Publications by authors named "Yuko Kato"

132 Publications

Glasgow prognostic score can be a prognostic indicator after percutaneous coronary intervention: a two-center study in Japan.

Heart Vessels 2021 Nov 22. Epub 2021 Nov 22.

Division of Cardiovascular Medicine, Department of Internal Medicine, Toho University Graduate School Medicine, 6-11-1 Omorinishi, Ota-ku, Tokyo, 143-8541, Japan.

Glasgow prognostic score (GPS) has been used to evaluate inflammatory response and nutritional status. This study aimed to investigate the impact of nutritional status on cardiac prognosis by using GPS in patients after undergoing percutaneous coronary intervention (PCI). We included 862 patients who underwent PCI for stable angina pectoris between 2015 and 2018. We used the original cutoff values, which were an albumin (Alb) level of 3.5 g/dl and a C-reactive protein (CRP) level of 0.3 mg/dl. We categorized them into the three groups: originally defined GPS (od-GPS) 0 (high Alb and low CRP), 1 (low Alb or high CRP), and 2 (low Alb and high CRP). Major adverse clinical events (MACEs) included all-cause death, nonfatal myocardial infarction, revascularization, and hospitalization for heart failure. The median follow-up period was 398.5 days. During the follow-up, MACEs occurred in 136 patients. Od-GPS 2 had higher prevalence rates in terms of chronic kidney disease (CKD; 31.7% [229/722] vs. 44.9% [53/118] vs. 63.6% [14/22], p < 0.001), hemodialysis (6.4% [46/722] vs. 14.4% [17/118] vs. 31.8% [7/22], p < 0.001), and heart failure cases (HF; 9.1% [66/722] vs. 14.4% [17/118] vs. 27.3% [6/22], p = 0.007), with higher creatinine (1.17 ± 1.37 mg/dl vs. 1.89 ± 2.60 mg/dl vs. 3.49 ± 4.01 mg/dl, p < 0.001) and brain natriuretic peptide levels (104.1 ± 304.6 pg/ml vs. 242.4 ± 565.9 pg/ml vs. 668.1 ± 872.2 pg/ml, p < 0.001) and lower low-density lipoprotein cholesterol (101.5 ± 32.9 mg/dl vs. 98.2 ± 28.8 mg/dl vs. 77.1 ± 24.3 mg/dl, p = 0.002) than od-GPS 0 and 1.Od-GPS 2 (HR 2.42; 95% CI 1.16-5.02; p = 0.018), od-GPS 1 (HR 2.09; 95% CI 1.40-3.13; p < 0.001), diabetes (HR 1.41; 95% CI 1.00-1.99; p = 0.048), CKD (HR 2.10; 95% CI 1.49-2.96; p < 0.001), and HF (HR 1.64; 95% CI 1.05-2.56; p = 0.029) were independent predictors of MACEs. A scoring system using CRP and Alb levels with a milder definition than GPS suitably predicted the risk of MACEs in the patients who underwent PCI.
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http://dx.doi.org/10.1007/s00380-021-01986-wDOI Listing
November 2021

Identifying risk patterns in older adults with atrial fibrillation by hierarchical cluster analysis: A retrospective approach based on the risk probability for clinical events.

Int J Cardiol Heart Vasc 2021 Dec 28;37:100883. Epub 2021 Sep 28.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan.

Background: Older adults with atrial fibrillation (AF) have highly diverse risk levels for mortality, heart failure (HF), thromboembolism (TE), and major bleeding (MB), thus an integrated risk-pattern algorithm is warranted.

Methods: We analyzed 573 AF patients aged ≥ 75 years from our single-center cohort (Shinken Database 2010-2018). The 3-year risk scores (risk probability) for mortality (M-score), HF (HF-score), TE (TE-score), and MB (MB-score) were estimated for each patient by logistic regression analysis. Using the four risk scores, cluster analysis was performed with Ward's linkage hierarchical algorithm.

Results: Three clusters were identified: Clusters 1 (n = 429, 74%), 2 (n = 24, 5%), and 3 (n = 120, 21%). The clusters were characterized as standard risk (Cluster 1), high TE- and MB-risk (Cluster 2), and high M- and HF-risk (Cluster 3). Oral anticoagulants were prescribed for over 80% of the patients in each cluster. Catheter ablation for AF was performed only in Cluster 1 (8.9%). Compared with Cluster 1, Cluster 2 was more closely associated with males, asymptomatic AF, history of cerebral infarction or transient ischemic attack, history of intracranial hemorrhage, high HAS-BLED score (≥3), and low body mass index (<18.0 kg/m). Cluster 3 was more closely associated with old age, heart failure, and low estimated creatinine clearance (<30 mL/min).

Conclusion: The cluster analysis identified those at a high risk for all-cause death and HF or a high risk for TE and MB and could support decision making in older adults with AF.
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http://dx.doi.org/10.1016/j.ijcha.2021.100883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487977PMC
December 2021

Evaluation of Wearable Cameras for Monitoring and Analyzing Calf Behavior: A Preliminary Study.

Animals (Basel) 2021 Sep 7;11(9). Epub 2021 Sep 7.

Field Center of Animal Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.

Understanding cattle behavior is important for discerning their health and management status. However, manual observations of cattle are time-consuming and labor-intensive. Moreover, during manual observations, the presence or position of a human observer may alter the normal behavior of the cattle. Wearable cameras are small and lightweight; therefore, they do not disturb cattle behavior when attached to their bodies. Thus, this study aimed to evaluate the suitability of wearable cameras for monitoring and analyzing cattle behavior. From December 18 to 27, 2017, this study used four 2-month-old, group-housed Holstein calves at the Field Science Center of the Obihiro University of Agriculture and Veterinary Medicine, Japan. Calf behavior was recorded every 30 s using a wearable camera (HX-A1H, Panasonic, Japan) from 10:00 to 15:30 and observed directly from 11:00 to 12:00 and 14:00 to 15:00. In addition, the same observer viewed the camera recordings corresponding to the direct observation periods, and the results were compared. The correlation coefficients of all behavioral data from direct and wearable camera video observations were significant ( < 0.01). We conclude that wearable cameras are suitable for observing calf behavior, particularly their posture (standing or lying), as well as their ruminating and feeding behaviors.
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http://dx.doi.org/10.3390/ani11092622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470911PMC
September 2021

Association between number of medications and mortality among older adult patients in a specialized cardiology hospital.

