Sally C. Greaves

Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition

Left ventricular dysfunction can be improved with angiotensin-converting-enzyme inhibition started 1 week after myocardial infarction or later. To see whether earlier intervention may confer greater benefit, a double-blind study was carried out in which 100 patients with Q wave myocardial infarction, but without clinical heart failure, were randomly allocated treatment with captopril 50 mg twice daily or placebo starting 24-48 h after onset of symptoms. Left ventricular volumes were measured regularly during 3 months of treatment and after a 48 h withdrawal period by means of two-dimensional echocardiography. The placebo group showed significant increases in left ventricular end-diastolic (LVEDVI) and end-systolic (LVESVI) volume indices, with the ejection fraction unchanged. By contrast, the captopril group showed a slight but not significant rise in LVEDVI and a significant reduction in LVESVI with ejection fraction increased significantly. At 3 months there was a 4.6% difference in the change in ejection fraction from baseline between the groups (p less than 0.0001). Most of the treatment benefit was evident at 1 month and there were no changes in left ventricular volumes after 48 h withdrawal of treatment at 3 months. Heart failure requiring treatment with frusemide developed in 7 patients in each group during the study period; 3 of these (1 captopril-treated, 2 placebo-treated) had to be withdrawn from the trial with severe heart failure requiring open treatment. Thus early treatment with captopril is effective in preventing the ventricular dilatation that can occur after Q wave myocardial infarction.

Early Versus Delayed Angiotensin-Converting Enzyme Inhibition Therapy in Acute Myocardial Infarction The Healing and Early Afterload Reducing Therapy Trial

BACKGROUND Although ACE inhibitor therapy has been shown to reduce mortality in patients with acute myocardial infarction (MI), the optimal dose and the timing of its initiation have not been determined. METHODS AND RESULTS In a double-blind trial of 352 patients with anterior MI, we compared the safety and effectiveness of early (day 1) versus delayed (day 14) initiation of the ACE inhibitor ramipril (10 mg) on echocardiographic measures of left ventricular (LV) area and ejection fraction (EF). An early, low-dose ramipril (0.625 mg) arm was also evaluated. Clinical events did not differ. During the first 14 days, the risk of manifesting a systolic arterial pressure of < or = 90 mm Hg was increased in both ramipril groups. LVEF increased in all groups during this period, but the early, full-dose ramipril group had the greatest improvement in EF (increase: full, 4.9 +/- 10.0; low, 3.9 +/- 8.2%; delayed, 2.4 +/- 8.8%; P for trend < .05) and was the only group that did not demonstrate a significant increase in LV diastolic area. CONCLUSIONS The results of the present study demonstrated that in patients with anterior MI, the early use of ramipril (titrated to 10 mg) attenuated LV remodeling and was associated with a prompter recovery of LVEF. The use of low-dose regimen did not prevent hypotension and had only intermediate benefits on LV size and function. The more favorable effects on LV topography of the early use of full-dose ramipril support the results of the major clinical trials, which have demonstrated an early survival benefit of ACE inhibition.

Recovery of Ventricular Function after Myocardial Infarction in the Reperfusion Era: The Healing and Early Afterload Reducing Therapy Study

