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Time Course of the Effects of Temocapril on Cardiovascular Structure and Function in Patients with Essential Hypertension

Takata, Masanobu; Ueno, Hitoshi; Hirai, Tadakazu; Oh-hashi, Shinya; Yasumoto, Kotaro; Inoue, Hiroshi

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Journal of Cardiovascular Pharmacology: October 1999 - Volume 34 - Issue 4 - p 561-566
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Abstract

Current knowledge on essential hypertension has suggested the importance of cardiovascular hypertrophy, which is postulated to contribute not only to increased vascular resistance but also to the maintenance of hypertension (1-3). Various functional and structural cardiovascular changes also ultimately lead to end-organ damage. Therapeutic interventions that reverse the cardiovascular abnormalities as well as normalize blood pressure are increasingly appreciated as being important, because the ultimate goal of antihypertensive treatment is to reduce hypertension-induced mortality and morbidity (4).

Previous studies showed that some classes of antihypertensive agents cause regression of hypertrophied cardiovascular structures in animal models (5,6). It is well known that angiotensin-converting enzyme (ACE) inhibitors reverse hypertensive left ventricular hypertrophy more effectively than do other classes of antihypertensive drugs (7-9). As shown with the reversal of left ventricular hypertrophy, ACE inhibitors may also cause regression of arteriolar abnormalities seen in hypertension (10,11). However, the long-term effect of ACE inhibitors on large arteries is unclear, although that on the radial artery has been examined (12).

Decrease in arterial pressure by ACE inhibitors undoubtedly contributes to regression of cardiovascular hypertrophy, but involvement of other factors cannot be excluded. Particularly blockade of the renin-angiotensin system per se could lead to the improvement of cardiovascular structure and function without reducing blood pressure (13,14). These observations have stimulated a great deal of interest regarding pharmacologic intervention to suppress or reverse cardiovascular structural changes in hypertensive patients (4,14).

Temocapril (CS 622) is a novel ACE inhibitor that is equally excreted via the renal and hepatic pathways (15). Prolonged administration of temocapril suppresses the increased myogenic tone of aorta in spontaneously hypertensive rats, and the decrease in myogenic tone paralleled the decrease in blood pressure induced by this drug (16). The purpose of our study was to determine the time course of regression of vascular structural changes during 1-year monotherapy with temocapril. To this end, we determined the time course of the following changes in untreated patients with essential hypertension; cardiac structure and function, postischemic forearm minimal vascular resistance, and arterial distensibility (stiffness β of carotid artery).

PATIENTS AND METHODS

Patients

Fifteen outpatients (six men and nine women) with mild to moderate essential hypertension (WHO stages I and II) were entered in the study. The mean age was 52 years (range, 22-69 years) of 13 patients who continued the study for 1 year. These patients had not previously received antihypertensive treatment. At the start of the study, cardiac enlargement or left ventricular hypertrophy, as detected by radiographs or electrocardiograms (ECG) or both, were present in 10 patients. All patients had normal renal function (serum creatinine, <1.3 mg/dl). No abnormalities were found on urinalysis. Blood pressure was measured by using a standard cuff sphygmomanometer after 5-10 min of rest in the sitting position. During a control period of 4 weeks, a placebo was given. In each patient, the systolic or diastolic blood pressure was ≥160 or 95 mm Hg, respectively, on three separate occasions during the control period. After the purpose and procedures of the study had been explained, all patients gave informed consent to participation.

Study protocol

After the placebo period, patients were treated with temocapril. The test drug was introduced at a dose of 1 mg once a day. This dosage was doubled every 2 weeks to a maximum dose of 4 mg daily until blood pressure was reduced by >20 mm Hg in systolic and 10 mm Hg in diastolic pressure, or to <90 mm Hg in diastolic pressure. After 8 weeks, an adequate decrease of blood pressure was observed in all patients. The patients then remained on the same dosage until the end of the study. Blood pressure and pulse rate were measured fortnightly with a sphygmomanometer throughout the study. Detailed testing was performed at the end of the placebo period and after 2, 6, and 12 months of temocapril monotherapy. On the test day, patients had refrained from caffeine, alcohol, and smoking since the previous evening and ate only a light breakfast 3 h before the investigation. Patients were asked to take the prescribed dose of temocapril or placebo before coming to the hospital in the morning.

