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AIMS: Elevated lipoprotein (a) (Lp[a]), predominantly determined by genetic variability, causes atherosclerotic cardiovascular disease (ASCVD), particularly in patients with familial hypercholesterolemia (FH). We aimed to elucidate the clinical impact of Lp(a) and cumulative exposure to low-density lipoprotein cholesterol (LDL-C) on CAD in patients with FH. METHODS: One hundred forty-seven patients clinically diagnosed with heterozygous familial hypercholesterolemia (HeFH) were retrospectively investigated. Patients were divided into 2 groups according to the presence of CAD. Their clinical characteristics and lipid profiles were evaluated. RESULTS: There were no significant differences in untreated LDL-C levels between the 2 groups (p=0.4), whereas the cumulative exposure to LDL-C and Lp(a) concentration were significantly higher in patients with CAD (11956 vs. 8824 mg-year/dL, pï¼0.01; 40 vs. 14 mg/dL, pï¼0.001, respectively). A receiver operating characteristic (ROC) curve analysis demonstrated that the cutoff values of Lp(a) and cumulative LDL-C exposure to predict CAD in patients with FH were 28 mg/dL (AUC 0.71) and 10600 mg-year/dL (AUC 0.77), respectively. A multivariate analysis revealed that cumulative LDL-C exposure ≥ 10600 mg-year/dL (pï¼0.0001) and Lp(a) level ≥ 28 mg/dL (pï¼0.001) were independent predictors of CAD. Notably, the risk of CAD remarkably increased to 85.7% with smoking, Lp(a) ≥ 28 mg/dL, and cumulative LDL-C exposure ≥ 10600 mg-year/dL (odds ratio: 46.5, 95%CI: 5.3-411.4, pï¼0.001). CONCLUSIONS: This study demonstrated an additive effect of Lp(a) and cumulative LDL-C exposure on CAD in patients with HeFH. Interaction with traditional risk factors, particularly smoking and cumulative LDL-C exposure, enormously enhances the cardiovascular risk in this population.
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AIMS: Little data exists for evaluating the prevalence and patient characteristics of familial hypercholesterolemia (FH) according to the latest 2022 guidelines for FH published by the Japan Atherosclerosis Society (JAS), which revised the Achilles tendon thickness (ATT) threshold from 9.0 mm in both sexes to 8.0 mm in men and 7.5 mm in women. This study used a nationwide registry of patients with acute coronary syndrome (ACS) to evaluate the prevalence of FH according to the latest diagnostic criteria for FH and to investigate the application of Achilles tendon imaging in the diagnosis of FH.A previous prospective observational study at 59 Japanese centers involving consecutive patients with ACS who were managed between April 2015 and August 8, 2016 was conducted to explore lipid management and persistent risk in patients hospitalized for ACS (EXPLORE-J). The study population consisted of 1,944 EXPLORE-J enrollees. RESULTS: According to the diagnostic criteria for FH in the 2022 JAS guidelines, the prevalence of probable or definite was among patients with ACS was 6.6% (127/1944). Among patients with premature ACS (male, age ï¼55 years; female, age ï¼65 years), the prevalence of FH was 10.1% (43/427). The mean ages were of the probable FH and definite FH groups were 59.9 and 61.0 years, respectively, while the mean age of the possible-or-unlikely FH group was 66.4 years (significantly older). Relative to the possible-or-unlikely FH group, the low-density lipoprotein cholesterol (LDL-C) levels were similar in the probable FH group and and significantly higher in the definite FH group. CONCLUSIONS: The prevalence of FH was considerably higher than previously reported, especially for patients with premature ACS. The age and LDL-C levels of the patients in the probable FH and definite FH groups were similar.
