FH Patients Research Articles

What characterizes event-free elderly FH patients? A comprehensive lipoprotein profiling

Background and aimsFamilial hypercholesterolemia (FH) is a genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary heart disease (CHD). Cholesterol-lowering therapy (statins) reduces CHD risk, but have been available only in the last 25 years, thus, elderly FH patients have been exposed to elevated LDL-C levels most of their life. Surprisingly, some of these have never experienced any CHD event, raising the question whether they present CHD resistant characteristics.Identifying possible cardioprotective biomarkers could contribute to future CHD preventive treatment, therefore, we aimed to identify metabolic markers in event-free elderly FH subjects. Methods and resultsWe used a high-throughput nuclear magnetic resonance (NMR) spectroscopy platform to quantify a large number of metabolites in serum samples from 83 FH patients ≥65 years, and analyze differences between subjects with (n = 39) and without (n = 44) CHD.Mean age was 70 years in both groups (57% and 38% female in the event-free group and CHD group, respectively). The event-free group had significantly higher levels of large and extra-large high-density lipoprotein (HDL) particles, and higher concentration of Apolipoprotein A1 (ApoA1) and cholesterol in HDL and HDL2 particles, compared to the CHD group (p ≤ 0.05 for all). ConclusionCHD resistant elderly FH patients have higher levels of large HDL particles. The mechanisms behind the event-free survival among these patients remain unclear; hence, a deeper understanding of the metabolic profile in event-free elderly FH subjects may lead to development of novel preventive therapies.

Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients

Background and aimsFamilial hypercholesterolemia (FH) is the most relevant genetic cause of early cardiovascular disease (CVD). FH is suspected when low density lipoprotein cholesterol (LDL-C) levels exceed the 95th percentile of the population distribution. Different diagnostic scoring systems have been developed, as the Dutch Lipid Clinic Network (DLCN) score, used worldwide. The aim of the study is to describe the characteristics of FH patients of a large cohort of more than eight hundred genotyped subjects enrolled in an Italian Lipid Clinic, and evaluate the DLCN score performance applied retrospectively to the case study. Methods836 hypercholesterolemic patients with LDL-C > 4.88 mmol/L were genotyped for FH causative gene variants in the LDLR, PCSK and APOB genes. Relatives of mutated patients were also analyzed by cascade screening. ResultsGene variant carriers were younger, presented higher LDL-C and DLCN score and lower HDL-C levels in comparison with hypercholesterolemic (HC) non-carriers and presented a five-fold higher prevalence of previous CV events. Carotid US data available in 490 subjects showed that variant carriers had an odds ratio of 3.66 (1.43–10.24) for atherosclerotic plaques in comparison with non-carriers. Scoring system were evaluated by ROC analysis in 203 subjects without missing DLCN items and with available pre-therapy LDL-C levels, and LDL-C levels (A.U.C. = 0.737) resulted to be more performing than the DLCN score (A.U.C. = 0.662), even including carotid US data (A.U.C. = 0.641) in a modified DLCN score version. Conclusionsthe DLCN score failed to demonstrate a clear superiority in predicting FH gene variants in comparison with the measure of LDL-C levels in a retrospective case study.

Targeted exome sequencing in South Indian patients with Familial hypercholesterolemia

BackgroundFamilial hypercholesterolemia (FH) is an autosomal dominant genetic disorder with elevated LDL-C levels which can ultimately lead to premature Coronary Artery Disease (CAD). ObjectivesIn presence of limited genetic data on FH in India, the present study was aimed to determine the mutation spectrum in Indian FH patients using a targeted exome sequencing. Methods54 FH cases (31 index cases + 23 extended family members) were categorized according to Dutch Lipid Clinic Network Criteria (DLCNC). Targeted exome sequencing was performed using 23 gene panel associated with lipid metabolism. ResultsAll subjects showed the presence of family history of CAD, 38(70%) patients had corneal arcus whereas only 06(11%) subjects had xanthomas. As per the DLCNC, definite, probable, possible and unlikely FH were 48%, 30%, 11% and 11% respectively. Mutations were observed in 12 of the 23 gene panel with CETP, APOA5, EPHX2 and SREBP2 genes were identified for the first time in Indian FH patients. All 19 mutations including a novel frame-shift mutation in LDLR gene were reported for the first time in Indian FH patients. These mutations were identified in 28(52%) subjects and interestingly ∼73% of the clinically identified FH patients didn’t harbour mutations in FH classical genes (LDLR, ApoB, PCSK9). ConclusionThis is the first study in the South Indian FH patients to perform targeted exome sequencing. Absence of mutations in the FH classical genes strongly indicates the polygenic nature of FH, further underscoring the importance of targeted exome sequencing for identifying mutations in genetically diverse Indian population.

