RESUMEN
BACKGROUND: In observational studies of patients undergoing percutaneous coronary intervention (PCI), surgical ineligibility is associated with increased mortality. Whether the use of hemodynamic support during PCI can mitigate the adverse prognostic importance of surgical ineligibility is unknown. METHODS AND RESULTS: We sought to evaluate the association between request for surgical consultation (presumed surgical ineligibility) prior to PCI and clinical outcomes in 427 patients with multivessel coronary artery disease or unprotected left main disease and severely reduced left ventricular systolic function undergoing PCI assisted by hemodynamic support (intraaortic balloon pump or Impella) from the PROTECT II randomized trial. Patients in whom surgical consultation was requested prior to PCI (n = 201) were compared with those in whom surgical consultation was not requested (n = 226). The primary endpoint of this analysis was the composite of 90-day major adverse cardiac and cerebrovascular events (MACCE). Demographic and procedural variables were similar between patients receiving surgical consultation and patients not receiving surgical consultation, with the exception that the prevalence of prior coronary artery bypass graft surgery was significantly higher in patients not receiving surgical consultation (42.0% vs 25.4%; P<.001); these patients also had a higher proportion of lesions within a saphenous vein graft, and a greater prevalence of moderate/severe vessel calcification. MACCE rate at 90 days was similar in patients receiving surgical consultation compared with patients not receiving surgical consultation (23.4% vs 29.0%, respectively; P=.19). CONCLUSIONS: In this high-risk cohort of patients undergoing hemodynamically supported PCI, clinical outcome was not associated with an antecedent request for surgical consultation (presumed surgical ineligibility). Whether the use of hemodynamically supported PCI can lessen the risk conferred by surgical ineligibility requires further study.
Asunto(s)
Enfermedad de la Arteria Coronaria/terapia , Corazón Auxiliar , Hemodinámica/fisiología , Contrapulsador Intraaórtico , Intervención Coronaria Percutánea/métodos , Derivación y Consulta , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico , Estudios de Seguimiento , Humanos , Estudios Prospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model.
Asunto(s)
Proteínas Portadoras/genética , Citocinas/genética , Terapia Genética , Isquemia/terapia , Músculo Esquelético/irrigación sanguínea , Fragmentos de Péptidos/genética , Animales , Proteínas Portadoras/metabolismo , Movimiento Celular , Transformación Celular Neoplásica/metabolismo , Células Cultivadas , Vasos Coronarios/patología , Citocinas/metabolismo , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Miembro Posterior/irrigación sanguínea , Miembro Posterior/patología , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Músculo Esquelético/patología , Mioblastos/metabolismo , Mioblastos/trasplante , Miocardio/patología , Miocitos del Músculo Liso/fisiología , Neovascularización Fisiológica , Fragmentos de Péptidos/metabolismoRESUMEN
We compared therapeutic benefits of intramyocardial injection of unfractionated bone marrow cells (BMCs) versus BMC extract as treatments for myocardial infarction (MI), using closed-chest ultrasound-guided injection at a clinically relevant time post-MI. MI was induced in mice and the animals treated at day 3 with either: (i) BMCs from green fluorescent protein (GFP)-expressing mice (n = 14), (ii) BMC extract (n = 14), or (iii) saline control (n = 14). Six animals per group were used for histology at day 6 and the rest followed to day 28 for functional analysis. Ejection fraction was similarly improved in the BMC and extract groups versus control (40.6 +/- 3.4 and 39.1 +/- 2.9% versus 33.2 +/- 5.0%, P < 0.05) with smaller scar sizes. At day 6 but not day 28, both therapies led to significantly higher capillary area and number of arterioles versus control. At day 6, BMCs increased the number of cycling cardiomyocytes (CMs) versus control whereas extract therapy resulted in significant reduction in the number of apoptotic CMs at the border zone (BZ) versus control. Intracellular components within BMCs can enhance vascularity, reduce infarct size, improve cardiac function, and influence CM apoptosis and cycling early after therapy following MI. Intact cells are not necessary and death of implanted cells may be a major component of the benefit.
Asunto(s)
Células de la Médula Ósea/fisiología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Corazón/fisiología , Infarto del Miocardio/terapia , Animales , Apoptosis , Células de la Médula Ósea/metabolismo , Ecocardiografía , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/citología , Miocitos Cardíacos/fisiologíaRESUMEN
Efficacy of potential treatments for myocardial infarction (MI) is commonly assessed by histological measurement of infarct size in rodent models. In experiments involving an acute MI setting, measurement of the infarcted area in tissue sections of the left ventricle is a standard approach to determine infarct size. This approach has also been used in the chronic infarct setting to measure infarct area several weeks post-MI. We tested the hypothesis that, because wall thinning is known to occur in the chronic setting, the area measurement approach would be less appropriate. We compared infarct measurements in tissue sections based on 1) infarct area, 2) epicardial and endocardial infarct arc lengths, and 3) midline infarct arc length. Infarct sizes from all three measurement approaches correlated significantly with left ventricular ejection fraction and wall motion abnormality. However, the infarct size values derived from the area measurement approach were significantly smaller than those from the other two measurement approaches, and the range of values obtained was compressed 0.4-fold. The midline method allowed detection of the expected size differences between infarcts of variable severity resulting from proximal vs. distal ligation of the coronary artery. Segmental infarct size was correlated with segmental wall motion abnormality. We conclude that both area- and length-based measurements can be used to determine relative infarct size over a wide range of severity, although the area-based measurements are substantially more compressed due to wall thinning, and that the estimation of infarct midlines is a simple, reliable approach to infarct size assessment.
Asunto(s)
Anatomía Transversal/métodos , Modelos Animales de Enfermedad , Interpretación de Imagen Asistida por Computador/métodos , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/patología , Animales , Enfermedad Crónica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , UltrasonografíaRESUMEN
The major vascular endothelial growth factor (VEGF) isoforms are splice variants from a single gene that differ in their extent of heparin affinity due to the absence of the heparin binding domain in the smallest isoform (mouse VEGF120, human VEGF121). A long-held assumption that has guided the use of VEGF isoforms clinically has been that their differences in heparin binding dictate their ability to diffuse through tissue, with VEGF121 moving most freely and that the distribution of recombinant VEGF would have therapeutically relevant consequences. To test this assumption, we delivered the genes encoding these isoforms by myoblast-mediated gene transfer, a means of delivering genes to highly localized sites within muscle. Surprisingly, all isoforms induced comparable extremely localized physiological effects. Significantly, irrespective of the isoform delivered, the vessels passing within several micrometers of muscle fibers expressing VEGF displayed sharply delineated changes in morphology. The induction of capillary wrapping around VEGF-producing fibers, and of vascular malformations in the muscle at high levels, did not differ among isoforms. These results indicate that heparin binding is not essential for the localization of VEGF in adult tissue and suggest that the preferential delivery of VEGF121 cDNA for clinical applications may not have a physiological basis.