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(Hypertension. 1996;27:1031-1038.)
© 1996 American Heart Association, Inc.
Articles |
Improvement of Coronary Flow Reserve After Long-term Therapy With Enalapril
From the Department of Medicine, Ernst-Moritz-Arndt-University of Greifswald, Cardiovascular Center Karlsburg (W.M.), and Department of Medicine, Heinrich-Heine-University of Duesseldorf (B.E.S.) (FRG).
Correspondence to Wolfgang Motz, MD, Department of Medicine, Ernst-Moritz-Arndt-University, Friedrich-Loeffler-Straße 23, D-17487 Greifswald, FRG.
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Abstract |
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Abstract To date, no clinical study shows an improvement in coronary flow reserve due to long-term antihypertensive therapy. In view of the contribution of the renin-angiotensin system to the process of hypertensive remodeling of the heart and coronary circulation, angiotensin-converting enzyme (ACE) inhibitors might act as cardioreparative drugs in arterial hypertension. Accordingly, our objective in this investigation was to examine under clinical conditions to what extent long-term antihypertensive treatment with an angiotensin-converting enzyme inhibitor improved the diminished coronary flow reserve in hypertensive patients with microvascular angina pectoris. For the purpose of comparison, we also treated a normotensive control group of 6 patients with hypertrophic nonobstructive cardiomyopathy. Fifteen hypertensive individuals (10 men, 5 women; age, 58±6 years) were treated with enalapril (10 to 20 mg/d; mean, 16.7±4.9 mg/d) for 11 to 13 months. At the end of the treatment period, systolic pressure decreased from 178±14 to 137±12 mm Hg and diastolic pressure from 102±11 to 86±4 mm Hg under ambulatory conditions. Left ventricular muscle mass index decreased by 8%, from 149±32 to 137±28 g/m2 (P<.05). Maximal coronary blood flow after dipyridamole was increased by 43%, from 181±69 to 258±116 mL/min per 100 g (P<.001), and minimal coronary vascular resistance was diminished by 29%, from 0.66±0.23 to 0.47±0.24 mm Hg·min·100 g·mL-1 (P<.001) after enalapril treatment. Consequently, the calculated coronary reserve increased from 2.2±0.6 to 3.3±1.2 (P<.001). After enalapril therapy, the functional class of angina pectoris according to the Canadian classification system had changed from 2.5±0.6 to 1.5±0.6 (P<.01). The maximal working capacity had increased from 23.775±3.970 to 26.255±4.598 J (mean±SE, P<.05). The maximal ST-segment depression at maximal workload was reduced from 0.18±0.02 to 0.06±0.02 mV (mean±SE, P<.01). In summary, long-term therapy with the angiotensin-converting enzyme inhibitor enalapril must be considered a cardioreparative treatment with respect to the coronary microcirculation in hypertensive heart disease.
Key Words: angina pectoris • coronary circulation • hypertrophy, left ventricular • angiotensin-converting enzyme inhibitors • enalapril
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Introduction |
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In patients with arterial hypertension, coronary flow reserve is impaired because of functional and structural alterations of the coronary microcirculation and left ventricular hypertrophy.1 2 3 In view of the emerging importance of the renin-angiotensin system in the process of hypertensive remodeling of the heart and coronary circulation,4 5 it would seem logical to use ACE inhibitors in the medical treatment of arterial hypertension. Experimental and clinical studies have clearly shown that therapy with ACE inhibitors induces regression of myocardial hypertrophy.6 7 8 9 Brilla and coworkers10 have found a reversal of interstitial collagen formation as well as a decrease in the medial wall thickness of coronary resistance vessels in experiments in the spontaneously hypertensive rat after long-term treatment with the ACE inhibitor lisinopril.
