Atherosclerosis newsletter
Highlighted articles from June issue Vol 393
Newsletter by Editor in Chief Prof Arnold von Eckardstein, and Editorial Office Manager Simona Negrini
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ApoB containing lipoproteins are a causal risk factor of atherosclerotic cardiovascular disease. This Newsletter summarizes several articles published in the June issue of Atherosclerosis that addressed novel questions to the interaction of plasma levels of apoB containing lipoproteins with other risk factors in the determination of cardiovascular risk or treatment effectiveness, the effectiveness of familial hypercholesterolemia (FH) screening, the treatment of homozygous FH, or novel targets for cholesterol lowering therapies.
Differential age-specific associations of LDL cholesterol and body mass index with coronary heart disease
Aging leads to an increased incidence of coronary heart disease (CHD). Low‐density lipoprotein cholesterol (LDLc) and body mass index (BMI) are well-established determinants of CHD. However, LDLc and BMI are not always correlated and their relationship is probably dependent on age, indicating differential age-specific associations of these factors with health outcomes. Xiao et al. aimed to discriminate the roles of LDLc and BMI in CHD across different age groups.
In this prospective cohort study of 368,274 participants aged 38–73 years and free of CHD at baseline, LDLc and BMI were measured at baseline, and incident CHD was the main outcome. Cox proportional hazards model and restricted cubic spline (RCS) regression were used to estimate hazard ratio and 95% confidence interval of exposure on CHD.
After a mean of 12 years of follow-up, similar relationships of LDLc and BMI with CHD risk were observed in the overall population but in differential age-specific patterns. Across the age groups of <50, 50–54, 55–59, 60–64 and ≥ 65 years, the LDLc-CHD association diminished with the adjusted HRs decreasing from 1.35, 1.26, 1.19, 1.11 to 1.08; while no declining trend was found in BMI-CHD relationship with the adjusted HRs of 1.15, 1.11, 1.12, 1.13 and 1.15, respectively. The interactions and mediation between LDLc and BMI on CHD risk were more pronounced at young-age groups. LDLc-CHD but not BMI-CHD association was dependent on sex, metabolic syndrome and lipid-lowering drugs use.
The age-specific benefits from lipids management or weight control on coronary heart disease should be discriminated in future studies.
Impact of optimal cholesterol levels on subclinical atherosclerosis in the absence of risk factors in young adults
Some studies have shown a higher likelihood of subclinical atherosclerosis and elevated cardiovascular disease (CVD) risk with lipid levels below the thresholds used to define dyslipidemia according to current guidelines. Data on whether these associations exist among young individuals with a low cardiovascular risk factor (CVRF) burden and lipid levels within optimal ranges are less clear. Masrouri et al. aimed to assess the association of blood lipids with the prevalence, incidence, and progression of subclinical atherosclerosis among young individuals without dyslipidemia and other traditional CVRFs.
A total of 1270 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study aged 32–46 years free of cardiovascular disease, diabetes, hypertension, current smoking, and dyslipidemia were included in the analysis. A subgroup with optimal lipids within the low-CVRF group was defined with TC < 200 mg/dL, LDL-C < 100 mg/dL, non-HDL-C < 130 mg/dL, and women with HDL-C ≥ 50 mg/dL.
1-SD higher TC, LDL-C, and non-HDL-C were associated with a greater risk of presence, incidence, and progression of coronary artery calcium (CAC) and a 42–44% greater odds of composite mean carotid intima-media thickness (CIMT) ≥ 75th percentile. Repeating the analyses in a subset of participants with a CAC score of zero did not alter the association of TC, LDL-C, and non-HDL-C with CIMT. In the subgroup with optimal lipids, these lipid indices remained associated with an increased risk of presence and incidence of CAC and greater CIMT measures. Among adults aged 32–46 years, in the absence of traditional CVRFs, elevated cholesterol levels, even within what is considered optimal, are associated with atherosclerosis and arteriopathy.
Remnant cholesterol, LDL cholesterol, and apoB absolute mass changes explain results of the PROMINENT trial
The Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabetes (PROMINENT) trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. A better understanding of the results from the trial may emerge examining the effects on total atherogenic cholesterol and total number of atherogenic lipoprotein particles. Doi et al. tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B could explain the results of the PROMINENT trial.
Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT.
In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL change in remnant cholesterol, +10 mg/dL LDL cholesterol, and +5 mg/dLapolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 for a -7 mg/dL change in remnant cholesterol, 1.04 for a +10 mg/dL change in LDL cholesterol, and 1.02 for a +5 mg/dL change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 in the CGPS mimicking PROMINENT compared to 1.03 in the PROMINENT trial.
Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL higher total atherogenic cholesterol, together with 5 mg/dL higher apolipoprotein B, seems to explain the trend toward more ASCVD in the pemafibrate arm.
Enhanced identification of familial hypercholesterolemia using central laboratory algorithms
Familial hypercholesterolemia (FH) is a highly prevalent genetic disorder resulting in markedly elevated low density lipoprotein (LDL) cholesterol levels and premature coronary artery disease, yet global diagnosis rates remain <1 %. FH underdiagnosis and undertreatment require novel detection methods. Ibrahim et al. evaluated the effectiveness of using an LDL cholesterol cut-off ≥99.5th percentile (sex- and age-adjusted) to identify clinical and genetic FH, and investigated underutilization of genetic testing and undertreatment in FH patients.
