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LPa & Heart Disease Risk
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Consumption of a defined, plant-based diet reduces lipoprotein(a), inflammation, and other atherogenic lipoproteins and particles within 4 weeks
Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein structurally similar to low-density lipoprotein cholesterol (LDL-C), although synthesis occurs through independent pathways. Key differences include the linkage of apolipoprotein B100 (Apo-B) to apolipoprotein(a) on the LDL surface.1, 2 It has been estimated that expression of the genomic region encoding apolipoprotein(a) (LPA gene) accounts for approximately 90% of plasma Lp(a) concentrations.3 Elevated Lp(a) is independently associated with cardiovascular disease,4 and the LPA gene was observed to have the strongest genetic link to cardiovascular disease.5 Individuals with Lp(a) plasma concentrations >20 mg/dL have twice the risk of developing cardiovascular disease and approximately 25% of the population may have this plasma concentration.6 The mode of action by which Lp(a) exerts its atherogenic effect is likely similar to that of LDL-C, by deposition in the sub-endothelial space and uptake by macrophages mediated via the VLDL receptor.7 Lp(a) is particularly atherogenic due to its unique property of being a carrier of oxidized phospholipids, in addition to its higher binding affinity to negatively charged endothelial proteoglycans.8 Lp(a) can facilitate endothelial dysfunction when concentrations are elevated likely due to this effect.9
While PCSK9 inhibitors, high dose atorvastatin, ezetimibe and niacin have resulted in significant reductions in Lp(a),10-12 lifestyle interventions have not reliably demonstrated reduced Lp(a) to a clinically significant degree. Interestingly, even high saturated fat and high cholesterol diets known to induce hypercholesterolemia have had little influence on plasma Lp(a) concentrations.13 Despite the lack of evidence in the literature indicating a relationship between diet and Lp(a) concentrations, a defined, plant-based has not been previously evaluated with respect to its potential effect to reduce Lp(a). Previous investigations have found that a very-high fiber diet comprised of vegetables, fruits and nuts can reduce LDL-C by 33% and Apo-B by 26%,14 although Lp(a) was not measured. Since such a diet can result in dramatic reductions in LDL-C and Apo-B, secondary analysis of a previously published investigation15 employing a similar plant-based diet were analyzed to evaluate if Lp(a) could be significantly reduced after 4 weeks among other inflammatory indicators and atherogenic lipoproteins and particles.
https://onlinelibrary.wiley.com/doi/full/10.1002/clc.23027
Intervention
Participants were instructed to consume a defined, plant-based diet for 4 weeks ad-libitum which included the consumption of foods within a food classification system.15 These foods fell within food levels 0 to 4b of the food classification system (Table S1, Supporting information). Briefly, excluded were animal products, cooked foods, free oils, soda, alcohol, and coffee. Allowed for consumption were raw fruits, vegetables, seeds, and avocado. Small amounts of raw buckwheat and oats were also permitted. Vitamin, herbal, and mineral supplements were to be discontinued unless otherwise clinically indicated. All meals and snacks were provided to subjects, although they were free to consume food on their own within food levels 0 to 4b. In addition, subjects were not advised to alter their exercise habits. Adherence was measured daily as previously described15 with an adherence assessment tool. Participants indicated in writing each day whether they were adherent. Dietary recalls (24-hour) were conducted by a trained nutritionist at baseline and at 4 weeks. Nutrient intake was analyzed by the Nutrition Data System for Research software (University of Minnesota, version 2016). No lipid lowering medications were altered throughout the intervention.
Results
Significant reductions were observed for serum Lp(a) (-32.0 ± 52.3 nmol/L, P = 0.003), apolipoprotein B (-13.2 ± 18.3 mg/dL, P < 0.0005), low-density lipoprotein (LDL) particles (-304.8 ± 363.0 nmol/L, P < 0.0005) and small-dense LDL cholesterol (-10.0 ± 9.2 mg/dL, P < 0.0005). Additionally, serum interleukin-6 (IL-6), total white blood cells, lipoprotein-associated phospholipase A2 (Lp-PLA2), high-sensitivity c-reactive protein (hs-CRP), and fibrinogen were significantly reduced (P ≤ 0.004).
