Protein Cardiovascular Disease Research Articles

The Clinical Utility of High-Sensitivity C-Reactive Protein in Cardiovascular Disease and the Potential Implication of JUPITER on Current Practice Guidelines

High-sensitivity C-reactive protein (hsCRP) testing is relatively inexpensive and has been shown to predict the risk of cardiovascular disease (CVD) and diabetes in multiple patient groups, including those treated with statin therapy. JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) is a recently completed large multicenter randomized clinical trial that tested whether statin therapy should be given to apparently healthy individuals with lower LDL cholesterol (LDL-C) concentrations but increased hsCRP concentrations. This review discusses the literature on hsCRP in asymptomatic populations, analyzes it according to CVD and diabetes, and provides summary recommendations for the use of hsCRP in clinical practice. In this context, we highlight recent data from the landmark JUPITER trial, which demonstrated that hsCRP can be used to target high-risk patients who have typical LDL-C concentrations and no known vascular disease or diabetes and who would benefit from statin use. We also summarize evidence that among patients treated with statin therapy, achieving low hsCRP concentrations may be a clinically relevant therapeutic goal along with achieving very low LDL-C concentrations. JUPITER has demonstrated that combining hsCRP testing with traditional testing of lipids can reduce incident CVD in high-risk asymptomatic individuals by 44% and all-cause mortality by approximately 20%, extending the therapeutic use of statins for the primary prevention of CVD. Guidelines for practitioners could include testing asymptomatic individuals for increased concentrations of hsCRP in men > or =50 years and women > or =60 years when LDL-C concentrations are not increased and for whom the decision to treat with statin therapy is not otherwise clear.

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction

Clinical Significance of High-Sensitivity C-Reactive Protein in Cardiovascular Disease

Large-scale prospective cohort studies consistently demonstrate a strong, independent relationship between high-sensitivity (hs) C-reactive protein (CRP) and incident cardiovascular events, with a magnitude of effect similar to, or larger than, that of blood pressure and lipid levels. As a biomarker of inflammation, hsCRP levels also predict incident Type 2 diabetes and modify the risk associated with the metabolic syndrome. Recent work further demonstrates that the addition of hsCRP to information provided by traditional risk factors improves risk classification, particularly for individuals otherwise considered to be at intermediate risk. Although there remains no direct evidence that lowering hsCRP lowers vascular risk, optimal clinical outcomes have been observed in statin trials among patients who not only reduced low-density lipoprotein cholesterol below 1.8 mmol/l (70 mg/dl), but who also reduced hsCRP below 2 mg/l. In addition to statins, CRP levels are lowered by diet, exercise and smoking cessation, all of which are known to lower vascular event rates. Whether or not CRP represents a causal agent in atherosclerosis is controversial and an area in need of further research. However, this controversy does not diminish the clinical utility of hsCRP as a biomarker of risk that, if appropriately used in clinical practice, can substantially improve clinical care.

Lectin‐like Oxidized Low‐density Lipoprotein Receptor‐1, a New Promising Target for the Therapy of Atherosclerosis?

Endothelial activation and dysfunction induced by oxidized modified low-density lipoprotein (ox-LDL) is one of the key steps in the initiation of atherosclerosis. Recent studies have shown that a new lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mediates the recognition and internalization of ox-LDL. LOX-1 is the main receptor for ox-LDL and may play an important role in the pathogenesis of hypertension, diabetes, and, especially, of atherosclerosis. The potential role of LOX-1 in the pathogenesis of atherosclerosis includes: endocytosis of ox-LDL, expression co-location with atherosclerosis enhanced by atherosclerosis-related risk factors, elevated LOX-1 protein in cardiovascular disease, effects related to atherosclerosis and eliminated by antiatherosclerotic drugs. Identification and regulation of LOX-1 and understanding its signal transduction pathways might improve our insight toward the pathogenesis of atherosclerosis and provide a selective treatment approach. LOX-1 might be a potential and promising target for the development of novel antiatherosclerotic drugs. However, due to limited knowledge about LOX-1, there are still many questions to be answered.

Stressing the obvious? Cell stress and cell stress proteins in cardiovascular disease

It is only some forty years since the discovery of the heat shock or cell stress response and just over twenty years since the heat shock/cell stress response was linked to protein misfolding. The plethora of intracellular proteins which promote correct protein folding in the cell, variously termed molecular chaperones, heat shock proteins, or cell stress proteins, have only been identified in the last fifteen years. During this period it has also been discovered that: (i) molecular chaperones are potent immunogens with immunomodulatory activity and (ii) they can be secreted by cells and exhibit intercellular signaling actions. These various functions of molecular chaperones are increasingly being linked to the pathology of the cardiovascular system. Molecular chaperones within cells can exhibit cardioprotection if their levels are artificially elevated, suggesting that these proteins may have therapeutic activity. In contrast, there is evidence that atherogenesis may be linked to immunity to one specific molecular chaperone, Hsp60. This may offer the possibility of treating atherosclerosis by vaccination. However, there is also growing evidence that secreted molecular chaperones have pro- or anti-inflammatory actions that are relevant to cardiovascular pathology. This review brings these various strands of research together to provide an overview of the role of molecular chaperones in cardiovascular disease.

Chemical knockout of C-reactive protein in cardiovascular disease

Human C-reactive protein (CRP) has been implicated in the inflammatory responses associated with heart attacks and strokes. A small-molecule inhibitor of CRP limits myocardial infarction in rats and should facilitate mechanistic studies of cardiovascular disease.

High sensitivity C-reactive protein in cardiovascular disease and type 2 diabetes: evidence for a clinical role?