To date, no clinical study exists that confirms an improvement in coronary flow reserve after long-term antihypertensive therapy. A relative improvement in coronary reserve induced metabolically by reduced coronary flow at rest was observed only within the framework of regression of hypertrophy after aortic valve replacement in patients with aortic stenosis.11
Accordingly, our objective in this investigation was to examine under clinical conditions to what extent long-term antihypertensive treatment with an ACE inhibitor can improve the diminished coronary reserve in patients with arterial hypertension and microvascular angina pectoris.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients
Patients With Arterial Hypertension
Inclusion criteria for the study were primary arterial hypertension, a normal coronary angiogram, and electrocardiographic evidence of ischemia. Myocardial ischemia had to be indicated by an abnormal resting electrocardiogram or a positive exercise tolerance test with horizontal or downsloping ST segments of at least 0.1 mV in two leads. The diagnosis of arterial hypertension had to be confirmed by at least three consecutive blood pressure measurements within 3 weeks with a systolic pressure greater than 160 mm Hg and/or diastolic pressure greater than 95 mm Hg.
Patients with valvular heart disease, dilated cardiomyopathy, hypertrophic obstructive cardiomyopathy, left or right bundle-branch block, atrial fibrillation, diabetes mellitus, alcoholism, hypothyroidism or hyperthyroidism, renal insufficiency, or pulmonary disease with impairment of ventilation or gas exchange were excluded. All secondary forms of arterial hypertension were also an exclusion criterion.
Normotensive Group
Since ACE inhibition eventually increases coronary flow
reserve even in healthy individuals, a normotensive control group was
provided. For ethical reasons, healthy control subjects could not be
included into the protocol that required invasive cardiac
catheterization studies twice. Since
angiotensin II is considered to play an important part in
hypertensive cardiac remodeling, long-term ACE inhibition should be
beneficial in reducing myocardial mass in patients with hypertrophic
cardiomyopathy. Consequently, for the purposes of
comparison, we treated with enalapril six normotensive patients (four
men, two women) who had hypertrophic nonobstructive
cardiomyopathy. Since ACE inhibition is potentially
harmful in patients with obstructive cardiomyopathy
because of afterload reduction, only those patients were enrolled in
the protocol in whom an intraventricular gradient
had been clearly excluded by cardiac
catheterization.
Study Protocol
Patients With Arterial Hypertension
After patients had discontinued any preexisting
cardiovascular medication for at least 5 days, resting
electrocardiogram, exercise tolerance test,
echocardiography, right ventricular
catheterization, and coronary flow measurement
were performed, and the ACE inhibitor treatment with
enalapril was started. The dosage was gradually increased to a maximum
of 20 mg/d to achieve effective blood pressure lowering to a
systolic pressure less than 160 mm Hg and diastolic
pressure less than 90 mm Hg.
After 9 to 14 months, the enalapril treatment was stopped again. After a 1-week washout period, resting electrocardiogram, exercise tolerance test, right ventricular catheterization, and coronary flow measurement were performed again to obtain information on the chronic rather than acute cardiac effects of enalapril therapy.
Twenty patients who fulfilled the inclusion criteria were enrolled in the study protocol. Five of the 20 patients were excluded from the study, 2 because of insufficient blood pressure control by enalapril, 1 because of complaint of a dry cough, and 2 who did not undergo the second coronary flow reserve measurement. Thus, 15 hypertensive patients (10 men, 5 women) completed the study protocol. The patient age was 58±6 years. Systolic pressure was 178±14 mm Hg, and diastolic pressure was 102±11 mm Hg. All patients had either angina pectoris at rest (n=7) and/or exercise-related angina pectoris (n=13), exertional dyspnea (n=9), or a pathological exercise tolerance test (n=13). The severity of angina pectoris was scored according to the Canadian classification system (III/IV, n=3; III, n=3; II, n=9).
The mean enalapril dosage over the entire study period was 16.7±4.9 mg/d (range, 10 to 20). The mean duration of the enalapril treatment was 12±2 months (range, 9 to 14).
Normotensive Control Group
Six normotensive patients (four men, two women) with
hypertrophic nonobstructive cardiomyopathy
completed the study protocol. The patient age was 62±7 years.
