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Imaging. Impact of Progression of Diastolic Dysfunction on Mortality in Patients With Normal Ejection Fraction

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Impact of Progression of Diastolic Dysfunction on Mortality

in Patients With Normal Ejection Fraction

Wael AlJaroudi, MD; M. Chadi Alraies, MD; Carmel Halley, MD; Leonardo Rodriguez, MD;

Richard A. Grimm, DO; James D. Thomas, MD; Wael A. Jaber, MD

Background—Diastolic dysfunction is an independent predictor of mortality in patients with normal left ventricular ejection fraction. There are limited data, however, on whether worsening of diastolic function is associated with worse prognosis.

Methods and Results—We reviewed clinical records and echocardiograms of consecutive patients who had baseline echocardiograms between January 1, 2005, and December 31, 2009, that showed left ventricular ejection fractionⱖ55% and who subsequently had a follow-up echocardiogram within 6 to 24 months. Diastolic function was labeled as normal, mild, moderate, or severe dysfunction. All-cause mortality was determined by use of the Social Security Death Index. Kaplan-Meier survival analysis and Cox regression analysis with a proportional hazard model were performed to assess outcomes. A total of 1065 outpatients were identified (mean⫾SD age, 67.9⫾13.9 years; 58% male). Baseline diastolic dysfunction was present in 770 patients (72.3%), with mild being the most prevalent. On follow-up testing (mean⫾SD, 1.1⫾0.4 years), 783 patients (73%) had stable, 168 (16%) had worsening, and 114 (11%) had improved baseline diastolic function. Eighty-eight patients (8.3%) had a decrease in left ventricular ejection fraction to⬍55% and were more likely to have advanced diastolic dysfunction (P⫽0.002). After a mean⫾SD follow-up (from the second study) of 1.6⫾0.8 years, 142 patients (13%) died. On multivariate analysis, a decrease in left ventricular ejection fraction to ⬍55% and any worsening of diastolic function were independently associated with increased risk of mortality (hazard ratio, 1.78; 95% confidence interval, 1.10 –2.85;P⫽0.02; and hazard ratio, 1.78; 95% confidence interval, 1.21–2.59; P⫽0.003, respectively).

Conclusion—In patients with normal baseline left ventricular ejection fraction, worsening of diastolic function is an independent predictor of mortality. (Circulation. 2012;125:782-788.)

Key Words:mortality 䡲 outpatients 䡲 diastole 䡲 progression

T

he assessment of diastolic function is required for a full and detailed examination of the heart by echocardiogra-phy.1,2Diastolic dysfunction (DD) is believed to be

associ-ated with congestive heart failure symptoms in patients with preserved left ventricular ejection fraction (LVEF)3,4and has

recently been shown in the largest single-center study (⬇36 000 outpatients with normal LVEF) to be an indepen-dent predictor of all-cause mortality.5 When present, it is

graded as mild (impaired relaxation), moderate (pseudonor-mal), or severe (restrictive filling).2The more advanced the

stage is, the higher the filling pressures are6 – 8and the worse

the outcomes are.5 Furthermore, these stages have been

shown to vary dynamically with passage from 1 stage to the next on repeat echocardiogram (mean follow-up time ⱖ4 years)9,10and were associated with the development of heart

failure.10There are limited data, however, on the association

of progression of DD and mortality. The only study to date (n⫽184) showed that the improvement in diastolic function

was associated with better survival (P⫽0.05) in a mixed cohort of inpatients and outpatients and with normal or mild systolic dysfunction.9

Editorial see p 743

Clinical Perspective on p 788

The aim of this study was to evaluate whether the progres-sion of diastolic function is associated with increased mor-tality in a large cohort of outpatients with normal baseline LVEF.

Methods

Study Design

The study cohort consisted of consecutive patients who underwent an outpatient echocardiogram test with LVEFⱖ55% at the Cleveland Clinic or its satellite facilities between January 1, 2005, and December 31, 2009, and who had a follow-up outpatient echocar-diogram 6 to 24 months after the first echocarechocar-diogram. We excluded

Received September 6, 2011; accepted December 12, 2011.

