Publications by authors named "Atsuhiko T Naito"

67 Publications

Optimizing the Direction and Order of the Motion Unveiled the Ability of Conventional Monolayers of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Show Frequency-Dependent Enhancement of Contraction and Relaxation Motion.

Front Cell Dev Biol 2020 10;8:542562. Epub 2020 Sep 10.

Department of Pharmacology, Faculty of Medicine, Toho University, Tokyo, Japan.

Contractility of the human heart increases as its beating rate is elevated, so-called positive force-frequency relationship; however, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been reported to exert a negative force-frequency relationship. We tested the hypothesis that the regulation of motion directions by electrical pacing and/or oxygen supply may improve the electro-mechanical properties of hiPSC-CMs monolayers. To better evaluate the spatial and temporal relationship between electrical excitation and contractile motion, we simultaneously observed the field potential and motion vector of hiPSC-CMs sheets. Under spontaneous contraction, although an electrical excitation originating from a region propagated unidirectionally over the cell sheet, contraction wave started from multiple sites, and relaxation wave was initiated from a geometric center of hiPSC-CMs sheet. During electrical pacing, contraction and relaxation waves were propagated from the stimulated site. Interestingly, the maximum contraction speed was more increased when the hiPSC-CMs sheet was stimulated at an area relaxation initiated under spontaneous condition. Furthermore, motion vector analysis demonstrated that "positive contraction velocity-frequency relationship" in contraction and "frequency-dependent enhancement of relaxation" were produced in the cell sheet by optimizing the direction and order of the contractile motion with pacing at the relaxation-initiating area. A close analysis of motion vectors along with field potential recording demonstrated that relaxation process consists of fast and slow phases, and suggest that intracellular Ca dynamics may be closely related to functions of Ca-ATPase pump and Na-Ca exchangers. Namely, the slow relaxation phase occurred after the second peak of field potential, suggesting that the slow phase may be associated with extrusion of Ca by Na-Ca exchangers during repolarization. Increase of oxygen concentration from 20 to 95% as well as β-adrenergic stimulation with isoproterenol accelerated the fast relaxation, suggesting that it could depend on Ca uptake via Ca-ATPase during the depolarization phase. The ratio of maximum contraction speed to field potential duration was increased by the β-adrenergic stimulation, indicating the elevated contraction efficiency per Ca-influx. Thus, these findings revealed potential ability of conventional monolayers of hiPSC-CMs, which will help apply them to translational study filling the gap between physiological as well as pharmacological studies and clinical practice.
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http://dx.doi.org/10.3389/fcell.2020.542562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511828PMC
September 2020

Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure.

Nat Commun 2020 08 31;11(1):4364. Epub 2020 Aug 31.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Pathophysiological roles of cardiac dopamine system remain unknown. Here, we show the role of dopamine D1 receptor (D1R)-expressing cardiomyocytes (CMs) in triggering heart failure-associated ventricular arrhythmia. Comprehensive single-cell resolution analysis identifies the presence of D1R-expressing CMs in both heart failure model mice and in heart failure patients with sustained ventricular tachycardia. Overexpression of D1R in CMs disturbs normal calcium handling while CM-specific deletion of D1R ameliorates heart failure-associated ventricular arrhythmia. Thus, cardiac D1R has the potential to become a therapeutic target for preventing heart failure-associated ventricular arrhythmia.
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http://dx.doi.org/10.1038/s41467-020-18128-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459304PMC
August 2020

Experimental analysis of the onset mechanism of TdP reported in an LQT3 patient during pharmacological treatment with serotonin-dopamine antagonists against insomnia and nocturnal delirium.

Heart Vessels 2020 Apr 18;35(4):593-602. Epub 2019 Oct 18.

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.

Torsade de pointes (TdP) occurred in a long QT syndrome type 3 (LQT3) patient after switching perospirone to blonanserin. We studied how their electropharmacological effects had induced TdP in the LQT3 patient. Perospirone hydrochloride (n = 4) or blonanserin (n = 4) of 0.01, 0.1, and 1 mg/kg, i.v. was cumulatively administered to the halothane-anesthetized dogs over 10 min. The low dose of perospirone decreased total peripheral vascular resistance, but increased heart rate and cardiac output, facilitated atrioventricular conduction, and prolonged J-Tc. The middle dose decreased mean blood pressure and prolonged repolarization period, in addition to those observed after the low dose. The high dose further decreased mean blood pressure with the reduction of total peripheral vascular resistance; however, it did not increase heart rate or cardiac output. It tended to delay atrioventricular conduction and further delayed repolarization with the prolongation of T-T, whereas J-Tc returned to its baseline level. Meanwhile, each dose of blonanserin decreased total peripheral vascular resistance, but increased heart rate, cardiac output and cardiac contractility in a dose-related manner. J-Tc was prolonged by each dose, but T-T was shortened by the middle and high doses. These results indicate that perospirone and blonanserin may cause the hypotension-induced, reflex-mediated increase of sympathetic tone, leading to the increase of inward Ca current in the heart except that the high dose of perospirone reversed them. Thus, blonanserin may have more potential to produce intracellular Ca overload triggering early afterdepolarization than perospirone, which might explain the onset of TdP in the LQT3 patient.
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http://dx.doi.org/10.1007/s00380-019-01521-yDOI Listing
April 2020

In vivo characterization of rate-dependent impact on the QT interval of microminipig assessed by atrial electrical pacing: Development of correction formulae of QT interval.