Systolic pressure was 138±8 mm Hg, and diastolic
pressure was 80±9 mm Hg. All patients had either angina pectoris at
rest (n=1) and/or exercise-related angina pectoris (n=3),
exertional dyspnea (n=6), or a pathological resting
electrocardiogram (n=4). Three patients had asymmetric
septum hypertrophy, and three had apical left
ventricular hypertrophy. Most of them were sent
to coronary angiography because of suspected coronary
artery disease The mean enalapril dosage over the entire study period
was 15.0±5.5 mg/d (range, 10 to 20). The mean duration of the
enalapril treatment was 12±1 months (range, 11 to 13).
The study protocol was approved by the Ethics Committee of the Heinrich-Heine-University of Düsseldorf. All patients gave written informed consent for all procedures.
Echocardiography
For determination of left ventricular dimensions and
hypertrophy, an ultrasonoscope (model SSH 40 A, Toshiba)
with a 2.4-MHz transducer was used. With the patients in a left lateral
position, M-mode echocardiographic recordings
were made in the short axis view under two-dimensional
echocardiographic control. In accordance with the
criteria of the American Society of
Echocardiography (ASE), the left
ventricular internal end-diastolic diameter
(PED), interventricular septal thickness (IVS), and
left ventricular posterior wall thickness (LVPW) were
measured just below the level of the mitral valve at the beginning of
the electrocardiographic QRS complex. Left ventricular
muscle mass (LVMM) was calculated on the basis of the ASE method as
follows12 : LVMM
(ASE)=1.04 ·[(IVS+PED+LVPW)3-PED3].
Ventriculography and Coronary Angiography
In all patients, coronary angiography was performed
according to the technique of Judkins to exclude obstructive
coronary lesions. Quantitative biplane ventriculography was
performed (30° right anterior oblique, 60° left anterior oblique)
by injection of 40 mL nonionic contrast medium into the left ventricle
through a pigtail catheter at a speed of 12 mL/s. The ejection
fraction was determined semiautomatically from these ventriculograms
(AVD System, Fa Siemens). Left ventricular peak
systolic and end-diastolic pressures were
measured through a fluid-filled catheter. To avoid any interference
by the contrast medium, we performed coronary angiography and
ventriculography at least 48 hours before coronary flow reserve
measurements.
Right Ventricular and Pulmonary Artery
Catheterization
At the time of coronary blood flow measurements, the
right atrial, right ventricular, pulmonary
arterial, and pulmonary capillary wedge pressures
were measured with a Swan Ganz flotation catheter. Cardiac output was
determined by the thermodilution technique.
Coronary Blood Flow Measurements
Coronary blood flow was measured quantitatively by the
gas chromatographic argon method described in detail
previously.13 14 For the measurements, a 7F multipurpose
catheter (Cordis Corp) was placed in the coronary sinus and
another in the descending aorta. While the patient was breathing an
oxygen-argon mixture (21% oxygen, 79% argon), coronary
venous and arterial blood samples were withdrawn
simultaneously over 5 minutes. After this time, the argon
concentrations in the coronary sinus blood had reached a steady
state, and another blood sample was taken for determination of the end
concentration of argon. The quotient of the end concentration and the
difference between the mean arterial and coronary
venous concentrations of argon during the saturation period is a
measure of coronary blood flow. If we assume a tissue blood
partition coefficient of 1.1, coronary blood flow can be
calculated quantitatively per 100 g myocardium.
Determination of coronary blood flow by the argon method is
very precise and has a high reproducibility of 5% up to
coronary blood flow values of 500 mL/min per 100
mL.13 The argon concentrations of the blood samples were
determined by gas chromatography (Fa Carlo Erba).
Oxygen was removed from the blood samples by addition of sodium
dithionite because for technical reasons chromatographic
separation of argon and oxygen is practically impossible.
Coronary resistance was calculated as the quotient of coronary perfusion pressure and coronary blood flow. Aortic pressure was measured through a fluid-filled catheter in the descending aorta. The mean aortic pressure was determined electromagnetically, and heart rate was determined from electrocardiographic tracings.
