Familial Hypercholesterolemia Registry Research Articles

Unveiling homozygous familial hypercholesterolemia in Greece: a comprehensive analysis of baseline traits and LDL goal achievement in adults from the HELLAS-FH Registry

Abstract Background Homozygous familial hypercholesterolemia (HoFH) is a severe genetic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels. This study aimed to analyze demographic characteristics, lipid profile, and rate in achieving LDL-C targets in adult HoFH patients in Greece. Methods This is a cross-sectional analysis of the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Adults with genetically or clinically diagnosed HoFH were included. Median LDL-C levels were assessed during HoFH diagnosis and enrollment. Results Seventeen HoFH adults (mean age 41 years and mean age at diagnosis 31 years, men 58.8%). Genetic confirmation of HoFH was available in 10 patients, while the remaining were diagnosed based on clinical criteria. Family history of atherosclerotic cardiovascular disease was documented in 70.5% of patients. Clinical presentations varied, with 47.0% exhibiting tendon xanthomas, 17.6% xanthelasmas, 23.5% corneal arcus, and 52.9% premature coronary artery disease (CAD). Predominant treatment involved statins (88.2%), ezetimibe (58.8%),PCSK9i (23.5%), lomitapide (29.4%), while LDL apheresis was utilized in 23.5%. Median LDL-C levels were 407 mg/dL (10.53 mmol/L) at diagnosis and 226 mg/dL (5.84 mmol/L) at enrollment. None of the patients achieved the LDL-C target set by the 2019 EAS/ESC Guidelines. Conclusion The challenges of delayed diagnosis, undertreatment, and unattained LDL-C targets persist in HoFH management in Greece, emphasizing the critical need for effective lipid-lowering interventions to mitigate cardiovascular risk.

A contemporary snapshot of familial hypercholesterolemia registries

Purpose of review Familial hypercholesterolemia (FH) registries can capture unique data on FH concerning real-world practice, clinic epidemiology, natural history, cascade testing, cardiovascular consequences of late diagnosis, and use of healthcare resources. Such registries are also valuable for identifying and bridging the gaps between guidelines and clinical practice. We reviewed recent findings from the principal FH registries. Recent findings Most adult patients with heterozygous FH (HeFH) are diagnosed late, undertreated, and do not reach guideline-recommended low density lipoprotein-cholesterol (LDL-C) goals. In children and adolescents with HeFH, detection relies principally on genetic testing and measurement of LDL-C levels. Similarly, the majority of patients with homozygous FH (HoFH) receive sub-optimal cholesterol-lowering treatments and do not attain recommended LDL-C goals, gaps being wider in lower income than higher income countries. In HeFH patients, men have a higher risk of atherosclerotic cardiovascular disease than women. Summary The evolving data from FH registries provide real-world evidence for developing implementation strategies to address gaps across the continuum of care of FH worldwide.

The effect of lipid-lowering treatment on indices of MASLD in familial hypercholesterolemia patients

Background & AimsThe effect of lipid-lowering treatment (LLT) on metabolic dysfunction associated steatotic liver disease (MASLD) is unclear. This is relevant for patients with familial hypercholesterolemia (FH) who are on lifelong LLT. We aimed to evaluate the effect of LLT on MASLD indices in this population. MethodsPatients with at least possible diagnosis of FH were included into the Hellenic FH Registry (HELLAS-FH) registry. We analyzed the effect of statin monotherapy, statin/ezetimibe and statin/ezetimibe/proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) on MASLD indices, i.e., original triglyceride-glucose index (TyGO) and triglyceride-glucose index (TyG). We compared changes of TyG and TyGO before any treatment and after at least one year of stable LLT. ResultsWe included 1289 patients: n=569 in the statin monotherapy group (mean age=51±15 years, 52.7% males), n=629 in the statin/ezetimibe group (52±14 years, 51.8%), and n=91 in the statin/ezetimibe/PCSK9i group (54±13 years, 58.2%). Compared with baseline, TyGO and TyG decreased significantly following statin monotherapy (8.61 vs 8.49 and 4.65 vs 4.59, respectively, both p<0.01), statin/ezetimibe (8.59 vs 8.41 and 4.64 vs 4.55, respectively, both p<0.01) and statin/ezetimibe/PCSK9i (8.79 vs 8.55 and 4.74 vs 4.62, respectively, both p<0.01). There was no difference regarding the change of TyGO and TyG between groups after adjusting for baseline levels. A greater percentage of patients in the statin/ezetimibe and statin/ezetimibe/PCSK9i groups exhibited TyGO-defined MASLD resolution compared with statin monotherapy (p<0.05). After adjustment for possible confounders, LLT was significantly associated with MASLD resolution. ConclusionsMASLD indices were significantly improved in all LLT groups in FH patients. Statin/ezetimibe and statin/ezetimibe/PCSK9i were associated with greater TyGO-defined MASLD resolution compared with statin monotherapy.

