RESUMEN
BACKGROUND: Transgenic mice expressing the dominant interfering p193 protein in cardiomyocytes (MHC-1152stop mice) exhibit an induction of cell cycle activity and altered remodelling after experimental myocardial infarction (MI). OBJECTIVE: To determine whether the altered remodelling results in improved cardiac function in the MHC-1152stop mice after MI, as compared with non-transgenic mice. METHODS: MHC-1152stop mice and non-transgenic littermates were subjected to experimental MI via permanent occlusion of the coronary artery. Infarct size was determined at 24 h and at 4 weeks after MI, and left ventricular pressure-volume measurements were performed at 4 weeks after MI in infarcted and sham-operated animals. RESULTS: Infarct size in MHC-1152stop mice and non-transgenic littermates was not statistically different at 24 h after MI, as measured by tetrazolium staining. Morphometric analysis showed that infarct scar expansion at 4 weeks after MI was reduced by 10% in the MHC-1152stop mice (p<0.05). No differences in cardiac function were detected between sham-operated MHC-1152stop mice and their non-transgenic littermates. However, at 4 weeks after MI, the ventricular isovolumic relaxation time constant (tau) was decreased by 19% (p<0.05), and the slope of the dP/dt(max)-EDV relationship was increased 99% (p<0.05), in infarcted MHC-1152stop mice as compared with infarcted non-transgenic littermates. CONCLUSION: Expression of the dominant interfering p193 transgene results in a decrease in infarct scar expansion and preservation of myocardial function at 4 weeks after MI. Antagonism of p193 activity may represent an important strategy for the treatment of MI.
Asunto(s)
Proteínas Cullin/genética , Mutación/genética , Infarto del Miocardio/genética , Miocardio/metabolismo , Transgenes/genética , Animales , Western Blotting , Cicatriz/genética , Proteínas Cullin/metabolismo , Hemodinámica/fisiología , Ratones , Ratones Transgénicos , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Remodelación Ventricular/genéticaRESUMEN
Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the appearance of benign tumors in multiple organs, including the heart. Disease progression is accompanied by homozygous mutation at 1 of 2 loci (designated TSC1 or TSC2), leading to the suggestion that these genes function as tumor suppressors. In this study, we generated a series of TSC2 cDNAs in which one or more structural motifs were deleted, with the hope that expression of the modified gene product would override the growth-inhibitory activity of the endogenous TSC2 gene product. Several of the modified cDNAs enhanced growth rate, increased endocytosis, and promoted aberrant protein trafficking when expressed in NIH-3T3 cells, thereby mimicking phenotypes typical of TSC2-deficient cells. Surprisingly, targeted expression of the most potent TSC2 cDNA to the heart did not perturb cardiac development. However, the level of cardiomyocyte DNA synthesis in adult transgenic mice was elevated >35-fold during isoproterenol-induced hypertrophy compared with their nontransgenic siblings. These results suggest that alteration of TSC2 gene activity in combination with beta-adrenergic stimulation can reactivate the cell cycle in a limited number of terminally differentiated adult cardiomyocytes.
Asunto(s)
Cardiomegalia/metabolismo , ADN/biosíntesis , Miocardio/metabolismo , Proteínas Represoras/fisiología , Células 3T3 , Animales , División Celular/fisiología , ADN Complementario/metabolismo , ADN Complementario/fisiología , Endocitosis , Eliminación de Gen , Corazón/crecimiento & desarrollo , Ratones , Ratones SCID , Ratones Transgénicos/genética , Miocardio/citología , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/fisiología , Valores de Referencia , Proteínas Represoras/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de TumorRESUMEN
Increased transforming growth factor (TGF)-beta(1) activity has been observed during pathologic cardiac remodeling in a variety of animal models. In an effort to establish a causal role of TGF-beta(1) in this process, transgenic mice with elevated levels of active myocardial TGF-beta(1) were generated. The cardiac-restricted alpha-myosin heavy chain promoter was used to target expression of a mutant TGF-beta(1) cDNA harboring a cysteine-to-serine substitution at amino acid residue 33. This alteration blocks covalent tethering of the TGF-beta(1) latent complex to the extracellular matrix, thereby rendering a large proportion (>60%) of the transgene-encoded TGF-beta(1) constitutively active. Although similar levels of active TGF-beta(1) were present in the transgenic atria and ventricles, overt fibrosis was observed only in the atria. Surprisingly, increased active TGF-beta(1) levels inhibited ventricular fibroblast DNA synthesis in uninjured hearts and delayed wound healing after myocardial injury. These data suggest that increased TGF-beta(1) activity by itself is insufficient to promote ventricular fibrosis in the adult mouse ventricle.
