| 1.
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Ashitate, Toshihiro ; Osanai, Tomohiro ; Tanaka, Makoto ; Magota, Koji ; Echizen, Takashi ; Tomita, Hirofumi ; Okumura, Ken
概要:
We showed that endogenous prostacyclin inhibitor coupling factor 6 （CF6） is released from vascularendothelial cells and
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its release is stimulated by tumor necrosis factor-α, which is related to congestive heart failure（CHF）. We also showed that CF6 increases the gene expression related to CHF. To investigate the role of CF6 inthe genesis of CHF, we generated CF6-overexpressing transgenic（ TG） mice, and characterized the phenotype. DNAfragment consisting of human elongation factor 1α promoter, and human calcitonin/CF6 fused gene was injected intothe embryo of C57BL/6J mouse, and homozygous TG mice were generated. In TG mice, CF6 gene was overexpressedby two fold in overall tissues compared with wild type（ WT） mice. Under normal salt diet, blood pressure, heart rate,and the expression of energy metabolism-related genes were similar between TG and WT mice. When the mice werefed with 8% -salt diet for 35 weeks, the mortality of TG mice was higher than that of WT mice（ survival rate; 50% inTG versus 92% in WT, p<0.05 by log-rank test）. This preliminary report indicates that further examination, especiallyanalysis of the cardiac function, is needed to clarify the cause of high mortality of TG mice under high salt intake.
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| 2.
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Hanada, Kenji ; Osanai, Tomohiro ; Sukekawa, Takanori ; Ohya, Fumie ; Izumiyama, Kei ; Sagara, Shigeki ; Itoh, Taihei ; Yamamoto, Yuko ; Shibutani, Shuji ; Tomita, Hirofumi ; Okumura, Ken
概要:
Background: P38 mitogen-activated protein kinase（MAP kinase）plays on important role for progression of pathological card
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iac hypertrophy. However, the role of p38 MAP kinase in cardiac hypertrophy induced by pressure overload remains unclear. We investigated the effect of chronic treatment with p38 MAP kinase inhibitor on the development of heart failure induced by transverse aortic constriction（TAC）in mice. Methods and Results: TAC increased left ventricular septal wall thickness（LVSWT）and cross-sectional area（CSA）of cardiomyocyte, and decreased LV fractional shortening（FS）compared with sham operation after 6 weeks. TAC also increased phosphorylation of p38 MAP kinase, whereas other hypertrophic signals were unchanged. In another experiment, TAC mice and sham operated mice were treated with subcutaneous injection of p38 MAP kinase inhibitor SB202190（5mg/kg/day）or placebo five times a week for six weeks. Treatment with p38 MAP kinase inhibitor attenuated the increase in LVSWT and CSA, and the decrease in FS in mice with TAC.Conclusions: Inhibition of p38 MAP kinase attenuated left ventricular hypertrophy and inhibited progression of systolic dysfunction in pressure overload-induced cardiac hypertrophy. These results suggest that inhibition of p38 MAP kinase has a protective effect for development of heart failure induced by pressure overload.
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| 3.
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Shibutani, Shuji ; Osanai, Tomohiro ; Ohya, Fumie ; Sagara, Shigeki ; Izumiyama, Kei ; Yamamoto, Yuko ; Hanada, Kenji ; Tomita, Hirofumi ; Okumura, Ken
概要:
Coronary artery spasm plays an important role in the etiology of coronary spastic angina（CSA）and other acute coronary sy
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ndromes. Mice with a targeted disruption of the ATP-binding cassette transporter C9‒ABCC9 gene were developed as an animal model of CSA. Thus, the ABCC9 may be involved in the regulation of coronary artery vasomotility. The aim of this study was to investigate whether mutation in the coding region of the ABCC9 gene is detected in Japanese patients with CSA. The study included 9 Japanese patients with CSA （6 men and 3 women with a mean age of 51±13 years）. Genomic DNA was extracted from the whole blood, and Mutation analysis of the coding region of ABCC9 was performed by direct sequencing. In one CSA patient, we found a single base substitution（G to A）at nucleotide position 126 in exon 21 of the coding region, which was heterozygous and did not cause amino acid substitution（T878T, silent mutation）.In the remaining 8 patients, no base substitution wasdetected in the coding region of the ABCC9 gene. The results indicate that the mutation of the ABCC9 gene may not be involved in the genetic pathogenesis of CSA in humans.