Alterations in serum levels of calcium, vitamin D, phosphorus, and parathyroid hormone in patients with clinically confirmed familial hypercholesterolemia: a cross-sectional study

Background: Familial hypercholesterolemia (FH), an autosomal dominant disease, is associated with increased risk of premature cardiovascular disease (CVD). This study aimed to examine the variations in serum levels of calcium, vitamin D, phosphorus, and parathyroid hormone (PTH) among FH patients, as these factors have been associated with an increased susceptibility to CVD. Materials and Methods: In this cross-sectional study, we used data from Isfahan FH registry. The Dutch Lipid Clinic Network (DLCN) criteria was used for diagnoses of FH patients. Control group included participant with hyperlipidemia and were unlikely FH according to DLCN criteria. All biochemical parameters were measured using standard methods. Results: A total of 131 patients (mean age, 53.1 ± 12.2; male, 51.4%) were included in the analysis. Patients with FH had lower serum vitamin D level compared with control groups in unadjusted model (P= 0.028). The relationship between serum vitamin D and FH was not significant after adjustment for traditional risk factor (P= 0.184). No significant association was observed between FH and serum calcium (P= 0.886), phosphorus (P= 0.463), and PTH (P= 0.849). Besides, there was no significant association between LDL-C or total cholesterol and serum minerals in FH patients. Conclusion: This study found no significant changes in serum calcium, vitamin D, phosphorus, and PTH in patients with FH.

Treatment status of LDL-C lowering therapy according to genetic variant in familial hypercholesterolemia: From the Korean familial hypercholesterolemia (KFH) registry

Treatment status of LDL-C lowering therapy according to genetic variant in familial hypercholesterolemia: From the Korean familial hypercholesterolemia (KFH) registry

Insights into the Vietnam familial hypercholesterolemia registry: Characterizing mutations in LDLR, APOB and PCSK9 proteins at a structural and functional level

Insights into the Vietnam familial hypercholesterolemia registry: Characterizing mutations in LDLR, APOB and PCSK9 proteins at a structural and functional level

The Danish familial hypercholesterolemia registry: Monitoring of diagnostics, detection, and treatment quality in Denmark.

The Danish familial hypercholesterolemia registry: Monitoring of diagnostics, detection, and treatment quality in Denmark.

Ocular manifestations of severe familial hypercholesterolemia

BackgroundTo study ocular manifestations of patients with severe familial hypercholesterolemia (FH). MethodsIn this population-based case-control study, patients suffering from severe familial hypercholesterolemia from the Lebanese Familial Hypercholesterolemia Registry, along with age and gender-matched healthy controls were recruited. All participants underwent a comprehensive eye examination, and patients underwent fluorescein angiography as well. Logistic regression models were used to identify any association between patients with severe familial hypercholesterolemia and abnormal eye findings, while adjusting for hypertension and pack-year smoking. The main outcome measure of this study was the development of ocular vascular abnormalities. Results28 patients and 28 controls were recruited. Patients with severe familial hypercholesterolemia had significantly greater odds of developing corneal arcus and xanthelasmas than the control group (p < 0.001). Retinal vascular abnormalities (plaques) were exclusively and more significantly present in patients with familial hypercholesterolemia (18 %). Similarly, retinal arteriosclerosis was exclusively and significantly more prevalent in the familial hypercholesterolemia group (p < 0.001, adjusted odds ratio 6.8). Stratification by LDL levels and genotypes did not show any significant change in the prevalence of any ocular finding. ConclusionIn addition to the well-established increase in incidence of corneal arcus and xanthelasmas, severe familial hypercholesterolemia patients have more prevalent retinal vascular abnormalities that include vascular plaques and arteriosclerosis.

Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry.

Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals. Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD. Adult patients ( n = 2156, mean age 50 ± 15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets. The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

Abstract 17207: Usefulness of Polygenic Risk Score for Intraventricular Septal Diameter in Patients With Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant monogenic disease characterized by thickened heart muscles, particularly at the intraventricular septum (IVS), and an increased risk of arrythmias and sudden death. Recently, in addition to monogenic screening, the polygenic risk score (PRS) has been proposed as a potentially useful tool for risk stratification in several cardiovascular diseases. However, it remains unclear whether PRS is also beneficial for risk stratification of patients with HCM. Methods: We recruited and genotyped HCM patients from the Kanazawa University Mendelian Disease (KUMD) HCM registry and controls from the KUMD non-HCM familial hypercholesterolemia registry. The PRS was calculated from over 3 million genotyped with imputed variants of each participant for IVS diameter (PRS IVS ) using a publicly available summary statistic at the National Bioscience Database Center. We assessed the PRS IVS distributions among the monogenic HCM, causal variant negative HCM, and control groups. We also tested the associations of PRS IVS with the IVS diameters within each group. Results: We evaluated a total of 400 participants (267 HCM patients, including 79 with monogenic HCM and 188 with causal variant negative HCM, and 133 controls) for the analyses. Compared to the controls, PRS IVS was significantly higher in both monogenic HCM (0.12923 in Monogenic HCM vs. 0.09057 in controls, age- and sex-adjusted p = 0.02) and causal variant negative HCM patients (0.11127 in causal variant negative HCM vs. 0.09057 in controls, p = 9.9x10 -4 ). However, no associations were found between PRS IVS and IVS diameters in any of the groups. Conclusions: In this study, both the monogenic HCM and causal variant negative HCM groups demonstrated significantly higher PRS IVS than non-HCM controls. However, we found no evidence to suggest that PRS IVS might be useful for risk stratification in patients with HCM.

Compliance of heterozygous familial hypercholesterolemia patients: 5-years follow-up of the Russian familial hypercholesterolemia registry

Compliance of heterozygous familial hypercholesterolemia patients: 5-years follow-up of the Russian familial hypercholesterolemia registry

Genetic testing for familial hypercholesterolemia in Quebec, Canada: a single-centre retrospective cohort study.

Familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease caused by elevated low-density lipoprotein cholesterol (LDL-C) levels. We determined the impact of a full next-generation sequencing (NGS) genetic panel on reclassification of patients with a clinical diagnosis of FH in Quebec compared to the partial genetic panel currently offered by the Quebec Ministère de la Santé et des Services sociaux (Ministry of Health and Social Services) (MSSS), which includes 11 variants that are common in French Canadians. We conducted a retrospective cohort study in a subgroup of patients in the Canadian FH Registry seen at the McGill University Health Centre Preventive Cardiology/Lipid Clinic, Montréal, between September 2017 and September 2021 who were clinically diagnosed with severe hypercholesterolemia, probable FH or definite FH according to the Canadian definition of FH. Next-generation sequencing of the LDLR, APOB and PCSK9 genes, and multiplex ligation-dependent probe amplification of the LDLR gene to detect genetic variants, were performed. Among 335 consecutive patients with heterozygous FH (184 men [54.9%] and 151 women [45.1%]), the baseline LDL-C level was 6.96 (standard deviation 1.79) mmol/L. Patients identified through cascade screening were 11 years younger on average than index patients, and smaller proportions presented to the clinic with cardiovascular risk factors. A pathogenic FH variant was identified in 169 (73.8%) of the 229 patients who underwent genetic testing; the majority had variants in the LDLR (146 [86.4%]) or APOB (24 [14.2%]) gene. The genetic panel offered by the MSSS accounted for only 48% of the variants identified with the full NGS panel. Of the 229 patients, 90 (39.3%, 95% confidence interval 32.9%-46.0%) were reclassified from a clinical diagnosis of probable FH to definite FH after genetic screening with a full FH panel. Genetic testing in patients suspected of having FH provided diagnostic certainty and permitted many patients with a clinical diagnosis of probable FH to be reclassified as having definite FH. Genetic screening allows for increased identification of patients with FH and may therefore help reduce the burden of cardiovascular disease and mortality rates among Canadians with FH. Trial registration: ClinicalTrials.gov, no. NCT02009345.

