Heart failure with preserved ejection fraction (HFpEF) may be characterized as impaired left ventricular (LV) relaxation and/or left atrial (LA) function, both of which are age and gender dependent. The aim of this study was to investigate LV relaxation and the LA function in HFpEF. A total of 71 HFpEF (mean age 73 years, 38 men) were studied. Late transmitral flow velocity ( A ), late mitral annular velocity ( a ‘), and early mitral annular velocity ( e ‘) were measured and compared with age- and gender-matched normal control subjects (CTL; n = 71) and hypertensive patients (HT; n = 71). To clarify prognostic impact of the LA function, cardiac event-free survival was compared between high a ‘ (≥7.9 cm/s, n = 36) and low a ‘ (<7.9 cm/s, n = 35) groups. Cardiac event was defined as a composite of all-cause death and hospitalization due to recurrent congestive heart failure. In both HFpEF and HT groups, e ‘ was significantly and similarly decreased compared with CTL group (p = 0.005). Although A was similar among the 3 groups, a ‘ was significantly lower in HFpEF group than in HT and CTL groups (7.9 ± 2.1 vs 9.0 ± 1.9 vs 9.3 ± 1.96 cm/s, p <0.0001). HFpEF with low a ‘ showed significantly lower cardiac event-free survival than HFpEF with high a ‘ (log rank, p = 0.02). By multivariate Cox proportional analysis, low a ‘ was the only independent predictor of cardiac events (hazard ratio 2.896, 95% confidence interval 1.004 to 8.355, p = 0.049). Both LV relaxation and LA function are impaired in HFpEF. Impaired LA function may be associated with worse prognosis in HFpEF.
Recent trials have consistently reported that about a half of the patients with heart failure has normal or preserved ejection fraction (EF). Impaired left ventricular (LV) diastolic function is suspected as one of the predisposing causes for the development of heart failure with preserved ejection fraction (HFpEF). Although increased LV filling pressure as a result of impaired LV relaxation and increased LV stiffness are causes of signs and symptoms in patients with HFpEF, impaired left atrial (LA) function may also be responsible for the development of HFpEF. Previous studies have shown that LV relaxation and LA function are age and gender dependent. Therefore, to clarify whether LV relaxation and LA function of the HFpEF are truly impaired, it is essential to compare these indexes with age- and gender-matched subjects. We hypothesized that both impaired LV relaxation and decreased LA function might be responsible for the development of HFpEF. Accordingly, the aim of this study was to assess LV diastolic function and LA function using tissue Doppler imaging (TDI) in patients with HFpEF compared with age- and gender-matched controls.
Methods
From 2002 to October 2005, a total of 71 patients with HFpEF (mean age 73 years, 38 men) were consecutively enrolled and studied. Echocardiographic indexes were compared with age- and gender-matched normal control subjects (CTL group; n = 71, mean age 73 years, 38 men) and hypertensive patients without a history of heart failure (HT group; n = 71, mean age 73 years, 38 men) selected from echocardiographic database. HT group includes both medically treated patients and drug-naive patients. Heart failure was diagnosed according to the Framingham Heart Study criteria. Patients were diagnosed as HFpEF if (1) LVEF >50%; (2) significant mitral or aortic valvular disease was not present; (3) LV diastolic function was impaired (septal e ‘ <8.0 cm/s) ; and (4) noncardiogenic causes of pulmonary congestion, such as renal failure, severe anemia, or acute respiratory distress syndrome, were excluded.
All patients underwent 2-dimensional and Doppler echocardiographic examinations with patients in the left lateral decubitus position using a commercially available echocardiographic machine (GE medical, Vivid 7, Milwaukee, Wisconsin) that had a broadband (1.5 to 4 MHz) phased array transducer. Echocardiographic equipment was managed and maintained according to the current guideline. LA dimension, LV end-diastolic dimension, and LV end-systolic dimension were measured from parasternal long-axis view. LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LVEF were calculated using biplane modified Simpson method. LV wall motion score index was calculated based on the standard 16-segment model. Transmitral flow velocity signals were recorded from the apical 4-chamber view, and the early ( E ) and late ( A ) transmitral flow velocities were measured. Deceleration time of the E was also measured. TDI of the mitral annulus was obtained from the apical 4-chamber view. A sample volume of the pulsed-wave Doppler was positioned at the septal side of the mitral annulus, and then, the spectral signal of the mitral annular velocity was recorded. The peak early ( e ‘) and late ( a ‘) mitral annular velocity were measured. E / e ‘ was calculated as E divided by e ‘, and A / a ‘ was calculated as A divided by a ‘. All patients gave informed consent.