Geriatr Gerontol Int 2021 Nov 21;21(11):985-995. Epub 2021 Sep 21.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan.

Aim: Although polypharmacy has been associated with poor clinical outcomes, whether taking an increased number of medications is harmful or beneficial for older adult patients treated for cardiovascular diseases might require further discussion.

Methods: We analyzed data of 2089 patients aged ≥75 years in a single hospital-based cohort. The study population was divided into three groups according to the tertiles of the number of medications at baseline: <3 (n = 647), 3-7 (n = 707) and ≥8 (n = 735).

Results: The cumulative incidences of all-cause death at 3 years among patients taking less than three, three to seven and eight or more medications were 3.7%, 4.1% and 7.8%, respectively (log-rank test P = 0.015). In a Cox regression analysis, taking eight or more total medications (vs 0-2) was independently associated with all-cause death (hazard ratio 1.67, 95% CI 1.01-2.78). For predicting mortality using the number of medications, the maximum Youden Index was 7. In subgroups with certain heart diseases, no regular tendency of an increase in the risk of all-cause death was observed with an increase in the number of medications.

Conclusions: The number of medications taken was independently associated with mortality among older adult patients, with a relatively high cut-off point. This association was not observed in patients with certain heart diseases, possibly indicating the merit - rather than the harm - of medical treatment in the cardiovascular field. Geriatr Gerontol Int 2021; 21: 985-995.
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http://dx.doi.org/10.1111/ggi.14275DOI Listing
November 2021

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial.

Brain Stimul 2021 Sep-Oct;14(5):1095-1105. Epub 2021 Jul 29.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Department of Psychiatry, Monash University, Camberwell, Victoria, Australia.

Introduction: Theta burst pattern repetitive transcranial magnetic stimulation (TBS) is increasingly applied to treat depression. TBS's brevity is well-suited to application in accelerated schedules. Sizeable trials of accelerated TBS are lacking; and optimal TBS parameters such as stimulation intensity are not established.

Methods: We conducted a three arm, single blind, randomised, controlled, multi-site trial comparing accelerated bilateral TBS applied at 80 % or 120 % of the resting motor threshold and left unilateral 10 Hz rTMS. 300 patients with treatment-resistant depression (TRD) were recruited. TBS arms applied 20 bilateral prefrontal TBS sessions over 10 days, while the rTMS arm applied 20 daily sessions of 10 Hz rTMS to the left prefrontal cortex over 4 weeks. Primary outcome was depression treatment response at week 4.

Results: The overall treatment response rate was 43.7 % and the remission rate was 28.2 %. There were no significant differences for response (p = 0.180) or remission (p = 0.316) across the three groups. Response rates between accelerated bilateral TBS applied at sub- and supra-threshold intensities were not significantly different (p = 0.319). Linear mixed model analysis showed a significant effect of time (p < 0.01), but not rTMS type (p = 0.680).

Conclusion: This is the largest accelerated bilateral TBS study to date and provides evidence that it is effective and safe in treating TRD. The accelerated application of TBS was not associated with more rapid antidepressant effects. Bilateral sequential TBS did not have superior antidepressant effect to unilateral 10 Hz rTMS. There was no significant difference in antidepressant efficacy between sub- and supra-threshold accelerated bilateral TBS.
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http://dx.doi.org/10.1016/j.brs.2021.07.018DOI Listing
November 2021

Increased Plasma Levels of Myosin Heavy Chain 11 Is Associated with Atherosclerosis.

J Clin Med 2021 Jul 16;10(14). Epub 2021 Jul 16.

Department of Physiology, Tokyo Medical University, 6-6-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.

Many studies have revealed numerous potential biomarkers for atherosclerosis, but tissue-specific biomarkers are still needed. Recent lineage-tracing studies revealed that smooth muscle cells (SMCs) contribute substantially to plaque formation, and the loss of SMCs causes plaque vulnerability. We investigated the association of SMC-specific myosin heavy chain 11 (myosin-11) with atherosclerosis. Forty-five patients with atherosclerosis and 34 control subjects were recruited into our study. In the atherosclerosis patients, 35 patients had either coronary artery disease (CAD) or peripheral artery disease (PAD), and 10 had both CAD and PAD. Coronary arteries isolated from five patients were subjected to histological study. Circulating myosin-11 levels were higher in the CAD or PAD group than in controls. The area under the receiver operating characteristic curve of myosin-11 was 0.954. Circulating myosin-11 levels in the CAD and PAD group were higher than in the CAD or PAD group, while high-sensitivity C-reactive protein concentrations did not differ between these groups. Multinomial logistic regression analyses showed a significant association of myosin-11 levels with the presence of multiple atherosclerotic regions. Myosin-11 was expressed in the medial layer of human atherosclerotic lesions where apoptosis elevated. Circulating myosin-11 levels may be useful for detecting spatial expansion of atherosclerotic regions.
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http://dx.doi.org/10.3390/jcm10143155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304775PMC
July 2021

Relationship between number of medications and incidence of falls or bone fracture in elderly patients with non-valvular atrial fibrillation: Shinken database analysis.

Geriatr Gerontol Int 2021 Sep 15;21(9):802-809. Epub 2021 Jul 15.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan.

Aim: Polypharmacy is known to be a risk factor for falls or bone fracture (F/F) in elderly patients. However, this relationship is not fully described in patients with non-valvular atrial fibrillation (NVAF), for which F/F may lead to serious clinical outcomes, including major bleeding.

