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BACKGROUND: The guideline-recommended low-density lipoprotein cholesterol target level of <70 mg/dL may not be achieved with statin administration in some patients with acute coronary syndrome (ACS). Therefore, the proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody can be added to high-risk patients with ACS. Nevertheless, the optimal duration of PCSK9 antibody administration remains unclear. METHODS AND RESULTS: Patients were randomized to receive either 3 months of lipid lowering therapy (LLT) with the PCSK9 antibody followed by conventional LLT (with-PCSK9-antibody group) or 12 months of conventional LLT alone (without-PCSK9-antibody group). The primary endpoint was the composite of all-cause death, myocardial infarction, stroke, unstable angina, and ischemia-driven revascularization. A total of 124 patients treated with percutaneous coronary intervention (PCI) were randomly assigned to the two groups (n = 62 in each). The primary composite outcome occurred in 9.7% and 14.5% of the patients in the with- and without-PCSK9-antibody groups, respectively (hazard ratio: 0.70; 95% confidence interval: 0.25 to 1.97; p = 0.498). The two groups showed no significant differences in hospitalization for worsening heart failure and adverse events. CONCLUSIONS: In ACS patients who underwent PCI, short-term PCSK9 antibody therapy with conventional LLT was feasible in this pilot clinical trial. Long-term follow-up in a larger scale clinical trial is warranted.
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Accumulating evidence has revealed pivotal roles of glycogen synthase kinase-3ß (GSK3ß) inactivation on cardiac protection. Because the precise mechanisms of cardiac protection against ischemia/reperfusion (I/R) injury by GSK3ß-inactivation remain elusive, we investigated the relationship between GSK3ß-mediated mitochondrial hexokinase II (mitoHK-II; a downstream target of GSK3ß) dissociation and mitochondrial permeability transition pore (mPTP) opening. In Langendorff-perfused hearts, GSK3ß inactivation by SB216763 improved the left ventricular-developed pressure and retained mitoHK-II binding after I/R. In permeabilized myocytes, GSK3ß depolarized mitochondrial membrane potential with accelerated mitochondrial calcein release (suggesting GSK3ß-mediated mPTP opening) and decreased mitoHK-II bindings. GSK3ß-mediated mPTP opening depended on mitoHK-II binding, i.e., it was accelerated by dissociation of mitoHK-II (dicyclohexylcarbodiimide) and attenuated by enhancement of mitoHK-II binding (dextran). However, inactivation of mitoHK-II by glucose-depletion or glucose-6-phosphate inhibited the GSK3ß-mediated mPTP opening. We conclude that GSK3ß-mediated mPTP opening may be involved in I/R injury and regulated by mitoHK-II binding and activity.
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Glucógeno Sintasa Quinasa 3 beta/farmacología , Hexoquinasa/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias Cardíacas/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Animales , Masculino , Mitocondrias Cardíacas/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Miocitos Cardíacos/metabolismo , Permeabilidad/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Experimental testicular teratomas (ETTs) can be induced in 129/Sv mouse by E12.5 fetal testes transplant into adult testes. Previously, we conducted linkage analysis to explore candidate genes possibly involved in ETT development using F2 intercross fetuses derived from F1[LTXBJ × 129/Sv- + /Ter (+ /+)] hybrids. By linkage analysis on Chr 18 and Chr 19, we identified the genomic locus for experimental testicular teratoma 1 (ett1) on Chr 18. In the present study, we conducted additional mapping and linkage analysis on teratoma susceptibility and genome composition on Chr 1-17. The results revealed two new candidate loci, experimental testicular teratoma 2 (ett2) and experimental testicular teratoma 3 (ett3), on Chr 3 and 7. Interestingly, the rates of ETT generation were increased in the case of ett2 and ett3 regions replaced with LTXBJ strain. To determine whether a polymorphic gene was present, we performed exome analysis of 129/Sv- + /Ter (+ /+) and LTXBJ. This revealed the presence of SNPs in all three loci, ett1 to ett3. ett1 contains polymorphic Mc4r; ett2 contains polymorphic Polr3c, Cd160, and Pdzk1; and ett3 contains polymorphic Prmt3. We found additional loci responsible for ETT formation, namely, ett2 and ett3, and identified candidate genes in these regions by exome analysis.
