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• Providing cardiovascular risk based on genetic testing further reduced LDL-C levels. • Inconsistent effects exist according to the variant status on LDL-C levels. • Beneficial effects were attenuated after 48 weeks of the intervention. Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH. We aimed to evaluate the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program. We conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24. Fifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n = 24) or the wait-list control group (n = 26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p = 0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers. In addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers. Japan Registry of Clinical Trials (jRCTs04218002). URL: https://jrct.niph.go.jp/latest-detail/jRCTs042180027 [Display omitted] [ABSTRACT FROM AUTHOR]

No previous study has investigated the association between attainment of low-density lipoprotein (LDL) cholesterol treatment target and better prognosis in patients with familial hypercholesterolemia (FH). The current research aimed to examine the association between attainment of LDL cholesterol treatment target and major adverse cardiac events (MACEs) in patients with FH to validate the current LDL cholesterol treatment targets in primary (<100 mg/dL) and secondary (<70 mg/dL) prevention settings. The data of patients with FH who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed-up were retrospectively reviewed. The number of MACEs, including mortality associated with cardiovascular disease, unstable angina, and myocardial infarction per 1000 person-years, was calculated for each stratum for the attainment of LDL cholesterol target. The median follow-up duration was 12.6 years. In total, 132 MACEs were recorded during the follow-up period. The numbers of patients who attained the LDL cholesterol target in the primary and secondary prevention groups were 228 (31.9%) and 40 (11.9%), respectively. The event rates per 1000 person-years for LDL cholesterol levels of <100 and ≥100 mg/dL in the primary prevention group were 2.6 and 4.4, respectively. The event rates per 1000 person-years for LDL cholesterol levels of <70 and ≥70 mg/dL in the secondary prevention group were 15.3 and 27.5, respectively. Attainment of the LDL cholesterol target is associated with better prognosis in patients with FH. However, the attainment rate is currently inadequate among Japanese. [Display omitted] • Attainment of the LDL cholesterol target is currently inadequate in FH. • Attainment of the LDL cholesterol target is associated with better prognosis in FH. • PCSK9 inhibitor is associated with better attainment rate of the LDL cholesterol target. [ABSTRACT FROM AUTHOR]

• Pathogenic variants are associated with higher risk for CVD among FH patients. • LDL cholesterol level differs according to types of variants among FH patients. • VUS was significantly associated with poor outcomes in FH patients. Data on the effect of variants of uncertain significance (VUS) of LDL receptor (LDLR) on familial hypercholesterolemia (FH) phenotype is limited. To investigate the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and occurrence of major adverse cardiac events (MACEs), in FH patients (N = 1050, male/female = 490/560). We retrospectively assessed the data of patients with FH admitted at Kanazawa University Hospital between 1990 and 2020. Based on genotype, the patients were divided into patients without variants, with VUS of LDLR , and with pathogenic variants. Cox proportional hazard model was used to identify the factors associated with MACEs. The median follow-up duration was 12.6 years (interquartile range: 9.5–17.9 years). Altogether, 777 patients had FH mutation and 273 had pathogenic mutation, with 92 having VUS. Over the follow-up duration, 175 MACEs were observed. LDL cholesterol level was found to be significantly higher in patients with pathogenic variants (251 mg/dL) than in patients with VUS (225 mg/dL) and without variants (203 mg/dL). Pathogenic variants and VUS are significantly associated with MACEs (hazard ratio [HR] = 1.52, 95% confidence interval [CI] = 1.02–2.02, P = 0.033 and HR = 3.18, 95% CI = 2.00–4.36, P = 1.9 × 10−5, relative to patients without any variants, respectively), independent of classical risk factors. VUS of LDLR was significantly associated with poor outcomes in FH patients. Genetic testing is useful for the diagnosis and risk stratification of FH patients. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is an autosomal dominant disorder mainly caused by mutations in the low-density lipoprotein (LDL) receptor or associated genes, resulting in elevated serum cholesterol levels and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the prognostic impact of cascade screening for FH. We retrospectively investigated the health records of 1050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened, who were referred to our institute. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiac events (MACE). The median period of follow-up evaluating MACE was 12.3 years (interquartile ranges [IQR] = 9.1–17.5 years), and MACE included death associated with ASCVD, or acute coronary syndrome. During the observation period, 113 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P < 0.0001), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.67; 95%CI = 0.44 to 0.90; P = 0.0044) when compared with the probands, even after adjusting for those known risk factors, including age, and prior ASCVD. The identification of patients with FH via cascade screening appeared to result in better prognosis. • Cascade-screened FH patients were younger than the probands. • Cascade-screened FH patients were under milder LDL-lowering therapies. • Cascade-screened FH patients exhibited better prognosis than the probands. [ABSTRACT FROM AUTHOR]