After completion of coronary blood flow measurements under baseline conditions, a 10-minute period of argon-free breathing followed. Then, 0.5 mg/kg body wt dipyridamole IV was administered over 5 minutes to accomplish maximal coronary vasodilation, and the oxygen saturation in the coronary sinus, mean aortic pressure, and heart rate were determined. Argon breathing with simultaneous withdrawal of coronary venous and arterial blood samples was resumed. Neither sedation nor any other drug was used at the time of the coronary flow study.
The coronary vasodilator capacity, ie, the coronary reserve (CorRes), was calculated as the ratio of coronary resistance under baseline conditions (Rcor) to coronary resistance after dipyridamole-induced coronary vasodilation (Rmin): CorRes=Rcor (mm Hg·min·100 g·mL-1)/Rmin (mm Hg·min·100 g·mL-1).
Myocardial oxygen consumption
(M
O2) was determined from the
arteriocoronary venous oxygen difference
(AVDO2) and baseline coronary blood
flow (Vcor):
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where SO2 indicates oxygen saturation; art, arterial; cs, coronary sinus (percent); and Hb, hemoglobin concentration (grams per liter).
Resting Electrocardiogram and Exercise
Tolerance Test
In all patients, a 12-lead resting
electrocardiogram in a supine position was obtained. A
symptom-limited bicycle exercise tolerance test in a sitting
position was carried out in all patients. The workload was increased in
25-W steps. Leads I, II, III, V2,
V4, and V6 were recorded
simultaneously. Cuff blood pressures were measured at each
workload. Conventional clinical interruptive criteria were
used.15 Before and after enalapril treatment, the exercise
tolerance test was performed the day before coronary flow
measurement. The occurrence of horizontal or descending ST-segment
depression of at least 0.1 mV in at least two
electrocardiogram leads was rated as positive with
regard to myocardial ischemia. In patients with an already
abnormal resting electrocardiogram, ST-segment
depression had to occur in leads additional to those already altered
under resting conditions.
Angina Score
The severity of angina pectoris was graded according to the
functional classification of the Canadian
Cardiovascular Society.16
Statistical Evaluation
The numerical data are mean±SD unless otherwise stated.
Individual parameters—coronary flow and
resistance, myocardial energy consumption, systolic and
diastolic pressures, heart rate, and left
ventricular muscle mass before and after therapy—were
tested for parametric distribution (Kolmogorov-Smirnov goodness
test). Since not all data showed a parametric distribution, a
nonparametric Wilcoxon test was applied for
statistical analysis. A value of P<.05 was
considered significant.17
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Results |
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Arterial Blood Pressure
Patients With Arterial Hypertension
Three months after initiation of enalapril therapy, systolic pressure was lowered from 178±14 to 144±11 mm Hg (P<.01) and diastolic pressure from 102±11 to 89±6 mm Hg under ambulatory conditions (P<.01). At the end of the antihypertensive treatment period, systolic pressure was 137±12 mm Hg and diastolic pressure was 86±4 mm Hg under ambulatory conditions (Fig 1
).
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During the hospital stay, systolic and diastolic
pressures dropped spontaneously to 154±14 and 95±8 mm Hg,
respectively, the day before the initial coronary flow study
and rose to 152±14 and 95±7 mm Hg, respectively, after enalapril was
discontinued before the final coronary flow studies. Thus,
arterial blood pressures were at a comparable hypertensive
level at the time of initial and second coronary flow
measurements (Fig 2).
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Heart rate remained unchanged (69±9 versus 71±12 beats per minute [bpm]).
Normotensive Patients With Hypertrophic
Cardiomyopathy
During enalapril therapy, systolic pressure was lowered
from 138±8 to 129±7 mm Hg (P<.05) and
diastolic pressure from 80±9 to 76±5 mm Hg
(P=NS). After discontinuation of enalapril therapy,
systolic pressure rose to 135±6 mm Hg and
diastolic pressure to 78±8 mm Hg the day before
coronary flow measurement. Heart rate remained unchanged (66±6
versus 68±6 bpm).
