RESUMEN

BACKGROUND: To investigate the potential of intravenously administered porcine recombinant interferon-ß1a (IFN-ß1a) for myocardial protection during acute ischemia-reperfusion (IR) injury in an experimental animal model. METHODS: Twenty-two piglets (mean ± standard deviation, 26.7 ± 1.65 kg) were assigned to either the IFN group (n = 12) or the control group (n = 10). IR injury was induced by occluding the distal left descending coronary artery for 30 minutes, with a reperfusion period of 6 h. In the IFN group, the animals received 12.5 µg IFN-ß1a intravenously repeatedly; the control group received saline solution. The levels of interleukin-6 (IL-6) and cardiac troponin I (TnI) were measured, and the amount of myocardial damage was quantified by analyzing myocardial apoptosis and the mean fluorescence intensity (MFI) of methylene blue-stained cardiac tissue. RESULTS: In the IFN group, significantly more premature deaths occurred compared with the control group (25% versus 17%, P = .013). Between the groups, the mean heart rate was higher in the IFN group (102 ± 22 versus 80 ± 20 beats per minute, P = .02). IL-6 and TnI levels were comparable between the groups, with no significant difference, and there was no difference between the study groups in myocardial apoptosis in the infarcted myocardium. The percentage of MFI differed significantly between the IFN and control groups (90.75% ± 4.90% versus 96.02% ± 2.73%, P = .01). CONCLUSION: In this acute IR injury animal model, IFN-ß1a did not protect the myocardium from IR injury, but rather increased some of the unfavorable outcomes studied.

Asunto(s)

Interferón beta-1a/administración & dosificación , Infarto del Miocardio/complicaciones , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocardio/patología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Apoptosis , Modelos Animales de Enfermedad , Inyecciones Intravenosas , Infarto del Miocardio/diagnóstico , Daño por Reperfusión Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/etiología , Porcinos

RESUMEN

BACKGROUND: Assessment of myocardial viability is often needed in patients with chest pain and reduced ejection fraction. We evaluated the performance of reduced resting MBF, perfusable tissue fraction (PTF), and perfusable tissue index (PTI) in the assessment of myocardial viability in a pig model of myocardial infarction (MI). METHODS AND RESULTS: Pigs underwent resting [15O]water PET perfusion study 12 weeks after surgical (n = 16) or 2 weeks after catheter-based (n = 4) occlusion of the proximal left anterior descending coronary artery. MBF, PTF, and PTI were compared with volume fraction of MI in matched segments as assessed by triphenyl tetrazolium chloride staining of LV slices. MBF and PTF were lower in infarcted than non-infarcted segments. Segmental analysis of MBF showed similar area under the curve (AUC) of 0.85, 0.86, and 0.90 with relative MBF, PTF, and PTI for the detection of viable myocardium defined as infarct volume fraction of < 75%. Cut-off values of relative MBF of ≥ 67% and PTF of ≥ 66% resulted in accuracies of 90% and 81%, respectively. CONCLUSIONS: Our results indicate that resting MBF, PTF, and PTI based on [15O]water PET perfusion imaging are useful for the assessment of myocardial viability.

Asunto(s)

Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/patología , Tomografía de Emisión de Positrones , Animales , Circulación Coronaria , Modelos Animales de Enfermedad , Infarto del Miocardio/fisiopatología , Radioisótopos de Oxígeno , Valor Predictivo de las Pruebas , Curva ROC , Porcinos , Supervivencia Tisular

RESUMEN

We evaluated the relationships between regional myocardial strain measured by speckle tracking echocardiography and viability, fibrosis, hypertrophy and oxygen consumption in the infarcted or remote myocardium in a pig model of chronic myocardial infarction (MI). Thirteen farm pigs with surgical occlusion of the left anterior descending coronary artery and five sham-operated pigs were studied 3 mo post-MI. Computed tomography revealed significant left ventricle remodeling. Reduced radial or circumferential strain identified areas of transmural infarction (area under the curve: 0.82 and 0.79, respectively). In the remote non-infarcted area, radial strain correlated inversely with the amount of fibrosis (r = -0.66, p = 0.04) and myocyte hypertrophy (r = -0.68, p = 0.03). Radial strain rate inversely correlated with myocardial resting oxygen consumption assessed with 11C-labeled acetate positron emission tomography (r = -0.71, p = 0.006). In conclusion, myocardial strain and strain rate reflect fibrosis, hypertrophy and oxygen consumption of the remote areas after MI.

