Summary
Paul Saladino and Dave Feldman discuss in depth a recent study Feldman conducted about LDL cholesterol and cardiovascular risk. They examine whether elevated LDL in metabolically healthy individuals truly poses a risk, the difference between familial hypercholesterolemia phenotypes and genotypes, and what this research may mean for the future of medicine.
Key Points
- New study data on LDL and cardiovascular risk in healthy individuals
- Familial hypercholesterolemia: phenotype vs. genotype distinction
- Polygenetic vs. monogenetic cholesterol elevation
- Challenging conventional lipid hypothesis with new data
- Implications for future cardiovascular risk assessment
Key Moments
Lean mass hyperresponders: high LDL with no plaque on CT angiography
Dave Feldman describes the lean mass hyperresponder phenotype he identified in 2017: a triad of LDL above 200, HDL above 80, and triglycerides below 70. Each marker is rare individually in the general population, yet all three appear together in metabolically healthy people on low-carb diets. Feldman designed a longitudinal study with Matthew Budoff at the Lundquist Institute to examine cardiovascular risk in this population, which had never before been studied in isolation from metabolic dysfunction.
"this is the triad of lean mass hypersponders. It's an LDL of 200 or higher, HDL of 80 or higher, and triglycerides of 70 or lower."
No correlation between LDL and plaque in metabolically healthy people
The key finding from Feldman's study is that there is no correlation between detected LDL levels at baseline and resulting plaque burden in lean mass hyperresponders. People with LDL as high as 591 mg/dL showed no relationship between their cholesterol levels and cardiovascular disease on CCTA imaging. Some of the highest LDL scores had zero plaque burden. When compared to a control group with average LDL at Miami Heart, the incidence of cardiovascular disease was the same.
"There's just no correlation between detected LDL levels at baseline and resulting plaque."
FH genotype versus phenotype: why high LDL is not automatically familial hypercholesterolemia
Saladino and Feldman distinguish between the genetic reality of familial hypercholesterolemia (monogenetic FH from specific receptor mutations) and the phenotypic diagnosis (LDL above 190 equals automatic FH). They explain that people with FH have dysfunctional macrophage uptake of LDL in vessel walls, a fundamentally different mechanism than a lean person whose LDL rose from dietary changes. Monogenetic and polygenetic FH have different cardiovascular outcomes even at the same LDL levels.
"it was so unlikely that somebody would have an LDL, say, of 190, 200, especially 250, 300, et cetera, that it was an easy conclusion for them to draw that it must be a genetic abnormality."