From the Department of Cardiovascular Medicine, Heart and Vascular Imaging Institute (W.A., C.H., L.R., R.A.G., J.D.T., W.A.J.), and Department of Hospital Medicine (M.C.A.), Cleveland Clinic, Cleveland, OH.

Correspondence to Wael AlJaroudi, MD, Sydell and Arnold Miller Family Heart and Vascular Institute, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, 9500 Euclid Ave/J1-5, Cleveland, OH 44195. E-mail aljarow@ccf.org

© 2012 American Heart Association, Inc.

Circulationis available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.111.066423

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patients with prior mitral valve surgery, severe valvular stenosis, or regurgitation; those who lacked a valid US Social Security Number; and those in whom diastolic function was not reported. The inability to assess diastolic function was common in certain clinical scenarios such as in patients with tachycardia, atrial fibrillation, or poor acoustic window and in limited echocardiograms performed on an urgent basis.

During the study period, 1065 patients were included from a total of 3223 patients who underwent 2 consecutive echocardiographic tests (Figure 1). The survival rate of patients who were excluded for reasons other than an unavailable Social Security Number was not different from that of patients included in the study (log-rank

P⫽0.09).

Echocardiographic Methods

Patients were imaged in the left lateral decubitus position with commercially available systems (Philips Electronics, Andover, MA; Sequoia, Siemens, Mountain View, CA; GE Medical Systems, Milwaukee, WI). Diastolic function was assessed in our institution in a standardized method and in accordance with the published and relevant guidelines by use of a combination of echocardiographic variables (transmitral inflow pattern, mitral annular velocities with tissue Doppler imaging,11and pulmonary venous flow pattern).12In patients with atrial fibrillation, if diastolic function was assessed, it was based on deceleration time of mitral E-wave velocity13and tissue Doppler imaging (ie, peak early mitral inflow velocity/diastolic early tissue velocity [E/e⬘]14).

Diastolic function was then labeled as normal or abnormal (DD). DD was then categorized as mild (grade 1, impaired relaxation), moderate (grade 2, pseudonormal), or severe (grade 3, restrictive).1 There were only 2 patients with severe DD at baseline (0.2%) and 4 at follow-up (0.4%); therefore, patients with grade 2 and 3 were grouped together. LVEF was assessed by quantitative and/or visual evaluation in accordance with published guidelines. Both DD and LVEF were interpreted by an experienced, board-certified reader. The interobserver agreement of reproducibility and DD classification extrapolated from our ongoing quality assurance effort was on average 83%, and the intraobserver agreement was 94%.

Clinical Data

Clinical data were obtained from review of the electronic medical records from a period starting 6 months before the first echocardio-graphic testing and ending 6 months after the second one. The clinical diagnosis of conditions, including coronary artery disease, peripheral vascular disease, diabetes mellitus, hypertension, atrial fibrillation, congestive heart failure, dyslipidemia, chronic obstruc-tive pulmonary disease, and chronic renal insufficiency, was estab-lished by reviewing records documented by a healthcare provider in an electronic medical record system (EpicCare, Epic Systems Corp,

Madison, WI) and was retrieved for analysis. All-cause mortality was obtained from the Social Security Death Index with previously reported high specificity.15The censoring date was June 1, 2011. The study was approved by the Cleveland Clinic institutional review board with waiver of consent.

