PLOS ONERESEARCH ARTICLE

Clinical impact of pathology-proven etiologyof severely stenotic aortic valves on mid-term
outcomes in patients undergoing surgicalaortic valve replacement
Shiro Miura ID1*, Katsumi Inoue2☯, Hiraku Kumamaru3☯, Takehiro Yamashita1‡,
Michiya Hanyu4‡, Shinichi Shirai5‡, Kenji Ando5‡

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1 Department of Cardiology, Hokkaido Ohno Memorial Hospital, Sapporo, Japan, 2 Department ofLaboratory Medicine, Kokura Memorial Hospital, Kitakyushu, Japan, 3 Department of Healthcare Quality
Assessment, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 4 Cardiovascular Center,Tazuke Kofukai Foundation Medical Research Institute, Kitano Hospital, Osaka, Japan, 5 Department of
Cardiology, Kokura Memorial Hospital, Kitakyushu, Japan☯ These authors contributed equally to this work.
‡ These authors also contributed equally to this work.
* s.miura@ohno-kinen.or.jp

OPEN ACCESS
Citation: Miura S, Inoue K, Kumamaru H,
Yamashita T, Hanyu M, Shirai S, et al. (2020)
Clinical impact of pathology-proven etiology ofseverely stenotic aortic valves on mid-term
outcomes in patients undergoing surgical aortic
valve replacement. PLoS ONE 15(3): e0229721.
https://doi.org/10.1371/journal.pone.0229721
Editor: Wen-Chih Wu, Providence VA Medical
Center, UNITED STATESAbstract
BackgroundThe use of transcatheter or surgical aortic valve replacement (AVR) for severe aortic stenosis (AS) has considerably increased in recent years. However, the association between AS
etiology and mid-term clinical outcomes after surgical AVR has not been fully investigated.

Received: July 9, 2019

Methods and results

Accepted: February 12, 2020

We retrospectively included 201 patients (mean age, 75 years; 43%, men) who underwent
surgical AVR for severe native AS (aortic valve area �1.0 cm2 on preoperative transthoracic
echocardiography examination). The following valve etiologies were postoperatively identified on pathological examination: post-inflammatory (n = 28), congenital (n = 35), and calcific/degenerative (n = 138). The median follow-up interval was 4.1 years following surgical
AVR. Of the 201 patients, 27% were asymptomatic, 40% had a history of heart failure, and
11% underwent previous heart surgery. The cumulative incidence of cardiac events (allcause death, aortic valve deterioration requiring repeated AVR, and hospitalization for heart
failure) and combined adverse events, which included non-fatal stroke, unplanned coronary
revascularization, pacemaker implantation, and gastrointestinal bleeding along with cardiac
events, was significantly higher in the calcific/degenerative group (p = 0.02 and p = 0.02,
respectively). In multivariate analysis adjusted for age, sex, renal function, heart failure,atrial fibrillation, concomitant surgical procedures, and EuroSCORE II, AS etiology was
independently associated with an increased risk of combined adverse events (congenitalvs. post-inflammatory: hazard ratio [HR], 4.13; p = 0.02 and calcific/degenerative vs. postinflammatory: HR, 5.69; p = 0.002).

Published: March 10, 2020
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https://doi.org/10.1371/journal.pone.0229721
Copyright: © 2020 Miura et al. This is an open
access article distributed under the terms of theCreative Commons Attribution License, which
permits unrestricted use, distribution, andreproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data arewithin the paper and its Supporting Information
files.

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1 / 15PLOS ONE

Funding: The authors received no specific funding
for this work.
Competing interests: NO authors have competinginterests.

Clinical outcome by aortic stenosis etiology after surgical aortic valve replacement

Conclusions
Pathology-proven AS etiology could aid in predicting the mid-term outcomes after surgical
AVR, supporting the importance of accurate identification of severe AS etiology with or without postoperative pathological examination.

