Therapeutic effects of captopril on ischemia and dysfunction of the left ventricle after Q-wave and...

American Heart Journal Founded in 1925

January 1994 Volume 127, Number 1

CLINICAL INVESTIGATIONS

Therapeutic effects of captopril on ischemia and dysfunction of the left ventricle after Q-wave and non-Q-wave myocardial infarction

Treatment with angiotensin-converting enzyme inhibitors has a beneficial effect on myocardial ischemia and left ventricular dysfunction after myocardial infarction. The effect of captopril on myocardial ischemia was evaluated in 58 patients with left ventricular dysfunction (ejection fraction <45%) after Q-wave or non-Q-wave myocardial infarction in a placebo-controlled, parallel, double-blind study. Patients were randomized on day 7 to either placebo or captopril (50 mg daily) and monitored for a period of 180 days by serial echocardiography and ambulatory ( ST-segment monitoring. There was a significant effect of captopril on the duration of ambulatory ST depression during the 180 days: The values per day were reduced from 28 f 5 min at baseline to 2 + 1 min on day 180 in the Q-wave group @ < 0.01) and from 39 k 10 min at baseline to 6 + 1 min on day 180 in the non-Q-wave group (p < 0.05). In the placebo group the duration of ST depression on day 180 were 21 + 8 min in the Q-wave group and 22 + 7 min in the non-Q-wave group, thus being significantly higher as compared with the corresponding captopril groups (p < 0.01 and p < 0.05, respectively). In the placebo Q-wave group there was a significant increase in left ventricular end-diastolic volume index from 74 f 3.5 to 89 k 4.5 ml/m* (p < 0.01) during the study period, which was in contrast to unchanged values of 75.5 k 3.0 and 75.0 + 3.5 ml/m* (not significant [NS]) in the captopril Q-wave group. There were no volume changes in either of the two non-Q-wave groups. In the Q-wave infarct group there was a positive correlation between the percentage changes in left ventricular end-diastolic volume index and the duration of ST depression (rho = 0.74, p < 0.001). There was no such correlation in the non-Q-wave group (rho = 0.19, NS). The results indicate an antiischemic effect of captopril mediated by prevention of left ventricular dilatation in Q-wave infarctions and an antiischemic effect independent of volume as demonstrated in non-Q-wave infarctions. Thus angiotensin-converting enzyme-inhibition should probably be used more widely after myocardial infarction. (AM HEART J 1994;127:1-7.)

Peter S#gaard, MD, Aage Nplgaard, MD, Carl-Otto Ggltzsche, MD, Jan Ravkilde, MD, and Kristian Thygesen, MD Aarhus, ‘Denmark

Clinical studies have shown, in recent years, a beneficial effect of treatment with angiotensin-converting enzyme (ACE) inhibitors on both myocardial remodeling and left ventricular (LV) function after Q-wave

From the Department of Medicine and Cardiology, Aarhus University Hos- pital.

Received for publication Feb. 3,1993; accepted May 3, 1993.

Reprint requests: Peter Sfigaacd, MD, Department of Medicine and Cardi- ology, Aarbus University Hospital, Tage Hansensgade 2-4,800O Aarhus C, DK-Denmark. Copyright :b 1994 by Mosby-Year Book, Inc. 0002.8703/94/$1.00 + .lO 4/l/50707

myocardial infarction (MI).lm3 In addition, a positive effect on myocardial ischemia and reinfarction have been shown in patient with either heart failure or postmyocardial infarction.4-6 However, the underly- ing mechanisms behind the antiischemic effect of ACE-inhibition are still unknown. Thus both an in- direct effect via prevention of LV dilatation and a direct effect mediated via different mechanisms, in- cluding inhibition of the local renin angiotensin system have been suggested. 4,6-g Therefore the aim of the present study was to determine whether the effect of the ACE inhibitor captopril on myocardial ischemia after MI depends on LV volume. This was

1

2 S#gaard et al. January 1994

American Hean Journal

Table I. Medication in the first week after myocardial infarction

Q-wave Non- MI Q-wave MI Placebo Captopril

(n = 41) (n = 17) (n = 29) (n = 29)

