0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Left Ventricular Function and Exercise Capacity FREE

Jasmine Grewal, MD; Robert B. McCully, MD; Garvan C. Kane, MD; Carolyn Lam, MD; Patricia A. Pellikka, MD
[+] Author Affiliations

Author Affiliations: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.


JAMA. 2009;301(3):286-294. doi:10.1001/jama.2008.1022.
Text Size: A A A
Published online

Context Limited information exists regarding the role of left ventricular function in predicting exercise capacity and impact on age- and sex-related differences.

Objectives To determine the impact of measures of cardiac function assessed by echocardiography on exercise capacity and to determine if these associations are modified by sex or advancing age.

Design Cross-sectional study of patients undergoing exercise echocardiography with routine measurements of left ventricular systolic and diastolic function by 2-dimensional and Doppler techniques. Analyses were conducted to determine the strongest correlates of exercise capacity and the age and sex interactions of these variables with exercise capacity.

Setting Large tertiary referral center in Rochester, Minnesota, in 2006.

Participants Patients undergoing exercise echocardiography using the Bruce protocol (N = 2867). Patients with echocardiographic evidence of exercise-induced ischemia, ejection fractions lower than 50%, or significant valvular heart disease were excluded.

Main Outcome Measure Exercise capacity in metabolic equivalents (METs).

Results Diastolic dysfunction was strongly and inversely associated with exercise capacity. Compared with normal function, after multivariate adjustment, those with moderate/severe resting diastolic dysfunction (−1.30 METs; 95% confidence interval [CI], −1.52 to −0.99; P < .001) and mild resting diastolic dysfunction (−0.70 METs; 95% CI, −0.88 to −0.46; P < .001) had substantially lower exercise capacity. Variation of left ventricular systolic function within the normal range was not associated with exercise capacity. Left ventricular filling pressures measured by resting E/e′ of 15 or greater (−0.41 METs; 95% CI, −0.70 to −0.11; P = .007) or postexercise E/e′ of 15 or greater (−0.41 METs; 95% CI, −0.71 to −0.11; P = .007) were similarly associated with a reduction in exercise capacity, each in separate multivariate analyses. Individuals with impaired relaxation (mild dysfunction) or resting E/e′ of 15 or greater had a progressive increase in the magnitude of reduction in exercise capacity with advancing age (P < .001 and P = .02, respectively). Other independent correlates of exercise capacity were age (unstandardized β coefficient, −0.85 METs; 95% CI, −0.92 to −0.77, per 10-year increment; P < .001), female sex (−1.98 METs; 95% CI, −2.15 to −1.84; P < .001), and body mass index greater than 30 (−1.24 METs; 95% CI, −1.41 to −1.10; P < .001).

Conclusion In this large cross-sectional study of those referred for exercise echocardiography and not limited by ischemia, abnormalities of left ventricular diastolic function were independently associated with exercise capacity.

Figures in this Article

Many factors, including age, female sex, body mass index, and comorbid medical conditions, are known to be associated with a decrement in exercise capacity, as reflected by a decrease in maximal workload achieved or maximal oxygen consumption.16 Aerobic exercise capacity decreases progressively with age and is associated with reductions in functional capacity, increases in disability, and decreases in independence and quality of life. Determining the most important parameters affecting exercise performance, especially in relation to age, is complex, given the numerous confounding factors. The most consistently reported mechanism contributing to this decrease in exercise capacity with aging is a reduction in maximal heart rate; this appears to be a nonmodifiable and inevitable consequence of aging.7 Similarly, the difference in exercise capacity between men and women has largely been attributed to nonmodifiable differences in cardiac output and skeletal muscle mass.8,9 Identifying potentially reversible mechanisms underlying the decline in maximal exercise capacity with aging and between men and women could have important implications.

Elucidating the mechanisms of cardiac-related exercise limitation has been technically difficult to date. Previous studies have suggested that measurements of left ventricular systolic function do not predict maximal exercise time in individuals with normal or impaired left ventricular systolic function.10,11 However, differences in exercise capacity related to small changes in ejection fraction within the normal range would require evaluation in a large population. Doppler echocardiography can now characterize left ventricular diastolic function through a combination of measurements, which show evidence of slowed ventricular relaxation, increased left ventricular stiffness, or abnormal left ventricular filling. Doppler echocardiography can also provide an estimate of left ventricular filling pressures, one component of diastolic function that reflects pulmonary capillary wedge pressure. In prior small series, these parameters have been shown to correlate with exercise capacity.1214 Whether abnormalities of diastolic function explain age- or sex-related changes in exercise capacity is unknown. The aims of this study were to determine the relationship between left ventricular diastolic function parameters as determined by echocardiography and exercise capacity and to determine if there is a difference in the magnitude of association of diastolic function parameters with exercise capacity with advancing age or sex.

Patient Population

This study was approved by the Mayo Clinic institutional review board, and verbal consent was obtained at the time of the stress echocardiogram. During 2006, 4705 patients had a clinically indicated exercise echocardiogram at the Mayo Clinic, Rochester, Minnesota. For this analysis, we excluded patients who underwent exercise testing with a protocol other than the Bruce protocol (n = 365); refused to participate in research (n = 230); were in atrial fibrillation/flutter at the time of exercise (n = 118); had moderate or severe valvular heart disease (n = 76); had poor image quality, which prohibited a final impression (n = 7); had ejection fractions of less than 50% (n = 88); or had echocardiographic evidence of exercise-induced myocardial ischemia (n = 790). The latter group of patients was excluded because symptoms or signs of ischemia would be expected to contribute to premature termination of exercise. Assessment of diastolic function was not possible in 164 patients because of missing values that were the result of fusion of pulsed-wave Doppler measurements of the early and late mitral inflow velocities or poor apical windows; baseline characteristics of these patients were similar to those studied.