Statistical Analysis

Continuous variables were expressed as mean⫾SD and compared by use of the unpaired Student t test or Wilcoxon rank test as appropriate. Categorical variables were expressed as percentages and compared by use of the Fisher exact test or␹2test as appropriate. The indications for echocardiographic testing (baseline and follow-up) were compared by use of the Cohen␬statistics. Comparisons between categorical variables at examinations 1 and 2 were made with the McNemar test; continuous variables were compared by use of Pairedttest. For survival analysis, Kaplan-Meier curves were generated and compared by use of the log-rank test. Survival analyses treated the time of the second echocardiogram as time 0 and analyzed survival after the second echocardiogram. The effect of diastolic function and its progression on outcomes was investigated with Cox regression analysis with a proportional hazards model. The variables entered into the model were age, sex, race, diabetes mellitus, hypertension, dyslipidemia, smoking, atrial fibrillation, peripheral vascular disease, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, chronic renal insuf-ficiency, and EF. Baseline diastolic function and its progression were forced into the final model. We also reran the model and used diastolic function at follow-up instead of baseline diastolic function. Variables with collinearity were entered into the model one at a time. Stepwise forward selection was used to create the final model. All statistical tests were 2 sided. A value ofP⬍0.05 was set a priori and considered statistically significant. All statistical analyses were performed with the Statistical Package for Social Sciences version 11.5 for Windows (SPSS, Chicago, IL).

Results

Clinical Data

A total of 1065 outpatients were identified (mean⫾SD age, 67.9⫾ 13.9 years; mean LVEF, 59%4; 58% male). Clinical

character-istics and medications are summarized in Tables 1 and 2. Established cardiovascular disease such as coronary artery disease, prior revascularization, and congestive heart failure symptoms were not uncommon, prevalent in 27%, 12%, and 15% of the cohort, respectively. The 3 most common indica-tions for baseline testing included symptom evaluation (44%) and valvular (37%) and ventricular (14%) function. Similarly,

Figure 1.Study population selection. LVEF indicates left ventricular ejection fraction.

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the indications for follow-up testing were comparable with a high agreement rate (␬⫽0.99).

Diastolic Function at Baseline and Follow-Up

The echocardiographic parameters at baseline and follow-up are presented in Table 3. Of the 290 patients who had normal

diastolic function, 260 (88%) had no significant valvular disease and were labeled as having a normal echocardiogram. Baseline DD was present in 770 patients (72.3%), with mild being the most prevalent (64.9%) and moderate or severe DD in only 7.4%. DD was associated with increasing age and hypertension (Table 1). There was no significant change in medications at baseline and follow-up (Table 2). On follow-up echocardiographic testing (mean⫾SD, 1.1⫾0.4 years), 783 patients (73%) had stable, 168 (16%) had wors-ening, and 114 (11%) had improved baseline diastolic func-tion (100 patients by 1 grade and 14 by 2 grades; Figure 2). The change in diastolic function did not differ by race (P⫽0.3) or sex (P⫽0.4). Furthermore, 88 patients (8.3%) had a decrease in LVEF to ⬍55% (mean LVEF, 46%8) on

follow-up testing; of those patients, 60 had stable, 19 had worsening, and 9 had improved diastolic function (P⫽0.3). Patients with a decrease in LVEF to⬍55% were more likely to have advanced DD: 14 (5.3%) had normal diastolic function, 56 (8.1%) had mild DD, and 18 (16%) had moder-ate/severe DD (P⫽0.002).

Table 1. Baseline Patient Characteristics (Overall and by Diastolic Stage at First Echocardiogram)

Variable Total (n⫽1065), n (%) Normal (n⫽295) Grade 1 (n⫽691) Grade 2 or Higher (n⫽79) P* Ageⱖ65 y, n (%) 645 (61) 160 (54) 437 (63) 48 (61) 0.03 Male sex, n (%) 615 (58) 165 (56) 404 (59) 46 (58) 0.7 White, n (%) 616 (58) 176 (60) 396 (57) 44 (56) 0.7 CAD, n (%) 292 (27) 87 (30) 188 (27) 17 (22) 0.3 Revascularization, n (%) 128 (12) 37 (13) 83 (12) 8 (10) 0.8 Atrial fibrillation, n (%) 87 (8) 24 (8) 57 (8) 6 (8) 1.0 Diabetes mellitus, n (%) 125 (12) 33 (11) 87 (13) 5 (6) 0.2 Hypertension, n (%) 941 (88) 249 (84) 621 (90) 71 (90) 0.045 Dyslipidemia, n (%) 730 (69) 192 (65) 481 (70) 57 (72) 0.3 Peripheral vascular disease, n (%) 62 (6) 15 (5) 41 (6) 6 (8) 0.7 Congestive heart failure, n (%) 158 (15) 40 (14) 105 (15) 13 (17) 0.7

