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Prof. Salvatore Novo,
Results from our study on 150 patients together with findings from Framingham Heart and TNT suggest a possible “synergistic” role of low HDL-C and inflammation on the atherosclerotic disease progression from subclinical lesions to clinical events. It is possible to assert that the presence of subclinical carotid atherosclerosis together with low HDL-cholesterol concentrations points to a category of subjects at “high” CV risk.
The priority of primary cerebrovascular and cardiovascular disease prevention, must be placed on the identification of asymptomatic subjects at high risk of future events. “Global cardiovascular risk” (GCVR) is able to stratify the probable incidence of events through the evaluation of several traditional and emerging risk factors. The awareness of the role that dyslipidemia plays in the determinism of this risk has greatly influenced the management of subjects both in primary and secondary prevention.
Overwhelming evidence supports the causal relationship between elevated levels of low VA-HIT (LDL-C) and an increased risk of coronary artery disease (CAD), - CAD being the leading cause of death and morbidity worldwide. Benefits, as a consequence, arise from pharmacological treatments aimed at reducing LDL-C plasma levels (in addition to healthy diet and lifestyle). The AHA’s guidelines state that this treatment has, in general, a crucial role in reducing the risk of heart attacks and CV events in patients with CAD.
Statins are the preferred first-line pharmacological agents for their long, well-regarded history of efficacy and safety. Recent evidence indicate that lipid lowering strategies should be implemented at an early age, particularly in populations at high risk for CVD. Several agents have been evaluated in children, nevertheless as it is the case in adults, statins are the preferred drugs in paediatric practice. However, it is appropriate to raise a note of caution because this kind of therapy, initiated in childhood, needs to be studied in order to confirm its lifelong benefit (1).
Earlier scientific evidence on the effectiveness of statins has come from the WOSCOPS (West of Scotland Coronary Prevention Study) and from 4S (Scandinavian Simvastatin Survival Study).
Both studies showed a significant reduction not only in the LDL-C plasma levels (of about 26% and 35% respectively), but also in the relative risk of fatal and non-fatal myocardial infarction (of about 31% and 34%).
Although treatment goals are clearly defined, many patients do not reach their recommended LDL-C goals by simply using “starting doses” of statins. For such patients at high GCVR, a moreintensive therapy (ie with high-dose statins) is warranted. There is also the possibility of an intensive lipid-lowering treatment - by associating Ezetimibe to statins- which enhances the effect of statin but does not, in the meantime increase adverse complications (especially myopathy) (4). For potency in lowering LDL-C, favourable tolerability and patient acceptance/adherence profile, Ezetimibe/statin combination regimens arguably provide the maximum likelihood for subjects to reach new, lower LDL-C targets. A recent meta-analysis in patients with acute or chronic ischemic heart disease confirms the benefits arising from more aggressive lipid-lowering targets: “lower is better” (5). It is interesting to note however that an approach aimed only at reducing LDL-C has begun to show its limitations. Indeed a significant subject cohort in spite of a good control of the LDL-C remains at high risk (6). New strategies to reduce “residual” CV risk have paid attention to “levels” and “qualities” of HDL cholesterol (HDL-C).
Low HDL-C plasma levels can be considered an “independent” and “negative” prognostic factor in CV outcome. Its therapeutical modulation reduces CV risk, however optimal target levels have not yet been clearly defined. Statins are able to slightly increase HDL-C concentrations. High levels of HDL-C have anti-atherosclerotic properties, although the biological basis for this effect is not entirely clear. The "reverse cholesterol transport" model (plaque? macrophages? liver? biliary excretion) is currently the most widely used explanation for the protective role of HDL against the atherosclerotic disease. High-density lipoproteins, however, not only provide for a "forced" cholesterol flow from peripheral tissues to the liver, but are also involved in the control of cellular cholesterol homeostasis. Many other mechanisms are potentially involved, ie: preservation of endothelial function (7), anti-inflammatory activity and antioxidant effects, especially in terms of LDL. The oxidation of LDL causes a significant increase in the atherogenic potential of this class of lipoproteins.
