Laurens F. Reeskamp

Multiple germline and somatic genomic factors are associated with risk of coronary artery disease, but there is no single measure of risk that integrates all information from a DNA sample. To address this gap, we develop an integrated genomic model that includes six germline and somatic genetic drivers for coronary artery disease, including polygenic risk score, genetically-proxied proteomic/metabolomic risk scores, and clonal hematopoiesis of indeterminate potential. We evaluated its predictive power in the UK Biobank (N = 391,536), and validate it using data from the TOPMed program (N = 34,177). The 10-year coronary artery disease risk based on the integrated genomic model profile ranges from 1.1% to 15.5% in the UK Biobank and from 3.8% to 33.0% in TOPMed, with a more pronounced gradient in males than females. The integrated genomic model captures the cumulative effect of multiple genetic drivers, identifying individuals at high risk for coronary artery disease despite lacking any single high-risk genetic factor, as well as individuals at low risk despite carrying known high-risk factors. In middle age, the integrated genomic model augments the performance of the Pooled Cohort Equations, a clinical risk calculator for coronary artery disease. While the integrated genomic model yields only modest incremental predictive value over polygenic risk score at the population level, it identifies approximately 13% of high-risk individuals not detected by polygenic risk score alone.

Aims: Elevated high-sensitivity C-reactive protein (hsCRP) concentrations are associated with an increased atherosclerotic cardiovascular risk, but this has not been extensively investigated in multi-ethnic populations, including South Asians, who are characterized by an increased cardiometabolic risk. Methods and results: In this general population study, 14 663 participants from the HEalthy Life In an Urban Setting (HELIUS) study were included (Dutch, South Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin). Mortality and cardiovascular event data were collected from nationwide registries. Differences in hsCRP levels and the association between hsCRP and cardiovascular events across the ethnic groups were assessed. The mean age was 44 ± 13 years; 55% were female. Median hsCRP at the baseline was 1.0 (0.5–2.1) mg/L in the European, 1.3 (0.6–2.7) mg/L in the African, and 1.6 (0.7–3.3) mg/L in the South Asian participants (P < 0.001). A total number of 568 cardiovascular and mortality events were recorded over a median follow-up time of 8.8 (7.8–9.7) years. hsCRP was associated with cardiovascular events in the European and African participants [adjusted HR per 1 mg/L increase in hsCRP: 1.08 (95% CI 1.00–1.16); and 1.09 (95% CI 1.03–1.16), respectively], but not in the South Asian participants, despite having the highest event rate. Conclusion: hsCRP was associated with incident cardiovascular and mortality events in individuals of European and African descent but not in South Asian individuals, despite higher hsCRP values. These findings suggest the need to find alternative inflammatory biomarkers to allow for a more reliable assessment of the increased cardiometabolic risk in South Asian individuals.

Background and Aims: Recent data from a large American cohort of women strongly support universal one-time screening for LDL cholesterol, high-sensitivity C-reactive protein (hsCRP), and lipoprotein(a) [Lp(a)] in primary prevention. This study addresses the validity and generalizability of this novel primary prevention strategy in a large prospective European cohort of initially healthy men and women. Methods: Plasma levels of LDL cholesterol, hsCRP, and Lp(a) were measured at study entry in 17 087 participants from the EPIC-Norfolk study who were subsequently followed over a period of 20 years for major adverse cardiovascular events (MACEs). Competing risk- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MACE across quintiles of each biomarker and sought evidence of independent as well as additive effects over time were calculated. Results: During the 20-year follow-up, a total of 3249 MACEs occurred. Increasing quintiles of baseline LDL cholesterol, hsCRP, and Lp(a) all predicted 20-year risks; the multivariable-adjusted HRs in a comparison of the top to bottom quintile were 1.78 (95% CI: 1.57–2.00) for LDL cholesterol, 1.55 (95% CI: 1.37–1.74) for hsCRP, and 1.19 (95% CI: 1.07–1.33) for Lp(a). Compared with individuals with no biomarker elevations, the multivariable-adjusted HRs for incident MACE were 1.33, 1.68, and 2.41 for those with one, two, or three biomarkers in the top quintile, respectively (all P < .001). Each biomarker demonstrated independent contributions to overall risk and findings were consistent in analyses stratified by sex. Conclusions: A single combined measure of LDL cholesterol, hsCRP, and Lp(a) among initially healthy European men and women was predictive of incident MACE during a 20-year period. These data replicate findings from a recent American cohort and strongly support universal screening for all three biomarkers in primary prevention.

Aims: Both plasma levels of remnant cholesterol and low-density lipoprotein (LDL) cholesterol levels are independent risk factors for atherosclerotic cardiovascular disease. However, only remnant cholesterol has consistently been associated with systemic inflammation. In this study, we aimed to assess the extent to which inflammation mediates the effect of remnant and LDL cholesterol on (non)fatal major adverse cardiovascular events (MACE), comprising of coronary artery disease and ischaemic stroke. Methods and results: This prospective study included 16,445 participants without prior atherosclerotic cardiovascular disease from the EPIC-Norfolk study, with a mean age of 58.8 ± 9.1 years, of which 9,357 (56.9%) were women. Every 1 mmol/L higher remnant cholesterol was associated with 29.5% higher high-sensitivity C-reactive protein (hsCRP) levels [95% Confidence Interval (CI): 22.1, 37.4, P < 0.001], whereas LDL cholesterol was not significantly associated with hsCRP levels in the fully adjusted model. Additionally, each 1 mmol/L higher remnant cholesterol was associated with a hazard ratio (HR) of 1.31 (95% CI: 1.14, 1.50, P < 0.001) for MACE, compared with an HR of 1.21 (95% CI: 1.13, 1.31, P < 0.001) for LDL cholesterol. Mediation analysis showed that hsCRP mediated 5.9% (95% CI: 1.2, 10.6%, P < 0.001) of the effect of remnant cholesterol on MACE, whereas hsCRP did not mediate the effect of LDL cholesterol. Conclusion: Plasma remnant cholesterol levels are independently associated with systemic inflammation and cardiovascular events. Inflammation, as measured with hsCRP, contributed minorly to the association between remnant cholesterol and MACE. This underscores the need to address both remnant cholesterol and systemic inflammation separately in the clinical management of cardiovascular disease. Lay summary: This study finds that systemic inflammation does not influence the effect remnant cholesterol has on cardiovascular disease risk, suggesting the importance of addressing both remnant cholesterol and inflammation to manage cardiovascular health.

Shirin Ibrahim, MD, G Kees Hovingh, MD PhD, Barbara A Hutten, MD PhD, Erik S G Stroes, MD PhD, Laurens F Reeskamp, MD PhD; Impact of cumulative LDL-C and o

Background: The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low‐density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE. Methods and Results: We performed a randomized, double‐blind, placebo‐controlled, cross‐over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run‐in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m ² , and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared with placebo (−118.7% versus +2.3%, P P =0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus −3.64%, P =0.002) when compared with placebo. Conclusions: UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.