Asunto(s)

Ecocardiografía/métodos , Corazón/diagnóstico por imagen , Corazón/fisiopatología , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/fisiopatología , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Masculino , Porcinos

RESUMEN

BACKGROUND: Receptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart. METHODS: RTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass, was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays. RESULTS: In addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation. CONCLUSIONS: Several novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury.

Asunto(s)

Cardiomiopatías/enzimología , Infarto del Miocardio/enzimología , Daño por Reperfusión Miocárdica/enzimología , Miocitos Cardíacos/enzimología , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Animales , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/genética , Cardiomiopatías/patología , Estudios de Casos y Controles , Línea Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Regulación Enzimológica de la Expresión Génica , Humanos , Terapia Molecular Dirigida , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/antagonistas & inhibidores , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Transducción de Señal , Sus scrofa

RESUMEN

OBJECTIVE: We wanted to determine the impact of different doses of a pegylated and liposomal formulation of the cardiotoxic drug doxorubicin on cardiac function, fibrosis and survival in mice. The drug causes myocardial damage by producing reactive oxygen species, mitochondrial damage and lipid peroxidation. Thymosin beta 4 is a peptide with cardioprotective, anti-oxidant and anti-fibrotic properties and we further investigated whether the peptide could attenuate this drug-induced injury by measuring cardiac function and fibrosis. RESULTS: Mice receiving high doses of doxorubicin died early during follow-up. Lowering the dose improved survival but did not markedly impair cardiac function on echocardiography and caused only limited fibrosis on histology. Thymosin beta 4 had only a mild protective effect on early cardiac function and did not significantly influence myocardial fibrosis. In conclusion, the use of pegylated and liposomal doxorubicin was not appropriate for inducing experimental cardiomyopathy. Thymosin beta 4 therapy was not beneficial in this setting.

Asunto(s)

Cardiomiopatías/inducido químicamente , Cardiomiopatías/prevención & control , Cardiotoxicidad/prevención & control , Doxorrubicina/análogos & derivados , Timosina/farmacología , Animales , Modelos Animales de Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/toxicidad , Electrocardiografía , Masculino , Ratones , Polietilenglicoles/administración & dosificación , Polietilenglicoles/toxicidad

RESUMEN

The aims of the study are to describe the long-term survival of patients undergoing primary open ascending aortic surgery and to portray the evolution of aortic surgery during six decades in a single centre. Included were all 614 patients who underwent primary ascending aortic surgery in 1968-2014 at one Nordic university hospital. Patients were identified and data were collected from patient records and surgical logs. Mortality data were acquired from the national registry. Median follow-up was 11.2 years using reverse Kaplan-Meier method. Overall 30-day survival was 91.2% and for 30-day survivor rates were 86.9, 77.6, 52.1, 38.3 and 26.7% at 5, 10, 20, 30 and 40 years. There was no significant difference in long-term survival for 30-day survivors (p = 0.105) between patients treated emergently for dissection/rupture and electively (mainly ascending aortic aneurysms). On Cox regression era of surgery (p = 0.006), increasing age (p < 0.001) and indication (p < 0.001) were predictors of 30-day mortality. Arch involvement indicated twofold risk (HR 2.09, p = 0.05) compared to non-arch involved. Only increasing age (p < 0.001) predicted long-term mortality. There was a sixfold risk of 30-day mortality in the earliest era compared to the latest (p = 0.03). After the early postoperative phase following ascending aortic surgery, the surgical indication and urgency of the index operation have no significant impact on long-term survival. The very long term survival after ascending aortic surgery is excellent for 30-day survivors and improved through the era. Surgical treatment has improved and perioperative mortality has decreased significantly in 47 years.

