Download The effect of angiotensin converting enzyme inhibition on

European Journal of Cardio-thoracic Surgery 13 (1998) 42 – 48
The effect of angiotensin converting enzyme inhibition on myocardial
function and blood pressure after coronary artery bypass surgery— a
randomised study
Carolyn M. Webb a, Richard Underwood b, Constantinos Anagnostopoulos b,
J. Graeme Bennett c, John Pepper c, Christopher Lincoln c, Peter Collins a,*
a
Di6ision of Cardiac Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, Do6ehouse Street,
London SW2 6LY, UK
b
Department of Nuclear Medicine, Royal Brompton Hospital, London, UK
c
Department of Cardiothoracic Surgery, Imperial College School of Medicine at the National Heart and Lung Institute,
Royal Brompton Hospital, London, UK
Received 24 June 1997; received in revised form 6 October 1997; accepted 21 October 1997
Abstract
Objectives: To investigate the effect of 6 weeks’ pre-operative treatment with the angiotensin converting enzyme inhibitor,
quinapril, on left ventricular function when measured 3 months after coronary artery bypass graft surgery and to examine the
safety of such treatment. Patients and methods: Patients (96) (86 males, 10 females; mean age 61 years) with chronic stable angina,
on the waiting list for coronary artery bypass graft surgery, underwent measurement of left ventricular function by resting
radionuclide ventriculography. Patients were then randomised to quinapril 20 mg once daily or placebo in a double-blind fashion,
in addition to existing anti-anginal therapy and this regimen was continued for up to 6 weeks prior to operation. Measurement
of left ventricular function was repeated 3 months following surgery, after recommencement of pre-surgery anti-anginal therapy
for 1 week. Effects on systemic vascular resistance (SVR) during bypass were calculated from perfusion records and vasoconstrictor use during operation was documented. The safety of the addition of quinapril to the anti-anginal regimen was assessed by
measurement of systemic blood pressure (BP) after the first dose of study medication, measurement of intra-operative BP,
administration of inotropes and any intra-operative complications. Results: There was no difference between treatment groups in
the pre-study left ventricular ejection fraction (mean (S.D.); 54.9 (13.8)% versus 55.6 (13.2)%, quinapril versus placebo,
respectively), or 3 months after surgery (58.1 (13.6)% versus 56.9 (12.6)%, quinapril versus placebo, respectively). Left ventricular
ejection fraction 3 months after surgery did not change significantly from pre-treatment in either group (2.8 (10.7)% and 1.5
(10.1)%; quinapril and placebo, respectively). There was no first-dose hypotension (systolic BP B 100 mmHg). The intra-operative
BP and the SVR during bypass in the two treatment groups were not significantly different. The ischaemic time (mean =56 min)
and the use of inotropes were the same in both groups and there was no mortality. Conclusions: Angiotensin converting enzyme
inhibitor treatment before coronary artery bypass graft surgery does not have a significant beneficial effect on left ventricular
function following coronary artery bypass graft surgery. Angiotensin converting enzyme inhibition, administered in addition to
anti-anginal therapy, does not cause first-dose hypotension or increase morbidity or mortality and can safely be used in patients
with coronary heart disease prior to coronary artery bypass graft surgery. © 1998 Elsevier Science B.V.
Keywords: Angiotensin converting enzyme-inhibitors; Revascularisation; Left ventricular function; Blood pressure
* Corresponding author. Tel.: +44 171 3518112; fax: + 44 171 8233392.
1010-7940/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved.
PII S 1 0 1 0 - 7 9 4 0 ( 9 7 ) 0 0 2 8 4 - 4
C.M. Webb et al. / European Journal of Cardio-thoracic Surgery 13 (1998) 42–48
1. Introduction
Coronary artery bypass grafting is an accepted and
widely used method of treating patients with coronary
artery disease (CAD), relieving angina in over 85% of
cases [1,2]. Conflicting data exist on the effect of coronary artery bypass graft surgery on left ventricular
function, with studies showing improvement, no change
or deterioration [3– 5]. Left ventricular function is a
potent predictor of patient survival for patients with
CAD [6] and is also a major determinant of prognosis
after coronary artery bypass graft surgery [2]. In the
coronary artery surgery study (CASS) improvement in
survival achieved by surgical revascularisation occurred
primarily in patients with impaired left ventricular function [7]. Improvement of left ventricular function following coronary artery bypass graft surgery may, therefore,
beneficially affect postoperative morbidity and mortality.
