• Dr Shawn M. Carney

Heart Disease - The Risk Factors Your Cardiologist Didn't Test You For

Updated: Apr 14

Testing cardiovascular risk factors can be much more accurate than the still commonly ordered standard lipid panel. Cardiologists know about these, but do you?

**image credits


Prevalence of Cardiovascular Disease

Heart disease remains the leading cause of death for men, women, and people of most racial and ethnic groups in the United States.1 One person dies every 36 seconds in the United States from cardiovascular disease (CVD).1 There was even a study back in 2009 which reviewed over 100,000 hospitalized cases and found nearly half of all heart attack patients did not demonstrate prior risk which would indicate they were heading toward an attack.2 Some risk factors for heart disease are more obvious than others. Things that increase one's risk include smoking, having high blood pressure or diabetes, having a family history, being overweight or over 45 years of age if a male and over 50 years of age if female, as well as being under significant stress. But these are not the only risk factors.


Because lipoprotein particles play a key role in atherogenesis, they are useful biomarkers for assessing CVD risk as well as for monitoring lipid-lowering therapy. Lipoproteins have long been measured using lipid panels. Lipid panels have been the standard of heart disease risk and cholesterol assessment for literally decades. But we've learned a lot since then. For over ten years in the peer review literature, tests that better indicate true risk have existed and been available commercially. Despite this, standard lipid panels still serve as an initial broad medical assessment tool for abnormalities in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol (calculated), and cholesterol/HDL ratio (calculated). A lipid panel is used to identify hyperlipidemia, which may indicate an increased risk for cardiovascular disease. But the pivotal LDL you review with your physician is actually a calculation, not even an actual direct measurement, that is unless your triglyceride level is greater than 400 mg/dL, then a measure of 'Direct LDL' is done.


What are some of the more accurate ways to have heart disease risk factors tested? And what other risk factors can a patient be informed about if they are getting tested anyway? I'm glad you asked.


Lipoprotein Subfractionation

Lipoprotein subfractionation is the measurement of different sized particles, within a particular lipoprotein group. This is accomplished using various methods at different laboratories. Individual lipoprotein subclasses are separated and direct quantification of lipoproteins provides precise particle counts for each lipoprotein type and subclass.


LDL Particle Number (LDL-P) - LDL-P is a term you may not have heard about from your primary care physician or cardiologist, but it has been in the scientific literature for years. In fact, the risk of CVD has been shown to follow LDL-P so much, that in 2008 the American Diabetes Association (ADA) and American College of Cardiology (ACC) issued a joint statement suggesting direct LDL-P measurement by nuclear magnetic resonance (NMR) as a superior method for assessing individual risk on this topic.5 I have often found an elevated LDL particle number in a patient that had a first degree relative suffer from some form of heart disease. Some of these patients have had standard lipid panel measurements of LDL and total cholesterol within range. For such people, LDL-P exposes an increased CVD risk which was heretofore being overlooked.


LDL Small - This reflects the presence of predominately small size LDL particles, which are highly atherogenic. There is a 1.3x increased CVD risk associated with the small LDL trait.


LDL Medium - Elevations of LDL-medium bring with them a 1.4x increased risk for CVD.


HDL Large - This protective type of lipoprotein, the HDL Large subclass, is the most efficient cholesterol reabsorbing HDL particle in the body. It best reflects the lowering of cholesterol from body tissues and cholesterol clearance by the liver. Low levels of large HDL are correlated with a 1.8x increased CVD risk.


Apolipoproteins

Apoprotein B-100 (Apo B) - Apo B is the predominant apoprotein attached to LDL, intermediate-density lipoproteins (IDL), and very-low-density lipoproteins (VLDL); since each of these lipid particles carries only one Apo B molecule, this is a very accurate way to assess particle number. It has been found to have a better clinical correlation with risk of CVD risk than the LDL which is still routinely measured on common lipid panels. Several decades of scientific literature support the measurement of Apo B for monitoring response to statin therapy. Apo B Elevated Apo B is associated with a 2.0–2.5x increased CVD risk.


Lipoprotein(a) [Lp (a)] - Associated with increased coagulation and increased incidence of CVD, the level of Lp(a) is genetically determined and is not easily modified by lifestyle changes, supplements or drugs, though some interventions can help. Elevated Lp (a) is associated with increased coagulation and a 1.5–5.3x increased incidence of CVD and has been linked to the promotion of both early and advanced stage atherosclerosis.