Conclusions
A defined, plant-based diet has a favorable impact on Lp(a), inflammatory indicators, and other atherogenic lipoproteins and particles. Lp(a) concentration was previously thought to be only minimally altered by dietary interventions. In this protocol however, a defined plant-based diet was shown to substantially reduce this biomarker. Further investigation is required to elucidate the specific mechanisms that contribute to the reductions in Lp(a) concentrations, which may include alterations in gene expression.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400957/
Nutrients. 2020 Jul; 12(7): 2024.
Conclusions
There is a renewed interest in Lp(a) as a clinical indicator of CVD risk and a potential treatment target. While new pharmacological therapeutics show promise in lowering Lp(a), the clinical significance is still being evaluated. In terms of non-pharmacological therapy, there is a well-established dogma that diet has no effect on Lp(a) and to date there have been few well-controlled clinical investigations of the effect of dietary modification on Lp(a). We have summarized the evidence to date, which suggests that dietary interventions affect Lp(a), although often Lp(a) is increased especially when SFA is replaced by other macronutrients; the clinical significance of this increase is unclear. In addition, we identified heterogeneity in the reported dietary interventions, methods used to measure Lp(a), and a lack of research about the underlying mechanisms. Therefore, further investigation of the effect of well-defined diets is needed to examine dietary modulation of Lp(a). Finally, it will be important to evaluate whether diet-induced Lp(a) effects are modified by other biological (e.g., race/ethnicity), genetic (e.g., apo(a) size) and metabolic (high vs. low burden) phenotypes. These findings will help prevention and treatment guidelines to evolve in order to further reduce CVD risk.
Lipoprotein(a) [Lp(a)] Is an Independent, Causal, Genetically Determined Cardiovascular Disease (CVD) Risk Factor
A large body of concordant evidence shows that an elevated level of plasma Lp(a)-a highly-heritable trait-is independently and causally associated with CVD. The findings in early case-control studies linking Lp(a) with coronary heart disease (CHD) have been confirmed in subsequent prospective, genetic epidemiological, and Mendelian randomization studies [20,21,22,23,24,25,26]. Several original and updated meta-analyses based on a large number of prospective studies compiling data from a few thousand to >100 thousand participants have found significant associations between Lp(a) and CHD. The findings of these meta-analyses demonstrate a 70% increased risk of CHD in subjects in the top vs. the bottom tertile of Lp(a) [27], a persistent independent and continuous association of Lp(a) with the risk of future CHD after adjusting for established risk factors [28] and a continuous association of Lp(a) level with the risks of CHD and stroke independent of traditional risk factors [29]. Studies using Mendelian randomization approaches based on the apo(a) size polymorphism have provided support for the causal role of Lp(a) in CHD. The presence of a small apo(a) size genotype was associated with both a high Lp(a) level phenotype and the presence of CHD [30,31,32,33]. Consistent with these findings, with increasing numbers of KIV repeats, Lp(a) levels decreased as expected, and an increase in risk of myocardial infarction (MI) was observed with increasing Lp(a) levels as well as with decreasing numbers of KIV repeats [32]. In another study using the same Mendelian randomization, Lp(a) levels and apo(a) KIV repeat tertiles were associated with risks of coronary, carotid and femoral atherosclerotic stenosis [33], providing mechanistic insights into Lp(a) pathogenicity. Another meta-analysis demonstrated that carriers of small apo(a) isoforms have a 2-fold higher risk of CHD or ischemic stroke compared with carriers of large isoforms [34].
Since 2016, several national or international guidelines and consensus statements on Lp(a) testing and treatment have been published. These guidelines issued by authorities such as the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force [8], the American Society for Apheresis [57], the Canadian Cardiovascular Society [58], the National Lipid Association [59], and the HEART UK Medical, Scientific and Research Committee [60] are in general agreement to measure Lp(a) in individuals at intermediate to high risk for CVD and those with family history of premature CVD and define Lp(a) risk threshold at > 30 mg/dL to > 50 mg/dL (>75 nmol/L to >125 nmol/L). In addition, the 2019 European Society of Cardiology and European Atherosclerosis Society guideline recommends that Lp(a) levels should be measured at least once in each adult person's lifetime to identify those with very high inherited Lp(a) levels >180 mg/dL (>430 nmol/L) who may have a lifetime risk of CVD comparable to those with heterozygous familial hypercholesterolemia (FH) [61]. The ACC/AHA Task Force on Clinical Practice Guideline recognizes Lp(a) as a risk-enhancing factor at levels >50 mg/dL (>125 nmol/L) [8]. Regarding therapeutic guidance, the American Society for Apheresis consensus recommends nicotinic acid (1-3 g/day) as the first-line of treatment, and if refractory, weekly selective lipid apheresis to lower Lp(a) [57].