Search for familial hypercholesterolemia patients in an Italian community: A real-life retrospective study

Background and aimsFamilial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism that causes elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Despite the availability of effective treatments, FH remains underdiagnosed and undertreated. The aims of the study were to identify putative FH subjects using data from laboratory and cardiology databases, genetically characterize suspected FH patients referred to the Lipid Clinic and monitor attainment of treatment goals in identified patients. Methods and resultsWe retrieved the electronic health records of 221,644 individuals referred to laboratory for routine assessment and of 583 ASCVD patients (age ≤65) who underwent percutaneous transluminal coronary angioplasty (PTCA). We monitored the lipid profiles of subjects with LDL-C ≥ 250 mg/dl identified by laboratory survey (LS-P), PTCA patients and patients from the Lipid Clinic (LC-P). The laboratory survey identified 1.46% of subjects with LDL-C ≥ 190 mg/dl and 0.08% with LDL-C ≥ 250 mg/dl. Probable/definite FH was suspected in 3% of PTCA patients. Molecularly-confirmed FH was found in 44% of LC-P subjects. Five new LDLR mutations were identified. The 50% LDL-C reduction target was achieved by 70.6% of LC-P patients. Only 18.5% of PTCA patients reached the LDL-C < 55 mg/dl target. ConclusionBy using a combined approach based on laboratory lipid profiles, documented ASCVD and Lipid Clinic data, we were able to identify subjects with a high probability of being FH. Attainment of LDL-C goals was largely suboptimal. Efforts are needed to improve FH detection and achievement of lipid targets.

Case Study of Hypertriglyceridemia from COVID-19 Pfizer-BioNTech Vaccination in a Patient with Familial Hypercholesteremia

Lead Author's Financial DisclosuresNothing to disclose.Study FundingNone.Background/SynopsisFamilial hypercholesterolemia (FH) is an autosomal codominant genetic disorder with very high levels of low-density lipoprotein cholesterol (LDL-C) due to defective hepatic uptake via LDL receptors. Little data are available about the impacts of a Coronavirus Disease 2019 (COVID-19) Pfizer-BioNTech vaccine on serum lipids in patients with FH.Objective/PurposeTo evaluate a FH patient presenting with severe hypertriglyceridemia after receiving his COVID-19 Pfizer-BioNTech vaccination.MethodsA history, physical examination, lipoprotein testing, and standard clinical chemistry laboratory testing were performed. Dextran sulfate cellulose LDL apheresis was performed with the Kaneka Medical America LLC Liposorber LA-15 system.ResultsA 60-year-old man has been treated for years with weekly or biweekly LDL apheresis treatments for FH, which was diagnosed >10 years ago using a Dutch Lipid Clinic Network score of 11. He has a history of hypertension, hypothyroidism, ischemic cardiomyopathy, heart failure with reduced ejection fraction, 5 myocardial infarctions (MI), status post coronary artery bypass graft, and 20 coronary artery stents. Medications include rosuvastatin 40 mg/d, ezetimibe 10 mg/d, fenofibrate 145 mg/d, icosapent ethyl 2 grams twice daily, alirocumab 150 mg biweekly, and levothyroxine 200 mcg/d. Prior to each apheresis treatment, he receives hydrocortisone 50 mg intravenously due to prior intolerance. He has maintained a Mediterranean diet and regularly exercises. Family history includes his father, paternal aunt, and paternal grandfather who all had MIs at or before the age of 50. Physical exam has been nonrevealing.He received his Pfizer-BioNTech vaccination doses on 3/10/21 and 3/31/2021. His lipid panel on 4/1/2021 revealed in mg/dL: triglyceride (TG) of 1308; total cholesterol (TC) of 285; direct LDL-C of 102; high-density lipoprotein cholesterol (HDL-C) of 35 (Table 1). LDL apheresis was attempted on 4/1/21, but failed, as the apparatus had very poor flow due to his very elevated triglycerides and cloudy blood (confirmed by Kaneka). He received apheresis 7 days later without complications with his pre-treatment lipid panel revealing in mg/dL: TG of 196; TC of 188; LDL-C of 106; HDL-C of 43. Prior to this, TG levels for the past 8 years averaged 277 mg/dL and 114 mg/dL pre- and post-apheresis, respectively.ConclusionsA potential increase in TG due to COVID-19 vaccination occurred in a patient with FH and serious atherosclerosis, which prevented a potentially life-saving treatment. This underscores the need to address any rare complications from novel COVID-19 treatments, minimize ASCVD risk, and determine if this is a common side effect of COVID-19 vaccination.