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BACKGROUND: The atherogenic characteristics of heterozygous familial hypercholesterolemia (HeFH) increase the risk of premature atherosclerotic cardiovascular disease including not only coronary artery disease but ischemic stroke. Asymptomatic intracranial artery stenosis/occlusion (IASO) is a major cause of ischemic stroke, but it has not yet been fully characterized in patients with HeFH. METHODS AND RESULTS: This study analyzed 147 clinically diagnosed subjects with HeFH who underwent magnetic resonance imaging/magnetic resonance angiography imaging for evaluation of IASO (≥50% diameter stenosis). Major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, and acute coronary syndrome) were compared in patients with HeFH with and without asymptomatic IASO. Asymptomatic IASO was observed in 13.6% of patients with HeFH. The untreated low-density lipoprotein cholesterol level (240±95 versus 244±75 mg/dL; P=0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, P=0.71; high-intensity statin, P=0.81; ezetimibe, P=0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, P=0.39; low-density lipoprotein apheresis, P=0.14), on-treatment low-density lipoprotein cholesterol level in patients with both HeFH and IASO was still suboptimally controlled (97±62 versus 105±50 mg/dL; P=0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; P=0.001). During the 12.4-year observational period (interquartile range, 6.2-24.6 years), asymptomatic IASO exhibited a 4.04-fold greater likelihood of experiencing a major adverse cardiovascular event (95% CI, 1.71-9.55; P=0.001) in patients with HeFH. This increased risk of a major adverse cardiovascular event was consistently observed in a multivariate Cox proportional hazards model adjusting clinical characteristics (hazard ratio, 4.32 [95% CI, 1.71-10.9]; P=0.002). CONCLUSIONS: A total of 13.6% of Japanese subjects with HeFH presented with asymptomatic IASO. Despite lipid-lowering therapies, patients with both HeFH and IASO more likely had elevated risk of cerebrovascular and cardiovascular events. Our findings highlight asymptomatic IASO as a phenotypic feature of HeFH-related atherosclerosis, which ultimately affects future outcomes.
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Enfermedades Asintomáticas , Hiperlipoproteinemia Tipo II , Angiografía por Resonancia Magnética , Humanos , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Heterocigoto , Adulto , Factores de Riesgo , Estudios Retrospectivos , Constricción Patológica , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/etiología , Anciano , LDL-Colesterol/sangre , Japón/epidemiologíaRESUMEN
BACKGROUND: The prevalence of cardiovascular disease (CVD) is rising in Japan with its aging population, but there is a lack of epidemiological data on sex differences in CVD, including acute coronary syndrome (ACS), acute heart failure (AHF), and acute aortic disease. METHODSâANDâRESULTS: This retrospective study analyzed data from 1,349,017 patients (January 2012-December 2020) using the Japanese Registry Of All Cardiac and Vascular Diseases database. ACS patients were youngest on average (70.5±12.9 years) and had the lowest female proportion (28.9%). AHF patients had the oldest mean age (79.7±12.0 years) and the highest proportion of females (48.0%). Acute aortic disease had the highest in-hospital mortality (26.1%), followed by AHF (11.5%) and ACS (8.9%). Sex-based mortality differences were notable in acute aortic disease, with higher male mortality in Stanford Type A acute aortic dissection (AAD) with surgery (males: 14.2% vs. females: 10.4%, P<0.001) and similar rates in Type B AAD (males: 6.2% vs. females: 7.9%, P=0.52). Aging was a universal risk factor for in-hospital mortality. Female sex was a risk factor for ACS and acute aortic disease but not for AHF or Types A and B AAD. CONCLUSIONS: Sex-based disparities in the CVD-related hospitalization and mortality within the Japanese national population have been highlighted for the first time, indicating the importance of sex-specific strategies in the management and understanding of these conditions.
