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Panvascular disease, or PVD, is an emerging clinical concept referring to a multisite atherosclerotic process that occurs simultaneously or sequentially, affecting multiple vascular beds (e.g., coronary, cerebral, peripheral, etc.). With this approach as its focus, the journal Lipids in Health and Disease published a review which looked at the significance of lipoprotein(a) in PVD.
Lipoprotein(a) [Lp(a)] is a complex lipoprotein particle that may be one of the best independent predictors of risk for PVD, though it is often not measured, given that it is considered an “unmodifiable” risk factor. This recent review highlights its structure and genetic background, role in various cardiovascular diseases, optimal measurement, and possible strategies to reduce the associated risk.
Lp(a) is a lipid-carrying particle formed by the linkage of an LDL-like particle containing apolipoproteinB-100 (apoB) to apolipoprotein(a) (apo(a)) by a disulfide bond. Apo(a) is uniquely found in Lp(a) and explains its special role in cardiovascular pathology, as other lipoprotein particles (e.g., LDL, VLDL) only contain apoB-100. Lp(a)’s normal physiological function is not known, but it does have an established causal role in coronary artery disease; it is a carrier of oxidized phospholipids and activates immune and inflammatory pathways, such as IL-6 and NF-kB. It promotes endothelial injury (with a stronger affinity for vascular lesions than low-density lipoproteins (LDL)), as well as platelet aggregation and activation, plaque instability and rupture, oxidative stress, and inflammation.
Approximately 90% of the plasma levels of Lp(a) are determined by genes alone, with levels varying up to three orders of magnitude between individuals (e.g., from below 0.1 to over 200 mg/dL). No one standard exists for risk levels of Lp(a), in part due to a lack of consistency in how it is measured and differences in the mass of apo(a) between individuals (there is a 10-20 fold variation in particle mass between people, making risk assessment challenging). But some individual organizations have defined thresholds, such as the American Heart Association and American College of Cardiology guidelines, which indicate that an Lp(a) concentration above ≥ 50 mg/dL (≥ 125 nmol/L) is an independent risk factor for cardiovascular disease.
Elevated Lp(a) levels are associated with an increased risk for coronary artery disease (CAD), including an increase in risk for both the incidence and severity of myocardial infarction. Its association with ischemic stroke risk is less clear, but Mendelian randomization suggests it may play a causal role here too, particularly for large vessel strokes. Lp(a) has a roughly linear association with heart failure (a population attributable fraction of 9%), where again Mendelian randomization suggests it is causal. It is independently associated with aortic stenosis, with individuals who have both an elevated Lp(a) and C-reactive protein at highest risk, a 1.6-fold increase. Increased risk and Mendelian analysis also point to a causal role in atrial fibrillation.
Regarding the measurement of Lp(a), it has been suggested that everyone should have it assessed at least once in life. Because it is primarily genetically determined, it is less likely to fluctuate than typical lipid analytes. Yet it often remains unmeasured, largely for this same reason, i.e., why measure it if it can’t be modified? It’s worth noting that although it is an independent risk factor for cardiovascular disease, other traditional risk factors can amplify the risk. This includes hypertension (which helps to promote endothelial injury and the deposition of Lp(a) into vascular tissues), insulin resistance (which can upregulate Lp(a) synthesis), and elevated LDL-C, which can also promote oxidative stress and atherosclerosis. Thus, in a patient with any of these traditional risk factors and an elevated Lp(a), at the very least, a more aggressive approach may be warranted. Given that screening only needs to occur once, the latex-enhanced turbidimetric immunoassay (LETIA) appears to be the best method.
There are therapies that reduce Lp(a) levels, though it’s not clear that the magnitude of reduction is significant enough to be clinically meaningful. For example, in a review published in the Journal of Clinical Medicine, lifestyle changes that may impact Lp(a) levels include intense physical activity, a reduction in ultra-processed foods and body weight, and a reduced energy/carbohydrate diet. But the changes in Lp(a) with the above interventions are not always consistently observed and tend to be small, with generally small studies supporting their effectiveness.
Similarly, L-carnitine supplementation has been shown to lower Lp(a) levels, but only by a mean of 7.13 mg/dL, using doses of at least 1.5 g per day. CoQ10 has also been shown to reduce Lp(a) by a mean of 3.54 mg/dL. Nano-curcumin has also shown promise, and should be considered especially with an elevated CRP, as it has been shown to reduce both CRP and Lp(a) among diabetic participants with mild to moderate CAD. Niacin has perhaps the largest effect on Lp(a) levels, demonstrating a 21% reduction in the AIM-HIGH trial (extended release niacin) when combined with other therapies, yet there was no evidence that it reduced cardiovascular events after 1 year (or after 4 in the HPS2-Thrive study). There are, however, no studies that evaluate these therapies in combination. For example, how effective would intense physical activity and weight loss combined with L-carnitine, curcumin, and CoQ10 be in terms of reducing both Lp(a) and cardiovascular events? For now, assessment at least once, combined with more aggressive therapy, may be the best option.
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