Elevated LDL-C Research Articles

Double trouble: Pathogenic LDLR and SCARB1 variants in the same family

Background and Aims : LDLR and SCARB1 are the key membrane receptors LDL and HDL. Mutations in the LDLR and SCARB1 genes are identified in 80% of patients with familial hypercholesterolemia and in <<< 1% of patients with hyperalphalipoproteinemia. Mutations in the both genes act co-dominantly, heterozygous carriers demonstrate intermediate levels of LDL-C or HDL-C between wild-type and homozygous individuals. Here we describe a family with extremely high levels of lipoproteins (above the 90th percentile for age and sex) with a rare variant in one or both genes.Methods: NGS was performed by Ion S5 system. Variant validation was performed by PCR-direct sequencing.Results: The proband was admitted to the cardiology department with recurrent fainting and elevated LDL-C levels. We identified two pathogenic variants in a heterozygous state – LDLR(NM_000527.5):c.986G>A (p.Cys329Tyr) (HGMD - CM981186) and SCARB1(NM_005505.5):c.727-2A>C (rs201068540, according to the ACMG criteria the variant is pathogenic). We then determined that sibling is also the carrier of both mutations, the mother has only the SCARB1 variant, the father has only the LDLR variant. Segregation of variants correlates with the lipid profile of patients. The mutation in the SCARB1 gene correlates with a high HDL-C phenotype, and the LDLR mutation with a high LDL-C phenotype.Conclusions: Our findings suggest mutations in the SCARB1 gene are a rare but recurring cause of elevated HDL-C levels. The finding of the combined variants in LDLR/SCARB1 genes triggering hypercholesterolemia and hyperalphalipoproteinemia phenotypes is essential to elaborate the spectrum of variants causing dyslipidemia and to understand the genotype-phenotype correlation. Background and Aims : LDLR and SCARB1 are the key membrane receptors LDL and HDL. Mutations in the LDLR and SCARB1 genes are identified in 80% of patients with familial hypercholesterolemia and in <<< 1% of patients with hyperalphalipoproteinemia. Mutations in the both genes act co-dominantly, heterozygous carriers demonstrate intermediate levels of LDL-C or HDL-C between wild-type and homozygous individuals. Here we describe a family with extremely high levels of lipoproteins (above the 90th percentile for age and sex) with a rare variant in one or both genes. Methods: NGS was performed by Ion S5 system. Variant validation was performed by PCR-direct sequencing. Results: The proband was admitted to the cardiology department with recurrent fainting and elevated LDL-C levels. We identified two pathogenic variants in a heterozygous state – LDLR(NM_000527.5):c.986G>A (p.Cys329Tyr) (HGMD - CM981186) and SCARB1(NM_005505.5):c.727-2A>C (rs201068540, according to the ACMG criteria the variant is pathogenic). We then determined that sibling is also the carrier of both mutations, the mother has only the SCARB1 variant, the father has only the LDLR variant. Segregation of variants correlates with the lipid profile of patients. The mutation in the SCARB1 gene correlates with a high HDL-C phenotype, and the LDLR mutation with a high LDL-C phenotype. Conclusions: Our findings suggest mutations in the SCARB1 gene are a rare but recurring cause of elevated HDL-C levels. The finding of the combined variants in LDLR/SCARB1 genes triggering hypercholesterolemia and hyperalphalipoproteinemia phenotypes is essential to elaborate the spectrum of variants causing dyslipidemia and to understand the genotype-phenotype correlation.

