Reappearance of myocytes in ovine infarcts produced by six hours of complete ischemia followed by reperfusion.

BACKGROUND: In this study we tested the hypothesis that delayed reperfusion of ischemic myocardium-too late to save myocytes-attenuates infarct expansion and improves collagen synthesis. METHODS: The hypothesis was tested in a sheep model of anteroapical infarction that has no collateral blood flow to the area at risk. After coronary ligation or arterial occlusion for 1 or 6 hours, sheep had serial hemodynamic and quantitative echocardiographic studies before and after infarction and 2, 5, 8, and 12 weeks later. Hearts were examined by light and electron microscopy at 2 and 12 weeks; hydroxyproline and ratios of type I/III collagen were measured at 12 weeks. RESULTS: After coronary occlusion, left ventricular (LV) function progressively decreased and size increased to form an anteroapical aneurysm. After 1 hour of ischemia, neither resting LV size nor function changed; the infarct contained a midmyocardial scar between epicardial and endocardial muscle. After 6 hours of ischemia, LV function was significantly better than that in nonperfused sheep. Two weeks after 6 hours of ischemia, no viable myocytes were visible by light microscopy, but electron micrographs showed rare intact nucleated myocytes with scarce cytoplasmic myofibrils. At the 12th week epicardial and endocardial myocytes reappeared in the infarct. Infarct collagen type I/III ratios were 1.2 in reperfused groups and 0.7 in nonperfused sheep. CONCLUSIONS: Delayed reperfusion causes loss and subsequent reappearance of ovine epicardial myocytes, improves collagen type I/III ratios, and attenuates LV dilatation and loss of function. One hypothesis to explain the reappearance of myocytes is that reperfusion partially reverses an incomplete apoptotic process.

Restraining acute infarct expansion decreases collagenase activity in borderzone myocardium.

BACKGROUND: After acute myocardial infarction, regional myocardial wall strains and stresses change and a complex cellular and biochemical response is initiated to remodel the ventricle. This study tests the hypothesis that changes in regional ventricular wall strains affect regional collagen accumulation and collagenase activity. METHODS: Fourteen sheep had acute anteroapical infarction that progressively expands into left ventricular aneurysm within 8 weeks. In 7 sheep, infarct expansion was restrained by prior placement of mesh over the area at risk. Fourteen days after infarction, and after hemodynamic and echocardiographic measurements, animals were euthanized for histology, measurements of hydroxyproline, matrix metalloproteinase-1 (MMP-1 or collagenase) and MMP-2 (gelatinase) activity, as well as collagen type I and III in infarcted, borderzone, and remote myocardium. RESULTS: Restraining infarct expansion does not change collagen content or MMP-1 or MMP-2 activity in the infarct, but significantly increases the ratio of collagen I/III. In borderzone and remote myocardium infarct, restraint significantly increases collagen content and significantly reduces MMP-1 activity. MMP-2 activity is reduced (p = 0.059) in borderzone myocardium only. Between groups, the ratio of type I/III fibrillar collagen does not change in borderzone myocardium. CONCLUSIONS: Fourteen days after acute myocardial infarction, restraining infarct expansion increases collagen accumulation in borderzone and remote myocardium, which may prevent expansion of hypocontractile, fully perfused "remodeling myocardium" adjacent to the infarct. This study demonstrates that changes in regional myocardial wall strain alter the cellular and biochemical processes involved in postinfarction ventricular remodeling.

Frequency, risk factors, and clinical outcomes of left ventricular assist device-associated ventricular thrombus.

A retrospective, transesophageal study of 51 consecutive patients receiving a left ventricular (LV) assist device (AD) over a 2-year period showed that LVAD-associated LV thrombosis (16%) was predicted by acute myocardial infarction, atrial cannulation, and postimplantation bleeding, and was associated with a fourfold increased risk of stroke compared with patients without thrombosis. LV cannulation, when using short-term LVADs, may decrease the incidence of LV thrombosis, and early transition to Heartmate-LVAD support may improve outcome.

Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions.

BACKGROUND: Bicuspid aortic valves (BAVs) are associated with premature valve stenosis, regurgitation, and ascending aortic aneurysms. We compared aortic size in BAV patients with aortic size in control patients with matched valvular lesions (aortic regurgitation, aortic stenosis, or mixed lesions) to determine whether intrinsic aortic abnormalities in BAVs account for aortic dilatation beyond that caused by valvular hemodynamic derangement alone. METHODS AND RESULTS: Diameters of the left ventricular outflow tract, sinus of Valsalva, sinotubular junction, and proximal aorta were measured from transthoracic echocardiograms in 118 consecutive BAV patients. Annular area was measured by planimetry, and BAV eccentricity was expressed as the ratio of the right leaflet area to the total annular area. Seventy-seven control patients with tricuspid aortic valves were matched for sex and for combined severity of regurgitation and stenosis. BAV patients (79 men and 39 women, aged 44.1+/-15.5 years) had varying degrees of regurgitation (84 patients [71%]) and stenosis (48 patients [41%]). Within the bicuspid group, multivariate analysis demonstrated that aortic diameters increased with worsening aortic regurgitation (P:<0.001) and advancing age (P:<0.05) but not with the severity of aortic stenosis. BAV patients had larger aortic diameters than did control patients at all ascending aortic levels measured (P:<0.01), despite advanced age in the control patients. CONCLUSIONS: Aortic dimensions are larger in BAV patients than in control patients with comparable degrees of tricuspid aortic valve disease. Although more severe degrees of aortic regurgitation are associated with aortic dilatation in BAV patients, intrinsic pathology appears to be responsible for aortic enlargement beyond that predicted by hemodynamic factors.

Ten weeks of rapid ventricular pacing creates a long-term model of left ventricular dysfunction.

OBJECTIVE: Rapid ventricular pacing produces a reliable model of heart failure. Cessation after 4 weeks of rapid ventricular pacing results in rapid normalization of left ventricular function, but the left ventricle remains persistently dilated. We present novel data that show that prolonged rapid ventricular pacing (10 weeks) creates a model of chronic left ventricular dysfunction. METHODS: In 9 dogs undergoing 10 weeks of rapid ventricular pacing, left ventricular function and volumes were serially assessed by using 2-dimensional echocardiography and pressure-volume analysis for 12 weeks after cessation of pacing. RESULTS: Increased end-diastolic volume and decreased systolic and diastolic function were seen at the end of pacing. By 2 weeks of recovery from rapid ventricular pacing, end-diastolic volume and ejection fraction were partially recovered but did not improve further thereafter. Load-independent and load-sensitive indices of function obtained by pressure-volume analysis at 8 and 12 weeks of recovery confirmed a persistence of both systolic and diastolic dysfunction. In addition, left ventricular mass increased with pacing and remained elevated at 8 and 12 weeks of recovery. Four of these dogs studied at 6 months of recovery showed similar left ventricular abnormalities. CONCLUSION: Ten weeks of rapid ventricular pacing creates a long-term model of left ventricular dysfunction.

Left ventricular remodelling in post-myocardial infarction patients with left ventricular ejection fraction 40-50% vs 25-39%. Influence of nisoldipine treatment? An echocardiographic substudy from the DEFIANT II study.

