ABSTRACT
Cardiogenic shock complicates approximately 5-10% of cases with acute myocardial infarction and carries a poor prognosis. Early revascularization remains the cornerstone treatment of cardiogenic shock complicating myocardial infarction. Inotropic and/or vasopressor agents can be used for haemodynamic stabilization, although this comes at the expense of increased myocardial oxygen consumption and extended myocardial ischaemia. In recent years, the use of mechanical circulatory support has significantly increased. However, there is only limited data available from randomized trials evaluating the different percutaneous support systems. This review summarizes the available literature concerning the management of cardiogenic shock and gives an overview of the recommendations of the European and German-Austrian guidelines on cardiogenic shock.
Subject(s)
Myocardial Infarction/complications , Myocardial Infarction/therapy , Shock, Cardiogenic/complications , Shock, Cardiogenic/therapy , Assisted Circulation/methods , Disease Management , Humans , Mechanical Thrombolysis/methods , Percutaneous Coronary Intervention/methods , Randomized Controlled Trials as TopicABSTRACT
AIMS: There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/-)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(-/-)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(-/-)Fbn1(C1039G+/-) mice and was associated with myocardial infarction, stroke, and sudden death. METHODS AND RESULTS: Female ApoE(-/-)Fbn1(C1039G+/-) and ApoE(-/-) mice were fed a WD for up to 35 weeks. Compared to ApoE(-/-) mice, plaques of ApoE(-/-)Fbn1(C1039G+/-) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(-/-)Fbn1(C1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-)Fbn1(C1039G+/-) mice died suddenly, whereas all ApoE(-/-) mice survived. ApoE(-/-)Fbn1(C1039G+/-) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke. CONCLUSIONS: Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(-/-)Fbn1(C1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.
Subject(s)
Death, Sudden/etiology , Elastin/metabolism , Myocardial Infarction/etiology , Plaque, Atherosclerotic/etiology , Stroke/etiology , Animals , Aorta , Apolipoproteins E/deficiency , Biomarkers/metabolism , Brachiocephalic Trunk , Cardiomegaly/etiology , Cardiomegaly/physiopathology , Carotid Artery, Common , Cerebrovascular Circulation/physiology , Diet, Western , Disease Models, Animal , Female , Fibrillin-1 , Fibrillins , Hemorrhage/etiology , Hypoxia, Brain/etiology , Hypoxia, Brain/physiopathology , Mice , Microfilament Proteins/deficiency , Microvessels , Myocardial Infarction/physiopathology , Neovascularization, Pathologic/etiology , Neovascularization, Pathologic/physiopathology , Nervous System Diseases/etiology , Nervous System Diseases/physiopathology , Plaque, Atherosclerotic/physiopathology , Rupture, Spontaneous/etiology , Rupture, Spontaneous/physiopathology , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/physiopathologyABSTRACT
AIM: Transglutaminase 2 (TG2) is important for the deposition and stability of the extracellular matrix via effects on cross-linking of matrix proteins and transforming growth factor beta (TGFbeta) activity. The purpose of this study was to investigate the effect of TG2 deficiency on the composi- tion of atherosclerotic plaques. METHODS: Apolipoprotein E (ApoE)(-/-) mice were crossbred with TG2(-/-) mice to obtain ApoE(-/-)TG2(-/-) mice. ApoE(-/-) and ApoE(-/-)TG2(-/-) mice were fed a Western-type diet for 16 or 30 weeks to determine the effect of TG2 deficiency on early and advanced atherosclerosis, respectively. RESULTS: Atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice showed decreased cross-linking of matrix proteins, as well as decreased nuclear staining for phospho-Smad2/-Smad3, indicative of decreased TGFbeta activity. Compared to ApoE(-/-) mice, plaque area was decreased by 45 and 48% in ApoE(-/-)TG2(-/-) mice after 16 and 30 weeks, respectively. Sirius red staining showed a significant decrease in collagen content in early and advanced atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice. Furthermore, there was a significant increase in macrophages in advanced atherosclerotic plaques of ApoE(-/-)TG2(-/-) mice. CONCLUSION: TG2 deficiency resulted in a decreased collagen content and increased inflammation, which are features of a more unstable plaque.
Subject(s)
Apolipoproteins E/deficiency , Atherosclerosis/enzymology , GTP-Binding Proteins/deficiency , Inflammation/enzymology , Transglutaminases/deficiency , Animals , Apolipoproteins E/genetics , Atherosclerosis/genetics , Atherosclerosis/pathology , Atherosclerosis/prevention & control , Collagen/metabolism , Disease Models, Animal , Disease Progression , Extracellular Matrix Proteins/metabolism , Female , Fibrosis , GTP-Binding Proteins/genetics , Inflammation/genetics , Inflammation/pathology , Macrophages/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Glutamine gamma Glutamyltransferase 2 , Rupture , Time Factors , Transforming Growth Factor beta/metabolism , Transglutaminases/geneticsABSTRACT
BACKGROUND: Arterial stiffness has been associated with an increased cardiovascular risk. The aim of this study was to investigate the interaction between arterial stiffness and atherosclerosis. METHODS AND RESULTS: Mice with a mutation C1039G+/-) in the fibrillin-1 gene leading to fragmentation of the elastic fibers were crossbred with apolipoprotein E-deficient (ApoE-/-) mice. Subsequently, ApoE-/- and ApoE-/-C1039G+/- mice were fed a Western-type diet for 10 or 20 weeks. Our results show that the interaction between arterial stiffness and atherosclerosis is bidirectional. On the one hand, arterial stiffness in ApoE-/-C1039G+/- mice increased more rapidly in the presence of atherosclerotic plaques. On the other hand, arterial stiffness promoted the development of larger and more unstable plaques in ApoE-/-C1039G+/- mice. The plaque area at the aortic root was increased 1.5- and 2.1-fold in ApoE-/-C1039G+/- mice after 10 and 20 weeks of Western-type diet, respectively. After 10 weeks of Western-type diet, plaques of ApoE-/-C1039G+/- mice showed increased apoptosis of smooth muscle cells, which was associated with a decrease in collagen content, an enlargement of the necrotic core, and an increase in macrophages. After 20 weeks of Western-type diet, the number of buried fibrous caps was increased in atherosclerotic lesions of ApoE-/-C1039G+/- mice, not only at the level of the aortic valves but also in the brachiocephalic artery and in the upper, middle, and lower thoracic aorta. Furthermore, acute plaque rupture was observed. CONCLUSIONS: These results indicate that fragmentation of the elastic fibers leads to increased vascular stiffness, which promotes features of multifocal plaque instability.
