RESUMEN
UNLABELLED: We compared two routes for myocardial delivery of therapeutics, transendocardial (TE) delivery with an intramyocardial injection catheter, and retrograde coronary venous (RCV) delivery with a balloon occlusion catheter in the interventricular vein. METHODS: TE and RCV injection of 15 microM, neutron-activatable microspheres was compared in healthy pigs (Group I, n = 3), pigs with a 1-week-old myocardial infarction (MI; group II, n = 5), and pigs with a 2-weeks-old MI (group III, n = 4). The MI was induced by a 1-hr balloon occlusion in the LAD. Both methods were compared in the same animal using different microspheres. The RCV catheter allowed for continuous measurement of distal pressure and 2.5 x 10(6) microspheres were injected in 10 ml at 300 mmHg above balloon occlusion pressure. The TE injections were targeted to the infarct zone and 2.5 x 10(6) microspheres were distributed over 10 injections of 200 microl. RESULTS: The retention of microspheres decreased with increase in MI age, but was comparable between devices within the groups. RCV delivery resulted in (14.3 +/- 0.9)% microsphere retention in Group I, (10.3 +/- 0.2)% in Group II, and (6.4 +/- 0.1)% in group III (P < 0.05 versus group I). Microsphere retention after TE was (15.1 +/- 0.7)% in group I, (18.9 +/- 0.6)% in group II, (4.1 +/- 0.1)% in Group III (P < 0.05 versus groups I and II). The RCV catheter delivered primarily to midventricular, antero-septal segments, whereas TE targeted apical areas predominantly. CONCLUSIONS: Delivery efficacy was comparable between devices in each group however RCV targeted midventricular areas whereas TE targeted apical areas.
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Cateterismo Cardíaco , Vasos Coronarios/cirugía , Endocardio/cirugía , Bombas de Infusión Implantables , Infarto del Miocardio/terapia , Anastomosis Quirúrgica , Animales , Oclusión con Balón/instrumentación , Cateterismo Cardíaco/instrumentación , Medios de Contraste/administración & dosificación , Circulación Coronaria , Modelos Animales de Enfermedad , Tabiques Cardíacos/cirugía , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Microesferas , Infarto del Miocardio/fisiopatología , Pericardio/cirugía , Proyectos Piloto , Volumen Sistólico , PorcinosRESUMEN
Stress-induced release of IL-1alpha and fibroblast growth factor-1 is dependent on intracellular copper and is a major driver of neointimal hyperplasia. Therefore, we assessed the effect of tetrathiomolybdate (TTM), a clinically proven copper chelator, on in-stent restenosis. Nine pigs were treated with TTM (5 mg/kg po) twice daily for 2 wk before stent implantation and for 4 wk thereafter, and nine pigs served as controls. In-stent restenosis was assessed by quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), and histomorphometry. Serum ceruloplasmin activity was used as a surrogate marker of copper bioavailability. In TTM-treated animals, ceruloplasmin dropped 70 +/- 10% below baseline levels. Baseline characteristics were comparable in TTM-treated and control animals. At 4-wk follow-up, all parameters relevant to in-stent restenosis were significantly reduced in TTM-treated animals: minimal lumen diameter by QCA was 2.03 +/- 0.57 and 1.47 +/- 0.45 mm in TTM-treated and control animals, respectively (P < 0.05), percent stenosis diameter was 39% less in TTM-treated animals (27.1 +/- 16.6% vs. 44.5 +/- 16.1%, P < 0.05), minimal lumen area by IVUS was 60% larger in TTM-treated animals (4.27 +/- 1.56 vs. 2.67 +/- 1.19 mm(2), P < 0.05), and neointimal volume by histomorphometry was 37% less in TTM-treated animals (34.9 +/- 11.5 vs. 55.2 +/- 19.6 mm(3), P < 0.05). We conclude that systemic copper chelation with a clinically approved chelator significantly inhibits in-stent restenosis.