There have been no studies to assess the effect of drug
therapy on left ventricular function before and after
coronary artery bypass graft surgery. Angiotensin converting enzyme inhibitors are accepted therapies for
hypertension and heart failure, have been shown to
improve myocardial function in patients with heart
failure [8,9] and after myocardial infarction [10 – 15] and,
therefore, could have a beneficial effect in improving left
ventricular function after coronary artery bypass graft
surgery. Experimental data show that angiotensin converting enzyme inhibition can reduce infarct size in dogs
[16]. In this study captopril increased regional myocardial blood flow in the area of infarction, decreased mean
arterial pressure and decreased left atrial pressure. Animals treated with captopril had smaller infarct size
compared to placebo-treated animals. The favourable
action of captopril was attributed to the increase in
perfusion of ischaemic tissues as well as to the reduction
in pre-load and after-load. Angiotensin converting enzyme inhibitors may, therefore, offer a cardioprotective
effect to patients who experience a myocardial ischaemic
event whilst taking the drug.
Discrete episodes of ischaemia which are insufficient
to jeopardise the viability of the tissue may impair
myocardial function permanently or for as long as
myocardial perfusion is inadequate. The improvement of
left ventricular function after coronary artery bypass
graft surgery may be improved further by angiotensin
converting enzyme inhibition which is started before
operation. Datasheets on angiotensin converting enzyme
inhibitors call for caution in patients on angiotensin
converting enzyme inhibitors undergoing major surgery
with regard to peri- and post-operative hypotension.
Therefore, the purpose of this study was 2-fold; firstly to
investigate the effect of pre-operative treatment with
quinapril (a non-sulphydryl containing angiotensin converting enzyme inhibitor) on left ventricular function
43
before and after patients underwent coronary artery
bypass graft surgery and secondly to examine the effect
on blood pressure (BP) and SVR during cardiopulmonary bypass and the safety of such treatment.
2. Patients and methods
2.1. Patients
Patients with chronic stable angina (with no myocardial infarction within the previous 6 months) and not
currently taking an angiotensin converting enzyme inhibitor were recruited from the routine list for coronary
artery bypass graft surgery at the Royal Brompton
Hospital. Patients were included only if they were having
first-time coronary artery bypass graft surgery with no
underlying valvar or congenital heart disease. Written
informed consent was obtained from all patients, following the Royal Brompton Hospital Ethics Committee
guidelines. Medical history, physical examination and
routine blood tests were performed.
2.2. Study design
Left ventricular function (left ventricular ejection fraction (%)) was measured by a resting radionuclide ventriculogram. Eligible patients were then randomised to
receive an angiotensin converting enzyme inhibitor,
quinapril 20 mg once daily (Accupro, Parke Davis) or
placebo in a double-blind fashion, in addition to existing
anti-anginal therapy. The study treatment was continued
for up to 6 weeks prior to operation, with the final day
of treatment being the morning of surgery. After recommencement of pre-operative anti-anginal therapy for 1
week, left ventricular function assessment was repeated
3 months following surgery. Cardioprotection used during surgery was dependent on the surgeon; either blood
cardioplegia via the perfusion pump or St. Thomas’
crystalloid via the aortic root and hypothermia to
20–32°C.
2.3. Left 6entricular function measurement
Equilibrium radionuclide ventriculography was performed following in vivo erythrocyte labelling with 740
MBq technetium-99m pertechnetate. A large field of
view g camera (Sopha Medical, Buc, France; model
DS7) was used with a low energy all purpose collimator
to acquire a 16 frame ventriculogram in a left anterior
oblique projection optimised for best separation of the
left and right ventricles and with 15° of caudal tilt.