Streptokinase 36 11 24 23 Metoprolol 33 11 22 22 Diltiazem 5 5 6 4 Isosorbide 7 3 5 5

mononitrate Furosemide 29 7 16 20 Acetylsalicylic acid 41 17 29 29

Between-group comparisons were NS.

achieved by comparing the course of events in Q-wave and non-Q-wave MI, because these two entities are associated with differences in LV dilatation.lO, l1

METHODS Patient selection. Patients with an established diagno-

sis of MI based on World Health Organization criteria12 were included, providing they had an LV ejection fraction (EF) 545% on day 5 and were <70 years of age. Patients with a history of congestive heart failure and patients re- quiring an ACE inhibitor or digoxin were excluded. Fur- ther, patients with systolic blood pressure <lOO mm Hg, atria1 fibrillation, diseases of the heart valves, bundle branch block, heart aneurysm, severe systemic disease, and liver or kidney disease were also excluded. Patients sub- jected to invasive revascularization were excluded during follow-up, because such a procedure may affect the ischemia during the remainder of the follow-up period.13 All of the patients gave their informed consent after both oral and written information. The study was carried out in agreement with the Helsinki II declaration and was ap- proved by the regional Scientific Ethical Committee and the Danish National Board of Health.

Study design. Patients were randomized on the seventh day after MI to receive either captopril or placebo in a double-blind parallel trial. The dose of captopril was increased to 25 mg twice daily during a 2-week period. This medication was continued for the 180 remaining days of the trial period.

Measurements. Echocardiography (ECG) was carried out according to a standard procedure on day 5 after the onset of MI and repeated at all of the outpatient examinations on days 30,90, and 180. Patients lay in the left lateral position during the examination; echocardiographic recordings were obtained at the end of the expiratory phase during normal breathing and an apical four-chamber view was used. The LV end-diastolic volume was measured by using ECG triggered recordings at the onset of the QRS complex and the LV end-systolic volume at the end of the T wave. The single plain area length method14 was used for calculation of the volumes on the screen of the echocardio-

graph; the mean of three measurements were used. LV end-diastolic volume index ml/m3 (LVEDVI) and LV end- systolic volume index ml/m2 (LVESVI) were derived by using the surface area estimated. The interobserver coeffi- cient of variation (CV) was 2 %, and the intraobserver CV was 1.2% for repeated measurements of consecutive sam- ples.4

Twenty-four hours of calibrated ambulatory ECG monitoring with a Reynolds Tracker (Reynolds Medical, Hert- ford, U. K.) was carried out for the first. time on day 6 after MI and repeated at all of the outpatient examinations on days 30,90, and 180. ECG mapping was carried out before electrode positioning, and leads showing infarct related Q-waves, prolonged ST-segment deviation, and significant postural changes were discarded. Tapes were replayed un- der visual observation at 60 times the recording speed on a Reynolds Pathfinder 3ST connected to an ST scope. ST- segment depression was considered significant providing it was horizontal or downsloping with a duration of at least 1 min measured 80 msec after the J-point with a depression of at least 0.1 mV. All significant events were printed out for visual evaluation before final acceptance. ST-segment elevation and isolated changes in the T vector were not accepted as signs of ischemia.

Additional medication. Treatment with the throm- bolytic agent streptokinase and oral treatment during days 0 to 5 with low-dose acetylsalicylic acid, @-blockers, ni- trates, calcium antagonists, and diuretics followed the normal routine of the department; the use of additional medication is shown in Table I.

Statistical analyses. The baseline data were compared using the chi-squared test for categoric variables, and the unpaired t test for continuous variables. The effect of treatment within and between groups were tested by using the Kruskal-Wallis test. Correlation analyses were per- formed by using the Spearman test. A p value <0.05 was considered statistically significant. NS denotes values not statistically significant.

