Lp (a)
Lp (a) is an LDL-C macromolecule partly covered with apoprotein (a) and is more easily oxidized and more easily penetrates the endothelium making it more atherogenic than LDL-C. Lp (a) Promotes arteriosclerosis, inflammation, calcification, and thrombosis. Increased Lp (a) levels are associated with increased cardiovascular risk in most studies.
Lp (a) is associated with increased clotting risk. Altered fibrin clot structure with reduced permeability and impaired fibrinolysis. Lp (a) has not been conclusively shown to increase risk of venous thromboembolism, from my review of available studies so far.
Lp (a) has been linked to atherosclerosis, ischemic stroke, aortic valve stenosis, peripheral arterial disease.
In many studies, statin therapy increases Lp (a), even up to 20% and those affected individuals carry a higher risk of major adverse cardiovascular events (MACE).
Lp (a) has been studied in COVID 19 infection and implicated in increased thrombosis. Lp (a) increased at baseline or those with increased levels after COVID 19 infection seem to be at higher risk. Maybe destabilization of existing atherosclerosis. Lp (a) molecules seem to inhibit thrombolysis and enhance inflammation through its oxidized phospholipid content. The LPA gene that codes for Lp (a) contains an IL6 response element that may induce acute-phase reactant increase in Lp (a) levels in cytokine storm.
Advocates in favor of prescribing statin therapy to lower LDL-C commonly refer to familial hypercholesterolemia (FH) as an example of the harm of LDL-C and the support for aggressively lowering. In FH, the prevailing narrative has been that the high LDL-C results in premature cardiovascular disease. This was thought to be true because individuals with FH have an inherited defect in the gene that encodes the cells LDL receptors, resulting in less LDL receptors. With less LDL receptors, the thought is, less LDL-C is removed from the blood, which allows for a larger concentration of LDL-C in the blood, and more likely atherosclerosis.
Over time, what has been noted is that in FH, you cannot demonstrate an association between LDL-C, degree of atherosclerosis, or coronary calcium scores. So far to date, no RCT LDL-C lowering study restricted to those with FH had demonstrated a benefit. A number of studies suggested that procoagulant or high platelet reactivity may be the primary risk factors in FH. It seems that those with FH that die prematurely have higher Lp (a), higher factor VIII, and/or higher fibrinogen compared to those with FH that have a normal lifespan. Lp (a) is an LDL-C macromolecule partly covered with apoprotein (a). The structure of apoprotein (a) is almost identical to the fibrinolytic pro-enzyme plasminogen. With this in mind, apo (a) could compete with plasminogen for endothelial cell binding sites and impair production of plasmin which is required for thrombolysis. Lp (a) also stimulates platelet aggregation, increasing cellular elements to an area of atherosclerosis. Interestingly, PCSK9 inhibitors may lower fibrinogen, platelet reactivity, and thrombogenesis. PCSK9 inhibitors strongly reduce LDL-C, but this may have negative health consequences if you consider that those with the very lowest LDL-C levels have higher mortality. Maybe the risk for MACE has nothing to do with the LDL-C, but instead, the coagulation disorder that is seen commonly in those also affected by FH. If that is so, we are targeting treatment incorrectly.
Elevated Lp (a) levels are associated with increased risk of MACE with and without SARS-COV2 infection. Inflammation is a well-accepted stimulus for atherosclerosis. Carbohydrate-restricted diet has been shown to significantly decrease Lp (a), as well as other inflammatory markers including TNF-alpha, and C reactive protein levels. Less glucose in the circulation results in less endothelial dysfunction and improved nitric oxide levels, less chance of vascular dysfunction. Of course, a carbohydrate- restricted diet such as keto or carnivore is a relatively low-risk intervention. Why not consider this diet as a preventative measure to lower Lp (a) and possibly lower your risk for MACE?
References:
Atherosclerosis. 2019 Oct; 289: 173–175.
https://www.atherosclerosis-journal.com/article/S0021-9150(19)31423-6/abstract
10.1161/CIRCULATIONAHA.120.045826
Effect of an increase in Lp (a) following statin therapy on cardiovascular prognosis in secondary prevention population of coronary artery disease. BMC Cardiovascular Disorders voluem 22, article number: 474 (2022), Lijun Zhu, Yangliang Fang, Beibei Gao, Xiangbon Jin, Jiamin Zheng, Ying He, Jinyu Huang
https://doi.org/10.1186/s12872-022-02932-y
Effects of a carbohydrate-restricted diet on emerging plasma markers for cardiovascular disease.