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Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry
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Original article
Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry Masaki Izumo (MD)a,*, Masaaki Takeuchi (MD, FJCC)b, Yoshihiro Seo (MD, FJCC)c, Eiji Yamashita (MD)d, Kengo Suzuki (MD, FJCC)a, Tomoko Ishizu (MD, FJCC)c, Kimi Sato (MD)c, Shigeru Oshima (MD, FJCC)d, Kazutaka Aonuma (MD, FJCC)c, Yutaka Otsuji (MD, FJCC)e, Yoshihiro J. Akashi (MD, FJCC)a a
Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan Department of Laboratory and Transfusion Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan d Division of Cardiology, Gunma Prefectural Cardiovascular Center, Gunma, Japan e Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 September 2015 Received in revised form 11 January 2016 Accepted 23 January 2016 Available online xxx
Background: Current prognostic implication of symptomatic patients with aortic stenosis (AS) remains undetermined. This study investigated the current prognostic implications of AS-related symptoms and the effect of aortic valve replacement (AVR) on outcome. Methods: We enrolled 586 consecutive patients with severe AS (aortic valve area <1.0 cm2) with preserved left ventricular ejection fraction (50%). All patients were stratified into the following four groups based on the predominant symptoms: Group 1, asymptomatic (n = 316); Group 2, chest pain (n = 41); Group 3, heart failure (n = 192); or Group 4, syncope (n = 37). Results: AS-related symptoms were diagnosed in 270 patients (46.1%), among whom 182 patients (32.2%) received AVR. Thirty-nine patients (6.7%) had cardiac death during the mean follow-up of 16 14 months. AVR was associated with significant reduction in cardiac death in Groups 3 (p < 0.001) and 4 (p = 0.004) whereas no significant prognostic advantage of AVR was observed in Groups 1 or 2. Cox proportional-hazard multivariate analysis revealed that age, heart failure, and mean pressure gradient (PG) were associated with increased risk of cardiac death in all patients regardless of AVR [hazard ratio (HR): 1.079, 2.090, and 1.008 respectively, all p < 0.05]. In the patients without AVR, age, heart failure, syncope, and mean PG were independently associated with cardiac death (HR: 1.130, 3.639, 4.638, and 1.008, all p < 0.05). Conclusion: This retrospective study demonstrated the current associations between the types of AS symptoms and prognosis in Japanese patients with severe AS. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Aortic valve stenosis Prognosis Echocardiography
Introduction Senile degenerative aortic stenosis (AS) is the most common form of valvular heart disease in developed countries, and its prevalence is rapidly increasing along with the aging population [1]. There is general agreement among physicians and surgeons
* Corresponding author at: Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City 216-8511, Japan. Tel.: +81 44 977 8111x3313; fax: +81 44 976 7093. E-mail address: [email protected] (M. Izumo).
that aortic valve replacement (AVR) should be performed in patients with symptomatic severe AS because of the wellestablished unfavorable outcomes in unoperated cases and overall excellent surgical outcomes with relatively low perioperative mortality and morbidity [2–8]. Despite the lack of data from randomized clinical trials, various professional organizations consider symptomatic severe AS as a class I indication for aortic valve surgery [9,10]. Nowadays, the predominant cause of AS has changed from rheumatic valve disease to degenerative disease [11]; the number of aging patients has been increasing over the past few decades in developed countries [12]. The current associations between the types of symptoms and prognosis in
http://dx.doi.org/10.1016/j.jjcc.2016.01.015 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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severe degenerative AS patients treated with and without AVR are not readily available in Japan. Therefore, this multicenter study investigated the impact of symptomatic status on future prognosis in severe AS patients with preserved left ventricular ejection fraction (LVEF) treated with AVR and those treated with conservative medical therapy. Methods Study population This retrospective study included 663 patients with aortic valve area (AVA) <1.0 cm2 treated at one of the four Japanese tertiary cardiovascular centers between 2008 and 2012, St Marianna University (n = 100), University of Occupational and Environmental Health (n = 254), University of Tsukuba (n = 122), and Gunma Prefectural Cardiovascular Center (n = 187). Patients with additional hemodynamically significant (moderate and severe) valve lesions were excluded from the study. The study protocol was approved by the ethics committee in each hospital. Demographic data collection Clinical data, including age, sex, body surface area, brachial blood pressure, heart rate, documented diagnoses of hypertension, dyslipidemia, diabetes mellitus, coronary artery disease, previous history of myocardial infarction, coronary artery bypass grafting, and hemodialysis due to chronic renal failure, were collected at the time of echocardiographic examination. Echocardiographic measurements and prognoses were compared across the groups. The medical records of all patients reported by the primary physicians in each hospital were carefully reviewed by cardiologists. All study patients were stratified into the following four groups based on predominant symptoms at baseline: Group 1, asymptomatic; Group 2, chest pain (Canadian Cardiovascular Society class I); Group 3, heart failure (New York Heart Association functional classification II); and Group 4, syncope. Patients with presyncope were also included in Group 4, and patients with chest heaviness and chest discomfort were included in Group 2. When the patients had multiple symptoms, primary physicians or experienced cardiologists who reviewed the medical records diagnosed their predominant symptoms. Follow-up information was obtained regularly at the outpatient clinics. Patients, physicians, and next of kin were contacted by telephone when patients had been treated in the other hospitals. Echocardiographic study Comprehensive transthoracic echocardiography, including Mmode, two-dimensional, and Doppler echocardiography, was performed using commercially available ultrasound equipment in each hospital according to the guidelines described by the American Society of Echocardiography [13]. An aortic valve jet velocity was recorded from multiple acoustic windows, such as apical, right parasternal, and suprasternal windows, to yield the highest-velocity signal [9]. The LV end-diastolic and end-systolic volumes, stroke volume (SV), and LVEF were measured according to the biplane Simpson’s method in the apical 4- and 2-chamber views. Relative wall thickness was estimated as 2 (diastolic LV posterior wall thickness)/LV end-diastolic diameter [13]. LV mass was calculated using Devereux’s formula [14]. The maximum left atrial volume was measured using the biplane Simpson’s method and indexed to body surface area [13]. Peak early and late diastolic velocities of the left ventricular inflow (E and A velocities), deceleration time of E velocity, and peak early diastolic velocity at the septal corner of the mitral annulus (e0 ) were measured in the
apical 4-chamber view. As a measure of global LV afterload, the valvulo-arterial impedance was determined using the following formula: valvulo-arterial impedance = (systolic arterial pressure + mean pressure gradient)/SV index. Systemic arterial compliance was calculated using the following formula: systemic arterial compliance = stroke volume index/brachial pulse pressure [15]. Using the aortic cross-sectional area at the sinotubular junction, energy loss coefficient was determined as AVA aortic cross-sectional area at the sinotubular junction/(aortic crosssectional area at the sinotubular junction AVA) [15]. AVA was calculated using the continuity equation [9,10]. SV was determined by two-dimensional echocardiography, and AVA was calculated as AVA = SV (two-dimensional biplane Simpson’s method)/velocity time integral of peak aortic valve velocities [9,10]. AVA was indexed to body surface (indexed AVA). Study endpoint The primary study endpoint was cardiac death regardless of aortic valve surgery. The secondary endpoint was major cardiocerebrovascular events defined as AVR plus cardio-cerebrovascular events, including cardiac death, nonfatal myocardial infarction, hospitalization for heart failure, stroke and ventricular tachyarrhythmia. Statistical analysis Results are expressed as mean standard deviation or percentage unless otherwise specified. Data were compared among the four subgroups using one-way analysis of variance with post hoc Turkey’s test. Probabilities of event-free survival among the four subgroups were obtained using Kaplan–Meier analysis and compared using the two-sided log-rank test. The impact of group classification on eventfree survival was assessed using the Cox proportional-hazard model in univariate and multivariate analyses. Variables with a univariate value of p < 0.05 were incorporated into the multivariate models. Because of collinearity, the variables included in the multivariate models were selected with special care. The group classification was entered into the model; Group 1 was considered as a reference. Values of p < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS 18.0 (SPSS, Inc, Chicago, IL, USA). Results Patients’ characteristics Among the 663 study patients, 77 patients were excluded from the analysis due to LVEF < 50% (n = 55), unknown symptoms (n = 6), and follow-up data unavailable (n = 16). Thus, the final group consisted of 586 patients (mean age, 76 9 years, 211 men) with severe AS and LVEF 50% were included. According to their predominant symptoms at baseline, all patients were stratified into asymptomatic (Group 1, n = 316); chest pain (Group 2, n = 41); heart failure (New York Heart Association functional class II, Group 3, n = 192), and syncope (Group 4, n = 37; Fig. 1). Clinical characteristics of the total population are shown in Table 1. Most of the patients were female, with a higher prevalence of hypertension. No differences in the demographic findings except systolic and diastolic blood pressure or the use of b-blockers and diuretics were observed across the four subgroups (Table 1). The baseline echocardiographic findings of the four groups are shown in Table 2. Asymptomatic group (Group 1) demonstrated greater AVA, indexed AVA, and energy loss coefficient and lower peak velocity and mean pressure gradient (PG) compared to the other three symptomatic groups. No significant differences in the LV end-diastolic volume, end-diastolic volume index, SV, or SV index were observed among the four groups, whereas the group of
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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patients with chest pain (Group 2) demonstrated significantly lower LV end-systolic volume and end-systolic volume index and greater LVEF than the other three groups. Clinical outcomes
Fig. 1. Study flowchart. AVA, aortic valve area; AVR, aortic valve replacement.