A minority of patients experience progression to clinically significant left ventricular dysfunction and enlargement after myocardial infarction (1). However, patients with worsening left ventricular function after myocardial infarction are at significantly greater risk for congestive heart failure and death (2, 3). Advances in the care of acute myocardial infarction over the past decadeparticularly the use of mechanical and pharmacologic reperfusion therapieshave reduced the risk for left ventricular dysfunction (4) and improved morbidity and mortality after myocardial infarction (5). Improvements in left ventricular function can be apparent shortly after myocardial infarction and have generally been attributed to recovery from myocardial stunning (6). However, the great heterogeneity in patients after myocardial infarction underscores the importance of identifying factors that influence the progression and regression of left ventricular dysfunction. The Healing and Early Afterload Reduction Therapy (HEART) trial (7) was a randomized, double-blind study of the hemodynamic effects of early versus delayed administration of three regimens of ramipril, an angiotensin-converting enzyme (ACE) inhibitor, after myocardial infarction. Patients were followed by performing serial echocardiography within the first 24 hours after myocardial infarction and at 14 and 90 days after myocardial infarction. Patients treated with ramipril experienced significant improvements in ejection fraction at 14 days after myocardial infarction, but all echocardiographic measures of ventricular size and function were similar in the three treatment groups by 90 days (7). The present analysis assessed clinical and echocardiographic predictors of recovery of ventricular function in the 88% of patients in HEART who underwent reperfusion therapy (65% received thrombolysis alone, 15% had percutaneous transluminal coronary angioplasty alone, and 8% had both). Methods Patients The HEART study enrolled 352 patients with acute anterior Q-wave myocardial infarction. Patients with ST-segment elevation or new Q waves in two or more contiguous leads were also eligible. Patients underwent echocardiography within 24 hours after myocardial infarction (before randomization [day 1]) and at 14 and 90 days after myocardial infarction. Patients were randomly assigned to receive one of three dosing regimens of ramipril: placebo for 14 days, followed by full-dose (10 mg) ramipril; low-dose (0.625 mg) ramipril for 90 days; or full-dose ramipril for 90 days. Thus, by day 14, all patients were treated with ACE inhibition. Inclusion and exclusion criteria and details of the titration scheme and patient characteristics are described elsewhere (7). Serial echocardiographic data from days 1, 14, and 90 were available in 249 patients. Baseline data were available for an additional 12 patients who died during follow-up. Patients with day-1 echocardiograms of insufficient quality and those who were alive at 90 days but for whom echocardiograms at this time point were not available were excluded from analysis. Of the 352 patients enrolled in the study, 48 did not have echocardiograms of sufficient quality for analysis, and 18 (including 13 who died) did not have all three echocardiograms. We also excluded 25 patients who did not receive reperfusion therapy. Echocardiographic Analysis Echocardiographic measurements were made in triplicate by using a Nova Microsonics (Mahwah, New Jersey) workstation, as described elsewhere (7). The echocardiographic reader was blinded to treatment assignment. Endocardial borders from end-diastolic and end-systolic frames were digitized manually, and left ventricular volumes were assessed by using the Simpson rule method. Infarct segment length was assessed by manually tracing the akinetic or dyskinetic segment and was expressed as a percentage of the endocardial perimeter. The reproducibility of the echocardiographic measurements is reported elsewhere (7). Statistical Analysis Patients were categorized into three groups according to degree of recovery of left ventricular function. Patients were categorized as having 1) complete recovery of function if functional abnormalities observed on day 1 improved to normal [left ventricular ejection fraction > 0.55 and absence of regional akinesis or dyskinesis], 2) partial recovery of function if ejection fraction improved and the extent of regional akinesis or dyskinesis decreased from day 1, or no 3) recovery if neither of these criteria was fulfilled or death occurred before 90 days. Left ventricular enlargement (remodeling) was defined as an increase in ventricular end-diastolic volume between day 1 and day 90 and was treated as a continuous variable. Univariate and multivariate logistic regression were used to assess relationships between day 1 values and recovery of function. Values are expressed as the mean (SD). A P value less than 0.05 was considered statistically significant. Stata statistical software (Stata Corp., College Station, Texas) was used for analyses. Results Baseline Characteristics and Left Ventricular Enlargement Clinical and echocardiographic data were obtained on day 1 before randomization (Table 1). Included and excluded patients differed significantly only with regard to age (59.4 12.3 years vs. 64.2 12.9 years; P�=�0.001). Patients with partial recovery had lower ejection fraction and larger volumes than did those with no recovery or complete recovery, and patients with full recovery had shorter infarct segments than did those with partial recovery or no recovery (Table 1). Fewer patients in the complete recovery group than in the partial or no recovery groups were diabetic, but this difference was not statistically significant. The recovery groups did not significantly differ with regard to other baseline characteristics or in the distribution of drug treatment. Table 1. Baseline Characteristics of Patients by Recovery Group Recovery of Left Ventricular Function On day 1, only 9 of 261 (3.4%) patients had normal ventricular function (ejection fraction > 0.55 and no akinesis or dyskinesis). The change in left ventricular ejection fraction varied widely and improved by day 90 in 171 of 261 (66%) patients (Figure 1). The mean change in ejection fraction during this time was 0.045 0.098. Most of this change occurred in the first 14 days (mean change in ejection fraction from day 1 to 14, 0.038 0.091); minimal additional change occurred between days 14 and 90 (Table 2). Of the 252 patients with abnormal left ventricular function on day 1 (ejection fraction < 0.55 or any akinesis or dyskinesis), 13% had complete recovery of ventricular function by day 14 and 22% of patients had complete recovery by day 90. An additional 36% of patients had partial recovery of function by day 90, defined as improvement in ejection fraction from day 1 values and shortening of the akinetic or dyskinetic segment. The remaining patients had functional deterioration (decrease in ejection fraction or increase in the length of the infarct segment from day 1; 103 patients) or died (12 patients). At 90 days, 53% (132 of 249) of patients had greater than 5% improvement in ejection fraction from baseline, but only 16% (39 of 249) had a decrease in ejection fraction greater than 5%. The length of the infarct segment decreased in the group as a whole from 27.0% 10.9% at day 1 to 19.1% 13.1% at day 14 and 16.9% 13.7% at day 90. Figure 1. Distribution of change in ejection fraction from day 1 to 90. Table 2. Echocardiographic Variables throughout the Study We previously reported a statistically significant increase in ejection fraction from day 1 to 14 in patients receiving full-dose (10 mg) ramipril (7), although ejection fraction did not differ among the groups by day 90. In the current analysis, we found no differences in the percentage of patients with full recovery of function by day 14 or day 90 according to treatment group. In addition, recovery groups did not differ in time to reperfusion (Table 1) or the proportion of patients who recovered according to type of reperfusion therapy. Predictors of Recovery of Function Baseline clinical characteristics, including age, sex, and Killip class, did not predict recovery of function. In contrast, peak creatine kinase level (which occurred a mean of 27 17 hours after onset of symptoms), a crude assessment of the extent of necrosis, and left ventricular function on day 1 (ejection fraction and extent of akinesis or dyskinesis) were significant predictors of recovery of function in univariate and multivariate analyses. The percentage of patients with complete recovery of function decreased as the creatine kinase quartile increased (P for trend < 0.001) (Figure 2). In a multiple logistic regression analysis that included peak creatine kinase level, baseline ejection fraction, infarct segment length, Killip class, age, sex, and drug therapy, peak creatine kinase level remained the strongest independent predictor of recovery. Each 100-unit increase in creatine kinase level was associated with a 4.3% decreased odds of full recovery (P�=�0.001). Figure 2. Percentage of patients with complete recovery of function by increasing quartile of peak creatine kinase level. P Left Ventricular Enlargement and Recovery of Function Overall, left ventricular enlargement (remodeling) was inversely related to improvement in ejection fraction over 90 days (r = 0.27; P�<�0.001). Nevertheless, during this time, ejection fraction improved by 4.5% 9.5% despite an increase in end-diastolic volume of 5.6 25.7 mL. The majority of this change occurred in the first 14 days after myocardial infarction. Patients who recovered function demonstrated the least enlargement. Left ventricular volume decreased by 7.6 18.4 mL from day 1 to day 90 in patients with complete recovery of function, compared with an increase of 9.4 26.3 mL in all other patients (P�<�0.001). Left ventricular e

