Publications by authors named "Kyoko Honda-Kohmo"

10 Publications

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Mild Hypertensive Retinopathy and Risk of Cardiovascular Disease: The Suita Study.

J Atheroscler Thromb 2022 Jan 15. Epub 2022 Jan 15.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center.

Aims: This study aimed to investigate the association of mild hypertensive retinopathy with cardiovascular disease (CVD) risk.

Methods: A total of 7,027 residents aged 30-79 years without a history of CVD participated in the annual health checkups and retinal photography assessments. Retinal microvascular abnormalities were graded using the standard protocols and classified according to the Keith-Wagener-Barker classification. Mild hypertensive retinopathy was defined as grades 1 and 2. Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for total CVD and its subtypes according to the presence and absence of mild hypertensive retinopathy.

Results: During a median follow-up of 17 years, 351 incident stroke and 247 coronary heart disease (CHD) cases were diagnosed. After adjustment for traditional cardiovascular risk factors, mild hypertensive retinopathy was positively associated with risk of CVD (multivariable HR=1.24; 95% CI, 1.04-1.49) and stroke (1.28; 1.01-1.62) but not with risk of CHD (1.19; 0.89-1.58). Generalized arteriolar narrowing and enhanced arteriolar wall reflex were positively associated with CVD risk, the multivariable HR (95% CI) was 1.24 (1.00- 1.54)and 1.33 (1.02-1.74), respectively. Moreover, mild hypertensive retinopathy was positively associated with stroke risk in normotensive participants.

Conclusion: Mild hypertensive retinopathy was positively associated with CVD and stroke risk in the urban Japanese population. Especially, generalized arteriolar narrowing and enhanced arteriolar wall reflex were positively associated with CVD risk. These findings suggested that retinal photography could be helpful for cardiovascular risk stratification in the primary cardiovascular prevention.
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http://dx.doi.org/10.5551/jat.63317DOI Listing
January 2022

Developing a Stroke Risk Prediction Model Using Cardiovascular Risk Factors: The Suita Study.

Cerebrovasc Dis 2021 Nov 29:1-8. Epub 2021 Nov 29.

Division of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

Introduction: Stroke remains a major cause of death and disability in Japan and worldwide. Detecting individuals at high risk for stroke to apply preventive approaches is recommended. This study aimed to develop a stroke risk prediction model among urban Japanese using cardiovascular risk factors.

Methods: We followed 6,641 participants aged 30-79 years with neither a history of stroke nor coronary heart disease. The Cox proportional hazard model estimated the risk of stroke incidence adjusted for potential confounders at the baseline survey. The model's performance was assessed using the receiver operating characteristic curve and the Hosmer-Lemeshow statistics. The internal validity of the risk model was tested using derivation and validation samples. Regression coefficients were used for score calculation.

Results: During a median follow-up duration of 17.1 years, 372 participants developed stroke. A risk model including older age, current smoking, increased blood pressure, impaired fasting blood glucose and diabetes, chronic kidney disease, and atrial fibrillation predicted stroke incidence with an area under the curve = 0.76 and p value of the goodness of fit = 0.21. This risk model was shown to be internally valid (p value of the goodness of fit in the validation sample = 0.64). On a risk score from 0 to 26, the incidence of stroke for the categories 0-5, 6-7, 8-9, 10-11, 12-13, 14-15, and 16-26 was 1.1%, 2.1%, 5.4%, 8.2%, 9.0%, 13.5%, and 18.6%, respectively.

Conclusion: We developed a new stroke risk model for the urban general population in Japan. Further research to determine the clinical practicality of this model is required.
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http://dx.doi.org/10.1159/000520100DOI Listing
November 2021

Weight Change Since Age 20 and the Risk of Cardiovascular Disease Mortality: A Prospective Cohort Study.

J Atheroscler Thromb 2021 Nov 20. Epub 2021 Nov 20.

Division of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center.

Aim: Weight change could have many health outcomes. This study aimed to investigate the association between weight change and mortality risk due to total cardiovascular disease (CVD), ischemic heart disease (IHD), and stroke among Japanese.

Methods: We used Suita Study data from 4,746 people aged 30-79 years in this prospective cohort study. Weight change was defined as the difference between baseline weight and weight at age 20. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total CVD, IHD, and stroke mortality for 1) participants with a weight change (>10, 5 to 10, -5 to -10, and <-10 kg) compared to those with stable weight (-4.9 to 4.9 kg) and 2) participants who moved from one body mass index category (underweight, normal weight, or overweight) to another compared to those with normal weight at age 20 and baseline.

