Plasma Angiotensin-Converting Enzyme Activity and Left Ventricular Dilation After Myocardial Infarction
Background Left ventricular dilation after acute myocardial infarction (MI) is mainly determined by infarct size. In addition, this detrimental structural adaptation seems to be augmented in patients with the ACE DD genotype. The ACE DD genotype is associated with increased ACE activity. The aim of the present study was to evaluate whether ACE activity per se may carry prognostic significance for subsequent left ventricular dilation as assessed by echocardiography during 1-year follow-up after acute MI.
Methods and Results Left ventricular end-systolic and end-diastolic volume indexes were assessed by two-dimensional echocardiography. In 102 consecutive patients, plasma ACE activity was determined 3.7±0.1 hours after the onset of MI. In 64 of these patients, left ventricular volume indexes obtained at baseline and 1 year after MI were used for the present analysis. Patients were divided into a group having low ACE activity (≤12 IU/L, n=15) and a group having high ACE activity (>12 IU/L, n=49). Infarct size was a significant predictor of the increase in left ventricular volume indexes (P=.0001) in these patients. Multivariate regression analysis, after correction for infarct size, demonstrated that elevated plasma ACE activity is a significant predictor of the increase in left ventricular end-diastolic and end-systolic volume indexes (P=.0006 and P=.02, respectively) 1 year after MI.
Conclusions Elevated plasma ACE activity determined soon after the onset of MI may be a significant predictor of the development of left ventricular dilation and may identify patients at risk.
The increase in LV volume during the period after a myocardial infarction is related to the patient’s long-term prognosis. This process is most eminent in the early healing period and is largely predicted by infarct size.1 2 However, genetic predisposition may also be involved. An insertion/deletion polymorphism of the human ACE gene has been described, with subjects homozygous for the D allele having higher ACE activities.3 Previously, we demonstrated that after myocardial infarction, LV dilation is augmented in patients with the ACE DD genotype.4 However, it is unknown whether increased levels of plasma ACE activity per se, determined soon after the onset of symptoms, are associated with an increase in LV volume in the chronic phase. Therefore, the aim of the present study was to evaluate whether ACE activity has prognostic significance for subsequent LV dilation as assessed by echocardiography during 1-year follow-up.
A post hoc analysis was performed in patients enrolled in CATS for whom plasma ACE activity data were available. In CATS, 298 patients with a first anterior-wall myocardial infarction were randomized to captopril or placebo after completion of streptokinase infusion. In 102 consecutive patients, plasma ACE activity was determined after thrombolysis and immediately before the administration of study medication. In 64 of these patients, LV volume indexes had been obtained at baseline and 1 year after myocardial infarction. The primary end point of CATS was LV volume assessed by two-dimensional echocardiography during the course of 1 year. The main results have been reported elsewhere.5
LV end-diastolic and end-systolic volumes were assessed by two-dimensional echocardiography on apical four- and two-chamber views. LV volumes were calculated by use of the biplane (modified) Simpson’s rule. LVEDVI and LVESVI were derived from body surface area. Echocardiographic determination of LV volumes obtained at baseline (within 24 hours after admission) and 1 year after myocardial infarction was used for the present analysis.
Enzymatic Infarct Size
Infarct size was estimated from the cumulative release of α-hydroxybutyrate dehydrogenase activity (in international units per liter of plasma) within the first 72 hours, calculated from serial plasma α-hydroxybutyrate dehydrogenase determinations from blood samples taken twice daily during the first 5 days, as described by van der Laarse et al.6 These investigators demonstrated that this method is independent of the result of thrombolysis, ie, the presence or absence of reperfusion.6 Infarct size was considered small if the enzyme release was <730 IU/L, medium if it was ≥730 and ≤1460 IU/L, and large if it was >1460 IU/L. Cutoff points were derived from tertiles of all randomized infarct sizes, as has been reported elsewhere.7
Plasma ACE Activity
Samples for plasma ACE activity were taken at a mean of 3.7±0.1 hours after the onset of chest pain. This sample was taken on average ≈1 hour after initiation of thrombolytic therapy but before administration of captopril or placebo in all patients. Because the distribution of plasma ACE activity was not normal and was slightly skewed to the right, ACE levels were stratified into quartiles. Thereafter, coefficients for each quartile were determined. No linearity could be demonstrated. Therefore, the variable was categorized by combining the quartiles with similar coefficients. The first quartile was compared with the other three quartiles. Plasma ACE activity at admission was considered low if ACE activity was ≤12 IU/L and high if ACE activity was >12 IU/L.
For the comparison of relevant clinical baseline characteristics, a χ2 test and two-sample Wilcoxon or Student’s t test were used where appropriate. Group differences were tested by ANOVA in which volume data were corrected for infarct size. To determine confounding parameters related to the increase in LV volume, a multivariate regression analysis was performed. By univariate analysis, factors significantly contributing to the increase in LV volume were identified. Covariates included baseline LV volume indexes, infarct size, and treatment. Results were presented as mean±SEM and were considered statistically significant if P<.05.
