The KETO-CTA study, published in JACC: Advances in 2025, set out to investigate the amount of plaque progresion that occurs in a group of 100 individuals following a ketogenic diet who met the criteria for the “Lean Mass Hyper-Responder” (LMHR) phenotype—defined by markedly elevated LDL cholesterol, high HDL cholesterol, and low triglycerides. Using coronary computed tomography angiography (CCTA), the study aimed to evaluate progression of non-calcified plaque volume over one year. Though framed as exploratory, the study presents conclusions that may be misinterpreted as minimizing cardiovascular risk despite high LDL-C. The following is my letter to the editor—declined for publication—that outlines concerns regarding scientific integrity, patient safety, author bias, and the need for stronger safeguards in peer review and editorial oversight.
The Perils of Causal Claims in the KETO-CTA Observationl Cohort Study.
To the Editor:
The KETO-CTA investigators failed to clearly report their pre-registered primary endpoint: percent change in non-calcified plaque volume (NCPV) [1]. This omission undermines transparency and removes critical safeguards against selective reporting and potential author bias. Additionally, the study employs causal language to describe exploratory associations, as seen in its title, “Plaque Begets Plaque, ApoB Does Not.” This undermines scientific clarity and risks causing patient harm.
The phrase “Plaque Begets Plaque” reflects a well-established pathophysiologic principle. Patients with coronary artery calcium (CAC) scores greater than zero typically have diffuse atherosclerosis that predictably progresses with continued exposure to vascular risk factors. Notably, subjects in this study lacked other major cardiovascular risk factors aside from markedly elevated ApoB. Those with CAC > 0 demonstrated rapid progression of NCPV and clearly warrant aggressive lipid-lowering interventions through lifestyle changes or medical therapy.
As expected, individuals with CAC = 0 were heterogeneous in baseline NCPV and in subsequent progression. Contemporary guidelines support treating major risk factors such as smoking, hypertension, and severe hypercholesterolemia irrespective of CAC status. Delaying treatment until calcification appears increases the risk of disease progression and cardiovascular complications that may not be reversible [2]. Although novel imaging and biomarkers may one day enhance risk stratification, they remain investigational and do not justify withholding established safe and cost effective therapies. The use of coronary CT angiography (CCTA) for this purpose is not currently supported by clinical guidelines [3].
The authors erroneously conclude that “ApoB Does Not” cause plaque progression in the KETO-CTA cohort. This inference is drawn from an exploratory analysis of a small, homogenous population with uniformly elevated ApoB/LDL-C levels. The lack of a control group, the compressed range of high ApoB/LDL-C, and the absence of a properly powered prospective design preclude any meaningful conclusions about the causal role of ApoB in plaque progression. As Sniderman and Akl have emphasized, “the evidence that LDL-C plays a causal role in the pathophysiology of atherosclerosis is so strong that a negative association observed in a small cohort over a short duration is not compelling” [2]. Decades of consistent genetic, epidemiologic, and interventional data affirm the causal role of ApoB-containing lipoproteins in atherosclerosis [4].
The omission of the primary endpoint, combined with the use of causal language to interpret exploratory findings, reflects a concerning lapse in scientific standards by the authors, the Lundquist Institute, and the Journal of the American College of Cardiology (JACC). Misuse of causal claims in this context may lead clinicians to delay or forgo proven lipid-lowering therapies, increasing the risk of preventable cardiovascular events in patients with elevated ApoB. I respectfully urge the Journal and the authors to retract the paper or correct these assertions in order to protect patient outcomes, preserve scientific integrity, and maintain public trust.
Michael Mindrum, MD FRCPC
References
- Budoff MJ, Lopez-Jimenez F, Vergara P, et al. Effect of a High-Fat, Low-Carbohydrate Diet on Noncalcified Coronary Plaque and LDL Cholesterol: A Randomized Controlled Trial. JACC: Advances. 2025;4(4):101686. doi:10.1016/j.jacadv.2025.101686.
- Akl EA, Sniderman AD. Cholesterol, Coronary Calcification, and Cardiovascular Prevention: Lessons We Can Learn From the Western Denmark Heart Registry. Circulation. 2023;147(14):1064-1066.
- Shaw LJ, Blankstein R, Bax JJ, et al. Society of Cardiovascular Computed Tomography/North American Society of Cardiovascular Imaging – Expert Consensus Document on Coronary CT Imaging of Atherosclerotic Plaque. J Cardiovasc Comput Tomogr. 2021;15(2):93–109.
- Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: evidence from genetic, epidemiologic, and clinical studies. Eur Heart J. 2017;38(32):2459–2472. doi:10.1093/eurheartj/ehx144.