Left Ventricular Muscle Mass
Patients With Arterial Hypertension
Left ventricular muscle mass index decreased by 8%,
from 149±32 to 137±28 g/m2 (P<.05) (Fig 1
),
interventricular septal thickness decreased from
12.1±2.6 to 11.3±2.4 mm (P<.05), and left
ventricular posterior wall thickness remained unchanged
(10.5±1.0 versus 10.9±1.1 mm). Left ventricular
end-diastolic diameter also did not change (49.4±4.2
versus 49.1±4.0 mm).
Normotensive Patients With Hypertrophic
Cardiomyopathy
Three patients had asymmetric septal hypertrophy, and
three had apical left ventricular hypertrophy.
Because of the irregular form of hypertrophy, left
ventricular muscle mass was not calculated. After enalapril
therapy, no change in septal thickness (before, 12.8±2.3 mm; after,
12.3±2.4 mm), left ventricular posterior wall thickness
(before, 10.5±0.8 mm; after, 10.3±0.5 mm), and
end-diastolic diameter (before, 47.0±2.0 mm; after,
47.7±2.7 mm) occurred.
Right Ventricular and Pulmonary Artery
Catheterization and Thermodilution
Patients With Arterial Hypertension
Long-term enalapril therapy had no effect on mean
pulmonary artery pressure (16.1±4.1 versus 16.1±3.5 mm Hg),
pulmonary artery wedge pressure (8.0±2.7 versus 8.5±3.1 mm
Hg), cardiac index (3.9±0.7 versus 3.3±0.6 L/min per m2),
or stroke volume index (47.1±13.7 versus 46.5±7.6 mL/m2).
All these parameters were initially within the normal
range.
Normotensive Patients With Hypertrophic
Cardiomyopathy
Long-term enalapril treatment had no effect on mean
pulmonary artery pressure (22.0±1.5 versus 21.5±2.9 mm Hg),
pulmonary artery wedge pressure (10.2±2.9 versus 9.7±4.2 mm
Hg), cardiac index (3.1±0.4 versus 3.2±0.8 L/min per m2),
or stroke volume index (46.8±6.2 versus 47.2±5.5
mL/m2).
Coronary Hemodynamics
Patients With Arterial Hypertension
Baseline conditions. Baseline coronary blood flow
(82.9±12.2 versus 85.2±8.0 mL/min per 100 g) and coronary
resistance (1.35±0.25 versus 1.31±0.15 mm Hg·min·100
g·mL-1) were identical before and
after enalapril therapy. Coronary artery perfusion pressure,
heart rate, myocardial oxygen consumption, and
arteriocoronary venous oxygen difference also did not
differ before and after enalapril therapy.
After dipyridamole administration. The maximal
achievable coronary blood flow after
dipyridamole (0.5 mg/kg body wt) was increased by 43%,
from 181±69 to 258±116 mL/min per 100 g (P<.001), and the
minimal coronary vascular resistance as the reciprocal
parameter of coronary artery conductance was
diminished by 29%, from 0.66±0.23 to 0.47±0.24 mm Hg·min·100
g·mL-1 (P<.001) after
enalapril treatment. Consequently, the calculated coronary
reserve increased from 2.2±0.6 to 3.3±1.2 (P<.001) (Fig 3).
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indicates before treatment; 
, after
treatment. *P<.001.Before and after enalapril therapy, the acute hemodynamic responses to dipyridamole were similar. Heart rate increased from 72±9 to 83±10 bpm before treatment and from 75±14 to 88±13 bpm after treatment. The mean aortic pressure dropped slightly under both conditions, from 112±19 to 107±16 and from 111±12 to 106±19 mm Hg, respectively.