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Sitios Genéticos , Genoma , Polimorfismo Genético , Teratoma/genética , Neoplasias Testiculares/genética , Animales , Masculino , Ratones , Ratones de la Cepa 129 , Teratoma/metabolismo , Neoplasias Testiculares/metabolismoRESUMEN
BACKGROUND: Emerging evidence suggested the preferable effects of eicosapentaenoic acid (EPA; n-3 polyunsaturated fatty acid) against cardiac lipotoxicity, which worsens cardiac function by means of excessive serum free fatty acids due to chronic adrenergic stimulation under heart failure. Nonetheless, the precise molecular mechanisms remain elusive. In this study, we focused on dynamin-related protein-1 (Drp1) as a possible modulator of the EPA-mediated cardiac protection against cardiac lipotoxicity, and investigated the causal relation between AMP-activated protein kinase (AMPK) and Drp1. METHODS AND RESULTS: When differentiated H9c2 myocytes were exposed to palmitate (PAL; saturated fatty acid, 400µM) for 24h, these myocytes showed activation of caspases 3 and 7, enhanced caspase 3 cleavage, depolarized mitochondrial membrane potential, depleted intracellular ATP, and enhanced production of intracellular reactive oxygen species. These changes suggested lipotoxicity due to excessive PAL. PAL enhanced mitochondrial fragmentation with increased Drp1 expression, as well. EPA (50µM) restored the PAL-induced apoptosis, mitochondrial dysfunction, and mitochondrial fragmentation with increased Drp1 expression by PAL. EPA activated phosphorylation of AMPK, and pharmacological activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleotide ameliorated the PAL-induced apoptosis, mitochondrial dysfunction, and downregulated Drp1. An AMPK knockdown via RNA interference enhanced Drp1 expression and attenuated the protective effects of EPA against the PAL-induced lipotoxicity. CONCLUSION: EPA ameliorates the PAL-induced lipotoxicity via AMPK activation, which subsequently suppresses mitochondrial fragmentation and Drp1 expression. Our findings may provide new insights into the molecular mechanisms of EPA-mediated myocardial protection in heart failure.
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Cardiotónicos/farmacología , Ácido Eicosapentaenoico/farmacología , Mioblastos Cardíacos/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Línea Celular , Dinaminas/genética , Dinaminas/metabolismo , Mioblastos Cardíacos/metabolismo , Palmitatos/toxicidad , Ratas , Transducción de SeñalRESUMEN
Although beneficial effects of non-secreting intracellular renin (ns-renin) against ischemia have been reported, the precise mechanism remains unclear. In this study, we investigated the roles of ns-renin and mitochondrial extracellular signal-related kinase (ERK) 1/2 on mitochondrial permeability transition pore (mPTP) opening during ischemia in diabetes mellitus (DM) hearts. When isolated hearts from Wistar rats (non-DM hearts) and Goto-Kakizaki rats (DM hearts) were subjected to ischemia for 70 min by left anterior descending coronary artery ligation, DM hearts exhibited higher left ventricular (LV) developed pressure and lower LV end-diastolic pressure than non-DM hearts, suggesting ischemic resistance. In addition, DM hearts showed increased intracellular renin (int-renin, including secreting and non-secreting renin) in the ischemic area, and a direct renin inhibitor (DRI; aliskiren) attenuated ischemic resistance in DM hearts. ERK1/2 was significantly phosphorylated after ischemia in both whole cell and mitochondrial fractions in DM hearts. In isolated mitochondria from DM hearts, rat recombinant renin (r-renin) significantly phosphorylated mitochondrial ERK1/2, and hyperpolarized mitochondrial membrane potential (ΔΨm) in a U0126 (an inhibitor of mitogen-activated protein kinases/ERK kinases)-sensitive manner. R-renin also attenuated atractyloside (Atr, an mPTP opener)-induced ΔΨm depolarization and Atr-induced mitochondrial swelling in an U0126-sensitive manner in isolated mitochondria from DM hearts. Furthermore, U0126 attenuated ischemic resistance in DM hearts, whereas it did not alter the hemodynamics in non-DM hearts. Our results suggest that the increased int-renin during ischemia may inhibit mPTP opening through activation of mitochondrial ERK1/2, which may be involved in ischemic resistance in DM hearts.