Moving beyond the role of Lp(a) in CVD risk in the general population, a recent meta-analysis attempted to clarify Lp(a)-attributable residual CVD risk in patients with established CVD or on statin therapy [62]. This study using patient-level data from seven placebo-controlled statin trials encompassing 29,069 patients analyzed the relation of baseline and on-treatment Lp(a) concentration to risk of major adverse cardiovascular events (MACE). Statin therapy, as expected, reduced LDL-C level; after accounting for the contribution of Lp(a) the degree of reduction was 39%. However, the statin effect on Lp(a) was heterogeneous with three trials showing an increase (2% to 15%) and four trials showing a decrease (-1% to -13%) [62]. Elevated Lp(a) concentration exceeding 50 mg/dL at baseline or on-treatment was associated with an increased HR of MACE independent of other CVD risk factors. Interestingly, this association was stronger in patients receiving statins than those on placebo, suggesting that residual risk is present in patients with elevated Lp(a) that is not addressed by statins [62]. In patients with elevated Lp(a) levels who managed their LDL-C-attributable risk with statin therapy, specific therapies to lower Lp(a) may alleviate Lp(a)-induced CVD risk.
Lp(a), Lipid-Lowering Therapeutics and Cardiovascular Benefit
Apart from lipid apheresis that induces a consistent large reduction (>65%) in Lp(a) concentration with a subsequent improvement in CVD outcomes (e.g., 86% reduction in MACE) [63,64], other lipid-lowering therapeutics have produced heterogeneous effects on Lp(a) and their cardiovascular benefits are mostly absent or remain to be proven. The effect of lipid-lowering therapeutics on Lp(a) range from no response to opposing directions of change (i.e., increases vs. lowering). As noted earlier, statins have generated a highly variable response in Lp(a) in clinical trials [62]. Randomized placebo-controlled clinical trials of anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, reported a 37% reduction in Lp(a) concentration, but no significant cardiovascular benefit in statin-treated high-risk patients [65]. Another CETP-inhibitor (TA-8995) dose dependently reduced Lp(a) (range: ∼27% to 37%) in patients with mild dyslipidemia [66], but its effect on CVD risk is yet to be established. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial using a combination of extended-release niacin and statin showed a modest decrease (19%) in Lp(a) compared with the placebo without significant reductions in cardiovascular events [67].
A newer class of lipid-lowering drugs called proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors has been shown to reduce Lp(a) by ∼25% [68] and this Lp(a)-lowering effect was evident across apo(a) size distributions [69]. A post hoc analysis of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial demonstrated that evolocumab, a PCSK9 inhibitor, reduced Lp(a) in patients with established CVD by ∼27% [70]. As expected, elevated Lp(a) concentrations were associated with an increased risk of cardiovascular events irrespective of LDL-C. Notably, patients with higher baseline Lp(a) concentrations experienced greater absolute reductions in their Lp(a) and tended to derive greater coronary benefit (CHD deaths, MI, or urgent revascularization) compared in those with lower baseline concentrations [70].
Evidence from a recent meta-analysis of two PCSK9 inhibitor trials-the FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome during Treatment with Alirocumab)-supports Lp(a) as a risk mediator of venous thromboembolism (VTE) as PCSK9 inhibition significantly reduced VTE, which was associated with the degree of Lp(a) lowering, but not LDL-C lowering [71]. The ODYSSEY OUTCOMES trial also reports a similar role for Lp(a) in PAD risk as PCSK9 inhibition with alirocumab reduced the risk of major PAD events by 31%, which was associated with baseline Lp(a), but not LDL-C levels [72]. Furthermore, in the ORION 1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol), another PCSK9-modulating agent-inclisiran (a small interference RNA)-resulted in a large interindividual variability in Lp(a) response (-14% to -18% in the single-dose groups and -15% to -26% in the 2-dose groups), which contributed to a non-significant effect of the agent on Lp(a) [73].