Testing began at 9:30 a.m. and lasted for ∼3 h. After 1 h of resting in the supine position in a quiet room, the supine blood pressure and heart rate were measured at 5-min intervals. The room temperature was kept at 22-26°C. Echocardiography was done after ∼30 min of rest in the supine position, and then maximal forearm blood flow was measured. Finally, large arterial distensibility (stiffness β of carotid artery) was determined by the ultrasonic tracking method.

We used 15 age-matched normotensives as controls (seven men and eight women aged 41-60 years; mean age, 52 ± 11 years).

Echocardiography

M-mode echocardiography was performed with two-dimensional monitoring by using a Toshiba SSH-160A phased array ultrasonic sector scanner and a Toshiba FR-08A recorder (Toshiba, Tokyo, Japan). All patients were studied in the supine or left lateral position with a transducer placed in intercostal spaces three to five at the left sternal border, and tracings of left ventricular diameters and posterior wall and septal thickness were measured at the level of the tip of the mitral valve leaflets, according to the criteria of the American Society of Echocardiography (17). The echocardiograms were read blindly in random order by two independent observers. Left ventricular mass was calculated with the method of Devereux, corrected with appropriate regression equation (18). The left ventricular mass index was derived by dividing the calculated left ventricular mass by the patient's body surface area. The percentage of left ventricular fractional shortening was determined as a marker of left ventricular systolic function. Transmittal Doppler flow recordings also were obtained in the apical two-chamber view with the sample volume placed at the mitral annulus. The peak velocity of early filling to peak velocity of late filling ratio was obtained as a marker of left ventricular diastolic function (19).

Forearm plethysmography

Blood flow was recorded in the right forearm by venous occlusion plethysmography with mercury-in-Silastic gauges (20,21). The pressure of venous occlusion or congesting cuff was 40 mm Hg. The strain gauge was placed ∼5 cm below the antecubital line. Circulation to the hand was arrested by inflating a pediatric cuff around the wrist to 50 mm Hg above the systolic blood pressure for 1 min before starting blood-flow measurement. Blood pressure was measured in the other arm with a sphygmomanometer. Maximal forearm blood flow was measured during reactive hyperemia, which was induced by cutting off blood flow to the forearm with a cuff inflated to 50 mm Hg above the systolic blood pressure of the upper arm for 10 min. The average of three measurements represented the maximal forearm blood flow in each patient. Minimal forearm vascular resistance was calculated by dividing the mean arterial pressure (diastolic pressure plus one third of the pulse pressure) by maximal forearm blood flow (mm Hg/ml/min per 100 ml tissue: PRU).

Measurement of arterial distensibility

The transverse displacement of the arterial wall was measured with an ultrasonic phase-locked echo-tracking system, which was equipped with a 7.5-MHz real-time linear array scanner. The details of this method have been described elsewhere (22,23). In brief, this technique was based on a phase-locked loop method that allows the zero-crossing phase of the echoes reflected from the arterial wall to be tracked, allowing noninvasive recording of the transverse displacement of the walls of the right and left carotid arteries. Then the brachial arterial pressure was measured by sphygmomanometer. The index "β," a measure of the vascular wall stiffness, was calculated as follows: Equation (1) where Ps is systolic pressure, Pd is diastolic pressure, Ds is the external diameter at systole, and Dd is the external diameter at diastole. This stiffness index provides a reliable measure of elasticity because it is independent of arterial pressure.

Statistics

All values are expressed as mean ± standard deviation. Two-way analysis of variance followed by partitioning analysis (24) was used for the four studies done before and after temocapril. Data for blood pressure and pulse rate after temocapril therapy were analyzed by two-way analysis of variance followed by paired t test. Unpaired t test was used for parameters between hypertensives and controls. Correlations were calculated by linear-regression analysis. Differences were considered significant at p < 0.05.