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| 4.
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Suzuki, Akiko ; Osanai, Tomohiro ; Tanaka, Makoto ; Endo, Tomohide ; Murakami, Kazuo ; Tomita, Hirofumi ; Okumura, Ken
概要:
Abstract Objectives: Vascular endothelial cells are exposed to an acidic pH, but its influence on chemokine receptors ex
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pressed in the vascular endothelial cells is unclear. We investigated the role of coupling factor 6 (CF6), a novel stimulator of proton importer, in the regulation of chemokine receptors in the vascular endothelial cells.Methods and Results: In microarray analysis, there were the increased expression of CC chemokine receptor 9 (CCR9) and CX3C chemokine receptor 1 (CX3CR1) and the decreased expression of CXC chemokine receptor 4 (CXCR4) in the human umbilical vascular endothelial cells (HUVEC) that were exposed to CF6. The ratio of CXCR4 to GAPDH mRNA was decreased in HUVEC that were exposed to either CF6 at 10-7M or hypoxia to a similar degree. Apoptotic cells, measured by annexin-V propidium iodide kit, were increased in HUVEC that were exposed to CF6 for 24 hours in normoxia.Conclusions: CF6 influences the expression of chemokine receptors and induces apoptosis in the vascular endothelial cells.
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| 5.
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Murakami, Kazuo ; Osanai, Tomohiro ; Tanaka, Makoto ; Kinjo, Takahiko ; Tanno, Tomohiro ; Narita, Ikuyo ; Kawai, Misato ; Tomita, Hirofumi ; Okumura, Ken
概要:
Background: We reported that enhanced phospholipase C （PLC）-δ1, which was detected in patients with coronary spasm, caus
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ed coronary spasm in mice. We investigated the role of protein kinase C（ PKC） in acetylcholine （ACh）-induced Ca2+ influx under enhanced PLC-δ1 using human embryonic kidney（ HEK）-293 cells. Methods and Results: Intracellular free Ca2+ concentration （[Ca2+]i） was measured by fura-2, and Ca2+ influx was evaluated by the increase in [Ca2+]i after addition of extracellular Ca2+. ACh-induced Ca2+ influx（ nM） in HEK-293 cells was 21±2 in control HEK-293 cells, 52±6 in the cells with PLC-δ1 overexpression, and 75±9 in those with PLC-δ1 overexpression and PKC down-regulation （all p<0.05 among 3 groups）. Ca2+ influx under treatment with nifedipine at 10-5M was 2.9±0.1 times higher in the cells with PLC-δ1 overexpression and 5.6±0.2 times higher in those with PLC-δ1 overexpression and PKC down-regulation compared with the control cells（ all p<0.05 among 3 groups）. Conclusions: ACh-induced Ca2+ influx was enhanced by PLC-δ1 overexpression, but was attenuated by PKC activation. PKC plays an important role in Ca2+ influx under enhanced PLC-δ1 in a negative feedback fashion.
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| 6.
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Nozaki, Shuhei ; Ogata, Yoshiki ; Yonekura, Manabu ; Han, Chong ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Hirota, Kazuyoshi ; Matsuzaki, Yasushi ; Tomita, Hirofumi ; Imaizumi, Tadaatsu ; Itagaki, Shirou ; Sawamura, Daisuke ; Murakami, Manabu
概要:
We analyzed the effects of halothane as an inhalational anesthetic agent on electrocardiogram （ECG）parameters in C57/BL6
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mice. Following induction of anesthesia using 2% halothane, the ECGs showed a regularpattern and the heart rate （HR） was within an acceptable range （~500 bpm）. The HR decreased with increasinghalothane concentration in a concentration-dependent fashion. The frequency domain analysis showed that the high-frequency （HF） component decreased and the lowfrequency（LF） component increased in a concentration-dependent fashion. Therefore, the LF/HF ratio increasedwith increasing halothane concentration, suggesting effects on the autonomic nervous system. We analyzed the pharmacological response to sympathetic blockade with propranolol, a typical adrenergicβ-blocker, under halothane anesthesia. Propranolol administration resulted in a decreased HR; interestingly,intraperitoneal injection of propranolol （120 μg/kg body weight） resulted in arrhythmia （sick sinus syndrome）during anesthesia with 3% halothane. Our results indicate the importance of selecting a suitable anesthetic agent for C57/BL6 mice in pharmacological studies
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| 7.
