The Real Villains of Heart Disease

The Thrombogenic Theory of Heart Disease

The thrombogenic (clot-forming) theory of heart disease offers that, right from the start, plaque development and progression are clotting events from blood vessel injury. The blood clot that forms a heart attack isn’t just the end of the story; vessel injury, inflammation and blood clotting are the very engine that builds the plaque from the beginning. So what causes blood vessel injury, inflammation, blood clots and plaques?

Let’s explore our blood vessels and the more likely root cause of heart disease. 

Arteries and veins have an inner (lumen) lining where the blood flows, called the endothelium. This impenetrable layer has a vital, soft, weblike and slippery inner coating called the glycocalyx. If you have ever picked up a slippery fish, you have firsthand knowledge of what a glycocalyx feels like! Just like the glycocalyx on a fish’s scales, our glycocalyx acts to keep the blood flowing smoothly and prevents blood clots.

The glycocalyx does this through producing nitric oxide, the most powerful anticoagulant and dilator of blood vessels (vasodilator) we make. But this critical and functional layer is also quite delicate. Things that injure this glycocalyx and the underlying endothelium break this balance. High blood pressure, smoking, high blood glucose, chronic stress, toxins (such as lead and mold), inflammatory conditions like rheumatoid arthritis and chronic kidney failure all dig holes at high-pressure points in the arterial vessels. Our clever body then goes into repair mode. Through a complicated coagulation cascade, our body fills in the endothelial injury with a tiny blood clot, just like it does if we cut ourselves shaving.

In any blood clot, we will find all the constituents of blood: red blood cells, platelets, fibrin (a glue-like substance), white blood cells and yes, even cholesterol! The cholesterol in our blood clots and forms subsequent plaques was part of the repair process to the injury of blood vessels.

Inflammation, toxins and elevated insulin are the ROOT CAUSE of heart disease: cholesterol is a key part of the repair process. Put another way, inflammation lit the fire, and cholesterol is the firefighter that put it out. Don’t blame the cholesterol for what the inflammation did!

So what happens to the blood clot in our artery?

Unlike a scab that falls off from a skin cut, the blood clots in our vessels can’t merely fall off, or it would get stuck in the artery and cut off the blood supply farther down. Instead, our body has another spectacular response. The bone marrow sends into the blood a special “band aid,” an endothelial progenitor cell that lies on top of the blood clot, forming a blood clot sandwich (ew!). The clot is now safely out of the blood vessel lumen, the new endothelial cell can create a new glycocalyx and order is restored. However, if we continue to damage the endothelium (stress, smoking, uncontrolled high blood pressure, toxins, high-carb diet), we outpace our capacity to repair.

As this damage continues, calcium is deposited, transforming the blood clot into a hardened, bony structure. As this calcified, fibrous plaque pushes into the inner space (lumen) of the artery, blood flow is reduced, and the vessel loses its elasticity. This repetitive cycle creates calcified plaque that we can quantify with a coronary calcium artery (CAC) score to screen for atherosclerosis, coronary heart disease. 

Our LDL Obsession

As statins gained popularity in the 1990’s during my medical training, there was wide speculation that heart surgeons and cardiologists would one day be out of work. With one in every three US adults now on a statin to reduce LDL, have we crushed heart disease? Not a chance. Because we are attacking the wrong bad guy. It is our high triglycerides and low HDL that are more strongly tied to heart disease.

³ However, we have no drug to lower triglycerides and no drug to raise HDL. So we target LDL because it is the only part of the lipid blood panel that can be treated with a drug. As guidelines for “acceptable” LDL levels keep getting lowered, statins have become one of the most prescribed drugs in the world. This fuels the pharmaceutical industry for trillions of dollars annually. These funds help to support their industry-sponsored research, creating biased studies which support their work and are read by physicians.

Rather than addressing the root cause of heart disease, requiring an often complex and personalized approach, medicine has created a simple LDL-statin reflex loop. We have been convinced by the pharmaceutical industry to chase our tail to lower LDL. But there are too many inconsistencies to state that LDL causes heart disease. Nearly 75% of patients who present with a heart attack will have a normal LDL.⁴ Patients who have their first heart attack get prescribed a statin and still return with subsequent heart attacks. And since veins and arteries have the same blood, the same LDL levels, then why don’t veins also get plaques if high LDL causes atherosclerosis? And if LDL caused atherosclerosis, everyone with an elevated LDL would have atherosclerosis. My LDL has been significantly elevated for over three decades, yet my CAC score in October 2025 was zero. 

