(Circulation. 1997;96:864-873.)
© 1997 American Heart Association, Inc.
Articles |
Comparative Effects of Enalapril and Verapamil on Myocardial Blood Flow in Systemic Hypertension
From the Institute of Clinical Physiology of the National Council of Research, Pisa, Italy, and the Istituto di Clinica Medica Generale e Cardiologia, Università di Firenze (Italy) (M.G., I.S.).
Correspondence to Oberdan Parodi, MD, CNR Institute of Clinical Physiology, Via Paolo Savi, 8, I-56100, Pisa, Italy. E-mail parodi{at}po.ifc.pi.cnr.it
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Abstract |
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Background The comparative effects of calcium channel blockers and ACE inhibitors on myocardial blood flow (MBF) in hypertensive patients after long-term treatment are still unknown.
Methods and Results Twenty hypertensive subjects with normal coronary arteries were randomly assigned to verapamil 240 to 480 mg/d or enalapril 10 to 40 mg/d. MBF was quantified at rest, during pacing tachycardia, and after dipyridamole by positron emission tomography and 13N-ammonia before and 6 months after treatment after 1 week of pharmacological washout. In both groups, blood pressure and heart rate during flow measurements were not different before and after therapy. Before treatment, mean MBF at rest, during pacing tachycardia, and after dipyridamole infusion was similar in the two groups; however, pacing and dipyridamole flows were significantly lower than those obtained in a control group of normotensive subjects. After treatment, in the enalapril-treated patients, MBF did not change in the three study conditions. In the verapamil-treated patients, MBF did not change at rest and significantly increased during pacing and after dipyridamole. The inhomogeneity of regional MBF distribution, evaluated from the coefficient of variation, decreased at rest after both treatments and, in the enalapril group, also during pacing. No relation was found between changes in MBF and changes in left ventricular mass.
Conclusions In arterial hypertension, MBF during pacing tachycardia and after dipyridamole is impaired. Successful therapy with verapamil increases MBF response to these stimuli, independent of changes in perfusion pressure and left ventricular mass. These results suggest that verapamil directly improves coronary microcirculatory function in hypertension. Enalapril does not significantly change MBF but reduces the inhomogeneity of regional flow distribution.
Key Words: hypertension • calcium channels • tomography • microcirculation
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Introduction |
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In the past, it was increasingly recognized that patients with arterial hypertension show reduced coronary vasodilatory reserve despite angiographically normal coronary arteries.1 2 Abnormal coronary flow reserve may prevent an adequate increase in MBF in response to increases in metabolic demand3 and may precipitate myocardial ischemia in these patients.4 Reduction in coronary flow reserve in hypertensive patients was ascribed mainly to the hemodynamic, metabolic, and anatomic effects of LVH on coronary circulation,1 2 4 5 6 suggesting that antihypertensive treatment able to normalize blood pressure and to revert LVH would also favorably affect coronary flow reserve. However, according to both experimental and clinical studies, factors other than LVH were recognized to affect MBF in hypertension, including diastolic ventricular dysfunction,2 7 structural remodeling, and functional abnormalities of the coronary small vessels.3 8 9 10 11 12 13 14 15 Although many clinical studies demonstrated that long-term antihypertensive treatment is effective in reducing LV mass,16 17 18 very few reports evaluated the effects of antihypertensive drugs on myocardial perfusion.19 20 21 22 This issue is particularly interesting because some antihypertensive agents, such as ACE inhibitors or calcium channel blockers, may, in addition to their action on blood pressure and myocardial mass, affect the structural and functional properties of the coronary microcirculation.
In the present study, we conducted a randomized, single-blind trial in which MBF of 20 patients with mild to moderate arterial hypertension, with or without LVH, and with normal coronary arteries was measured before and after 6 months of chronic therapy with enalapril or verapamil. MBF was quantitatively assessed at rest, during atrial pacing tachycardia, and after intravenous dipyridamole infusion by means of dynamic PET and 13N-ammonia.22 23 The study was aimed at evaluating the chronic efficacy of the selected antihypertensive agents on coronary microcirculatory properties independent of the presence of LVH and on the acute effects of the drugs on pressure levels and coronary flow. Accordingly, the PET study after treatment was performed 1 week after the discontinuation of therapy, when blood pressure had returned to baseline levels. Data obtained in the study population were compared with those obtained in 14 normal subjects and 8 additional hypertensive patients in whom the PET study was repeated within 4 hours to assess the reproducibility of flow measurements.