Methods: We analyzed 509 elderly (aged ≥75 years) patients with NVAF who had recently visited a hospital specializing in cardiology, of which 272 patients had paroxysmal atrial fibrillation (PAF) and 237 had persistent/permanent atrial fibrillation (PeAF). Patients were divided into four groups according to the number of medications: ≤3, 4-6, 7-9, and ≥10. The relationship between the number of medications and incidence rate of F/F in AF patients was analyzed. In addition, this relationship was analyzed in patients with each AF type.

Results: Cumulative incidence of F/F at 3 years in the respective categories was 3.7%, 5.4%, 4.3% and 5.7% for PAF, and 5.2%, 7.5%, 7.8% and 25.0% for PeAF (log-rank test, P = 0.930 and 0.003, respectively). In a multivariable model, patients with ≥10 medications showed a significantly higher risk for F/F compared with those with ≤3 medications as reference only in PeAF (adjusted hazard ratio 4.82, 95%CI 1.42-16.33), without significant interaction (P = 0.081).

Conclusions: Elderly NVAF patients using ≥10 medications showed a higher risk for F/F. In subgroup analysis, this association was observed only in patients with PeAF, although there was no significant interaction between number of medications and AF type. Geriatr Gerontol Int 2021; 21: 802-809.
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http://dx.doi.org/10.1111/ggi.14242DOI Listing
September 2021

Left atrial dimension and ischemic stroke in patients with and without atrial fibrillation.

Heart Vessels 2021 Dec 4;36(12):1861-1869. Epub 2021 Jun 4.

Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19 Nishiazabu, Minato-Ku, Tokyo, 106-0031, Japan.

The incidence of ischemic stroke (IS) increases in patients with enlarged left atrium (LA) irrespective of whether or not the existence of atrial fibrillation (AF). In such situation, it is unclear whether the impact of LA on incidence of IS still significant in young, non-AF patients with enlarged LA who are primarily unconcerned on anticoagulation therapy. The study population consisted of 18,511 consecutive patients not receiving oral anticoagulants and undergoing echocardiography with measurement of LAD at baseline. The incidence rate of ischemic stroke was calculated in 3 groups according to left atrial dimension (LAD; < 30, 30-45 and ≥ 45 mm) in AF and non-AF patients. Further subgroup analysis was performed in stratification by elderly and young (aged ≥ 65 and < 65 years, respectively). The incidences of IS (per 100 patient-years) were 0.11 and 0.71 in non-AF and AF patients with LAD < 30 mm, respectively, which increased to 0.58 and 1.35 in LAD ≥ 45 mm (adjusted hazard ratios [HRs]; 1.95 [95% confidence intervals, CIs: 0.76-5.01] and 1.22 [95% CIs: 0.27-5.58], interaction P was 0.246). In non-AF patients, the incidences of IS were 0.30 and 0.04 in elderly and young patients with LAD < 30 mm, which increased to 0.67 and 0.48 in LAD ≥ 45 mm (adjusted HRs; 1.34 [95% CIs: 0.43-4.15] and 4.21 [95% CIs: 0.77-23.12], interaction P was 0.158). The incidence of IS significantly increased with increase of LAD in non-AF, especially in non-AF and young patients, although the difference was not independent of other clinical factors. The impact of LAD on IS was numerically larger in non-AF than in AF, and larger in young and non-AF than in elderly counterpart, although a significant interaction was not observed in this small population. Further studies with large population are necessary to judge whether these population with enlarged LA need antithrombotic therapy.
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http://dx.doi.org/10.1007/s00380-021-01879-yDOI Listing
December 2021

Transcriptome Analysis Reveals Differential Gene Expression between the Closing Ductus Arteriosus and the Patent Ductus Arteriosus in Humans.

J Cardiovasc Dev Dis 2021 Apr 16;8(4). Epub 2021 Apr 16.

Department of Physiology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.

The ductus arteriosus (DA) immediately starts closing after birth. This dynamic process involves DA-specific properties, including highly differentiated smooth muscle, sparse elastic fibers, and intimal thickening (IT). Although several studies have demonstrated DA-specific gene expressions using animal tissues and human fetuses, the transcriptional profiles of the closing DA and the patent DA remain largely unknown. We performed transcriptome analysis using four human DA samples. The three closing DA samples exhibited typical DA morphology, but the patent DA exhibited aorta-like elastic lamellae and poorly formed IT. A cluster analysis revealed that samples were clearly divided into two major clusters, the closing DA and patent DA clusters, and showed distinct gene expression profiles in IT and the tunica media of the closing DA samples. Cardiac neural crest-related genes such as were highly expressed in the tunica media and IT of the closing DA samples compared to the patent DA sample. Abundant protein expressions of jagged 1 and the differentiated smooth muscle marker calponin were observed in the closing DA samples but not in the patent DA sample. Second heart field-related genes such as were enriched in the patent DA sample. These data indicate that the patent DA may have different cell lineages compared to the closing DA.
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http://dx.doi.org/10.3390/jcdd8040045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073410PMC
April 2021

Relationship between resting 12-lead electrocardiogram and all-cause death in patients without structural heart disease: Shinken Database analysis.

BMC Cardiovasc Disord 2021 02 10;21(1):83. Epub 2021 Feb 10.

Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19 Nishiazabu, Minato-Ku, Tokyo, 106-0031, Japan.

Background: Resting 12-lead electrocardiography is widely used for the detection of cardiac diseases. Electrocardiogram readings have been reported to be affected by aging and, therefore, can predict patient mortality.

Methods: A total of 12,837 patients without structural heart disease who underwent electrocardiography at baseline were identified in the Shinken Database among those registered between 2010 and 2017 (n = 19,170). Using 438 electrocardiography parameters, predictive models for all-cause death and cardiovascular (CV) death were developed by a support vector machine (SVM) algorithm.

Results: During the observation period of 320.4 days, 55 all-cause deaths and 23 CV deaths were observed. In the SVM prediction model, the mean c-statistics of 10 cross-validation models with training and testing datasets were 0.881 ± 0.027 and 0.927 ± 0.101, respectively, for all-cause death and 0.862 ± 0.029 and 0.897 ± 0.069, respectively for CV death. For both all-cause and CV death, high values of permutation importance in the ECG parameters were concentrated in the QRS complex and ST-T segment.