During a mean follow-up of 16 14 months (median, 12 months; range, 1–59 months), 39 patients reached their primary end point (cardiac death); 258 patients developed major cardio-cerebrovascular events including cardiac death (n = 39), development or exacerbation of heart failure required for admission (n = 33), cerebral infarction (n = 3), ventricular fibrillation (n = 1), and AVR (n = 182); of the AVR patients, 31 patients underwent combined coronary artery bypass grafting. No differences were noted regarding the ratio of AVR
Table 1 Baseline characteristics.
Age (years) Female (%) Body surface area (m2) Body mass index (kg/m2) SBP (mmHg) DBP (mmHg) Heart rate (beats/min) Hypertension (%) Diabetes (%) Dyslipidemia (%) History of smoking (%) Coronary artery disease (%) Prior MI or CABG (%) Chronic kidney disease (%) Hemodialysis (%) History of AF (%) Cerebrovascular event (%) Hemoglobin (mg/l) BNP (pg/ml) Medications ACEI/ARB b-Blockers Diuretics
Overall (N = 586)
Asymptomatic (N = 316)
Chest pain (N = 41)
Heart failure (N = 192)
Syncope (N = 37)
76 9 64 1.48 0.20 22.6 3.5 139 24 73 14 71 15 75 29 44 30 25 7 47 9.2 14 14 12 5 187 (67–383)
76 10 62 1.48 0.19 22.3 3.5 143 24 74 13 72 15 74 29 41 29 24 7 46 10 12 15 12 6 115 (46–273)
74 9 63 1.53 0.16 23.0 3.2 133 16 69 11 69 13 73 41 63 26 34 8 37 7 15 8 12 2 177 (40–463)
77 8 68 1.47 0.22 22.8 3.8 136 23 71 16 71 16 75 28 43 26 22 7 52 8 15 13 12 2 243 (80–464)
77 7 62 1.49 0.18 22.7 3.1 138 25 73 12 72 18 73 24 49 32 35 3 38 8 16 24 12 2 124 (41–527)
53 21 31
50 17 23
59 34 24
56 25 50
46 16 39
p-Value 0.291 0.616 0.632 0.054 0.004 0.010 0.554 0.980 0.301 0.058 0.824 0.665 0.772 0.193 0.905 0.798 0.239 0.889 0.021 0.466 0.029 <0.001
Values are n (%) or mean SD. SBP, systolic blood pressure; DBP, diastolic blood pressure; MI, myocardial infarction; CABG, coronary artery bypass grafting; AF, atrial fibrillation; BNP, brain natriuretic peptide; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Table 2 Echocardiographic findings.
LV end-diastolic volume (ml) LV end-diastolic volume index (ml/m2) LV end-systolic volume (ml) LV end-systolic volume index (ml/m2) LV ejection fraction (%) Stroke volume (ml) Stroke volume index (ml/m2) LA volume index (ml/m2) E/A E/e0 LV mass index (g/m2) Relative wall thickness (%) Peak aortic jet velocity (m/s) Mean pressure gradient (mmHg) AVA (cm2) Indexed AVA (cm2/m2) Energy loss coefficient (cm2/m2) Valvulo-arterial impedance (mmHg/ml/m2) Systemic arterial compliance (ml/m2/mmHg)
Overall (N = 586)
Asymptomatic (N = 316)
Chest pain (N = 41)
Heart failure (N = 192)
Syncope (N = 37)
p-Value
80 28 54 18 29 14 20 9 65 9 51 17 34 11 46 20 0.78 0.74 20 10 123 65 0.55 0.33 3.9 0.9 38 24 0.62 0.26 0.43 0.27 0.63 0.40 5.4 2.3 0.55 0.24
81 28 55 17 31 14 21 9 63 8 51 17 34 10 45 17 0.75 0.29 19 9 116 36 0.55 0.41 3.6 0.9 34 26 0.67 0.26 0.45 0.15 0.74 0.41 5.4 2.3 0.53 0.23
76 29 49 17 24 13 16 8 69 8 51 18 33 10 41 22 0.74 0.21 19 10 117 37 0.54 0.13 4.2 0.7 43 15 0.55 0.27 0.36 0.15 0.50 0.27 5.8 2.1 0.54 0.19
79 28 53 19 27 14 19 9 66 8 51 19 35 13 49 23 0.87 1.2 21 11 135 41 0.56 0.23 4.1 0.9 43 21 0.58 0.27 0.42 0.42 0.48 0.34 5.3 2.4 0.58 0.26
79 23 54 17 30 12 30 12 63 9.0 49 15 34 11 45 17 0.76 0.39 20 8.0 122 30 0.57 0.15 4.4 1.1 50 26 0.53 0.24 0.36 0.17 0.50 0.37 6.0 2.1 0.56 0.23
0.594 0.232 0.008 0.002 <0.001 0.966 0.924 0.059 0.582 0.373 0.419 0.969 <0.001 <0.001 <0.001 0.045 <0.001 0.228 0.328
Values are mean SD. LV, left ventricle; LA, left atrium; AVA, aortic valve area.
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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including combined coronary artery bypass grafting between the four groups (17.6% vs. 35.0% vs. 22.4% vs. 18.2%, respectively, p = 0.167). The 1- and 3-year survival rates for cardiac death were 98 1% and 88 2% in Group 1, 95 1% and 89 2% in Group 2, 98 2% and 66 4% in Group 3, and 96 2% and 65 4% in Group 4 (log rank p = 0.020, Fig. 2A). The event-free survival rates for major cardiocerebrovascular events at 1- and 3-year follow-up were 92 1% and 70 3% in Group 1, 82 3% and 58 3% in Group 2, 64 2% and 22 4%, in Group 3, and 48 1% and 19 2% in Group 4 (log rank p = 0.001, Fig. 2B), respectively. Predictors of cardiac death The Cox-hazard multivariate analysis revealed that older age (p = 0.005), body surface area (p = 0.015), chronic kidney disease (p = 0.034), heart failure (p = 0.025), and mean PG (p = 0.002) were associated with an increased risk of cardiac death in all patients (Table 3). When asymptomatic status was set as a reference, the hazard ratio of heart failure was 2.090 (95% confidence interval 1.099–3.977, p = 0.025). Moreover, in the patients without AVR,
older age (p = 0.002), heart failure (p = 0.001), syncope (p = 0.006), and mean PG (p < 0.001) were closely associated with an increased risk of cardiac death (Table 4). According to these results, not only symptomatic status but also age and the echocardiographic parameter were also important findings for predicting prognosis in patients with AS. Effect of AVR on prognosis Fig. 3 shows effect of symptomatic status on cardiac death-free survival according to patients who had received AVR and those without AVR. Among the patients with AVR, no significant differences in cardiac death-free survival among the four groups (Fig. 3A) were observed; however, the groups of patients who had heart failure or syncope (Groups 3 and 4) had lower survival rates than groups of patients who were asymptomatic or had chest pain (Groups 1 and 2) among the patients without AVR (log rank p = 0.001; Fig. 3B). AVR was associated with significantly better survival in Groups 3 and 4, whereas there was no benefit of AVR on future survival in Groups 1 and 2 (Fig. 4). In both asymptomatic and
Fig. 2. Kaplan–Meier analysis of major cardio-cerebrovascular events and cardiac death-free survival in all patients. Cardiac death-free (A) and major cardio-cerebrovascular events-free (B) survival rates in all groups.
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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Table 3 Univariate and multivariate analyses of cardiac mortality in all patients. Univariate analysis
Age (years) Male Body surface area (m2) Chronic kidney disease Cerebrovascular event Anemia LV end-diastolic volume (ml) LV end-systolic volume (ml) LV ejection fraction (%) Mean pressure gradient (mmHg) Indexed AVA (cm2/m2) Energy loss coefficient (cm2/m2) Asymptomatic Chest pain Heart failure Syncope
Multivariate analysis
HR
95% CI
p-Value
HR
95% CI
p-Value
1.056 1.385 0.281 2.785 0.891 0.580 1.003 1.001 1.009 1.009 1.169 0.407 Referent 2.351 2.445 2.17
1.007–1.108 0.701–2.737 0.061–1.289 1.427–5.435 0.263–3.016 0.580 0.993–1.014 0.979–1.023 0.972–1.044 1.003–1.014 0.480–2.842 0.133–1.246
0.007 0.349 0.015 0.003 0.891 0.112 0.555 0.944 0.679 0.001 0.731 0.115
1.079
1.024–1.138
0.005
0.160 2.133
0.037–0.703 1.061–4.290
0.015 0.034
1.008
1.002–1.013
0.005
1.053–5.251 1.24–4.821 0.702–6.713
0.041 0.003 0.291
2.090
1.099–3.977
0.198 0.025 0.097
HR, hazard ratio; CI, confidence interval; LV, left ventricle; AVA, aortic valve area.