Asunto(s)

Aorta/cirugía , Aneurisma de la Aorta Torácica/cirugía , Disección Aórtica/cirugía , Implantación de Prótesis Vascular/métodos , Procedimientos Quirúrgicos Electivos/métodos , Predicción , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Disección Aórtica/mortalidad , Aneurisma de la Aorta Torácica/mortalidad , Femenino , Finlandia/epidemiología , Estudios de Seguimiento , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Persona de Mediana Edad , Reoperación , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendencias , Resultado del Tratamiento , Adulto Joven

RESUMEN

BACKGROUND: Radiolabeled RGD peptides detect αvß3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased αvß3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αvß3 integrin is expressed in viable ischemic or injured myocardium. METHODS: We studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology. RESULTS: Stent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of αvß3 integrin that was expressed in the injured myocardial areas. CONCLUSIONS: Cardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial αvß3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects αvß3 integrin expression associated with repair of recent myocardial injury.

Asunto(s)

Acetatos/química , Radioisótopos de Galio/química , Compuestos Heterocíclicos con 1 Anillo/química , Integrina alfaVbeta3/metabolismo , Isquemia Miocárdica/diagnóstico por imagen , Oligopéptidos/química , Tomografía de Emisión de Positrones , Acetatos/farmacocinética , Animales , Autorradiografía , Circulación Coronaria , Radioisótopos de Galio/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Cinética , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Miocardio/patología , Oligopéptidos/farmacocinética , Sus scrofa , Distribución Tisular

RESUMEN

BACKGROUND: We evaluated echocardiographic area-length methods to measure left ventricle (LV) volumes and ejection fraction (EF) in parasternal short axis views in comparison with cardiac computed tomography (CT) in pigs with chronic myocardial infarction (MI). METHODS: Male farm pigs with surgical occlusion of the left anterior descending coronary artery (n = 9) or sham operation (n = 5) had transthoracic echocardiography and cardiac-CT 3 months after surgery. We measured length of the LV in parasternal long axis view, and both systolic and diastolic LV areas in parasternal short axis views at the level of mitral valve, papillary muscles and apex. Volumes and EF of the LV were calculated using Simpson's method of discs (tri-plane area) or Cylinder-hemiellipsoid method (single plane area). RESULTS: The pigs with coronary occlusion had anterior MI scars and reduced EF (average EF 42 ± 10%) by CT. Measurements of LV volumes and EF were reproducible by echocardiography. Compared with CT, end-diastolic volume (EDV) measured by echocardiography showed good correlation and agreement using either Simpson's method (r = 0.90; mean difference -2, 95% CI -47 to 43 mL) or Cylinder-hemiellipsoid method (r = 0.94; mean difference 3, 95% CI -44 to 49 mL). Furthermore, End-systolic volume (ESV) measured by echocardiography showed also good correlation and agreement using either Simpson's method (r = 0.94; mean difference 12 ml, 95% CI: -16 to 40) or Cylinder-hemiellipsoid method (r = 0.97; mean difference:13 ml, 95% CI: -8 to 33). EF was underestimated using either Simpson's method (r = 0.78; mean difference -6, 95% CI -11 to 1%) or Cylinder-hemiellipsoid method (r = 0.74; mean difference -4, 95% CI-10 to 2%). CONCLUSION: Our results indicate that measurement of LV volumes may be accurate, but EF is underestimated using either three or single parasternal short axis planes by echocardiography in a large animal model of chronic MI.

Asunto(s)

Ecocardiografía/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Infarto del Miocardio/diagnóstico , Tomografía Computarizada por Rayos X/métodos , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Masculino , Reproducibilidad de los Resultados , Porcinos

RESUMEN

The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI.

