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INTRODUCTION: Right ventricular (RV) pacing sometimes causes left ventricular (LV) systolic dysfunction, also known as pacing-induced cardiomyopathy (PICM). However, the association between specifically paced QRS morphology and PICM development has not been elucidated. This study aimed to investigate the association between paced QRS mimicking a complete left bundle branch block (CLBBB) and PICM development. METHODS: We retrospectively screened 2009 patients who underwent pacemaker implantation from 2010 to 2020 in seven institutions. Patients who received pacemakers for an advanced atrioventricular block or bradycardia with atrial fibrillation, baseline LV ejection fraction (LVEF) ≥ 50%, and echocardiogram recorded at least 6 months postimplantation were included. The paced QRS recorded immediately after implantation was analyzed. A CLBBB-like paced QRS was defined as meeting the CLBBB criteria of the American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society in 2009. PICM was defined as a ≥10% LVEF decrease, resulting in an LVEF of <50%. RESULTS: Among the 270 patients analyzed, PICM was observed in 38. Baseline LVEF was lower in patients with PICM, and CLBBB-like paced QRS was frequently observed in PICM. Multivariate analysis revealed that low baseline LVEF (odds ratio [OR]: 0.93 per 1% increase, 95% confidence interval [CI]: 0.89-0.98, p = 0.006) and CLBBB-like paced QRS (OR: 2.69, 95% CI: 1.25-5.76, p = 0.011) were significantly associated with PICM development. CONCLUSION: CLBBB-like paced QRS may be a novel risk factor for PICM. RV pacing, which causes CLBBB-like QRS morphology, may need to be avoided, and patients with CLBBB-like paced QRS should be followed-up carefully.
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Potenciales de Acción , Bloqueo de Rama , Estimulación Cardíaca Artificial , Cardiomiopatías , Electrocardiografía , Frecuencia Cardíaca , Valor Predictivo de las Pruebas , Volumen Sistólico , Función Ventricular Izquierda , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Bloqueo Atrioventricular/fisiopatología , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/terapia , Bloqueo Atrioventricular/etiología , Bloqueo de Rama/fisiopatología , Bloqueo de Rama/diagnóstico , Bloqueo de Rama/terapia , Bloqueo de Rama/etiología , Estimulación Cardíaca Artificial/efectos adversos , Cardiomiopatías/fisiopatología , Cardiomiopatías/etiología , Cardiomiopatías/terapia , Cardiomiopatías/diagnóstico , Diagnóstico Diferencial , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Función Ventricular DerechaRESUMEN
Background: Recent revisions of clinical guidelines by the Japanese Circulation Society, American Heart Association/American College of Cardiology, and European Society of Cardiology updated the management of antithrombotic strategies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, the extent to which these guidelines have been implemented in real-world daily clinical practice is unclear. MethodsâandâResults: We conducted surveys on the status of antithrombotic therapy for patients with AF undergoing PCI every 2 years from 2014 to 2022 in 14 cardiovascular centers in Japan. The primary use of drug-eluting stents increased from 10% in 2014 to 95-100% in 2018, and the use of direct oral anticoagulants increased from 15% in 2014 to 100% in 2018, in accordance with the revised practice guidelines. In patients with acute coronary syndrome, the duration of triple therapy within 1 month was approximately 10% until 2018, and increased to >70% from 2020. In patients with chronic coronary syndrome, the duration of triple therapy within 1 month was approximately 10% until 2016, and >75% from 2018. Since 2020, the most common timing of discontinuation of dual antiplatelet therapy to transition to anticoagulation monotherapy during the chronic phase of PCI has been 1 year after PCI. Conclusions: Japanese interventional cardiologists have updated their treatment strategies for patients with AF undergoing PCI according to revisions of clinical practice guidelines.
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Pulmonary vein isolation (PVI), which creates electrical blocks between pulmonary veins and left atrium, is an established way of catheter ablation for atrial fibrillation (AF). PVI is usually performed via the femoral vein access, using two or three long preshaped sheaths, followed by atrial-septal puncture to approach the left atrium. Here, we treated an AF patient with a permanently implanted inferior vena cava filter (IVC-F) due to deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE). The patient had symptomatic paroxysmal AF for over a decade, which was not controlled under antiarrhythmic drugs including beta-blockers. Therefore, we recommended PVI to treat the AF. However, as the IVC-F was an obstacle to perform conventional PVI, we changed the combination of vascular access sites and devices to perform it safely. Notably, insertions of a single steerable sheath through IVC-F and an intracardiac ultrasound catheter from the right internal jugular vein were useful for the successful completion of the procedure.
