Heart failure (HF) with depressed left ventricular ejection fraction (LVEF) has long been the focus of research. With further investigation, it has been realized that nearly half of patients with symptoms of HF have a nearly normal LVEF. In 2007, a consensus statement by the Heart Failure and Echocardiography Associations of the European Society of Cardiology prefers to characterize patients presenting with HF without depressed LVEF as heart failure with normal left ventricular ejection fraction (HFNEF) rather than with diastolic heart failure (DHF). The prevalence of patients with HFNEF ranges from 40% to 71% (with a mean of 56%) and increases with age.1 However, no treatment has yet been shown to convincingly reduce morbidity and mortality in patients with HFNEF.2 Some studies show improved survival in patients with HFNEF, whereas others find similar survival rates regardless of the ejection fraction.3 Due to its high prevalence, poor prognosis and unstandardized treatment, this study aimed to investigate the clinical characteristics, treatment, and prognosis of HFNEF in elderly patients.
Inclusion criteria: Consecutive elderly patients (≥60 years old) hospitalized for the first episode of HF in Beijing Hospital from January 1, 2003 to December 31, 2009 were retrospectively recruited. All patients met the diagnostic criteria of the American College of Cardiology (ACC)/American Heart Association (AHA) 2009 guidelines for the diagnosis and management of heart failure in adults.4 Four hundred and twenty-nine potential candidates were identified for the study. Exclusion criteria: Patients were excluded if they had no documented echocardiography or if the echocardiography showed congenital heart disease or significant cardiac valvular disease. A total of 119 patients were excluded, 310 patients were eligible for this study.
Clinical data including age, gender, body mass index (BMI), blood pressure at admission, medical history, laboratory tests, electrocardiograph, chest X-ray, echocardiography on admission, medical treatment and outcomes were obtained. LVEF was determined during hospitalization by echocardiography using the biplane Simpson's method. A cut-off value of 50% was used to distinguish HFNEF (LVEF ≥50%) from heart failure with reduced left ventricular ejection fraction (HFREF, LVEF <50%) according to the consensus statement on the diagnosis of HFNEF by the Heart Failure and Echocardiography Associations of the European Society of Cardiology (ESC).5 Among the 310 patients recruited, 13 cases had died in our hospital during the first episode of heart failure. We followed the remaining 297 patients by telephone from discharge to March 20, 2010 for the first time period and from March 20, 2010 to December 10, 2010 for the second time period and recorded the outcome. If the patient was admitted to our hospital or died at our hospital, we reviewed related medical records. The main end points were total mortality and cardiac mortality.
Data were analyzed with the SPSS13.0 statistical package (SPSS Inc., USA). Continuous variables were expressed as mean ± standard deviation (SD) and compared using the Student's t test. Numeration variables were summarized by frequency percentages and analyzed with chi-square test. The Log Rank test Kaplan-Meier curves were used to illustrate the survival rate of patients. Multiple Logistic regression analysis was used to assess the risk factors for heart failure mortality. A P value <0.05 was considered statistically significant.
General patient clinical characteristics
A total of 310 patients (159 males and 151 females) aged (75.4±7.4) years were retrospectively recruited with 169 (54.5%) patients in the HFNEF group and 141 (45.5%) patients in the HFREF group. The percentage of NYHA class III to IV patients was comparable with 92.4% in the HFNEF group and 93.9% in the HFREF group respectively.
General clinical characteristic of elderly patients with HFNEF and with HFREF are displayed in Table 1. Compared with HFREF, the group of elderly patients with HFNEF had a higher proportion of females (62.1% vs. 32.6%, P<0.001), higher BMI ((24.9±4.7) vs. (23.5±4.0) kg/m2, P=0.011), higher systolic blood pressure at admission ((141.5±22.6) vs. (134.3±18.6) mmHg, P=0.002), but lower hemoglobin levels ((118.3±22.7) vs. (125.8±23.8) g/L, P=0.005). The incidence of coronary heart disease and myocardial infarction was significantly lower in elderly patients with HFNEF than in those with HFREF (P <0.001).
