- Email: [email protected]
Transient myocardial ischemia in hypertensive heart disease
Transient Myocardial Ischemia Hypertensive Heart Disease
in
Sibylle Scheler, MD, Wolfgang Motz, MD, Joanna Vester, and Bodo E. Strauer, MD, FESC
This study detemhed whether episedes of myocardial ischemia eccur in hypertensfve patients with normal coronary angiograms. ST-segment analysis during 24-heur Hefter efectrocardffraphy was determined in 46 patients (24 men and 24 women, mean age 54.6 f 10.4 years) with essential arterial hypertension (systofii/diastdic blood pressure 166.7 f 2S196.S f 15 mm Hg). The thkkness of left ventriwkr pesterior wall and septum were measured with echocardiography. Stenosis of coronary vessefs were excfuded en angiography in all patients. In 24 of 46 patients, 12.8 f 13.8 epfsodes of transfent myocardiaf ischemia (ST-segment depression 21 mm, duration of the episode 11 minute) were observed. The duration of the episodes was 46.1 f 69.93 minutes and the maximal ST-segment w was 1.91 f 0.82 mm. In 95% of the episodes the patients did not experience any angina pectoris. The degree of teft ventricular wall thickness dii not differ in hypertensive patients with and without transient myecardial lschemia (septum thii 11 f 2 mm). It is concluded that transient myocardial ischemia often occurs in hypertensive patients. Thus, left ventrkuiar hypertrophy does not appear to play any important role. The underlying cause appears to be the impaired ceronary dilation capacity, i.e., vascular alterations. (Am J Cardid 1990;65:SlG-556)
From the Department of Medicine, Cardiology, Pneumology, and Angiology, University of Duesseldorf, Federal Republic of Germany. Address for reprints: Sibylle Scheler, MD, Medizinische Klinik und Poliklinik B der Universitit Diisseldorf, Moorenstrasse 5, D-4000 Diisseldorf 1, Federal Republic of Germany.
I
n hypertensive patients, coronary regulatory capacity is clearly restricted, even with an existent normal coronary angiograml as a result of structural changes within the coronary resistance vessels or of functional alterations.2,3 Clinical manifestation for restricted coronary regulatory reserve in hypertensive patients with smooth coronary arteries is angina pectoris as well as occurrence of ischemia during exercise electrocardiogra@ye2 ST-segment analyses in long-term electrocardiography indicated episodes of myocardial ischemia in patients with coronary artery disease during ambulatory conditions without angina pectoris (“silent ischemia”) appearing clinically.4 These painless ST-segment depressions differ neither in analytic form nor on the basis of their hemodynamic effects from ST-segment depressions that are associated with symptoms of angina pectoris.5p6 Because a latent coronary insufficiency frequently occurs in hypertensive patients on the basis of the restricted coronary reserve, *-3 we questioned if, and to what extent, transient myocardial ischemia can be confirmed by means of ambulatory ST-segment monitoring in hypertensive patients with a normal coronary angiogram. METHODS Patienta We examined 48 hypertensive patients con-
secutively (24 men and 24 women, average age 54.6 f 10.4 [mean f standard deviation] years). Secondary forms of hypertension such as renovascular or parenchymatous hypertension, coarctation of the aorta, pheochromocytoma, Cushing’s disease or hyperthyroidosis were ruled out. Between October 1987 and June 1988, all patients who had undergone coronary angiography because of clinical indications such as angina pectoris or positive findings during exercise tolerance testing were included in the study if (1) the coronary angiogram showed smooth epicardial coronary arteries and (2) 3 consecutive examinations within 3 weeks revealed a systolic blood pressure > 160 mm Hg and a diastolic blood pressure 195 mm Hg. Patients indicating an additional occurrence of valvular lesions as well as signs of hypertrophic obstructive or hypertrophic nonobstructive cardiomyopathy or mitral valve prolapse were not included in the study. Furthermore, there could be no occurrence of bundle branch block patterns in the electrocardiogram (ECG), and no Wolff-Parkinson-White syndrome, digitalis medication or electrolyte disturbances. Diabetics were not included in the study because of possible diabetic coronary mi-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
APRIL 3. 1990
510
A SYMPOSIUM:
TABLE
ARTERIAL
I Clinical
Sex Age (years) Systolic blood
Data
pressure
(mm W Diastolic blood pressure (mm W Pathologic exercise ECG Normal exercise ECG ECG = electrocardiogram;
HYPERTENSION
of Hypertensive
-CARDIAC
HYPERTROPHY
Hypertensives Without ST 1 (n = 24)
14women/lOmen 56.1 f 9.3 190.8 f 23.4
12women/l2men 55.3 f 10.9 188 f 33
102.4
98.1
f 12.5
f 17.1
-
14 10
24
ST = ST-segment
FAILURE
ST-segment depressions of at least 1 mm in depth 80 ms after the J point and lasting at least 1 minute were regarded as positive for myocardial ischemia. The assessment appeared in lead CM5. The intervals of time between any 2 episodes had to amount to at least 1 minute. The following parameters were analyzed in each episode: (1) duration, (2) heart rate at the beginning of STsegment depression, and (3) maximal depth of the STsegment depression. Exercise electrocardiigram: A symptom-limited exercise ECG (bicycle ergometry) was performed in all patients in the sitting position. The load was increased in steps of 25 W. Common clinical interruptive criteria were used.’ Leads I, II, III and Vz, Vq, V6 were recorded simultaneously. Arterial blood pressure was measured in every phase of stress. The emergence of horizontal or descending ST-segment depressions of more than 0.1 mV in at least 2 electrocardiographic leads were rated positive with regard to myocardial ischemia. Determination of left ventricular hypertrophy: The dimensions of the left ventricle and the thickness of septum and posterior wall were determined by echocardiography. M-mode echocardiograms were obtained from the short parasternal view using the 2-dimensional view as a quality control on the accuracy of the M-mode registration. Measurements were obtained just below the mitral valve using the leading edge convention according to the recommendations of the American Society of Echocardiography.8 Statistiil evaluation: All data in the tables and iigure are expressed as mean f standard deviation. After monitoring variables in compliance with normal distribution, the statistical evaluation by means of paired Student t tests was performed. Statistically significant differences were assumed at p <0.05.
