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1.
Clin Case Rep ; 12(2): e8304, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38314191

RESUMEN

Key Clinical Message: A 15-year-old girl developed inherited cardiomyopathy and macrothrombocytopenia revealing pathogenic variants of both MYH7 and MYH9 genes. This underlies the importance of repeated genetic testing in diagnosing and managing inherited disorders. Abstract: The MYH7 and MYH9 genes encode for distinct myosin heavy chain proteins. Our case features a 15-year-old girl, presenting with inherited cardiomyopathy and macrothrombocytopenia, revealing distinct pathogenic variants of both MYH7 and MYH9 genes. This underlines the relevance of genetic testing and personalized medicine in diagnosing and managing inherited disorders.

2.
Circ J ; 87(12): 1790-1797, 2023 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-37866911

RESUMEN

BACKGROUND: The prognostic effect of concomitant hypertrophic cardiomyopathy (HCM) on adverse events in patients with atrial fibrillation (AF) has not been evaluated in a multicenter prospective cohort study in Japan.Methods and Results: Using the Hokuriku-Plus AF Registry, 1,396 patients with nonvalvular AF (1,018 men, 72.3±9.7 years old) were assessed prospectively; 72 (5.2%) had concomitant HCM. During a median follow-up of 5.0 years (interquartile range 3.5-5.3 years), 79 cases of thromboembolism (1.3 per 100 person-years) and 192 of heart failure (HF) (3.2 per 100 person-years) occurred. Kaplan-Meier analysis revealed that the HCM group had a significantly greater incidence of thromboembolism (P=0.002 by log-rank test) and HF (P<0.0001 by a log-rank test) than the non-HCM group. The Cox proportional hazards model demonstrated that persistent AF (adjusted hazard ratio 2.98, 95% confidence interval 1.56-6.21), the CHA2DS2-VASc score (1.35, 1.18-1.54), and concomitant HCM (2.48, 1.16-4.79) were significantly associated with thromboembolism. Conversely, concomitant HCM (2.81, 1.72-4.43), older age (1.07, 1.05-1.10), lower body mass index (0.95, 0.91-0.99), a history of HF (2.49, 1.77-3.52), and lower left ventricular ejection fraction (0.98, 0.97-0.99) were significantly associated with the development of HF. CONCLUSIONS: Concomitant HCM predicts the incidence of thromboembolism and HF in AF patients.


Asunto(s)
Fibrilación Atrial , Cardiomiopatía Hipertrófica , Insuficiencia Cardíaca , Accidente Cerebrovascular , Tromboembolia , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/epidemiología , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/complicaciones , Estudios Prospectivos , Sistema de Registros , Factores de Riesgo , Accidente Cerebrovascular/etiología , Volumen Sistólico , Tromboembolia/etiología , Tromboembolia/complicaciones , Función Ventricular Izquierda , Femenino
3.
Europace ; 25(6)2023 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-37386841

RESUMEN

AIMS: Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). METHODS AND RESULTS: We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. CONCLUSION: These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.


Asunto(s)
Síndrome de QT Prolongado , Torsades de Pointes , Humanos , Torsades de Pointes/diagnóstico , Torsades de Pointes/genética , Simulación por Computador , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética , Mutación , Proteínas de Unión al ADN , Canal de Potasio ERG1/genética
4.
Circulation ; 147(25): 1902-1918, 2023 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-37128901

RESUMEN

BACKGROUND: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3, regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure. METHODS: We generated the knock-in mice (Mylk3+/fs and Mylk3fs/fs) with a familial dilated cardiomyopathy-associated MYLK3 frameshift mutation (MYLK3+/fs) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154). RESULTS: Both mice (Mylk3+/fs and Mylk3fs/fs) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose-dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_MYLK3 vector. Human induced pluripotent stem cell-derived cardiomyocytes with MYLK3+/fs mutation reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the Vmax for ventricular myosin regulatory light chain phosphorylation without affecting the Km. LEUO-1154 treatment of human induced pluripotent stem cell-derived cardiomyocytes with MYLK3+/fs mutation restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3/PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes. CONCLUSIONS: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure.