Echocardiography results of elderly patients with HFNEF and HFREF are showed in Table 2. Left ventricular end-diastolic dimension (LVEDd) in the HFNEF group was significantly smaller than in the HFREF group ((45.6±5.5) vs. (56.8±9.4) mm, P <0.001). The elderly patients with HFNEF also had a lower proportion of segmental wall motion abnormality compared with the HFREF group (11.3% vs. 51.8%, P < 0.001).
Medical therapy of elderly patients with HFNEF and HFREF at discharge is displayed in Table 3. Angiotensin converting enzyme inhibitors (ACEI), beta blockers, loop diuretics, and digoxin were prescribed less frequently in elderly patients with HFNEF. The HFNEF group had a higher calcium-channel blocker prescription rate.
With a mean follow-up of 33.5 (0.5-93) months, 120 patients (38.7%) died, including 94 (30.3%) cardiac deaths. The HFNEF group had fewer deaths than the HFREF group (at the end of the first follow-up, 46/169 (27.2%) vs. 58/141 (41.1%); at the end of the second follow-up, 56/169 (33.1%) vs. 64/141 (45.4%)). Kaplan-Meier survival analysis showed a significantly higher survival rate in elderly patients with HFNEF than in those with HFREF (P=0.021 for total mortality and P <0.001 for cardiac mortality) (Figures 1 and 2).
Multiple Logistic regression analysis of risk factors for total mortality
The relationship between total mortality and cardiovascular risk factors in all recruited elderly patients was analyzed using conditional Logistic regression (Table 4). The results showed that mortality in elderly HF patients with LVEF <50% was 3.668 times that of those with LVEF ≥50%. Therefore, LVEF <50% was an independent risk factor for total mortality in elderly patients with HF.
HF has been classified as DHF or systolic heart failure (SHF). Although the former presumably accounts for approximately one-third of all patients with HF, its natural history was previously considered to be more benign than SHF with a lower morbidity and mortality rate.6 After years of focus on SHF, there has been a growing interest in DHF due to its increasing prevalence. In 2007, the Heart Failure and Echocardiography Associations of ESC began using the term “heart failure with normal ejection fraction” rather than “diastolic heart failure”.5
A cross-sectional echocardiographic study1 reported the proportion of patients with HFNEF as 40% to 71%, with a mean of 56%. In a 5-year prospective population-based study the proportion of HFNEF among HF patients was 55.6%.7 In our study, the proportion of HFNEF among elderly HF patients was 53.6%. In accordance with figures reported in previous studies,1,7 elderly patients with HFNEF included a high percentage of women, a lower incidence of coronary heart disease, myocardial infarction or dilated cardiomyopathy, and lower hemoglobin concentrations as compared to those with HFREF. Even in the absence of overt anemia, decreased hemoglobin concentrations may contribute to LA enlargement in patients with normal LV systolic function irrespective of gender.8,9
It is clear that HFNEF and HFREF are caused by different pathophysiological mechanisms. HFNEF generally exhibits concentric hypertrophy, normal or reduced LV volume, concentric remodeling, and abnormal diastolic function leading to pulmonary congestion without cardiomegaly as seen on chest X-ray.10 However, our study showed a high proportion of elderly patients in both the HFNEF and HFREF groups with cardiomegaly on chest X-ray; 48.1% and 50.7% respectively. There was no significant difference between the two groups. This could possibly be due to supine positoning with portable chest X-rays.
The morphologic features and function of the left ventricle (LV) in HFNEF were analyzed and summarized.10 In contrast to HFREF, patients in our study with HFNEF more often had concentric LV hypertrophy, normal left ventricular end-diastolic volume, normal LVEF and a dilated left atrium. A higher LV mass index is due to increased LV stiffness and elevation of LV filling pressure, which induce left atrial (LA) enlargement.11 During diastole, the left atrium is directly exposed to pressures in the left ventricle that increase with decreasing LV compliance. LA pressure increases to maintain adequate filling, and the increased atrial wall tension leads to LA dilatation.12 LA volume likely reflects the long-term exposure of the left atrium to abnormal LV diastolic function and increased filling pressures.13 In addition, we found that the proportion of segmental wall motion abnormalities in elderly patients with HFNEF was significantly lower than HFREF. This is consistent with the relatively low incidence of myocardial infarction in the HFNEF group.