• One-sixth of all patients with acute coronary syndrome (ACS) had concomitant peripheral artery disease as determined by decreased ankle-brachial index (ABI). • Decreased ABI was one of the major predictors of 30-day bleeding in ACS patients. • Combination of ABI and classical bleeding risk factors might help in risk assessment. • Both decreased ABI and 30-day bleeding also affect long-term prognosis in ACS. Although concomitant peripheral artery disease in patients with acute coronary syndrome (ACS) has been considered as a high-risk subgroup with a greater incidence of bleeding after percutaneous coronary intervention (PCI), few data exist regarding the clinical utility of the ankle-brachial index (ABI) for predicting bleeding complications, which affects the subsequent outcome. Eight hundred and twenty-four consecutive patients with ACS who underwent PCI and ABI examination were analyzed retrospectively. Decreased-ABI was defined as ABI <0.9. The primary outcome was bleeding complications within 30 days, which was defined according to the Bleeding Academic Research Consortium classification grade ≥3. The secondary endpoint was all-cause death during follow-up. Of the 824 patients with ACS, 137 (16.6%) exhibited decreased-ABI. The incidence of bleeding complications was significantly higher in patients with decreased-ABI, compared with the remaining patients (21.9% vs. 6.0%, p < 0.001). In multivariate analysis, anemia [odds ratio (OR) 2.14], estimated glomerular filtration rate < 60 mL/min/1.73 m2 (OR 2.14), femoral access (OR 3.31), use of an intra-aortic balloon pump (OR 3.16), and decreased-ABI (OR 2.58) were independent predictors of 30-day bleeding complications. Assigning 1 point for each variable, we developed a new bleeding risk score (range, 0–5). The area under the receiver-operating characteristic curve for the probability of 30-day bleeding for the new risk score was significantly superior than that of the traditional one (0.82 vs. 0.76, p < 0.05). During the median 4-year follow-up, there were 98 incidents of all-cause death. Multivariate Cox-proportional hazard analysis revealed that decreased-ABI [hazard ratio (HR) 1.91, 95% confidence interval (CI) 1.15–3.13, p < 0.05] and 30-day bleeding (HR 3.00, 95% CI 1.76–4.97, p < 0.001) were associated with an increased risk of all-cause mortality. Assessment of ABI provides useful information for predicting 30-day bleeding complications and long-term mortality in patients with ACS after PCI. [ABSTRACT FROM AUTHOR]

Background: Anticoagulation is recommended for hypertrophic cardiomyopathy (HCM) with nonvalvular atrial fibrillation (NVAF) according to European and American guidelines. However, it is unclear whether HCM is a risk factor for thromboembolism in NVAF in Japan, and the management for NVAF with HCM is not established.Objective: We studied the impact of concomitant HCM on predicting thromboembolism in NVAF.Methods: We retrospectively studied consecutive 2374 Japanese patients with NVAF (1682 men, 70.9%; mean age 71±10 years). Clinical factors were evaluated using the Cox proportional hazards model. We also investigated whether adding HCM to CHADS2 or CHA2DS2-VASc score improved the prediction of thromboembolism.Results: Thromboembolism was observed in 122 patients (5.1%) during the median follow-up of 2.4 years (interquartile range 2.0-3.2 years). The Cox proportional hazards model showed that HCM was significantly associated with thromboembolism after adjustment for CHADS2 or CHA2DS2-VASc score (hazard ratio 3.41; 95% confidence interval [CI] 1.98-5.73; P<.0001 and hazard ratio 3.38; 95% CI 1.97-5.64; P<.0001, respectively). NVAF with HCM had significantly higher thromboembolism rates, even in those with a CHADS2 or CHA2DS2-VASc score of 1 or 0-1, respectively. Based on the comparison of C-statistics, the addition of HCM to CHADS2 or CHA2DS2-VASc score significantly improved the prediction of thromboembolism (C-statistics 0.75 vs 0.71; P=.003 and C-statistics 0.77 vs 0.71; P=.0001, respectively).Conclusion: HCM is an independent risk factor for thromboembolism in patients with NVAF. A markedly high incidence of thromboembolism is observed in NVAF patients with HCM with CHA2DS2-VASc score of both ≥2 and 0-1, and anticoagulation therapy is recommended for them. [ABSTRACT FROM AUTHOR]

