Changing the Heart Cholesterol Hypothesis Paradigm

Groundbreaking Data on LDL Levels and Heart Disease in LMHR individuals

At the 2024 Metabolic Health Conference, I had the opportunity to speak with Dave Feldman. When it comes to understanding LDL cholesterol and the phenomenon known as Lean Mass Hyper-Responder (LMHR), Dave stands as a guide, dedicating his life's work to unraveling the intricacies of the truth and following it wherever it leads him.

He shared the latest insights on the Lean Mass Hyper Responder (LMHR) CT angiogram study led by UCLA cardiologist Dr. Matt Budoff, Dave Feldman, Nick Norwitz, and the Citizen Science Foundation (see references); they’ve achieved remarkable milestones in funding and initiating this research, all without relying on pharma support. Their recent comprehensive update has once again reshaped the understanding of the heart cholesterol hypothesis paradigm.

The study delves into the effects of a ketogenic diet on lean, otherwise healthy individuals. This dietary approach significantly elevates LDL cholesterol (LDL-C) levels, a phenomenon that most healthcare providers assume leads to atherosclerotic plaques in the coronary arteries, potentially resulting in a heart attack. Given that heart disease remains the leading cause of death in the Western world, this investigation holds paramount importance. Dave Feldman has extensively documented these findings on his website, www.cholesterolcode.com, and he coined the term Lean Mass Hyper-responders (LMHR). Typically, individuals falling under this category experience a remarkable increase in LDL levels while following a ketogenic diet, often ranging between 180 and 500 mg/dl (normal levels are considered below 130).

TITLE: The Keto Trial Match Analysis Provides Groundbreaking Data on LDL Levels and Heart Disease

Dr. Matthew Budoff presented the matched analysis of KETO (#LMHRstudy) vs Control (#MiHeart) cohorts in this video. In this article we’ll focus on the LMHR individuals. Dr. Budoff’s study centers around 80 otherwise healthy people (without obesity, high blood sugar, high blood pressure, high fasting insulin, etc.) who adopted a ketogenic diet (KD), which resulted in a substantial increase in LDL cholesterol. These lean individuals generally tend to have a remarkable increase of LDL-C with a ketogenic diet. Some individuals had LDL increases of more than 500 mg/dl. Think about that for a moment when most healthcare professionals aim for an LDL cholesterol below 130 mg/dl. 

The primary analysis of these individuals included a High-resolution CT angiogram and CAC heart scan (#CCTA) allow for primary analysis of Total Plaque Score (TPS), Total Stenosis Score (TSS), and Segment Involvement Score (SIS). Many of these individuals also undergo frequent blood testing to measure their lipids and other markers.

RESULTS - The mean age was 55.5 years, with a mean #LDL cholesterol of 272 mg/dL (max LDL-C 591) mg/dl and a mean of 4.7 years on a ketogenic diet. There was no significant difference in the coronary plaque burden of #LMHRstudy (mean LDL-C 272) cohort compared to #MiHeart controls (mean LDL-C 123 mg/dl). It’s important to know that pre-ketogenic diet, these individual’s LDL-C was 122 mg/dl. There was no significant difference in CAC (median and IQR) [0 (0,56)] versus [1 (0,49)], p = 0.520.

That was a lot of complicated scientific reading, and the main takeaways from all this is that in this subgroup of people (LMHR) who increased their LDL cholesterol a lot, they had no detectable plaque formation in their coronary arteries after 5 years.  

Key Points

• No relationship exists between LDL-C elevations and plaque in these LMHR individuals.

• Keto diet is a “Mediterranean” style with >4:1 unsaturated to saturated fat ratio.

• No genetic abnormalities were found to explain the lack of coronary plaque in LMHRs.

• No detectable plaque in CT Angiogram after nearly 5 years of follow-up.

• Thus far, 5 years into the study, the authors did not see any evidence that an LDL of 272 induced more atherosclerosis. 

• These people have among the highest LDL cholesterol of the US population.

• Interestingly, the average age of the participants is 53 years, 2/3 of whom are 50 and older, and 66% are male.

