Methods

From January 2006 to December 2006, the patients who underwent clinically indicated exercise echocardiography at Mayo Clinic (Rochester, Minnesota) and were without evidence of exercise-induced wall motion abnormalities were studied. All study patients performed symptom-limited treadmill exercise using the Bruce protocol and had been referred for testing for the following reasons: 1,424 (50.2%) for chest pain or dyspnea, 558 (19.7%) with multiple cardiovascular risk factors and suspected CAD, 286 (10.1%) because of abnormal electrocardiographic findings, 259 (9.1%) for additional evaluation of known CAD, 243 (8.6%) for preoperative risk stratification, and 65 (2.3%) for abnormal findings on a coronary calcium study using computed tomography. Patients with nonsinus rhythm (n = 120), valvular heart disease (n = 76), poor imaging quality (n = 7), an ejection fraction at rest of <50% (n = 88), echocardiographic evidence of stress-induced myocardial ischemia (n = 790), and those not consenting to research participation (n = 143) were excluded. Of the 3,105 patients who met the eligibility criteria for the present study, 169 living outside the United States were excluded because of difficulty verifying mailing addresses. Also, 101 patients were excluded because of an inability to accurately assess the diastolic function grade, leaving a final study population of 2,835 patients.

Echocardiographic assessment of diastolic function included pulsed wave Doppler of early (E) and late (A) transmitral velocities, deceleration time, early velocity of the medial (septal) mitral annulus (e′) using tissue Doppler, noninvasive assessment of LV filling pressures (E/e′), and left atrial volume. E/e′ was measured at rest and after exercise, within 4 minutes of the regional wall motion assessment. An elevated LV filling pressure was defined as an E/e′ ≥15. The left atrial volume was measured in biplane views and indexed to the body surface area. Diastolic function at rest was graded as normal, mild DD, or moderate to severe DD and classified as such using previously published definitions. Normal diastolic function was defined as an E/A of 0.75 to 1.5, a normal left atrial volume index (<28 ml/m ² ), and a normal LV filling pressure (E/e′ <10). Mild DD was defined as an E/A of <0.75 and E/e′ <10. Moderate to severe DD was defined as an E/A >1.5, left atrial volume index ≥28 ml/m ² , and E/e′ ≥10.

Clinical outcomes were assessed through a review of the medical records and interviews of the study participants using a standardized mailed survey packet. Prospective interviews of the study participants were included to reduce the likelihood of missing events that might have occurred within the patient’s community healthcare system. An initial survey packet was sent to all participants, followed by a second mailing and/or telephone interview to nonresponders 60 to 90 days after the initial mailing. Excluding 76 patients identified as deceased during the medical record abstraction, surveys were sent to 2,759 patients; however, 108 surveys were returned as nondeliverable. Of the remaining 2,651 surveys, 1,172 were returned within the study period (response rate 44.2%). All patients, regardless of the response status, had their records reviewed for clinical events that had occurred since their index exercise echocardiogram in 2006.

The study end points included all-cause mortality, cardiovascular events (i.e., death, myocardial infarction [MI], or stroke), and HF or interval to first hospitalization for any cause. An a priori event definition form was used to determine the clinical end points. MI was considered to have occurred if 2 of 3 of the following were observed: symptoms of myocardial ischemia and biomarker evidence of myocardial injury (elevated cardiac biomarkers) or new Q waves present in ≥2 leads. Stroke was considered to have occurred if a neurologic deficit of acute onset was present with neuroimaging confirmation of stroke, or, in patients without neuroimaging data, stroke was suspected on the basis of an evaluation by a neurologist. An HF event was defined as clinical symptoms with supporting signs according to the modified Framingham criteria and including treatment with an intravenous diuretic or vasodilator that required hospitalization of the patient for ≥24 hours. Hospitalization for any cause (except HF) was defined as inpatient admission for acute medical care. The institutional review board approved the present study, and participants provided written informed consent for participation.