Cardiovascular disease in children with homozygous familial hypercholesterolemia

Background and Aims : Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder leading to extremely increased LDL-C, resulting in high risk for cardiovascular disease (CVD) in early childhood. Earliest initiation of lipid lowering treatment is required to prevent premature CVD. Therapy consists of fat-reduced diet, lipid-lowering medication (LLM), and additional lipid apheresis (LA) in severe cases. The aim of the study was to evaluate cardiovascular pathology in children with hoFH.Results: All children needed LLM, and four children additional LA with weekly or biweekly intervals starting at the age of 3 to 5 years, due to extremely elevated LDL-C levels, which reduced LDL-C by >60% (Table 1). Three children had increased IMT. After initiation of LA, IMT improved or remained stable. Initially, cCT showed regular cardiac results. Despite LA, after five to six years three children developed mild calcification of the aorta ascendens or the aortic valve. Moreover, one ten-year-old girl developed a severe aortic valve calcification with high-grade stenosis (aortic jet velocity 3.8 m/s), now under consideration for cardiac surgery.Conclusions: We could show that intensive LLM and LA starting at early age seem to prevent rapid coronary atherosclerosis; nevertheless, aortic calcification (including the valve) may occur. Regular screening for CVD in hoFH children is crucial. Background and Aims : Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder leading to extremely increased LDL-C, resulting in high risk for cardiovascular disease (CVD) in early childhood. Earliest initiation of lipid lowering treatment is required to prevent premature CVD. Therapy consists of fat-reduced diet, lipid-lowering medication (LLM), and additional lipid apheresis (LA) in severe cases. The aim of the study was to evaluate cardiovascular pathology in children with hoFH. Results: All children needed LLM, and four children additional LA with weekly or biweekly intervals starting at the age of 3 to 5 years, due to extremely elevated LDL-C levels, which reduced LDL-C by >60% (Table 1). Three children had increased IMT. After initiation of LA, IMT improved or remained stable. Initially, cCT showed regular cardiac results. Despite LA, after five to six years three children developed mild calcification of the aorta ascendens or the aortic valve. Moreover, one ten-year-old girl developed a severe aortic valve calcification with high-grade stenosis (aortic jet velocity 3.8 m/s), now under consideration for cardiac surgery. Conclusions: We could show that intensive LLM and LA starting at early age seem to prevent rapid coronary atherosclerosis; nevertheless, aortic calcification (including the valve) may occur. Regular screening for CVD in hoFH children is crucial.

Elevated Lipoprotein(a) prevalence and association with family history of premature cardiovascular disease in general population with moderate cardiovascular risk and increased LDL cholesterol.

BackgroundElevated Lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular disease (CVD) risk. There are discrepancies regarding its epidemiology due to great variability in different populations. This study aimed to evaluate the prevalence of elevated Lp(a) in people with moderate CVD risk and increased LDL-c and to determine the association between family history of premature CVD and elevated Lp(a).MethodsRandom subjects from the CESCAS population-based study of people with moderate CVD risk (Framingham score 10–20 %) and LDL-c ≥ 130 mg/dL, were selected to evaluate Lp(a) by immunoturbidimetry independent of the Isoforms variability. The association between family history of premature CVD and elevated Lp(a) was evaluated using multivariate logistic regression models. Elevated Lp(a) was defined as Lp(a) ​​≥ 125 nmol/L.ResultsLp(a) was evaluated in 484 samples; men = 39.5 %, median age = 57 years (Q1-Q3: 50–63), mean CVD risk = 14.4 % (SE: 0.2), family history of premature CVD = 11.2 %, Lp(a) median of 21 nmol/L (Q1-Q3: 9–42 nmol/L), high Lp(a) = 6.1 % (95 % CI = 3.8–9.6). Association between family history of premature CVD and elevated Lp(a) in total population: OR 1.31 (95 % CI = 0.4, 4.2) p = 0.642; in subgroup of people with LDL-c ≥ 160 mg%, OR 4.24 (95 % CI = 1.2, 15.1) p = 0.026.ConclusionsIn general population with moderate CVD risk and elevated LDL-c from the Southern Cone of Latin America, less than one over ten people had elevated Lp(a). Family history of premature CVD was significantly associated with the presence of elevated Lp(a) in people with LDL-c ≥ 160 mg/dL.

Metabolic risk factors in first acute coronary syndrome (MERIFACS) Study

ObjectivesIn acute coronary syndrome (ACS) patients the focus is on major conventional risk factors - CRF [diabetes, hypertension, elevated low-density cholesterol (LDL-C) and smoking] whereas others - specific metabolic risk factors - MRF [high-density lipoprotein cholesterol (HDL-C), body-mass index (BMI), waist-hip ratio (WHR), and triglycerides, and HbA1c get less attention. MethodsThis is a prospective case–control observational study from 15 tertiary care hospitals in India. CRF and MRF in patients presenting with first incidence of ACS (n = 2153) were compared with matched controls (n = 1210). ResultsPropensity score matching (PSM) yielded 1193 cases and matched 1210 controls. Risk factor prevalence in cases vs. controls were CRF: hypertension - 39.4% vs 16.4% (p < 0.0001), diabetes - 42.6% vs 12.7% (p < 0.0001), smoking - 28.3% vs 9.3% (p < 0.0001) and elevated LDL-C - 70.2% vs 57.9% (p < 0.0001). MRF: High BMI - 54.7% vs 55.1% (p = 0.84), increased waist: hip ratio 79.5% vs 63.6% (p < 0.0001), high HbA1c - 37.8% vs 14.9% (p < 0.0001), low HDL-C - 56.2% vs 42.8% (p < 0.0001) and elevated triglycerides - 49.7% vs 44.2% (p = 0.007). Adjusted Odds ratios by multivariate analysis were CRF: hypertension - 2.3 (p < 0.001), diabetes - 4.7 (p < 0.001), high LDL-C - 3.3 (p < 0.001) and smoking- 6.3 (p < 0.001). MRF: High waist: hip ratio - 2.4 (p < 0.001) high HbA1c - 3.2 (p < 0.001), low HDL-C 2.2 (p < 0.001) and elevated triglycerides - 0.878 p = 0.17. ConclusionIn India, the risk of ACS conferred by specific metabolic risk factors (High waist: hip ratio, Low HDL-C and High HbA1c) is comparable to that caused by CRF.