COPD, n (%) 186 (18) 49 (17) 122 (18) 15 (19) 0.9

Chronic renal insufficiency, n (%) 334 (31) 103 (35) 208 (30) 23 (29) 0.3 Body mass indexⱖ30 kg/m2, n (%) 511 (48) 136 (46) 339 (49) 36 (46) 0.6 Creatinine, mean (SD), mg/dL 1.1⫾1.1 1.2⫾1.2 1.1⫾1.1 1.0⫾0.9 0.3 Hemoglobin, mean (SD), g/dL 12.0⫾2.7 12.1⫾2.5 11.9⫾2.8 12.2⫾2.5 0.5 Systolic blood pressure, mean (SD), mm Hg 129⫾17 129⫾17 129⫾17 131⫾16 0.3 Diastolic blood pressure, mean (SD), mm Hg 66⫾12 65⫾12 66⫾13 65⫾13 0.5 Time between tests, y 1.1⫾0.4 1.1⫾0.4 1.2⫾0.4 1.2⫾0.4 0.07 Follow-up time, y† 1.6⫾0.8 1.6⫾0.8 1.6⫾0.8 1.7⫾0.8 0.5

Indication for echocardiographic testing, n (%)‡ 0.4

Assessment of valvular function 393 (37) 98 (33) 269 (39) 26 (33) Symptom evaluation§ 463 (44) 132 (45) 295 (43) 36 (46) Assessment of ventricular function 152 (14) 54 (18) 87 (13) 11 (14) Suspected or known CAD 37 (4) 10 (3) 23 (3) 4 (5)

Abnormal ECG 17 (2) 1 (0.3) 14 (2) 2 (2)

CAD indicates coronary artery disease; COPD, chronic obstructive pulmonary disease.

*Comparing means or proportions of baseline characteristics across diastolic function categories. †Follow-up time after the second echocardiographic test.

‡Indication for the first test.

§The most common symptoms were shortness of breath, palpitations, fatigue, and atypical chest pain.

Table 2. Medications at Baseline and at Follow-Up for All Patients Examination 1, n (%) Examination 2, n (%) P Aspirin 666 (63) 669 (63) 0.38 ␤-blockers 497 (47) 500 (47) 0.25 Calcium channel blockers 338 (32) 348 (33) 0.21 Angiotensin-converting enzyme

inhibitor/receptor blocker

263 (25) 269 (25) 0.42

Diuretics 174 (16) 173 (16) 1.0

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Outcomes

After a mean⫾SD follow-up (from the second study) of 1.6⫾0.8 years, 142 patients (13%) died: 20 (7.6%) with normal diastolic function, 102 (14.8%) with mild (grade 1) DD, and 20 (17.9%) with at least moderate DD (unadjusted mortality; log-rankP⫽0.01; Figure 3). Worsening of diastol-ic function was associated with increased mortality compared with those who had no change or an improvement in diastolic function (unadjusted mortality, 21% versus 12%; log-rank

P⫽0.001; Figure 4). Patients who had improved diastolic function had a mortality similar to that of patients without change (11.4% versus 11.8%;P⫽0.88); however, those who had improvement in DD by ⱖ2 grades (n⫽14) had lower mortality compared with those with 1 grade improvement (n⫽100), but the difference was not statistically significant (7% versus 12%; P⫽0.59). After multivariate analysis, a

decrease in LVEF to⬍55% and any worsening of diastolic function were independently associated with increased risk of mortality (hazard ratio [HR], 1.78; 95% confidence interval [CI], 1.10 –2.85;P⫽0.02; and HR, 1.78; 95% CI, 1.21–2.59;

P⫽0.003, respectively). Similarly, worsening of diastolic function from normal to abnormal and from mild to moderate or severe DD was associated with an increase in mortality (HR, 3.58; 95% CI, 1.71–7.53;P⫽0.001; and HR, 2.13; 95% CI, 1.19 –3.83;P⫽0.01, respectively; Table 4). Similar find-ings and HRs were obtained when diastolic function at follow-up (instead of baseline) was forced into the model.