To further investigate clinical impact of the LA function, patients with HFpEF were grouped as either high or low a ‘ based on the median value. Cardiac event-free survival was compared between high and low a ‘ groups. Cardiac event was defined as a composite of all-cause death and hospitalization due to recurrent congestive heart failure (CHF). Clinical events were documented by a chart review and/or a telephone contact.
Continuous data are expressed as mean ± SD or median with interquartile range, depending on the distribution of the variable. The differences between 2 groups for the parametrical data were tested by unpaired t test or the Mann–Whitney U test. Categorical variables between 2 groups were compared using the chi-square test or Fisher’s exact test. The differences among the 3 groups were compared using the analysis of variance test and a post hoc analysis with Sheffe method. Cardiac event-free survival between the 2 groups was compared using Kaplan–Meier method and log-rank test. The Cox univariate regression hazard model was used to identify the factors associated with the cardiac event. Factors with p value <0.10 on univariate analysis were entered into the Cox multivariate regression hazard model to define independent risk factors for the cardiac event. A significance was set at p <0.05. Statistical analysis was performed using commercially available software (StatView; Abacus Concepts, California).
Results
Clinical characteristics and medications of the HFpEF, HT, and CTL are provided in Table 1 . Because hypertensive patients and control subjects were selected from echocardiographic database, medications were not available. Table 2 and Figure 1 shows the echocardiographic data comparing the 3 groups. LVEDV and LVESV were significantly larger in HFpEF than in HT or CTL groups. LA diameter was also significantly larger in HFpEF than in HT or CTL groups. By Doppler echocardiography ( Figure 1 ), E velocity was significantly higher in HFpEF than in HT or CTL groups. In contrast, A velocity was similar among the 3 groups. By tissue Doppler, e ‘ in HFpEF and HT groups were similar and significantly lower than in CTL group. In contrast, a ‘ in HFpEF was significantly lower in HFpEF than in HT and CTL groups. As a result, E / e ‘ was significantly higher in HFpEF than in HT and CTL groups. Similarly, A / a ‘ was significantly higher in HFpEF than in HT and CTL groups.
| HFpEF (n=71) | HT (n=71) | CTL (n=71) | |
|---|---|---|---|
| Age, years | 73.6±9.6 | 72.6±8.4 | 73.3±10.8 |
| Men | 38 (54%) | 38 (54) | 38 (54) |
| NYHA functional class | |||
| I/II/III/IV, n | 0/30/36/5 | – | – |
| Hypertension | 44 (62%) | 71 (100) | 0 (0) |
| Hyperlipidemia | 8 (11%) | NA | NA |
| Diabetes mellitus | 18 (25%) | NA | NA |
| Smoker | 6 (8%) | NA | NA |
| Prior myocardial infarction | 8 (11%) | 0 (0) | 0 (0) |
| Medications | |||
| Aspirin | 27 (38%) | NA | 0 (0) |
| Beta blockers | 11 (15%) | NA | 0 (0) |
| ACEI / ARB | 32 (45%) | NA | 0 (0) |
| Nitrates | 19 (27%) | NA | 0 (0) |
| Calcium channel blockers | 27 (38%) | NA | 0 (0) |
| Loop diuretics | 29 (41%) | NA | 0 (0) |
| Statins | 7 (10%) | NA | 0 (0) |
