RESUMEN
We previously showed that digitoxin prolongs the survival of rats with heart failure due to myocardial infarction (MI). In this study, we evaluated the effect of digitoxin on myocardial structure, ventricular function, and proteins involved in calcium kinetics. Seventy-two rats with MI >35% of the left ventricle were randomly assigned to 4 treatment groups: sham (n = 15), digitoxin (n = 11), infarction (n = 20), and infarction + digitoxin (n = 26). The rats were assessed 120 days after surgery by echocardiogram, hemodynamics, papillary muscle mechanics, collagen content, cardiomyocyte nuclear volume, and Western blot analysis of proteins involved in calcium kinetics. Digitoxin was administered via the rat chow. Two-way analysis of variance was used for comparisons. Myocardial infarction caused inotropic impairment, pulmonary congestion, increase of nuclear volume, myocardial collagen, and Na+/Ca2+ exchanger levels, and decreased SERCA2 and phosphorylated phospholamban levels. Treatment with digitoxin showed improvements in cardiac remodeling, inotropism, ventricular performance, pulmonary congestion, collagen accumulation, nuclear volume, and proteins involved in calcium kinetics. In rats with heart failure due to MI, long-term treatment with digitoxin attenuates congestive heart failure, mitigates myocardial remodeling and contractile impairment, and preserves myocardial levels of proteins involved in calcium kinetics.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Cardiotónicos/farmacología , Digitoxina/farmacología , Insuficiencia Cardíaca/prevención & control , Hipertrofia Ventricular Izquierda/prevención & control , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Miocardio/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Calcio/metabolismo , Señalización del Calcio , Modelos Animales de Enfermedad , Femenino , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/patología , Cinética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/patología , Ratas WistarRESUMEN
The present study aimed to analyze the effects of reperfusion of a distant coronary artery on cardiac function, the ultrastructure, and the molecular environment of the remote myocardium immediately after the completion of myocardial regional necrosis: delayed reperfusion (DR). Additionally, the effects of prior exercise on the outcomes of DR were investigated. Female rats with permanent occlusion or delayed reperfusion were randomly assigned to an exercise (swimming, 1 h/day, 5 days/week for 8 weeks) or sedentary protocol. Thus, the study included the following four groups: sedentary permanent occlusion, exercise permanent occlusion, sedentary delayed reperfusion, and exercise delayed reperfusion. The descending coronary artery was occluded for 1 h. Reperfusion was confirmed by contrast echocardiography, and the rats were observed for 4 weeks. Permanent occlusion and DR caused similar myocardial infarction sizes among the four groups. Interestingly, exercise significantly decreased the mortality rate. Delayed reperfusion resulted in significant benefits, including enhanced hemodynamics and papillary muscle contraction, as well as reduced apoptosis and collagen content. Protein calcium kinetics did not change. Meanwhile, developed tension and the Frank-Starling mechanism were enhanced, suggesting that calcium sensitivity was intensified in myofilaments. Remarkable remote myocardial benefits occurred after distant DR, and prior exercise intensified cardiac recovery. Our findings provide valuable information about DR. Our data might explain the better clinical outcomes in recent studies showing that late reperfusion could improve heart failure in patients with myocardial infarction. In conclusion, DR has remote myocardial benefits, including inotropism enhancement, pulmonary congestion reduction, and collagen and apoptosis attenuation, which are enhanced by prior exercise.
RESUMEN
BACKGROUND: Myocardial infarction (MI) is accompanied by cardiac growth, increased collagen deposition, cell death and new vascularization of the cardiac tissue, which results in reduced ventricular compliance. The MiRNA-29 family (29a, 29b, and 29c) targets mRNAs that encode collagens and other proteins involved in fibrosis. In this study we assessed the effects of swimming training (ST) on expression of the cardiac miRNA-29 family and on genes encoding collagen after MI in rats. METHODS: ST consisted of 60 min/day/10 weeks and began four weeks after MI. MiRNA and collagen expression analysis were performed in the infarcted region (IR), border region (BR) of the infarcted region and in the remote myocardium (RM) of the left ventricle. RESULTS: MiRNA-29a expression increased 32% in BR and 52% in RM in the TR-INF compared with SED-INF. MiRNA-29c increased by 63% in BR and 55% in RM in TR-INF compared with SED-INF group. COL IAI and COL IIIAI decreased by 63% and 62% in TR-INF, respectively, compared with SED-INF. COLIIIAI expression decreased by 16% in TR-INF compared with SED-INF. CONCLUSION: Altogether, our results showed that ST restores cardiac miRNA-29 (a and c) levels and prevents COL IAI and COL IIIAI expression in BR and RM, which may contribute to the improvement in ventricular function induced by swimming training, after MI. © 2014 S. Karger AG, Basel.