Normotensive Patients With Hypertrophic
Cardiomyopathy
Baseline conditions. Baseline coronary blood flow
(75.3±5.9 versus 75.5±6.0 mL/min per 100 g) and coronary
resistance (1.16±0.11 versus 1.18±0.14 mm Hg·min·100
g·mL-1) were identical before and
after enalapril therapy. No differences in coronary perfusion
pressure, heart rate, myocardial oxygen consumption, and
arteriocoronary venous oxygen difference were found
before and after enalapril therapy.
After dipyridamole administration. The maximal achievable coronary blood flow after dipyridamole (146±33.5 versus 142±27.6 mL/min per 100 g) and the minimal coronary vascular resistance as the reciprocal parameter of coronary artery conductance (0.62±0.15 versus 0.63±0.16 mm Hg·min·100 g·mL-1) remained unchanged after enalapril treatment. Consequently, the calculated coronary reserve also was unaltered (1.95±0.36 versus 1.97±0.37).
Before and after enalapril therapy, the acute hemodynamic responses to dipyridamole were similar. Heart rate increased from 68±7 to 75±8 bpm before treatment and from 66±7 to 76±7 bpm after treatment. The mean aortic pressure dropped slightly under both conditions, from 88±10 to 84±10 and from 89±9 to 83±9 mm Hg, respectively.
Angina Pectoris Score and Exercise Tolerance Test
Patients With Arterial Hypertension
Three patients were referred to the emergency room because of
severe angina pectoris at rest, which responded promptly to
intravenous nitrate administration. These three patients
were not able to climb more than one flight of stairs and were rated as
Canadian class IV. Three patients were initially in class III and nine
in class II. After enalapril therapy, the functional class of angina
pectoris according to the Canadian classification system had changed
from 2.5±0.6 to 1.5±0.6 (P<.01) (Fig 4).
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The maximal working capacity increased from 23.775±3.970 to
26.255±4.598 J (mean±SE, P<.05; Table).
The maximal ST-segment depression at maximal workload was reduced from
0.18±0.02 to 0.06±0.02 mV (mean±SE, P<.01; Fig 4).
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Normotensive Patients With Hypertrophic
Cardiomyopathy
Before, during, and after enalapril treatment, no significant
change in clinical symptoms occurred. The maximal working capacity and
maximal ST segment depression at maximal work load also did not change
with enalapril therapy.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study in patients with hypertensive microvascular angina, a pronounced increase in coronary flow reserve was found after long-term antihypertensive treatment with the ACE inhibitor enalapril. The increase in coronary flow reserve was associated with improvement of the patients' clinical symptoms and with a significant reduction in electrocardiographic signs of myocardial ischemia. The improvement in coronary flow reserve was still present after discontinuation of the enalapril therapy, followed by a rise in systolic and diastolic arterial pressures to pretreatment hypertensive levels. Consequently, regression of myocardial and vascular structural alterations as long-term treatment effects of enalapril rather than as acute drug effects are probably the underlying cause. Although enalapril had been discontinued for 1 week, which is equivalent to 15 half-life periods, a persisting unpredictable tissue effect caused by local ACE inhibition cannot be excluded.
Treatment-induced alterations of the coronary microvasculature may consist of a decrease in medial wall thickness, an increase in capillary density, a reduction in perivascular fibrosis, and/or an improvement in endothelial function.10 18 19 20 21 22 A decrease in myocytic hypertrophy and a conceivable regression of the amount of interstitial collagen must also be considered as further extravascular myocardial causes for the enhanced flow reserve.
Keely et al23 have shown that inhibition of ACE activity by enalapril during a period of rapid growth reduces accumulation of vascular collagen in normotensive individuals, with arterial blood pressure almost unaltered. Their data support the fact that angiotensin II is important in normal development and growth. The in vitro study of Brilla et al5 demonstrates that aldosterone alters collagen turnover but does not alter cell growth. In a recent retrospective survey, hypertensive patients were evaluated in whom myocardial biopsies were taken for clinical reasons at least twice. In 6 of 11 hypertensive patients, interstitial collagen was found to be lower after ACE inhibitor therapy with enalapril.24 Thus, the obvious improvement in coronary flow reserve after enalapril in the study group may indeed reflect a decrement in the accumulation of vascular collagen even in adult hypertensive humans without a necessary effect on vascular cell growth.