RESULTS Baseline evaluation. Fifty-eight patients completed

the study period of 180 days; 41 patients had Q-wave MIS and 17 patients non-Q-wave MIS. The demo-

graphic data did not differ between the Q wave and non-Q-wave MI groups apart from the distribution of men/women. There were major differences between the groups at baseline with respect to clinical data, as is seen in Table IIA. The LVEDVI was significantly higher and the EF significantly lower in the Q-wave MI group as compared with the non-Q-wave MI groups (p < 0.05 and p < 0.01, respectively). The mean peak creatine kinase-B U/L value was significantly higher in the Q-wave MI group (p < 0.05), whereas the amount of myocardial ischemia detected during ambulatory ST-segment monitoring was sig-

nificantly higher in non-Q-wave MI (p < 0.05). Clin-

volume 127, Number 1 American Heart Journal S~ggaard et al. 3

Table IIA. Demographic and clinical data at baseline

Q-waue Non-Q-wave MI MI

(n = 41) (n = 17) P Value

Men/women Age (yr) Height (cm) Weight (kg) Congestive heart fail-

ure (n) Peak CK-B (U/L) LVEDVI (ml/m2) Ejection fraction %

(W Ambulatory ST de-

pression (min)

40/l 13/4 59 + 2 59 f 2

177 + 2 174 + 3 81 + 2 80 k 4

29 I

93 + 9 60 + 11 75 f 2.5 65 * 3.5 37 c 0.6 41 f 1

27 zt 6.0 31 + 1.2

<0.05 NS NS NS NS

<0.05 -co.05 <O.Ol

<0.05

Data given as mean + SEM. CK-B, Creatine kinase-B.

ical and demographic data for the placebo and captopril groups are shown in Table IIB.

Echocardiography during follow-up. Both the LVEDVI and LVESVI increased significantly from day 7 to day 180 in the placebo Q-wave MI group, from 74 to 89 ml/m2 (22 % ) and from 46 to 54 ml/m2 (17 %), respectively (p < 0.01). In the captopril Q-wave group the LVEDVI remained constant at 75 ml/m2, but the LVESVI was reduced by 17 % from 47 to 39 ml/m2 (p < O.Ol), giving rise to a significant difference between the captopril and placebo groups in both LVEDVI and LVESVI at the completion of the study (p < 0.01) (Table III). No significant changes were observed in the non-Q-wave captopril and placebo groups, neither within nor between groups (Table III).

Ambulatory ischemia during follow-up. No significant difference was noted between captopril and placebo groups (both Q-wave and non-Q-wave groups) in the duration of ambulatory ST depression at baseline and day 30. Both the captopril non-Q-wave and Q-wave groups showed a significant reduction at the completion of the study in the amount of ischemia, from 39 to 6 min (p < 0.05) and from 28 to 2 min (p < O.Ol), respectively. These changes gave rise to a significant difference between captopril and placebo in the non-Q-wave groups (p < 0.05) and Q-wave groups (p < O.Ol), respectively, at the completion of the study (Table IV).

lschemic events during follow-up. Six reinfarctions were observed during the follow-up period; all oc- curred in the placebo group (p < 0.05 as compared with the captopril group). There was no significant difference in respect of the placebo Q-wave and non- Q-wave groups because there were three in each.

Table IIB. Demographic and clinical data at baseline in

placebo and captopril groups

Men/women (n) Age W Height (cm) Weight (kg) Congestive heart failure

h) Peak CK-B (U/L) LVEDVI (ml/m2) Ejection fraction % (EF) Ambulatory ST-depression

(min)

Placebo Captopril (n = 29) (n = 29)

2712 2613 58 k 2 60 k 2

176 * 2 175 tr 3 83 + 2 77 + 4

16 20

86 + 9 82 + 11 71 i- 3.5 73 + 3.3 40 f 0.6 39 t 1 30 t 6.0 32 f 5.2

Data given as mean ? SEM. Between-group comparisons are NS. CK-B, Creatine kinase-B.

Correlation between LV volume and ischemia. There was a positive correlation in the Q-wave MI group between the changes in duration of ambulatory ST depression and the percentage changes in LVEDVI from day 30 to day 180 (rho = 0.74, p < 0.001) (Fig. 1, A). There was no such correlation in the non-Q- wave MI group (rho = 0.19, NS) (Fig. 1, B).