The remaining 2867 patients constituted the study population. Of these, 1402 (49%) were referred for exercise echocardiography for shortness of breath or chest pain, 632 (21%) because of the presence of multiple risk factors for cardiovascular disease, 278 (10%) because of abnormal resting electrocardiogram findings, 250 (9%) for evaluation of suspected coronary artery disease, 232 (8%) for preoperative assessment, and 73 (2%) for increased coronary calcium scores on computed tomography.

Clinical variables and body mass index (calculated as weight in kilograms divided by height in meters squared) were recorded at the time of the exercise echocardiogram. Medication use and a history of diabetes mellitus, hypertension, hyperlipidemia, smoking, and coronary artery disease were abstracted from the medical record and entered into a prospectively maintained database by specially trained nurses. Coronary artery disease was defined as previous coronary revascularization or history of myocardial infarction.

Exercise Echocardiography

Echocardiography was performed before starting exercise and immediately after symptom-limited treadmill exercise according to the Bruce protocol. The Diastolic Function Initiative of 2006, undertaken at the Mayo Clinic, was a routinely performed assessment of left ventricular diastolic function done in addition to assessment of regional wall motion according to the usual exercise echocardiography protocol. The baseline resting assessment included pulsed-wave Doppler measurements of the early (E) and late (A) mitral inflow velocities, deceleration time of early left ventricular filling, the peak early diastolic velocity of the medial mitral annulus (e′) with tissue Doppler in the 4-chamber view, and 2-dimensional measurement of the left atrial size.

The ratio E/e′, a measurement of left ventricular filling pressures, was feasible in all patients at rest. Shortly after exercise, mitral inflow and annulus Doppler data were obtained again. These were measured in early recovery (within 2-7 minutes of cessation of exercise) after regional wall motion assessment and at the earliest time that the E and A velocities were sufficiently separated to permit measurement. Measurement of postexercise E/e′ was feasible in 2366 patients (82%). Increased left ventricular filling pressure at rest and with exercise was defined as an E/e′ of 15 or greater.15,16 Resting diastolic function was graded as normal, mild dysfunction (impaired relaxation), moderate dysfunction (pseudonormal), or severe dysfunction (restrictive). The classification of diastolic function was modified from the algorithm outlined by Khouri et al.17 Instead of pulmonary vein flow measurements, left atrial volume was measured as part of our assessment because it has been shown to be a marker of diastolic dysfunction.18,19 Relaxation and restrictive abnormalities were classified based on the mitral inflow patterns, an E/A less than 0.75 and E/A greater than 1.5, respectively.

To diagnose a restrictive abnormality, left atrial volume index had to be increased 28 mL/m2 or more, and E/e′ had to be increased 10 or more, respectively; otherwise, patients were classified as normal. This is especially important in young people because a normal E/A is often greater than 1.5 due to increased early filling with no other echocardiographic evidence of diastolic dysfunction.18 To distinguish pseudonormal from normal diastolic function (0.75 ≤ E/A ≤ 1.5), both left atrial volume index and E/e′ had to be increased as described. Left atrial volume was measured according to the area-length method and indexed to body surface area.20 Left ventricular ejection fraction was assessed by a combination of the modified Quinones method21 and visual assessment.

Wall motion was scored according to a 16-segment model, in which 1 was considered normal or hyperdynamic, 2 was hypokinetic, 3 was akinetic, 4 was dyskinetic, and 5 was aneurysmal. The exercise echocardiogram was considered normal if there were no wall motion abnormalities at rest or with exercise. “Fixed” wall motion abnormalities were those present at rest and unchanged by exercise. Global hypokinesis present at rest and improved with exercise was considered to represent cardiomyopathy. Baseline and peak exercise blood pressure, heart rate, and pulse pressure (systolic − diastolic blood pressure) were determined. Heart rate increase with exercise was defined as the difference between peak exercise heart rate and baseline heart rate.

Statistics

The primary end point was maximal exercise tolerance defined by the achieved metabolic equivalents (METs). Data are expressed as mean and standard deviation or number and percentage. Multiple comparisons of continuous variables were made with analysis of variance. Tukey honestly significant difference approach was used to adjust for multiple comparisons. Categorical data were compared by the χ2 test. Collinearity diagnostics were performed to look for multicollinearity between the independent variables in the linear models. Collinearity between systolic blood pressure and pulse pressure was present, and the latter was included in the final multivariate models. Similarly, diastolic function grade and resting E/e′ demonstrated collinearity, and 2 separate multivariate models were constructed to evaluate each of these separately in the 2867 patients with baseline diastolic function assessment.

Stepwise multivariate linear regression models were used to estimate the relative contributions of the baseline clinical and echocardiographic variables to exercise performance. Because of the small numbers of patients with moderate and severe diastolic dysfunction, these groups were combined for analysis. In a subgroup of 2366 patients in whom postexercise E/e′ measurements were also feasible, a separate multivariate linear regression model was used to evaluate the relative contributions of the peak exercise clinical and echocardiographic variables to exercise performance. The distribution of continuous variables was tested to ensure that normality assumptions were fulfilled. Interaction terms of diastolic function parameters with age and sex were also evaluated to determine whether the magnitude of reduction in exercise capacity among those with abnormal diastolic parameters varied with increasing age or between sexes. To detect a clinically meaningful difference in exercise capacity of 0.5 METs22 with 90% power, a sample size of n = 256 was required in each diastolic function group (normal, mild dysfunction, and moderate/severe dysfunction). This was with an SD of 3.5 METs, assuming a 2-sided analysis and α = .05. An a priori level of significance was assigned at less than .05. All computations were performed using JMP statistical software for Windows (version 6.0; SAS Institute Inc, Cary, North Carolina).

