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Late recurrence of left ventricular dysfunction after aortic valve replacement for severe chronic aortic regurgitation
International Journal of Cardiology 224 (2016) 240–244
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Late recurrence of left ventricular dysfunction after aortic valve replacement for severe chronic aortic regurgitation☆ Masashi Amano a, Chisato Izumi a,⁎, Sari Imamura a, Naoaki Onishi a, Yodo Tamaki a, Soichiro Enomoto a, Makoto Miyake a, Toshihiro Tamura a, Hirokazu Kondo a, Kazuaki Kaitani a, Kazuo Yamanaka b, Yoshihisa Nakagawa a a b
Department of Cardiology, Tenri Hospital, Tenri, Japan Department of Cardiovascular Surgery, Tenri Hospital, Tenri, Japan
a r t i c l e
i n f o
Article history: Received 14 May 2016 Received in revised form 5 September 2016 Accepted 15 September 2016 Available online 17 September 2016 Keywords: Aortic regurgitation Aortic valve replacement Late recurrence of left ventricular dysfunction Long-term follow-up
a b s t r a c t Background: Aortic valve replacement (AVR) for chronic aortic regurgitation (AR) with a decreased ejection fraction (EF) leads to improvement in left ventricular (LV) function, but there are no reports on late recurrence of LV dysfunction over long-term after AVR. This study aimed to identify frequency and predictors of late recurrent LV dysfunction after AVR. Methods: We retrospectively investigated 58 consecutive patients undergoing AVR for severe chronic AR and with follow-up echocardiography for N 5 years after AVR. Late recurrence of LV dysfunction was defined as an EF of b 50% late after AVR and a 10% reduction in the EF compared with that observed at 1 year after AVR. Results: The mean follow-up period was 10.3 ± 5.2 years. The preoperative EF was b50% in 21 (36%) patients, but it was normalized at 1 year after AVR in all patients except for one. However, late recurrence of LV dysfunction developed in 7 (12%) of the 58 patients. These patients showed significantly higher LV end-diastolic and endsystolic diameters before and at 1 year after AVR, a lower EF and relative wall thickness before AVR, a higher LV mass index at 1 year after AVR, and a higher incidence of preoperative and postoperative atrial fibrillation than those without late recurrence. Conclusions: Late recurrent LV dysfunction may occur after AVR for severe chronic AR despite EF being once normalized. Early surgery proceeding remarkable LV enlargement and maintaining sinus rhythm are important for LV function over the long-term after AVR. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In the current American Heart Association/American Colleague of Cardiology guidelines and the European Society of Cardiology/ European Association for Cardio-Thoracic Surgery guidelines, aortic valve replacement (AVR) is recommended for patients with severe chronic aortic regurgitation (AR) who have symptoms and/or left ventricular (LV) dysfunction (ejection fraction (EF) b50%, LV enddiastolic diameter (LVDd) N65 or 70 mm, and/or LV end-systolic diameter (LVDs) N 50 mm) [1,2]. This is because that previous studies have shown that outcomes of surgical intervention for patients with severe chronic AR and a low EF are poor [3–5], thus AVR is
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Department of Cardiology, Tenri Hospital, 200 Mishima-cho, Tenri, Nara 632-8552, Japan. E-mail address: [email protected] (C. Izumi).
http://dx.doi.org/10.1016/j.ijcard.2016.09.032 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
recommended before LV dysfunction develops [6]. On the other hand, the natural history of AR has also been well described and is characterized by a long asymptomatic period followed by a relatively rapid period of worsening after the onset of cardiac symptoms [7–9]. Therefore, patients with severe chronic AR sometimes exhibit LV dysfunction at the initial diagnosis. A recent report [10] described that survival after AVR in patients with preoperative severe LV dysfunction improved dramatically since 1985 and became equivalent to that of patients with non-severe LV dysfunction. In addition, it has been reported that LV function improves on a comparatively short-term after AVR [11,12]. However, in clinical settings, we have experienced some cases in which late recurrence of LV dysfunction developed despite EF being normalized early after AVR. There are few reports on the long-term chronological changes in LV function and no reports on recurrence of LV dysfunction after AVR. The present study aimed to evaluate chronological changes in LV function after AVR in patients with severe chronic AR, and to identify frequency and predictors of late recurrent LV dysfunction during long-term follow-up periods.
M. Amano et al. / International Journal of Cardiology 224 (2016) 240–244 2. Methods 2.1. Study populations
241
Table 1 Clinical characteristics of the study population. 58 patients
We retrospectively investigated 58 consecutive patients (44 males, age at AVR: 56 ± 15 years) with severe chronic AR who underwent AVR at our institution between 1995 and 2010 and were followed up with echocardiography for N5 years after AVR in order to evaluate chronological changes in LV function during long-term follow-up periods. Patients who had other severe valvular disease or severe coronary artery disease, defined as N90% stenosis of more than one-vessel or old myocardial infarction, were excluded. Late recurrence of LV dysfunction was defined as an EF of b50% late after AVR and a 10% reduction in the EF compared with that observed at 1 year after AVR. Furthermore, in order to determine the predictors of late recurrent LV dysfunction after AVR, preoperative laboratory data, medications, and clinical background data were evaluated. All patients gave their written informed consent on the local institutional form to participate in this study. The study protocol was approved by the institutional ethics committee at Tenri Hospital, judging it complaint to the principles outlined in the Helsinki Declaration. 2.2. Clinical characteristics We investigated the pre- and postoperative clinical characteristics, including underlying disease, smoking habits, medications, and cardiac rhythm. The examined underlying disease included hypertension, hyperlipidemia, diabetes mellitus, cerebral infarction, chronic obstructive pulmonary disease, and connective tissue disease including aortitis. To evaluate the effects of medications, we investigated the use of antiplatelet drugs, anticoagulants, statins, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, β-blockers, diuretics, and digoxin. Preoperative laboratory data were investigated, including hemoglobin concentrations, white blood cell count, eosinophil count, estimated glomerular filtration rate (eGFR), and blood levels of urea nitrogen, creatinine, total cholesterol, and B-type natriuretic peptide. Moreover, the medications at 3 years after AVR were investigated. Patients were classified into the treatment group for a particular medication if they were taking it for Nhalf of the follow-up period. Pre- and postoperative atrial fibrillation was investigated. Here, atrial fibrillation indicated permanent atrial fibrillation, which was defined as detection on an electrocardiogram at least three times during N6 months. Pre- and postoperative hospitalization due to heart failure and occurrence of ventricular tachycardia was also evaluated. 2.3. Echocardiographic examination and parameters Comprehensive transthoracic echocardiography was performed before AVR, and 1 year and beyond 5 years after AVR, using high-quality, commercially available ultrasound systems [a Toshiba SSH 140-A Ultrasound System (Toshiba Medical Systems, Tochigi, Japan), an Acuson Sequoia C256 Echocardiography System (Acuson Corp, Mountain view, USA), a Vivid E9 Ultrasonic Unit (GE Health Care, Tokyo, Japan)]. By reviewing the recorded images of all study patients, LVDd, LVDs, septal wall thickness, and posterior wall thickness were measured from parasternal views and EF was measured using the modified Simpson's method by two experienced sonographers. LV mass was calculated using the formula for estimating LV mass from LV linear dimensions as described in the guidelines of the American Society of Echocardiography [13]. Moreover, we examined loading condition at each echocardiographic examination, which may influence EF. 2.4. Statistical analysis Statistical analyses were performed using SPSS for Windows 22.0 (SPSS, Chicago, IL, USA). All data are expressed as mean ± SD values. Differences in parameters between 2 groups were determined using the Mann–Whitney U-test for continuous variables or Fisher's exact test for discrete variables. One-way repeated-measures analysis of variance (ANOVA) and a post hoc test (Turkey-Kramer test) were used to test for significance adjustment for multiple comparisons. Statistical significance was set at a p value of b0.05.