Abstract Background Little data exist regarding the clinical application of whole exome sequencing (WES) for the molecular diagnosis of severe hypertriglyceridemia (HTG). Methods WES was performed for 28 probands exhibiting severe HTG (≥1000 mg/dl) without any transient causes. We evaluated recessive and dominant inheritance models in known monogenic HTG genes, followed by disease-network gene prioritization and copy number variation (CNV) analyses to identify causative variants and a novel genetic mechanism for severe HTG. Results We identified possible causative variants for severe HTG, including three novel variants, in nine probands (32%). In the recessive inheritance model, we identified two homozygous subjects with lipoprotein lipase (LPL) deficiency and one subject harboring compound heterozygous variants in both LPL and APOA5 genes (hyperchylomicronemia). In the dominant inheritance model, we identified probands harboring deleterious heterozygous variants in LPL , glucokinase regulatory protein, and solute carrier family 25 member 40 genes, possibly associated with this extreme HTG phenotype. However, gene prioritization and CNV analyses did not validate the novel genes associated with severe HTG. Conclusions In 28 probands with severe HTG, we identified potential causative variants within nine genes associated with rare Mendelian dyslipidemias. Clinical WES may be feasible for such extreme cases, potentially leading to appropriate therapies. Highlights • Whole exome sequencing identified causative mutations in 32% of the individuals with severe HTG. • LPL and its associated proteins play an important role in this extreme situation. • Molecular diagnosis may provide appropriate therapies. [ABSTRACT FROM AUTHOR]