On a high-fat keto or carnivore diet, LDL may decrease, stay the same or rise. Interestingly, we have emerging evidence of people with profoundly elevated LDL on one of these low-inflammatory diets with zero atherosclerosis on imaging studies. For some lean individuals, the increase can be profound, known as a lean mass hyperresponder (LMHR). This response, speculated in the lipid energy model, occurs as lean individuals who use fat as their primary fuel, shuttling it through the blood. A recent study looked at 100 such LMHR, all in their 50’s, with CT angiography. Over one year, the vast majority had no plaque development despite extremely high LDL values.⁵ For anyone interested in this, I would highly recommend watching “The Cholesterol Code” documentary by Dave Feldman.

High LDL has been shown to be protective as we age and is associated with greater longevity.⁶ This is because LDL also has immunological functions, helping us to fight infections and cancer. Elevated LDL does not cause heart disease. We need to attack the correct villain, but there is no drug for a broken lifestyle. 

Recognizing an Old Villain:

I am grateful that one heart disease villain is finally getting proper attention: Lpa. This is a type of LDL that has an extra sticky apo, a protein wrapped on the outside.

Although we ALL have some Lpa, about 20% of us have an elevated amount, doubling or tripling the risk of heart disease. Our levels are 90% determined by our genes, but lifestyle factors do play a role.

For women, menopause can increase Lpa by up to 30%. Increases in visceral fat will also drive up Lpa values. Lpa’s apo a is like a strip of double-sided duct tape. Higher Lpa creates inflammation and makes blood hypercoagulable, more likely to clot. Any exposed endothelium will attract Lpa and the coagulation cascade. There was much research performed on Lpa in the 1980’s, but it was put on the back burner when it was discovered statins made Lpa worse. Now that there is a drug in phase three trials, interest in screening among cardiologists and other physicians is increasing. 

Cholesterol is a nutrient; it is not a disease. Atherosclerosis is the disease we need to prevent and attack. The bad guys we need to fight are inflammation and insulin resistance. So we have a new set of heart disease prevention rules. 

1. We need to protect the endothelium and prevent blood clots if we want to prevent arterial plaque. We need to control blood pressure, prevent kidney disease and avoid toxins.

2. We need to aggressively control inflammation in our diet and lifestyle. We need to treat our low-carbohydrate diet, sleep and stress management as critical healing tools.

3. And we need tests that are better markers of metabolic health and cardiac risk. In predicting who will have a heart attack, it is elevated blood glucose, high triglycerides, low HDL, high Lpa and inflammation that have the greatest predictive power. The American College of Cardiology and American Heart Association finally recommended in March 2026 that people check their cardiac risk through ordering CAC, hsCRP and Lpa.⁸ 

   
   

   By being aware of our genetic, acquired and lifestyle individual risks, we can address the root causes of heart disease to better prevent and treat our number one killer. The reflex loop of high LDL and statin prescription hasn’t been working except for pharmaceutical shareholders. 

   
   

I have great hope for medicine, as patients demand more and metabolic approaches take root.

References: 

3) da Luz PL, Favarato D, Faria-Neto JR Jr, Lemos P, Chagas AC. High ratio of triglycerides to HDL-cholesterol predicts extensive coronary disease. Clinics (Sao Paulo). 2008 Aug;63(4):427-32. doi: 10.1590/s1807-59322008000400003. PMID: 18719750

4) Amit Sachdeva, MD,Christopher P. Cannon, MD,Prakash C. Deedwania, MD,Kenneth A. LaBresh, MD,Sidney C. Smith, Jr,David Dai, Adrian Hernandez, MD,Gregg C. Fonarow, MD Lipid levels in patients hospitalized with coronary artery disease: An analysis of 136,905 hospitalizations in Get With The Guidelines Am Heart Journal January 2009

5) Budoff M, Manubolu VS, Kinninger A, Norwitz NG, Feldman D, Wood TR, Fialkow J, Cury R, Feldman T, Nasir K. Carbohydrate Restriction-Induced Elevations in LDL-Cholesterol and Atherosclerosis: The KETO Trial. JACC Adv. 2024 Aug 28;3(8):101109. doi: 10.1016/j.jacadv.2024.101109. PMID: 39372369; PMCID 

6) Kip KE, Diamond D, Mulukutla S, Marroquin OC. Is LDL cholesterol associated with long-term mortality among primary prevention adults? A retrospective cohort study from a large healthcare system. BMJ Open. 2024 Mar 28;14(3):e077949. doi: 10.1136/bmjopen-2023-077949. PMID: 38548371 

7) https://www.amgen.com/stories/2023/02/8-things-to-know-about-lipoproteina

8) Blumenthal, Roger S., et al. "2026 

ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines." Circulation, vol. 153, 13 Mar. 2026. AHA Journals, doi:10.1161/CIR.0000000000001423.