• The mean LDL cholesterol before the ketogenic diet was 135, just a little above the average mean for the population. Still, the mean average now in this group is 233, which isn’t just in the top 1% per the NHANES study; it’s in the top 10% of the top 1%, so the very highest LDL. 

What The Study Is

One of the most fascinating bits is that 2/3 of these individuals have calcification of 0 and no total plaque score. What does that mean? Despite 5 years of their LDLs being in the top 0.1% in the US, as best as we can detect, they have not yet developed any atherosclerosis in their coronary arteries.

 Dr. Budoff chose 80 subjects with no usual markers expected in people with high LDL cholesterol, such as obesity, high blood sugar, high blood pressure, high fasting insulin, etc.

The subjects were / still on a KD for an average of 4.7 years. Before the KD diet, their LDL cholesterol on average was 122, which rose to 272 on the KD diet. Dr. Budoff used data from the Miami Heart Study (MiHeart) as controls. In his design, Dr. Budoff studied 80 people from the LMHR study who were matched to age range 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 an extremely high mean cholesterol of 272 (the maximum LDL was 591 in one individual) and a mean of 4.7 years on a ketogenic diet.

What The Study Isn’t

This study doesn’t involve individuals from the general population seeking routine cardiovascular assessments in a cardiologist or internal medicine office. The participants are distinct in that they do not follow a standard American diet, nor do they exhibit conditions such as diabetes, obesity, hyperlipidemia, hypertension, heart disease, or existing coronary artery disease. Essentially, this study focuses on a healthier population—specifically, Lean Mass Hyper-Responders (LMHR)—who willingly undergo more extensive testing, including coronary artery calcium (CAC) and CT scans, beyond what is typically recommended in standard medical practice. Importantly, the study does not include definitive cardiovascular outcomes like mortality.

Why this Study is Important

LMHR individuals defy conventional recommendations by adhering to the ketogenic diet. This dietary approach, known for its richness in saturated fat, high animal protein, red meat, and often low fiber, often leads to elevated total cholesterol and a specific triad of high LDL, high HDL, and low triglycerides. Notably, these individuals tend to maintain a lean physique. Research suggests that a low ratio of triglycerides to HDL may have protective effects. Many LMHR individuals face resistance from their physicians, who, troubled by their elevated cholesterol, recommend cholesterol-lowering statins while discouraging the adoption of the ketogenic diet. Consequently, patients may become disheartened, leading them to abandon their dietary choices and opt for statin medications like Lipitor. Stories abound of lean individuals adopting the carnivore diet, a variant of the keto diet, experiencing notable health improvements, yet grappling with increased cholesterol levels and subsequent admonitions from their healthcare providers.

Important Questions:

So, what’s actually going on here?

A high LDL is conventionally considered a significant risk factor for heart disease. However, in Lean Mass Hyper-Responders (LMHRs), we observe an increase in cholesterol levels when they adopt a low-carb ketogenic diet (KD). This phenomenon appears closely linked to the individuals' leanness and other common markers associated with good metabolic health, including fasting glucose, insulin, CRP, and vitamin D levels. This raises several intriguing questions: To what extent can LDL cholesterol levels rise in this situation? Are the leanest individuals in this group consuming the highest amounts of saturated fat? Perhaps most crucially, do we observe the development of heart disease in the most extreme cases?

How is the total plaque buildup score measured?

The total plaque score measures various aspects of plaque buildup in the coronary arteries by taking the coronary artery calcium (CAC) scan and the CT angiogram; a total plaque score can be obtained. Nothing is more sensitive non-invasively than a CAC scan plus a CT angiogram combination, which is used in this study. They look at how many segments grade the plaque as mild to moderate or severe. They’re using a 15-segment model, and you can have a score of 3 for each segment so that the total score can go up to 45. A score under 10 is considered good, and a score of 45 is considered very bad.

So, when we talk about using CT angiography to look at atherosclerosis, there’s remarkable data regarding its robustness and reproducibility. We can look at the severity and find patients non-invasively who have significant stenosis. Still, if you look at the number of lesions and see how many different plaques are present, we can look at plaque volume, lumen volume, artery size, and high-risk blockages. This is a modality to look for and grade atherosclerosis; it’s dependable and robust. To give perspective, all large pharmaceutical companies use serial CT angiography to see if their drug affects atherosclerosis.