Determinants of Left Ventricular Hypertrophy and Systolic Dysfunction in Chronic Renal Failure

To evaluate determinants of left ventricular hypertrophy (LVH) and left ventricular (LV) systolic dysfunction in chronic renal failure (CRF), M-mode and two-dimensional echocardiography were performed in 38 undialyzed patients with CRF (serum creatinine > or = 3.4 mg/dL), 54 patients receiving continuous ambulatory peritoneal dialysis, 30 patients receiving hemodialysis, and 59 healthy age- and sex-matched volunteers. Left ventricular (LV) wall thickness and LV dimensions were greatest in dialysis patients, intermediate in CRF patients, and least in control subjects. LV mass index calculated from M-mode measurements was 78.7 g/m2 +/- 14.8 g/m2 in controls, 120.5 g/m2 +/- 28.7 g/m2 in CRF patients, and 136 +/- 45.0 g/m2 in dialysis patients (P < 0.0001). LV fractional shortening and LV velocity of circumferential shortening were lower in dialysis patients than in CRF patients and controls (fractional shortening 36.5% +/- 5.6% in controls, 36.2% +/- 7.2% in CRF patients, and 29.8% +/- 8.9% in dialysis patients; P < 0.0001). Echocardiography was normal in only 24 dialysis patients (29%) and 14 CRF patients (37%) (P = NS). Thirty-nine dialysis patients (46%) and 10 CRF patients (26%) had LVH (P = NS). Thirty dialysis patients (36%) and five CRF patients (13%) had LV systolic dysfunction (P < 0.05). LV hypertrophy with LV systolic dysfunction was present in 15 dialysis patients but no CRF patients (P < 0.05). There were no significant differences between hemodialysis patients and continuous ambulatory peritoneal dialysis patients in M-mode echocardiographic measurements or the frequency of LVH and LV systolic dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Incidence and Natural History of Left Ventricular Thrombus Following Anterior Wall Acute Myocardial Infarction

