1 – LDL-cholesterol
A) Necessity for lowering high LDL-cholesterol levels.
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.
B) Means for lowering high LDL-cholesterol levels.
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).
- WOSCOPS (2) was a trial of primary prevention conducted with pravastatin on 6595 subjects with hypercholesterolemia but with no past history of CAD.
- 4S (3) was a trial of secondary prevention analysing the effects of simvastatin (vs placebo) on 4444 patients with chronic ischemic heart disease and hypercholesterolemia (with a mean follow-up of 5.4 years).
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).
2 - HDL cholesterol
A) Low-HDL cholesterol is a negative prognostic factor for CV outcome. Optimal levels however are not known. Statins only available drug and has limited effect.
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.
- The Framingham Heart Study showed an increase in the risk of cardiovascular and coronary death in patients with low HDL-C, independently from other traditional risk factors (7). It has been estimated that the reduction of 1 mg/dl of HDL-C leads to an increase in risks by about 2-3% (8). In addition, a recent metanalysis registered a reduction in mortality (about 30%) when an increase (about 13 mg/dl) in HDL-C occurred (9).
- In the TNT study more than 10.000 subjects were treated with atorvastatin (10 mg or 80 mg) reaching a reduction in LDL concentrations (to about 99 mg/dl and 73 mg/dl respectively). Furthermore, this study demonstrated a “significant” correlation between low HDL-C and CV risk, even in those subjects within their LDL-C goals (< 70 mg/dl) (10).
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.
B) High Density Lipoproteins “big and rich in cholesterol and ApoA-1” (versus small and poor) have a protective role against CV events.
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).
- The Framingham Offspring Study found significantly lower levels of this kind of HDL (in spite of higher levels of HDL small and poor) in patients with ischemic heart disease (13).
- Furthermore, the VA-HIT confirmed the significant inverse correlation between HDL “big and rich” and CV events, even after adjustment for other risk factors; in particular, the study detected an increase (by about 13%) in the relative risk of coronary events in those subjects reaching a reduction (of 1 mg/dL) in the levels of HDL “big and rich” (14).
C) Low HDL-cholesterol concentrations could be involved in the development of atherosclerotic disease and in accelerating its progression from subclinical lesions (IMT/ACP) to clinical events.
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).
- A recent meta-analysis of 8 population studies (Kuopio IHD-RF Study, ARIC Study, Rotterdam Study, CVH Study, Malmo Diet and Cancer Study, Longitudinal Investigation for the Longevity and Aging in Hokkaido Country, CAPS and Kitamura Study) investigated the association between carotid IMT and vascular events in 37197 subjects. This analysis registered an increased rate of myocardial infarction (15%) and stroke (18%) for every increase of 0.1 mm in the IMT value (21). According to this data, IMT may be a “more powerful” predictor than other traditional risk factors. Recent studies also suggest that patients with abnormal IMT should be treated more aggressively than those with normal IMT (22).
- Interesting evidence on the effectiveness of lipid lowering therapy on IMT values came from the METEOR (Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin) study. This recent double-blind, randomised placebo-controlled trial evaluated the effect of rosuvastatin on the rate of change of IMT in 984 low-risk subjects. It detected a reduction in the progression of carotid atherosclerosis within 12 months of intensive lipid-lowering treatment. (23).
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.
- In a recent published paper (24), we aimed at evaluating cerebro-and CV morbidity/mortality in a cohort of subjects with these features. We also searched (among all clinical baseline and laboratory parameters) for independent variables with a predictive role for such occurred events. We enrolled 150 patients (all referred to our Center for the Study of Preclinical Atherosclerosis and Cardiovascular Prevention, for a clinical evaluation between 1997 and 2000) in a prospective study and performed a 5-year follow-up. We registered clinical events in 21% of patients (including transient ischemic attack, stroke, effort or unstable angina, acute myocardial infarction, peripheral arterial disease, cerebro and cardiovascular death). Events occurred only once in patients, with the sole exception of angina that occurred twice in three patients.
Our study found an independent predictive role for lower HDL-cholesterol levels, for family history of CAD and for elevated fibrinogen concentrations. There was a significant association of HDL-C and ischemic stroke (p=.0164), with peripheral arterial disease (p=.0248) and with the presence of any clinical event (p=.0105). These associations remained significant even after adjustment for BMI and plasma lipids (total cholesterol, triglycerides and LDL-C).
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.
- Recently the CARDIA study demonstrated that elevated levels of fibrinogen in young subjects are independently associated with an increased prevalence of subclinical disease (high quantity of coronary artery calcifications and increase in the age-adjusted scores of carotid IMT) in the following years (25).
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).