Pre- and postoperative characteristics Age (years) Sex (male), n (%) Height (cm) Body weight (kg) Body mass index (kg/m2) Body surface area (m2) Extracorporeal circuit (min) Mean blood pressure (mmHg) Heart rate (bpm) LVDd (mm) LVDs (mm) EF (%) Hypertension, n (%) Diabetes, n (%) Cerebral infarction, n (%) COPD, n (%) Connective tissue disease, n (%) Smoking habit, n (%) Preoperative AF, n (%) Preoperative occurrence of VT, n (%) Preoperative hospitalization due to heart failure, n (%) Postoperative AF, n (%) Postoperative occurrence of VT, n (%) Postoperative hospitalization due to heart failure, n (%)
56.3 ± 15.0 44 (75.9) 164.2 ± 9.1 60.8 ± 13.0 22.4 ± 3.2 1.7 ± 0.2 122.3 ± 37.1 89.7 ± 11.3 73.0 ± 14.5 67.9 ± 7.5 47.2 ± 9.2 53.5 ± 13.6 31 (53.4) 4 (6.9) 4 (6.9) 2 (3.4) 4 (6.9) 23 (39.6) 8 (13.8) 2 (3.4) 22 (37.9) 14 (24.1) 3 (5.2) 5 (8.6)
Preoperative laboratory data Hb (g/L) WBC count (109/L) Eosinophils (%) BUN (mmol/L) Cr (μmol/L) eGFR (mL/min/1.73m2) BNP (pmol/L) Total cholestelol (mmol/L) LDL (mmol/L)
12.8 ± 1.7 6041 ± 2120 2.9 ± 2.2 6.9 ± 2.8 88.4 ± 26.5 61.5 ± 21.6 136.0 ± 313.0 4.6 ± 0.8 2.9 ± 0.6
Preoperative medications ACE I/ARB, n (%) β-blockers, n (%) Digoxin, n (%) Diuretics, n (%) Statins, n (%) Anti-platelets, n (%) Anti-coagulates, n (%)
37 (63.8) 11 (19.0) 14 (24.1) 32 (55.2) 5 (8.6) 4 (6.9) 3 (5.2)
Postoperative medications (three years) ACE I/ARB, n (%) β-blockers, n (%) Digoxin, n (%) Diuretics, n (%) Statins, n (%) Anti-platelets, n (%) Anti-coagulates, n (%)
27 (46.7) 27 (46.7) 9 (15.5) 21 (36.2) 11 (19.0) 21 (36.2) 45 (77.6)
Values are presented as mean ± SD or n (%). LVDd = left ventricular end-diastolic diameter; LVDs = left ventricular end-systolic diameter; EF = ejection fraction; COPD =
3. Results
chronic obstructive pulmonary disease; AF = atrial fibrillation; VT = ventricular tachycardia; Hb = hemoglobin; WBC = white blood cell; BUN = blood urea nitrogen; Cr =
3.1. Baseline characteristics
creatinine; eGFR = estimated glomerular filtration rate; BNP = B-type natriuretic peptide; LDL = low-density lipoprotein; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker.
The baseline characteristics of all patients are described in Table 1. The mean follow-up period was 10.3 ± 5.2 years. The etiology of AR was as follows: degenerative valve in 24 patients, annuloaortic ectasia in 10, valve prolapse in 8, bicuspid valve in 8, rheumatic valve in 5, and others in 3. AVR was performed with a bioprosthesis (18 patients) or a mechanical prosthesis (40 patients). AVR alone was performed in 51 patients and concomitant replacement of the ascending aorta was performed in 7 patients.
but it was normalized at 1 year after AVR in all patients except for one. At 5–10 years after AVR, EF improved in one patient with EF of b 50% at 1 year after AVR, however, 7 of the 57 patients with EF N50% at 1 year after AVR showed recurrent LV dysfunction. Therefore, late recurrence of LV dysfunction developed in 7 (12%) of the 58 patients. 3.3. Predictors of late recurrent LV dysfunction
3.2. Chronological changes in LV function The chronological changes in echocardiographic data of LV function are shown in Fig. 1. The preoperative EF was b 50% in 21 (36%) patients,
In order to clarify the predictors of late recurrent LV dysfunction, we compared the parameters between 7 patients with late recurrence of LV dysfunction and 51 patients without it. The etiology of AR in 7 patients
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M. Amano et al. / International Journal of Cardiology 224 (2016) 240–244
Fig. 1. Chronological changes in echocardiographic data of 58 patients who were followed up with echocardiography for N5 years. Seven patients showed late recurrence of LV dysfunction (arrow). Pre = preoperative; y = year; LVDd = left ventricular end-diastolic diameter; LVDs = left ventricular end-systolic diameter; EF = ejection fraction.