Discussion

To the best of our knowledge, this is the largest study to assess the association of progression of diastolic function and mortality in outpatients with normal baseline LVEF. Wors-ening of diastolic function and a decrease in LVEF to⬍55% were independently associated with increased risk of mortality.

Prevalence and Progression of Diastolic Function

Our study shows that DD not only is quite prevalent among outpatients with normal LVEF, similar to recently published data,5but also is dynamic. Although a recent study showed

that 32% of patients had a change in diastolic function after a mean⫾SD follow-up of 4⫾0.3 years,10 the present study

showed that similar changes in diastolic function occur much sooner (mean⫾SD follow-up, 1.1⫾0.4 years; Figure 2). Such progression of DD has recently been shown by Kane et al10to

be associated with an increase in cumulative heart failure incidence during 6.3⫾2.3 years of follow-up after the second echocardiogram (2.6% for patients whose diastolic function remained normal or normalized, 7.8% for patients who had persistent or progression to mild DD, and 12.2% for patients with persistent or progression to moderate/severe DD;

P⬍0.001). However, in that article, a link between progres-sion of DD and total mortality was not investigated. Another

Table 3. Echocardiographic Parameters at Baseline and Follow-Up (n1065) Examination 1 Examination 2 P LVEFⱖ55%, n (%) 1065 (100) 977 (92) ⬍0.001 LVEF, mean (SD), % 59.1 (4.3) 58.1 (5.9) ⬍0.001 LV dimensions* LVEDD/height, mean (SD), mm/m 26.3 (5.3) 26.5 (6.0) 0.10 LVESD/height, mean (SD), mm/m 16.7 (4.4) 17.1 (4.7) 0.01 LVEDVi, mL/m2 60.3 (25) 60.5 (24) 0.10 LVESVi, mL/m2 24.2 (12) 25.7 (13) 0.0075 Left atrium area, cm2 18.8 (4.6) 19.0 (4.9) 0.11 Ventricular filling, mean (SD)†

E, m/s 0.87 (0.31) 0.92 (0.30) ⬍0.001 E/A 1.05 (0.53) 1.19 (0.39) ⬍0.001 Deceleration time, ms 201 (43) 227 (56) ⬍0.001 e⬘, m/s 0.10 (0.06) 0.09 (0.02) ⬍0.001 E/e⬘ 8.8 (4.4) 10.2 (6.4) ⬍0.001 Estimated PASP, mm Hg 33.4 (10.8) 33.9 (12.6) 0.08 Valvular heart disease, n (%)‡

Moderate mitral stenosis 1 (0.09) 1 (0.09) 1.0 Moderate mitral regurgitation 60 (5.6) 54 (5.1) 0.26 Moderate tricuspid regurgitation 45 (4.2) 63 (5.9) 0.06 Moderate aortic stenosis 1 (0.09) 2 (0.18) 1.0 Moderate aortic regurgitation 41 (3.8) 42 (3.9) 1.0 Moderate pulmonary

insufficiency

8 (0.75) 13 (1.2) 0.18 LVEF indicates left ventricular ejection fraction; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; LVEDVi, left ventricular end-diastolic volume index; LVESVi, left ventricular end-systolic volume index; and PASP, pulmonary artery systolic pressure.

*Measured in 947 and 970 patients at examinations 1 and 2, respectively, for LVEDD/height and LVESD/height; in 767 and 771 for LVEDVi; in 663 and 669 for LVESVi; and in 976 and 955 for left atrial areas.