Conclusions: Parameters acquired from 12-lead resting electrocardiography could be applied to predict the all-cause and CV deaths of patients without structural heart disease. The ECG parameters that greatly contributed to the prediction were concentrated in the QRS complex and ST-T segment.
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http://dx.doi.org/10.1186/s12872-021-01864-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874456PMC
February 2021

Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia.

J Hum Genet 2021 Jun 6;66(6):597-606. Epub 2021 Jan 6.

Department of Psychiatry, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

The importance of epigenetic control in the development of the central nervous system has recently been attracting attention. Methylation patterns of lysine 4 and lysine 36 in histone H3 (H3K4 and H3K36) in the central nervous system are highly conserved among species. Numerous complications of body malformations and neuropsychiatric disorders are due to abnormal histone H3 methylation modifiers. In this study, we analyzed a Japanese family with a dominant inheritance of symptoms including Marfan syndrome-like minor physical anomalies (MPAs), intellectual disability, and schizophrenia (SCZ). We performed positional cloning for this family using a single nucleotide polymorphism (SNP) array and whole-exome sequencing, which revealed a missense coding strand mutation (rs1555289644, NM_032590.4: c.2173G>A, p.A725T) in exon 15 on the plant homeodomain of the KDM2B gene as a possible cause of the disease in the family. The exome sequencing revealed that within the coding region, only a point mutation in KDM2B was present in the region with the highest logarithm of odds score of 2.41 resulting from whole genome linkage analysis. Haplotype analysis revealed co-segregation with four affected family members (IV-9, III-4, IV-5, and IV-8). Lymphoblastoid cell lines from the proband with this mutation showed approximately halved KDM2B expression in comparison with healthy controls. KDM2B acts as an H3K4 and H3K36 histone demethylase. Our findings suggest that haploinsufficiency of KDM2B in the process of development, like other H3K4 and H3K36 methylation modifiers, may have caused MPAs, intellectual disability, and SCZ in this Japanese family.
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http://dx.doi.org/10.1038/s10038-020-00889-4DOI Listing
June 2021

Decline in eGFR over time and incidence of cardiovascular events: Shinken database analysis.

J Cardiol 2021 06 30;77(6):626-633. Epub 2020 Dec 30.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan.

Background: It has been reported that a large decline in estimated glomerular filtration rate (eGFR) over time is associated with increased incidence of cardiovascular disease. We investigated whether this association differs according to the baseline eGFR.

Methods: A total of 4666 patients (male 71%) with measurements of eGFR at both baseline and 1 year and that had no cardiovascular events at 1-year follow-up were retrieved from the Shinken Database between June 2004 and March 2015. The study population was divided into three groups by baseline eGFR (mL/min/1.73 m): high (≥60, n = 1650), intermediate (45-59, n = 1947), and low (<45, n = 1069) eGFR groups. Each eGFR group was further divided into two groups by eGFR slope (change at 1 year, <-10 and ≥-10 mL/min/1.73 m). The patient characteristics and the incidences of cardiovascular events within 3 years (after 1-year follow-up) were compared between the negatively large eGFR slope (<-10) and others (≥-10) in each eGFR group.

Results: A total of 187 cardiovascular events occurred during the mean follow-up of 2.8 ± 0.6 years. The adjusted hazard ratios of eGFR slope (<-10 with reference to ≥-10) were 2.37 (95% CI, 1.28-4.40), 3.10 (95% CI, 1.78-5.40), and 2.66 (95% CI, 1.15-6.13) in the high, middle, and low eGFR groups, respectively. Similar results were found in patients with structural heart disease, but not in those without.

Conclusions: Decline in eGFR was associated with an increase in cardiovascular events, and this effect was consistent regardless of the baseline eGFR.
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http://dx.doi.org/10.1016/j.jjcc.2020.12.007DOI Listing
June 2021

Prediction of current and new development of atrial fibrillation on electrocardiogram with sinus rhythm in patients without structural heart disease.

Int J Cardiol 2021 03 11;327:93-99. Epub 2020 Nov 11.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan.

Background: Diagnosis of atrial fibrillation (AF) based on electrocardiogram (ECG) with sinus rhythm remains a major challenge. Obtaining a panoramic view with hundreds of automatically measured ECG parameters at sinus rhythm on the predictive capability for AF would be informative.

Methods: We used a single-center database of a specialist cardiovascular hospital (Shinken Database 2010-2017; n = 19,170). We analyzed 12,863 index ECGs with sinus rhythm after excluding those showing AF rhythm, other atrial tachyarrhythmia, pacing beat, or indeterminate axis, and those of patients with structural heart diseases. We used 438 automatically measured ECG parameters in the MUSE data management system. The predictive models were developed using random forest algorithm with the 10-fold cross-validation method.

Results: In 12,863 index ECGs with sinus rhythm, a predictive capability for current paroxysmal AF (n = 1131) by c-statistics was 0.99981 ± 0.00037 for training dataset and 0.91337 ± 0.00087 for testing dataset, respectively. Excluding AF at baseline (n = 11,732), a predictive capability for newly developed AF (n = 98) by c-statistics was 0.99973 ± 0.00086 for training dataset and 0.99160 ± 0.00038 for testing dataset, respectively. The distribution of parameter importance was mostly similar among P, QRS, and ST-T segment for both current and newly developed AF.

Conclusions: This study intended to provide panoramic information in relation between ECG parameters and AF. The parameter importance of ECG parameters for predicting AF was mostly similar in P, QRS, and ST-T segment in models for both current and future AF.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.012DOI Listing
March 2021

Correction to: Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.

J Hum Genet 2021 Mar;66(3):345

Department of Psychiatry, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.

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http://dx.doi.org/10.1038/s10038-020-00856-zDOI Listing
March 2021

Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.