Individuals with at least one prior LDL cholesterol level ≥99.5th percentile were selected from a laboratory database containing lipid profiles of 590,067 individuals. The study comprised three phases: biochemical validation of hypercholesterolemia, clinical identification of FH, and genetic determination of FH.
Of 5614 selected subjects, 2088 underwent lipid profile reassessment, of whom 1103 completed the questionnaire. In these 1103 subjects, mean LDL cholesterol was 4.0 ± 1.4 mmol/l and 722 (65%) received lipid-lowering therapy. FH clinical diagnostic criteria were met by 282 (26%) individuals, of whom 85% had not received guideline-recommended genetic testing and 97% failed to attain LDL cholesterol targets. Of 459 individuals consenting to genetic validation, 13% carried an FH-causing variant, which increased to 19% in clinically diagnosed FH patients.
This study highlights how a laboratory-based approach can effectively identify and optimize treatment for FH patients.
Improved lipid-lowering treatment and reduction in cardiovascular disease burden in homozygous familial hypercholesterolemia: The SAFEHEART follow-up study
Homozygous familial hypercholesterolemia (HoFH) is a rare and severe genetic disease, caused by loss-of-function pathogenic variants in both alleles of the low-density lipoprotein receptor (LDLR) gene. Pathogenic variants in the apolipoprotein B (ApoB) and the proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are also causative of HoFH, but less frequently found. Previous report of HoFH patients included in the SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) with a median follow-up of 6.9 years showed that most patients do not attain the LDL-C treatment goals with high intensity statins plus ezetimibe. In addition, few patients were under lipoprotein-apheresis. Since then, more patients have been included in this registry, and the availability of PCSK9i and Lomitapide in Spain with the indication of HoFH has allowed patients to be treated more intensively. Alonso et al. aimed to describe clinical and genetic characteristics, lipid-lowering treatment and atherosclerotic cardiovascular disease (ASCVD) outcomes over a long-term follow-up in HoFH.
SAFEHEART is a long-term study in molecularly diagnosed FH. Data analyzed in HoFH were prospectively obtained from 2004 until 2022. ASCVD events, lipid profile and lipid-lowering treatment were determined.
Thirty-nine HoFH patients were analyzed. The mean age was 42 ± 20 years and 19 (49%) were women. Median follow-up was 11 years. Median age at genetic diagnosis was 24 years. At enrolment, 33% had ASCVD and 18% had aortic valve disease. Patients with new atherosclerotic cardiovascular disease (ASCVD) events and aortic valve disease at follow-up were six (15%), and one (3%), respectively. Median untreated LDL-C levels were 555 mg/dL, and median LDL-C levels at last follow-up was 122 mg/dL. Most patients (92%) were on high intensity statins and ezetimibe, 28% with PCSK9i, 26% with lomitapide, and 23% with lipoprotein-apheresis. Fourteen patients (36%) attained an LDL-C level below 100 mg/dL, and 10% attained an LDL-C below 70 mg/dL in secondary prevention. Patients with null/null variants were younger, had higher untreated LDL-C and had the first ASCVD event earlier. Free-event survival is longer in patients with defective variant compared with those patients with at least one null variant.
HoFH is a severe life threating disease with a high genetic and phenotypic variability. The improvement in lipid-lowering treatment and LDL-C levels have contributed to reduce ASCVD events.
These results are commented in the editorial by Harada-Shiba.
The LEPIS-HuR-TMOD4 axis regulates hepatic cholesterol homeostasis and accelerates atherosclerosis
Several long non-coding RNAs (lncRNAs), including lncRNAs involved in cholesterol metabolism, inflammatory cascades and apoptosis, have been shown to regulate key steps in the progression of atherosclerosis. In their previous study, Lv et al. confirmed that ApoE−/− mice overexpressing proline/serine-rich coiled-coil protein 1 (PSRC1) in the liver had lower lipid levels and a lower atherosclerotic burden than control mice. Based on these results, they hypothesized that a PSRC1-induced lncRNA may be an effective target for the prevention and treatment of atherosclerosis. In this study, the authors identified an uncharacterized lncRNA, Liver Expressions by PSRC1 Induced Specifically (LEPIS), and they aimed to clarify the mechanism though which LEPIS affects atherosclerosis.
The expression of LEPIS and its potential target, tropomodulin 4 (TMOD4), was increased in the livers of ApoE−/− mice fed a high-fat diet (HFD). An ApoE−/− mouse model in which LEPIS or TMOD4 was overexpressed in the liver was established. The plaque load in the aorta was assessed, plasma was collected to measure blood lipid levels, and the liver was collected to study cholesterol metabolism.
Both LEPIS and TMOD4 increased the atherosclerosis burden and reduced hepatic cholesterol levels. Moreover, LEPIS and TMOD4 affected the expression of genes related to hepatic cholesterol homeostasis, including proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR), which are closely related to hypercholesterolemia. Mechanistically, human antigen R (HuR), an RNA-binding protein (RBP), was shown to be critical for the regulation of TMOD4 by LEPIS. Furthermore, overexpression of LEPIS promoted the shuttling of HuR from the nucleus to the cytoplasm, enhanced the stability of TMOD4 mRNA, and promoted the expression of TMOD4. In addition, TMOD4 was found to affect intracellular cholesterol levels through PCSK9.
These results suggest that the LEPIS-HuR-TMOD4 axis is a potential intervention target for dysregulated hepatic cholesterol homeostasis and atherosclerosis and may provide the basis for further reductions in the circulating LDL-C concentration and arterial plaque burden.