Study Population

The baseline clinical and echocardiographic characteristics are outlined in Table 1 and Table 2. Normal diastolic function was present in 1784 patients (62%), mild diastolic dysfunction in 785 (27%), and moderate/severe diastolic dysfunction in 298 (10%). The exercise echocardiogram was normal in 2655 patients (93%), showed a fixed abnormality in 202 (7%), and was considered to indicate dilated cardiomyopathy in 10 (0.3%). Target heart rate (≥85% age-predicted maximal heart rate) was achieved in 2146 patients (75%). The primary reason for stopping exercise was fatigue in 1759 patients (61%), dyspnea in 801 (28%), leg discomfort in 281(10%), arrhythmias in 18 (1%), and atypical chest discomfort in 8 (0.3%).

Table Graphic Jump LocationTable 2. Echocardiography Characteristicsa
Clinical and Echocardiographic Correlates of Exercise Capacity

Resting univariate and multivariate correlates of exercise capacity as measured by METs are shown in Table 3 and Table 4. Compared with normal diastolic function, the presence of mild and moderate/severe diastolic dysfunction were associated with a mean (SD) reduction in exercise capacity of 2.17 (0.10) METs and 2.74 (0.15) METs, respectively, before adjusting for other clinical and echocardiographic factors (Table 3). Considering all variables in Table 3 in the multivariate analysis, the strongest independent correlates of reduced exercise tolerance were increasing age, female sex, body mass index greater than 30, moderate/severe diastolic dysfunction vs normal, and mild diastolic dysfunction vs normal as shown by the standardized β coefficients in Table 4.

Table Graphic Jump LocationTable 3. Univariate Analysis of Association of Resting Clinical and Echocardiographic Variables With Exercise Capacity in Metabolic Equivalents
Table Graphic Jump LocationTable 4. Multivariate Analysis of Association of Resting Clinical and Echocardiographic Variables With Exercise Capacity in Metabolic Equivalentsa

The presence of mild or moderate/severe diastolic dysfunction as compared with normal was associated with a mean (SD) reduction of exercise capacity of 0.70 (0.10) METs (95% confidence interval [CI], −0.88 to −0.46) and 1.30 (0.13) METs (95% CI, −1.52 to −0.99), respectively. Every 10-beat increase in resting heart rate was associated with a mean (SD) reduction of 0.24 (0.03) METs (95% CI, −0.30 to −0.18) in exercise capacity. In multivariate analysis, increasing age was associated with a reduction of 0.85 (0.04) METs (95% CI, −0.92 to −0.77) per 10 years of age. Overall, women exercised 1.98 (0.07) METs less than their male counterparts (95% CI, −2.15 to −1.84). Patients with a body mass index greater than 30 exercised 1.24 (0.08) METs less than those with a body mass index of 30 or lower (95% CI, −1.41 to −1.10).

The other correlates in the final multivariate model, although significant, were associated with smaller reductions in exercise capacity: previous/current smoker vs nonsmoker (−0.43 [0.07] METs; 95% CI, −0.59 to −0.29), β-blocker vs no β-blocker (−0.39 [0.09] METs; 95% CI, −0.61 to −0.21), hypertension vs no hypertension (−0.27 [0.88] METs; 95% CI, −0.48 to −0.13), and diabetes vs no diabetes (−0.36 [0.12] METs; 95% CI, −0.67 to −0.16). The R2 of this model was 0.51; with exclusion of diastolic function grade, R2 decreased to 0.40.

This multivariate model did not include resting E/e′ because of its collinearity with diastolic function grade, and a separate multivariate model substituting diastolic function grade with resting E/e′ was constructed (Table 4). Resting E/e′ of 15 or greater was associated with a mean (SD) reduction in exercise capacity of 1.81 (0.19) METs compared with E/e′ of less than 15 in univariate analysis (Table 3). After adjustment for clinical and echocardiographic variables, resting E/e′ of 15 or greater was associated with a reduction in exercise capacity of 0.41 (0.15) METs compared with E/e′ of less than 15 (95% CI, −0.70 to −0.11) (Table 4).

In univariate analysis, postexercise E/e′ of 15 or greater was associated with a −1.86 (0.20) MET change in exercise capacity (P < .001), every 10-beat increase in the change in heart rate from rest to exercise with a 0.77 (0.02) MET increase in exercise capacity (P < .001), and every 10-beat increment in peak exercise heart rate with a 0.59 (0.02) MET increase in exercise capacity (P < .001). After adjusting for clinical and echocardiographic parameters in multivariate analysis, the strongest peak exercise correlates of exercise capacity were heart rate increase (0.45-MET increase in exercise capacity per 10-beat increment) and postexercise E/e′ of 15 or greater (0.41-MET reduction [0.15] in exercise capacity; 95% CI, −0.71 to −0.11) (Table 5).

Table Graphic Jump LocationTable 5. Multivariate Analysis of Association of Exercise Clinical and Echocardiographic Variables With Exercise Capacity in Metabolic Equivalentsa

Heart rate at rest was increased and the increase at peak exercise was blunted with diastolic dysfunction (Table 1). The correlation between resting heart rate and diastolic function was poor (r = 0.08, P < .001) as was the relationship with resting E/e′ (r = 0.13, P < .001) and postexercise E/e′ (r = 0.09, P < .001). There was only a modest correlation between heart rate increase and worsening diastolic function (r = 0.31, P < .001), resting E/e′ (r = 0.24, P < .001), and postexercise E/e′ (r = 0.23, P < .001).