J Hum Genet 2021 Mar 12;66(3):243-249. Epub 2020 Sep 12.

Department of Psychiatry, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by the recurrence of depressive and manic episodes. Its heritability is high, and many linkage and association studies have been performed. Although various linkage regions and candidate genes have been reported, few have shown sufficient reproducibility, and none have identified the pathogenic genes based on the results of the linkage analysis. To find functional variants that are expected to be rare and have strong genetic effects, we recruited ten healthy individuals, two individuals with unknown status, and six patients with BD or recurrent major depressive disorder (MDD) from a Japanese family consisting of 21 members. We performed a genome-wide linkage analysis using a 100K single-nucleotide polymorphism (SNP) array and microsatellite markers to narrow linkage regions within this family. Subsequently, we performed whole-exome sequencing for two patients with BD to identify genetic mutations in the narrowed linkage regions. Then, we performed co-segregation analysis for DNA variants obtained from the results of the exome sequencing. Finally, we identified a rare heterozygous mutation in exon 31 of DOCK5 (c.3170A>G, p.E1057G). Convergent functional genomics analysis revealed that DOCK5 was listed as one of the biomarkers for mood state and suicidality. Although DOCK5 is still a functionally unknown gene, our findings highlight the possibility of a pathological relationship between BD and DOCK5.
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http://dx.doi.org/10.1038/s10038-020-00840-7DOI Listing
March 2021

Seasonal Variations in the Incidence of Ischemic Stroke, Extracranial and Intracranial Hemorrhage in Atrial Fibrillation Patients.

Circ J 2020 09 28;84(10):1701-1708. Epub 2020 Aug 28.

Department of Cardiovascular Medicine, The Cardiovascular Institute.

Background: Ischemic stroke (IS) and major bleeding, which are serious adverse events in patients with atrial fibrillation (AF), could have seasonal variations, but there are few reports.Methods and Results:In the Shinken Database 2004-2016 (n=22,018), 3,581 AF patients (average age, 63.5 years; 2,656 men, 74.2%; 1,388 persistent AF, 38.8%) were identified. Median CHADSand HAS-BLED scores were both 1 point. Oral anticoagulants were prescribed for 2,082 (58.1%) patients (warfarin, 1,214; direct oral anticoagulants [DOACs], 868). Incidence and observation period (maximum 3 years) of IS, extracranial hemorrhage (ECH), and intracranial hemorrhage (ICH) were counted separately for the northern hemisphere seasons. During the mean follow-up period of 2.4 years, there were totals of 90 IS, 73 ECH, and 33 ICH cases. The respective incidence rates per 1,000 patient-years in spring, summer, autumn, and winter were 8.5, 8.8, 7.5, and 16.8 for IS, 7.2, 9.7, 3.8, and 13.1 for ECH, and 2.7, 1.9, 3.8, and 7.0 for ICH. The number of patients with DOACs relatively increased among those with ECH in summer.

Conclusions: Significant seasonal variations were observed for IS, ECH, and ICH events in AF patients, and were consistently the highest in winter. A small peak of ECH was observed in summer, which seemed, in part, to be related to increased DOAC use.
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http://dx.doi.org/10.1253/circj.CJ-20-0134DOI Listing
September 2020

Ventilatory efficiency during ramp exercise in relation to age and sex in a healthy Japanese population.

J Cardiol 2021 01 5;77(1):57-64. Epub 2020 Aug 5.

Committee on Exercise Prescription for Patients (CEPP), Japan.

Background: The current understanding of ventilator efficiency variables during ramp exercise testing in the normal Japanese population is insufficient, and the responses of tidal volume (VT) and minute ventilation (V̇E) to the ramp exercise test in the normal Japanese population are not known.

Methods: A total of 529 healthy Japanese subjects aged 20-78 years underwent cardiopulmonary exercise testing using a cycle ergometer with ramp protocols. VT and V̇E at rest, at anaerobic threshold, and at peak exercise were determined. The slope of V̇E versus carbon dioxide (V̇CO) (V̇E vs. V̇CO slope), minimum V̇E/V̇CO, and oxygen uptake efficiency slope (OUES) were determined.

Results: For males and females in their 20 s, peak VT (VTpeak) was 2192 ± 376 and 1509 ± 260 mL (p < 0.001), peak V̇E (V̇Epeak) was 80.6 ± 18.7 and 57.7 ± 13.9 L/min (sex differences p < 0.001), the V̇E vs. V̇CO slope was 24.4 ± 3.2 and 25.7 ± 3.2 (p = 0.035), the minimum V̇E/V̇CO was 24.2 ± 2.3 and 27.0 ± 2.8 (p < 0.001), and the OUES was 2452 ± 519 and 1991 ± 315 (p < 0.001), respectively. VTpeak and V̇Epeak decreased with age and increased with weight and height. The V̇E vs. V̇CO slope and minimum V̇E/V̇CO increased with age, while conversely, the OUES decreased with age.

Conclusions: We have established the normal range of VT and V̇E responses, the V̇E vs. V̇CO slope, the minimum V̇E/V̇CO, and the OUES for a healthy Japanese population. Some of these parameters were influenced by weight, height, sex, and age. These results provide useful reference values for interpreting the results of cardiopulmonary exercise testing in cardiac patients.
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http://dx.doi.org/10.1016/j.jjcc.2020.07.008DOI Listing
January 2021

Association Between Dose and Plasma Concentration of Bisoprolol in Patients with Heart Failure (CVI ARO 6).

Int Heart J 2020 Jul 18;61(4):748-754. Epub 2020 Jul 18.

Department of Cardiovascular Medicine, The Cardiovascular Institute.

