Familial Hypercholesterolemia Patients Research Articles

Lipid residual cardiovascular risk parameters in patients with familial hypercholesterolemia - importance of triglyceride to high-density lipoprotein ratio

Introduction. Familial hipercholesterolemia is monogenetic disorder associated with early onset of cardiovascular disease. The measurement of low density cholesterol is the primary therapeutic goal in familial hypercholesterolemia patients, but despite the lipid-lowering therapy cardiovascular disease still occurs. It became clear that it?s necessary to consider residual cardiovascular risk. The aim of study was to evaluate residual cardiovascular risk in familial hipercholesterolemia. Material and Methods. In this cross-sectional study we included 291 familial hipercholesterolemia patients with and without previously diagnosed diabetes. Based on value of the Dutch Lipid Clinical Network score criteria, familial hipercholesterolemia patients without diabetes was further divided into: possible (3-5 points), probable (6-8 points), and definite (>8 points) familial hypercholesterolemia. Triglyceride to high density cholesterol ratio, non-HDL-cholesterol and remnant cholesterol were used as parameters of lipid residual cardiovascular risk. Results. We found statistically significant differences in total cholesterol, low and high density cholesterol, triglycerides and apolipoprotein B between the groups (p>0.05). The definite and probable group had higher non-HDL-cholesterol values than possible and familial hypercholesterolemia with diabetes (p<0.01) groups. Familial hypercholesterolemia with diabetes group had higher values of triglyceride to high density cholesterol ratio and remnant cholesterol than definite and probable group (p<0.01). Regression analysis showed that triglyceride to high density cholesterol ratio was independent predictor of appearance of coronary artery disease in addition to elevated low density cholesterol and non-HDL-cholesterol (p<0.01). Conclusion. Triglyceride to high density cholesterol ratio is the most important parameter of the lipid residual cardiovacular risk that strongly linked with cardiovascular disease in familal hypercholesterolemia patients, especially with associated diabetes.

Addressing the underdiagnosis of familial hypercholesterolemia: A mixed methods study exploring the knowledge and practice behaviors of cardiology healthcare providers

Familial hypercholesterolemia (FH) is vastly underdiagnosed and causes an increased risk for sudden cardiac death. Cardiology providers (CHCPs) are in an ideal position to care for FH patients. This research aimed to understand the practice behaviors of CHCPs in the screening, diagnosis, and management of FH. Adaptation of an existing FH knowledge tool guided survey development. The results of the quantitative survey guided development of the interview protocol. CHCPs were recruited in the Division of Cardiology at Columbia University Irving Medical Center (CUIMC). A review of the educational materials offered by the Division of Cardiology was conducted to identify FH knowledge domains presented. CHCPs with MDs, at CUIMC for 6-10 years, in clinical practice for 1-5 years, and in inpatient services had the highest average total knowledge scores. CHCPs with RNs, at CUIMC for less than 1 year, in clinical practice for 6-10 years, and in Cath Lab had the lowest average knowledge scores. Four themes emerged - variability in FH care; issues related to addressing FH at institutional, practice setting, and individual levels; importance of identifying FH early; and intervention approaches to overcome barriers to caring for FH patients in cardiology. CHCPs with MDs or with experiential FH knowledge described FH care beyond screening. The document review revealed that only MDs were provided lectures pertaining to FH. Future interventions should increase didactic and experiential FH knowledge incorporating institutional, local, and national FH resources. Improving FH care can reduce FH-related morbidity and mortality, as well as improve FH health outcomes.

Семейная гиперхолестеринемия в педиатрической практике

Familial hypercholesterolemia (FH) is a hereditary disease characterized by elevated levels of low-density lipoproteins, early onset and progressive course of atherosclerosis (usually at a young age), and high risk of cardiovascular complications. Detection of mutations in family members enables the diagnosis of FH. However, approximately 20% of FH patients are tested negative for the FH-associated mutations. This results in a delayed diagnosis and late therapy initiation, especially in children. Therefore, raising awareness about FH both among healthcare professionals and in the society is very important. Key words: children, lipid-lowering therapy, familial hypercholesterolemia, screening, registry

Identifying possible homozygous familial hypercholesterolemia patients: an Italian experts' opinion

