Familial Hypercholesterolemia Group Research Articles

Association Between Patient Sex and Familial Hypercholesterolemia and Long-Term Cardiovascular Risk Factor Management 5 Years After Acute Coronary Syndrome.

Long-term control of cardiovascular risk factors after acute coronary syndrome (ACS) is the cornerstone for preventing recurrence. We investigated the extent of cardiovascular risk factor management in males and females with and without familial hypercholesterolemia (FH) 5 years after ACS. We studied patients hospitalized for ACS between 2009 and 2017 in a Swiss multicenter prospective cohort study. FH was defined based on clinical criteria from the Dutch Lipid Clinic Network and Simon Broome definitions. Five years post-ACS, we assessed low-density lipoprotein-cholesterol (LDL-c) levels, lipid-lowering therapy (LLT), and other cardiovascular risk factors, comparing males to females with and without FH using generalized estimating equations. A total of 3139 patients were included; mean age was 61.4 years (SD, 12.1), 620 (19.8%) were female, and 747 (23.5%) had possible FH. Compared with males at 5-years post-ACS, females were more likely to not use statins (odds ratio, 1.61 [95% CI, 1.28-2.03]) and less likely to have combination LLT (odds ratio, 0.72 [95% CI, 0.55-0.93]), without difference between patients with FH and without FH. Females in both FH and non-FH groups less frequently reached LDL-c values ≤1.8 mmol/L (odds ratio, 0.78 [95% CI, 0.78-0.93]). Overall, patients with FH were more frequently on high-dose statins compared with patients without FH (51.0% versus 42.9%; P=0.001) and presented more frequently with a combination of 2 or more LLT compared with patients without FH (33.8% versus 17.7%; P<0.001), but less frequently reached LDL-c targets of ≤1.8 mmol/L (33.5% versus 44.3%; P<0.001) or ≤2.6 mmol/L (70.2% versus 78.1%; P=0.001). Five years after ACS, females had less intensive LLT and were less likely to reach target LDL-c levels than males, regardless of FH status. Males and females with FH had less optimal control of LDL-c despite more frequently taking high-dose statins or combination LLT compared with patients without FH. Long-term management of patients with ACS and FH, especially females, warrants optimization.

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.

Carotid intima-medial thickness in patients with severe hypertriglyceridemia

Background and aimsSevere hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) concentration > 10 mmol/L, is relatively uncommon, and its implications for atherosclerotic cardiovascular disease (ASCVD) risk remain somewhat unclear. We evaluated the association between severe HTG and carotid intima-media thickness (IMT), a marker for ASCVD. MethodsWe studied three clinical cohorts: 88 patients with severe HTG (mean TG level 20.6 mmol/L), 271 patients with familial hypercholesterolemia (FH) as a contrast group, and 70 normolipidemic controls. Carotid IMT was measured using standardized ultrasound imaging. Statistical analysis was conducted using one-way analysis of variance (ANOVA) to compare mean IMT values, analysis of covariance (ANCOVA) to adjust for confounding variables, specifically age and sex, as well as Spearman pairwise correlation analysis between variables. ResultsUnadjusted mean carotid IMT was greater in severe HTG and FH groups compared to controls, however, this was no longer significant for severe HTG after adjustment for age and sex. In contrast, adjusted carotid IMT remained significantly different between the FH and control groups. ConclusionsOur findings suggest that extreme TG elevations in severe HTG patients are not significantly associated with carotid IMT, in contrast to the increased IMT seen in FH patients. These findings add perspective to the complex relationship between severe HTG and ASCVD risk.

Abstract P516: Vascular Risk Assessment in Youth With Familial Hypercholesterolemia and Combined Dyslipidemia of Obesity