Introduction
The most common form of stenotic aortic valves in Europe and the United States is calcific/
degenerative, followed by those due to congenital malformations. Although rheumatic etiology
is now infrequent in the West, it remains prevalent in developing countries [1]. Since the firststudy on the incidence of aortic valve calcification according to its etiology with increasing
age in 1968 [2], these major etiologies have dominated the potential etiology of stenotic aortic
valves. Transthoracic echocardiography (TTE) examination plays a central role in identifying
the etiology of stenotic aortic valves by evaluating the valve appearance, number of cusps, pattern of thickening, and valve mobility [3]. However, in highly progressed aortic stenosis (AS),TTE can result in an inaccurate diagnosis, mainly because of severe aortic valve calcification orlimited acoustic windows [4]. Thus, the evaluation and use of multimodality imaging, including transesophageal echocardiography, cardiac magnetic resonance imaging, and cardiac
computed tomography, are highly recommended. Nevertheless, in selected cases such as congenital AS, there are still challenges in the preoperative identification of accurate AS etiology[5, 6]. When these stenotic aortic valves meet the standardized criteria for severe status insymptomatic patients irrespective of their etiology, most patients are referred to cardiovascularsurgeons for surgical or transcatheter aortic valve replacement (AVR). An essential clinicalimplication in the identification of the accurate etiology of severe AS in patients undergoing
AVR can be risk stratification by predicting its natural history, estimating surgical risk, orassessing potential comorbidities associated with its etiology. Nonetheless, there is uncertainty
in the strength of the association between aortic valve etiology validated by postoperative histopathological examination and mid-term outcomes following surgical AVR.
This study aimed to (i) describe the incidence of each aortic valve etiology validated bypathological examination, highlighting the differences and similarities in clinical, echocardiographic, and operative data among AS patients with different valve etiologies requiring surgical
AVR, and (ii) compare the clinical outcomes following surgical AVR with and without statistical adjustments for established risk factors.

Materials and methods
Study population
Among 595 consecutive patients who were initially diagnosed with severe AS with an aortic
valve area (AVA) �1.0 cm2 on TTE examination [7] between August 2009 and February 2012
and followed up at our institution up to June 2015, 210 underwent surgical AVR, whereas 360
were medically managed, 18 were treated with transcatheter AVR, and follow-up data werelost for 7 (Fig 1). It is to be noted that no patient underwent other surgical aortic valve procedures, such as aortic valve repair, AVR with human homograft, or Ross procedure. Following
exclusion of patients with a previous history of cardiac surgery on the aortic valve (n = 5),
unavailability of pathology data (n = 2), and unidentified valve etiology (n = 2), the remaining
201 patients were included in the final analysis. Patients were divided into the following threegroups according to accurate aortic valve etiology verified only by postoperative histologicalexaminations: post-inflammatory (n = 28, 14%), congenital (n = 35, 17%), and calcific/

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Fig 1. Study population flow chart.
https://doi.org/10.1371/journal.pone.0229721.g001

degenerative (n = 138, 69%). Pathological features of the surgically excised aortic valves wereclassified based on gross and histological findings by experienced pathologists without knowledge of the patients’ prognosis in 201 cases based on the main pathology criteria defined inprevious reports [8–12]. Representative images from the gross examinations of the surgicallyexcised aortic valves are presented in Fig 2. A comparison of the pathological diagnosis of theaortic valve etiology by clinical pathologists revealed a 79% (159/201 cases) concordance withthe preoperative diagnosis by the attending physicians using imaging modalities (mainly
TTE). Written informed consent was waived due to the retrospective nature of this study,
which was reviewed and approved by the institutional review board (IRB) of Kokura Memorial
Hospital. We followed the appropriate ethical protocols and privacy guidelines approved by
the IRB when contacting the patients and/or their relatives.

Clinical data
Preoperative patient characteristics included age, sex, body surface area, body mass index,
symptomatic status, and laboratory data. Additionally, data on the presence of comorbidities
of atrial fibrillation (AF), prior admission for heart failure (HF), previous history of cardiac

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3 / 15PLOS ONEClinical outcome by aortic stenosis etiology after surgical aortic valve replacement

