Hemodynamic and Humoral Correlates in Essential Hypertension
Relationship Between Patterns of LVH and Myocardial Ischemia
Abstract While evaluating 45 hypertensive patients with left ventricular hypertrophy (LVH) for enrollment in a clinical research protocol, we had the opportunity to compare anatomic and functional characteristics of those with LVH and ischemia on an exercise tolerance test (ETT), but without coronary artery disease by angiography (group I, n=8), versus those with a normal ETT (group II, n=37). There were no differences in age, sex, severity, and duration of hypertension between the two groups, but group I patients were significantly more overweight and had a worse lipid profile. Blood pressure at peak ETT was higher in group I despite shorter exercise duration, although resting and ambulatory pressures were similar. Group I patients had evidence of more pronounced cardiac enlargement and LVH by both ECG and echo criteria and a characteristic pattern of more pronounced thickening at the apex, but both groups had equally good systolic function and similar degrees of mild diastolic dysfunction. Analysis of 24-hour ambulatory ECG showed a significantly greater propensity to ventricular arrhythmias in group I, as shown by the presence of late potentials in 4 patients, the presence of couplets in 3, runs of ventricular tachycardia in 2 (while none of group II patients had late potentials or complex arrhythmias), and an average frequency of isolated premature ventricular contractions approximately three times higher in group I than group II patients. Our data demonstrate that hypertensives with LVH associated with myocardial ischemia at stress but with normal coronary arteriograms tend to be more overweight, attain a higher systolic blood pressure at ETT despite a shorter duration, have a higher propensity for severe arrhythmias, and have an adverse lipid profile. LVH in these subjects is more pronounced by both ECG and echo criteria and is characterized by predominantly apical hypertrophy with left atrial and ventricular dilatation rather than overall LV wall thickening.
Left ventricular hypertrophy is an adaptive process of the normal myocardium working against elevated systemic vascular resistance. As such, it is reported to occur in hypertension at a rate varying between 5% and 50%, depending on whether it is defined by ECG or echocardiographic criteria. Although initially compensatory, LVH is now recognized to be an independent risk factor for cardiac morbidity and mortality,1 2 3 evidently because it predisposes to electrophysiological instability4 and eventually to congestive heart failure.5
Echocardiography is by far the most sensitive and accurate method for the diagnosis of LVH.6 In the course of recruiting hypertensive patients with LVH for participation in a clinical research protocol, we had the opportunity to screen an untreated hypertensive population by echocardiography. Forty-five patients who fulfilled the criteria for LVH underwent extensive functional evaluation, including an exercise tolerance test (ETT). Eight patients were ETT-positive for ischemic changes and then underwent coronary arteriography, which revealed no significant coronary obstruction. In this article, we report the comparison of these two hypertensive groups with LVH in terms of a number of anatomic, functional, and humoral parameters.
The study comprised 45 hypertensive patients (40 men, 5 women; mean age, 52±10 years; range, 30 to 68) with mild to moderate essential hypertension evaluated in the Hypertension Clinic of Tzanio Hospital. They were recruited for participation in a clinical research trial because they had echocardiographic evidence of LVH. Informed consent was obtained from each participant, and the study was approved by the local hospital ethics committee. In previously treated patients, antihypertensive medications were discontinued and replaced by a single-blind placebo period of 4 weeks, at the end of which the following evaluation took place:
All patients underwent two-dimensional and Doppler echocardiography, blood pressure measurements in the clinic and after isometric exercise, ambulatory blood pressure monitoring, ambulatory ECG monitoring, and late potentials. All patients underwent ETT with hormone measurements at rest and peak exercise. Patients with a positive ETT underwent repeated testing with 201Th scintigraphy followed, if positive, by coronary arteriography to exclude coronary artery disease.
Office Blood Pressure Measurement
Sitting blood pressure was taken in triplicate, and the blood pressure was defined as the mean of three readings taken 2 minutes apart after 10 minutes of rest.
The isometric exercise test was performed using a handgrip at one third the maximum force for 3 minutes. Measurements of blood pressure were taken at baseline and at peak isometric effort.
