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Statins exert a number of beneficial effects on endothelial function and atherosclerotic plaque, modulating oxidative stress and inflammation, with subsequent, well documented, primary and secondary prevention of coronary artery disease. Periprocedural myocardial infarction and contrast induced nephropathy, after percutaneous coronary intervention (PCI), are associated with a worse outcome on long term follow-up. In the ARMYDA study, pretreatment with statins before elective PCI reduces periprocedural myocardial infarction in patients with stable angina. Moreover, the ARMYDA ACS was the first randomized, prospective trial that demonstrated that an acute loading with a high dose of atorvastatin prevents myocardial damage in patients with unstable syndromes undergoing early (<48 hours) coronary angiography and consequent angioplasty. Statins could also have beneficial effects by reducing expression of adhesion molecules in endothelial cells (ICAM-1 and E-Selectin) as demonstrated in the ARMYDA-CAMS study. Furthermore, patients receiving statins at the time of procedure show a significantly reduced incidence of contrast-induced nephropathy. All this evidence may strongly influence the clinical practice of an interventional cardiologist.
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PMID:Percutaneous coronary interventions and statins therapy. 1912 13

Myocardial infarction and stroke are caused by blood clots forming over a ruptured or denuded atherosclerotic plaque (atherothrombosis). Production of prostaglandin E(2) (PGE(2)) by an inflamed plaque exacerbates atherothrombosis and may limit the effectiveness of current therapeutics. Platelets express multiple G-protein coupled receptors, including receptors for ADP and PGE(2). ADP can mobilize Ca(2+) and through the P(2)Y(12) receptor can inhibit cAMP production, causing platelet activation and aggregation. Clopidogrel (Plavix), a selective P(2)Y(12) antagonist, prevents platelets from clotting but thereby increases the risk of severe or fatal bleeding. The platelet EP(3) receptor for PGE(2), like the P(2)Y(12) receptor, also inhibits cAMP synthesis. However, unlike ADP, facilitation of platelet aggregation via the PGE(2)/EP(3) pathway is dependent on co-agonists that can mobilize Ca(2+). We used a ligand-based design strategy to develop peri-substituted bicylic acylsulfonamides as potent and selective EP(3) antagonists. We show that DG-041, a selective EP(3) antagonist, inhibits PGE(2) facilitation of platelet aggregation in vitro and ex vivo. PGE(2) can resensitize platelets to agonist even when the P(2)Y(12) receptor has been blocked by clopidogrel, and this can be inhibited by DG-041. Unlike clopidogrel, DG-041 does not affect bleeding time in rats, nor is bleeding time further increased when DG-041 is co-administered with clopidogrel. This indicates that EP(3) antagonists potentially have a superior safety profile compared to P(2)Y(12) antagonists and represent a novel class of antiplatelet agents.
ACS Chem Biol 2009 Feb 20
PMID:Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding. 1919 56

Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying cerebral amyloidoses. Here we report the chemical design of pentameric thiophene derivatives, denoted luminescent conjugated oligothiophenes (LCOs), which could be used for real-time visualization of cerebral protein aggregates in transgenic mouse models of neurodegenerative diseases by multiphoton microscopy. One of the LCOs, p-FTAA, could be utilized for ex vivo spectral assignment of distinct prion deposits from two mouse-adapted prion strains. p-FTAA also revealed staining of transient soluble pre-fibrillar non-thioflavinophilic Abeta-assemblies during in vitro fibrillation of Abeta peptides. In brain tissue samples, Abeta deposits and neurofibrillary tangles (NFTs) were readily identified by a strong fluorescence from p-FTAA and the LCO staining showed complete co-localization with conventional antibodies (6E10 and AT8). In addition, a patchy islet-like staining of individual Abeta plaque was unveiled by the anti-oligomer A11 antibody during co-staining with p-FTAA. The major hallmarks of Alzheimer's disease, namely, Abeta aggregates versus NFTs, could also be distinguished because of distinct emission spectra from p-FTAA. Overall, we demonstrate that LCOs can be utilized as powerful practical research tools for studying protein aggregation diseases and facilitate the study of amyloid origin, evolution and maturation, Abeta-tau interactions, and pathogenesis both ex vivo and in vivo.
ACS Chem Biol 2009 Aug 21
PMID:Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses. 1962 97

Nanomedicine approaches to atherosclerotic disease will have significant impact on the practice and outcomes of cardiovascular medicine. Iron oxide nanoparticles have been extensively used for nontargeted and targeted imaging applications based upon highly sensitive T2* imaging properties, which typically result in negative contrast effects that can only be imaged 24 or more hours after systemic administration due to persistent blood pool interference. Although recent advances involving MR pulse sequences have converted these dark contrast voxels into bright ones, the marked delays in imaging from persistent magnetic background interference and prominent dipole blooming effects of the magnetic susceptibility remain barriers to overcome. We report a T1-weighted (T1w) theranostic colloidal iron oxide nanoparticle platform, CION, which is achieved by entrapping oleate-coated magnetite particles within a cross-linked phospholipid nanoemulsion. Contrary to expectations, this formulation decreased T2 effects thus allowing positive T1w contrast detection down to low nanomolar concentrations. CION, a vascular constrained nanoplatform administered in vivo permitted T1w molecular imaging 1 h after treatment without blood pool interference, although some T2 shortening effects on blood, induced by the superparamagnetic particles, persisted. Moreover, CION was shown to encapsulate antiangiogenic drugs, like fumagillin, and retained them under prolonged dissolution, suggesting significant theranostic functionality. Overall, CION is a platform technology, developed with generally recognized as safe components, that overcomes the temporal and spatial imaging challenges associated with current iron oxide nanoparticle T2 imaging agents and which has theranostic potential in vascular diseases for detecting unstable ruptured plaque or treating atherosclerotic angiogenesis.
ACS Nano 2009 Dec 22
PMID:Conquering the dark side: colloidal iron oxide nanoparticles. 1990 50

To investigate whether pregnancy-associated plasma protein-A (PAPP-A) is a prognostic marker in patients admitted with high-risk acute coronary syndrome. In patients admitted with high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and ST-segment elevation myocardial infarction (STEMI), risk stratification is primarily determined by the markers of myocardial necrosis and known demographic risk profiles. However, it has recently been proposed that the presence and extent of vulnerable plaques might influence the prognosis significantly. A marker for the vulnerable plaque could identify patients at high risk who would potentially benefit from intensive treatment and surveillance. Two populations of consecutive patients admitted with high-risk NSTE-ACS (n = 123) and STEMI (n = 314) were evaluated with serial measurements of PAPP-A. The incidence of mortality and nonfatal myocardial infarction was prospectively registered for 2.66 to 3.47 years. In the patients with high-risk NSTE-ACS, PAPP-A was related to the risk of nonfatal myocardial infarction (p = 0.02) and death (p = 0.03). This result was consistent on multivariate analysis of the combination of mortality or nonfatal myocardial infarction (odds ratio 2.65, 95% confidence interval 1.40 to 5.03) but not for mortality alone (p = NS). In patients with STEMI, PAPP-A was related to the risk of death (p = 0.01) but not the composite outcome of myocardial infarction and death. This was also true after adjustment for other univariate predictors of death (odds ratio 2.19, 95% confidence interval 1.16 to 4.16). In conclusion, PAPP-A seems to be valuable in predicting the outcomes of patients admitted with high-risk NSTE-ACS or STEMI.
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PMID:Usefulness of pregnancy-associated plasma protein A in patients with acute coronary syndrome. 1993 76

DNA synthesis is catalyzed by an ensemble of proteins designated the replicase. The efficient assembly of this multiprotein complex is essential for the continuity of DNA replication and is mediated by clamp-loading accessory proteins that use ATP binding and hydrolysis to coordinate these events. As a consequence, the ability to selectively inhibit the activity of these accessory proteins provides a rational approach to regulate DNA synthesis. Toward this goal, we tested the ability of several non-natural nucleotides to inhibit ATP-dependent enzymes associated with DNA replicase assembly. Kinetic and biophysical studies identified 5-nitro-indolyl-2'-deoxyribose-5'-triphosphate as a unique non-natural nucleotide capable of selectively inhibiting the bacteriophage T4 clamp loader versus the homologous enzyme from Escherichia coli. Modeling studies highlight the structural diversity between the ATP-binding site of each enzyme and provide a mechanism accounting for the differences in potencies for various substituted indolyl-2'-deoxyribose-5'-triphosphates. An in vivo assay measuring plaque formation demonstrates the efficacy and selectivity of 5-nitro-indolyl-2'-deoxyribose as a cytostatic agent against T4 bacteriophage while leaving viability of the E. coli host unaffected. This strategy provides a novel approach to develop agents that selectively inhibit ATP-dependent enzymes that are required for efficient DNA replication.
ACS Chem Biol 2010 Feb 19
PMID:Selective inhibition of DNA replicase assembly by a non-natural nucleotide: exploiting the structural diversity of ATP-binding sites. 1999 7

Oxidized low-density lipoprotein (ox-LDL) is an instrumental factor in atherogenesis, however, the effects of ox-LDL on the balance of Th17/Treg in acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)] is still unclear. CD4(+)CD25(+) regulatory T (Treg) cells and Th17 cells, subsets of T-helper cells, play important roles in peripheral immunity and their imbalance leads to the development of tissue inflammation and autoimmune diseases. However, few studies have explored the effect of Th17/Treg balance in plaque destabilization and the onset of ACS. To explore the shift of Th17/Treg balance in ACS patients and the effect of ox-LDL on the balance, we examined the frequencies of Th17 and Treg cells, key transcription factors and relevant cytokines in patients with AMI, UA, stable angina (SA) and controls. We analysed the correlations of serum ox-LDL to Th17/Treg frequency, and the effects of ox-LDL on Th17/Treg cells in vitro. Our study demonstrated that ACS patients have shown a significant increase of Th17 frequency, RORgammat expression and serum Interleukin 17 (IL-17), and a obvious decline of Treg frequency, Foxp3 expression, suppressive function, and serum IL-10. Serum ox-LDL positively correlated with the frequency of Th17 cells and negatively correlated with the frequency of Treg cells. In vitro incubation of peripheral blood mononuclear cells from controls with ox-LDL resulted in a significant reduction of Treg cells and a significant elevation of Th17 cells in a dose- and time-dependant manner. Treg and Th17 cells from ACS patients were significantly more susceptible to ox-LDL-mediated alterations. Th17/Treg numerical and functional imbalance exists in ACS patients, and ox-LDL has a direct effect on Th17/Treg imbalance which may contribute to the occurrence of ACS.
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PMID:The role of oxidized low-density lipoprotein in breaking peripheral Th17/Treg balance in patients with acute coronary syndrome. 2030 43

Recent advances in multi-detector computed tomography(MDCT) have allowed us to assess coronary artery stenosis non -invasively. Moreover, recent MDCT studies revealed the differences in the plaque morphologies of culprit lesions in patients with ACS. Delayed-enhancement MRI is now recognized as the gold standard for identification of myocardial necrosis and myocardial viability compared with other imaging modalities. Cardiac MRI also allows simultaneous direct visualization of not only myocardial necrosis by delayed-enhancement MRI but also the area at risk by T2-weighted MRI. In this paper, we reviewed the role of MDCT and MRI in evaluating patients with acute coronary syndrome.
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PMID:[Diagnostic value of cardiac CT and MRI in acute coronary syndrome]. 2038 56

