Abstract
Background
We previously reported that an index of afterload‐related left ventricular diastolic function, operant diastolic elastance (Ed)/effective arterial elastance (Ea) = E/e’/(0.9 × systolic blood pressure), was significantly higher in elderly hypertensive women. We aimed to determine sex‐related differences in the E/e’‐related indices for left ventricular diastolic function and their related factors during admission in patients with heart failure with preserved ejection fraction (HFpEF).
Hypothesis
Elderly HFpEF women exhibit severe left ventricular diastolic dysfunction associated with different left atrioventricular volume ratio.
Methods
We divided 267 patients with HFpEF (men/women, 116/151) into two groups by age (≥75 years, n = 212; <75 years, n = 55). We examined the alterations of E/e’, E/e’/stroke volume index = Ed, and Ed/Ea, and cardiac structure during admission.
Results
Ed and Ea were significantly higher in women than in men, at admission, especially in patients ≥75 years. Before discharge, not only Ed and Ea but also Ed/Ea was significantly higher in women than in men, especially in patients ≥75 years. Elderly female patients had larger left atrial than left ventricular volume.
Conclusions
Higher afterload‐related left ventricular diastolic elastance, Ed/Ea, in association with higher arterial elastance, Ea, accompanied by left atrioventricular volume mismatch was observed in elderly HFpEF women.
Keywords: arterial elastance, diastolic function, elderly, left cardiac volume, sex
1. INTRODUCTION
The pathophysiological mechanism of heart failure with preserved ejection fraction (HFpEF) is multifactorial1 and may be caused by an extreme form of age‐related deterioration with arterial‐ventricular interrelation.2, 3, 4 E/e’‐related indices such as E/e’ and E/e’/stroke volume index (SVI) = operant diastolic elastance (Ed) reportedly reflect left ventricular (LV) diastolic function.3, 5 We previously reported the age‐ and sex‐related differences in LV diastolic function relative to arterial elasticity among hypertensive patients with preserved LV ejection fraction (LVEF) and no history of heart failure.6, 7 We found that afterload‐related diastolic function, Ed/effective arterial elastance (Ea) = Ed/Ea = E/e’/(0.9 × systolic blood pressure), was significantly impaired in elderly (≥75 years) hypertensive women and was coincident with cardiac structure alterations. It is well known that Ed and Ea are higher in women than in men, under stable conditions.8, 9 Since LV diastolic function is strongly affected by afterload extent, the elevated Ed in women could be an epiphenomenon because of an associated increase in Ea. In this sense, Ed must be corrected by indexing to Ea as Ed/Ea under the condition of a between‐sex difference in Ea. Alterations of LV diastolic function during admission in patients with HFpEF remains to be defined. Accordingly, we aimed to determine the sex‐ and age‐related serial differences in E/e’‐related indices regarding LV diastolic function in association with Ea alteration and their correlation with cardiac structure during admission in patients with HFpEF.
2. METHODS
2.1. The PURSUIT HFpEF registry
The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study is a prospective multicenter observational study in which collaborating hospitals in the Osaka region of Japan recorded clinical, echocardiographic, and outcome data of patients with congestive heart failure with preserved ejection fraction (UMIN‐CTR ID: UMIN000021831). The objectives of this registry are to collect uniform prospective data of patients with congestive heart failure that can be used to assess clinical variables, therapeutic procedures, and clinical events. Consecutive patients (N = 267; men/women, 116/151) hospitalized with heart failure who were registered in the PURSUIT HFpEF between June 2016 and August 2017 were included in the present study and divided into two groups by age (≥75 years, n = 212; <75 years, n = 55). This study complied with the Declaration of Helsinki, and its protocol was approved by the ethics committee of each participating hospital. Briefly, hospitalized patients with congestive heart failure and a preserved ejection fraction (LVEF ≥50%) were prospectively registered and agreed to be followed up for 5 years. Congestive heart failure was diagnosed if the following criteria were met: (a) clinical history of dyspnea at rest; (b) serum N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) ≥ 400 pg/mL; and (c) pulmonary congestion, pleural effusion, and/or leg edema. All patients provided written informed consent to participate.