with late recurrence of LV dysfunction was as follows: degenerative valve in 4 patients, annuloaortic ectasia in 1, valve prolapse in 1, rheumatic valve in 1. The 7 patients with late recurrence of LV dysfunction had a significantly larger LVDd and LVDs before (LVDd, p b 0.01; LVDs, p b 0.01) and at 1 year after AVR (LVDd, p = 0.02; LVDs, p = 0.01), a significantly lower EF before AVR (p b 0.01), a significantly lower relative wall thickness before AVR (p = 0.04), a significantly greater LV mass index at 1 year after AVR (p = 0.02), a higher incidence of preoperative and postoperative atrial fibrillation (preoperative, p = 0.02; postoperative, p = 0.01), and a higher postoperative administration rate of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (p = 0.03) compared with the 51 patients who did not suffer from late recurrence of LV dysfunction (Table 2). There were no significant differences in the preoperative creatinine levels (p = 0.30), eGFR (p = 0.30), total cholesterol levels (p = 0.78), ages at AVR (p = 0.29), medications except angiotensinconverting enzyme inhibitor or angiotensin II receptor blocker, underlying diseases, or preoperative occurrence of ventricular tachycardia or hospitalization due to heart failure between the 2 groups. Regarding the loading condition at each echocardiographic examination, there were no significant differences in mean blood pressure, heart rate, mitral regurgitation grade between patients with and without late recurrent LV dysfunction and between at 1 year and 5–10 years post operative follow-up echocardiography (Table 3).
4.1. Chronological changes in LV function; comparison with previous studies In our study, LVDd, LVDs, and EF were normalized at 1 year after AVR in all of the patients, except for one with preoperative LV dysfunction. Previous reports suggested that the improvements in LV function soon after AVR were due to an early reduction in volume overloading and a late remodeling process occurring after AVR [14,18]. Bonow et al. [14] reported that EF was normalized in 41% of patients who showed a low preoperative EF and the remaining patients showed a low EF at 6–8 months after AVR. However, in our study, all of the patients, except for one with a low preoperative EF, had normalized EF at 1 year after AVR. The discrepancy between our findings and those of Bonow et al. [14] might be due to differences in the length of the follow-up period. LV function of patients who have a low preoperative EF might markedly improve around the first year after AVR. Moreover, the present surgical techniques and postoperative outcomes have improved compared with those in 1980s when Bonow et al. reported the result [10]. Therefore, this might also affect to the discrepancy. Bonow et al. [14] also demonstrated that patients whose EF improved at 6–8 postoperative months did not suffer late recurrence of LV dysfunction. They also showed that Nhalf of the patients who showed a low EF at 6–8 months after AVR did not achieve any improvement in their LV function 3–7 years after AVR. Because the timing of follow-up was different from our study, late recurrence of LV dysfunction might not have been able to be detected in their study.
4. Discussion 4.2. Predictors of late recurrent LV dysfunction In the present study, we have newly identified the cases in which late recurrence of LV dysfunction developed during the long-term follow-up periods despite EF being normalized early after AVR for chronic AR. There are few longitudinal data about LV function although the improvement of postoperative outcomes in patients with preoperative LV dysfunction had been reported [10]. Moreover, many reports have demonstrated survival rate for N 10 years after AVR, but the follow-up periods of LV function were b 5 years in most previous studies [14–18]. Therefore, the chronological changes of LV function with longer follow-up period after AVR should be re-investigated.
In the present study, parameters of LV function, such as LVDd, LVDs, EF, relative wall thickness and LV mass index before and/or 1 year after AVR were indicators of late recurrent LV dysfunction. The preoperative large LVDd and LVDs might reflect the degree of eccentric hypertrophy due to volume overloading. Large LVDs and low relative wall thickness indicated increased wall stress, namely pressure overloading. Preoperative volume and pressure overloading due to severe AR were reduced by surgical intervention. In fact, EF had been normalized in all patients except for one at 1 year after AVR in the present study. However, chronic volume
M. Amano et al. / International Journal of Cardiology 224 (2016) 240–244 Table 2 Predictors of late recurrent left ventricular dysfunction.
Preoperative LVDd (mm) Preoperative LVDs (mm) Preoperative EF (%) Preoperative LV mass index (g/m2) Preoperative RWT Age (years) Sex (male), n (%) Body mass index (kg/m2) Body surface area (m2) Mean blood pressure (mmHg) Heart rate (bpm) Hypertension, n (%) Diabetes, n (%) Cerebral infarction, n (%) COPD, n (%) Connective tissue disease, n (%) Smoking habit, n (%) Preoperative AF, n (%) Preoperative occurrence of VT, n (%) Preoperative hospitalization due to heart failure, n (%) Hb (g/L) Eosinophils (%) Cr (μmol/L) e-GFR (ml/min/1.73m2) Total cholesterol (mmol/L) Preoperative ACE I/ARB, n (%) Preoperative β-blockers, n (%) Preoperative diuretics, n (%) 1 yr postoperative LVDd (mm) 1 yr postoperative LVDs (mm) 1 yr postoperative EF (%) 1 yr postoperative LV mass index (g/m2) 1 yr postoperative RWT Postoperative AF, n (%) Postoperative ACE I/ARB, n (%) Postoperative β-blockers, n (%) Postoperative diuretics, n (%)
243
Table 3 Loading condition at each echocardiographic examination.
