Author + information
- Received March 14, 2003
- Revision received August 21, 2003
- Accepted August 25, 2003
- Published online March 3, 2004.
- Philip M. Mottram, MBBS, FRACP*,
- Brian Haluska, MS*,
- Satoshi Yuda, MD*,
- Rodel Leano, BS* and
- Thomas H. Marwick, MBBS, PhD, FACC*,* ()
- ↵*Reprint requests and correspondence:
Prof. Thomas H. Marwick, Department of Medicine, University of Queensland, Princess Alexandra Hospital, Ipswich Road, Brisbane Q4102, Australia.
Objectives We sought to determine if a hypertensive response to exercise (HRE) is associated with myocardial changes consistent with early hypertensive heart disease.
Background An HRE predicts the development of chronic hypertension (HT) and may reflect a preclinical stage of HT.
Methods Patients with a normal left ventricular (LV) ejection fraction and a negative stress test were recruited into three matched groups: 41 patients (age 56 ± 10 years) with HRE (>210/105 mm Hg in men; >190/105 in women), comprising 22 patients with (HT+) and 19 without resting hypertension (HT−); and 17 matched control subjects without HRE. Long-axis function was determined by measurement of the strain rate (SR), peak systolic strain, and cyclic variation (CV) of integrated backscatter in three apical views.
Results An HRE was not associated with significant differences in LV mass index. Exercise performance and diastolic function were reduced in HRE(HT+) patients, but similar in HRE(HT−) patients and controls. Systolic dysfunction (peak systolic strain, SR, and CV) was significantly reduced in HRE patients (p < 0.001 for all). These reductions were equally apparent in patients with and without a history of resting HT (p = NS) and were independent of LV mass index and blood pressure (p < 0.01).
Conclusions An HRE is associated with subtle systolic dysfunction, even in the absence of resting HT. These changes occur before the development of LV hypertrophy or detectable diastolic dysfunction and likely represent early hypertensive heart disease.
A hypertensive response to exercise (HRE) is associated with an increased incidence of chronic hypertension (HT) during follow-up and has been proposed as a preclinical stage of HT (1). However, it is currently unclear as to whether HRE is associated with hypertensive end-organ damage or other cardiovascular complications.
Early cardiovascular disease may be identified using several new techniques, including quantitative echocardiographic parameters with strain rate (SR) imaging and integrated backscatter (IB). Application of these recently developed techniques to patients with HRE may allow the detection of subtle abnormalities of myocardial function. The aims of the study were to determine whether patients with HRE (without resting HT) have detectable abnormalities of myocardial function and to determine the relation of early systolic dysfunction to left ventricular (LV) hypertrophy and diastolic dysfunction in these patients.
We screened 400 consecutive patients referred for exercise electrocardiography or exercise echocardiography for clinical indications, mostly for investigation of chest pain syndromes. Patients with a history of ischemic heart disease were excluded. Exercise tests were performed using the Bruce protocol, with blood pressure (BP) by sphygmomanometry at the end of each 3-min stage. Entry criteria included the presence of normal regional and global resting systolic LV function, no significant (>mild) valvular dysfunction, and a negative maximum exercise electrocardiogram or exercise echocardiogram for inducible myocardial ischemia. A positive (HT+) or negative (HT−) clinical history of HT was defined by elevated BP (>140/90 mm Hg) documented by the referring physician and treated with antihypertensive medication. High normal blood pressure was defined as that exceeding 130/80 mm Hg. Resting blood pressure was measured at the time of the echocardiography. A hypertensive response to maximum exercise was defined by maximum systolic/diastolic BP ≥210/105 mm Hg in males and ≥190/105 mm Hg in females (1,2).
A detailed two-dimensional and Doppler echocardiogram (Vivid Five, GE Vingmed, Horton, Norway) was obtained in all patients. Left ventricular M-mode measurements of wall thickness and end-diastolic and end-systolic diameters were used for calculation of fractional shortening, relative wall thickness, and LV mass (3). Left ventricular hypertrophy was defined as LV mass index >116 g/m2in males and >104 g/m2in females (4). Comprehensive assessment of LV diastolic function included transmitral and pulmonary vein pulsed wave Doppler imaging from the apical four-chamber view, LV color flow propagation velocity, and mitral annular diastolic velocities with tissue Doppler imaging. Transmitral early diastolic velocity and deceleration time, late diastolic velocity, and isovolumic relaxation time were recorded. Systolic and diastolic velocities were measured in the right upper pulmonary vein, as was the velocity of the atrial reversal wave. Left ventricular color flow propagation velocity was measured as the slope of the first aliasing velocity of the early diastolic signal, from the plane of the mitral valve to a point 4 cm into the LV cavity (5). Systolic and early (Ea) and late (Aa) diastolic velocities were measured at the medial and lateral mitral annulus with pulsed wave tissue Doppler imaging in the apical four-chamber view. The ratio of peak early diastolic velocity to Ea was used to estimate LV filling pressures (6), and the Tei index was determined as an additional parameter of myocardial performance (7). Measurements were performed off-line and averaged from three consecutive cardiac cycles. Satisfactory measurements were obtained with all modalities except flow propagation velocity, which was obtainable in 57 subjects (98%).