Elevated Lipoprotein(a) Attenuates the Effect of Statin Therapy on Atherogenic Lipoproteins in Patients with Familial Hypercholesterolemia

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis Statin therapy increases lipo-protein(a) (Lp(a)), an important atherogenic lipoprotein that is an independent risk factor for cardiovascular disease. However, it is unclear if elevated Lp(a) attenuates the lipid lowering effect of statins on other atherogenic lipoproteins. Objective/Purpose To determine if the effects of statin therapy on the reduction of atherogenic lipoproteins is attenuated in familial hypercholesterolemia patients with elevated Lp(a). Methods This was a retrospective cohort study of 109 patients with familial hypercholesterolemia. The cohort was categorized into two groups based on Lp(a) with low risk defined as Lp(a) < 30mg/dL and high risk defined as Lp(a) ≥30mg/dL. The degree of reduction in fasting atherogenic lipoproteins (LDL-C, non-HDL-C and TC) was compared between both groups after initiation of statin therapy, using independent paired t-tests for continuous variables and Chi-square or Fisher's exact test as appropriate for categorical variables. Statistical analyses were performed using Microsoft Excel 2016 and PASW Statistics 18 software. Results A total of 109 patients with familial hypercholesterolemia (median age of 20, 49.5% females, 75.2% white) were included in the study. The low-risk group comprised 50.4% of the cohort and baseline characteristics were similar among both groups. There was a greater mean percent reduction of TC, LDL-C and non-HDL-C (35.2%, 43.6% and 42.0%) in the low-risk group compared to the high-risk group (27.5%, 35.9% and 32.7%) which was statistically significant (p-values <0.001). Conclusions Elevated Lp(a) mitigates the lipid lowering effects of statins on atherogenic lipoproteins in patients with FH and may signal residual cardiovascular risk unaddressed by statin therapy. These findings suggest that the presence of elevated Lp(a) in FH patients confers additional ASCVD risks due to compromised statin response. Nothing to disclose.

Generation of a non-integrated induced pluripotent stem cell line (SMBCi009-A) from urine-derived cells of a Chinese Familial hypercholesterolemia patient

Familial hypercholesterolemia (FH; OMIM: # 143890) is a common inherited autosomal dominant disease, characterized by high-level low-density lipoprotein cholesterol (LDL-C) in plasma. Elevated LDL-C levels is closely related with atherosclerotic plaques and premature cardiovascular disease if not treated in time. Here we generated an induced pluripotent stem cell (iPSC) line using urine cells (UCs) derived from an 8-year-old male FH patient who carrying two coding and pathogenic mutations of low-density lipoprotein receptor (LDLR) gene (exon12:c.C1747T and exon13: c. 1948 del G). This induced pluripotent stem cell line named SMBCi009-A can be used to understand more cellular details about FH.

Myocardial fibrosis assessed by magnetic resonance imaging in asymptomatic heterozygous familial hypercholesterolemia: the cholcoeur study.