Introduction: Pulse wave analysis (PWA) assesses vascular health by estimating arterial wave reflections noninvasively and is associated with cardiovascular (CV) events in adults in recent studies. However, data in youth are lacking. Individuals with CV risk factors such as familial hypercholesterolemia (FH) or combined dyslipidemia of obesity (CDO) have increased risk of adult-onset CV disease. Using PWA may help improve risk stratification of young patients with adverse CV risk factors and enhance disease management. Hypothesis: We hypothesized that youth with adverse CV risk factors would have differences in arterial wave reflections compared to controls. Methods: Demographic, anthropometric, and fasting lipid values were obtained in 124 patients aged 9-25 years in a study comparing vascular health among normolipidemic controls (N=47), FH (N=45), and CDO (N=32). PWA was obtained using the SphygmoCor XCEL device, and wave separation analyses were performed from brachial artery assessments. Group differences were assessed by chi-square, ANOVA, or Kruskal-Wallis test as appropriate by variable type and distribution normality. Results: There were significant differences between groups in adiposity (CDO with higher BMI, p&lt;0.001) and lipid levels with a more adverse lipid profile (higher TC, LDL, &amp; TG; lower HDL) for the FH and CDO groups versus controls (all p&lt;0.001). The CDO group had higher forward pulse wave amplitude (Pf) versus the control and FH groups (p=0.0002, Figure) and higher backward pulse wave amplitude (Pb) versus controls (p=0.0013). Differences in Pf or Pb between FH and controls did not reach significance. Conclusions: Adolescents and young adults with CDO have altered forward and backward wave reflections compared to normolipidemic controls. It is possible that PWA differences between the FH and control groups may become significant over time. These novel parameters suggest early vascular changes in youth with CDO and may help improve risk stratification in youth with adverse CV risk factors.

Gene expression profiling in elderly patients with familial hypercholesterolemia with and without coronary heart disease

Background and aimsElderly familial hypercholesterolemia (FH) patients are at high risk of coronary heart disease (CHD) due to high cholesterol burden and late onset of effective cholesterol-lowering therapies. A subset of these individuals remains free from any CHD event, indicating the potential presence of protective factors. Identifying possible cardioprotective gene expression profiles could contribute to our understanding of CHD prevention and future preventive treatment. Therefore, this study aimed to investigate gene expression profiles in elderly event-free FH patients. MethodsExpression of 773 genes was analysed using the Nanostring Metabolic Pathways Panel, in peripheral blood mononuclear cells (PBMCs) from FH patients ≥65 years without CHD (FH event-free, n = 44) and with CHD (FH CHD, n = 39), and from healthy controls ≥70 years (n = 39). ResultsNone of the genes were differentially expressed between FH patients with and without CHD after adjusting for multiple testing. However, at nominal p < 0.05, we found 36 (5%) differentially expressed genes (DEGs) between the two FH groups, mainly related to lipid metabolism (e.g. higher expression of ABCA1 and ABCG1 in FH event-free) and immune responses (e.g. lower expression of STAT1 and STAT3 in FH event-free). When comparing FH patients to controls, the event-free group had fewer DEGs than the CHD group; 147 (19%) and 219 (28%) DEGs, respectively. ConclusionsElderly event-free FH patients displayed a different PBMC gene expression profile compared to FH patients with CHD. Differences in gene expression compared to healthy controls were more pronounced in the CHD group, indicating a less atherogenic gene expression profile in event-free individuals. Overall, identification of cardioprotective factors could lead to future therapeutic targets.

Prevalence and Clinical Characteristics of Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome according to the Current Japanese Guidelines: Insight from the EXPLORE-J study.

Little data exists for evaluating the prevalence and patient characteristics of familial hypercholesterolemia (FH) according to the latest 2022 guidelines for FH published by the Japan Atherosclerosis Society (JAS), which revised the Achilles tendon thickness (ATT) threshold from 9.0 mm in both sexes to 8.0 mm in men and 7.5 mm in women. This study used a nationwide registry of patients with acute coronary syndrome (ACS) to evaluate the prevalence of FH according to the latest diagnostic criteria for FH and to investigate the application of Achilles tendon imaging in the diagnosis of FH.A previous prospective observational study at 59 Japanese centers involving consecutive patients with ACS who were managed between April 2015 and August 8, 2016 was conducted to explore lipid management and persistent risk in patients hospitalized for ACS (EXPLORE-J). The study population consisted of 1,944 EXPLORE-J enrollees. According to the diagnostic criteria for FH in the 2022 JAS guidelines, the prevalence of probable or definite was among patients with ACS was 6.6% (127/1944). Among patients with premature ACS (male, age ＜55 years; female, age ＜65 years), the prevalence of FH was 10.1% (43/427). The mean ages were of the probable FH and definite FH groups were 59.9 and 61.0 years, respectively, while the mean age of the possible-or-unlikely FH group was 66.4 years (significantly older). Relative to the possible-or-unlikely FH group, the low-density lipoprotein cholesterol (LDL-C) levels were similar in the probable FH group and and significantly higher in the definite FH group. The prevalence of FH was considerably higher than previously reported, especially for patients with premature ACS. The age and LDL-C levels of the patients in the probable FH and definite FH groups were similar.

