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(Circulation. 2004;109:972-977.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Mechanisms of Exercise Intolerance

Insights From Tissue Doppler Imaging

Stanislaw J. Skaluba, MD; Sheldon E. Litwin, MD

From the Division of Cardiology, University of Utah Health Sciences Center, and the Salt Lake City Veterans Affairs Medical Center, Salt Lake City, Utah.

Correspondence to Sheldon E. Litwin, MD, Division of Cardiology, University of Utah, 30 North 1900 East, Salt Lake City, UT 84132-2401. E-mail sheldon.litwin{at}hsc.utah.edu

Received April 21, 2003; de novo received July 28, 2003; revision received November 18, 2003; accepted November 18, 2003.

	Abstract

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Background— A decreased ratio of early to late diastolic mitral inflow velocities (E/A <1.0) reflects slowing of left ventricular (LV) relaxation. This finding is widely believed to indicate significant diastolic dysfunction. However, E/A <1.0 is common during normal aging and often is not associated with symptoms of heart failure. We asked (1) whether slowed LV relaxation is associated with exercise intolerance and (2) whether tissue Doppler imaging of the early diastolic mitral annular velocity (Ea) is helpful in understanding mechanisms of exercise intolerance.

Methods and Results— Patients (n=121) underwent echocardiography before maximal exercise testing. Fifty-nine subjects had E/A <1.0, and 36 subjects had E/Ea 10. Exercise capacity was similar in the population with a normal mitral inflow pattern and those with a slow relaxation pattern when E/Ea was <10. In contrast, the subjects with slow relaxation and E/Ea 10 had reduced exercise tolerance. Of all the echo and clinical parameters assessed, E/Ea had the best correlation with exercise capacity (r=-0.684, P<0.001) and was the strongest independent predictor of exercise capacity 7 METs by multivariate analysis (prevalence-corrected odds ratio=12.6, P<0.001). E/Ea continued to be strongly associated with exercise capacity in all age groups and in those with preserved or reduced systolic function.

Conclusions— Of the subjects with slow LV relaxation, only those with E/Ea 10 have objective evidence of reduced exercise tolerance. These data suggest that elevated LV filling pressures rather than slow relaxation per se reduce exercise capacity.

Key Words: echocardiography, Doppler • heart failure • diastole • exercise • imaging

	Introduction

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Diastolic abnormalities contribute to symptoms of heart failure.^1–3 However, the relative importance of systolic versus diastolic abnormalities is a topic of ongoing debate.^4–7 Some of the uncertainty in this field arises because diastolic "dysfunction" occurs with a spectrum of severity, although it is often considered to be a single entity. In contrast, most investigators recognize and account for different degrees of left ventricular (LV) systolic dysfunction. There are few data that allow us to quantify the relative importance of the early forms of diastolic dysfunction.^4,8

The rate of LV pressure decline during isovolumic relaxation becomes slower during the development of most forms of cardiovascular disease and also becomes slower during normal aging.^1,8–12 Slowed LV relaxation lowers the pressure gradient between the left atrium and the LV in early diastole.¹³ This is usually manifested as a decrease in the velocity of the early LV diastolic filling wave (E) with a compensatory increase in the A-wave velocity. A ratio of mitral E to A flow velocities <1.0 is referred to as a "slow relaxation" mitral inflow pattern.¹³

A slow LV relaxation pattern seen on transmitral Doppler spectroscopy is present in 70% of individuals over the age of 75 years.^1,8 Surprisingly, only a small fraction of people with a slow relaxation mitral flow pattern have symptoms or signs of congestive heart failure (2% to 3%).¹ Therefore, it is possible that slow LV relaxation alone does not directly produce heart failure symptoms.¹⁴