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Diabetes Mellitus Experimental/complicaciones , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Mitocondrias Cardíacas/enzimología , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Isquemia Miocárdica/complicaciones , Renina/farmacología , Animales , Atractilósido/farmacología , Butadienos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/enzimología , Activación Enzimática/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias Cardíacas/efectos de los fármacos , Poro de Transición de la Permeabilidad Mitocondrial , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/enzimología , Nitrilos/farmacología , Ratas , Proteínas Recombinantes/farmacologíaRESUMEN
The aim of this study was to reveal the pathogenesis of aortic stenosis (AS) and regurgitation (AR) by comparing differences in mechanical and biochemical alterations. We applied scanning acoustic microscopy (SAM) to measure the speed of sound (SOS) through valves to estimate the elasticity and monitor sensitivity to protease treatment, as the SOS is correlated with the stiffness of materials, which is reduced after digestion by proteases. The fibrosa of both the AS and AR groups were stiffer than the fibrosa of the normal group. The AR group displayed significantly stiffer fibrosa than the AS group, with the exception of calcified areas. The AS group showed significantly decreased SOS values following protease digestion, whereas the AR showed little reduction. The AS group presented type III collagen in the fibrosa and the ventricularis. In the AR group, both type I collagen and type III collagen coexisted in the fibrosa and the ventricularis. Upon immunostaining for advanced glycation end-products, the AS group showed sparse, weak staining, whereas the AR group presented a strong, band-like positive reaction in the fibrosa. In conclusion, tissue remodelling associated with damage and repair is associated with AS pathogenesis, whereas static chemical alterations with slow collagen turnover induce AR.
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Insuficiencia de la Válvula Aórtica/patología , Insuficiencia de la Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/fisiopatología , Válvula Aórtica/patología , Válvula Aórtica/fisiopatología , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Colágeno/metabolismo , Colágeno/ultraestructura , Módulo de Elasticidad , Femenino , Humanos , Masculino , Microscopía Acústica , Valores de ReferenciaRESUMEN
Cardiac involvement of sarcoid lesions is diagnosed by myocardial biopsy which is frequently false-negative, and patients with cardiac sarcoidosis (CS) who have impaired left ventricular (LV) systolic function are sometimes diagnosed with dilated cardiomyopathy (DCM). Late gadolinium enhancement (LE) in magnetic resonance imaging is now a critical finding in diagnosing CS, and the novel Japanese guideline considers myocardial LE to be a major criterion of CS. This article describes the value of LE in patients with CS who have impaired LV systolic function, particularly the diagnostic and clinical significance of LE distribution in comparison with DCM. LE existed at all LV segments and myocardial layers in patients with CS, whereas it was localized predominantly in the midwall of basal to mid septum in those with DCM. Transmural (nodular), circumferential, and subepicardial and subendocardial LE distribution were highly specific in patients with CS, whereas the prevalence of striated midwall LE were high both in patients with CS and with DCM. Since sarcoidosis patients with LE have higher incidences of heart failure symptoms, ventricular tachyarrhythmia and sudden cardiac death, the analyses of extent and distribution of LE are crucial in early diagnosis and therapeutic approach for patients with CS.
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A 78-year-old male was admitted to our hospital due to frequent palpitation. His electrocardiogram (ECG) presented regular narrow QRS tachycardia with 170 bpm, and catheter ablation was planned. During electroanatomical mapping of the right atrium (RA) with a multiloop mapping catheter, the catheter head was entrapped nearby the ostium of inferior vena cava. Rotation and traction of the catheter failed to detach the catheter head from the RA wall. Exfoliation of connective tissue twined around catheter tip by forceps, which were designed for endomyocardial biopsy, succeeded to retract and remove the catheter. Postprocedural echocardiography and pathologic examination proved the existence of Chiari's network. The handling of complex catheters in the RA has a potential risk of entrapment with Chiari's network.