J Vet Med Sci 2019 Dec 14;81(12):1735-1739. Epub 2019 Oct 14.

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.

Correction formulae of QT interval were developed for the halothane-anesthetized microminipigs by adopting atrial pacing (n=5), which were compared with Bazett's and Fridericia's formulae for humans, and Van de Water's one for dogs. The correction formulae: QTc=QT-0.2072 (RR-750) as linear and QTc=QT/(RR/750) as non-linear equations, were developed for microminipigs. These formulae can better correct the QT interval of the microminipigs compared with each of the conventional ones for humans and dogs. Moreover, analysis of the slope constant α values indicates that the rate-dependent change in the ventricular repolarization period of microminipig may better mimic that of humans than that of dogs.
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http://dx.doi.org/10.1292/jvms.19-0252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943312PMC
December 2019

Analysis of electro-mechanical relationship in human iPS cell-derived cardiomyocytes sheets under proarrhythmic condition assessed by simultaneous field potential and motion vector recordings.

J Pharmacol Sci 2019 Aug 19;140(4):317-320. Epub 2019 Jul 19.

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.

We investigated the electro-mechanical relationship of human iPS cell-derived cardiomyocyte sheets under arrhythmic condition, which was induced by digitalis intoxication along with the electrical train stimulation (n = 4). We adopted motion vector analysis by high-speed video microscopy and extracellular field potential recording by 64-microelectrode array system. The motion vector analysis uncovered local contractile events at resting phase, at which the field potential analysis showed no deflection in any cell sheet. Thus, motion vector analysis may provide supplemental information over field potential recording in detecting Ca-triggered arrhythmias, which may become a new strategy for assessing arrhythmic liability of test articles.
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http://dx.doi.org/10.1016/j.jphs.2019.07.006DOI Listing
August 2019

Dasatinib can Impair Left Ventricular Mechanical Function But May Lack Proarrhythmic Effect: A Proposal of Non-clinical Guidance for Predicting Clinical Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors.

Cardiovasc Toxicol 2020 02;20(1):58-70

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.

Tyrosine kinase inhibitors are known to clinically induce various types of cardiovascular adverse events; however, it is still difficult to predict them at preclinical stage. In order to explore how to better predict such drug-induced cardiovascular adverse events, we tried to develop a new protocol by assessing acute electrophysiological, cardiohemodynamic, and cytotoxic effects of dasatinib in vivo and in vitro. Dasatinib at 0.03 and 0.3 mg/kg was intravenously administered to the halothane-anesthetized dogs for 10 min with an interval of 20 min between the dosing (n = 4). Meanwhile, that at 0.1, 0.3, and 1 μM was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (n = 7). In the dogs, the low and high doses provided peak plasma concentrations of 40 ± 5 (0.08) and 615 ± 38 ng/mL (1.26 μM), respectively. The low dose decreased the heart rate, impaired the left ventricular mechanical function, and prolonged the ventricular effective refractory period. The high dose prolonged the repolarization period, induced hemorrhagic tendency, and increased plasma cardiac troponin I level in addition to enhancement of the changes observed after the low dose, whereas it neither affected the cardiac conduction nor induced ventricular arrhythmias. In the hiPSC-CMs, dasatinib prolonged the repolarization and refractory periods like in dogs, while it did not induce apoptotic or necrotic process, but that it increased the conduction speed. Clinically observed major cardiovascular adverse events of dasatinib were observed qualitatively by currently proposed assay protocol, which may become a useful guide for predicting the cardiotoxicity of new tyrosine kinase inhibitors.
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http://dx.doi.org/10.1007/s12012-019-09538-5DOI Listing
February 2020

Activation of DNA Damage Response and Cellular Senescence in Cardiac Fibroblasts Limit Cardiac Fibrosis After Myocardial Infarction.

Int Heart J 2019 Jul 28;60(4):944-957. Epub 2019 Jun 28.

Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine.

Cardiac fibrosis plays an important role in cardiac remodeling after myocardial infarction (MI). The molecular mechanisms that promote cardiac fibrosis after MI are well studied; however, the mechanisms by which the progression of cardiac fibrosis becomes attenuated after MI remain poorly understood. Recent reports show the role of cellular senescence in limiting tissue fibrosis. In the present study, we tested whether cellular senescence of cardiac fibroblasts (CFs) plays a role in attenuating the progression of cardiac fibrosis after MI. We found that the number of γH2AX-positive CFs increased up to day 7, whereas the number of proliferating CFs peaked at day 4 after MI. Senescent CFs were also observed at day 7, suggesting that attenuation of CF proliferation occurred simultaneously with the activation of the DNA damage response (DDR) system and the appearance of senescent CFs. We next cultured senescent CFs with non-senescent CFs and showed that senescent CFs suppressed proliferation of the surrounding non-senescent CFs in a juxtacrine manner. We also found that the blockade of DDR by Atm gene deletion sustained the proliferation of CFs and exacerbated the cardiac fibrosis at the early stage after MI. Our results indicate the role of DDR activation and cellular senescence in limiting cardiac fibrosis after MI. Regulation of cellular senescence in CFs may become one of the therapeutic strategies for preventing cardiac remodeling after MI.
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http://dx.doi.org/10.1536/ihj.18-701DOI Listing
July 2019

Author Correction: Activated β-catenin in Foxp3 regulatory T cells links inflammatory environments to autoimmunity.