Assessment of Low-density Lipoprotein Cholesterol Levels and Non-invasive Vascular Health in School-aged Children: A Study in Ogasa District, Shizuoka Prefecture.

The present study assessed low-density lipoprotein cholesterol (LDL-C) levels in school-aged children from the Ogasa District of Shizuoka Prefecture and evaluated the utility of non-invasive vascular tests, namely flow-mediated dilation (FMD) and intima-media thickness (IMT), in pediatric patients with familial hypercholesterolemia (FH). We analyzed the lipid test results of 8,568 students screened for prevention of lifestyle-related diseases and 78 children under 15 years old with cholesterol levels exceeding 220 mg/dL who visited Chutoen General Medical Center. We examined the LDL-C distribution from school-age screenings and conducted FMD and IMT assessments on those meeting the 2022 Pediatric FH Guidelines criteria. Among the screened students, 186 (2.2%) exhibited LDL-C levels above 140 mg/dL, including 123 fourth-graders (2.8%) and 63 first-year junior high students (1.5%). The mean LDL-C level across all students was 90.0 mg/dL (standard deviation: 21.3 mg/dL), with the 95th percentile at approximately 125.0 mg/dL. Of the 78 children who visited the hospital, 65 met the FH diagnostic criteria. In children ≥ 10 years old, no significant IMT differences were observed between the Definitive and Probable FH groups and the Possible FH group; however, a significant difference in the FMD percentage was noted between these groups (9.9% [8.1%-11.9%] vs. 14.2% [11.6%-16.3%], P=0.003). Our findings highlight the LDL-C distribution in FH screening and suggest a potential reduction in FMD in pediatric FH patients ≥ 10 years old. These results emphasize the importance of initiating pharmacological interventions in school-aged children to maintain optimal LDL-C levels for lifelong cardiovascular health.

Myocardial microvascular dysfunction in asymptomatic patients with hereditary dyslipidemia

Abstract Introduction Microvascular dysfunction underlies the pathophysiology of many cardiovascular disease (CVD) conditions and is strongly associated with future cardiovascular events. Hereditary forms of dyslipidaemia such as familial hypercholesterolemia (FH) and high levels of lipoprotein(a) [Lp(a)] are associated with premature atherosclerotic CVD but the degree of microvascular dysfunction in asymptomatic individuals is not fully explored. Purpose To evaluate the presence of microvascular dysfunction in asymptomatic individuals with the hereditary dyslipidaemias FH and high Lp(a). Methods Asymptomatic individuals without manifest CVD were recruited to four groups with 30 subjects in each; 1) controls with Lp(a)&amp;lt;30 nmol/L, 2) FH+Lp(a)&amp;lt;30 nmol/L, 3) FH+Lp(a)&amp;gt;125 nmol/L, and 4) isolated Lp(a)&amp;gt;125 nmol/L without FH. FH diagnoses were confirmed by genetic analysis. Transthoracic doppler echocardiography was used to record coronary flow in the distal part of the left anterior descending artery at rest and during hyperaemia induced by intravenous infusion of adenosine. Coronary flow reserve (CFR) was calculated by dividing hyperaemic to basal flow. Peripheral microvascular endothelial function was determined by recording reactive hyperaemia index (RHI) by peripheral arterial tonometry in the index fingers of both hands. CFR and RHI were considered impaired if values were &amp;lt;2.5 and &amp;lt;1.67, respectively. Results The four groups were balanced in age (mean 42.6±8.4 years), sex (50% females), BMI (mean 25.0±4.7 kg/m2), and smoking status (5.0% current smokers). Low-density lipoprotein cholesterol was also similar across the four groups (mean 2.8±1.1 mmol/L) with the two FH groups being on cholesterol lowering treatment while the other two were pharmacologically naïve. The three groups with hereditary dyslipidaemia had a higher proportion of subjects with impaired CFR, 30.0% in each group compared to 6.6% in controls (p=0.014) (Figure 1A). The FH+Lp(a)&amp;lt;30 nmol/L and FH+Lp(a)&amp;gt;125 nmol/L groups had received cholesterol lowering treatment for a median (inter quartile range, IQR) of 4.0 (8.0) and 11.0 (11.0) years respectively (p&amp;lt;0.001). In the FH+Lp(a)&amp;gt;125 nmol/L group individuals with normal CFR had received significantly longer treatment (p=0.006) but not in the FH+Lp(a)&amp;lt;30 nmol/L group (p=0.568) (Figure 1B). There were no major differences in median CFR (p=0.550) (Figure 2A) or median RHI (p=0.341) (Figure 2B) levels between the four groups. Conclusion Asymptomatic individuals with the hereditary dyslipidaemias FH and/or high Lp(a) have a higher degree of coronary microvascular dysfunction compared to healthy controls. For individuals with combined traits FH and high Lp(a), the total treatment years of cholesterol lowering is associated with preserved coronary microvascular function suggesting CFR as a potential useful non-invasive tool for cardiovascular risk-stratification in patients with hereditary dyslipidaemias.Figure 1Figure 2