Inflammation

Fibrinogen or Fibrinogen antigen (FA) - FA is a plasma glycoprotein that can be transformed into a fibrin clot in response to vascular or tissue injury. Most heart attacks and cardiac deaths are precipitated by acute clots, and clots participate in atherogenesis.16 Since levels of FA are correlated with the severity and extent of coronary, cerebral and peripheral atherosclerosis, these levels may contribute substantially to disease potential.


hs-C-reactive protein (hs-CRP) - A measurement of hs-CRP is a highly sensitive measurement of C-reactive protein; the hs-CRP blood level signals how much low-grade inflammation is present in the vessel wall. Patients with high CRP have a 1.5–2.0x increased risk of developing subsequent atherosclerotic disease compared with patients with low CRP levels. It’s also been demonstrated that lowering hs- CRP, independent of lipid levels, results in a 15% risk reduction of recurrent cardiovascular events.


Lipoprotein associated phospholipase A2 (Lp-PLA2) - Lp-PLA2 plays a causal role in the vascular inflammatory process, leading to the formation of vulnerable, rupture-prone plaque. Because of this, Lp-PLA2 can predict risk of a heart attack or stroke. Elevated Lp-PLA levels have been associated with a 1.7-2.9x increased risk of cardiovascular events and a 1.9-11.4x increased risk for stroke events. The risk associated with elevated Lp-PLA levels is substantially increased in patients when both Lp-PLA and hs-CRP are elevated and has even been associated with periodontitis.21


Other laboratory tests that contribute towards cardiovascular risk factors include two markers for heart failure (NT-proBNP and ST2 Soluble) and several related to metabolic health (glucose, insulin, Hemoglobin A1C, homocysteine, Omega-3 and Omega-6 fatty acids, and vitamin D). Check future blogs for more information about them and remember to be your own advocate in your healthcare!


References:

1. Centers for Disease Control and Prevention. Underlying Cause of Death, 1999–2018. CDC WONDER Online Database. Atlanta, GA: Centers for Disease Control and Prevention; 2018. Accessed March 12, 2020.

2. Sachdeva, A. et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J. 2009. Jan.

3. American Heart Association and American Stroke Association. Heart disease, stroke and research statistics at-a-glance. 2021.

4. Quest reference

5. Brunzell, J. et al. Lipoprotein Management in Patients With Cardiometabolic Risk. J Am Coll Cardiol. 2008. April.

6. Musunuru K, Orho-Melander M, Caulfield MP, et al. Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk. Arterioscler Thromb Vac Biol. 2009;29:1975-1980.

7. Melander O, Shiffman D, Caulfield MP, et al. Low-density lipoprotein particle number is associated with cardiovascular events among those not classified into statin benefit groups. J Am Coll Cardiol. 2015;65(23): 2571-2573.

8. Mora S, Caulfield MP, Wohlgemuth J, et al. Atherogenic lipoprotein subfractions determined by ion mobility and first cardiovascular events after random allocation to high-intensity statin or placebo: the justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER) trial. Circulation. 2015;132:2220-2229

9. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of low density lipoprotein cholesterol, nonhigh- density lipoprotein cholesterol, and apolipoprotein b as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337-345.

10. Nordesgaard B, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844-2853.

11. Roest M, Voorbij HAM, Van der Schouw YT, et al. High levels of urinary F2-isoprostanes predict cardiovascular mortality in postmenopausal women. J Clin Lipidol. 2008;2:298-303.

12. Meisinger C, Baumert J, Khuseyinova N, et al. Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population. Circulation. 2005;112:651-657.

13. Holvoet P, De Keyzer D, Jacobs DR. Oxidized LDL and the metabolic syndrome. Future Lipidol. 2008;3(6):637-649.

14. Willeit P, Freitag DF, Laukkanen JA, et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. J Am Heart Assoc. 2015;4e001833.

15. Kannel WB. Influence of fibrinogen on cardiovascular disease. Drugs. 1997;54 Suppl 3:32-40.

16. Heinrich, J et al. Fibrinogen and Cardiovascular Risk. J Cardiovasc Risk. 1995 Jun;2(3):197--205.

17. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.

18. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-979.

19. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565.

20. Cushman M, Judd S, Kissela, et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and coronary heart disease risk in a biracial cohort: the reasons for geographic and racial differences in stroke (REGARDS) Cohort. Atherosclerosis. 2015;241:e1-e31. [Abstract].

21. Koshy, B et al. The Association Between Periodontal Status, Serum Lipid Levels, Lipoprotein Associated Phospholipase A2 (Lp-PLA2) in Chronic Periodontitis Subjects and Healthy Controls. J Clin Diagn Res. 2017 Sep; 11(9): ZC17-ZC21.

22. **image credits Center For Disease Control_https://www.cdc.gov/cholesterol/index.htm


The content and any recommendations in this article are for informational purposes only. They are not intended to replace the advice of the reader's own licensed healthcare professional or physician and are not intended to be taken as direct diagnostic or treatment directives. Any treatments described in this article may have known and unknown side effects and/or health hazards. Each reader is solely responsible for his or her own healthcare choices and decisions. The author advises the reader to discuss these ideas with a licensed naturopathic physician.