RESULTS

Two patients withdrew after 6-7 weeks of treatment because of adverse effects, including cough in one (51 years old) and diarrhea in one patient (48 years old). The maintenance dose of temocapril was 1 mg/day in two patients, 2 mg/day in nine patients, and 4 mg/day in two patients. Thirteen patients continued the study for 12 months at their respective effective doses, and therefore constituted the study group.

Blood pressure and heart rate

During the placebo period, sitting blood pressure in the study group was 173 ± 17/103 ± 8 mm Hg and was higher than that in controls (105 ± 9/81 ± 7 mm Hg; p < 0.01 and p < 0.01, respectively). Temocapril decreased blood pressure to 139 ± 7/86 ± 3 mm Hg after 2 months (p < 0.01 and p < 0.01), and this hypotensive effect was sustained throughout the treatment period (F = 37.7 and 54.5, p < 0.01 and p < 0.01 for systolic and diastolic blood pressure, respectively; Table 1). The percentage decrease of mean blood pressure was correlated significantly with pretreatment blood pressure (r = −0.89, −0.77, and −0.89; p < 0.01, <0.01, and <0.01 at 2, 6, and 12 months, respectively). Heart rate remained unchanged (F = 1.7; NS).

TABLE 1
TABLE 1:
Hemodynamic and echocardiographic data during the placebo period and during temocapril monotherapy in patients with essential hypertension

Echocardiographic parameters

Two patients were excluded from this analysis because their recordings were poor in quality. Temocapril decreased the total peripheral resistance (F = 10.3; p < 0.01), but did not change the cardiac index (Table 1). Mean baseline left ventricular mass index in the study group was 120 ± 40 g/m2, and was greater than that in controls (85 ± 10 g/m2; p < 0.01). After starting treatment with temocapril, left ventricular mass index decreased to 106 ± 29 g/m2 in the second month, 98 ± 26 g/m2 in the sixth month, and 88 ± 21 g/m2 in the twelfth month (F = 13.3; p < 0.01; Fig. 1). The percentage decrease of left ventricular mass index was ∼23% at the end of the treatment period. Both interventricular septal thickness in diastole and the posterior wall thickness in diastole decreased significantly during temocapril therapy (F = 11.4 and 16.7; p < 0.01 and <0.01, respectively). However, the left ventricular internal diameter in diastole remained unchanged throughout the treatment phase. Thus the reduction of left ventricular mass index was mainly the result of a reduction of left ventricular posterior and interventricular thickness. Fractional shortening did not change significantly with temocapril therapy. The peak velocity of early filling to peak velocity of late filling ratio was also unchanged. Thus temocapril treatment for 1 year did not change either systolic or diastolic function.

FIG. 1
FIG. 1:
Time course of echocardiographic parameters during temocapril treatment. LVMI, left ventricular mass index; IVSTd, interventricular septal thickness in diastole; PWTd, posterior wall thickness in diastole; LVDd, left ventricular diameter in diastole. Values expressed as mean ± SD. **p < 0.01 versus placebo.

Forearm plethysmography and common carotid artery stiffness index

Maximal forearm blood flow was 57.6 ± 19.3 ml/min per 100 ml tissue during the placebo period, and tended to increase by the end of treatment. Minimal vascular resistance was significantly higher in the untreated hypertensive patients than in the normotensive subjects (2.1 ± 0.5 vs. 1.2 ± 0.3 PRU; p < 0.01). Minimal vascular resistance decreased to 1.8 ± 0.4 PRU in the second month, 1.7 ± 0.3 PRU in the sixth month, and 1.6 ± 0.4 PRU in the twelfth month of temocapril therapy (F = 6.27; p < 0.01; Fig. 2). Minimal vascular resistance decreased in 12 patients, but increased in one patient with normal resistance during the placebo period. The changes in minimal forearm vascular resistance did not correlate with age, estimated duration of hypertension, or blood pressure response to treatment.

FIG. 2
FIG. 2:
Time course of the minimal forearm vascular resistance and stiffness index β in patients during temocapril treatment.