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BACKGROUND: Because the prevalence of coronary artery calcification is lower among Japanese than among Western individuals, aspects of the Japanese lifestyle might be related to the development of calcification. We aimed to clarify the relationship between coronary artery calcium scores in Japanese patients and various lifestyle factors among the Japanese population. METHODS: Study subjects were patients aged ≥20 years who underwent multidetector-row computed tomography. A total of 201 patients agreed to take part in this study and answered a questionnaire regarding lifestyle, medical history, and other factors. RESULTS: Old age, current and former smoking, sedentary work, short sleep time, coronary artery stenosis, treatment with statins, medical history of cerebrovascular disease, medical history of angina pectoris, medical history of ischemic heart disease, and medical history of dyslipidemia were associated with higher odds ratios than the other factors examined, while the Japanese-style breakfast (e.g. boiled rice, miso soup, grilled fish) was associated with lower odds ratios. CONCLUSIONS: In this study, smoking, sedentary work, short sleep time, and the Japanese-style breakfast were lifestyle factors related to coronary artery calcification. The lifestyle of Japanese people may be related to coronary calcification.
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Enfermedad de la Arteria Coronaria/epidemiología , Anciano , Pueblo Asiatico , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/etiología , Dieta , Femenino , Humanos , Japón/epidemiología , Estilo de Vida , Masculino , Persona de Mediana Edad , Tomografía Computarizada Multidetector , Oportunidad Relativa , Prevalencia , Factores de Riesgo , Fumar/efectos adversos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Macrophages contribute to the progression and acute complications of atherosclerosis. Macrophage imaging may serve as a biomarker to identify subclinical inflamed lesions, to predict future risk, and to aid in the assessment of novel therapies. METHODS AND RESULTS: To test the hypothesis that nanoparticle-enhanced, high-resolution magnetic resonance imaging (MRI) can measure plaque macrophage accumulation, we used 3-T MRI with a macrophage-targeted superparamagnetic nanoparticle preparation (monocrystalline iron oxide nanoparticles-47 [MION-47]) in cholesterol-fed New Zealand White rabbits 6 months after balloon injury. In vivo MRI visualized thickened abdominal aortas on both T1- and T2-weighted spin-echo images (T1 spin echo, 20 axial slices per animal; T2 spin echo, 28 slices per animal). Seventy-two hours after MION-47 injection, aortas exhibited lower T2 signal intensity compared with before contrast imaging (signal intensity ratio, aortic wall/muscle: before, 1.44 ± 0.26 versus after, 0.95 ± 0.22; 164 slices; P<0.01), whereas T1 spin echo images showed no significant change. MRI on ex vivo specimens provided similar results. Histological studies colocalized iron accumulation with immunoreactive macrophages in atheromata. The magnitude of signal intensity reduction on T2 spin echo in vivo images further correlated with macrophage areas in situ (150 slices; r=0.73). Treatment with rosuvastatin for 3 months yielded diminished macrophage content (P<0.05) and reversed T2 signal intensity changes (P<0.005). Signal changes in rosuvastatin-treated rabbits correlated with reduced macrophage burden (r=0.73). In vitro validation studies showed concentration-dependent MION-47 uptake by human primary macrophages. CONCLUSION: The magnitude of T2 signal intensity reduction in high-resolution MRI after administration of superparamagnetic phagocytosable nanoparticles can assess macrophage burden in atheromata, providing a clinically translatable tool to identify inflamed plaques and to monitor therapy-mediated changes in plaque inflammation.
