European journal of preventive cardiology最新文献

Aims: Familial hypercholesterolaemia (FH) is a severely underdiagnosed, inherited disease, causing dyslipidaemia and premature atherosclerotic cardiovascular disease. In order to facilitate screening in a broad clinical spectrum, we aimed to analyse the current yield of routine genetic diagnostics for FH and to evaluate the performance of the Dutch Lipid Clinic Network Score (DLCNS) compared to a single value, the off-treatment LDL-cholesterol exceeding 190 mg/dL.

Methods and results: We investigated all patients that underwent molecular genotyping routinely performed for FH over a 4-year period in two Austrian specialist lipid clinics. Variants reported in FH-causing genes including LDLR, APOB, PCSK9, LDLRAP, and APOE were collected and classified. For clinical classification, the DLCNS was calculated retrospectively and compared to the original scores documented in patient charts. Additionally, a literature review on comparisons of DLCNS to LDL-C was performed. Of 469 patients tested, 21.3% had a disease-causing variant. A median of 3 out of 8 (excluding genotyping results and LDL-C) DLCNS criteria were unavailable. DLCNS was documented in 48% of cases, with significant discrepancies compared to retrospective scoring (P < 0.001). DLCNS did not outperform off-treatment LDL-C alone (Δ = 0.006; P = 0.660), analogously to several reports identified in the literature. A single cut-off of 190 mg/dL LDL-C compared to DLCNS ≥ 6 showed excellent sensitivity (84.9% vs. 53.8%) and acceptable specificity (39.0% vs. 84.1%).

Conclusion: Missing criteria and severe discrepancies observed between retrospective and on-site scoring by treating physicians were highly prevalent, confirming limited utility of DLCNS in clinical routine and warranting a single off-treatment LDL-C cut-off of 190 mg/dL for enhanced index-case identification.

Aim: Children with heterozygous familial hypercholesterolaemia (HeFH) show greater carotid intima-media thickness (cIMT). Evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody, substantially reduced low-density lipoprotein cholesterol (LDL-C) and modestly reduced lipoprotein(a) in children with HeFH. We investigated evolocumab's effect on cIMT progression.

Methods: HAUSER-RCT was a randomised, placebo-controlled trial. 157 paediatric patients with FH (age: 10-17 years) and LDL-C >130mg/dL despite statin therapy received monthly evolocumab 420mg or placebo for 24 weeks. Patients who continued into an open-label extension (HAUSER-OLE; n=150) received 80 weeks of monthly evolocumab plus statins. cIMT was measured by B-mode ultrasound scanning of right and left common carotid artery at baseline; week 24 of RCT [day 1 OLE]; and weeks 24, 48, and 80 of OLE. Descriptive analysis of cIMT was a prespecified HAUSER secondary endpoint, and inferential tests reported here were post-hoc.

Results: 151 patients had evaluable cIMT summary scores at ≥1 visit. From RCT baseline to week 24, mean cIMT increased by 0.006mm (SD=0.05) with placebo (n=37) and decreased by 0.003mm (SD=0.05) with evolocumab (n=76). From RCT baseline to OLE week 80, mean cIMT summary score decreased by 0.019mm (SD=0.04) and 0.012mm (SD=0.05), respectively, in patients who initially received placebo (n=34, P=0.007) versus receiving evolocumab throughout (n=59, P=0.067). Across patients who received evolocumab in OLE, mean cIMT significantly decreased by 0.011mm (SD=0.05) from OLE day 1 to week 80 (n=94, P=0.034).

Conclusions: In children with HeFH, evolocumab plus statin treatment up to 104 weeks led to regression in carotid arterial wall thickening.

Background: Familial Hypercholesterolaemia (FH) is an inherited disease of high LDL-cholesterol (LDL-C) caused by defects in LDLR, APOB, APOE and PCSK9 genes. A pathogenic variant cannot be found in ∼60% of clinical FH patients. Using whole genome sequencing (WGS) we examined genetic determinants of FH.

Methods: WGS data generated by the 100,000 Genomes Project (100KGP) included 536 FH patients diagnosed using the FH Simon Broome criteria. Rare variants in known FH genes were analysed. Genome-wide association study (GWAS) between 443 FH variant-negative unrelated FH cases and 77,275 control participants of the 100KGP was run using high coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (Lp(a) PRS) were computed.

Results: An FH-causing variant was found in 17.4% of FH cases. GWAS identified the LPA gene locus being significantly associated (p<1x10-8). FH variant-negative participants had higher LDL and Lp(a) PRSs in comparison to the controls (p<1.0×10-16 and p<4.09×10-6, respectively). Similar associations were found in the monogenic FH with both LDL and Lp(a) PRSs being higher than in controls (p<4.03×10-4 and p<3.01x10-3, respectively). High LDL PRS was observed in 36.4% of FH variant-negative cases, whereas high Lp(a) PRS in 18.5%, with 7.0% having both high LDL and Lp(a) PRSs.

Conclusions: This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogenous architecture of hypercholesterolaemia, with the LPA gene playing a significant role. Both Lp(a) and LDL-C should be measured for precision FH diagnosis. Specific therapies to lower Lp(a) should be targeted to those who will benefit most.

Aims: European clinical guidelines recommend that patients with atherosclerotic cardiovascular disease (ASCVD), including ischaemic heart disease (IHD), stroke, and peripheral arterial disease (PAD), are prescribed lipid lowering treatment (LLT) and treated to target low-density lipoprotein cholesterol (LDL-C) levels. This study aimed to document trends in ASCVD, including treatment, monitoring, and achievement of target LDL-C.

Methods and results: A retrospective observational population study was performed using linked healthcare data (2010-22). Over the study period, the number of patients with ASCVD increased from 181 153 to 207 747 (8882 to 9398 per 100 000). The proportion of patients prescribed LLT decreased from 75.3% in 2010 to 67.1% in 2022; high-intensity statin therapy increased from 9.4 to 25.2%, while non-high-intensity statin therapy decreased from 59.6 to 38.2%. The prescription of high-intensity statin therapy was consistently higher amongst patients with IHD (10.9% in 2010 increasing to 28.0% in 2022) than in patients with stroke (4.7-21.6%) or PAD (3.9-10.6%).The proportion of cases with documented LDL-C decreased from 58.0% in 2010 to 49.3% in 2022. Of those with documented LDL-C in 2022, 44.0% achieved LDL-C < 1.8 mmol/L, including 45.2% of those with IHD, 42.0% of those with stroke, and only 32.8% of those with PAD.

Conclusion: Prescription of LLT, including high-intensity statin therapy, documentation of LDL-C, and achievement of target LDL-C levels was relatively low, especially in PAD patients. Although target achievement in 'tested patients' increased over time, the proportion of patients undergoing lipid testing declined. More rigorous lipid management requires prioritisation, especially for PAD and stroke patients.