Electrocardiographic gating was used with rejection of
cycles following one with an RR interval outside 15% of
the mean. Acquisition was terminated at a total of 5
million counts. The left ventricle was identified auto-
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C.M. Webb et al. / European Journal of Cardio-thoracic Surgery 13 (1998) 42–48
matically using the end diastolic, end systolic, phase
and amplitude images, with manual correction if necessary. Background activity was estimated as 95% of the
lowest pixel within the end diastolic region of interest.
Left ventricular ejection fraction was calculated from
the background corrected activity-time curve generated
from the raw image data.
2.4. Assessment of safety
The first dose of study medication was administered
in hospital and systemic BP was measured at halfhourly intervals for 2 h for detection of first-dose
hypotension (systolic BPB100 mmHg). Patients suffering first-dose hypotension were excluded from the
study. Arterial BP was monitored constantly throughout and following surgery. For analysis we documented
the first four BPs after induction of anaesthesia (baseline), first four BPs immediately after cessation of bypass (post-bypass) and first four hourly BPs in the
intensive care unit (ITU). The four recordings at each
stage were then averaged. Details of number and type
of grafts, administration of inotropes and vasoconstrictors and any intra-operative complications were documented.
2.5. Systemic 6ascular resistance during
cardiopulmonary bypass
Mean arterial and venous BPs and pump flow data
were documented every 10 min on bypass to allow for
calculation of systemic vascular resistance (SVR) during
cardiopulmonary bypass. SVR was calculated using the
formula: SVR= ((mean arterial pressure − central
venous pressure)/cardiac output (pump flow))× 80 [17].
SVR was plotted against time for each patient and
the slopes of the regression lines were analysed using
ANOVA. Vasoconstrictors used during surgery were
documented.
their characteristics are described in Table 1. Patient 1
had one diseased coronary artery (placebo), 21 patients
had two-vessel disease (7 quinapril, 14 placebo) and 74
patients had three-vessel disease (40 quinapril, 34
placebo). Of these patients, 83 completed revascularisation whilst enroled in the study and 79 completed the
study. All patients completed assessment of left ventricular function by resting radionuclide ventriculography.
Patients (12) (7 quinapril, 5 placebo) were withdrawn
because their study medication ran out before surgery
could be performed and 1 patient was withdrawn due
to hypotension before the study medication was administered. Therefore, 83 patients (75 males, 8 females;
mean age 61 years) were included in efficacy analysis. A
further 4 patients withdrew during the 3 month followup period for personal reasons and post surgery left
ventricular ejection fraction assessments are not available for these patients.
3.2. Left 6entricular function
There was no difference between treatment groups in
the pre-study left ventricular ejection fraction (mean
(S.D.); 54.9 (13.8)% versus 55.6 (13.2)%, quinapril versus placebo, respectively), or 3 months after surgery
(58.1 (13.6)% versus 56.9 (12.6)%, quinapril versus
placebo, respectively). Left ventricular ejection fraction
3 months after surgery did not change significantly
from pre-treatment in either group (2.8 (10.7)% versus
1.5 (10.1)%; quinapril versus placebo, respectively).
Patients (7) had baseline left ventricular ejection fraction 5 35%. The changes in left ventricular ejection
fraction in quinapril treated patients (+ 29%, +22%,
+ 7%) compared to placebo (+ 14%, + 11%, 0%, −
8%) demonstrated a trend towards a post-operative
Table 1
Patient characteristics
Characteristic
Quinapril
(n =47)
Placebo
(n = 49)
Mean age (years)
Range
Sex
Male
Female
Hyperlipidaemia
Diabetes mellitus
Mean duration of angina
(years)
Range
Previous MI
Previous PTCA
Concomitant anti-anginal
Rx
B-blocker
Calcium antagonist
Long-term nitrate
62
44 – 78
61
39 – 77
43
4
15
1
4
43
6
13
1
6
0.2 – 27
18
2
0.4 – 24
17
0
32
34
28
35
30
35
2.6. Statistical analysis
Statistical analysis was carried out using the SAS
statistical package. Efficacy data was analysed using
analysis of covariance (ANCOVA). Intra-operative BPs
and systemic vascular resistance were analysed using
analysis of variance (ANOVA). P 50.05 as considered
statistically significant.