Recurrence of LV dysfunction
No recurrence of LV dysfunction
n=7
n = 51
77.4 ± 5.9 62.0 ± 6.9 35.6 ± 6.0 234.7 ± 49.8 0.25 ± 0.05 61.3 ± 14.0 6 (85.7) 21.5 ± 3.1 1.64 ± 0.18 93.4 ± 11.2 82.3 ± 21.6 4 (57.1) 0 (0.0) 1 (14.3) 0 (0) 0 (0) 5 (71.4) 3 (42.9) 1 (14.3) 4 (57.1)
66.6 ± 6.8 45.1 ± 7.5 55.9 ± 12.6 191.8 ± 47.5 0.31 ± 0.07 55.6 ± 15.1 38 (74.5) 22.5 ± 3.2 1.65 ± 0.20 88.7 ± 10.8 71.7 ± 12.7 27 (52.9) 4 (7.8) 3 (5.8) 2 (3.9) 4 (7.8) 18 (35.3) 5 (9.8) 1 (2.0) 18 (35.3)
b0.01 b0.01 b0.01 0.06 0.04 0.29 0.52 0.57 0.98 0.30 0.28 0.83 0.44 0.41 0.59 0.44 0.07 0.02 0.09 0.26
131.9 ± 13.9 1.7 ± 1.4 97.2 ± 17.7 53.6 ± 10.0 4.5 ± 0.7 5 (71.4) 1 (14.3) 5 (71.4) 54.3 ± 5.8 37.4 ± 5.2 59.0 ± 8.2 134.7 ± 22.7 0.38 ± 0.08 5 (71.4) 6 (85.7) 23 (39.7) 4 (57.1)
127.3 ± 16.8 3.1 ± 2.3 88.4 ± 26.5 62.7 ± 22.5 4.6 ± 0.8 32 (62.7) 10 (19.6) 27 (52.9) 48.8 ± 5.7 30.8 ± 5.5 65.1 ± 7.4 111.1 ± 29.2 0.42 ± 0.10 9 (17.6) 21 (41.2) 4 (57.1) 17 (33.3)
0.57 0.08 0.30 0.30 0.78 0.65 0.74 0.36 0.02 0.01 0.06 0.02 0.25 b0.01 0.03 0.55 0.22
p-value
Values are presented as mean ± SD or n (%). LVDd = left ventricular end-diastolic diameter; LVDs = left ventricular end-systolic diameter; EF = ejection fraction; RWT = relative wall thickness; yr = year; COPD = chronic obstructive pulmonary disease; AF = atrial fibrillation; VT = ventricular tachycardia, Hb = hemoglobin; Cr = creatinine; eGFR = estimated glomerular filtration rate; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker.
and pressure overloading can cause cardiac damage. Previous studies showed that chronic volume overloading can induce microvascular dysfunction and changes in the extracellular matrix [19] and chronic pressure overloading can increase cardiac oxidative damage, in association with cardiac hypertrophy and fibrosis [20,21]. Eventually, accumulating microvascular cardiac damage might result in late recurrence of LV dysfunction despite EF being normalized early after AVR. LVDd, LVDs and LV mass index also decreased at 1 year after AVR, but were not always normalized in patients with late recurrent LV dysfunction, and they were indicators of late recurrent LV dysfunction. In addition to LV function before and 1 year after AVR, postoperative atrial fibrillation was related to late recurrence of LV dysfunction. Atrial fibrillation leads to atrial dysfunction [22] and LV diastolic dysfunction. In addition, long-standing atrial fibrillation or atrial fibrillation with rapid conduction leads to LV systolic dysfunction. All of these conditions are potential causes of late recurrent LV dysfunction. Therefore, maintaining sinus rhythm is important, especially for patients with preoperative LV dysfunction, to prevent late recurrence of LV dysfunction after AVR. With respect to medications, the postoperative administration rate of angiotensin-converting enzyme inhibitor or angiotensin II receptor
Preoperative mean BP (mmHg) Preoperative HR (bpm) Preoperative MR (Nmoderate), n (%) 1 yr postoperative mean BP (mmHg) 1 yr postoperative HR (bpm) 1 yr postoperative MR (Nmoderate), n (%) 5–10 years postoperative mean BP (mmHg) 5–10 years postoperative HR (bpm) 5–10 years postoperative MR (Nmoderate), n (%)
Recurrence of LV dysfunction
No recurrence of LV dysfunction
n=7
n = 51
93.4 ± 11.2 82.3 ± 21.6 2 (28.6) 92.3 ± 9.6⁎
63.6 ± 13.3⁎ 0 (0)⁎
88.7 ± 10.8 71.7 ± 12.7 6 (11.8) 92.6 ± 10.0⁎ 68.1 ± 12.4⁎ 2 (3.9)⁎
0.30 0.28 0.23 0.93 0.26 0.59
93.1 ± 9.8
91.2 ± 8.8
0.59
71.7 ± 15.7 1 (14.3)
66.2 ± 9.9 3 (5.8)
0.40 0.41
p-value
Values are presented as mean ± SD or n (%). ⁎ p N 0.05 vs. 5–10 years. postoperative values. LV = left ventricular; BP = blood pressure; HR = heart rate; MR = mitral regurgitation; yr = year.
blocker was significantly higher in patients with late recurrence of LV dysfunction. These patients showed preoperative LV dysfunction, thus postoperative administration of these drugs was appropriate. However, they revealed late recurrence of LV dysfunction despite with administration of these drugs. 4.3. Limitations The present study has several limitations, mainly based upon its retrospective nature. First, not all of the patients could be followed up systematically, resulting in differences among the patients in the echocardiographic follow-up period after AVR (maximum difference: 5 years). This might have affected our results regarding the chronological changes in LV function after AVR. Second, the small number of patients is a major issue. Moreover, for statistical comparisons between the 2 groups, we had to use non-parametric statistics. The small number of subjects might have affected the statistical power of the variables. 5. Conclusions Late recurrence of LV dysfunction often occurs after AVR for severe chronic AR. Therefore, long-term follow-up is important even if EF is normalized. Early surgery preceding remarkable LV enlargement and maintenance of sinus rhythm are important for maintaining LV function over long-term follow-up after AVR. Conflict of interest The authors have no conflicts of interest to disclose. Acknowledgements The authors thank Hitoshi Ohbayashi for assisting with data analysis. References [1] R.A. Nishimura, C.M. Otto, R.O. Bonow, et al., 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J. Am. Coll. Cardiol. 63 (2014) 2438–2488. [2] A. Vahanian, O. Alfieri, F. Andreotti, et al., Guidelines on the management of valvular heart disease (version 2012), Eur. Heart J. 33 (2012) 2451–2496. [3] R.O. Bonow, D. Nikas, J.A. Elefteriades, Valve replacement for regurgitant lesions of the aortic or mitral valve in advanced left ventricular dysfunction, Cardiol. Clin. 13 (1995) 73–83 85. [4] K.S. Dujardin, M. Enriquez-Sarano, H.V. Schaff, K.R. Bailey, J.B. Seward, A.J. Tajik, Mortality and morbidity of aortic regurgitation in clinical practice. A long-term followup study, Circulation 99 (1999) 1851–1857.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Late recurrence of left ventricular dysfunction after aortic valve replacement for severe chronic aortic regurgitation☆ Masashi Amano a, Chisato Izumi a,⁎, Sari Imamura a, Naoaki Onishi a, Yodo Tamaki a, Soichiro Enomoto a, Makoto Miyake a, Toshihiro Tamura a, Hirokazu Kondo a, Kazuaki Kaitani a, Kazuo Yamanaka b, Yoshihisa Nakagawa a a b
Department of Cardiology, Tenri Hospital, Tenri, Japan Department of Cardiovascular Surgery, Tenri Hospital, Tenri, Japan
a r t i c l e
i n f o
Article history: Received 14 May 2016 Received in revised form 5 September 2016 Accepted 15 September 2016 Available online 17 September 2016 Keywords: Aortic regurgitation Aortic valve replacement Late recurrence of left ventricular dysfunction Long-term follow-up
