High cholesterol may not signal heart disease risk in metabolically healthy people

The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, in collaboration with researchers across multiple institutions, has published a new study that challenges the long-held belief that high cholesterol correlates and even directly causes coronary artery disease, or plaque buildup in the arteries in metabolically healthy individuals.

The study, published today in the Journal of the American College of Cardiology: Advances, recruited 100 metabolically healthy individuals following a long-term low-carbohydrate ketogenic diet who developed elevated levels of LDL cholesterol–dubbed Lean Mass Hyper-Responders (LMHRs). The researchers found that traditional cholesterol markers (ApoB and LDL-C) were not associated with baseline heart disease or progression in this population, calling for investments in further research and personalized treatment strategies.

Cardiovascular disease is the world's leading cause of death, making diagnosis and risk assessment a high priority. The prevailing theory of cardiovascular disease risk is the lipid hypothesis, which posits that elevations in apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) are significant risk factors that should be primary treatment targets. However, this new research questions the relevance of the lipid hypothesis in metabolically healthy individuals whose cholesterol levels rise in response to a low-carb ketogenic diet–often adopted to address significant mental or physical health challenges.

As evidence accumulates for the efficacy of therapeutic carbohydrate reduction to improve chronic conditions ranging from diabetes to inflammatory bowel disease to bipolar disorder, investigating the cardiovascular risk of diet-induced high cholesterol is becoming increasingly critical. Despite the striking beneficial effects that are seen following this therapy, adoption is often discouraged by medical doctors because of the presumed increased risk of heart disease.

The study investigated the relationship between LDL-C, ApoB, and heart plaque progression in a subpopulation of people who adopt low carbohydrate diets and fit the LMHR phenotype. This unique metabolic profile includes elevated LDL-C and ApoB levels despite otherwise healthy metabolic marker levels including low triglycerides, high HDL, low blood pressure, low insulin resistance, and low body mass index.

The researchers found no association between plaque progression and total exposure to, changes in, or baseline levels of ApoB and LDL-C. Rather, baseline plaque burden was identified as the strongest predictor of future plaque progression. These findings suggest that high cholesterol is not always a marker of cardiovascular plaque progression and that individuals with the LMHR phenotype may benefit from cardiac imaging to further assess their cardiovascular risk. 

The findings build on previous work from the research team demonstrating that LMHR individuals have similar levels of coronary plaque to a carefully-matched comparison group with normal LDL levels, underscoring that ketogenic diet-induced LDL increases may not indicate a higher risk of coronary plaque.

The research was co-led by senior author Dr. Matthew Budoff, MD, Investigator and Program Director and Director of Cardiac CT, and the endowed chair of preventative cardiology at The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center. The study leaders included independent researchers Nick Norwitz, PhD, Dr. Adrian Soto-Mota, MD, and Dave Feldman, founder of the Citizen Science Foundation, which, uniquely, crowd-sourced funding for the study.

"It is important that clinicians, along with the general public, are made aware that personalized, data-driven approaches to assessing risk should be considered based on individual conditions," said Dr. Budoff, who is also a Professor of Medicine at David Geffen School of Medicine at UCLA. "The existence of this phenotype suggests that alternative markers or tests should be used to establish metabolic health in some cases."

The study points to a clear need to expand cardiovascular disease risk assessment to include a personalized approach that can prioritize cardiac imaging. The researchers also call for an open-minded multidisciplinary approach to better understanding the heart disease risk of individuals with the LMHR phenotype, who often rely on low carbohydrate and ketogenic diets to keep chronic disease at bay.