Patients
Hypertensives With ST 1 (n = 24)
AND
depressions.
croangiopathy. For control purposes, 46 normotensive healthy volunteers (25 men and 21 women, mean age 23.4 f 4.2 years) were studied with ST-segment monitoring over 24 hours. Medical history, physical examination, resting ECG, exercise tolerance test and echocardiography did not indicate any cardiac disease or abnormalities. ST-segment analysis: Complete long-term electrocardiographic records of patients were kept over a period of at least 24 hours without the use of any effective cardiac medication. Drugs had been discontinued for a period of at least 1 week. Monitoring of data ensued using a double-channel, bipolar operating recorder employing an amplitude-modulated system with a complete digital mechanism (Marquette-Laser-Holter System: Software 5.5, Marquette Electronics Inc., Milwaukee, Wisconsin). After thorough preparation of the skin, electrodes were attached using monitors. The electrodes were attached in the area of the upper sternum and the precordial lead (CM2 corresponding to Vz, CM5 corresponding to VS) so that the R peak showed the highest possible amplitude. By means of monitory regulation, any modification in ST segment due to changes of position such as RESULTS standing, bending over, lying on the left or right side, or In 24 of the 48 hypertensive patients examined, with through hyperventilation (according to the patient’s his- normal coronary angiograms, transient myocardial ischtory) was excluded. Each patient was asked to record any emia was recorded on 24-hour electrocardiographic mondiscomfort, including intensity and frequency, and type itoring. The patients with and without ST-segment deand exact duration of activities. The patients’ records of pressions did not vary in respect to gender, age or levels of their activities and physical complaints, together with systolic and diastolic blood pressures (Table I). ST-segment analysis: In patients with significant STtheir exact duration, were correlated simultaneously with the ECG. segment depression, an average of 12.8 f 13.8 episodes The long-term ECG was then evaluated using the with a duration of 2.7 to 240 minutes (48.1 f 69.3 minMarquettsHolter System. Stored data were processed utes) were found in a total of 306 recorded episodes. The using a complete digital system. The isoelectric point in heart rate at the onset of electrocardiographic changes the PQ segment as well as the J and L points (80 or 60 ms ranged from 60 to 143 beats/min (Table II). Maximal ST-segment depression was 1.91 f 0.82 [dependent on heart rate] after the J point) to measure the ST segment was determined individually for each (- 1 to -3.3 mm). The episodes occurred most frequently patient. The evaluation followed semiautomatically un- during the day (Fig. 1). During the night only about 20% der visual control. Questionable findings were printed at a of the episodes were observed. The episodes of ST-segpaper speed of 25 mm/s and measured by the investiga- ment depression were 95% asymptomatic. tor. Left ventricular dimensions: The thickness of the inIn assessing the degree of ST-segment depression, terventricular septum was 11 f 2 mm in hypertensives intermittent patterns of bundle branch block, aberrant with and without ST-segment depressions. The thickness conduction, ventricular and supraventricular extreme of the posterior wall of the left ventricle was 10 f 1 mm in systole were not considered. Horizontal and descending hypertensives both with and without ST-segment depres-
526
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OF CARDIOLOGY
VOLUME
65
TABLE
II ST-Segment
Mean
Depressions
No. of Episodes
Maximal Duration (min)
Mean Duration (min)
STlmax (mm)
Heart Rate at Onset (beats/min)
2 5 2 8 4 3 2 1 5 2 24 10 7 20 10 1 40 26 27 40 9 40 15 3
6.7 21.5 3 13.4 14.5 5.5 4.5 4.2 2.7 5.2 240.5 49.2 27 27.5 40 2.7 150 24.2 56 121 240 68.5 7 18.5
5.1 f 2.3 3.2 f 0.8 1.85 f 0.6 7.23+6.13 3.5 f 1.8 1.5 f 0.6 1.8f0.3 1.78 f 0.5 3.95 f 1.8 19.4k52.5 11.7f 14.1 12.3 f 10.3 13.98 f 26.9 12.5f 12.7 14.9f21.3 6.8 f 6.65 5.33 f 7.0 7.5* 11.6 48.56 f 78.6 7.25 f 12.4 3.6 f 1.8 12.0 f 5.9
-1.5 -1 -1.1 -1 -2 -1 -1 -1.2 -1.2 -1.2 -2.0 -1.7 -3 -2.5 -2.3 -1.3 -3.7 -3.3 -2.5 -2.5 -3.0 -1.8 -1.5 -2.5
60 93-108 9(rloo 60-l 10 105-121 121-143 113-120 100 90-130 loo-130 60-70 90-110 90-130 70-100 100-130 82 106 93-101 97-129 94-105 87-155 65-80 75-122 8ChllO
12.8f
13.2 _-
48.1
f 69.93
9.18f