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) and massive risk of premature atheromasia and cardiovascular events. HoFH is caused by mutations in several genes, such as LDLR, APOB, PCSK9 and LDLRAP1. If untreated, the average age of death is 18 years old, but fatalities within the first 5 years of age have been recorded. Therefore, early diagnosis and treatment are crucial, in order to prevent and/or delay the cardiovascular complications of LDL-C exposure. Because HoFH is a rare disorder, it is not frequently encountered in daily clinical practice at the primary/secondary unspecialized cardiological centers. Then the availability of practical indications helping to identify HoFH patients or to arise a suspect of HoFH is particularly strategic to promptly start the appropriate lipid-lowering therapy. For such a purpose, a group of Italian experts suggests three useful algorithms to identify cases requiring accurate and specialized clinical evaluation as potential HoFH patients. These cases with suspected HoFH should be addressed to specialized centres for the optimal management of these patients.

Prevalence of Diabetes and Its Association with Atherosclerotic Cardiovascular Disease Risk in Patients with Familial Hypercholesterolemia: An Analysis from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH).

Familial hypercholesterolemia (FH) and type 2 diabetes mellitus (T2DM) are both associated with a high risk of atherosclerotic cardiovascular disease (ASCVD). Little is known about the prevalence of T2DM and its association with ASCVD risk in FH patients. This was a cross-sectional analysis from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH) including adults with FH (n = 1719, mean age 51.3 ± 14.6 years). Of FH patients, 7.2% had a diagnosis of T2DM. The prevalence of ASCVD, coronary artery disease (CAD), and stroke was higher among subjects with T2DM compared with those without (55.3% vs. 23.3%, 48.8% vs. 20.7%, 8.3% vs. 2.7%, respectively, p < 0.001). When adjusted for age, systolic blood pressure, smoking, body mass index, hypertension, waist circumference, triglyceride levels, high-density lipoprotein cholesterol levels, and gender, T2DM was significantly associated with prevalent ASCVD [OR 2.0 (95% CI 1.2-3.3), p = 0.004]. FH patients with T2DM were more likely to have undergone coronary revascularization than those without (14.2% vs. 4.5% for coronary artery bypass graft, and 23.9% vs. 11.5% for percutaneous coronary intervention, p < 0.001). T2DM is associated with an increased risk for prevalent ASCVD in subjects with FH. This may have implications for risk stratification and treatment intensity in these patients.

Assessment of global, segmental longitudinal deformation of the left ventricle and endothelial function in children with family hypercholesterolemia

Background . Familial hypercholesterolemia (FHC) is accompanied by a significant increase in the level of low-density lipoprotein cholesterol in the blood . The relevance of early diagnosis and treatment is due to the risk of premature development of atherosclerosis . Coronary heart disease due to atherosclerosis of the coronary arteries occurs among FHC patients up to 30 years . Currently , cardiac morphology and myocardial function in children with FHC are poorly understood . Objective . To assess global , segmental longitudinal deformation of the left ventricle and endothelial function in children with familial hypercholesterolemia . Design and methods . The study involved 25 healthy children and 34 children with FHC. Endothelin-1 and NO were determined by enzyme immunoassay . Echocardiographic study was carried . Assessment of global and segmental longitudinal deformation of the left ventricle was carried out in 4-chamber apical , 3-chamber and 2-chamber projections . Results . There were no statistically significant differences in global longitudinal strain (GLD) between groups . Individual analysis showed that 2 patients with FHC had a decrease in GLD. There was a statistically significant decrease in parameters in FHC patients at the level of the basal and apical anterior-septal , basal lower segments . Endothelin-1 and NO were increased in FHC compared to the control group . Conclusion . Speckle-tracking echocardiography allowed identifying patients with a decrease in global and segmental longitudinal deformation of the left ventricle among children with FHC.

Mitochondrial Genetic Background May Impact Statins Side Effects and Atherosclerosis Development in Familial Hypercholesterolemia

Heredity of familial hypercholesterolemia (FH) can present as a dominant monogenic disorder of polygenic origin or with no known genetic cause. In addition, the variability of the symptoms among individuals or within the same families evidence the potential contribution of additional factors than monogenic mutations that could modulate the development and severity of the disease. In addition, statins, the lipid-lowering drugs which constitute the first-line therapy for the disease, cause associated muscular symptoms in a certain number of individuals. Here, we analyze the evidence of the mitochondrial genetic variation with a special emphasis on the role of CoQ10 to explain this variability found in both disease symptoms and statins side effects. We propose to use mtDNA variants and copy numbers as markers for the cardiovascular disease development of FH patients and to predict potential statin secondary effects and explore new mechanisms to identify new markers of disease or implement personalized medicine strategies for FH therapy.