Transmitral flow pulsed-wave Doppler echocardiography is the most conventional method to evaluate LV diastolic function. With the opening of the mitral valve (MV), there is early diastolic filling (E wave) followed by deceleration of flow as left ventricular pressure rises to meet left atrial pressure. There is then another peak (A wave) with the left atrial contraction during late diastole if the patient is in sinus rhythm.14 The grading of LV diastolic dysfunction is defined using the ratio of E/A: normal has an E/A >1, an abnormal relaxation pattern has an E/A <1, a pseudonormal pattern an E/A >1, a restrictive pattern an E/A >>1.15 Our data demonstrated that the mitral E/A ratio in the HFREF group was significantly higher than in the HFNEF group; 1.3±0.8 and 1.0±0.6, respectively (P=0.002). The major challenge was to distinguish a normal from pseudonormal pattern given that further measurements using pulmonary venous flow velocities or tissue Doppler mitral annular velocities were not available in our study. However, Bursiet et al16 showed that among 248 HF patients with reduced EF, diastolic dysfunction was mild in 10 (4%), moderate in 138 (56%), and severe in 56 (23%). Diastolic function was normal in 13 patients (5%) and indeterminate in 31 patients (13%). Moderate or severe diastolic dysfunction was more common in patients with reduced EF than patients with preserved EF, LVEF ≥50% (odds ratio, 1.67; 95% CI 1.11-2.51 and P=0.01). So we think the higher E/A ratio in the HFREF group represented as pseudonormal pattern of LV diastolic dysfunction.
No treatment has yet been shown to convincingly reduce morbidity and mortality in patients with HFNEF.10 Evidence regarding outcomes with ARBs (CHARM-Preserved Trial17 and I-PRESERVE Trial18) is equivocal. The management of patients with HFNEF is based on the control of physiological factors that are known to exert important effects on ventricular relaxation.4 In our study, compared with the elderly patients with HFREF, ACEI, ARB, beta blockers, loop diuretics, aldosterone receptor antagonists and digoxin were prescribed significantly less frequently than in the HFNEF group. Because no proven therapy for HFNEF currently exists, there is a need for coordinated efforts to address this growing problem.
The prognosis of patients with HFNEF has long been unclear with considerably varied mortality reported in previous studies. Some studies report that mortality rates in patients with HFNEF is comparable to or slightly lower than in patients with HFREF.7,19 In contrast, a prospective observational cohort study in Japan20 reported that the prognosis of patients with HFNEF was better than in patients with HFREF. These apparent discrepancies probably result from different enrollment criteria. In our study, Kaplan-Meier survival analysis showed that the survival rate among the elderly patients with HFNEF was slightly higher than those with HFREF, although the prognosis remains poor. In addition, multiple Logistic regression analysis indicated that LVEF <50% was an independent predictor of mortality in the elderly patients with HF.
Our study was based on a single-center experience and restriction to hospitalized patients may have introduced bias. Therefore, the results may be difficult to generalize to all HF patients. Our baseline study data were collected retrospectively and the follow up was done by telephone call, both of which are subject to the limitations inherent in retrospective studies. Diagnosis of HFNEF is based on the LVEF, with a cutoff of 45%-50% in the literature. There is no consensus in the published data as to the most appropriate definition of a normal EF. In accordance with recent recommendations, we defined depressed ejection fraction as less than 50%.5,7,19 Echocardiography was not systematically performed during the first hours after the patient's admission. Additionally, the assessment of LVEF was not standardized, and therefore, variation among different operators and different techniques could cause misclassification of the patients. Assessment of LV diastolic function requires a meticulous and systematic approach. Mitral inflow interrogation is the cornerstone of initial physiologic evaluation of LV diastolic function.21 We need further measurements using pulmonary venous flow velocities or tissue Doppler mitral annular velocities to characterize the stage of LV diastolic abnormality.
More than half of elderly patients with HF have preserved LVEF. The prognosis of the elderly patients with HFNEF is poor, though slightly better than patients with HFREF. No proven therapy for HFNEF currently exists, and there is a need for coordinated efforts to address this growing problem.
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