Journal Logo

Article

Spontaneous Changes of Heart Rate, Blood Pressure, and Ischemia-Type ST-Segment Depressions in Patients with Hypertension without Significant Coronary Artery Disease: Beneficial Effects of β-Blockade

Christ, Michael*‡; Rauen, Peter*; Klauss, Volker*; Krüger, Thomas*; Frey, Axel; Theisen, Karl*; Wehling, Martin

Author Information
Journal of Cardiovascular Pharmacology: December 1996 - Volume 28 - Issue 6 - p 755-763
  • Free

Abstract

Increased myocardial oxygen demands are counter-balanced by an increase of perfusion, because oxygen extraction is near maximal in the heart during rest (1). In patients with hypertension without coronary artery disease (CAD) on angiograms, an impaired coronary flow reserve contributes to a mismatch of oxygen supply and demand, which is increased by left ventricular LV hypertrophy in ≤50% of patients with hypertension (2-7). Therefore angina pectoris and painless (“silent”) myocardial ischemia frequently occur in these patients, even in the absence of CAD or LV hypertrophy or both (8-10). These ischemic episodes may be stress dependent and expose a circadian rhythm with a higher frequency of myocardial ischemia during morning hours (11). Changes of the vascular tone of resistance arteries (12), impairment of endothelium-dependent coronary artery relaxation (13,14), changes of myocardial wall stress and myocardial geometry (15,16), or a combination of these seem to be the major causes of decreased coronary flow reserve in patients with hypertension without CAD. Thus pharmacologic therapy of hypertensive heart disease has to be focused not only on BP reduction but also on regression of myocardial hypertrophy (17) and microcirculatory changes (18). Because LV hypertrophy, disturbances of cardiac rhythm in combination with LV hypertrophy, and myocardial ischemia are independent risk factors for sudden cardiac death and are correlated with increased mortality (15,19-21), research on this pathologic entity should target the development of new therapeutic concepts for the treatment of cardiac complications in systemic hypertension.

The aim of our study was to evaluate the frequency of ischemia-type ST-segment depressions in patients with hypertension without significant CAD and further to characterize the pathophysiology of myocardial ischemia by simultaneous 24-h Holter and blood-pressure monitoring. These variables were compared with hemodynamic changes at rest and during exercise stress testing. Finally, the influence of long-term β-blockade by betaxolol on these variables was investigated in this group of patients in an open study design.

METHODS

Patients

Patients (age 30-75 years) with systemic hypertension (systolic BP ≥160 mm Hg or diastolic BP >90 mm Hg or both at three casual office recordings) and anginal pain were enrolled in the study. In all patients, heart catheterization was performed independent of the study because of suspected coronary heart disease. Patients with severe systemic hypertension (systolic BP > 195 mm Hg or diastolic BP > 110 mm Hg or both), secondary hypertension, severe heart disease (LV ejection fraction <50%), valvular heart disease, disturbances of excitation or propagation [bradycardia, sinoatrial (SA)-block, atrioventricular (AV)-block, left or right bundle branch block], ischemia-type ST-segment deviations (descending or horizontal depression ≥0.1 mV) at rest, renal failure (serum creatinine >1.5 mg/dl), pregnancy, disturbances of serum electrolytes, and relevant additional diseases (e.g., malignancies, thyrotoxicosis) or diseases that may influence cardiac microcirculation (diabetes mellitus, rheumatic diseases) were excluded.

Ambulatory blood-pressure monitoring and ST-segment analysis

Twenty-four-hour ambulatory blood-pressure measurement (ABPM), and 24-h Holter monitoring were performed simultaneously in all patients. For 24 h ABPM, the oscillometric recorder 90207 from SpaceLabs (SpaceLabs Inc., Redmond, WA, U.S.A.) was used (for accuracy and validation, see ref. 22). Application of the recorder and the first measurements were controlled by three consecutive parallel measurements of BP by the automatic monitor and by manual measurement according to the Riva-Rocci method with a standard sphygmomanometer. The cuff of the ABPM was placed on the left upper arm.

Measurement intervals were 10 min between 6 a.m. and 10 p.m. (daytime period) and 20 min between 10 p.m. and 6 a.m. (nighttime period). All 24-h measurements were completed.