Fig 2. Gross inspections of post-inflammatory (A), congenital (B), and calcific/degenerative (C) aortic stenosis in the representative cases fromour study. A: Post-inflammatory tricuspid aortic valve on the aortic side showing severe thickening of the cusps and fusion of the commissures withnodular calcification (asterisk). B: Bicuspid aortic valve on the aortic side demonstrating marked calcification of the raphe (black arrowheads) andheavy nodular calcification and severe fibrous thickening (red arrowheads). C: Calcific/degenerative tricuspid aortic valve characterized by patchy,
moderate fibrotic thickening and focal heavy calcification at the base on the aortic side of the three cusps with adjacent portions of the cusps partiallytranslucent.
https://doi.org/10.1371/journal.pone.0229721.g002

surgery, and history of percutaneous coronary intervention (PCI) were collected via medical
chart review. We evaluated renal function using the estimated glomerular filtration rate (GFR)
calculated with the Modification of Diet in Renal Disease Study equation arranged for the Japanese population, and chronic kidney disease was diagnosed if the estimated GFR was <60
mL/min/1.73 m2 or the urine albumin:creatinine ratio was >30 mg/g [13]. As an inclusive risk
assessment index, both the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II and the Society of Thoracic Surgeons (STS) score were calculated to compare thepotential operative risk among the groups [14–16].
Comprehensive TTE was conducted by experienced sonographers using commerciallyavailable ultrasound systems (Vivid 7 Dimension and Vivid E9, GE Healthcare, Horten, Norway; iE33, Philips Medical Systems, Best, The Netherlands; Aplio SSA-700A, Toshiba Medical
Systems, Tokyo, Japan) at 1 month before and after surgical AVR. Doppler echocardiographic
measurements comprised the aortic mean pressure gradient using the simplified Bernoulli
equation and the AVA and effective orifice area using a standard continuity equation. Strokevolume was calculated by Doppler using the velocity-time integral of the LV outflow tractand its diameter in the mid-systole of the aortic annulus in the parasternal long-axis view. For
patients with AF, velocities from two or three heat cycles were averaged to reduce the influenceof beat-to-beat variation. The severity of aortic, mitral, and tricuspid regurgitation wasassessed following international guidelines [7].

Definition of clinical outcome and follow-up
Clinical follow-up data after surgical AVR were obtained from medical records, patients, relatives, or attending physicians either in person or by telephone interviews until June 2015. Follow-ups were commenced on the day of index surgical AVR. Along with all-cause death as a
primary endpoint, cardiac events were defined as a composite of all-cause death, aortic valve
deterioration requiring repeated AVR, and hospitalization for HF. Combined adverse events
included, along with cardiac events, non-fatal stroke, new-onset ischemic heart disease requiring unplanned PCI and/or coronary artery bypass grafting (CABG), symptomatic

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4 / 15PLOS ONEClinical outcome by aortic stenosis etiology after surgical aortic valve replacement

bradycardia/ventricular tachycardia treated with pacemaker/implantable cardioverter defibrillator, and hospital admission for non-fatal gastrointestinal bleeding. Cardiovascular death was
defined as deaths from worsened HF, acute coronary syndrome and stroke, postoperative inhospital death, or sudden death. Perioperative death was defined as mortality within 30 days
following surgical AVR. These definitions of the clinical outcomes were established prior to
conducting this clinical study, based on our clinical interests and information from previous
studies [17, 18].

Statistical analysis
Descriptive statistics are expressed as mean ± SD or median (interquartile range), whereas
categorical variables are presented as number and percentage. Differences between patients indifferent groups were compared using one-way analysis of variance, followed by post-hoc Bonferroni correction for continuous variables and chi-square test or Fisher’s exact test for categorical variables. Kaplan-Meier curves and log-rank test for the time-to-event data were used
to assess the association between the three types of aortic valve etiology and all-cause death,cardiac events, and combined adverse events; inter-group differences were tested using the
log-rank test. Furthermore, the associations between aortic valve etiology and clinical outcomes were estimated using Cox proportional hazards regression models for cumulative clinical events, with adjustment for a comprehensive cardiac operative risk value (EuroSCORE II),
clinically relevant variables, and risk factors consistent with previous research [19]. The proportional hazards assumption was checked using statistical tests and graphical diagnostics
based on the scaled Schoenfeld residuals. A p-value <0.05 was considered statistically significant. All statistical analyses were performed using R statistical software version 3.3.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results
Preoperative characteristics of the study population
A comparison of preoperative clinical characteristics and medication use at discharge is presented in Table 1. Among 201 patients (mean age, 75±9 years; 43%, men), 27% were asymptomatic, 40% had a history of HF, and 11% underwent prior open heart surgery. Patients inthe calcific/degenerative group were older (p<0.001); had a higher prevalence of hypertension(p<0.001), dyslipidemia (p = 0.03), and coronary artery disease (p<0.001); had lower estimated GFR (p = 0.002); and were more frequently treated with antiplatelet therapy postoperatively (p = 0.001) than those in the other two groups. Patients in the post-inflammatory group
had a higher prevalence of AF (p<0.001), had higher EuroSCORE II (p = 0.003), and weremore frequently admitted for HF (p = 0.01). Patients in the congenital group had a higher
proportion of men (p = 0.001) and higher body surface area on average (p = 0.004).