Familial Hypercholesterolemia Patients with COVID-19-Effective Cholesterol-Lowering Therapy is Urgent both during and after Infection.

Heterozygous familial hypercholesterolemia (HeFH) patients are the prime example of subjects who are at high risk for both acute myocardial infarction (AMI) and ischemic stroke during, and post, SARS-CoV-2 infection. HeFH per se, if left untreated, results in premature clinical atherosclerosis often presenting in the fourth or fifth decade of life. The other concern in HeFH is endothelial dysfunction which is already evident from early childhood. In untreated HeFH patients, the severe hypercholesterolemia causes endothelial dysfunction from an early age, and as a result thereof, atherosclerotic lesions develop prematurely, particularly in the coronary arteries, and result in further endothelial dysfunction and inflammation in these critical segments of the arterial tree. As the pre-existing endothelial dysfunction in HeFH patients is most likely sensitive to further direct and indirect SARS-CoV-2 virus-dependent damage, we can infer that HeFH serves as an example of a comorbidity that predicts a poorer prognosis with COVID-19 infection. Indeed, a large US national database study showed that patients diagnosed with HeFH and SARS-CoV-2 infection had significantly increased Annualized Incidence Density Rates (AIDRs) of AMI when compared to matched HeFH controls not having been diagnosed with SARS-CoV-2 infection. Effective cholesterol lowering is essential for the prevention, or at least alleviation, of the detrimental effects of SARS-CoV-2 infection among HeFH patients. Due to the pre-existing subclinical or even clinical atherosclerotic cardiovascular disease in subjects with HeFH, cholesterol-lowering treatment needs to be continued or, better still, intensified during, and for an extended period post, SARS-CoV-2 infection.

Prevalence of familial hypercholesterolemia in patients with confirmed premature coronary artery disease in Ranchi, Jharkhand

BackgroundFamilial hypercholesterolemia (FH) is an under-diagnosed autosomal co-dominant genetic disorder characterized by very high plasma levels of low-density lipoprotein cholesterol (LDL-C), premature coronary artery disease (CAD) with arcus cornealis, and xanthomas. Among patients with CAD, the frequency of FH is significantly higher than that of the general population, but little data are available in India in this regard. This study aimed to assess the prevalence of FH in patients with premature coronary artery disease for the first time in the Jharkhand population.ResultsThe study was conducted on 200 premature CAD patients at RIMS hospital, Ranchi, from January 2020 to June 2021 with CAG-confirmed acute coronary syndrome. The study, without taking the aid of genetic profiling of the patients and using the Dutch Lipid Clinic Network Criteria, revealed quite a high (23.5%) prevalence of potential FH in patients with premature CAD apart from the conventional risk factors. Mean LDL-C levels among patients with definite, probable, possible, and no FH were recorded as 250.39, 184.32, 136.11, and 108.09 mg/dl, respectively. Arcus cornealis was seen in 55.31% of patients with potential FH, 90% in definite FH, and 44.40% with probable FH. Patients with potential FH were more likely to be younger (age < 40 years) males, having a history of CAD and a family history of premature CAD as compared to patients without FH.ConclusionsThere was no previous report of large studies on FH or its epidemiology and its natural history from India. The present study is the first one to show a high prevalence of potential FH in premature CAD (about 23.5%). This preliminary study revealed that the prevalence of FH in patients with premature CAD who came to the tertiary care hospital of Ranchi, Jharkhand, was high, apart from the conventional risk factors.

A new 165-SNP low-density lipoprotein cholesterol polygenic risk score based on next generation sequencing outperforms previously published scores in routine diagnostics of familial hypercholesterolemia

Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between their diagnosis performance and their practical use in routine practice is not clearly established. Consequently, we set up new PRS based on our routine panel for sequencing and compared their diagnostic performance with previously-published PRS. After a meta-analysis, four new PRS including 165 to 1633 SNP were setup using different softwares. They were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77, 95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10−4). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10−6). These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing.

The risk of various types of cardiovascular diseases in mutation positive familial hypercholesterolemia; a review.