Asunto(s)
Insuficiencia Cardíaca Sistólica , Células Madre Pluripotentes Inducidas , Humanos , Ratones , Animales , Quinasa de Cadena Ligera de Miosina/genética , Quinasa de Cadena Ligera de Miosina/metabolismo , Fosforilación , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Contracción Miocárdica/fisiología , ARN Mensajero/genética , Miosinas Cardíacas/genética , Miosinas Cardíacas/metabolismo
5.
Eur Heart J Open ; 3(3): oead046, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37193254

RESUMEN

Aims: We aimed to determine if coronary artery calcium (CAC) is associated with cardiovascular disease (CVD) events, defined as CVD-related death, unstable angina, myocardial infarction, or staged revascularization among patients with heterozygous familial hypercholesterolaemia (HeFH) under primary prevention settings. Methods and results: Data of patients with FH admitted to Kanazawa University Hospital between 2000 and 2020, who underwent CAC measurement and were followed up (n = 622, male = 306, mean age = 54 years), were retrospectively reviewed. Risk factors for CVD events were determined using the Cox proportional hazard model. The median follow-up duration was 13.2 years (interquartile range: 9.8-18.4 years). We observed 132 CVD events during the follow-up period. The event rate per 1000 person-years for CAC scores of 0 [n = 283 (45.5%)], 1-100 [n = 260 (41.8%)], and >100 [n = 79 (12.7%)] was 1.2, 17.0, and 78.8, respectively. Log (CAC score + 1) was a significant predictor of the occurrence of CVD events (hazard ratio: 3.24; 95% confidence interval: 1.68-4.80; P < 0.0001) in the multivariate Cox regression analysis, independent of other factors. The risk discrimination of CVD events was enhanced by adding CAC information to other conventional risk factors (C-statistics: 0.833-0.934; P < 0.0001). Conclusion: The CAC score helps in further risk stratification in patients with HeFH.

6.
JACC Asia ; 3(1): 152-160, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36873758

RESUMEN

Background: Pathogenic mutations are associated with poor outcomes in patients with familial hypercholesterolemia (FH). However, data on the effects of a healthy lifestyle on FH phenotypes are limited. Objectives: The authors investigated the interaction between a healthy lifestyle and FH mutation with prognosis in patients with FH. Methods: We investigated the associations of the interaction between genotypes and lifestyle, with the occurrence of major adverse cardiac events (MACE), such as cardiovascular-related mortality, myocardial infarction, unstable angina, and coronary artery revascularization, in patients with FH. We assessed their lifestyle based on 4 questionnaires (healthy dietary pattern, regular exercise, not smoking, and absence of obesity). The Cox proportional hazards model was used to assess the risk for MACE. Results: The median follow-up duration was 12.6 (IQR: 9.5-17.9) years. During the follow-up duration, 179 MACE were observed. Independent of classic risk factors, FH mutation and lifestyle score were significantly associated with MACE (HR: 2.73; 95% CI: 1.03-4.43; P = 0.02; and HR: 0.69, 95% CI: 0.40-0.98, P = 0.033, respectively). The estimated risk of coronary artery disease by 75 years of age varied according to lifestyle, ranging from 21.0% among noncarriers with a favorable lifestyle to 32.1% among noncarriers with an unfavorable lifestyle and ranging from 29.0% among carriers with a favorable lifestyle to 55.4% among carriers with an unfavorable lifestyle. Conclusions: A healthy lifestyle was associated with reduced risk for MACE among patients with FH with or without genetic diagnosis.

7.
J Mol Cell Cardiol ; 177: 50-61, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36898499

RESUMEN

Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P < 0.01 vs. kcnq1del/del). A study of two pathogenic variants (S277L and T587M) and one VUS (R451Q) associated with clinically definite LQTS showed that the APD90 of kcnq1del/del embryos with these mutant Kv7.1/MinK channels was significantly longer than that of Kv7.1 WT/MinK channels. Given the functional results of the zebrafish model, R451Q could be reevaluated physiologically from VUS to likely pathogenic. In conclusion, functional analysis using in vivo zebrafish cardiac arrhythmia model can be useful for determining the pathogenicity of loss-of-function variants in patients with LQTS.


Asunto(s)
Síndrome de QT Prolongado , Pez Cebra , Animales , Humanos , Canal de Potasio KCNQ1/genética , Síndrome de QT Prolongado/genética , Mutación , ARN Complementario , Virulencia , Pez Cebra/genética
8.
Atherosclerosis ; 371: 61-66, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36948965

RESUMEN

BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Attainment of the LDL cholesterol target is associated with better prognosis in patients with FH. However, the attainment rate is currently inadequate among Japanese.