Background The genetic background of severe familial hypercholesterolemia (FH) has yet to be determined. Objective We tested if genetic variants associated with low-density lipoprotein (LDL)–altering autosomal recessive diseases influenced LDL cholesterol levels and the odds for coronary artery disease in patients with high LDL cholesterol. Methods We recruited 500 individuals with elevated LDL cholesterol levels (≥180 mg/dL or ≥140 mg/dL for subjects <15 years). We sequenced the exons of 3 FH genes (LDLR , apolipoprotein B, and proprotein convertase subtilisin/kexin type 9) and 4 LDL-altering accessory genes (ABCG5 , ABCG8 , APOE , and LDL receptor adaptor protein 1). In addition, 4 single nucleotide polymorphisms associated with polygenic FH in East Asian subjects were genotyped. Oligogenic FH patients were defined as those who harbored damaging variants of both conventional FH genes and LDL-altering accessory genes. Results We identified damaging variants of conventional FH genes in 248 participants (50%). We also detected damaging variants in accessory genes in 57 patients (11%) and identified oligogenic FH in 27 of these patients (5%). Polygenic score in the subjects without any FH mutations was significantly higher than those in any other groups. Compared with monogenic FH, oligogenic FH exhibited significantly higher LDL cholesterol (265 mg/dL, 95% confidence interval [CI] 216–312, and 210 mg/dL, 95% CI 189–243; P =.04). Oligogenic FH exhibited higher odds for coronary artery disease when compared with monogenic FH, although it did not reach statistical significance (odds ratio 1.41, 95% CI 0.68–2.21, P =.24). Conclusions Among patients with elevated LDL cholesterol, those with oligogenic FH had higher LDL cholesterol than monogenic FH. Highlights • We identified oligogenic FH with additional variants in LDL-altering accessory genes. • Accessory variants significantly affected the LDL cholesterol level as well as CAD. • Comprehensive genotyping is useful in patients with severe hyper LDL cholesterolemia. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases and their risk factors are inheritable. Single nucleotide polymorphisms in the human genome are found in around 1 in 1000 base pairs, and this may affect the genetic variety of individuals. During meiosis, any genetic information is randomized and is independent of other characteristics. In a Mendelian randomization study (MRS), a genetic variant associated with biomarker is used as a proxy for the biomarker, and the outcomes are compared between the groups harboring the effect alleles and a group with the reference allele. An MRS using variants of both rare and modest effect sizes and variants of common and lower effect sizes provides an understanding of risk factors and their causality of cardiovascular disease; for example, an individual possessing an allele associated with lower low-density lipoprotein cholesterol (LDL-C) exhibits lower risk of coronary artery disease (CAD). Moreover, the log-transformed reduction rates of CAD are linearly correlated with the reduction value of LDL-C. High-density lipoprotein (HDL) removes cholesteryl esters from peripheral tissues, including atherosclerotic plaque to the liver. Numerous epidemiological studies have shown that HDL-cholesterol (HDL-C) levels are inversely associated with the frequency of the occurrence of CAD. However, genetic variants, which are only associated with higher HDL-C levels, do not decrease the frequency of myocardial infarction. This fact shows that HDL-C level is not a cause but a biomarker of CAD. Discoveries of rare variants in Mendelian disorders resulted in the successful development of drugs for the general population. An MRS may also predict the pharmacological effectiveness and adverse side effects of novel drugs targeting specific molecules. An MRS could become a standard process to be performed before the development of novel drugs. Furthermore, future guidelines for the prevention of CAD should consider the genetic information of individuals, which will result in precision medicine for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background The development of candidate gene approaches to enable molecular diagnosis of hypertrophic cardiomyopathy (HCM) has required extensive and prolonged efforts. Whole exome sequencing (WES) technologies have already accelerated genetic studies of Mendelian disorders, yielding approximately 30% diagnostic success. As a result, there is great interest in extending the use of WES to any of Mendelian diseases. This study investigated the potential of WES for molecular diagnosis of HCM. Methods WES was performed on seven relatives from a large HCM family with a clear HCM phenotype (five clinically affected and two unaffected) in the Kanazawa University Hypertrophic Cardiomyopathy Registry. Serial bioinformatics filtering methods as well as using combined annotation dependent depletion (CADD) score and high heart expression (HHE) gene data were applied to detect the causative variant. Moreover, additional carriers of the variant were investigated in the HCM registry, and clinical characteristics harboring the variant were collected and evaluated. Results WES detected 60020 rare variants in the large HCM family. Of those, 3439 were missense, nonsense, splice-site, or frameshift variants. After genotype–phenotype matching, 13 putative variants remained. Using CADD score and HHE gene data, the number of candidates was reduced to one, a variant in the myosin essential light chain (MYL3, NM_000258.2:c.281G>A, p.Arg94His) that was shared by the five affected subjects. Additional screening of the HCM registry ( n = 600) identified two more subjects with this variant. Serial assessments of the variant carriers revealed the following phenotypic characteristics: (1) disease-penetrance of 88%; (2) all clinically affected carriers exhibited asymmetric septal hypertrophy with a substantial maximum left ventricular wall thickness of 18 ± 3 mm without any obstruction. Conclusions WES combined with CADD score and HHE gene data may be useful even in HCM. Furthermore, the MYL3 Arg94His variant was associated with high disease penetrance and substantial interventricular septal hypertrophy. [ABSTRACT FROM AUTHOR]