Familial hypercholesterolemia (FH) is a common, inherited disease characterized by high levels of low-density lipoprotein Cholesterol (LDL-C) from birth. Any diseases associated with increased LDL-C levels including atherosclerotic cardiovascular diseases (ASCVDs) would be expected to be overrepresented among FH patients. There are several clinical scoring systems aiming to diagnose FH, however; most individuals who meet the clinical criteria for a FH diagnosis do not have a mutation causing FH. In this review, we aim to summarize the literature on the risk for the various forms of ASCVD in subjects with a proven FH-mutation (FH+). We searched for studies on FH+ and cardiovascular diseases and also included our and other groups published papers on FH + on a wide range of cardiovascular and other diseases of the heart and vessels. FH + patients are at a markedly increased risk of a broad range of ASCVD. Acute myocardial infarction (AMI) is the most common in absolute numbers, but also aortic valve stenosis is by far associated with the highest excess risk. Per thousand patients, we observed 3.6 incident AMI per year compared to 1.9 incident aortic valve stenosis, however, standardized incidence ratio (SIR) for incident AMI was 2.3 compared to 7.9 for incident aortic valve stenosis. Further, occurrence of ischemic stroke seems not to be associated with increased risk in FH+. Clinicians should be aware of the excess risk of almost all kind of ASCVD in FH+, and the neutral risk of stroke need to be studied further in FH + patients.

LDLR missense variants disturb structural conformation and LDLR activity in T-lymphocytes of Familial hypercholesterolemia patients

Familial hypercholesterolemia (FH) is caused by deleterious mutations in the LDLR that increase markedly low-density lipoprotein (LDL) cholesterol and cause premature atherosclerotic cardiovascular disease. Functional effects of pathogenic LDLR variants identified in Brazilian FH patients were assessed using in vitro and in silico studies. Variants in LDLR and other FH-related genes were detected by exon-target gene sequencing. T-lymphocytes were isolated from 26 FH patients, and 3 healthy controls and LDLR expression and activity were assessed by flow cytometry and confocal microscopy. The impact of LDLR missense variants on protein structure was assessed by molecular modeling analysis. Ten pathogenic or likely pathogenic LDLR variants (six missense, two stop-gain, one frameshift, and one in splicing region) and six non-pathogenic variants were identified. Carriers of pathogenic and non-pathogenic variants had lower LDL binding and uptake in activated T-lymphocytes compared to controls (p < 0.05), but these variants did not influence LDLR expression on cell surface. Reduced LDL binding and uptake was also observed in carriers of LDLR null and defective variants. Modeling analysis showed that p.(Ala431Thr), p.(Gly549Asp) and p.(Gly592Glu) disturb intramolecular interactions of LDLR, and p.(Gly373Asp) and p.(Ile488Thr) reduce the stability of the LDLR protein. Docking and molecular interactions analyses showed that p.(Cys184Tyr) and p.(Gly373Asp) alter interaction of LDLR with Apolipoprotein B (ApoB). In conclusion, LDLR null and defective variants reduce LDL binding capacity and uptake in activated T-lymphocytes of FH patients and LDLR missense variants affect LDLR conformational stability and dissociation of the LDLR-ApoB complex, having a potential role in FH pathogenesis.

Hepatic fat as a novel marker for high-risk coronary atherosclerotic plaque features in familial hypercholesterolaemia

Background & aimsHepatic steatosis has been associated with increased risk of coronary artery disease. Individuals with familial hypercholesterolaemia have accelerated but variable progression of coronary artery disease. We investigated whether hepatic steatosis is associated with novel coronary atherosclerosis biomarkers in adults with heterozygous familial hypercholesterolaemia, using comprehensive coronary computed tomographic angiography. MethodsWe conducted a cross-sectional study of 213 asymptomatic patients with familial hypercholesterolaemia (median age 54.0 years, 59 % female) who underwent coronary computed tomographic angiography for cardiovascular risk assessment in an outpatient clinic. High-risk plaque features, plaque volume and pericoronary adipose tissue attenuation were assessed. From concurrently captured upper abdominal images, severity of hepatic steatosis was computed, as liver minus spleen computed tomography attenuation and stratified into quartiles. ResultsOf 213 familial hypercholesterolaemia patients, 59 % had coronary artery calcium, 36 % obstructive coronary artery disease (≥50 % stenosis) and 77 % high-risk plaque features. Increasing hepatic steatosis was associated with higher calcium scores, more high-risk plaque features and presence of obstructive coronary artery disease. Hepatic steatosis was associated with the presence of high-risk plaque features (OR: 1.48; 95 % CI: 1.09–2.00; p = 0.01), particularly in the proximal coronary segments (OR: 1.52; 95 % CI: 1.18–1.96; p = 0.001). Associations persisted on multivariable logistic regression analysis adjusting for cardiometabolic factors, obstructive coronary artery disease and calcium score. Hepatic steatosis was associated with higher plaque volumes (Q4: 499 mm3 vs Q1: 414 mm3, p = 0.02), involving mainly low attenuation and noncalcified plaques (both p = 0.03). No differences in pericoronary adipose tissue attenuation were observed. ConclusionsHepatic steatosis is associated with multiple indices of advanced coronary atherosclerosis in familial hypercholesterolaemia patients, particularly high-risk plaque features, independent of conventional cardiovascular risk factors and markers. This may involve specific mechanisms related to hepatic steatosis.Clinical trial number: N/A.

