Heart Disease Risk Factors: Beyond the Big 5

Most everyone knows the ‘Big 5 Risk Factors’ for Heart Disease.  But did you know there are dozens of other risk factors that few doctors discuss with their patients?  Many of these risk factors don’t readily come to mind during a doctor-patient visit, often because the doctor has a limited amount of time with the patient and due to a lack of information the physician may have about this extended list of risk factors.

First, we will start with the simple ‘Big 5 Risk Factors’.


Hypertension (High Blood Pressure)



Family History

I often tell my patients that two things are needed for atherosclerotic plaque to form in their arteries. First, they need inflammation or damage to the endothelium, the single cell layer inside their blood vessels. Second, they need oxidized cholesterol particles, predominantly LDL. Both oxidative stress and mechanical damage to the endothelium denude the endothelial glycocalyx’s inner lining of the blood vessel of its protective layer. (More on the endothelial glycocalyx in another blog post).

Smoking accomplishes both of these prerequisites. The chemicals in the smoke directly damage the endothelium, and those same chemicals increase oxidative stress, which oxidizes the LDL particles so they can more readily ‘set up shop’ in the wall of the blood vessel.

Hypertension causes shear stress to the inner wall of the blood vessel. Imagine a water hose with a high-pressure nozzle (high blood pressure). When directed against a wall, that water will forcefully clean the dirt off the wall.  With high blood pressure, however, this constant increased high-pressure force on the inside of the blood vessels damages the endothelial layer, accomplishing the first prerequisite for atherosclerosis,  damage to the endothelium.

Diabetes does multiple things to promote atherosclerosis. Diabetics have higher average blood sugar levels than non-diabetics. Type 2 diabetics also typically have elevated triglyceride levels. High blood glucose levels and elevated triglyceride levels are associated with accelerated atherosclerosis. One way is through endothelial cell disruption due to the multiple inflammatory molecules (cytokines) associated with diabetes. Also, oxidative stress is elevated in type 2 diabetics. This oxidative stress oxidizes the LDL particles, making it easier for the LDL to enter the artery wall and begin forming a plaque. (Think of the endothelium as a screen.  Oxidized LDL particles are small, and non-oxidized LDL particles are large. The small oxidized LDL particles can squeeze through the holes in the screen, but the large ones cannot. This is why progressive cardiologists check particle number, particle size, or oxidized LDL levels in an advanced lipid panel when helping their patients reduce their risk.) The NLRP3 inflammasome is strongly associated with diabetes. The NLRP3 inflammasome promotes the development of atherosclerosis by increasing oxidative stress. The inflammatory state caused by diabetes also makes platelets stickier, increasing cardiovascular risk.

High Cholesterol levels are widely known to be a risk factor for heart disease. However, the landscape has changed over the past several decades. We now know that predominantly oxidized LDL is the bad actor in causing atherosclerosis. Apo B, however, has a stronger associated risk with atherosclerosis than LDL cholesterol.  (LDL is in the Apo B ‘bucket). Make sure your doctor is checking Apo B on your next lipid panel. Many patients come to me because they had slightly elevated LDL cholesterol on a standard lipid panel, and their doctor told them they had to go on a statin drug. First, LDL is often calculated and not directly measured. Second, the patient rarely arrives at my office with an advanced lipid panel measuring LDL particle number, particle size, oxidized LDL levels, or Apo B.  For me to provide my best recommendations, these numbers are essential.  If your LDL is slightly high and you do not have known coronary atherosclerosis or other risk factors, you need to know the size of the LDL particles to decide whether medications are needed for you. If your LDL is slightly high but you have predominantly large LDL particles, statins are not likely to do you any good and will only expose you to the well-known side effects of these drugs. (How can you know definitively whether you have any coronary atherosclerosis? Get a coronary CT angiogram with Cleerly AI plaque analysis). Then there is Lp(a), otherwise known as “Lp little a.” Lp(a) is a lipid particle similar to LDL cholesterol but worse.  It is associated with premature atherosclerosis and aortic valve disease. It is primarily genetically determined. If your Lp(a) is high, you can thank your parents for that – just kidding. Unfortunately, there are presently no drugs that lower Lp(a) (statins do not lower Lp(a)). Some natural supplements may help lower it, and some new drugs are likely to get FDA approval within the next year or two that can lower Lp(a) by as much as 90%.

