Optimal - The Podcast: Episode 2

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Optimal - The Podcast: Episode 2 Cholesterol

Dr. Dicken Weatherby & Beth Ellen DiLuglio, MS, RDN, LDN

Welcome to episode 2 of "Optimal - The Podcast". In this episode of Optimal, we are going to talk about Cholesterol. Yes. That very basic building block of human biochemistry and physiology that everyone seems to have such strong opinions about.

 In the first part of the Podcast, we’re going to be talking about Cholesterol the molecule and at the end of the podcast, we’ll dive into Cholesterol the biomarker and look at ranges, clinical implications, research, etc.

Episode Highlights:

• (02:22)What is cholesterol?
• (03:46) What does cholesterol do to the body?
• (05:37) The good and bad cholesterol
• (06:43) Oxidized cholesterol
• (08:36) How allopathic medicine shuts down cholesterol and its downside on human physiology
• (15:10) Maintaining total cholesterol, LDL and HDL
• (16:05) Cardiovascular risk
• (17:50) What happens when a patient is low in certain steroid hormones?
• (19:28) The main types of cholesterol
• (26:47) What does it mean when a person has an extremely high level of HDL?

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Further Reading

What is Cholesterol?

Cholesterol is an important sterol lipid made in the body; it is also found in animal-based foods. It's synthesized from acetyl-CoA which can be obtained from carbohydrate, fat, or protein.[i] [ii] An important player in its synthesis is an enzyme called HMG-CoA reductase. We will be talking about this enzyme a little bit later. Cholesterol is produced by every cell in the body though most production takes place in the liver. It is found in every cell membrane and is the most abundant lipid in the brain.[iii] Cholesterol is found in abundance in the central and peripheral nervous systems, especially the myelin sheath.[iv] It is rate limiting for myelination in the central nervous system. [v]

What does cholesterol do in the body?

It is the precursor to:

Steroid hormones

• • Glucocorticoids (corticosteroids) e.g. cortisol which mediates the stress response, suppresses inflammation.
  • Mineralocorticoidsg. aldosterone which increase sodium retention and potassium excretion increasing blood volume and blood pressure.
  • Pregnenolone (precursor to all steroid hormones)
  • DHEA (most abundant steroid hormone in the body, counteracts stress, supports immunity, modulates inflammation, precursor for testosterone and estrogen).[vi]
  • Progestogensg. progesterone which supports pregnancy
  • Androgensg. testosterone responsible for male secondary sex characteristics
  • Estrogens. estrone required for development of female secondary sex characteristics

Vitamin D: Cholesterol in the form of 7-dehydrocholesterol is the precursor to vitamin D synthesis in the skin when exposed to UV light/sunlight.

Bile salts: Cholesterol is needed for production of bile salts which facilitate digestion of fat and absorption of fat-soluble vitamins (ADEK).

Cholesterol possesses antioxidant activity:

The antioxidant functions of cholesterol were recognized early on and discussed in the 1970s. Cholesterol can intercept oxidants in a protective role though oxysterols are produced which then must be eliminated via bile and feces. Depletion of cholesterol will contribute to increased oxidative stress and, ironically, disrupt cell membrane function.[vii] [viii]

Unfortunately, the vital functions and benefits of cholesterol have been overshadowed by the assumption that cholesterol itself is a “bad thing.”

Dietary Cholesterol

Despite assumptions to the contrary, dietary cholesterol does itself does not contribute to elevated serum cholesterol or cardiovascular disease (though oxidized cholesterol is a cuprit). Most often dietary cholesterol will have an insignificant effect on blood cholesterol levels as it triggers a feedback loop (via HMG Co-A reductase) that reduces endogenous production. Also, a relative rise in blood cholesterol following dietary intake reflects a fairly balanced rise in both LDL and HDL cholesterol. Interestingly, a meta-analysis revealed that a pronounced increase in HDL cholesterol occurred with dietary cholesterol intake of 650-900 mg/day.[ix]

Dietary cholesterol promotes the repair of demyelinated lesions in the adult brain. In animal models of multiple sclerosis/demyelination, dietary cholesterol restored cholesterol levels depleted by acute disease and enhanced remyelination and diminished axon damage.[x] Even the much maligned egg has been pardoned as well-designed studies indicate that egg intake did not negatively impact blood lipids for most individuals. In some cases, eggs shifted LDL to the preferred larger “fluffier” LDL particles and did not appear to promote oxidized LDL cholesterol. Egg intake may be associated with cardiovascular disease in diabetics, but that association may be due to production of microbial production of TMAO from the phosphatidylcholine in the egg yolk.[xi] Those with familial hypercholesterolemia must be assessed and treated accordingly.

