Following myocardial Infarction (MI) the heart undergoes a process of remodeling characterized by considerable hypertrophy of the non-infarcted myocardium. We have recently characterized the molecular basis of key electrophysiologic alterations that may provide insight into the arrhythmogenecity of post-MI remodeled hypertrophied myocardium. To further characterize other key alterations in the pattern of cardiac gene expression in a time-dependent manner, we have measured mRNA and immunoreactive protein levels of selective cardiac genes in the remodeled hypertrophied left-ventricular (LV) myocardium of rats, 3 and 21 days after left-coronary ligation and compared the results with sham-operated rats. RNase protection assay was performed to assess the expression of c-fos, atrial natriuretic factor (ANF), brain natriuretic factor (BNF),α2/3isoform of Na–K ATPase, cardiacα/βisoform of myosin heavy chain (MHC). Compared to the sham group, the expression of c-foswas increased 10-fold (P<0.02) in the MI group on day 3, but unlike other overload hypertrophy models, the expression remained elevated by three-fold on day 21. Similar to other overload models, the ANF and BNF expression increased significantly. No alterations were observed in the expression of cardiacα-actin. There was reexpression of the fetal isogene form of MHC and Na–K ATPase after MI. Theβ-MHC mRNA levels, the fetal isoform of MHC, returned to basal levels after 21 days. After an initial five-fold decrease the adult isoform of αNa–K ATPase,α2Na–K ATPase mRNA, returned to control levels and similar changes were seen in the corresponding protein levels. These findings indicate that during LV remodeling and hypertrophy following MI, there is an upregulation of early response genes and fetal isogene expression. The pattern of activation, however, is distinct from that observed in other overload models, indicating the possible involvement of alternate signal transduction pathways.

OBJECTIVE: TO compare the utilization of echocardiography as a diagnostic tool by internists and cardiologists.DESIGN: Retrospective study.SETTING: Tertiary care university hospital.METHODS: Indications and clinical utility of echocardiographic studies ordered by cardiologists (group A, n = 301) and internists (group B, n = 297) were compared by chart review. The two groups of patients were analyzed to determine if the studies detected new cardiac pathology and/or altered patient management. RESULTS: The proportion of studies with abnormal results were similar in both groups (19% versus 14%, P >0.05). The results of echocardiography, however, led to a change in management more often when the study was ordered by cardiologists (16% versus 10%, P <0.05). A significantly greater proportion of studies were ordered for evaluation of valvular function by internists (44% versus 33%, P <0.05). Echocardiography detected valvular abnormalities in a similar proportion of cases in groups A and B (14% versus 10%, P >0.05). However, diagnostic yield was very poor when the study was performed in patients with suspected mitral valve prolapse in both groups. Cardiologists utilized echocardiography more often for evaluation of left ventricular function (35% versus 18%, P <0.01) and in the setting of atherosclerotic heart disease for detecting wall motion abnormalities (14% versus 5%, P <0.01).CONCLUSION: Diagnostic yield of echocardiography is similar when ordered by internists and cardiologists. With the information obtained, management is altered in a slightly greater proportion of cases involving a cardiologist. This may be due to utilization of echocardiography more often for estimating left ventricular function and for detecting wall motion abnormalities by cardiologists. (C) 1996 by Excerpta Medica, Inc.

We describe a case of diabetes mellitus induced by megestrol acetate in a patient with the acquired immunodeficiency syndrome. Metabolic studies including an arginine infusion test excluded an insulinopenic state and suggested insulin resistance as the underlying mechanism for hyperglycaemia. Withdrawal of megestrol acetate resulted in rapid correction of all metabolic abnormalities and eliminated the need for exogenous insulin therapy.

The cardiac L-type voltage-dependent calcium channel (VDCC) is a critical component of cardiac action potential and excitation-contraction coupling. The objective of the present study was to examine the changes in expression in Motif IV, an alternatively spliced region of the α-1 subunit of the VDCC channel in post-myocardial infarction (MI) remodeled rat left ventricle. RNase protection assay was used to determine alteration in isoform expression in the noninfarcted hypertrophied ventricular myocardium 21 days post myocardial infarction. Our study demonstrates that cardiac hypertrophy is associated with significant increase in the mRNA level of the fetal isoform, with the reversion of fetal:adult isoform ratio to the fetal phenotype. Changes in isoform expression in the post-MI remodeled ventricle, not previously reported, is a pertinent genetic marker of cardiac hypertrophy.