For Holter monitoring, the ELATEC recorder (No.2448+, ELA Medical GmbH, Hamburg, Germany) was used (double channel, bipolar; amplitude-modulated; frequency, 0.05-100 Hz; input impedance >100 Ω). The precordial leads were placed in the CM 2 and CM 5 positions (corresponding to V2 and V5) after preparation of the skin in accordance with the American Heart Association (AHA) guidelines (23). The monitor was calibrated before each recording. Artificial ST-segment deviations caused by changes of position or hyperventilation were excluded by simultaneous recording of the ECG tracking by a standard 12-lead ECG recorder (Cardioscript CD 6000 digital, Schwarzer Picker International, München, Germany). Preexisting ST-segment deviations were an exclusion criterion (see the preceding). The ECG evaluation was done by a computer-assisted measurement of ST-segment depressions after individual adjustment of the isoelectric point in the PR segment and at an automatically heart-rate-adjusted distance of 60-80 ms past the J-point (ELATEC Version 2.05, ELA Medical GmbH, Hamburg, Germany). The evaluation was under visual control of an unbiased observer. Ischemiatype ST-segment depression was defined as a horizontal or descending shift of the ST segment from baseline level (≥-0.1 mV) of a duration of ≥1 min. All episodes were printed (paper speed, 25 mm/s) and controlled manually. Episodes of ST-segment depression were counted individually if separated by ≥1 min.

Ambulatory BP over a 24-h period, during daytime and nighttime, during ischemia-like ST changes (defined by significant ST-segment deviation, see preceding text) was measured by ambulatory BP monitoring; mean heart rate (HR) over 24 h, the number of premature ventricular complexes and HRs before or during ischemia-type ST-segment deviation were determined from Holter monitoring. Clocks in both devices were manually synchronized during the setup of the systems and by simultaneous marker signals. The 24-h difference of time was <5 s.

Analysis of variables

The following variables were analyzed: (a) number of episodes in each patient, duration of ischemia-type episodes (min), and maximal depression of ST segments (mV); (b) HR was measured 60 min, 30 min, and 10 min before, at the onset, at maximal ST-segment depression, and after the episodes; (c) BP values were obtained from readings next to these time points, and the rate-pressure product (RPP) was calculated (HR × systolic BP) from these values. Because of the discontinuous measurement of BP by the ABPM, RPP, and readings of ST changes may not have been obtained at exactly the same time.

Episodes of ST-segment depression were considered as being preceded by an increase in HR if increases >15% between the plateau level, as averaged for 10 min and the 10-min period before the beginning of ST-segment deviation, were recorded, and as being preceded by an increase in BP if increases >20 mm Hg systolic or 10 mm Hg diastolic were measured.

Determination of LV dimensions

LV dimensions and the thickness of interventricular septum (IVS) and left posterior wall (LPW) were determined by M-mode echocardiography from standard parasternal long-and short-axis views (SSH-160-A with a 2.5-MHz transducer-PSF 25 DT, Toshiba, Japan). For each variable mean values of ≥5 measurements of two independent investigators were obtained.

Exercise stress testing

Patients were subjected to a routine ergometer stress test. Starting at 25 W, workload was increased in 25-W steps up to 75 W in one patient, to 100 W in four patients, to 125 W in seven patients, to 150 W in three patients, to 175 W in three patients, and to 200 W in one patient. A 12-lead ECG (Case 12, Marquette Electronics Inc., Milwaukee, WI, U.S.A.) was recorded continuously, and BP measurements were taken 1 min after each increase of workload. Variables were measured for ≤6 min in the recovery period. Reasons to stop stress test were exhaustion, dyspnea, angina, or ST changes ≥0.2 mV for ischemic or ≤0.2 mV for other reasons.

Laboratory methods

Venous blood samples of fasting patients were obtained after 30 min of rest in the supine position in a quiet environment at 8 a.m. Routine laboratory parameters in serum and urine were determined by standard tests in a BM/Hitachi 717 (distributor: Boehringer Mannheim, Mannheim, Germany).

Study protocol

Nineteen patients were enrolled after the following criteria were evaluated.

  1. Exclusion of significant coronary artery stenoses (≥50%) in a routine cardiac catherization. Coronary angiography was performed in multiple views (seven to nine views for the left, two to four views for the right coronary artery) by using the Judkins technique and a biplane cineangiographic facility (Philips, München, Germany). Evaluations of coronary angiograms were done by two independent observers.
  2. Anginal pain.
  3. Arterial hypertension in three casual consecutive office measurements (systolic BP >160 mm Hg or diastolic BP >90 mm Hg or both). Inclusion and exclusion criteria were checked in consecutive patients. If accepted, patients were enrolled within 8 days after catherization.