Asunto(s)
Miocardio/patología , Factor de Crecimiento Transformador beta/genética , Factores de Edad , Animales , Apoptosis/fisiología , División Celular/fisiología , Células Cultivadas , Colágeno/análisis , Colágeno/fisiología , ADN/biosíntesis , Proteínas de la Matriz Extracelular/análisis , Proteínas de la Matriz Extracelular/fisiología , Fibroblastos/patología , Fibroblastos/fisiología , Fibrosis , Expresión Génica/fisiología , Atrios Cardíacos/química , Atrios Cardíacos/citología , Atrios Cardíacos/patología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/química , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/patología , Humanos , Etiquetado Corte-Fin in Situ , Ratones , Ratones Endogámicos C3H , Ratones Transgénicos , Miocardio/química , Miocardio/citología , Transgenes/fisiología , Cicatrización de Heridas/fisiologíaRESUMEN
Thymoma is the most common tumor of the anterior-superior mediastinum. We have identified a line of transgenic mice which spontaneously and heritably develop thymomas at a very high penetrance. The available data suggest that thymoma formation in these mice results as a consequence of transgene insertional mutagenesis. Immune histologic analyses indicate that the thymomas are of epithelial cell origin. Survival studies indicate that tumor progression is more aggressive in females as compared to males (73.9 vs 41.7% mortality at 20 weeks of age, respectively). Fluorescent in situ hybridizations have localized the transgene integration site to the F2-G region of mouse chromosome 2. Translocation encompassing the syntenic region in humans has been implicated in lympho-epithelial thymoma. These animals may constitute a useful resource for the identification of gene(s) which participate in thymoma progression, as well as a model system for screening anti-thymoma therapeutic agents.
Asunto(s)
Timoma/etiología , Neoplasias del Timo/etiología , Factor de Crecimiento Transformador beta/fisiología , Animales , Femenino , Complejo Mayor de Histocompatibilidad , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Transgénicos , Mutación , Factor de Crecimiento Transformador beta/genéticaRESUMEN
BACKGROUND: Skeletal muscle ventricles (SMVs) are autologous pumping chambers constructed from skeletal muscle. Skeletal muscle ventricular rupture and thromboembolism have complicated chronic models of this method of skeletal muscle cardiac assist. METHODS: The SMVs were constructed from the latissimus dorsi muscle in 10 dogs. The inner surface of each SMV was lined with autologous pericardium harvested at the time of SMV construction. After a 3-week period of vascular delay and 6 weeks of electrical conditioning to convert the muscle to a fatigue-resistant state, SMVs were connected to the descending thoracic aorta and stimulated to contract during cardiac diastole. RESULTS: Initial hemodynamics revealed that SMV contraction at 33 Hz increased diastolic pressure 24.7% (60.8 +/- 7.3 mm Hg versus 80.3 +/- 8.8 mm Hg). Skeletal muscle ventricle relaxation decreased presystolic pressure 14.4% (59.9 +/- 7.7 mm Hg versus 51.3 +/- 7.5 mm Hg) and decreased peak systolic pressure 4.1% (90.2 +/- 7.3 mm Hg versus 86.5 +/- 5.8 mm Hg). Hemodynamics were assessed at 1 to 2 weeks, then at 1, 2, 3, and 6 months, and at 6-month intervals thereafter. Hemodynamic performance remained stable for the duration of this study. After 2 years of pumping continuously in circulation, SMV contraction resulted in a 34.8% augmentation of diastolic pressure (63.6 +/- 6.6 mm Hg versus 85.3 +/- 6.4 mm Hg), a 17.2% decrease in presystolic pressure (54.7 +/- 3.73 mm Hg versus 45.3 +/- 4.1 mm Hg), and a 4.2% decrease in peak systolic pressure (95.3 +/- 10.4 mm Hg versus 91.3 +/- 12.3 mm Hg). Three dogs survived to 2 years with the SMVs in circulation. No animal showed evidence of thromboembolism during serial echocardiography or at autopsy and no SMVs ruptured. CONCLUSIONS: These data demonstrate that SMVs can provide effective hemodynamic assist over an extended period without specific complications related to the SMVs.