OBJECTIVE: Left ventricular (LV) remodelling following acute myocardial infarction has generally been studied in patients with LV ejection fraction (EF) < 40%, and it has been shown that this process can be attenuated by ACE inhibitors. Little is known regarding LV remodelling in patients with LVEF > or = 40% or the effects of treatment in this patient cohort. The DEFIANT II study (Doppler Flow and Echocardiography in Functional cardiac insufficiency) included 542 post-infarction patients with LVEF 25-50% without overt heart failure within 13 days following acute myocardial infarction (AMI). They were then randomized to nisoldipine coat-core (CC) or placebo and followed up for 6 months. DESIGN: Two-dimensional echoes were obtained after 8 (5-13) days and 6 months following AMI. SETTING: LV end diastolic (ED) and end systolic (ES) volumes (V) were calculated in 503 patients with technically satisfactory paired echoes using the biplabe method of discs in a core laboratory. SUBJECTS: Group A. 217 patients with baseline EF 40-50%, of whom 112 were randomized to nisoldipine and 104 to placebo (one patient was taken off study medication). Group B. 286 patients with EF 25-39%, of whom 145 were randomized to nisoldipine and 141 to placebo. RESULTS: LVEDV was 175 (+/-45) ml in Group A vs 203 (+/-49) ml in Group B (p = 0.001) at baseline and 184 (+/-48) ml vs 213 (+/-56) ml (p = 0.001), respectively, at 6 months. LVESV at baseline was 97 (+/-42) ml in Group A vs 133 (+/-37) ml in Group B (p = 0.001), and 106 (+/-34) ml vs 134 (+/-45) ml (p = 0.001) at 6 months, respectively. The increase of LVESV was 9 (+/-29) ml in Group A vs 2 (+/-35) ml in Group B (p = 0.007). LVEF decreased by 2 (+/-6)% in Group A vs an increase of 3 (+/-6)% in Group B (p = 0.001). Treatment with nisoldipine had no influence on LV volumes in either of the two groups or in the total study group. CONCLUSION: LV dilatation 6 months following AMI in patients with EF 40-50% was similar in end diastole, but more pronounced in end systole vs patients with EF 25-39%. LV remodelling did not change significantly after nisoldipine treatment.

Restraining infarct expansion preserves left ventricular geometry and function after acute anteroapical infarction.

BACKGROUND: Expansion of an acute myocardial infarction predicts progressive left ventricular (LV) dilatation, functional deterioration, and early death. This study tests the hypothesis that restraining expansion of an acute infarction preserves LV geometry and resting function. METHODS AND RESULTS: In 23 sheep, snares were placed around the distal left anterior descending and second diagonal coronary arteries. In 12 sheep, infarct deformation was prevented by Marlex mesh placed over the anticipated myocardial infarct. Snared arteries were occluded 10 to 14 days later. Serial hemodynamic measurements and transdiaphragmatic quantitative echocardiograms were obtained up to 8 weeks after anteroapical infarction of 0.23 of LV mass. In sheep with mesh, circulatory hemodynamics, stroke work, and end-systolic elastance return to preinfarction values 1 week after infarction and do not change subsequently. Ventricular volumes and ejection fraction do not change after the first week postinfarction. Control animals develop large anteroapical ventricular aneurysms, increasing LV dilatation, and progressive deterioration in circulatory hemodynamics and ventricular function. At week 8, differences in LV end-diastolic pressure, cardiac output, end-diastolic and end-systolic volumes, ejection fraction, stroke work, and end-systolic elastance are significant (P<0.01) between groups. CONCLUSIONS: Preventing expansion of acute myocardial infarctions preserves LV geometry and function.

Modified rapid ventricular pacing: a chronic model of heart failure for evaluation of new surgical therapies.

Rapid ventricular pacing (RVP) in dogs creates a well characterized model of dilated cardiomyopathy. Standard pacing protocols use RVP at 240-260 beats/min for 2-4 weeks, and result in high mortality rates if continued longer. The authors describe a modification of RVP that results in significant heart failure by 4 weeks, but can be continued for up to 10 weeks with low mortality. Nineteen mongrels underwent RVP at 215 beats/min for 10 weeks. Serial pressure-volume analysis and echocardiography were performed in this model to assess longitudinally changes in left ventricular (LV) function and volumes. The mortality rate was 10%. Significant progressive LV dysfunction with concomitant LV enlargement was observed throughout the pacing period. Finally, norepinephrine levels were elevated at the end of pacing, consistent with an activated sympathetic system. This modified RVP protocol permits long-term pacing with a low mortality rate and results in progressive heart failure throughout the pacing period. This model would be useful in the long-term evaluation of newer surgical and medical therapies of the failing heart.