3. Results
3.1. Patients
Normotensive patients (96) (86 males, 10 females;
mean age 61 years) were randomised to treatment and
C.M. Webb et al. / European Journal of Cardio-thoracic Surgery 13 (1998) 42–48
45
Table 2
Operative mean BP recordings (mmHg)
Blood pressure
Baseline
Post-op
ITU
Quinapril
Placebo
Systolic
Diastolic
Mean
Systolic
Diastolic
Mean
110
85
110*
68
50
60
79
64
77*
112
88
120
70
53
64
79
67
82
* Indicates significant difference between quinapril and placebo (PB0.05).
improvement in left ventricular ejection fraction, however, this was not statistically significant.
3.3. Assessment of safety
There was no first-dose hypotension. Patients (65)
had complete records of intra-operative and immediate
post-operative BP readings (30 patients on quinapril
and 35 patients on placebo; Table 2). There was no
difference in BP between quinapril and placebo at
baseline or immediately after bypass. However, there
was a significant difference between groups in systolic
and mean BP in ITU (P B0.05). There was no significant difference between treatment groups in the requirement of inotropes (Table 3). The surgical
complications are presented in Fig. 1. The ischaemic
time was the same in both groups (range, 19 – 117 min;
quinapril mean, 57 min; placebo mean, 56 min) and
there was no significant difference in the number of
grafts applied or length of stay in ITU (Figs. 2 and 3,
respectively).
3.4. Systemic 6ascular resistance during
cardiopulmonary bypass
There was no difference in SVR during bypass at any
time point in the 82 patients with evaluable data. The
trend in SVR over time was not significantly different
in the treatment groups. The mean slope of the regression lines for patients receiving quinapril was − 2.01
and for patients receiving placebo was − 2.08 (P=
0.94). There was no difference in the use of vasoconstrictors during surgery between treatment groups.
4. Discussion
In the present study, left ventricular function 3
months after surgery was unaffected by the addition of
an angiotensin converting enzyme inhibitor to pre-operative anti-anginal therapy. Angiotensin converting enzyme inhibitor treatment tended to have a more
beneficial effect in the group of patients with left ventricular ejection fraction 5 35%, although the number
of patients in this group was too small to demonstrate
a significant effect. In the CONSENSUS-I study [8],
patients with NYHA class IV given enalapril after
anterior myocardial infarction demonstrated a favourable effect on left ventricular dilatation during a
1-year follow-up. The CASS study [7] demonstrated an
improvement in survival achieved by surgical revascularisation, occurring primarily in patients with impaired
left ventricular function. Patients with impairment of
left ventricular function pre-operatively may, therefore,
gain more benefit from administration of pre-operative
angiotensin converting enzyme inhibitor treatment than
those with normal left ventricular function. The majority of patients enroled in this study had normal pre-operative ejection fraction and this may explain the
negative result with regard to left ventricular function.
The preservation on myocardial function after surgery
may also reflect the choice of myocardial preservation
used during surgery; the type of cardioprotection used
and the mean ischaemic times did not differ between
treatment groups.
Table 3
Inotropic support
Number of inotropes
Quinapril
Placebo
0
1
2
3
4
23
14
1
1
1
23
14
5
0
0
All P= NS.
Fig. 1. Surgical complications for patients randomised to quinapril or
placebo. All P=NS.
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C.M. Webb et al. / European Journal of Cardio-thoracic Surgery 13 (1998) 42–48
Fig. 2. Number of bypass grafts received for patients randomised to
quinapril or placebo. All P =NS.