Results: Within a median follow-up period of 19.9 years, the numbers of total CVD, IHD, and stroke mortality were 268, 132, and 79, respectively. Weight loss of >10 kg was associated with the increased risk of total CVD mortality 2.07 (1.29, 3.32) and stroke mortality 3.02 (1.40, 6.52). Moving from normal weight at age 20 to underweight at baseline was associated with the increased risk of total CVD, IHD, and stroke mortality: 1.76 (1.12, 2.77), 2.10 (1.13, 3.92), and 2.25 (1.05, 4.83), respectively.

Conclusion: Weight loss, especially when moving from normal to underweight, was associated with the increased risk of CVD mortality.
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http://dx.doi.org/10.5551/jat.63191DOI Listing
November 2021

The Risk of Fasting Triglycerides and its Related Indices for Ischemic Cardiovascular Diseases in Japanese Community Dwellers: the Suita Study.

J Atheroscler Thromb 2021 Dec 28;28(12):1275-1288. Epub 2021 May 28.

Open Innovation Center, National Cerebral and Cardiovascular Center.

Aim: A prospective cohort study in a Japanese urban general population was performed to investigate whether triglyceride (TG) and its related indices were associated with the risk for the incidence of ischemic cardiovascular disease (CVD) after the adjustment for low-density lipoprotein cholesterol (LDL-C) in Asian community dwellers.

Methods: A 15.1-year prospective cohort study was performed in 6,684 Japanese community dwellers aged 30-79 years without a history of CVD and whose fasting TG levels were <400 mg/dL. After adjusting for covariates, including LDL-C, the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the deciles (D) of TG and those of 1-standard deviation (SD) increment of log-transformed TG (1-SD of TG) according to LDL-C level (≥ 140 and <140 mg/dL) for ischemic CVD incidence were estimated. The multivariable-adjusted HRs and 95%CIs of the quintiles (Q) of TG, TG/HDL-C, and the cardiometabolic index (CMI) for ischemic CVD were also estimated.

Results: In 101,230 person-years, 464 ischemic CVD cases occurred. For D of TG, the HR (95%CI) was 1.56 (1.05-2.32), and for 1-SD of TG, it was 1.30 (1.00-1.70) in participants with LDL-C <140 mg/dL and 1.07 (0.77-1.50) in those with LDL-C ≥ 140 mg/dL. For Q of the CMI, the multivariable-adjusted HR was higher than those of TG and TG/HDL-C.

Conclusions: Fasting TG was an independent predictor for ischemic CVD incidence after adjusting for LDL-C in Japanese community dwellers with TG <400 mg/dL. Among TG, TG/HDL-C, and the CMI, the CMI could be the most powerful predictor for ischemic CVD.
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http://dx.doi.org/10.5551/jat.62730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629703PMC
December 2021

A Prospective Longitudinal Study on the Relationship Between Glucose Fluctuation and Cognitive Function in Type 2 Diabetes: PROPOSAL Study Protocol.

Diabetes Ther 2020 Nov 5;11(11):2729-2737. Epub 2020 Sep 5.

Division of Diabetes and Lipid Metabolism, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Introduction: Although the risk of dementia among patients with type 2 diabetes mellitus (T2DM) is double that of those without T2DM, the mechanism remains to be elucidated and the glycemic goal to prevent progression of cognitive impairment is unclear. Results from cross-sectional studies suggest that glucose fluctuations are associated with impairment of cognitive function among T2DM patients. Therefore, the aim of the longitudinal study described here is to evaluate the relationships between glucose fluctuation indexes assessed by continuous glucose monitoring (CGM) and cognitive function among elderly patients with T2DM.

Methods: This will be a prospective, single-center, 2-year longitudinal study in which a total of 100 elderly patients with T2DM showing mild cognitive impairment (MCI) will be enrolled. Glucose fluctuations, assessed using the FreeStyle Libre Pro continuous glucose monitoring system (Abbott Laboratories), and results of cognitive tests, namely the Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale (ADAS), will be evaluated at baseline, 1-year visit and 2-year visit. The primary endpoint is the relationships between indexes of glucose fluctuation and change in MoCA and ADAS scores. Secondary endpoints are the relationships between the indexes of glucose fluctuation or cognitive scores and the following: indexes representing intracranial lesions obtained by magnetic resonance imaging and angiography of the head; Geriatric Depression Scale score; Apathy Scale score; carotid intima-media thickness assessed by echography; inflammatory markers; fasting glucose; glycated hemoglobin; blood pressure; and the development of cardiovascular and renal events.