Other emerging therapeutics such as those based on antisense oligonucleotide (ASO) targeting apoB-100 or apo(a) appear promising. Addition of mipomersen, an ASO to apoB-100, to a maximal medical therapy in patients with FH reduced Lp(a) by ∼26% [74]. An ASO-based approach targeting apo(a) synthesis in the liver reduced Lp(a) concentration by ∼35% to 80%, depending on dose and injection frequency, in individuals with established CVD and Lp(a) levels of at least 60 mg/dL [75].
These large reductions in Lp(a) may be the key to testing the Lp(a) hypothesis; the required degree of Lp(a) lowering to meaningfully reduce CHD outcomes has been a subject of debate. A 2018 Mendelian randomization analysis suggested that the clinical benefit of reducing Lp(a) may be proportional to the absolute reduction in Lp(a) concentration and a reduction in Lp(a) of 101.5 mg/dL may be required to produce a clinically relevant reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (i.e., 1 mmol/L) [76]. A subsequent 2019 Mendelian randomization analysis estimated that a much lower reduction in Lp(a) (65.7 mg/dL) would be equivalent to a 38.67 mg/dL reduction in LDL-C [77]. The authors noted that the influence of SNPs on Lp(a) concentration and standardization of the Lp(a) assay used may have led to an overestimation (101.5 mg/dL) in the past [77]. More recently, a population-based study concluded that high concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population and to achieve 20% and 40% MACE risk reduction in secondary prevention, Lp(a) should be lowered by 50 mg/dL and 99 mg/dL for 5 years, respectively [78].
As described, there has been significant investigation of pharmacological intervention for lowering Lp(a) and reducing residual risk conferred by high Lp(a). Heterogeneity is observed in the effect of current lipid-lowering drugs on Lp(a) and the clinical significance is still being investigated. Of note, first-line management of dyslipidemia is a healthy lifestyle including a healthy diet [8]. However, the effect of dietary modification on Lp(a) remains unclear. There is a prevailing perception that dietary modification has no significant effect on Lp(a) (2), which has likely hampered research efforts in this area. There have been several human clinical trials conducted, however that have measured Lp(a) in response to dietary interventions.
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Takeaway
Lipoprotein(a) or Lp(a) is a type of "bad" cholesterol-carriers, LDL. High Lp(a) levels independently increase your risk of heart disease.
The Lp(a) test is not routinely used, but your doctor will order it to better assess your risk of heart problems, if you have heart disease and/or high cholesterol levels run in your family.
Your genes have the largest influence on your Lp(a), so levels don't vary much over a person's lifetime. However, there are conditions, such as inflammation, that can increase Lp(a). In addition, many small-scale studies suggest that lifestyle and dietary changes may have small but significant effects on Lp(a).
If your Lp(a) is high, work with your doctor to decrease your overall risk of heart disease. This means keeping your weight, blood pressure, and cholesterol in healthy ranges. Other important strategies include eating a healthy and balanced diet, getting plenty of regular exercise, and finding ways to cope with stress, relax, and unwind.
What is Lipoprotein(a)?
Lipoproteins are a mesh of proteins and fats that help carry cholesterol in the blood. Examples include low-density lipoprotein (LDL), which carries "bad cholesterol" and high-density lipoprotein (HDL), which carries "good cholesterol" [1].
Lipoprotein(a), or Lp(a) is a type of LDL. It contains LDL and a protein called apolipoprotein(a) (not to be confused with apoA). Lp(a) is made in the liver and carries fats and other lipids such as cholesterol around the body [1, 2].
The exact function of Lp(a) is still an active area of research. What we do know is that high levels pose a health risk. In particular, higher Lp(a) levels have been associated with heart disease and stroke [3, 4, 5, 6, 7, 8].
Researchers think Lp(a) is involved in wound healing, tissue repair, immune response, and inflammation. However low or even undetectable Lp(a) levels are common and do not appear to have any negative health effects [9, 10, 11].