Echocardiographic evaluations and procedural details
Periprocedural echocardiographic and surgical characteristics are summarized in Table 2.
Overall, echocardiographic parameters with respect to left ventricular size and systolic function were similar in the three groups; the AVA improved from 0.66 cm2 to 1.40 cm2 with surgical AVR, with a drastic reduction in the mean aortic pressure gradient from 46 to 14 mmHg.
Of note, patients in the post-inflammatory group were remarkable for the highest proportionof indexed stroke volume �35 mL/m2 (p = 0.03), with moderate or severe regurgitation on theaortic (p<0.001), mitral (p = 0.02), and tricuspid (p<0.001) valves.

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5 / 15PLOS ONEClinical outcome by aortic stenosis etiology after surgical aortic valve replacement

Table 1. Preoperative characteristics according to aortic valve etiologies.
Overall(n = 201)

Post-inflammatory(n = 28)

Congenital(n = 35)

Calcific/degenerative(n = 138)p-value�

Clinical demographics
Age (years)

75 (9)

73 (7)

68 (13)76 (7)<0.00163 (31)

6 (21)

7 (20)

50 (36)

0.09

Male sex

87 (43)10 (36)25 (71)52 (38)0.001

BMI, kg/m2

22.7 (3.3)

21.7 (2.6)

22.2 (2.6)

23.1 (3.5)

0.08

BSA, m2

1.51 (0.16)

1.49 (0.16)

1.59 (0.17)

1.49 (0.16)

0.004

Age >80 years

Asymptomatic

54 (27)6 (21)

15 (43)33 (24)0.06

Hypertension

138 (69)

11 (39)19 (54)108 (78)<0.001Diabetes mellitus

57 (28)6 (21)

5 (14)

46 (33)0.06

Dyslipidemia

91 (45)

10 (36)

10 (29)71 (51)

0.03

Hyperuricemia

21 (10)4 (14)

3 (8.6)14 (10)0.75

Prior heart failure

81 (40)17 (61)8 (23)

56 (41)

0.01

Coronary artery disease72 (36)5 (18)

5 (14)

62 (45)<0.001

Old myocardial infarction

16 (8)

2 (7.1)2 (5.7)

12 (8.7)

0.83

Previous heart surgery

22 (11)7 (25)

2 (5.7)13 (9.4)

0.03

Chronic kidney disease

170 (85)

24 (86)28 (80)118 (86)

0.71

Hemodialysis

20 (10)

0 (0)

0 (0)

20 (15)0.01

Chronic lung disease

20 (10)3 (11)

4 (11)

13 (9)

0.93

Previous stroke

22 (11)1 (3.6)3 (8.6)18 (13)0.30

Atrial fibrillation

63 (31)21 (75)5 (14)

37 (27)<0.001

Peripheral vascular disease

17 (8.5)

1 (3.6)2 (5.7)14 (10)0.43

Aortic aneurysm or dissection

13 (6.5)

2 (7.1)4 (11)

7 (5.1)

0.39

Malignancy

17 (8.5)

3 (11)

3 (8.6)

11 (8)

0.89

Peptic ulcer disease

11 (5.5)0 (0)3 (8.6)8 (5.8)0.32

Current smoker

13 (6.5)0 (0)8 (23)

5 (3.6)<0.0010.001

Medication use at discharge
Antiplatelets

94 (47)8 (29)

9 (26)

77 (56)

Beta blockers

52 (26)

3 (11)

9 (26)

40 (29)

0.13

ACEIs

25 (12)3 (11)