The summary data for continuous variables are expressed as the mean ± SD or median and 25th to 75th interquartile range if the distributions were not normally distributed and counts and percentages for categorical variables. The patients were categorized into 3 groups: normal diastolic function, mild DD (impaired relaxation), and moderate to severe DD (pseudonormal or restrictive filling). Univariate analysis across the groups was performed using analysis of variance and Pearson’s chi-square test. The time to event analyses for mortality, cardiovascular events (i.e., composite of mortality, stroke, or MI), and HF or hospitalization for any cause were computed using the Kaplan-Meier method and compared using the log-rank test. The patients without events were censored at the last follow-up visit using our institution’s administrative records or the date from a completed survey. Cox proportional hazards regression analysis was used to assess the association of variables of interest with outcomes. The first set of variables examined were the clinical variables, which included hypertension, history of CAD, smoking status, body mass index, diabetes, history of MI, history of percutaneous coronary intervention or coronary artery bypass grafting, and systolic and diastolic blood pressure on the day of the exercise echocardiogram. These variables were considered for the multivariate model if the age- and gender-adjusted p value was <0.2. The second set of variables evaluated were the echocardiographic variables and included LV ejection fraction, wall motion score index, LV end diastolic dimension, left atrial volume index, E/A, E/e′, and e′. Again, variables with an age- and gender-adjusted p value <0.2 were assessed for an association with outcomes after adjusting for previously included clinical variables. Finally, the diastolic grade was forced into the Cox proportional hazard regression model. The individual diastolic indexes used to grade diastolic function were not fitted in the same models as diastolic grade to avoid potential problems with collinearity. The Statistical Analysis Systems, version 9.2, software program (SAS Institute, Cary, North Carolina) was used for all analyses, and the tests performed were 2 sided with differences considered significant at p <0.05.

Results

The mean age ± SD of the participants was 58.9 ± 12.8 years, 1,304 (46.0%) were men, and 875 (31.0%) had a body mass index >30 kg/m ² . The prevalence of co-morbidities included 1,409 (49.7%) with hypertension, 407 (14.4%) with CAD, 289 (10.2%) with diabetes, 193 (6.8%) with previous MI, and 1,247 (44.0%) with a history of smoking. Overall, 60.0% of participants had normal diastolic function, 28.2% had mild DD, and 11.8% had moderate to severe DD. The demographic and clinical characteristics of the study participants are listed in Table 1 stratified by diastolic function group. The echocardiographically determined characteristics of the participants stratified by diastolic function group at rest and after exercise are listed in Table 2 .

The clinical events are summarized in Table 3 . The 5-year mortality rate was 2.9% for patients with normal diastolic function and 5.6% and 8.0% for patients with mild DD and moderate to severe DD, respectively. Figure 1 shows the cumulative mortality rate for patients stratified by diastolic function grade during the study period (p <0.001, log-rank test). Figure 1 also illustrates the cumulative rates of the composite outcome of death, MI, and stroke. Patients with DD were more likely to experience the composite of HF or hospitalization than were those with normal diastolic function ( Figure 1 ). When patients were categorized by the single diastolic index of E/e′, the cumulative event rates for death and the composite of death, MI, and stroke were greater for those with an E/e′ ≥15 than for those with an E/e′ <15 ( Figure 2 ).

(A) Survival of patient cohort after negative findings on exercise echocardiogram by diastolic function grade. (B) Cumulative incidence of the composite outcome of death, MI, and stroke by diastolic function grade. (C) Cumulative incidence of HF or hospitalization for any cause by diastolic function grade.

(A) Survival of patient cohort after negative findings on exercise echocardiogram by Doppler-derived E/e′. (B) Cumulative incidence of the composite outcome of death, MI, and stroke by Doppler-derived E/e′.

Of the patients referred for testing, 1,424 (50.2%) were referred because of symptoms of chest pain or dyspnea. The survival estimates for mortality in this subgroup demonstrated that DD was associated with greater mortality during long-term follow-up ( Figure 3 ). In the age- and gender-adjusted models, moderate to severe DD, but not mild DD, was associated with mortality (hazard ratio [HR] 2.48, 95% confidence interval [CI] 1.05 to 5.88, p = 0.04); however, this association was attenuated after adjustment for previous coronary artery bypass grafting (HR 2.20, 95% CI 0.90 to 2.60, p = 0.08).

Survival of cohort of patients with chest pain or dyspnea as indication for exercise echocardiography by diastolic function grade.

The age- and gender-adjusted associations with outcome are listed in Table 4 . Smoking status was the only baseline covariate significantly associated with mortality (HR 1.65, 95% CI 1.05 to 2.61). The echocardiographic variables associated with mortality included LV ejection fraction, greater E/e′, and greater E/A ratios, although the magnitude of these estimates was modest. A greater exercise capacity was associated with reduced risk for all end points.