There is growing evidence that the structural remodeling of the myocardium associated with the process of arterial hypertension is not solely due to the physical pressure load on the cardiac myocytes but is caused by the interrelationship of mechanical stretch, ie, systolic wall stress, and hormonal stimulation. Apart from adrenergic activity,25 26 27 the renin-angiotensin system in particular modulates the process of hypertrophy of cardiac myocytes and vascular smooth muscle cells and furthermore reinforces the process of hypertensive cardiac remodeling by angiotensin II–mediated induction of proto-oncogenes.28 29 30 31 Schunkert and coworkers32 demonstrated a rise in ACE mRNA and enhanced conversion of angiotensin I to angiotensin II during the process of adaptive myocardial hypertrophy. Furthermore, the development of left ventricular hypertrophy due to coarctation of the abdominal aorta in rats could be prevented after pretreatment with an ACE inhibitor.33 Circulating and probably also local angiotensin II contribute to the regulation of cardiac fibroblast growth and consequently to interstitial and vascular collagen accumulation. Additionally, elevated circulating aldosterone is associated with the involvement and growth of cardiac fibroblasts.4 5
The activation of nonmyocytic cells such as cardiac fibroblasts and vascular smooth muscle cells characterizes the state of pathological hypertensive hypertrophy, which is associated with early diastolic and later systolic left ventricular dysfunction.34
Converting enzyme inhibition by captopril increased resting coronary blood flow when the renin-angiotensin system was chronically activated by diuretic pretreatment.35 This finding suggests that the stimulated renin-angiotensin system can exert a direct effect on coronary vasomotor activity and that converting enzyme inhibition will induce coronary vasodilatation under these conditions. However, in the present study, enalapril therapy had been discontinued for 1 week before the second coronary flow measurement was performed. Both resting coronary blood flow and coronary resistance under baseline conditions remained unchanged. Thus, it is very unlikely that such acute effects of angiotensin blockade on coronary circulation contributed to the improved coronary flow reserve in this study, which was clearly due to a reduced minimal coronary resistance after dipyridamole.
Experimental studies have shown an antiproliferative effect of ACE inhibitors on the vessel wall in conductance vessels36 37 and a reduction in the wall-to-lumen ratio of myocardial arterioles10 38 along with chronic blood pressure reduction. Consequently, the improved coronary flow reserve after enalapril observed in the present study might reflect a specific ACE inhibitory effect on the structure of the coronary microvasculature. Since ACE inhibition also has an effect on endothelial function, most likely through inhibition of bradykinin degradation, this pathway may also have contributed to the observed improvement in coronary flow reserve.39 In hypertensive patients, acutely administered captopril led to normalization of the diminished forearm vasodilation in response to acetylcholine, which did not result from reduction in blood pressure per se.22
The concomitant reversal of left ventricular hypertrophy along with blood pressure reduction inevitably leads to a decrease of the myocardial component of coronary resistance. Consequently, in laboratory experiments and particularly in clinical studies, it is difficult to differentiate exactly between the influence of myocardial factors, ie, hypertrophy and interstitial fibrosis, and vascular factors, ie, medial wall thickening, capillary density, and endothelium-mediated dilator capacity, on coronary flow reserve.
In the present study, a marked decrease of 29% in minimal coronary resistance as the reciprocal parameter of coronary conductance occurred along with a moderate degree of left ventricular muscle mass reduction of 8%. Anderson and coworkers40 experimentally found an enhanced coronary flow reserve despite a complete absence of reversal of myocardial hypertrophy after hydralazine treatment in spontaneously hypertensive rats. Brush and coworkers41 have shown that the coronary flow reserve can be impaired in hypertensive patients even in the absence of left ventricular hypertrophy. Moreover, despite reversal of myocardial hypertrophy, minimal coronary resistance remained almost unchanged after treatment with a ß-blocker in a clinical study.42 Thus, left ventricular hypertrophy as such is not a prerequisite for an impaired coronary flow reserve, and consequently, reversal of left ventricular hypertrophy does not necessarily in turn implicate an improvement in coronary flow reserve. The observed increment in coronary reserve on the basis of enhanced vascular conductance in the present study thus appears to be due to chronic microvascular effects of enalapril therapy. Evidence from an experimental study shows that ACE inhibition will also lead to regression of interstitial myocardial fibrosis.10 Accordingly, a potential effect on fibrous tissue accumulation by ACE inhibition might also have contributed extravascularly to the observed improvement in the coronary flow reserve.