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PURPOSE: To examine how left ventricular (LV) volume and function affect flow dynamics by analyzing 3D intra-LV vortex features using 4D-Flow. MATERIALS AND METHODS: Twenty-one patients with preserved (LVEF > 60%) and 14 with impaired LV function (LVEF < 40%) underwent 4D-Flow (at 3T). RESULTS: In patients with preserved LV function, the intra-LV vortices developed in both the early and late diastolic phases. The shift of inflow vectors at the basal LV toward the posterior-lateral side of the LV and the mid-ventricular turn of inflow vectors toward the LV outflow could explain clearer vortex formation in the late diastolic phase. In patients with impaired LV function, the intra-LV vortices during the diastolic phase located at the more apical LV were larger and more spherically shaped. Both the distance to the vortex core and the vortex area correlated significantly with LV end-diastolic volume (r = 0.66 and 0.73), LVEF (r = -0.74 and -0.68), LV sphericity index (r = -0.60 and -0.65), and peak filling rate (r = -0.61 and -0.64), respectively (P < 0.01). The intra-LV vortices developed during the systolic phase in 10 cases. In those, some of the particles at the apical LV rotated within the LV, whereas in patients with preserved LV function, all of the particles were directed straight to the ascending aorta with accelerated flow velocity (256.8 ± 120.2 cm/s vs. 414.3 ± 88.2 cm/s, P < 0.01). CONCLUSION: Vortex formation during the diastolic phase may be critical for both LV filling and ejection. 4D-Flow showed the 3D alterations of intra-LV flow dynamics by LV dilatation and dysfunction in a noninvasive and comprehensive manner. J. Magn. Reson. Imaging 2016;44:1493-1503.
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Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Imagenología Tridimensional/métodos , Imagen por Resonancia Cinemagnética/métodos , Volumen Sistólico , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Adulto , Algoritmos , Velocidad del Flujo Sanguíneo , Técnicas de Imagen Cardíaca/métodos , Medios de Contraste , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Angiografía por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Analysis of the hematopoiesis of non-human primates is important to clarify the evolution of primate-specific hematopoiesis and immune regulation. However, the engraftment and development of the primate hematopoietic system are well-documented only in humans and are not clear in non-human primates. Callithrix jacchus (common marmoset, CM) is a New World monkey with a high rate of pregnancy and small size that lives in closed colonies. As stem cell factor (SCF) is an essential molecule for hematopoietic stem cell development in mice and humans, we focused on CD117, the SCF receptor, and examined whether CD117-expressing cells possess the hematopoietic stem/progenitor cell characteristics of newborn marmoset-derived hematopoietic cells that can develop into T cells and B cells. When CD117(+) cell fractions of the bone marrow were transplanted into immunodeficient NOD (non-obese diabetic)/Shi-scid, common γc-null (NOG) mice, these cells engrafted efficiently in the bone marrow and spleens of the NOG mice. The CD117(+) cells developed into myeloid lineage cells, CD20(+) B cells and CD3(+) T cells, which could express CM cytokines in vivo. The development of B cells did not precede that of T cells. The development of CD8(+) T cells was dominant in NOG mice. The engraftment was comparable for both CD117(+)CD34(+) cells and CD117(+)CD34(-) cells. These results suggest that the CD117(+) cell fraction can differentiate into all three cell lineages, and the development of marmoset immunity in the xenogeneic environment follows diverse developmental pathways compared with human immunity.
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Diferenciación Celular , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Animales , Animales Recién Nacidos , Antígenos de Superficie/metabolismo , Callithrix , Autorrenovación de las Células , Sangre Fetal/citología , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Inmunofenotipificación , Linfocitos/citología , Linfocitos/metabolismo , Ratones , Células Mieloides/citología , Células Mieloides/metabolismo , FenotipoRESUMEN
The common marmoset (Callithrix jacchus) is a New World primate that is a useful model for medical studies. In this study, we report a convenient, reliable, and noninvasive procedure to genotype a living common marmoset by using fingernails. This method was used to successfully genotype DNA by restriction fragment length polymorphism (RFLP) PCR without prior purification, by using the KOD FX PCR enzyme kit. Additionally, there is no sample contamination from hematopoietic chimera derived from fused placenta in utero. We compared chimeric levels between various tissues in females with male littermates using quantitative fluorescent (QF)-PCR to prepare a reliable DNA source for genetic analyses, such as genotyping, gene mapping, or genomic sequencing. The chimerism detected appeared to be restricted to lymphatic tissues, such as bone marrow, thymus, spleen, lymph nodes and blood cells. As a result, DNA from fingernails with the quick is the best DNA source for genetic research in living marmosets.
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Callithrix/genética , ADN/genética , Técnicas de Genotipaje/métodos , Uñas/química , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Animales , Femenino , Masculino , Modelos AnimalesRESUMEN
The common marmoset, Callithrix jacchus, is used as a New World monkey species in biomedical studies because of its small body size and good reproduction in captivity. A modified artificial insemination technique was developed in this species to encourage breeding of lines carrying interesting genes and traits. Fresh semen was collected by penile vibratory stimulation. Medium containing highly motile sperm was inseminated into the uterus using a catheter. Seven females were inseminated using freshly prepared sperm from different males every day for 3 days including the expected ovulation day. As a result, four females conceived, and three females delivered six offspring in total (two singletons and one quadruplet). The paternity of the newborns was determined using microsatellite markers to accurately pinpoint the timing of insemination and ovulation. It is expected that our artificial insemination protocol can be effectively used to establish marmoset lines and genetically manage marmoset colonies.