3 (8.6)19 (14)

0.68

ARBs

82 (41)9 (32)

11 (31)62 (45)

0.21

Statins

80 (40)8 (29)

8 (23)

64 (46)0.02

Calcium channel blockers

79 (39)6 (21)

14 (40)59 (43)

0.11

Diuretics

71 (35)17 (61)7 (20)

47 (34)0.003

Anticoagulants

46 (23)20 (71)4 (11)

22 (16)<0.001

Hemoglobin (g/dL)

12.2 (1.9)

12.3 (2.1)

13.6 (1.5)

11.8 (1.7)<0.001

LDL cholesterol (mg/dL)

110 (31)115 (29)109 (38)

109 (30)

0.66

Uric acid (mg/dL)

5.6 (1.8)

5.9 (1.8)

6.1 (2.5)

5.4 (1.6)

0.10

Estimated GFR (mL/min/1.73 m2)

39.8 (20)

41.5 (13)50.3 (17)36.8 (21)0.002

148 [58, 348]

311 [143, 469]

81 [51, 312]

144 [57, 305]

0.006

Laboratory data

BNP plasma level (pg/mL)
EuroSCORE II (%)

2.3 [1.5, 3.8]

2.9 [2.0, 3.3]

1.9 [1.0, 2.4]

2.3 [1.5, 4.1]

0.003

STS score (PROM) (%)

3.1 [2.0, 4.2]

3.8 [3.2, 4.7]

1.5 [0.9, 2.3]

3.3 [2.2, 4.3]

<0.001

Data are presented as mean (SD), or median [interquartile range], or n (%). BMI indicates body mass index; BSA, body surface area; ACEIs, angiotensin-converting
enzyme inhibitors; ARBs, angiotensin II receptor blockers; LDL, low-density lipoprotein; GFR, glomerular filtration rate; BNP, B-type natriuretic peptide; EuroSCORE,
European System for Cardiac Operative Risk Evaluation; STS, Society of Thoracic Surgeons; PROM, predicted risk of mortality.
�
p-value refers to comparisons among the three groups at enrollment using analysis of variance.
https://doi.org/10.1371/journal.pone.0229721.t001

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6 / 15PLOS ONEClinical outcome by aortic stenosis etiology after surgical aortic valve replacement

Table 2. Preoperative and postoperative echocardiographic assessments and procedural surgical AVR characteristics.
Overall(n = 201)

Post-inflammatory(n = 28)

Congenital(n = 35)

Calcific/
degenerative(n = 138)p-value�63 (11)61 (12)62 (13)63 (10)0.57

12 (6)

3 (11)

2 (5.7)7 (5.1)

0.52

LV end-diastolic dimension (mm)46 (6)

46 (6)

46 (7)

46 (6)

0.91

LV end-systolic dimension (mm)30 (7)

30 (6)

31 (9)

30 (6)

0.56

Aortic root diameter (mm)31 (4)

31 (3)

34 (5)

31 (3)<0.001

Left atrial diameter (mm)42 (9)

49 (13)38 (9)

42 (7)<0.001

Pulmonary artery systolic pressure (mmHg)

35 (13)43 (21)32 (11)33 (12)0.001

SV (mL)

63 (15)58 (12)66 (18)64 (14)0.05

Indexed SV (mL/m2)

43 (10)39 (8)

42 (11)43 (9)

0.079
0.03

Echocardiographic parameters
LVEF (%)
LVEF �40%

Indexed SV �35 mL/m2

45 (23)

11 (41)

10 (29)24 (18)Preoperative AVA (cm2)0.66 (0.15)

0.71 (0.14)

0.63 (0.18)

0.66 (0.14)

0.1

Preoperative indexed AVA (cm2/m2)

0.46 (0.11)

0.47 (0.12)

0.41 (0.11)

0.47 (0.1)

0.02Preoperative Vmax (m/s)

4.4 (0.8)

4.1 (1)4.7 (0.7)

4.3 (0.8)

0.01

Preoperative MPG (mmHg)

46 (19)42 (22)54 (17)45 (18)0.02

Postoperative EOA (cm2)1.40 (0.37)

1.48 (0.20)

1.51 (0.43)

1.35 (0.36)