Although bisoprolol is used widely to treat patients with heart failure (HF), little information is available regarding the association between the dose of bisoprolol administered and the bisoprolol plasma concentration (Bis-PC) in real-world clinical practice.This was a single-center, observational study in 114 patients with HF receiving once-daily bisoprolol. After determination of trough Bis-PC, the relationship between the dose of bisoprolol and Bis-PC was analyzed. In a multiple linear regression model, the dose of bisoprolol and estimated creatinine clearance (reciprocal number) were identified as independent predictors. HF severity and hepatic function were not associated with Bis-PC.Bis-PC was increased by renal dysfunction, which explained most of the discrepancy between the dose of bisoprolol administered and Bis-PC.
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http://dx.doi.org/10.1536/ihj.20-052DOI Listing
July 2020

Fibulin-1 Integrates Subendothelial Extracellular Matrices and Contributes to Anatomical Closure of the Ductus Arteriosus.

Arterioscler Thromb Vasc Biol 2020 09 9;40(9):2212-2226. Epub 2020 Jul 9.

From the Cardiovascular Research Institute (S.I., U.Y., T.N., J.S., N.N., M.U., T.F., Y.I.), Yokohama City University, Japan.

Objective: The ductus arteriosus (DA) is a fetal artery connecting the aorta and pulmonary arteries. Progressive matrix remodeling, that is, intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomic DA closure. IT is comprised of multiple ECMs (extracellular matrices) and migrated smooth muscle cells (SMCs). Because glycoprotein fibulin-1 binds to multiple ECMs and regulates morphogenesis during development, we investigated the role of fibulin-1 in DA closure. Approach and Results: Fibulin-1-deficient () mice exhibited patent DA with hypoplastic IT. An unbiased transcriptome analysis revealed that EP4 (prostaglandin E receptor 4) stimulation markedly increased fibulin-1 in DA-SMCs via phospholipase C-NFκB (nuclear factor κB) signaling pathways. Fluorescence-activated cell sorting (FACS) analysis demonstrated that fibulin-1 binding protein versican was derived from DA-endothelial cells (ECs). We examined the effect of fibulin-1 on directional migration toward ECs in association with versican by using cocultured DA-SMCs and ECs. EP4 stimulation promoted directional DA-SMC migration toward ECs, which was attenuated by either silencing fibulin-1 or versican. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were coexpressed at the IT of wild-type DA, whereas 30% of versican-deleted mice lacking a hyaluronan binding site displayed patent DA. Fibulin-1 expression was attenuated in the EP4-deficient mouse () DA, which exhibits patent DA with hypoplastic IT, and fibulin-1 protein administration restored IT formation. In human DA, fibulin-1 and versican were abundantly expressed in SMCs and ECs, respectively.

Conclusions: Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region, at least, in part, in combination with EC-derived versican and its binding partner hyaluronan.
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http://dx.doi.org/10.1161/ATVBAHA.120.314729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447190PMC
September 2020

Ethyl acetate extract of Kaempferia parviflora inhibits Helicobacter pylori-associated mammalian cell inflammation by regulating proinflammatory cytokine expression and leukocyte chemotaxis.

BMC Complement Med Ther 2020 Apr 22;20(1):124. Epub 2020 Apr 22.

Research Unit of Innovative Diagnosis of Antimicrobial Resistance, Department of Transfusion Medicine and Clinical Microbiology, Faculty of Allied Health Sciences, Chulalongkorn University, Pathumwan, Bangkok, Thailand.

Background: Kaempferia parviflora (KP) has been used in traditional Thai medicine to cure gastrointestinal disorders since ancient times. Helicobacter pylori is an initiating factor in gastric pathogenesis via activation of massive inflammation, the cumulative effect of which leads to gastric disease progression, including gastric carcinogenesis. Accordingly, the effect of a crude ethyl acetate extract of KP (CEAE-KP) on proinflammatory cytokine production and cell chemotaxis was the focus of this study.

Methods: The cytotoxicity of CEAE-KP (8-128 μg/ml) on AGS (gastric adenocarcinoma) cells was determined at 6, 12 and 24 h using an MTT assay. The effect of CEAE-KP on H. pylori-induced interleukin (IL)-8 production by AGS cells was evaluated by ELISA and RT-PCR. The effect of CEAE-KP on monocyte and neutrophil chemotaxis to H. pylori soluble protein (sHP) and IL-8, respectively, was determined using a Boyden chamber assay with THP-1 or HL-60 cells.

Results: CEAE-KP reduced AGS cell viability in a concentration- and time-dependent manner, but at 8-16 μg/ml, it was not cytotoxic after 6-24 h of exposure. Coculture of AGS cells with CEAE-KP at a noncytotoxic concentration of 16 μg/ml and H. pylori reduced IL-8 secretion by ~ 60% at 12 h, which was consistent with the decreased level of mRNA expression, and inhibited neutrophil chemotaxis to IL-8. sHP (100 ng/ml) induced marked monocyte chemoattraction, and this was decreased by ~ 60% by CEAE-KP.

Conclusion: CEAE-KP might serve as a potent alternative medicine to ameliorate the inflammation mediated by H. pylori infection.
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http://dx.doi.org/10.1186/s12906-020-02927-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179042PMC
April 2020

Differences in treatment and prognosis by the experience of falls or bone fracture in elderly patients with atrial fibrillation.

Heart Vessels 2020 Sep 7;35(9):1234-1242. Epub 2020 Apr 7.

Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19 Nishiazabu, Minato-Ku, Tokyo, 106-0031, Japan.

Treatment and prognosis of elderly patients with atrial fibrillation (AF) may differ by the experience of fall or bone fracture. However, their current status is still unclear. From our institute database between 2010 and 2015, 674 AF patients with age ≥ 70 years were selected and were divided into those who experienced fall or fracture during the observation period (F/F group; n = 49) and those who did not (non-F/F group; n = 625). We compared the treatment and prognosis between the 2 groups. Patients in the F/F group were older (79 vs 76 years, P < 0.001) and had more comorbidities compared with those in the non-F/F group. The prescription rate of oral anticoagulant was similar between the two groups (77.6% vs 68.2%, P = 0.201), where warfarin was predominant. The F/F group was not associated with higher incidence of ischemic stroke. The F/F group was associated with a higher incidence of heart failure events (adjusted odds ratio (OR) 3.88; 95% confidence intervals (Cl) 1.70-8.85; P = 0.001), and cardiovascular events (OR 3.43; 95% Cl 1.71-6.85; P < 0.001). In elderly AF patients in a cardiovascular hospital, the experience of fall or fracture did not affect the prescription of oral anticoagulants and the incidence of ischemic stroke, but it was significantly associated with increase of heart failure.
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http://dx.doi.org/10.1007/s00380-020-01592-2DOI Listing
September 2020

Role of dipstick proteinuria for predicting cardiovascular events: a Japanese cardiovascular hospital database analysis.