Current research has shifted its focus away from cholesterol and toward systemic inflammation which is becoming one of the most likely of the usual suspects when it comes to cardiovascular disease.[xii] But we’ll save that hot topic for another day.

What is the downside of shutting down its production?

• Potential loss of cell membrane fluidity and function
• Reduction of most abundant lipid in the brain
• Reduction of precursor availability for production of steroid hormones, vitamin D, and bile salts.
• Loss of antioxidant capacity and increased potential for oxidative stress and damage
• Increased potential for oxidation of LDL cholesterol and related atherosclerosis
• Statin side-effects.
  • Statin drugs inhibit HMG-CoA reductase, a key enzyme in the synthesis of cholesterol and other biologically active compounds such as ubiquinone (Coenzyme Q10). CoQ10 plays a vital role in mitochondrial function, energy generation via the electron transport chain, and antioxidant activity.[xiii]
  • The recognized side effects of statins include primarily muscle and hepatic adverse effects (AEs). Risk of AEs is magnified by the presence metabolic or mitochondrial dysfunction, e.g. thyroid disorders, and metabolic syndrome.[xiv]
  • Statins caused significant dose-related decline of total serum level of coenzyme Q10 in both pravastatin group p<0.01 and lovastatin group P < 0.001.[xv]
  • 2003 review states statin-induced CoQ10 depletion is well documented in animal and human studies with detrimental cardiac consequences in both. This drug-induced nutrient depletion is dose related and more notable in settings of pre-existing CoQ10 deficiency such as in the elderly and in heart failure.[xvi]
  • 2003 randomized double-blind placebo-controlled study of acute MI patients found CoQ10 120 mg/day associated with significant reduction in total cardiac events, malondialdehyde, and fatigue and significant increase in plasma vitamin E and HDL levels.[xvii]
• One study looked at lowering LDL-C to extreme lows 15-40 mg/dL using monoclonal antibodies to liver protein PCSK9 which ultimately increases LDL receptors in liver and lowers circulating LDL.[xviii] [xix]
  • Researchers claim there were no significant reductions in cortisol, adrenal, or gonadal steroid hormone levels.
  • Vitamin E levels were reduced in serum but increased in HDL particles
  • Researchers concluded that “The supply of free cholesterol through alternative pathways such as de novo synthesis, reverse cholesterol transport, mobilization of stored cholesteryl esters, and intestinal absorption is sufficient for production of steroid hormones” (Qamar and Bhatt 2015)
  • They did not test vitamin D, CoQ10, or oxidative stress biomarkers.

• NOTE Wongcharoen study: LDL-C >100 mg/dl was associated with reduced risk of MACE as compared to LDL <70 mg/dl [xx]

Monday morning actionable actions:      

Complete a full assessment of cardiovascular risk factors, not just total cholesterol, including[xxi]

• Comorbidities e.g. diabetes, hypertension, obesity, metabolic syndrome, inflammatory conditions
• Psychosocial stressors
• Diet
• Exercise and physical activity
• Sleep habits
• Tobacco use

Complete full assessment of serum lipids including total, LDL and particle size/number, HDL and particle size/number, non-HDL, VLDL, triglycerides, ApoA-1, ApoB, Lp(a), etc.