a b s t r a c t Background: Aortic valve replacement (AVR) for chronic aortic regurgitation (AR) with a decreased ejection fraction (EF) leads to improvement in left ventricular (LV) function, but there are no reports on late recurrence of LV dysfunction over long-term after AVR. This study aimed to identify frequency and predictors of late recurrent LV dysfunction after AVR. Methods: We retrospectively investigated 58 consecutive patients undergoing AVR for severe chronic AR and with follow-up echocardiography for N 5 years after AVR. Late recurrence of LV dysfunction was defined as an EF of b 50% late after AVR and a 10% reduction in the EF compared with that observed at 1 year after AVR. Results: The mean follow-up period was 10.3 ± 5.2 years. The preoperative EF was b50% in 21 (36%) patients, but it was normalized at 1 year after AVR in all patients except for one. However, late recurrence of LV dysfunction developed in 7 (12%) of the 58 patients. These patients showed significantly higher LV end-diastolic and endsystolic diameters before and at 1 year after AVR, a lower EF and relative wall thickness before AVR, a higher LV mass index at 1 year after AVR, and a higher incidence of preoperative and postoperative atrial fibrillation than those without late recurrence. Conclusions: Late recurrent LV dysfunction may occur after AVR for severe chronic AR despite EF being once normalized. Early surgery proceeding remarkable LV enlargement and maintaining sinus rhythm are important for LV function over the long-term after AVR. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In the current American Heart Association/American Colleague of Cardiology guidelines and the European Society of Cardiology/ European Association for Cardio-Thoracic Surgery guidelines, aortic valve replacement (AVR) is recommended for patients with severe chronic aortic regurgitation (AR) who have symptoms and/or left ventricular (LV) dysfunction (ejection fraction (EF) b50%, LV enddiastolic diameter (LVDd) N65 or 70 mm, and/or LV end-systolic diameter (LVDs) N 50 mm) [1,2]. This is because that previous studies have shown that outcomes of surgical intervention for patients with severe chronic AR and a low EF are poor [3–5], thus AVR is
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Department of Cardiology, Tenri Hospital, 200 Mishima-cho, Tenri, Nara 632-8552, Japan. E-mail address: [email protected] (C. Izumi).
http://dx.doi.org/10.1016/j.ijcard.2016.09.032 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
recommended before LV dysfunction develops [6]. On the other hand, the natural history of AR has also been well described and is characterized by a long asymptomatic period followed by a relatively rapid period of worsening after the onset of cardiac symptoms [7–9]. Therefore, patients with severe chronic AR sometimes exhibit LV dysfunction at the initial diagnosis. A recent report [10] described that survival after AVR in patients with preoperative severe LV dysfunction improved dramatically since 1985 and became equivalent to that of patients with non-severe LV dysfunction. In addition, it has been reported that LV function improves on a comparatively short-term after AVR [11,12]. However, in clinical settings, we have experienced some cases in which late recurrence of LV dysfunction developed despite EF being normalized early after AVR. There are few reports on the long-term chronological changes in LV function and no reports on recurrence of LV dysfunction after AVR. The present study aimed to evaluate chronological changes in LV function after AVR in patients with severe chronic AR, and to identify frequency and predictors of late recurrent LV dysfunction during long-term follow-up periods.
M. Amano et al. / International Journal of Cardiology 224 (2016) 240–244 2. Methods 2.1. Study populations
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Table 1 Clinical characteristics of the study population. 58 patients
We retrospectively investigated 58 consecutive patients (44 males, age at AVR: 56 ± 15 years) with severe chronic AR who underwent AVR at our institution between 1995 and 2010 and were followed up with echocardiography for N5 years after AVR in order to evaluate chronological changes in LV function during long-term follow-up periods. Patients who had other severe valvular disease or severe coronary artery disease, defined as N90% stenosis of more than one-vessel or old myocardial infarction, were excluded. Late recurrence of LV dysfunction was defined as an EF of b50% late after AVR and a 10% reduction in the EF compared with that observed at 1 year after AVR. Furthermore, in order to determine the predictors of late recurrent LV dysfunction after AVR, preoperative laboratory data, medications, and clinical background data were evaluated. All patients gave their written informed consent on the local institutional form to participate in this study. The study protocol was approved by the institutional ethics committee at Tenri Hospital, judging it complaint to the principles outlined in the Helsinki Declaration. 2.2. Clinical characteristics We investigated the pre- and postoperative clinical characteristics, including underlying disease, smoking habits, medications, and cardiac rhythm. The examined underlying disease included hypertension, hyperlipidemia, diabetes mellitus, cerebral infarction, chronic obstructive pulmonary disease, and connective tissue disease including aortitis. To evaluate the effects of medications, we investigated the use of antiplatelet drugs, anticoagulants, statins, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, β-blockers, diuretics, and digoxin. Preoperative laboratory data were investigated, including hemoglobin concentrations, white blood cell count, eosinophil count, estimated glomerular filtration rate (eGFR), and blood levels of urea nitrogen, creatinine, total cholesterol, and B-type natriuretic peptide. Moreover, the medications at 3 years after AVR were investigated. Patients were classified into the treatment group for a particular medication if they were taking it for Nhalf of the follow-up period. Pre- and postoperative atrial fibrillation was investigated. Here, atrial fibrillation indicated permanent atrial fibrillation, which was defined as detection on an electrocardiogram at least three times during N6 months. Pre- and postoperative hospitalization due to heart failure and occurrence of ventricular tachycardia was also evaluated. 2.3. Echocardiographic examination and parameters Comprehensive transthoracic echocardiography was performed before AVR, and 1 year and beyond 5 years after AVR, using high-quality, commercially available ultrasound systems [a Toshiba SSH 140-A Ultrasound System (Toshiba Medical Systems, Tochigi, Japan), an Acuson Sequoia C256 Echocardiography System (Acuson Corp, Mountain view, USA), a Vivid E9 Ultrasonic Unit (GE Health Care, Tokyo, Japan)]. By reviewing the recorded images of all study patients, LVDd, LVDs, septal wall thickness, and posterior wall thickness were measured from parasternal views and EF was measured using the modified Simpson's method by two experienced sonographers. LV mass was calculated using the formula for estimating LV mass from LV linear dimensions as described in the guidelines of the American Society of Echocardiography [13]. Moreover, we examined loading condition at each echocardiographic examination, which may influence EF. 2.4. Statistical analysis Statistical analyses were performed using SPSS for Windows 22.0 (SPSS, Chicago, IL, USA). All data are expressed as mean ± SD values. Differences in parameters between 2 groups were determined using the Mann–Whitney U-test for continuous variables or Fisher's exact test for discrete variables. One-way repeated-measures analysis of variance (ANOVA) and a post hoc test (Turkey-Kramer test) were used to test for significance adjustment for multiple comparisons. Statistical significance was set at a p value of b0.05.