Asunto(s)
Cardiomioplastia , Animales , Cardiomioplastia/mortalidad , Perros , Electroforesis en Gel de Poliacrilamida , Femenino , Hemodinámica , Músculo Esquelético/química , Pericardio/trasplante , Factores de Tiempo , Trasplante AutólogoRESUMEN
Skeletal muscle ventricles (SMVs) constructed from electrically conditioned latissimus dorsi muscle (LDM) may become an alternative for assisting the failing heart. Left and right heart circulatory assist using SMVs has been performed successfully in both acute and chronic animal models. The configurations used to connect SMVs to the circulation have included a left atrium to aorta bypass, a left ventricle apex to aorta bypass, aortic counterpulsators, a cavopulmonary bypass, and a right ventricle to pulmonary artery bypass. One SMV used as an aortic counterpulsator functioned effectively in the circulation for more than 27 months. Recent application of the pericardium to the SMV as an inner layer and design changes in the connection of the SMV to the circulation have reduced the risk of thrombus formation and SMV rupture. Although several problems have yet to be solved, the goal of the SMV as a permanent circulatory assist device without the limitation of an external power source seems within reach.
Asunto(s)
Cardiomioplastia , Insuficiencia Cardíaca/cirugía , Músculo Esquelético/fisiología , Animales , Circulación Asistida/normas , Puente Cardiopulmonar , Circulación Coronaria/fisiología , Perros , Estimulación Eléctrica , Corazón Auxiliar , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/cirugía , Complicaciones Posoperatorias , Colgajos QuirúrgicosRESUMEN
BACKGROUND: Skeletal muscle ventricles (SMVs) are muscular pumping chambers constructed for cardiac assist. Skeletal muscle ventricles can be connected to the circulation in a variety of configurations for both left and right heart assist; when connected to the aorta and stimulated to contract during diastole, they function in a similar fashion as an intraaortic balloon pump. METHODS: Skeletal muscle ventricles were constructed in 18 dogs using the left latissimus dorsi muscle. In 10 of these dogs (group 1), the inner surface of the SMV was lined with autogenous pericardium obtained at the time of construction of the SMV. For the remaining 8, the SMVs were lined by fibrous tissue that forms in reaction to the synthetic mandrel around which the latissimus muscle is wrapped. After the muscles were electrically conditioned to a fatigue-resistant state, the mandrels were removed from the SMVs and the SMVs were connected to the descending thoracic aorta with a specially constructed base cap and two polytetrafluoroethylene conduits. RESULTS: Initial hemodynamic recordings revealed that the mean diastolic blood pressure increased by 24.7% in group 1 and by 29.8% in group 2. Diastolic augmentation was well maintained over time; augmentation in surviving group 1 animals was 30.0% after 18 months of pumping continuously in circulation. Long-term survival was greater in the dogs whose SMVs were constructed using an inner pericardial lining. At 90 days in circulation, 60% of the dogs in group 1 were alive with functioning SMVs, whereas only 13% of the dogs in group 2 were alive. The incidence of SMV rupture in the fibrouslined SMVs was 63%, whereas the incidence in the pericardial-lined SMVs was 0%. No evidence of thromboembolism occurred in either group. CONCLUSIONS: Lining the inner surface of an SMV with pericardium appears to provide structural integrity, which helps to prevent the complication of SMV rupture in this model of cardiac assist.