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Methods |
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Study Protocol
Twenty patients (13 men and 7 women; mean age, 53±7 years) with essential systemic hypertension constituted the study population for the pharmacological trial. Hypertension was defined as a history of elevated and sustained blood pressure values (systolic/diastolic pressure >160/90 mm Hg) documented during hospitalization. The history of hypertension was relatively recent (<1 year) in all patients; 16 were previously untreated, and none were under either ACE inhibitors or calcium channel blockers. All patients referred to coronary angiography for the evaluation of chest pain showed normal coronary arteries.
Eight additional patients (4 men and 4 women; mean age, 54±5 years) with essential systemic hypertension and angiographically normal coronary arteries were enrolled according to the same inclusion criteria as the main study population and constituted the group for the assessment of reproducibility of flow measurements.
Fourteen subjects (6 men and 8 women; mean age, 49±7 years), referred because of atypical chest pain, represented the control group. All had normal blood pressures, physical examinations, resting ECGs, chest X-rays, two-dimensional echocardiograms, and negative exercise stress tests. All had normal coronary angiograms and left ventriculograms.
All subjects accepted to participate in the study after being informed of the investigative nature of the protocol, which was approved by the local Ethics Committee on Human Studies.
After first referral, antihypertensive drugs were discontinued in the 4 hypertensive patients under treatment, and placebo was given to all subjects for 2 weeks. During placebo, all patients showed systolic/diastolic blood pressure >160/90 mm Hg during frequent blood pressure measurements. Thereafter, patients were hospitalized to perform coronary angiography.
Within 2 weeks of hospitalization, patients underwent two-dimensional echocardiography and PET study in a single-day protocol after an overnight fast. Once echocardiographic and MBF measurements were performed, 8 patients were submitted to a repeated study within 4 hours, and 23 patients were randomly assigned to a single-blind trial in which they initially received either 10 mg/d enalapril or 120 mg/d sustained-release verapamil in the morning. The dose regimen was increased weekly until blood pressure was controlled (reduction of the systolic and diastolic blood pressure >10% of the baseline values). Enalapril was increased up to 40 mg/d; verapamil, up to 480 mg/d. Diuretics (chlorthalidone 25 to 50 mg) were also allowed to control blood pressure if needed. Of the 23 patients initially enrolled in the pharmacological study, 2 were not controlled by therapy (1 on enalapril, 1 on verapamil), and 1 did not tolerate verapamil (bradycardia, constipation). Thus, only the 20 successfully treated patients were followed clinically, including blood pressure measurements, physical examinations, and ECGs every month. After 6 months of treatment, therapy was discontinued, placebo was given for 1 week, and evaluations of LV mass and MBF were repeated with the protocol used in the pretreatment study.
PET Protocol
All hypertensive patients and control subjects were studied
after an overnight fast; caffeine, theophylline, and theophylline
derivatives were withdrawn 24 hours before imaging. A right antecubital
vein was cannulated, and a bipolar pacing catheter was advanced into
the right atrium under fluoroscopy and continuous ECG monitoring in 22
hypertensive patients (14 in the treatment groups and 8 in the
reproducibility group) and 9 normotensive subjects. Six hypertensive
patients (3 in the enalapril group and 3 in the verapamil
group) and 5 normotensive subjects refused the atrial pacing procedure.