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Quelantes/farmacología , Cobre/metabolismo , Reestenosis Coronaria/prevención & control , Vasos Coronarios/fisiopatología , Molibdeno/farmacología , Stents , Animales , Ceruloplasmina/metabolismo , Quelantes/metabolismo , Terapia por Quelación/métodos , Angiografía Coronaria , Reestenosis Coronaria/patología , Reestenosis Coronaria/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Modelos Animales de Enfermedad , Masculino , Molibdeno/metabolismo , Porcinos , Factores de Tiempo , Túnica Íntima/efectos de los fármacos , Túnica Íntima/patología , Ultrasonografía IntervencionalRESUMEN
Experimental and clinical studies are progressing simultaneously to investigate the mechanisms and efficacy of progenitor cell treatment after an acute myocardial infarction and in chronic congestive heart failure. Multipotent progenitor cells appear to be capable of improving cardiac perfusion and/or function; however, the mechanisms still are unclear, and the issue of whether or not trans-differentiation occurs remains unsettled. Both experimentally and clinically, cells originating from different tissues have been shown capable of restoring cardiac function, but more recently multiple groups have identified resident cardiac progenitor cells that seem to participate in regenerating the heart after injury. Clinically, cells originating from blood or bone marrow have been proven to be safe whereas injection of skeletal myoblasts has been associated with the occurrence of ventricular arrhythmias. Myoblasts can transform into rapidly beating myotubes; however, thus far convincing evidence for electro-mechanical coupling between myoblasts and cardiomyocytes is lacking. Moving forward, mechanistic studies will benefit from the use of genetic markers and Cre/lox reporter systems that are less prone to misinterpretation than fluorescent antibodies, and a more convincing answer regarding therapeutic efficacy will come from adequately powered randomized placebo controlled trials.
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Enfermedades Cardiovasculares/terapia , Regeneración/fisiología , Trasplante de Células Madre/métodos , Animales , Terapia Combinada , Corazón/fisiología , Humanos , Investigación , Células Madre/fisiologíaRESUMEN
Numerous animal studies have established that neo-vascularization of ischemic tissue can be enhanced with exogenous growth factors and small clinical studies have shown encouraging results. However, the two largest randomized clinical trials to date were negative. Mechanistically, the major stimuli for neo-vascularization are hypoxia and inflammation. Hypoxia-inducible-factor (HIF-1) is a 'master switch' protein that is generated in response to hypoxia and binds to more than 40 hypoxia sensitive genes, inducing a panoply of angiogenic and protective metabolic responses. Inflammatory signals recruit T-lymphocytes and macrophages into areas of neo-vascularization which act as a source of angiogenic and arteriogenic factors. Although hypoxia and inflammation are interdependent in eliciting neo-vascular responses, angiogenesis appears to be hypoxia-dependent, whereas inflammation and hemodynamic factors drive arteriogenesis. The negative outcome of the two largest trials may have many reasons. There are issues relating to patient selection, choice of growth factor therapy, dosing and route administration, concomitant medication, trial design including the efficacy parameters that were selected and a lack of sufficient insight into the mechanisms that are responsible for neo-vascularization. In order to move forward the therapeutic objective should be switched to arteriogenesis although this process is even more poorly understood than angiogenesis. Genetic studies in mice with intrinsically different arteriogenic responses combined with studies in human populations with differences in the extent of collateral development may provide fundamental insight into arteriogenic mechanisms. Attention should also be focused on the way in which arteriogenesis is stimulated and the endpoints of clinical trials should be redefined.
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Neovascularización Fisiológica/fisiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Resultado del TratamientoRESUMEN
Several polymerase chain reaction (PCR) techniques are described in this review to give insight into the potential applications for cardiovascular research. Although PCR can be performed in several ways, all applications are based on the same general principle, the amplification of DNA or RNA by the enzyme polymerase. This amplification provides the opportunity to detect, identify and multiply a single copy of DNA or RNA, in or outside the cell. This powerful technique can be used in several directions of DNA and RNA research resulting in the ability to specifically detect the presence and activity of genes. The use of these techniques in cardiovascular research is discussed here.