An excessive rise in pulmonary capillary wedge pressure during exercise is the main cardiac cause of exertional dyspnea.¹⁵ Thus, tests that give information about LV filling pressures, rather than LV relaxation rate, may be more helpful in determining whether exertional dyspnea results from a cardiac pathogenesis. Traditional Doppler measurements of transmitral or pulmonary venous flow patterns have inconsistent relationships with LV filling pressures.^16,17 In contrast, several groups have shown that LV filling pressures correlate well with the ratio of mitral E to the early diastolic velocity of the mitral valve annulus (Ea).^17–19 Ea obtained by tissue Doppler imaging (TDI) is a relatively direct measure of LV relaxation rate in that Ea correlates closely with the time constant of isovolumic pressure decline () measured invasively.²⁰ Ea is relatively unaffected by heart rate or changes in preload or afterload.^21–23 Mitral E, conversely, is highly affected by alterations in preload.²³ Thus, the ratio of E and Ea provides reliable information about LV filling pressures.^17,18,23

The goals of our study were to determine (1) whether slowed myocardial relaxation is directly associated with overt or subclinical exercise intolerance and (2) whether TDI of the mitral annulus is useful in the prediction of exercise capacity in unselected patients.

	Methods

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The Institutional Review Board of the University of Utah Health Sciences Center and the Salt Lake City Veterans Affairs Medical Center approved the protocol. All subjects gave informed consent to participate in the study. We prospectively studied 121 nonconsecutive but unselected patients referred for exercise echocardiographic stress testing. The majority of patients in our study were referred for evaluation of suspected coronary artery disease (CAD). Eligible patients were >18 years old, in sinus rhythm, able to exercise on a treadmill, and without pacemakers, severe native valvular disease, or prosthetic heart valves. Patients with evidence of ischemia during the stress test were excluded. A history of diabetes mellitus (DM), hypertension (HTN), chronic obstructive pulmonary disease, or CAD was determined from the patient and confirmed by chart review. Chronic renal insufficiency (CRI) was defined as a documented serum creatinine >1.4 mg/dL. The demographics and clinical characteristics of the study group are shown in Table 1.

View this table: [in this window] [in a new window]   TABLE 1. Patient Demographics

Echocardiography was performed immediately before starting exercise (Acuson, Sequoia or GE, Vivid FiVe). Echo measurements were performed in a blinded manner.^24,25 LV ejection fraction (EF) was calculated using a biplane method of disks. We calculated LV mass using a Penn-cube formula.²⁶ LV hypertrophy (LVH) was considered to be present if LV mass/height was >143 g/m in men or >102 g/m in women.²⁷ Mitral regurgitation (MR) and aortic regurgitation (AR) were graded according to published criteria.²⁸ TDI was performed in an apical 4-chamber view, with the sample volume placed at the septal border of the mitral annulus. LV filling patterns were classified as normal, slow relaxation, pseudonormal, or restrictive.²⁹ A pseudonormal pattern was distinguished from normal filling by Ea velocity <8.5 cm/s and Ea/Aa <1.0.²³ The different transmitral and TDI patterns from our patients are shown in Figure 1.

View larger version (84K): [in this window] [in a new window]   Figure 1. Representative examples of Doppler tracings showing various mitral inflow patterns used in this study. E and A indicate early and late diastolic mitral inflow velocities; Ea and Aa, early and late diastolic mitral annular velocities.

After the echo, symptom-limited exercise was performed on a treadmill using a Bruce protocol. A physician who was unaware of the echo results was present during all of the studies to encourage maximal exertion. Patients were instructed to withhold ß-adrenergic–blocking medications on the day of the test. The primary end point was maximal exercise tolerance defined by the achieved metabolic equivalents (METs).³⁰ For analyses using a dichotomous end point, we defined reduced exercise tolerance as 7 METs.³¹

