Relations of physical signs to genotype, lipid and inflammatory markers, coronary stenosis or calcification, and outcomes in patients with heterozygous familial hypercholesterolemia

Background Although the presence of physical signs [tendon xanthomas and/or corneal arcus (TX/CA)], are associated with the risk of coronary artery disease in patients with heterozygous familial hypercholesterolemia (HeFH), their relationship with genotypes and clinical characteristics has not been fully determined. This study aimed to examine the association of TX/CA with genetic mutation, lipid- and inflammation-related markers, the severity of coronary stenosis or calcification, and cardiovascular events (CVEs) in patients with HeFH. Methods LDLR, APOB, and PCSK9 genes were screened in 523 HeFH patients, and patients with TX/CA (n = 50) were 1:4 propensity score-matched to patients without TX/CA (n = 200) to adjust for age and sex. Laboratory markers (proprotein convertase subtilisin/kexin type 9 [PCSK9], lipoprotein(a) and high-sensitivity C-reactive protein [hsCRP]), computed tomography angiography, coronary angiography, and follow-up for CVEs were performed. Results Patients with physical signs had significantly higher low-density lipoprotein cholesterol levels; higher PCSK9 or hsCRP concentrations; more LDLR positive mutations; and higher prevalence of high tertiles of Gensini, SYNTAX and Jeopardy scores as well as coronary artery calcium scores than did those without. Over an average follow-up of 3.7 years, the incidence of CVEs was significantly higher in patients with TX/CA (log-rank p < 0.001). Patients with physical signs and mutation positivity had threefold higher risks of CVEs (adjusted hazard ratio 3.34, 95% confidence interval 1.04–10.72, p = 0.024). Conclusions Physical signs were associated with genotypes and phenotypes, and worse outcomes in patients with HeFH, suggesting that these signs may help in risk stratification in these patients.

PCSK9 Inhibitor Induces a Transient Decrease in Neutrophil-Lymphocyte Ratio and Monocyte-Lymphocyte Ratio in Homozygous/Compound Heterozygous Familial Hypercholesterolemia Patients

Background: Homozygous/compound heterozygous familial hypercholesterolemia (HoFH/cHeFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels that have been reported to contribute to a long-term chronic systemic inflammation. The aims of this study are to describe the inflammatory profile of HoFH/cHeFH patients and explore the effect of PCSK9 inhibitor (PCSK9i) on a series of inflammatory biomarkers, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-HDL ratio (MHR), monocyte-lymphocyte ratio (MLR) and mean platelet volume-lymphocyte ratio (MPVLR). Methods: In this prospective cohort study, 21 definitive HoFH/cHeFH on high-intensity statins plus ezetimibe were placed on subcutaneous injections of PCSK9i 450mg every 4 weeks (Q4W). The biochemical parameters and inflammatory profile were analyzed at the day before PCSK9i therapy, 3 months and 6 months after PCSK9i therapy.Results: We found that HoFH/cHeFH on maximum tolerated statin dose plus ezetimibe displayed an elevated lipid and disturbed blood biomarker profile. After 3 months of add-on PCSK9i therapy, a significant reduction of LDL-C was observed. Meanwhile, percentage and count of neutrophils, monocyte counts, MPV, as well as two inflammatory biomarkers, NLR and MLR were reduced. However, at 6-month PCSK9i treatment, NLR and MLR returned to pre-PCSK9i treatment levels.Conclusions: PCSK9i induces a transient decrease in NLR and MLR in HoFH/cHeFH patients. Our results add evidence in evaluating the effects of PCSK9i on systemic inflammation.

Impact of diabetes on coronary severity and cardiovascular outcomes in patients with heterozygous familial hypercholesterolemia: an analysis of genotype and phenotype

Aims Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular disease. However, the association between T2DM and coronary artery disease (CAD) in patients with heterozygous familial hypercholesterolemia (HeFH) has not been thoroughly evaluated. Our study aimed to assess the effect of T2DM on CAD severity and hard cardiovascular endpoints in a HeFH cohort. Methods A total of 432 patients with HeFH with a molecular and/or clinical Dutch Lipid Clinic Network score ≥6 (definite and probable) were enrolled. Patients were divided into a T2DM group (n=99) and a non-T2DM group (n=333). Hard endpoints included a composite of non-fatal myocardial infarction, stroke, and cardiac death. Results No differences were observed regarding genetic mutations in patients with and without T2DM. Patients with T2DM demonstrated a greater number of diseased vessels (p=0.029) and more severe coronary lesions with high Gensini, SYNTAX, and Jeopardy score tertiles. Compared with patients without T2DM, patients with T2DM were at a significantly greater risk of hard endpoints (multivariate adjusted hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.02–4.84, p=0.025). Additionally, patients with T2DM and good glucose control (HbA1c &lt;7.0%) were at a lower risk of hard endpoints compared with those with poor glucose control (HbA1c ≥7.0%, HR 0.08, 95% CI 0.01–0.56, p=0.011). Conclusions We conclude that T2DM is an independent predictor of CAD severity when assessed by four different tests and worse cardiovascular outcomes, suggesting that T2DM could be further used for risk stratification of patients with HeFH. FUNDunding Acknowledgement Type of funding sources: None. Graphical abstract