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Callithrix/fisiología , Inseminación Artificial/veterinaria , Pene/fisiología , Motilidad Espermática/fisiología , Animales , Cruzamiento/métodos , Femenino , Inseminación Artificial/métodos , Masculino , Estimulación Física , Embarazo , Semen , Recolección de Tejidos y Órganos/métodos , Recolección de Tejidos y Órganos/veterinaria , VibraciónRESUMEN
BACKGROUND: The intra-left atrial (LA) blood flow from pulmonary veins (PVs) to the left ventricle (LV) changes under various conditions and might affect global cardiac function. By using phase-resolved 3-dimensional cine phase contrast magnetic resonance imaging (4D-Flow), the intra-LA vortex formation was visualized and the factors affecting the intra-LA flow dynamics were examined. METHODS AND RESULTS: Thirty-two patients with or without organic heart diseases underwent 4D-Flow and transthoracic echocardiography. The intra-LA velocity vectors from each PV were post-processed to delineate streamline and pathline images. The vector images revealed intra-LA vortex formation in 20 of 32 patients. All the vortices developed during the late systolic and early diastolic phases and were directed counter-clockwise when viewed from the subjects' cranial side. The flow vectors from the right PVs lengthened predominantly toward the mitral valves and partly toward the LA appendage, whereas those from the left PVs directed rightward along the posterior wall and joined the vortex. Patients with vortex had less organic heart diseases, smaller LV and LA volume, and greater peak flow velocity and volume mainly in the left PVs, although the flow directions from each PV or PV areas did not differ. CONCLUSIONS: 4D-Flow can clearly visualize the intra-LA vortex formation and analyze its characteristic features. The vortex formation might depend on LV and LA volume and on flow velocity and volume from PVs.
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Cardiomiopatías/fisiopatología , Atrios Cardíacos/fisiopatología , Hemorreología , Imagenología Tridimensional , Imagen por Resonancia Cinemagnética/métodos , Adulto , Velocidad del Flujo Sanguíneo , Cardiomiopatías/diagnóstico por imagen , Medios de Contraste , Ecocardiografía , Ecocardiografía Doppler , Femenino , Gadolinio , Atrios Cardíacos/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional/métodos , Masculino , Variaciones Dependientes del Observador , Estudios Prospectivos , Venas Pulmonares/diagnóstico por imagen , Venas Pulmonares/fisiopatologíaRESUMEN
Cardiac involvement in systemic sclerosis (SSc) is considerably frequent in autopsy, but the early identification is clinically difficult. Recent advantages in cardiac magnetic resonance (CMR) enabled to detect myocardial fibrotic scar as late gadolinium enhancement (LGE). We aimed to examine the prevalence and distribution of LGE in patients with SSc, and associate them with clinical features, electrocardiographic abnormalities and cardiac function. Forty patients with SSc (58 ± 14 years-old, 35 females, limited/diffuse 25/15, disease duration 106 ± 113 months) underwent serological tests, 12-lead electrocardiogram (ECG) and CMR. Seven patients (17.5 %) showed LGE in 26 segments of left ventricle (LV). LGE distributed mainly in the basal to mid inter-ventricular septum and the right ventricular (RV) insertion points, but involved all the myocardial regions. More patients with LGE showed NYHA functional class II and more (71 vs. 21 %, p < 0.05), bundle branch blocks (57 vs. 6 %, p < 0.05), LV ejection fraction (LVEF) < 50 % (72 vs. 6 %, p < 0.01), LV asynergy (43 vs. 0 %, p < 0.01) and RVEF < 40 % (100 vs. 39 %, p < 0.01). There was no difference in disease duration, disease types, or prevalence of positive autoimmune antibodies or high serum NT-proBNP level (>125 pg/ml). When cardiac involvement of SSc was defined as low LVEF, ECG abnormalities or high NT-proBNP, the sensitivity, specificity positive and negative predictive values of LGE were 36, 92, 71 and 72 %, respectively. We could clarify the prevalence and distribution of LGE in Japanese patients with SSc. The presence of LGE was associated with cardiac symptom, conduction disturbance and impaired LV/RV contraction.