RESUMEN
Several protein analysis techniques are described in this review to give insight into the potential applications for research. Protein analysis can be performed in several ways. All techniques are derived from the same general principle, the migration of charged particles in an electrical field. Electrophoresis of biomolecules, like proteins, provides the possibility to identify and characterise the molecules based upon different chemical properties. Immobilisation of the proteins after electrophoresis on paper is necessary to allow easy handling of the materials (blotting). These techniques also provide information on the state of a protein, whether it is activated or inactivated. To show the use of the described techniques in cardiology, two applications are provided in this review.
RESUMEN
Atherosclerotic mouse models develop little ischemic organ damage and no infarctions, despite the presence of large atherosclerotic lesions. Therefore, we hypothesize that luminal changes do not follow atherosclerotic lesion development. Because a phenomenon that may explain the discrepancy between luminal changes and lesion size is vascular remodeling, we measured parameters of vascular remodeling in the carotid arteries (CAs), thoracic aorta (TA), and abdominal aorta (AA) of apolipoprotein E (apoE)-deficient (apoE(-/-)) and apoE*3-Leiden mice, 2 well-known mouse models of atherosclerosis. Atherosclerotic lesions were classified (American Heart Association [AHA] types II through V), and plaque thickness, compensatory enlargement versus constrictive remodeling, lumen diameter, stenosis, and media thickness were measured relative to the nondiseased arterial wall. In CAs, plaque thickness increased during atherogenesis. CAs showed compensatory enlargement (apoE(-/-) 55%, apoE*3-Leiden 38%). Regression analysis revealed a positive correlation between plaque and lumen area (for apoE(-/-), R=0.95; for apoE*3-Leiden, R=0.90). Medial thinning and elastolysis were also observed. During atherogenesis, lumen diameter decreased (apoE(-/-) -69%, apoE*3-Leiden -40%), and stenosis >70% developed. TA and AA showed similar features, but neither developed a progressive decrease in lumen diameter or stenosis >70%. In CAs, TA, and AA of apoE(-/-) and apoE*3-Leiden mice, atherogenesis is associated with compensatory enlargement, medial thinning, and elastolysis. A progressive decrease in lumen diameter and stenoses >70% occur only in CAs. Vascular remodeling is more prominent in apoE(-/-) mice.
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Apolipoproteínas E/genética , Arteriosclerosis/fisiopatología , Modelos Animales , Animales , Aorta Abdominal , Aorta Torácica , Apolipoproteína E3 , Arteriosclerosis/patología , Arterias Carótidas , Femenino , Masculino , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: PTCA of a coronary stenosis without documented ischemia at noninvasive stress testing is often performed, but its benefit is unproven. Coronary pressure-derived fractional flow reserve (FFR) is an invasive index of stenosis severity that is a reliable substitute for noninvasive stress testing. A value of 0.75 identifies stenoses with hemodynamic significance. METHODS AND RESULTS: In 325 patients for whom PTCA was planned and who did not have documented ischemia, FFR of the stenosis was measured. If FFR was >0.75, patients were randomly assigned to deferral (deferral group; n=91) or performance (performance group; n=90) of PTCA. If FFR was <0.75, PTCA was performed as planned (reference group; n=144). Clinical follow-up was obtained at 1, 3, 6, 12, and 24 months. Event-free survival was similar between the deferral and performance groups (92% versus 89% at 12 months and 89% versus 83% at 24 months) but was significantly lower in the reference group (80% at 12 months and 78% at 24 months). In addition, the percentage of patients free from angina was similar between the deferral and performance groups (49% versus 50% at 12 months and 70% versus 51% at 24 months) but was significantly higher in the reference group (67% at 12 and 80% at 24 months). CONCLUSIONS: In patients with a coronary stenosis without evidence of ischemia, coronary pressure-derived FFR identifies those who will benefit from PTCA.