2.2. Data collection
Research cardiologists and specialized research nurses recorded the patients' data during their hospital stays. In‐hospital data were transmitted to the data collection center for processing and analysis. Collaborating hospitals were encouraged to enroll consecutive heart failure patients with preserved ejection fraction irrespective of their treatment. Blood samples and oral medications were obtained at admission and before discharge.
2.3. Echocardiographic examination
The transthoracic echocardiographic parameters were obtained immediately after admission and before discharge. Echocardiographic measurements such as chamber size (LA dimension [LAD], LA volume index [LAVI, modified Simpson's method], LV end‐diastolic volume index [LVEDVI, modified Simpson's method], and LV end‐systolic volume index [LVESVI]), LVEF, SVI, tricuspid regurgitation pressure gradient (TRPG), transmitral flow velocity (E/A), and tissue Doppler images of the mitral annular area (e’) were obtained according to the American or European Society of Echocardiography criteria.6, 10, 11 The index was calculated as the value divided by body surface area. Echocardiographic parameters were compared at admission and before discharge. Although septal e’ was examined at both timepoints, lateral e’ and LAVI were evaluated only before discharge. We also examined arterial stiffness using effective arterial elastance, Ea = (0.9 × systolic blood pressure)/SVI,12, 13 at both timepoints. As the indices of diastolic stiffness, we compared E/e’ (septal), E/e’/SVI (operant diastolic elastance = Ed),3 and Ed/Ea (afterload‐related diastolic elastance)6, 7, 14 during admission. We excluded the patients with significant mitral annular calcification, septal/lateral asynergy or right ventricular pacing. To ensure highly accurate measurements for echocardiographic data, short‐course training sessions for echo technicians in each participated hospital underwent several times.
2.4. Statistical analysis
Continuous variables are expressed as mean ± SD, while categorical variables are presented as frequency and percentage. Differences in categorical variables between groups were compared using a χ 2 test, while differences in continuous variables between groups were compared using a paired or unpaired t‐test. Multivariate logistic regression analysis was used to identify factors showing sex‐specific difference. The variables used were age and echocardiographic data showing inter‐sex difference in univariate analysis before discharge (LAVI, LVEDVI, TRPG, and Ed/Ea). P values <0.05 were considered significant. All analyses were performed using PASW Statistics, version 18 (SPSS, Chicago, Illinois).
3. RESULTS
3.1. Patient characteristics in men and women at admission
There were no differences in age, the grade of clinical scenario, blood pressure, heart rate, incidence of comorbidities such as atrial fibrillation, diabetes mellitus and hypertension, renal function, and serum NT‐proBNP level between sexes (Table 1). However, the cardiothoracic ratio was significantly larger and the incidence of chronic obstructive pulmonary disease or coronary artery disease was significantly lower in women than in men.
Table 1.
Patient characteristics
| Men (n = 116) | Women (n = 151) | P value | |
|---|---|---|---|
| Age, years | 79.9 ± 9.2 | 81.0 ± 9.9 | 0.354 |
| Body mass index | 24.8 ± 4.5 | 23.6 ± 4.9 | 0.045 |
| Clinical scenario, 1/2/3/4/5 | 63/49/1/0/2 | 73/71/2/1/2 | 0.781 |
| Cardiothoracic ratio, % | 59.6 ± 7.1 | 63.6 ± 6.9 | <0.001 |
| Systolic blood pressure, mmHg | 153 ± 27 | 146 ± 32 | 0.075 |
| Diastolic blood pressure, mmHg | 82 ± 20 | 78 ± 21 | 0.149 |
| Heart rate, bpm | 84 ± 32 | 86 ± 27 | 0.498 |
| Atrial fibrillation, n (%) | 51 (44) | 55 (36) | 0.131 |
| Chronic obstructive pulmonary disease, n (%) | 13 (11) | 5 (3) | 0.011 |
| Coronary artery disease, n (%) | 33 (28) | 27 (18) | 0.028 |
| Diabetes mellitus, n (%) | 45 (39) | 49 (32) | 0.171 |
| Dyslipidemia, n (%) | 46 (40) | 68 (45) | 0.224 |
| Hypertension, n (%) | 101 (87) | 122 (81) | 0.114 |
| Laboratory data | |||
| eGFR, mL/min/1.73 m2 | 43.6 ± 19.9 | 44.5 ± 22.6 | 0.740 |
| N‐terminal pro‐brain natriuretic peptide, pg/mL | 5895 ± 6495 | 6116 ± 7744 | 0.814 |
Abbreviation: eGFR, estimated glomerular filtration rate.