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Cardiomiopatías/diagnóstico , Medios de Contraste , Gadolinio , Imagen por Resonancia Magnética , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Esclerodermia Sistémica/complicaciones , Adolescente , Adulto , Anciano , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocardio/patología , Valor Predictivo de las Pruebas , Función Ventricular Izquierda , Adulto JovenRESUMEN
OBJECTIVE: The prognosis of apical hypertrophic cardiomyopathy (APH) has been benign, but apical myocardial injury has prognostic importance. We studied functional, morphological and electrocardiographical abnormalities in patients with APH and with apical aneurysm and sought to find parameters that relate to apical myocardial injury. STUDY DESIGN: a multicentre trans-sectional study. PATIENTS: 45 patients with APH and 5 with apical aneurysm diagnosed with transthoracic echocardiography (TTE) in the database of Hamamatsu Circulation Forum. MEASURE: the apical contraction with cine-cardiac MR (CMR), the myocardial fibrotic scar with late gadolinium enhancement (LGE)-CMR, and QRS fragmentation (fQRS) defined when two ECG-leads exhibited RSR's patterns. RESULTS: Cine-CMR revealed 27 patients with normal, 12 with hypokinetic and 11 with dyskinetic apical contraction. TTE misdiagnosed 11 (48%) patients with hypokinetic and dyskinetic contraction as those with normal contraction. Apical LGE was apparent in 10 (83%) and 11 (100%) patients with hypokinetic and dyskinetic contraction, whereas only in 11 patients (41%) with normal contraction (p<0.01). Patients with dyskinetic apical contraction had the lowest left ventricular ejection fraction, the highest prevalence of ventricular tachycardia, and the smallest ST depression and depth of negative T waves. The presence of fQRS was associated with impaired apical contraction and apical LGE (OR=8.32 and 8.61, p<0.05). CONCLUSIONS: CMR is superior to TTE for analysing abnormalities of the apex in patients with APH and with apical aneurysm. The presence of fQRS can be a promising parameter for the early detection of apical myocardial injury.
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The recent development of cardiac magnetic resonance (CMR) techniques has allowed detailed analyses of cardiac function and tissue characterization with high spatial resolution. We review characteristic CMR features in ischemic and non-ischemic cardiomyopathies (ICM and NICM), especially in terms of the location and distribution of late gadolinium enhancement (LGE). CMR in ICM shows segmental wall motion abnormalities or wall thinning in a particular coronary arterial territory, and the subendocardial or transmural LGE. LGE in NICM generally does not correspond to any particular coronary artery distribution and is located mostly in the mid-wall to subepicardial layer. The analysis of LGE distribution is valuable to differentiate NICM with diffusely impaired systolic function, including dilated cardiomyopathy, end-stage hypertrophic cardiomyopathy (HCM), cardiac sarcoidosis, and myocarditis, and those with diffuse left ventricular (LV) hypertrophy including HCM, cardiac amyloidosis and Anderson-Fabry disease. A transient low signal intensity LGE in regions of severe LV dysfunction is a particular feature of stress cardiomyopathy. In arrhythmogenic right ventricular cardiomyopathy/dysplasia, an enhancement of right ventricular (RV) wall with functional and morphological changes of RV becomes apparent. Finally, the analyses of LGE distribution have potentials to predict cardiac outcomes and response to treatments.
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Spontaneous testicular teratomas (STTs) composed by various kinds of tissues are derived from primordial germ cells (PGCs) in the fetal testes of the mouse. In contrast, intra-testicular grafts of the mouse strain (129/Sv-Ter (+/+)) fetal testes possessed the ability to develop the experimental testicular teratomas (ETTs), indistinguishable from the STTs at a morphological level. In this study, linkage analysis was performed for exploration of possible candidate genes involving in ETT development using F2 intercross fetuses derived from [LTXBJ × 129/Sv-Ter (+/+)] F1 hybrids. Linkage analysis with selected simple sequence length polymorphisms along chromosomes 18 and 19, which have been expected to contain ETT-susceptibility loci, demonstrated that a novel recessive candidate gene responsible for ETT development is located in 1.1 Mb region between the SSLP markers D18Mit81 and D18Mit184 on chromosome 18 in the 129/Sv-Ter (+/+) genetic background. Since this locus is different from the previously known loci (including Ter, pgct1, and Tgct1) for STT development, we named this novel gene "experimental testicular teratoma 1 (ett1)". To resolve the location of ett1 independently from other susceptibility loci, ett1 loci was introduced in a congenic strain in which the distal segment of chromosome 18 in LTXBJ strain mice had been replaced by a 1.99 Mbp genomic segment of the 129/Sv-Ter (+/+) mice. Congenic males homozygous for the ett1 loci were confirmed to have the ability to form ETTs, indicating that this locus contain the gene responsible for ETTs. We listed candidate genes included in this region, and discussed about their possible involvement in induction of ETTs.