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Mortalidad Hospitalaria , Hospitalización , Sistema de Registros , Humanos , Femenino , Masculino , Japón/epidemiología , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Hospitalización/estadística & datos numéricos , Factores Sexuales , Bases de Datos Factuales , Síndrome Coronario Agudo/mortalidad , Síndrome Coronario Agudo/epidemiología , Síndrome Coronario Agudo/terapia , Factores de Riesgo , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/epidemiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , Pueblos del Este de AsiaRESUMEN
AIMS: This was a retrospective cohort study that aimed to determine cutoff values for major adverse cardiovascular events (MACEs) in patients with heterozygous FH (HeFH) for Achilles tendon (AT) thickness (ATT) measured by ultrasonography (US-ATT) and radiography (Xp-ATT), AT softness, and intima-media thickness of carotid artery (C-IMT), and to examine the effectiveness of these values as well as AT calcification as indexes in assessing risk for MACEs. METHODS: The subjects were 391 clinically diagnosed HeFH patients. Kaplan-Meier curves were drawn based on the threshold values for the individual indexes calculated from ROC curves, and multivariate analysis was used to examine whether they were predictors of the development of MACEs. RESULTS: The median observation period was 1,239 days (700-1,827 days). Twenty-one subjects (5%) had MACEs during the observation period. The cutoff values for MACEs for US-ATT were 9.9 mm in males and 7.1 mm in females, and those for C-IMT were 1.6 mm in males and 1.5 mm in females. Subjects were classified into two groups according to whether they were above or below the cutoff values and presence of calcification, and we compared MACE rates between them. MACE rates were significantly increased in groups with AT thickening determined by ultrasonography (Pï¼0.001), AT softening (Pï¼0.001), presence of calcification in AT (P=0.016) and greater C-IMT (Pï¼0.001). However, classification according to Xp-ATT revealed no significant difference in MACE rate (P=0.112). CONCLUSIONS: These thresholds and examination for AT calcification will help in risk assessment for patients in Japanese FH practice and encourage stricter and more comprehensive management for patients who exceed the thresholds.
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Familial hypobetalipoproteinemia (FHBL) 1 is a rare genetic disorder with an autosomal codominant mode of inheritance and is caused by defects in the apolipoprotein (apo) B (APOB) gene that disable lipoprotein formation. ApoB proteins are required for the formation of very low-density lipoproteins (VLDLs), chylomicrons, and their metabolites. VLDLs transport cholesterol and triglycerides from the liver to the peripheral tissues, whereas chylomicrons transport absorbed lipids and fat-soluble vitamins from the intestine. Homozygous or compound heterozygotes of FHBL1 (HoFHBL1) are extremely rare, and defects in APOB impair VLDL and chylomicron secretion, which result in marked hypolipidemia with malabsorption of fat and fat-soluble vitamins, leading to various complications such as growth disorders, acanthocytosis, retinitis pigmentosa, and neuropathy. Heterozygotes of FHBL1 are relatively common and are generally asymptomatic, except for moderate hypolipidemia and possible hepatic steatosis. If left untreated, HoFHBL1 can cause severe complications and disabilities that are pathologically and phenotypically similar to abetalipoproteinemia (ABL) (an autosomal recessive disorder) caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene. Although HoFHBL1 and ABL cannot be distinguished from the clinical manifestations and laboratory findings of the proband, moderate hypolipidemia in first-degree relatives may help diagnose HoFHBL1. There is currently no specific treatment for HoFHBL1. Palliative therapy including high-dose fat-soluble vitamin supplementation may prevent or delay complications. Registry research on HoFHBL1 is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.