Nat Immunol 2019 07;20(7):943

Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41590-019-0438-6DOI Listing
July 2019

Electropharmacological effects of intracellular Ca handling modulator caldaret on the heart assessed in the halothane-anesthetized dogs.

J Pharmacol Sci 2019 Mar 24;139(3):180-185. Epub 2019 Jan 24.

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.

We analyzed how the enhancement of net sarcoplasmic reticulum (SR) Ca uptake may affect cardiac electrophysiological properties in vivo by using caldaret which can decrease SR diastolic Ca leak, enhance SR Ca reuptake and inhibit reverse-mode Na/Ca exchanger. Caldaret in doses of 0.5, 5 and 50 μg/kg was intravenously administered over 10 min to the halothane-anesthetized beagle dogs (n = 5), attaining pharmacologically active plasma concentration. The low and middle doses of caldaret increased the ventricular contraction, which could be explained by its on-target pharmacological activities. The high dose enhanced the sinus automaticity followed by its suppression in addition to the increase of the total peripheral resistance, which may be unfavorable for treating diastolic heart failure. The low and middle doses enhanced the atrioventricular conduction, which may have some potential for predisposing the atria to the onset of atrial fibrillation via an induction of mitral and/or tricuspid regurgitation. The middle and high doses of caldaret prolonged the ventricular effective refractory period without altering the intraventricular conduction or repolarization period, which may prevent the onset of ventricular arrhythmias. Thus, modulation of intracellular Ca handling by caldaret can induce not only inotropic effect, but also various electrophysiological actions on the in situ heart.
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http://dx.doi.org/10.1016/j.jphs.2019.01.004DOI Listing
March 2019

Characterization of microminipig as a laboratory animal for safety pharmacology study by analyzing fluvoxamine-induced cardiovascular and dermatological adverse reactions.

Cardiovasc Toxicol 2019 10;19(5):412-421

Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.

Fluvoxamine is a selective serotonin-reuptake inhibitor, of which IC values for serotonin- and noradrenaline-uptake process were reported to be 3.8 and 620 nmol/L, respectively, also known to directly inhibit cardiac Na, Ca, and K channels. We characterized microminipig as a laboratory animal by analyzing fluvoxamine-induced cardiovascular and dermatological responses under halothane anesthesia. Fluvoxamine maleate was infused in doses of 0.1, 1, and 10 mg/kg over 10 min with a pause of 20 min (n = 4). The peak plasma concentrations were 35, 320, and 1906 ng/mL, of which free plasma concentrations were estimated as 20, 187, and 1108 nmol/L, respectively. The low and middle doses did not alter any cardiovascular variable. The high dose increased heart rate and mean blood pressure, prolonged QRS width, but shortened QT interval, whereas no significant change was detected in PR interval or QTcF. Moreover, it induced systemic erythema on the skin. Pretreatment of H/5-HT antagonist cyproheptadine hydrochloride sesquihydrate in a dose of 0.3 mg/kg significantly attenuated the fluvoxamine-induced pressor response; but tended to further enhance sinus automaticity, atrioventricular nodal conduction; and ventricular repolarization in addition to intraventricular conduction delay; whereas it markedly suppressed onset of systemic erythema (n = 4). In microminipigs, cardiovascular adverse effects of the high dose may be manifested as a sum of its inhibitory action on the cardiac ionic channels and its stimulatory effects on serotonergic and adrenergic systems, whereas dermatologic reaction can be induced primarily through H/5-HT receptor-dependent mechanism. Thus, microminipigs may be used for analyzing such multifarious adverse events of clinical serotonergic pharmacotherapy.
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http://dx.doi.org/10.1007/s12012-019-09509-wDOI Listing
October 2019

Measurement of J-Tc along with QT-Interval Prolongation May Increase the Assay Sensitivity and Specificity for Predicting the Onset of Drug-Induced Torsade de Pointes: Experimental Evidences Based on Proarrhythmia Model Animals.