Asunto(s)
Anticolesterolemiantes , Hiperlipoproteinemia Tipo II , Infarto del Miocardio , Humanos , LDL-Colesterol , Anticolesterolemiantes/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/epidemiología , Colesterol , Pronóstico , Infarto del Miocardio/complicaciones
10.
Heart Vessels ; 38(3): 402-411, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36251049

RESUMEN

Evidence suggests that atrial fibrillation (AF) could increase the risk of worsening kidney function (WKF) which is linked to an increased risk of stroke, bleeding, and death in AF patients. However, limited data exist regarding the factors that could lead to WKF in these patients. Therefore, we sought to identify the potential factors associated with the development of WKF in patients with non-valvular AF (NVAF). We analyzed prospectively recruited 1122 NVAF patients [men 71.9%, median age 73.0 years (interquartile range: 66.0-79.0)] with a baseline estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 from the Hokuriku-Plus AF Registry. The primary outcome was incident WKF, defined as the %eGFR change from the baseline ≥ 30% during the follow-up period. We evaluated the association between baseline variables and incident WKF using univariate and multivariate Cox proportional hazard models. We also evaluated the non-linear association between the identified factors and incident WKF. During a median follow-up period of 3.0 years (interquartile range: 2.7-3.3), incident WKF was observed in 108 patients (32.6 per 1000 person-years). Compared to the patients without incident WKF, the patients with incident WKF were older and had a higher prevalence of heart failure (HF), diabetes mellitus (DM), and vascular disease at baseline. Those who experienced incident WKF also had higher diastolic blood pressure, lower hemoglobin, lower eGFR, higher B-type natriuretic peptide (BNP) and used warfarin more frequently. Upon multivariate analysis, age ≥ 75 years, HF, DM, and anemia were independently associated with incident WKF. Additionally, age and hemoglobin were linearly associated with the risk of incident WKF, whereas a J- or U-shaped association was observed for HbA1c and BNP. Age ≥ 75 years, HF, DM, and anemia were associated with the development of WKF in Japanese patients with NVAF. In patients with these risk factors, a careful monitoring of the kidney function and appropriate interventions may be important when possible.


Asunto(s)
Fibrilación Atrial , Insuficiencia Cardíaca , Masculino , Humanos , Anciano , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Fibrilación Atrial/complicaciones , Warfarina , Factores de Riesgo , Riñón , Sistema de Registros
11.
Am J Prev Cardiol ; 12: 100428, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36386253

RESUMEN

Objective: The synergistic effect of lipoprotein (a) [Lp(a)] and C-reactive protein (CRP) on major adverse cardiovascular events (MACE) among patients with familial hypercholesterolemia (FH) is unknown. This study aimed to investigate the relations between Lp(a) and CRP levels and MACE in patients with FH whose Lp(a) levels are elevated. Methods: We retrospectively investigated associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of MACE among patients with FH (N = 786, male/female: 374/412). A Cox proportional hazard model was used to identify factors associated with MACE, adjusting for traditional risk factors. Patients with FH were divided into four groups, based on their Lp(a) and CRP levels, and assessed using Kaplan-Meier curves. Results: The median follow-up was 12.6 years (interquartile range [IQR], 9.5-17.9 years). During follow-up, 129 MACE were observed. Median Lp(a) and CRP levels were 21.4 (10.9-38.3) mg/dL and 0.20 (0.11-0.29) mg/dL, respectively. Under these conditions, natural log-transformed Lp(a) and CRP were not associated with MACE (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.91-1.25; P = 0.220; and HR, 1.12; CI, 0.96-1.28; P = 0.190, respectively). However, in Group 4, Lp(a) and CRP were significantly associated with MACE (HR, 2.44; CI, 1.42-3.46; P = 1.8 × 10-7). Conclusions: In patients with FH, Lp(a) was significantly associated with MACE only when the CRP level was elevated. Patients with FH whose Lp(a) and CRP levels are elevated should be treated aggressively.

