An excess of the lipid transporter apolipoprotein B (apoB) is associated with an increased risk of myocardial infarction (MI) and atherosclerotic cardiovascular disease (ASCVD), according to a new study. The investigation of 95,108 individuals found that not only were excess apoB levels associated with a dose-dependent increased risk of MI and ASCVD, but also with all-cause mortality in women only. The research team added that in the general population, excess apoB can identify 1 in 10 individuals who had a substantially increased cardiovascular disease risk above that from low-density lipoprotein cholesterol (LDL-C) alone, and importantly, this was true across the entire LDL-C spectrum. “Notably, our results showed that by assessing excess apoB, 1 in 10 individuals (>90th percentile) in the general population had excess apoB associated approximately with a 50% higher risk of MI, a 35% higher risk of ASCVD, and a 15% higher risk for all-cause mortality (the last in women only) compared with what would be expected on the basis of LDL-C alone,” the paper’s authors said. Led by Camilla Ditlev Lindhardt Johannesen, MD, from the Copenhagen University Hospital–Herlev Gentofte in Denmark, the study of 53,484 women and 41,624 men not taking statins found that 2,048 MIs, 4,282 ASCVD events, and 8,873 deaths occurred during a median follow-up of 9.6 years. For ASCVD in women compared with those with excess apoB <11 mg/dL, the multivariable adjusted hazard ratio [HR] was 1.08 (95% confidence interval [CI]: 0.97-1.21) for excess apoB 11 to 25 mg/dL. Researchers noted the HR as 1.30 (95% CI: 1.14-1.48) for excess apoB 26 to 45 mg/dL, 1.34 (95% CI: 1.14-1.58) for 46 to 100 mg/dL, and 1.75 (95% CI: 1.08-2.83) for excess apoB >100 mg/dL. Corresponding HRs in men were 1.14 (95% CI: 1.02-1.26) for excess apoB 11 to 25 mg/dL, 1.41 (95% CI: 1.26-1.57) for excess apoB 26 to 45 mg/dL, 1.41 (95% CI: 1.25-1.60) for 46 to 100 mg/dL, and 1.52 (95% CI: 1.13-2.05) for excess apoB >100 mg/dL. Novel approach “The likely explanation for these findings is the increased atherogenicity from 2 contributions: first, the lipoprotein particles that are overlooked when assessing LDL-C only, in particular very-low-density lipoproteins and its remnants; and second, the increasing number of cholesterol-depleted LDL particles,” said the authors of the paper, which was published Monday online and in the June 11 issue of the Journal of the American College of Cardiology. Alan T. Remaley, MD, PhD, from the National Institutes of Health in Bethesda, Maryland, and Justine Cole, MD, and Allan D. Sniderman, MD from McGill University Health Centre in Montreal, focused on the study’s novel approach to discordance analysis as a test of LDL-C and apoB’s relative predictive powers. “They first related LDL-C and apoB in truly normotriglyceridemic subjects (i.e., triglycerides <1 mmol/L [89 mg/dL]),” the experts said in their accompanying editorial comment. “As illustrated …, the resulting regression expresses the minimum apoB for any given value of LDL-C.” They went on to explain that excess apoB was the difference between predicted and measured/observed apoB. “Because there is only 1 molecule of apoB per particle, excess apoB represents quantitatively the number of apoB particles in excess of that predicted by the regression,” they added. “The converse procedure was followed to estimate discordant cholesterol in relation to apoB.” LDL-C variance Commenting on the study’s analysis on the impact of variance in LDL-C at a constant apoB, the experts said that at any level of apoB, atherogenic risk increases as the apoB particles become depleted in cholesterol. According to the commentators, the finding was consistent with previous data demonstrating that smaller, cholesterol-depleted LDL particles are more atherogenic than larger cholesterol-replete particles are. They added that this trend was not as powerful as that associated with variance in apoB. Commenting on the study’s limitations, the experts pointed to its focus on a White-only population – an observation countered by results of A Global Study of Risk Factors in Acute Myocardial Infarction (INTERHEART). This investigation demonstrated that apoB was superior in predictive power to LDL-C and non-high-density lipoprotein cholesterol in all the major peoples of the world. The commentators concluded by stating the study offered “compelling evidence that apoB is clinically, not just statistically, superior to LDL-C and, critically, that this advantage applies to a substantial number of patients.” “Based on the totality of the evidence, we believe that apoB should be widely available for clinical care because more accurate estimation of cardiovascular risk and more precise estimation of the adequacy of therapy will lower the number of myocardial infarcts and strokes and save lives.” Study methodology The study included 53,484 women and 41,624 men not taking statins from the Copenhagen General Population Study. For individuals in the excess apoB <11 mg/dL group (n=45,902 [48%]), the median age was 54 years (interquartile range [IQR]: 46-65). The median age for the individuals in the 11 to 25 mg/dL (n=25,027 [26%]) was 58 years (IQR: 49-67), 59 years (IQR: 49-67) in the 26 to 45 mg/dL group (n=14,581 [16]), 58 years (IQR: 49-66) in the 46-100 mg/dL group (n=8,755 [9%]) and 55 years (IQR: 47-62) in the >100 mg/dL group (n=843 [1%]). Associations of excess apoB with the risk of MI, ASCVD, and all-cause mortality were estimated by Cox proportional hazards regressions with 95% CIs. Excess apoB was defined as measured levels of apoB minus expected levels of apoB from LDL-C alone; expected levels were defined by linear regressions of LDL-C levels vs apoB levels in individuals with triglycerides ≤1 mmol/L (89 mg/dL). Sources: Johannesen CDL, Langsted A, Nordestgaard BG, et al. Excess Apolipoprotein B and Cardiovascular Risk in Women and Men. J Am Coll Cardiol. 2023;83:2262–2273. Remaley AT, Cole J, Sniderman AD. ApoB Is Ready for Prime Time. J Am Coll Cardiol. 2023;83:2274–2275. Image Credit: Innovative Creation – stock.adobe.com