Association between Familial Hypercholesterolemia and Serum Levels of Cholesterol Synthesis and Absorption Markers: The CACHE Study FH Analysis.

Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Familial hypercholesterolemia (FH) is a well-known inherited disorder presenting elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and premature coronary disease. In this study, we aim to examine the differences in terms of serum markers of cholesterol metabolism between FH and non-FH individuals and to examine their associations with serum lipid levels. In this study, we utilized data on serum markers of cholesterol metabolism, namely, lathosterol (Latho, synthesis marker), campesterol (Campe, absorption marker), and sitosterol (Sito, absorption marker) measured by gas chromatography of the CACHE consortium, which comprised of 13 research groups in Japan. Clinical data were compiled using REDCap system. Among the 2944 individuals in the CACHE population, we selected individuals without lipid-lowering medications and hemodialysis patients for this CACHE study FH analysis. Multivariable adjustment was performed to assess the associations. In this study, we analyzed data from 51 FH patients and 1924 non-FH individuals. After adjustment for possible confounders, the FH group was shown to have significantly higher Campe and Sito concentrations and insignificantly higher Latho concentrations than the non-FH group. These marker concentrations showed nonlinear associations with TC in the FH group. Campe/Latho and Sito/Latho ratios were significantly higher in the FH group than in the non-FH group. FH group had significantly elevated serum Campe and Sito concentrations and insignificantly elevated Latho concentrations; thus, intestinal cholesterol absorption relative to hepatic cholesterol synthesis was suggested to be elevated in patients with FH. Serum Latho, Campe, and Sito concentrations showed nonlinear associations with TC in the FH group.

Aortic Wall Thickness as a Surrogate for Subclinical Atherosclerosis in Familial and Nonfamilial Hypercholesterolemia: Quantitative 3D Magnetic Resonance Imaging Study and Interrelations with Computed Tomography Calcium Scores, and Carotid Ultrasonography.

We aimed to compare the extent of subclinical atherosclerosis in the ascending and descending aortas by measuring wall area and thickness using 3D cardiovascular magnetic resonance imaging (aAWAI and dAWAI) in patients with asymptomatic familial hypercholesterolemia (FH) and nonfamilial hypercholesterolemia (NFH). We also aimed to establish the interrelations of CMR parameters with other subclinical atherosclerosis measurements, such as calcium scores, obtained using computed tomography in coronary arteries (CCS) and ascending and descending aorta (TCSasc and TCSdsc), as well as the carotid intima-media thicknesses (cIMT) using ultrasonography. A total of 60 patients with FH (29 men and 31 women), with a mean age of 52.3 ± 9.6 years, were analyzed. A subclinical atherosclerosis assessment was also performed on a group consisting of 30 age- and gender-matched patients with NFH, with a mean age of 52.5 ± 7.9 years. We found the ascending and descending aortic wall areas and thicknesses in the FH group to be significantly increased than those of the NFH group. A multivariate logistic regression analysis showed that a positive FH mutation value was a strong predictor of high aAWAI and dAWAI independent of the LDL cholesterol level. Correlations across CMR atherosclerotic parameters, calcium scores, and cIMT in the FH and NFH groups, were significant but low. Most of the atherosclerosis tests with high results belonged to the FH group. We found that patients with documented heterozygous FH had a higher atherosclerosis burden in the aorta compared to patients with severe hypercholesterolemia without FH gene mutation. Atherosclerosis is not severe in asymptomatic patients with FH, but is more pronounced and also more diffuse than in patients with NFH. The etiology of hypercholesterolemia, and not just cholesterol levels, plays a significant role in determining the degree of subclinical atherosclerosis.

Association between Eating Patterns and Quality of Life in Patients with Familial Hypercholesterolemia.