Objective: To test the hypothesis that coronary artery reperfusion performed too late to reduce infarct size improves survival by altering left ventricular remodeling and preventing progressive left ventricular dilation.Background: Several clinical trials have suggested that late coronary artery reperfusion without infarct size reduction is associated with a survival benefit. Although the mechanism is not known, survival benefits could be related to decreased infarct expansion associated with late coronary artery reperfusion. Decreased infarct expansion results in decreased left ventricular volume, and the resulting decreased wall stress could prevent or attenuate progressive left ventricular dilation and improve survival.Methods: Rats (n=84) were randomized to undergo sham operation, permanent left coronary artery ligation, or 2 hours of left coronary artery ligation followed by reperfusion. Ten weeks later, hemodynamic measurements were made before and after volume loading. The rats were killed, the hearts were removed, and passive pressurevolume curves were obtained. The hearts were fixed at a constant pressure and analyzed morphometrically.Results: When examined 10 weeks after experimental myocardial infarction, late reperfusion's effects on left ventricular remodeling resulted in reduced left ventricular volume when compared to hearts with infarcts supplied by a permanently occluded coronary artery (1.9 ± 0.1 ml/kg vs. 2.1 ± 0.2 ml/ kg; p < 0.01). Although there was a trend toward less thinning (0.95 ± 0.13 mm vs. 1.00 ± 0.10 mm; p=NS) and less expansion (2.3 ± 0.4 vs. 2.8 ± 0.9; p=NS) in reperfused hearts compared to hearts with a permanently occluded coronary artery, changes in infarct shape 10 weeks after infarction were not significantly different. Reperfusion's beneficial effects on remodeling of noninfarcted myocardium were associated with improved survival. Mortality was higher in the permanently occluded rats than in the reperfused rats (35% vs. 12%; p < 0.05).Conclusion: Late coronary artery reperfusion has a beneficial effect on remodeling of noninfarcted myocardium that results in reduced left ventricular volume in rat hearts examined 10 weeks after infarction. These beneficial effects on left ventricular remodeling are associated with improved survival.

The effects of metoprolol on early infarct expansion after acute myocardial infarction were studied in rats (n = 54) that underwent either left coronary artery ligation (MI) or sham operation. Immediately after surgery, the rats received either metoprolol (M) by mouth, which had been dissolved in drinking water, for 72 hours supplemented with three intraperitoneal doses over the first 24 hours or no treatment (H2O). Three 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 then fixed at a constant pressure and analyzed morphometrically. Infarct size was nonsignificantly lower in the metoprolol-treated group compared with the untreated group (38% ± 5% MI-M vs 48% ± 3% MI-H2O, p = 0.10) Compared with infarcted untreated rats, infarcted metoprolol-treated rats had a lower heart rate (322 ± 13 beats/min MI-M vs 452 ± 19 beats/min MI-H2O, p < 0.001), lower left ventricular systolic pressure (63 ± 4 mm Hg MI-M vs 90 ± 6 mm Hg MI-H2O, p = 0.004), and lower +dpdt (1340 ± 169 mm Hg/sec MI-M vs 2872 ± 273 mm Hg/sec MI-H2O, p < 0.001), but left ventricular end-diastolic pressure and cardiac index did not differ between the two groups. Left ventricular weight corrected for body weight was higher in infarcted rats treated with metoprolol compared with infarcted untreated rats (2.76 ± 0.07 gm/kg MI-M vs 2.41 ± 0.09 gm/kg MI-H2O, p < 0.05). The initial slope of the pressure-volume relationship Ki, an index of operative volume stiffness, was lower in infarcted rats treated with metoprolol compared with infarcted untreated rats (p = 0.03). There were, however, no significant differences in the expansion index, thinning ratio, or left ventricular volume between the two infarcted groups. Thus metoprolol therapy begun in the immediate postinfarction period promotes an increase in left ventricular weight and reduces operative volume stiffness but has no significant effect on indexes of early infarct expansion.

There is increasing evidence that significant primary alterations of cardiac electrophysiologic properties occur with the normal aging process. The age-related changes in cardiac electrophysiologic parameters are seen as alterations in the surface electrocardiogram, depressed sinus and atrioventricular nodal function, and increased refractoriness of the cardiac tissue. The mechanisms underlying these changes may consist of structural changes of the conduction system, autonomic nervous system dysfunction, or changes in cellular electrophysiology. As a result of these changes, the responsiveness of the aging heart to cardiotropic drugs is different from that of the younger heart. Elderly subjects are prone to certain electrophysiologic syndromes that merit special consideration.