A comparison of patients with and without available plasma ACE activity revealed no substantial differences. Patients in whom ACE activity had been determined and the LVEDVI and LVESVI had been obtained 1 year after myocardial infarction (n=64) were divided into two groups: a group of 15 patients having low ACE activity (≤12 IU/L) and a group of 49 patients having high ACE activity (>12 IU/L). At baseline, clinical characteristics including LV ejection fraction and infarct size were comparable between the two groups (Table 1⇓). Also, no relationship between the time of sampling and ACE activity was present. However, compared with patients with high ACE activity, patients with low ACE activity had significantly larger LV volume indexes at the first echocardiographic study, obtained 7.2±0.6 hours after samples of plasma ACE were taken (Table 1⇓). Therefore, baseline LV volume indexes were added to the multivariate model used for the evaluation of the prognostic significance of plasma ACE activity.
Effect of Plasma ACE Activity on LVEDVI and LVESVI
One year after myocardial infarction, patients with high ACE activity had a mean change in LVEDVI of 11.1±3 mL/m2 compared with −5.4±3 mL/m2 in patients with low ACE activity. The mean change in the LVESVI was 8.5±2 mL/m2 in patients with high ACE activity compared with 0.9±3 mL/m2 in patients with low ACE activity (Figure⇓). The increase in LV volume indexes was largely predicted by infarct size (P=.0001; Table 2⇓). Multivariate regression analysis with correction for infarct size demonstrated that elevated plasma ACE activity is also a significant predictor of the increase in LVEDVI and LVESVI (P=.0006 and P=.02, respectively) 1 year after myocardial infarction.
After correction for baseline differences in LV volume indexes, infarct size, and treatment, ACE activity remained a significant predictor of the increase in LV volume indexes. In this subgroup of CATS and in contrast to the entire study population, no statistically significant differences in LV volume indexes at 1 year after myocardial infarction were found between captopril- and placebo-treated patients (Table 2⇑).
Previously, we demonstrated that infarct size is the most powerful determinant of ventricular enlargement after a myocardial infarction.7 The present study demonstrates that plasma ACE activity may be an additional independent predictor of the increase in LV volume subsequent to myocardial infarction. In particular, patients with high ACE activity had increased LV volumes at 1-year follow-up that were independent of infarct size.
Recently, we reported that the increase in LV volume after myocardial infarction was augmented in patients carrying the deletion allele of the ACE gene.4 Tiret et al3 showed that plasma ACE activity is increased in patients with this genotype. However, to our knowledge, a direct relation between the increase in LV volume and high plasma ACE activity has not been reported before. The precise mechanism by which high plasma ACE activity may lead to LV dilation is unclear. High ACE levels may result in activation of the renin-angiotensin system with subsequently increased levels of local angiotensin II and catecholamines.8 9 10 This may directly affect myocardial cells by stimulating cellular growth11 or interstitial fibrosis and indirectly by an adverse effect on hemodynamics.12
We did not find any confounding factor that could have explained the association between ACE activity and increased LV volume. No relationship between the level of ACE activity and the time to the first sample could be demonstrated. Also, subsequent treatment was similar in patients with high and low ACE activities. No statistically significant differences in the effect of captopril and placebo on the LV volume indexes 1 year after myocardial infarction could be demonstrated, probably because the power of the present subgroup of the initial study was too small.
In conclusion, elevated plasma ACE activity determined shortly after the onset of myocardial infarction may be a significant predictor of the development of LV dilation and may identify patients at risk.
Selected Abbreviations and Acronyms
|CATS||=||Captopril and Thrombolysis Study|
|LVEDVI||=||left ventricular end-diastolic volume index|
|LVESVI||=||left ventricular end-systolic volume index|
- Received February 10, 1997.
- Revision received April 21, 1997.
- Accepted April 23, 1997.
- Copyright © 1997 by American Heart Association
White HD, Norris RM, Brown MA, Brandt PWT, Withlock RML, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987;76:44-51.
Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81:1161-1172.
Kingma JH, van Gilst WH, Peels CH, Dambrink J-HE, Verheugt FWA, Wielenga RP, for the CATS Investigators. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction. Eur Heart J. 1994;15:898-907.
van der Laarse A, Kerkhof PLM, Vermeer F, Serruys PW, Hermens WT, Verheugt FW, Bar FW, Krans XH, van der Wall EE, Simoons ML. Relation between infarct size and left ventricular performance assessed in patients with first acute myocardial infarction randomized to intracoronary thrombolytic therapy or to conventional treatment. Am J Cardiol. 1988;61:1-7.
McAlpine HM, Morton JJ, Leckie B, Rumley A, Gillen G, Dargie HJ. Neuroendocrine activation after acute myocardial infarction. Br Heart J. 1988;60:117-124.
Nabel EG, Topol EJ, Galeana A, Ellis SG, Bates ER, Werns SW, Walton JA, Muller DW, Swaiger M, Pitt B. A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator therapy in acute myocardial infarction. J Am Coll Cardiol. 1991;17:467-473.