Mesothelioma Illinois

Yaz Class Action: Alternatively, the possibility of direct contributions from CRP in athero- genesis and acute arterial thrombosis should be considered. CRP has been found within atherosclerotic lesions and is known to stimulate the expression of tissue factor, influence leukocytes , and activate complement. Notably, the lack of association between hs-CRP elevation and the burden of coronary atherosclerosis assessed either angiographically or with electron- beam computed tomography (180) support the notion that hs-CRP levels instead reflect pathobiological properties of the atheroma and vascular endothelium (i.e., plaque vulnerability rather than severity). Recent studies demonstrating an associ­ation between elevated hs-CRP and endothelial dysfunction determined in stud­ies of human forearm blood flow lend additional credence to this argument. Further investigation directed at elucidating the precise relationships between the elevation of acute-phase reactants, cytokines, and intercellular adhe­sion molecules and adverse cardiovascular prognosis will continue to advance.

If inflammatory markers such as hs-CRP are to become useful in clinical practice, there must be evidence that they add to the prognostic information offered by traditional cardiovascular risk factors. In the case of hs-CRP, baseline ele­vation of the inflammatory marker remains highly predictive of future events after adjustment for traditional risk factors including age, hypertension, diabetes, body mass, index, and smoking status. When used in conjunction with lipid measurements in the Women’s Health Study and Physicians Health Study, hs-CRP added to the predictive information offered by the total to high-density cholesterol ratio (TC:HDL). Moreover, in a prospective evaluation in healthy women that compared traditional (TC and TC : HDL) as well as several ‘‘novel’’ (lipoprotein(a), homocysteine, hs-CRP) markers of cardiovascular risk, the combination of hs-CRP and the TC : HDL ratio was found to be the strongest predictor of first myocardial infarction.

Although the epidemiological data supporting the prognostic utility of hs-CRP are strong and consistent, the inflammatory marker is unlikely to carry significant impact on clinical strategies for management of atherosclerotic vascular disease if the associated risk cannot be modified by available therapies. Thus, data sug­gesting important interactions between hs-CRP and specific pharmacological therapies are of particular clinical as well as experimental interest.

Aspirin, an agent with both antiplatelet and anti-inflammatory effects, was the first specific pharmacological therapy tested for CRP interaction. In the Physi­cians Health Study, participants were randomly assigned to low-dose aspirin (325 mg p.o. q.o.d.) or placebo with a 44% reduction in the risk of first MI associated with aspirin use (p < 0.001). However, in a nested case control analysis, stratification by quartiles of baseline hs-CRP revealed an increasing gradient of benefit with aspirin, such that those in the highest quartile of hs-CRP realized a 55.7% (p = 0.002) reduction in the risk of first MI compared with 13.9% (p = 0.77) among those in the lowest quartile of hs-CRP concentration. Similar differential effects of aspirin on clinical outcomes in the presence or absence of elevated CRP levels has recently been reported in the setting of unstable angina. Indeed, in this setting, the prognostic value of CRP was found to be quite limited once patients had been treated with aspirin. These data suggest that at least part of the benefit of aspirin may result from an interaction with underlying low-grade vascular inflammation. To date, however, data have been conflicting as to whether aspirin use reduces CRP levels. Whether other COX-1 and/or COX-2 inhibitors impact upon CRP levels is currently under investigation.

Yaz Class Action

Yaz Class Action: While data on aspirin are important pathophysiologically, the most provocative data regarding preventive medical therapy interacting with CRP involves the hy- droxymethylglutaryl coenzyme A reductase inhibitors, or ‘‘statins.’’ In this re­gard, experimental evidence has for some time supported the idea that, in addition to lowering LDL cholesterol, statins may have relevant anti-inflammatory and thus plaque-stabilizing effects. For example, statins have been shown to reduce macrophage content within atherosclerotic plaques, decrease neointimal inflam­mation, and suppress matrix metalloproteinase expression, all processes involved in the vulnerability of luminal plaque.

Clinical evidence demonstrating anti-inflammatory and plaque-stabilizing effects of statin drugs has only recently become available. The first study to address whether patients with evidence of inflammation benefited from statin therapy was performed within the Cholesterol and Recurrent Events (CARE) trial, a secondary-prevention evaluation of pravastatin. Consistent with studies of primary prevention, participants in the CARE trial with elevated CRP levels were found to have higher risks of recurrent coronary events than those with lower levels of CRP. However, a clinically apparent interaction between statin therapy and inflammation was also observed in that the proportion of recurrent events prevented by pravastatin was 54% among those with inflammation com­pared with 25% among those without inflammation.

Moreover, long-term therapy with pravastatin significantly reduced plasma levels of CRP in a manner that was not related to this agent’s effects on LDL cholesterol. In fact, in this hypothesis-generating study, there was no relationship between the change in CRP and the change in LDL cholesterol at the end of the 5-year follow-up period. Thus, these initial data provided clinical evidence that statin therapy may well have anti-inflammatory properties. While the mechanism of this effect is uncertain, the CARE data provide evidence for possible clinical relevance of laboratory observations demonstrating nonlipid effects of the HMG-CoA reductase inhibitors, such as modulation of immune function, antiproliferative effects on vascular smooth muscle, and antithrombotic properties, as well as morphological ef­fects.

Indeed, taken together with data from animal studies demonstrating that both dietary and statin-induced lipid low­ering result in reduction in metalloproteinase activity, the data from CARE serve to raise the possibility that statin therapy may achieve a reduction in cardiovascular events through both lipid-dependent and lipid-independent ef­fects on inflammatory cell function and related plaque vulnerability. However, the hypothesis-generating data from CARE—while provocative and initially controversial—require direct evaluation in hypothesis-testing trials.

Yaz Class Action