Dyslipidemias:

• Primary disorders of lipid metabolism such as familial hypercholesterolemia (FH), chylomicronemia, familial combined hyperlipidemia, familial dysbetalipoproteinemia classify according to Fredrickson phenotype.[R]
• Secondary dyslipidemia can result from diabetes mellitus, hypothyroidism, obstructive liver diseases, chronic renal failure, drugs that increase LDL-C including retinoids, cyclosporine A, and phenothiazines and drugs that decrease HDL-C including progestins, androgens, beta-blockers, and anabolic steroids.[xxii]

Assess for familial hypercholesterolemia (FH)[xxiii]

• Heterozygous FH: Total cholesterol 350-550 mg/dL
• Homozygous FHL Total cholesterol 650-1,000 mg/dL
• Suspect FH in adults: Fasting LDL-C >190 mg/dL
• Physical signs of FH:
  • arcus corneae, xanthelasma, tendon xanthomas, or tuberous xanthomas, premature CHD.

Assess antioxidant potential and oxidative stress risk (start with diet & environment)

Assess downstream metabolites (steroid hormones, vitamin D, etc.)

Assess additional cardiovascular biomarkers e.g.

• Glucose, eAG, HbA1c, fasting insulin
• Ferritin
• Hs-CRP
• Omega-3 Index
• TMAO
• IL-6
• Fibrinogen

Cholesterol Biomarkers

Alright, let’s get back to our topic of the month and that’s Cholesterol and I want to take the last 10 – 15 minutes looking at Cholesterol biomarkers.

Because cholesterol is basically lipophilic, it must be transported in the blood inside lipoprotein carriers including VLDL, LDL, and HDL which can be easily measured.[xxiv] And these form the traditional cholesterol biomarkers that make up the standard Lipid Panel.

Total cholesterol

Let’s start with the one that people probably have the most opinions about and that’s total cholesterol. Total cholesterol levels are just one piece of the cardiovascular disease puzzle and must be assessed further. A low cholesterol level may reflect malnutrition or severe oxidative stress. Total cholesterol does not provide enough information about CVD risk for those who do not have familial hypercholesterolemia.

Cholesterol levels and ranges

Let’s take a look at Standard total cholesterol recommendations for adults:

2013 American College of Cardiologists/American Heart Association Guidelines

Therapeutic goals for total cholesterol ranged from 220 mg/dL to below 200 mg/dl (5.69-5.17 mmol/L).^[xxv]

Interestingly, in the executive summary of 2019 Updated ACC/AHA guidelines they don’t discuss Total Cholesterol but instead emphasize lifestyle and dietary changes. They focus less on total cholesterol levels but do provide guidance for LDL and non-HDL[xxvi] Their recommendations for a cut-off for a diagnosis of Primary hypercholesterolemia:      

• LDL-C 160–189 mg/dL [4.1–4.8 mmol/L]
• non–HDL-C 190–219 mg/dL [4.9–5.6 mmol/L]

Familial hypercholesterolemia should be suspected in adults when [xxvii]

• fasting LDL-C is >190 mg/dL
• Patients with heterozygous FH can have total cholesterol levels in the 350-550 mg/dL range.
• Patients with homozygous FH have total cholesterol levels in the 650-1,000 mg/dL range.

 National Lipid Association Recommendations

Total cholesterol

Borderline high: 200-239 mg/dL (5.17-6.18 mmol/L)

High: 240 mg/dL   (6.2 mmol/L) or above ^[xxviii]   

US National Library of Medicine: “Healthy” levels of total cholesterol

Men and women age 20 or older: Total Cholesterol 125 to 200 mg/dL  ^[xxix]

Interestingly, a low cholesterol below 160 mg/dL and high cholesterol >240 mg/dL is associated with severe acute pancreatitis[xxx]

So that’s the standard or “normal” range . And because this podcast and the work of Optimal DX is “Don’t settle for normal, strive for optimal” I do want to take a quick look at Optimal ranges for total cholesterol

A retrospective study that appeared in the journal “Lipid Health Disorders” in January 2019 looked at 1754 healthcare workers at low risk of cardiovascular disease examined the screening value of total cholesterol levels.

