High levels of lipoprotein(a) cholesterol (Lp(a)-C) as part of low-density lipoprotein cholesterol (LDL-C) makeup were associated with raised coronary heart disease (CHD) risk in a new wide-scale European population study. Meanwhile, the current estimated measure to determine LDL-C without Lp(a)-C content – known as "corrected LDL-C" – provided "no meaningful information on CHD-risk estimation at the population level," authors of the 68,748-subject research concluded. Assessing patients' lipid profile without taking into account specific Lp(a) values, therefore, gives "incomplete information" on CHD risk, especially in those with high Lp(a) values, the researchers warned. The findings from the European Union-funded study – named BiomarCaRE – were published online Monday ahead of the July 9 issue of the Journal of American College of Cardiology, led by authors Natalie Arnold, MD, and Christopher Blaum, MD, from University Medical Center Hamburg, Germany. An unspecific measure LDL-targeted therapy has become a "cornerstone" in the management of atherosclerotic cardiovascular disease, yet conventional assays are not specific in measuring the constituent atherogenic lipoproteins that make up LDL-C, the authors noted. Instead, these assays tend to encompass not only cholesterol bound to LDL but also cholesterol bound to intermediate density lipoprotein and Lp(a)-C. "This methodologic limitation might have a significant clinical impact, particularly in the setting of high [Lp(a)]," they said. "Although a fasting status results in almost negligible contribution of cholesterol bound to intermediate-density lipoprotein to measured LDL-C, an elevated Lp(a)-C could, by contrast, account for a substantial proportion of conventionally measured LDL-C and, in this scenario, the real cholesterol content of LDL would be much lower than previously appreciated," the authors added. While some recognition of this phenomenon has come in the form of the introduction of a "corrected LDL-C" measure – designed to measure LDL-C without its Lp(a)-C content – Lp(a)-C is commonly calculated as an estimate of 30% of Lp(a) mass. The estimation may be flawed, however, with recent research suggesting much higher variability of Lp(a)-C related to Lp(a) mass, the researchers noted. BiomarCaRE was therefore set up to assess the CHD effects associated with Lp(a)-C. BiomarCaRE design The study included subjects – who were CHD-free at baseline – from eight population-based cohorts across Europe. At baseline, Lp(a) mass was measured from stored blood samples in BiomarCaRE central laboratories, and Lp(a) levels were used to stratify the subjects into two groups – <90th percentile (61,861 subjects with a median Lp(a) of 8 mg/dL [interquartile range (IQR): 3.8-15.2]), and ≥90th percentile (6,887 participants with a median Lp(a) of 60.5mg/dL [IQR: 52.1-70.3]). Systolic blood pressure (median 131mm Hg for both groups), body mass index (median 26.3 kg/m2 in <90th percentile vs. 26.2 kg/m2 in ≥90th percentile), hypertension rates (40.2% vs. 41.5%), and diabetes (3.9% vs. 3.3%) were similar at baseline. The participants were followed-up prospectively for an overall range of 2.5 to 25 years for incident CHD events, including fatal or nonfatal (definite or possible) myocardial infarction (MI), coronary death, unstable angina pectoris, cardiac revascularization and unclassifiable death. CHD risk, Lp(a)-C and apoB The "simple categorization" of Lp(a)-C mass into the high vs. low percentiles highlighted a higher association between incident CHD and uncorrected LDL-C when Lp(a)-C was ≥90th percentile than when Lp(a)-C was <90th percentile (≥90th percentile subdistribution hazard ratio [sHR]: 4.38; 95% confidence interval [CI]: 2.08-9.22 vs. <90th percentile sHR: 2.60; 95% CI: 2.21-3.07; P interaction = 0.39). In order to circumvent the potential inaccuracies of the conventionally used methods to correct LDL-C for Lp(a)-C, The researchers also investigated whether a similar pattern of association might be observed for other lipid parameters, such as apolipoprotein B (apoB). However, apoB risk estimates were lower in subjects with higher Lp(a) mass than those in <90th percentiles (sHR: 2.43; 95% CI: 1.34-4.40 vs. sHR: 3.34; 95% CI: 2.78-4.01; P interaction = 0.49). 'No meaningful information' from 'corrected LDL-C' Besides investigating a potential link between higher Lp(a) levels and raised CHD risk, the researchers also looked into the "potential inaccuracies" of the conventionally used corrected LDL-C methods. "To account for the variability of Lp(a)-C in relation to Lp(a) mass, we used 2 different estimations, 1 calculating Lp(a)-C as 30%, the other as 17.3% of total Lp(a) mass," the researchers said. Using this conventional measure resulted in "no meaningful information" on CHD-risk estimation at population level, the authors said. The authors also used Fine-Gray competing risk-adjusted models to analyze the effect of the variability of Lp(a)-C as it is related to Lp(a) mass, which showed “very comparable” subdistribution HRs to those of uncorrected LDL-C. For uncorrected LDL-C, the subdistribution HR was 2.73 (95% CI: 2.34-3.20; P<0.001), while the subdistribution HR was 2.51 (95% CI: 2.15-2.93; P<0.001) for aLDL-C corrected for 30% total Lp(a) mass, 2.64 (95% CI: 2.26-3.10; P<0.001 for LCL-C corrected for 17.3% total Lp(a) mass. The finding highlights "the need not only of understanding the underlying pathophysiological mechanisms of the role of Lp(a) in LDL-C– or apoB-related risk of future CHD, but also the necessity to establish a more practical solution of how to deal with such complex and variable relationships between these entities," the researchers said. In an accompanying editorial, the University of California-San Diego's Sotirios Tsimikas, MD, and colleagues noted that the study "addresses an important and emerging concept of clinical importance as therapies are being developed beyond lowering LDL-C". However, the editorialists stressed that the findings should be considered "hypothesis-generating pending future studies," highlighting caveats including "limited generalizability to populations with elevated Lp(a), which represent >20% of the population, where Lp(a)-C may be most relevant in its contribution to LDL-C". Nevertheless, they concluded that: "The issue of 'what is the real LDL-C in my patient' is now highly relevant as potent drugs targeting multiple lipoprotein pathways are brought to the clinic. Continued research to optimally define CVD risk, identify the responsible lipoproteins, treat early with specific agents targeting the responsible lipoprotein(s), and optimize CVD event prevention is an achievable goal for preventive cardiology over the next decade." Sources: Arnold N, Blaum C, Goßling A, et al. Impact of Lipoprotein(a) Level on Low-Density Lipoprotein Cholesterol– or Apolipoprotein B–Related Risk of Coronary Heart Disease. J Am Coll Cardiol 2024;84:165-177. Tsimikas S, Yeang C, Kronenberg F. In Search of an Accurate Measurement of LDL-C: Correction for Lp(a)-Cholesterol to Predict Clinical Outcomes. J Am Coll Cardiol 2024;84:178-181. Image Credit: Hound – stock.adobe.com