Among the 2366 patients with postexercise E/e′, 742 had mild or moderate/severe resting diastolic dysfunction and resting E/e′ less than 15. Of these, 57 (8%) developed an E/e′ of 15 or greater after exercise. This is in contrast to the 1472 individuals with normal diastolic function and resting E/e′ less than 15 of whom 38 (2.6%) developed postexercise E/e′ of 15 or greater. Of the 179 patients with postexercise E/e′ of 15 or greater, 95 (53%) had a resting E/e′ of less than 15. Mild or moderate/severe diastolic dysfunction was present in 138 of 179 patients (77%) with postexercise E/e′ of 15 or greater.

Age and Sex Interactions With Exercise Capacity

Although men had a greater exercise capacity than women, the magnitude of this difference decreased with age (P < .001). Compared with those with normal diastolic function, patients with mild diastolic dysfunction (impaired relaxation) had a progressive increase in the magnitude of reduction in exercise capacity with advancing age (Figure 1). In contrast, individuals with moderate/severe diastolic dysfunction had a reduced exercise capacity compared with those with normal function, but the magnitude of this reduction was similar across the age spectrum (P = .46). This was also true for those with resting E/e′ of 15 or greater (P = .46). Compared with those with a postexercise E/e′ of less than 15, however, individuals with a postexercise E/e′ of 15 or greater had a progressive increase in the magnitude of reduction in exercise capacity with advancing age (Figure 1). Although an increase in resting heart rate had a negative correlation with exercise capacity, the strength of this correlation diminished with age. Specifically, every 10-beat increase in resting heart rate predicted a 0.54-MET decrease in exercise capacity among patients younger than 50 years and a 0.24-MET decrease in patients 50 years or older (P < .001). Exercise capacity was reduced in women as compared with men, and the magnitude of this reduction in each diastolic dysfunction grade was similar between the sexes (Figure 2). This was also true for resting and postexercise E/e′ (P = .14 and P = .20, respectively).

Place holder to copy figure label and caption
Figure 1. Association of Diastolic Parameters With Exercise Capacity by Age
Graphic Jump Location

In the mild diastolic dysfunction group vs the normal function group, exercise capacity was reduced, but the steeper slope in the mild group indicates that the magnitude of this reduction increased with age. Derived from age × diastolic function interaction analysis, a P < .001 for the diastolic function comparison shows that the slopes of the 2 lines are statistically different. Exercise capacity was also reduced in the group with a postexercise E/e′ ratio of 15 or greater vs that with E/e′ less than 15. The magnitude of this reduction also increased with age, as shown by the steeper slope in the group with E/e′ of 15 or greater. A P = .02, derived from analysis of age × diastolic function interaction, shows that the slopes of the 2 lines are statistically different. All curves were fit to the data by group using linear regression analysis. Dashed lines indicate the upper and lower 95% confidence limits for the mean values. E/e′ indicates the ratio of the Doppler measurements of the early (E) mitral inflow velocity and the peak early diastolic velocity of the medial mitral annulus (e′). METs indicates metabolic equivalents.

Place holder to copy figure label and caption
Figure 2. Association of Diastolic Function Grade With Exercise Capacity by Sex
Graphic Jump Location

Compared with men, women had a lower exercise capacity within each diastolic function grade. However, the P value derived from sex × diastolic function interaction analysis (P = .36) was nonsignificant, suggesting that the magnitude of reduction in exercise capacity within each diastolic function grade is similar between the sexes. Boxes indicate interquartile range; horizontal lines, median; error bars, range. METs indicates metabolic equivalents.

In a large, consecutive population free of valvular heart disease or exercise-induced ischemia referred for exercise echocardiography, we found resting diastolic function to be the strongest echocardiographic correlate of exercise tolerance. This was superseded only by the clinical factors of advancing age, female sex, and increasing body mass index. This relationship remained significant after taking into account resting heart rate, blood pressure, medication use, comorbid medical conditions, and other echocardiographic parameters.

Unlike previous studies that have shown modest correlations of E/A ratio and deceleration time with exercise capacity, we found that diastolic function grade was strongly associated with a decrement in exercise capacity. Similarly, resting left ventricular filling pressure (E/e′) was also found to correlate with exercise capacity, although this association was less robust. E/e′ could be used as a surrogate if assessment of diastolic function grade is not feasible. In a previous smaller study, exercise E/e′ of 15 or greater was shown to strongly correlate with invasively determined left ventricular end-diastolic pressure at peak exercise16; we found that increased filling pressures with exercise were also associated with a decrement in exercise capacity. We found that exercise capacity is not importantly influenced by variations of ejection fraction within the broad range of normal values; for example, an ejection fraction of 70% would not portend a better exercise capacity than an ejection fraction of 55%.

We also documented that a history of previous or current smoking is associated with exercise limitation. An increase in resting heart rate was also a marker of poor exercise capacity; resting heart rate was higher in those with worse diastolic function. However, this may be a marker of overall deconditioning and had a minimal relationship with the extent of diastolic dysfunction or filling pressures. Similarly, a large chronotropic response was associated with improved exercise capacity but was only modestly associated with diastolic function grade and filling pressures. Clearly, the mechanisms underlying relationships of heart rate with exercise capacity are complex and cannot be entirely explained by diastolic dysfunction parameters.