Data are expressed as mean±SD. Pearson correlation was used to determine the associations between individual continuous variables and exercise capacity. Multivariate linear and logistic regression models were used to estimate the relative contributions of the different independent variables to exercise performance. We performed collinearity diagnostics to look for multicollinearity between the independent variables in linear and logistic models. To assess outliers and influential cases, we performed residual diagnostics, Cook’s distance, and leverage values. No corrections were made for one outlier. We tested different transformations of each continuous variable (quadratic, logarithmic, inverse, and exponential) versus exercise tolerance. In each case, linear fits yielded correlation coefficients very close to those for the fits of the transformed variables. We calculated the heuristic shrinkage estimator to show that inclusion of 8 variables did not introduce excessive "noise" into our logistic regression model. Odds ratios were corrected for the prevalence of the outcome (7 METs).³² A receiver operating characteristic (ROC) curve was plotted to determine the sensitivity and specificity of the different E/Ea values to predict reduced capacity of 7 METs. A probability value of <0.05 was considered to be significant. Analyses were performed with SPSS for Windows, version 11.0.

	Results

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Most of the subjects (84%) had a normal LVEF (Table 1). Twenty-six of 121 patients (21%) achieved 7 METs, 59 of 121 (49%) had E/A <1.0, and 36 of 121 (30%) had E/Ea 10. Achieved METs for patients with E/Ea <10 was 11.5±2.5, versus 6.5±1.7 for those with E/Ea 10 (P<0.001; Figure 3A).

View larger version (27K): [in this window] [in a new window]   Figure 3. A, Exercise capacity in patients with normal or increased E/Ea (<10 vs 10). Exercise capacity was greater by a mean of 5.0 METs in patients with E/Ea <10. B, Exercise capacity in patients categorized by their mitral inflow pattern. Patients in slow relaxation group were subdivided into those with normal or increased E/Ea. Box plot shows median (center line), first and third quartiles (top and bottom of box), and lowest and highest values (vertical lines) of exercise performance.

Traditional measurements of mitral inflow (ie, E/A, E-deceleration time [DT]) correlated weakly with exercise capacity (Table 2). The same was true for measures of LV size, right ventricular size, LVEF, and left atrial area. LV mass correlated moderately with exercise capacity. Among all of the echo parameters measured, the best individual correlate of exercise performance was E/Ea (r=-0.684; Table 2; Figure 2A). Using 7 METs as a cutoff to separate reduced from normal exercise capacity,³¹ the ROC curve showed that E/Ea=10.6 had a sensitivity of 85% and a specificity of 88% (Figure 2B). This compares well with previous studies showing that E/Ea 10 had optimal sensitivity and specificity for detecting pulmonary capillary wedge pressure >15 mm Hg.²¹ Patients with E/Ea <10 performed better on the treadmill than the patients with E/Ea 10 by a mean of 5.0 METs (P<0.001; Figure 3A).

View this table: [in this window] [in a new window]   TABLE 2. Correlation of Resting Echocardiographic Measurements With Exercise Capacity

View larger version (26K): [in this window] [in a new window]   Figure 2. A, Correlation between E/Ea and exercise performance. Each point represents 1 individual patient. 95% CIs are shown. B, ROC curve showing sensitivity and specificity of different E/Ea values to predict functional capacity. E/Ea=10.6 had optimal sensitivity and specificity to predict exercise capacity 7 METs.

Achieved METs in subjects with normal mitral flow patterns was 12.1±2.5, compared with 9.6±3.0 and 6.5±1.7 in subjects with a slow relaxation mitral inflow pattern (E/A ratio <1.0) and those with pseudonormal/restrictive filling patterns, respectively. Interestingly, there was similar exercise capacity in the patients with a normal mitral inflow pattern and those with a slow relaxation pattern when E/Ea was <10 (11.1±2.4 METs; Figure 3B). In contrast, the subjects with slow relaxation and E/Ea 10 performed nearly as poorly on the treadmill as did the groups with pseudonormal/restrictive LV filling patterns (6.7±1.8 versus 6.5±1.7 METs; Figure 3B).

