Low Carb High Fat - Ketogenic

Summary

Dr. Matthew Budoff, a professor of medicine at UCLA School of Medicine, presented findings from the Keto Trial, a prospective study investigating the effects of carbohydrate-restricted ketogenic diets on LDL cholesterol elevation and coronary plaque progression in a specific subgroup called "lean mass hyperresponders." These individuals, despite being metabolically healthy and lean, experience significant LDL cholesterol increases (greater than 190 mg/dL) when on a ketogenic diet. The study enrolled 100 participants who strictly adhered to a ketogenic diet (<30 grams of carbohydrates per day) for one year, with rigorous cardiac CT angiography imaging at baseline and follow-up to assess coronary plaque changes.

The trial focused primarily on changes in total non-calcified coronary plaque volume and secondary changes in low attenuation plaque (LAP), which is associated with vulnerable plaque and higher cardiovascular risk. Multiple analytic tools were employed, including semi-quantitative total plaque score assessments, Clearly software analysis, and advanced AI-based HeartFlow plaque quantification validated against the invasive gold standard intravascular ultrasound (IVUS).

Results demonstrated that about 40-50% of participants showed plaque progression, while 50-60% showed no change or even regression, depending on the measurement method. The HeartFlow AI tool and blinded total plaque scores were consistent, revealing some regression in a minority of patients, whereas the Clearly software indicated nearly universal progression, showing discordance with the other methods.

Importantly, low attenuation plaque was rare and did not significantly increase over the year, suggesting limited development of vulnerable plaque in this cohort despite elevated LDL. Patients with zero baseline coronary calcium scores (calcium score of zero) generally showed minimal or no progression, consistent with prior studies that identify zero calcium as a strong predictor of low risk.

The findings suggest that while LDL cholesterol rises dramatically in lean mass hyperresponders on ketogenic diets, this does not universally translate into rapid or extensive coronary plaque progression within one year. Some individuals even exhibited plaque regression, and vulnerable plaque remained uncommon. Further detailed analyses using the Medis Qangio software are pending, with final results expected in 2025.

Highlights

• 🥑 Ketogenic diet induces significant LDL cholesterol elevation in lean mass hyperresponders.
• 🫀 100 metabolically healthy patients followed for one year with cardiac CT imaging.
• 💻 HeartFlow AI plaque quantification validated by invasive intravascular ultrasound, showing high accuracy.
• 📊 About 40-50% showed plaque progression; 50-60% had no change or regression depending on measurement method.
• 🔵 Low attenuation plaque (vulnerable plaque) was rare and did not increase significantly.
• 🧮 Patients with zero baseline coronary calcium score had minimal plaque progression.
• 🔍 Discordant results between Clearly software and other plaque assessment tools highlight methodological challenges.

Key Insights

• 🩺 Lean mass hyperresponders show significant LDL increases but heterogeneous plaque responses: Despite LDL cholesterol levels rising to an average of 272 mg/dL, only a subset of patients showed measurable coronary plaque progression. This challenges the simplistic notion that elevated LDL universally accelerates atherosclerosis in the short term, especially in metabolically healthy individuals. It underscores the complexity of cardiovascular risk beyond lipid levels alone.

• 🤖 AI-based HeartFlow plaque analysis correlates strongly with invasive gold standards: The HeartFlow software demonstrated excellent concordance with intravascular ultrasound (IVUS), affirming its utility as a reliable non-invasive tool for quantifying coronary plaque volume and composition. This technology represents a significant advance in cardiovascular imaging and risk stratification, enabling more precise monitoring of plaque changes over time.

• ⚠️ Low attenuation plaque remains uncommon despite high LDL: Vulnerable plaque, characterized by low attenuation on CT and associated with higher risk of cardiovascular events, was infrequent and stable in this cohort. This is clinically reassuring and suggests that short-term LDL elevation induced by ketogenic diets may not immediately promote the formation of high-risk plaque phenotypes, at least in the absence of other metabolic dysfunction.

• 📉 Plaque regression occurs in some patients, indicating potential protective mechanisms or variability in plaque biology: Approximately 6% of patients demonstrated plaque regression, confirmed by both HeartFlow and blinded semi-quantitative scoring. This finding highlights heterogeneity in individual responses to diet-induced lipid changes and raises questions about the role of diet, inflammation, genetics, and other modulators in plaque dynamics.

• 💡 Baseline coronary calcium score remains a powerful predictor of plaque progression: Patients with a zero calcium score at baseline tended to have little to no plaque progression or even slight regression, while those with positive calcium scores had more plaque progression. This aligns with established literature emphasizing the prognostic value of coronary calcium as a marker of atherosclerotic burden and risk.

• 🔄 Discordance among plaque assessment tools underscores the importance of method selection: The Clearly software indicated nearly universal plaque progression, contradicting HeartFlow and blinded scoring results. This discrepancy highlights challenges in plaque quantification methodologies, the need for standardized assessment tools, and cautious interpretation of AI-driven outputs without validation.

• 🔮 Long-term implications of diet-induced LDL elevation require further study: While one year of ketogenic diet-induced LDL elevation showed mild plaque progression, the absence of significant vulnerable plaque growth provides some reassurance. However, longer follow-up is essential to understand if these changes translate into clinical events or accelerated atherosclerosis over time, particularly as the ketogenic diet gains popularity.

Conclusion

The Keto Trial provides a nuanced view of cardiovascular effects in lean mass hyperresponders on ketogenic diets, revealing that dramatic LDL cholesterol elevations do not necessarily equate to widespread or rapid coronary plaque progression within a year. Advanced imaging techniques, especially AI-validated HeartFlow analysis, offer detailed and reliable insights into plaque biology, identifying both progression and regression patterns. The rarity of vulnerable plaque and the protective profile of zero calcium score patients add important clinical context to interpreting lipid elevations in this setting. This study advances the understanding of diet-induced lipid changes and their impact on coronary artery disease risk, while emphasizing the need for ongoing research and individualized cardiovascular risk assessment.