Table 4 Univariate and multivariate analyses of cardiac mortality in patients without aortic valve replacement. Univariate analysis HR Age (years) Male Body surface area (m2) SBP (mmHg) Chronic kidney disease Cerebrovascular event Anemia LV end-diastolic volume (ml) LV end-systolic volume (ml) LV ejection fraction (%) Indexed AVA (cm2/m2) Energy loss coefficient (cm2/m2) Mean pressure gradient (mmHg) Asymptomatic Chest pain Heart failure Syncope
1.072 1.356 0.692 0.988 2.534 0.909 1.648 1.007 1.010 0.991 1.126 0.323 1.009 Referent 2.475 5.232 9.072
95% CI 1.011–1.137 0.636–2.887 0.119–4.035 0.973–1.003 1.167–5.505 0.203–4.067 0.768–3.534 0.996–1.019 0.986–1.034 0.948–1.036 0.156–8.136 0.093–1.124 1.003–1.014 0.876–6.988 2.267–12.075 2.307–35.672
Multivariate analysis p-Value 0.021 0.430 0.682 0.128 0.019 0.901 0.200 0.225 0.409 0.686 0.907 0.176 0.001 0.087 <0.001 <0.001
HR
95% CI
p-Value
1.130
1.061–1.203
0.002
0.237
1.008
1.002–1.013
0.005
3.639 4.638
1.677–7.895 1.559–13.80
0.102 0.001 0.006
HR, hazard ratio; CI, confidence interval; SBP, systolic blood pressure; LV, left ventricle; AVA, aortic valve area.
symptomatic groups, the patients with AVR were younger and they had more severe AS than those without AVR (Tables 5 and 6). Furthermore, the patients without AVR revealed a higher prevalence of chronic kidney disease and tended to have lower BMI than those with AVR in the symptomatic group (Table 5). These results suggested that the reason why some symptomatic AS patients did not receive AVR should be their advanced age and the prevalence of comorbidity and frailty.
Discussion Although the accurate determination of symptomatic status is of paramount importance for the subsequent appropriate surgical treatment in patients with severe AS, it is often difficult in the current aged AS patients who have limited exercise capacity and comorbidities. The main findings of this study were that (1) age and heart failure were found to be significant predictors for cardiac death; (2) age, heart failure, and syncope were independently associated with cardiac death in AS patients who did not receive AVR; and (3) AVR was associated with significantly better survival
in the patients with heart failure and syncope, but not those with chest pain and without symptoms. Since unfavorable prognosis has been reported in patients with symptomatic AS, AVR is universally performed in those patients as a class I indication [9,10]. Average survival after the symptom onset was reported as 2 years in patients with heart failure, 3 years with syncope, and 5 years with angina in patients with AS in the established review [2]. However, the earlier studies cited in the widely accepted guidelines were conducted on a highly selected group of patients because of their study designs, such as small study population and single-center experience [2–4,6]. In previous studies, rheumatic valve disease and congenital diseases were the predominant causes of AS, whereas degenerative calcified valve has emerged as the main cause in recent 10 years. In addition, the mean age of symptom onset was 48 years in the earlier studies in contrast to 70s in the present and recent studies [16–18]. Although earlier studies demonstrated the prognostic significance of symptoms in patients with degenerative AS [6,8,14,19], they did not evaluate the associations between the types of symptoms and prognosis. Our study results are consistent with those of earlier reports; most AS patients suffered from heart failure, and the
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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Fig. 3. Kaplan–Meier analysis of cardiac death-free survival in patients with (A) and without (B) aortic valve replacement (AVR).
3-year survival rate was 66% in symptomatic AS. Accordingly, the results of earlier studies investigating the presence and absence of symptoms seemed to be influenced by heart failure. When comparing each symptom between our study and earlier studies [2–4], the cardiac death-free survival rates of heart failure and syncope were similar, while chest pain was the only symptom that differed. Livanainen et al. investigated the natural history of calcified AS of varying severity in elderly patients [5]. They reported that 8% of elderly participants demonstrated moderate or severe AS, and they had a four- to six-fold relative risk for death even after adjustment for age and sex. The authors also reported that history of cardiac symptoms at entry did not predict the fouryear outcome. In the recent retrospective study investigating the current mortality in medically treated patients with severe AS and preserved LVEF, 47% of those survived during the mean follow-up period of 25 months and the survivors revealed a high prevalence of angina [20]. They also reported that older age, a history of hypertension, and elevated pulmonary artery systolic pressure indicating elevated LV filling pressure secondary to impaired LV diastolic function were independent predictors of death in patients
with medically treated AS. In the present study, however, only older age, heart failure, syncope, and mean PG were closely associated with an increased risk of cardiac death. These differences were due to the patients’ background in each study. The average age in their study was 83 years, whereas that in the present study was 77 years (in the patients without AVR). The pulmonary vasculature may be affected by age-associated arterial remodeling, leading to pulmonary vascular stiffening and increasing pulmonary artery systolic pressure. In addition, E/A, one of the LV diastolic function parameters, was 1.0 in their study and 0.78 in the present study. Pulmonary artery systolic pressure also directly affected by downstream left heart filling pressure which may increase with age-related LV diastolic dysfunction. The rate of symptomatic patients without AVR was approximately 80% in their study and 34% in the present study. These comparisons suggested that their study included more patients who had comorbidity and did not receive AVR. LV systolic parameters, such as LV end-systolic volume and LVEF, were most preserved in the patients with chest pain compared to those in the other three groups in this study. LV systolic function also closely correlated
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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Fig. 4. Cardiac death-free survival in the four patient groups as a function of the type of treatment: medical vs. surgical. (A) Asymptomatic (Group 1), (B) chest pain (Group 2), (C) heart failure (Group 3), (D) syncope (Group 4). AVR, aortic valve replacement.
Table 5 Comparisons in clinical characteristics between patients with and without AVR in asymptomatic and symptomatic groups. Symptomatic
Asymptomatic
Age (years) Female (%) Body surface area (m2) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats/min) Hypertension (%) Diabetes (%) Dyslipidemia (%) History of smoking (%) Coronary artery disease (%) Prior MI or CABG (%) Chronic kidney disease (%) Hemodialysis (%) History of AF (%) Cerebrovascular event (%) Hemoglobin (mg/l) BNP (pg/ml) Medications ACEI/ARB b-Blockers Diuretics
AVR (N = 51)
No AVR (N = 265)
p-Value
AVR (N = 131)
No AVR (N = 139)
p-Value
71 7 59 1.51 0.18 22.5 3.7 138 20 72 11 70 15 69 22 43 36 31 8 47 14 11 15 13 2 158 (50–483)
77 10 63 1.47 0.19 22.2 3.4 144 25 75 14 72 15 75 30 41 27 23 7 39 9 18 14 12 6 115 (44–255)
<0.001 0.608 0.134 0.672 0.135 0.277 0.451 0.322 0.214 0.791 0.217 0.204 0.866 0.288 0.311 0.214 0.870 0.513 0.477
75 8 66 1.51 0.18 23.2 3.4 133 19 70 16 71 13 72 27 52 29 28 4 40 7 17 11 12 2 182 (44–439)
78 8 66 1.46 0.23 22.5 3.8 138 24 71 13 70 16 78 31 42 25 24 9 54 9 14 17 12 2 253 (102–471)
<0.001 0.998 0.051 0.096 0.063 0.676 0.794 0.234 0.560 0.108 0.457 0.382 0.104 0.016 0.469 0.461 0.201 0.300 0.071
39 24 29
53 16 22
0.075 0.209 0.271
50 22 36
59 28 42
0.157 0.263 0.271
Values are n (%) or mean SD. AVR, aortic valve replacement; MI, myocardial infarction; CABG, coronary artery bypass grafting; AF, atrial fibrillation; BNP, brain natriuretic peptide; ACEI, angiotensinconverting enzyme inhibitor; ARB, angiotensin II receptor blocker.