Assessment of patterns of dyslipidaemia amongst hypertensive patients

Background: Abnormalities in serum lipid and lipoprotein levels (Dyslipidaemia) are recognized as major modifiable cardiovascular disease (CVD) risk factors and have been identified as independent risk factors for essential hypertension giving rise to the term dyslipidemic hypertension. The present study was conducted to assess patterns of dyslipidaemia amongst hypertensive patients.Materials and Methods: 76 hypertensive patients of both genders were recruited. Group I consisted of hypertensive patients and group II had healthy control. Systolic (SBP) and diastolic (DBP) blood pressures, Body mass index (BMI), Fasting blood glucose and fasting serum lipid profile was recorded.Results: Group I had 40 males and 36 females and group II had 38 males and 38 females. In group I and group II, SBP (mm Hg) was 162.4 and 116.4, DBP (mm Hg) was 98.4 and 70.2, BMI (kg/m2) was 28.6 and 26.2, WC (cm) was 96.4 and 90.4, WHR was 0.98 and 0.94, FBS (mmol/L) was 5.1 and 4.6, TG was 1.24 and 1.10, HDL-c was 1.26 and 1.24, LDL- c was 3.01 and 2.42 and TC was 4.82 and 4.15 respectively. Elevated TC (≥5.2 mmol/L) was seen in 34% and 7.5%, elevated TG (≥1.7 mmol/L) in 7% and 1%, elevated LDL-C (≥3.4 mmol/L) in 29% and 6.2%, low HDL-C (2 lipid abnormality in 24% and 12% in group I and II respectively. Conclusion: There was high patterns of dyslipidemia amongst hypertensive patients as compared to healthy subjects.

444-P: Associations of LDL-C with New-Onset Coronary Artery Disease (CAD) According to HDL-C Levels and Glucose Status

Whereas elevated LDL-C is a major risk factor for CAD, the inverse association between HDL-C levels and risk of CAD is well-known. Although insulin resistance and glucose intolerance are associated with low HDL-C levels, it is not clear whether the association of LDL-C with CAD differs depending on glucose status and HDL-C values. We examined associations of LDL-C with new-onset CAD according to HDL-C and glucose status using a nationwide claims database on 600,6individuals during 2008-20with no history of CAD. Cox proportional hazards model identified risks of CAD events among combinations of tertiles of HDL-C and sextiles of LDL-C according to glucose status. During a mean follow-up period of 5.6 years, 2,391 CAD events occurred. CAD risk increased from lower LDL-C levels accompanied by lower HDL-C levels regardless of glucose status (Table) . Compared with the highest tertile of HDL-C and lowest sextile of LDL-C, groups with the highest tertile of HDL-C and highest sextile of LDL-C and the lowest tertile of HDL-C and highest sextile of LDL-C had approximately 4-fold and 9-fold, respectively, increased risks of CAD regardless of glucose status. Despite the necessity of a lower LDL-C target for people with than without diabetes, our results demonstrated that the necessity of modulating the LDL-C target according to HDL-C levels is not affected by concomitant diabetes. Disclosure M.H.Yamada: None.