Values are mean ± SD or number (%).
3.2. Sex‐ and age‐related differences in echocardiographic data during admission
We divided our patients into those ≥75 years (n = 212) and < 75 years (n = 55). There were no inter‐sex differences in LAD at admission or before discharge in either age group. No differences were also observed in LAD between those at admission and before discharge both in men and women (Table 2). In contrast, LAVI was significantly larger in women than in men before discharge in both age groups (≥75 years, P = 0.021; <75 years, P = 0.006). However, LVEDVI and LVESVI were significantly lower in women than in men at admission (P < 0.001 and P = 0.002, respectively) and before discharge (both P < 0.001) in patients ≥75 years but not in those <75 years. In multivariate logistic regression analysis, sex‐specific difference was independently observed in LAVI (P = 0.016) and LVEDVI (P = 0.004) in addition with Ed/Ea (P = 0.002) before discharge. The LAVI/LVEDVI ratio before discharge was significantly higher in women than in men (1.28 ± 0.87 vs 0.83 ± 0.38, P < 0.001), especially in patients ≥75 years (1.36 ± 0.91 vs 0.87 ± 0.39, P < 0.001). The incidence of atrial fibrillation did not differ significantly between sexes in both age groups (≥ 75 years, men 44%, women 39%, P = 0.456; < 75 years, men 42%, women 24%, P = 0.152). When we examined the correlation between age and logarithmic value of LAVI, log (LAVI), before discharge, the correlation was significant in each sex (Figure 1A). Especially, a significant and negative correlation was observed between age and log (LVEDVI) only in women and the slope of the regression line was significantly different between sexes (Figure 1B). In patients ≥75 years, SVI differed significantly between the sexes at admission (P = 0.009) and before discharge (P = 0.003), although no difference in LVEF was observed between the sexes at admission or before discharge (Table 2). Tricuspid regurgitation pressure gradient was equivalently high in both sexes at admission but was reduced significantly before discharge irrespective of age or sex. There were no inter‐sex differences in LV mass index or interventricular septum or LV posterior wall thickness at admission (data not shown). Systolic blood pressure (men, 116 ± 16 mmHg; women, 116 ± 17 mmHg; P = 0.985) and heart rate (men, 70 ± 15 bpm; women, 71 ± 15 bpm; P = 0.550) did not differ significantly between sexes before discharge.
Table 2.
Age‐ and sex‐related changes in echocardiographic data during admission in patients with HFpEF
| Age ≥ 75 years | P value | Age < 75 years | P value | ||||
|---|---|---|---|---|---|---|---|
| Men (n = 90) | Women (n = 122) | (M vs W) | Men (n = 26) | Women (n = 29) | (M vs W) | ||
| LAD | Admission | 43.8 ± 6.9 | 44.0 ± 8.5 | 0.901 | 43.8 ± 7.8 | 43.6 ± 9.1 | 0.905 |
| mm | Discharge | 43.8 ± 7.4 | 44.2 ± 8.3 | 0.684 | 42.8 ± 8.9 | 42.5 ± 8.9 | 0.916 |
| P value | 0.969 | 0.792 | 0.669 | 0.667 | |||
| (Adm vs Dis) | |||||||
| LAVI | Admission | ‐ | ‐ | ‐ | ‐ | ||
| mL/m2 | Discharge | 50.6 ± 19.2 | 59.9 ± 29.3 | 0.021 | 36.7 ± 16.3 | 53.7 ± 20.9 | 0.006 |
| P value | |||||||
| (Adm vs Dis) | |||||||
| LVEDVI | Admission | 63.1 ± 19.4 | 51.7 ± 16.7 | <0.001 | 58.1 ± 11.1 | 56.8 ± 22.4 | 0.843 |
| mL/m2 | Discharge | 62.2 ± 26.2 | 49.4 ± 18.5 | <0.001 | 54.3 ± 11.9 | 65.7 ± 23.6 | 0.064 |
| P value | 0.843 | 0.411 | 0.369 | 0.211 | |||
| (Adm vs Dis) | |||||||
| LVESVI | Admission | 25.6 ± 9.9 | 20.1 ± 8.3 | 0.002 | 20.8 ± 4.3 | 23.5 ± 10.0 | 0.361 |
| mL/m2 | Discharge | 25.1 ± 14.7 | 18.2 ± 8.2 | <0.001 | 21.3 ± 7.5 | 25.7 ± 10.9 | 0.142 |
| P value | 0.833 | 0.137 | 0.833 | 0.499 | |||
| (Adm vs Dis) | |||||||
| SVI | Admission | 37.5 ± 11.6 | 31.7 ± 11.5 | 0.009 | 37.3 ± 9.9 | 33.3 ± 13.7 | 0.363 |