with the clinical outcome in AS patients irrespective of AV surgery [21–23]. These findings appear to support why the AS patients with chest pain had better prognosis in this study. AS-related symptoms are difficult to judge in some AS cases in clinical practice. The symptoms of heart failure and syncope can be
easily detected; however, chest pain is difficult to diagnose, particularly in elderly patients. Furthermore, comorbidities are frequent in the elderly and presumed to affect risk-benefit analyses because these influence life expectancy regardless of valvular disease as well as operative risk and late outcome after AVR. Chest
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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Table 6 Comparisons in echocardiographic findings between patients with and without AVR in asymptomatic and symptomatic groups. Symptomatic
Asymptomatic
LV end-diastolic volume (ml) LV end-diastolic volume index (ml/m2) LV end-systolic volume (ml) LV end-systolic volume index (ml/m2) LV ejection fraction (%) Stroke volume (ml) Stroke volume index (ml/m2) LA volume index (ml/m2) E/A E/e0 LV mass index (g/m2) Relative wall thickness Peak aortic jet velocity (m/s) Mean gradient (mmHg) AVA (cm2) Indexed AVA (cm2/m2) Energy loss coefficient (cm2/m2) Valvulo-arterial impedance (mmHg/ml/m2) Systemic arterial compliance (ml/m2/mmHg)
AVR (N = 51)
No AVR (N = 265)
p-Value
AVR (N = 131)
No AVR (N = 139)
p-Value
83 32 55 19 28 16 19 10 67 10 54 19 36 11 48 19 0.75 0.30 20 10 135 45 0.59 0.12 4.5 1.0 53 27 0.59 0.27 0.37 0.15 0.63 0.40 5.5 2.2 0.59 0.26
81 27 55 17 31 14 21 9 63 8 50 16 34 10 44 17 0.75 0.21 19 9 113 32 0.54 0.44 3.4 0.8 30 24 0.69 0.25 0.35 0.15 0.77 0.40 5.4 2.3 0.52 0.22
0.679 0.877 0.235 0.100 0.001 0.084 0.220 0.189 0.882 0.406 <0.001 0.519 <0.001 <0.001 0.001 <0.001 0.016 0.631 0.065
76 28 50 18 26 14 17 9 67 9 50 16 34 10 47 18 0.73 0.29 20 11 125 35 0.57 0.11 4.6 0.8 53 19 0.49 0.19 0.36 0.18 0.47 0.21 5.9 2.0 0.57 0.27
80 27 55 18 28 13 19 8 65 8 52 18 36 12 47 26 0.94 0.46 21 10 110 38 0.52 0.14 3.8 0.9 35 18 0.63 0.36 0.44 0.19 0.69 0.31 5.2 2.3 0.57 0.23
0.229 0.060 0.153 0.032 0.072 0.471 0.090 0.887 0.127 0.232 0.187 0.280 <0.001 <0.001 0.067 <0.001 <0.001 0.005 0.896
Values are mean SD. AVR, aortic valve replacement; LV, left ventricle; LA, left atrium; AVA, aortic valve area.
pain is also caused by not only AS but also coronary artery disease. Although no statistical significance was found, the present study demonstrated a trend toward a higher prevalence of combined AVR and coronary artery bypass grafting in patients with chest pain. The surgical mortality of AVR was 3–4%; however, that of combined AVR and coronary artery bypass grafting was 5–7% [24]. It has been reported that chest pain does not greatly influence prognosis in coronary artery disease [25,26]. Approximately 6 million patients present to the emergency department with chest pain each year; 60–90% of these individuals have no underlying cardiovascular disease [27]. The epidemiology of chest pain markedly differs between outpatients and emergency cases [27]. Cardiovascular disease is the most commonly reported cause of chest pain among outpatients, accounting for approximately 20% of those cases, whereas musculoskeletal conditions, gastrointestinal disease, and panic disorder are also frequently identified. The results of this study suggest that physicians should carefully observe AS symptoms in patients with chest pain. No patients with chest pain died within 1 year in the present study. The understanding of surgical risks and benefit, more detailed diagnosis, and the evaluation of disease severity should be indispensable for the treatment of AS in the current clinical framework. Clinical implications In clinical practice, the diagnosis of AS symptoms is difficult in some patients, particularly chest pain because it can occur in various diseases. The results of this study demonstrated that AVR contributed to better prognosis in patients with heart failure and syncope, but not chest pain. It is likely that more expensive treatments, such as newly developed transcatheter aortic valve replacement, will become an increasingly popular strategy for symptomatic patients with severe AS. To ensure the provision of appropriate and effective treatment, more careful examinations for chest pain are required, such as semi-quantification of the symptoms and stress testing if the symptoms are equivocal. The results of this study will hopefully serve as a warning against rapid decision making regarding the treatment regimen without a comprehensive history taking.
Study limitation Several limitations should be addressed in this study. First, retrospective analysis could produce selection bias, even though we performed a multicenter study. Second, the designation of symptomatic status might not be accurate due to the lack of standardization of history taking. However, the present study employed the designation of symptomatic status which was previously adopted in the earlier published retrospective studies [17,18]. The results of this study reflect the reality of daily clinical practice. Clavel et al. classified AS into three categories, i.e. no symptoms, mild symptoms (dyspnea, New York Heart Association functional class II; angina, Canadian Cardiovascular Society class I or II; and/or fatigue), or moderate-severe symptoms (dyspnea, New York Heart Association functional class III or IV; angina, Canadian Cardiovascular Society class III or IV; and/or syncope) and demonstrated that only moderate-severe symptoms affected the event-free survival [19]. In the clinical setting, it is often difficult to distinguish dyspnea from chest pain. Therefore, the quantitative assessment of symptom status would play a crucial role in daily clinical practice. Third, the mean follow-up term was 16 14 months; thus, longer follow-up, particularly in patients with chest pain, is required to validate our results. Fourth, there was no standardized indication of the assessment of coronary artery disease in the present study; particularly, silent myocardial ischemia in patients with diabetes mellitus was not completely ruled out. Fifth, we could not deny the possibility of the influence of b-blockers on their prognosis, whereas no significant differences in the prescription rate of b-blockers were found between the patients with chest pain who had subsequently received AVR and those without AVR (p = 0.423) in this study. The patients with chest pain revealed slightly but significantly higher rate of b-blocker prescription because of a tendency toward the higher complication rate of coronary artery disease. The use of b-blockers in AS patients with coronary artery disease is described by the American College of Cardiology/American Heart Association guidelines, although no definitive evidence has been presented [9]. Thus, the beneficial effect of b-blockers on prognosis in AS also remains unclear. Sixth, more patients without AVR were prescribed angiotensin-converting enzyme inhibitors (ACEIs) than those with AVR in the asymptomatic
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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group. We could not deny the possibility of the influence of ACEIs on their prognosis. Nadir et al. have suggested that ACEIs possibly improve prognosis in patients with AS [28]. However, the effect of ACEIs on prognosis in AS remains controversial [29]; thus, further studies are called for. Lastly, we did not analyze the effect of frailty and dementia in this study. Since aged-people are progressively increasing in Japan, the presence of frailty and dementia could influence their therapeutic strategy, and thus, affect their prognosis differently. Conclusions This study establishes the current associations between the type of symptoms and prognosis in patients with severe AS and preserved LVEF. Funding This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors. Disclosures The authors declare that there is no conflict of interest. References [1] Carabello BA, Paulus WJ. Aortic stenosis. Lancet 2009;373:956–66. [2] Ross Jr J, Braunwald E. Aortic stenosis. Circulation 1968;38:V61–7. [3] Schwarz F, Baumann P, Manthey J, Hoffmann M, Schuler G, Mehmel HC, Schmitz W, Ku¨bler W. The effect of aortic valve replacement on survival. Circulation 1982;66:1105–10. [4] Turina J, Hess O, Sepulcri F, Krayenbuehl HP. Spontaneous course of aortic valve disease. Eur Heart J 1987;8:471–83. [5] Livanainen AM, Lindroos M, Tilvis R, Heikkila J, Kupari M. Natural history of aortic valve stenosis of varying severity in the elderly. Am J Cardiol 1996;78:97–101. [6] Kelly TA, Rothbart RM, Cooper CM, Kaiser DL, Smucker ML, Gibson RS. Comparison of outcome of asymptomatic to symptomatic patients older than 20 years of age with valvular aortic stenosis. Am J Cardiol 1988;61:123–30. [7] Lund O, Flø C, Jensen FT, Emmertsen K, Nielsen TT, Rasmussen BS, Hansen OK, Pilegaard HK, Kristensen LH. Left ventricular systolic and diastolic function in aortic stenosis. Prognostic value after valve replacement and underlying mechanisms. Eur Heart J 1997;18:1977–87. [8] Roberts WC, Vowels TJ, Filardo G, Ko JM, Mathur RP, Shirani J. Natural history of unoperated aortic stenosis during a 50-year period of cardiac valve replacement. Am J Cardiol 2013;112:541–53. [9] Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin III JP, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt III TM, Thomas JD, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;63:e57–185. [10] Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96.
