Cardiovascular Biomarkers: Small Dense LDL-Cholesterol

Optimal Takeaways

Although cholesterol is important to many structural and metabolic functions in the body, it can increase the risk of atherosclerosis and heart disease when carried on small dense lipoprotein carriers called sdLDL. The sdLDL-cholesterol is highly susceptible to oxidation and other changes, making it much more likely to cause atherosclerosis and heart disease. Elevated levels are associated with cardiovascular disease, metabolic syndrome, diabetes, and subclinical hypothyroidism. Any increase in sdLDL-C over time should be investigated further. Low levels of sdLDL-C are likely associated with a reduced risk of cardiometabolic disease.

Standard Range: Below 50 mg/dL (1.3. mmol/L)

The ODX Range:    1 - 36 mg/dL (0.026 – 0.93 mmol/L)

Low sdLDL-C is associated with a reduced risk of cardiometabolic disease but otherwise not likely to be clinically significant.

High sdLDL-cholesterol is associated with atherosclerotic cardiovascular disease (Izeki 2021), myocardial infarction (Superko 2022), inflammation, obesity, metabolic syndrome (Fan 2019, Hoogeveen 2014), low adiponectin (Satoh 2008), diabetes (Hoogeveen 2014), subclinical hypothyroidism (Saric 2017), and genetic factors (Liou 2020).

Overview

Small low-density lipoproteins, a feature of the high-risk phenotype B pattern, are considered highly atherogenic due to their increased susceptibility to oxidation, glycation, and other detrimental modifications, as well as their inadequate levels of protective antioxidants. These smaller modified LDL particles can more easily penetrate the artery wall and contribute to atherosclerosis and plaque development. They are considered biomarkers of cardiovascular risk. An increase in sdLDLs, as well as the cholesterol they carry (sdLDL-C) is also associated with increased risk of CVD, even if LDL-cholesterol is low (Ivanova 2017).

A systemic review and meta-analysis of 21 studies comprising 30,628 individuals confirmed sdLDL-C as a risk factor or coronary heart disease, independent of conventional CVD risk factors and other lipid subfractions. However, sdLDL-C is influenced by genetic factors including a number of single nucleotide polymorphisms (SNPs). The largest study analyzed included 10,225 subjects and found that CHD risk increased significantly as sdLDL-C increased above 35.8 mg/dL (0.93 mmol/L) (Liou 2020). The highest quartile for sdLDL-C in this large study (Hoogeveen 2014) was 45.4–51.2 mg/dL (1.18-1.33 mmol/L), and was associated with higher BMI, increased hs-CRP, hypertension, metabolic syndrome, and diabetes. Levels were significantly higher in diabetics than in non-diabetics.

Further review of the literature revealed that a higher sdLDL-C detects residual risk of CVD events in stable patients on statin drugs despite lower LDL-C levels. One study suggests that an sdLDL-C above 35 mg/dL (0.91 mmol/L) was associated with significant risk of CVD events in stable CHD patients. Another 8-year study found that an sdLDL-C of 43.7 mg/dL (1.13 mmol/L) or above had a 5.4-fold increased risk of coronary heart disease compared to the lowest quartile of 24.4 mg/dL (0.63 mmol/L) or below (Superko 2022).

A 16-year follow-up of individuals initially free from atherosclerotic cardiovascular disease (ASCVD) found that sdLDL-C was the most atherogenic lipoprotein and most significant lipid parameter that can be used to evaluate risk. Individuals who developed ASCVD maintained a median sdLDL-C of 50.7 mg/dL (1.31 mmol/L) while those still free of ASCVD maintained a median sdLDL-C of 41.7 mg/dL (1.08 mmol/L) (Izeki 2021).

Analysis of data from the Framingham Offspring found that both men and women with established coronary heart disease had a significantly higher percentage of LDL-C as sdLDL-C. Both men and women with CHD had a mean sdLDL-C of 32.05 mg/dL (0.83 mmol/L), a level significantly higher than healthy female controls with a mean sdLDL-C of 26.25 mg/dL (0.68 mmol/L) (Ali 2010).