In experimental studies, a decrease in medial wall thickness was also described after spontaneously hypertensive rats were treated with the calcium channel blockers nifedipine19 and felodipine18 as well as with ACE inhibitors.10 37 An increased capillary density was also reported after nifedipine.20 On the basis of these experimental results, which also demonstrate coronary vascular reparative effects of calcium channel blockade, the improvement in coronary reserve in hypertensive patients observed in the present study cannot merely be interpreted as the result of specific ACE inhibition but rather as the effect of long-term treatment with an arteriolar vasodilator.
In most of the patients, the ACE inhibitor treatment was accompanied by symptomatic improvement with respect to exercise-related angina pectoris and exertional dyspnea. In the initial phase of treatment, a decrease in exercise-related myocardial ischemia might result from an energy-saving effect due to a reduction in blood pressure and consequently in myocardial oxygen demand. However, even after discontinuation of enalapril treatment, the electrocardiographic signs of ischemia were reduced in the exercise tolerance test along with symptomatic improvement in 13 of 15 patients. A symptom-limited exercise tolerance test is affected by training. Accordingly, the observed moderate improvement in the maximal working capacity by 10% may not be purely due to enalapril treatment. It is possible that the effect of physical training contributes to the improved exercise tolerance. However, despite the increase in blood pressure after enalapril treatment was stopped, it does not seem impossible that enalapril improved exercise tolerance by improving muscular or pulmonary blood flow during exercise.
ACE inhibition might increase coronary flow reserve even in healthy individuals. The absence of any increase in coronary reserve in the normotensive patients with hypertrophic nonobstructive cardiomyopathy clearly speaks against a direct microvascular effect of chronic ACE inhibition unrelated to systemic arterial hypertension. Consequently, the observed increment in coronary flow reserve in the hypertensive patients is the result of chronic blood pressure reduction on both the myocardium and the coronary microvasculature by chronic ACE inhibition. Moreover, as a side aspect, the observed lack of reversal of left ventricular hypertrophy in the normotensive patients with hypertrophic nonobstructive cardiomyopathy indicates that the process of myocardial hypertrophy differs fundamentally from that in arterial hypertension and seems not to be related to or causally influenced by the renin-angiotensin system.
It is known that in about 10% of all cases, maximal coronary blood flow cannot be achieved by administration of dipyridamole in a dose of 0.5 mg/kg body wt.43 Since before and after enalapril therapy in all individuals the same dosage of 0.5 mg/kg body wt was used, any achievement of submaximal coronary blood flow is not relevant for the interpretation of the results.
Since all hypertensive patients in this study had undergone coronary angiography because of clinically suspected coronary artery disease, the study population does not reflect ordinary hypertensive patients. Accordingly, the results obtained here are strictly limited to the specific study group of hypertensive patients with microvascular angina.
In one patient (No. 3) minimal coronary resistance was not lowered despite blood pressure control by enalapril. It is possible that in this patient irreversible structural alterations of the coronary microvasculature and myocardium were already present that could no longer be influenced.
In summary, long-term therapy with the ACE inhibitor enalapril must be considered a cardioreparative treatment with respect to the coronary microcirculation in hypertensive heart disease.
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Acknowledgments |
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We greatly appreciate the efforts of Martin Vogt, MD, for assistance in performing the investigations and preparing the manuscript.
Received August 22, 1995; first decision October 9, 1995; accepted January 24, 1996.
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References |
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