Cardiovasc Toxicol 2019 08;19(4):357-364

Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.

dl-Sotalol which can block both K channel and ß-adrenoceptor has been shown to prolong the J-Tc of electrocardiogram in beagle dogs but tended to shorten it in microminipigs, although the drug prolonged the QT interval in both animals under physiologically maintained experimental condition. In order to estimate how the changes in the J-Tc in the normal hearts would be reflected in the pathologic hearts, we compared proarrhythmic effects of dl-sotalol by using proarrhythmia models of beagle dogs and microminipigs, of which atrioventricular node had been ablated > 2 months and 8-9 weeks before, respectively (n = 4 for each species). dl-Sotalol in an oral dose of 10 mg/kg induced torsade de pointes in three out of four beagle dogs, which degenerated into ventricular fibrillation. In microminipigs, the same dose did not trigger torsade de pointes at all, whereas intermittent ventricular pauses were observed in each animal after the drug treatment. These results indicate that assessment of the J-Tc along with the QT-interval prolongation in healthy subjects may provide reliable information of risk prediction for patients susceptible to the drug-induced torsade de pointes.
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http://dx.doi.org/10.1007/s12012-019-09506-zDOI Listing
August 2019

Characterization of a small molecule that promotes cell cycle activation of human induced pluripotent stem cell-derived cardiomyocytes.

J Mol Cell Cardiol 2019 03 23;128:90-95. Epub 2019 Jan 23.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. Electronic address:

Background: Since regenerative capacity of adult mammalian myocardium is limited, activation of the endogenous proliferative capacity of existing cardiomyocytes is a potential therapeutic strategy for treating heart diseases accompanied by cardiomyocyte loss. Recently, we performed a compound screening and developed a new drug named TT-10 (CHFNOS) which promotes the proliferation of murine cardiomyocytes via enhancement of YES-associated protein (YAP)-transcriptional enhancer factor domain (TEAD) activity and improves cardiac function after myocardial infarction in adult mice.

Methods And Results: To test whether TT-10 can also promote the proliferative capacity of human cardiomyocytes, we investigated the efficacy of TT-10 on human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSCMs). The hiPSCs were established from monocytes obtained from healthy donors and cardiac differentiation was performed using a chemically defined protocol. As was observed in murine cardiomyocytes, TT-10 markedly promoted cell cycle activation and increased cell division of hiPSCMs. We then evaluated other effects of TT-10 on the functional properties of hiPSCMs by gene expression and cell motion analyses. We observed that TT-10 had no unfavorable effects on the expression of functional and structural genes or the contractile properties of hiPSCMs.

Conclusions: Our results suggest that the novel drug TT-10 effectively activated the cell cycle of hiPSCMs without apparent functional impairment of myocardium, suggesting the potential of clinical usefulness of this drug.
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http://dx.doi.org/10.1016/j.yjmcc.2019.01.020DOI Listing
March 2019

High-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload.

J Mol Cell Cardiol 2019 03 3;128:77-89. Epub 2019 Jan 3.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address:

Background: The heart responds to hemodynamic overload through cardiac hypertrophy and activation of the fetal gene program. However, these changes have not been thoroughly examined in individual cardiomyocytes, and the relation between cardiomyocyte size and fetal gene expression remains elusive. We established a method of high-throughput single-molecule RNA imaging analysis of in vivo cardiomyocytes and determined spatial and temporal changes during the development of heart failure.

Methods And Results: We applied three novel single-cell analysis methods, namely, single-cell quantitative PCR (sc-qPCR), single-cell RNA sequencing (scRNA-seq), and single-molecule fluorescence in situ hybridization (smFISH). Isolated cardiomyocytes and cross sections from pressure overloaded murine hearts after transverse aortic constriction (TAC) were analyzed at an early hypertrophy stage (2 weeks, TAC2W) and at a late heart failure stage (8 weeks, TAC8W). Expression of myosin heavy chain β (Myh7), a representative fetal gene, was induced in some cardiomyocytes in TAC2W hearts and in more cardiomyocytes in TAC8W hearts. Expression levels of Myh7 varied considerably among cardiomyocytes. Myh7-expressing cardiomyocytes were significantly more abundant in the middle layer, compared with the inner or outer layers of TAC2W hearts, while such spatial differences were not observed in TAC8W hearts. Expression levels of Myh7 were inversely correlated with cardiomyocyte size and expression levels of mitochondria-related genes.

Conclusions: We developed a new image-analysis pipeline to allow automated and unbiased quantification of gene expression at the single-cell level and determined the spatial and temporal regulation of heterogenous Myh7 expression in cardiomyocytes after pressure overload.
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http://dx.doi.org/10.1016/j.yjmcc.2018.12.018DOI Listing
March 2019

Pressure Overload Impairs Cardiac Function in Long-Chain Fatty Acid Transporter CD36-Knockout Mice.

Int Heart J 2019 Jan 5;60(1):159-167. Epub 2018 Dec 5.

Rinku General Medical Center.