12.
J Clin Lipidol ; 16(6): 863-869, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36229376

RESUMEN

BACKGROUND: Data on the effect of variants of uncertain significance (VUS) of LDL receptor (LDLR) on familial hypercholesterolemia (FH) phenotype is limited. OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.


Asunto(s)
Variación Genética , Hiperlipoproteinemia Tipo II , Femenino , Masculino , Humanos , Estudios Retrospectivos , Hiperlipoproteinemia Tipo II/diagnóstico , Receptores de LDL/genética , LDL-Colesterol/genética , Fenotipo , Mutación
13.
Circ Rep ; 4(7): 298-307, 2022 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-35860347

RESUMEN

Background: Few studies in Japan have reported on follow-up data regarding the clinical course and risk factors for adverse outcomes in elderly patients with non-valvular atrial fibrillation (NVAF), vs. younger patients, when considering the competing risk of death. Methods and Results: We prospectively studied 1,328 patients with NVAF (965 men; mean [±SD] age 72.4±9.7 years) from the Hokuriku-Plus AF Registry with a median follow-up of 5.0 years (interquartile range 3.5-5.3 years) and evaluated the incidence of thromboembolism or major bleeding in elderly (age ≥75 years; n=595) and non-elderly (age <75 years; n=733) patients. Analysis using the Gray method showed no significant difference in the incidence of thromboembolism; however, the incidence of major bleeding was significantly higher in the elderly than non-elderly group. The Fine-Gray model, after adjustment for age and sex in the elderly group, showed that age (hazard ratio [HR] 1.08; 95% confidence interval [CI] 1.02-1.13; P=0.004) and warfarin use (HR 1.87; 95% CI 1.12-3.14; P=0.02) were significantly associated with major bleeding. In the elderly group, those using warfarin had a higher incidence of thromboembolism and major bleeding than those using direct oral anticoagulants (DOACs). Conclusions: The efficacy and safety of DOACs were remarkable in elderly compared with non-elderly patients with NVAF considering the competing risk of death. DOACs may be a favorable choice in elderly patients with NVAF.

14.
Front Genet ; 13: 872056, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35480308

RESUMEN

Objective: It has been shown that pathogenic variants are associated with poor clinical outcomes in patients with familial hypercholesterolemia (FH). However, data on the effect of different types of pathogenic variants on FH phenotype is limited. Methods: We retrospectively investigated the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of major adverse cardiac events (MACEs), defined as cardiovascular death, myocardial infarction, unstable angina, or coronary artery revascularization, in patients with FH (N = 1,050, male/female = 490/560). Based on genotype, the patients were divided into the following three groups: patients without pathogenic variants, patients with missense variants, and patients with protein-truncating variants (PTVs). Cox proportional hazard model was used to identify the factors associated with MACEs. Results: The median follow-up duration was 12.6 years (interquartile range = 9.5-17.9 years). There were 665 patients with FH-mutation (277 patients with missense variants and 388 patients with PTVs) and 385 patients without FH-mutation. Over the follow-up duration, 175 MACEs were observed. We identified 89 different pathogenic variants in the 665 patients with FH. LDL cholesterol level was found to be significantly higher in patients with PTVs (256 mg/dl) than in patients with missense variants (236 mg/dl) and patients without pathogenic variants (216 mg/dl). It was also found that PTVs and missense variants are significantly associated with MACEs (hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.08-2.08, p = 0.0033 and HR = 3.24, 95% CI = 2.12-4.40, p = 3.9 × 10-6, respectively), independent of classical risk factors. Conclusion: Pathogenic variants, especially PTVs, are significantly associated with poor outcomes in patients with FH. Genetic testing is useful for the diagnosis and risk stratification of patients with FH.

15.
J Cardiol ; 79(2): 233-239, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34551866

RESUMEN

Cardiovascular disease (CVD) is a major cause of death worldwide. Given that CVD is a highly heritable trait, researchers have attempted to fully understand the genetic basis of CVD for a long time. The human genome comprises 3,100 Mbp per haploid genome and 6,200 Mbp in total (diploid genome). However, there is a tendency for rare genetic variations to exhibit a large effect size, whereas common genetic variations have a small effect on diseases, because of natural selection. In this sense, dividing genetic variations into two groups based on allele frequency (and effect sizes on diseases) is a good idea. We know there are several important genes (especially lipid-related genes) in which rare genetic variations are apparently associated with CVD risk, while a polygenic risk score comprising common genetic variations appears to work quite well among general populations. That information can be used not only for risk stratification but also for discoveries for novel pharmacologic targets. In this review article, we provide the important and simple idea that human genetics is important for CVD because it is a highly heritable trait, and we believe that it will lead to precision medicine in this field.