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Ogata, Yoshiki ; Yonekura, Manabu ; Yamaki, Rouichi ; Han, Chong ; Fujiwara, Tomonori ; Seya, Kazuhiko ; Niwa, Hidetoshi ; Kushikata, Tetsuya ; Imaizumi, Tadaatsu ; Hirota, Kazuyoshi ; Tomita, Hirofumi ; Murakami, Manabu
概要:
We examined the effects of enflurane anesthesia on the mouse cardiac autonomic nervous system usingelectrocardiogram（ EC
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G） analysis. Enflurane had a lower effect on heart rate（ HR） compared to isoflurane, which ismore widely used in small animal studies. Under anesthesia with 3 or 4% of enflurane, administration of propranololhad a significant effect on HR. Enflurane increased R-R interval length in a dose-dependent fashion, and the R-Rinterval became unstable at high concentrations. Although HR decreased with high doses of enflurane, we observednormal sinus rhythm and no arrhythmia. These results suggest that the effect of enflurane anesthesia is acceptableeven though the drug can lead to cardiac instability. No remarkable changes were observed in HR frequency. These results suggest that enflurane anesthesia may be suitable for cardiac autonomic nervous system analysis.
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| 8.
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Han, Chong ; Inaba, Wataru ; Yonekura, Manabu ; Ogata, Yoshiki ; Ohba, Takayoshi ; Kushikata, Tetsuya ; Niwa, Hidetoshi ; Yanagisawa, Teruyuki ; Tomita, Hirofumi ; Itagaki, Shirou ; Hirota, Kazuyoshi ; Akai, Hiroaki ; Mizukami, Hiroki ; Murakami, Manabu
概要:
Persistent hyperglycemia is implicated in the pathogenesis of chronic diabetic complications, such asneuropathy. Theref
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ore, we investigated Electrocardiogram（ ECG）-related changes, including various ECG parametersand heart rate variability, and neuropathic changes in diabetic Goto-Kakizaki （GK） rats, a spontaneous model fortype 2 diabetes. GK rats （50 weeks old） showed increased plasma glucose and decreased R-R interval variability,which was likely due to diabetic polyneuropathy in the autonomic nervous system. Interestingly, GK rats showed adecreased baroreflex compared with control Wistar rats. Furthermore, GK rats showed limited fluctuation changesin beat-to-beat dynamics. In the frequency domain analysis, the low-frequency component was similar but the highfrequencycomponent was significantly decreased in GK rats, suggesting decreased parasympathetic nerve regulationand conserved sympathetic nerve regulation. In addition, GK rats showed a limited response to high-dose atropine, amuscarinic receptor antagonist, indicating modified parasympathetic nerve regulation in GK rats. Our data stronglysuggests that GK rat could be a nice animal model for chronic cardiovascular disease related to diabetic neuropathy.
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| 9.
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Shoji, Yoshihiro ; Sasaki, Shingo ; Toyama, Yuichi ; Nishizaki, Kimitaka ; Kinjo, Takahiko ; Ishida, Yuji ; Endo, Tomohide ; Nishizaki, Fumie ; Itoh, Taihei ; Yokota, Takashi ; Yokoyama, Hiroaki ; Yamada, Masahiro ; Horiuchi, Daisuke ; Kimura, Masaomi ; Higuma, Takumi ; Okumura, Ken ; Tomita, Hirofumi
概要:
Wearable cardioverter-defibrillator （WCD） is an external device capable of automatic detection and treatment of ventric
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ular tachycardia（VT）/ventricular fibrillation（ VF）. We examined whether WCD use for patients at high risk for VT/VF is associated with shortening the length of stay in the intensive care unit （ICU） and safemanagement in the general ward until implantable cardioverter-defibrillator（ ICD） implantation. From June 2012 to May 2014, ICD was implanted in 44 patients for secondary prevention of VT/VF （control group）. From June 2014 to May 2016, WCD was prescribed in 50 patients for secondary prevention, of which 29 patients had ICD implantation（ WCD group）. The median length（ 25th–75th percentiles） of the ICU stay was 3（ 1–7）days in the control and 0（ 0–1.5） days in the WCD group（ p<0.05）. The period until ICD implantation in the general ward was 0（ 0–3） days in the control and 10（ 5–19） days in the WCD group（ p<0.05）. No sudden cardiac death and no readmission to the ICU were reported in both groups before ICD implantation. In patients with indication for ICD implantation for secondary prevention, WCD use can shorten the length of ICU stay and provide a safe management in a general ward.