Patients underwent testing on the treadmill (Quinton Q5000) according to the Bruce protocol.7 The test was interrupted if the patient developed a systolic blood pressure ≥230 mm Hg, fatigue, or ischemic electrocardiographic changes. Manual measurements of blood pressure were carried out before, every 2 minutes during exercise, at peak exercise, and every 2 minutes after the end of the ETT until the blood pressure reading returned to baseline. During and after exercise, only systolic blood pressure was evaluated.
Patients with a positive ETT (at least 1 mm of additional horizontal or downsloping ST-segment depression at 80 ms after the J-point compared with the baseline values at rest) underwent repeated ETT with 201Th scintigraphy, and if that test indicated ischemic changes, coronary arteriography was performed to exclude coronary artery disease.
Blood samples for plasma renin activity (PRA), catecholamines [norepinephrine (NE) and epinephrine (E)], and arginine vasopressin (AVP) were drawn before and at peak exercise. Samples of 7 mL for each hormone were collected in EDTA, in chilled tubes, on ice. They were centrifuged immediately and the plasma separated and frozen immediately at −80°C until assay for PRA by radioimmunoassay,8 for NE and E by HPLC,9 and for AVP by radioimmunoassay.10
Echocardiographic examination was performed with a Hewlett-Packard imaging system (Sonos 1000). Complete M-mode, two-dimensional, and pulsed-wave Doppler echocardiographic studies were obtained. The tracings were recorded on 3.5-in. tape at 50 mm/sec. At the end of the study, echocardiograms were numerically coded and read in a random sequence by two physicians according to the recommendation of the American Society of Echocardiography.11 The Penn convention was used to calculate left ventricular mass (LVM). Quantitative analysis of M-mode echocardiograms provided the following parameters, thus allowing the assessment of left ventricular anatomy and function: end-diastolic (LVDD) and end-systolic diameters (LVSD), interventricular septum (IVSD) and posterior wall (PWD) thickness in diastole at three sequential levels: the mitral valve (MV), papillary muscles (PM), and apex.12 The LVM index (LVMI) was also calculated as the ratio of LVM to body surface. Fractional shortening (FS=[LVDD−LVSD]/LVDD×100) was used as an index of systolic function. Diastolic function was assessed by calculating the early diastolic filling velocity (E wave), late diastolic filling velocity (A wave), and E-to-A ratio (<1 being indicative of diastolic dysfunction).
For the Doppler studies the sample volume was positioned just below the level of the mitral annulus and between the tips of the mitral leaflets as they opened during diastole. The Doppler beam was aligned so that the angle between the ultrasound beam and the blood flow vector was as close to zero as possible.
Ambulatory Blood Pressure Monitoring
Ambulatory blood pressure was monitored with an automatic device (Spacelabs 90207, Spacelabs Inc). Measurements were made every half hour throughout the day (7 am to midnight) and hourly at night. During each measurement, patients were asked to keep their cuff arm still. The mean blood pressure was calculated from the readings over the whole 24-hour period. Ambulatory monitoring was deemed acceptable if more than 85% of readings were recorded.
Standard 12-lead electrocardiograms were recorded. The Estes scoring system,13 Sokolow index, duration of P wave and PQ duration, QRS complex, axis and total voltage14 were measured. Left ventricular strain was defined as ST-segment depression or T-wave inversion in leads V5-V6.
Ambulatory ECG Monitoring
Patients underwent 24-hour ECG monitoring using a three-channel Marquette 8500 recorder (Marquette Electronic). They were asked to carry out their normal activities during the ambulatory ECG monitoring and keep a diary of their symptoms and activities. All patients completed 24 hours of continuous ECG recording. The tapes were analyzed by two independent observers using the Marquette 8000 Laser Holter System to identify and label each QRS complex. Ventricular arrhythmias were classified according to the Lown and Wolf classification15 : grade 0, no premature ventricular complexes: grade 1, fewer than 30 premature ventricular complexes per hour; grade 2, more than 30 premature complexes per hour; grade 3, multiform ventricular complexes; grade 4A, couplets; grade 4B, more than three consecutive premature ventricular complexes at a rate greater than 110 beats per minute; and grade 5, R-on-T phenomenon. An episode of ventricular tachycardia (VT) was defined as three or more consecutive ventricular extrasystoles with a rate higher than 100 per minute lasting 30 seconds or less (nonsustained VT) or longer than 30 seconds (sustained VT).