Planned Outcomes: The current study is scheduled for completion in June 2022. The results could lead to the elucidation of novel glycemic goals to prevent the progression of cognitive impairment and/or of relationships between glucose fluctuations and cognitive function among T2DM patients. The findings of the study will be reported in publications and conference presentations.

Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN000038546).
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http://dx.doi.org/10.1007/s13300-020-00916-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547936PMC
November 2020

Small-Dense Low-Density Lipoprotein Cholesterol: A Subclinical Marker for the Primary Prevention of Coronary Heart Disease.

J Atheroscler Thromb 2020 Jul 29;27(7):641-643. Epub 2020 May 29.

Department of Preventive Cardiology, National Cerebral and Cardiovascular Center.

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http://dx.doi.org/10.5551/jat.ED134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406410PMC
July 2020

The efficacy of glycemic control with continuous glucose monitoring on atheroma progression: rationale and design of the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL).

Cardiovasc Diagn Ther 2019 Oct;9(5):431-438

Department of Cardiovascular Medicine, National Cerebral & Cardiovascular Center, Osaka, Japan.

Background: Patients with type 2 diabetes mellitus (T2DM) are high-risk subjects who more frequently have micro- and macrovascular diseases including coronary artery disease (CAD). Since impaired glycemic homeostasis directly influences the formation and propagation of atherosclerotic plaques, optimal management of glycemic status is required for the prevention of diabetic atherosclerosis. Continuous glucose monitoring (CGM) provides not only average glucose level but also the degree of glucose fluctuation and hypoglycemia. Given the association of glycemic variability with diabetic macrovascular diseases, CGM-based glycemic management could favorably modulate glycemic fluctuation, thereby potentially modifying atheroma burden in T2DM subjects. To test this hypothesis, the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL) study has been designed (Japan Registry of Clinical Trials: jRCT1052180152, University Hospital Medical Information Network Clinical Trial Registry UMIN000036721).

Methods: The OPTIMAL is a single-center, randomized trial to evaluate the efficacy of CGM-based glycemic control on atheroma progression in T2DM patients with CAD by using serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. A total of 90 eligible subjects will be randomized 1:1 into two groups to receive either CGM-based glycemic control or HbA1c-baded glycemic management. Coronary angiography and NIRS/IVUS imaging is repeated at the end of the assigned treatment period.

Results: The primary endpoint is the normalized absolute change in total atheroma volume (TAV) from baseline to 12 months. The secondary endpoints include (I) the absolute change in percent atheroma volume, (II) the percent change in lipid core burden index, (III) the change in coefficient variance measured by CGM, (IV) the change in atherogenic markers (high-density lipoprotein functionality, proprotein convertase subxilisin/kexin type 9 and fatty-acid binding proteins), and (V) the frequency of hypoglycemia. Safety will also be evaluated.

Conclusions: The collaboration of CGM use with serial NIRS/IVUS imaging will enable to compare atheroma progression rate under CGM-based glycemic management and HbA1c-based approach.
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http://dx.doi.org/10.21037/cdt.2019.09.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837914PMC
October 2019

Perfluoroalkyl substances are inversely associated with coronary heart disease in adults with diabetes.

J Diabetes Complications 2019 06 20;33(6):407-412. Epub 2019 Feb 20.

Department of Epidemiology, West Virginia University, Morgantown, WV, USA; Department of Community Health, University of Texas Health Science Center at Tyler, Tyler, TX, USA. Electronic address:

Aims: Perfluoroalkyl substances (PFAS) are environmentally and biologically persistent synthetic environmental contaminants linked to adverse health outcomes. Though null to modest inverse relationships between PFAS and coronary heart disease (CHD) have been reported, studies regarding relationships in high risk populations such as those with diabetes are sparse. We investigated the relationship of PFAS with CHD in persons with diabetes.

Methods: Data on 5270 adults, aged ≥20 years, with diabetes were obtained from the C8 Health Project. Four PFAS were investigated separately: perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA).