After enrollment, any antiischemic or antihypertensive premedication was discontinued for ≥3 days under control of a physician. In the case of β-blockers, stepwise reduction of dose from 100 to 75 to 50% and 0 was done before this washout phase. No adverse reactions or consequent problems were noticed in connection with discontinuation of β-blocker treatment, which was done within 7 days. As emergency medication (systolic BP >180 mm Hg, or diastolic BP >110 mm Hg, anginal pain) nifedipine capsules (10 mg; patients were instructed to bite the capsules and to swallow the contents (24) or nitrates were tolerated. On day zero, the following measurements were performed: (a) venous blood-sampling for determination of laboratory variables (serum electrolytes, glucose, cholesterol, triglycerides, creatinine, hemoglobin); (b) assessment of the patients' history and clinical examination; (c) routine 12-lead ECG; (d) exercise stress testing; (e) 24-h monitoring of HR and BP, as described; (f) 24-h sampling of urine. Treatment by betaxolol was started at a dose of 10 mg/day given in a single oral dose with breakfast. Betaxolol is a β1-selective β-blocker with a plasma half-life of 16-22 h in humans, commonly used in the treatment of hypertension (Kerlone; Synthelabo, Puchheim, Germany).

On day 7, a clinical examination and BP measurement were performed. If systolic BP exceeded 160 mm Hg or diastolic BP exceeded 90 mm Hg, dose was increased to 20 mg/day in a single dose. In patients in whom a dose adjustment was necessary, additional clinical investigations and BP measurements were performed on days 14 and 21. All measurements done on day 0 were repeated on day 28.

Ethical approval

The study protocol and the methods used were approved by the ethical committee of the University of Munich; the study was performed in accordance with the Declaration of Helsinki and the principles of good clinical practice.

Statistical methods

All data were analyzed by using the StatView SE + Graphics software for the Macintosh (Abacus Concepts, Berkeley, CA, U.S.A.) and are expressed as means ± SD. Comparisons between two groups were done by t test for paired or unpaired data, analysis of variance (ANOVA), or χ2 tests, as indicated. Linear regression analysis (Spearman) was performed to establish a possible correlation between two variables. For all tests, p values ≤0.05 were considered statistically significant.

RESULTS

Nineteen patients (nine women, 10 men; mean age, 58 ± 9 years; range, 43-70 years; mean body weight, 78 ± 11 kg) fulfilled the requirements for enrollment in the study. Invasive right and LV hemodynamic variables were within normal limits (Table 1). Mean HR was 68.8 ± 9.8 beats per min (beats/min), systolic BP was 160.5 ± 17.1 mm Hg, and diastolic BP was 93.2 ± 7.9 mm Hg in three consecutive measurements after 5 min of rest on day 0. Arterial hypertension was documented in seven (36.8%) patients for >10 years, in five (26.3%) patients for 5-10 years, and in seven (36.8%) patients for <5 years. In six (31.6%) patients, angina pectoris was known for >5 years, in four (21.1%) patients for 1-5 years, and in nine (47.7%) patients for <1 year. Pretest antihypertensive medication consisted of β-blockers (n = 9), diuretics (n = 6), calcium antagonists (n = 6), and angiotensin-converting enzyme (ACE) inhibitors (n = 6). Because intermittent first-degree AV-block was found in one patient after discontinuation of drug treatment, only 18 patients were treated with betaxolol.

Simultaneous 24-h ABPM and Holter monitoring were obtained from all 19 patients, and satisfactory echocardiographic recordings in 16 patients. In nine of 19 patients, 25 periods of ischemia-type ST-segment depressions were recorded with a duration between 8 and 70 min (mean duration, 28.3 ± 25.4 min) and a maximal ST-segment deviation between -0.13 mV and -0.44 mV (mean, -0.31 ± 0.13 mV). Angina pectoris coincided with ST-segment depressions in four (19%) cases only, whereas most episodes of ischemia (79%) were painless. Patients with or without ischemia-type ST-segment depressions did not significantly differ with respect to age, gender, office or ambulatory BP, number of premature ventricular complexes, or ejection fraction (Table 2), but there was a significant difference for the mean systolic BP between day and night values only (p < 0.05). This indicates a larger nocturnal decrease in systolic BP in those patients with than those without significant ST-segment depressions. Increased wall thickness (≥12 mm IVS or LPW) was found in one (5.3%) patient only, who also had frequent premature ventricular complexes and nonsustained ventricular tachycardia.