A familial hypercholesterolemia registry as the main tool for adequate management of the disease.

To evaluate the experience of FH registry conducted in Karelia Republic. FH registry in Karelia is existing from 2004, it includes 350 patients with heterozygous FH (110 with definite FH), the mean age is 48 ± 2.3 years. The genetic study was performed in 102 patients (29.1%). The creation of the registry has contributed to the active identification of FH, and now the estimated frequency of FH occurrence in Karelia may be 1:300, in patients with cardiovascular disease 1:10. We also analyzed genetic features of FH in our republic and found that the LDL-C level, above which the probability of LDL receptor mutation increases in Karelia, is 6.5 mmol/L. We analyzed risk factors of ischemic heart disease and the prognosis in FH. The creation and maintenance of a registry is an effective way of organizing timely diagnosis and adequate treatment of FH patients.

EPH37 High Cardiovascular Disease Risk and Low Lipid-Lowering Treatment in Heterozygous Familial Hypercholesterolemia Patients: A French Nationwide Registry

Heterozygous familial hypercholesterolemia (HFH) is increasingly better diagnosed and treatments can improve the cardiovascular prognosis. We evaluated the long-term cardiovascular risk of HFH using the French REFERCHOL registry.

An evaluation of the effectiveness of a lipid clinic in identifying people with familial hypercholesterolaemia and reducing their risk of cardiovascular disease

Abstract Introduction The NHS Long Term Plan aims to ‘prevent up to 150,000 heart attacks, strokes and dementia cases over the next 10 years’.1 People with Familial Hypercholesterolaemia (FH) are considered to be at high-risk of heart attack, stroke and dementia but an estimated 90% remain undiagnosed.1 The Chesterfield and Dronfield Primary Care Network were commissioned to set-up a 12-month pharmacist-led clinic across 9 practices to identify, treat and refer FH patients. Patients with suspected FH benefit from referral to specialist services.2 Aim This study aimed to evaluate the number of FH patients identified and any unintended benefits of the Lipid Clinic. Methods Ethical approval was not required for this service evaluation. Informed consent was sought prior to data collection and the dataset was anonymised. Searches of practice patient records identified patients with a previously raised lipid level (total Cholesterol &amp;gt;7.5mmol/L and/or non-HDL-C &amp;gt; 5.9mmol/L)2 for review in the Lipid Clinic. Patients reviewed in the Lipid Clinic were initiated/optimised on lipid lowering medication as appropriate.2 Data were collected for patients invited for review in the Lipid Clinic between May-July 2022. Patients’ attendance as well as decline/non-response to the Clinic was recorded. The data collected included family history, QRISK score (where applicable), lipid lowering treatment the patient was taking (if any) and blood tests results (serum lipids, HBA1c and thyroid function tests). If bloods were deranged it was documented whether or not it was a new finding. The data was analysed by categorising patients into potential FH, primary/secondary prevention of cardiovascular disease and whether they needed referral to secondary care. Results Out of the 260 patients invited for review, 219 attended the clinic. Of these, 30 (13.7%) were provided with lifestyle advice as they did not meet the criteria for treatment. Twenty-three patients (10.5%) met the Simon-Broom criteria for possible FH. A further 3 patients identified were known to have FH but had not undergone genetic cascade testing. These 26 patients (11.8%) were referred to secondary care for genetic testing and specialist input. Newly raised HbA1c indicative of either diabetes or non-diabetic hyperglycaemia was incidentally found in 39 patients (17.8%). Lipid-lowering medication was initiated/titrated in 189 patients (86.3%). Discussion/Conclusion The significant proportion of patients requiring follow up in secondary care (11.8%) suggesting targeted searches are effective in identifying patients with possible FH. Identifying FH patients, testing and treating their family members appropriately reduces their risk of cardiovascular events.2 The Lipid Clinic has identifying that nearly a fifth of patients were previously undiagnosed with either diabetes or non-diabetic hyperglycaemia (17.8%) suggests that this is also an opportunity to identify and treat these patients earlier than they would otherwise have been identified. The results highlight the need for primary care staff education on the new AAC NHS Guidelines2 relating to managing lipid results. One limitation of the study is although the Lipid Clinic has received good informal feedback, formal feedback is yet to be collected from patients and stake holders. In addition, the clinic is still ongoing, and more data is being collected.