Lithium-Air Battery (LAB) is expected to develop ultra-high energy density batteries, but the low rate performance and poor cycle life of present LAB cells hinder practical development. Here we report that a highly porous carbon nanotube (CNT) cathode dramatically enhances the rate capability of LAB. Single-walled CNTs (SWCNTs) with wavy patterns prepared from the Super-Growth (SG) method successfully provided CNT sheets with high porosity of up to 94%. The pore structure was characterized by two distinct pores in size, namely, highly extended mesoscale (approximately 5–200 nm) pores formed inside CNT bundles that provide large surface area for oxygen reduction reaction (ORR) and inter-bundle gaps in a micrometer scale that works for oxygen diffusion path. This porous CNT sheet cathode significantly increased the discharge rate of LAB cells, specifically enabling a high discharge current density of 3.0 mA/cm2 securing practical cell capacity of 3.3 mAh/cm2, which is comparable to the current LiB technology that provides ∼3 mAh/cm2 cell capacity at ∼1C rate (∼3 mA/cm2) discharge. Furthermore, this highly porous cathode was also effective for extending the cycle life of LAB cells. Such bimodal pore architecture of the CNT sheet cathode paves the new strategy for developing high-power energy-dense LAB. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Smoking is implicated in chronic obstructive pulmonary disease (COPD) and hyperhomocysteinemia. To elucidate the role of hyperhomocysteinemia in COPD, we examined the relationship between plasma total homocysteine (tHcy) and spirometric declines in patients with COPD. We recruited 7 male never-smokers, 16 male control smokers, and 24 male patients with COPD. We investigated whether or not smoking might induce hyperhomocysteinemia in subjects predisposed to COPD, and then prospectively examined the relationship between plasma tHcy concentration and annual decline in FEV1.0 in the COPD group. We found that plasma tHcy concentrations declined among groups in the following order: COPD group>control group>never-smoker group. Furthermore, plasma tHcy concentrations in the COPD group were significantly correlated with %FEV1.0 (r s =0.46). Also, COPD patients with severe airflow limitation showed a significant decrease in PaO2, which might be involved in the decreased tHcy in those patients. The prospective analysis revealed that plasma tHcy concentration, but not a history of smoking, were significantly correlated with the annual decline in FEV1.0 calculated by the difference in FEV1.0 between the first examination and an examination the following year (r s =0.40). The present study suggests that smoking might increase plasma tHcy concentrations, leading to spirometric declines in subjects predisposed to COPD. [Copyright &y& Elsevier]

Although ebselen, a seleno-organic compound, inhibits inflammation in various animal models, its efficacy as an anti-asthma drug remains to be clarified. In this study, we investigated the inhibitory effect of ebselen on a guinea pig asthma model. Ebselen was orally administered at dosages of 1–20 mg/kg 2 h before an ovalbumin (OA) challenge, and then airway responses, airway inflammation, the generation of superoxide, H2O2, and nitrotyrosine, and the induction of inducible nitric oxide synthase (iNOS) were evaluated. Sensitized animals challenged with OA aerosol showed dual airflow limitations, i.e., immediate and late airway responses (IAR and LAR). Ebselen significantly inhibited LAR at dosages greater than 10 mg/kg, but did not inhibit IAR at any dosage. Bronchoalveolar lavage (BAL) examination showed that airway inflammation was significantly suppressed by ebselen at 10 mg/kg. The generation of superoxide and H2O2 occurred on endothelial cells of LAR bronchi, and was inhibited by 10 mg/kg of ebselen. Superoxide generation was inhibited by diphenyleneiodonium chloride (DPI), a NAD(P)H oxidase inhibitor, but not by allopurinol, a xanthine oxidase inhibitor. Immunoreactivities for iNOS and nitrotyrosine were also observed on endothelial cells of LAR bronchi and were abolished in ebselen-treated animals. The present findings suggest that ebselen can be applied as a new therapeutic agent for asthma. The possible mechanisms by which ebselen inhibits LAR likely involve suppression of oxidant formation and iNOS induction in endothelial cells. [Copyright &y& Elsevier]

Little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH). We aimed to catalog the pathogenic mutations of LDL receptor gene in the 2 major Japanese FH-care centers (Kanazawa University and National Cerebral and Cardiovascular Center Research Institute), where genetic testing of FH has been performed centrally on requests from institutes all over Japan during more than past 2 decades. 796 FH subjects from 472 families who had nonsynonymous mutations in LDL receptor gene were included in this study. Genetic mutations were analyzed for mutations by Sanger sequencing as well as by multiplex ligation probe dependent amplification technique for large rearrangements. Pathogenic mutations were defined either as 1) protein truncated variants, 2) registered as pathogenic in ClinVar, or Human Gene Mutation Database (HGMD), or meet the criteria of American College of Medical Genetics and Genomics guideline, or 3) CADD score > 10. We found 138 different mutations. Among them, 132 mutations were considered as pathogenic, including 19 large rearrangement mutations. However, 6 missense mutations were classified as variants of unknown significance. A single mutation accounted for as much as 41% of the FH subjects recruited from Kanazawa University mainly due to founder gene effect, whereas many singleton mutations were found from National Cerebral and Cardiovascular Center Research Institute located in Osaka. We provided the largest catalog of pathogenic mutations of LDL receptor gene in Japanese FH. This could aid to determine the pathogenicity of the LDL receptor genetic mutations not only in Japanese but also in other ethnicities. • 132 pathogenic mutations of LDL receptor gene in Japanese FH subjects are illustrated. • Mutation distribution appears to be unique according to the region. • 12% of the FH subjects had large rearrangement mutations in LDL receptor gene. [ABSTRACT FROM AUTHOR]