PCSK-9 Inhibitors

Hyperlipidemia (elevated levels of LDL-C) is a well-known risk factor of cardiovascular diseases (CVD). Statins are well known and proven drugs for the lipid management of those who are at elevated risk for developing CVD events1. However, the patients who do not tolerate statin therapy, develop any cardiovascular disease despite maximal tolerated statins, or with severe hypercholesterolemia i.e familial hypercholesterolemia had limited options. Recently the Food and Drug Administration (FDA) approved medications (PCSK-9 inhibitors) which act on a novel pathway to reduce LDL-C levels in blood.&#x0D; HOW DO PCSK9 INHIBITORS WORK?&#x0D; PCSK-9 inhibitors (monoclonal antibodies) act on proprotein convertase subtilsin-kexin type 9 (PCSK9) and inactivate it. The PCSK9 protein has strongly inhibit recycling of the LDL receptor (LDLR). It is predominantly produced by hepatocytes, with other sites being kidneys and intestines.2,3 On the surface of liver cell, LDL binds to its receptor called LDLR. This LDL-LDLR complex is then internalized, after which the LDLR is recycled back to the cell surface up to 150 times.4 The role of PCSK9 protein is to bind the LDLR on the surface of the hepatocyte, causing internalization and degradation of the LDL receptors in the lysosomes, this process in turn reduces the number of LDL receptors on the cell surface. So, by Inhibition of PCSK9, number of available LDL receptors on the cell surface is increased and uptake of LDL?C into the cell is augmented. PCSK9 inhibition thus offers a novel therapeutic approach for the lowering of LDL-C levels.5 Currently, the only FDA?approved PCSK9 inhibitors are two human monoclonal antibodies which bind extracellular PCSK9: alirocumab6 and evolocumab.7&#x0D; FDA APPROVAL OF PCSK9 INHIBITORS AND REDUCTION IN LDL-C:&#x0D; Alirocumab (Praluent) was approved by FDA in 2015 for adult patients with heterozygous familial hypercholesterolemia or for patients with clinically significant atherosclerotic CVD requiring additional LDL lowering despite being on diet control and maximal tolerated statin therapy. Alirocumab’s long-term safety and efficacy was evaluated in ODYSSEY trials which include CHOICE I, CHOICE II, OLE, LONG TERM, COMBO I, COMBO II, FH I, FH II, HIGH FH, MONO, ALTERNATIVE, OPTIONS I and OPTIONS II. There was a 65% LDL-C levels reduction in a dose dependent fashion at maximal doses.8&#x0D; FDA also approved Evolocumab (Repatha) in 2015 for use in adult patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, or clinical atherosclerotic CVD requiring additional lowering of LDL cholesterol despite being on a controlled diet and maximally-tolerated statin therapy. PROFICIO (Program to reduce LDL-C and cardiovascular outcomes following inhibition of PCSK9 in different populations) phase III 14 trials were designed to evaluate efficacy and long-term safety of evolocumab. Every two-week regimen reduced LDL-C levels by up to 65% as compared to approximately 50% with every 4-wk regimen.&#x0D; DOSAGE:&#x0D; Alirocumab (Praluent) is given in dosage of 75-150 mg every two weeks while Evolocumab (Repatha) is given in dosage of 140 mg every two weeks or 420 mg monthly&#x0D; ADVERSE EFFECTS AND LIMITATIONS&#x0D; The most common adverse effects observed with Alirocumab include nasopharyngitis, erythema, itchiness, swelling, pain or tenderness, influenza, urinary tract infection, diarrhea, bronchitis, myalgia, muscle spasms, sinusitis and cough. The most common adverse effects of Evolocumab include nasopharyngitis, upper respiratory tract infection, back pain and nausea. A small percentage (2.4%) of some serious cardiac adverse events were also noted which include palpitations, angina pectoris, and ventricular premature contractions.&#x0D; Some common limitations of PCSK9 inhibitors are that they are very expensive, not readily available in our country and are required in injection form.&#x0D; CONCLUSION:&#x0D; PCSK9 inhibitors are exciting and very welcome new treatment option for patients who require treatment for their elevated LDL-C levels. They have proven to be very effective in reducing LDL-C levels and in-turn reducing ASCVD events

Differential Associations of Intakes of Whole Grains and Coarse Grains with Risks of Cardiometabolic Factors among Adults in China.

There is a lack of studies on the association between whole grain intake and cardiometabolic risk factors in China and the current definition of whole grains is inconsistent. This study defined whole grains in two ways, Western versus traditional, and examined their associations with the risks of major cardiometabolic factors (CMFs) among 4706 Chinese adults aged ≥18 years, who participated in surveys both in 2011 and in 2015. Diet data were collected by consecutive 3 d 24 h recalls, together with household seasoning weighing. Whole grains were defined as grains with a ratio of fiber to carbohydrate of ≥0.1, while coarse grains were defined as grains except for rice and its products, and wheat and its products. Multivariable logistic regressions were modeled to analyze the associations of intakes of whole grains and coarse grains, respectively, with risks of major CMFs including obesity-, blood pressure-, blood glucose- and lipid-related factors, which were defined by International Diabetes Federation and AHA/NHLBI criteria. After adjusting for potential confounders, the odds of elevated LDL-C decreased with the increasing intake levels of whole grains (OR 0.64, 95% CI 0.46–0.88, p-trend < 0.05). Moreover, adults with the whole grain intake of 50.00 to 150.00 g/day had 27% lower odds of overweight and obesity (OR 0.73, 95% CI 0.54–0.99) and 31% lower odds of elevated LDL-C (OR 0.69, 95% CI 0.49–0.96), as compared with non-consumers. In conclusion, given the significant nutrient profiles of whole grains and coarse grains, the adults with higher intakes of whole grains only may have a lower risk of LDL-C and overweight and obesity.