Subjects were then transferred to the PET room and positioned on the
bed of a two-ring positron tomograph (ECAT III, CTI Inc). Transmission
and emission scan modalities and clinical PET protocol at rest, during
atrial pacing tachycardia, and during
dipyridamole infusion have been previously
described.24 In the 20 hypertensive patients in the
treatment groups and in the 14 control subjects, 50 minutes after the
pacing acquisition or the baseline acquisition in those who refused the
pacing study, dipyridamole (0.56 mg/kg body
weight) was infused intravenously over 4 minutes; then, 3
minutes after the end of infusion, 13N-ammonia was
injected. Aminophylline (120 to 240 mg IV) was always injected 
3
minutes after 13N-ammonia injection to antagonize the
effects of dipyridamole. In the 8 hypertensive patients
in the reproducibility group, baseline and pacing flow study was
repeated within 4 hours from the first study following the same
protocol. A three-lead ECG was continuously monitored, and a nine-lead
ECG and arterial blood pressure by cuff manometer were
obtained during tracer injection at rest and every minute during both
pacing and dipyridamole tests. No side effects or
complications occurred during either atrial pacing or
dipyridamole testing in any patient.
Computation of absolute MBF was performed by one experienced cardiologist unaware of the clinical findings and pharmacological treatment according to a previously validated method.23 24 Regional MBF (from two posterolateral, two anterior, and two septal wall regions of interest) times 13N-ammonia extraction values were expressed in milliliters per minute per gram. A dedicated program was used to perform automatic edge detection of the LV wall to measure myocardial thickness and to correct for the partial volume effect. Actual regional flow values were then calculated by use of the experimental relation between ammonia uptake and microsphere-determined MBF as obtained in an animal study.23 The homogeneity of MBF distribution throughout the left ventricle was evaluated by the coefficient of variation of the flow measurements in the six myocardial regions of interest (calculated as the ratio of the SD to the mean). Because the purpose of the present study was to compare the effect of different treatments on absolute MBF in the whole myocardium, the values of flow in the six LV myocardial regions were averaged to obtain a mean MBF value. Coronary flow reserve was calculated as the ratio between mean MBF after dipyridamole infusion and resting mean MBF; coronary resistance was calculated as the ratio of mean systemic arterial pressure and mean MBF.
Echocardiographic Protocol
Echocardiography was performed with a
Hewlett Packard 77020A phased-array ultrasound instrument with a
2.5-MHz transducer. All echocardiograms were evaluated blindly by two
independent echocardiographers who were not aware of the
clinical and scintigraphic findings and were not involved in the
pharmacological trial. Four consecutive beats were digitalized. The LV
volumes were computed from the two-dimensional and M-mode
echocardiographic recordings.25 LV
mass was calculated from the end-diastolic wall thickness
and cavity dimensions by use of Devereux's formula,26
with appropriate correction of echocardiographic data
according to the recommendations of the American Society of
Echocardiography. LV mass index was obtained by
dividing mass by body surface area (grams per square meter).
Intraobserver and interobserver variabilities for mass calculation in
our laboratory average 5%. LVH was defined as LV mass index >150
g/m2 for men and 120 g/m2 for
women.27
Statistical Analysis
All data are expressed as mean±SD. Two-tailed ANOVA, followed
by Scheffé's F test, was used for multiple comparisons among
groups and to compare data obtained in the same patients under
different conditions. Student's t test for paired samples
was used to compare data obtained in the same patient or under the same
condition in repeated studies. The efficacy of treatment on MBF was
defined as a flow increase after therapy exceeding the intermeasurement
variability in the reproducibility group (2 SD of the mean of the
difference between the two repeated measurements). Simple regression
analysis was used to correlate MBF and LV mass values. Values
of P<.05 were considered significant.
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Results |
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Clinical Characteristics
Table 1
gives the baseline
demographic, echocardiographic, and pressure data of
the 10 patients assigned to enalapril, the 10 patients assigned to
verapamil, the 8 patients in the reproducibility group, and
the 14 normotensive subjects. All the patients showed normal LV
function at the echocardiographic examination.