Asunto(s)
Colágeno/biosíntesis , Regulación de la Expresión Génica , MicroARNs/biosíntesis , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Condicionamiento Físico Animal , Natación , Animales , Masculino , Infarto del Miocardio/patología , Miocardio/patología , Ratas , Ratas WistarRESUMEN
BACKGROUND: The aim of the present study was to evaluate if the influence of digitalis on survival depends on the severity of cardiac dysfunction in heart failure (HF). METHODS AND RESULTS: Doppler echocardiogram (DE) parameters were analyzed in 84 Wistar control (C) and 80 Wistar rats treated with 0.1mg/100g/day of digitoxin (D) five days after coronary occlusion. The DE variables correlated with the survival of the animals were: myocardial infarction size, left chamber dimensions, fractional area change and E/A ratio. The animals were observed for up to 280 days. Mortality was worsened in rats in the D group with a myocardial infarction (MI)<37% and with better DE predictors of survival. Digitoxin was found to prolong survival in rats with an MI ≥ 37% and worse DE predictors. CONCLUSION: For the first time our study has shown experimentally that the action of digitalis glycosides can positively or negatively influence survival during treatment of HF. It prolongs survival of those in advanced state and compromises survival when there is less severity of the disease. In fact, the greater benefits occur when digitoxin was used in heightened ventricular dilatations and worse ventricular performance.
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Digitoxina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/mortalidad , Índice de Severidad de la Enfermedad , Animales , Digitalis , Femenino , Insuficiencia Cardíaca/patología , Infarto del Miocardio/patología , Ratas , Ratas Wistar , Tasa de Supervivencia/tendenciasRESUMEN
Cardiomiopatia hipertrófica apical (CMHA) é uma forma relativamente rara de cardiomiopatia hipertrófica, na qual a hipertrofia miocárdica envolve, predominantemente, o ápice do ventrículo esquerdo. Este artigo propõe uma revisão de seus aspectos históricos, diagnóstico, incidência, sintomas e exame físico, além de suas complicações e evolução. O ecocardiograma mostra-se um exame fundamental no diagnóstico e acompanhamento de pacientes portadores desta patologia.
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Humanos , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/diagnóstico , Ecocardiografía/efectos adversosRESUMEN
BACKGROUND: Cardiac cell transplantation is compromised by low cell retention and poor graft viability. Here, the effects of co-injecting adipose tissue-derived stem cells (ASCs) with biopolymers on cell cardiac retention, ventricular morphometry and performance were evaluated in a rat model of myocardial infarction (MI). METHODOLOGY/PRINCIPAL FINDINGS: 99mTc-labeled ASCs (1x10(6) cells) isolated from isogenic Lewis rats were injected 24 hours post-MI using fibrin a, collagen (ASC/C), or culture medium (ASC/M) as vehicle, and cell body distribution was assessed 24 hours later by gamma-emission counting of harvested organs. ASC/F and ASC/C groups retained significantly more cells in the myocardium than ASC/M (13.8+/-2.0 and 26.8+/-2.4% vs. 4.8+/-0.7%, respectively). Then, morphometric and direct cardiac functional parameters were evaluated 4 weeks post-MI cell injection. Left ventricle (LV) perimeter and percentage of interstitial collagen in the spare myocardium were significantly attenuated in all ASC-treated groups compared to the non-treated (NT) and control groups (culture medium, fibrin, or collagen alone). Direct hemodynamic assessment under pharmacological stress showed that stroke volume (SV) and left ventricle end-diastolic pressure were preserved in ASC-treated groups regardless of the vehicle used to deliver ASCs. Stroke work (SW), a global index of cardiac function, improved in ASC/M while it normalized when biopolymers were co-injected with ASCs. A positive correlation was observed between cardiac ASCs retention and preservation of SV and improvement in SW post-MI under hemodynamic stress. CONCLUSIONS: We provided direct evidence that intramyocardial injection of ASCs mitigates the negative cardiac remodeling and preserves ventricular function post-MI in rats and these beneficial effects can be further enhanced by administering co-injection of ASCs with biopolymers.
