Lipoprotein Subfractionation: HDL Particle Number (NMR)

Optimal Takeaways  

High-density lipoprotein is a multipurpose molecule with specific cardioprotective, antioxidant, and anti-inflammatory functions. It plays a very important role in reverse cholesterol transport, the process of collecting cholesterol from pro-atherogenic immune cells and arterial plaque and returning it to the liver for disposal. A low number of HDL particles is associated with cardiovascular risk, acute inflammation, and environmental factors such as air pollution that can make HDL dysfunctional. An elevated level of HDL particles is likely due to genetic factors.

Standard Range: 21.10 – 43.40 umol/L

The ODX Range: 32.8 – 43.40 umol/L

Low HDL-P may be associated with acute inflammation (Bardagiy 2019), atrial fibrillation (Trieb 2019), air pollution (Wilkins 2019), cardiovascular risk, increased cardiovascular incidents (Mackey 2012), and low HDL in general, which may be associated with metabolic syndrome, liver disease, hypoproteinemia, and familial low HDL (Pagana 2021).

High HDL-P may be associated with elevated HDL, which can be caused by familial HDL lipoproteinemia or excessive exercise (Pagana 2021)

Overview    

High-density-lipoproteins (HDLs) are considered cardioprotective in general due to their important role in reverse cholesterol transport (efflux), an atheroprotective process. HDL has antioxidant, antithrombotic, immunologic, and antiapoptotic effects as well. HDL may support vasodilation by facilitating smooth muscle release of nitric oxide (Wilkins 2019), inhibits cell adhesion and leukocyte activation de Miranda 2019), reduce platelet activation and inflammatory response, and support glucose metabolism (Orozco-Beltran 2017). HDL appears to support healthy glucose metabolism by directly improving beta-cell function and preventing excess cholesterol accumulation (Bardagiy 2019).

HDL functions also include the prevention of LDL oxidation, removal of oxidized compounds from LDL, removal of beta-amyloid plaque, inhibition of alpha-synuclein aggregation, and inhibition of viral pathogens such as the SARS-CoV-2 virus. In general, healthy functional HDL is enriched with ApoA-1 and cholesterol, while dysfunctional HDL is triglycerides, apoC-III, and serum amyloid A (SAA) (Cho 2022).

Acute inflammation can lower levels of both HDL and ApoA-1. This is partly due to the displacement of ApoA-1 from HDL by serum amyloid A (SAA). Serum amyloid A is a pro-inflammatory molecule that can bind to the arterial wall and cause HDL to be pulled from circulation. The binding of SAA to HDL also makes HDL dysfunctional and unable to perform its antioxidant, anti-inflammatory, and reverse cholesterol transport duties (Bardagiy 2019).

If HDL is pathologically altered, it can have negative vascular effects (Marz 2017). HDL can be modified by immune cell factors and pro-inflammatory mediators and become dysfunctional and atherogenic (Shah 2019). For example, glycated HDL was found to lose its antioxidant activity (Cho 2022), and exposure to pesticides can impair the ability of HDL to function as an antioxidant (Ljunggren 2014). Adherence to a Mediterranean diet enriched with virgin olive oil can support HDL functions and composition (Wilkins 2019).

Measurement of high-density lipoprotein particle number (HDL-P) provides an accounting of actual circulating HDL particles versus HDL cholesterol. HDL particles have a density of 1.063 g/mL, can range in size from 7-12 nanometers (nm), and can contain up to 95 different proteins, including apoA-1, enzymes, protease inhibitors, acute-phase proteins, and complement proteins (Wilkins 2019). In general, a higher HDL-P is considered cardioprotective, while a low HDL-P is associated with increased cardiovascular risk.

High-density lipoproteins (HDLs) have antioxidant, anti-inflammatory, and anti-thrombotic properties that are cardioprotective. A higher number of HDL particles (HDL-P) is associated with a lower risk of cardiovascular disease and heart failure mortality, an observation independent of HDL-C levels. A lower HDL-P is also associated with atrial fibrillation (AF), a condition characterized by inflammation and oxidative stress. Research on 54 atrial fibrillation patients found that acute AF was associated with significantly reduced HDL-P of 29.79 umol/L compared to 36.15 umol/L in healthy controls. Notably, HDL-P improved when sinus rhythm was restored (Trieb 2019). Low HDL is also associated with increased overall cardiovascular risk, metabolic syndrome, vascular dementia, and Alzheimer's (Cho 2022).

The number of circulating HDL particles is positively associated with cholesterol efflux, the ability of HDL to scavenge cholesterol from macrophage foam cells and atherosclerotic plaque and return it to the liver via reverse cholesterol transport (Lee 2021). The apoA-1 protein supports the antioxidant, anti-inflammatory, and RCT functions of HDL and accounts for 70% of its protein composition. HDL also carries several antioxidant enzymes, such as paraoxonase 1 (PON1) and lecithin-cholesterol acyltransferase (LCAT), that can remove oxidized lipids from LDL and prevent further LDL oxidation and subsequent inflammation (Bardagiy 2019).