Patients with E/Ea 10 were more likely to be male and to be older and had higher systolic blood pressure, higher body mass index (BMI), and increased prevalence of smoking, CAD, DM, HTN, CRI, LVH, and presence of more than trivial AR and MR (Table 1). To determine whether the aforementioned clinical conditions or E/Ea were more directly associated with exercise capacity, we performed logistic regression analysis using the different conditions as independent dichotomous variables and exercise capacity 7 METs as the dependent dichotomous variable (Table 3). Several clinical and echocardiographic parameters were significant univariate predictors of achieving 7 METs. However, only E/Ea 10 continued to be a significant independent predictor of reduced exercise tolerance in the multivariate analysis.

View this table: [in this window] [in a new window]   TABLE 3. Logistic Regression Analysis of E/Ea and Clinical Conditions to Predict Reduced Exercise Capacity (7 METs)

To further define the role of E/Ea, age, BMI, and LV mass on exercise tolerance, we performed multivariate linear regression analysis (Table 4). The slope of the regression line (B) for each of the independent variables versus METs is shown for a given change in the independent variable (Table 4). The standardized coefficient (ß) allows direct comparison of the different slopes even though the original units for each variable are different. Once again, this analysis reveals that E/Ea has a much stronger association with exercise capacity than any of the other individual factors.

View this table: [in this window] [in a new window]   TABLE 4. Multivariate Linear Regression Analysis of Factors That May Contribute to Reduced Exercise Capacity

Because increased age is a major determinant of slowed LV relaxation, we did a separate analysis on the interaction of E/Ea and age. As expected, there was a moderate inverse linear relationship between age and exercise tolerance (r=-0.410, P<0.001). However, for the group with a slow relaxation mitral inflow pattern (n=59), age and E/Ea did not correlate (r=0.078, P=0.56). Moreover, the correlation between E/Ea and exercise capacity grew stronger with increasing age (r=-0.498, -0.635, and -0.693 in patients 18 to 49, 50 to 65, and >65 years old, respectively; P<0.001). Thus, increasing age does not negate the powerful association between increased LV filling pressures and reduced exercise capacity, nor does the presence of slowed LV relaxation.

We also performed subgroup analyses based on the presence of coexisting illnesses. Correlations between E/Ea and exercise tolerance were higher in patients with each of following conditions versus those without: HTN (-0.689 versus -0.518), DM (-0.752 versus -0.532), CAD (-0.702 versus -0.611), LVH (-0.769 versus -0.616), and BMI >30 (-0.687 versus -0.608); P<0.001 for all comparisons.

Last, we asked whether the use of hemodynamically active cardiovascular medications influenced the ability of E/Ea to predict functional capacity. Compared with those on no cardiac medications, the correlations between E/Ea and METs were stronger in patients taking cardiac medications than in those who did not (Table 5).

View this table: [in this window] [in a new window]   TABLE 5. Correlation Between E/Ea and Exercise Capacity According to the Use of Cardiac Medications

In summary, evidence of elevated LV filling pressures as determined by combined mitral inflow and TDI of the mitral annulus, was the strongest independent predictor of reduced exercise tolerance. The correlation between E/Ea and exercise tolerance was strong regardless of age, use of medications, coexisting medical conditions, or evidence of slowed LV relaxation on transmitral Doppler.

	Discussion

Top Abstract Introduction Methods Results Discussion Conclusions References

 
There is ongoing debate about the relative importance of systolic and diastolic dysfunction in the genesis of heart failure symptoms.^4,6 Part of the uncertainty may arise because transmitral Doppler spectroscopy provides a highly sensitive method for detecting early abnormalities of LV relaxation, whereas the usual methods for assessing systolic function (ie, LVEF) are less sensitive.⁵

Because most people with E/A <1.0 do not meet defined criteria for heart failure, some investigators have hypothesized that impaired relaxation is a precursor to overt heart failure.¹ If this is the case, then symptoms of heart failure should be unmasked during symptom-limited stress testing in patients with this abnormality. Alternatively, elevated LV filling pressures may be necessary to cause exertional dyspnea and heart failure. It is not known whether impaired LV relaxation invariably leads to elevated pulmonary capillary wedge pressure during exercise. Therefore, we asked prospectively whether LV relaxation abnormalities are associated with reduced exercise tolerance.