| mL/m2 | Discharge | 37.2 ± 13.9 | 31.2 ± 12.6 | 0.003 | 33.0 ± 6.4 | 39.9 ± 14.1 | 0.054 |
| P value | 0.881 | 0.742 | 0.145 | 0.119 | |||
| (Adm vs Dis) | |||||||
| LVEF | Admission | 60.1 ± 7.2 | 61.8 ± 8.0 | 0.219 | 62.5 ± 5.9 | 59.9 ± 6.1 | 0.088 |
| % | Discharge | 60.9 ± 7.7 | 61.5 ± 7.1 | 0.582 | 62.2 ± 7.2 | 60.7 ± 6.1 | 0.462 |
| P value | 0.556 | 0.822 | 0.889 | 0.339 | |||
| (Adm vs Dis) | |||||||
| TRPG | Admission | 35.6 ± 10.2 | 35.3 ± 10.9 | 0.815 | 33.1 ± 12.8 | 36.5 ± 15.1 | 0.381 |
| mmHg | Discharge | 26.4 ± 8.3 | 29.4 ± 9.2 | 0.020 | 24.4 ± 6.0 | 28.5 ± 9.7 | 0.097 |
| P value | <0.001 | <0.001 | 0.007 | 0.027 | |||
| (Adm vs Dis) | |||||||
Data are mean ± SD.
Abbreviations: Adm, admission; Dis; discharge; HFpEF, heart failure with preserved ejection fraction; LAD, left atrial dimension; LAVI, left atrial volume index; LVEDVI, left ventricular end‐diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end‐systolic volume index; SVI, stroke volume index; TRPG, tricuspid regurgitation pressure gradient.
Figure 1.
The sex‐linked difference in the correlation between age and cardiac structure such as left atrial volume index (LAVI) or left ventricular end‐diastolic volume index (LVEDVI) as their logarithmic values before discharge. Blue symbol represents men and red symbol represents women. A significant positive correlation was observed between age and log (LAVI) in each sex and the correlation was not different between sexes (A). In contrast, a significant negative correlation was observed between age and log (LVEDVI) only in women and the slope of the regression line was significantly different between sexes (P = 0.030) (B). “W” represents the regression line in women
3.3. Alterations of LV diastolic function and arterial elastance during admission
Although no inter‐sex difference was observed in E/e’, Ed was significantly higher in women than in men, at admission (Table 3). Furthermore, Ea was also significantly different between the sexes, at admission. When LV diastolic function was evaluated by the afterload‐related diastolic index, Ed/Ea, no significant difference was observed at admission between sexes. During admission, Ed tended to be reduced in both sexes, and there were significant differences in three E/e’‐related indices for LV diastolic function between sexes before discharge. In all patients, no significant differences were observed in E/e’, Ed, Ea, and Ed/Ea during admission (data not shown). There was no significant correlation between age and Ed (men, r = 0.122, P = 0.274; women, r = 0.182, P = 0.056), Ea (men, r = 0.024, P = 0.808; women, r = 0.120, P = 0.209), or Ed/Ea (men, r = 0.142, P = 0.204; women, r = 0.171, P = 0.072) before discharge in either sex. There was a weak but significant positive correlation between systolic blood pressure and E/e’ before discharge (r = 0.199, P = 0.005). E/A before discharge did not differ between sexes (men, 0.92 ± 0.45; women, 1.00 ± 0.53; P = 0.411) in patients without atrial fibrillation, although E/A was significantly reduced during admission only in men as similar to E/e’ in these patients (data not shown). When we divided our patients into those ≥75 years and < 75 years, similar changes in LV diastolic function were observed in both age groups, especially in those ≥75 years. Significantly higher levels of Ed, Ea, and even Ed/Ea were observed before discharge in women ≥75 years. These results were similar when we divided our patients into those ≥80 years and < 80 years (data not shown). Although we used septal e’ value in calculation of E/e’, a significant positive correlation was found between E/e’ (septal) and E/e’ (average) before discharge (r = 0.927, P < 0.001).