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Hipobetalipoproteinemias , Humanos , Hipobetalipoproteinemias/diagnóstico , Hipobetalipoproteinemias/genética , Hipobetalipoproteinemias/terapia , Manejo de la Enfermedad , Hipobetalipoproteinemia Familiar por Apolipoproteína BAsunto(s)
Homocigoto , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/terapia , Pronóstico , LDL-Colesterol/sangre , Fenotipo , Predisposición Genética a la Enfermedad , Mutación , Factores de Riesgo , Receptores de LDL/genética , Anticolesterolemiantes/uso terapéutico , Biomarcadores/sangreRESUMEN
AIMS: Obicetrapib is a highly selective cholesteryl ester transfer protein (CETP) inhibitor shown to reduce low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), when taken as monotherapy and in combination with ezetimibe on a background of statins, in clinical trials predominantly conducted in Northern European/Caucasian participants. We characterized the efficacy, safety, and tolerability of obicetrapib within an Asian-Pacific region population. METHODS: This double-blind, randomized, phase 2 trial examined obicetrapib 2.5, 5, and 10 mg/d, compared with placebo, for 8 weeks as an adjunct to stable statin therapy (atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d) in Japanese men and women who had not achieved 2022 Japan Atherosclerosis Society Guidelines and had LDL-C ï¼70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ï¼100 mg/dL and triglycerides (TG) ï¼400 mg/dL. Endpoints included LDL-C, non-HDL-C, HDL-C, very low-density lipoprotein cholesterol, apolipoproteins, TG, steady state pharmacokinetics (PK) in obicetrapib arms, safety, and tolerability. RESULTS: In the 102 randomized subjects (mean age 64.8 y, 71.6% male), obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C at all doses; responses in the obicetrapib 10 mg group were -45.8%, -29.7%, -37.0%, and +159%, respectively (all pï¼0.0001 vs. placebo). The PK profile demonstrated near complete elimination of drug by 4 weeks. Obicetrapib was well tolerated and there were no adverse safety signals. CONCLUSIONS: All doses of obicetrapib taken as an adjunct to stable statin therapy significantly lowered atherogenic lipoprotein lipid parameters, showed near complete elimination of drug by 4 weeks, and were safe and well tolerated in a Japanese population, similar to previous studies of obicetrapib conducted in predominantly Caucasian participants.
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Synthetic siRNA molecules without chemical modifications are easily degraded in the body, and 2'-O-modifications are frequently introduced to enhance stability. However, such chemical modifications tend to impact the gene knockdown potency of siRNA negatively. To circumvent this problem, we previously developed a prodrug-type siRNA bearing 2'-O-methyldithiomethyl (MDTM) groups, which can be converted into unmodified siRNA under the reductive environment in cells. In this study, we developed a nuclease-resistant prodrug-type 2'-O-MDTM siRNA for deployment in future animal experiments. To rationally design siRNA modified with a minimal number of 2'-O-MDTM nucleotide residues, we identified the sites susceptible to nuclease digestion and tolerant to 2'-O-methyl (2'-OMe) modification in the antisense strand of apolipoprotein B-targeted siRNA. Subsequently, we optimized the positions where the 2'-OMe and 2'-O-MDTM groups should be incorporated. siRNA bearing the 2'-O-MDTM and 2'-OMe groups at their respective optimized positions exhibited efficient knockdown potency in vitro and enhanced stability in serum.
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Profármacos , ARN Interferente Pequeño/química , Profármacos/farmacología , Profármacos/química , Silenciador del Gen , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismoRESUMEN
Transitional medicine refers to the seamless continuity of medical care for patients with childhood-onset diseases as they grow into adulthood. The transition of care must be seamless in medical treatment as the patients grow and in other medical aids such as subsidies for medical expenses in the health care system. Inappropriate transitional care, either medical or social, directly causes poorer prognosis for many early-onset diseases, including primary dyslipidemia caused by genetic abnormalities. Many primary dyslipidemias are designated as intractable diseases in the Japanese health care system for specific medical aids, as having no curative treatment and requiring enormous treatment costs for lipid management and prevention of complications. However, there are problems in transitional medicine for primary dyslipidemia in Japan. As for the medical treatment system, the diagnosis rate remains low due to the shortage of specialists, their insufficient link with generalists and other field specialists, and poor linkage between pediatricians and physicians for adults. In the medical care system, there is a mismatch of diagnostic criteria of primary dyslipidemias between children and adults for medical care expense subsidization, as between The Program for the Specific Pediatric Chronic Diseases and the Program for Designated Adult Intractable Diseases. This could lead some patients subsidized in their childhood to no longer be under the coverage of the aids after transition. This review intends to describe these issues in transitional medicine of primary dyslipidemia in Japan as a part of the efforts to resolve the problems by the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare of Japan.