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Tejido Adiposo/citología , Biopolímeros/farmacología , Corazón/fisiopatología , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/cirugía , Trasplante de Células Madre , Células Madre/metabolismo , Animales , Biopolímeros/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Colágeno/administración & dosificación , Colágeno/farmacología , Femenino , Fibrina/administración & dosificación , Fibrina/farmacología , Corazón/efectos de los fármacos , Inyecciones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Ratas , Ratas Endogámicas Lew , Células Madre/citología , Células Madre/efectos de los fármacosRESUMEN
Myocardial hypertrophy and dysfunction occur in response to excessive catecholaminergic drive. Adverse cardiac remodelling is associated with activation of proinflammatory cytokines in the myocardium. To test the hypothesis that exercise training can prevent myocardial dysfunction and production of proinflammatory cytokines induced by beta-adrenergic hyperactivity, male Wistar rats were assigned to one of the following four groups: sedentary non-treated (Con); sedentary isoprenaline treated (Iso); exercised non-treated (Ex); and exercised plus isoprenaline (Iso+Ex). Echocardiography, haemodynamic measurements and isolated papillary muscle were used for functional evaluations. Real-time RT-PCR and Western blot were used to quantify tumour necrosis factor alpha, interleukin-6, interleukin-10 and transforming growth factor beta(1) (TGF-beta(1)) in the tissue. NF-B expression in the nucleus was evaluated by immunohistochemical staining. The Iso rats showed a concentric hypertrophy of the left ventricle (LV). These animals exhibited marked increases in LV end-diastolic pressure and impaired myocardial performance in vitro, with a reduction in the developed tension and maximal rate of tension increase and decrease, as well as worsened recruitment of the Frank-Starling mechanism. Both gene and protein levels of tumour necrosis factor alpha and interleukin-6, as well as TGF-beta(1) mRNA, were increased. In addition, the NF-B expression in the Iso group was significantly raised. In the Iso+Ex group, the exercise training had the following effects: (1) it prevented LV hypertrophy; (ii) it improved myocardial contractility; (3) it avoided the increase of proinflammatory cytokines and improved interleukin-10 levels; and (4) it attenuated the increase of TGF-beta(1) mRNA. Thus, exercise training in a model of beta-adrenergic hyperactivity can avoid the adverse remodelling of the LV and inhibit inflammatory cytokines. Moreover, the cardioprotection is related to beneficial effects on myocardial performance.
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Cardiomiopatías/prevención & control , Cardiomiopatías/fisiopatología , Citocinas/metabolismo , Condicionamiento Físico Animal/fisiología , Receptores Adrenérgicos beta/fisiología , Agonistas Adrenérgicos beta/farmacología , Animales , Western Blotting , Cardiomegalia/inducido químicamente , Cardiomegalia/fisiopatología , Cardiomiopatías/inducido químicamente , Cardiotónicos/farmacología , Circulación Coronaria/fisiología , Ecocardiografía , Inmunohistoquímica , Inflamación/metabolismo , Isoproterenol/farmacología , Masculino , Contracción Miocárdica/fisiología , Miocardio/metabolismo , FN-kappa B/biosíntesis , Ratas , Ratas Wistar , Receptores Adrenérgicos beta/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/metabolismo , Función Ventricular Izquierda/fisiologíaRESUMEN
BACKGROUND: Since the cell therapy benefits for myocardial infarction are mainly related to infarct reduction by regenerating lost myocardium or increasing survival of tissues at risk, we evaluated the effects of bone marrow-derived mononuclear cells (MNC), implanted after the completion of necrosis, on infarct progression and cardiac remodeling. METHODS: After 48 h of induction of myocardial infarction (MI), Lewis-inbred rats were injected with 6 × 10(6) cells (MI+MNC) or saline (MI). After six weeks, scar dimension, ventricular morphology and function were analyzed by echocardiography followed by histomorphology of the infarcted and border zones. RESULTS: After therapy, the relative size of the infarct was smaller in MI+MNC (37 ± 1% of the left ventricle) than in MI (43 ± 1%). While the MI group exhibited parallel elongation of the infarcted (31.6 ± 3.8% increase) and reminiscent ventricular portions (33.5 ± 3.7%), MNC therapy preserved the initial infarct length. Infarcted walls were thicker (979 ± 31 mm) in the MNC group than in the untreated group (709 ± 41 mm), also demonstrating an absence of infarct expansion. In the border zones, MNC led to increased capillary densities and capillary/myocyte ratios. The cardiac systolic function remained depressed in MI, but improved by 19 ± 5% in MI+MNC which reduced the incidence of pulmonary arterial hypertension (37.5% in MI and 6.25% in MI+MNC). CONCLUSION: MNC therapy prevented the infarct expansion and thinning related to cardiac remodeling and was associated with an improvement of border zone microcirculation: as a result, MNC therapy reduced typical MI dysfunctional repercussions.