BackgroundFamilial Hypercholesterolemia (FH) is an underdiagnosed condition with an increased cardiovascular risk. It is unknown whether lipid accumulation plays a role in structural myocardial changes. Cardiovascular Magnetic Resonance (CMR) is the reference technique for the morpho-functional evaluation of heart chambers through cine sequences and for myocardial tissue characterization through late gadolinium enhancement (LGE) and T1 mapping images. We aimed to assess the prevalence of myocardial fibrosis in FH patients.MethodsSeventy-two asymptomatic subjects with genetically confirmed FH (mean age 49·24, range 40 to 60 years) were prospectively recruited along with 31 controls without dyslipidaemia matched for age, sex, BMI, and other cardiovascular risk factors. All underwent CMR including cine, LGE, pre- and post-contrast T1 mapping. Extracellular volume (ECV) and enhancement rate of the myocardium (ERM = difference between pre- and post-contrast myocardial T1, normalized by pre-contrast myocardial T1) were calculated.FindingsFive FH patients and none of the controls had intramyocardial LGE (p= 0·188). While no changes in Native T1 and ECV were found, post-contrast T1 was significantly lower (430·6 ± 55ms vs. 476·1 ± 43ms, p<0·001) and ERM was higher (57·44± 5·99 % vs 53·04±4·88, p=0·005) in HeFH patients compared to controls. Moreover, low post-contrast T1 was independently associated with the presence of xanthoma (HR 5·221 [1·04-26·28], p= 0·045). A composite score combining the presence of LGE, high native T1 and high ERM (defined as ≥ mean ± 1·5 SD) was found in 20·8% of the HeFH patients vs. 0% in controls (p<0·000, after adjustment for main confounders).InterpretationCMR revealed early changes in myocardial tissue characteristics in HeFH patients, that should foster further work to better understand and prevent the underlying pathophysiological processes.

Mitochondrial changes caused by LDL in hippocampal neurons

AbstractBackgroundFamilial hypercholesterolemia (FH) is characterized by high plasma accumulation of low‐density lipoproteins (LDL) due to mutations in the LDL receptor gene (Hobbs et al., Hum. Mutat., 1: 445‐466, 1992). Furthermore, FH patients present a high incidence of cognitive impairments (Zambón et al., Am J ed, 123:267‐274, 2010; Ariza et al., Eur J Intern Med., 34:e29‐e31, 2016). Experimental studies also demonstrated that FH leads to an increase in blood‐brain‐barrier permeability (De Oliveira et al., J Alzheimers Dis, 78:97‐115, 2020), which could allow the LDL to pass from the peripheral system to the central nervous system. Importantly, the cellular mechanisms responsible for neurotoxicity induced by LDL are unclear. Herein, we aimed to investigate whether LDL causes mitochondrial alterations in neurons.MethodWe exposed HT‐22 cells (Mouse Hippocampal Neuronal Cell) to human isolated LDL (50 and 300 ug/mL) for 24 hours. Furthermore, mass and potential mitochondrial were evaluated by Mitotracker green (MTG) and red (MTR), respectively, and the reactive species generation was evaluated by DCF.ResultNotably, when HT‐22 cells were incubated with LDL (50 ug/mL), MTR fluorescence was decreased compared with control cells. The ratio between MTG and MTR fluorescence showed increased mitochondria mass compared to their activity, suggesting an increase of swollen and non‐functional mitochondria. We observed in HT‐22 cells exposed to LDL (300 ug/mL) that both MTG, MTR, and ratio MTR/MTG were decreased, suggesting mitochondrial dysfunction. It is known that mitochondrial dysfunction leads to the excessive production of reactive species, and this may cause damage to essential cell components. In this regard, next, we evaluated the reactive species formation using DCF. The reactive species formation was significantly increased in cells exposed to both concentrations of LDL (50 and 300 ug/mL) in two times of exposure (1 and 24 hours) compared with the control cells.ConclusionThese findings indicate that LDL causes mitochondrial dysfunction, which appears to be a relevant event in hypercholesterolemia‐induced cerebral dysfunction.

Carotid Artery Temperature Reduction with Statin Therapy in Patients with Familial Hyperlipidemia Syndromes.