DISCUSSION

Q-wave and non-Q-wave Ml. Several studies have shown that there are major differences between Q-wave and non-Q-wave MI.15-16 Patients suffering a Q-wave MI have considerably more myocardial dam- age with a subsequent greater loss of viable myocardium, lower EF, and a higher frequency of congestive heart failure.16 In contrast, patients who have a non- Q-wave MI are more likely to experience recurrent ischemia than their Q-wave counterparts.16

LV volumes after Ml. When larger parts of the left ventricle are damaged after MI, stretching and remodeling occurs with progressive dilatation of the ventricle17; previous studies have shown that this process begins during the early phase after MI.1° Di- latation of the left ventricle after MI is the forerun- ner to congestive heart failure and a predictor of poor survival.ls, lg

Our results confirm that patients with a non-Q- wave MI, although having reduced LV function, do not undergo extensive remodeling of the heartll; this could be the result of a higher frequency of patent infarct-related coronary arteries in this type of MI. In addition, we found that the process of remodeling in patients with Q-wave MI begins during the early phase,lO as demonstrated by the significant difference in volumes at baseline. Finally we found, as

4 S4gaard et al. January 1994

American Heatl Journal

Table III. LV volumes during follow-up

Baseline 30 Days 90 Days 180 Days

LVEDVI ml/m2 Placebo Q-wave MI (n = 21) Captopril Q-wave MI (IZ = 20) Placebo non-Q-wave MI (n = 8) Captopril non-Q-wave MI (n = 9)

LVESVI ml/m2 Placebo Q-wave MI Captopril Q-wave MI Placebo non-Q-wave MI Captopril non-Q-wave MI

Data given as mean + SEM. *p < 0.01.

74 f 3.5 75 -t 3.0 64 + 3.7 67 k 4.1

46 k 2.4 47 + 2.6 37 f 2.7 41 +- 2.9

77 k 3.8 84 + 4.2 76 + 2.5 75 * 3.0 65 + 3.6 66 + 3.2 67 k 3.0 68 k 3.2

48 f 2.9 50 f 3.2 45 k 2.5 41 of: 2.3 38 + 2.9 38 + 3.1 40 k 2.6 38 k 2.5

89 f 4.5* * 75 It 3.5 I 66 e 3.5 67 + 3.1

54 rt 3.4* * 39 + 2.5* I 38 f 3.1 37 t 2.7

Table IV. ST depression during 24-hour ambulatory monitoring

Duration (min.)

Placebo Q-wave MI Captopril Q-wave MI

Placebo non-Q-wave MI Captopril non-Q-wave MI

Data given as mean f SEM *p < 0.01. **p < 0.05.

Baseline

21 t 7 28 t 5

36 IL 6 39 f 10

Day 30

11 z!z 7 9+4

21 + 6 20 t 5

Day 90

20 * 7 5+2

21 k 5 9+2

Day 180

21k8 * 2 t 1* I

**

22k7 I 6 + l**

Sharp et a1.2 and Pfeffer et a1.3 that the progressive dilatation of the heart in Q-wave MI was prevented by captopril. A reduction in preload and afterload with a following reduction in wall stress, in combina- tion with effects on the local renin angiotensin system, are probably responsible for the combined result on myocardial remodeling.

The LVESVI was significantly reduced in the captopril Q-wave group; there was also a trend toward a reduction in the captopril non-Q-wave group. That the latter was nonsignificant may be the result of the low number of patients. The stroke volume was increased without loss of volume control, and we conclude that the systolic function was improved, presumably as a result of a reduction in afterload.

Myocardial ischemia after MI. Myocardial ischemia is the result of an imbalance between myocardial oxygen requirement and supply and indicates stenosis of the coronary arteries or infarct extension after re- occlusion. Holter monitoring is a noninvasive method of evaluating myocardial ischemia in patients with ischemic heart disease via analysis of spontaneous ST-segment depression during normal daily activity; there are, however, factors that can affect the ST-

segment analysis with an increased risk of false-positive findings. 2o We have attempted to avoid these factors by means of ECG mapping before the choice of the electrode positioning. Thus we have eliminated leads with Q-waves, infarct-related ST-segment de- viations, and significant postural-induced ST-segment changes. Further, patients with intraventricu- lar block, patients with signs of hypertrophy of the LV, and patients receiving treatment with digoxin have been excluded from the investigation.