Early Initiation of Evolocumab Treatment in Chinese Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Evolocumab has been shown to improve cardiovascular outcomes in patients with stable atherosclerotic disease. Whether this benefit persists in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) remains undetermined. This study aimed to evaluate the efficacy and safety of the early initiation of evolocumab in Chinese patients with ACS undergoing PCI. This retrospective cohort study involved 1564 consecutive patients who had been hospitalized with ACS and underwent PCI, and who had elevated LDL-C levels (≥1.8 mmol/L after receiving high-intensity statin therapy for ≥4 weeks; ≥2.3 mmol/L after receiving low- or moderate-intensity statin; or ≥3.2 mmol/L without statin therapy). Patients who received evolocumab (initiated in-hospital and after 18 months) were included in the evolocumab group (n=414), and all other patients were included in the control group (n=1150). The primary outcome at 18 months was a composite of ischemic stroke, cardiovascular death, myocardial infarction, hospitalization for unstable angina, or coronary revascularization. The evolocumab treatment effect on the primary outcome was assessed in all prespecified subgroups. At 18 months, evolocumab combined with statins reduced LDL-C levels from baseline levels by 42.48% compared with statins alone. After multivariable adjustment, evolocumab combined with statins significantly reduced the primary outcome (8.2% vs 12.4%; adjusted hazard ratio, 0.65; 95% CI, 0.45-0.95; P=0.025). In addition, evolocumab consistently reduced the primary outcome across the major subgroups. For the safety outcomes, no significant differences between the groups were observed in any adverse events. Among Chinese patients who underwent PCI for ACS, the early initiation of evolocumab combined with statin treatment effectively reduced LDL-C levels and lowered the incidence of recurrent ischemic cardiovascular events, with satisfactory tolerability and safety. Chinese Clinical Trial Registry identifier: ChiCTR2100049364.

Familial hypercholesterolemia in community-based KHDC Nepal program-baseline data

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): HUG and Republic and Canton of Geneva – Service de solidarité internationaleBP Koirala Institute of Health Sciences Familial hypercholesterolemia (FH) is either underdiagnosed or diagnosed after primary coronary events. Although homozygous variant of FH is considered rare, heterozygous FH is estimated to occur in about 1 in 200 to 300 individuals. There is no study pertaining to prevalence of FH in Nepal which could be a factor influencing cardiovascular morbidity and mortality. We present a baseline data of FH in an ongoing in participants of community-based cardiovascular and kidney diseases preventive (KHDC Nepal) program in Mechinagar municipality in Eastern Nepal. KHDC is a program to collaborate among health post, primary health center or equivalent, and local government along with community representatives created to educate, screen, and intervene for selective NCDs. This program is in alignment with the World Health Organization’s Package of Essential Noncommunicable (WHO PEN) disease interventions for primary health care in low-resource settings. General health status and lifestyle habits, physical examination, and blood pressure were assessed. Blood tests done included fasting lipid profile, serum creatinine, FBS, and HbA1c. A mechanism was developed to follow-up screened positive persons in the primary health centers. Referrals were made to the tertiary care center as needed. We analyzed initial 7289 participants, 20 years or above, who were enrolled in KHDC program in the year 2020. We assessed for FH using Dutch Lipid Clinic Network(DLCN), Simon Broome and AHA criteria. Participants were categorized as definite, probable, possible, or no FH based on the scores of DLCN criteria; as definite and probable based on Simon Broome criteria and as clinically diagnosed FH based on AHA criteria. The median age of the patient was 54 years, the majority being females (62.7%). A total of 70(0.96%) of the participants had elevated LDL-C levels of more than 190mg/dl detected during the screening and had no secondary cause for hyperlipidemia. According to DLCN criteria, 65(0.89%) participants were grouped under possible FH, 5(0.06%) were grouped under probable FH while none of them could be delineated as definite FH. According to Simon Broome criteria, 14(0.2%) participants were grouped under probable and none of them could be delineated as definite. According to AHA criteria, 10 (0.13%) participants were categorized as clinically diagnosed FH. DNA analysis was not available in our setup. Clinically manifested atherosclerotic disease was recorded in 5 participants. None of the participants were aware of the FH. This community-based program of the adult population help create baseline data of FH in Nepal. Larger study with genetic analysis is likely to reveal true prevalence of FH in Nepal.