Table 3.
Changes in left ventricular diastolic function and effective arterial elastance during admission in patients with HFpEF: Age‐ and sex‐related differences
| All | P value | Age ≥ 75 years | P value | Age < 75 years | P value | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Men | Women | (M vs W) | Men | Women | (M vs W) | Men | Women | (M vs W) | ||
| E/e’ | Admission | 16.5 ± 7.2 | 18.1 ± 9.4 | 0.129 | 16.6 ± 7.5 | 18.5 ± 9.4 | 0.130 | 16.0 ± 6.2 | 16.6 ± 9.4 | 0.815 |
| Discharge | 15.0 ± 5.6 | 18.0 ± 8.3 | 0.001 | 15.6 ± 5.7 | 18.0 ± 7.8 | 0.018 | 12.5 ± 4.3 | 17.5 ± 10.4 | 0.037 | |
| P value | 0.074 | 0.754 | 0.167 | 0.626 | 0.143 | 0.717 | ||||
| (Adm vs Dis) | ||||||||||
| Ed = E/e’/SVI | Admission | 0.501 ± 0.264 | 0.655 ± 0.436 | 0.015 | 0.518 ± 0.288 | 0.704 ± 0.465 | 0.017 | 0.439 ± 0.144 | 0.496 ± 0.271 | 0.448 |
| m2/mL | Discharge | 0.449 ± 0.217 | 0.648 ± 0.423 | <0.001 | 0.464 ± 0.227 | 0.672 ± 0.400 | <0.001 | 0.396 ± 0.173 | 0.536 ± 0.509 | 0.272 |
| P value | 0.574 | 0.906 | 0.563 | 0.788 | 0.990 | 0.532 | ||||
| (Adm vs Dis) | ||||||||||
| Ea | Admission | 3.52 ± 1.14 | 4.09 ± 1.39 | 0.009 | 3.51 ± 1.21 | 4.12 ± 1.36 | 0.012 | 3.57 ± 0.89 | 3.96 ± 1.50 | 0.406 |
| mmHg*m2/mL | Discharge | 3.40 ± 1.24 | 3.72 ± 1.52 | 0.095 | 3.35 ± 1.31 | 3.87 ± 1.53 | 0.022 | 3.58 ± 0.95 | 3.13 ± 1.33 | 0.226 |
| P value | 0.998 | 0.368 | 0.919 | 0.519 | 0.820 | 0.389 | ||||
| (Adm vs Dis) | ||||||||||
| Ed/Ea | Admission | 0.137 ± 0.064 | 0.154 ± 0.082 | 0.072 | 0.139 ± 0.068 | 0.157 ± 0.082 | 0.106 | 0.130 ± 0.048 | 0.143 ± 0.080 | 0.488 |
| /mmHg | Discharge | 0.136 ± 0.052 | 0.170 ± 0.079 | <0.001 | 0.143 ± 0.053 | 0.171 ± 0.071 | 0.003 | 0.112 ± 0.038 | 0.167 ± 0.113 | 0.036 |
| P value | 0.994 | 0.048 | 0.917 | 0.073 | 0.721 | 0.422 | ||||
| (Adm vs Dis) | ||||||||||
Data are mean ± SD.
Abbreviations: Adm, admission; Dis; discharge; Ea, effective arterial elastance; Ed, operant left ventricular diastolic elastance; HFpEF, heart failure with preserved ejection fraction; SVI, stroke volume index.
When we evaluated the correlation between E/e’‐related indices and cardiac structure (LAVI and LVEDVI), E/e’ and Ed/Ea, but not Ed, were positively correlated with log (LAVI) only in women (Figure 2A). However, Ed, but not E/e’ nor Ed/Ea, was negatively correlated with log (LVEDVI) in both sexes (Figure 2B).
Figure 2.
