RESUMEN
BACKGROUND: Left ventricular remodeling after an acute myocardial infarction may result in progressive left ventricular dilation that may be associated with increased mortality. We studied the effects of the phosphodiesterase inhibitor milrinone on left ventricular remodeling after acute myocardial infarction. METHODS AND RESULTS: Rats (n = 90) were randomized to undergo either left coronary artery ligation or sham operation. Three weeks after surgery, rats received either no treatment or milrinone, which was continued until 2 days before the rats were killed. Ninety days after the initial surgery, hemodynamic measurements were made before and after volume loading. The rats were killed, the hearts were removed, and passive pressure-volume curves were obtained. The hearts were fixed at a constant pressure and analyzed morphometrically. Compared with untreated infarcted rats, milrinone-treated infarcted rats had a lower left ventricular end-diastolic pressure (1.7 +/- 0.4 versus 4.3 +/- 1.4 mm Hg, p less than 0.05), a lower left ventricular volume (1.25 +/- 0.20 versus 2.37 +/- 0.30 ml/kg, p less than 0.001) and a lower left ventricular wall stress index (1.3 +/- 0.2 versus 1.7 +/- 0.1, p less than 0.05). Left ventricular chamber stiffness was higher in milrinone-treated infarcted rats than in untreated infarcted rats. Milrinone had no cardiac effect on uninfarcted animals. CONCLUSION: Chronic milrinone therapy after acute myocardial infarction improves cardiac hemodynamic indexes and attenuates progressive left ventricular dilation.
Asunto(s)
Corazón/efectos de los fármacos , Infarto del Miocardio/fisiopatología , Piridonas/farmacología , Animales , Femenino , Corazón/fisiopatología , Ventrículos Cardíacos , Hemodinámica/efectos de los fármacos , Milrinona , Miocardio/patología , Inhibidores de Fosfodiesterasa/farmacología , Ratas , Ratas Endogámicas , Estrés MecánicoRESUMEN
The "no-reflow" phenomenon, the occurrence of areas with very low flow in hearts reperfused after ischemia, is thought to be largely established at the time of reperfusion as a result of microvascular damage induced by ischemia. In the present study we sought to determine whether additional impairment of tissue perfusion might also occur during the course of reperfusion. Open-chest dogs were subjected to 90 minutes of left circumflex coronary artery occlusion and reperfused for 2 minutes (n = 7) or 3.5 hours (n = 8). Myocardial perfusion was visualized in left ventricular slices following in vivo injection of the fluorescent dye thioflavin-S just before killing. The area of impaired perfusion (absent thioflavin) averaged 9.5 +/- 3.0% of the risk region in dogs reperfused for 2 minutes, whereas it was nearly three times as large in dogs reperfused for 3.5 hours (25.9 +/- 8.2% of the risk region, p less than 0.05). Serial measurements of flow by microspheres during reperfusion demonstrated zones within the postischemic myocardium that were hyperemic 2 minutes after reperfusion, with adequate flow still present at 30 minutes, but with a subsequent marked fall in perfusion. After 3.5 hours these areas showed negligible flow (0.13 +/- 0.3 ml/min/g) and no thioflavin uptake. Tissue samples showing postischemic impairment in perfusion has received virtually no collateral flow during ischemia (less than 0.01 ml/min/g), whereas collateral flow was significantly higher in adjacent thioflavin-positive zones (0.04 +/- 0.01 ml/min/g in endocardial samples and 0.07 +/- 0.02 ml/min/g in samples from the midmyocardium, p less than 0.001 vs. thioflavin-negative areas). Areas that showed late impairment of flow invariably demonstrated contraction band necrosis, which contrasted with the pattern of coagulation necrosis observed in areas of "true" (i.e., immediate) no-reflow. Intracapillary erythrocyte stasis and marked intravascular neutrophil accumulation (to levels greater than 20-fold that found after 2 minutes reperfusion) were typically observed in areas of delayed impairment to flow. Obstruction to flow at the capillary level was confirmed in additional dogs in which the heart was injected postmortem with silicone rubber to delineate the microvascular filling pattern. Areas of absent capillary filling were much more extensive after 3.5 hours than after 2 minutes reperfusion. Thus, this study shows that the occurrence of areas of markedly impaired perfusion in postischemic myocardium is related only in part to an inability to reperfuse certain areas on reflow. A more important factor is represented by a delayed, progressive fall in flow to areas that initially received adequate reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Daño por Reperfusión Miocárdica/patología , Reperfusión Miocárdica/métodos , Miocardio/patología , Animales , Circulación Colateral/fisiología , Circulación Coronaria/fisiología , Perros , Femenino , Masculino , Microcirculación/patología , Microscopía Electrónica , Daño por Reperfusión Miocárdica/etiología , Neutrófilos/fisiología , Factores de TiempoRESUMEN
After acute transmural myocardial infarction, the heart may undergo major remodeling characterized by thinning and dilation of the infarct zone and overall enlargement of the heart. The effect of increased left ventricular pressure on infarct expansion and the extent to which it alters postinfarction remodeling were studied in a rat model. Rats with either aortic banding or a sham operation and a survival period of 3 weeks were further randomized to sham thoracotomy or left coronary ligation. Surviving rats were killed 7 days later and the hearts were fixed in diastole for morphologic analysis. Hearts with aortic banding had a mean peak to peak gradient of 20.7 +/- 4.9 mm Hg across the aortic band at death and a significantly thicker heart than that of the comparison group without an aortic band. Infarct size, as a percent of total left ventricular mass, at the time of death was less in the group with aortic banding, yet infarct expansion was more marked. However, when original infarct size was estimated taking into account the effects of aortic banding, scar formation, infarct expansion and infarct-induced hypertrophy, it was found to be similar in both infarct groups (45.50 +/- 4.2 versus 47.90 +/- 3.1%). Infarct expansion, as measured by cavity dilation and infarct thinning, occurred in both infarct groups but was greater in the group with aortic banding.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Infarto del Miocardio/fisiopatología , Animales , Aorta , Volumen Sanguíneo , Cardiomegalia/etiología , Vasos Coronarios , Femenino , Ligadura , Infarto del Miocardio/complicaciones , Infarto del Miocardio/patología , Miocardio/patología , Ratas , Ratas EndogámicasRESUMEN