Table 4

Univariate clinical and echocardiographic associations with clinical events

	Death		Death, MI, Stroke		HF or Hospitalization
	HR (95% CI)	p Value ∗	HR (95% CI)	p Value ∗	HR (95% CI)	p Value ∗
BMI (kg/m 2 )	0.98 (0.93–1.03)	0.49	1.00 (0.96–1.04)	0.98	1.03 (1.02–1.05)	<0.001
Hypertension	1.26 (0.78–2.04)	0.35	1.28 (0.86–1.92)	0.23	1.30 (1.09–1.54)	0.003
LV hypertrophy	0.89 (0.36–2.21)	0.80	0.91 (0.42–1.96)	0.81	1.11 (0.79–1.55)	0.55
History of CAD	1.21 (0.73–2.02)	0.46	1.84 (1.22–2.77)	0.004	1.55 (1.26–1.89)	<0.001
Previous/current smoker	1.65 (1.05–2.61)	0.03	1.78 (1.21–2.61)	0.004	1.29 (1.10–1.51)	0.002
Diabetes mellitus	0.89 (0.45–1.78)	0.74	0.85 (0.47–1.55)	0.59	1.51 (1.21–1.88)	<0.001
Previous CABG	1.54 (0.80–2.96)	0.19	1.46 (0.82–2.59)	0.20	1.28 (0.94–1.76)	0.12
Previous MI	0.78 (0.36–1.70)	0.53	1.02 (0.56–1.87)	0.94	1.67 (1.30–2.14)	<0.001
Previous PCI	1.03 (0.53–2.02)	0.92	1.91 (1.19–3.06)	0.007	1.50 (1.18–1.91)	<0.001
Wall motion score index at rest	2.04 (0.99–4.21)	0.05	1.97 (1.05–3.71)	0.03	1.36 (0.93–1.98)	0.12
LVEF at rest (per 5%)	0.97 (0.94–1.00)	0.02	0.98 (0.95–1.00)	0.04	0.98 (0.97–1.00)	0.01
Baseline systolic blood pressure (per 10 mm Hg)	1.00 (0.99–1.01)	0.62	1.00 (0.99–1.01)	0.47	1.00 (1.00–1.01)	0.35
Baseline diastolic blood pressure (per 10 mm Hg)	0.99 (0.97–1.01)	0.25	1.00 (0.98–1.02)	0.97	1.00 (1.00–1.01)	0.44
LV end-diastolic dimension (per 1 mm)	1.01 (0.96–1.06)	0.79	1.02 (0.98–1.07)	0.36	1.02 (1.00–1.04)	0.04
LA volume index (per 1 ml/m 2 )	1.01 (0.98–1.03)	0.57	1.01 (0.99–1.03)	0.40	1.01 (1.00–1.02)	0.004
E/e′ at rest	1.06 (1.02–1.11)	0.008	1.06 (1.03–1.10)	<0.001	1.05 (1.03–1.07)	<0.001
Mitral septal (medial) e′	1.01 (0.91–1.13)	0.80	0.96 (0.88–1.05)	0.39	0.91 (0.88–0.95)	<0.001
DT at rest (per 10 ms)	1.00 (1.00–1.01)	0.88	1.00 (0.99–1.00)	0.91	1.00 (0.99–1.00)	0.19
E/A ratio	2.08 (1.05–4.10)	0.04	1.43 (0.79–2.58)	0.24	0.71 (0.55–0.92)	0.01
Exercise capacity (per 1 METS)	0.76 (0.68–0.86)	<0.001	0.78 (0.71–0.86)	<0.001	0.85 (0.82–0.89)	<0.001
Normal diastolic function	1.0 (ref)		1.0 (ref)		1.0 (ref)
Mild DD	0.74 (0.42–1.29)	0.29	0.88 (0.56–1.39)	0.59	1.59 (1.30–1.94)	<0.001
Moderate/severe DD	1.30 (0.70–2.39)	0.40	1.19 (0.70–2.04)	0.52	2.00 (1.57–2.54)	<0.001
Normal diastolic function	1.0 (ref)		1.0 (ref)		1.0 (ref)
Mild, moderate, severe DD	0.89 (0.54–1.48)	0.66	0.97 (0.63–1.48)	0.88	1.71 (1.42–2.06)	<0.001

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