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September 13, 2021

Assessing Cardiovascular Disease - Beyond Cholesterol

To conduct a comprehensive evaluation of cardiovascular risk, the clinician must evaluate a more complex pattern of biomarkers and risk factors including the following: [1] [2] [3] [4] [5] [6]


Risk Factors

  • Homocysteine
  • Hs-CRP
  • Lipoprotein evaluation
  • ApoB, ApoA-1
  • Lipoprotein(a)
  • LDL
  • Oxidized LDL-C
  • Non-HDL
  • VLDL
  • Subfractionation of lipoprotein particle size and number
  • Triglycerides
  • Blood glucose dysregulation
  • Diabetes, diabesity
  • Exposure to pesticides, industrial toxins, heavy metals, mercury
  • Hypertension
  • Inflammation
  • Metabolic Syndrome

Additional Factors to Consider

Vitamin D Insufficiency

Vitamin D insufficiency can have a range of detrimental cardiovascular effects. A comprehensive meta-analysis of 81 studies highlighted the association between low levels of 25(OH) vitamin D and CVD risk. Results indicate that vitamin D supplementation significantly improves systolic and diastolic blood pressure; serum parathyroid hormone; total cholesterol, LDL, and HDL-cholesterol; triglycerides; and hs-CRP. The meta-analysis noted that increased risk of CVD or mortality was associated with a serum 25(OH) vitamin D of less than 10 or 15 ng/mL (25 or 37 nmol/L).[7]

The Third National Health and Nutrition Examination Survey (NHANES) revealed a “strong and independent” relationship between 25(OH) vitamin D deficiency below 20 ng/mL (50 nmol/L) and cardiovascular disease in US adults.[8]

Vitamin K Status  

The preventive and therapeutic role that vitamin K plays in vascular health and CVD is being studied, though more research is needed.[9] [10] Researchers suggest the presence of a synergistic effect between vitamin K and vitamin D.

Hormonal Associations

Estrogens and androgens may underlie the clinical, pathophysiological, and prognostic differences in CVD between men and women.[11] In the population-based Health in Men cohort study, lower free testosterone of 100 vs. 280 pmol/L (29 - 81 pg/mL) was found to be a clinical predictor of mortality from CVD.[12]

While controlling for total cholesterol and other cardiovascular risk factors, the Multi-ethnic Study of Atherosclerosis (MESA) found that higher levels of total testosterone, lower levels of estradiol, and increased testosterone/estradiol ratio were associated with increased risk for CVD, coronary heart disease, and heart failure in post-menopausal women. Further analysis revealed that free testosterone was inversely associated with coronary heart disease while sex hormone-binding globulin was positively associated with CHD.[13]


Fibrinogen is an acute-phase protein. Levels may increase from 2-4 mg/mL in healthy individuals to greater than 7 mg/mL in the event of acute inflammation. Elevated levels have been associated with an increased incidence of CVD.[14]  

Trimethylamine N-oxide (TMAO)

A number of disorders, including cardiovascular disease, atherosclerosis, hypertension, ischemic stroke, and metabolic syndrome have been associated with elevated levels of trimethylamine N-oxide. The precursor to TMAO is trimethylamine (TMA), a compound produced by intestinal bacteria from dietary elements including choline, carnitine, dimethylglycine, and betaine. The TMA can then be oxidized to TMAO by hepatic enzymes. Levels of TMAO are found in increase as body weight and adipose tissue increase. Levels of 8.74 uM or above are predictive of metabolic syndrome, a disorder that significantly increases CVD risk.[15] The standard reference range for TMAO is less than 6.2 uM.[16]

TMAO metabolism is complex and depends on the consumption of preformed TMA, TMAO, and their precursors, as well as hepatic enzyme activity and composition of the gut microbiome. Its application as a CVD biomarker is not established at this time.[17]

CVD - More That Just One's Cholesterol Levels

It is clear that there is much more to the cardiovascular disease model than just one’s cholesterol level. Fortunately, the contemporary focus for primary disease prevention has shifted away from cholesterol and toward lifestyle, diet, and psychosocial factors, an approach long embraced by naturopathic practitioners and nutritionists.

An unhealthy diet high in refined/processed foods, sugar-sweetened beverages, and trans fats and lacking in whole foods, fruits, and vegetables is a major risk factor for CVD. An unhealthy lifestyle that includes cigarette smoking, excess alcohol, inadequate physical activity, and excess body fat predisposes any individual to disease, including CVD. These factors promote oxidative stress and inflammation and even have unfavorable effects on cholesterol, particularly in promoting the oxidation of cholesterol.[18]

Diet Quality

Nutrient density and quality of the diet is crucial to cardiovascular health. The Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet are distinct patterns of eating based on whole unprocessed foods. An abundance of fruits, vegetables, and other plant-based foods provides protective phytonutrients, antioxidants, healthy fats, and fiber which can reduce the risk of cardiovascular disease.[19]

Research reveals a significant inverse relationship between a Mediterranean pattern of eating and risk of coronary heart disease and stroke. Further analysis of dietary patterns reveals:[20]

Increased risk of CVD associated with the consumption of:

  • Eggs but only for diabetics
  • High glycemic load
  • Red meat
  • Saturated fat
  • Sugar-sweetened beverages
  • Trans fat
  • Western-style diet

Lower risk of CVD associated with:

  • Alcohol in moderation (1 drink/day)
  • Carotenoids
  • Coffee
  • Dairy
  • DASH diet
  • Flavonoids
  • Folate
  • Fruits
  • Legumes
  • Magnesium
  • Mediterranean diet
  • Nuts
  • Potassium
  • Unsaturated fat
  • Vegetables
  • Vitamins B6, C, E, folate
  • Whole grains
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[1] 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

[2] Talikoti, Prashanth et al. “Hyperhomocysteinemia, Insulin Resistance and High HS- CRP Levels in Prehypertension.” Journal of clinical and diagnostic research : JCDR vol. 8,8 (2014): CC07-9. doi:10.7860/JCDR/2014/8945.4669

[3] Talikoti, Prashanth et al. “Hyperhomocysteinemia, Insulin Resistance and High HS- CRP Levels in Prehypertension.” Journal of clinical and diagnostic research : JCDR vol. 8,8 (2014): CC07-9. doi:10.7860/JCDR/2014/8945.4669

[4] Zhong, Shanshan et al. “An update on lipid oxidation and inflammation in cardiovascular diseases.” Free radical biology & medicine vol. 144 (2019): 266-278. doi:10.1016/j.freeradbiomed.2019.03.036

[5] Hyman, Mark A. “Environmental toxins, obesity, and diabetes: an emerging risk factor.” Alternative therapies in health and medicine vol. 16,2 (2010): 56-8.

[6] Rice, Kevin M et al. “Environmental mercury and its toxic effects.” Journal of preventive medicine and public health = Yebang Uihakhoe chi vol. 47,2 (2014): 74-83. doi:10.3961/jpmph.2014.47.2.74

[7] Mirhosseini, Naghmeh et al. “Vitamin D Supplementation, Serum 25(OH)D Concentrations and Cardiovascular Disease Risk Factors: A Systematic Review and Meta-Analysis.” Frontiers in cardiovascular medicine vol. 5 87. 12 Jul. 2018, doi:10.3389/fcvm.2018.00087

[8]Kendrick, Jessica et al. “25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey.” Atherosclerosis vol. 205,1 (2009): 255-60. doi:10.1016/j.atherosclerosis.2008.10.033 Top of Form

[9] van Ballegooijen, A J, and J W Beulens. “The Role of Vitamin K Status in Cardiovascular Health: Evidence from Observational and Clinical Studies.” Current nutrition reports vol. 6,3 (2017): 197-205. doi:10.1007/s13668-017-0208-8

[10] Chen, Heng-Gui et al. “Association of vitamin K with cardiovascular events and all-cause mortality: a systematic review and meta-analysis.” European journal of nutrition vol. 58,6 (2019): 2191-2205. doi:10.1007/s00394-019-01998-3.

[11] Rosano, G M C et al. “Cardiovascular disease in women, is it different to men? The role of sex hormones.” Climacteric : the journal of the International Menopause Society vol. 20,2 (2017): 125-128. doi:10.1080/13697137.2017.1291780

[12] Hyde, Zoë et al. “Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study.” The Journal of clinical endocrinology and metabolism vol. 97,1 (2012): 179-89. doi:10.1210/jc.2011-1617

[13] Zhao, Di et al. “Endogenous Sex Hormones and Incident Cardiovascular Disease in Post-Menopausal Women.” Journal of the American College of Cardiology vol. 71,22 (2018): 2555-2566. doi:10.1016/j.jacc.2018.01.083

[14] Wolberg, Alisa S. “Primed to Understand Fibrinogen in Cardiovascular Disease.” Arteriosclerosis, thrombosis, and vascular biology vol. 36,1 (2016): 4-6. doi:10.1161/ATVBAHA.115.306754

[15] Gatarek, Paulina, and Joanna Kaluzna-Czaplinska. “Trimethylamine N-oxide (TMAO) in human health.” EXCLI journal vol. 20 301-319. 11 Feb. 2021, doi:10.17179/excli2020-3239

[16] Quest Diagnostics. TMAO.

[17] Janeiro, Manuel H et al. “Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target.” Nutrients vol. 10,10 1398. 1 Oct. 2018, doi:10.3390/nu10101398

[18] Yu, Edward et al. “Diet, Lifestyle, Biomarkers, Genetic Factors, and Risk of Cardiovascular Disease in the Nurses' Health Studies.” American journal of public health vol. 106,9 (2016): 1616-23. doi:10.2105/AJPH.2016.303316

[19] Casas, Rosa et al. “Nutrition and Cardiovascular Health.” International journal of molecular sciences vol. 19,12 3988. 11 Dec. 2018, doi:10.3390/ijms19123988

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ().

[20] Yu, Edward et al. “Diet, Lifestyle, Biomarkers, Genetic Factors, and Risk of Cardiovascular Disease in the Nurses' Health Studies.” American journal of public health vol. 106,9 (2016): 1616-23. doi:10.2105/AJPH.2016.303316

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