Strain rate imaging
Three consecutive cardiac cycles of color Doppler data were digitally recorded in each of six walls (i.e., septum, lateral, anterior, inferior, anteroseptum, and posterior) in three standard apical views. Strain and SR are sensitive measures of long-axis systolic LV function that represent dimensionless descriptions of length changes due to the deformation of tissue caused by applied or developed force. The rate of regional myocardial deformation (SR) was derived from instantaneous differences in myocardial velocities within an 11-mm region of interest (8), using developmental software (TVIv61, GE Vingmed, Milwaukee, Wisconsin). Percent deformation of the segment (myocardial strain) was obtained by integration of the SR curve. Mean SR and peak systolic strain were calculated in each patient by averaging the results of each wall and were obtainable in 343 (99%) of 348 segments.
Long-axis systolic LV function was also assessed by cyclic variation (CV) of IB, as a means of corroborating the SR results. Gray-scale loops of three consecutive cardiac cycles were acquired at frame rates of 80 to 120 frames/s in three standard apical views, saved in raw data format, and analyzed off-line (Echopac 6.1, GE Vingmed, Milwaukee, Wisconsin). The IB information in the three cycles was averaged; then, the CV of IB during systole was determined for each of the 16 LV segments (9)by tracking a fixed 11 × 11 pixel region of interest in the mid-myocardium in each frame. The magnitude of CV was determined by the difference between the minimum and maximum values of IB in a cardiac cycle (10). Mean CV was calculated in each patient by averaging the results of 16 individual segments.
Calibrated IB, a measure of myocardial ultrasound reflectivity or tissue density, was obtained from the septum and posterior wall in the parasternal view by subtracting average pericardial IB intensity from average myocardial IB intensity (11). Measurements were obtained by adjusting the position of the sample volume in each frame so that it was maintained within the same region of the septum, posterior wall, or pericardium throughout the cardiac cycle. The CV of IB was measurable in 874 (94%) of 928 segments, and calibrated IB in 108 (93%) of 116 segments.
Sample size and statistical analysis
Sample size calculations were based on previous data from our laboratory comparing patients with hypertensive LV hypertrophy with control subjects (10). These results revealed a 17% to 22% reduction in CV of IB, SR, and peak systolic strain in patients with hypertensive LV hypertrophy. By applying the variance seen in these patients, a significant difference (p < 0.05) of 15% between groups was predicted with a sample size of 17 patients per group at 90% power for CV of IB and >90% for SR and peak systolic strain.
Continuous variables are presented as the mean value ± SD. Group differences were compared using analysis of variance (ANOVA); post-hoc multiple group comparisons were assessed with the Bonferroni method, adjusting for three-way comparisons. Linear regression was used to determine correlations between continuous variables. The relationship of strain and IB parameters with LV mass, BP, and body weight was examined in a multiple linear regression model. Data were analyzed using standard statistical software (SPSS version 9, Chicago, Illinois). A p value of <0.05 was considered significant.
Clinical and exercise characteristics
Of the screened group, 41 patients (19 HT− and 22 HT+) demonstrated HRE and met the entry criteria. There were no significant age or gender differences between the HT− and HT+ patients and the 17 age- and gender-matched control subjects with no clinical history of HT and a normotensive response to exercise (Table 1).
The HRE(HT−) patients had high normal resting BP (mean value 136/86 mm Hg) with elevated BP at peak exercise, but an exercise duration and maximal work load similar to controls. The HRE(HT+) patients had higher resting BP, higher peak systolic BP, and lower exercise performance compared with both HRE(HT−) patients and controls. The increase in systolic BP normalized for exercise capacity was similar in both HRE groups (Table 1).