The sex‐linked difference in the correlation between E/e’‐related indices regarding left ventricular diastolic function and cardiac structure such as left atrial volume index (LAVI) or left ventricular end‐diastolic volume index (LVEDVI) as their logarithmic values before discharge. Blue symbol represents men and red symbol represents women. E/e’ and Ed/Ea were weakly correlated with log (LAVI) only in women (A) and Ed was significantly and negatively correlated with log (LVEDVI) in both sexes (B). ‘W’ represents the regression line in women
Medications such as beta‐blockers, calcium‐channel blockers, diuretics, renin‐angiotensin‐aldosterone system inhibitors, and statins did not differ significantly at admission or before discharge between sexes in each age group (data not shown). No inter‐sex differences were observed in NT‐proBNP level (men, 2723 ± 9386 pg/mL; women, 2320 ± 3589 pg/mL; P = 0.652) or estimated glomerular filtration rate (men, 46.1 ± 25.8 mL/min/1.73 m2; women, 40.7 ± 19.2 mL/min/1.73 m2; P = 0.055) before discharge.
4. DISCUSSION
Significant inter‐sex differences in the E/e’‐related three indices of LV diastolic function were observed before discharge. These observations were mainly in patients ≥75 years. Furthermore, sex‐linked differences in LV diastolic function was coincident with the differences in LA volume and LV volume before discharge. A difference in arterial elastance, Ea, was also observed between sexes during admission, mainly in patients ≥75 years.
4.1. Sex‐related differences in LV diastolic function and arterial elastance
At admission in our patients with HFpEF, Ed and Ea were significantly higher in women than in men. The augmentation of arterial elastance may have a role in heart failure in patients with HFpEF, especially women, a finding that is in accordance with those of the previous report.2, 15, 16 When LV diastolic function was evaluated by afterload‐related diastolic elastance, Ed/Ea, impaired LV diastolic function was equivalently observed in both sexes at admission. During admission, Ea decreased possibly because of medication‐induced pathophysiological stable state but Ea was still significantly higher in women than in men of elderly patients before discharge. Even under these conditions, an inter‐sex difference was observed in Ed/Ea before discharge, especially in elderly patients. Ed/Ea could represent an index for LV diastolic function as a physiologically specific value in each individual because of no correlation with LVEDVI. In this sense, Ed/Ea may be a suitable and sensitive index for the pathophysiological ascertainment of HFpEF among the indices of LV diastolic function. It is essential to clarify whether the inter‐sex difference in Ed/Ea before discharge relates to the future incidence of readmission for congestive heart failure and/or mortality in patients with HFpEF.
4.2. Related factors for the changes in LV diastolic function
The sex‐linked difference in LV diastolic function was coincident with the inter‐sex differences in LA volume before discharge. This issue is in accordance with the results of our previous study showing that Ed/Ea is significantly higher in elderly hypertensive women than in men and is coincident with the alteration of cardiac dimensions such as LAVI.6, 7 Impaired LV diastolic function evaluated by Ed or Ed/Ea was less severe in men than in women, and the enlargement of LV may preserve stroke volume during admission with no alteration of arterial elastance. In contrast, LV diastolic function evaluated by Ed or Ed/Ea was more impaired in women than in men, and greater arterial stiffness occurred without LV enlargement at the onset of heart failure, leading to the reduced stroke volume in women. LV diastolic function was persistently impaired during admission, represented by the increase in Ed/Ea in HFpEF women. Furthermore, inefficient cardiac function represented by a larger LA volume relative to the smaller LV volume still existed even before discharge in elderly women, showing the persistence of an ill‐matched left atrioventricular correlation. Since these findings were observed in elderly HFpEF women, the mechanism by which congestive heart failure occurs in patients with preserved LVEF may differ by age and sex. Mechanistic basis for the sex‐related difference in LV diastolic function is reported to be related to sex‐hormone17 or nitric oxide.18 The cardiac remodeling process may occur much earlier in men than in women, but the process may rapidly occur in elderly women in relation to LV collagen deposition.19
4.3. Clinical implication
Since E/e’ was not significantly reduced during admission, the changes in E/e’ by medications may be slow, or E/e’ may not show LA filling pressure directly during the acute phase of congestive heart failure. E/e’‐related indices would exhibit a certain aspect of LV diastolic function per se. Larger LA volume, relatively smaller LV volume, and higher Ed/Ea associated with a higher Ea found in elderly women may represent the pathophysiological characteristics in patients with HFpEF, possibly leading to heart failure recurrence after discharge. To resolve this possibility, our large‐scale prospective study (PURSUIT HFpEF study) is being considered to clarify the differences in clinical outcomes such as the incidence of readmission due to heart failure between sexes in patients with HFpEF with various extents of diastolic function, which can be evaluated by several indices of diastolic function including Ed/Ea.