One mechanism by which diastolic parameters may affect exercise capacity relates to their role in generating a maximal cardiac output. During exercise, the maintenance of adequate left ventricular filling to ensure a normal cardiac output includes the ability to achieve diastolic filling rates greater than the ejection rates during systole. In the setting of exercise-induced tachycardia, abnormalities in diastolic relaxation and filling of the left ventricle can result in filling rates that might be too low to achieve adequate cardiac output during exercise even if ventricular systolic properties are normal.23 Also, left atrial pressure must increase to a level that creates a pressure gradient large enough to provide adequate ventricular filling during exercise in the setting of impaired left ventricular relaxation.12

It has been suggested that stimulation of J receptors in the lungs by congestion or increases in transmitted left atrial pressures to the pulmonary vascular system would tend to result in more tachypneic breathing, thus altering the normal breathing patterns and resulting in exercise intolerance.24,25 A normal diastolic function response to exercise is characterized by normal and similar resting and exercise E/e′ measurements.26 In our study, just over half of the patients that developed increased filling pressures with exercise had a resting E/e′ of less than 15, suggesting that they adapted poorly to the cardiac physiology of exercise contributing to exercise intolerance. In part, this may be related to resting diastolic abnormalities, because 77% of patients with postexercise E/e′ of 15 or greater had evidence of resting diastolic dysfunction. Additionally, only 8% of patients with resting diastolic dysfunction and E/e′ of less than 15 developed increased filling pressures after exercise. This suggests that the mechanism by which diastolic dysfunction contributes to exercise intolerance is not limited to the development of increased filling pressures.

As shown in our study and others, older age is strongly associated with decreased exercise capacity. Mechanisms proposed to explain this association include reduced peak heart rates or a decrease in arteriovenous oxygen content difference affecting maximal cardiac output generation.27,28 Aging is also associated with a reduction in skeletal muscle mass and decreases in muscle capillarization and mitochondrial enzyme activity, all of which can also contribute to reduced exercise capacity.8 While aging is known to be associated with an increasing prevalence of impaired cardiac relaxation, our study shows that even after adjusting for age, diastolic function was strongly associated with exercise capacity. Moreover, our findings reveal that an important interaction between age and diastolic dysfunction exists, such that absolute reduction in exercise capacity among those with impaired relaxation vs those with normal diastolic function progressively increases with advancing age. This remains the case for those with elevated exercise filling pressures.

Although women have a lower exercise capacity compared with men, our findings confirm that there is a greater age-associated decline in exercise capacity in men.3,29 Further, our data suggest that the absolute reduction in exercise capacity in women vs men is similar across the spectrum of diastolic dysfunction, so diastolic parameters do not account for the sex differences in exercise tolerance.

In identifying diastolic function parameters as strong correlates of exercise capacity, we have identified potentially modifiable and preventable factors in the development of exercise intolerance. It is well known that exercise training improves diastolic function in healthy individuals, demonstrating an increase in peak diastolic filling rates.30,31 However, although patients with diastolic dysfunction show an improvement in exercise tolerance with training, the effects of training on diastolic function are less clear.32,33 Similarly, pharmacologic treatment of patients with diastolic dysfunction enhances exercise capacity, but improvement in diastolic function is limited and occurs in few patients.34,35 Treatment with angiotensin receptor blockers has appeared to be most promising because they block angiotensin II action that is thought to be responsible for slowed left ventricular relaxation during exercise. Although data with respect to modifying diastolic function are unclear and merit further study, current approaches should include aggressive treatment of risk factors such as hypertension and coronary artery disease to prevent development of diastolic abnormalities and related exercise limitations.

Although this is a very large study characterizing the association of age and sex with exercise capacity, results are limited to patients in whom a complete echocardiographic assessment as outlined was possible. This should not affect overall results, because the demographic characteristics of patients who did not have baseline diastolic function assessment were similar to those who did. The mechanism by which diastolic dysfunction affects exercise capacity may relate to cardiac output. This was not measured in these patients and was not our focus but merits further study.

Because patients recruited into our study were middle-aged and referred for a clinically indicated stress echocardiogram, there is the potential for a referral bias related to a higher prevalence of comorbidities. However, compared with a contemporary community-based cohort of Olmsted County, the prevalence of systolic and diastolic dysfunction was only slightly higher. Our results should be validated in other populations.36

The presence of anemia and obstructive lung disease was not ascertained, although we did account for a smoking history. Lastly, we used calculated METs rather than oxygen consumption as a measure of exercise tolerance. Although the latter is preferable, calculation of achieved METs is a widely accepted clinical tool for determining functional capacity that is relevant to the daily activities of patients. Absolute exercise capacity measured in METs has been shown to be the most powerful predictor of long-term mortality.22

In this large population referred for exercise echocardiography and not limited by ischemia, we demonstrated that diastolic dysfunction was strongly related to decreased exercise capacity. Increased resting and postexercise left ventricular filling pressures are also associated with a reduction in exercise capacity. Other correlates of exercise intolerance include age, sex, and body mass index. Although these data require confirmation in prospective studies, they point to a potential modifiable factor that might be a target for interventions that could maintain exercise capacity with aging. Unlike many other factors that are an inevitable consequence of aging, diastolic dysfunction may be a preventable factor in the development of exercise intolerance.

Corresponding Author: Patricia A. Pellikka, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (pellikka.patricia@mayo.edu).

Author Contributions: Dr Pellikka had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Grewal, McCully, Kane, Pellikka.

Acquisition of data: McCully, Pellikka.

Analysis and interpretation of data: Grewal, McCully, Kane, Lam, Pellikka.

Drafting of the manuscript: Grewal, Lam, Pellikka.

Critical revision of the manuscript for important intellectual content: Grewal, McCully, Kane, Lam, Pellikka.

Statistical analysis: Grewal, Lam.

Obtained funding: Pellikka.

Administrative, technical, or material support: McCully, Pellikka.

Study supervision: McCully, Pellikka.

Financial Disclosures: None reported.

Funding/Support: This study was supported in part by grant No. 1 UL1 RR024150 (for biostatistical analysis) from the National Center for Research Resources, a component of the National Institutes of Health (NIH); the NIH Roadmap for Medical Research; and the Mayo Foundation (data management).