Dasatinib suppresses atherosclerotic lesions by suppressing cholesterol uptake in a mouse model of hypercholesterolemia

Although the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia is known to cause vascular adverse events (VAEs), the frequency of VAEs during dasatinib administration is not high, and the same holds for atherosclerosis-related VAEs. However, its effect on atherosclerosis remains controversial. In this study, our primary objective was to investigate how dasatinib affects atherosclerosis. Ldlr−/−/Apobec1−/− mice, which are highly prone to develop atherosclerosis, were administered dasatinib. After 16 weeks, we evaluated their atherosclerotic lesions. We used bone-marrow-derived macrophages to investigate the uptake of oxidized low-density lipoprotein (LDL) complexed with DiI dye (DiI-oxLDL). RNA sequencing and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were performed to explore the potential effects of dasatinib on cholesterol metabolism. Dasatinib administration significantly reduced atherosclerotic lesions (P < 0.001 and P = 0.013) and DiI-oxLDL uptake (P < 0.001) unlike other TKIs. RNA sequencing and RT-qPCR suggested that Sort1, which encodes sortilin, a known regulator of LDL uptake, and Cd36 were potential targets of dasatinib. In conclusion, dasatinib induced elevated LDL-C levels, but oxLDL uptake in macrophages were suppressed, resulting in reducing atherosclerotic lesions. These results further our understanding of the differences in VAEs between dasatinib and other TKIs.

Prevalence of autosomal dominant mutations of Familial hypercholesterolemia in Finnish patients with premature coronary artery disease and elevated LDL-C levels

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract 400: Cardiometabolic Profile Of Haptoglobin Genotype In A Multi-Ethnic Diabetes Cohort

Background: Haptoglobin has three common genotypes: Hp 1-1, Hp 2-1, and Hp 2-2. The Hp 2-2 genotype, known to have poorer antioxidizing capacity, is associated with worse cardiovascular outcomes in select patients with diabetes. In this study, we explore the association between various cardiometabolic biomarker profiles and the three Hp genotypes in a multiethnic population. Methods: A cross-sectional analysis was performed for all participants with diabetes in the Dallas Heart Study and Multi-Ethnic Study of Atherosclerosis cohorts. Hp genotype was measured in 1,158 participants (399 from DHS and 759 from MESA) using ELISA technique (Savyon Diagnostics, Ltd). Associations between Hp genotype and 26 cardiometabolic circulating and imaging biomarkers were assessed by ANOVA and stratified by ethnicity. Results: The study included 51% women, 44% Black (513 of 1,158: Hp 1-1=45%, Hp 2-1=35%, Hp 2-2=20%), 26% Hispanic (300 of 1,158: Hp 1-1=25%, Hp 2-1=49%, Hp 2-2=26%), 20% White (237 of 1,158: Hp 1-1=16%, Hp 2-1=56%, Hp 2-2=28%), and 9.2% Asian/Pacific Islander/East Indian (107 of 1,158: Hp 1-1=15%, Hp 2-1=36%, Hp 2-2=49%) participants. Significant differences were seen in lipid metabolism as well as atherosclerosis, inflammatory, structural, and endothelial markers with no significant differences seen in imaging biomarkers. In White participants, Hp 1-1 was associated with elevated total cholesterol (p=0.016), LDL-p (p=0.001), and LDL-C (p=0.004). In Asian/Pacific Islander/East Indian participants, Hp 2-2 was associated with elevated systolic blood pressure (p=0.029), BMI (p=0.029), and inflammatory markers such as IL-6 (p=0.018) and D-dimer (p=0.027). In Black participants, Hp 2-2 was associated with elevated ICAM (p=0.048) and BMI (p=0.007). Lastly, in Hispanic participants, no significant associations were seen. In exploratory analysis, when comparing Hp 1-1 and Hp 2-1 with Hp 2-2, there was greater magnitude effect size of certain biomarkers in Black and Asian participants, suggesting potential differential effects by ethnicity. Conclusion: Associations between Hp genotype and various cardiometabolic biomarkers are varied and ethnicity dependent with further studies needed to investigate the underlying physiologic mechanisms.