4.4. Limitations
We evaluated LV diastolic stiffness by evaluating Ed as E/e’/SVI.3 However, Ed was calculated as E/e’/LVEDV in another report.9 Since SVI and LVEDVI were similarly and significantly smaller in women than in men in our study, these equations for Ed measurement will yield similar results. The mean age of our study participants (80 years) was markedly higher than the age in other HFpEF studies such as the PARAMOUNT trial (71 years) 9, 20 and the CHART‐2 study (70.5 yeas).21 Since the number of patients <75 years was relatively small in this study, age‐related differences in the incidence of coronary artery disease, LV diastolic function, arterial elastance, and cardiac structure should be interpreted with caution, although the subjects of our study consisted of a real‐world population in Japan.
5. CONCLUSION
Higher afterload‐related left ventricular diastolic elastance, Ed/Ea, in association with higher arterial elastance, Ea, accompanied by left atrioventricular volume mismatch was observed in elderly HFpEF women.
CONFLICTS OF INTEREST
The authors declare no potential conflict of interests.
Supporting information
Appendix S1. Investigators’ list.
Hoshida S, Watanabe T, Shinoda Y, et al. Sex‐related differences in left ventricular diastolic function and arterial elastance during admission in patients with heart failure with preserved ejection fraction: The PURSUIT HFpEF study. Clin Cardiol. 2018;41:1529–1536. 10.1002/clc.23073
Contributor Information
Shiro Hoshida, Email: shiro.hoshida@hosp-yao.osaka.jp.
on behalf of PURSUIT HFpEF Investigators:
Shunsuke Tamaki, Masatake Fukunami, Takahisa Yamada, Takaharu Hayashi, Yasuharu Takeda, Yoshiharu Higuchi, Masaharu Masuda, Mitsutoshi Asai, Toshiaki Mano, Hisakazu Fuji, Yoshihiro Takeda, Yoshihiro Takeda, Yoshiyuki Nagai, Shizuya Yamashita, Yusuke Nakagawa, Shuichi Nozaki, Haruhiko Abe, Yasunori Ueda, Masaaki Uematsu, Yukihiro Koretsune, Kunihiko Nagai, Masamichi Yano, Masami Nishino, Jun Tanouchi, Takatsugu Segawa, Shinji Hasegawa, Syouhei Yoshima, Minoru Ichikawa, Yoshiyuki Kijima, Eisai Rin, Tetsuya Watanabe, Shiro Hoshida, Masahiro Izumi, Hiroyoshi Yamamoto, Hiroyasu Kato, Kazuhiro Nakatani, Hisatoyo Hiraoka, Keiji Hirooka, Mayu Nishio, Takahiro Yoshimura, Yuji Okuyama, Tatsuya Sasaki, Akihiro Tani, Yasushi Okumoto, Hideharu Akagi, Yasunaka Makino, Katsuomi Iwakura, Yuzuru Takano, Nagahiro Nishikawa, Takashi Kitao, Hideyuki Kanai, Wataru Shioyama, Mikio Mukai, Masashi Fujita, Koichiro Harada, Osamu Nakagawa, Ryo Araki, Takayuki Yamada, Yoshio Yasumura, Fusako Sera, Kei Nakamoto, Yasumasa Tsukamoto, Onishi Toshinari, Hidetaka Kioka, Tomohito Ohtani, Hiroya Mizuno, Takayuki Kojima, Tomoharu Dohi, Shinichiro Suna, Shungo Hikoso, Daisaku Nakatani, Toshihiro Takeda, Akito Nakagawa, Yasushi Matsumura, and Yasushi Sakata
REFERENCES
- 1. Jeong EM, Dudley SC. Diastolic dysfunction. Circ J. 2015;79:470‐477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003;107:714‐720. [DOI] [PubMed] [Google Scholar]
- 3. Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age‐ and gender‐related ventricular–vascular stiffening. A community‐based study. Circulation. 2005;112:2254‐2262. [DOI] [PubMed] [Google Scholar]
- 4. Frenneaux M, Williams L. Ventricular‐arterial and ventricular‐ventricular interactions and their relevance to diastolic filling. Prog Cardiovasc Dis. 2007;49:252‐262. [DOI] [PubMed] [Google Scholar]
- 5. Her AY, Kim JY, Choi EY, et al. Value of ventricular stiffness index and ventriculoarterial interaction in patients with nonischemic dilated cardiomyopathy. Circ J. 2009;73:1683‐1690. [DOI] [PubMed] [Google Scholar]