Background: Microwave radiometry (MWR) assesses non-invasive carotid artery temperatures reflecting inflammation. In the present study, we aimed to investigate the impact of hypolipidemic therapy either with simvastatin or with combination simvastatin plus ezetimibe on carotid artery temperatures of patients with familial hyperlipidemia syndromes (FHS). Methods: Consecutive patients with diagnosis of either familial heterozygous hypercholesterolemia (heFH) or familial combined hyperlipidemia (FCH) were included in the study. Patients were assigned to either simvastatin 40 mg or simvastatin 40 mg plus ezetimibe 10 mg, according to the discretion of the physician. FHS patients who refused statin therapy were used as a control group. Common carotid intima-media thickness (ccIMT) was measured and ΔΤ (maximum-minimum) temperature measurements were performed across each carotid during MWR evaluation. RESULTS: In total, 115 patients were included in the study. Of them, 40 patients received simvastatin (19 heFH and 21 FCH), 41 simvastatin + ezetimibe (31 heFH and 10 FCH), and 34 (21 heFH and 13 FCH) no statin. Carotid artery temperatures were significantly reduced at 6 months in FH patients who received hypolipidemic treatment (0.83 ± 0.34 versus 0.63 ± 0.24 °C, p = 0.004 for simvastatin, 1.00 ± 0.38 versus 0.69 ± 0.23 °C, p < 0.001 for simvastatin + ezetimibe), but no change was recorded in controls (0.72 ± 0.26 versus 0.70 ± 0.26 °C, p = 0.86). Conclusions: Hypolipidemic therapy reduced carotid temperatures in FHS patients.

LDL-cholesterol and PCSK9 in patients with familial hypercholesterolemia: influence of PCSK9 variants under lipid-lowering therapy.

BackgroundFamilial hypercholesterolemia (FH), an autosomal dominant genetic disease with the elevated levels of low‐density lipoprotein (LDL) cholesterol (LDL‐C), increases the risk of coronary artery disease (CAD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is associated with FH. There is a positive relationship between circulating LDL‐C and PCSK9 levels, a potential CAD condition, without lipid‐lowering therapy (LLT); however, we do not know whether their correlation exists in FH patients under LLT.MethodsThis study compared the correlation of PCSK9 variants among patients with FH under LLT (n = 70; mean age, 53 years; male, 63%). LDLR, PCSK9 and APOB variants were analyzed using next‐generation sequencing.ResultsThe LDL‐C and PCSK9 levels in patients with gain‐of‐function (GOF) variants of PCSK9 (n = 7) were mostly similar to those in patients with LDLR variants (n = 17) or variant‐negative patients (n = 46). A significant positive correlation was observed between LDL‐C and PCSK9 levels in patients with GOF variants of PCSK9 (r = 0.79, p = 0.04), but not in patients with LDLR variants or variant‐negative patients.ConclusionThe LDL‐C‐PCSK9 correlation is suggested to be retained in FH patients with GOF variants of PCSK9 even under LLT, and these variants can be used as molecular markers for additional treatment with statins in FH patients.

Increased lipoprotein(a) multiplies coronary heart disease risk in patients with familial hypercholesterolemia

Abstract Background Familial hypercholesterolemia (FH) and elevated lipoprotein(a) (Lp[a]) are individually associated with increased coronary heart disease (CHD) risk. Purpose To determine the independent and joint associations of FH and Lp(a) with CHD. Methods This was a cross-sectional study including adult patients with dyslipidemia followed at our University General Hospital, Greece. FH diagnosis was based on the Dutch Clinic Lipid Network Criteria (score ≥5), while elevated Lp(a) levels were defined as &amp;gt;30 mg/dL. Independent and joint associations of FH and Lp(a) with CHD prevalence were determined using binary logistic regression models adjusted for traditional cardiovascular risk factors. Results Among 941 participants (49 years, 47% males, 54% with FH, 36% with increased Lp[a]), the prevalence of CHD was 7.7% (n=72). Compared with subjects without FH and non-elevated Lp(a) (n=296), those with either FH (adjusted OR: 3.21, 95% CI: 1.35–7.62, n=271) or elevated Lp(a) (adjusted OR: 1.89, 95% CI: 0.76–4.69, n=180) were at higher CHD risk. The patients with both FH and elevated Lp(a) had the highest CHD risk (adjusted OR: 7.31; 95% CI: 3.09–17.32, n=195). Among FH patients, increased Lp(a) doubled CHD risk (adjusted OR: 2.22, 95% CI: 1.02–4.83), whereas among patients with elevated Lp(a), FH was associated with a 5-fold increase in CHD risk (adjusted OR: 4.96, 95% CI: 1.83–13.43). Conclusions FH and elevated Lp(a) have independent and additive associations with CHD prevalence. This may have therapeutic implications regarding treatment intensity. Funding Acknowledgement Type of funding sources: None.