Ample evidence supports the causal relationship of reduced levels of HDL-C (< 35/40 mg /dl) and the development of atherosclerotic diseases.
In light of the above considerations, it is possible to assert that low HDL-C concentrations can be considered a negative factor in CV outcome and are associated with an increased CV risk (11).
International guidelines agree to recommend HDL-C therapeutical modulation (11, 12). In spite of these assessments optimal levels of treatment goals have not been clearly defined, pharmacological drugs available are limited (with poor data regarding their use and effectiveness). Statins are only able to slightly increase HDL concentrations.
Another item to be taken into consideration has a “quality factor”, supposing a protective role for HDL “big” and “rich in cholesterol and ApoA-I” (which is the main enzyme involved in antioxidant effects).
Although it is well known that low HDL-cholesterol concentrations are associated with the development of atherosclerosis, recent evidence suggests that low HDL may further aggravate the atherosclerotic process. Lower HDL-C levels may potentially accelerate the progression from subclinical lesions (intima-media thickness=IMT; asymptomatic atherosclerotic carotid plaque=ACP) to clinical events. This effect could be due to the up-regulation of the inflammatory pathway: HDL-C seems to promote inflammation in the acute phase. Inflammation has been shown to be crucial in the evolution from endothelial dysfunction to plaque rupture and thrombosis.
IMT is the distance (assessed by B-mode ultrasonography) between two echogenic lines: the media-adventitia interface and the intima-media interface. Its measurement is a non-invasive, low cost and highly reproducible procedure. According to the joint ESH/ESC’s guidelines (15), the presence of subclinical carotid atherosclerosis is considered at IMT > 0.9 mm. Carotid pre-ATS is an independent marker of “multifocal” lesions in other arterial beds, with high sensitivity and specificity. Indeed an increased carotid IMT is significantly correlated to the number of coronary arteries with significant (> 50%) stenoses (16) and to a higher incidence of CAD. Therefore, detecting the presence of carotid wall lesions, even those taken early, is able to predict the occurence of future cardiovascular and cerebrovascular events (17-20).
It is possible to assert that the presence of subclinical carotid atherosclerosis together with low HDL-cholesterol concentrations points to a category of subjects at “high” CV risk.
The common denominator affecting fibrinogen levels and atherosclerosis is inflammation. Fibrinogen is a 340K dalton glycoprotein involved “early” in the formation and growth of atheroma.
Fibrinogen is also involved in a number of mechanisms with a crucial role in the “progression” of atherosclerotic lesions and it has been identified in large prospective studies as an independent risk factor for CAD (26, 27) and strong predictor for CV events ( 28, 29).
In our study, we found a significant inverse correlation between HDL-C levels and fibrinogen concentrations (p=.0302). These findings suggest a possible “synergistic” role of low HDL-C and inflammation on the atherosclerotic disease progression from subclinical lesions to clinical events. Therapeutical implications must be established in future studies. Recent studies have underlined that therapeutical modulation of markers of inflammation (such as increased levels of C-reactive protein and fibrinogen) is important in managing higher risk patients for comprehensive cerebro- and cardiovascular prevention (30, 31). Many agents (including aspirin and platelet aggregation inhibitors, lipid lowering, anti-hypertensive and antidiabetic agents, as well as antioxidants) are able to potentially reduce the levels of these markers and statins have been found particularly beneficial (32, 33).
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33) Atalar E, Ozmen F, Haznedaroglu I, Acil T, Ozer N, Ovunc K, Aksoyek S, Kes S. Effects of hort-term atorvastatin treatment on global fibrinolytic capacity, and sL-selectin and sFas levels n hyperlipidemic patients with coronary artery disease. Int J Cardiol 2002; 84: 227-31. You may send an e-mail here should you wish to receive pubmed links to articles listed in reference.
*Novo S, Carità P, Corrado E, D’Ambrosi A, Novo G *Director Chair of Cardiovascular Disease, post-graduate School of Cardiology, Master of Vascular Diseases, Master of Echocardiography, Center for the Study of Preclinical Atherosclerosis and Secondary Prevention and Division of Cardiology, University Hospital “P. Giaccone”, University of Palermo.
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