Correlation of cardiovascular risk predictors with overweight and obesity in patients with familial hypercholesterolemia.

We aimed to analyze the correlation between overweight and obesity-related indicators and cardiovascular risk predictors in patients with familial hypercholesterolemia (FH) and to evaluate their mutual predictive properties. A total of 103 patients with FH included from 2004 to 2017 were retrospectively analyzed. Pearson correlation analysis and multiple linear regression analysis were used to assess the correlation between overweight and obesity-related indicators and cardiovascular risk predictors in FH patients. Subject operating characteristic (ROC) curve was used to analyze their reciprocal predictive performance. (1) Atherogenic index of plasma (AIP) (β = 0.020) and ApoB/ApoA1 Ratio (BAR) (β = 0.015) were independently correlated with body mass index (BMI) (P < 0.05); AIP (β = 1.176) was independently correlated with waist-to-hip ratio (WHR) (P < 0.01); AIP (β = 1.575), BAR (β = 0.661) and atherogenic coefficient (AC) (β = 0.427) were independently correlated with waist-to-height ratio (WHtR) (P < 0.05). (2) The area under the ROC (AUC) for overweight corresponding to AIP, BAR, and AC were 0.695 (95% CI = 0.593-0.797, P < 0.01), 0.660 (95% CI = 0.555-0.766, P < 0.01), and 0.632 (95% CI = 0.525-0.740, P < 0.05), respectively; and AUCs for central obesity corresponding to AIP, BAR and AC were 0.757 (95% CI = 0.656-0.857, P < 0.001), 0.654 (95% CI = 0.536-0.771, P < 0.05) and 0.651 (95% CI = 0.538-0.764, P < 0.05), respectively. The AUCs for moderate risk of AIP corresponding to BMI, WHR, and WHtR were 0.709 (95% CI = 0.608-0.811, P < 0.001), 0.773 (95% CI = 0.678-0.867, P < 0.001), 0.739 (95% CI = 0.641-0.836, P < 0.001), respectively, and BMI, WHR and WHtR corresponded to an AUC of 0.691 (95% CI = 0.585-0.797, P < 0.01), 0.734 (95% CI = 0.632-0.835, P < 0.001), and 0.706 (95% CI = 0.603-0.810, P < 0.01) for high risk of AIP, respectively. AIP has independent positive linear correlation with indicators related to overweight and obesity in FH patients; AIP has good predictive performance for overweight and obesity in FH patients, and WHR has good performance for identifying moderate and high risk of AIP in FH patients.

Persistence with long-term PCSK9 inhibitor treatment and its effectiveness in familial hypercholesterolaemia: data from the SAFEHEART study.