The angiotensin converting enzyme inhibitor was administered before the ischaemic event (i.e. surgery) in
the present study, whereas, in all the studies of angiotensin converting enzyme inhibition in myocardial
infarction and heart failure the angiotensin converting
enzyme inhibitor was by definition given after the ischaemic event, or after the development of heart failure. Similarly, by giving an angiotensin converting
enzyme inhibitor before surgery we were attempting to
attenuate potential peri-operative myocardial damage
regardless of pre-operative left ventricular function.
We have demonstrated that angiotensin converting
enzyme inhibition may be used safely before coronary
artery bypass graft surgery in conjunction with other
anti-anginal drugs. This statement is based on our
finding that there was no difference in incidence of
hypotension during cardiac anaesthesia in patients randomised to either quinapril or placebo, no difference in
ischaemic time during surgery and no difference in
mortality. In the immediate post-operative hours the
quinapril treated group had lower systemic BP, but
there was no difference between treatment groups in the
requirement of inotropic support or post-operative outcome.
Myocardial ischaemia activates the renin-angiotensin
system, which results in increased production of the
Fig. 3. Length of post-surgical stay in the ITU. All P= NS.
potent vasoconstrictor and positive inotrope, angiotensin-II, via the conversion of angiotensin-I by
angiotensin converting enzyme. Increased angiotensinII levels may thus further the imbalance between oxygen supply and demand during myocardial ischaemia.
Inhibiting the conversion of angiotensin-I to angiotensin-II with an angiotensin converting enzyme inhibitor may, therefore, be beneficial to patients when
administered soon after an ischaemic event. A causative
relationship has been suggested between angiotensin-II
levels and vasoconstriction during non-pulsatile cardiopulmonary bypass. Peripheral vascular resistance
has been observed to increase progressively during the
perfusion period of operation and persists for the first
few hours of the post-operative period, an effect which
may be due to effects on the renin-angiotensin system.
Cardiopulmonary bypass increases plasma renin levels
and activity [18,19], increase angiotensin-I [18] and
angiotensin-II levels in animals [20]. Similar results
have been demonstrated in humans, where a highly
significant correlation was shown between increases in
peripheral vascular resistance index and angiotensin-II
levels during cardiopulmonary bypass [21]. Treatment
with an angiotensin converting enzyme inhibitor 2 h
after bypass in dogs has been shown to decrease peripheral vascular resistance index and angiotensin-II levels
compared to control animals [22]. Angiotensin-II specifically reduces subendocardial blood flow [23]. This,
together with the potent vasoconstrictor action of angiotensin-II, may tend to reduce left ventricular function. Specific angiotensin-II blockade by angiotensin
converting enzyme inhibition may, therefore, be cardioprotective via blockade of coronary vasoconstriction,
enhancing myocardial perfusion in addition to reducing
after-load. However, in the present study no significant
rise in SVR with time on bypass was demonstrated in
either treatment group. Angiotensin levels were not
measured.
The important haemodynamic effects of angiotensin
converting enzyme inhibitors have been comprehensively investigated, mainly with captopril [10–16,24].
Ertl et al. [16] reported a potent effect of angiotensin
converting enzyme inhibition on reduction of infarct
size in dogs after coronary occlusion and hypothesised
that this was due to increased collateral flow to the
ischaemic zone and reduction of after-load. Captopril
exerted a reduction in myocardial damage in a pig
model after coronary occlusion then reperfusion for 1 h
[24]. The mechanism of myocardial protection by captopril versus placebo was investigated in humans,
added to cardioplegia solution during coronary artery
bypass graft surgery [25]. Blood samples taken throughout the surgical procedure demonstrated no difference
in adrenaline levels but a significant decrease in noradrenaline and creatinine kinase and a non-significant
increase in angiotensin-I levels in patients given capto-
C.M. Webb et al. / European Journal of Cardio-thoracic Surgery 13 (1998) 42–48
pril. The latter suggests blockade of angiotensin converting enzyme and a decrease in angiotensin-II levels.
Since local or systemic angiotensin-II influences coronary vascular tone and coronary flow, decreasing angiotensin-II levels might favour dilatation of the
coronary vascular bed and enhance myocardial perfusion.