The stiffness index β was higher in untreated hypertensive patients than in controls (11.4 ± 4.9 and 7.5 ± 2.5; p < 0.05). When the regression equation corrected by age derived from 40- to 80-year-old normotensive subjects was applied (23), the control stiffness index would be 8.5 ± 1.6. In 12 of the 13 patients (except one aged 41 years), the β value was higher than the predicted normal value. After starting temocapril, β was 10.1 ± 4.1 in the second month, 11.5 ± 4.3 in the sixth month, and 11.6 ± 3.8 in the twelfth month (F = 1.1; NS). Thus treatment with temocapril for 1 year did not change the carotid artery stiffness index.

DISCUSSION

The major findings of this study were as follows. First, the regression of structural changes of left ventricle and arterioles were found within 2 months after temocapril and occurred gradually and progressively for 1-year treatment. Second, 1-year treatment with ACE inhibition did not affect large arteries in spite of the regression of structural changes of left ventricle and arterioles. To our knowledge, this was the first report to indicate that the time course of left ventricular and vascular structural changes seen in essential hypertension after ACE inhibition does not evolve in parallel.

There is a general consensus that ACE inhibitors are particularly effective in reducing left ventricular hypertrophy. Dahlöf et al. (7,25) reported that ACE inhibitors decrease left ventricular mass significantly when compared with other first-line agents including diuretics, β blockers, or calcium antagonists, which is reinforced by a recent meta-analysis of randomized double-blind studies (9). Our study demonstrated that the degree of regression of left ventricular mass index induced by temocapril was similar to that achieved by other ACE inhibitors. Left ventricular mass regression was mainly due to diminished wall thickness, whereas the left ventricular diameter was not changed after temocapril treatment. In the course of regression of left ventricular mass, temocapril monotherapy decreased left ventricular hypertrophy gradually and progressively for ≥1 year. These results were comparable with those achieved by using α blocker, β blocker, or another ACE inhibitor (26-28). Recently Franz et al. (29) studied the left ventricular hypertrophy in 23 patients for 3 years of treatment with quinapril. They showed that the reversal of left ventricular hypertrophy was a time-consuming process and that the complete normalization was found in 90.5% of the patients after 38.3 ± 3 months with the treatment. These results suggest that a period of >1 year would be needed to assess the regression of left ventricular mass, although the average treatment period was only ∼6 months in the meta-analyses (7,9). Despite the regression of left ventricular hypertrophy, neither systolic nor diastolic function was affected by temocapril. The reason for this may be that left ventricular function during the placebo period was not abnormal, because subjects with mild to moderate hypertension were enrolled in this study.

As Folkow (1) first proposed on the basis of experimental evidence, essential hypertension may be the consequence of a vicious circle, in which the structure of resistance vessels changes in response to slightly elevated pressure, and these changes in turn elevate arterial pressure further, thereby maintaining hypertension. The minimal vascular resistance of the forearm and the histologic evidence obtained by Mulvany's method have shown that hypertension is associated with an increased wall/lumen ratio, although it is unclear whether this increased ratio is caused by vascular growth or vascular rearrangement (3). Similar to left ventricular hypertrophy, smooth muscle vascular cells seem to adapt to pressure changes as a compensatory response that prevents increase in wall tension or stress because of Laplace's law. Experimental studies have demonstrated that arteriolar structural changes are reversible by long-term antihypertensive treatment, but different drugs seem to have different effects (30). In human hypertension, there have been a large number of studies on left ventricular hypertrophy and a smaller number of studies suggesting that arteriolar structural changes can also be reversed by ACE inhibitors.

However, little information is available concerning the time course of regression of vascular changes. Schiffrin et al. (31,32) reported that 1-year treatment with cilazapril decreased the media-to-lumen ratio of small arteries obtained by gluteal biopsy from patients with essential hypertension, although it remained greater than that of vessels from normotensive subjects. In their studies, after 2 years, the ratio decreased further to the level seen in normotensive subjects. However, the luminal diameter was decreased at 1 year, but then returned to the pretreatment level, possibly due to the heterogeneity of small arteries. Thybo et al. (33) reported that perindopril treatment caused a decrease in the media-to-lumen ratio of small arteries, an effect not seen with atenolol, supporting the possibility that ACE inhibitors achieve greater normalization of the resistance vessels than do β blockers. The minimal forearm vascular resistance obtained by plethysmography is an indirect parameter of arteriolar structural changes, and reflects the media-to-lumen ratio of omental or subcutaneous small arteries (34). It is reported that calcium blockers, ACE inhibitors, and combined antihypertensive drugs all reduce minimal vascular resistance (10,21,35,36). In our study, minimal forearm vascular resistance decreased gradually from 2 months after starting temocapril. At the end of the study, a significant decline of minimal vascular resistance was observed, but complete normalization was not achieved. Thus improvement of small arteries seems to be evident as early as 2 months after the start of temocapril treatment, but proceeds gradually and progressively for ≥1 year.