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Original article
Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry Masaki Izumo (MD)a,*, Masaaki Takeuchi (MD, FJCC)b, Yoshihiro Seo (MD, FJCC)c, Eiji Yamashita (MD)d, Kengo Suzuki (MD, FJCC)a, Tomoko Ishizu (MD, FJCC)c, Kimi Sato (MD)c, Shigeru Oshima (MD, FJCC)d, Kazutaka Aonuma (MD, FJCC)c, Yutaka Otsuji (MD, FJCC)e, Yoshihiro J. Akashi (MD, FJCC)a a
Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan Department of Laboratory and Transfusion Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan d Division of Cardiology, Gunma Prefectural Cardiovascular Center, Gunma, Japan e Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 September 2015 Received in revised form 11 January 2016 Accepted 23 January 2016 Available online xxx
Background: Current prognostic implication of symptomatic patients with aortic stenosis (AS) remains undetermined. This study investigated the current prognostic implications of AS-related symptoms and the effect of aortic valve replacement (AVR) on outcome. Methods: We enrolled 586 consecutive patients with severe AS (aortic valve area <1.0 cm2) with preserved left ventricular ejection fraction (50%). All patients were stratified into the following four groups based on the predominant symptoms: Group 1, asymptomatic (n = 316); Group 2, chest pain (n = 41); Group 3, heart failure (n = 192); or Group 4, syncope (n = 37). Results: AS-related symptoms were diagnosed in 270 patients (46.1%), among whom 182 patients (32.2%) received AVR. Thirty-nine patients (6.7%) had cardiac death during the mean follow-up of 16 14 months. AVR was associated with significant reduction in cardiac death in Groups 3 (p < 0.001) and 4 (p = 0.004) whereas no significant prognostic advantage of AVR was observed in Groups 1 or 2. Cox proportional-hazard multivariate analysis revealed that age, heart failure, and mean pressure gradient (PG) were associated with increased risk of cardiac death in all patients regardless of AVR [hazard ratio (HR): 1.079, 2.090, and 1.008 respectively, all p < 0.05]. In the patients without AVR, age, heart failure, syncope, and mean PG were independently associated with cardiac death (HR: 1.130, 3.639, 4.638, and 1.008, all p < 0.05). Conclusion: This retrospective study demonstrated the current associations between the types of AS symptoms and prognosis in Japanese patients with severe AS. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Aortic valve stenosis Prognosis Echocardiography
Introduction Senile degenerative aortic stenosis (AS) is the most common form of valvular heart disease in developed countries, and its prevalence is rapidly increasing along with the aging population [1]. There is general agreement among physicians and surgeons
* Corresponding author at: Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City 216-8511, Japan. Tel.: +81 44 977 8111x3313; fax: +81 44 976 7093. E-mail address: [email protected] (M. Izumo).
that aortic valve replacement (AVR) should be performed in patients with symptomatic severe AS because of the wellestablished unfavorable outcomes in unoperated cases and overall excellent surgical outcomes with relatively low perioperative mortality and morbidity [2–8]. Despite the lack of data from randomized clinical trials, various professional organizations consider symptomatic severe AS as a class I indication for aortic valve surgery [9,10]. Nowadays, the predominant cause of AS has changed from rheumatic valve disease to degenerative disease [11]; the number of aging patients has been increasing over the past few decades in developed countries [12]. The current associations between the types of symptoms and prognosis in
http://dx.doi.org/10.1016/j.jjcc.2016.01.015 0914-5087/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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severe degenerative AS patients treated with and without AVR are not readily available in Japan. Therefore, this multicenter study investigated the impact of symptomatic status on future prognosis in severe AS patients with preserved left ventricular ejection fraction (LVEF) treated with AVR and those treated with conservative medical therapy. Methods Study population This retrospective study included 663 patients with aortic valve area (AVA) <1.0 cm2 treated at one of the four Japanese tertiary cardiovascular centers between 2008 and 2012, St Marianna University (n = 100), University of Occupational and Environmental Health (n = 254), University of Tsukuba (n = 122), and Gunma Prefectural Cardiovascular Center (n = 187). Patients with additional hemodynamically significant (moderate and severe) valve lesions were excluded from the study. The study protocol was approved by the ethics committee in each hospital. Demographic data collection Clinical data, including age, sex, body surface area, brachial blood pressure, heart rate, documented diagnoses of hypertension, dyslipidemia, diabetes mellitus, coronary artery disease, previous history of myocardial infarction, coronary artery bypass grafting, and hemodialysis due to chronic renal failure, were collected at the time of echocardiographic examination. Echocardiographic measurements and prognoses were compared across the groups. The medical records of all patients reported by the primary physicians in each hospital were carefully reviewed by cardiologists. All study patients were stratified into the following four groups based on predominant symptoms at baseline: Group 1, asymptomatic; Group 2, chest pain (Canadian Cardiovascular Society class I); Group 3, heart failure (New York Heart Association functional classification II); and Group 4, syncope. Patients with presyncope were also included in Group 4, and patients with chest heaviness and chest discomfort were included in Group 2. When the patients had multiple symptoms, primary physicians or experienced cardiologists who reviewed the medical records diagnosed their predominant symptoms. Follow-up information was obtained regularly at the outpatient clinics. Patients, physicians, and next of kin were contacted by telephone when patients had been treated in the other hospitals. Echocardiographic study Comprehensive transthoracic echocardiography, including Mmode, two-dimensional, and Doppler echocardiography, was performed using commercially available ultrasound equipment in each hospital according to the guidelines described by the American Society of Echocardiography [13]. An aortic valve jet velocity was recorded from multiple acoustic windows, such as apical, right parasternal, and suprasternal windows, to yield the highest-velocity signal [9]. The LV end-diastolic and end-systolic volumes, stroke volume (SV), and LVEF were measured according to the biplane Simpson’s method in the apical 4- and 2-chamber views. Relative wall thickness was estimated as 2 (diastolic LV posterior wall thickness)/LV end-diastolic diameter [13]. LV mass was calculated using Devereux’s formula [14]. The maximum left atrial volume was measured using the biplane Simpson’s method and indexed to body surface area [13]. Peak early and late diastolic velocities of the left ventricular inflow (E and A velocities), deceleration time of E velocity, and peak early diastolic velocity at the septal corner of the mitral annulus (e0 ) were measured in the
apical 4-chamber view. As a measure of global LV afterload, the valvulo-arterial impedance was determined using the following formula: valvulo-arterial impedance = (systolic arterial pressure + mean pressure gradient)/SV index. Systemic arterial compliance was calculated using the following formula: systemic arterial compliance = stroke volume index/brachial pulse pressure [15]. Using the aortic cross-sectional area at the sinotubular junction, energy loss coefficient was determined as AVA aortic cross-sectional area at the sinotubular junction/(aortic crosssectional area at the sinotubular junction AVA) [15]. AVA was calculated using the continuity equation [9,10]. SV was determined by two-dimensional echocardiography, and AVA was calculated as AVA = SV (two-dimensional biplane Simpson’s method)/velocity time integral of peak aortic valve velocities [9,10]. AVA was indexed to body surface (indexed AVA). Study endpoint The primary study endpoint was cardiac death regardless of aortic valve surgery. The secondary endpoint was major cardiocerebrovascular events defined as AVR plus cardio-cerebrovascular events, including cardiac death, nonfatal myocardial infarction, hospitalization for heart failure, stroke and ventricular tachyarrhythmia. Statistical analysis Results are expressed as mean standard deviation or percentage unless otherwise specified. Data were compared among the four subgroups using one-way analysis of variance with post hoc Turkey’s test. Probabilities of event-free survival among the four subgroups were obtained using Kaplan–Meier analysis and compared using the two-sided log-rank test. The impact of group classification on eventfree survival was assessed using the Cox proportional-hazard model in univariate and multivariate analyses. Variables with a univariate value of p < 0.05 were incorporated into the multivariate models. Because of collinearity, the variables included in the multivariate models were selected with special care. The group classification was entered into the model; Group 1 was considered as a reference. Values of p < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS 18.0 (SPSS, Inc, Chicago, IL, USA). Results Patients’ characteristics Among the 663 study patients, 77 patients were excluded from the analysis due to LVEF < 50% (n = 55), unknown symptoms (n = 6), and follow-up data unavailable (n = 16). Thus, the final group consisted of 586 patients (mean age, 76 9 years, 211 men) with severe AS and LVEF 50% were included. According to their predominant symptoms at baseline, all patients were stratified into asymptomatic (Group 1, n = 316); chest pain (Group 2, n = 41); heart failure (New York Heart Association functional class II, Group 3, n = 192), and syncope (Group 4, n = 37; Fig. 1). Clinical characteristics of the total population are shown in Table 1. Most of the patients were female, with a higher prevalence of hypertension. No differences in the demographic findings except systolic and diastolic blood pressure or the use of b-blockers and diuretics were observed across the four subgroups (Table 1). The baseline echocardiographic findings of the four groups are shown in Table 2. Asymptomatic group (Group 1) demonstrated greater AVA, indexed AVA, and energy loss coefficient and lower peak velocity and mean pressure gradient (PG) compared to the other three symptomatic groups. No significant differences in the LV end-diastolic volume, end-diastolic volume index, SV, or SV index were observed among the four groups, whereas the group of
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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patients with chest pain (Group 2) demonstrated significantly lower LV end-systolic volume and end-systolic volume index and greater LVEF than the other three groups. Clinical outcomes
Fig. 1. Study flowchart. AVA, aortic valve area; AVR, aortic valve replacement.