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Angioplastia Coronaria con Balón , Circulación Coronaria , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/fisiopatología , Índice de Severidad de la Enfermedad , Angina de Pecho/prevención & control , Angioplastia Coronaria con Balón/efectos adversos , Velocidad del Flujo Sanguíneo , Presión Sanguínea , Angiografía Coronaria , Enfermedad Coronaria/terapia , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Hipolipemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Selección de Paciente , Valor Predictivo de las Pruebas , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales/farmacología , Plaquetas , Medios de Contraste/farmacología , Fragmentos Fab de Inmunoglobulinas/farmacología , Trombina/biosíntesis , Abciximab , Anticuerpos Monoclonales/efectos de los fármacos , Anticoagulantes/farmacología , Plaquetas/metabolismo , Sinergismo Farmacológico , Hemostáticos/antagonistas & inhibidores , Hemostáticos/metabolismo , Humanos , Fragmentos Fab de Inmunoglobulinas/efectos de los fármacos , Iones , Ácido Yoxáglico/farmacología , Trombina/antagonistas & inhibidores , Trombina/efectos de los fármacosRESUMEN
AIM: To investigate the APO(*)E3-Leiden mouse as an animal model for age related maculopathy (ARM) related extracellular deposits. METHODS: Eyes were obtained from APO(*)E3-Leiden transgenic mice on a high fat/cholesterol (HFC) diet (n=12) or on a normal mouse chow (n=6), for 9 months. As controls, eyes were collected from APO-E knockout mice on the same diets. From each mouse one eye was processed for microscopic evaluation and immunohistochemistry with a polyclonal antibody directed against human apo-E. Electron microscopy was also performed. RESULTS: All 12 eyes of the APO(*)E3-Leiden mice on an HFC diet contained basal laminar deposit (BLD; class 1 to class 3), whereas two of six APO(*)E3-Leiden mice on normal chow showed BLD class 1. The ultrastructural aspects of this BLD were comparable with those seen in early BLD in humans, and BLD showed immunoreaction with anti-human-apo-E antibodies. No BLD was found in any of the control mice. Drusen were not detected in any of the mice. CONCLUSION: These results indicate that APO(*)E3-Leiden mice can be used as animal model for the pathogenesis of BLD, and that a HFC diet enhances the accumulation of this deposit. Furthermore, this study supports the previously suggested involvement of dysfunctional apo-E in the accumulation of extracellular deposits in ARM.
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Apolipoproteínas E/genética , Modelos Animales de Enfermedad , Degeneración Macular/patología , Ratones Transgénicos/genética , Animales , Apolipoproteína E3 , Apolipoproteínas E/metabolismo , Membrana Basal/ultraestructura , Grasas de la Dieta/administración & dosificación , Humanos , Técnicas para Inmunoenzimas , Degeneración Macular/etiología , Degeneración Macular/metabolismo , Ratones , Retina/metabolismo , Retina/ultraestructuraRESUMEN
BACKGROUND: In-vivo visualisation and quantification of the extent and time-frame of cell death after acute myocardial infarction would be of great interest. We studied in-vivo cell death in the hearts of patients with an acute myocardial infarction using imaging with technetium-99m-labelled annexin-V-a protein that binds to cells undergoing apoptosis. METHODS: Seven patients with an acute myocardial infarction and one control were studied. All patients were treated by percutaneous transluminal coronary angioplasty (six primary and one rescue), resulting in thrombolysis in myocardial infarction (TIMI) III flow of the infarct-related artery. 2 h after reperfusion, 1 mg annexin-V labelled with 584 MBq Tc-99m was injected intravenously. Early (mean 3.4 h) and late (mean 20.5 h) single-photon-emission computed tomographic (SPECT) images of the heart were obtained. Routine myocardial resting-perfusion imaging was also done to verify infarct localisation. FINDINGS: In six of the seven patients, increased uptake of Tc-99m-labelled annexin-V was seen in the infarct area of the heart on early and late SPECT images. No increased uptake was seen in the heart outside the infarct area. All patients with increased Tc-99m-labelled annexin-V uptake in the infarct area showed a matching perfusion defect. In a control individual, no increased uptake in the heart was seen. INTERPRETATION: Increased uptake of Tc-99m-labelled annexin-V is present in the infarct area of patients with an acute myocardial infarction, suggesting that programmed cell death occurs in that area. The annexin-V imaging protocol might allow us to study the dynamics of reperfusion-induced cell death in the area at risk and may help to assess interventions that inhibit cell death in patients with an acute myocardial infarction.