(1) Background: Familial hypercholesterolemia (FH) is a genetic disease that has autosomal dominant inheritance, being characterized by increased levels of low-density lipoproteins (LDLs) due to a decreased clearance of the circulant LDLs. Alimentation is a key factor in patients with FH. Implementing a restrictive diet may have a significant impact on their quality of life, besides the social and environmental factors. (2) Methods: We realized a prospective study that was conducted in the Cardiovascular Rehabilitation Clinic from the Clinical Rehabilitation Hospital and that included 70 patients with FH and 20 controls (adults with no comorbidities). We evaluated their lipid profile, their quality of life through the Short Form-36 Questionnaire, and their eating habits. (3) Results: Lower scores in the quality-of-life questionnaire were obtained in the FH group both in the case of the physical (73.06 vs. 87.62) and the mental component (75.95 vs. 83.10). Women had better physical function (85 vs. 75) and physical role than men (100 vs. 75). The group aged over 65 has the score lowest for all 10 components. Overeating was driven by boredom and was more frequent on weekends in the FH group. None of the patients in the control group felt loneliness or depression associated with overeating. (4) Conclusions: Overeating in patients with FH is associated with a lower quality of life. The complexity of these patients needs a multidisciplinary approach. Thus, the quality-of-life questionnaire should be implemented in their periodic follow-ups in order to increase their general status, paying special attention to geriatric patients.

Early echocardiographic signs of cardiovascular affection in pediatric familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a rare autosomal dominant genetic disorder caused by defective low-density lipoprotein (LDL) receptors or abnormal apolipoprotein B. FH raises the risk of premature atherosclerotic disease and cardiovascular death in young adults. However, cardiovascular affection in children needs to be more adequately studied. Our study aimed to evaluate the effect of hypercholesterolemia on the cardiovascular system of pediatric patients with homozygous FH using conventional and advanced echocardiographic parameters such as tissue Doppler imaging (TDI) and 2-dimensional speckle-tracking echocardiography (2D-STE). This case-control study matched 25 healthy children with 21 patients with homozygous FH. Both groups had conventional echocardiography, TDI, and 2D-STE. Myocardial velocities of the left and right ventricles, left ventricular strain, and aortic stiffness parameters were measured. The FH group had greater systolic blood pressure, dilated coronary arteries, and hypertrophied left ventricle (LV) compared to the control (P = 0.0001, P = 0.001, P = 0.01, respectively). The mitral E/E′ ratio was higher in the patient group than in the control group (P = 0.007), indicating LV diastolic dysfunction in patients. At the same time, LV systolic function evaluated by 2D-STE was comparable to that in the control group. The abdominal aorta circumferential strain and ascending aorta M-mode-derived strain were significantly lower in patients compared to those in the control (P = 0.024, P = 0.0001, respectively), indicating increased aortic stiffness in the patients’ group; moreover, 85.7% of patients had mild aortic insufficiency. Conclusion: Mild aortic insufficiency, coronary artery dilatation, left ventricular (LV) diastolic dysfunction, and increased aortic stiffness are among early cardiovascular markers in pediatric patients with homozygous FH before impaired LV systolic function.What is Known:• Familial hypercholesterolemia (FH) in adults is associated with accelerated atherosclerosis, aortic valvopathy, dilated coronary arteries, ischemic heart disease, and premature cardiovascular death.• The cardiovascular effects of FH in children require additional research.What is New:• Pediatric patients with familial hypercholesterolemia tend to have an early affection for left ventricular diastolic function before the affection for the systolic function.• The diastolic dysfunction associated with pediatric FH is correlated to the aortic stiffness and low-density lipoprotein levels.

Lipoprotein profile assessed by 1H NMR, BMI and blood pressure are associated with vascular alterations in children with familial hypercholesterolaemia