The presence of ST-segment depression during Holter monitoring plays a considerable role in the prognosis of patients with unstable angina pectoris.21, 22 The reported prevalence of ST-segment depression during ambulatory monitoring of postin- farct patients have varied considerably,4, 23-24 but a clear relationship between the presence of ST-segment depression and short- and long-term prognosis has been demonstrated.24, 25 In addition, in the present study and previously it has been demonstrated that there is an increased severity of ambulatory ischemia in patients who have survived a non- Q-wave MI.26

Angiotensin II is a potent vasoconstrictor of both

Volume 127, Number 1

American Heart Journal S$gaard et al. 5

B

Percentage changes in EDVI from day 30 to day 180 after Q-wave MI

2 40-

gc -‘s .

E@ 20- z L ms 26 e

, .

?S 1

ti: O------ -----.,*.-I-*--:-------------------

.: . 5P i l

m E 00 .; co -20 - I lo’ , .

2% =zi I

5s I I J-

i%O -40 I 1 I I 1

c* -10 -5 0 5 10 15 m>. 63 Percentage changes in EDVI from day 30

to day 180 after non Q-wave MI

Fig. 1. A, Correlation between percentage changes in LVEDVI and changes in ST-segment depression (minutes) from day 30 to day 180 after Q-wave MI (rho = 0.74, p < 0.001, n = 41). B, Correlation between percentage changes in LVEDVI and changes in ST-segment depression (minutes) from day 30 to day 180 after non-Q-wave MI. arrow, Coordinate of +3, -85 (rho = 0.19, not significant, n = 17).

the coronary and systemic arteries, and ACE inhib- captopril has an effect on infarct size, explained via itors prevent to a certain extent the formation of an- an increased coronary perfusion, especially of the is- giotensin ILz7 A beneficial effect of captopril on the chemic area.2g The effect on the peripheral circula- coronary circulation has been demonstrated in ex- tion causes a reduction in both the preload and perimental studies. 28 It has also been shown that afterload and thus decreases the myocardial work-

6 @guard et al.

load. This decrease in workload produces a decrease in the myocardial oxygen demand and a fall in blood pressure without a reflectory increase in heart rate, leading to reduced myocardial oxygen consump- tion.2g7 3o Thus there appears to be indications that there is an antiischemic effect of ACE inhibition mediated via hemodynamic effects on the oxygen supply and demand of the myocardium. However, several less extensive clinical studies have shown conflicting results30-33; in particular, Cleland et a1.31 found that captopril treatment of patients with heart failure and angina caused more severe angina. As a result of the short duration of the study it is, however, most likely that the results observed merely reflect the results of an acute reduction in blood pressure in patients with increased levels of renin. In contrast, captopril given to post-MI patients with LV dysfunction does not have its effect via direct reduction in blood pressure.4 Further, we were unable to demonstrate any acute antiischemic effect resulting from captopril interven- tion; this is supported by earlier findings30 and is in complete agreement with more extensive investigations where the effect of treatment with an ACE inhibitor on acute myocardial ischemic syndromes (fa- tal-nonfatal MI and unstable angina) can first be demonstrated after several months of treatment.5a 6

Further, we have previously demonstrated that the process of myocardial remodeling is closely related to the ischemic burden in post-MI patients with a significant correlation between the percentage changes in LVEDVI and the amount of ischemia detected during 24 hours of ambulatory ST-segment monitoring.4 This is probably the result of an increased myocardial oxygen demand. ACE inhibitor treatment reduces the end-diastolic pressure of the left ventri- cle3; as a result, the diastolic function and coronary perfusion are improved; in turn, ischemia is reduced. We have previously observed that captopril treatment prevents the development of diastolic dysfunction in both Q-wave and non-Q-wave post-MI patients.l This too will probably contribute to an additional reduction in myocardial ischemia.

We observed a significant effect of captopril on the amount of myocardial ischemia in both Q-wave and non-Q-wave MI. With respect to Q-wave MI the antiischemic effect of captopril is presumably, to a great extent, a result of interference in LV remodeling as demonstrated by the positive correlation between volume changes and the duration of ischemia; however, the effect observed in the captopril non-Q-wave MI group, where no association between LV volume changes and the amount of ST-depression was seen, indicates that captopril also has an antiischemic ef-

January 1994 American Heart Journal

feet per se. This effect could be mediated via a beneficial hemodynamic effect as mentioned earlier, but other factors, such as an effect on thrombocyte function and vascular remodeling, could also play a part. 34-36 Finally, the distribution of reinfarctions in the study supports the assumption that captopril has a beneficial effect on the myocardial oxygen requirement and supply.