• Researchers suggest that an upper cutoff point of 230 mg/dL for fasting total cholesterol would help identify those with LDL cholesterol levels of 160 mg/dL or greater, and/or non-HDL cholesterol levels of 190 mg/dL or greater, levels which may indicate alterations in lipid metabolism that warrant further assessment.
• They note that a total cholesterol cut off of 210 mg/dL can help identify those with an LDL-cholesterol of 130 mg/dL or greater and/or non-HDL cholesterol levels of 160 mg/dL or greater.^[xxxi]

In view of the vital importance of cholesterol to cellular metabolism and its vulnerability to oxidation and inflammation, a reasonable and optimal total cholesterol level would be 160 - 200 mg/dl   

Additional assessment in those with cardiovascular disease or at risk for cardiovascular disease should be considered.

So, Beth, it looks as if Total Cholesterol as a biomarker is controversial, but really its importance is somewhat overblown and the more important players on the lipid panel are LDL, HDL and Non-HDL. Can you take us on a quick journey on those?

LDL cholesterol

A prospective cohort study revealed that subclinical atherosclerosis was present in half of the 1,779 participants who had no major cardiovascular risk factors. The most extensive atherosclerosis was found in those mean levels of total cholesterol of 201 mg/dL, LDL-C of 132 mg/dL, and oxidized LDL-C of 50 mg/dL. Atherosclerosis was also associated with hemoglobin A1C of greater than 5.7%.[xxxii]

• Many CardioVascular Risk-Free middle-aged individuals have atherosclerosis.
• This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals.
• Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n = 4,184) without conventional CVRFs were evaluated (n = 1,779; 45.0 ± 4.1 years, 50.3% women).
• CVRF freedom was defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol<240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol ≥40 mg/dl.

HDL cholesterol (reverse cholesterol transport)

HDL is an important factor in reverse cholesterol transport, taking cholesterol, including oxidized cholesterol, from the cells back to the liver for processing. Optimal levels range from 55-70 mg/dL, however elevated HDL-C of 90 mg/dL or greater have been associated with an increased risk of cardiovascular events and mortality.[xxxiii]
Although it is traditionally accepted that increased HDL represents decreased risk of coronary artery disease independent of LDL levels,[xxxiv] additional research reveals that extremely high HDL levels are associated with increased risk of cardiovascular events and mortality.[xxxv]

Japanese cohort: the highest level of HDL-C (≥ 90 mg/dL) for both men and women was associated with increased risk of mortality from atherosclerotic CVD, CHD, and ischemic stroke

Danish cohort: In fully adjusted models for men, baseline HDL-C at 73 mg/dL (95% CI, 42-77 mg/dL) was associated with the lowest mortality. In fully adjusted models for women, the lowest mortality was seen at a baseline HDL-C of 93mg/dL (95% CI, 66-239 mg/dL). 

VLDL cholesterol

VLDL is a lipoprotein that mainly carries triglycerides with some cholesterol. Once triglycerides are dropped off, VLDL becomes IDL and finally LDL. It’s important to assess VLDL size and number.

Non-HDL cholesterol is potentially atherogenic, representing LDL, IDL, VLDL, and lipoprotein(a). It is significantly associated with increased incidence of major adverse cardiovascular events (MACEs). Post-acute MI patients with non-HDL of greater than 130 mg/dL had three times the risk of long-term MACEs than those with non-HDL of less than 100 mg/dL.

Surprisingly, a mean LDL-C of greater than 100 mg/dL was associated with fewer cardiovascular events than a mean LDL-C of less than 70 mg/dL (1.8 mmol/L) (a common goal of statin therapy[xxxvi]), an observation attributed to larger LDL size in the higher LDL-C group[xxxvii]

Cholesterol Ratios

I want to finish up by looking at something that Beth and I have been reporting on for a while and that’s the value of ratios and there are a few very important ratios that appear on the standard lipid panel: Total Cholesterol:HDL, LDL:HDL, and ApoB:Apo A1.  

Assessing the ratios of total cholesterol/HD, LDL/HDL, and ApoB/ApoA-1 provide greater predictive value in terms of cardiovascular risk than assessing either value alone. [xxxviii]

Total cholesterol:HDL-C (“atherogenic or Castelli index)

• Optimal range would be below 3

• Optimal Men <2.34       Women <2

ApoB/ApoA-1

• Primary target men <0.9         women <0.8
• Secondary target men <0.7         women <0.6   

References

[i] Mahan, L. Kathleen; Raymond, Janice L. Krause's Food & the Nutrition Care Process - E-Book (Krause's Food & Nutrition Therapy) (p. 427). Elsevier Health Sciences. Kindle Edition.