Background and aimsChildren with familial hypercholesterolaemia (FH) have elevated low-density lipoprotein cholesterol (LDL-C) concentrations since birth, which increases the risk of cardiovascular disease in adulthood. Arterial injury and stiffness parameters, including carotid intima media thickness (cIMT), pulse wave velocity (PWV) and distensibility (DIST), can be detected early in childhood. We studied the associations between cIMT, PWV and DIST with the lipoprotein profile assessed by proton nuclear magnetic resonance (1H NMR) and with influential variables such as blood pressure (BP) or body mass index (BMI) in children with FH. Methods and resultsIn this cross-sectional study, we included 201 children (96 with FH and 105 non-FH controls). Clinical history, physical examination and standard biochemical studies were performed. FH genetic testing was performed when clinically indicated. Carotid ultrasonography and an advanced lipoprotein profile by 1H NMR were performed. Multivariate and classification methods were used.There were no differences between cIMT, PWV and DIST between FH and non-FH children. FH children presented more total LDL and large, medium and small particles. Small LDL particles, BMI and systolic BP determined the presence of pathological IMT in the FH group. LDL size, high-density lipoproteins and very low-density lipoprotein particles together with blood pressure determined the presence of pathological arterial wall elasticity. ConclusionsAlterations in lipoprotein parameters assessed by are associated with early structural and functional arterial characteristics in children with FH. BMI and BP act as boosting factors. Cardiovascular prevention should start early in children with FH, encompassing all components of a healthy lifestyle.

Increased extracellular vesicles (EVs) related to T cell-mediated inflammation and vascular function in familial hypercholesterolemia

Background and aimsOxLDL modulates innate and adaptive immunity, and extracellular vesicles (EVs) released from both non-immune and immune cells are proposed key players in atherosclerosis development. In the present study, we aimed to investigate EVs expressing markers related to adaptive immunity-driven inflammation and endothelial activation/dysfunction in hypercholesterolemic patients. MethodsEVs were phenotyped in thirty patients with familial hypercholesterolemia (FH) and twenty-three healthy controls using the Extracellular Vesicle (EV) Array with antibodies targeting proteins expressed on B and T cells, and endothelial cells. ResultsFH patients had a higher atherosclerotic burden, as determined by the mean carotid intima-media thickness (IMT) (0.64 ± 0.12 mm vs. 0.58 ± 0.07 mm; p = 0.033), higher oxLDL levels (p < 0.0001), and showed increased levels of EV-specific markers: CD9 (p = 0.017), CD63 (p = 0.045), CD81 (p = 0.003), Annexin V (p = 0.018), and EV markers related to adaptive/lymphocyte immunity: CD28 (p = 0.034), CD4 (p = 0.049), CD152 (p = 0.029), LFA-1 (p = 0.024), and endothelial function: CD62E (p = 0.032), CD144 (p = 0.018), tPA (p = 0.017), CD31 (p = 0.024). Linear regression revealed a positive relationship between carotid IMT and several of the increased markers observed within the FH group, including CD9 (β = 0.33; p = 0.022), CD63 (β = 0.35; p 225 = 0.026), CD28 (β = 0.37; p = 0.026), CD4 (β = 0.40; p = 0.025), CD152 (β = 0.41; p = 0.017), LFA-1 (β = 0.42; p = 0.014) and CD62E (β = 0.38; p = 0.024). ConclusionEVs associated with adaptive immunity and endothelial dysfunction are elevated in FH patients, and several markers related to a higher atherosclerotic burden.

Safety and Effectiveness of Alirocumab, a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitor, in Patients With Familial or Non-Familial Hypercholesterolemia - A Post-Marketing Survey (J-POSSIBLE).

This study evaluated the safety and effectiveness of alirocumab in Japanese patients with familial hypercholesterolemia (FH) or non-FH in a real-world clinical setting.Methods and Results: This post-marketing surveillance study had a 2-year standard observation period. The study included Japanese patients with hypercholesterolemia who were treatment naïve to alirocumab, had a high risk of developing cardiovascular events, and had an insufficient response to, or were unsuitable for, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Alirocumab was administered at a dose of 75 or 150 mg via subcutaneous injection every 2 or 4 weeks. Overall, 1,177 and 1,038 patients were included in the safety and effectiveness analysis populations, respectively. The incidence of adverse drug reactions (ADRs) was 3.4% (40/1,177). The time to ADR occurrence was within 4 weeks in half the patients experiencing ADRs (n=20). There were no meaningful differences in the ADRs experienced in the FH and non-FH groups. The mean (±SE) percentage changes in low-density lipoprotein cholesterol from baseline to last observation carried forward were -46.9±2.1% and -42.7±2.0% in the non-FH and FH groups, respectively. Total cholesterol, triglycerides, apolipoprotein B/E, and lipoprotein(a) concentrations were decreased at Week 4 and maintained until Week 104 in the overall population. Alirocumab was well tolerated and showed effectiveness in Japanese patients with hypercholesterolemia in a real-world clinical setting.