Analysis of HR and BP during ST-segment depressions

During maximal ischemia-type ST-segment depressions, a mean increase of HR by 43.3 ± 25.5 beats/min and systolic BP by 26.1 ± 46.9 mm Hg was found. In 84% of ischemia-like episodes, significant increases were observed of HR (>15% of preepisode value) at the beginning and in all episodes during maximal ST-segment deviation. In 11 episodes, a significant increase of systolic BP (>20 mm Hg preepisode value) was seen during maximal ST-segment depression. No episode was accompanied by a decrease in BP by >20 mm Hg. HR, systolic BP, and RPP were determined 60 min, 30 min, and 10 min before, at the beginning, at the maximum of the ST-segment depression, and at the end of each episode. As can be seen in Fig. 1, there were significant increases of HR, systolic BP, and RPP at the beginning and at maximal ST-segment depression, if compared with the values 30 and 60 min before the episodes (ANOVA, p < 0.001). A mean increase of HR by 29 ± 18 beats/min was seen before the beginning of ischemia-like ST changes, with a large scatter of individual values ranging from 5 to 80 beats/min.

Of ST-segment depressions, 80% occurred between 5 a.m. and 12 a.m. (Fig. 2). There were significant correlations between the extent of the ST-segment depressions and HR or RPP during maximal ST-segment depression (p < 0.05; Fig. 3), and significant negative correlations between duration of ischemic episodes and the HR at the beginning of ST-segment deviation (p < 0.05, not shown).

Comparison of ischemic episodes in 24-h monitoring and during exercise stress testing

Stress test showed significant ST-segment depressions in 11 of the 19 patients studied (58%), occurring at a mean workload of 129 ± 31 W, a mean HR of 143 ± 17 beats/min, and a mean systolic BP of 232 ± 31 mm Hg. Seven of the nine patients (78%) who showed ST-segment depressions in the Holter had ST-segment depressions in the stress test, whereas seven of 11 patients with pathologic stress tests (64%) also had significant ST-segment depressions in the Holter. Six (55%) of 11 patients with pathologic stress tests had anginal pain during exercise.

Hemodynamic variables for stress exercise tests were compared between patients with or without ST-segment depression. The only significant difference was found for systolic BP 2 min after the end of exercise, which was 199 ± 24 versus 166 ± 34 mm Hg (p < 0.05), indicating a delayed decrease in systolic BP after exercise in patients with significant ST-segment depressions.

Treatment period

Eighteen patients were included in the treatment period with betaxolol: one patient (5.6%) was excluded during the treatment period because of sleepiness and withdrawal of consent, and one (5.6%) patient was excluded because of optical sensations, which may have been caused by betaxolol therapy. Fatigue was reported in four (27%), and tibial edema and headache in one (6%) case each.

Effects of β1-blockade on HR and BP

After 1 week of antihypertensive treatment (day 7) with 10 mg/day betaxolol, office systolic and diastolic BP was ≤160/90 mm Hg in nine (52.9%) of 17 patients; in eight patients, the dose of betaxolol was increased to 20 mg/day. One patient had increased office BP on day 14 and was excluded from the study because of lack of antihypertensive efficacy. After 28 days of antihypertensive therapy with 10-20 mg/day betaxolol, mean HR and systolic and diastolic pressure in the remaining 15 patients decreased significantly in 24-h measurements and during exercise stress testing (p < 0.05; Fig. 4).

Effects of β1-blockade on ischemic episodes and exercise tolerance

After 28 days of antihypertensive treatment with betaxolol, only 6 ischemic episodes (p < 0.01, χ2 test compared with pretreatment value, Table 3) in four of 15 patients (p < 0.01, χ2 test compared with pretreatment value) were recorded (total duration, 38 min; p < 0.05, χ2 test compared with pretreatment value) with a mean duration of 6.3 ± 2.3 min and mean ST-segment depressions of 0.156 ± 0.05 mV (range, -0.1 to -0.25 mV). The number of nitrate applications was reduced from 37 to 21, and the number of episodes with angina pectoris from 42 to 18 (p < 0.03; Fig. 2). There were no significant correlations between the reduction of numbers of ST-segment depressions and the extent of HR or BP reductions. This is possibly the result of scattering and the small total numbers of ischemia-type episodes.