Clinical features of familial hypercholesterolaemia in children and adults – the PMMHRI Registry

Abstract Background Familial hypercholesterolaemia (FH) affects approximately 150,000 people in Poland. However, there are many patients still unaware of this diagnosis. On the other hand, it might lead to early cardiovascular mortality and morbidity due to the lifetime exposure to high levels of LDL-C. Therefore, increased awareness of FH is very important. Purpose We aimed to evaluate the clinical features of FH in children and adults based on the preliminary data from the Polish Mother's Memorial Hospital Research Institute (PMMHRI) Registry. Methods The registry of children and adults with FH conducted in PMMHRI (2nd largest, supra-regional hospital in Poland) was established to investigate the clinical characteristics, management and clinical outcomes data of FH patients. All consecutive patients with diagnosed (genetically and/or phenotypically) FH were included in the study. Results Of 103 patients with FH, there were 16 children aged 9±3 and 87 adults aged 41±16; 59% were female. The diagnosis of FH in adults was late – at the mean age of 41 years. Among children with FH, as compared with adults, the levels of highest TC and LDL-C ever were similar. However, children presented higher mean levels of total cholesterol, LDL-C and HDL-C measured at baseline visit (Table). Interestingly there was no difference in BMI between children and adults (Table). Among adults, chronic coronary syndrome was diagnosed in 11.5% patients, from which 5.7% patients had a history of myocardial infarction and 7% patients required revascularization. The prevalence of chronic coronary disease, peripheral artery disease as well as stroke in family history was definitely higher (in 44 patients – 50%, 17 patients – 20% and 22 patients – 25%, respectively). Most of adult patients at baseline visit were prescribed statins (rosuvastatin or atorvastatin). 14 patients (13.6%) declared statin intolerance, most of them complained of muscle pain, 4.6% patients reported hepatic disturbances. The frequency of statin use in children was lower – 56% children were prescribed statin, 19% declared statin intolerance with muscle pain as the side-effect of treatment. Ezetimibe, as a part of combination therapy, was taken by 29% adult patients. PCSK9 inhibitors were prescribed (within drug program) for 11.5% adult patients. Fibrates were prescribed for 13.7% adult patients, the same was for n-3 fatty acids. Conclusions Despite definitely younger age of FH diagnosis children present higher mean levels of LDL cholesterol than adults. Therefore, the lifetime exposure to LDL cholesterol starts at a very young age. As a result, there is a need to the earlier initiation of therapy and strict monitoring of the atherosclerosis progression. On the other hand, late diagnosis of FH in adults is an unmet need, that might be associated with poorer prognosis. Funding Acknowledgement Type of funding sources: None.

Hemoglobin concentration, hematocrit and red blood cell count predict major adverse cardiovascular events in patients with familial hypercholesterolemia

Background and aimsFamilial hypercholesterolemia (FH) is a genetic disease associated with an important risk of premature and recurrent atherosclerotic cardiovascular disease (ASCVD). Red blood cell (RBC) parameters such as cell count and hematocrit (HCT) have previously been associated with ASCVD risk in the general population. However, little is known concerning their effect in FH. The aim of the present study is to investigate the effect of the different RBC parameters on the incidence of major adverse cardiovascular events (MACE) in FH patients. MethodsIn this prospective cohort study, genetically-confirmed FH patients aged between 18 and 65 years and without history of a prior ASCVD event were included. MACE included myocardial infarction, stroke, coronary revascularization, unstable angina or cardiovascular death. ResultsA total of 482 subjects (6217 person-years of follow-up) were included in the analysis. Hemoglobin (HB), RBC count, and HCT were significant predictors of MACE risk (HR 1.04 (95% CI 1.01–1.06) p = 0.001, HR 2.69 (95% CI 1.49–4.86) p = 0.001, and HR 1.16 (95% CI 1.08–1.26) p < 0.0001, respectively) and these associations remained significant when adjusted for traditional cardiovascular risk factors. In addition, the frequency of recurrent MACE was 4-fold and 7-fold higher in the group above vs below the median for HB (p = 0.002) and RBC count (p = 0.001), respectively. ConclusionsHB, RBC count and HCT were significant predictors of incident and recurring MACE in FH patients. These parameters could therefore be used to further refine the ASCVD risk prediction in this vulnerable population.