CD36 is one of the important transporters of long-chain fatty acids (LCFAs) in the myocardium. We previously reported that CD36-deficient patients demonstrate a marked reduction of myocardial uptake of LCFA, while myocardial glucose uptake shows a compensatory increase, and are often accompanied by cardiomyopathy. However, the molecular mechanisms and functional role of CD36 in the myocardium remain unknown.The current study aimed to explore the pathophysiological role of CD36 in the heart. Methods: Using wild type (WT) and knockout (KO) mice, we generated pressure overload by transverse aortic constriction (TAC) and analyzed cardiac functions by echocardiography. To assess cardiac hypertrophy and fibrosis, histological and molecular analyses and measurement of ATP concentration in mouse hearts were performed.By applying TAC, the survival rate was significantly lower in KO than that in WT mice. After TAC, KO mice showed significantly higher heart weight-to-tibial length ratio and larger cross-sectional area of cardiomyocytes than those of WT. Although left ventricular (LV) wall thickness in the KO mice was similar to that in the WT mice, the KO mice showed a significant enlargement of LV cavity and reduced LV fractional shortening compared to the WT mice with TAC. A tendency for decreased myocardial ATP concentration was observed in the KO mice compared to the WT mice after TAC operation.These data suggest that the LCFA transporter CD36 is required for the maintenance of energy provision, systolic function, and myocardial structure.
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http://dx.doi.org/10.1536/ihj.18-114DOI Listing
January 2019

Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury.

JACC Basic Transl Sci 2018 Oct 12;3(5):639-653. Epub 2018 Nov 12.

Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.

Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YES-associated protein and transcriptional enhancer factor domain activities in cardiomyocytes. We synthesized a novel fluorine-containing TT-10 (CHFNOS) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted antioxidant and antiapoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction-induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes with nuclear YES-associated protein expression. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.
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http://dx.doi.org/10.1016/j.jacbts.2018.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234526PMC
October 2018

Use of microminipigs for unveiling unknown mechanisms of azithromycin-induced cardiovascular death.

J Pharmacol Sci 2018 Nov 17;138(3):198-202. Epub 2018 Oct 17.

Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan; Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan. Electronic address:

Although azithromycin can suppress cardiac I, I, I, I and I, its onset mechanisms for cardiovascular death have not been fully investigated. We examined electropharmacological effects of azithromycin in intravenous doses of 0.3, 3 and 30 mg/kg using microminipigs under the halothane anesthesia (n = 4), which provided plasma concentrations of 3.1, 11.2 and 120.4 μg/mL, respectively. The low dose did not alter any of the cardiohemodynamic or electrocardiographic variables. The middle dose significantly shortened QT interval for 10-20 min and QTc for 10-30 min. The high dose significantly decreased mean blood pressure for 5-60 min, prolonged QRS width at 20 min, but shortened QT interval for 15-20 min and QTc for 15-30 min (n = 3). Cardiohemodynamic collapse occurred in 1 animal after the start of the high dose infusion, which might be associated with the cardiovascular death in patients with vasomotor dysfunction. Prolongation of QRS width indicates that azithromycin may suppress ventricular I in vivo, which may unmask latent type of Brugada electrocardiographic genotype. Meanwhile, abbreviation of the QTc might cause potentially lethal, short QT-related, cardiac arrhythmia syndrome. These findings with microminipigs suggest the possible entry point for analyzing the mechanisms of cardiovascular death clinically seen with this antibiotic.
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http://dx.doi.org/10.1016/j.jphs.2018.10.003DOI Listing
November 2018

Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure.

Nat Commun 2018 10 30;9(1):4435. Epub 2018 Oct 30.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.
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http://dx.doi.org/10.1038/s41467-018-06639-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207673PMC
October 2018

Activated β-catenin in Foxp3 regulatory T cells links inflammatory environments to autoimmunity.

Nat Immunol 2018 12 29;19(12):1391-1402. Epub 2018 Oct 29.

Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.

Foxp3 regulatory T cells (T cells) are the central component of peripheral immune tolerance. Whereas a dysregulated T cytokine signature has been observed in autoimmune diseases, the regulatory mechanisms underlying pro- and anti-inflammatory cytokine production are elusive. Here, we identify an imbalance between the cytokines IFN-γ and IL-10 as a shared T signature present in patients with multiple sclerosis and under high-salt conditions. RNA-sequencing analysis on human T subpopulations revealed β-catenin as a key regulator of IFN-γ and IL-10 expression. The activated β-catenin signature was enriched in human IFN-γ T cells, as confirmed in vivo with T-specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional T phenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-γ and IL-10 production under a high-salt environment, with skewed activation of the β-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-β-catenin loop in T cells linking environmental high-salt conditions to autoimmunity.
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http://dx.doi.org/10.1038/s41590-018-0236-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240373PMC
December 2018

Author Correction: Activation of endothelial β-catenin signaling induces heart failure.

Sci Rep 2018 Oct 29;8(1):15858. Epub 2018 Oct 29.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-34062-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206138PMC
October 2018

Application of human induced pluripotent stem cell-derived cardiomyocytes sheets with microelectrode array system to estimate antiarrhythmic properties of multi-ion channel blockers.

J Pharmacol Sci 2018 Aug 4;137(4):372-378. Epub 2018 Aug 4.