In the stress test, there was no significant effect on maximal work load by drug treatment. Significant decreases of HR at rest (76 ± 14 to 56 ± 8 beats/min; p < 0.001), at 2 min, 75 W (114 ± 16 to 85.3 ± 10 beats/min; p < 0.001), and at maximal work load (150 ± 19 to 111 ± 15 beats/min) were recorded. A significant reduction of systolic BP was found at 2 min, 75 W (187 ± 19 to 169 ± 16 mm Hg; p < 0.01) and at maximal work load (222 ± 30 to 201 ± 20 mm Hg; p <0.02), and therefore significant reductions of RPP at this levels could be documented (11, 149 ± 2,554 to 7,866 ± 1,284 mm Hg/min; 21,199 ± 3,147 to 14,403 ± 1,640 mm Hg/min; 33,257 ± 6,784 to 22,210 ± 4,051 mm Hg/min; p < 0.001). Significant reductions of workloads at which ST-segment depressions were observed were found for β-blocker treatment (109 ± 23 W vs. 117 ± 57 W; p < 0.05).

DISCUSSION

In this study, hemodynamic determinants of ST-segment depressions as signs of myocardial ischemia were investigated in patients with hypertension with angina pectoris but without significant CAD; in addition, the effects of β-blockade were tested on the incidence of ST-segment depressions and the correlation to hemodynamic variable.

The main findings of the study are the following:

  1. In ≈50% of these patients, significant ST-segment depressions were observed and positively correlated to increases in HR.
  2. β1-adrenergic receptor blockade by 10-20 mg/day betaxolol efficiently lowered HR and BP and reduced the incidence of ST-segment depressions.

These findings are in agreement with those of former studies in which an incidence of ST-segment depressions in patients with hypertension without CAD of 24-73% was found, depending on variable inclusion criteria (9,10,25-28). In our study, only patients with hypertension with previously documented thoracic pain were included after independent coronary angiography because of suspected CAD. Others (9,29) studied a more heterogeneous patient group without mandatory cardiac catheterization, which probably explains differences in the incidences of ST-segment depressions.

Of these ischemic episodes, >85% seem to be asymptomatic (9,10,26,30). Holter determinations in these patients are more sensitive than stress tests (mean incidence of ST-segment depressions, ≈50 vs. 30% in stress tests; 26) as they seem to detect spontaneous changes of myocardial perfusion also depending on determinants other than stress.

Despite those measures against Holter artifacts described previously (hyperventilation, posture tests, frequency-adapted ST-segment reading), frequency-dependent ST-segment depressions could occur unrelated to ischemia. However, this also is unlikely because in control groups of healthy volunteers, significant ST-segment depressions are seen in only 2-8% of subjects studied (31-33), and 24-h monitoring complying with the recommendations of Tzivoni et al. (34) seems to be sufficient for evaluation of ischemia during daily activities, as shown by Zehender et al. (28) in a placebo-controlled group.

On the other hand, thallium scintigraphy, as an alternative means of detecting myocardial ischemia, seems to be inappropriate for the group of patients studied here because a generalized decrease of perfusion rather than regional perfusion defects is expected (see the following).

As a note of caution, it should be mentioned that the findings reported here were obtained in a group of patients with moderate hypertension with anginal pain, and generalization to the total population of patients with hypertension is not warranted by these data. In the pathophysiology of this phenomenon, the observation of a reduced coronary flow reserve seems to play a key role (35-39). The impaired flow reserve results in an inadequate increase of flow under conditions of increased oxygen demand; on the other hand, LV hypertrophy and hypercontractility may contribute to ischemia because of an increased oxygen demand, which adds to the mismatch between oxygen supply and demand. LV hypertrophy is frequent in patients with hypertension with an incidence of ≤50% (3,40). However, LV hypertrophy does not appear to be the only determinant of myocardial ischemia, because in our study and other studies, ischemic episodes have been shown in patients with hypertension without hypertrophy (9,26). LV hypercontractility has been described in severe hypertension (41). We observed hypercontractility, defined as an excess of >10% over the normal mean ejection fraction, in 64% of patients with hypertension without significant CAD (42).

These data support the observation that an increase of HR and therefore of oxygen demand seems to be one of the major trigger mechanisms for the beginning of ischemic episodes, as suggested by others in patients with hypertension (9,25) and patients with CAD (43). Asmar et al. (29) hypothesized that decreased oxygen supply is the trigger for ischemic episodes in their group of patients with hypertension patients, because BP and HR were not significantly modified during the ischemia-like ST changes in nearly 50% of patients, and only minor increases of HR were found. As can be seen from our study (Fig. 3, top), a clear-cut threshold HR for the occurrence of ST-segment depressions cannot be given, but for the total group of patients, a mean increase of HR by 29 beats/min appeared to precede ischemia (Fig. 1, top), with a large interindividual variation. However, a reverse causal relation (ischemia first, followed by an increase of HR) cannot be ruled out completely.