Clinical implication. The administration of captopril to patients with reduced LV function after MI has a beneficial effect both on the amount of ischemia and the LV function. The results indicate an antiischemic effect of captopril, mediated by prevention of LV dilatation in Q-wave MI and an antiischemic effect independent of volume as demonstrated in non-Q- wave MI. Thus ACE inhibition should probably be used more widely after MI.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

G#tzsche C-O, S#ogaard P, Ravkilde 3, Thygesen K. Effects of captopril on left ventricular systolic and diastolic function after acute myocardial infarction. Am J Cardiol1992;70:156-60. Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G. Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting enzyme inhibitor. Lancet 1991;337:872-6. Pfeffer MA, Lamas GA, Vaughan DE, Paresi AF, Braunwald E. Effects of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 319:80-6. S$gaard P, G$tzsche C-O, Ravkilde J, Thygesen K. Effects of captopril on ischemia and dysfunction of the left ventricle after myocardial infarction. Circulation 1993;87:1093-9. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddv TE. Davis BR. Geltman EM. Goldman S. Flaker GC. Klein”M, Lamas GA, Packer M, Rouleau 3, Rouieau JL, Ru: therford J, Wertheimer JH, Hawkins CM. Effects of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992; 327569-71. Yusuf S, Pepine CJ, Garces C, Pouleur H, Jaleem 0, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fraction. Lancet 1992;340:1173-8. Ertl G. Angiotensin-converting enzyme inhibition and is- chaemic heart disease. Eur Heart J 1988;9:716-27. Schultheiss HP, Ullrich G, Schindler M, Schultze K, Strauer BE. The effect of ACE inhibition on myocardial energy metabolism. Eur Heart J 1990;11(suppl B):116-22. Przyklenk K, Kloner A. Relationships between structure and effects of ACE inhibitors: comparative effects in myocardial ischemic/reperfusion injury. Br J Clin Pharmacol1989;28:167- 75. Eaton LW, Weiss JL, Bulkley BH, Garrison JB, Weisfeldt ML. Regional cardiac dilatation after acute mvocardial infarction. N Engl J Med 1979;300:57-62. Hutchins GM, Bulkley BH. Infarct expansion versus extension: Two different complications of acute myocardial infarction. Am J Cardiol 1978;41:1127-32. World Health Organization. Report on the fifth working group on the establishment of ischemic heart disease registers. Copenhagen: WHO Regional Office for Europe, 1971. Egstrup K. Asymptomatic myocardial &hernia as a predictor

Volume 127, Number 1

American Heart Journal @guard et al. 7

14.

15.

16.

17.

18.

19.

20.

21.

22.

of cardiac events after coronary bypass grafting for stable angina. Am J Cardiol 1988;61:248-52. Wahr DW, Wang YS, Schiller NB. Left ventricular volumes determined by two-dimensional echocardiography in normal adult population. J Am Co11 Cardiol 1983;1:863-8. Maisel AS, Ahnve S, Gilpin E, Henning H, Goldberger AL, Collins D, Lewinther M, Ross J Jr. Prognosis after extension of myocardial infarction: the role of Q-wave or non-Q-wave infarction. Circulation 1985;71:211-7. Berger CJ, Murabito JM, Evans JC, Anderson KM, Levy D. Prognosis after first myocardial infarction. Comparison of Q-wave and non-Q-wave myocardial infarction in the Framing- ham Heart Study: JAMA i992;268:1545-51. Gaudron P. Eilles C. Ertl G. Koschsiek K. Comnensatorv and noncompensatory left ventricular dilatation after myocardial infarction: time course and hemodynamic consequences at rest and during exercise. AM HEART J 1992;123:377-85. White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;‘76:44-51. Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial infarction: the Framingham study. Am J Cardiol 1979;44:53-9. Kennedy HL. Ambulatory electrocardiography strategies used in assessing silent myocardial ischaemia. Eur Heart J 1988: S(supp1 Nfi70-7. Johnson SM. Mauritson DR. Winniford MD. Willerson JT. Firth BG, dary JR, Hillis ‘LD. Continuous electrocardio: graphic monitoring in patients with unstable angina pectoris: identification of high-risk subgroup with severe coronary disease, variant angina, and/or impaired early prognosis. AM HEART J 1982;103:4-12. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits D, Gerstenblith G. Silent ischemia predicts infarction and death during 2-year follow-up of unstable angina. J Am Co11 Cardiol 1987;10:756- 60.