Design, Rationale, and Preliminary Results of the Canadian Homozygous Familial Hypercholesterolemia Registry: 2008 to 2022 Update

&#x0D; Homozygous familial hypercholesterolemia (HoFH) is an orphan disease characterized by extreme elevations of low-density lipoprotein cholesterol (LDL-C) in the blood and premature atherosclerotic cardiovascular disease.&#x0D; Untreated, survival beyond 30 years is rare.&#x0D; The Canadian HoFH Registry was created by clinicians from across Canada to understand the burden of disease, current treatments, outcomes, and costs to society.&#x0D; The registry will be used to inform decisions for access to specialized therapies, such as LDL apheresis and orphan medications.&#x0D; To date, 79 cases of HoFH have been identified across the country, and 52 patients from 5 provinces have been enrolled.&#x0D;

The Association of Thyroid-Stimulating Hormone (TSH) Levels and Lipid Profile in Euthyroid Patients with Familial Hypercholesterolemia.

Previous studies reported a relationship between thyroid-stimulating hormone (TSH) and low-density lipoprotein cholesterol (LDL-C) levels. In this study, we aim to evaluate the impact of TSH levels on lipid profile in patients with familial hypercholesterolemia (FH) and euthyroid state. Patients were selected from the Isfahan FH registry. The Dutch Lipid Clinic Network (DLCN) criteria are used to detect FH. Patients were classified into no FH, possible FH, probable FH, and definite FH groups based on the DLCN scores. Patients with any cause of secondary hyperlipidemia, including hypothyroidism, were excluded from this study. The study group consisted of 103 patients with possible FH, 25 patients with definite FH, and 63 individuals with no FH. The mean TSH and LDL-C levels among participants were 2.10 ± 1.22 mU/l and 142.17 ± 62.56 mg/dl, respectively. No positive or negative correlation was found between serum TSH and total cholesterol (P value = 0.438), high-density lipoprotein cholesterol (P = 0.225), triglycerides (P value = 0.863), and LDL-C (P value = 0.203). We found no correlation between serum TSH levels and lipid profiles in euthyroid patients with FH.

Primary Care Physicians' Perspectives on Identifying Familial Hypercholesterolaemia in Primary Care: A Qualitative Study.

Context Familial hypercholesterolaemia (FH) is a common autosomal dominant disorder, causing elevated cholesterol from birth, premature heart disease, and early death. Objective This study explored primary care physicians' experiences and perspectives on identifying FH in Malaysian primary care. Study Design and Analysis A qualitative study involving semi-structured interviews and focus group discussions with 22 primary care physicians (PCPs) in two primary care clinic settings. The interviews and focus group discussions were audio recorded, and the recordings were transcribed verbatim. The data in the transcripts were analysed using thematic approach. Setting Primary Care Clinics Population Studied Primary Care Physicians in two primary care clinics. Intervention A qualitative study involving semi-structured interviews and focus group discussions Outcome Measures Primary Care Physicians' perceptions and experiences of identifying individuals at high risk of FH in their clinical practice, and the acceptability and perceived challenges of trying to do this were explored during the interviews and focus group discussions. Findings PCPs felt there was potential for FH to be identified earlier in primary care. They had some existing knowledge and awareness of diagnostic criteria for FH but highlighted several challenges. In their practice, this included limited time in routine clinical care, availability of medication and clinical expertise; and critical lack of family history and physical examination findings in health records. The barriers on a systemic level were shortage of lipid specialist services and the absence of local care pathways for FH. The PCPs recommended a user-friendly case-finding tool for FH, and establishing FH registry and clinical practice guideline in Malaysia, alongside a national FH screening strategy and awareness campaigns for both clinicians and general public. Conclusions PCPs are positive about improving the identification of FH in primary care. However greater support in their practice and wider system developments and change are needed.

