A New Study Reveals That Very High Cholesterol Does Not Cause Atherosclerosis in Some Lean People

Dr. Matthew Budoff presented data on December 9, 2023, demonstrating that a subgroup of individuals with very high total cholesterol and LDL do not seem to develop heart disease. You can watch his presentation here. The subjects are known as "Lean Mass Hyper Responders." The group became notable during the rise in popularity of ketogenic diets. This post will cover what a ketogenic diet is, what a lean mass hyper responder is, the possible mechanism of why they seem to be immune to heart disease, and the study itself.

Ketogenic Diet

The ketogenic diet allows for very little to zero carbohydrates. Normally, carbohydrates from sugar, flour, and other fruits and vegetables are broken down into sugar for use as energy or stored in the liver as glycogen for later use. Since ketogenic diets don't contain enough carbohydrates to use for energy, fats are used instead. The body becomes so efficient at using fat (Ketones) for energy that it will readily break down bodily fat stores when energy is needed. Ketones are a kind of fat that can be measured in the blood, urine, or breath of ketogenic individuals. The most common one is beta-hydroxybutyrate. The "keto" part of the diet's name comes from the ketones. Fat loss is one of the reasons that the ketogenic diet is so popular.

Lean Mass Hyper Responders (LMHR)

Certain people respond to ketogenic diets by raising their total cholesterol, including HDL and LDL. These individuals are always lean. They present with the triad of high LDL, high HDL, and low triglycerides. A low ratio of triglycerides to HDL appears to be protective in studies. For more, see this post. In other words, they have lean mass and hyper respond to a ketogenic diet by increasing their cholesterol. Their physicians are usually dismayed by their high cholesterol and recommend cholesterol-lowering statins while trying to dissuade their patients from eating the keto diet. The result is that unsuspecting patients will also become dismayed. The result is that they quit their diet and go on medications like Lipitor. I wrote about a lean relative who went on the carnivore diet, which is a form of the keto diet, and had numerous improvements in his health, but whose cholesterol shot up, and he was reprimanded by his doctor. You can read his story here. Thankfully, he stuck to his diet.

The Lipid Energy Model

Courtesy of Dr. Matthew Budoff

A proposed mechanism for the hyper response is called the lipid energy model. In the model, stores of glycogen in the liver become depleted. The depletion is not cause for concern. However, the LMHR is so efficient at burning fat that the liver dumps high amounts of stored fat into the blood for use as energy. Fat, like cholesterol, can't dissolve in blood and needs to be carried by special particles. The particle that carries the fat is called a very low-density lipoprotein, or VLDL. Within minutes, the fat is delivered for use, and the particle shrinks into an LDL particle. Hence, there is an increase in LDL and total cholesterol. For more information on the subject, Dave Feldman's Cholesterol Code is a fantastic source of information.

The LMHR Study

Cedars-Sinai.org

Dr. Budoff chose 100 subjects who had none of the usual markers expected in people with high cholesterol, such as obesity, high blood sugar, high blood pressure, high fasting insulin, etc. People with genetically induced high cholesterol were eliminated. The subjects were on a keto diet for an average of 4.7 years and had LDL cholesterol before the diet of a mean of 122, which rose to 272 on the diet. He used data from the Miami Heart Study (MiHeart) as controls. In his design, Budoff used eighty people from the LMHR study who were matched to age range and were then matched 1:1 for age, gender, race, diabetes mellitus, hyperlipidemia, hypertension, and past smoking to asymptomatic subjects from the MiHeart study. The primary analysis used high-resolution heart scans, allowing for primary analysis of Total Plaque Score (TPS), Total Stenosis Score (TSS), and Segment Involvement Score (SIS), which are indicators of atherosclerotic heart disease. The matched mean age was 55.5 years, with a very high mean cholesterol of 272 (the maximum LDL was 591 in one individual) and a mean of 4.7 years duration on a ketogenic diet.

The results were:

•  There was no significant difference in coronary plaque burden of the LMHR subjects, who had a mean LDL of 272, and the MiHeart controls, who had a mean LDL of 123.

•  There was no significant difference in CAC, which is a measure of coronary artery calcification, which makes it one of the best indicators of heart disease. 

• No relationship was found between LDL elevations and coronary plaque.

Conclusion

The study is ongoing, and more scans will be done next year. However, the initial results indicate that in the absence of any other cardiac and metabolic risks, LMHR individuals do not seem to develop cardiovascular disease. This does not mean that high LDL is not a concern. A Danish study of people with a genetic condition that raises total cholesterol and LDL showed that the higher they were, the more atherosclerosis and death occurred. 1 (If you have any concerns about your heart health, consult with a physician, who may opt to have you take a calcium scan, which is the best way to determine if atherosclerotic heart disease is present). However, the LMHR study points to LDL levels needing cofactors like inflammation, obesity, high blood pressure, and high blood sugar to cause atherosclerosis. Time will tell.