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Anexina A5 , Infarto del Miocardio/diagnóstico por imagen , Miocardio/patología , Radiofármacos , Pertecnetato de Sodio Tc 99m , Anciano , Angioplastia Coronaria con Balón , Apoptosis , Muerte Celular , Circulación Coronaria/fisiología , Vasos Coronarios/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Corazón/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Infarto del Miocardio/terapia , Compuestos Organofosforados , Compuestos de Organotecnecio , Unión Proteica , Radiofármacos/administración & dosificación , Daño por Reperfusión/diagnóstico por imagen , Pertecnetato de Sodio Tc 99m/administración & dosificación , Tecnecio Tc 99m Sestamibi , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
OBJECTIVES: How effective and safe is rescue percutaneous transluminal coronary angioplasty [PTCA] compared with primary PTCA, and is it cost effective? BACKGROUND: In acute myocardial infarction (AMI), primary PTCA has been shown to be beneficial in terms of clinical outcome. In contrast, the value of rescue PTCA has not been established. METHODS: In a retrospective analysis, we compared the angiographic and clinical outcomes of 317 consecutive patients who had rescue PTCA approximately 90 min after failed thrombolysis and 442 patients treated with primary PTCA. An estimation of interventional costs was compared with the strategies of primary and rescue PTCA or with the strategy of thrombolysis with rescue PTCA, when indicated. RESULTS: Baseline characteristics between primary and rescue PTCA were comparable for most variables. Treatment delay was longer for patients who had rescue PTCA: 240 min. versus 195 min. Coronary patency after PTCA was comparable: 90.2% for rescue PTCA and 91.4% for primary PTCA (p = 0.67, power 71.9%). In-hospital mortality rates were 4.7% and 6.6%, respectively (p = 0.37). Also, the other complications were fairly similar during the in-hospital phase and during one-year follow-up. Predictors of death were age, infarct size, localization of AMI, failed PTCA and left main stem occlusion. The estimated interventional costs during one-year follow-up were $7,377 for primary PTCA and $8,246 for rescue PTCA: difference $869 (11.7%). CONCLUSIONS: In this retrospective analysis of 759 patients with AMI, rescue angioplasty early after failed thrombolysis seems to be as effective and safe as primary PTCA. In the present evaluation, interventional costs of primary PTCA are less than those of rescue PTCA (p = 0.0001).
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Angioplastia Coronaria con Balón , Infarto del Miocardio/terapia , Angioplastia Coronaria con Balón/economía , Angioplastia Coronaria con Balón/mortalidad , Angiografía Coronaria , Análisis Costo-Beneficio , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/mortalidad , Países Bajos/epidemiología , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Atherosclerosis is a systemic disease of the large arteries, and activation of inflammatory pathways is important in its pathogenesis. Increasing evidence supports the importance of CD40-CD154 interactions in atherosclerosis, interactions originally known to be essential in major immune reactions and autoimmune diseases. CD40 is present on atheroma-derived cells in vitro and in human atheromata in situ. Ligation of CD40 on atheroma-associated cells in vitro activates the production of chemokines, cytokines, matrix metalloproteinases, adhesion molecules and tissue factor, substances responsible for lesion progression and plaque destabilization. Administration of antibody against CD154 to low-density lipoprotein receptor-deficient mice has been shown to reduce atherosclerosis and decrease T-lymphocyte and macrophage content; however, only initial lesions were studied. Here, we determined the effect of genetic disruption of CD154 in ApoE-/- mice in both initial and advanced atherosclerotic lesions. Plaque area was reduced 550%. In contrast to previous reports, initial lesion development was not affected. Advanced plaques in CD154-/-ApoE-/- mice had a less-lipid-containing, collagen-rich, stable plaque phenotype, with a reduced T-lymphocyte/macrophage content. These data indicate that CD40-CD154 signaling is important in late atherosclerotic changes, such as lipid core formation and plaque destabilization.