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Aorta Abdominal/patología , Aterosclerosis/patología , Macrófagos/patología , Imagen por Resonancia Magnética/métodos , Nanopartículas del Metal , Animales , Aterosclerosis/inducido químicamente , Aterosclerosis/tratamiento farmacológico , Colesterol en la Dieta/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Óxido Ferrosoférrico , Fluorobencenos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Nanopartículas , Pirimidinas/uso terapéutico , Conejos , Rosuvastatina Cálcica , Sulfonamidas/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: The elevated D-dimer value is one of the clues used to diagnose acute aortic dissection (AAD), but the rapid D-dimer assay is not used at all emergency hospitals. The fibrinogen/fibrin degradation products (FDP) value is also an indicator of enhanced fibrinolysis and may therefore be a useful marker in patients with AAD. In addition, the association between FDP values and partial thrombosis of the false lumen is not elucidated. PATIENTS: The present study enrolled 50 patients (66.5±11.2 years of age; median, 66.5 years of age, male subjects comprised 60.0% of the series) with AAD who were admitted to the hospital between July 2005 and December 2007 and 57 patients with acute myocardial infarction (AMI; 70.8±10.4 years of age; median, 71.0 years of age, male subjects comprised 71.9% of the current series) served as a control group. RESULTS: The FDP values (µg/mL) in patients with AAD were significantly higher than those of AMI patients (40.2±78.6; median, 14.7 vs. 5.2±9.8; median, 1.7, p<0.001). A receiver operating characteristic curves analysis showed that an elevated FDP level (2.05 µg/mL) was predictive of a diagnosis of AAD with a sensitivity and specificity of 98% and 54%, respectively. The FDP levels of patients (n=14) who had partial thrombosis of the false lumen were significantly higher than in discharged patients without a surgical repair (n=21) who had a patent or complete thrombosis of the false lumen (35.8±43.2; median, 18.8 vs. 14.0±21.3; median, 5.5, p=0.01). CONCLUSION: The measurement of FDP may therefore be useful for the initial assessment of patients with suspected AAD and in the prediction of thrombotic status of the false lumen.
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Aneurisma de la Aorta/sangre , Aneurisma de la Aorta/diagnóstico , Disección Aórtica/sangre , Disección Aórtica/diagnóstico , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Microvascular dysfunction has been proposed as the most likely mechanism of the coronary slow flow phenomenon (CSFP). OBJECTIVES: To determine the effects of isosorbide dinitrate and nicorandil on the CSFP. METHODS: Changes in thrombolysis in myocardial infarction (TIMI) frame count following the intracoronary administration of isosorbide dinitrate and nicorandil were assessed in 11 patients with the CSFP. RESULTS: After the administration of isosorbide dinitrate, the median TIMI frame count decreased to 32 (range 20-60) [p = 0.003], which was lower than that of the control [43 (29-73)]. The count decreased further to 25 (12-34) [p = 0.041] after the administration of nicorandil. The count after the subsequent administration of contrast medium was increased to 32 (20-49) [p = 0.03]. CONCLUSIONS: These angiographic findings indicate that the intracoronary administration of nicorandil is superior to isosorbide dinitrate with regard to improving the CSFP. These findings suggest that microvascular spasm is the main factor in the pathogenesis of the CSFP.
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Dinitrato de Isosorbide/uso terapéutico , Nicorandil/uso terapéutico , Fenómeno de no Reflujo/tratamiento farmacológico , Vasodilatadores/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Angiografía Coronaria , Circulación Coronaria/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
We report three cases of thoracic aortic aneurysm and dissection in a Japanese family. Marfan-related genes were analyzed; FBN1 and TGFBR2 gene mutations were observed in this family.
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Aneurisma de la Aorta Abdominal/etiología , Aneurisma de la Aorta Torácica/etiología , Disección Aórtica/etiología , Síndrome de Marfan/complicaciones , Proteínas de Microfilamentos/genética , Mutación Missense , Complicaciones Cardiovasculares del Embarazo/etiología , Proteínas Serina-Treonina Quinasas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/tratamiento farmacológico , Disección Aórtica/cirugía , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/cirugía , Rotura de la Aorta/etiología , Cesárea , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Fibrilina-1 , Fibrilinas , Genotipo , Humanos , Recién Nacido , Síndrome de Marfan/genética , Linaje , Embarazo , Complicaciones Cardiovasculares del Embarazo/diagnóstico por imagen , Complicaciones Cardiovasculares del Embarazo/cirugía , Receptor Tipo II de Factor de Crecimiento Transformador beta , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Activated macrophages contribute to the pathogenesis of inflammatory diseases such as atherosclerosis. Although Notch signaling participates in various aspects of immunity, its role in macrophage activation remains undetermined. METHODS AND RESULTS: To explore the role of Notch signaling in inflammation, we examined the expression and activity of Notch pathway components in human primary macrophages in vitro and in atherosclerotic plaques. Macrophages in culture express various Notch pathway components including all 4 receptors (Notch1 to Notch4). Notch3 selectively increased during macrophage differentiation; however, silencing by RNA interference demonstrated that all receptors are functional. The ligand Delta-like 4 (Dll4) increased in macrophages exposed to proinflammatory stimuli such as lipopolysaccharide, interleukin-1beta, or minimally-modified low-density lipoprotein in a Toll-like receptor 4- and nuclear factor-kappaB-dependent fashion. Soluble Dll4 bound to human macrophages. Coincubation of macrophages with cells that expressed Dll4 triggered Notch proteolysis and activation; increased the transcription of proinflammatory genes such as inducible nitric oxide synthase, pentraxin 3 and Id1; resulted in activation of mitogen-activated protein kinase, Akt, and nuclear factor-kappaB pathways; and increased the expression of Dll4 in macrophages. Notch3 knockdown during macrophage differentiation decreased the transcription of genes that promote inflammation, such as inducible nitric oxide synthase, pentraxin 3, Id1, and scavenger receptor-A. These in vitro findings correlate with results of quantitative immunohistochemistry, which demonstrated the presence of Dll4 and other Notch components within macrophages in atherosclerotic plaques. CONCLUSION: Dll4-triggered Notch signaling may mediate inflammatory responses in macrophages and promote inflammation.