Association between Nordic and Mediterranean diets with lipoprotein phenotype assessed by 1HNMR in children with familial hypercholesterolemia

Background and aimsBoth Nordic and Mediterranean diets are considered healthy despite notable regional differences. Although these dietary patterns may lower cardiovascular risk, it is unclear if they improve the lipoprotein phenotype in children with familial hypercholesterolemia (FH). The aim is to determine the impact of Nordic and Mediterranean diets on the advanced lipoprotein profile in children with heterozygous FH (HeFH). MethodsThis was a cross-sectional study performed in children with FH recruited from the Lipid Clinics at Sant Joan University Hospital in Reus (Spain) and Oslo University Hospital (Norway).Two-hundred fifty-six children (mean age 10 y/o; 48% girls): 85 Spanish and 29 Norwegian FH children, and 142 non-FH healthy controls (119 from Spain and 23 from Norway) were included in the study. A pathogenic FH-associated genetic variant was present in 81% of Spanish children with FH and all Norwegian children with FH. An 1H NMR based advanced lipoprotein test (Nightingale®) providing information on the particle number, size and lipid composition of 14 lipoprotein subclasses was performed and correlated to the dietary components. ResultsLevels of LDL-C, HDL-C and triglycerides were not significantly different between the Nordic and Mediterranean FH groups. Spanish children with FH had more LDL particles, mainly of the large and medium LDL subclasses, than Norwegian FH children. Spanish FH children also had more HDL particles, mainly medium and small, than Norwegian FH children. The mean LDL size of Spanish FH children was larger, while the HDL size was smaller than that of the Norwegian FH children. The HDL particle number and size were the main determinants of differences between the two groups. In Norwegian children with FH, dietary total fat and MUFAs showed a significant correlation with all apolipoprotein B-containing lipoproteins and LDL size, whereas there was no correlation to SFA. A weaker association pattern was observed in the Spanish children. ConclusionsThe lipoprotein profiles of Spanish and Norwegian children showed differences when studied by 1H NMR. These differences were in part associated with differences in dietary patterns.

Health-related quality of life and physical activity in Ukrainian pediatric patients with heterozygous familial hypercholesterolemia

Introduction. Familial hypercholesterolemia (FH) is a genetically determined disease characterized by elevated low-density lipoprotein levels since birth and predisposes a person to develop atherosclerosis-induced cardiovascular disease. Healthcare providers should monitor the health status and physical activity level in pediatric patients with FH, as a high-risk group for cardiovascular disease. Purpose - to investigate the self-reported health-related quality of life (HRQoL) and physical activity energy expenditure based on the questionnaire data (PAEEq) in children with heterozygous FH compared with healthy peers to assess the health status. Materials and methods. The HRQoL scores were assessed using the KINDLR questionnaire in 15 patients with FH and 21 healthy peers. The physical activity level was evaluated using the C(Y)PAQ questionnaire. The KINDLR data together with other variables such as age, weight, height, sex, BMI and the PAEEq scores were analyzed in SAS® OnDemand for Academics. Results. HRQoL scores in FH children were similar to those of the control group (p&gt;0.05). There was no association between PAEEq and the HRQoL scores in the FH (r=0.37, p=0.29) and the control group (r=0.43, p=0.20). The KINDLR Physical well-being score in the 5-9 years age group was significantly higher for FH children than for controls (p&lt;0.01), while the total HRQoL score was not significantly different between FH children and controls. The group of FH children aged 5-9 with an intermediate level of PAEEq was the most physically active among the surveyed children. The controls aged 15-18 with low levels of PAEEq was the least active. All other age groups were characterized by a low intermediate level of PAEEq. Conclusions. Children with FH have HRQoL scores that are comparable to those of healthy peers. The FH and control groups were relatively satisfied with their quality of life. Thus, FH children consider themselves to be healthy, and from this underestimation of their cardiovascular risk they may have low adherence. Most FH children were found to have the low intermediate levels of PAEEq, which may indicate a lack of exercise and poor quality of life later on. Children with FH may have significant health problems in adulthood if they are not treated early and appropriately. In a similar manner, low PAEEq levels were demonstrated by the controls, so they should be also informed about the significance of regular physical activity and properly motivated. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patients was obtained for conducting the studies. No conflict of interests was declared by the authors.

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.