sions. All patients studied had a normal end-diastolic and end-systolic diameter of the left ventricle and normal fractional shortening. Thus, hypertensives with and without ST-segment changes did not differ with respect to the amount of left ventricular wall thickness or left ventricular geometry. Exercise toterance test: All hypertensives without transient ST-segment changes (n = 24) had normal results during exercise tolerance testing. However, 14 of the 24 patients with ST-segment changes had a pathologic ischemic reaction during the exercise tolerance test such as significant ST-segment depressions (Table I). High grade ventricular arrhythmias did not occur. Results of exercise stress testing were normal in all control persons.
10.2
-1.91
f 0.82
Hourly Course of Episodes of ST- Segment Depressions
20IlOIOOgo6070-
DISCUSSION
In the diagnosis of patients with coronary artery disease, ST-segment analysis during Holter electrocardiography over a period of 24 hours is an important supplement to exercise electrocardiography because, under everyday conditions, frequent episodes of transient myocardial ischemia appear without the accompanying symptoms of angina pectoris, i.e., silent ischemia.9-12 This method of continual ST-segment electrocardiography has been used almost exclusively in patients with a diagnosis of coronary artery disease.11J3 Electrocardiographic signs of myocardial ischemia without evidence of coronary artery disease appear in published reports as so-called “false-positive” findings at
6050403020lo-
O-6h
FIGURE ischemia.
1. burly
THE AMERICAN
6-12h
12-16h
IS-24h
course of episodes in hnsienl
JOURNAL
OF CARDIOLOGY
APRIL
myocardiil
3. 1990
536
A SYMPOSIUM:
ARYERIAL
HYPERYENSION
-CARDIAC
HYPERTRDPHY
a frequency of 3 to 8.3%. 14-16A normal coronary angiogram only excludes a coronary macroangiopathy, so that these so-called false-positive findings could well be attributed to disturbances of coronary resistance vessels in addition to, e.g., rheologically induced coronary insufficiency. Furthermore, clinical symptoms of a coronary microangiopathy do not differ from those of coronary macroangiopathy. Treis-Mtiller et all4 showed that &hernia-typical STsegment abnormalities, which can be interpreted as “false-positive,” appeared in only 6% of 100 healthy persons. In our own investigations in young healthy (normotensive) volunteers, we found ST-segment depressions in 2.5%, which we describe as “false-positive” because of the absence of any obvious coronary artery disease. Based on reported data14-16 and our own control group, one must assume that approximately 2.5 to 8.3% of so-called false-positive findings occur in long-term STsegment electrocardiography without evidence of an anatomically induced coronary insufficiency. For the first time we were able to show that in about 50% of hypertensive patients with a normal coronary angiogram, ischemia-typical ST-segment abnormalities appeared during Holter monitoring, which were similar to the abnormalities observed in patients with coronary macroangiopathy with respect to heart rate at the onset of the symptoms, their daily variations (Fig. l), as well as duration and extent of ST-segment abnormalities. Because the rate of false-positive findings is inaccurate by 2.5 to 8.3%, it is unlikely that our discoveries in hypertensive patients with smooth coronary arteries deal with artifacts or nonspecific ST-segment depressions. Medication such as digitalis, electrolyte disturbance, hyperventilation, a mitral valve prolapse, transient intraventricular lead disturbances as well as vegetative influences can also lead to ST-segment changes in the ECG. These reasons of ST-segment changes were of course excluded in our study. Accordingly, it is much more likely that the monitored episodes are actual evidence of myocardial ischemia resulting from left ventricular hypertrophy or coronary microangiopathy.1-3 In advanced left ventricular hypertrophy, downsloping ST-segment changes (“strains”) are a frequent finding in the resting ECG. To avoid any impact of left ventricular hypertrophy, we included only patients without any abnormalities in the resting ECG. Furthermore, all hypertensives who underwent studies did not show significant left ventricular hypertrophy in the echocardiogram. Hypertensives with ST-segment changes did not differ with respect to left ventricular wall thickness from those without ST-segment changes. Because left ventricular hypertrophy does not explain the frequent occurrence of transient ST-segment depressions in hypertensive patients in this study, vascular alterations in such patients may be the underlying reason of the ST-segment depressions. In hypertensive patients with a normal coronary angiogram, coronary regulatory capacity is usually markedly diminished.2 The minimal coronary resistance under maximal vasodilation after administration of dipy-
540
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AND
FAILURE