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Arteriosclerosis/inmunología , Glicoproteínas de Membrana/inmunología , Animales , Secuencia de Bases , Ligando de CD40 , Colesterol/sangre , Cartilla de ADN , Progresión de la Enfermedad , Humanos , Inmunohistoquímica , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T/inmunología , Triglicéridos/sangreRESUMEN
OBJECTIVES: The study assessed the value of the electrocardiogram (ECG) as predictor of the left anterior descending coronary artery (LAD) occlusion site in relation to the first septal perforator (S1) and/or the first diagonal branch (D1) in patients with acute anterior myocardial infarction (AMI). BACKGROUND: In anterior AMI, determination of the exact site of LAD occlusion is important because the more proximal the occlusion the less favorable the prognosis. METHODS: One hundred patients with a first anterior AMI were included. The ECG showing the most pronounced ST-segment deviation before initiation of reperfusion therapy was evaluated and correlated with the exact LAD occlusion site as determined by coronary angiography. RESULTS: ST-elevation in lead aVR (ST elevation(aVR)), complete right bundle branch block, ST-depression in lead V5 (ST depression(V5)) and ST elevation(V1) > 2.5 mm strongly predicted LAD occlusion proximal to S1, whereas abnormal Q-waves in V4-6 were associated with occlusion distal to S1 (p = 0.000, p = 0.004, p = 0.009, p = 0.011 and p = 0.031 to 0.005, respectively). Abnormal Q-wave in lead aVL was associated with occlusion proximal to D1, whereas ST depression(aVL) was suggestive of occlusion distal to D1 (p = 0.002 and p = 0.022, respectively). For both the S1 and D1, inferior ST depression > or = 1.0 mm strongly predicted proximal LAD occlusion, whereas absence of inferior ST depression predicted distal occlusion (p < or = 0.002 and p < or = 0.020, respectively). CONCLUSIONS: In anterior AMI, the ECG is useful to predict the LAD occlusion site in relation to its major side branches.
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Vasos Coronarios/patología , Electrocardiografía , Infarto del Miocardio/patología , Adulto , Anciano , Anciano de 80 o más Años , Arterias/patología , Constricción Patológica , Angiografía Coronaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/fisiopatología , Valor Predictivo de las PruebasRESUMEN
OBJECTIVES: We studied the effects of chronic left coronary artery ligation on cardiac structure and function in the mouse. METHODS: Morphometric studies of the left ventricle were performed in coronary artery-ligated and sham-operated animals at one, two, three and five weeks after surgery. The fraction of DNA-synthesizing cells was determined as the fraction of cells incorporating 5'-bromo-2'-deoxyuridine, which was infused by osmotic minipumps one week before sacrifice. Collagen content of the septum was determined morphometrically. Left ventricular pressure and its derivatives were measured in separate groups of animals at one and three weeks after surgery. RESULTS: Ligation of the main left coronary artery resulted in antero-apical infarction of the left ventricular wall, involving approximately 40% of left ventricular circumference. Infarction resulted in thinning of the infarcted area and left ventricular dilatation. DNA synthesis increased, peaking between one and two weeks in the border-zone of the infarct (22-fold), septum (ten-fold) and right ventricle (five-fold). At five weeks, DNA synthesis was still increased in the border zone of the infarct. Septal collagen content increased approximately eight-fold in infarcted mice at two weeks, and decreased thereafter; it was still significantly elevated at five weeks. Left ventricular systolic pressure, and maximal positive and negative dP/dt decreased following infarction; left ventricular end-diastolic pressure was elevated at three weeks, but this effect was not statistically significant. CONCLUSION: These data provide basic information on changes in cardiac structure and function in mice following chronic coronary artery ligation. They indicate the feasibility of induction of chronic myocardial infarction in this species. Furthermore, they show the similarity of cardiac structural and functional consequences of chronic myocardial infarction in mice to those previously described in rats.