RESUMEN

BACKGROUND: Levosimendan is an inotropic agent with cardioprotective and vasodilating properties used for the management of acutely decompensated heart failure. We studied the effects of levosimendan treatment on the size of myocardial infarction (MI) and left ventricular (LV) function in experimental pig model of post MI heart failure. METHODS: After occlusion of the left anterior descending (LAD) coronary artery, animals received levosimendan 5 mg/kg/day orally for 8 weeks (n=7) or no treatment (n=18). One week after stopping treatment, transthoracic echocardiography, CT scan and positron emission tomography were performed to evaluate myocardial function, perfusion and oxidative metabolism. Histology was used to confirm the size of MI and features of LV remodelling. RESULTS: The size of MI was significantly smaller in the levosimendan group than in the controls (12±13% vs 27±15% of the LV, p=0.03). End-diastolic volume (EDV) and end-systolic volume (ESV) were smaller in the levosimendan than in the control group (EDV 161±29 mL vs 245±84 mL, p=0.06; ESV 81±18 mL vs 149±67 mL, p=0.03), whereas ejection fraction tended to be higher in the levosimendan group (50±6% vs 41±8%, p=0.06). CONCLUSIONS: Eight weeks of levosimendan therapy after recent LAD occlusion decreases the size of MI and leads to better preservation of LV function as well as reduced LV remodelling.

Asunto(s)

Oclusión Coronaria/complicaciones , Hidrazonas/uso terapéutico , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Miocardio/patología , Piridazinas/uso terapéutico , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Enfermedad Aguda , Animales , Cardiotónicos/uso terapéutico , Diástole , Modelos Animales de Enfermedad , Estudios de Seguimiento , Masculino , Contracción Miocárdica/fisiología , Infarto del Miocardio/etiología , Infarto del Miocardio/fisiopatología , Simendán , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Porcinos , Sístole , Función Ventricular Izquierda/fisiología

RESUMEN

OBJECTIVE: Inflammation is an important contributor to atherosclerosis progression. A glucose analogue 18F-fluorodeoxyglucose ([18F]FDG) has been used to detect atherosclerotic inflammation. However, it is not known to what extent [18F]FDG is taken up in different stages of atherosclerosis. We aimed to study the uptake of [18F]FDG to various stages of coronary plaques in a pig model. METHODS: First, diabetes was caused by streptozotocin injections (50 mg/kg for 3 days) in farm pigs (n = 10). After 6 months on high-fat diet, pigs underwent dual-gated cardiac PET/CT to measure [18F]FDG uptake in coronary arteries. Coronary segments (n = 33) were harvested for ex vivo measurement of radioactivity and autoradiography (ARG). RESULTS: Intimal thickening was observed in 16 segments and atheroma type plaques in 10 segments. Compared with the normal vessel wall, ARG showed 1.7±0.7 times higher [18F]FDG accumulation in the intimal thickening and 4.1±2.3 times higher in the atheromas (P = 0.004 and P = 0.003, respectively). Ex vivo mean vessel-to-blood ratio was higher in segments with atheroma than those without atherosclerosis (2.6±1.2 vs. 1.3±0.7, P = 0.04). In vivo PET imaging showed the highest target-to-background ratio (TBR) of 2.7. However, maximum TBR was not significantly different in segments without atherosclerosis (1.1±0.5) and either intimal thickening (1.2±0.4, P = 1.0) or atheroma (1.6±0.6, P = 0.4). CONCLUSIONS: We found increased uptake of [18F]FDG in coronary atherosclerotic lesions in a pig model. However, uptake in these early stage lesions was not detectable with in vivo PET imaging. Further studies are needed to clarify whether visible [18F]FDG uptake in coronary arteries represents more advanced, highly inflamed plaques.