Transmyocardial laser revascularization fails to prevent left ventricular functional deterioration and aneurysm formation after acute myocardial infarction in sheep.

OBJECTIVE: Transmyocardial laser revascularization is an investigational technique for revascularizing ischemic myocardium in patients with inoperable coronary arterial disease. This study tests the hypothesis that laser revascularization prevents left ventricular functional deterioration and aneurysm formation after acute anteroapical myocardial infarction. METHODS: An ultrasonic ascending aortic flow probe and snares around the distal left anterior descending and second diagonal coronary arteries were placed in 26 Dorsett hybrid sheep. Ten to 14 days later, snared arteries were occluded to produce an anteroapical infarction of 23% of left ventricular mass. Before infarction 14 animals had 34 +/- 4 transmyocardial perforations in the area of the anticipated infarction made with a carbon dioxide laser. Twelve animals served as controls. Hemodynamic measurements and transdiaphragmatic quantitative echocardiograms were obtained before, immediately after, and 2, 5, and 8 weeks after infarction. Eighteen sheep completed the protocol. RESULTS: All animals had large anteroapical left ventricular aneurysms with massive ventricular enlargement. Immediately after infarction the anterior wall became thinner and dyskinetic in all sheep. At 8 weeks aneurysmal size and shape were indistinguishable between groups. Two days after infarction, laser holes were filled with fibrin. At 5 and 8 weeks the infarct consisted of dense collagen, fibroblasts, scattered calcifications, myocyte fragments, neutrophils, macrophages, and no laser holes. There were no significant differences at any time between groups for cardiac pressures or output, ventricular volumes, ejection fraction, stroke work, and the stroke work-left ventricular end-diastolic pressure index. CONCLUSION: Transmyocardial laser perforations do not revascularize acute myocardial infarction in sheep.

Quantitation of left ventricular volumes and ejection fraction in post-infarction patients from biplane and single plane two-dimensional echocardiograms. A prospective longitudinal study of 371 patients.

AIMS: To determine whether left ventricular volumes and ejection fractions calculated from single plane two-dimensional echocardiograms using the algorithm (0.85A2L) correlate with those calculated using the biplane Simpson's method, and whether small changes in volumes and ejection fraction occurring post-infarction could be detected from single-plane as well as from biplane two-dimensional echocardiograms. METHODS AND RESULTS: Serial two-dimensional echocardiograms were obtained in 371 patients from the DEFIANT II trial a mean of 2 days, 1 week and 6 months post-infarction. Single plane volumes from the apical four chamber and apical long axis correlated closely with biplane Simpson's left ventricular volumes. Both single-plane left ventricular volumes significantly over-estimated biplane Simpson's volumes. Biplane Simpson's ejection fractions were consistently slightly under-estimated from the single-plane images. Differences between biplane Simpson's and single-plane volumes increased independently with increasing left ventricular size and distortion. The small changes in left ventricular volumes and ejection fraction over time were as reliably detected from single plane as from biplane images. CONCLUSION: Single-plane left ventricular volumes over-estimate biplane Simpson's volumes and under-estimate ejection fraction, and these discrepancies are amplified in dilated hearts with abnormal shape.

Cerebrovascular emboli related to pulmonary venous thrombosis after lung transplantation.

We describe a case of cerebral emboli related to pulmonary venous thrombosis after bilateral lung transplantation in a young man with cystic fibrosis. The diagnosis was made by transesophageal echocardiography, leading to aggressive anticoagulation within 24 hours of surgery. Hemodynamic deterioration in the following hours was of concern for the development of obstructive thrombus but was found to be due to pericardial tamponade, which, remarkably, resolved during a repeat transesophageal echocardiography.

Infarct size and location determine development of mitral regurgitation in the sheep model.