Abstract We present the first case of sitosterolemia caused by double heterozygous mutations in adenosine triphosphate-binding cassette subfamily G members 5 and 8 (ABCG5 and ABCG8) genes. A 1-year-old girl was admitted to Kanazawa University Hospital due to her hyper low-density lipoprotein (LDL)-cholesterolemia (453 mg/dL) as well as intertriginous xanthomas associated with breastfeeding. Initially, she was suspected as familial hypercholesterolemia (FH). However, her LDL cholesterol level significantly reduced after her weaning from breastfeeding. In addition, cascade screening did not show any evidence supporting dominant inheritance pattern as FH. Genetic analyses were performed using custom panel focusing on exome regions of 21 lipid-associated genes, including FH-causing genes (LDL receptor, proprotein convertase subtilisin/kexin type 9, apolipoprotein B), and ABCG5 and ABCG8 genes. In addition to a single deleterious mutation in ABCG5 gene (NM_022436.2:c.1166G>A or NP_071881.1:p.Arg389His), single deleterious mutation in ABCG8 gene (NM_022437.2:c.1285A>C or NP_071882.1:p.Met429Leu) was also identified. Segregations of those mutations from her parents were confirmed. Her serum sitosterol level was significantly elevated to 15.9 μg/mL, leading to her definite diagnosis as sitosterolemia. The ABCG5 and ABCG8 proteins form heterodimers and act as a complex. To the best of our knowledge, this is the first case exhibiting sitosterolemia caused by both ABCG5 and ABCG8 gene mutations. Highlights • We present the first case of sitosterolemia with mutations in ABCG5 and ABCG8 genes. • Comprehensive genetic analyses are useful in extreme cases. • Infant with sitosterolemia had very high LDL cholesterol during breastfeeding. [ABSTRACT FROM AUTHOR]

• LiNO 2 was investigated as a novel electrolyte salt for Lithium-air battery. • NO 2 − anion acts as a redox mediator for reducing the charging voltage. • N -methyl-2-pyrrolidone promotes the LiNO 2 dissociation to enhance the redox mediator function. • LiNO 2 / N -methyl-2-pyrrolidone electrolyte improves the cycle life of Lithium-air battery. Lithium nitrate (LiNO 3) has been used as the electrolyte salt for Lithium-air battery (LAB), both to protect the lithium metal anode and to generate NO 2 − anions that function as the redox mediator (RM) reducing the charging voltage. However, this RM effect minimally improves cycling performance because only a low NO 2 − concentration is produced. Instead, the use of lithium nitrite (LiNO 2) as the supporting electrolyte salt can overcome this limitation. In this study, 1 M solutions of LiNO 3 or LiNO 2 in tetraethylene glycol dimethyl ether (TEGDME) or N -methyl-2-pyrrolidone (NMP) were prepared as LAB electrolytes. Walden plots of these electrolytes established a higher degree of dissociation in the NMP having a greater dielectric constant, thus enhancing ionic conductivity. Electrochemical impedance spectroscopy determined that an LAB cell incorporating the LiNO 2 /NMP electrolyte exhibited reduced diffusion resistance during discharge-charge cycling as a consequence of the enhanced RM effect of NO 2 − anions. Microscopic observation and pore distribution analysis of cathodes confirmed that the clogging of pores was minimized with the LiNO 2 /NMP electrolyte. As a result, the LAB cell using this electrolyte extended the cycle performance, more than doubling the cycle life. LiNO 2 is considered to be an effective alternative for electrolyte salt for LAB. [Display omitted] [ABSTRACT FROM AUTHOR]