Role of the Sponsor: The funding sources had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Woo JS, Derleth C, Stratton JR, Levy WC. The influence of age, gender, and training on exercise efficiency.  J Am Coll Cardiol. 2006;47(5):1049-1057
PubMed   |  Link to Article
Hossack KF, Bruce RA. Maximal cardiac function in sedentary normal men and women: comparison of age-related changes.  J Appl Physiol. 1982;53(4):799-804
PubMed
Weiss EP, Spina RJ, Holloszy JO, Ehsani AA. Gender differences in the decline in aerobic capacity and its physiological determinants during the later decades of life.  J Appl Physiol. 2006;101(3):938-944
PubMed   |  Link to Article
Shubair MM, Kodis J, McKelvie RS, Arthur HM, Sharma AM. Metabolic profile and exercise capacity outcomes: their relationship to overweight and obesity in a Canadian cardiac rehabilitation setting.  J Cardiopulm Rehabil. 2004;24(6):405-413
PubMed   |  Link to Article
Enright PL, McBurnie MA, Bittner V,  et al; Cardiovascular Health Study.  The 6-min walk test: a quick measure of functional status in elderly adults.  Chest. 2003;123(2):387-398
PubMed   |  Link to Article
Ellstad MH. Stress Testing: Principles and Practice. Philadelphia, PA: FA Davis; 1996:75-110
Ogawa T, Spina RJ, Martin WH III,  et al.  Effects of aging, sex, and physical training on cardiovascular responses to exercise.  Circulation. 1992;86(2):494-503
PubMed   |  Link to Article
Coggan AR, Spina RJ, King DS,  et al.  Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women.  J Gerontol. 1992;47(3):B71-B76
PubMed   |  Link to Article
Proctor DN, Beck KC, Shen PH, Eickhoff TJ, Halliwill JR, Joyner MJ. Influence of age and gender on cardiac output-VO2 relationships during submaximal cycle ergometry.  J Appl Physiol. 1998;84(2):599-605
PubMed
Franciosa JA, Pork M, Levine TB. Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure.  Am J Cardiol. 1981;47(1):33-39
PubMed   |  Link to Article
Higginbotham MB, Morris KG, Cohn EH, Coleman RE, Cobb FR. Determinants of variable exercise performance among patients with severe left ventricular dysfunction.  Am J Cardiol. 1983;51(1):52-60
PubMed   |  Link to Article
Okura H, Inoue H, Tomon M,  et al.  Impact of Doppler-derived left ventricular diastolic performance on exercise capacity in normal individuals.  Am Heart J. 2000;139(4):716-722
PubMed   |  Link to Article
Vanoverschelde JJ, Essomri B, Vanbutsele R, d’Hondt A, Cosyns JR, Detry JR. Contribution of left ventricular diastolic function to exercise capacity in normal subjects.  J Appl Physiol. 1993;74(5):2225-2233
PubMed
Skaluba SJ, Litwin SE. Mechanisms of exercise intolerance: insights from tissue Doppler imaging.  Circulation. 2004;109(8):972-977
PubMed   |  Link to Article
Ommen SR, Nishimura RA, Appleton CP,  et al.  Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study.  Circulation. 2000;102(15):1788-1794
PubMed   |  Link to Article
Burgess MI, Jenkins C, Sharman JE, Marwick TH. Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of ventricular filling pressure with exercise.  J Am Coll Cardiol. 2006;47(9):1891-1900
PubMed   |  Link to Article
Khouri S, Maly G, Suh D, Walsh T. A practical approach to the echocardiographic evaluation of diastolic function.  J Am Soc Echocardiogr. 2004;17(3):290-297
PubMed   |  Link to Article
Gilman G, Nelson T, Hansen W, Khanderia B, Ommen S. Diastolic function: a sonographer's approach to the essential echocardiographic measurements of left ventricular diastolic dysfunction.  J Am Soc Echocardiogr. 2007;20(2):199-209
PubMed   |  Link to Article
Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden.  Am J Cardiol. 2002;90(12):1284-1289
PubMed   |  Link to Article
Lang RM, Bierig M, Devereaux RB,  et al; Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography.  Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.  J Am Soc Echocardiogr. 2005;18(12):1440-1463
PubMed   |  Link to Article
Quinones MA, Waggoner AD, Reduto LA,  et al.  A new, simplified and accurate method for determining ejection fraction with two-dimensional echocardiography.  Circulation. 1981;64(4):744-753
PubMed   |  Link to Article
Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing.  N Engl J Med. 2002;346(11):793-801
PubMed   |  Link to Article
Oldershaw PJ, Dawkins KD, Ward DE, Gibson DG. Diastolic mechanisms of impaired exercise tolerance in aortic valve disease.  Br Heart J. 1983;49(6):568-573
PubMed   |  Link to Article
Paintal AS. Mechanism of stimulation of type J pulmonary receptors.  J Physiol. 1969;203(3):511-532
PubMed
Roberts AM, Bhattacharya J, Schultz HD, Coleridge HM, Coleridge JC. Stimulation of pulmonary vagal afferent C-fibers by lung edema in dogs.  Circ Res. 1986;58(4):512-522
PubMed   |  Link to Article
Ha JW, Lulic F, Bailey KR,  et al.  Effects of treadmill exercise on mitral inflow and annular velocities in healthy adults.  Am J Cardiol. 2003;91(1):114-115
PubMed   |  Link to Article
Higginbotham MB, Morris KG, Williams RS, Coleman RE, Cobb FR. Physiologic basis for the age-related decline in aerobic work capacity.  Am J Cardiol. 1986;57(15):1374-1379
PubMed   |  Link to Article
Julius S, Amery A, Whitlock LS, Conway J. Influence of age on the hemodynamic response to exercise.  Circulation. 1967;36(2):222-230
PubMed   |  Link to Article
Buskirk ER, Hodgson JL. Age and aerobic power: the rate of change in men and women.  Fed Proc. 1987;46(5):1824-1829
PubMed
Brandao MU, Wajngarten M, Rondon E, Giorgi MC, Hironaka F, Negrao CE. Left ventricular function during dynamic exercise in untrained and moderately trained subjects.  J Appl Physiol. 1993;75(5):1989-1995
PubMed
Levy WC, Cerqueira MD, Abrass IB, Schwartz RS, Stratton JR. Endurance exercise training augments diastolic filling at rest and during exercise in healthy young and older men.  Circulation. 1993;88(1):116-126
PubMed   |  Link to Article
Smart N, Haluska B, Jeffriess L, Marwick TH. Exercise training in systolic and diastolic dysfunction: effects on cardiac function, functional capacity, and quality of life.  Am Heart J. 2007;153(4):530-536
PubMed   |  Link to Article
Brassard P, Legault S, Garneau C, Bogaty P, Dumesnil JG, Poirier P. Normalization of diastolic dysfunction in type 2 diabetics after exercise training.  Med Sci Sports Exerc. 2007;39(11):1896-1901
PubMed   |  Link to Article
Warner JG Jr, Metzger DC, Kitzman DW, Wesley DJ, Little WC. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise.  J Am Coll Cardiol. 1999;33(6):1567-1572
PubMed   |  Link to Article
Little WC, Zile MR, Klein A, Appleton CP, Kitzman DW, Wesley-Farrington DJ. Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction.  Am J Cardiol. 2006;98(3):383-385
PubMed   |  Link to Article
Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.  JAMA. 2003;289(2):194-202
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Association of Diastolic Parameters With Exercise Capacity by Age
Graphic Jump Location