[ii] Craig, Micah. and Ahmad Malik. “Biochemistry, Cholesterol.” StatPearls, StatPearls Publishing, 17 April 2019. [R]

[iii] Agranoff BW, Benjamins JA, Hajra AK. Properties of Brain Lipids. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999. Available from: [R]

[iv] Snipes, G J, and U Suter. “Cholesterol and myelin.” Sub-cellular biochemistry vol. 28 (1997): 173-204. doi:10.1007/978-1-4615-5901-6_7 [R]

[v] Berghoff, Stefan A et al. “Dietary cholesterol promotes repair of demyelinated lesions in the adult brain.” Nature communications vol. 8 14241. 24 Jan. 2017, doi:10.1038/ncomms14241 [R]

[vi] Rutkowski, Krzysztof et al. “Dehydroepiandrosterone (DHEA): hypes and hopes.” Drugs vol. 74,11 (2014): 1195-207. doi:10.1007/s40265-014-0259-8 [R]

[vii] Butterfield, J D Jr, and C P McGraw. “Free radical pathology.” Stroke vol. 9,5 (1978): 443-5. doi:10.1161/01.str.9.5.443 [R]

[viii] Smith, L L. “Another cholesterol hypothesis: cholesterol as antioxidant.” Free radical biology & medicine vol. 11,1 (1991): 47-61. doi:10.1016/0891-5849(91)90187-8 [R]

[ix] Soliman, Ghada A. “Dietary Cholesterol and the Lack of Evidence in Cardiovascular Disease.” Nutrients vol. 10,6 780. 16 Jun. 2018, doi:10.3390/nu10060780 [R] This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([R]).

[x] Berghoff, Stefan A et al. “Dietary cholesterol promotes repair of demyelinated lesions in the adult brain.” Nature communications vol. 8 14241. 24 Jan. 2017, doi:10.1038/ncomms14241 [R]

[xi] Blesso, Christopher N, and Maria Luz Fernandez. “Dietary Cholesterol, Serum Lipids, and Heart Disease: Are Eggs Working for or Against You?.” Nutrients vol. 10,4 426. 29 Mar. 2018, doi:10.3390/nu10040426 [R]

[xii] Tsoupras, Alexandros et al. “Inflammation, not Cholesterol, Is a Cause of Chronic Disease.” Nutrients vol. 10,5 604. 12 May. 2018, doi:10.3390/nu10050604 [R] 

[xiii] Nawarskas, James J. “HMG-CoA reductase inhibitors and coenzyme Q10.” Cardiology in review vol. 13,2 (2005): 76-9. doi:10.1097/01.crd.0000154790.42283.a1 [R]

[xiv] Golomb, Beatrice A, and Marcella A Evans. “Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism.” American journal of cardiovascular drugs : drugs, devices, and other interventions vol. 8,6 (2008): 373-418. doi:10.2165/0129784-200808060-00004 [R]

[xv] Mortensen, S A et al. “Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors.” Molecular aspects of medicine vol. 18 Suppl (1997): S137-44. doi:10.1016/s0098-2997(97)00014-9 [R]

[xvi] Langsjoen, Peter H, and Alena M Langsjoen. “The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications.” BioFactors (Oxford, England) vol. 18,1-4 (2003): 101-11. [R]

[xvii] Singh, Ram B et al. “Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction.” Molecular and cellular biochemistry vol. 246,1-2 (2003): 75-82. [R]

[xviii] Qamar, Arman, and Deepak L Bhatt. “Effect of Low Cholesterol on Steroid Hormones and Vitamin E Levels: Just a Theory or Real Concern?.” Circulation research vol. 117,8 (2015): 662-4. doi:10.1161/CIRCRESAHA.115.307345 [R]

[xix] Blom, Dirk J et al. “Effects of Evolocumab on Vitamin E and Steroid Hormone Levels: Results From the 52-Week, Phase 3, Double-Blind, Randomized, Placebo-Controlled DESCARTES Study.” Circulation research vol. 117,8 (2015): 731-41. doi:10.1161/CIRCRESAHA.115.307071 [R]