Other angiotensin converting enzyme inhibitors have
been developed and with them other mechanisms have
become evident. Quinapril, used in the present study
and ramipril differ from captopril in that they do not
contain a sulphydryl group. Van Gilst et al. [26] investigated the effect of ramipril, in comparison to captopril,
on the coronary circulation of isolated rat hearts. Both
agents increased coronary flow compared to saline, but
captopril increased flow more than ramipril, both in
rate of onset and magnitude. Ramipril, however, increased prostacyclin synthesis, an effect which has been
confirmed in other studies [27]. This suggests that different molecular structures of angiotensin converting
enzyme inhibitors may act by different mechanisms.
Other proposed mechanisms for the myocardial protective effect of angiotensin converting enzyme inhibitor
include potentiation of bradykinin [28], which may
assist in the anti-remodelling effect of angiotensin converting enzyme inhibition after myocardial infarction
[29]. Protection may also be due, in part, to suggested
anti-oxidant properties of the sulphydryl-containing
compounds [29].
Although the present study failed to demonstrate a
significant improvement in left ventricular function with
pre-operative quinapril treatment, we have demonstrated the safety of such therapy. The trend towards a
more favourable effect on post-operative left ventricular function in patients with pre-operative impairment
of left ventricular function may be an indication that
such patients would benefit from angiotensin converting enzyme inhibition prior to coronary artery bypass
graft surgery, however, this hypothesis requires further
investigation in patients with a pre-operative left ventricular ejection fraction less than 35%. The results
from this study would also suggest that angiotensin
converting enzyme inhibitors may safely be used in
patients undergoing major surgery other than coronary
artery bypass graft surgery.
Acknowledgements
The authors would like to thank Parke Davis for
financial and statistical assistance, Debbie Clarke for
technical help and the staff of the Nuclear Medicine
Department and Department of Cardiac Surgery at the
Royal Brompton Hospital.
47
References
[1] Rahimtoola SH. Coronary bypass surgery for chronic angina—
1981. A perspective. Circulation 1982;65:225 – 41.
[2] Ross RS. Ischemic heart disease: an overview. Am J Cardiol
1975;36:496 – 505.
[3] Taylor NC, Barber RW, Crossland P, English TA, Wraight EP,
Petch MC. Effects of coronary artery bypass grafting on left
ventricular function assessed by multiple gated ventricular
scintigraphy. Br Heart J 1983;50:149 – 56.
[4] Wolf NM, Kreulen TH, Bove AA, et al. Left ventricular function following coronary bypass surgery. Circulation 1978;58:63–
70.
[5] Hammermeister KE, Kennedy JW, Hamilton GW, et al. Aortocoronary saphenous-vein bypass. Failure of successful grafting to
improve resting left ventricular function in chronic angina. New
Engl J Med 1974;290:186 – 92.
[6] Nelson GR, Cohn PF, Gorlin R. Prognosis in medically-treated
CAD: influence of ejection fraction compared to other parameters. Circulation 1975;52:408 – 12.
[7] Alderman EL, Fisher LD, Litwin P, et al. Results of coronary
artery surgery in patients with poor left ventricular function
(CASS). Circulation 1983;68:785 – 95.
[8] The CONSENSUS Trial Study Group. Effects of enalapril on
mortality in severe congestive heart failure. Results of the CONSENSUS. New Engl J Med 1987;316:1429 – 35.
[9] The SOLVD Investigators. Effect of enalapril on survival in
patients with reduced left ventricular ejection fractions and congestive heart failure. New Engl J Med 1991;325:293 – 302.
[10] The CONSENSUS II study group, Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H. Effects of the early
administration of enalapril on mortality in patients with acute
myocardial infarction. Results of the CONSENSUS II. New
Engl J Med 1992;327:678 – 84.
[11] Pfeffer MA, Braunwald E, Moy LA, et al. Effect of captopril on
mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and
ventricular enlargement trial. New Engl J Med 1992;327:669–77.
