Background: While reducing LDL cholesterol (LDL-C) remains central focuses of conventional preventive cardiology, substantial heterogeneity exists in the cardiovascular risk associated with even extreme LDL-C elevations, likely depending heavily on the broader metabolic context. Specifically, the lean mass hyper-responder (LMHR) phenotype—characterized by markedly elevated LDL-C with elevated high-density lipoprotein cholesterol (HDL-C) and low triglycerides in the setting of a ketogenic diet—has recently been described, though its long-term risk profile remains poorly defined. Case Presentation: We describe a male in his 30s without any congenital dyslipidemia who adopted a ketogenic diet for the management of ulcerative colitis and who subsequently exhibited a sixfold increase in LDL-C from a baseline of 95 mg/dL to 574 mg/dL, with total cholesterol of up to 705 mg/dL, HDL-C at 124 mg/dL, and triglycerides at 34 mg/dL. Despite maintaining these extreme lipid levels for nearly seven years, he demonstrated no coronary plaque or stenosis on coronary computed tomography angiography (CCTA; CAD-RADS = 0). Additionally, quantification of coronary plaque as assessed by AI-guided quantified analysis by Heartflow® identified 0 mm3 plaque in any vessels, placing him in the lowest percentile for atherosclerotic plaque. Conclusions: This case represents an extreme and extensively characterized example of the LMHR phenotype and highlights the limitations of extrapolating cardiovascular risk from LDL-C levels alone without consideration of broader patient context and the etiology of hypercholesterolemia. While a single case cannot redefine clinical practice, this well-characterized case is consistent with emergent literature on LMHR, and careful study of such individuals may provide valuable insights into lipid metabolism, atherosclerosis biology, and precision cardiovascular risk assessment.
Norwitz et al. (Mon,) studied this question.