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Dislipidemias , Humanos , Dislipidemias/terapia , Dislipidemias/epidemiología , Japón/epidemiología , Adulto , Transición a la Atención de Adultos , NiñoRESUMEN
AIMS: Paraoxonase 1 (PON1) binds to high-density lipoprotein (HDL) and protects against atherosclerosis. However, the relationship between functional PON1 Q192R polymorphism, which is associated with the hydrolysis of paraoxon (POXase activity) and atherosclerotic cardiovascular disease (ASCVD), remains controversial. As the effect of PON1 Q192R polymorphism on the HDL function is unclear, we investigated the relationship between this polymorphism and the cholesterol efflux capacity (CEC), one of the biological functions of HDL, in association with the PON1 activity. METHODS: The relationship between PON1 Q192R polymorphisms and CEC was investigated retrospectively in 150 subjects without ASCVD (50 with the PON1 Q/Q genotype, 50 with the Q/R genotype, and 50 with the R/R genotype) who participated in a health screening program. The POXase and arylesterase (AREase: hydrolysis of aromatic esters) activities were used as measures of the PON1 activity. RESULTS: The AREase activity was positively correlated with CEC independent of the HDL cholesterol levels. When stratified by the PON1 Q192R genotype, the POXase activity was also positively correlated with CEC independent of HDL cholesterol. PON1 Q192R R/R genotype carriers had a lower CEC than Q/Q or Q/R genotype carriers, despite having a higher POXase activity. Moreover, in a multiple regression analysis, the PON1 Q192R genotype was associated with the degree of CEC, independent of the HDL cholesterol and POXase activity. CONCLUSIONS: The PON1 Q192R R allele is associated with reduced CEC in Japanese people without ASCVD. Further studies on the impact of this association on the severity of atherosclerosis and ASCVD development are thus called for.
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AIMS: Acute myocardial infarction (AMI) causes irreversible damage to cardiomyocytes due to the discontinuation of oxygen supply and leads to systemic oxidative stress. It has been reported that high-density lipoprotein (HDL) particles have antioxidant capacity, and reduced antioxidant capacity is associated with decreased cholesterol efflux capacity (CEC). The purpose of this study was to clarify the usefulness of CEC measurement in patients with AMI. METHODS: We investigated the association between CEC and oxidative stress status in a case-control study. This study included 193 AMI cases and 445 age- and sex-matched controls. We examined the associations of CEC with HDL-cholesterol (HDL-C) and oxidized human serum albumin (HSA), an index of systemic oxidative stress status, and the effect of aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which has been reported to affect HDL-C level and risk for MI, on these associations. RESULTS: Both bivariable and multivariable analyses showed that CEC was positively correlated with HDL-C levels in both AMI cases and controls, with a weaker correlation in AMI cases than in controls. In AMI cases, oxidized HSA levels were associated with CEC in both bivariable and multivariable analyses, but not with HDL-C. These associations did not differ among the ALDH2 genotypes. CONCLUSIONS: CEC, but not HDL-C level, reflects systemic oxidative stress status in patients with AMI. CEC measurement for patients with AMI may be useful in that it provides information on systemic oxidative stress status as well as atherosclerosis risk.