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Trasplante de Médula Ósea , Oclusión Coronaria/cirugía , Infarto del Miocardio/patología , Infarto del Miocardio/prevención & control , Remodelación Ventricular , Animales , Células de la Médula Ósea/citología , Trasplante de Médula Ósea/métodos , Trasplante de Médula Ósea/patología , Oclusión Coronaria/complicaciones , Femenino , Infarto del Miocardio/etiología , Ratas , Ratas Endogámicas Lew , Remodelación Ventricular/fisiologíaRESUMEN
BACKGROUND: We analyzed whether digitoxin affects the survival of rats with congestive heart failure. METHODS AND RESULTS: The influence of digitoxin (0.1 mg.100 g.day, orally) on the survival of infarcted female rats (n=170) randomized as Control Infarcted (CI, n=85) or Digitoxin (D, n=85) was evaluated for 280 days. Mean survival was 235+/-7 days for CI and 255+/-5 days for D (log-rank test: P=.0602). Digitoxin did not affect survival in rats with congestive heart failure from myocardial infarction <40% of the left ventricle, but did prolong survival in rats with infarction >or=40%. The log-rank test defined higher mortality (P=.0161) in CI >40% (56%) than in D >40% (34%), with a hazard ratio of 2.03. Pulmonary water content and papillary muscle mechanics were analyzed in CI (n=7) and D (n=14) survivors. Significant differences were observed regarding pulmonary water content (CI: 82+/-0.3; D: 80+/-0.3%; P=.0014), developed tension (CI: 2.7+/-0.3; D: 3.8+/-0.3g/mm(2); P=.0286) and +dT/dt (CI: 24+/-3; D: 39+/-4 mg mm(2).s; P=.0109). CONCLUSION: In conclusion, long-term digitoxin administration reduced cardiac impairment after myocardium infarction, attenuated myocardial dysfunction, reduced pulmonary congestion, and provided the first evidence regarding the efficiency of digitoxin in prolonging survival in experimental cardiac failure.
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Digitoxina/uso terapéutico , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/mortalidad , Animales , Femenino , Insuficiencia Cardíaca/etiología , Infarto del Miocardio/complicaciones , Ratas , Ratas Wistar , Tasa de Supervivencia/tendencias , Resultado del TratamientoRESUMEN
BACKGROUND: The purpose of the current study was to create a model of myocardial infarction (MI) that is homogeneous in size with a low immediate (24 hours) mortality. METHODS AND RESULTS: Male and female rats (n = 256) underwent left ventricle (LV) ablation (Ab) by a radiofrequency current (1000 kHz; 12 watts for 12 seconds) to promote a MI. A transmural MI occurred in all rats. Post-Ab complex arrhythmias were frequent (atrioventricular block, ventricular tachycardia, and fibrillation), which rapidly and spontaneously reverted to sinus rhythm. Among 66 male rats, immediate mortality occurred in 7.5%. Small MI size dispersion was characterized by smaller variability following Ab (x +/- SD: 45 +/- 8%) when compared with coronary occlusion (Oc; 40 +/- 19%). The histopathologic evaluations identified lesions similar to those which occurred following Oc, with scarring complete at 4 weeks. The hemodynamic and Doppler echocardiograms showed comparable increases in LV dimension, end-diastolic pressure, and pulmonary water content 1 and 4 weeks post-MI. Papillary muscle mechanics 6 weeks post-MI had matched inotropic and lusitropic dysfunction. CONCLUSIONS: LV Ab gave rise to a MI within a narrow size limit and with a low immediate mortality. LV Ab resulted in histopathologic evolution, ventricular dilation, and dysfunction, impairment in myocardial mechanics, and congestive outcome that reproduced a MI from Oc.