Pre- and postoperative characteristics Age (years) Sex (male), n (%) Height (cm) Body weight (kg) Body mass index (kg/m2) Body surface area (m2) Extracorporeal circuit (min) Mean blood pressure (mmHg) Heart rate (bpm) LVDd (mm) LVDs (mm) EF (%) Hypertension, n (%) Diabetes, n (%) Cerebral infarction, n (%) COPD, n (%) Connective tissue disease, n (%) Smoking habit, n (%) Preoperative AF, n (%) Preoperative occurrence of VT, n (%) Preoperative hospitalization due to heart failure, n (%) Postoperative AF, n (%) Postoperative occurrence of VT, n (%) Postoperative hospitalization due to heart failure, n (%)
56.3 ± 15.0 44 (75.9) 164.2 ± 9.1 60.8 ± 13.0 22.4 ± 3.2 1.7 ± 0.2 122.3 ± 37.1 89.7 ± 11.3 73.0 ± 14.5 67.9 ± 7.5 47.2 ± 9.2 53.5 ± 13.6 31 (53.4) 4 (6.9) 4 (6.9) 2 (3.4) 4 (6.9) 23 (39.6) 8 (13.8) 2 (3.4) 22 (37.9) 14 (24.1) 3 (5.2) 5 (8.6)
Preoperative laboratory data Hb (g/L) WBC count (109/L) Eosinophils (%) BUN (mmol/L) Cr (μmol/L) eGFR (mL/min/1.73m2) BNP (pmol/L) Total cholestelol (mmol/L) LDL (mmol/L)
12.8 ± 1.7 6041 ± 2120 2.9 ± 2.2 6.9 ± 2.8 88.4 ± 26.5 61.5 ± 21.6 136.0 ± 313.0 4.6 ± 0.8 2.9 ± 0.6
Preoperative medications ACE I/ARB, n (%) β-blockers, n (%) Digoxin, n (%) Diuretics, n (%) Statins, n (%) Anti-platelets, n (%) Anti-coagulates, n (%)
37 (63.8) 11 (19.0) 14 (24.1) 32 (55.2) 5 (8.6) 4 (6.9) 3 (5.2)
Postoperative medications (three years) ACE I/ARB, n (%) β-blockers, n (%) Digoxin, n (%) Diuretics, n (%) Statins, n (%) Anti-platelets, n (%) Anti-coagulates, n (%)
27 (46.7) 27 (46.7) 9 (15.5) 21 (36.2) 11 (19.0) 21 (36.2) 45 (77.6)
Values are presented as mean ± SD or n (%). LVDd = left ventricular end-diastolic diameter; LVDs = left ventricular end-systolic diameter; EF = ejection fraction; COPD =
3. Results
chronic obstructive pulmonary disease; AF = atrial fibrillation; VT = ventricular tachycardia; Hb = hemoglobin; WBC = white blood cell; BUN = blood urea nitrogen; Cr =
3.1. Baseline characteristics
creatinine; eGFR = estimated glomerular filtration rate; BNP = B-type natriuretic peptide; LDL = low-density lipoprotein; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker.
The baseline characteristics of all patients are described in Table 1. The mean follow-up period was 10.3 ± 5.2 years. The etiology of AR was as follows: degenerative valve in 24 patients, annuloaortic ectasia in 10, valve prolapse in 8, bicuspid valve in 8, rheumatic valve in 5, and others in 3. AVR was performed with a bioprosthesis (18 patients) or a mechanical prosthesis (40 patients). AVR alone was performed in 51 patients and concomitant replacement of the ascending aorta was performed in 7 patients.
but it was normalized at 1 year after AVR in all patients except for one. At 5–10 years after AVR, EF improved in one patient with EF of b 50% at 1 year after AVR, however, 7 of the 57 patients with EF N50% at 1 year after AVR showed recurrent LV dysfunction. Therefore, late recurrence of LV dysfunction developed in 7 (12%) of the 58 patients. 3.3. Predictors of late recurrent LV dysfunction
3.2. Chronological changes in LV function The chronological changes in echocardiographic data of LV function are shown in Fig. 1. The preoperative EF was b 50% in 21 (36%) patients,
In order to clarify the predictors of late recurrent LV dysfunction, we compared the parameters between 7 patients with late recurrence of LV dysfunction and 51 patients without it. The etiology of AR in 7 patients
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M. Amano et al. / International Journal of Cardiology 224 (2016) 240–244
Fig. 1. Chronological changes in echocardiographic data of 58 patients who were followed up with echocardiography for N5 years. Seven patients showed late recurrence of LV dysfunction (arrow). Pre = preoperative; y = year; LVDd = left ventricular end-diastolic diameter; LVDs = left ventricular end-systolic diameter; EF = ejection fraction.