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Aldehído Deshidrogenasa Mitocondrial , HDL-Colesterol , Infarto del Miocardio , Estrés Oxidativo , Humanos , Masculino , Femenino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/sangre , Estudios de Casos y Controles , HDL-Colesterol/sangre , HDL-Colesterol/metabolismo , Persona de Mediana Edad , Aldehído Deshidrogenasa Mitocondrial/metabolismo , Aldehído Deshidrogenasa Mitocondrial/genética , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Colesterol/metabolismo , Pronóstico , Albúmina Sérica Humana/metabolismoRESUMEN
Aim: To evaluate the safety and efficacy of lomitapide in real-world clinical practice in Japan. Patients & methods: Interim analysis of 39 patients with homozygous familial hypercholesterolemia from an all-case surveillance study. Results: Median lomitapide dose (across 42 months) was 9.8 mg/day. 74 drug-related adverse events (AEs) were reported in 24 (61.5%) patients, including 14 (35.9%) with liver-related AEs, 19 (48.7%) with gastrointestinal disorders and 1 (2.6%) bleeding disorder. Lomitapide dose was reduced for 39.2% of drug-related AEs, withdrawn temporarily for 12.2%, and discontinued for 1 event (1.4%). Mean ± SD blood LDL-C level decreased from 225.9 ± 172.0 mg/dl (5.8 ± 4.5 mmol/l) predose to 159.4 ± 93.0 mg/dl (4.1 ± 2.4 mmol/l) at 12 months (p = 0.0245). Conclusion: This interim analysis suggests lomitapide is safe and effective in real-world clinical practice in Japan.
What is this article about? Lomitapide is a drug used to treat homozygous familial hypercholesterolemia (HoFH), a rare inherited disorder that causes very high cholesterol levels. Because HoFH is rare, only a limited number of patients were enrolled into the clinical trials that showed it was safe and effective, before its approval. Therefore, a study is now underway to evaluate the efficacy and safety of lomitapide when it is used in daily clinical practice in Japan. We have analyzed data for 39 patients who have been enrolled in this study so far. What are the results? We found that although most patients experienced some side effects, only one patient had to discontinue lomitapide. Most side effects could be managed without having to alter lomitapide treatment, or in some cases by reducing the dose or stopping the drug temporarily. We also found that lomitapide reduced cholesterol levels. What do the results mean? The results suggest that lomitapide is generally safe and effective in patients with HoFH being treated in routine clinical practice. The study is ongoing and additional analyses will be performed when a greater number of patients have been treated.
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Anticolesterolemiantes , Bencimidazoles , Hipercolesterolemia Familiar Homocigótica , Hiperlipoproteinemia Tipo II , Humanos , JapónRESUMEN
AIM: Hypertensive disorders of pregnancy (HDP) are among the obstetric complications reportedly associated with later-life cardiovascular disease (CVD). This study examined physicians' recognition of reproductive history by elucidating their attitude and knowledge. METHODS: This study included council members of the Japan Atherosclerosis Society. An Internet-based survey was conducted between August 9 and September 9, 2022. RESULTS: A total of 137 council members completed the questionnaire (response rate: 36%). In terms of the internal medicine subspeciality of the participants, endocrinology was the most common (46%), followed by cardiology (38%). About 70% of the participants considered reproductive history to be important and obtained more information than those who considered it otherwise. In the questionnaire for knowledge about HDP and future diseases, physicians correctly answered 6.8 of 9 questions. Endocrinologists were more likely to ask regarding reproductive history at the initial visit than cardiologists (82.5% vs. 61.5%; p=0.012) and obtained more information from women below 50 years old. Contrarily, cardiologists obtained information on reproductive history from older women (those approaching menopause and those in their 60s and 70s). CONCLUSION: We found that physicians had a high level of knowledge about HDP and the importance of reproductive information. However, the manner of obtaining information, including the target population, differed depending on the subspeciality. In the future, effective interventions for women with a history of HDP need to be developed in order to encourage physicians to obtain reproductive information to prevent CVD.