Infarct expansion is acute regional dilatation and thinning of the infarct zone. There are several possibilities for the mechanism of this alteration in cardiac shape: thinning could be caused by 1) cell rupture, 2) a reduction in the intercellular space, or 3) stretching of myocytes or 4) slippage of groups of myocytes so that less cells are distributed across the wall. To determine the relative contributions of these cellular mechanisms of wall thinning and dilatation, detailed study of transverse histological sections of rat hearts with infarct expansion was performed 1, 2, and 3 days after coronary ligation. The number of cells across the wall was determined in six regions within, adjacent to, and remote from the infarct. Cell counting was performed so that the total number of cells across the wall and the number of cells per unit length (cell density) across the wall were determined. The transmural cell count and the cell density were correlated with the wall thickness in each region. Myocyte cross-sectional areas and sarcomere lengths were also measured. The results from the infarct expansion hearts were compared with those of sham-operated control hearts that had been similarly analyzed. To ensure that mechanisms identified in the rat were applicable to human infarct expansion, five hearts from patients who died within 3 days of infarction and two hearts from patients without coronary disease were studied histologically in a similar fashion. Wall thinning occurred in all regions of the rat infarct expansion hearts compared with controls (p less than 0.0001) but, as expected, was most pronounced in the infarct zone. A decrease in the number of cells across the wall accompanied the wall thinning at each site (p less than 0.0001), and this change in cell number was highly correlated with the changes in wall thickness (r = 0.915, p less than 0.001). Cell density increased from controls only within the infarct zone (p less than 0.001) and accounted for at most 20% of the thinning in that region. The change in cell density was attributable to both cell stretch (measured by increased sarcomere length and decreased myocyte cross-sectional area) and a decrease in the intercellular space. A similar strong correlation between wall thinning and decreased number of cells across the wall was identified in the human hearts (r = 0.94, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Cardiomegalia/patología , Infarto del Miocardio/patología , Miocardio/patología , Animales , Recuento de Células , Colágeno/análisis , Endocardio/patología , Femenino , Humanos , Miocardio/ultraestructura , Ratas , Ratas Endogámicas , Sarcómeros/ultraestructuraRESUMEN
Whether steroids lead to thinner scars and larger aneurysms by delaying collagen deposition or worsening infarct expansion before significant collagen deposition begins is unknown. Rats underwent either transmural infarction by left coronary ligation or sham operation. Both infarct and sham rats were randomized to methylprednisolone 50 mg/kg i.p. X 4 or saline treatment within 24 h after operation. Sacrifice occurred before (3 d) or after (7 d) collagen deposition typically begins. Despite similar infarct size, infarct wall thickness was 1.35 +/- 0.08 mm in the saline and 0.99 +/- 0.12 mm in the methylprednisolone group (P less than 0.001) at 3 d. This decrease in wall thickness was explained by a decrease in the number of myocytes across the infarct wall (r = 0.99; P less than 0.001), suggesting that steroids promote myocyte slippage. Furthermore, methylprednisolone caused no further infarct thinning or cavity dilatation beyond 3 d. Thus, high-dose methylprednisolone given within 24 h after transmural infarction worsens infarct expansion before collagen is laid down by promoting the slippage of necrotic myocytes.
Asunto(s)
Metilprednisolona/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Animales , Colágeno/metabolismo , Vasos Coronarios , Femenino , Ligadura , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
Infarct expansion, regional dilation and thinning of the infarct zone, occurs within 1 day after myocardial infarction. Whether the early change in regional shape of infarct expansion affects the architecture of remote normal regions is unknown. To study this question, 45 rats with a transmural infarct were killed at 1, 2 and 3 days after infarction and their hearts were examined for infarct size and extent of expansion. Wall thickness and radius of curvature were measured within, adjacent to and remote from the infarct zone. Equivalent regions were analyzed in eight control hearts. The extent of disproportionate wall thinning and increased radius of curvature within the infarct zone of hearts with expansion was not dependent on infarct size. Significant wall thinning and increased regional radius of curvature were also seen in adjacent and remote regions of the hearts with expansion (p less than 0.001). These structural changes outside of the infarct occurred independent of infarct age and size, and were not seen in hearts without infarct expansion. Thus, when disproportionate thinning and dilation occur in the infarct region, they are accompanied by a distortion in shape of the entire heart including remote normal myocardium. This remote remodeling of noninfarcted myocardium correlates with extent of expansion, but not with age or size of the infarct.