†Measured in 631 and 628 patients at examinations 1 and 2, respectively, for E and E/A; in 848 and 710 for deceleration time; in 320 and 636 for e⬘; in 317 and 625 for E/e⬘; and in 623 and 681 for PASP.

‡Patients with more than moderate stenosis or regurgitation were excluded from the study.

Figure 2.Baseline and follow-up diastolic function. Green indi-cates normal diastolic function; orange, grade 1 diastolic dys-function; and red, grade 2 or higher diastolic dysfunction.

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study showed a higher progression rate of diastolic function (48% of patients) in a smaller cohort (n⫽184) and after a mean follow-up of 3.6 years.9However, there were several

important differences in and limitations of that study: (1) Patients with baseline normal diastolic function were ex-cluded; (2) the study included echocardiograms performed on inpatients who might have different loading conditions every day and more aggressive day-to-day titration of medications, particularly those admitted with congestive heart failure, and that can influence diastolic function16,17; (3) the cutoff EF was

45%, and many patients had mildly reduced systolic function, although the actual number or percentage of these patients was not disclosed; and most important (4) tissue Doppler imaging was not used to assess diastolic function.

In addition, our study shows that 11% of patients with baseline DD (84 of 770) return to normal diastolic function

on follow-up echocardiogram (Figure 2). Although the reason is not well known, it could perhaps be related to medication, diuresis, and treatment of risk factors. Although Achong et al9

did not report any improvement in diastolic function back to normal, probably because that subgroup was excluded from the start, a recent study confirmed that diastolic function may indeed return to normal in up to 27% of patients (70 of 252) after a long follow-up period.10

Furthermore, although previous articles focused on analyz-ing diastolic progression in predominantly white populations (⬎95%),9,10 our study was more reflective of the current

demographic nature of the US population and had a large representation of blacks, Hispanics, and Asians (42% of the total cohort).

Traditional risk factors such as age, hypertension, diabetes, obesity, and fluid overload with elevated filling pressures

Figure 3.Kaplan-Meier analysis of survival of 1065 patients who had an outpatient echocardiogram with normal ejection frac-tion (between January 1, 2005, and Decem-ber 31, 2009) and a follow-up echocardio-gram 6 to 24 months later stratified according to diastolic stage (determined from the second echocardiogram).

Figure 4.Kaplan-Meier analysis of sur-vival of 1065 patients who had an outpa-tient echocardiogram with normal ejection fraction (between January 1, 2005, and December 31, 2009) and a follow-up echocardiogram 6 to 24 months later stratified according to diastolic stage progression.

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have been associated with worsening diastolic function.5,10

Hence, aggressive risk factor modification, particularly blood pressure control, weight loss, and exercise, and salt restric-tion, are important steps that might halt diastolic progression.

Mortality

The presence of DD has been shown to be an independent predictor of all-cause mortality.5In our study, 142 patients

(13%) died (7.6% with normal diastolic function, 14.8% with mild DD, 17.9% with moderate or severe DD; P⫽0.01; Figure 3). All-cause mortality, however, was strikingly higher than previously reported in patients with normal LVEF (13% and a follow-up time of 1.6⫾0.8 years versus. 16% and follow-up time of 6.2⫾2.3 years5). Although both studies

consisted of outpatients with normal LVEF, our cohort had patients with more prevalent cardiovascular risk factors and disease (Table 1).

In addition, 8.3% of patients had a decrease in LVEF to

⬍55% and were more likely to have advanced DD (P⫽0.002), but there was no difference when stratified by the change in diastolic function (P⫽0.3). An abnormal LVEF on follow-up echocardiogram, however, was an independent predictor of mortality (HR, 1.78; 95% CI, 1.10 –2.85;

P⫽0.02). Similarly, any worsening of diastolic function was also an independent predictor of death even after adjustment for change in EF and diastolic function (whether obtained at baseline or at follow-up; HR, 1.78; 95% CI, 1.21–2.59;

P⫽0.003; Table 4). Those with stable or improved diastolic function, however, had similar good outcomes (overlapping survival curves; Figure 3). In the only other study, Achong et al9 showed that improvement of diastolic function was

associated with better outcome (P⫽0.05); however, HRs were not calculated, patients with normal baseline diastolic function were excluded, inpatients and those with mild systolic dysfunction were included, and tissue Doppler imag-ing was not used to assess DD.