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All 20 patients in the treatment study tolerated the assigned drug well
during the 6 months of therapy; 4 patients in the enalapril group and 2
patients in the verapamil group needed additional therapy
with chlorthalidone. In both groups, adequate blood pressure control
was achieved after 1 month and maintained throughout the 6 months of
therapy (systolic/diastolic blood pressure
<160/90 mm Hg in all but 3 patients, who had values
<165/100 mm Hg). At the end of the 6-month treatment and
after the withdrawal of therapy, blood pressure returned to
pretreatment values within 1 week in both groups. After treatment,
there was no significant change in LV volume and function, as expressed
by values of fractional shortening, in both groups. According to the
echocardiographic criteria of LVH indicated above, 10
patients in the pharmacological trial at the pretreatment evaluation (4
in the enalapril and 6 in the verapamil group) and 5
patients in the reproducibility group were defined as hypertrophic. As
an average, LV mass index did not show significant changes after 6
months of therapy, whereas septal wall thickness decreased
significantly only in the verapamil-treated patients.
Nevertheless, LV mass index or septal wall thickness was reduced in 3
and 1 of the 4 hypertrophic patients in the enalapril group and in 3
and 5 of the 6 hypertrophic patients in the verapamil
group, respectively. Table 2 summarizes
LV mass index and volumes, fractional shortening, wall thickness, and
blood pressure data.
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Pretreatment MBF Study
The hemodynamic and MBF data obtained in the 28
hypertensive patients in the pretreatment study were compared with
those obtained in the group of normotensive subjects (Table 3). Mean MBF did not differ between
hypertensive and normotensive subjects at rest. During atrial pacing
tachycardia, MBF increased significantly in both groups but
was significantly lower in hypertensive than in normotensive subjects.
After dipyridamole infusion, mean MBF increased
significantly compared with baseline values in both groups but was
significantly lower in hypertensive patients; similarly,
coronary flow reserve was significantly depressed in
hypertensive patients compared with normotensive subjects (Table 3 and
Fig 1). Coronary resistance was
significantly higher in hypertensive patients than in control subjects
under all the study conditions (Table 3). Regional MBF distribution,
evaluated by the coefficient of variation, was significantly more
dyshomogeneous in the hypertensive group than in normal
subjects.
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) and for hypertensive patients (
).
*P<.05; **P<.01.
Data from hypertensive patients with and without LVH were comparatively
analyzed; no significant differences could be found in
hemodynamic, MBF, and coronary resistance data
between the two groups of patients (Table 4). Compared with the nonhypertrophic
patients, the hypertrophic patients showed a tendency toward a higher
dyshomogeneity of MBF under all the study conditions, although these
differences did not reach statistical significance.
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Fourteen hypertensive patients—5 in the enalapril group, 4 in the
verapamil group, and 5 in the reproducibility group—showed
transient ST-segment depression (1.5 mm at 0.08 second after the
J point) during pacing tachycardia. Four hypertensive
patients—1 in the enalapril group and 3 in the verapamil
group—showed transient ST-segment depression (1.5 mm at 0.08
second after the J point) during dipyridamole
administration.
Reproducibility of MBF Measurements
Both resting and pacing flow measurements were repeated in 8
hypertensive patients (reproducibility group) within 4 hours from the
first study under superimposable hemodynamic conditions
and according to the same protocol. At rest, in the repeated measures,
mean MBF was 0.80±0.17 versus 0.82±0.28 mL ·
min-1 · g-1
(P=NS), and mean coronary resistance was 139±34
versus 137±45 mm Hg/mL ·
min-1 · g-1
(P=NS). During atrial pacing, the repeated measures of mean
MBF were 1.20±0.20 versus 1.27±0.52 mL ·
min-1 · g-1
(P=NS); of mean coronary resistance, 105±25 versus
108±44 mm Hg · mL-1 ·
min-1 · g-1
(P=NS). The mean±SD of the difference between the two
repeated flow measurements was 0.021±0.165 mL ·
min-1 · g-1.
We chose 2 SD of the mean of the difference (0.33 mL ·
min-1 · g-1)
as the cutoff value to define a change in individual MBF between
repeated studies not caused by the intrinsic or
physiological variability of PET measurements.
Effect of Therapy on MBF
No significant difference was found between the two groups of
hypertensive patients enrolled in the pharmacological trial in the
hemodynamic and flow data obtained before treatment
under all study conditions (Table 5). In
each group, no significant difference was observed in the
hemodynamic measurements obtained during the PET study
before and after treatment (Fig 2).