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan; Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan. Electronic address:

We examined electrophysiological indices of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets in order to quantitatively estimate Na, K and Ca channel blocking actions of bepridil and amiodarone using microelectrode array system in comparison with that of E-4031. We analyzed the field potential duration, effective refractory period, current threshold and conduction property using a programmed electrical stimulation protocol to obtain the post repolarization refractoriness and coefficient a of the relationship between the pacing cycle length and field potential duration. Electropharmacological profile of each drug was successfully characterized; namely, 1) the changes in the current threshold and conduction property provided basic information of Na channel blocking kinetics, 2) the relationship between pacing cycle length and field potential duration reflected drug-induced inhibition of human ether-à-go-go-related gene (hERG) K channel, 3) the post repolarization refractoriness indicated the relative contribution of these drugs to Na and K channel blockade, and 4) L-type Ca channel blocking action was more obvious in the field potential waveform of the hiPSC-CMs sheets than that expected in the electrocardiogram in humans. Thus, this information may help to better utilize the hiPSC-CMs sheets for grasping the properties and net effects of drug-induced Na, Ca and K channel blockade.
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http://dx.doi.org/10.1016/j.jphs.2018.07.011DOI Listing
August 2018

Phenotypic Screening Using Patient-Derived Induced Pluripotent Stem Cells Identified Pyr3 as a Candidate Compound for the Treatment of Infantile Hypertrophic Cardiomyopathy.

Int Heart J 2018 Sep 11;59(5):1096-1105. Epub 2018 Aug 11.

Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by hypertrophy of the myocardium. Some of the patients are diagnosed for HCM during infancy, and the prognosis of infantile HCM is worse than general HCM. Nevertheless, pathophysiology of infantile HCM is less investigated and remains largely unknown. In the present study, we generated induced pluripotent stem cells (iPSCs) from two patients with infantile HCM: one with Noonan syndrome and the other with idiopathic HCM. We found that iPSC-derived cardiomyocytes (iPSC-CMs) from idiopathic HCM patient were significantly larger and showed higher diastolic intracellular calcium concentration compared with the iPSC-CMs from healthy subject. Unlike iPSC-CMs from the adult/adolescent HCM patient, arrhythmia was not observed as a disease-related phenotype in iPSC-CMs from idiopathic infantile HCM patient. Phenotypic screening revealed that Pyr3, a transient receptor potential channel 3 channel inhibitor, decreased both the cell size and diastolic intracellular calcium concentration in iPSC-CMs from both Noonan syndrome and idiopathic infantile HCM patients, suggesting that the target of Pyr3 may play a role in the pathogenesis of infantile HCM, regardless of the etiology. Further research may unveil the possibility of Pyr3 or its derivatives in the treatment of infantile HCM.
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http://dx.doi.org/10.1536/ihj.17-730DOI Listing
September 2018

Electropharmacological characterization of microminipigs as a laboratory animal using anti-influenza virus drug oseltamivir.

J Toxicol Sci 2018 ;43(8):507-512

Department of Pharmacology, Toho University Graduate School of Medicine.

We analyzed electropharmacological characteristics of microminipigs under halothane-anesthesia using anti-influenza virus drug oseltamivir, which has been known to possess multi-channel blocking properties, including Na, Ca and K channels (n = 4). Oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously infused over 10 min with an interval of 20 min, which provided peak plasma concentrations 1.4, 7.4 and 125.5 µg/mL, respectively. The low dose did not alter any of the cardiovascular variables. The middle dose decreased the heart rate at 30 min after the start of the infusion. The high dose transiently returned the heart rate toward the baseline for 10-15 min, but decreased it for 20-60 min; decreased the mean blood pressure for 5-60 min; prolonged the PR interval for 10-60 min, and the QRS width for 10-20 min; but shortened the QT interval for 10-30 min, and the QTc for 5-60 min. Thus, oseltamivir can suppress the sinus automaticity, and atrioventricular nodal and intraventricular conduction; and decrease the mean blood pressure, extents of which were greater in microminipigs than in beagle dogs in our previous observation in spite of similar plasma concentrations, reflecting higher sensitivity of microminipigs for Na and Ca channel inhibition than that of beagle dogs. In contrast to beagle dogs, oseltamivir shortened the repolarization period in microminipigs, indicating that oseltamivir can more potently inhibit the inward currents than the outward ones in the hearts of microminipigs. This information may help improve utilizatione of microminipigs as a laboratory animal.
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http://dx.doi.org/10.2131/jts.43.507DOI Listing
August 2018

Generation of Fabry cardiomyopathy model for drug screening using induced pluripotent stem cell-derived cardiomyocytes from a female Fabry patient.

J Mol Cell Cardiol 2018 08 23;121:256-265. Epub 2018 Jul 23.

Department of Cardiovascular Medicine, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Tokyo 113-8655, Japan.

Background: Fabry disease is an X-linked disease caused by mutations in α-galactosidase A (GLA); these mutations result in the accumulation of its substrates, mainly globotriaosylceramide (Gb3). The accumulation of glycosphingolipids induces pathogenic changes in various organs, including the heart, and Fabry cardiomyopathy is the most frequent cause of death in patients with Fabry disease. Existing therapies to treat Fabry disease have limited efficacy, and new approaches to improve the prognosis of patients with Fabry cardiomyopathy are required.