OBJECTIVE: This study tests the hypothesis that neither small nor large myocardial infarctions that include the anterior papillary muscle produce mitral regurgitation in sheep. METHODS: Coronary arterial anatomy to the anterior left ventricle and papillary muscle was determined by dye injection in 41 sheep hearts and by triphenyl tetrazolium chloride in 13. Development of acute or chronic mitral regurgitation and changes in left ventricular dimensions were studied by use of transdiaphragmatic echocardiography in 21 sheep after infarction of 24% and 33% of the anterior left ventricular mass. These data were compared with previous data from large and small posterior left ventricular infarctions. RESULTS: Ligation of two diagonal arteries infarcts 24% of the left ventricular mass and 82% of the anterior papillary muscle. Ligation of both diagonals and the first circumflex branch infarcts 33% of the left ventricle and all of the anterior papillary muscle. Neither infarction causes mitral regurgitation, although left ventricular cavity dimensions increase significantly at end systole. After the smaller infarction, the left ventricular cavity enlarges 150% over 8 weeks without mitral regurgitation. CONCLUSIONS: In sheep small and large infarctions of the anterior wall that include the anterior papillary muscle do not produce either acute or chronic mitral regurgitation despite left ventricular dilatation. In contrast large posterior infarctions produce immediate mitral regurgitation owing to asymmetric annular dilatation and discoordination of papillary muscle relationships to the valve. After small posterior infarctions that include the posterior papillary muscle, mitral regurgitation develops because of annular and ventricular dilatation during remodeling.

Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial.

BACKGROUND: We quantified cardiovascular death and/or left ventricular (LV) dilatation in patients from the SAVE trial to determine whether dilatation continued beyond 1 year, whether ACE inhibitor therapy attenuated late LV dilatation, and whether any baseline descriptors predicted late dilatation. METHODS AND RESULTS: Two-dimensional echocardiograms were obtained in 512 patients at 11+/-3 days and 1 and 2 years postinfarction to assess LV size, percentage of the LV that was akinetic/dyskinetic (%AD), and LV shape index. LV function was assessed by radionuclide ejection fraction. Two hundred sixty-three patients (51.4%) sustained cardiovascular death and/or LV diastolic dilatation; 279 (54.5%) had cardiovascular death and/or systolic dilatation. In 373 patients with serial echocardiograms, LV end-diastolic and end-systolic sizes increased progressively from baseline to 2 years (both P<.01). More patients with LV dilatation had a decrease in ejection fraction: 24.8% versus 6.8% (P<.001) (diastole) and 25.7% versus 5.3% (P<.001) (systole). Captopril attenuated diastolic LV dilatation at 2 years (P=.048), but this effect was carried over from the first year of therapy because changes in LV size with captopril beyond 1 year were similar to those with placebo. Predictors of cardiovascular death and/or dilatation were age (P=.023), prior infarction (P<.001), lower ejection fraction (P<.001), angina (P=.007), heart failure (P=.002), LV size (P<.001), and infarct size (%AD) (P<.001). CONCLUSIONS: Cardiovascular death and/or LV dilatation occurred in >50% of patients by 2 years. LV dilatation is progressive, associated with chamber distortion and deteriorating function that is unaffected by captopril beyond 1 year.

Stabilization of chronic remodeling by asynchronous cardiomyoplasty in dilated cardiomyopathy: effects of a conditioned muscle wrap.