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Mean MBF at rest did not change after therapy with respect to
pretreatment values in both the enalapril (0.96±0.22 versus 0.91±0.27
mL · min-1 ·
g-1, P=NS) and
verapamil (0.95±0.23 versus 0.96±0.27 mL ·
min-1 · g-1,
P=NS) groups; mean MBF during pacing tachycardia
did not change after enalapril (1.68±0.45 versus 1.50±0.29 mL
· min-1 ·
g-1, P=NS) but significantly
increased after treatment with verapamil (2.34±0.65 versus
1.71±0.42 mL · min-1 ·
g-1, P<.01). Similarly, mean MBF
after dipyridamole infusion did not change in the
enalapril group (2.29±0.80 versus 2.17±0.77 mL ·
min-1 · g-1,
P=NS) but increased significantly in the
verapamil group (3.47±1.65 versus 2.69±1.35 mL ·
min-1 · g-1,
P<.05; Fig 3).
Coronary reserve did not change in the enalapril-treated
patients (2.37±0.59 versus 2.42±0.72, P=NS) and increased
at 6 months in the verapamil-treated patients (3.73±1.79
versus 2.74±0.80, P<.05). The inhomogeneity of regional
MBF distribution, evaluated by the coefficients of variation, decreased
at rest after both treatments and during pacing tachycardia
in the enalapril-treated patients (Fig 3). At rest, coronary
resistance after therapy was at the pretreatment level in both the
enalapril (130±27 versus 145±37 mm Hg/mL ·
min-1 · g-1,
P=NS) and verapamil (140±34 versus 141±49
mm Hg/mL · min-1 ·
g-1, P=NS) groups. After therapy,
coronary resistance during pacing tachycardia and
after dipyridamole was significantly reduced compared
with the pretreatment values in the verapamil group (63±23
versus 82±28 mm Hg ·
mL-1 ·
min-1 · g-1,
P<.01; 43±19 versus 52±19 mm Hg ·
mL-1 ·
min-1 · g-1,
P<.05, respectively) but not in the enalapril group (77±17
versus 86±20 mm Hg ·
mL-1 ·
min-1 · g-1;
57±22 versus 60±17 mm Hg ·
mL-1 ·
min-1 · g-1,
respectively, P=NS).
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According to the cutoff values defined in the reproducibility study, in
the enalapril group, 2 of 10 patients showed an increase and 2 of 10
patients a decrease in resting MBF, 1 of 7 patients showed an increase
and 1 of 7 patients showed a decrease in pacing MBF, and 4 of 10
had an increase and 2 of 10 patients had a decrease in
dipyridamole MBF after treatment. In the
verapamil group, 1 of 10 patients showed an increase and 1
of 10 patients showed a decrease in resting MBF, while MBF increased in
6 of 7 patients during pacing and in 7 of 10 patients after
dipyridamole. Scans obtained before and after therapy
in two representative patients of the enalapril and
verapamil groups are represented in the top and
bottom, respectively, of Fig 4. Fig 5 shows the individual MBF changes after
therapy.
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Among the 9 patients with ST-segment depression during the pretreatment pacing study, 3 (2 on enalapril and 1 on verapamil) showed a normal ECG response during atrial pacing 6 months after therapy. Among the 4 patients with ST-segment depression during the pretreatment dipyridamole study, 2 (1 on enalapril and 1 on verapamil) showed a normal ECG response during dipyridamole 6 months after therapy.
Of the 10 patients with LVH at the pretreatment evaluation, 6 had shown a reduction in LV mass after 6 months of therapy. No correlation was found in hypertrophic patients between percent change in LV mass index after treatment and percent change in resting MBF (r=.28, P=NS), pacing MBF (r=.54, P=NS), and dipyridamole MBF (r=.49, P=NS).