- 6. Hoshida S, Shinoda Y, Ikeoka K, Fukuoka H, Inui H, Watanabe T. Age‐ and sex‐related differences in diastolic function and cardiac dimensions in a hypertensive population. ESC Heart Fail. 2016;3:270‐277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Hoshida S, Shinoda Y, Ikeoka K, et al. Fluctuation of dynamic diastolic function relative to static cardiac structure ‐ new insights into the underlying mechanism of heart failure with preserved ejection fraction in elderly patients. Circ J. 2017;81:755‐758. [DOI] [PubMed] [Google Scholar]
- 8. Goto T, Ohte N, Fukuta H, Wakami K, Tani T, Kimura G. Relationship between effective arterial elastance, total vascular resistance, and augmentation index at the ascending aorta and left ventricular diastolic function in older women. Circ J. 2013;77:123‐129. [DOI] [PubMed] [Google Scholar]
- 9. Gori M, Lam CSP, Gupta DK, et al. Sex‐specific cardiovascular structure and function in heart failure with preserved ejection fraction. Eur J Heart Fail. 2014;16:535‐542. [DOI] [PubMed] [Google Scholar]
- 10. Lang RM, Bierig M, Devereux RB, et al. 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;18:1440‐1463. [DOI] [PubMed] [Google Scholar]
- 11. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10:165‐193. [DOI] [PubMed] [Google Scholar]
- 12. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Phys. 1983;245:H773‐H780. [DOI] [PubMed] [Google Scholar]
- 13. Kelly RP, Ting CT, Yang TM, et al. Effective arterial elastance as index of arterial vascular load in humans. Circulation. 1992;86:513‐521. [DOI] [PubMed] [Google Scholar]
- 14. Minamisaka T, Watanabe T, Shinoda Y, et al. Transient manifestation of left ventricular diastolic dysfunction following ablation in patients with paroxysmal atrial fibrillation. Clin Cardiol. 2018;41:978‐984. 10.1002/clc.22990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Chow B, Rabkin SW. The relationship between arterial stiffness and heart failure with preserved ejection fraction: a systematic meta‐analysis. Heart Fail Rev. 2015;20:291‐303. [DOI] [PubMed] [Google Scholar]
- 16. Kim HL, Lim WH, Seo JB, et al. Association between arterial and left ventricular diastolic function in relation to gender and age. Medicine. 2017;96:e5783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Shah RU, Klein L, Lloyd‐Jones DM. Heart failure in women: epidemiology, biology and treatment. Womens Health. 2009;5:517‐527. [DOI] [PubMed] [Google Scholar]
- 18. Paulus WJ. Beneficial effects of nitric oxide on cardiac diastolic function: the flip side of the coin. Heart Fail Rev. 2000;5:337‐344. [DOI] [PubMed] [Google Scholar]
- 19. Xu Y, Arenas IA, Armstrong SJ, Davidge ST. Estrogen modulation of left ventricular remodeling in the aged heart. Cardiovasc Res. 2003;57:388‐394. [DOI] [PubMed] [Google Scholar]
- 20. Solomon SD, Zile M, Pieske B, et al. Prospective comparison of ARNI with ARB on management of heart failUre with preserved ejectioN fracTion (PARAMOUNT) investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double‐blind randomised controlled trial. Lancet. 2012;380:1387‐1395. [DOI] [PubMed] [Google Scholar]
- 21. Ushigome R, Sakata Y, Nochioka K, et al. On behalf of the CHART‐2 investigators. Temporal trend in clinical characteristics, management and prognosis of patients with symptomatic heart failure in Japan. –report from the CHART studies. Circ J. 2015;79:2396‐2407. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1. Investigators’ list.