Previous studies have reported left ventricular (LV) thrombus in 20% to 56% of patients after anterior wall acute myocardial infarction (AMI). The Healing and Early Afterload Reducing Therapy (HEART) study was a prospective study comparing effects of early (24 hours) or delayed (14 days) initiation of ramipril, an angiotensin-converting enzyme inhibitor, on LV function after anterior wall AMI. This ancillary study assessed prevalence of LV thrombus. Two-dimensional echocardiography was performed on days 1, 14, and 90 after myocardial infarction. The cohort consisted of 309 patients. Q-wave anterior wall AMI occurred in 78%; 87% received reperfusion therapy. The prevalence of LV thrombus was 2 of 309 (0.6%) at day 1, 11 of 295 (3.7%) at day 14, and 7 of 283 (2.5%) at day 90. One patient had thrombus at 2 examinations. The day 1 echocardiogram was not correlated with thrombus development. LV size increased more in patients with thrombus than in those without thrombus. Patients with thrombus had more wall motion abnormality after day 1 than patients without thrombus (p = 0.03). Thus, the current prevalence of LV thrombus in anterior wall AMI is lower than previously reported, possibly due to changes in AMI management. Preservation of LV function is likely to be an important mechanism. Most thrombi are seen by 2 weeks after AMI. Resolution documented by echocardiography is frequent.

Current incidence and determinants of perioperative myocardial infarction in coronary artery surgery.

Increasingly, patients undergoing coronary artery bypass grafting (CABG) are elders, have had previous CABG, and have poor left ventricular function. To evaluate determinants of perioperative myocardial infarction (PMI) after isolated CABG, 499 consecutive patients were reviewed. Definite PMI (total peak creatine kinase [CK] > 700 U/L, creatine kinase MB [CK-MB] > 30 ng/ml, and new pathologic electrocardiographic Q waves) occurred in 25 patients (5.0%) and probable PMI (total peak CK > 700 U/L, CK-MB > 30 ng/ml, and a new wall-motion abnormality) occurred in 10 (2.0%) patients. According to multivariate logistic regression analysis, independent risk factors for definite or probable PMI (adds ratios; 95% confidence intervals) were emergency surgery (3.1; 1.1 to 8.4; p = 0.003), aortic cross-clamp time > 100 minutes (4.2; 1.6 to 11.2; p = 0.004), myocardial infarction in the preceding week (2.6; 1.0 to 6.4; p = 0.04), and previous revascularization (2.4; 1.1 to 5.2; p = 0.02). In conclusion, both preoperative and intraoperative factors influence the risk of PMI after CABG. Despite changes in the profile of patients undergoing CABG, the incidence of PMI in this tertiary center is comparable with that found in earlier series, probably because of improvements in surgical techniques and postoperative care.

Associations between plasma natriuretic peptide levels, symptoms, and left ventricular function in patients with chronic aortic regurgitation

In 40 patients with chronic moderate to severe aortic regurgitation, brain natriuretic peptide, N-brain natriuretic peptide, and atrial natriuretic peptide were higher in symptomatic patients compared with asymptomatic patients after adjustment for age, gender, and ejection fraction, but each natriuretic peptide correlated weakly with echocardiographic measures of left ventricular size and function. In patients with chronic aortic regurgitation, measurement of natriuretic peptide levels may provide information on left ventricular function in addition to echocardiography.

Temporal dissociation of left ventricular function and remodeling following experimental myocardial infarction in rats.