[12] The acute infarction ramipril efficacy (AIRE) study investigators. Effect of ramipril on mortality and morbidity of survivors
of acute myocardial infarction with clinical evidence of heart
failure. The AIRE study investigators. Lancet 1993;342:821–8.
[13] Gruppo Italiano per lo studio della Sopravvivenza nell’Infarto
Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and
ventricular function after acute myocardial infarction. Lancet
1994;343:1115– 22.
[14] Ambrosioni E, Borghi C, Magnani B. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality
and morbidity after anterior myocardial infarction. The Survival
of myocardial infarction long-term evaluation (SMILE) study
investigators. New Engl J Med 1995;332:80 – 5.
[15] Fourth international study of infarct survival (ISIS-4) collaborative group. ISIS-4: a randomised factorial trial assessing early
oral captopril, oral mononitrate and intravenous magnesium
sulphate in 58050 patients with suspected acute myocardial
infarction. Lancet 1995;345:669 – 85.
[16] Ertl G, Kloner RA, Alexander RW, Braunwald E. Limitation of
experimental infarct size by an angiotensin-converting enzyme
inhibitor. Circulation 1982;65:40 – 8.
[17] Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. London: Arnold, 1990.
[18] Favre L, Vallotton MB, Muller AF. Relationship between
plasma concentrations of angiotensin-I, angiotensin-II and
plasma renin activity during cardio-pulmonary bypass in man.
Eur J Clin Invest 1974;4:135 – 40.
C.M. Webb et al. / European Journal of Cardio-thoracic Surgery 13 (1998) 42–48
48
[19] Roberts AJ, Niarchos AP, Subramanian VA, et al. Systemic
hypertension associated with coronary artery bypass surgery.
Pre-disposing factors, hemodynamic characteristics, humoral
profile and treatment. J Thorac Cardiovasc Surg 1977;74:846 –
59.
[20] Taylor KM, Morton IJ, Brown JJ, Bain WH, Caves PK. Hypertension and the renin-angiotensin system following open-heart
surgery. J Thorac Cardiovasc Surg 1977;74:840–5.
[21] Taylor KM, Bain WH, Morton JJ. The role of angiotensin-II in
the development of peripheral vasoconstriction during openheart surgery. Am Heart J 1980;100(6):935–7.
[22] Taylor KM, Casals JG, Mittra SM, Brannan JJ, Morton JJ.
Haemodynamic effects of angiotensin converting enzyme inhibition after cardiopulmonary bypass in dogs. Cardiovasc Res
1980;14:199 – 205.
[23] Gavras H, Kremer D, Brown JJ, et al. Angiotensin- and norepinephrine-induced myocardial lesions: experimental and clinical
studies in rabbits and man. Am Heart J 1975;89:321–32.
[24] de Graeff PA, van Gilst WH, Bel K, de Langen CD, Kingma
JH, Wesseling H. Concentration-dependent protection by capto-
.
.
[25]
[26]
[27]
[28]
[29]
pril against myocardial damage during ischemia and reperfusion
in a closed chest pig model. J Cardiovasc Pharmacol
1987;9(2):S37 – 42.
Di Pasquale P, Paterna S, Valenza M, et al. Effects of captopril
on myocardial protection during cardioplegia. Int J Cardiol
1993;42:225 – 30.
van Gilst WH, Scholtens E, de Graeff PA, de Langen CD,
Wesseling H. Differential influences of angiotensin convertingenzyme inhibitors on the coronary circulation. Circulation
1988;77:I24 – 9.
Linz W, Scholkens BA, Han YF. Beneficial effects of the converting enzyme inhibitor, ramipril, in ischemic rat hearts. J
Cardiovasc Pharmacol 1986;8(10):S91– 9.
Linz W, Scholkens BA. A specific B2-bradykinin receptor antagonist HOE 140 abolishes the anti-hypertrophic effect of ramipril.
Br J Pharmacol 1992;105:771 – 2.
Przyklenk K, Kloner RA. Angiotensin converting enzyme inhibitors improve contractile function of stunned myocardium by
different mechanisms of action. Am Heart J 1991;121:1319–30.