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Cromosomas de los Mamíferos/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Teratoma/genética , Neoplasias Testiculares/genética , Animales , Femenino , Masculino , Ratones de la Cepa 129 , Polimorfismo Genético , Teratoma/patología , Neoplasias Testiculares/patología , Testículo/embriología , Testículo/patologíaRESUMEN
We recently have reported on a novel ankylosis gene that is closely linked to the Enpp1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene on chromosome 10. Here, we have discovered novel mutant mice in a Jcl:ICR closed colony with ankylosis in the toes of the forelimbs at about 3 weeks of age. The mutant mice exhibited rigidity in almost all joints, including the vertebral column, which increased with age. These mice also showed hypogrowth with age after 16 weeks due to a loss of visceral fat, which may have been caused by poor nutrition. Histological examination and soft X-ray imaging demonstrated the ectopic ossification of various joints in the mutant mice. In particular, increased calcium deposits were observed in the joints of the toes, the carpal bones and the vertebral column. We sequenced all exons and exon/intron boundaries of Enpp1 in the normal and mutant mice, and identified a G-to-T substitution (c.259+1G>T) in the 5' splice donor site of intron 2 in the Enpp1 gene of the mutant mice. This substitution led to the skipping of exon 2 (73 bp), which generated a stop codon at position 354 bp (amino acid 62) of the cDNA (p.V63Xfs). Nucleotide pyrophosphohydrolase (NPPH) activity of ENPP1 in the mutant mice was also decreased, suggesting that Enpp1 gene function is disrupted in this novel mutant. The mutant mice reported in this study will be a valuable animal model for future studies of human osteochondral diseases and malnutrition.
Asunto(s)
Alelos , Ratones Mutantes , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/aislamiento & purificación , Pirofosfatasas/genética , Pirofosfatasas/aislamiento & purificación , Animales , Anquilosis/genética , Secuencia de Bases , Cromosomas de los Mamíferos/genética , Modelos Animales de Enfermedad , Femenino , Transferencia de Gen Horizontal , Humanos , Masculino , Desnutrición/genética , Ratones , Ratones Endogámicos ICR , Datos de Secuencia Molecular , Mutación , Osteocondrodisplasias/genéticaRESUMEN
BACKGROUND: Microtubule (MT) disorganization is related to cardiac disorders. To elucidate the mechanism by which disorganization of the MT network deteriorates cardiac function, the relationship between MT disorganization and mitochondrial permeability transition pore (mPTP) in cardiac myocytes was investigated. METHODS AND RESULTS: The effects of MT stabilization (by paclitaxel) and MT disruption (by nocodazole) on mitochondrial membrane potential (ΔΨm) and the opening of mPTP were measured in permeabilized Sprague-Dawley rat myocytes. Both paclitaxel and nocodazole depolarized ΔΨm and opened mPTP. When isolated mitochondria were exposed to paclitaxel or nocodazole, there were no changes in ΔΨm. The effects of paclitaxel or nocodazole on ΔΨm depolarization and mPTP were inhibited by cyclosporin A. Treatment of myocytes with 0Ca+BAPTA or inhibition of sarcoplasmic reticulum (SR) Ca(2+) uptake by thapsigargin prevented the effect of paclitaxel on mPTP, but not that of nocodazole. Inhibition of the mitochondrial Ca(2+) uniporter by Ru360 did not alter the effect of paclitaxel on mPTP. Paclitaxel reduced the expression of the mitochondrial fusion protein, mitofusin-2, and induced mitochondrial fragmentation. CONCLUSIONS: Disruption of the MT network by nocodazole might destroy the MT-mitochondria connection and alter mitochondrial function. MT disorganization by paclitaxel could regulate mPTP through the outer mitochondrial membrane complex and the Ca(2+)-sensitive signaling pathway, which also interacts with the mitochondrial fusion protein, mitofusin-2.