During a mean follow-up of 16 14 months (median, 12 months; range, 1–59 months), 39 patients reached their primary end point (cardiac death); 258 patients developed major cardio-cerebrovascular events including cardiac death (n = 39), development or exacerbation of heart failure required for admission (n = 33), cerebral infarction (n = 3), ventricular fibrillation (n = 1), and AVR (n = 182); of the AVR patients, 31 patients underwent combined coronary artery bypass grafting. No differences were noted regarding the ratio of AVR
Table 1 Baseline characteristics.
Age (years) Female (%) Body surface area (m2) Body mass index (kg/m2) SBP (mmHg) DBP (mmHg) Heart rate (beats/min) Hypertension (%) Diabetes (%) Dyslipidemia (%) History of smoking (%) Coronary artery disease (%) Prior MI or CABG (%) Chronic kidney disease (%) Hemodialysis (%) History of AF (%) Cerebrovascular event (%) Hemoglobin (mg/l) BNP (pg/ml) Medications ACEI/ARB b-Blockers Diuretics
Overall (N = 586)
Asymptomatic (N = 316)
Chest pain (N = 41)
Heart failure (N = 192)
Syncope (N = 37)
76 9 64 1.48 0.20 22.6 3.5 139 24 73 14 71 15 75 29 44 30 25 7 47 9.2 14 14 12 5 187 (67–383)
76 10 62 1.48 0.19 22.3 3.5 143 24 74 13 72 15 74 29 41 29 24 7 46 10 12 15 12 6 115 (46–273)
74 9 63 1.53 0.16 23.0 3.2 133 16 69 11 69 13 73 41 63 26 34 8 37 7 15 8 12 2 177 (40–463)
77 8 68 1.47 0.22 22.8 3.8 136 23 71 16 71 16 75 28 43 26 22 7 52 8 15 13 12 2 243 (80–464)
77 7 62 1.49 0.18 22.7 3.1 138 25 73 12 72 18 73 24 49 32 35 3 38 8 16 24 12 2 124 (41–527)
53 21 31
50 17 23
59 34 24
56 25 50
46 16 39
p-Value 0.291 0.616 0.632 0.054 0.004 0.010 0.554 0.980 0.301 0.058 0.824 0.665 0.772 0.193 0.905 0.798 0.239 0.889 0.021 0.466 0.029 <0.001
Values are n (%) or mean SD. SBP, systolic blood pressure; DBP, diastolic blood pressure; MI, myocardial infarction; CABG, coronary artery bypass grafting; AF, atrial fibrillation; BNP, brain natriuretic peptide; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Table 2 Echocardiographic findings.
LV end-diastolic volume (ml) LV end-diastolic volume index (ml/m2) LV end-systolic volume (ml) LV end-systolic volume index (ml/m2) LV ejection fraction (%) Stroke volume (ml) Stroke volume index (ml/m2) LA volume index (ml/m2) E/A E/e0 LV mass index (g/m2) Relative wall thickness (%) Peak aortic jet velocity (m/s) Mean pressure gradient (mmHg) AVA (cm2) Indexed AVA (cm2/m2) Energy loss coefficient (cm2/m2) Valvulo-arterial impedance (mmHg/ml/m2) Systemic arterial compliance (ml/m2/mmHg)
Overall (N = 586)
Asymptomatic (N = 316)
Chest pain (N = 41)
Heart failure (N = 192)
Syncope (N = 37)
p-Value
80 28 54 18 29 14 20 9 65 9 51 17 34 11 46 20 0.78 0.74 20 10 123 65 0.55 0.33 3.9 0.9 38 24 0.62 0.26 0.43 0.27 0.63 0.40 5.4 2.3 0.55 0.24
81 28 55 17 31 14 21 9 63 8 51 17 34 10 45 17 0.75 0.29 19 9 116 36 0.55 0.41 3.6 0.9 34 26 0.67 0.26 0.45 0.15 0.74 0.41 5.4 2.3 0.53 0.23
76 29 49 17 24 13 16 8 69 8 51 18 33 10 41 22 0.74 0.21 19 10 117 37 0.54 0.13 4.2 0.7 43 15 0.55 0.27 0.36 0.15 0.50 0.27 5.8 2.1 0.54 0.19
79 28 53 19 27 14 19 9 66 8 51 19 35 13 49 23 0.87 1.2 21 11 135 41 0.56 0.23 4.1 0.9 43 21 0.58 0.27 0.42 0.42 0.48 0.34 5.3 2.4 0.58 0.26
79 23 54 17 30 12 30 12 63 9.0 49 15 34 11 45 17 0.76 0.39 20 8.0 122 30 0.57 0.15 4.4 1.1 50 26 0.53 0.24 0.36 0.17 0.50 0.37 6.0 2.1 0.56 0.23
0.594 0.232 0.008 0.002 <0.001 0.966 0.924 0.059 0.582 0.373 0.419 0.969 <0.001 <0.001 <0.001 0.045 <0.001 0.228 0.328
Values are mean SD. LV, left ventricle; LA, left atrium; AVA, aortic valve area.
Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015
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including combined coronary artery bypass grafting between the four groups (17.6% vs. 35.0% vs. 22.4% vs. 18.2%, respectively, p = 0.167). The 1- and 3-year survival rates for cardiac death were 98 1% and 88 2% in Group 1, 95 1% and 89 2% in Group 2, 98 2% and 66 4% in Group 3, and 96 2% and 65 4% in Group 4 (log rank p = 0.020, Fig. 2A). The event-free survival rates for major cardiocerebrovascular events at 1- and 3-year follow-up were 92 1% and 70 3% in Group 1, 82 3% and 58 3% in Group 2, 64 2% and 22 4%, in Group 3, and 48 1% and 19 2% in Group 4 (log rank p = 0.001, Fig. 2B), respectively. Predictors of cardiac death The Cox-hazard multivariate analysis revealed that older age (p = 0.005), body surface area (p = 0.015), chronic kidney disease (p = 0.034), heart failure (p = 0.025), and mean PG (p = 0.002) were associated with an increased risk of cardiac death in all patients (Table 3). When asymptomatic status was set as a reference, the hazard ratio of heart failure was 2.090 (95% confidence interval 1.099–3.977, p = 0.025). Moreover, in the patients without AVR,
older age (p = 0.002), heart failure (p = 0.001), syncope (p = 0.006), and mean PG (p < 0.001) were closely associated with an increased risk of cardiac death (Table 4). According to these results, not only symptomatic status but also age and the echocardiographic parameter were also important findings for predicting prognosis in patients with AS. Effect of AVR on prognosis Fig. 3 shows effect of symptomatic status on cardiac death-free survival according to patients who had received AVR and those without AVR. Among the patients with AVR, no significant differences in cardiac death-free survival among the four groups (Fig. 3A) were observed; however, the groups of patients who had heart failure or syncope (Groups 3 and 4) had lower survival rates than groups of patients who were asymptomatic or had chest pain (Groups 1 and 2) among the patients without AVR (log rank p = 0.001; Fig. 3B). AVR was associated with significantly better survival in Groups 3 and 4, whereas there was no benefit of AVR on future survival in Groups 1 and 2 (Fig. 4). In both asymptomatic and
Fig. 2. Kaplan–Meier analysis of major cardio-cerebrovascular events and cardiac death-free survival in all patients. Cardiac death-free (A) and major cardio-cerebrovascular events-free (B) survival rates in all groups.
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Table 3 Univariate and multivariate analyses of cardiac mortality in all patients. Univariate analysis
Age (years) Male Body surface area (m2) Chronic kidney disease Cerebrovascular event Anemia LV end-diastolic volume (ml) LV end-systolic volume (ml) LV ejection fraction (%) Mean pressure gradient (mmHg) Indexed AVA (cm2/m2) Energy loss coefficient (cm2/m2) Asymptomatic Chest pain Heart failure Syncope
Multivariate analysis
HR
95% CI
p-Value
HR
95% CI
p-Value
1.056 1.385 0.281 2.785 0.891 0.580 1.003 1.001 1.009 1.009 1.169 0.407 Referent 2.351 2.445 2.17
1.007–1.108 0.701–2.737 0.061–1.289 1.427–5.435 0.263–3.016 0.580 0.993–1.014 0.979–1.023 0.972–1.044 1.003–1.014 0.480–2.842 0.133–1.246
0.007 0.349 0.015 0.003 0.891 0.112 0.555 0.944 0.679 0.001 0.731 0.115
1.079
1.024–1.138
0.005
0.160 2.133
0.037–0.703 1.061–4.290
0.015 0.034
1.008
1.002–1.013
0.005
1.053–5.251 1.24–4.821 0.702–6.713
0.041 0.003 0.291
2.090
1.099–3.977
0.198 0.025 0.097
HR, hazard ratio; CI, confidence interval; LV, left ventricle; AVA, aortic valve area.