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Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/patología , Animales , Enfermedad Crónica , Colágeno/análisis , Colágeno/metabolismo , ADN/biosíntesis , Masculino , Ratones , Ratones Endogámicos , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Presión VentricularRESUMEN
OBJECTIVE: To study the amount and phenotype of DNA-synthesizing and apoptotic cells during atherogenesis. METHODS: Atherosclerotic lesions (n = 76), obtained at autopsy (N = 6) or during vascular surgery (N = 8), were classified [type I-VI; American Heart Association (AHA) classification], immunolabeled with MIB 1 or the TUNEL technique and double stained with cell-type-specific antibodies. Subsequently, the labeled fractions were quantified. RESULTS: In type II-VI lesions, intimal DNA synthesis was increased compared to that of the non-diseased (ND) arterial wall. DNA synthesis peaked in early type II lesions (2.7 +/- 0.5 vs. 0.02 +/- 0.02% in ND; p < 0.05), and declined to 0.7 +/- 0.2% in type V lesions (p < 0.05). Interestingly, a second peak of DNA synthesis of 1.7 +/- 0.1%, was observed in type VI (ruptured plaque) lesions. Double staining revealed that DNA synthesis was mostly confined to the macrophage-derived foam cell (51.9%). In type II lesions, 100.0% of all DNA-synthesizing cells were present in the intimal foam cell-rich area, while in advanced type III, IV and V lesions, DNA synthesis had shifted to the shoulder region (74.8, 78.5 and 68.1%, respectively). In type VI lesions, DNA synthesis was present in the area underlying the plaque rupture (52.7%). Apoptosis was only elevated in advanced type IV, V and VI lesions (0.8 +/- 0.1, 0.8 +/- 0.1 and 1.1 +/- 0.1%, respectively, vs. 0.0 +/- 0.0% in ND) and was predominant in the lipid core (90.5% in type IV lesions; 54.2% in type V lesions) or equally divided between the lipid core and the region underlying the plaque rupture (31.8 and 34.6% in type VI lesions). In type III-VI lesions, 50.0, 38.9, 42.6 and 42.8% of the TUNEL-positive cells were macrophages. CONCLUSIONS: In stable atherosclerotic lesions, DNA synthesis is an early event, while apoptosis is a late event. Ruptured plaques show a second peak of cell turnover. Lastly, cell turnover is mostly confined to the macrophage-derived foam cell.
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Arteriosclerosis/patología , Túnica Íntima/patología , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Apoptosis , División Celular , ADN/biosíntesis , Femenino , Células Espumosas/patología , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
BACKGROUND: This study documents (1) the progression of atherosclerosis along the entire arterial tree in APOE*3-Leiden mice after 1, 4, 6, 9, and 12 months of a high-fat/high-cholesterol (HFC) diet and (2) the amount and phenotype of DNA-synthesizing and apoptotic cells in different lesion types after 6 months of HFC diet. METHODS AND RESULTS: Diet duration was correlated with a craniocaudal progression of lesion development and with an increase in severity of the lesion. Typically, the lesions contained smooth muscle cells, macrophages, and T lymphocytes and were covered by an intact endothelium. Whereas DNA synthesis (BrdU uptake) was usually elevated in type II lesions (8.6+/-0.8% versus 1.0+/-0.2% in the nondiseased arterial wall; P<0.05), apoptosis was found primarily in advanced lesions (type IV, 1.3+/-0.1% and type V, 1.2+/-0.2% versus 0.04+/-0.04% in the nondiseased arterial wall [P<0.05]). Cell phenotyping revealed that the majority of DNA synthesis and apoptosis was confined to the macrophage-derived foam cell (68.6+/-3. 0% and 82.2+/-4.6%, respectively). CONCLUSIONS: This study shows that in APOE*3-Leiden mice, duration of an HFC diet is associated with (1) a craniocaudal progression of lesion development and (2) an increased complexity of atherosclerotic lesions. Furthermore, DNA synthesis is predominant in early lesions, whereas apoptosis is present mainly in more advanced lesions. Both parameters of cell turnover are confined primarily to the macrophage-derived foam cell.