ridamole is about 30 to 50% higher than in normotensive subjects.1,3 Morphologic analysis of arteries of animals with experimental hypertension (spontaneously hypertensive rats) have shown hypertrophy of the media, which means hypertrophy of smooth muscle cells and an increased collagen concentration.‘7Js The ratio of the wall of the vessel to its lumen is increased.19 Consequently, an increase in vascular tone by sympathetic stimulation will result in a much higher vascular resistance in hypertensive modulated resistance arteries through luminal encroachment than would occur in normotensives.20 Therefore, the impaired coronary reserve is most probably a result of structural changes of the resistance vessels in hypertensives. Thus, transient variations in the vascular tone due to alterations in sympathetic activity could explain the frequent occurrence of episodes of transient myocardial ischemia. This explanation is supported by the finding that only in approximately 40% of the hypertensive patients who had ST-segment changes during Holter monitoring were ST-segment depressions provokable during the exercise tolerance test. Heart rate at the onset of the episodes of transient myocardial ischemia during Holter monitoring was
REFERENCES 1. Strauer BE. Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol /979;44:999-1006. 2. Strauer BE. Hypertensive Heart Disease. Springer, New York, 1980. 3. Strauer BE. Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve. Am J Cardiol 1979;44:730740. 4. Stern S, Tzivoni D. Early detection of silent ischaemic heart disease by 24 hour electrocardiographic monitoring of active subjects. Er Heart J 1974;36:481486. 5. Chierchia S, Lazzari M, Freedman B, Brunelli C, Maseri A. Impairment of mywardial perfusion and function during painless myocardial ischemia. JACC 1983:1:924-930. 6. Cohn PF, Brown EJ Jr, Wynne J, Holman BL, Atkins HL. Global and regional left ventricular ejection fraction abnormalities during exercise in patients with silent myocardial ischemia. JACC /983:1:93/L933. 7. Sheffield LTh. Exercise stress testing. In: Braunwald, ed. Heart Disease. A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders, 1988:223241. 9. Sahn DJ, DeMaria JA, Kisslo J, Weyman A. Recommendations regarding quantification in M-mode echocardiography. Results of a survey of echocardiographic measurements. Circulation 1978;58:1072-1083. 9. Epstein SE, Quyyumi AA, Bonow RO. Myocardial &hernia-silent or symptomatic. N Engl J Med 1988:318:1038-1043. 10. Rozanski A, Bairey C. Krantz DS, Friedman J, Resser JD, Rorell M, Hilton-
Chalfen S, He&in L, Bietendorf J, Berman DS. Mental stress and the induction of silent myocardial ischemia in patients with coronary artery disease. N Engl J Med 1988;318:1005-1012. 11. Selwyn A, Ganz P. Myocardial ischemia in coronary disease. N Engl J Med 1988;318:1058-1060. 12. Cohn PF. Silent myocardial ischemia: dimensions of the problem in patients with and without angina. Am J Med 1986;8lJ;suppl:3C-8C. 13. Deanfield JE, Shea MJ, Selwyn AP. Clinical evaluation of transient myocardial ischemia during daily life. Am J Med 1985;79.wppI;18A-24A. 14. Treis-Miiller I, Osterspey A, Lo& T, Eggeling Th, Giinther H, HSpp HW, Hombach V. ST-Segment-Verlnderungen im Langzeit-EKG bei Herzgesunden. Z Kardiol 1988;77:160-164. 15. 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-l 325, 16. Quyyumi A, Wright C, Fox K. Ambulatory electrocardiographic ST-segment changes in healthy volunteers. Er Heart J 1983;50:460-464. 17. Klepzig M, Eisenlohr H, Steindl S, Strauer BE. Increased coronary vascular resistance in SHR. Prog Appl Microcirc 1985;18:105-110. 18. Klepzig M, Eisenlohr H, Steindl S, Schmiebusch H, Strauer BE. Media hypertrophy in hypertensive coronary resistance vessels. J Cardiouasc Pharmacol 1987;10:97-102. 19. Folkow B, Lundgren Y, Weiss L. Background of increased flow resistance in SHR. Acta Physiol Stand 1970;80:93-106. 20. Folkow B. Constriction-distension relationship of resistance vessels in normoand hypertension. Clin Sci 1979;57:23s-25s.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
APRIL 3, 1990
550
in
Sibylle Scheler, MD, Wolfgang Motz, MD, Joanna Vester, and Bodo E. Strauer, MD, FESC
This study detemhed whether episedes of myocardial ischemia eccur in hypertensfve patients with normal coronary angiograms. ST-segment analysis during 24-heur Hefter efectrocardffraphy was determined in 46 patients (24 men and 24 women, mean age 54.6 f 10.4 years) with essential arterial hypertension (systofii/diastdic blood pressure 166.7 f 2S196.S f 15 mm Hg). The thkkness of left ventriwkr pesterior wall and septum were measured with echocardiography. Stenosis of coronary vessefs were excfuded en angiography in all patients. In 24 of 46 patients, 12.8 f 13.8 epfsodes of transfent myocardiaf ischemia (ST-segment depression 21 mm, duration of the episode 11 minute) were observed. The duration of the episodes was 46.1 f 69.93 minutes and the maximal ST-segment w was 1.91 f 0.82 mm. In 95% of the episodes the patients did not experience any angina pectoris. The degree of teft ventricular wall thickness dii not differ in hypertensive patients with and without transient myecardial lschemia (septum thii 11 f 2 mm). It is concluded that transient myocardial ischemia often occurs in hypertensive patients. Thus, left ventrkuiar hypertrophy does not appear to play any important role. The underlying cause appears to be the impaired ceronary dilation capacity, i.e., vascular alterations. (Am J Cardid 1990;65:SlG-556)