Analysis of ventricular late potentials was performed by the signal-averaging (SAECG) technique. Predictor I (Corasonix) was used to acquire and analyze data. For SAECG, the standard orthogonal leads x, y, and z were employed. The sampling frequency was 2000 Hz. A bidirectional 40- to 250-Hz band-pass filter was used. Between 150 and 300 beats of each lead were averaged to obtain a noise level of 0.5 μV or less. Criteria for abnormal late potentials included QRS duration >114 ms, root mean square (RMS) voltage of the last 40 ms <20 μV, and the duration of low-amplitude signals (LAS) below 40 μV >38 ms. Late potentials were considered present if any two parameters were abnormal.
Results were analyzed by ANOVA for repeated measures (within groups) or unpaired t test (between groups) and by linear regression analysis and are presented as mean±SD. Differences were considered to be significant if P<.05.
Of the 45 patients, eight had ischemic ECG changes during the ETT (group I). Six of them had a positive repeated ETT with 201Th scintigraphy, which revealed defects in the posterior and lateral wall suggestive of ischemia. All six underwent coronary arteriography to exclude coronary artery disease. In all six patients the coronary arteriograms were normal. The remaining 37 patients with a negative ETT were designated as group II and compared with group I. Demographic data of the two groups are shown on Table 1⇓. Both groups were similar for age, smoking, duration of hypertension, and previous treatment, but group I patients were more overweight than patients of group II.
Blood Pressure Measurements
All patients had similar clinic and ambulatory blood pressures, although patients of group I had a tendency to higher systolic blood pressure during isometric exercise by handgrip. During ETT in group I patients, systolic blood pressure at peak exercise did increase significantly, despite somewhat shorter duration on the treadmill. These data are shown in Table 2⇓.
Table 3⇓ presents the echocardiographic data of LV anatomy and function. There was no difference in posterior wall and interventricular septum thickness in diastole, but patients of group I had a thicker apex, greater LVDD and LVMI, and a larger left atrium. All patients had normal systolic function, with an ejection fraction >50%, but all had some degree of diastolic dysfunction, with an E-A ratio <1.
Table 4⇓ presents the ECG data at rest and during ambulation. In the resting ECG, patients of group I had a higher Romhilt-Estes point score and total voltage, indicating an overall greater degree of LVH.
Ambulatory ECG Monitoring: Late Potentials
Analysis of late potentials revealed that group I patients had significantly higher QRS duration versus group II, but the rest of the criteria were similar. Four patients from group I had positive late potentials, 1 by all criteria and 3 by two criteria. Two patients from group I had runs of asymptomatic nonsustained VT, while none from group II had complex arrhythmia. Isolated PVCs were observed in 22 patients (5, or 63% from group I and 17, or 46% from group II), and couplets were observed in 3 patients (all from group I).
Total cholesterol and triglycerides were higher in group I versus group II (254±28 versus 218±24 mg/dL, P<.001 and 173±16 versus 123±62 mg/dL, P<.05, respectively), whereas HDL cholesterol was lower (38±11 versus 44±7, P<.001). Their fasting blood sugar was similar (105±36 versus 104±23 mg/dL, respectively).
The plasma levels at rest and peak exercise for NE, E, PRA, and AVP are shown in Fig 1⇓. There were no significant differences between the two groups.
The purpose of this study was to compare a number of anatomic and functional characteristics between two groups of hypertensive patients with LVH, classified according to the presence (group I) or absence (group II) of myocardial ischemia; absence of coronary artery obstruction was documented by coronary arteriography in patients who had a positive ETT with 201Th scintigraphy, so that ischemic changes would be attributable to the particular characteristics accompanying LVH in these patients. Our data indicate that the two groups did not differ in terms of age, sex, severity and duration of hypertension or smoking habits, but the group I patients, who had more pronounced LVH, were significantly more overweight and had a more adverse lipid profile. Although resting office BPs and ambulatory BPs were similar in the two groups, the maximal systolic BP attained by isometric effort (handgrip exercise) tended to be higher in group I, and the systolic BP attained at peak exercise on the treadmill was significantly higher, despite somewhat shorter duration. A significant correlation between LV mass and systolic BP at 3 minutes of exercise, but not at rest, has been described by other investigators,16 and our data are in keeping with this finding.