The HRE(HT−) patients had cardiac dimensions and LV mass index similar to control subjects (Table 2). The HRE(HT+) patients had increased wall thickness and relative wall thickness but did not have a significantly different LV mass index (p = 0.08 by ANOVA). Only 4 of the 41 patients with HRE had LV hypertrophy, three of whom were in the HRE(HT+) subgroup.
The HRE(HT+) patients had impaired LV diastolic function, as evidenced by a reduced early/late diastolic velocity ratio, prolonged deceleration time and isovolumic relaxation time, and reduced velocities of flow propagation and lateral Ea (Tables 2 and 3). ⇓The early/late diastolic velocity ratio and lateral Ea velocity were less in HRE(HT+) than in HRE(HT−) patients. The HRE(HT−) patients showed no abnormalities in diastolic function (Table 3). There was no significant difference in mitral annular peak systolic velocities between HRE patients and control subjects.
The ratios of peak early diastolic transmitral velocity to Ea for HRE(HT+) and HRE(HT−) patients and controls were 7.3, 6.6, and 6.7 (p = 0.31), respectively, using septal Ea, and 6.4, 5.9, and 5.6 (p = 0.25), respectively, using lateral Ea. These results suggest that LV filling pressures were normal in study patients and similar in all three groups. Results for the Tei index were concordant with the abnormalities of diastolic function demonstrated in the HRE(HT+) group (Tables 2 and 3). This parameter increased between controls (0.409 ± 0.178), HRE(HT−) patients (0.504 ± 0.153), and HRE(HT+) patients (0.603 ± 0.187; p = 0.004), consistent with a stepwise reduction in myocardial performance. Post hoc testing with Bonferroni adjustment revealed a significant difference between HRE(HT+) patients and controls (p = 0.003), but the difference between HRE(HT−) patients and controls was not significant (p = 0.22).
Strain and IB
Patients with HRE had impaired long-axis LV function, as evidenced by significantly reduced SR, peak systolic strain, and CV of backscatter (Figs. 1 and 2). ⇓⇓These reductions were equally apparent in patients with and without a history of resting HT.
In a multiple linear regression model, the lower values of SR (p < 0.001), peak strain (p < 0.01), and CV (p = 0.01) in HRE patients remained significant after correcting for the effects of differences in LV mass index, systolic and diastolic BP, and body weight. In HRE patients, there was a trend toward a negative correlation of peak systolic strain with diastolic BP (r = −0.32, p = 0.054), but not systolic BP (r = −0.15, p = 0.38). There was no relation of BP to either SR or CV. Thirteen of the 22 HRE(HT+) patients were taking negatively inotropic agents for treatment of HT. There was no difference in SR (p = 0.29) or peak systolic strain (p = 0.88) between those taking and those not taking these agents. Interestingly, CV was higher in patients on negatively inotropic medication (6.72 vs. 5.82 dB, p = 0.02).
In contrast to the observed reductions in myocardial systolic function, HRE patients showed no disturbances in myocardial reflectivity (Table 4), suggesting that myocardial density is not altered in this group.
Although HRE patients had similar exercise capacity, cardiac dimensions, and diastolic function, compared with control subjects with a normotensive exercise response, they demonstrated a mild decrease in LV segmental deformation. This impairment of LV long-axis systolic function was evident even in patients without a history of resting HT. These results suggest that cardiac damage is evident in a patient group that many observers would consider to be “prehypertensive” (12).
HRE in patients without diagnosed HT
Although it is not surprising that HRE patients with background HT (albeit largely controlled) have mildly abnormal LV function, the detection of abnormal function in the HT− group is a significant finding. These HRE(HT−) patients had high normal (13)resting BP (mean 136/86 mm Hg), and previous studies have demonstrated that subjects with high normal BP have a several-fold increased risk of progression to HT during follow-up (14)and are at increased risk of cardiovascular events (15). Furthermore, an HRE itself is associated with the subsequent development of HT (1). The present study underscores the importance of HRE in association with high normal BP by demonstrating that subtle myocardial dysfunction is already present in these patients.
Cardiac complications of early HT and HRE
Left ventricular hypertrophy
The lack of association between HRE and LV hypertrophy in the present study is consistent with the results of the Framingham investigators (2), which showed no difference in the prevalence of LV hypertrophy in HRE after correcting for age, systolic BP, and body mass index. Indeed, previous studies suggesting that LV hypertrophy (rather than dysfunction) is the earliest cardiac abnormality in both early HT (16)and HRE (17)did not include sensitive measures of systolic and diastolic function. Furthermore, in the present study, there was no significant correlation of either strain or backscatter indexes with LV mass index in HRE patients, and the reductions in these parameters, compared with controls, remained significant after correcting for group differences in LV mass index. Such results suggest that abnormalities of strain and backscatter in HRE patients relate to a degree of myocardial damage and are not explained by myocardial hypertrophy.