Most published studies have shown relatively weak or inconsistent relationships between the mitral flow profile and exercise capacity or LV filling pressures.^16,21 Correlations are even worse if patients with preserved LV systolic function are included.¹⁸ The poor correlations occur because transmitral flow velocities are influenced not only by LV relaxation rate but also by preload, heart rate, age, and LV compliance.^13,20,21,23 Conversely, several groups have shown excellent correlations between E/Ea and LV diastolic pressures or pulmonary capillary wedge pressure.^18,19,21,23 The correlations continue to be robust during sinus tachycardia and during acute manipulations in preload.^21,23

Like previous investigators, we found that E/A, E-DT, and isovolumic relaxation time were weak predictors of exercise performance (Table 2). In contrast, we showed a strong negative correlation between E/Ea and exercise capacity (Table 2; Figure 2A). This correlation was the highest among all of the echocardiographic and clinical variables tested. We also divided patients with slow relaxation into 2 groups according to E/Ea <10 or 10. Our results clearly show that the population with impaired LV relaxation was not uniform with regard to exercise capacity. Only those with high E/Ea had reduced exercise tolerance (Figure 3). This important result indicates that not everyone with impaired myocardial relaxation has physiologically significant diastolic dysfunction. Rather, slow relaxation detected by Doppler alone may simply reflect normal aging.

Transmitral flow parameters alone are particularly difficult to interpret in studies with significant numbers of patients having preserved systolic function.^18,33 This is because the distinction between normal and pseudonormal filling patterns is more difficult in such a population. Of our patients, 84% had normal LV systolic function (EF 55%). We found that TDI was effective in predicting exercise capacity in persons with LVEF 50% as in those with EF <50% (r=-0.65 and -0.83, respectively).

Study Limitations
We recorded mitral annular velocities only from the septal aspect of the annulus. This is acceptable because medial annular velocity has a slightly better correlation with mean LV diastolic pressure than lateral annular velocity.¹⁸ In addition, it is technically easier to achieve a favorable orientation between the ultrasound beam and the medial annulus. Septal Ea is potentially unreliable in patients with adjacent wall motion abnormalities. Fortunately, our population included few patients with abnormal wall motion. BMI was obtained by patient reporting of height and weight. Minor inaccuracies in estimation of BMI are unlikely to change our conclusion that BMI had only a moderate correlation with exercise performance. Last, we used calculated METs as our index of exercise tolerance rather than measuring oxygen consumption. Although direct measurement of oxygen consumption is desirable, we believe our approach is valid, because calculation of achieved METs is a widely accepted clinical tool for determining functional capacity that has clear relevance to the day-to-day activities of patients.³¹ Moreover, absolute exercise capacity measured in METs has been shown to be the most powerful predictor of long-term mortality in a large group of patients.³⁴

	Conclusions

Top Abstract Introduction Methods Results Discussion Conclusions References

 
Transmitral E/A <1.0 is only weakly associated with achieved workload. In contrast, combined transmitral flow velocities and TDI of the mitral annulus accurately predict exercise capacity. Thus, elevated LV filling pressures, rather than slow relaxation per se, seem to be a more direct cause of decreased exercise tolerance. It will be important to gain a better understanding of why some patients with slowed LV relaxation develop higher LV filling pressures than others. The combination of impaired relaxation and other diseases such as HTN, CAD, DM, or obesity may have an additive effect that results in elevated LV filling pressures and exercise intolerance. Prospective studies will be needed to determine whether members of an apparently healthy population with slow LV relaxation and normal E/Ea remain asymptomatic or eventually develop heart failure or reduced exercise capacity.

	Acknowledgments

 
This study was supported by grants from the Department of Veterans Affairs and the National Institute of Health (HL-52338-06, U01-70525, T32-HL-7576).

	References

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