1 Despite such findings, whether circulating hsCRP is clinically useful in identifying healthy individuals at elevated CHD risk remains contentious. Similarly, the causality of CRP in CHD and type 2 diabetes is the subject of ongoing debate. The following short synopsis charts firstly the evidence-base that stimulated initial enthusi- asm for considering hsCRP in CHD risk prediction, then more recent studies that question the strength of associations of hsCRP with future CHD and type 2 diabetes and the possible causality of such associations (table 1). Early evidence linking hsCRP and cardiovascular disease In a meta-analysis of studies published prior to 2000 which related baseline hsCRP to future CHD risk, apparently healthy men and women with hsCRP levels in the top third of the population, had on average a two-fold higher risk for a CHD event (95% CI, 1.6 to 2.5) compared to men and women with hsCRPs in the bottom tertile. 2 The strength of the association of elevated hsCRP with subsequent CHD events appeared to be greater than for some other pro- posed novel biomarkers (e.g. homocysteine, lipoprotein(a), ICAM-1) and comparable to that of the clinically established total cholesterol:HDL-cholesterol ratio in the Nurses Health Study. 3 The evidence was consistent regardless of age, gen- der, length of follow-up or presence or absence of existing vascular disease. Based on the accumulation of such evi- dence, a statement in 2003 from the CDC and the AHA concluded that measurement of CRP be considered as an adjunct to the measurement of established risk factors in order to assess the risk of CHD. 4

CRP—Marker or Maker of Cardiovascular Disease?

C-reactive protein (CRP) has emerged as an interesting novel and potentially clinically useful marker for increased cardiovascular risk.1,2 This is an attractive concept because atherosclerosis is a disease characterized by chronic arterial inflammation3,4 and suggests the possibility that subclinical states of atherosclerosis can be identified by an increase in circulating markers of inflammation before acute events occur. Based on data obtained primarily from in vitro studies it has also been proposed that CRP in itself is actively contributing to disease progression and that it should be considered as true risk factor and consequently as a target for intervention. However, in the present issue of Arteriosclerosis, Thrombosis, and Vascular Biology , two independent reports demonstrate that transgenic overexpression of CRP does not affect the development of atherosclerosis in mice, suggesting that this is not the case. See pages 1635 and 1641 The association between moderately elevated CRP levels and an increased risk for development of cardiovascular disease is well established. Although the increase in risk may have been overestimated in initial studies, recent meta-analysis comprising >7000 patients with coronary events shows that subjects with CRP in the upper tertile have a 50% increased risk for development of acute cardiovascular events.2 There are several possible explanations for this association (Figure). (1) The inflammatory process in arterial tissue affected by atherosclerosis results in release of cytokines into the circulation that subsequently activates expression of CRP in the liver. Plasma CRP levels would then reflect the severity of atherosclerosis and, as a consequence, the risk for development of clinical events. If CRP in addition …

Role of C-reactive protein in cardiovascular disease.

To discuss the role of C-reactive protein (CRP) in cardiovascular disease as a predictor of vascular events and identify key factors that increase or decrease this inflammatory marker. Articles were identified through searches of MEDLINE (1966-July 2003), International Pharmaceutical Abstracts (1970-June 2003), and bibliographies of selected articles. Search terms included C-reactive protein, HMG-CoA reductase inhibitors, fenofibrate, niacin, aspirin, estrogen, thiazolidinediones, and raloxifene. data selection and data extraction: All studies relevant to CRP and cardiovascular disease or the effects of pharmacologic and nonpharmacologic interventions on CRP levels were evaluated. All information deemed relevant to this review was included. Numerous studies have shown a strong association between CRP levels and future vascular events (i.e., coronary, cerebrovascular, peripheral vascular disease), with minimal correlation to low-density-lipoprotein cholesterol. Clinical guidelines have recently been published indicating that CRP levels of <1, 1-3, and >3 mg/L correspond to low, moderate, and high risk, respectively, for future vascular events. Drugs including statins, fibrates, niacin, thiazolidinediones, and antiplatelet agents, as well as weight loss and exercise, have demonstrated efficacy in lowering CRP levels. CRP appears to be a valuable tool for predicting future vascular events in patients striving for primary or secondary prevention of cardiovascular disease. While several pharmacologic and nonpharmacologic interventions have been shown to lower CRP levels, the impact on clinical outcomes requires further study.

Heat shock proteins in cardiovascular disease a new therapeutic target.

Cells have the capability of defending themselves from various stressors by activating a genetic program with the production of substances known as heat shock proteins and their regulatory partners, the heat shock transcription factors. In this article, heat shock proteins are discussed, including their roles in pathophysiology and as possible pharmacologic targets to treat disease. Multiple investigations have demonstrated an elevation in heat shock proteins in patients with systemic hypertension, coronary artery disease, carotid atherosclerosis, and myocardial infarction and ischemia. As we further understand how to manipulate their expression, we can explore pharmacologic interventions and gene transfection techniques that can safely be used in humans.

Stress-Response Proteins in Cardiovascular Disease

Recent years have witnessed a quiet revolution in biology as seemingly disparate fields, as far apart as biophysics and medical specialties such as human genetics and cardiovascular diseases, have begun to merge. Studies of molecular chaperones have bridged the gaps between biophysics and medical genetics, and they provide a clear example of promise of the new synthetic approach. Biophysicists, using nuclear magnetic resonance spectroscopy and other techniques in cell-free systems, have elucidated some of the basic mechanisms of protein folding, and they have shown that chaperone proteins participate in multiple steps in the folding pathway of model substrates (Dobson and Ellis 1998; Richardson et al.