23.

24.

Mickley H, Pless P, Nielsen JR, Berning J, M$ller M. Throm- bolysis significantly reduces transient myocardial ischaemia following first acute myocardial infarction. Eur Heart J 1992;13:484-90. Ouyang P, Chandra NC, Gottlieb SO. Frequency and impor- tance of silent mvocardial ischaemia identified with ambulatory electrocardiographic monitoring in the early in-hospital period after acute myocardial infarction. Am J Cardiol 1990;65:267-70.

25. Gottlieb SO, Gottlieb SH, Achuff SC, Baumgardner R. Mel-

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

lits ED, Weisfeldt ML, Gerstenblith G. Silent ischemia on Holter monitoring predicts mortality in high-risk post-infarction patients. JAMA 1988;259:1030-5. Mickley H, Pless P, Nielsen JR, M@ler M. Residual ischaemia in first non-Q-wave versus Q-wave infarction: maximal exercise testing and ambulatory ST-segment monitoring. Eur Heart J 1993;14:18-25. Tarazi RC, Zanchetti A. Prospectives for angiotensin-convert- ingenzyme inhibition in heart disease. J Hvnertens 1985:3(sun- p12):99-103. van Gilst WH, de Graeff PA, de Leeuw MJ, Scholtens E, Wes- seling H. Converting enzyme inhibitors and the role of the sulfhydryl group in the potentiation of exogenous and endo- genous nitrovasodilators. J Cardiovasc Pharmacol 1991;18: 429-36. Ertl G, Kloner RA, Alexander RW, Braunwald E. Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor. Circulation 1982;65:40-8. Dalv P. Mettauer B. Rouleau JL. Cousinaeu D. Bureess JH. Lack of reflex increase in myocardial sympathetic tone after captopril: potential antianginal effect. Circulation 1985;2:317- 25. Cleland JGF, Henderson E, McLenachan J, Findlay IN, Dargie HJ. Effect of captopril, an angiotensin-converting enzyme inhibitor, in patients with angina pectoris and heart failure. J Am Co11 Cardiol 1991;17:733-9. Gibbs JSR, Crean PA, Mockus I, Wright C, Sutton GC, Fox KM. The variable effects of angiotensin-converting enzyme inhibition on myocardial ischaemia in chronic stable angina. Br Heart J 1989;62:112-7. Tzivoni D, Gottlieb S, Khurmi NS, Medina A, Gavish A, Stern S. Effect of benazepril on myocardial ischaemia in patients with chronic stable angina pectoris. Eur Heart J 1992;13:1129- 34. James IM, Dickenson EJ, Gurgoyne W, Jeremy JY, Barradas MA, Mikhailidis DP, Dandona P. Treatment of hypertension with captopril: preservation of regional blood flow and reduced platelet aggregation. J Hum Hypertens 1988;2:21-5. Kiowski W, Zuber M, Elsasser S, Erne P, Pfisterer M, Burkart F. Coronary vasodilatation and improved myocardial lactate metabolism after angiotensin-converting enzyme inhibition with enalapril in patients with congestive heart failure. AM HEART J 1991;122:1382-8. Ontkean MT, Gay R, Greenberg B. Effects of chronic captopril therapy on endothelium-derived relaxing factor activity in heart failure. J Am Co11 Cardiol 1992;19(suppl Al:768-74.

Therapeutic effects of captopril on ischemia and dysfunction of the left ventricle after Q-wave and...

Documents

Transcript of Therapeutic effects of captopril on ischemia and dysfunction of the left ventricle after Q-wave and...