with late recurrence of LV dysfunction was as follows: degenerative valve in 4 patients, annuloaortic ectasia in 1, valve prolapse in 1, rheumatic valve in 1. The 7 patients with late recurrence of LV dysfunction had a significantly larger LVDd and LVDs before (LVDd, p b 0.01; LVDs, p b 0.01) and at 1 year after AVR (LVDd, p = 0.02; LVDs, p = 0.01), a significantly lower EF before AVR (p b 0.01), a significantly lower relative wall thickness before AVR (p = 0.04), a significantly greater LV mass index at 1 year after AVR (p = 0.02), a higher incidence of preoperative and postoperative atrial fibrillation (preoperative, p = 0.02; postoperative, p = 0.01), and a higher postoperative administration rate of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (p = 0.03) compared with the 51 patients who did not suffer from late recurrence of LV dysfunction (Table 2). There were no significant differences in the preoperative creatinine levels (p = 0.30), eGFR (p = 0.30), total cholesterol levels (p = 0.78), ages at AVR (p = 0.29), medications except angiotensinconverting enzyme inhibitor or angiotensin II receptor blocker, underlying diseases, or preoperative occurrence of ventricular tachycardia or hospitalization due to heart failure between the 2 groups. Regarding the loading condition at each echocardiographic examination, there were no significant differences in mean blood pressure, heart rate, mitral regurgitation grade between patients with and without late recurrent LV dysfunction and between at 1 year and 5–10 years post operative follow-up echocardiography (Table 3).
4.1. Chronological changes in LV function; comparison with previous studies In our study, LVDd, LVDs, and EF were normalized at 1 year after AVR in all of the patients, except for one with preoperative LV dysfunction. Previous reports suggested that the improvements in LV function soon after AVR were due to an early reduction in volume overloading and a late remodeling process occurring after AVR [14,18]. Bonow et al. [14] reported that EF was normalized in 41% of patients who showed a low preoperative EF and the remaining patients showed a low EF at 6–8 months after AVR. However, in our study, all of the patients, except for one with a low preoperative EF, had normalized EF at 1 year after AVR. The discrepancy between our findings and those of Bonow et al. [14] might be due to differences in the length of the follow-up period. LV function of patients who have a low preoperative EF might markedly improve around the first year after AVR. Moreover, the present surgical techniques and postoperative outcomes have improved compared with those in 1980s when Bonow et al. reported the result [10]. Therefore, this might also affect to the discrepancy. Bonow et al. [14] also demonstrated that patients whose EF improved at 6–8 postoperative months did not suffer late recurrence of LV dysfunction. They also showed that Nhalf of the patients who showed a low EF at 6–8 months after AVR did not achieve any improvement in their LV function 3–7 years after AVR. Because the timing of follow-up was different from our study, late recurrence of LV dysfunction might not have been able to be detected in their study.
4. Discussion 4.2. Predictors of late recurrent LV dysfunction In the present study, we have newly identified the cases in which late recurrence of LV dysfunction developed during the long-term follow-up periods despite EF being normalized early after AVR for chronic AR. There are few longitudinal data about LV function although the improvement of postoperative outcomes in patients with preoperative LV dysfunction had been reported [10]. Moreover, many reports have demonstrated survival rate for N 10 years after AVR, but the follow-up periods of LV function were b 5 years in most previous studies [14–18]. Therefore, the chronological changes of LV function with longer follow-up period after AVR should be re-investigated.
In the present study, parameters of LV function, such as LVDd, LVDs, EF, relative wall thickness and LV mass index before and/or 1 year after AVR were indicators of late recurrent LV dysfunction. The preoperative large LVDd and LVDs might reflect the degree of eccentric hypertrophy due to volume overloading. Large LVDs and low relative wall thickness indicated increased wall stress, namely pressure overloading. Preoperative volume and pressure overloading due to severe AR were reduced by surgical intervention. In fact, EF had been normalized in all patients except for one at 1 year after AVR in the present study. However, chronic volume
M. Amano et al. / International Journal of Cardiology 224 (2016) 240–244 Table 2 Predictors of late recurrent left ventricular dysfunction.
Preoperative LVDd (mm) Preoperative LVDs (mm) Preoperative EF (%) Preoperative LV mass index (g/m2) Preoperative RWT Age (years) Sex (male), n (%) Body mass index (kg/m2) Body surface area (m2) Mean blood pressure (mmHg) Heart rate (bpm) Hypertension, n (%) Diabetes, n (%) Cerebral infarction, n (%) COPD, n (%) Connective tissue disease, n (%) Smoking habit, n (%) Preoperative AF, n (%) Preoperative occurrence of VT, n (%) Preoperative hospitalization due to heart failure, n (%) Hb (g/L) Eosinophils (%) Cr (μmol/L) e-GFR (ml/min/1.73m2) Total cholesterol (mmol/L) Preoperative ACE I/ARB, n (%) Preoperative β-blockers, n (%) Preoperative diuretics, n (%) 1 yr postoperative LVDd (mm) 1 yr postoperative LVDs (mm) 1 yr postoperative EF (%) 1 yr postoperative LV mass index (g/m2) 1 yr postoperative RWT Postoperative AF, n (%) Postoperative ACE I/ARB, n (%) Postoperative β-blockers, n (%) Postoperative diuretics, n (%)
243
Table 3 Loading condition at each echocardiographic examination.