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Inflamación/genética , Péptidos y Proteínas de Señalización Intercelular/fisiología , Macrófagos/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales , Aterosclerosis/patología , Proteínas de Unión al Calcio , Células Cultivadas , Regulación de la Expresión Génica , Humanos , Activación de Macrófagos , Macrófagos/citología , Receptor Notch3 , Receptores Notch/fisiología , Transcripción GenéticaRESUMEN
HMG-CoA reductase inhibitors and calcium channel blockers have antiatherogenic effects; however, their mechanisms remain to be elucidated. This study examined the effect of cerivastatin and/or nifedipine on the endothelial dysfunction in porcine balloon-injured coronary arteries. Normal male pigs were randomly divided into the following four groups: control, cerivastatin (1 mg/kg/d PO), nifedipine (4 mg/kg/d PO), and their combination (n = 10 each). We started the treatments 3 days before balloon injury in the proximal left coronary arteries and continued for 4 weeks after the procedure. Then, we examined endothelial vasodilator functions ex vivo in organ chambers and in vitro by Western blotting for eNOS expression. Endothelium-dependent relaxations to serotonin, but not those to bradykinin or the calcium ionophore A23187 or endothelium-independent relaxations to sodium nitroprusside, were significantly impaired by balloon injury. The monotherapy with cerivastatin or nifedipine partially improved, and their combination supernormalized the relaxations to serotonin without affecting those to bradykinin or A23187 or endothelium-independent relaxations to sodium nitroprusside. The expression of eNOS was significantly reduced by balloon injury and normalized by the combination therapy. These results indicate that the combination therapy improves endothelial dysfunction after balloon injury, in which the up-regulation of eNOS may be involved.
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Vasos Coronarios/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Nifedipino/farmacología , Piridinas/farmacología , Administración Oral , Animales , Análisis Químico de la Sangre , Western Blotting , Bradiquinina/farmacología , Calcimicina/farmacología , Cateterismo/efectos adversos , Cateterismo/métodos , Angiografía Coronaria/métodos , Vasos Coronarios/lesiones , Vasos Coronarios/fisiopatología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Endotelio Vascular/lesiones , Endotelio Vascular/fisiopatología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Técnicas In Vitro , Masculino , Nifedipino/administración & dosificación , Nifedipino/uso terapéutico , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Nitroprusiato/farmacología , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Serotonina/farmacología , Porcinos , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
OBJECTIVE: We recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis. In this study, we examined whether Rho-kinase is also involved in in-stent restenosis and if so, what mechanism is involved. METHODS AND RESULTS: Pigs underwent stent implantation in the left coronary artery with or without administration of fasudil (30 mg/kg per day orally), a specific Rho-kinase inhibitor, starting 2 days before the procedure for a duration of 4 weeks. On day 28, reductions in coronary diameter and neointimal formation associated with macrophage accumulation, collagen deposition, and transforming growth factor (TGF)-beta1 expression were noted at the stent site, and all were significantly suppressed by fasudil. On day 7, fasudil significantly increased the frequency of TUNEL-positive apoptotic cells, while it tended to reduce that of bromodeoxyuridine-positive proliferating cells in the neointima. Western blot analysis on day 7 demonstrated that phosphorylations of the ezrin/radixin/moesin family (a marker of Rho-kinase activity in vivo) and protein expression of monocyte chemoattractant protein-1and bcl-2 were upregulated at the stent site and were significantly suppressed by fasudil. CONCLUSIONS: These results indicate that long-term inhibition of Rho-kinase suppresses in-stent neointimal formation by multiple mechanisms, including reduced vascular inflammation, enhanced apoptosis, and decreased collagen deposition.