It should not be surprising that group I patients, those with myocardial ischemia at stress and without coronary obstruction, had a significantly greater degree of LVH by both ECG and echocardiographic criteria. Changes in the architecture of the hypertrophied heart exacerbate the imbalance between energy expenditure and energy production.5 These changes include an increase in the distance between capillaries,17 resulting in underperfusion and diminished diffusion of oxygen, as well as a decrease in coronary reserve.18 The greater LVMI of these patients was associated with overall more cardiac enlargement, as indicated by the significantly more dilated left ventricle and left atrium. However, the thickening of various cardiac structures, such as the interventricular septum and posterior wall, was no different between groups at the level of the mitral valve and papillary muscles but differed at the level of the apex only, giving the left ventricle a characteristic configuration (Fig 2⇓).
Two different patterns of LVH (eccentric and concentric) were described several years ago19 and depend on the type of hemodynamic load. Concentric hypertrophy, with symmetrical thickening of the LV wall but no enlargement of the chambers, was considered to be typical of hypertension. This was evidently the pattern in the majority of our patients. However, the patients of group I had concentric hypertrophy with a slightly different pattern, a more pronounced apical thickening, which would appear to represent a more advanced or severe stage of hypertensive LVH. Because the apical area supplies most of the force for contraction, it would also have the greatest energy demand and hence sustain a more pronounced deficit under conditions of relative hypoperfusion, which might explain the ischemic changes under stress in these patients. In the resting state, our patients exhibited essentially normal fractional shortening and ejection fraction, indicating normal overall systolic capacity (although some degree of diastolic dysfunction was present in all of them, as indicated by an E-A wave ratio <1). However, under stress, such patients have been described to exhibit impaired LV functional reserve with a lesser increase in ejection fraction.20 Interestingly, other studies in hypertensives with angina and normal coronary angiograms have suggested that reduced coronary reserve is also the result of LVH,21 whereas others suggested that it may be a characteristic of the hypertensive state per se and not necessarily correlated with LV mass.22
As mentioned earlier, an important consequence of LVH is electrophysiological instability.4 Indeed, several studies have documented the association between LVH and ventricular ectopy, including complex arrhythmias and runs of ventricular tachycardia,23 24 which probably account for the long-known higher incidence of sudden death in such patients.25 In keeping with these reports, 4 of our 8 group I patients had positive late potentials when their ambulatory ECG tapes were analyzed by SAECG technique, indicating increased propensity to ventricular arrhythmias.26 As a result, this group was found to be more prone to frequent isolated PVCs as well as episodes of complex arrhythmias, such as couplets and runs of nonsustained ventricular tachycardia. A significant correlation between evidence of hypoperfused segments of the myocardium by stress testing with 201Th scintigraphy and a propensity to severe arrhythmias has been described in other patient populations with LVH.27
An abnormal hemodynamic state is only one of the causes of LVH. Another is the trophic action of neurohormones, especially angiotensin II and catecholamines.28 29 30 Several studies in the past, including our own, have found significant differences in the profile of pressor hormones at rest and/or in response to stress between hypertensives with and without LVH.16 31 In the present study, there were no significant differences between the two groups, but it should be noted that both groups had LVH that differed in severity only.
In conclusion, our data demonstrate that hypertensives with LVH associated with myocardial ischemia at stress but normal coronary arteriograms tend to be more overweight, attain a higher systolic blood pressure at ETT despite a shorter duration, have a higher propensity to severe arrhythmias, and have an adverse lipid profile. LVH in these subjects is more pronounced by both ECG and echo criteria and is characterized by predominantly apical hypertrophy with left atrial and ventricular dilatation, rather than overall LV wall thickening.
Selected Abbreviations and Acronyms
|ETT||=||exercise tolerance test|
|LVH||=||left ventricular hypertrophy|
|PRA||=||plasma renin activity|
- Received March 16, 1997.
- Revision received April 22, 1997.
- Accepted May 7, 1997.
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