Research suggests that HDL-P level has an inverse relationship with cardiovascular endpoints and appears to be a superior biomarker to HDL-C for ascertaining risk. One cohort study of 214 men with stable coronary artery disease found that HDL-P was significantly lower in those who died during the mean 12.5 year follow-up period versus those who survived, i.e., 24.6 umol/L versus 27.5 umol/L respectively. It is noted that both groups had an HDL-P below optimal. The group of deceased patients also had a higher heart rate, more severe atherosclerosis, higher hs-CRP, smoked more, and were more likely to have diabetes (Duparc 2020).

The HDL particle may be affected by a number of environmental factors. An inverse association has been observed between HDL-P and particulate air pollution. One study of 6,654 subjects found that a 5 ug/m3 increase in exposure to fine particulate matter correlated with a 0.64 umol/L decrease in HDL-P, even though it was not associated with a lower HDL-C. A decrease in HDL-P was also associated with traffic-related black carbon pollution (Bell 2017).

A healthy diet can support HDL particle number and function and should include at least 4-5 cups of fruits and vegetables daily, two or more servings of fish per week, and three or more servings of whole grains per day. Excess sodium (especially from processed foods) and sugar-sweetened foods and beverages should be limited. A plant-based dietary pattern such as the Mediterranean diet meets these criteria and can support heart health and HDL function. (Bardagiy 2019). Interestingly, in one 4-week animal study, significantly lower HDL-particle number was associated with a low-protein diet and increased oxidative stress (Wada 2020).

References  

Bardagjy, Allison S, and Francene M Steinberg. “Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review.” Nutrients vol. 11,6 1231. 30 May. 2019, doi:10.3390/nu11061231

Bell, Griffith et al. “Association of Air Pollution Exposures With High-Density Lipoprotein Cholesterol and Particle Number: The Multi-Ethnic Study of Atherosclerosis.” Arteriosclerosis, thrombosis, and vascular biology vol. 37,5 (2017): 976-982. doi:10.1161/ATVBAHA.116.308193

Cho, Kyung-Hyun. “The Current Status of Research on High-Density Lipoproteins (HDL): A Paradigm Shift from HDL Quantity to HDL Quality and HDL Functionality.” International journal of molecular sciences vol. 23,7 3967. 2 Apr. 2022, doi:10.3390/ijms23073967

de Miranda Teixeira, Raissa et al. “HDL Particle Size and Functionality Comparison between Patients with and without Confirmed Acute Myocardial Infarction.” Cardiology research and practice vol. 2019 3074602. 3 Mar. 2019, doi:10.1155/2019/3074602

Duparc, Thibaut et al. “Serum level of HDL particles are independently associated with long-term prognosis in patients with coronary artery disease: The GENES study.” Scientific reports vol. 10,1 8138. 18 May. 2020, doi:10.1038/s41598-020-65100-2 

Lee, Jane J et al. “Cholesterol Efflux Capacity and Its Association With Adverse Cardiovascular Events: A Systematic Review and Meta-Analysis.” Frontiers in cardiovascular medicine vol. 8 774418. 13 Dec. 2021, doi:10.3389/fcvm.2021.774418

Ljunggren, Stefan A et al. “Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.” Environment international vol. 65 (2014): 93-9. doi:10.1016/j.envint.2013.12.017

Mackey, Rachel H et al. “High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis).” Journal of the American College of Cardiology vol. 60,6 (2012): 508-16. doi:10.1016/j.jacc.2012.03.060

Marz, Winfried et al. “HDL cholesterol: reappraisal of its clinical relevance.” Clinical research in cardiology: official journal of the German Cardiac Society vol. 106,9 (2017): 663-675. doi:10.1007/s00392-017-1106-1

Orozco-Beltran, Domingo et al. “Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.” PloS one vol. 12,10 e0186196. 18 Oct. 2017, doi:10.1371/journal.pone.0186196 Correction

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Shah, Prediman K, and Dalgisio Lecis. “Inflammation in atherosclerotic cardiovascular disease.” F1000Research vol. 8 F1000 Faculty Rev-1402. 9 Aug. 2019, doi:10.12688/f1000research.18901.1

Trieb, Markus et al. “Atrial fibrillation is associated with alterations in HDL function, metabolism, and particle number.” Basic research in cardiology vol. 114,4 27. 8 May. 2019, doi:10.1007/s00395-019-0735-0

Wada, Yasuaki et al. “A More Oxidized Plasma Albumin Redox State and Lower Plasma HDL Particle Number Reflect Low-Protein Diet Ingestion in Adult Rats.” The Journal of nutrition vol. 150,2 (2020): 256-266. doi:10.1093/jn/nxz223

Wilkins, John T, and Henrique S Seckler. “HDL modification: recent developments and their relevance to atherosclerotic cardiovascular disease.” Current opinion in lipidology vol. 30,1 (2019): 24-29. doi:10.1097/MOL.0000000000000571