Asunto(s)
Aorta Torácica/cirugía , Cardiomioplastia , Músculo Esquelético/trasplante , Animales , Contrapulsación , Perros , Hemodinámica , Pericardio/trasplante , RoturaRESUMEN
The chronic changes of the end-systolic pressure-volume relationship (ESPVR) after regional myocardial infarction were evaluated in a sheep model. Pressure-volume area (PVA) obtained from the pressure-volume diagram and left ventricular oxygen consumption (LVO2) were studied. The regional myocardial infarction was created by ligating distal branches of the left coronary artery. ESPVR was obtained using a conductance catheter during transient inferior vena cava occlusion. Measurements were performed at baseline (n = 13), 1 hour (n = 8), 3 months (n = 9), and 6 months (n = 4) after infarction. Ees, the slope of the ESPVR did not change at 1 hour after infarction and remained the same at 3-month and 6-month measurements (baseline 2.26 +/- 1.24 mmHg/mL, 1 hour 2.71 +/- 1.06, 3 months 3.46 +/- 1.51, 6 months 2.45 +/- 0.64, NS). Because of the ventricular dilatation, which was demonstrated as an increase in changes of end-systolic volume (Ves) correlating with the time course after infarction (y = -3.21 + 0.12x, r = 0.454, p < 0.05), V0, the volume intercept of the ESPVR increased at 1 hour after the infarction, and showed a tendency to increase at 3 months and 6 months after the infarction (baseline -18.0 +/- 22.5 mL; 1 hour -0.9 +/- 11.6; 3 months 5.4 +/- 10.9, 6 months 9.2 +/- 23.1, baseline vs 3 months p < 0.05, baseline vs 6 months p < 0.05). PVA and LVO2 were unchanged over time after infarction (PVA: baseline 2097 +/- 1526 mmHg/mL per 100 g-1; 1 hour 1771 +/- 699; 3 months 2483 +/- 1086; 6 months 1,608 +/- 1,010, NS), (LVO2: baseline 40.6 +/- 13.1 x 10(-3) mL/100 g-1 per beat-1; 1 hour 42.9 +/- 9.7; 3 months 35.0 +/- 8.6; 6 months 31.2 +/- 18.1, NS). Chronic regional infarction in the sheep model did not affect Ees over 6 months, but significantly increased V0 after the increase in the acute phase. PVA and LVO2 were not affected by this regional infarction either acutely or over 6 months.
Asunto(s)
Infarto del Miocardio/fisiopatología , Volumen Sistólico , Animales , Presión Sanguínea , Masculino , Miocardio/metabolismo , Consumo de Oxígeno , Presión , Ovinos , Sístole , Función Ventricular IzquierdaRESUMEN
Skeletal muscle ventricles (SMVs) were constructed from the latissimus dorsi muscle in 15 beagles. The animals were divided into two groups based on modifications in the SMV construction: group I consisted of 5 animals and group II of 10 animals. After a 3-week vascular delay and 6 to 8 weeks of 2-Hz electrical conditioning, the SMVs were connected to the thoracic aorta. In group I, counterpulsation at 33 Hz resulted in an initial 24.4% augmentation of the mean diastolic pressure, a 27.1% decrease in the presystolic pressure, and a 15.9% increase in the endocardial viability ratio. In group II, the mean diastolic pressure rose by 24.7%, the presystolic pressure decreased by 14.3%, and the endocardial viability ratio increased by 24.5%. During propranolol-induced heart failure, the percentage increase in the mean diastolic pressure was improved (12.9% before propranolol infusion versus 27.6% during propranolol infusion), as was the percentage increase in the endocardial viability ratio (11.2% versus 28.7%). Under low cardiac output conditions, SMV contraction resulted in small but statistically significant increases in the total cardiac output (4.3% at 33 Hz, 7.6% at 85 Hz). One animal in group I survived for 589 days with a functioning SMV before progressive dilation of the SMV (impending rupture) developed. Delayed rupture of the SMV sewing ring anastomosis occurred in 2 dogs. Five animals in group II are all alive, with functioning SMVs in the circulation for 377 to 464 days. No animals in group II had rupture of their SMV or showed evidence of thrombus formation.