Elastic arteries also play an important role in cardiovascular homeostasis through their conduit and buffering functions (37). Medial hypertrophy is induced by an increase in smooth-muscle cell mass, an increase in connective tissue components synthesized by these cells, such as collagen and glycosaminoglycans, and an increase in intracellular calcium that enhances arterial stiffness (6). The type of arterial-wall mass change differs along the arterial tree. Large conduit arteries show an increase of collagen and a loss of elasticity in hypertension, thereby losing pressure-equalizing and buffering function. Reduced compliance in large arteries implies an increased load on the heart, thus facilitating the development of cardiac hypertrophy. Safar et al. (12,38) demonstrated an increase in brachial artery diameter and compliance in hypertensive patients after treatment with ACE inhibitors or calcium antagonists. They demonstrated by using perindopril that these actions were not simply due to flow-dependent dilatation, but involved a drug-related relaxation of arterial smooth muscle. However, it is unclear whether long-term ACE inhibitor monotherapy can improve the structure and function of large elastic arteries in patients with essential hypertension, although an experimental study demonstrated that ACE inhibitors suppress the accumulation of elastin and collagen (39). Heterogeneity of the arterial tree is known to exist in humans (23,40). The carotid artery is an elastic artery like the thoracic aorta, whose wall characteristics differ from those of large muscular arteries such as the brachial artery or femoral artery. The stiffness index β reflects the entire deformation of the vascular wall, independent of intraluminal pressure over the physiologic range (22,23). This study demonstrated that the stiffness index of the carotid artery was unchanged by 1 year of temocapril therapy.

The mechanism of cardiovascular changes induced by ACE inhibition is unclear. Catecholamines, angiotensin, and aldosterone, as well as blood pressure per se, are known to influence the progression and regression of left ventricular hypertrophy. ACE also possesses kininase activity, and its inhibition therefore increases systemic and local levels of bradykinin. Recent studies suggest that bradykinin may play the principal role in the beneficial cardiovascular effects of ACE inhibition and that the mechanisms underlying these effects may be mediated by nitric oxide (41,42). Changes in vascular structure observed during the treatment may be due to a direct action of drugs on the vessel wall or to changes of hemodynamics, nervous activity, or plasma hormone levels. Sada et al. (43) demonstrated that long-term treatment with temocapril decreases the intracellular calcium level and decreases myogenic tone in aorta isolated from spontaneously hypertensive rats.

Because the purpose of the study was to assess the time course of regression of cardiovascular hypertrophy, it was important to choose a drug that did not require titration and promptly decreased arterial pressure as monotherapy in the majority of patients. In patients requiring a higher dose (4 mg/day, n = 2) of temocapril, the hypotensive period is shorter than in those requiring a lower dose (1 mg/day, n = 2), which may influence the results of cardiovascular changes after the short-term treatment. In our study, minimal vascular resistance, left ventricular mass, and stiffness β did not differ among three groups before and after temocapril, although higher-dose and lower-dose groups consisted of only two patients each (data not shown). Therefore we analyzed the data from 13 patients as a whole.

In conclusion, temocapril monotherapy improved structural changes in left ventricle and resistant vessels progressively for 1 year, but not large arterial stiffness. These results indicate that ACE inhibition has beneficial effects on cardiovascular abnormality, but that regression of left ventricular and vascular structural changes in essential hypertension after ACE inhibition does not evolve in parallel.

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Keywords:

Left ventricular hypertrophy; Vascular hypertrophy; Arterial distensibility; Angiotensin-converting enzyme inhibitor; Essential hypertension

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