Multiplicative Effects of Lipoprotein(a)
- High lipoprotein(a) ((Lp(a)) level is a putative independent risk factor for premature heart attack and stroke.1 The Framingham Offspring Study and several systematic reviews support a 2-fold risk of CAD (coronary artery disease) in people with elevated levels in the absence of any other risk factors.2-4
- More recent studies, however, have highlighted the important role of Lp(a) in accentuating the risk associated with virtually all conventional and emerging risk factors (Figure 037).5
- The multiplicative effects of excess Lp(a) on CAD risk with other risk factors suggest a need for a change from the conventional practice of measuring Lp(a) only in those individuals who have none or few other risk factors.5-10
- In the Framingham Heart Study, the adverse effect of Lp(a) was particularly daunting in patients with low HDL-C with some studies showing an 8-fold increase in CVD (cardiovascular disease) risk.6, 11-13 Angiographic studies have shown 7-fold increase in the progression of atherosclerosis in patients with high Lp(a) and low HDL-C.12 This combination appears to be particularly important among Asian Indians who have both high Lp(a) and low HDL levels.14
- The risk of CAD is increased 3-4 fold with either high LDL or high Lp(a) but increases 12 to 14-fold among those with concomitant elevations of both Lp(a) and LDL-C. 5, 15-22
- High TC/HDL-C ratio (which is another powerful predictor of CAD risk) when combined with a high Lp(a) level, increases CAD risk exponentially to 25-fold.5, 7, 12, 13, 20, 23-25 In the INTERHEART Study, Asian Indians had the highest TC/HDL ratio (5.7) and blacks had the lowest (3.9).26
- High triglycerides that produce small dense LDL particles also lead to small, dense Lp(a) and small dense HDL particles, further increasing the atherogenicity of these lipoproteins.1 The risk from Lp(a) may also be increased by high triglyceride levels by this mechanism.1
- High triglyceride levels are associated with lower Lp(a) levels in some studies.27, 28 Conversely, decreasing elevated triglycerides with fibrate therapy may increase Lp(a) levels.29
- The risk amplification of Lp(a) is not limited to various lipoproteins. Several traditional risk factors are known to magnify the risk as well.1 In patients with high blood pressure, Lp(a) excess is a determinant of poor outcome and target organ damage.8, 30
- The CAD risk is increased 12- to 30-fold with concomitant elevations in Lp(a) and homocysteine.5, 31, 32 Homocysteine increases the affinity of Lp(a) to plasmin modified fibrin 20 fold.5, 33 Other studies have shown synergistic adverse effects of Lp(a) with fibrinogen and the apolipoprotein epsilon 4 (apo ε4) allele.34, 35
- High Lp(a) levels increase the risk of CAD associated with other risk factors by a factor of 2 to 10. 5 More importantly, subjects with high levels of Lp(a), homocysteine and high TC/HDL ratio have a 122-fold risk of CAD if any one of the conventional risk factors is also present.1 Certainly, the presence of additional risk factors can further double or triple the risk from Lp(a).36 For comparison, the CAD risk is only 20-fold in patients with all five major risk factors combined.37
- These multiplicative effects of conventional and emerging risk factors appear to provide a plausible explanation for the excess burden of CAD among Asian Indians.1
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