The larger nocturnal decrease in BP in the group of patients with ST-segment depression may indicate an additional sensitivity of underlying mechanisms to changes of BP rather than its absolute levels, but the limited data do not warrant a more extensive analysis at this point.

Present concepts of anithypertensive therapy must address organ-specific complications of the disease. These complications govern the decision of therapeutic choice, which must target an effective control of BP along with a beneficial impact on complications as shown earlier for patients with CAD (44). β-Blockade seems to be a promising strategy to achieve these goals. This was expected because of the profound effects of β-blockade on HR and, less pronounced, on BP, which were expected to improve the mismatch between myocardial oxygen supply and demand. The data of our study demonstrate that in patients with hypertension without CAD, as well as in patients with CAD, β-blockade efficiently reduces the incidence and duration of episodes with ST-segment depressions and also reduces the number of episodes with anginal pain (at borderline significance). Patients with unstable angina have a high incidence of ischemia-type ECG changes without accompanying symptoms [i.e., silent ischemia (45)]: the presence of a significant degree of ischemia, detected by Holter monitoring, is a predictor of unfavorable outcome during hospital admission and during follow-up (46,47), and therefore emphasizes its potential significance in other conditions as well. In the ASIST Trial, the investigators were able to demonstrate a reduced risk for adverse outcome in patients with asymptomatic ischemia and CAD by atenolol treatment (48), although a direct extension of their findings to our group of patients is hypothesized. Favorable results also were found in a group of elderly patients with hypertension (±CAD) treated with a calcium antagonist (felodipine) probably because of the reduction in HR. Treatment with a diuretic did not change ischemia-like ST changes, although BP was comparably reduced (49). However, whereas the impact of the reduction of asymptomatic ST changes during adequate therapy on death and morbidity was sufficiently addressed in patients with CAD by the ASIST study (48), this is not yet the case for patients with hypertension without angiographically documented CAD and will have to be investigated in future studies.

In conclusion, the noninvasive methods used in this study may facilitate the study of myocardial ischemia along with hemodynamic variables of potential causal significance in patients with hypertension. They may warrant an overall judgement on therapeutic efficacy not only with regard to BP control, but also with regard to reduction of episodes with myocardial ischemia. If more widely used, this combination of 24-h measurements might eventually become an appropriate tool for identification of optimal strategies in the differential therapy of arterial hypertension. More studies of this kind will be required to (a) assess the relative efficacy of different drugs and drug combinations with regard to the combined treatment of arterial hypertension and myocardial ischemia, and (b) to demonstrate that beneficial effects on myocardial ischemia in these patients are associated with a favorable prognostic outcome.

Acknowledgment: The study was supported by the “Deutsche Forschungsgemeinschaft” (We 1184/4-2, We 1184/6-1, Sc 4/9-4).

FIG. 1.
FIG. 1.:
Heart rate (beats/min), systolic blood pressure (mm Hg), and the rate-pressure product [(beats/min × mm Hg)/100] are shown for different periods before and during ischemic episodes in 19 patients with hypertension without coronary artery disease. Because of discontinuous determinations of blood pressure (see Methods), the reading next to the time indicated is given. Means ± SD are given. Analysis of variance was significant for all three diagrams at p < 0.001.
FIG. 2.
FIG. 2.:
Circadian distribution of the incidence of significant ST-segment depressions in 19 patients without antihypertensive therapy (top) and of 15 patients after 4 weeks of betaxolol therapy (bottom).
FIG. 3.
FIG. 3.:
Correlations between the extent of ST-segment depression and heart rate (top), systolic blood pressure (middle), and rate-pressure product (bottom) in 19 patients with hypertension without coronary artery disease. The linear regression equation is inserted.
FIG. 4.
FIG. 4.:
Casual ambulatory heart rate and systolic and diastolic blood pressure in 15 patients with hypertension without coronary artery disease before and after 4 weeks of betaxolol therapy (A-C). Heart rate and systolic and diastolic blood pressure in the same patients under stress conditions (100 W) before and after therapy with betaxolol for 4 weeks (D,E). The t test for paired data was used.