BACKGROUND: Dynamic cardiomyoplasty is a promising new therapy for dilated cardiomyopathy. The girdling effects of a conditioned muscle wrap alone have recently been postulated to partly explain its mechanism. We investigated this effect in a canine model of chronic dilated cardiomyopathy. METHODS AND RESULTS: Twenty dogs underwent rapid ventricular pacing (RVP) for 4 weeks to create a model of dilated cardiomyopathy. Seven dogs were then randomly selected to undergo subsequent cardiomyoplasty, and all dogs had 6 weeks of additional RVP. The cardiomyoplasty group also received 6 weeks of concurrent skeletal muscle stimulation consisting of single twitches delivered asynchronously at 2 Hz to transform the wrap without active assistance. All dogs were studied by pressure-volume analysis and echocardiography at baseline and after 4 and 10 weeks of pacing. Systolic indices, including ejection fraction (EF), end-systolic elastance (Ees), and preload-recruitable stroke work (PRSW) were all increased at 10 weeks in the wrap versus controls (EF, 34.0 versus 27.1, P=.008; Ees, 1.65 versus 1.26, P=.09; PRSW, 35.9 versus 25.5, P=.001). Ventricular volumes, diastolic relaxation, and left ventricular end-diastolic pressures stabilized in the cardiomyoplasty group but continued to deteriorate in controls. Both the end-systolic and end-diastolic pressure-volume relationships shifted farther rightward in controls but remained stable in the cardiomyoplasty group. CONCLUSIONS: In addition to potential benefits from active systolic assistance, benefits from dynamic cardiomyoplasty appear to be partially accounted for by the presence of a conditioned muscle wrap alone. This conditioned wrap stabilizes the remodeling process of heart failure, arresting progressive deterioration of systolic and diastolic function.

Distortions of the mitral valve in acute ischemic mitral regurgitation.

BACKGROUND: In the absence of papillary muscle rupture, the precise deformations that cause acute postinfarction mitral valve regurgitation are not understood and impair reparative efforts. METHODS: In 6 Dorsett hybrid sheep, sonomicrometry transducers were placed around the mitral annulus (n = 6) and at the tips and bases of both papillary muscles (n = 4). Later, specific circumflex coronary arteries were occluded to infarct approximately 32% of the posterior left ventricle and produce acute 2 to 3+ mitral regurgitation. Before and after infarction, distance measurements between sonomicrometry transducers produced three-dimensional coordinates of each transducer every 5 ms. RESULTS: After infarction, the annulus dilated asymmetrically orthogonal to the line of leaflet coaptation, but the annular area increased only 9.2% +/- 6.3% (p = 0.02). At end-systole, posterior papillary muscle length increased 2.3 +/- 0.9 mm (p = 0.005); the posterior papillary muscle tip moved closer to the annular plane and centroid, and the anterior papillary muscle tip moved away. CONCLUSIONS: Small deformations in mitral valvular spatial geometry after large posterior infarctions are sufficient to produce moderate to severe mitral regurgitation. The most important changes are asymmetric annular dilatation, prolapse of leaflet tissue tethered by the posterior papillary muscle, and restriction of leaflet tissue attached to the anterior papillary muscle.

Dynamic cardiomyoplasty: its chronic and acute effects on the failing heart.

OBJECTIVES: Dynamic cardiomyoplasty is an alternative therapy for end-stage heart failure. We investigated the mechanisms, both acute and chronic, by which a synchronously stimulated conditioned muscle wrap affects left ventricular function in a chronic canine model of dilated cardiomyopathy. METHODS: Nineteen dogs underwent rapid ventricular pacing at a rate of 215 beats/min for 4 weeks to create a model of heart failure. Eight dogs were then randomly selected to undergo cardiomyoplasty, and all dogs received 6 additional weeks of rapid ventricular pacing. The cardiomyoplasty group also received a graded muscle conditioning protocol of synchronized burst stimulation to transform the muscle wrap. All dogs were studied with pressure-volume analysis and echocardiography at baseline and after 4 and 10 weeks of rapid ventricular pacing. Data in the cardiomyoplasty group were analyzed with the stimulator off, with it augmenting every beat (1:1), and with it augmenting only every other beat (1:2). RESULTS: Stimulator "of" data at 10 weeks of rapid pacing demonstrated chronic effects by enhanced ventricular function (end-systolic elastance = 1.80 after myoplasty vs 1.17 for controls, p = 0.005) and a stabilization of volumes and composite end-systolic and end-diastolic pressure-volume relations in the cardiomyoplasty group when compared with controls. Myoplasty stimulation increased apparent contractility (preload recruitable stroke work = 31.3 for stimulator "of" vs 40.6 for stimulator 1:2 assisted beats [p < 0.05] and vs 45.4 for stimulator 1:1 [p < 0.05]). CONCLUSIONS: Benefits from dynamic cardiomyoplasty are by at least two mechanisms: (1) the girdling effects of a conditioned muscle wrap, which halts the chronic remodeling of heart failure, and (2) active systolic assistance, which augments the apparent contractility of the failing heart.