Absence of coronary artery calcium does not exclude coronary artery disease in FH patients

Absence of coronary artery calcium does not exclude coronary artery disease in FH patients

LDL-c response with different statin treatment intensities in fh patients: A sex-specific analysis

Background and Aims: Previous studies showed that women are undertreated with statins. Our aim was to investigate sex differences in prescription of statin treatment and effect of statins in Familial Hypercholesterolemia (FH).

Majority of clinically diagnosed familial hypercholesterolaemia in an Asian community inherit variants of FH candidate AND/OR associated genes.

Background and Aims: There were many reports on the identification of LDL receptor gene (LDLR) variants among Malaysian FH patients. However, the identification of multiple causative genes on FH individuals were yet to be reported. Therefore, we aimed to investigate the prevalence of monogenic and non-monogenic FH in Malaysia.

Cutaneous manifestations in familial hypercholesterolaemia

Background and aimsFamilial hypercholesterolaemia (FH) is associated with high cardiovascular risk and underdiagnosed. Cutaneous manifestations are traditionally used as a major criterion of FH. They are included in the Dutch Lipid Clinic Network or Simon Broome registry criteria. The objective of this study was to evaluate cutaneous manifestations in contemporary FH patients. MethodsWe prospectively analysed the clinical presentation of FH patients referred to a University lipid clinic and validated these data in the German FH registry CaRe High. ResultsPhysical examination revealed that only 14.4% of the FH patients in the lipid clinic cohort (n = 223) showed cutaneous manifestations. An arcus cornealis was present in 0.9%, xanthomata in 1.8%, and xanthelasmata in 12.1%. Xanthelasmata are not part of the clinical scores, but represented 84.4% of all cutaneous manifestations. In 42.6% (n = 95) of the patients, genetic analysis was available. A causal FH mutation was detected in 50.5%. Among carriers, 66.7% had no cutaneous manifestation, 8.3% exhibited an arcus cornealis or xanthomata, and 25.0% had xanthelasmata.In the CaRe High FH registry, data on cutaneous manifestations were available in n = 1274 patients. 3.5% had xanthomata, 5.7% an arcus cornealis, and 7.7% at least one of both; xanthelasmata were present in 10.3%. ConclusionsCutaneous manifestations are only present in a minority of contemporary patients with FH including the subgroup with monogenic FH mutations. Although rare, the cutaneous signs have value in terms of specificity. However, the clinical characteristics shared by the majority of FH patients may be better suited for screening purposes.

Paternal inheritance predicts earlier cardiovascular event onset in patients with familial hypercholesterolemia

Background and aimsFamilial hypercholesterolemia (FH) is a genetic disease, with an autosomal codominant inheritance, predisposing to premature atherosclerotic cardiovascular disease (ASCVD). Paternal or maternal inheritance of the FH-causing mutation may affect the FH phenotype in offspring, but the effect of the genetic transmission on cardiovascular disease risk remains to be established.The aim of the present study is to compare the incidence of cardiovascular events between patients with maternal vs paternal inheritance of familial hypercholesterolemia. MethodsWe prospectively studied 725 genetically-confirmed FH patients (33,805 person-years), including 268 with maternal inheritance and 321 with paternal inheritance of the mutation. ASCVD was defined as angina, myocardial infarction, coronary angioplasty, coronary bypass surgery, claudication, peripheral angioplasty, peripheral arterial surgery, transient ischemic attack, stroke, carotid endarterectomy and CV death. Cox-proportional hazard models and Kaplan-Meier analysis were used to compare the two groups. ResultsBefore 50 years of age, paternal inheritance of FH was associated with a 1.5-fold increased risk for ASCVD, as compared to maternal inheritance (HR 1.59, 95% CI 1.11–2.28, p = 0.01). This association remained significant after adjusting for confounding factors (HR 1.49, 95% CI 1.00–2.23, p = 0.05). The age of first ASCVD event was also significantly lower in the paternal inheritance group (42 years) than in the maternal inheritance group (46 years), p = 0.02. ConclusionsThis study suggests that paternal inheritance of the FH-causing mutation was associated with an earlier cardiovascular event onset compared to maternal inheritance. The mechanisms behind these findings remain to be established.

Implementation of a Machine-Learning Algorithm in the Electronic Health Record for Targeted Screening for Familial Hypercholesterolemia: A Quality Improvement Study.

Implementation of a Machine-Learning Algorithm in the Electronic Health Record for Targeted Screening for Familial Hypercholesterolemia: A Quality Improvement Study.