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1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Reestenosis Coronaria/enzimología , Inhibidores Enzimáticos/farmacología , Proteínas Serina-Treonina Quinasas/fisiología , Stents , Túnica Íntima/patología , Animales , Apoptosis/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Cateterismo/efectos adversos , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Colágeno/metabolismo , Reestenosis Coronaria/patología , Reestenosis Coronaria/prevención & control , Estenosis Coronaria/cirugía , Estenosis Coronaria/terapia , Proteínas del Citoesqueleto/metabolismo , Evaluación Preclínica de Medicamentos , Genes bcl-2 , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas de la Membrana/metabolismo , Proteínas de Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Método Simple Ciego , Porcinos , Túnica Íntima/efectos de los fármacos , Túnica Íntima/enzimología , Quinasas Asociadas a rhoRESUMEN
OBJECTIVE: We have recently demonstrated that protein kinase C (PKC) and Rho-kinase play important roles in coronary vasospasm in a porcine model. However, it remains to be examined whether there is an interaction between the two molecules to cause the spasm. METHODS AND RESULTS: A segment of left porcine coronary artery was chronically treated with IL-1beta-bound microbeads in vivo. Two weeks after the operation, phorbol ester caused coronary spasm in vivo and coronary hypercontractions in vitro at the IL-1beta-treated segment; both were significantly inhibited by hydroxyfasudil, a specific Rho-kinase inhibitor. Guanosine 5'-[gamma-thio]triphosphate (GTPgammaS), which activates Rho with a resultant activation of Rho-kinase, enhanced Ca2+ sensitization of permeabilized vascular smooth muscle cells, which were resistant to the blockade of PKC by calphostin C. The GTPgammaS-induced Ca2+ sensitization was greater in the spastic segment than in the control segment. Western blot analysis revealed that only PKCdelta isoform was activated during the hypercontraction. CONCLUSIONS: These results demonstrate that PKC and Rho-kinase coexist on the same intracellular signaling pathway, with PKC located upstream on Rho-kinase, and that among the PKC isoforms, only PKCdelta may be involved. Thus, the strategy to inhibit Rho-kinase rather than PKC may be a more specific and useful treatment for coronary spasm.
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1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Vasoespasmo Coronario/enzimología , Modelos Animales de Enfermedad , Proteína Quinasa C/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Animales , Western Blotting , Calcio/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Vasoespasmo Coronario/metabolismo , Vasos Coronarios/química , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/enzimología , Vasos Coronarios/metabolismo , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas de Unión al GTP Monoméricas/metabolismo , Proteínas de Unión al GTP Monoméricas/fisiología , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso Vascular/química , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/enzimología , Forbol 12,13-Dibutirato/metabolismo , Forbol 12,13-Dibutirato/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/fisiología , Porcinos , Quinasas Asociadas a rhoRESUMEN
OBJECTIVE: This study was designed to examine why in WHHL rabbits, muscular arteries, such as the carotid artery, are relatively resistant to atherosclerosis compared with the aorta, with a special reference to monocyte chemoattractant protein (MCP)-1. METHODS AND RESULTS: MCP-1 mRNA expression was quantitated by Northern blot analysis, and its protein expression was quantitated by immunostaining and ELISA at the age of 1, 3, 6, and 12 months (n=5 to 6 each). In the aorta, atherosclerotic lesions were progressively developed with aging, and MCP-1 was highly expressed in endothelial cells and infiltrating macrophages. By contrast, in the carotid artery, atherosclerotic lesions and MCP-1 immunoreactivity were not evident throughout the experimental period. Unexpectedly, however, the extent of MCP-1 mRNA expression was comparable between the aorta and the carotid artery throughout the experimental period. Endothelial cells in primary culture from the aorta and the carotid artery expressed the same extent of MCP-1 mRNA on stimulation by oxidized LDL. There was no abnormality in primary structure of MCP-1 cDNA in WHHL. CONCLUSIONS: These results suggest that in WHHL, the atherosclerosis process, including MCP-1 protein expression, may be reduced in the carotid artery (and possibly in other muscular arteries), accounting in part for the regional resistance to atherosclerosis.