Heart Vessels 2020 Sep 4;35(9):1256-1269. Epub 2020 Apr 4.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Nishiazabu 3-2-19, Minato-ku, Tokyo, 1060031, Japan.

Initial screening for proteinuria by urine dipstick test (UDT) may be useful for predicting clinical outcomes. The Shinken Database includes all the new patients visiting the Cardiovascular Institute Hospital in Tokyo, Japan. Patients for whom UDT was performed at their initial visit between 2004 and 2010 (n = 7131) were divided into three groups according to the test results: negative, trace, and positive (1+ to 4+) proteinuria. During the mean follow-up period of 3.4 years, 233 (3.1%) deaths, 255 (3.6%) heart failure (HF) events, and 106 (1.5%) ischemic stroke (IS) events occurred. Prevalence of atherothrombotic risks increased with an increase in the amounts of proteinuria. The incidence of all-cause death, HF and IS events increased significantly from negative to trace to positive proteinuria groups (log rank test, P for trend < 0.001). Multivariate analysis revealed independent association between proteinuria and all-cause death [hazard ratio (HR): 1.50, 95% confidence interval (CI) 1.07-2.10], HF (HR: 1.55, 95% CI 1.14-2.12), and IS (HR: 2.08, 95% CI 1.26-3.45). Even trace proteinuria was independently associated with HF (HR: 1.64, 95% CI 1.07-2.53) and IS (HR: 2.17, 95% CI 1.14-4.11) and with all-cause death (HR: 1.56, 95% CI 0.99-2.47). In conclusions, dipstick proteinuria was independently associated with cardiovascular events and death, suggesting that the UDT is a useful tool for evaluating patients' risk for such adverse events.
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http://dx.doi.org/10.1007/s00380-020-01596-yDOI Listing
September 2020

Association between bisoprolol plasma concentration and worsening of heart failure: (CVI ARO 6).

Drug Metab Pharmacokinet 2020 Apr 13;35(2):228-237. Epub 2020 Jan 13.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan.

Background: Although bisoprolol has been established to prevent heart failure (HF), finding the optimal dose remains a challenge. It is crucial to understand the distribution of bisoprolol plasma concentration (Bis-PC) and association with outcomes.

Methods: This was a single-center observational study in 114 HF patients under once-daily bisoprolol. After obtaining trough Bis-PC, patients were followed-up for 1 year. The primary endpoint was worsening of HF. Patients were divided according to the tertiles of Bis-PC.

Results: In multivariate logistic regression analysis, independent predictors of high Bis-PC (1st tertile: ≥ 5.38 ng/mL) were age, eGFR, and bisoprolol dose. The cumulative incidence rates of the primary endpoint were 10.5%/13.2%/26.3% in low/middle/high Bis-PC categories, respectively (log rank test, p = 0.087). Bis-PC was independently associated with the primary endpoint (hazard ratio [HR], 1.19 [per ng/mL], 95% CI 1.03-1.36). In subgroups, high Bis-PC was independently associated with the primary endpoint in elderly (HR 6.32, 95% CI 1.34-29.83) and HF with preserved ejection fraction (HFpEF) (HR 3.52, 95% CI 1.06-11.70).

Conclusions: Bis-PC was increased by age and renal dysfunction, and high Bis-PC was associated with worsening of HF in elderly and HFpEF patients. Care should be taken to avoid overdose.
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http://dx.doi.org/10.1016/j.dmpk.2020.01.002DOI Listing
April 2020

The caveolar-mitochondrial interface: regulation of cellular metabolism in physiology and pathophysiology.

Biochem Soc Trans 2020 02;48(1):165-177

VA San Diego Healthcare System, San Diego, CA, U.S.A.

The plasma membrane is an important cellular organelle that is often overlooked in terms of a primary factor in regulating physiology and pathophysiology. There is emerging evidence to suggest that the plasma membrane serves a greater purpose than a simple barrier or transporter of ions. New paradigms suggest that the membrane serves as a critical bridge to connect extracellular to intracellular communication particularly to regulate energy and metabolism by forming physical and biochemical associations with intracellular organelles. This review will focus on the relationship of a particular membrane microdomain - caveolae - with mitochondria and the particular implication of this to physiology and pathophysiology.
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http://dx.doi.org/10.1042/BST20190388DOI Listing
February 2020

Regulation of breast cancer resistance protein and P-glycoprotein by ezrin, radixin and moesin in lung, intestinal and renal cancer cell lines.

J Pharm Pharmacol 2020 Apr 24;72(4):575-582. Epub 2020 Jan 24.

Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan.

Objectives: Ezrin (Ezr), radixin (Rdx) and moesin (Msn) (ERM) proteins anchor other proteins to the cell membrane, serving to regulate their localization and function. Here, we examined whether ERM proteins functionally regulate breast cancer resistance protein (BCRP) and P-glycoprotein in cell lines derived from lung, intestinal and renal cancers.

Methods: ERM proteins were each silenced with appropriate siRNA. BCRP and P-gp functions were evaluated by means of efflux and uptake assays using 7-ethyl-10-hydroxycamptothecin (SN-38) and rhodamine123 (Rho123) as specific substrates, respectively, in non-small cell lung cancer HCC827 cells, intestinal cancer Caco-2 cells and renal cancer Caki-1 cells.