Asunto(s)

Aterosclerosis/diagnóstico por imagen , Diabetes Mellitus/diagnóstico por imagen , Fluorodesoxiglucosa F18/metabolismo , Animales , Aterosclerosis/sangre , Autorradiografía , Glucemia/metabolismo , Colesterol/sangre , Circulación Coronaria , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Ayuno/sangre , Microvasos/diagnóstico por imagen , Microvasos/patología , Miocardio/patología , Tomografía de Emisión de Positrones , Sus scrofa , Distribución Tisular , Tomografía Computarizada por Rayos X

RESUMEN

AIMS: Large animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology. METHODS AND RESULTS: Male farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [(15)O]water and oxygen consumption using [(11)C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs. CONCLUSIONS: The chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.

Asunto(s)

Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Consumo de Oxígeno , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/fisiopatología , Remodelación Ventricular , Animales , Enfermedad Crónica , Ecocardiografía/métodos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Masculino , Imagen de Perfusión Miocárdica/métodos , Tomografía de Emisión de Positrones/métodos , Porcinos , Tomografía Computarizada por Rayos X/métodos , Disfunción Ventricular Izquierda/etiología

RESUMEN

Thymosin ß4 (Tß4) is a peptide known for its abilities to protect and facilitate regeneration in a number of tissues following injury. Its cardioprotective effects have been evaluated in different animal models and, currently, a clinical trial is being planned in patients suffering from acute myocardial infarction. This paper focuses on the effects of Tß4 on cardiac function in animal studies utilizing different imaging modalities for outcome measurements.

Asunto(s)

Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Timosina/metabolismo , Timosina/uso terapéutico , Animales , Modelos Animales de Enfermedad , Humanos

RESUMEN

BACKGROUND: Levosimendan is a calcium sensitizer that has been shown to prevent myocardial contractile depression in patients post cardiac surgery. This drug exhibits an anti-apoptotic property; however, the underlying mechanism remains elusive. In this report, we characterized the myocardial protective of levosimendan in preventing cardiomyocyte apoptosis and post-operative stunning in an experimental ischemia-reperfusion model. METHODS: Three groups of pigs (n = 8 per group) were subjected to 40 min of global, cardioplegic ischemia followed by 240 min of reperfusion. Levosimendan (65 µg/kg body weight) was given to pigs by intravenous infusion (L-IV) before ischemia or intracoronary administration during ischemia (L-IC). The Control group did not receive any levosimendan. Echocardiography was used to monitor cardiac function in all groups. Apoptosis levels were assessed from the left ventricle using the terminal transferase mediated dUTP nick end labeling (TUNEL) assay and immunocytochemical detection of Caspase-3. RESULTS: Pigs after ischemia-reperfusion had a much higher TUNEL%, suggesting that our treatment protocol was effective. Levels of apoptosis were significantly increased in Control pigs that did not receive any levosimendan (0.062 ± 0.044%) relative to those received levosimendan either before (0.02 ± 0.017%, p = 0.03) or during (0.02 ± 0.017%, p = 0.03) the ischemia phase. Longitudinal left ventricular contraction in pigs that received levosimendan before ischemia (0.75 ± 0.12 mm) was significantly higher than those received levosimendan during ischemia (0.53 ± 0.11 mm, p = 0.003) or Control pigs (0.54 ± 0.11 mm, p = 0.01). CONCLUSION: Our results suggested that pigs received levosimendan displayed a markedly improved cell survival post I-R. The effect on cardiac contractility was only significant in our perfusion heart model when levosimendan was delivered intravenously before ischemia.

RESUMEN

PURPOSE: 6-[(18)F]Fluorodopamine (4-(2-aminoethyl)-5-[(18)F]fluorobenzene-1,2-diol, 6-[(18)F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[(18)F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15 GBq/µmol. We also sought to determine an extensive biodistribution pattern for 6-[(18)F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[(18)F]FDA. In addition, to investigate the safety profile of 6-[(18)F]FDA in larger animals, we performed in vivo studies in pigs. METHODS: 6-[(18)F]FDA was synthesised using high SA electrophilic [(18)F]F(2) as the labelling reagent. Biodistribution and metabolism of 6-[(18)F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs. RESULTS: 6-[(18)F]FDA was synthesised with 2.6 ± 1.1% radiochemical yield. The total amount of purified 6-[(18)F]FDA was 663 ± 291 MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2 ± 2.7 GBq/µmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[(18)F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[(18)F]FDA in rat plasma declined rapidly, with a half-life of 2 min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects. CONCLUSION: 6-[(18)F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[(18)F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[(18)F]FDA was specific in various peripheral organs, indicating that 6-[(18)F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved.

