RESUMEN
Exposure to ultrafine particles (UFPs) by inhalation increases the number and severity of cardiac events. The specific mechanism(s) of action are unknown. This study was designed to examine whether UFPs could exert a direct effect on the cardiovascular system without dependence upon lung-mediated responses. The direct effects of UFPs were determined in normal rats (infused intravenously with UFPs), and in the isolated Langendorff perfused rat heart. UFPs from either ambient air (UFAAs) or diesel engine exhaust (UFDGs) were studied. Infusion of UFDGs prepared in our laboratory caused ventricular premature beats (VPBs) in 2 of 3 rats in vivo. Ejection fraction increased slightly (approximately 4.5%) in rats receiving UFPAA and was unchanged in the UFDG and saline groups in vivo. In the isolated rat heart, perfused according to Langendorff, UFDGs caused a marked increase in left-ventricular end-diastolic pressure (LVEDP; from 12.0 +/- 4.6 mmHg to 24.8 +/- 11.2 mmHg, p < 0.05) after 30 min of exposure. UFPs isolated from industrial diesel particulate matter (UFIDs), obtained from the National Institute of Standards and Technology, caused a significant decrease in left-ventricular systolic pressure (LVSP; from 85.7 +/- 4.0 mmHg to 37.9 +/- 20.3 mmHg, p < 0.05) and +/- dP/dt (from 2,365 +/- 158 mmHg/s to 1,188 +/- 858 mmHg/s, p < 0.05) at 30 min after the start of infusion. This effect was absent when the soluble fraction (containing no particles) isolated from the UFIDs was studied. These findings indicate that UFPs can have direct effects on the cardiovascular system that are independent of effects of particles on the lungs.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Arritmias Cardíacas/inducido químicamente , Corazón/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Animales , Arritmias Cardíacas/fisiopatología , Femenino , Corazón/fisiopatología , Hemodinámica/fisiología , Técnicas In Vitro , Inyecciones Intravenosas , Perfusión , Ratas , Ratas Sprague-Dawley , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.
Asunto(s)
Terapia Genética , Isquemia Miocárdica/genética , Isquemia Miocárdica/terapia , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Interferencia de ARN , Animales , Ensayos Clínicos como Asunto , Terapia Combinada , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/uso terapéutico , Perfilación de la Expresión Génica , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/terapia , Humanos , Infusiones Intraarteriales , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Neovascularización Fisiológica/genética , Trasplante de Células Madre , Factores de Crecimiento Endotelial Vascular/genética , Factores de Crecimiento Endotelial Vascular/uso terapéutico , Remodelación Ventricular/genéticaRESUMEN
Cardiovascular disease is a leading cause of mortality in the United States, and is a significant cause of death worldwide. In 2002, it accounted for 38.0% of all deaths in the US, and approximately one-third of all global deaths. It has a significant economic impact, with an estimated cost in the US of 393.5 billion US dollars for 2005. The most common form of heart disease is coronary heart disease (CHD)(1)/coronary artery disease (CAD) resulting from atherosclerosis. Thirteen million Americans are affected by CHD annually, with 7.1 million of these experiencing a myocardial infarction (MI). Five to ten percent of new MI's occur in individuals younger than age 50, and the lifetime risk of developing CAD after age 40 ranges from 32% in women to 49% in men. Because of its major impact on morbidity and mortality, as well as its contribution to annual health care costs, it is of the utmost importance that improved strategies for preventing and treating CAD be developed. A promising, but inherently difficult, area of study is the identification of genes that predispose to or directly cause CAD. The identification of these genes may lead to screening tests that will allow persons at risk for developing CAD to be identified early enough that prevention/intervention strategies can be implemented to prevent or ameliorate the disease process, and may also lead to the development of gene therapy mechanisms useful in the treatment of ischemic heart disease (IHD). Because an exhaustive review of all the genes being studied in relation to CAD and MI is difficult within the confines of a review article, this review will focus on describing representative studies investigating the genes considered most likely to potentially contribute toward an increased risk for CAD and MI. Genes resulting in inherited disorders with which an increased risk of CAD and MI is associated will be discussed, as well as a number of candidate genes that may play a role in the multifactorial inheritance of CHD risk.