Acute systolic and diastolic indices of left ventricular function after cardiomyoplasty in a chronic model of heart failure.

Recent experimental studies have suggested that the initial nonstimulated stage of dynamic cardiomyoplasty acutely impairs ventricular function. Those investigations were performed on normal hearts and primarily examined diastolic alterations as a result of the passive muscle wrap. The purpose of this study was to assess the acute systolic and diastolic effects of a nonstimulated muscle wrap in chronic heart failure induced by rapid ventricular pacing in canines. Pressure-volume analysis of ventricular function based on conductance catheter volume and micromanometer pressure data was used. Each animal was studied before rapid pacing, before cardiomyoplasty, and immediately after wrap. By the end of the pacing period and before wrap, left ventricular dysfunction developed in all dogs, manifested by significant deterioration of both systolic and diastolic indices of ventricular function, as well as progressive increases in left ventricular volumes. However, no further deterioration with load insensitive indices of systolic or diastolic indicators of ventricular function was found as a result of the passive muscle wrap. These results suggest that the cardiomyoplasty procedure can be safely performed on failing hearts without prohibitive acute impairment of ventricular function.

Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril.

BACKGROUND: Left ventricular enlargement after myocardial infarction increases the likelihood of an adverse outcome. In an echocardiographic substudy of the Survival and Ventricular Enlargement (SAVE) Trial, we assessed whether captopril would attenuate progressive left ventricular enlargement in patients with left ventricular dysfunction after acute myocardial infarction and, if so, whether this would be associated with improved clinical outcome. METHODS AND RESULTS: Two-dimensional transthoracic echocardiograms were obtained in 512 patients at a mean of 11.1 +/- 3.2 days after infarction and were repeated at 1 year in 420 survivors. Left ventricular size was assessed as left ventricular cavity areas at end diastole and end systole and left ventricular function as percent change in cavity area from end diastole to end systole. Patients were randomly assigned to placebo or captopril, and the incidence of adverse cardiovascular events consisting of cardiovascular death, heart failure requiring either hospitalization or open-label angiotensin-converting enzyme inhibitor therapy, and recurrent infarction were determined over a follow-up period averaging 3.0 +/- 0.6 years. Irrespective of treatment assignment, baseline left ventricular systolic area and percent change in area were strong predictors of cardiovascular mortality and adverse cardiovascular events. At 1 year, left ventricular end-diastolic and end-systolic areas were larger in the placebo than in the captopril group (P = .038, P = .015, respectively), and percent change in cavity area was greater in the captopril group (P = .005). One hundred eleven of the 420 1-year survivors with 1-year echo measurements (26.4%) experienced a major adverse cardiovascular event, and these patients had more than a threefold greater increase in left ventricular cavity areas than those with an uncomplicated course. Sixty-nine patients with adverse cardiovascular events were in the placebo group compared with 42 patients in the captopril-treated group (a risk reduction of 35%, P = .010). CONCLUSIONS: Two-dimensional echocardiography provides important and independent prognostic information in patients after infarction. Left ventricular enlargement and function after infarction are associated with the development of adverse cardiac events. Attenuation of ventricular enlargement with captopril in these patients was associated with a reduction in adverse events. This study demonstrates the linkage between attenuation of left ventricular enlargement by captopril after infarction and improved clinical outcome.