From the Department of Medicine, Cardiology, Pneumology, and Angiology, University of Duesseldorf, Federal Republic of Germany. Address for reprints: Sibylle Scheler, MD, Medizinische Klinik und Poliklinik B der Universitit Diisseldorf, Moorenstrasse 5, D-4000 Diisseldorf 1, Federal Republic of Germany.
I
n hypertensive patients, coronary regulatory capacity is clearly restricted, even with an existent normal coronary angiograml as a result of structural changes within the coronary resistance vessels or of functional alterations.2,3 Clinical manifestation for restricted coronary regulatory reserve in hypertensive patients with smooth coronary arteries is angina pectoris as well as occurrence of ischemia during exercise electrocardiogra@ye2 ST-segment analyses in long-term electrocardiography indicated episodes of myocardial ischemia in patients with coronary artery disease during ambulatory conditions without angina pectoris (“silent ischemia”) appearing clinically.4 These painless ST-segment depressions differ neither in analytic form nor on the basis of their hemodynamic effects from ST-segment depressions that are associated with symptoms of angina pectoris.5p6 Because a latent coronary insufficiency frequently occurs in hypertensive patients on the basis of the restricted coronary reserve, *-3 we questioned if, and to what extent, transient myocardial ischemia can be confirmed by means of ambulatory ST-segment monitoring in hypertensive patients with a normal coronary angiogram. METHODS Patienta We examined 48 hypertensive patients con-
secutively (24 men and 24 women, average age 54.6 f 10.4 [mean f standard deviation] years). Secondary forms of hypertension such as renovascular or parenchymatous hypertension, coarctation of the aorta, pheochromocytoma, Cushing’s disease or hyperthyroidosis were ruled out. Between October 1987 and June 1988, all patients who had undergone coronary angiography because of clinical indications such as angina pectoris or positive findings during exercise tolerance testing were included in the study if (1) the coronary angiogram showed smooth epicardial coronary arteries and (2) 3 consecutive examinations within 3 weeks revealed a systolic blood pressure > 160 mm Hg and a diastolic blood pressure 195 mm Hg. Patients indicating an additional occurrence of valvular lesions as well as signs of hypertrophic obstructive or hypertrophic nonobstructive cardiomyopathy or mitral valve prolapse were not included in the study. Furthermore, there could be no occurrence of bundle branch block patterns in the electrocardiogram (ECG), and no Wolff-Parkinson-White syndrome, digitalis medication or electrolyte disturbances. Diabetics were not included in the study because of possible diabetic coronary mi-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
APRIL 3. 1990
510
A SYMPOSIUM:
TABLE
ARTERIAL
I Clinical
Sex Age (years) Systolic blood
Data
pressure
(mm W Diastolic blood pressure (mm W Pathologic exercise ECG Normal exercise ECG ECG = electrocardiogram;
HYPERTENSION
of Hypertensive
-CARDIAC
HYPERTROPHY
Hypertensives Without ST 1 (n = 24)
14women/lOmen 56.1 f 9.3 190.8 f 23.4
12women/l2men 55.3 f 10.9 188 f 33
102.4
98.1
f 12.5
f 17.1
-
14 10
24
ST = ST-segment
FAILURE
ST-segment depressions of at least 1 mm in depth 80 ms after the J point and lasting at least 1 minute were regarded as positive for myocardial ischemia. The assessment appeared in lead CM5. The intervals of time between any 2 episodes had to amount to at least 1 minute. The following parameters were analyzed in each episode: (1) duration, (2) heart rate at the beginning of STsegment depression, and (3) maximal depth of the STsegment depression. Exercise electrocardiigram: A symptom-limited exercise ECG (bicycle ergometry) was performed in all patients in the sitting position. The load was increased in steps of 25 W. Common clinical interruptive criteria were used.’ Leads I, II, III and Vz, Vq, V6 were recorded simultaneously. Arterial blood pressure was measured in every phase of stress. The emergence of horizontal or descending ST-segment depressions of more than 0.1 mV in at least 2 electrocardiographic leads were rated positive with regard to myocardial ischemia. Determination of left ventricular hypertrophy: The dimensions of the left ventricle and the thickness of septum and posterior wall were determined by echocardiography. M-mode echocardiograms were obtained from the short parasternal view using the 2-dimensional view as a quality control on the accuracy of the M-mode registration. Measurements were obtained just below the mitral valve using the leading edge convention according to the recommendations of the American Society of Echocardiography.8 Statistiil evaluation: All data in the tables and iigure are expressed as mean f standard deviation. After monitoring variables in compliance with normal distribution, the statistical evaluation by means of paired Student t tests was performed. Statistically significant differences were assumed at p <0.05.
Patients
Hypertensives With ST 1 (n = 24)
AND
depressions.
croangiopathy. For control purposes, 46 normotensive healthy volunteers (25 men and 21 women, mean age 23.4 f 4.2 years) were studied with ST-segment monitoring over 24 hours. Medical history, physical examination, resting ECG, exercise tolerance test and echocardiography did not indicate any cardiac disease or abnormalities. ST-segment analysis: Complete long-term electrocardiographic records of patients were kept over a period of at least 24 hours without the use of any effective cardiac medication. Drugs had been discontinued for a period of at least 1 week. Monitoring of data ensued using a double-channel, bipolar operating recorder employing an amplitude-modulated system with a complete digital mechanism (Marquette-Laser-Holter System: Software 5.5, Marquette Electronics Inc., Milwaukee, Wisconsin). After thorough preparation of the skin, electrodes were attached using monitors. The electrodes were attached in the area of the upper sternum and the precordial lead (CM2 corresponding to Vz, CM5 corresponding to VS) so that the R peak showed the highest possible amplitude. By means of monitory regulation, any modification in ST segment due to changes of position such as RESULTS standing, bending over, lying on the left or right side, or In 24 of the 48 hypertensive patients examined, with through hyperventilation (according to the patient’s his- normal coronary angiograms, transient myocardial ischtory) was excluded. Each patient was asked to record any emia was recorded on 24-hour electrocardiographic mondiscomfort, including intensity and frequency, and type itoring. The patients with and without ST-segment deand exact duration of activities. The patients’ records of pressions did not vary in respect to gender, age or levels of their activities and physical complaints, together with systolic and diastolic blood pressures (Table I). ST-segment analysis: In patients with significant STtheir exact duration, were correlated simultaneously with the ECG. segment depression, an average of 12.8 f 13.8 episodes The long-term ECG was then evaluated using the with a duration of 2.7 to 240 minutes (48.1 f 69.3 minMarquettsHolter System. Stored data were processed utes) were found in a total of 306 recorded episodes. The using a complete digital system. The isoelectric point in heart rate at the onset of electrocardiographic changes the PQ segment as well as the J and L points (80 or 60 ms ranged from 60 to 143 beats/min (Table II). Maximal ST-segment depression was 1.91 f 0.82 [dependent on heart rate] after the J point) to measure the ST segment was determined individually for each (- 1 to -3.3 mm). The episodes occurred most frequently patient. The evaluation followed semiautomatically un- during the day (Fig. 1). During the night only about 20% der visual control. Questionable findings were printed at a of the episodes were observed. The episodes of ST-segpaper speed of 25 mm/s and measured by the investiga- ment depression were 95% asymptomatic. tor. Left ventricular dimensions: The thickness of the inIn assessing the degree of ST-segment depression, terventricular septum was 11 f 2 mm in hypertensives intermittent patterns of bundle branch block, aberrant with and without ST-segment depressions. The thickness conduction, ventricular and supraventricular extreme of the posterior wall of the left ventricle was 10 f 1 mm in systole were not considered. Horizontal and descending hypertensives both with and without ST-segment depres-
526
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
TABLE
II ST-Segment
Mean
Depressions
No. of Episodes
Maximal Duration (min)
Mean Duration (min)
STlmax (mm)
Heart Rate at Onset (beats/min)
2 5 2 8 4 3 2 1 5 2 24 10 7 20 10 1 40 26 27 40 9 40 15 3