| HFpEF (n=71) | Hypertension (n=71) | Normal (n=71) | P value | |
|---|---|---|---|---|
| LVEDV, ml | 84.0±33.8 | 65.5±18.3 ∗ | 63.7±18.0 ∗ | <0.0001 |
| LVESV, ml | 32.1±15.4 | 22.8±8.5 ∗ | 22.7±8.7 ∗ | <0.0001 |
| LVEF, % | 62.0±7.8 | 65.3±7.4 ∗ | 64.9±6.4 ∗ | 0.02 |
| LV mass, g | 174.5±85.2 | 146.2±44.1 | 125.0±35.7 ∗ | <0.0001 |
| LAD, mm | 41.0±7.2 | 38.3±6.4 ∗ | 36.2±5.4 ∗ | <0.0001 |
| E/A | 0.92±0.44 | 0.70±0.17 ∗ | 0.73±0.22 ∗ | <0.0001 |
| Deceleration time, msec | 215.3±57.3 | 240.6±52.3 | 233.2±54.9 | 0.02 |
| PAP, mmHg | 39.2±13.5 | 31.8±7.9 ∗ | 29.6±5.5 ∗ | <0.0001 |
| Heart rate, beat/min | 72.8±12.8 | 68.1±11.9 | 71.8±11.9 | 0.100 |
Median value of a ‘ in HFpEF was 7.9 cm/s. Cardiac events were compared between HFpEF with high (≥7.9 cm/s) and low (<7.9 cm/s) a ‘ value. Table 3 provides comparison between high and low a ‘ groups. Age, gender, and coronary risk factors were similar between the 2 groups, except for the higher prevalence of smoking in low a ‘ group. Aspirin and loop diuretics were more frequently prescribed in low a ‘ group. Echocardiography shows that LVEDV and LVESV were significantly bigger, and LVEF was significantly lower in low a ‘ group than in high a ‘ group. By Doppler echocardiography, E , E / A , and E / e ‘ were significantly higher, and e ‘ was significantly lower in low a ‘ group. During follow-up (mean 1.5 ± 1.2 years), cardiac event-free survival was significantly lower in HFpEF with low a ‘ than high a ‘ ( Figure 2 ). By univariate analysis, low a ‘ (hazard ratio [HR] 3.035, 95% confidence interval [CI] 1.061 to 8.683, p = 0.038) was a significant predictor and age (HR 1.063, 95% CI 0.999 to 1.063, p = 0.053) was a borderline predictor of cardiac events. By multivariate Cox analysis, low a ‘ (HR 2.896, 95% CI 1.004 to 8.355, p = 0.049) was the only independent predictor of cardiac events.
| Variable | High a’ (n=36) | Low a’ (n=35) | p value |
|---|---|---|---|
| Age (years) | 72.6±8.4 | 73.3±10.8 | NS |
| Men | 20 (56%) | 18 (51) | NS |
| Hypertension | 20 (56%) | 24 (69) | NS |
| Hyperlipidemia | 5 (14%) | 3 (9) | NS |
| Diabetes mellitus | 9 (25%) | 9 (26) | NS |
| Smoker | 0 | 6 (17) | 0.009 |
| Prior myocardial infarction | 4 (11%) | 4 (11) | NS |
| Medications | |||
| Aspirin | 9 (25%) | 18 (51) | 0.02 |
| Beta blockers | 4 (11%) | 7 (20) | NS |
| ACEI / ARB | 13 (36%) | 9 (26) | NS |
| Nitrates | 9 (25%) | 10 (29) | NS |
| Calcium channel blockers | 9 (25%) | 18 (51) | NS |
| Loop diuretics | 10 (28%) | 19 (54) | 0.02 |
| Statins | 3 (8%) | 4 (11) | NS |
| NYHA classification (%) | NS | ||
| I | 0 | 0 | |
| II | 16 | 12 | |
| III | 18 | 21 | |
| IV | 2 | 2 | |
| Echocardiography | |||
| LVEDV, ml | 72.7±25.9 | 95.7±37.3 | 0.004 |
| LVESV, ml | 25.6±9.7 | 38.8±17.4 | 0.0002 |
| LVEF, % | 64.1±7.9 | 60.0±7.3 | 0.03 |
| LAD, mm | 45.7±6.3 | 50.3±5.3 | 0.001 |
| E, m/sec | 0.70±0.29 | 0.87±0.31 | 0.02 |
| A, m/sec | 0.88±0.23 | 0.92±0.22 | NS |
| E/A | 0.77±0.33 | 1.07±0.50 | 0.004 |
| Deceleration time, msec | 220.0±52.6 | 210.4±62.2 | NS |
| e’, cm/sec | 5.1±1.3 | 4.5±1.2 | 0.06 |
| a’, cm/sec | 9.5±1.5 | 6.2±1.2 | – |
| E/e’ | 13.9±4.3 | 19.9±7.1 | <0.0001 |
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