Asunto(s)

Técnicas de Química Sintética/métodos , Dopamina/análogos & derivados , Animales , Transporte Biológico , Dopamina/síntesis química , Dopamina/metabolismo , Dopamina/farmacocinética , Masculino , Tomografía de Emisión de Positrones , Radioquímica , Ratas , Porcinos

RESUMEN

PURPOSE: We evaluated four potential gallium-68 (68Ga)-labeled tracers for positron emission tomography (PET) imaging of myocardial perfusion in comparison with oxygen-15-labeled water ([15O]water) in healthy pigs. Four hexadentate salicylaldimine ligands derived from bis(3-aminopropyl)ethylenediamine (BAPEN) that showed promise in previous rat experiments were selected for this study. METHODS: Following an evaluation of myocardial blood flow with [15O]water PET, the pigs (total n=14) underwent a dynamic 90-min PET study with one of four 68Ga-labeled BAPEN derivatives (n=3-5 per tracer) either at rest or under adenosine stress. Serial arterial blood samples were collected during the imaging for the measurements of total radioactivity, radiometabolites, plasma protein binding and blood-to-plasma ratio for the 68Ga chelates. Time-activity curves of the left ventricular blood pool and myocardium were derived from PET images, and metabolite-corrected arterial input function was used for kinetic modeling. Also, ex vivo biodistribution of 68Ga radioactivity was analyzed. RESULTS: All four 68Ga tracers showed undesirably slow myocardial accumulation over time, but their in vivo stability, clearance from blood and the kinetics of the myocardium uptake varied. [68Ga][Ga-(sal)2BAPDMEN]1+ showed the highest myocardial uptake in PET images and tissue samples (myocardium-to-blood ratio 7.63±1.89, myocardium-to-lung ratio 3.03±0.33 and myocardium-to-liver ratio 1.80±0.82). However, there was no correlation between the myocardial perfusion measured with [15O]water and the net uptake rates or K1 values of the 68Ga chelates. CONCLUSION: Our results revealed that myocardial accumulation of the 68Ga chelates proposed for myocardial perfusion imaging with PET was slow and not determined by myocardial perfusion in a large animal model. These findings suggest that the studied tracers are not suitable for clinical imaging of myocardial perfusion.

Asunto(s)

Etilenodiaminas , Imagen de Perfusión Miocárdica/métodos , Compuestos Organometálicos , Tomografía de Emisión de Positrones/métodos , Animales , Transporte Biológico , Proteínas Sanguíneas/metabolismo , Etilenodiaminas/sangre , Etilenodiaminas/metabolismo , Etilenodiaminas/farmacocinética , Femenino , Radioisótopos de Galio , Ligandos , Miocardio/metabolismo , Compuestos Organometálicos/sangre , Compuestos Organometálicos/metabolismo , Compuestos Organometálicos/farmacocinética , Trazadores Radiactivos , Porcinos

RESUMEN

Local inflammation after a surgical incision is an essential prerequisite for wound healing and later scar formation both in children and adults. However, the underlying regulatory mechanisms are still poorly known and need further investigations. In this study, one hundred sternotomy patients, operated on routinely for cardiac disease, were studied with the Cellstick device to harvest wound inflammatory cells for differential count and subsequent computerized analysis using an artificial neural network. As a result a nonparametric line of ranked nodes was obtained reflecting wound inflammatory cell response in individual patients at hour 24 post surgery. A number of preoperative and operative parameters were recorded to see their possible correlation with the node values of wound inflammatory cell response. It was found that the age of the patient had a remarkable role in this respect while a majority of laboratory values, if within reference values of healthy persons, had a minor correlation or no correlation at all. Therefore, individual and genetic factors seemed to play a dominant role providing that the patient had a good or moderate general condition and surgical site infection was avoided.