Asunto(s)
Bioprótesis , Contrapulsación/métodos , Ventrículos Cardíacos , Músculo Esquelético/trasplante , Animales , Gasto Cardíaco , Perros , Estimulación Eléctrica , Hemodinámica , Músculo Esquelético/fisiología , Miocardio/metabolismo , Consumo de Oxígeno , Factores de Tiempo , Función Ventricular , Función Ventricular IzquierdaRESUMEN
Skeletal muscle ventricles (SMVs) were constructed either extrathoracically or intrathoracically in 44 dogs using the left latissimus dorsi muscle. These SMVs functioned as aortic counterpulsators for from several hours to 216 days. In this study, the relationship between the morphologic changes in the SMVs and their time course in the circulation was evaluated retrospectively. The average volume of the SMV chamber after it had been excised and fixed in formalin was 21.3 +/- 11.0 mL (mean +/- the standard deviation) for extrathoracic SMVs and 20.0 +/- 7.5 mL for intrathoracic SMVs. The volume of the SMV chamber did not correlate with the time course in the circulation. The SMV wall was mainly composed of three components: muscular, fibrous, and fatty aspects. The overall thickness of the wall appeared to be preserved over time in the circulation. However, the thickness of the muscular component tended to decrease over time. SMV rupture occurred in 15 dogs between postoperative days 4 and 39. All ruptures occurred at the suture line between the SMV and the vascular conduits. There was some degree of thrombus in 24 SMVs. Before SMVs can be applied clinically for the purpose of cardiac assist, problems with rupture and thrombus formation must be solved. A better understanding of the morphologic changes that take place in the SMV over time also is needed.
Asunto(s)
Contrapulsación/métodos , Ventrículos Cardíacos/cirugía , Hemodinámica , Músculos/trasplante , Enfermedades Musculares/patología , Complicaciones Posoperatorias/patología , Colgajos Quirúrgicos/métodos , Trombosis/patología , Animales , Dorso , Causas de Muerte , Modelos Animales de Enfermedad , Perros , Estimulación Eléctrica , Estudios de Evaluación como Asunto , Enfermedades Musculares/etiología , Enfermedades Musculares/mortalidad , Enfermedades Musculares/fisiopatología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/fisiopatología , Rotura Espontánea , Índice de Severidad de la Enfermedad , Trombosis/clasificación , Trombosis/etiología , Trombosis/mortalidad , Trombosis/fisiopatología , Factores de TiempoRESUMEN
The mechanism of effectiveness of cardiomyoplasty was evaluated in the setting of chronic left ventricular dysfunction in terms of the pressure-volume relationship. The distal branches of the left coronary artery were ligated in 12 sheep. Seven sheep died and the 5 survivors underwent cardiomyoplasty using a left latissimus dorsi graft 10 to 12 weeks later. These muscle grafts were then electrically conditioned for 2 months. The systemic pressure and cardiac output were not different between the postinfarction and postcardiomyoplasty period with the pacemaker off or on. However, the pressure-volume loops were altered by cardiomyoplasty in all 5 animals. Emax, which is an index of ventricular contractility, increased after cardiomyoplasty from 2.66 +/- 0.92 to 4.59 +/- 1.73 mm Hg/mL (mean +/- the standard deviation; p < 0.05), but did not change between the pacemaker off and on situations. The pressure-volume area, which strongly correlates with myocardial oxygen consumption, decreased after cardiomyoplasty (1,932 +/- 615 mm Hg.mL), compared with before cardiomyoplasty (3,776 +/- 1,201 mm Hg.mL) (p < 0.05), but did not change between pacemaker off and on. The probable mechanism responsible for the effectiveness of cardiomyoplasty is an "active" support or constraint of the damaged myocardium by the latissimus dorsi and the prevention of further ventricular dilation. This suggests that left ventricular systolic function can be augmented by cardiomyoplasty, but that it is a secondary mechanism of action.