Lipid profile peculiarities and matrix Gla protein concentration in Ukrainian pediatric patients with heterozygous familial hypercholesterolemia

Atherosclerotic changes in the vascular walls begin early in childhood, especially in association with familial hypercholesterolemia (FH). The process may be subclinical, which nevertheless requires therapeutic and preventive measures. Purpose - to evaluate baseline lipid profiles, the thickness of carotid intima-media complexes, blood pressure indices and the association with concentration changes of dephosphorylated-uncarboxylated matrix Gla protein (dp-uc MGP) as a marker of subclinical arterial lesions in different age groups of pediatric patients with FH. Materials and methods. Children with heterozygous FH (n=15), stratified by age and sex, were included in the study. The control group consisted of healthy peers (n=21). Blood samples were analyzed to determine levels of total (TC), low-density (LDL-C), very-low-density (VLDL-C), high-density (HDL-C), remnant (rC) and non-high-density (non-HDL-C) cholesterol, triglycerides (TG), apolipoproteins A1 (apoA1) and B (apoB), lipoprotein (a), and dp-uc MGP. The intima-media complex thickness of the common carotid artery and blood pressure were measured in all study subjects. The obtained data were processed using the accepted methods of medical statistics and SAS® OnDemand for Academics. Results. Lipid profile changes in pediatric patients with FH were characterized by high levels of LDL-C, non-HDL-C and lipoprotein (a) in the 5-9 years age group; in the 10-14 years age group - high levels of LDL-C, TG, rC, non-HDL-C and lipoprotein (a); in the 15-18 years age group - high levels of LDL-C, TG, non-HDL-C and lipoprotein (a). At the same time, the most marked dyslipidemia changes were evident in children aged 10-14 years in the FH group. apoA1 levels were significantly decreased in all FH children. Elevated levels of lipoprotein (a) (&gt;30 mg/dL) in FH children were found in all age groups, suggesting that elevated lipoprotein (a) levels can be used as a factor for cardiovascular risk stratification. Dp-uc MGP levels were significantly elevated in all age groups of FH children compared to healthy peers. Conclusions. A lipid profile examination is necessary to diagnose FH in children, along with family health history and cascade screening. As atherosclerotic changes at 5-18 years of age remain subclinical, and the instrumental tests available in routine medical practice are not sensitive enough to detect them, therefore, preventive or therapeutic measures cannot be initiated promptly. The evaluation of circulating matrix Gla protein in pediatric patients with FH can be used as a marker of vascular wall calcification, which may allow early preventive measures against microcalcification to be developed. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Abstract 12665: Using Healthcare Claims Data and Machine Learning to Identify Health Disparities for Individuals With Diagnosed and Undiagnosed Familial Hypercholesterolemia

Introduction: Individuals with Familial Hypercholesterolemia (FH) warrant intensive lipid lowering therapy starting with statins and adding ezetimibe and PCSK9 inhibitors (PCSK9i) as needed to achieve LDL-C treatment targets. Little data exists on whether disparities exist in the US FH population for ezetimibe, PCSK9i or the combination of statins + ezetimibe + PCSK9i. Methods: We queried the Family Heart Database, a healthcare claims database from the Family Heart Foundation, for filled prescriptions for statins, ezetimibe, and PCSK9i in patients with an ICD-10 diagnosis of FH (E.78.01) as well as undiagnosed FH patients (Probable FH) identified by the Family Heart Foundation’s FIND-FH® machine learning algorithm. Data were analyzed in multivariable models including age, education, income, race/ethnicity, and gender. Results: Among 77,671,959 individuals, 280,426 had an ICD-10 diagnosis of FH (51% female, 79.5% White, 11.8% Black, and 8.7% Hispanic) and 899,027 had Probable FH (48% female, 78.7% White, 12.9% Black, and 8.5% Hispanic). Diagnosed and Probable FH males were 46% and 48% more likely, respectively, than females to receive high intensity statins. Individuals in the $100,000+ income bracket - both the diagnosed and Probable FH groups - were 30 to 50% more likely to receive ezetimibe, PCSK9i, or statin + ezetimibe + PCSK9i (Table). The highest education level was associated with 51% higher odds of statin + ezetimibe + PCSK9i use in diagnosed FH patients. Whites were 6-30% more likely to get ezetimibe, PCSK9i, and the combination of statin + ezetimibe + PCSK9i compared to Blacks. Conclusions: Real world patterns of medical care reveal appropriate lipid lowering therapy is more often prescribed for individuals with FH who are White, have high income, or have advanced education. Efforts are warranted to improve equity and provide all individuals with FH an opportunity for cardiovascular risk reduction.