Asunto(s)
Enfermedades Cardiovasculares , Enfermedades Cardiovasculares/genética , Predisposición Genética a la Enfermedad , Genética Humana , Humanos
16.
J Atheroscler Thromb ; 29(7): 1059-1068, 2022 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-34334529

RESUMEN

AIMS: Measurement of protein S (PS) activity in patients taking direct oral anticoagulants (DOACs) using reagents based on a clotting assay results in falsely high PS activity, thus masking inherited PS deficiency, which is most frequently seen in the Japanese population. In this study, we investigated the effect of factor Xa (FXa) inhibitors on PS activity using the reagent on the basis of the chromogenic assay, which was recently developed in Japan. METHODS: The study enrolled 152 patients (82 males and 70 females; the average age: 68.5±14.0 years) receiving three FXa inhibitors (rivaroxaban, edoxaban, and apixaban). PS activity was measured using the reagents on the basis of the clotting and chromogenic assays. RESULTS: PS activity measured by the clotting assay reagents exhibited falsely high values depending on the plasma concentrations of FXa inhibitors in patients taking either rivaroxaban or edoxaban. However, none of the three FXa inhibitors affected PS activity when measured using the chromogenic assay. CONCLUSION: In patients taking rivaroxaban or edoxaban, inherited PS deficiency is likely missed because the levels of PS activity measured using the reagents based on the clotting assay are falsely high. However, we report that three FXa inhibitors do not affect PS activity measured by the chromogenic assay. When measuring the levels of PS activity in patients undergoing DOACs, the principles of each reagent should be understood. Furthermore, plasma samples must be collected at the time when plasma concentrations of DOACs are lowest or the DOAC-Stop reagent should be used.


Asunto(s)
Inhibidores del Factor Xa , Proteína S/análisis , Rivaroxabán , Administración Oral , Anciano , Anciano de 80 o más Años , Anticoagulantes/farmacología , Coagulación Sanguínea , Factor Xa/farmacología , Inhibidores del Factor Xa/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rivaroxabán/farmacología , Rivaroxabán/uso terapéutico , Trombofilia
18.
J Hum Genet ; 66(1): 67-74, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32772049

RESUMEN

Personalized medicine is an emerging concept involving managing the health of patients based on their individual characteristics, including particular genotypes. Cardiovascular diseases are heritable traits, and family history information is useful for risk prediction. As such, determining genetic information (germline genetic mutations) may also be applied to risk prediction. Furthermore, accumulating evidence suggests that genetic background can provide guidance for selecting effective treatments and preventive strategies in individuals with particular genotypes. These concepts may be applicable both to rare Mendelian diseases and to common complex traits. In this review, we define the concept and provide examples of personalized medicine based on human genetics for cardiovascular diseases, including coronary artery disease, arrhythmia, and cardiomyopathies. We also provide a particular focus on Mendelian randomization studies, especially those examining loss-of function genetic variations, for identifying high-risk individuals, as well as signaling pathways that may be useful targets for improving healthy living without cardiovascular events.


Asunto(s)
Arritmias Cardíacas/genética , Cardiomiopatías/genética , Enfermedades Cardiovasculares/genética , Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal , Medicina de Precisión/métodos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Cardiomiopatías/diagnóstico , Cardiomiopatías/terapia , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/terapia , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/terapia , Genotipo , Humanos , Análisis de la Aleatorización Mendeliana
19.
Clin Case Rep ; 8(9): 1809-1813, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32983501

RESUMEN

Most cases of swallowing-induced atrial tachycardia require radiofrequency catheter ablation for a permanent cure; however, the arrhythmia subsided after temporary prescription of verapamil in a patient with genotyped hypertrophic cardiomyopathy.

20.
BMJ Open ; 10(9): e038623, 2020 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-32912992

RESUMEN

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.


Asunto(s)
Hiperlipoproteinemia Tipo II , Estudios de Cohortes , Humanos , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Japón/epidemiología , Estudios Prospectivos , Sistema de Registros
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