Reperfusion that is too late to salvage ischemic myocardium reduces early infarct expansion, and captopril therapy favorably alters long-term left ventricular remodeling. To study whether the beneficial effects of these two therapies are additive, we examined the effects of captopril therapy after late reperfusion on left ventricular remodeling after acute myocardial infarction. Female Sprague-Dawley rats (n = 67) were randomly assigned to one of four groups: group 1, sham surgery and no treatment; group 2, left coronary artery ligation and no treatment (myocardial infarction [r MI]); group 3, left coronary artery ligation, reperfusion 2 hours later, and no treatment (late reperfusion [LR]); and group 4, left coronary artery ligation, reperfusion 2 hours later, and captopril treatment (LR-Cap). Captopril therapy (2 gm/L of drinking water) was begun in the LR-Cap group in the immediate post-operative period and continued for 20 days. Twenty-one days postoperatively, hemodynamic measurements were made before and after volume loading. The rats were killed, their hearts were removed, and passive pressure-volume curves were obtained. The hearts were then fixed at a constant pressure for morphometric analysis. Compared with the MI group, the LR group had a lower expansion index and a higher thinning ratio. There were no differences in hemodynamics, left ventricular volumes, or other morphometric indexes between the two groups. Compared with the MI and LR groups, the LR-Cap group had lower peak left ventricular end-diastolic pressure, lower left ventricular volume, lower left and right ventricular weights, and a leftward shift of pressure-volume curves. There were no differences in the expansion index or the thinning ratio between the LR and LR-Cap groups. Thus captopril therapy after late reperfusion additionally improves hemodynamics, attenuates left ventricular cavity dilation, attenuates an increase in left and right ventricular weights, and alters the pressure-volume relationship of the left ventricle.

Left ventricular remodeling following acute transmural myocardial infarction may result in early left ventricular enlargement. To characterize the effects of milrinone on components of early left ventricular dilation, rats (n = 120) underwent left coronary artery ligation or sham surgery. In the immediate postoperative period, rats received either no treatment or milrinone (3.17 ± 0.08 mg/kg/day) dissolved in drinking water for 20 days. Twenty-one days after the initial surgery, hemodynamic measurements were made. The rats were then put to death and the hearts arrested in diastole were excised and fixed at a constant pressure for morphometric analysis. To examine the effects of milrinone on the relative contribution of infarcted and noninfarcted segments to early left ventricular dilation after acute myocardial infarction, a subgroup of infarcted rats chosen randomly was put to death 3 days after the initial surgery for morphometric analysis. Compared with infarcted untreated rats, infarcted milrinone-treated rats had a lower left ventricular volume (1.41 ± 0.07 ml/kg vs 2.16 ± 0.19 ml/kg, p < 0.001), lower left ventricular wall stress (0.64 ± 0.03 vs 0.91 ± 0.06, p < 0.001), and a lower expansion index (1.61 ± 0.12 vs 2.61 ± 0.22, p < 0.001). Morphometric analysis revealed that the noninfarcted segment length did not differ between the two infarcted groups either 3 days or 21 days after left coronary artery ligation. Infarct segment length also did not differ between the two infarcted groups at 3 days, but at 21 days infarct segment was shorter in the milrinone-treated group compared with the untreated group (p < 0.03). An increase in infarct segment length/total endocardial circumference ratio between day 3 and day 21 was observed only in the untreated group of rats. Thus milrinone begun in the immediate postinfarction period in a rat myocardial infarction model attenuates left ventricular dilation when hearts are examined 3 weeks later. This attenuation of early postinfarction left ventricular dilation with milrinone appears to be related to its effects on infarct zone remodeling.

The routine medical management of patients with acute myocardial infarction (AMI) has undergone major changes in the last decade. Several large-scale trials have firmly established the effectiveness of thrombolytic therapy, beta blockers, and aspirin in the treatment of AMI. The critical issues include reducing myocardial oxygen demand and restoring adequate blood supply to the ischemic regions of the myocardium. As a result, the ability to intervene in patients with AMI has improved significantly. The purpose of this review is to discuss briefly the results of major trials of primary and secondary pharmacological intervention which had a direct impact on the care of patients with AMI. It concludes with current recommendations for the management of patients with AMI.

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.