BACKGROUND Left ventricular function early after myocardial infarction (MI) predicts subsequent clinical outcome. Nevertheless, the relationship between early changes in left ventricular function and subsequent left ventricular remodeling has not been well defined. METHODS AND RESULTS To explore the temporal relationship between left ventricular function and remodeling after MI, rats (n = 63) underwent coronary artery ligation with and without reperfusion at 45 or 180 minutes or a sham operation. All animals were followed up by serial echocardiography preligation; 4, 24, and 48 hours; and 1, 2, 3, 4, 6, and 9 weeks after MI. Measures of global left ventricular size and function and regional wall motion were obtained at physiological heart rates. Histological infarct sizes (range, 0% to 52%) were determined in all animals. Within 4 hours of MI, fractional area change (FAC) decreased dramatically in association with an increase in left ventricular systolic cavity area, whereas diastolic area increased more gradually. Early FAC was related to infarct size (r = -0.82; P < .000), predicted the extent of left ventricular enlargement (P = .0001), and remained depressed throughout the duration of follow-up. Regional wall motion excursion and systolic wall thickness decreased in the infarcted and noninfarcted regions in animals with large infarctions. CONCLUSIONS The rate of left ventricular dilatation after MI in rats is proportional to initial left ventricular function, although left ventricular function remains relatively constant as the ventricle progressively enlarges. Regional myocardial function after a large MI is abnormal in noninfarcted as well as infarcted regions.

Early experience with the mosaic bioprosthesis: a new generation porcine valve.

BACKGROUND The Mosaic bioprosthesis is a new generation stented porcine valve. METHODS Between May 1995 and April 1998, this valve was implanted in the aortic position in 98 patients (70 men; mean age, 69.2 years [34.2 to 83.6 years]). Preoperatively 35 patients were in New York Heart Association functional class 3 or 4. Fifty-nine patients underwent concomitant procedures. The mean duration at follow-up in January 1999 was 23.7 +/- 10.2 months (0.3 to 39.4 months) and totaled 193 patient-years. All but one survivor was in New York Heart Association class 1 or 2. RESULTS Early complications included 1 death, 3 reoperations for bleeding, greater than mild regurgitation (paravalvar) in 1 patient and thromboembolism in 4 patients. Late complications included four deaths, study-valve endocarditis in 3 patients, more than mild regurgitation or hemolysis in 2, and thromboembolism in 2 patients. Late follow-up echocardiography in all survivors showed a mean transaortic gradient of 13.6 +/- 6.7 mm Hg, and an aortic valve area of 1.80 +/- 0.61 cm2. Valve replacement was followed by a significant and sustained decrease in left ventricular mass for all valve sizes. There has been no primary structural valve failure. CONCLUSIONS The early experience with the Mosaic valve in the aortic position has been promising.

Assessment of Regional Left Ventricular Wall Stress After Myocardial Infarction by Echocardiography-based Structural Analysis

OBJECTIVES The objective of this study was to determine the distribution of regional left ventricular (LV) wall stress after myocardial infarction (MI). BACKGROUND After a large MI, structural changes occur in the heart that ultimately may lead to alterations in LV size and shape, a process generally referred to as ventricular remodeling. Regional variation in myocardial wall stress may be responsible for initiation of physiologic and cellular changes that result in myocardial hypertrophy, dilatation, and remodeling after MI. Simplified geometric analytic methods of estimating global LV wall stress cannot determine regional variation such as that occurring after MI. METHODS AND RESULTS To assess regional LV wall stress after MI, we applied the finite element method to patient-specific end-systolic LV models generated from echocardiographic imaging. After validation by comparison with analytic solutions of LV wall stress in idealized ventricles, LV models were constructed from rotated orthogonal apical images from 13 normal volunteers, 16 patients with recent (<4 days) anterior MI, and 7 patients with recent infero-posterior MI. The mean Von Mises stress was calculated for the entire LV and for 5 separate regions of the LV. Von Mises LV wall stress was increased globally in patients with anterior MI (211 +/- 46 kdyne/cm2; P < .002) or infero-posterior MI (175 +/- 23 kdyne/cm2; P = .04) compared with normal patients (144 +/- 57 kdyne/cm2). Global wall stress correlated directly with ejection fraction (P < .0001) and inversely with wall motion index (P < .004) in patients with anterior MI. Wall stress in the apical regions was increased by a factor of 2.3 in patients with anterior MI (P < .0001), whereas other regions did not differ from normal patients. There were no individual regions that were significantly different from normal in patients with infero-posterior MI. CONCLUSIONS Anterior MI is associated with an increase in apical end-systolic wall stress compared with normal and infero-posterior MI. This may be an important stimulus for LV remodeling after anterior MI.