Methods And Results: We generated induced pluripotent stem cell (iPSC) lines from a female patient and her son. Each iPSC clone from the female patient showed either deficient or normal GLA activity, which could be used as a Fabry disease model or its isogenic control, respectively. Erosion of the inactivated X chromosome developed heterogeneously among clones, and mono-allelic expression of the GLA gene was maintained for a substantial period in a subset of iPSC clones. Gb3 accumulation was observed in iPSC-derived cardiomyocytes (iPS-CMs) from GLA activity-deficient iPSCs by mass-spectrometry and immunofluorescent staining. The expression of ANP was increased, but the cell surface area was decreased in iPS-CMs from the Fabry model, suggesting that cardiomyopathic change is ongoing at the molecular level in Fabry iPS-CMs. We also established an algorithm for selecting proper Gb3 staining that could be used for high-content analysis-based drug screening.

Conclusions: We generated a Fabry cardiomyopathy model and a drug screening system by using iPS-CMs from a female Fabry patient. Drug screening using our system may help discover new drugs that would improve the prognosis of patients with Fabry cardiomyopathy.
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http://dx.doi.org/10.1016/j.yjmcc.2018.07.246DOI Listing
August 2018

Analysis of torsadogenic and pharmacokinetic profile of E-4031 in dogs bridging the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects.

J Pharmacol Sci 2018 Jun 18;137(2):237-240. Epub 2018 Jun 18.

Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan. Electronic address:

We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively (n = 2). These results bridge the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects.
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http://dx.doi.org/10.1016/j.jphs.2018.06.005DOI Listing
June 2018

Analysis of Safety Margin of Lithium Carbonate Against Cardiovascular Adverse Events Assessed in the Halothane-Anesthetized Dogs.

Cardiovasc Toxicol 2018 12;18(6):530-536

Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.

Lithium is one of the classical drugs that have been widely used for treating bipolar disorder. However, several cardiac side effects including sick sinus syndrome, bundle branch block, ventricular tachycardia/fibrillation, non-specific T-wave abnormalities in addition to Brugada-type electrocardiographic changes have been noticed in patients who were given antidepressant, anticonvulsant, and/or antipsychotic drugs besides lithium. In this study, we assessed cardiohemodynamic and electrophysiological effects of lithium carbonate by itself to begin to analyze onset mechanisms of its cardiovascular side effects. Lithium carbonate in intravenous doses of 0.1, 1, and 10 mg/kg over 10 min was cumulatively administered with an interval of 20 min to the halothane-anesthetized beagle dogs (n = 4), which provided peak plasma Li concentrations of 0.02, 0.18, and 1.79 mEq/L, respectively, reflecting sub-therapeutic to toxic concentrations. The low and middle doses prolonged the ventricular effective refractory period at 30 min and for 5-30 min, respectively. The high dose decreased the heart rate for 45-60 min, delayed the intraventricular conduction for 15-20 min and the ventricular repolarization at 45 min, and prolonged the effective refractory period for 5-60 min. No significant change was detected in the other cardiovascular variables. Thus, lithium alone may have a wide safety margin against hemodynamic adverse events; however, it would directly and/or indirectly inhibit Na and K channels, which may synergistically increase the ventricular refractoriness from the sub-therapeutic concentration and decrease the heart rate at the supra-therapeutic one. These findings may partly explain its clinically observed various types of arrhythmias as well as electrocardiographic changes.
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http://dx.doi.org/10.1007/s12012-018-9464-0DOI Listing
December 2018

Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction.

Cancer Chemother Pharmacol 2018 07 2;82(1):65-75. Epub 2018 May 2.

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.

Purpose: Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I  were measured.

Methods: Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval.

Results: Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30-60 min after the high dose without altering the other biomarkers.

Conclusions: Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.
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http://dx.doi.org/10.1007/s00280-018-3593-9DOI Listing
July 2018

Effects of moxifloxacin on the proarrhythmic surrogate markers in healthy Filipino subjects: Exposure-response modeling using ECG data of thorough QT/QTc study.

J Pharmacol Sci 2018 Apr 27;136(4):234-241. Epub 2018 Mar 27.

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan. Electronic address:

Effects of moxifloxacin on QTc as well as proarrhythmic surrogate markers including J-Tc, T-T and short-term variability (STV) of repolarization were examined by using both standard E14 time-based evaluation and exposure-response modeling. The study was conducted with a single-blind, randomized, single-dose, placebo-controlled and two-period cross-over design in healthy Filipino subjects. QT interval was corrected by Fridericia's formula (QTcF). In the E14 time-based evaluation of ECG data, the largest ΔΔQTcF with 90% confidence interval was 14.1 ms (11.2-16.9) with C of 3.39 μg/mL at 3 h post-dose (n = 69; male: 35, female: 34), indicating a positive effect on the QTcF. Moxifloxacin significantly increased the ΔΔJ-Tc and ΔΔT-T, whereas the ΔΔSTV was not altered. Meanwhile in the exposure-response modeling of the same ECG data, the slope of moxifloxacin plasma concentration-ΔΔQTcF relationship was 4.84 ms per μg/mL and the predicted ΔΔQTcF with 90% confidence interval was 13.8 ms (13.1-15.1) at C, also indicating a positive effect on the QTcF. Importantly, results in each proarrhythmic surrogate marker obtained by the exposure-response modeling also showed high similarity to those obtained by the E14 statistical evaluation. Thus, these results of moxifloxacin may become a guide to estimate proarrhythmic potential of new chemical entities.
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http://dx.doi.org/10.1016/j.jphs.2018.01.009DOI Listing
April 2018

Comparison of electropharmacological effects between terfenadine and its active derivative fexofenadine using a cross-over study in halothane-anesthetized dogs to analyze variability of pharmacodynamic and pharmacokinetic profiles of terfenadine and torsadogenic risk of fexofenadine.