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 &lt; 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 &lt; 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.

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.

SEX DISPARITIES IN TREATMENT AND CLINICAL OUTCOMES OF FAMILIAL HYPERCHOLESTEROLEMIA

SEX DISPARITIES IN TREATMENT AND CLINICAL OUTCOMES OF FAMILIAL HYPERCHOLESTEROLEMIA

Association between lipoprotein(a) concentrations and atherosclerotic cardiovascular disease risk in patients with familial hypercholesterolemia: An analysis from the hellas-fh

Background and Aims : Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, such a role in patients with familial hypercholesterolemia (FH) is less documented. The purpose of this study was to evaluate the association between Lp(a) concentrations and ASCVD prevalence in adult patients with FH.Methods: This was a cross-sectional study from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Patients were categorized into 3 tertiles according to Lp(a) levels.Results: A total of 541 adult patients (249 males) with heterozygous FH (HeFH) were included (mean age 48.5±15.0 years at registration, 40.8±15.9 years at diagnosis). Median (interquartile range) Lp(a) concentrations in the 1st, 2nd and 3rd Lp(a) tertile were 6.4 (3.0-9.7), 22.4 (16.0-29.1) and 77.0 (55.0-102.0) mg/dL, respectively. There was no difference in lipid profile across Lp(a) tertiles. The overall prevalence of CVD was 9.4% in the first, 16.1% in the second and 20.6% in the third tertile (p=0.012 among tertiles). This was also the case for premature ASCVD, with prevalence rates of 8.5%, 13.4% and 19.8%, respectively (p=0.010 among tertiles). A trend for increasing prevalence of coronary artery disease (8.3%, 12.2% and 16.1%, respectively; p=0.076 among tertiles) was also observed. No difference in the prevalence of stroke and peripheral artery disease was found across tertiles.Conclusions: Elevated Lp(a) concentrations are significantly associated with increased prevalence of ASCVD in patients with HeFH. Background and Aims : Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, such a role in patients with familial hypercholesterolemia (FH) is less documented. The purpose of this study was to evaluate the association between Lp(a) concentrations and ASCVD prevalence in adult patients with FH. Methods: This was a cross-sectional study from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Patients were categorized into 3 tertiles according to Lp(a) levels. Results: A total of 541 adult patients (249 males) with heterozygous FH (HeFH) were included (mean age 48.5±15.0 years at registration, 40.8±15.9 years at diagnosis). Median (interquartile range) Lp(a) concentrations in the 1st, 2nd and 3rd Lp(a) tertile were 6.4 (3.0-9.7), 22.4 (16.0-29.1) and 77.0 (55.0-102.0) mg/dL, respectively. There was no difference in lipid profile across Lp(a) tertiles. The overall prevalence of CVD was 9.4% in the first, 16.1% in the second and 20.6% in the third tertile (p=0.012 among tertiles). This was also the case for premature ASCVD, with prevalence rates of 8.5%, 13.4% and 19.8%, respectively (p=0.010 among tertiles). A trend for increasing prevalence of coronary artery disease (8.3%, 12.2% and 16.1%, respectively; p=0.076 among tertiles) was also observed. No difference in the prevalence of stroke and peripheral artery disease was found across tertiles. Conclusions: Elevated Lp(a) concentrations are significantly associated with increased prevalence of ASCVD in patients with HeFH.

Detection of comorbidities in patients with familial hypercholesterolemia in the Ukrainian familial hypercholesterolemia registry

Detection of comorbidities in patients with familial hypercholesterolemia in the Ukrainian familial hypercholesterolemia registry