In the mild diastolic dysfunction group vs the normal function group, exercise capacity was reduced, but the steeper slope in the mild group indicates that the magnitude of this reduction increased with age. Derived from age × diastolic function interaction analysis, a P < .001 for the diastolic function comparison shows that the slopes of the 2 lines are statistically different. Exercise capacity was also reduced in the group with a postexercise E/e′ ratio of 15 or greater vs that with E/e′ less than 15. The magnitude of this reduction also increased with age, as shown by the steeper slope in the group with E/e′ of 15 or greater. A P = .02, derived from analysis of age × diastolic function interaction, shows that the slopes of the 2 lines are statistically different. All curves were fit to the data by group using linear regression analysis. Dashed lines indicate the upper and lower 95% confidence limits for the mean values. E/e′ indicates the ratio of the Doppler measurements of the early (E) mitral inflow velocity and the peak early diastolic velocity of the medial mitral annulus (e′). METs indicates metabolic equivalents.

Place holder to copy figure label and caption
Figure 2. Association of Diastolic Function Grade With Exercise Capacity by Sex
Graphic Jump Location

Compared with men, women had a lower exercise capacity within each diastolic function grade. However, the P value derived from sex × diastolic function interaction analysis (P = .36) was nonsignificant, suggesting that the magnitude of reduction in exercise capacity within each diastolic function grade is similar between the sexes. Boxes indicate interquartile range; horizontal lines, median; error bars, range. METs indicates metabolic equivalents.

Tables

Table Graphic Jump LocationTable 3. Univariate Analysis of Association of Resting Clinical and Echocardiographic Variables With Exercise Capacity in Metabolic Equivalents
Table Graphic Jump LocationTable 4. Multivariate Analysis of Association of Resting Clinical and Echocardiographic Variables With Exercise Capacity in Metabolic Equivalentsa
Table Graphic Jump LocationTable 5. Multivariate Analysis of Association of Exercise Clinical and Echocardiographic Variables With Exercise Capacity in Metabolic Equivalentsa
Table Graphic Jump LocationTable 2. Echocardiography Characteristicsa