Recurrence of LV dysfunction
No recurrence of LV dysfunction
n=7
n = 51
77.4 ± 5.9 62.0 ± 6.9 35.6 ± 6.0 234.7 ± 49.8 0.25 ± 0.05 61.3 ± 14.0 6 (85.7) 21.5 ± 3.1 1.64 ± 0.18 93.4 ± 11.2 82.3 ± 21.6 4 (57.1) 0 (0.0) 1 (14.3) 0 (0) 0 (0) 5 (71.4) 3 (42.9) 1 (14.3) 4 (57.1)
66.6 ± 6.8 45.1 ± 7.5 55.9 ± 12.6 191.8 ± 47.5 0.31 ± 0.07 55.6 ± 15.1 38 (74.5) 22.5 ± 3.2 1.65 ± 0.20 88.7 ± 10.8 71.7 ± 12.7 27 (52.9) 4 (7.8) 3 (5.8) 2 (3.9) 4 (7.8) 18 (35.3) 5 (9.8) 1 (2.0) 18 (35.3)
b0.01 b0.01 b0.01 0.06 0.04 0.29 0.52 0.57 0.98 0.30 0.28 0.83 0.44 0.41 0.59 0.44 0.07 0.02 0.09 0.26
131.9 ± 13.9 1.7 ± 1.4 97.2 ± 17.7 53.6 ± 10.0 4.5 ± 0.7 5 (71.4) 1 (14.3) 5 (71.4) 54.3 ± 5.8 37.4 ± 5.2 59.0 ± 8.2 134.7 ± 22.7 0.38 ± 0.08 5 (71.4) 6 (85.7) 23 (39.7) 4 (57.1)
127.3 ± 16.8 3.1 ± 2.3 88.4 ± 26.5 62.7 ± 22.5 4.6 ± 0.8 32 (62.7) 10 (19.6) 27 (52.9) 48.8 ± 5.7 30.8 ± 5.5 65.1 ± 7.4 111.1 ± 29.2 0.42 ± 0.10 9 (17.6) 21 (41.2) 4 (57.1) 17 (33.3)
0.57 0.08 0.30 0.30 0.78 0.65 0.74 0.36 0.02 0.01 0.06 0.02 0.25 b0.01 0.03 0.55 0.22
p-value
Values are presented as mean ± SD or n (%). LVDd = left ventricular end-diastolic diameter; LVDs = left ventricular end-systolic diameter; EF = ejection fraction; RWT = relative wall thickness; yr = year; COPD = chronic obstructive pulmonary disease; AF = atrial fibrillation; VT = ventricular tachycardia, Hb = hemoglobin; Cr = creatinine; eGFR = estimated glomerular filtration rate; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker.
and pressure overloading can cause cardiac damage. Previous studies showed that chronic volume overloading can induce microvascular dysfunction and changes in the extracellular matrix [19] and chronic pressure overloading can increase cardiac oxidative damage, in association with cardiac hypertrophy and fibrosis [20,21]. Eventually, accumulating microvascular cardiac damage might result in late recurrence of LV dysfunction despite EF being normalized early after AVR. LVDd, LVDs and LV mass index also decreased at 1 year after AVR, but were not always normalized in patients with late recurrent LV dysfunction, and they were indicators of late recurrent LV dysfunction. In addition to LV function before and 1 year after AVR, postoperative atrial fibrillation was related to late recurrence of LV dysfunction. Atrial fibrillation leads to atrial dysfunction [22] and LV diastolic dysfunction. In addition, long-standing atrial fibrillation or atrial fibrillation with rapid conduction leads to LV systolic dysfunction. All of these conditions are potential causes of late recurrent LV dysfunction. Therefore, maintaining sinus rhythm is important, especially for patients with preoperative LV dysfunction, to prevent late recurrence of LV dysfunction after AVR. With respect to medications, the postoperative administration rate of angiotensin-converting enzyme inhibitor or angiotensin II receptor
Preoperative mean BP (mmHg) Preoperative HR (bpm) Preoperative MR (Nmoderate), n (%) 1 yr postoperative mean BP (mmHg) 1 yr postoperative HR (bpm) 1 yr postoperative MR (Nmoderate), n (%) 5–10 years postoperative mean BP (mmHg) 5–10 years postoperative HR (bpm) 5–10 years postoperative MR (Nmoderate), n (%)
Recurrence of LV dysfunction
No recurrence of LV dysfunction
n=7
n = 51
93.4 ± 11.2 82.3 ± 21.6 2 (28.6) 92.3 ± 9.6⁎
63.6 ± 13.3⁎ 0 (0)⁎
88.7 ± 10.8 71.7 ± 12.7 6 (11.8) 92.6 ± 10.0⁎ 68.1 ± 12.4⁎ 2 (3.9)⁎
0.30 0.28 0.23 0.93 0.26 0.59
93.1 ± 9.8
91.2 ± 8.8
0.59
71.7 ± 15.7 1 (14.3)
66.2 ± 9.9 3 (5.8)
0.40 0.41
p-value
Values are presented as mean ± SD or n (%). ⁎ p N 0.05 vs. 5–10 years. postoperative values. LV = left ventricular; BP = blood pressure; HR = heart rate; MR = mitral regurgitation; yr = year.
blocker was significantly higher in patients with late recurrence of LV dysfunction. These patients showed preoperative LV dysfunction, thus postoperative administration of these drugs was appropriate. However, they revealed late recurrence of LV dysfunction despite with administration of these drugs. 4.3. Limitations The present study has several limitations, mainly based upon its retrospective nature. First, not all of the patients could be followed up systematically, resulting in differences among the patients in the echocardiographic follow-up period after AVR (maximum difference: 5 years). This might have affected our results regarding the chronological changes in LV function after AVR. Second, the small number of patients is a major issue. Moreover, for statistical comparisons between the 2 groups, we had to use non-parametric statistics. The small number of subjects might have affected the statistical power of the variables. 5. Conclusions Late recurrence of LV dysfunction often occurs after AVR for severe chronic AR. Therefore, long-term follow-up is important even if EF is normalized. Early surgery preceding remarkable LV enlargement and maintenance of sinus rhythm are important for maintaining LV function over long-term follow-up after AVR. Conflict of interest The authors have no conflicts of interest to disclose. Acknowledgements The authors thank Hitoshi Ohbayashi for assisting with data analysis. References [1] R.A. Nishimura, C.M. Otto, R.O. Bonow, et al., 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J. Am. Coll. Cardiol. 63 (2014) 2438–2488. [2] A. Vahanian, O. Alfieri, F. Andreotti, et al., Guidelines on the management of valvular heart disease (version 2012), Eur. Heart J. 33 (2012) 2451–2496. [3] R.O. Bonow, D. Nikas, J.A. Elefteriades, Valve replacement for regurgitant lesions of the aortic or mitral valve in advanced left ventricular dysfunction, Cardiol. Clin. 13 (1995) 73–83 85. [4] K.S. Dujardin, M. Enriquez-Sarano, H.V. Schaff, K.R. Bailey, J.B. Seward, A.J. Tajik, Mortality and morbidity of aortic regurgitation in clinical practice. A long-term followup study, Circulation 99 (1999) 1851–1857.
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