Asunto(s)
Estimulación Eléctrica , Insuficiencia Cardíaca/cirugía , Músculos/trasplante , Animales , Presión Sanguínea , Procedimientos Quirúrgicos Cardíacos/métodos , Volumen Cardíaco , Enfermedad Coronaria/fisiopatología , Electroencefalografía , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Masculino , Contracción Muscular , Ovinos , Colgajos Quirúrgicos , Función Ventricular IzquierdaRESUMEN
We previously found that double cardiomyoplasty using both acutely raised, unconditioned latissimus dorsi muscles increased cardiac output by 9.6% (1,547 +/- 154 versus 1,695 +/- 166 mL/min), stroke volume by 18.2% (12.1 +/- 0.6 versus 14.3 +/- 0.7 mL), peak left ventricular pressure by 18.4% (98 +/- 3 versus 116 +/- 5 mm Hg), and peak right ventricular pressure by 62.5% (24 +/- 2 versus 39 +/- 4 mm Hg) (p < 0.05 for all differences). In this study 10 dogs underwent double cardiomyoplasty: 3 died perioperatively, and 7 underwent 8 weeks of muscle conditioning. After the conditioning period, the muscle flaps did not contract in 2 of the 7 dogs. Hemodynamics were measured in the remaining 5 dogs. Using fatigue-resistant muscle, cardiac output decreased by 3.7% (1,279 +/- 262 versus 1,233 +/- 274 mL/min), stroke volume decreased by 9.0% (9.5 +/- 1.2 versus 8.8 +/- 1.2 mL), and peak left ventricular pressure increased by 10.6% (82.1 +/- 6.5 versus 90.8 +/- 3.2 mm Hg), but not significantly. Peak right ventricular pressure increased significantly by 31.3% (24.3 +/- 2.1 versus 31.9 +/- 3.6 mm Hg; p < 0.05). Hemodynamic effects of individual left or right muscle contractions versus bilateral muscle stimulation were not significantly different except for a greater percentage increase in peak right ventricular pressure (right, 24.9 +/- 2.1 mm Hg unstimulated versus 28.0 +/- 2.1 stimulated; left, 26.3 +/- 0.9 mm Hg unstimulated versus 30.7 +/- 2.4 mm Hg stimulated; bilateral, 24.3 +/- 2.1 mm Hg unstimulated versus 31.9 +/- 3.4 mm Hg stimulated; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Colgajos Quirúrgicos , Animales , Gasto Cardíaco , Perros , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Skeletal muscle ventricles are constructed from canine latissimus dorsi muscle. These skeletal muscle ventricles can be placed subcutaneously on the chest wall or inside the chest cavity. Skeletal muscle ventricles are connected to the descending thoracic aorta and activated to pump blood as aortic diastolic counterpulsators. The skeletal muscle ventricle in 1 animal pumped blood in the circulation for 27 months. Skeletal muscle ventricles can also function effectively under the condition of low cardiac output. Although thrombus has been detected in some skeletal muscle ventricles, thromboembolism to distal organs has been detected only rarely during the past few years. This research appears promising; however, skeletal muscle ventricle rupture remains a problem and currently accounts for about 30% of the mortality in the long-term experiments. It occurs at the site between the skeletal muscle ventricle outlet and the Dacron sewing ring that is necessary to connect conduits from the skeletal muscle ventricle to the animal's circulation. We believe that skeletal muscle ventricle rupture is likely to be a solvable problem. Once a solution has been found, skeletal muscle ventricles may be ready for clinical use in patients with chronic congestive heart failure.