Most heterozygous familial hypercholesterolaemia (FH) patients require intensive lipid-lowering therapy (LLT) including PCSK9 inhibitors (PCSK9is) to reach current low-density lipoprotein cholesterol (LDL-C) goals. Persistence with chronic treatment is important to reduce the burden of atherosclerotic cardiovascular disease. We analysed persistence, efficacy, and impact on quality of life (QoL) of PCSK9i in FH patients in clinical practice setting. Spanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART) is an open, prospective study in genetically defined FH patients in Spain. Patients ≥18 years of age (n = 696, 46% females) on stable LLT treated with PCSK9i were analysed. Median LDL-C at starting PCSK9i was 145 mg/dL [interquartile range (IQR), 123-177], 3.8 mmol/L (IQR 3.2-4.6). After a median follow up of 3.7 years (IQR 2.3-4.8), 27 patients (4%) discontinued PCSK9i treatment: 5 temporarily (0.7%) and 22 permanently (3.2%). Persistence with PCSK9i was 96.1% in the whole period. Median LDL-C levels and % LDL-C reduction attained after 1 year of treatment and in the last follow-up visit were 63 mg/dL (IQR 43-88), 1.6 mmol/L (IQR 1.1-2.23); 61 mg/dL (IQR 44-82), 1.6 mmol/L (IQR 1.1-2.1); 57.6% (IQR 39.5-69); and 58% (IQR 44-68), respectively. 2016 and 2019 ESC/EAS LDL-C goals were attained by 77 and 48% of patients, respectively, at the last follow-up visit (P < 0.001). Mean QoL score increased slightly in the first year and remained stable. Long-term persistence with PCSK9i in FH patients is very high, with a good QoL. Effectiveness in LDL-C reduction and LDL-C goal achievement dramatically improved with PCSK9i in this high-risk population in clinical practice setting. ClinicalTrials.gov number NCT02693548.

Recent Advances in Gene Therapy for Familial Hypercholesterolemia: An Update Review.

(1) Background: Existing lipid-lowering therapies have difficulty in achieving lipid target levels in patients with familial hypercholesterolemia (FH), especially in the treatment of patients with homozygous familial hypercholesterolemia. (2) Method: All of the literature data containing "Familial hypercholesterolemia" and "Gene Therapy" in PubMed and Clinical Trials from 2018 to 2022 were selected. (3) Results: The rapid development of gene therapy technology in recent years is expected to change the treatment status of FH patients. As emerging gene therapy vectors, the optimized adeno-associated viruses, exosomes, and lipid nanoparticles have demonstrated an improved safety and higher transfection efficiency. Various RNA-targeted therapies are in phase 1-3 clinical trials, such as small interfering RNA-based drugs inclisiran, ARO-ANG3, ARO-APOC3, olpasiran, SLN360, and antisense oligonucleotide-based drugs AZD8233, vupanorsen, volanesorsen, IONIS-APO(a)Rx, etc., all of which have demonstrated excellent lipid-lowering effects. With gene editing technologies, such as CRISPR-Cas 9 and meganuclease, completing animal experiments in mice or cynomolgus monkeys and demonstrating lasting lipid-lowering effects, patients with FH are expected to reach a permanent cure in the future. (4) Conclusion: Gene therapy is being widely used for the lipid-lowering treatment of FH patients and has shown excellent therapeutic promise, but the current delivery efficiency, economic burden, immunogenicity and the precision of gene therapy can be further optimized.

Subclinical atherosclerosis determined by coronary artery calcium deposition in patients with clinical familial hypercholesterolemia

Background and aimsLimited knowledge exists regarding the association between coronary artery calcium (CAC) deposition in patients with clinical familial hypercholesterolemia (FH) and FH subtypes such as polygenic causes. We studied CAC score in patients with clinical FH and subtypes including polygenic causes of FH compared to healthy controls. MethodsIn a case-control study, we identified potential clinical FH cases registered with an LDL-C >6.7 mmol/l within a nationwide clinical laboratory database on the Faroe Islands and invited them for diagnostic evaluation according to clinical FH scoring systems. Controls were identified in the background population. All subjects were aged 18–75 years and without a history of cardiovascular disease. FH mutation testing and genotypes of twelve LDL-C associated single nucleotide polymorphisms were determined using conventional methods in selected individuals. CAC scores were assessed by cardiac CT. Odds ratios obtained using multivariate logistic regression were used as measures of association. ResultsA total of 120 clinical FH patients and 117 age- and sex-matched controls were recruited. We found a very low frequency of monogenic FH (3%), but a high level of polygenic FH (60%) in those genetically tested (54%). There was a statistically significant association between the CAC score and a diagnosis of clinical FH with the highest observed odds ratio of 5.59 (95% CI 1.65; 18.94, p = 0.006) in those with a CAC score ≥300 compared to those with a CAC of zero. In supplemental analyses, there was a strong association between CAC scores and clinical FH of a polygenic cause. ConclusionWe found a statistically significant association between CAC levels and clinical FH with the highest observed risk estimates among clinical FH cases of a presumed polygenic cause.