To study the effect of aging on orexin-A, we measured plasma orexin-A concentrations in 82 healthy volunteers (55 men and 27 women) over a wide range of ages (mean 50.2±13.9 years, ranging from 23 to 79 years). Correlation analyses revealed that plasma orexin-A concentrations correlated with age (r=0.50, P<0.01). When comparing three age groups, it appeared that the concentrations in the group of more than 60 years were significantly higher than those in the group of less than 39 years in both genders (P<0.05). These findings suggest that orexin-A could be involved in aging in a healthy population. [Copyright &y& Elsevier]

Background: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.Objectives: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.Methods: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.Results: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).Conclusions: ANGPTL3 deficiency is associated with protection from CAD. [ABSTRACT FROM AUTHOR]

Background: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation.Objectives: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD.Methods: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD.Results: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk.Conclusions: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases. [ABSTRACT FROM AUTHOR]

Background: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement.Objectives: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.Methods: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.Results: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.Conclusions: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD. [ABSTRACT FROM AUTHOR]

Classic electrocardiographic (ECG) voltage indexes have been applied to screen for left ventricular (LV) hypertrophy in hypertrophic cardiomyopathy (HC). However, it is unclear whether low ECG voltage reflects deteriorated electrical forces because of replacement of the myocardium by fibrotic tissues in HC. We investigated correlations between classic ECG voltage indexes (Cornell, total QRS voltage, and Sokolow-Lyon) and cardiac magnetic resonance (CMR) parameters focusing on the impact of low ECG voltage on the LV ejection fraction (LVEF) and myocardial fibrosis in HC. We studied 108 consecutive patients with HC who underwent CMR imaging with late gadolinium enhancement (LGE). Nineteen patients with complete right or left bundle branch block were excluded, leaving 89 patients for analysis (age 61.0 ± 13.9 years; 58 men). Of the 3 voltage indexes, the total QRS voltage and Sokolow-Lyon indexes were positively correlated with LVEF. For discriminating patients with end-stage HC (LVEF <50%) from patients with HC and preserved LVEF (≥ 50%), receiver-operating characteristic analysis revealed an excellent area under the curve of 0.87 for the total QRS voltage index and 0.90 for the Sokolow-Lyon index, whereas the area under the curve for the Cornell index was only 0.54 (p <0.01). Moreover, these 2 voltage indexes were negatively correlated with the extent of LGE-determined myocardial fibrosis when adjusted by the LV maximal wall thickness. In conclusion, low ECG voltage indexes may reflect increased myocardial fibrosis in patients with HC. [ABSTRACT FROM AUTHOR]

Objective Molecular diagnosis for subjects with extremely low HDL-C through candidate-gene approaches requires huge effort. Whole exome-sequencing (WES) has already shown approximately ∼30% success in the diagnosis of Mendelian disorders. Moreover, novel in silico prediction software for the pathogenicity of novel missense variants named Combined Annotation Dependent Depletion (CADD) has recently been developed, enabling the objective integration of many diverse annotations into a single measure (C-score) for each variant. Here, we investigated whether WES combined with integrated variant annotation prediction could facilitate the molecular diagnosis of this rare condition. Methods WES was performed on 8 individuals including 2 individuals exhibiting extremely low HDL-C (2 mg/dl and 6 mg/dl), 2 unaffected family members, and 4 unrelated individuals as controls. We filtered out the following variants: 1) Benign variants predicted by SnpEff; 2) Minor allele frequency (MAF) > 1%; 3) Segregation unmatched for the recessive form of inheritance; 4) C-score < 10. Results Among 305,202 variants found in those individuals, we found 21,708 nonsense, missense, or splice site variants, of which 5192 were rare (MAF ≤ 1% or not reported). Filtering assuming a recessive pattern of inheritance, combined with the use of the C-score, successfully narrowed down the candidates to compound heterozygous mutations in the ABCA1 gene (c.6230C > A or p.P2077H/c.6137G > A or p.S2046N, and c.2842G > A or p.G948R/c.1130C > T or p.P377L). Conclusions WES combined with integrated variant annotation prediction successfully identified asymptomatic Tangier disease with novel ABCA1 mutations. This comprehensive approach is useful to determine causative variants, especially in recessive inherited diseases. [ABSTRACT FROM AUTHOR]