Where did the LMHRs land in the overall risk level?

Among the Lean Mass Hyper-Responder (LMHR) participants, a significant majority—two-thirds—displayed no discernible plaque buildup. This implies that they had a total plaque score of 0 or close to 0. The remaining one-third exhibited a total plaque score ranging between 1 and 8, with the highest observed score in this study being 8. It's important to note that the maximum score possible on this total plaque score is 45. In essence, the overall risk level appears to be low. Even among those participants who demonstrated an increase in plaque, the extent was relatively modest or mild.

Is LMHR the Same as Familial Hypercholesterolemia (FH)?

An important question is whether Lean Mass Hyper-Responder (LMHR) individuals with high LDLs are comparable to individuals with genetically induced high cholesterol, specifically familial hypercholesterolemia (FH), who also have elevated LDLs. The succinct answer is no, as people with FH were intentionally excluded from the study. The study participants had been on a ketogenic diet (KD) for an average of 4.7 years, starting with an average LDL cholesterol level of 122 before the diet, which then increased to an average of 272 on the KD. LMHR individuals differ from those with FH, despite both groups having extremely high LDL cholesterol levels. LMHR individuals exhibit normal cholesterol levels when adhering to a regular diet, and their LDL rises dramatically only when on a low-carb diet. They are otherwise healthy individuals.

In contrast, FH is a congenital disorder, and individuals with FH have persistently high LDL levels throughout their lives, unrelated to their dietary choices. A published case series involving an infant diagnosed with homozygous FH, having an LDL level of 548, illustrates the stark contrast. This child began multiple medications around the age of 2 to lower LDL levels, and despite interventions that reduced LDL to 139, a CT angiogram at age 8 revealed plaque buildup in multiple arteries. This comparison is intriguing because both the homozygous FH patient and some LMHR patients had a similar two-year exposure to LDL levels around 500. However, the older LMHR patients, who had additional exposure to normal LDL levels for over two decades of life, demonstrated a complete absence of detectable plaque.

So, what’s the proposed mechanism?

A proposed mechanism for the hyper-response is called the lipid energy model (LEM). In the LEM model, stores of glycogen in the liver become depleted. The LMHRs are 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 particular 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. 

We know that in lean metabolically healthy subjects’ carbohydrate restriction will deplete liver glycogen, and we think that leads to a lipoprotein lipase-mediated turnover, which increases LDL. More LDL-mediated LDL turnover leads to higher export of VLDL. When you have more VLDL and lipoprotein lipase, you end up with more HDL, more LDL, and fewer triglycerides. In other words, you process that VLDL and convert it into LDL. This is all very complex science.

Is this study just a one-off and cannot be repeated?

This study looks at five years of high LDL versus a lifetime of high LDL. But thus far, the LMHR study is reproducible. One such study that is important to consider is the Denmark study, which studied the association of coronary plaque with LDL cholesterol levels and the rates of cardiovascular disease.

The Danish study looked at 11,800 patients with CAC scores and LDLs above 190, very similar to what’s presented in the LMHR study, and you’ll see that more than 50% of these patients with a lifetime LDL above 190, and they didn’t have any appreciable coronary calcium plaque formation. Their hazard ratio for having a high LDL was 1. A hazard ratio of 1 means no difference between the two groups. A hazard ratio of greater than 1 or less than 1 means survival was better in one of the groups. So, not all LDL automatically promotes atherosclerosis, especially without coronary calcium.

Pointed Questions for Dr. Budoff

One cardiologist said, “So we are seeing these people in clinical practice, and it makes us feel very uncomfortable when somebody walks in with this. So, would you recommend that we just ignore the LDL and not treat them if they walk in?”

Dr. Budoff answered, “So, get a calcium score. Suppose we have significant data that a calcium score of error does not induce long-term risk. In that case, a calcium score of 0 in this population should reassure you that the Denmark study was FH lifetime LDL, and they had no increased risk of high LDL if their calcium score was zero.” 