Lp(a) levels are largely determined by genetics and remain more or less stable throughout your life. However, some conditions can increase Lp(a), including hormonal imbalances, inflammatory diseases, metabolic issues, and kidney disease [12, 11, 13].
Although largely genetic, some newer studies suggest that certain lifestyle and dietary interventions may help slightly reduce lipoprotein(a) levels [12, 11, 13].
Lipoprotein(a) Test
Lipoprotein(a) levels are measured with a blood test. You don't need to prepare for the test. However, you will need to fast for 9-12 hours before getting a blood draw if you are doing a lipid panel along with Lp(a).
This test is not a routinely ordered test. Your doctor will usually order it if you have other risk factors for heart disease, such as [14]:
• Heart disease runs in your family
• You have a genetic condition that causes high cholesterol levels (familial hypercholesterolemia)
• Your heart disease is worsening despite treatment with statins
Lp(a) test helps your doctor determine your heart disease risk.
Typically, Lp(a) test is only done once, because it's pretty constant across your lifetime. On occasion, your doctor may order a second Lp(a) test to confirm the first one:
• If it was measured when you were ill
• After menopause, because Lp(a) levels increase as estrogen levels drop
Normal Range
The normal range for Lp(a) is <75 nmol/L or <30 mg/dL [15].
About 70% of people fall within this range [14].
Studies suggest that Lp(a) levels are higher in people of African descent than in people of European or Asian descent [16, 17].
Causes of High Lipoprotein(a) Levels
Lipoprotein levels above 75 nmol/L or 30 mg/dL indicate an increased risk of hardening of the arteries (atherosclerosis), heart disease, and stroke. Your doctor will interpret this test, taking into account your medical history, symptoms, and other tests.
Causes shown below have been associated with high Lp(a). Work with your doctor or another health care professional to get an accurate diagnosis.
1) Genetics
Lp(a) levels are largely determined by genetics. Mutations in the LPA gene can lead to high levels [11].
Mutations in this gene can result in different sizes of apolipoprotein(a). Research has found that people with smaller apolipoprotein(a) particles have higher Lp(a) levels [11].
Kidney Disease
People who have kidney disease can have higher Lp(a) levels which decrease with proper treatment [52].
Certain Drugs
Although statins are effective for lowering LDL levels, studies suggest they may actually increase Lp(a) levels [57].
Other drugs that can increase Lp(a) levels include:
• Insulin [58]
• Pioglitazone (Actos), Troglitazone (Rezulin), and metformin (Glumetza, Glucophage), used to treat type 2 diabetes [59, 60]
• Anti-seizure drugs [61]
• Growth hormone [62, 63]
• Finasteride (Propecia), used to treat an enlarged prostate (BPH) [64]
Heart Disease
Like LDL, lipoprotein(a) can build up in blood vessels, leading to fatty plaques, calcium deposits, and hardened arteries (atherosclerosis). Hardened arteries cannot properly expand. As a result, high Lp(a) levels are linked with an increased risk of heart disease [65, 66, 67, 68, 4, 5, 6, 7, 8, 69]
Another hazard is that Lp(a) is similar to a protein called plasminogen. The body converts plasminogen into plasmin, which dissolves blood clots that can lead to heart attack and stroke. Lp(a) interferes with the conversion, lowering plasmin [70, 71, 72].
Multiple studies have found that high Lp(a) levels are linked to an increased risk of heart disease. A meta-analysis of 31 studies found that levels above 50 mg/dL increased the risk of heart disease by 50% compared to levels below 5 mg/dL [3, 4, 5, 6, 7, 8].
Lp(a) is an independent risk factor: its link with heart disease still holds even after other risk factors - such as cholesterol, obesity, and smoking - are accounted for [73].
In heart failure, the heart doesn't pump blood as well as it should. In a study of over 98k people, compared to those with Lp(a) levels below 8 mg/dL, people with levels above 68 mg/dL had a 50% increased risk of heart failure [74].
Higher Lp(a) levels increase the risk of both milder and deadly heart attacks [75, 76].
https://labs.selfdecode.com/blog/lipoproteina/
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