References

Woo JS, Derleth C, Stratton JR, Levy WC. The influence of age, gender, and training on exercise efficiency.  J Am Coll Cardiol. 2006;47(5):1049-1057
PubMed   |  Link to Article
Hossack KF, Bruce RA. Maximal cardiac function in sedentary normal men and women: comparison of age-related changes.  J Appl Physiol. 1982;53(4):799-804
PubMed
Weiss EP, Spina RJ, Holloszy JO, Ehsani AA. Gender differences in the decline in aerobic capacity and its physiological determinants during the later decades of life.  J Appl Physiol. 2006;101(3):938-944
PubMed   |  Link to Article
Shubair MM, Kodis J, McKelvie RS, Arthur HM, Sharma AM. Metabolic profile and exercise capacity outcomes: their relationship to overweight and obesity in a Canadian cardiac rehabilitation setting.  J Cardiopulm Rehabil. 2004;24(6):405-413
PubMed   |  Link to Article
Enright PL, McBurnie MA, Bittner V,  et al; Cardiovascular Health Study.  The 6-min walk test: a quick measure of functional status in elderly adults.  Chest. 2003;123(2):387-398
PubMed   |  Link to Article
Ellstad MH. Stress Testing: Principles and Practice. Philadelphia, PA: FA Davis; 1996:75-110
Ogawa T, Spina RJ, Martin WH III,  et al.  Effects of aging, sex, and physical training on cardiovascular responses to exercise.  Circulation. 1992;86(2):494-503
PubMed   |  Link to Article
Coggan AR, Spina RJ, King DS,  et al.  Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women.  J Gerontol. 1992;47(3):B71-B76
PubMed   |  Link to Article
Proctor DN, Beck KC, Shen PH, Eickhoff TJ, Halliwill JR, Joyner MJ. Influence of age and gender on cardiac output-VO2 relationships during submaximal cycle ergometry.  J Appl Physiol. 1998;84(2):599-605
PubMed
Franciosa JA, Pork M, Levine TB. Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure.  Am J Cardiol. 1981;47(1):33-39
PubMed   |  Link to Article
Higginbotham MB, Morris KG, Cohn EH, Coleman RE, Cobb FR. Determinants of variable exercise performance among patients with severe left ventricular dysfunction.  Am J Cardiol. 1983;51(1):52-60
PubMed   |  Link to Article
Okura H, Inoue H, Tomon M,  et al.  Impact of Doppler-derived left ventricular diastolic performance on exercise capacity in normal individuals.  Am Heart J. 2000;139(4):716-722
PubMed   |  Link to Article
Vanoverschelde JJ, Essomri B, Vanbutsele R, d’Hondt A, Cosyns JR, Detry JR. Contribution of left ventricular diastolic function to exercise capacity in normal subjects.  J Appl Physiol. 1993;74(5):2225-2233
PubMed
Skaluba SJ, Litwin SE. Mechanisms of exercise intolerance: insights from tissue Doppler imaging.  Circulation. 2004;109(8):972-977
PubMed   |  Link to Article
Ommen SR, Nishimura RA, Appleton CP,  et al.  Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study.  Circulation. 2000;102(15):1788-1794
PubMed   |  Link to Article
Burgess MI, Jenkins C, Sharman JE, Marwick TH. Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of ventricular filling pressure with exercise.  J Am Coll Cardiol. 2006;47(9):1891-1900
PubMed   |  Link to Article
Khouri S, Maly G, Suh D, Walsh T. A practical approach to the echocardiographic evaluation of diastolic function.  J Am Soc Echocardiogr. 2004;17(3):290-297
PubMed   |  Link to Article
Gilman G, Nelson T, Hansen W, Khanderia B, Ommen S. Diastolic function: a sonographer's approach to the essential echocardiographic measurements of left ventricular diastolic dysfunction.  J Am Soc Echocardiogr. 2007;20(2):199-209
PubMed   |  Link to Article
Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden.  Am J Cardiol. 2002;90(12):1284-1289
PubMed   |  Link to Article
Lang RM, Bierig M, Devereaux RB,  et al; Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography.  Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.  J Am Soc Echocardiogr. 2005;18(12):1440-1463
PubMed   |  Link to Article
Quinones MA, Waggoner AD, Reduto LA,  et al.  A new, simplified and accurate method for determining ejection fraction with two-dimensional echocardiography.  Circulation. 1981;64(4):744-753
PubMed   |  Link to Article
Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing.  N Engl J Med. 2002;346(11):793-801
PubMed   |  Link to Article
Oldershaw PJ, Dawkins KD, Ward DE, Gibson DG. Diastolic mechanisms of impaired exercise tolerance in aortic valve disease.  Br Heart J. 1983;49(6):568-573
PubMed   |  Link to Article
Paintal AS. Mechanism of stimulation of type J pulmonary receptors.  J Physiol. 1969;203(3):511-532
PubMed
Roberts AM, Bhattacharya J, Schultz HD, Coleridge HM, Coleridge JC. Stimulation of pulmonary vagal afferent C-fibers by lung edema in dogs.  Circ Res. 1986;58(4):512-522
PubMed   |  Link to Article
Ha JW, Lulic F, Bailey KR,  et al.  Effects of treadmill exercise on mitral inflow and annular velocities in healthy adults.  Am J Cardiol. 2003;91(1):114-115
PubMed   |  Link to Article
Higginbotham MB, Morris KG, Williams RS, Coleman RE, Cobb FR. Physiologic basis for the age-related decline in aerobic work capacity.  Am J Cardiol. 1986;57(15):1374-1379
PubMed   |  Link to Article
Julius S, Amery A, Whitlock LS, Conway J. Influence of age on the hemodynamic response to exercise.  Circulation. 1967;36(2):222-230
PubMed   |  Link to Article
Buskirk ER, Hodgson JL. Age and aerobic power: the rate of change in men and women.  Fed Proc. 1987;46(5):1824-1829
PubMed
Brandao MU, Wajngarten M, Rondon E, Giorgi MC, Hironaka F, Negrao CE. Left ventricular function during dynamic exercise in untrained and moderately trained subjects.  J Appl Physiol. 1993;75(5):1989-1995
PubMed
Levy WC, Cerqueira MD, Abrass IB, Schwartz RS, Stratton JR. Endurance exercise training augments diastolic filling at rest and during exercise in healthy young and older men.  Circulation. 1993;88(1):116-126
PubMed   |  Link to Article
Smart N, Haluska B, Jeffriess L, Marwick TH. Exercise training in systolic and diastolic dysfunction: effects on cardiac function, functional capacity, and quality of life.  Am Heart J. 2007;153(4):530-536
PubMed   |  Link to Article
Brassard P, Legault S, Garneau C, Bogaty P, Dumesnil JG, Poirier P. Normalization of diastolic dysfunction in type 2 diabetics after exercise training.  Med Sci Sports Exerc. 2007;39(11):1896-1901
PubMed   |  Link to Article
Warner JG Jr, Metzger DC, Kitzman DW, Wesley DJ, Little WC. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise.  J Am Coll Cardiol. 1999;33(6):1567-1572
PubMed   |  Link to Article
Little WC, Zile MR, Klein A, Appleton CP, Kitzman DW, Wesley-Farrington DJ. Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction.  Am J Cardiol. 2006;98(3):383-385
PubMed   |  Link to Article
Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic.  JAMA. 2003;289(2):194-202
PubMed   |  Link to Article

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles