Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is a vascular inflammatory disease resulting from lipid deposition within vascular wall and changes in structure and function of the vascular wall. Atherosclerosis is accelerated when total and LDL cholesterol are elevated and/or HDL is low. Free radical production is increased in hypercholesterolemia leading to oxidative transformation of both parts of LDL particles, protein and lipid part. Small, dense LDL particles have extreme atherogenic potential; they can be easily oxidized and strongly maintain vascular inflammation. Oxidized LDL particles (oxLDL) support further free radical production. OxLDL are removed by macrophages into sub epithelial space. During that process macrophages produce inflammatory cytokines and induce the production of adhesion molecules, which further cause adherences of new macrophages and further support inflammation. OxLDL also induce sinthesis of endothelial growth factor receptors, which enable transduction of different signals important for: vascular remodeling, cellular migration, mitosis and NF-kappaB activation and increased metalloproteinase activity. HDL particles have an important role in the reverse cholesterol path and protective effects in vascular inflammation and atherogenesis. The ratio of apoprotein AI and AII, amount of CETP, LCAT and paraoxsonase, determine the function of HDL particles. Increased levels of triglycerides in the morning and especially postprandial levels are an independent risk factor for coronary heart disease, and heighten the risk when associated with other lipid disturbances. An increased triglyceride level is associated with the increased PAI I and reduced fibrinolisis. The ratio of total cholesterol/HDL cholesterol, as well as the levels of markers of inflammation such as CRP or IL-6, have great predictive value for the development of ischemic heart disease and cardiovascular diseases.
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PMID:[Vascular inflammation: effect of proatherogenic dyslipidemic trio or quartet]. 1970 14

The clinical trials described in this article were presented at the Late Breaking Trials and the Clinical Science: Clinical Reports sessions of the American Heart Association Congress held in November 2010 in Chicago. The sessions and topics chosen for this article reflect the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses may be done, which could alter the final publication of the results of these studies. PROTECT (ProBNP Outpatient Tailored Chronic Heart Failure Therapy) was designed to test the hypothesis that adjustment of intensity of chronic heart failure (HF) therapy on the basis of NT-proBNP plasma level monitoring would improve outcomes. The results provided some support of this concept, but needs further evaluation in larger, blinded trials. REVEAL (Reduction of Infarct Expansion and Ventricular Remodeling with erythropoietin after large myocardial infarctions) evaluated in the clinical setting of ischemia-reperfusion following STEMI that erythropoietin could salvage ischemic myocardium. The results did not show a reduction in infarct size, but, in contrast, an increase in adverse event rates in the erythropoietin group. GRAVITAS (Gauging Responsiveness with a VerifyNow assay-Impact on Thrombosis and Safety trial) investigated the effect of a standard vs. high maintenance clopidogrel dose in patients with stable myocardial ischemia or NSTEMI and drug-eluting stent insertion. Patients with high PRU values as determined by VerfyNow assay were randomized to 75 mg or 150 mg clopidogrel daily. The study did not show a significant difference in primary event rate between both groups. The Cholesterol Treatment Trialists' Collaboration Studies group evaluated the concept proposed in the JUPITER study that HDL levels on statin treatment may not provide useful prognostic information. The CTTC in a large sample size of statin-treated patients observed, on the contrary, a significantly increased risk of CV events, even in patients with low LDL cholesterol levels. DEFINE (Determining the Efficacy and Tolerability of CETP inhibition with Anacetrapib) evaluated possible safety aspects with the CETP inhibitor anacetrapib (increase in blood pressure). The study did not show adverse safety aspects, but significantly reduced LDL cholesterol and increased HDL cholesterol levels. ASSERT, a phase 2 dose-ranging study, investigated whether RVX-208 would increase Apo-A1 production. Apo-A1 may induce cholesterol efflux from macrophages and facilitate atherosclerosis regression. The study did not meet its primary endpoint, but significant prominent effects on lipids were found. ASCEND-HF was a large trial of nesiritide in >7000 patients with acute heart failure. The study did not show convincing symptom benefit, but on the other hand did not show harmful effects of nesiritide. EMPHASIS-HF evaluated the long term effects of eplerenone in patients with mild (NYHA class II) heart failure and systolic dysfunction. The study was prematurely ended because of highly significant beneficial effects. CUPID (Calcium Up-regulation by Percutaneous administration of gene therapy In cardiac Disease) is the first human study with gene transfer of SERCA2a (AVV1/SERCA2a: Mydicar). In a small placebo-controlled dose-ranging study in advanced heart failure patients a multiple endpoint analysis provided positive effects of the highest dose on symptomatic, functional and structural efficacy endpoints without adverse effects.
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PMID:Clinical Trials Update AHA Congress 2010. 2134 May 29