Abstract 508: Combined Lipoprotein Lipase And Ldl Receptor Deficiency Increases Atherosclerosis: Hyperchylomicronemia Is Not Benign

We tested whether accumulation of chylomicrons as an addition to LDL would enhance atherosclerosis. To do this, whole body LpL deficiency was combined with LDL receptor (LDLR) deficiency. Induced global LpL deficiency (i Lpl -/- ) was created by tamoxifen injections to activate beta actin-driven cre recombinase in mice. To knock down hepatic LDLR we utilized anti-sense oligonucleotides (ASOs) or a PCSK9 expressing AAV. i Lpl -/- mice on chow diet have elevated plasma TGs, increased VLDL cholesterol, and lower LDL-C compared to control Lpl fl/fl mice. In contrast, when hepatic LDLR was knocked down, the mice displayed elevated LDL-C (~150 mg/dl), similar to the levels seen in control mice with LDLR knockdown. i Lpl -/- mice fed a Western diet for 12 weeks developed severe hypertriglyceridemia (1400-7000 mg/dl) and increased total cholesterol reaching ~1500 mg/dl. LDL-C levels were lower in iLpL -/- mice (160 mg/dl vs 359 mg/dl) and the increase in cholesterol was primarily in chylomicrons compared to the control mice with LDLR knockdown (1064 mg/dl vs 238 mg/dl). i Lpl -/- mice had bigger lesions in the brachiocephalic artery (46000 um 2 vs 13000 um 2 ) but macrophage content was lower than the control LDLR-deficient mice (24% vs 69%). Aortic root lesion size was larger (60000 um 2 vs 26000 um 2 ), due to a greater the percentage of collagen (34% vs 23%), but not macrophages (60% vs 58%) or neutral lipid content (34% vs 35%). The lack of differences in macrophage accumulation and neutral lipid content and the increase in the collagen content indicates an advanced lesion in the iLpl -/- mice. Thus, our data suggest that intact chylomicrons contribute to atherosclerosis.

Determination of Serum Progranulin in Patients with Untreated Familial Hypercholesterolemia.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated LDL-C concentrations and is associated with an increased risk of premature atherosclerosis. Progranulin (PGRN) is a multifunctional protein that is known to have various anti-atherogenic effects. To date, the use of serum PGRN in patients with FH has not been studied. Methods: In total, 81 untreated patients with heterozygous FH (HeFH) and 32 healthy control subjects were included in this study. Serum PGRN, sICAM-1, sVCAM-1, oxLDL and TNFα concentrations were determined by ELISA. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Results: We could not find a significant difference between the PGRN concentrations of the HeFH patients and controls (37.66 ± 9.75 vs. 38.43 ± 7.74 ng/mL, ns.). We found significant positive correlations between triglyceride, TNFα, sVCAM-1, the ratio of small HDL subfraction and PGRN, while significant negative correlations were found between the ratio of large HDL subfraction and PGRN both in the whole study population and in FH patients. PGRN was predicted by sVCAM-1, logTNFα and the ratio of small HDL subfraction. Conclusions: The strong correlations between HDL subfractions, inflammatory markers and PGRN suggest that PGRN may exert its anti-atherogenic effect in HeFH through the alteration of HDL composition and the amelioration of inflammation rather than through decreasing oxidative stress.

Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia.

Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR, APOB, PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in CYP7A1, p.(Val1382Phe) in LRP6 and p.(Ser202His) in LDLRAP1. A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in CYP7A1; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in LRP6; and p.(Ser202LeufsTer19) in LDLRAP1. All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in CYP7A1 showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four LRP6 mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the LDLRAP1 p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype.

Homozygous familial hypercholesterolemia in China: Genetic and clinical characteristics from a real-world, multi-center, cohort study

BackgroundThere is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia. ObjectiveTo define the characteristics of phenotypic and genetic HoFH probands from mainland China. MethodsWe collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test. ResultsA total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH. ConclusionsThis report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH.

Phenotypic and genotypic characterization of familial hypercholesterolemia in French adult and pediatric populations

BackgroundFamilial hypercholesterolemia (FH) is the most common genetic disorder associated with a high risk for premature atherosclerotic cardiovascular disease attributable to increased levels of LDL-cholesterol (LDL-C) from birth. FH is both underdiagnosed and undertreated. ObjectiveWe describe the clinical, biological, and genetic characteristics of 147 patients in France with clinical FH (including a group of 26 subjects aged < 20 years); we explore how best to detect patients with monogenic FH. MethodsWe retrospectively reviewed all available data on patients undergoing genetic tests for FH from 2009 to 2019. FH diagnoses were based on the Dutch Lipid Clinics Network (DLCN) scores of adults, and elevated LDL-C levels in subjects < 20 years of age. We evaluated LDLR, APOB, and PCSK9 status. ResultsThe mutations of adults (in 25.6% of all adults) were associated with DLCN scores indicating “possible FH,” "probable FH, and “definitive FH” at rates of 4%, 16%, and 53%, respectively. The areas under the ROC curves of the DLCN score and the maximum LDL-C level did not differ (p = 0.32). We found that the pediatric group evidenced more monogenic etiologies (77%, increasing to 91% when an elevated LDL-C level was combined with a family history of hypercholesterolemia and/or premature coronary artery disease). ConclusionDiagnosis of monogenic FH may be optimized by screening children in terms of their LDL-C levels, associated with reverse-cascade screening of relatives when the children serve as index cases.