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Apolipoproteínas E/genética , Arteriosclerosis/patología , Animales , Apolipoproteína E3 , Apoptosis , ADN/biosíntesis , Dieta Aterogénica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Células Espumosas/patología , Masculino , Ratones , Ratones Transgénicos , FenotipoRESUMEN
Progress in molecular genetics has changed cardiovascular research. The mouse has turned out to be an invaluable model for mammalian genetic modifications to mimic and analyse cardiovascular pathology. Through the introduction of transgene and gene targeting technology, regulatory systems can be studied at the molecular level. Recent technical developments have down-sized the equipment for physiological measurements to the mouse level. Micro-surgery has developed to the level where most manipulations previously performed in larger animals can now be applied to mice. However, different investigators report considerable differences in values for physiological parameters. Whether these differences are related to the variation in mouse strains or experimental procedures remains to be established, but awareness of the variation can be relevant for prospective mouse investigators. In the present review, the physiological measurements performed in mice to date are discussed and complemented with results from genetically manipulated animals. In addition the various surgical procedures and their practical application are illustrated.
Asunto(s)
Enfermedades Cardiovasculares , Modelos Animales de Enfermedad , Corazón/fisiología , Animales , Enfermedades Cardiovasculares/fisiopatología , Ecocardiografía , Electrocardiografía , Electrofisiología , Corazón/anatomía & histología , Corazón/fisiopatología , Ratones , Ratones Endogámicos , Ratones Mutantes , FenotipoRESUMEN
INTRODUCTION: Incessant monomorphic ventricular tachycardia (VT) with a right bundle branch block morphology and a northwest axis is a rare arrhythmic complication in a patient with hypertrophic cardiomyopathy and apical left ventricular aneurysm. METHODS AND RESULTS: The origin of this VT was localized using the following criteria: the presence of entrainment without fusion, equal intervals from the stimulus to the beginning of the QRS complex and from the electrogram to the QRS complex during VT, and the first postpacing interval identical to the tachycardia cycle length. Radiofrequency energy applied to the septoapical part of the apical left ventricular aneurysm terminated the tachycardia within 2 seconds. CONCLUSION: Using criteria to guide radiofrequency (RF) ablation of VT in patients with coronary artery disease, an incessant monomorphic VT in a patient with hypertrophic cardiomyopathy was successfully ablated.
Asunto(s)
Cardiomiopatía Hipertrófica/complicaciones , Ablación por Catéter , Taquicardia Ventricular/complicaciones , Anciano , Antiarrítmicos/uso terapéutico , Cardiomiopatía Hipertrófica/cirugía , Ablación por Catéter/métodos , Estimulación Eléctrica , Electrofisiología , Potenciales Evocados/fisiología , Femenino , Aneurisma Cardíaco/complicaciones , Ventrículos Cardíacos , Humanos , Masculino , Metoprolol/uso terapéutico , Marcapaso Artificial , Procainamida/uso terapéutico , Taquicardia Ventricular/cirugíaRESUMEN
Distal coronary hemoperfusion during percutaneous transluminal coronary angioplasty (PTCA)-with an autoperfusion balloon or active system-facilitates prolonged balloon inflation. Prolonged inflations may tack up intimal dissections and improve the primary angioplasty result in complex lesions. Additionally, distal perfusion may reduce the likelihood of cardiogenic shock during high-risk PTCA. Autoperfusion balloons are most frequently used to treat acute or threatened closure. There currently is no prospective clinical study showing that stent implantation for this complication is more successful and more cost-effective. The blood flow rates through autoperfusion balloons may not abolish myocardial ischemia, and higher flow rates can often be achieved with pumps. Therefore, during high-risk PTCA, pumps may be preferred to prevent hemodynamic collapse. Clinical application of perfusion pumps is hampered by the risk for mechanical hemolysis during prolonged perfusion and the high velocity of the bloodstream that exits the PTCA catheter, causing distal vessel wall trauma.