Diastolic dysfunction is thought to develop relatively early in the course of systemic HT, and former clinical studies have suggested that diastolic dysfunction precedes systolic dysfunction in the progression of hypertensive heart disease (18). In these studies, however, systolic LV function was assessed with chamber dynamics, which do not accurately reflect myocardial systolic function in the presence of concentric remodeling (19). In the present study, patients at an earlier stage of HT had normal LV structure (dimensions, mass, and calibrated IB) and normal transmitral flow; however, despite reduced annular diastolic velocity in only hypertensive patients with HRE, parameters of impaired long-axis contractility were present in all HRE patients. These findings suggest that segmental systolic dysfunction occurs before global diastolic dysfunction and may be the earliest abnormality in hypertensive heart disease. However, they do not exclude the presence of segmental diastolic dysfunction in this group, as diastolic SR imaging was not performed.
Although overt systolic dysfunction is associated with advanced hypertensive heart disease, animal studies have demonstrated impaired velocity of myocardial contraction in the presence of hypertensive hypertrophy (20). Similarly, despite the presence of a normal ejection fraction in patients with hypertensive LV hypertrophy, human studies have shown reduced mid-wall shortening (21), which is an independent predictor of cardiac death in hypertensive patients (22). The present study extends these findings by demonstrating impaired systolic LV function in both hypertensive patients with minimal increases in LV mass and HRE patients with normal LV mass and normal global diastolic function.
A recent study of hypertensive patients with concentric remodeling found that fractional shortening and systolic mitral annular velocities were decreased in the long axis, but not in the short axis, as compared with controls (23). These results suggest that impairment of long-axis systolic function may occur before changes in radial contractile function in hypertensive heart disease and are consistent with reduced long-axis strain and IB parameters demonstrated in patients without concentric remodeling in the present study.
Mechanism of LV dysfunction in HRE
The mechanism of subtle systolic dysfunction in HRE patients is unclear. Although it may reflect periodic surges in BP related to exertion and possibly emotional stress, in the majority of patients, BP only reached excessive levels at or near peak exercise and was in the normal range at work loads reflective of normal daily activities. We therefore suspect that myocardial dysfunction developed after long-term exposure to high normal levels of BP.
Although we believe that reductions in SR and backscatter parameters in HRE patients reflect intrinsic myocardial damage, an alternative explanation might invoke the presence of increased afterload. However, several lines of evidence refute the suggestion that afterload differences are responsible for our results. First, previous work in patients with hypertensive LV hypertrophy has shown that afterload is not a determinant of shortening in the long-axis plane (21). Second, previous work with systolic myocardial velocity (the local gradient of which is used to generate SR curves) showed this was relatively independent of hemodynamic factors (24). Third, the strain results are independently supported by CV of IB, which is relatively independent of load (25). Finally, there was no significant relationship between BP and long-axis systolic function in the present study; indeed, despite a progressive increment in resting mean BP in control subjects and HRE(HT−) and HRE(HT+) patients, strain and CV parameters were reduced equally in both of the HRE groups. Thus, although SR is unlikely to be entirely independent of afterload, the effects at physiologic loads are likely to be small.
As our understanding of the risk of end-organ damage due to HT has evolved, guidelines for target BP in hypertensive patients have periodically been revised downward. The present study adds further support to this trend by identifying impaired myocardial function in patients with high to normal resting BP who exhibit HRE. These changes may represent the earliest cardiac abnormality in hypertensive heart disease and may identify patients at risk of developing clinical heart failure.
The findings suggest that SR imaging and CV of IB are promising quantitative techniques for noninvasive myocardial characterization, which may aid in the early detection of hypertensive heart disease. More importantly, they may allow monitoring of the response to treatment interventions with greater sensitivity than, for example, serial measurement of LV dimensions with M-mode imaging. Important questions to be addressed include whether the observed systolic dysfunction is reversible with effective treatment of HT, and what is the relation of decreased CV and strain parameters to clinical risk?
☆ This study was supported in part by a scholarship from the National Heart Foundation of Australia.
- late diastolic mitral annular velocity
- blood pressure
- cyclic variation
- early diastolic mitral annular velocity
- hypertensive response to exercise
- integrated backscatter
- left ventricle/ventricular
- strain rate
- Received March 14, 2003.
- Revision received August 21, 2003.
- Accepted August 25, 2003.
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