J Toxicol Sci 2018 ;43(3):183-192

Department of Pharmacology, Faculty of Medicine, Toho University.

In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and quantitatively examine the proarrhythmic potential of its major active metabolite fexofenadine in comparison with that of terfenadine, we directly compared their electropharmacological effects with halothane-anesthetized dogs (n = 3). For this purpose, we adopted a cross-over design, which can directly compare the effects of terfenadine and fexofenadine under the identical metabolic condition. Terfenadine in doses of 0.03 and 0.3 mg/kg increased the mean blood pressure, but that of 3 mg/kg decreased it. Terfenadine also increased the heart rate and ventricular contractility in a dose-related manner; but delayed the atrioventricular nodal and intraventricular conductions as well as repolarization suggesting its proarrhythmic potential. Meanwhile, fexofenadine in the same dose increased the mean blood pressure in a dose-related manner without affecting any of the electrophysiological variables in the same animals that proarrhythmic risk of terfenadine was confirmed, indicating its lack of proarrhythmic risk. Peak plasma concentrations for fexofenadine were 3.7, 8.1 and 11.2 times greater than for terfenadine at each matching dose, indicating terfenadine may be metabolized much faster than fexofenadine. Taken together, after the low and middle doses of terfenadine, vasopressor effect of a metabolite fexofenadine could be greater than the depressor effect of parent compound terfenadine, but its reverse would be correct after the high dose. Thus, the cross-over analysis can be an effective way to better understand drug-induced cardiovascular responses.
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http://dx.doi.org/10.2131/jts.43.183DOI Listing
August 2018

Changes of electrocardiogram and hemodynamics in response to dipyridamole: In vivo comparative analyses using anesthetized beagle dogs and microminipigs.

J Pharmacol Sci 2018 Feb 2;136(2):86-92. Epub 2018 Feb 2.

Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan; Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan. Electronic address:

Microminipigs are expected as a novel animal model for cardiovascular pharmacological experiments. Since inherent vulnerability of coronary circulation of microminipigs has not been characterized, we performed dipyridamole-stress test to both microminipigs and beagle dogs, and compared the results. Dipyridamole in doses of 0.056 and 0.56 mg/kg were intravenously infused over 10 min (n = 4 for each animal). Dipyridamole decreased the systolic/diastolic blood pressures and double product in dogs as well as in microminipigs; but it did not significantly alter the heart rate or the global balance between the myocardial oxygen demand and supply in either animal. While organic coronary arterial stenosis was not detected in either animal, dogs have well-developed epicardial intracoronary networks unlike microminipigs. Like in humans, dipyridamole did not affect the ST segment of microminipigs, whereas it substantially depressed that in dogs. The results indicate the onset of subendocardial ischemia by dipyridamole in dogs may be partly associated with their well-developed native coronary collateral channels. Microminipigs would be more useful to evaluate the drugs which may affect the coronary circulation in the pre-clinical study than dogs.
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http://dx.doi.org/10.1016/j.jphs.2018.01.002DOI Listing
February 2018

Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling.

Sci Rep 2018 01 31;8(1):1998. Epub 2018 Jan 31.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically heterogeneous. Cardiac function is improved after treatment in some cardiomyopathy patients, but little is known about genetic predictors of long-term outcomes and myocardial recovery following medical treatment. To elucidate the genetic basis of cardiomyopathy in Japan and the genotypes involved in prognosis and left ventricular reverse remodeling (LVRR), we performed targeted sequencing on 120 DCM (70 sporadic and 50 familial) and 52 HCM (15 sporadic and 37 familial) patients and integrated their genotypes with clinical phenotypes. Among the 120 DCM patients, 20 (16.7%) had TTN truncating variants and 13 (10.8%) had LMNA variants. TTN truncating variants were the major cause of sporadic DCM (21.4% of sporadic cases) as with Caucasians, whereas LMNA variants, which include a novel recurrent LMNA E115M variant, were the most frequent in familial DCM (24.0% of familial cases) unlike Caucasians. Of the 52 HCM patients, MYH7 and MYBPC3 variants were the most common (12 (23.1%) had MYH7 variants and 11 (21.2%) had MYBPC3 variants) as with Caucasians. DCM patients harboring TTN truncating variants had better prognosis than those with LMNA variants. Most patients with TTN truncating variants achieved LVRR, unlike most patients with LMNA variants.
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http://dx.doi.org/10.1038/s41598-018-20114-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792481PMC
January 2018