Table 4 Univariate and multivariate analyses of cardiac mortality in patients without aortic valve replacement. Univariate analysis HR Age (years) Male Body surface area (m2) SBP (mmHg) Chronic kidney disease Cerebrovascular event Anemia LV end-diastolic volume (ml) LV end-systolic volume (ml) LV ejection fraction (%) Indexed AVA (cm2/m2) Energy loss coefficient (cm2/m2) Mean pressure gradient (mmHg) Asymptomatic Chest pain Heart failure Syncope
1.072 1.356 0.692 0.988 2.534 0.909 1.648 1.007 1.010 0.991 1.126 0.323 1.009 Referent 2.475 5.232 9.072
95% CI 1.011–1.137 0.636–2.887 0.119–4.035 0.973–1.003 1.167–5.505 0.203–4.067 0.768–3.534 0.996–1.019 0.986–1.034 0.948–1.036 0.156–8.136 0.093–1.124 1.003–1.014 0.876–6.988 2.267–12.075 2.307–35.672
Multivariate analysis p-Value 0.021 0.430 0.682 0.128 0.019 0.901 0.200 0.225 0.409 0.686 0.907 0.176 0.001 0.087 <0.001 <0.001
HR
95% CI
p-Value
1.130
1.061–1.203
0.002
0.237
1.008
1.002–1.013
0.005
3.639 4.638
1.677–7.895 1.559–13.80
0.102 0.001 0.006
HR, hazard ratio; CI, confidence interval; SBP, systolic blood pressure; LV, left ventricle; AVA, aortic valve area.
symptomatic groups, the patients with AVR were younger and they had more severe AS than those without AVR (Tables 5 and 6). Furthermore, the patients without AVR revealed a higher prevalence of chronic kidney disease and tended to have lower BMI than those with AVR in the symptomatic group (Table 5). These results suggested that the reason why some symptomatic AS patients did not receive AVR should be their advanced age and the prevalence of comorbidity and frailty.
Discussion Although the accurate determination of symptomatic status is of paramount importance for the subsequent appropriate surgical treatment in patients with severe AS, it is often difficult in the current aged AS patients who have limited exercise capacity and comorbidities. The main findings of this study were that (1) age and heart failure were found to be significant predictors for cardiac death; (2) age, heart failure, and syncope were independently associated with cardiac death in AS patients who did not receive AVR; and (3) AVR was associated with significantly better survival
in the patients with heart failure and syncope, but not those with chest pain and without symptoms. Since unfavorable prognosis has been reported in patients with symptomatic AS, AVR is universally performed in those patients as a class I indication [9,10]. Average survival after the symptom onset was reported as 2 years in patients with heart failure, 3 years with syncope, and 5 years with angina in patients with AS in the established review [2]. However, the earlier studies cited in the widely accepted guidelines were conducted on a highly selected group of patients because of their study designs, such as small study population and single-center experience [2–4,6]. In previous studies, rheumatic valve disease and congenital diseases were the predominant causes of AS, whereas degenerative calcified valve has emerged as the main cause in recent 10 years. In addition, the mean age of symptom onset was 48 years in the earlier studies in contrast to 70s in the present and recent studies [16–18]. Although earlier studies demonstrated the prognostic significance of symptoms in patients with degenerative AS [6,8,14,19], they did not evaluate the associations between the types of symptoms and prognosis. Our study results are consistent with those of earlier reports; most AS patients suffered from heart failure, and the
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Fig. 3. Kaplan–Meier analysis of cardiac death-free survival in patients with (A) and without (B) aortic valve replacement (AVR).
3-year survival rate was 66% in symptomatic AS. Accordingly, the results of earlier studies investigating the presence and absence of symptoms seemed to be influenced by heart failure. When comparing each symptom between our study and earlier studies [2–4], the cardiac death-free survival rates of heart failure and syncope were similar, while chest pain was the only symptom that differed. Livanainen et al. investigated the natural history of calcified AS of varying severity in elderly patients [5]. They reported that 8% of elderly participants demonstrated moderate or severe AS, and they had a four- to six-fold relative risk for death even after adjustment for age and sex. The authors also reported that history of cardiac symptoms at entry did not predict the fouryear outcome. In the recent retrospective study investigating the current mortality in medically treated patients with severe AS and preserved LVEF, 47% of those survived during the mean follow-up period of 25 months and the survivors revealed a high prevalence of angina [20]. They also reported that older age, a history of hypertension, and elevated pulmonary artery systolic pressure indicating elevated LV filling pressure secondary to impaired LV diastolic function were independent predictors of death in patients
with medically treated AS. In the present study, however, only older age, heart failure, syncope, and mean PG were closely associated with an increased risk of cardiac death. These differences were due to the patients’ background in each study. The average age in their study was 83 years, whereas that in the present study was 77 years (in the patients without AVR). The pulmonary vasculature may be affected by age-associated arterial remodeling, leading to pulmonary vascular stiffening and increasing pulmonary artery systolic pressure. In addition, E/A, one of the LV diastolic function parameters, was 1.0 in their study and 0.78 in the present study. Pulmonary artery systolic pressure also directly affected by downstream left heart filling pressure which may increase with age-related LV diastolic dysfunction. The rate of symptomatic patients without AVR was approximately 80% in their study and 34% in the present study. These comparisons suggested that their study included more patients who had comorbidity and did not receive AVR. LV systolic parameters, such as LV end-systolic volume and LVEF, were most preserved in the patients with chest pain compared to those in the other three groups in this study. LV systolic function also closely correlated
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Fig. 4. Cardiac death-free survival in the four patient groups as a function of the type of treatment: medical vs. surgical. (A) Asymptomatic (Group 1), (B) chest pain (Group 2), (C) heart failure (Group 3), (D) syncope (Group 4). AVR, aortic valve replacement.
Table 5 Comparisons in clinical characteristics between patients with and without AVR in asymptomatic and symptomatic groups. Symptomatic
Asymptomatic
Age (years) Female (%) Body surface area (m2) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats/min) Hypertension (%) Diabetes (%) Dyslipidemia (%) History of smoking (%) Coronary artery disease (%) Prior MI or CABG (%) Chronic kidney disease (%) Hemodialysis (%) History of AF (%) Cerebrovascular event (%) Hemoglobin (mg/l) BNP (pg/ml) Medications ACEI/ARB b-Blockers Diuretics
AVR (N = 51)
No AVR (N = 265)
p-Value
AVR (N = 131)
No AVR (N = 139)
p-Value
71 7 59 1.51 0.18 22.5 3.7 138 20 72 11 70 15 69 22 43 36 31 8 47 14 11 15 13 2 158 (50–483)
77 10 63 1.47 0.19 22.2 3.4 144 25 75 14 72 15 75 30 41 27 23 7 39 9 18 14 12 6 115 (44–255)
<0.001 0.608 0.134 0.672 0.135 0.277 0.451 0.322 0.214 0.791 0.217 0.204 0.866 0.288 0.311 0.214 0.870 0.513 0.477
75 8 66 1.51 0.18 23.2 3.4 133 19 70 16 71 13 72 27 52 29 28 4 40 7 17 11 12 2 182 (44–439)
78 8 66 1.46 0.23 22.5 3.8 138 24 71 13 70 16 78 31 42 25 24 9 54 9 14 17 12 2 253 (102–471)
<0.001 0.998 0.051 0.096 0.063 0.676 0.794 0.234 0.560 0.108 0.457 0.382 0.104 0.016 0.469 0.461 0.201 0.300 0.071
39 24 29
53 16 22
0.075 0.209 0.271
50 22 36
59 28 42
0.157 0.263 0.271
Values are n (%) or mean SD. AVR, aortic valve replacement; MI, myocardial infarction; CABG, coronary artery bypass grafting; AF, atrial fibrillation; BNP, brain natriuretic peptide; ACEI, angiotensinconverting enzyme inhibitor; ARB, angiotensin II receptor blocker.