Elevated sdLDL-C is associated with dyslipidemia, inflammation, and obesity, factors that in turn, are associated with metabolic syndrome. One cross-sectional study of 1,065 Chinese males undergoing health screening found that sdLDL-C was significantly higher in those diagnosed with metabolic syndrome versus those without it, i.e., 47.5 mg/dL (1.23 mmol/L) versus 36.3 mg/dL (0.95 mmol/L) respectively. Researchers note that higher sdLDL-C is associated with metabolic syndrome independent of inflammation and central obesity. The ratio of sdLDL-C to LDL-C was higher in metabolic syndrome as well, i.e., 34.79% versus 25.91%. The lowest incidence of metabolic syndrome was in the group maintaining a ratio of 20% or below (Fan 2019).

A higher sdLDL-C was also significantly associated with metabolic syndrome in a study of 214 outpatients with at least one risk factor for CVD, but without unstable angina or history of MI or CHF. Not only was higher sdLDL-C found to be associated with metabolic syndrome, i.e., 35.1 mg/dL (0.91 mmol/L) versus 28.5 mg/dL (0.74 mmol/L), but the ratio of sdLDL-C to LDL-C was also significantly higher with metabolic syndrome at 36% versus 32% without. A higher ratio was associated significantly with increasing HbA1c and decreasing HDL-C as well. Adiponectin was significantly lower, i.e., 6.8 ug/mL versus 9.3 ug/mL, in those with metabolic syndrome and elevated sdLDL-C and sdLDL-C:LDL-C as well. Weight loss, exercise, and diet improvements resulted in significantly decreased sdLDL-C:LDL-C ratios and increased adiponectin over a 1-year period (Satoh 2008).

Subclinical hypothyroidism has also been associated with high sdLDL-C as observed in a clinical study of 100 women aged 21-75 years. Those diagnosed with subclinical hypothyroidism had significantly higher sdLDL-C than euthyroid subjects. Elevated sdLDL-C was defined as above 42.08 mg/dL (1.099 mmol/L) in those aged 21-54 and 48.6 mg/dL (1.259 mmol/L) in those aged 55-75 (Saric 2017).

References

Ai, Masumi et al. “Small dense LDL cholesterol and coronary heart disease: results from the Framingham Offspring Study.” Clinical chemistry vol. 56,6 (2010): 967-76. doi:10.1373/clinchem.2009.137489

Fan, Jiahua et al. “Small dense LDL cholesterol is associated with metabolic syndrome traits independently of obesity and inflammation.” Nutrition & metabolism vol. 16 7. 21 Jan. 2019, doi:10.1186/s12986-019-0334-y

Hoogeveen, Ron C et al. “Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk In Communities (ARIC) study.” Arteriosclerosis, thrombosis, and vascular biology vol. 34,5 (2014): 1069-77. doi:10.1161/ATVBAHA.114.303284

Ikezaki, Hiroaki et al. “Small Dense Low-Density Lipoprotein Cholesterol Is the Most Atherogenic Lipoprotein Parameter in the Prospective Framingham Offspring Study.” Journal of the American Heart Association vol. 10,5 (2021): e019140. doi:10.1161/JAHA.120.019140

Ivanova, Ekaterina A et al. “Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases.” Oxidative medicine and cellular longevity vol. 2017 (2017): 1273042. doi:10.1155/2017/1273042

Liou, Lathan, and Stephen Kaptoge. “Association of small, dense LDL-cholesterol concentration and lipoprotein particle characteristics with coronary heart disease: A systematic review and meta-analysis.” PloS one vol. 15,11 e0241993. 9 Nov. 2020, doi:10.1371/journal.pone.0241993

Saric, Maida Seferovic et al. “Dyslipidemia in subclinical hypothyroidism requires assessment of small dense low density lipoprotein cholesterol (sdLDL-C).” Romanian journal of internal medicine = Revue roumaine de medecine interne vol. 55,3 (2017): 159-166. doi:10.1515/rjim-2017-0015

Superko, Harold, and Brenda Garrett. “Small Dense LDL: Scientific Background, Clinical Relevance, and Recent Evidence Still a Risk Even with 'Normal' LDL-C Levels.” Biomedicines vol. 10,4 829. 1 Apr. 2022, doi:10.3390/biomedicines10040829

Satoh, Noriko et al. “Small dense LDL-cholesterol relative to LDL-cholesterol is a strong independent determinant of hypoadiponectinemia in metabolic syndrome.” Circulation journal : official journal of the Japanese Circulation Society vol. 72,6 (2008): 932-9. doi:10.1253/circj.72.932