Cage-like protein nanoparticles are promising platforms for cell- and tissue-specific targeted delivery of imaging and therapeutic agents. Here, we have successfully modified the 12 nm small heat shock protein from Methanococcus jannaschii (MjHsp) to detect atherosclerotic plaque lesions in a mouse model system. As macrophages are centrally involved in the initiation and progression of atherosclerosis, targeted imaging of macrophages is valuable to assess the biologic status of the blood vessel wall. LyP-1, a nine residue peptide, has been shown to target tumor-associated macrophages. Thus, LyP-1 was genetically incorporated onto the exterior surface of MjHsp, while a fluorescent molecule (Cy5.5) was conjugated on the interior cavity. This bioengineered protein cage, LyP-Hsp, exhibited enhanced affinity to macrophage in vitro. Furthermore, in vivo injection of LyP-Hsp allowed visualization of macrophage-rich murine carotid lesions by in situ and ex vivo fluorescence imaging. These results demonstrate the potential of LyP-1-conjugated protein cages as nanoscale platforms for delivery of imaging agents for the diagnosis of atherosclerosis.
ACS Nano 2011 Apr 26
PMID:Protein cage nanoparticles bearing the LyP-1 peptide for enhanced imaging of macrophage-rich vascular lesions. 2139 20

Pitavastatin is the newest member of the HMG-CoA reductase inhibitor family and is approved as adjunctive therapy to diet to reduce elevated levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein (Apo) B, and triglycerides and to increase levels of high-density lipoprotein (HDL) cholesterol in adult patients with primary hyperlipidemia or mixed dyslipidemia. Pitavastatin undergoes minimal metabolism by cytochrome P450 (CYP) enzymes and, therefore, has a low propensity for drug-drug interactions with drugs metabolized by CYP enzymes or the CYP3A4 substrate grapefruit juice. In clinical trials, pitavastatin potently and consistently reduced serum levels of total, LDL, and non-HDL cholesterol, and triglycerides in patients with primary hypercholesterolemia where diet and other non-pharmacological measures were inadequate. Mean reductions from baseline in serum total and LDL cholesterol and triglyceride levels were 21-32%, 30-45%, and 10-30%, respectively. Moreover, a consistent trend towards increased HDL cholesterol levels of 3-10% was seen. Long-term extension studies show that the beneficial effects of pitavastatin are maintained for up to 2 years. Pitavastatin produces reductions from baseline in serum total and LDL cholesterol levels to a similar extent to those seen with the potent agent atorvastatin and to a greater extent than those seen with simvastatin or pravastatin. In the majority of other studies comparing pitavastatin and atorvastatin, no significant differences in the favorable effects on lipid parameters were seen, although pitavastatin was consistently associated with trends towards increased HDL cholesterol levels. Pitavastatin also produces beneficial effects on lipids in patients with type 2 diabetes mellitus and metabolic syndrome without deleterious effects on markers of glucose metabolism, such as fasting blood glucose levels or proportion of glycosylated hemoglobin. Pitavastatin appears to exert a number of beneficial effects on patients at risk of cardiovascular events independent of lipid lowering. In the JAPAN-ACS (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome) study, pitavastatin was non-inferior to atorvastatin at reducing plaque volume in patients with ACS undergoing percutaneous coronary intervention. Further beneficial effects, including favorable effects on the size and composition of atherosclerotic plaques, improvements in cardiovascular function, and improvements in markers of inflammation, oxidative stress, and renal function, have been demonstrated in a number of small studies. Pitavastatin is generally well tolerated in hyperlipidemic patients with or without type 2 diabetes, with the most common treatment-related adverse events being musculoskeletal or gastrointestinal in nature. Increases in plasma creatine kinase levels were seen in <5% of pitavastatin recipients and the incidence of myopathy or rhabdomyolysis was extremely low. In summary, pitavastatin, the latest addition to the statin family, produces potent and consistent beneficial effects on lipids, is well tolerated, and has a favorable pharmacokinetic profile. The combination of a potent decrease in total and LDL cholesterol levels and increase in HDL cholesterol levels suggest that pitavastatin may produce substantial cardiovascular protection.
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PMID:Are all statins the same? Focus on the efficacy and tolerability of pitavastatin. 2144 76


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