in which many of them have been demonstrated to have similar ability to inhibit platelet aggregation and integrin-mediated cell adhesion as the disintegrins. This super-family includes a large number of snake venom metalloproteinases and disintegrin related, RGD-containing snake venom proteins (disintegrin-like proteins) such as dendroaspin. Recently, a family of homologues of the snake venom metalloproteinases have been found in a wide variety of mammalian tissues as well as in other eukaryotic organisms termed ADAM (a disintegrin-like and metalloproteinase) proteins. ADAMs are members of the metazincins that also include the related matrix metalloprotease (MMPs). Some of ADAM proteins have now shown to interact with integrins, and the disintegrin-like domain may be crucial part in their function as proteases. A description of structure-activity relationships of snake venom proteins containing a disintegrin-like domain is outlined in this review, along with reports of the modulation of protein activity by recombinant mutation. Comparison is also made of the structural and functional features of the metalloproteinases in snakes compared with those from other species. The review is intended to provide insights in which may assist the development of new therapeutic approaches.
[Back
to top] Role of Cardiovascular Aldosterone in Hypertension
Yoshiyu Takeda
Aldosterone plays an important role in the pathogenesis of cardiovascular disease. We have reported that aldosterone is synthesized in cardiovascular tissues and local aldosterone synthesis plays important roles for hypertension and cardiac hypertrophy. High sodium intake develops and accelerates vascular injury and cardiac hypertrophy in SHRSP. Plasma aldosterone concentrations and PRA were decreased by high salt intake in SHRSP. Aldosterone production, the expression of CYP11B2 mRNA and angiotensin II receptor AT1R mRNA in blood vessels were significantly increased by high salt intake. These results suggest that high salt intake increases aldosterone production and expression of the AT1R mRNA in the vascular tissue in SHRSP, which may contribute to the development of malignant hypertension in salt-loaded SHRSP. However, there are several reports of conflicting data. Mineralocorticoid receptor (MR) binding is tightly regulated by the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) which selectively metabolizes glucocorticoids to inactive metabolites, thus allowing for MR activation by aldosterone. We have reported that decreased 11ß-HSD2 in blood vessels in Dahl salt-sensitive (DS) rats, a model for salt-sensitive hypertension. Local aldosterone excess may play a significant role in the salt sensitivity and development of hypertension. High sodium intake decreased circulating rennin-angiotensin-aldosterone system and increased blood pressure and cardiac hypertrophy in DS rats, which were prevented by the treatment with a selective MR antagonist, eplerenone. Eplerenone also improved endothelial nitric oxide synthase (eNOS) activity and eNOS mRNA expression in blood vessels in DS rats. These results further suggest that not only circulating aldosterone but also local aldosterone is of critical importance in the pathophysiology of cardiovascular disorders.
[Back
to top] Influence of Impaired Liver Methionine Metabolism on the
Development of Vascular Disease and Inflammation
M.A. Avila, C. Berasain, J. Prieto, J.M. Mato, E.R. Garcia-Trevijano and F.J. Corrales
Methionine (Met) metabolism involves the sequential formation of S-adenosylmethionine (SAM, the main biological methyl donor), S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hcy can be remethylated to Met or catabolized through the trans-sulfuration pathway. In mammals, as much as 48% of Met metabolism and up to 85% of all transmethylation reactions occur in the liver. These figures underscore the central role played by this organ in Met metabolism. Maintaining the homeostasis of this metabolic cycle has proved to be essential for the preservation of liver function up to the point of preventing its neoplastic transformation. However, an adequate hepatic metabolism of Met is not only important for the liver parenchymal cell. Evidence has accumulated over the past few years supporting the involvement of Met-derived metabolites in the triggering or attenuation of pathological processes with systemic implications. This is best illustrated by the fact that a deteriorated liver function has emerged as a major factor in the development of hyperhomocysteinemia. Elevated plasma levels of Hcy have been related to several disorders including cardiovascular and cerebrovascular diseases. On the other end, liver damage also leads to deficient SAM synthesis. Among the consequences of impaired SAM synthesis in liver tissue are the enhanced production of pro-inflammatory cytokines and mediators. In this review, we will address the mechanisms and consequences of abnormal Met metabolism in liver injury, the systemic implications of such impairment and finally the potential therapeutic interventions.