Does this study blow away the LDL hypothesis? With the mean LDL being at 233, something is going on with the ketogenic diet.

Dr. Budoff answered, “no, I think it’s essential to recognize and let me just go back here because this is the LDL hypothesis in this population of patients from Denmark with FH. If they had coronary calcium and a high LDL, they were 3.5 times more likely to suffer MI and 2.4 times more likely to die. So, there’s still a solid relationship between LDL and cardiovascular events, but I don’t think everybody is susceptible to LDL. Again, I think it is a unique population whose LDL increases for a different reason than genetically elevated LDL cholesterol.”

Conclusion

Many cardiologists are disturbed by this study because it again questions the heart cholesterol diet hypothesis. Even Dr. Budoff once thought that if you had a population of patients with LDL of 233, he’d say 90% had FH. So far, this study has shown that if we look at the statistics based on people whose LDLs are at that level, we have 1% in this population.

The study is ongoing, and more scans will be done in the near future. However, the initial results indicate that without any other cardiac and metabolic risks, LMHR individuals do not seem to develop cardiovascular disease. This doesn’t mean that high LDL is not a concern. The 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. 

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 one of the best ways 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. The research is early, and confirmatory studies are needed. This is genuinely novel data, unlike any we’ve seen up to this point. Finally, we can find people with similar cardiovascular risk factors, age, gender, and ethnicity. See what the prevalence of plaque in the population of people who look like this leaves LMHRs without the LDL and what the LDL adds or doesn’t add. Regarding cardiovascular risk, there’s a straightforward sugar hack anyone can do to balance glucose levels almost overnight. This study challenges the conventional narrative that not all atherosclerotic plaques are necessarily pathological.

The principal investigator, Professor Matt Budoff, and his colleagues at the Harbor UCLA Center have no conflicts of interest with them regarding this and the funding that a Citizen Science Foundation has provided; no pharma dollars are used. 

I need to give a couple of important disclaimers. One, this article does not constitute medical advice or establish a patient-doctor relationship, and we remind you that existing guidelines in major institutions focused on heart disease strongly advise against high cholesterol levels.

References and Further Reading

Norwitz NG, Mindrum MR, Giral P, Kontush A, Soto-Mota A, Wood TR, D'Agostino DP, Manubolu VS, Budoff M, Krauss RM. Elevated LDL-cholesterol levels among lean mass hyper-responders on low-carbohydrate ketogenic diets deserve urgent clinical attention and further research. J Clin Lipidol. 2022 Nov-Dec;16(6):765-768. doi: 10.1016/j.jacl.2022.10.010. Epub 2022 Nov 2. PMID: 36351849.

Norwitz NG, Soto-Mota A, Feldman D, Parpos S, Budoff M. Case Report: Hypercholesterolemia "Lean Mass Hyper-Responder" Phenotype Presents in the Context of a Low Saturated Fat Carbohydrate-Restricted Diet. Front Endocrinol (Lausanne). 2022 Apr 14;13:830325. doi: 10.3389/fendo.2022.830325. PMID: 35498420; PMCID: PMC9048595.

Norwitz NG, Cromwell WC. Oreo Cookie Treatment Lowers LDL Cholesterol More Than High-Intensity Statin therapy in a Lean Mass Hyper-Responder on a Ketogenic Diet: A Curious Crossover Experiment. Metabolites. 2024 Jan 22;14(1):73. doi: 10.3390/metabo14010073. PMID: 38276308; PMCID: PMC10818743.

Cooper ID, Sanchez-Pizarro C, Norwitz NG, Feldman D, Kyriakidou Y, Edwards K, Petagine L, Elliot BT, Soto-Mota A. Thyroid markers and body composition predict LDL-cholesterol change in lean healthy women on a ketogenic diet: experimental support for the lipid energy model. Front Endocrinol (Lausanne). 2023 Dec 21;14:1326768. doi: 10.3389/fendo.2023.1326768. PMID: 38189051; PMCID: PMC10768172.

Schugar RC, Crawford PA. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care. 2012 Jul;15(4):374-80. doi: 10.1097/MCO.0b013e3283547157. PMID: 22617564; PMCID: PMC3679496.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2788975