[xx] Wongcharoen, Wanwarang et al. “Is non-HDL-cholesterol a better predictor of long-term outcome in patients after acute myocardial infarction compared to LDL-cholesterol? : a retrospective study.” BMC cardiovascular disorders vol. 17,1 10. 5 Jan. 2017, [R]

[xxi] Arnett, Donna K et al. “2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.” Journal of the American College of Cardiology vol. 74,10 (2019): 1376-1414. doi:10.1016/j.jacc.2019.03.009 [R]

[xxii] Lee Y, Siddiqui WJ. Cholesterol Levels. [Updated 2019 Jun 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: [R]

[xiii] Pejic, Rade N. “Familial hypercholesterolemia.” The Ochsner journal vol. 14,4 (2014): 669-72. [R]

[xxiv] Huff, Trevor, et al. “Physiology, Cholesterol.” StatPearls, StatPearls Publishing, 15 April 2020. [R] 

[xxv] Stone NJ, Robinson JG, Lichtenstein AH, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1-45. [R]

[xxvi] Arnett, Donna K et al. “2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.” Journal of the American College of Cardiology vol. 74,10 (2019): 1376-1414. doi:10.1016/j.jacc.2019.03.009 [R]

[xxvii] Pejic, Rade N. “Familial hypercholesterolemia.” The Ochsner journal vol. 14,4 (2014): 669-72. [R]

[xxviii] Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, Wilson DP, Brown WV. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol. 2015 Mar-Apr;9(2):129-69. Doi: 10.1016/j.jacl.2015.02.003. Epub 2015 Apr 7. PubMed PMID: 25911072. [R]

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[xxx] Hong, Wandong et al. “Association of total cholesterol with severe acute pancreatitis: A U-shaped relationship.” Clinical nutrition (Edinburgh, Scotland) vol. 39,1 (2020): 250-257. doi:10.1016/j.clnu.2019.01.022 [R]

[xxxi] Nantsupawat N, Booncharoen A, Wisetborisut A, et al. Appropriate Total cholesterol cut-offs for detection of abnormal LDL cholesterol and non-HDL cholesterol among low cardiovascular risk population. Lipids Health Dis. 2019 Jan 26;18(1):28. [R] 

[xxxii] Fernández-Friera, Leticia et al. “Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors.” Journal of the American College of Cardiology vol. 70,24 (2017): 2979-2991. doi:10.1016/j.jacc.2017.10.024 [R]

[xxxiii] Riggs, Kayla A, and Anand Rohatgi. “HDL and Reverse Cholesterol Transport Biomarkers.” Methodist DeBakey cardiovascular journal vol. 15,1 (2019): 39-46. doi:10.14797/mdcj-15-1-39 [R]

[xxxiv] Upadhyay, Ravi Kant. “Emerging risk biomarkers in cardiovascular diseases and disorders.” Journal of lipids vol. 2015 (2015): 971453. doi:10.1155/2015/971453 [R] 

[xxxv] Riggs, Kayla A, and Anand Rohatgi. “HDL and Reverse Cholesterol Transport Biomarkers.” Methodist DeBakey cardiovascular journal vol. 15,1 (2019): 39-46. doi:10.14797/mdcj-15-1-39 [R]

[xxxvi] Leibowitz, Morton et al. “Targeting LDL Cholesterol: Beyond Absolute Goals Toward Personalized Risk.” Current cardiology reports vol. 19,6 (2017): 52. doi:10.1007/s11886-017-0858-6 [R]

[xxxvii] Wongcharoen, Wanwarang et al. “Is non-HDL-cholesterol a better predictor of long-term outcome in patients after acute myocardial infarction compared to LDL-cholesterol? : a retrospective study.” BMC cardiovascular disorders vol. 17,1 10. 5 Jan. 2017, doi:10.1186/s12872-016-0450-9 [R]

[xxxviii] Millán, Jesús et al. “Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention.” Vascular health and risk management vol. 5 (2009): 757-65. [R]