6.7 21.5 3 13.4 14.5 5.5 4.5 4.2 2.7 5.2 240.5 49.2 27 27.5 40 2.7 150 24.2 56 121 240 68.5 7 18.5
5.1 f 2.3 3.2 f 0.8 1.85 f 0.6 7.23+6.13 3.5 f 1.8 1.5 f 0.6 1.8f0.3 1.78 f 0.5 3.95 f 1.8 19.4k52.5 11.7f 14.1 12.3 f 10.3 13.98 f 26.9 12.5f 12.7 14.9f21.3 6.8 f 6.65 5.33 f 7.0 7.5* 11.6 48.56 f 78.6 7.25 f 12.4 3.6 f 1.8 12.0 f 5.9
-1.5 -1 -1.1 -1 -2 -1 -1 -1.2 -1.2 -1.2 -2.0 -1.7 -3 -2.5 -2.3 -1.3 -3.7 -3.3 -2.5 -2.5 -3.0 -1.8 -1.5 -2.5
60 93-108 9(rloo 60-l 10 105-121 121-143 113-120 100 90-130 loo-130 60-70 90-110 90-130 70-100 100-130 82 106 93-101 97-129 94-105 87-155 65-80 75-122 8ChllO
12.8f
13.2 _-
48.1
f 69.93
9.18f
sions. All patients studied had a normal end-diastolic and end-systolic diameter of the left ventricle and normal fractional shortening. Thus, hypertensives with and without ST-segment changes did not differ with respect to the amount of left ventricular wall thickness or left ventricular geometry. Exercise toterance test: All hypertensives without transient ST-segment changes (n = 24) had normal results during exercise tolerance testing. However, 14 of the 24 patients with ST-segment changes had a pathologic ischemic reaction during the exercise tolerance test such as significant ST-segment depressions (Table I). High grade ventricular arrhythmias did not occur. Results of exercise stress testing were normal in all control persons.
10.2
-1.91
f 0.82
Hourly Course of Episodes of ST- Segment Depressions
20IlOIOOgo6070-
DISCUSSION
In the diagnosis of patients with coronary artery disease, ST-segment analysis during Holter electrocardiography over a period of 24 hours is an important supplement to exercise electrocardiography because, under everyday conditions, frequent episodes of transient myocardial ischemia appear without the accompanying symptoms of angina pectoris, i.e., silent ischemia.9-12 This method of continual ST-segment electrocardiography has been used almost exclusively in patients with a diagnosis of coronary artery disease.11J3 Electrocardiographic signs of myocardial ischemia without evidence of coronary artery disease appear in published reports as so-called “false-positive” findings at
6050403020lo-
O-6h
FIGURE ischemia.
1. burly
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a frequency of 3 to 8.3%. 14-16A normal coronary angiogram only excludes a coronary macroangiopathy, so that these so-called false-positive findings could well be attributed to disturbances of coronary resistance vessels in addition to, e.g., rheologically induced coronary insufficiency. Furthermore, clinical symptoms of a coronary microangiopathy do not differ from those of coronary macroangiopathy. Treis-Mtiller et all4 showed that &hernia-typical STsegment abnormalities, which can be interpreted as “false-positive,” appeared in only 6% of 100 healthy persons. In our own investigations in young healthy (normotensive) volunteers, we found ST-segment depressions in 2.5%, which we describe as “false-positive” because of the absence of any obvious coronary artery disease. Based on reported data14-16 and our own control group, one must assume that approximately 2.5 to 8.3% of so-called false-positive findings occur in long-term STsegment electrocardiography without evidence of an anatomically induced coronary insufficiency. For the first time we were able to show that in about 50% of hypertensive patients with a normal coronary angiogram, ischemia-typical ST-segment abnormalities appeared during Holter monitoring, which were similar to the abnormalities observed in patients with coronary macroangiopathy with respect to heart rate at the onset of the symptoms, their daily variations (Fig. l), as well as duration and extent of ST-segment abnormalities. Because the rate of false-positive findings is inaccurate by 2.5 to 8.3%, it is unlikely that our discoveries in hypertensive patients with smooth coronary arteries deal with artifacts or nonspecific ST-segment depressions. Medication such as digitalis, electrolyte disturbance, hyperventilation, a mitral valve prolapse, transient intraventricular lead disturbances as well as vegetative influences can also lead to ST-segment changes in the ECG. These reasons of ST-segment changes were of course excluded in our study. Accordingly, it is much more likely that the monitored episodes are actual evidence of myocardial ischemia resulting from left ventricular hypertrophy or coronary microangiopathy.1-3 In advanced left ventricular hypertrophy, downsloping ST-segment changes (“strains”) are a frequent finding in the resting ECG. To avoid any impact of left ventricular hypertrophy, we included only patients without any abnormalities in the resting ECG. Furthermore, all hypertensives who underwent studies did not show significant left ventricular hypertrophy in the echocardiogram. Hypertensives with ST-segment changes did not differ with respect to left ventricular wall thickness from those without ST-segment changes. Because left ventricular hypertrophy does not explain the frequent occurrence of transient ST-segment depressions in hypertensive patients in this study, vascular alterations in such patients may be the underlying reason of the ST-segment depressions. In hypertensive patients with a normal coronary angiogram, coronary regulatory capacity is usually markedly diminished.2 The minimal coronary resistance under maximal vasodilation after administration of dipy-