Asunto(s)

Inflamación/patología , Cuidados Preoperatorios , Esternotomía/efectos adversos , Cicatrización de Heridas , Adulto , Factores de Edad , Anciano , Intervalos de Confianza , Femenino , Humanos , Inflamación/etiología , Masculino , Persona de Mediana Edad , Redes Neurales de la Computación , Estadística como Asunto , Estadísticas no Paramétricas , Factores de Tiempo

RESUMEN

BACKGROUND: Retrograde delivery is associated with inadequate perfusion of cardioplegia to all regions of the heart, but the effects on cardiomyocyte death and functional outcome remain unknown. We compared antegrade and retrograde cardioplegia in a randomized clinical trial to see whether it has effect on cardiomyocyte apoptosis and left ventricular function. METHODS: Patients underwent elective aortic valve replacement surgery due to aortic valve stenosis. They were randomly allocated to receive antegrade (n = 10) or retrograde (n = 10) cardioplegia. Apoptotic cardiomyocytes (terminal transferase-mediated dUTP nick end labeling, caspase activation) and RNA levels of apoptosis-regulating proteins were studied in transmyocardial biopsies obtained before and after the operation. Magnetic resonance imaging and transesophageal echocardiography were performed, and cardiac enzymes were measured. RESULTS: Clinical outcome and cardiac enzyme release were comparable between the groups. Cardiomyocyte apoptosis was significantly increased (terminal transferase-mediated dUTP nick end labeling) in the left ventricle after the operation in the retrograde, but not in the antegrade group (respectively, 0.00% [0.039%] versus 0.092% [0.205%], p = 0.01; and 0.00% [0.00%] versus 0.023% [0.054%], p = 0.14). Expression of apoptosis-regulating proteins BAX, BAD, and BCL-2 were comparable between groups. By transesophageal echocardiography, the systolic mitral annulus movement was decreased immediately after the operation in the retrograde group. By magnetic resonance imaging, the left ventricle mass index was reduced preoperatively to 9 months postoperatively in the antegrade group. CONCLUSIONS: In contrast to antegrade cardioplegia, retrograde cardioplegia is associated with increased cardiomyocyte apoptosis, impaired immediate postoperative systolic function, and lack of long-term favorable left ventricle remodeling after aortic valve replacement, suggesting inadequate myocardial protection.

Asunto(s)

Estenosis de la Válvula Aórtica/cirugía , Apoptosis , Paro Cardíaco Inducido/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Ventrículos Cardíacos/patología , Miocitos Cardíacos/patología , Disfunción Ventricular Izquierda/diagnóstico , Anciano , Estenosis de la Válvula Aórtica/diagnóstico , Biopsia , Ecocardiografía Transesofágica , Femenino , Estudios de Seguimiento , Paro Cardíaco Inducido/métodos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Humanos , Etiquetado Corte-Fin in Situ , Imagen por Resonancia Cinemagnética/métodos , Masculino , Pronóstico , Volumen Sistólico , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/fisiología