A Family History of early coronary artery disease will increase the risk to the offspring. Multiple factors are at play here. Elevated Lp(a) is inherited, as is familial hypercholesterolemia. Additionally, multiple genetic SNPs (single nucleotide polymorphisms) can greatly increase cardiovascular risk.  We measure these with a specialized cardiac genetic panel. Knowing your genetic risk factors can help guide the recommendations and how aggressive to be with diet, lifestyle, medications, and supplements. One more well-known genetic risk factor is APO E.  You get one APO E gene from each parent.  The major alleles are e2, e3, and e4. E3 is an average risk for both cardiovascular disease and Alzheimer’s disease. E2 is a lower risk, and E4 is a higher risk. So, having APO e2/e2 (one e2 from each parent) is the lowest possible risk for cardiovascular disease and Alzheimer’s disease. Apo e3/e3 is the average risk, and APO e4/e4 is the highest risk; thus, these persons need the most aggressive preventive measures possible.

So, now on to the other cardiovascular risk factors. Anything that causes inflammation, oxidative stress, or immune dysfunction can negatively affect the walls of arteries, increasing atherosclerosis. More than 50% of persons with heart disease don’t have any of the ‘Big 5″

Here is a partial list of risk factors beyond the ‘Big 5’.

Obesity, especially visceral fat, increases oxidized LDL levels and produces inflammatory cytokines that can directly damage the endothelial cells.

Hyperuricemia (gout) leads to excessive oxidative stress, which increases atherosclerosis.

Micronutrient Deficiencies, especially vitamin D and vitamin K, increase cardiovascular risk. Many micronutrients, when present in sufficient amounts, suppress inflammatory molecules. Those inflammatory compounds wreak havoc on the blood vessels when these vitamins are deficient.

Lack of Adequate Sleep triggers chronic inflammation which increases plaque formation in the blood vessels.

Low Testosterone in men increases LDL by altering the expression of PCSK9 and LDLR.

Low Estrogen in women. After menopause women’s risk of heart disease approaches that of men. THis is because estrogen has a protective effect on the heart and the blood vessels and with menopause, estrogen levels decline.

Epicardial fat – fat around the heart produces inflammatory compounds that directly affect the coronary arteries.

Kidney disease increases inflammation throughout the body and accelerates the progression of atherosclerosis.

High fibrinogen levels – can increase blood clotting.

Intake of Trans-fats (often found in fried food) is a fast track to forming plaque in arteries.

Low intake of Omega 3 fatty acids. This can be measured with a test called the Omega 3 index. Being in the group of persons with the lowest level of Omega 3 fatty acids places you at a 75% increased risk of a cardiac event.

Low potassium, low magnesium, and high sodium levels increase heart risk.

Immune system problems increase immune cell function at damaged sites in the blood vessel, increasing plague formation.

Stress and anxiety increase cortisol levels, which triggers the production of inflammatory compounds.

High Homocysteine levels can damage the arteries’ endothelium and smooth muscle cells.

Hypothyroidism can constrict blood vessels and increase cholesterol levels.

Long-standing smoldering infections. These increase inflammatory compounds that circulate through the body and damage blood vessels.

Heavy metal toxicity increases inflammation throughout the body and in the blood vessels specifically.

Environmental pollution Increases inflammation.

Organic toxins increase inflammation.

Mold exposure increases inflammation.

The above is only a partial list of other heart disease risk factors. Many others exist as well. The good news is most of these can be tested for and treated to reduce your risk. So, do yourself a favor. If you know you have any of the above, find ways to address each condition. Let us know if you have questions or need help with any of these. If you don’t know but are concerned one or more of these factors may be present, get tested by a physician knowledgeable in this expanded list of risk factors. Most of these risk factors are modifiable. We can help reduce your risk!

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