A decrease in high density lipoprotein-cholesterol (HDL-C) is a strong risk factor for atherosclerotic disorders in Japan, probably more important than an increase in low density lipoprotein-cholesterol (LDL-C). While there are rational grounds for the argument that elevation of HDL-C leads to decreased risk, there has as yet been no direct evidence of such an effect. If elevation of HDL-C decreases the risk, this effect is expected throughout the normal range of HDL-C or perhaps even higher than that. Simulation based on epidemiological data indicated that it may eventually reduce the incidence of ischemic heart disease by 60-70% in Japan. In the risk management guideline, "low" HDL-C is presently defined as 40 mg/dL or below. While there is no evidence that strongly urges a change in this definition, the results of epidemiological studies support "The higher the HDL-C level, the lower the risk,"even in the "normal range". Elevation of the HDL-C level may reduce the risk, probably at least up to 70 mg/dL; however, there are no supportive data for this effect still being obtained over 80 mg/dL. Patients with homozygous CETP deficiency should be followed-up while controlling other risk factors, so as not to dismiss the possibility of a risk increase with an extremely elevated HDL-C level.
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PMID:Background to discuss guidelines for control of plasma HDL-cholesterol in Japan. 2224 Sep 11

Dyslipidaemia is a critical risk factor for the development of cardiovascular complications such as ischemic heart disease and stroke. Although statins are effective anti-dyslipidemic drugs, their usage is fraught with issues such as failure of adequate lipid control in 30% of cases and intolerance in select patients. The limited potential of other alternatives such as fibrates, bile acid sequestrants and niacin has spurred the search for novel drug molecules with better efficacy and safety. CETP inhibitors such as evacetrapib and anacetrapib have shown promise in raising HDL besides LDL lowering property. Microsomal triglyceride transfer protein (MTP) inhibitors such as lomitapide and Apo CIII inhibitors such as mipomersen have recently been approved in Familial Hypercholesterolemia but experience in the non-familial setting is pretty much limited. One of the novel anti-dyslipidemic drugs which is greatly anticipated to make a mark in LDL-C control is the PCSK9 inhibitors. Some of the anti-dyslipidemic drugs which work by PCSK9 inhibition include evolocumab, alirocumab and ALN-PCS. Other approaches that are being given due consideration include farnesoid X receptor modulation and Lp-PLA2 inhibition. While it may not be an easy proposition to dismantle statins from their current position as a cholesterol reducing agent and as a drug to reduce coronary and cerebro-vascular atherosclerosis, our improved understanding of the disease and appropriate harnessing of resources using sound and robust technology could make rapid in-roads in our pursuit of the ideal anti-dyslipidemic drug.
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PMID:Looking into the crystal ball-upcoming drugs for dyslipidemia. 2507 74

Comorbidity or a combination of several diseases in the same individual is a common and widely investigated phenomenon. However, the genetic background for non-random disease combinations is not fully understood. Modern technologies and approaches to genomic data analysis enable the investigation of the genetic profile of patients burdened with several diseases (polypathia, disease conglomerates) and its comparison with the profiles of patients with single diseases. An association study featuring three groups of patients with various combinations of cardiovascular disorders and a control group of relatively healthy individuals was conducted. Patients were selected as follows: presence of only one disease, ischemic heart disease (IHD); a combination of two diseases, IHD and arterial hypertension (AH); and a combination of several diseases, including IHD, AH, type 2 diabetes mellitus (T2DM), and hypercholesterolemia (HC). Genotyping was performed using the "My Gene" genomic service (www.i-gene.ru). An analysis of 1,400 polymorphic genetic variants and their associations with the studied phenotypes are presented. A total of 14 polymorphic variants were associated with the phenotype "IHD only," including those in the APOB, CD226, NKX2-5, TLR2, DPP6, KLRB1, VDR, SCARB1, NEDD4L, and SREBF2 genes, and intragenic variants rs12487066, rs7807268, rs10896449, and rs944289. A total of 13 genetic markers were associated with the "IHD and AH" phenotype, including variants in the BTNL2, EGFR, CNTNAP2, SCARB1, and HNF1A genes, and intragenic polymorphisms rs801114, rs10499194, rs13207033, rs2398162, rs6501455, and rs1160312. A total of 14 genetic variants were associated with a combination of several diseases of cardiovascular continuum (CVC), including those in the TAS2R38, SEZ6L, APOA2, KLF7, CETP, ITGA4, RAD54B, LDLR, and MTAP genes, along with intragenic variants rs1333048, rs1333049, and rs6501455. One common genetic marker was identified for the "IHD only" and "IHD and AH" phenotypes: rs4765623 in the SCARB1 gene; two common genetic markers, rs663048 in SEZ6L and intragenic rs6501455, were identified for the "IHD and AH" phenotype and a combination of several diseases (syntropy); there were no common genetic markers for the "syntropy" and "IHD only" phenotypes. Classificatory analysis of the relationships between the associated genes and metabolic pathways revealed that lipid-metabolizing genes are involved in the development of all three CVC variants, whereas immunity-response genes are specific to the "IHD only" phenotype. The study demonstrated that comorbidity presents additional challenges in association studies of disease predisposition, since the genetic profile of combined forms of pathology can be markedly different from those for isolated "single" forms of a disease.
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PMID:Genomic Study of Cardiovascular Continuum Comorbidity. 2648 64