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ridamole is about 30 to 50% higher than in normotensive subjects.1,3 Morphologic analysis of arteries of animals with experimental hypertension (spontaneously hypertensive rats) have shown hypertrophy of the media, which means hypertrophy of smooth muscle cells and an increased collagen concentration.‘7Js The ratio of the wall of the vessel to its lumen is increased.19 Consequently, an increase in vascular tone by sympathetic stimulation will result in a much higher vascular resistance in hypertensive modulated resistance arteries through luminal encroachment than would occur in normotensives.20 Therefore, the impaired coronary reserve is most probably a result of structural changes of the resistance vessels in hypertensives. Thus, transient variations in the vascular tone due to alterations in sympathetic activity could explain the frequent occurrence of episodes of transient myocardial ischemia. This explanation is supported by the finding that only in approximately 40% of the hypertensive patients who had ST-segment changes during Holter monitoring were ST-segment depressions provokable during the exercise tolerance test. Heart rate at the onset of the episodes of transient myocardial ischemia during Holter monitoring was
REFERENCES 1. Strauer BE. Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol /979;44:999-1006. 2. Strauer BE. Hypertensive Heart Disease. Springer, New York, 1980. 3. Strauer BE. Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve. Am J Cardiol 1979;44:730740. 4. Stern S, Tzivoni D. Early detection of silent ischaemic heart disease by 24 hour electrocardiographic monitoring of active subjects. Er Heart J 1974;36:481486. 5. Chierchia S, Lazzari M, Freedman B, Brunelli C, Maseri A. Impairment of mywardial perfusion and function during painless myocardial ischemia. JACC 1983:1:924-930. 6. Cohn PF, Brown EJ Jr, Wynne J, Holman BL, Atkins HL. Global and regional left ventricular ejection fraction abnormalities during exercise in patients with silent myocardial ischemia. JACC /983:1:93/L933. 7. Sheffield LTh. Exercise stress testing. In: Braunwald, ed. Heart Disease. A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders, 1988:223241. 9. Sahn DJ, DeMaria JA, Kisslo J, Weyman A. Recommendations regarding quantification in M-mode echocardiography. Results of a survey of echocardiographic measurements. Circulation 1978;58:1072-1083. 9. Epstein SE, Quyyumi AA, Bonow RO. Myocardial &hernia-silent or symptomatic. N Engl J Med 1988:318:1038-1043. 10. Rozanski A, Bairey C. Krantz DS, Friedman J, Resser JD, Rorell M, Hilton-
Chalfen S, He&in L, Bietendorf J, Berman DS. Mental stress and the induction of silent myocardial ischemia in patients with coronary artery disease. N Engl J Med 1988;318:1005-1012. 11. Selwyn A, Ganz P. Myocardial ischemia in coronary disease. N Engl J Med 1988;318:1058-1060. 12. Cohn PF. Silent myocardial ischemia: dimensions of the problem in patients with and without angina. Am J Med 1986;8lJ;suppl:3C-8C. 13. Deanfield JE, Shea MJ, Selwyn AP. Clinical evaluation of transient myocardial ischemia during daily life. Am J Med 1985;79.wppI;18A-24A. 14. Treis-Miiller I, Osterspey A, Lo& T, Eggeling Th, Giinther H, HSpp HW, Hombach V. ST-Segment-Verlnderungen im Langzeit-EKG bei Herzgesunden. Z Kardiol 1988;77:160-164. 15. 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-l 325, 16. Quyyumi A, Wright C, Fox K. Ambulatory electrocardiographic ST-segment changes in healthy volunteers. Er Heart J 1983;50:460-464. 17. Klepzig M, Eisenlohr H, Steindl S, Strauer BE. Increased coronary vascular resistance in SHR. Prog Appl Microcirc 1985;18:105-110. 18. Klepzig M, Eisenlohr H, Steindl S, Schmiebusch H, Strauer BE. Media hypertrophy in hypertensive coronary resistance vessels. J Cardiouasc Pharmacol 1987;10:97-102. 19. Folkow B, Lundgren Y, Weiss L. Background of increased flow resistance in SHR. Acta Physiol Stand 1970;80:93-106. 20. Folkow B. Constriction-distension relationship of resistance vessels in normoand hypertension. Clin Sci 1979;57:23s-25s.
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