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Aorta Torácica/metabolismo , Arterias Carótidas/metabolismo , Quimiocina CCL2/biosíntesis , ARN Mensajero/biosíntesis , Factores de Edad , Animales , Aorta Torácica/química , Aorta Torácica/citología , Aorta Torácica/patología , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Arterias Carótidas/química , Arterias Carótidas/citología , Arterias Carótidas/patología , Línea Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/inmunología , Quimiocina CCL2/metabolismo , ADN Complementario/genética , Modelos Animales de Enfermedad , Endotelio Vascular/química , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Ensayo de Inmunoadsorción Enzimática , Immunoblotting/métodos , Lipoproteínas LDL/metabolismo , Macrófagos/química , Oxidación-Reducción , Conejos , Análisis de Secuencia de ADN/métodosRESUMEN
OBJECTIVE: Matrix metalloproteinases (MMPs) cause extracellular matrix degradation and may be involved in the rupture of atherosclerotic plaques by degrading fibrous cap, resulting in the intravascular thrombus formation. Here we examined whether local overexpression of MMP-9 alters the characteristics of arteriosclerotic vascular lesions and promotes thrombosis after balloon injury in porcine coronary arteries in vivo. METHODS AND RESULTS: Balloon angioplasty was performed in the left coronary arteries followed by injection of adenovirus vector solution encoding either MMP-9 or beta-galactosidase (beta-gal) gene into the injured coronary arteries. Three weeks after the gene transfer, histological examination demonstrated that macroscopic intravascular thrombus formation was noted at the MMP-9-transfected site but not at the beta-gal-transfected site. Microscopic intramural thrombus area was significantly larger at the MMP-9-transfected site as compared to the beta-gal-transfected site. Co-transfection of tissue inhibitor of metalloproteinase-1 (TIMP-1) with MMP-9 prevented the intravascular thrombus formation in vivo. Western blot analysis revealed the reduced expression of intact tissue factor pathway inhibitor-1 and the increased tissue factor (TF) expression at the MMP-9-transfected sites. CONCLUSION: These results provide the first in vivo evidence that overexpression of MMP-9 promotes intravascular thrombus formation after balloon injury due in part to the activation of TF-mediated coagulation cascade.
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Angioplastia Coronaria con Balón/efectos adversos , Trombosis Coronaria/enzimología , Metaloproteinasa 9 de la Matriz/fisiología , Adenoviridae/genética , Animales , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/terapia , Trombosis Coronaria/etiología , Trombosis Coronaria/patología , Vectores Genéticos , Lipoproteínas/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Porcinos , Tromboplastina/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/fisiología , TransfecciónRESUMEN
Although the importance of monocytes/macrophages in the pathogenesis of arteriosclerosis is widely accepted, effective and safe treatment to inhibit those inflammatory cells remains to be developed. It was recently found that propagermanium, which is clinically used for the treatment of chronic hepatitis type B in Japan, markedly suppresses monocyte chemotaxis in response to macrophage chemoattractant protein-1 (MCP-1) through inhibition of its receptor, C-C chemokine receptor 2, in vitro. This prompted examination of whether propagermanium suppresses the macrophage-mediated formation of coronary arteriosclerotic lesions in our porcine model in vivo. It was first confirmed that propagermanium inhibited the migration of porcine monocytes in response to MCP-1 at therapeutic concentrations in vitro. Pigs were randomly divided into two groups; one group was orally treated with propagermanium (1 mg/kg, three times/day) and another group served as a control (n = 6 each). Porcine coronary segment was treated from the adventitia with MCP-1 and oxidized low-density lipoprotein for 2 weeks. In the control group, this treatment resulted in the development of stenotic coronary lesions with hyperconstrictive responses to serotonin where arteriosclerotic lesions (neointimal formation and constrictive remodeling) were developed. Immunohistochemical analysis demonstrated the macrophage accumulation in the adventitia and the media. By contrast, in the propagermanium group, angiographic coronary stenosis, hyperconstrictive responses, histologic changes, and macrophage accumulation were all significantly suppressed. These results indicate that propagermanium suppresses macrophage-mediated formation of coronary arteriosclerotic lesions in vivo, suggesting its potential usefulness for the treatment of arteriosclerotic vascular diseases.