Results: In logistic regression analyses adjusting for age, sex, diabetes duration, BMI, smoking, lipids, WBC, CRP, eGFR, uric acid, hemoglobin and iron, all PFAS were inversely associated with CHD, ORs (95% CIs): PFHxS; 0.72 (0.65-0.79), PFOA; 0.90 (0.81-0.96), PFOS; 0.90 (0.81-0.99), PFNA; 0.88 (0.76-1.02). Stratification by chronic kidney disease status revealed similar inverse relationships for those with and without chronic kidney disease.

Conclusions: In this cross-sectional study of over 5000 adults with diabetes, PFAS showed inverse associations with CHD. These findings may, if confirmed in future studies, provide new physiologic understanding of CHD prevention strategies.
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http://dx.doi.org/10.1016/j.jdiacomp.2019.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511468PMC
June 2019

Evaluation of quantitative parameters for distinguishing pheochromocytoma from other adrenal tumors.

Hypertens Res 2018 Mar 18;41(3):165-175. Epub 2018 Jan 18.

Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Adrenal tumors are increasingly found incidentally during imaging examinations. It is important to distinguish pheochromocytomas from other adrenal tumors because of the risk of hypertensive crisis. Although catecholamines and their metabolites are generally used to diagnose pheochromocytoma, false-positive test results are common. An effective screening method to distinguish pheochromocytoma from adrenal incidentalomas is needed. We analyzed 297 consecutive patients with adrenal incidentalomas. Our findings included 162 non-functioning tumors, 47 aldosterone-producing adenomas, 26 metastases, 22 cases of subclinical Cushing's syndrome, 21 pheochromocytomas, 12 cases of Cushing's syndrome, and 7 adrenocortical cancers. We checked quantitative parameters such as age, blood, and urine catecholamines and their metabolites, neuron-specific enolase, size and computed tomography (CT) attenuation values. Among catecholamine-related parameters, the sum of urine metanephrine and normetanephrine (urineMNM) levels produced the highest area under the receiver operating characteristic curve regarding discrimination of pheochromocytoma from other lesions. Size and CT attenuation values also differed significantly. However, size was correlated with catecholamine levels. CT attenuation was not correlated with other factors. The optimal thresholds were 19 Hounsfield units (HU) for CT attenuation (sensitivity, 100%; specificity, 60%) and 0.43 mg/24 h for urineMNM (sensitivity, 89%; specificity, 96%). No pheochromocytomas were evident when CT attenuation values were under 19 HU. Even in adrenal tumors with CT attenuation values ≥ 19 HU, when urineMNM was < 0.43 mg/24 h, the frequency of pheochromocytoma was only 4.3%, when urineMNM was ≥ 0.43 mg/24 h, the frequency of pheochromocytoma was 93% and when urineMNM was > 0.77 mg/24 h the frequency of pheochromocytoma was 100%. CT attenuation value and urineMNM represented the most useful combination for diagnosis of pheochromocytoma.
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http://dx.doi.org/10.1038/s41440-017-0002-4DOI Listing
March 2018

Significance of dopamine D receptor signalling for steroidogenic differentiation of human induced pluripotent stem cells.

Sci Rep 2017 11 9;7(1):15120. Epub 2017 Nov 9.

Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Human induced pluripotent stem cells (hiPSCs) are expected to be both a revolutionary cell source for regenerative medicine and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. In the present study, we tried to elucidate the steroidogenic differentiation processes using hiPSC-derived intermediate mesoderm (IM) that is known to be the origin of the human adrenal cortex and gonads. We first performed chemical screening to identify small molecules that induce steroidogenic differentiation of IM cells expressing Odd-skipped related 1 (OSR1), an early IM marker. We identified cabergoline as an inducer of 3β-hydroxysteroid dehydrogenase, an essential enzyme for adrenogonadal steroidogenesis. Although cabergoline is a potent dopamine D receptor agonist, additional experiments showed that cabergoline exerted effects as a low-affinity agonist of D receptors by increasing intracellular cyclic AMP. Further analysis of OSR1 cells transfected with steroidogenic factor-1/adrenal 4 binding protein revealed that D receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones synergistically with adrenocorticotropic hormone. These results suggest the importance of dopamine D receptor signalling in steroidogenic differentiation, which contributes to effective induction of steroidogenic cells from hiPSCs.
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http://dx.doi.org/10.1038/s41598-017-15485-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680317PMC
November 2017
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