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Discussion |
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This is the first single-blind, randomized trial in which PET was used to quantify absolute MBF, coronary resistance, and MBF reserve in a group of hypertensive patients with angiographically normal coronary arteries before and 6 months after successful therapy with enalapril or verapamil (titrated to obtain effective blood pressure control). The main purpose of the study was to assess the differential effects of long-term treatment with ACE inhibitors or calcium channel blockers on the vasodilating properties of the coronary microcirculation in patients with systemic hypertension. To exclude either the acute pharmacological effects of the drugs or the possible interference of different blood pressure levels with the coronary circulatory function, the posttherapy PET study was performed 1 week after the discontinuation of treatment, when blood pressure had returned to pretreatment levels.
Successful long-term therapy with verapamil did not change myocardial perfusion at rest but significantly reduced coronary resistance and increased MBF during both metabolic and pharmacological vasodilation. The favorable changes in coronary resistance and MBF after treatment were unrelated to changes in LV mass, suggesting that the improvement in coronary vasodilating capability after verapamil was due mainly to regression of coronary microcirculatory abnormalities. Conversely, patients treated with enalapril did not show significant changes in MBF with respect to the pretreatment evaluation. Nevertheless, both treatments, particularly enalapril, caused a more homogeneous MBF distribution compared with the pretreatment study, suggesting an improved matching between myocardial mass and perfusion after therapy.
Coronary Microvascular Abnormalities in Systemic
Hypertension
Angina, a common symptom in systemic hypertension, frequently
occurs in the absence of angiographically evident coronary
atherosclerosis. In these patients, an abnormal
coronary vasodilatory reserve, demonstrated in previous
studies,1 2 may prevent an adequate MBF response to an
increase in metabolic demand,3 thus eventually
causing myocardial ischemia.4 To explain these
observations, the relation between systemic hypertension, associated
myocardial-vascular changes, and coronary microcirculatory
function was investigated.
Experimental studies suggest that "myocardial remodeling," including myocyte hypertrophy, interstitial fibrosis, and inappropriate vascular growth secondary to high blood pressure, may limit maximal coronary flow28 29 and cause diastolic dysfunction and subendocardial ischemia during stress.30 31 Also in human studies, the reduction of coronary flow reserve in hypertensive patients has been ascribed mainly to a myocardial factor, ie, the hemodynamic, metabolic, and anatomic effects of LVH,1 2 4 5 6 as in patients with aortic stenosis32 and hypertrophic cardiomyopathy.33 However, reduced coronary flow reserve was also described in hypertensive patients without LVH3 and in the nonhypertrophied walls of patients with hypertrophic cardiomyopathy34 ; furthermore, in large populations of hypertensive patients, no direct correlation between myocardial mass and coronary vascular resistance could be demonstrated.14 35 These observations, together with further experimental results, suggested that in hypertension a process of "vascular remodeling,"9 36 beyond a possible compensatory role to protect the myocardium against excessive perfusion pressures,37 may limit the vasodilating capability of the coronary microcirculation independent of myocardial changes.9 10 Besides structural changes of the coronary microvessels, abnormalities of coronary microcirculatory function were also demonstrated in hypertension, including an upward shift in the lower range of coronary flow autoregulation38 and endothelial dysfunction.12 13
Even if the primary goal of this study was not to explore the mechanisms of MBF abnormalities in hypertension, the present results may add useful information compared with previous clinical reports. In the present study, PET permitted an absolute estimate of MBF per gram of tissue at rest and during metabolic and pharmacological vasodilating stimuli. The study population was made up of mostly untreated patients with recently diagnosed mild to moderate hypertension, with and without LVH, and with angiographically normal coronary arteries. In the pretreatment study performed in 28 hypertensive patients, coronary resistance at rest was elevated but MBF was not different from that measured in normal subjects, in patients both with and without LVH. These results are consistent with those obtained in the few clinical studies in which absolute flow values per gram of tissue could be obtained2 3 10 and suggest that coronary vascular growth is appropriate to ensure an adequate resting perfusion of myocardial mass in hearts exposed to high blood pressure, in keeping with some experimental observations.39 Absolute MBF values during pacing tachycardia or after dipyridamole were actually reduced in hypertensive patients compared with normal subjects, again both in patients with and without LVH. This abnormality may depend on multiple vascular mechanisms, including adenosine metabolism in the myocardium,40 myogenic regulation of coronary resistance in response to elevated pressure,41 structural changes of the intramyocardial coronary arterioles,8 9 10 and endothelial dysfunction.42 Myocardial remodeling28 29 and extravascular compressive forces may have had an additional role in limiting MBF in the study population. However, although increased end-diastolic wall stress was demonstrated to cause reduced subendocardial coronary reserve in response to adenosine infusion in dogs with severe LVH,31 the role of structural alterations of the myocardium has been questioned.31 In the present study, only half of the hypertensive patients had LVH; both patients with and without LVH had normal values of MBF per unit mass at rest and a similar reduction of MBF during stress. Accordingly, structural alterations of the myocardium possibly associated with LVH do not seem to play a major role in limiting myocardial perfusion in this population. Because diastolic dysfunction may be associated with the hypertensive disease even in the absence of LVH,44 45 the relative role of such abnormalities in limiting MBF to the subendocardial layers in this population cannot be inferred.