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Enfermedades Cardiovasculares , Hipertensión Inducida en el Embarazo , Médicos , Humanos , Femenino , Japón/epidemiología , Embarazo , Hipertensión Inducida en el Embarazo/epidemiología , Enfermedades Cardiovasculares/epidemiología , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto , Médicos/psicología , Masculino , Conocimientos, Actitudes y Práctica en Salud , Anciano , Historia Reproductiva , Actitud del Personal de SaludRESUMEN
Off-target interactions between antisense oligonucleotides (ASOs) with state-of-the-art modifications and biological components still pose clinical safety liabilities. To mitigate a broad spectrum of off-target interactions and enhance the safety profile of ASO drugs, we here devise a nanoarchitecture named BRace On a THERapeutic aSo (BROTHERS or BRO), which is composed of a standard gapmer ASO paired with a partially complementary peptide nucleic acid (PNA) strand. We show that these non-canonical ASO/PNA hybrids have reduced non-specific protein-binding capacity. The optimization of the structural and thermodynamic characteristics of this duplex system enables the operation of an in vivo toehold-mediated strand displacement (TMSD) reaction, effectively reducing hybridization with RNA off-targets. The optimized BROs dramatically mitigate hepatotoxicity while maintaining the on-target knockdown activity of their parent ASOs in vivo. This technique not only introduces a BRO class of drugs that could have a transformative impact on the extrahepatic delivery of ASOs, but can also help uncover the toxicity mechanism of ASOs.
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Oligonucleótidos Antisentido , Ácidos Nucleicos de Péptidos , Masculino , Humanos , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/metabolismo , ARN/metabolismo , Unión Proteica , Hibridación de Ácido Nucleico , Oligonucleótidos Fosforotioatos/químicaRESUMEN
Background: The studies evaluating patients' characteristics and lipid-lowering therapy for patients with homozygous familial hypercholesterolemia (HoFH) are scarce. Objectives: This study aims to evaluate the characteristics of and treatments for patients with HoFH. Methods: This study included 201 patients who were diagnosed with definite or probable HoFH from the National Database of the Japanese Ministry of Health, Labour, and Welfare. Results: The patients' median age at diagnosis was 27 years and exhibited a bimodal distribution. Approximately 70% of patients had coronary artery disease. Regarding genetic backgrounds, mutations in the low-density lipoprotein (LDL) receptor (LDLR) were identified in most of the patients, followed by proprotein convertase subtilisin/kexin type 9 (PCSK9) and double heterozygotes of LDLR. High-intensity statins were introduced to 74% of the patients, lipoprotein apheresis was performed in 21%, and PCSK9 inhibitors were administered to 50%. The mean of LDL cholesterol before and after treatment were 10.1 mmol/L and 3.9 mmol/L, respectively. Patients with coronary artery disease had significantly decreased LDL cholesterol. A quarter of the patients (n = 49, 24%) exhibited valvular diseases, particularly aortic valvular disease (n = 34, 61%). Conclusions: The national epidemiological study of patients with HoFH showed patient's clinical and genetic characteristics and LDL-lowering therapy in Japan. There was considerable diversity in the severity of phenotypes, including LDL cholesterol levels, among patients with HoFH. In Japan, the management of LDL cholesterol in HoFH is still inadequate despite the availability of intensive lipid-lowering therapies.
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Various chemical modifications have been developed to create new antisense oligonucleotides (AONs) for clinical applications. Our previously designed prodrug-type phosphotriester-modified oligonucleotide with cyclic disulfides (cyclic SS PTE ON) can be converted into unmodified ON in an intracellular-mimetic reducing environment. However, the conversion rate of the cyclic SS PTE ON was very low, and the AON with cyclic SS PTE modifications showed much weaker antisense activity than corresponding to the fully phosphorothioate-modified AON. In this study, we synthesized several types of PTE ONs containing linear disulfides (linear SS PTE ONs) and evaluated their conversion rates under reducing conditions. From the results, the structural requirements for the conversion of the synthesized linear SS PTE ONs were elucidated. Linear SS PTE ON with promising promoieties showed a nuclease resistance up to 4.8-fold compared to unmodified ON and a cellular uptake by endocytosis without any transfection reagent. In addition, although the knockdown activity of the linear SS PTE gapmer AON is weaker than that of the fully phosphorothioate-modified gapmer AON, the knockdown activity is slightly stronger than that of the cyclic SS PTE gapmer AON. These results suggest that the conversion rates may be related to the expression of the antisense activity.