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| 10.
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Senoo, Maiko ; Yokoyama, Hiroaki ; Kato, Tomo ; Kudo, Natsumi ; Yokono, Yoshikazu ; Tsushima, Michiko ; Toyama, Yuichi ; Narita, Noritomo ; Narita, Masato ; Tomita, Hirofumi
概要:
Background: It remains uncertain whether snow shoveling has effects on long-term prognosis in patients with acute myocar
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dial infarction（ AMI）.Patients/Methods: Consecutive 355 patients who underwent emergency percutaneous coronary intervention within 24 hours of the AMI onset during the winter months （November to March） between 2008 and 2014 years were retrospectively studied.Results: Of the 355 patients, 36（ 11%） had snow shoveling-related AMI, defined as the AMI onset during or within 6 hours after snow shoveling. These patients suffered fewer adverse cardiovascular events than the non-snow shoveling AMI patients during a median follow-up period of 3.8 years. Notably, snow shoveling did not affect the events for patients with left ventricular ejection fraction （LVEF） <40% at the acute phase, but it was a significant better predictor of events for those with LVEF ≥40%.Conclusion: Snow shoveling may have important clinical implications for the AMI onset and the prognostic outcome in snowy areas.
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| 11.
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Narita, Noritomo ; Hanada, Kenji ; Senoo, Maiko ; Kato, Tomo ; Kudo, Natsumi ; Yokono, Yoshikazu ; Tsushima, Michiko ; Toyama, Yuichi ; Narita, Masato ; Tomita, Hirofumi
概要:
Background: Endothelin （ET） is a strong vasoconstrictor that plays important roles in the pathogenesis and progression o
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f cardiovascular remodeling. ET receptor（ ET-R） antagonists have recently become established as a drug essential for treating pulmonary arterial hypertension（ PAH）. β-arrestin was originally identified as a regulator of G-protein coupled receptor recycling, but it recently became apparent that β-arrestins act as scaffolds in their own signaling pathway. In this study, we examined the role of β-arrestin in ET-R signaling and explored its possible role in the pathogenesis of PAH.Methods and Results: The knockdown of β-arrestin1 or β-arrestin2 in human kidney embryonic 293 cells resulted in nhanced extracellular signal-regulated kinase （ERK） 1/2 phosphorylation in response to ET. Confocal microscopy showed that, in the absence of stimulation, transiently transfected green fluorescent protein-tagged epidermal growth factor receptors（ EGFRs） were located on the plasma membrane, whereas they were internalized in response to ET, as shown by their redistribution into cellular aggregates. Pretreatment with Ro318425（ a protein kinase C inhibitor） or AG1478（ an EGFR antagonist） suppressed ERK1/2 phosphorylation in response to ET.Conclusions: β-arrestins and EGFR transactivation are involved in ET-R signaling. These new insights may contribute to elucidating further layers in the pathogenesis of PAH.
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| 12.
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Kato, Tomo ; Yokota, Takashi ; Kitayama, Kazutaka ; Miura, Naotake ; Nozaka, Masashi ; Tsushima, Michiko ; Kudo, Natsumi ; Yokono, Yoshikazu ; Toyama, Yuichi ; Endo, Tomohide ; Nishizaki, Fumie ; Hanada, Kenji ; Yokoyama, Hiroaki ; Yamada, Masahiro ; Tomita, Hirofumi
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Background: We previously reported that ST-segment elevation myocardial nfarction（ STEMI） patients with large residual t
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hrombus burden after thrombectomy before stent implantation had more severe microvascular dysfunction, and greater yocardial damage compared with those with small residual thrombus. However, linical significance of residual thrombus after stent implantation in STEMI atients is unclear.Aims: This study aimed to evaluate the incidence of thrombus by optical coherence tomography （OCT） after stent implantation, and to investigate its clinical mpact in STEMI patients.Methods and Results: A total of 180 STEMI patients within 12 hours after onset of symptoms were studied. Patients were divided into two groups according to OCT indings after stent implantation: thrombus group（ n = 73） and nonthrombus group（ n = 107）. Peak CPK levels were greater in thrombus group than in non-thrombus group with close to significance （3649 {1752-7053｝ versus. 2563 {1201-4282｝IU/L, p = 0.053）. Thrombus after stent implantation was independently associated with peak CPK levels by a stepwise multivariate analysis.Conclusions: Residual thrombus on OCT after stent implantation was detected in 1% of STEMI patients. The residual thrombus was associated with greater myocardial damage assessed by peak CPK levels, indicating clinical impact of OCT-detected thrombus in STEMI patients.