Effects of Antihypertensive Treatment on MBF in Systemic
Hypertension
Alterations in the interstitium, with interstitial and
perivascular fibrosis possibly involving the coronary
vasculature,46 are assumed to contribute to the adverse
prognostic role of LVH in hypertensive patients.47
Accordingly, most therapeutic trials in hypertension have focused on
the ability of different drugs not only to lower blood pressure but
also to cause regression of myocardial hypertrophy and
remodeling. These studies have shown that although not all forms of
antihypertensive therapy lead to a regression of myocardial
hypertrophy,48 49 ACE inhibitors
and calcium channel blockers are effective in reducing both blood
pressure and LV mass.50 51 52 53 There is also experimental
evidence that both ACE inhibitors and calcium channel
blockers lead to a regression of myocardial fibrosis,54 55
which may contribute to the improvement of diastolic
function observed after long-term treatment.56
Because antihypertensive treatments are able to reverse peripheral vascular abnormalities in hypertension,57 58 59 it is conceivable that they may have a similar favorable effect on the coronary circulation. In experimental models, ACE inhibitors prevented myointimal proliferation, attenuated the medial thickening of intramyocardial coronary arteries, and enhanced coronary vascular reserve.54 60 Similarly, some calcium channel blockers have been shown to reverse media hypertrophy of coronary resistance vessels.61 The few available studies in diseased populations showed a variable effect on coronary blood flow of acute administration of ACE inhibitors19 62 63 and a favorable effect of calcium channel blockers.21 22 64
Our results, obtained after long-term antihypertensive treatment in a population of patients with mild to moderate hypertension, indicate that the calcium channel blocker verapamil reduces coronary resistance and increases MBF in response to pacing tachycardia and dipyridamole infusion compared with the pretreatment study. As far as the mechanisms of this beneficial effect are concerned, it is unlikely that myocardial and hemodynamic factors played a major role because flow improvement was present in patients with and without LVH at enrollment and at comparable blood pressure and cardiac work levels between the pretreatment and posttreatment studies. Resting MBF and coronary resistance did not change after verapamil treatment, suggesting that autoregulatory myogenic mechanisms were not involved. Accordingly, the net effect of verapamil in reducing total coronary resistance and increasing MBF during vasodilating stimuli can be explained only by a partial regression of structural and/or functional abnormalities of the coronary microcirculation at the level of either the arteriolar segments responsive to metabolic stimuli and/or the small vessel segment that is more dependent on endothelial function and nitric oxide synthesis.42 The mechanisms for this effect cannot be stated from the present study and could involve the amelioration of one or more of the following abnormalities already demonstrated in clinical hypertension: vascular remodeling,10 endothelial dysfunction,11 12 13 15 22 or diastolic LV dysfunction.44 45 56 65 A possible antiischemic effect of verapamil66 could not be assessed because the drug was withdrawn 1 week before the atrial pacing evaluation. The ACE inhibitor enalapril could improve myocardial perfusion in a minority of patients, but in the whole treated group, MBF and coronary resistance at rest, during atrial pacing, and after dipyridamole infusion were not significantly changed. A few studies on a limited number of patients are available on the acute or chronic effects of ACE inhibitors on coronary flow in hypertensive patients with no evidence of ischemic heart disease.19 62 67 68 The primary direct evidence of a favorable effect of ACE inhibition in these patients comes from the study of Magrini et al19 in which the acute administration of cilazapril induced an increase in coronary blood flow at rest and during isometric exercise in patients with renovascular hypertension and high plasma renin activity. However, only the direct effect of this drug on coronary microcirculation could be assessed because flow measurements were performed