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Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Modelos Animales de Enfermedad , Macrófagos/efectos de los fármacos , Compuestos Organometálicos/farmacología , Animales , Enfermedad de la Arteria Coronaria/patología , Relación Dosis-Respuesta a Droga , Germanio , Macrófagos/patología , Masculino , Compuestos Organometálicos/uso terapéutico , Propionatos , PorcinosRESUMEN
Macrophages play an important role in the pathogenesis of atherosclerosis, for which monocyte chemoattractant protein (MCP)-1 and CCR2 chemokine receptors may be involved. The authors have recently demonstrated that propagermanium exerts inhibitory effect on the CCR2 receptors. In the current study, the authors examined whether the organic germanium suppresses the MCP-1-induced monocyte migration in vitro and the development of atherosclerosis in WHHL rabbits in vivo. In the in vitro experiment, propagermanium concentration-dependently suppressed the MCP-1-induced migration of THP-1 cells. In the in vivo experiment, 20 WHHL rabbits were randomly divided into two groups; one group was treated with oral administration with propagermanium (9 mg/kg/day) for 3 months, and another group served as a control (n = 10 each). After 3 months, the aorta was isolated and stained with oil red O staining, and neointimal formation was quantified. Macrophage accumulation in the aorta was also evaluated by immunostaining. Long-term treatment with propagermanium did not affect the serum lipid profiles. However, the treatment significantly suppressed the oil red O-positive area of the total aorta (p < 0.05). Similarly, propagermanium significantly suppressed the intimal lesions (maximal intimal thickness and intimal area) and macrophage staining-positive area (all p < 0.05). A significant positive correlation was noted between macrophage staining-positive area and intimal lesions (p < 0.0001). These results indicate that long-term treatment with propagermanium suppresses the development of atherosclerosis in WHHL rabbits, suggesting its usefulness for the treatment of atherosclerotic vascular disease in humans.
Asunto(s)
Arteriosclerosis/prevención & control , Compuestos Organometálicos/administración & dosificación , Receptores de LDL/deficiencia , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/patología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/patología , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/genética , Arteriosclerosis/patología , Línea Celular , Germanio , Humanos , Propionatos , Conejos , Receptores CCR2 , Receptores de Quimiocina/antagonistas & inhibidores , Receptores de LDL/genéticaRESUMEN
Recent studies demonstrated that neointimal formation, which is caused by both neointimal proliferation and organized mural thrombus, is responsible for in-stent restenosis. Although various types of heparin coatings were effective in reducing (sub)acute thrombosis, most of them failed to reduce neointimal proliferation. This study was designed to examine the effect of the stent coated with multiple layers of releasable heparin complex from which heparin diffuses into the surrounding tissue and exerts its beneficial effects. Male Yorkshire pigs underwent balloon expandable stenting for coronary segments of both the left anterior and the left circumflex coronary arteries with a comparable diameter (n = 10). The stent implantation site was randomized for either control or heparin-coated stent. Four weeks after the procedure, quantitative coronary angiography (QCA) and intravascular ultrasonographic imaging (IVUS) were performed followed by histologic analysis. In additional animals, staining for proliferating cell nuclear antigen (PCNA) was performed 10 d after the procedure (n = 3). QCA demonstrated that coronary diameter (mm) was significantly larger at the heparin-coated stent site (2.32 +/- 0.14) compared with the control stent site (1.81 +/- 0.17) (p < 0.01). IVUS also showed that the neointimal area (mm2) was significantly suppressed at the heparin-coated stent site (2.12 +/- 0.58) compared with the control stent site (3.92 +/- 0.33) (p < 0.01). Histologic analysis also demonstrated that neointimal area (mm2) was significantly less at the heparin-coated stent (2.94 +/- 0.43) than at the control stent site (4.41 +/- 0.38) (p < 0.01), which was also the case for organized thrombus area (x10-4 mm2) (6.61 +/- 2.67 vs. 19.36 +/- 4.38, p < 0.01). The frequency of PCNA-positive vascular smooth muscle cells (%) was significantly less at the heparin-coated stent (10.8 +/- 1.0) than at the control stent site (19.1 +/- 1.7) (p < 0.01). These results suggest that the stent coated with releasable heparin is beneficial in reducing neointimal formation and subsequent in-stent restenosis.