Limitations

The study has several limitations. It is a retrospective study from a single tertiary center. The readers were unblinded to the medical history of patients and had access to their previous echocardiograms. In addition, a normal systolic function and LVEF ⱖ55% are not synonymous, although they are used interchangeably in clinical practice. There was no systematic review of the echocardiograms to reassess

diastolic function; rather, the data were extracted from prior reads, which is comparable to what is done in clinical practice. There is always potential error in interpreting diastolic function, particularly in distinguishing normal and pseudonormal. Although left atrial indexed volumes are necessary for complete evaluation of diastolic function, the data were not available for most patients but rather only the left atrial area. However, tissue Doppler imaging was avail-able at the time of the read and used in addition to other echocardiographic variables in most studies, hence minimiz-ing potential error. In addition, there were only 2 patients (0.2%) with severe DD at baseline; thus, they were grouped with those with moderate DD. This low percentage, however, is not unusual in this cohort of patients and was similarly found in another study (127 of 36 261, 0.35%).5 Although

all-cause mortality is an objective and nonbiased primary outcome in our study, other outcomes such as cardiac death or hospitalization for heart failure were not assessed. Further-more, clinical data were recorded between 6 months before the first test and 6 months after the second test. Hence, relevant clinical information or changes beyond this time interval were not captured. Finally, other unmeasured or unobserved variables, including malignancy and adherence and compliance to medical therapy, were not accounted for.

Conclusion

In outpatients with preserved LVEF at the baseline echocar-diogram, worsening of diastolic function on a follow-up study is an independent predictor of all-cause mortality.

Disclosures

None.

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Table 4. Echocardiographic Parameters as a Risk Factor for Mortality

Echocardiographic Parameters

Adjusted HR

(95% CI) P Decrease in left ventricular ejection fraction

to⬍55%

1.78 (1.10 –2.85) 0.02 Any worsening in diastolic function 1.78 (1.21–2.59) 0.003 Progression from normal to abnormal

diastolic function

3.58 (1.71–7.53) 0.001 Progression from mild to moderate/severe

diastolic function

2.13 (1.19–3.83)] 0.01 HR indicates hazard ratio; CI, confidence interval.

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changes in myocardial relaxation: a mechanism for diastolic dysfunction. Cardiovasc Res. 1999;43:344 –353.

CLINICAL PERSPECTIVE

Diastolic dysfunction is an independent predictor of mortality in patients with normal ejection fraction. Diastolic function, whether normal or abnormal (stage 1, 2, or 3), varies dynamically and can pass from 1 stage to the other and in either direction. Although worsening of diastolic function has been associated with the development of congestive heart failure, there have been limited data on mortality with this progression. The present study showed that worsening of diastolic function in outpatients with normal ejection fraction (n⫽1065; age, 69⫾13 years) was associated with increased risk of death (hazard ratio, 1.78; 95% confidence interval, 1.21–2.59;P⫽0.003) independently of baseline or current diastolic function. This hazard ratio was equivalent to that from worsening of systolic function in the same population. Furthermore, progression from normal to abnormal diastolic function and from stage 1 to 2 or 3 diastolic dysfunction was associated with increased mortality (hazard ratio, 3.58; 95% confidence interval, 1.71–7.53; P⫽0.0001; and hazard ratio, 2.13; 95% confidence interval, 1.19 –3.83;P⫽0.01, respectively). Given the present findings, it is important for clinicians not only to recognize the importance of progression of diastolic function for their patients but also to promote aggressive risk factor modifications, particularly blood pressure control, weight loss, exercise, and salt restriction; these risk factors have traditionally have been associated with worsening of diastolic function.

References

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