under enalapril. In the present study, despite the beneficial effects of enalapril on blood pressure and LVH, MBF showed no significant change after treatment during vasodilating stimuli with a high variability of individual behaviors. Unlike previous reports, in this study enalapril was administered orally, and measurements were obtained 1 week after the drug withdrawal, so its direct pharmacological effect on coronary circulation was not evaluated. The possible relationship between individual plasma renin activity and the response of coronary flow to ACE inhibitor treatment69 also was not assessed. Moreover, because the most favorable effects of ACE inhibition are exerted on myocardial and vascular remodeling, which accompany long-standing hypertension with LVH, it is conceivable that they would be less evident in our population of patients with mild to moderate hypertension in whom hypertrophy was present in 50%.
A final result to be underlined is the efficacy that both chronic treatments, particularly enalapril, showed to reduce the inhomogeneity of regional MBF distribution. The coefficient of variation, an index of flow inhomogeneity, was increased in hypertensive patients compared with normal subjects under all study conditions. After treatment, it showed a tendency toward normalization that was significant at rest after verapamil and both at rest and during pacing after enalapril. The favorable effects that both drugs could have on myocardial remodeling, particularly on the collagen content of the heart muscle and the metabolic requirements of the myocardium, could reduce inhomogeneity of myocardial structure and function and consequently reduce inhomogeneity in perfusion.
Study Limitations and Conclusions
The limitations of the present study include the lack of a
placebo-controlled group and the absence of flow data during treatment.
Instead, the purpose of the study was to evaluate whether successful
antihypertensive therapy could exert a beneficial effect on
coronary vasculature altered by the hypertensive state.
The definition of blood pressure control (reduction of systolic and diastolic blood pressure >10% of the baseline values) might have resulted in the possibility of inadequate control in a number of patients. However, because all patients had mild to moderate hypertension, the response to therapy was adequate in all. Moreover, because of the small number of patients enrolled, the results should be extrapolated cautiously to the general population of hypertensive patients. Exclusion from analysis of those patients with no satisfactory control of blood pressure by therapy does not allow these findings to be expanded to unsuccessfully treated patients.
In conclusion, our pharmacological trial in patients with mild to moderate hypertension indicates that successful long-term therapy with verapamil is able to improve MBF response to tachycardia and coronary flow reserve. This effect is not related to the reduction in LV mass and persists 1 week after the withdrawal of the drug, suggesting that verapamil favorably affects functional or structural abnormalities of coronary circulation present in systemic hypertension. Long-term antihypertensive treatment, particularly with enalapril, is also able to reduce the inhomogeneity of regional MBF distribution, exerting a favorable effect on the matching between myocardial mass and perfusion.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by the CNR-Targeted Project Prevention and Control of Disease Factors, subproject Control of Cardiovascular Disease, from the National Council of Research, Rome, Italy. We are indebted to Nicola Nista, Giacomo Puccini, and Oreste Sorace from the PET unit; to Piero Salvadori, Lucio Fusani, Sonia Di Sacco, and Alessandro Riva from the Cyclotron unit for their technical collaboration in the acquisition of the scintigraphic data; and to Ilaria Citti for her assistance in the preparation of the manuscript.
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This study was presented in part at the 65th Annual Scientific Sessions of the American Heart Association, New Orleans, La, November 16-19, 1992.
Received August 13, 1996; revision received February 10, 1997; accepted February 13, 1997.
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