REFERENCES

1. Feigl EO. Coronary physiology. Physiol Rev 1983;63:1-205.
2. Fortiun NJ, Weiss JL. Exercise stress testing. Circulation 1977;65:699-712.
3. Hartford MJ, Wilkstrand J, Ljungman S, Wilhelmsen L, Berglund G. Diastolic function of the heart in untreated primary hypertension. Hypertension 1984;6:329-38.
4. Opherk D, Mall G, Zebe H, Schwarz F, Weihe E, Manthey J. Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation 1984;69:1-7.
5. Roitmann D, Jones WB, Sheffield LT. Comparison of submaximal exercise ECG test with coronary cineangiocardiogramm. Ann Intern Med 1970;72:641-7.
6. Scheler S, Motz W, Strauer BE. Mechanism of angina pectoris in patients with systemic hypertension and normal epicardial coronary arteries by arteriogram. Am J Cardiol 1994;73:478-82.
7. Wroblewski EM, Pearl FJ, Hammer WJ, Bove AA. False positive stress tests due to undetected left ventricular hypertrophy. Am J Epidemiol 1982;115:412-7.
8. Siegel D, Cheitlin MD, Seeley DG, Black DM, Hulley SB. Silent myocardial ischemia in men with systemic hypertension and without clinical evidence of coronary artery disease. Am J Cardiol 1992;70:86-90.
9. Trenkwalder P, Dobrindt R, Plaschke M, Lydtin H. Usefulness of simultaneous ambulatory electrocardiographic and blood pressure monitoring in detecting myocardial ischemia in patients >70 years of age with systemic hypertension. Am J Cardiol 1993;72:927-31.
10. Wehling M, Lössl M, Theisen K, Frey A. ST-Streckensenkungen korrelieren bei Patienten mit hypertensiver Herzerkrankung mit spontanen Änderungen des Blutdruckes. Z Kardiol 1991;80:144-8.
11. Deedwania PC, Nelson JR. Pathophysiology of silent myocardial ischemia during daily life. Circulation 1990;41:189-93.
12. Brush JE Jr, Canon RO III, Schenke WH, Bonow RO, Leon MB, Maron BJ. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med 1988;319:1302-7.
13. Motz W, Vogt M, Rabenau O, Scheler S, Lückhoff A, Strauer BE. Evidence of endothelial dysfunction in coronary resistance vessels in patients with angina pectoris and normal coronary angiograms. Am J Cardiol 1991;68:996-1003.
14. Treasure CB, Klein JL, Vita JA, Manouhian SV, Renwick GH, Selwyn AP. Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circulation 1993;87:86-93.
15. Froehlich ED, Apstein C, Chobanian A, Devereux AV, Dustan HP, Dzau V. The heart in hypertension. N Engl J Med 1992;327:998-1008.
16. Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension 1994;23:869-77.
17. Fröhlich ED. Is reversal of left ventricular hypertrophy in hypertension beneficial? Hypertension 1991;18:133-8.
18. Schiffrin EL, Deng LY, Larochelle P. Effects of a beta-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension. Hypertension 1994;23:83-91.
19. Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Fröhlich ED. Hypertension and sudden death: increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med 1984;77:18-22.
20. McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ventricular arrythmias with hypertensive left ventricular hypertrophy. N Engl J Med 1987;317:787-92.
21. Aronow WS, Epstein S, Koenigsberg M, Schwartz KS. Usefulness of echocardiographic left ventricular hypertrophy, ventricular tachycardia and complex ventricular arrhythmias in predicting ventricular fibrillation or sudden cardiac death in elderly patients. Am J Cardiol 1988;62:1124-5.
22. O'Brien E, Mee F, Atkins N, O'Malley K. Accuracy of the Space-Labs 90207 determined by the British Hypertension Society Protocol. J Hypertens 1991;9:573-4.
23. Fletcher GF, Froelicher VF, Hartley LH, Haskell WL, Pollock ML. Exercise standards: a statement for health professionals from the American Heart Association. Circulation 1990;82:2286-320.
24. Van Harten J, Burggraaf K, Danhof M, van Brummelen P, Breimer DD. Negligible sublingual absorption of nifedipine. Lancet 1987;ii:1363-5.
25. Lanitz EC, Gonska BD, Schrader J. Variation in blood pressure and transient myocardial ischemia in patients with essential hypertension. Z Kardiol 1992;81(suppl 2):37-9.
26. Scheler S, Motz W, Strauer BE. Transiente Myokardischämien bei Hypertonikern. Z Kardiol 1989;78:197-203.
