Update to equation for estimating LDL-C proposed

Researchers recently described a more accurate equation for estimating low-density lipoprotein cholesterol (LDL-C) and identifying high-risk patients who could benefit from more intensive lipid-lowering therapy (Clin Chem 2025; doi:org/10.1093/clinchem/hvaf099).

The original Sampson-NIH equation has been used widely to standardize routine LDL-C assays because of its accuracy, especially in individuals with high triglycerides or very low LDL-C levels. The equation uses standard lipid panel measurements, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides, to calculate LDL-C without the need for a specialized ultracentrifuge.

The researchers aimed to improve the equation because recent guidelines emphasize the need to lower LDL-C levels. They developed and tested a modified Sampson equation by least-squares regression to match LDL-C by the β-quantification reference method. They combined terms into non-HDL-C, which is defined as non-HDL-C total cholesterol minus HDL-C, and forced the coefficient to be 1. Then they applied the equation to 24,590 lipid panel results from Mayo Clinic and 9,605 from the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk clinical trial of evolocumab.

The modified Sampson equation showed significant improvement in concordance with the reference methods when compared with other equations. By overall kappa analysis, it showed the best agreement at the 55 mg/dL cutoff point of 0.98, as compared with 0.96 for the original equation, 0.96 for Martin-Hopkins, and 0.94 for Friedewald. At the 70 mg/dL cutoff point, those figures were 0.97 for the modified equation, 0.94 for the original equation, 0.95 for Martin-Hopkins, and 0.92 for Friedewald.

Based on its net reclassification index, the new equation increases the percentage of correctly classified patients with low LDL-C by approximately 10%−20% compared with the other equations.

The equation could improve identification of high-risk and very high-risk patients who fall short of LDL-C goals and need more lipid-lowering therapy. The researchers called for further testing of it in more cohorts.

Plasma profile linked to family history of early onset heart disease

A specific pattern of plasma proteins in the blood may indicate an increased risk of hereditary coronary atherosclerosis, a recent study finds (Circ Genom Precis Med 2025; doi: 10.1161/CIRCGEN.124.005220).

Much coronary heart disease (CHD) heritability can be explained by risk factors, but a significant proportion of CHD remains unexplained. The researchers wanted to identify circulating proteins associated with a family history of early-onset CHD and conduct further examination of the relationship between identified proteins and coronary atherosclerotic burden in subjects with and without a family history of CHD.

The researchers studied data on coronary atherosclerotic burden from computed tomography angiography and proteonomics for 4,521 Swedish subjects without known CHD. They retrieved records of myocardial infarction and coronary revascularization therapies in any parent or sibling of subjects from national registers in Sweden and adjusted the linear associations between family history for age, sex, and study site. The researchers also studied statistical interactions between proteins and family history to better understand the association between proteins and the coronary atherosclerotic burden. Then, they performed Mendelian randomization for causal associations between proteins and CHD by using genome-wide association study summary data from the UK Biobank Pharma Proteomics Project, an international effort that combines data from large scale genetic studies to identify risk loci for coronary artery disease and myocardial infarction, and FinnGen, a Finnish genomics and personalized medicine research project.

The researchers found family history of early-onset CHD in 9.5% of subjects and associations between family history and features of inflammation, lipid metabolism, and vascular function. The strongest associations were for follistatin and cathepsin D, neither of which were attenuated by adjusting for cardiovascular risk factors. Eighteen proteins were statistical interactors with family history in the association between each protein and the coronary atherosclerotic burden, especially the LDL receptor, transferrin receptor protein 1, and platelet endothelial cell adhesion molecule 1 (PECAM1).

Further analysis revealed a new association for follistatin and myocardial infarction, plus previously seen associations for proprotein convertase subtilisin/kexin type 9 (PCSK9) and PECAM1.

These findings establish a possible causal relationship between PCSK9, PECAM1, and follistatin and myocardial infarction, with implications for further understanding of the pathophysiology of CHD, the researchers wrote.

Gene therapy gives long-term immune protection from rare disease

Long-term findings in patients with severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency (ADA-SCID) point to the efficacy and safety of autologous CD34+ hematopoietic stem-cell lentiviral gene therapy for the disorder (N Engl J Med 2025; doi: 10.1056/NEJMoa2502754).

The current standard treatments for ADA-SCID — allogeneic hematopoietic stem-cell transplantation (HSCT) from a matched donor or weekly enzyme injections — have limitations and potential long-term risks. However, HSCT outcomes showed improvement in recent years, especially with the widespread adoption of newborn screening for SCID.

Clinical trials have examined lentiviral gene therapy for the life-threatening inborn error of metabolism. Third-generation self-inactivating lentiviral vectors have been engineered for improved safety by removing transforming elements that are part of the lentivirus genome to avoid transactivation of oncogenes. The researchers previously developed and reported on a self-inactivating lentiviral vector, EFS-ADA LV, in a study of fewer patients. They aimed to test its efficacy and safety in a comprehensive long-term follow-up.

Between 2012 and 2019, the researchers treated 62 patients who had ADA-SCID with busulfan nonmyeloablative conditioning, followed by transplantation with autologous CD34+ hematopoietic stem cells transduced ex vivo with a lentiviral vector encoding human ADA. The primary efficacy end points were overall survival and event-free survival, defined as survival free from rescue allogeneic hematopoietic stem-cell transplantation, reinitiation of enzyme-replacement therapy, and additional gene therapy. Secondary end points included no receipt of immunoglobulin-replacement therapy, the presence of protective titers to tetanus or pneumococcal vaccines, and sustained discontinuation of fungal or viral prophylaxis.

The experimental gene therapy restored and maintained immune system function in 59 of the 62 patients. Overall survival was 100%, and event-free survival was 95%. All 59 patients who underwent successful gene-marked engraftment at 6 months lacked sustained need for enzyme-replacement therapy and had stable gene marking, ADA enzyme activity, metabolic detoxification, and immune reconstitution through the last follow-up. No patients had leukoproliferative events or clonal expansions, the researchers reported.