with the clinical outcome in AS patients irrespective of AV surgery [21–23]. These findings appear to support why the AS patients with chest pain had better prognosis in this study. AS-related symptoms are difficult to judge in some AS cases in clinical practice. The symptoms of heart failure and syncope can be
easily detected; however, chest pain is difficult to diagnose, particularly in elderly patients. Furthermore, comorbidities are frequent in the elderly and presumed to affect risk-benefit analyses because these influence life expectancy regardless of valvular disease as well as operative risk and late outcome after AVR. Chest
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Table 6 Comparisons in echocardiographic findings between patients with and without AVR in asymptomatic and symptomatic groups. Symptomatic
Asymptomatic
LV end-diastolic volume (ml) LV end-diastolic volume index (ml/m2) LV end-systolic volume (ml) LV end-systolic volume index (ml/m2) LV ejection fraction (%) Stroke volume (ml) Stroke volume index (ml/m2) LA volume index (ml/m2) E/A E/e0 LV mass index (g/m2) Relative wall thickness Peak aortic jet velocity (m/s) Mean gradient (mmHg) AVA (cm2) Indexed AVA (cm2/m2) Energy loss coefficient (cm2/m2) Valvulo-arterial impedance (mmHg/ml/m2) Systemic arterial compliance (ml/m2/mmHg)
AVR (N = 51)
No AVR (N = 265)
p-Value
AVR (N = 131)
No AVR (N = 139)
p-Value
83 32 55 19 28 16 19 10 67 10 54 19 36 11 48 19 0.75 0.30 20 10 135 45 0.59 0.12 4.5 1.0 53 27 0.59 0.27 0.37 0.15 0.63 0.40 5.5 2.2 0.59 0.26
81 27 55 17 31 14 21 9 63 8 50 16 34 10 44 17 0.75 0.21 19 9 113 32 0.54 0.44 3.4 0.8 30 24 0.69 0.25 0.35 0.15 0.77 0.40 5.4 2.3 0.52 0.22
0.679 0.877 0.235 0.100 0.001 0.084 0.220 0.189 0.882 0.406 <0.001 0.519 <0.001 <0.001 0.001 <0.001 0.016 0.631 0.065
76 28 50 18 26 14 17 9 67 9 50 16 34 10 47 18 0.73 0.29 20 11 125 35 0.57 0.11 4.6 0.8 53 19 0.49 0.19 0.36 0.18 0.47 0.21 5.9 2.0 0.57 0.27
80 27 55 18 28 13 19 8 65 8 52 18 36 12 47 26 0.94 0.46 21 10 110 38 0.52 0.14 3.8 0.9 35 18 0.63 0.36 0.44 0.19 0.69 0.31 5.2 2.3 0.57 0.23
0.229 0.060 0.153 0.032 0.072 0.471 0.090 0.887 0.127 0.232 0.187 0.280 <0.001 <0.001 0.067 <0.001 <0.001 0.005 0.896
Values are mean SD. AVR, aortic valve replacement; LV, left ventricle; LA, left atrium; AVA, aortic valve area.
pain is also caused by not only AS but also coronary artery disease. Although no statistical significance was found, the present study demonstrated a trend toward a higher prevalence of combined AVR and coronary artery bypass grafting in patients with chest pain. The surgical mortality of AVR was 3–4%; however, that of combined AVR and coronary artery bypass grafting was 5–7% [24]. It has been reported that chest pain does not greatly influence prognosis in coronary artery disease [25,26]. Approximately 6 million patients present to the emergency department with chest pain each year; 60–90% of these individuals have no underlying cardiovascular disease [27]. The epidemiology of chest pain markedly differs between outpatients and emergency cases [27]. Cardiovascular disease is the most commonly reported cause of chest pain among outpatients, accounting for approximately 20% of those cases, whereas musculoskeletal conditions, gastrointestinal disease, and panic disorder are also frequently identified. The results of this study suggest that physicians should carefully observe AS symptoms in patients with chest pain. No patients with chest pain died within 1 year in the present study. The understanding of surgical risks and benefit, more detailed diagnosis, and the evaluation of disease severity should be indispensable for the treatment of AS in the current clinical framework. Clinical implications In clinical practice, the diagnosis of AS symptoms is difficult in some patients, particularly chest pain because it can occur in various diseases. The results of this study demonstrated that AVR contributed to better prognosis in patients with heart failure and syncope, but not chest pain. It is likely that more expensive treatments, such as newly developed transcatheter aortic valve replacement, will become an increasingly popular strategy for symptomatic patients with severe AS. To ensure the provision of appropriate and effective treatment, more careful examinations for chest pain are required, such as semi-quantification of the symptoms and stress testing if the symptoms are equivocal. The results of this study will hopefully serve as a warning against rapid decision making regarding the treatment regimen without a comprehensive history taking.
Study limitation Several limitations should be addressed in this study. First, retrospective analysis could produce selection bias, even though we performed a multicenter study. Second, the designation of symptomatic status might not be accurate due to the lack of standardization of history taking. However, the present study employed the designation of symptomatic status which was previously adopted in the earlier published retrospective studies [17,18]. The results of this study reflect the reality of daily clinical practice. Clavel et al. classified AS into three categories, i.e. no symptoms, mild symptoms (dyspnea, New York Heart Association functional class II; angina, Canadian Cardiovascular Society class I or II; and/or fatigue), or moderate-severe symptoms (dyspnea, New York Heart Association functional class III or IV; angina, Canadian Cardiovascular Society class III or IV; and/or syncope) and demonstrated that only moderate-severe symptoms affected the event-free survival [19]. In the clinical setting, it is often difficult to distinguish dyspnea from chest pain. Therefore, the quantitative assessment of symptom status would play a crucial role in daily clinical practice. Third, the mean follow-up term was 16 14 months; thus, longer follow-up, particularly in patients with chest pain, is required to validate our results. Fourth, there was no standardized indication of the assessment of coronary artery disease in the present study; particularly, silent myocardial ischemia in patients with diabetes mellitus was not completely ruled out. Fifth, we could not deny the possibility of the influence of b-blockers on their prognosis, whereas no significant differences in the prescription rate of b-blockers were found between the patients with chest pain who had subsequently received AVR and those without AVR (p = 0.423) in this study. The patients with chest pain revealed slightly but significantly higher rate of b-blocker prescription because of a tendency toward the higher complication rate of coronary artery disease. The use of b-blockers in AS patients with coronary artery disease is described by the American College of Cardiology/American Heart Association guidelines, although no definitive evidence has been presented [9]. Thus, the beneficial effect of b-blockers on prognosis in AS also remains unclear. Sixth, more patients without AVR were prescribed angiotensin-converting enzyme inhibitors (ACEIs) than those with AVR in the asymptomatic
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group. We could not deny the possibility of the influence of ACEIs on their prognosis. Nadir et al. have suggested that ACEIs possibly improve prognosis in patients with AS [28]. However, the effect of ACEIs on prognosis in AS remains controversial [29]; thus, further studies are called for. Lastly, we did not analyze the effect of frailty and dementia in this study. Since aged-people are progressively increasing in Japan, the presence of frailty and dementia could influence their therapeutic strategy, and thus, affect their prognosis differently. Conclusions This study establishes the current associations between the type of symptoms and prognosis in patients with severe AS and preserved LVEF. Funding This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors. Disclosures The authors declare that there is no conflict of interest. References [1] Carabello BA, Paulus WJ. Aortic stenosis. Lancet 2009;373:956–66. [2] Ross Jr J, Braunwald E. Aortic stenosis. Circulation 1968;38:V61–7. [3] Schwarz F, Baumann P, Manthey J, Hoffmann M, Schuler G, Mehmel HC, Schmitz W, Ku¨bler W. The effect of aortic valve replacement on survival. Circulation 1982;66:1105–10. [4] Turina J, Hess O, Sepulcri F, Krayenbuehl HP. Spontaneous course of aortic valve disease. Eur Heart J 1987;8:471–83. [5] Livanainen AM, Lindroos M, Tilvis R, Heikkila J, Kupari M. Natural history of aortic valve stenosis of varying severity in the elderly. Am J Cardiol 1996;78:97–101. [6] Kelly TA, Rothbart RM, Cooper CM, Kaiser DL, Smucker ML, Gibson RS. Comparison of outcome of asymptomatic to symptomatic patients older than 20 years of age with valvular aortic stenosis. Am J Cardiol 1988;61:123–30. [7] Lund O, Flø C, Jensen FT, Emmertsen K, Nielsen TT, Rasmussen BS, Hansen OK, Pilegaard HK, Kristensen LH. Left ventricular systolic and diastolic function in aortic stenosis. Prognostic value after valve replacement and underlying mechanisms. Eur Heart J 1997;18:1977–87. [8] Roberts WC, Vowels TJ, Filardo G, Ko JM, Mathur RP, Shirani J. Natural history of unoperated aortic stenosis during a 50-year period of cardiac valve replacement. Am J Cardiol 2013;112:541–53. [9] Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin III JP, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt III TM, Thomas JD, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;63:e57–185. [10] Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96.
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Please cite this article in press as: Izumo M, et al. Prognostic implications in patients with symptomatic aortic stenosis and preserved ejection fraction: Japanese multicenter aortic stenosis, retrospective (JUST-R) registry. J Cardiol (2016), http://dx.doi.org/10.1016/ j.jjcc.2016.01.015