27. Yurenev AP, DeQuattro V, Devereux RB. Hypertensive heart disease: relationship of silent ischemia to coronary artery disease and left ventricular hypertrophy. Am Heart J 1990;120:928-33.
28. Zehender M, Meinertz T, Hohnloser S, et al. Prevalence of circadian variations and spontaneous variability of cardiac disorders and ECG changes suggestive of myocardial ischemia in systemic arterial hypertension. Circulation 1992;85:1808-15.
29. Asmar R, Benetos A, Pannier B, et al. Prevalence and circadian variations of ST-segment depression and its concomitant blood pressure changes in asymptomatic systemic hypertension. Am J Cardiol 1996;77:384-90.
30. Pringle SD, Dunn FG, Tweddel AC, et al. Symptomatic and silent myocardial ischemia in hypertensive patients with left ventricular hypertrophy. Br Heart J 1992;67:377-82.
31. Deanfield JE, Ribiero P, Oakley K, Krikler S, Selwyn AP. Analysis of ST-segment changes in normal subjects: implications for ambulatory monitoring in angina pectoris. Am J Cardiol 1984;54:1321-5.
32. Quyyumi A, Wright C, Fox K. Ambulatory electrocardiographic ST-segment changes in healthy volunteers. Br Heart J 1983;50:460-4.
33. Treis-Müller I, Osterspey A, Loskamp T, Eggeling GH, Höpp HW, Hombach V. ST segment changes in long-term ECG in healthy heart probands. Z Kardiol 1988;77:160-4.
34. Tzivoni D, Gavish A, Benmorin J, Banai S, Keren A, Stern S. Day-to-day variability of myocardial ischemic episodes in coronary artery disease. Am J Cardiol 1987;60:1003-5.
35. Cannon RO III, Schenke WH, Leon MB, Rosing DR, Urquart J, Epstein SE. Limited coronary flow reserve after dipyridamole in patients with ergonovine-induced coronary vasoconstriction. Circulation 1987;75:163-74.
36. Legrand V, Hodgson JM, Bates ER, et al. Abnormal coronary flow reserve and abnormal radionuclide exercise test results in patients with normal coronary angiograms. J Am Coll Cardiol 1985;6:1245-53.
37. Strauer BE. Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol 1979;44:999-1006.
38. Strauer BE. Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve. Am J Cardiol 1979;44:730-40.
39. James TN. Morphologic characteristics and functional significance of focal fibro-muscular dysplasia of small coronary arteries. Am J Cardiol 1990;65:12G-22G.
40. Ibrahim MM, Tarazi CR, Dustan H, Bravo E, Gifford R. Hyperkinetic heart in severe hypertension: a separate clinical hemodynamic entity. Am J Cardiol 1975;35:667-74.
41. Julius S, Conway J. Hemodynamic studies in patients with borderline blood pressure elevation. Circulation 1968;38:282-8.
42. Wehling M, Camacho J, Christ M, Theisen K. Left ventricular hypercontractility in hypertensive patients with anginal pain and normal coronary angiograms. Z Kardiol 1995;84:606-13.
43. Davies AB, Bala-Subramanian V, Cashman PM, Raftery EB. Simultaneous recording of continuous arterial pressure, heart rate, and ST-segment in ambulant patients with stable angina pectoris. Br Heart J 1983;50:85-91.
44. Imperi GA, Lambert CR, Coy K, Pepine CJ. Effects of titrated betablockade (metropolol) on silent myordial ischemia in ambulatory patients with coronary artery disease. Am J Cardiol 1987;60:579-84.
45. Deanfield JE, Shea M, Ribiero P, et al. Transient ST segment depression as a marker of myocardial ischemia during daily life. Am J Cardiol 1984;54:1195-200.
46. Langer A, Freeman MR, Armstrong-PW. ST segment shift in unstable angina: pathophysiology and association with coronary anatomy and hospital outcome. J Am Coll Cardiol 1989;13:1495-502.
47. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenbith G. Silent ischemia as a marker for early unfavourable outcomes in patients with unstable angina. N Engl J Med 1986;314:1214-9.
48. Pepine CJ, Cohn PF, Deedwania PC, et al. Effects of treatment on outcome in mildly symptomatic patients with ischemia during daily life: the Atenolol Silent Ischemia Study (ASIST). Circulation 1994;90:762-8.
49. Trenkwalder P, Dobrindt R, Aulehner R, Lydtin H. Antihypertensive treatment with felodipine but not with a diuretic reduces episodes of myocardial ischemia in elderly patients with hypertension. Eur Heart J 1994;15:1673-80.
Keywords:

Hypertension; Myocardial ischemia; Heart diseases; β-Adrenergic receptor blockade

© Lippincott-Raven Publishers