RESUMEN

BACKGROUND & AIMS: Hepatic lipotoxicity results from and contributes to obesity-related disorders. It is a challenge to study human metabolism of fatty acids (FAs) in the liver. We combined (11)C-palmitate imaging by positron emission tomography (PET) with compartmental modeling to determine rates of hepatic FA uptake, oxidation, and storage, as well as triglyceride release in pigs and human beings. METHODS: Anesthetized pigs underwent (11)C-palmitate PET imaging during fasting (n = 3) or euglycemic hyperinsulinemia (n = 3). Metabolic products of FAs were measured in arterial, portal, and hepatic venous blood. The imaging methodology then was tested in 15 human subjects (8 obese subjects); plasma (11)C-palmitate kinetic analyses were used to quantify systemic and visceral lipolysis. RESULTS: In pigs, PET-derived and corresponding measured FA fluxes (FA uptake, esterification, and triglyceride FA release) did not differ and were correlated with each other. In human beings, obese subjects had increased hepatic FA oxidation compared with controls (mean +/- standard error of the mean, 0.16 +/- 0.01 vs 0.08 +/- 0.01 micromol/min/mL; P = .0007); FA uptake and esterification rates did not differ between obese subjects and controls. Liver FA oxidation correlated with plasma insulin levels (r = 0.61, P = .016), adipose tissue (r = 0.58, P = .024), and systemic insulin resistance (r = 0.62, P = .015). Hepatic FA esterification correlated with the systemic release of FA into plasma (r = 0.71, P = .003). CONCLUSIONS: PET imaging can be used to measure FA metabolism in the liver. By using this technology, we found that obese individuals have increased hepatic oxidation of FA, in the context of adipose tissue insulin resistance, and increased FA flux from visceral fat. FA flux from visceral fat is proportional with the mass of the corresponding depot.

Asunto(s)

Ácidos Grasos/sangre , Grasa Intraabdominal/metabolismo , Lipólisis , Hígado/diagnóstico por imagen , Obesidad/diagnóstico por imagen , Tomografía de Emisión de Positrones , Animales , Radioisótopos de Carbono , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Ayuno/sangre , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/diagnóstico por imagen , Insulina/sangre , Resistencia a la Insulina , Grasa Intraabdominal/patología , Hígado/irrigación sanguínea , Hígado/metabolismo , Imagen por Resonancia Magnética , Persona de Mediana Edad , Obesidad/sangre , Obesidad/patología , Oxidación-Reducción , Ácido Palmítico , Estudios Prospectivos , Radiofármacos , Porcinos , Triglicéridos/sangre , Regulación hacia Arriba

RESUMEN

PURPOSE: Acute mesenteric ischaemia (AMI) is a lethal disease with an increasing incidence. Despite the availability of effective treatment, AMI remains a vascular emergency with over 60% mortality rate mainly due to late diagnosis. The difficulty in diagnosing this fatal condition stems from non-specific clinical and laboratory findings and lack of appropriate imaging study. Our aim was to test a non-invasive method of identifying AMI using PET. METHODS: The study was conducted in normal pigs (n = 14), sham-operated pigs (n = 4) and pigs undergoing ischaemia and reperfusion of intestine (n = 6). Liver blood flow was imaged by H(2) (15)O PET and liver blood content by C(15)O PET. Both scans were performed during intestinal ischaemia and during reperfusion. RESULTS: AMI was identified by PET imaging of hepatic perfusion and blood pool. The H(2) (15)O PET scan during AMI detected a 40% decrease in total liver perfusion, which was caused by a 45% reduction of portal blood flow and no alteration in arterial blood flow. Compromised hepatic perfusion during AMI was accompanied by a 75% decrease in hepatic blood pool recognized by the C(15)O PET scan. The striking reduction of liver blood flow and blood content persisted during reperfusion of intestine. CONCLUSION: Our results demonstrate that AMI can be readily recognized by PET imaging of liver blood flow and blood content. Moreover, PET can be used in detection of perfusion abnormalities after revascularization. This non-invasive imaging tool could represent a novel approach to diagnose AMI.

Asunto(s)

Isquemia/diagnóstico por imagen , Arterias Mesentéricas/diagnóstico por imagen , Arterias Mesentéricas/patología , Animales , Intestinos/irrigación sanguínea , Intestinos/diagnóstico por imagen , Isquemia/sangre , Isquemia/fisiopatología , Hígado/irrigación sanguínea , Hígado/diagnóstico por imagen , Circulación Hepática , Tomografía de Emisión de Positrones , Porcinos