Intermittent fasting and changes in Galectin-3: A secondary analysis of a randomized controlled trial of disease-free subjects

Background and aimsIntermittent fasting reduces risk of interrelated cardiometabolic diseases, including type 2 diabetes and heart failure (HF). Previously, we reported that intermittent fasting reduced homeostasis model assessment of insulin resistance (HOMA-IR) and Metabolic Syndrome Score (MSS) in the WONDERFUL Trial. Galectin-3 may act to reduce insulin resistance. This post hoc evaluation assessed whether intermittent fasting increased galectin-3. Methods and resultsThe WONDERFUL Trial enrolled adults ages 21–70 years with ≥1 metabolic syndrome features or type 2 diabetes who were not taking anti-diabetic medication, were free of statins, and had elevated LDL-C. Subjects were randomized to water-only 24-h intermittent fasting conducted twice-per-week for 4 weeks and once-per-week for 22 weeks or to a parallel control arm with ad libitum energy intake. The study evaluated 26-week change scores of galectin-3 and other biomarkers. Overall, n = 67 subjects (intermittent fasting: n = 36; control: n = 31) completed the trial and had galectin-3 results. At 26-weeks, the galectin-3 change score was increased by intermittent fasting (median: 0.793 ng/mL, IQR: −0.538, 2.245) versus control (median: −0.332 ng/mL, IQR: −0.992, 0.776; p = 0.021). Galectin-3 changes correlated inversely with 26-week change scores of HOMA-IR (r = −0.288, p = 0.018) and MSS (r = −0.238, p = 0.052). Other HF biomarkers were unchanged by fasting. ConclusionA 24-h water-only intermittent fasting regimen increased galectin-3. The fasting-triggered galectin-3 elevation was inversely correlated with declines in HOMA-IR and MSS. This may be an evolutionary adaptive survival response that protects human health by modifying disease risks, including by reducing inflammation and insulin resistance. Trial registrationClinicaltrials.gov, NCT02770313 (registered on May 12, 2016; first subject enrolled: November 30, 2016; final subject's 26-week study visit: February 19, 2020).

Association of Dyslipidemia and Type-I Diabetes Mellitus Among Children Up to 16 Years of Age

Introduction: Diabetes is associated with a high risk of cardiovascular disease (CVD). Hypertriglyceridemia &amp; low HDL-C values are the most common symptoms of diabetic dyslipidemia. Elevated LDL-C is a well-known CVD risk factor. Objective: To determine the association of dyslipidemia and type 1 diabetes mellitus among children up to 16 years of age. Material &amp; Method Study design: Case-control study Settings: Outpatient department, National Institute of Child Health (NICH) Duration: Six months from 26th February 2018 to 28th August 2018 Data Collection procedure: All patients age 9 to16 years of either gender were included. Cases were defined as presence of fasting plasma glucose of &gt; to 126.0 mg/dL (7.0 mmol/L) for more than one year whereas all patients with fasting plasma glucose of less than 126 mg/dL (7.0 mmol/L) were P a g e | 2 defined as controls. The blood sample was collected in a sterile manner after an overnight fasting of 8 hours and was sent to hospital laboratory and verified by pathologist. Results: Out of total 60 patients, the mean age of the patients was 11.23 ±1.76 years. Dyslipidemia was found to be significantly higher (n=26, 86.7%) among diabetic patients as compared to non-diabetic patients (n=18, 60%). (p-value 0.020) Moreover, the risk of dyslipidemia was 4.33 times higher among diabetic patients than that of non-diabetics (OR 4.33). Patients having &gt;10 years of age and diabetes were 8.01 times more likely (OR 8.01, p-value 0.042) and diabetic males were 8.40 times more likely (OR 8.40, p-value 0.008) to have dyslipidemia. Conclusion: Highly significant association of dyslipidemia and type 1 diabetes mellitus was found among children up to 16 years of age. Keywords: Dyslipidemia, diabetes mellitus, children