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| 13.
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Kudo, Natsumi ; Hanada, Kenji ; Kawamura, Yosuke ; Nakata, Masamichi ; Nozaka, Masashi ; Kitayama, Kazutaka ; Miura, Naotake ; Tanaka, Makoto ; Osanai, Tomohiro ; Tomita, Hirofumi
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Coronary spastic angina （CSA） has become increasingly important for clinical practice. β-arrestin regulates a large netw
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ork of cellular responses including inflammation and muscle contraction. However, little is known about its role in the pathogenesis of CSA. In this study, we performed mutational analysis of β-arrestin1 and β-arrestin2 genes in CSA patients. The study population included 20 CSA patients and 5 control subjects. Mutational analyses of the coding egions of β-arrestins were performed by direct sequencing. In β-arrestin1, single base heterozygous substitution at nucleotide position 176 in exon 5 was detected in 2 of 20 CSA patients, whereas no substitution was detected in control subjects. We subsequently performed an association study involving 50 CSA patients and 50 control subjects. No ifference was found in the incidence of the mutation between the two groups （p=0.44）. In β-arrestin2, single base substitution at nucleotide position 61 in exon 11 was detected. This substitution was homozygous in 13 and heterozygous in 7 of 20 CSA patients, whereas all homozygous in 5 control subjects. These substitutions were well-annotated SNPs rs877711 and rs1045280, respectively） and did not cause amino acid replacement. No significant substitution of the oding regions of β-arrestins was detected in Japanese CSA patients.
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Toyama, Yuichi ; Yonekura, Manabu ; Arakawa, Yoshiaki ; Higuchi, Shoki ; Tomita, Hirofumi ; Murakami, Agnieszka ; Itagaki, Shirou ; Murakami, Manabu
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The cardiac action potential in the sinoatrial node is important, as it propagates throughout the heart and determines cardiac rhythm. Because of the anatomical complexity, pacemaker cells in the sinoatrial node can be difficult
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to identify for ectrophysiological analysis. Also, analysis of pacemaker cells requires a specialized technique. In this study, we tried to analyze pacemaking in the sinoatrial node. First, we evaluated the expression of various factors that participate in pacemaking or modify cardiac rhythm. Next, we evaluated recordings of the action potential in the sinoatrial node by a conventional lectrophysiological technique and using oxonol V, a fluorescent voltage-sensitive dye.
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Kitayama, Kazutaka ; Saito, Shin ; Hamadate, Misato ; Miura, Naotake ; Yamada, Natsumi ; Shiroto, Hiroshi ; Metoki, Norifumi ; Hagii, Joji ; Kamada, Takaatsu ; Takanashi, Shingo ; Tomita, Hirofumi
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Background: Implantable cardiac monitor（ ICM） is an effective tool to detect atrial fibrillation（ AF） in patients withem
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bolic stroke undetermined sources（ ESUS）. We investigated predictive factors for AF detection in ESUS patientswith ICM implantation.Methods: A total of 29 ESUS patients who underwent ICM implantation （median 71 ［66-84］ years and 18 males）were followed-up for a median of 253［ 44-570］ days.Results: AF was detected in 10 patients（ 34.5%）. The median time from ICM implantation to AF detection was 41.5［33.25-59.25］ days and that from stroke onset to AF detection was 62.5 ［52.25-71.75］ days. AF was detected within90 days after ICM implantation in 90% （9/10） of the study patients. Plasma brain natriuretic peptide level wassignificantly higher in patients with AF detection than in those without it（ 125［ 49.8-550.8］ versus 18.2［ 14.1-60.0］ pg/mL, p=0.007）. More frequent supraventricular premature contraction （SVPC） on Holter electrocardiogram （ECG）was observed in patients with AF detection than in those without it（ 1.81［ 0.40-4.80］ versus 0.04［ 0.02-0.13］ %/day,p<0.001）. Cox proportional hazards model showed that the frequent SVPCs was a significant factor for AF detection.Conclusions: The frequent SVPCs on Holter ECG is an independent predictor for covert AF in ESUS patients.
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