Key Findings: In HCC827 cells, the efflux rates of SN-38 and Rho123 were significantly decreased by knockdown of Ezr or Msn, but not Rdx. However, BCRP function was unaffected by Ezr or Rdx knockdown in Caco-2 cells, which do not express Msn. In Caki-1 cells, Rdx knockdown increased the intracellular SN-38 concentration, while knockdown of Ezr or Msn had no effect.

Conclusions: Our findings indicate that regulation of BCRP and P-gp functions by ERM proteins is organ-specific. Thus, if the appropriate ERM protein(s) are functionally suppressed, accumulation of BCRP or P-gp substrates in lung, intestine or kidney cancer tissue might be specifically increased.
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http://dx.doi.org/10.1111/jphp.13225DOI Listing
April 2020

Laparoscopic transhiatal suture closure for spontaneous esophageal rupture: a case report.

Surg Case Rep 2019 Oct 22;5(1):149. Epub 2019 Oct 22.

Department of General surgery, Nagoya City West Medical Center, 1-1-1 Hirate-cho, Kita-Ku, Nagoya, 462-8508, Japan.

Background: Spontaneous esophageal rupture is a rare but serious disease with high mortality. Conservative treatment and endoscopic therapy have been reported, but surgical treatment is still a basic modality of therapy. In addition to thoracotomy, recent studies have reported treatment with thoracoscopic surgery and laparoscopic transhiatal repair. In this study, we report a patient who underwent laparoscopic transhiatal suture closure for spontaneous esophageal rupture with favorable postoperative course. We also discuss indication for laparoscopic surgery for spontaneous esophageal rupture.

Case Presentation: A 70-year-old man visited our hospital with chief complaints of epigastric pain and vomitus niger. He was diagnosed with spontaneous esophageal rupture in the left wall of the lower esophagus by computed tomography and upper gastrointestinal (GI) series. At 11 h after the onset of symptoms, we performed laparoscopic transhiatal suture closure and lavage drainage. We performed transhiatal esophageal replacement using the 5-hole approach. We observed a perforation of 2 cm in diameter at the site of the rostral portion approximately 4 cm from the esophageal hiatus. All layers were closed with three stitches using 3-0 absorbable sutures. No perforation was observed in the thoracic cavity. The total operative time was 178 min, and total bleeding was 2 ml. He had no postoperative complications and was discharged on day 15 after the procedure. He received continuous proton pump inhibitor therapy as an outpatient. Healing cicatrization was found at the site of rupture by esophagogastroscopy. The patient was advised to improve his lifestyle and has shown no signs of recurrence over 2 years from the date of surgery.

Conclusions: Simple closure of all the layers using laparoscopic transhiatal simple closure was useful in the treatment of esophageal rupture as a less invasive approach for patients who meet the following conditions: stable general condition, intrathoracic perforation, and the perforation site is identified as the lower esophagus by pre-operative examination.
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http://dx.doi.org/10.1186/s40792-019-0711-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805831PMC
October 2019

Myocardial bridging is an independent predictor of positive spasm provocation testing by intracoronary ergonovine injections: a retrospective observational study.

Heart Vessels 2020 Apr 27;35(4):474-486. Epub 2019 Sep 27.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Nishiazabu 3-2-19, Minato-ku, Tokyo, 1060031, Japan.

The relationship between myocardial bridging (MB) and coronary spasms during spasm provocation testing (SPT) remains unclear. We aimed to investigate whether MB was correlated with the SPT by ergonovine (ER) injections in a retrospective observational study. Of the 3340 patients who underwent a first coronary angiography, 166 underwent SPT using ER injections and were divided into 2 groups: MB(+) (n = 23), and MB(-) (n = 143). MB was defined as an angiographic reduction in the diameter of the coronary artery during systole. The patients who had severe organic stenosis in the left anterior descending coronary artery were excluded. The MB(+) group more frequently had diabetes mellitus and chronic kidney disease, and a thicker interventricular septum thickness. The rate of SPT-positivity was higher in the MB(+) group than MB(-) group (56.5% vs. 22.4%, P = 0.001). A multivariate regression analysis showed that the presence of MB was independently associated with SPT-positivity (odds ratio 5.587, 95% confidence interval 2.061-15.149, P = 0.001). In conclusion, coronary spasms during provocation tests with ER independently correlated with the MB. MB may predict coronary spasms.
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http://dx.doi.org/10.1007/s00380-019-01518-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085475PMC
April 2020

A Simple Formula for Predicting the Maintenance Dose of Warfarin with Reference to the Initial Response to Low Dosing at an Outpatient Clinic.

Intern Med 2020 Jan 11;59(1):29-35. Epub 2019 Sep 11.

Department of Cardiovascular Medicine, The Cardiovascular Institute, Japan.

Objective The pharmacodynamic effect of warfarin varies among individuals, and its maintenance dose is widely distributed. Although many formulae for predicting the maintenance dose of warfarin have been developed, most of them are complex and not in practical use. Methods and Materials Among 12,738 new patients visiting the Cardiovascular Institute between 2004 and 2009, we identified 127 patients (66.6±8.8 years, 89 men) with atrial fibrillation for whom warfarin was newly started with an initial dose of 2 mg/day and the international normalized ratio (INR) at 1 year after warfarin was started was within the therapeutic range. The prediction models for the maintenance dose were developed by an exponential equation and a first-order equation. Results The initial response of the INR to the dose of 2 mg/day (initial INR) ranged from 1.00-3.24 (mean 1.43), while the maintenance dose of warfarin ranged from 0.5-14 mg (mean 3.8 mg). The maintenance dose showed an exponential correlation to the initial INR: (predicted maintenance dose) =5.522× (initial INR) (R=0.795, p<0.001). Excluding the patients with a poor response to the initial dose (initial INR <1.1, n=32) permitted a simple correlation with a first-order approximation: (predicted maintenance dose) =-2.009× (initial INR) +6.172 (R=0.706, p<0.001). Conclusion We developed a simple formula for predicting the maintenance dose of warfarin using the initial response of the INR to low-dose warfarin.
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http://dx.doi.org/10.2169/internalmedicine.3415-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995699PMC
January 2020
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