0.28

Postoperative Vmax (m/s)

2.5 (0.5)

2.3 (0.5)

2.5 (0.6)

2.6 (0.5)

0.02

Postoperative MPG (mmHg)

14 (6)

11 (5)

14 (7)

15 (6)

0.04

Moderate or severe AR

17 (8.5)

8 (29)

2 (5.7)7 (5.1)<0.001Moderate or severe MR

20 (10)7 (25)

2 (5.7)

11 (8.0)

0.02

Moderate or severe TR

16 (8.0)

8 (29)

3 (8.6)5 (3.6)<0.001

Bioprosthetic valve

160 (80)

19 (68)22 (63)119 (86)

0.002

Mechanical valve

41 (20)9 (32)

13 (37)19 (14)

Surgical data

16 mm

1 (0.5)

0 (0)

0 (0)

1 (0.7)17 mm

7 (3.5)

1 (3.6)

1 (2.9)5 (3.6)

0.01

18 mm

1 (0.5)

0 (0)

0 (0)

1 (0.7)19 mm

87 (43)

12 (43)6 (17)

69 (50)20 mm

2 (1.0)1 (3.6)

1 (2.9)

0 (0)

21 mm

66 (33)9 (32)

11 (31)46 (33)22 mm

1 (0.5)0 (0)1 (2.9)

0 (0)

23 mm

26 (13)3 (11)

10 (29)13 (9.4)

24 mm

2 (1.0)0 (0)1 (2.9)1 (0.7)25 mm

8 (4.0)2 (7)4 (11)

2 (1.4)98 (49)23 (82)13 (37)62 (45)CABG

40 (20)1 (3.6)3 (8.6)36 (26)

0.004

Mitral valve replacement or repair

49 (24)23 (82)2 (5.7)24 (17)<0.001

Tricuspid valve replacement or repair

17 (8.5)

10 (36)2 (5.7)5 (3.6)<0.001

Ascending aorta replacement

13 (6.5)

1 (3.6)8 (23)

4 (2.9)<0.001Maze operation

4 (2)4 (14)

0 (0)

0 (0)

<0.001

Concomitant procedures

0.001

Data are presented as mean (SD) or n (%). AVR indicates aortic valve replacement; LVEF, left ventricular ejection fraction; LV, left ventricular; SV, stroke volume; AVA,
aortic valve area; Vmax, peak aortic jet velocity; MPG, mean aortic pressure gradient; EOA, effective orifice area; AR, aortic regurgitation; MR, mitral regurgitation; TR,
tricuspid regurgitation; CABG, coronary artery bypass grafting.
�

p-value refers to comparisons among the three groups using analysis of variance.

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With respect to procedural details, 80% (n = 160) of patients underwent replacement with abioprosthetic valve and 49% underwent concomitant surgical procedures. Among them,
CABG was most frequently performed in the calcific/degenerative group (p = 0.004), and procedures on the mitral and tricuspid valves were the most common in the post-inflammatorygroup (p<0.001 each). Patients in the congenital group most frequently underwent ascending
aorta replacement at 23% (p<0.001).
Impact of the aortic valve etiology on mid-term outcome. A comparison of detailed
clinical events among the three groups is presented in Table 3. During a median follow-up
period of 4.1 years (interquartile range: 2.7–5.1 years) with a 97% follow-up rate at 3 years, 30
patients (15%) died, with cardiovascular death reported in 13 (7%) of the total patients. Only
one dialysis-dependent patient underwent a redo AVR performed at 3.1 years after the first
AVR due to aortic valve deterioration. With respect to individual clinical events, there were no
statistical differences in event rates among the three groups. The Kaplan-Meier curves for allcause death, cardiac events, and combined adverse events are shown in Fig 3. The 3-year survival rates were 96%, 94%, and 83% for the post-inflammatory, congenital, and calcific/degenerative groups, respectively. Similarly, the 3-year survival rates free from cardiac events were92%, 88%, and 75%, respectively, whereas the 3-year survival rates free from combined adverse
events were 84%, 70%, and 64%, respectively. The cumulative incidence of both cardiac eventsand combined adverse events was significantly higher in the calcific/degenerative group(p = 0.02 and p = 0.02, respectively).
The Cox proportional hazards analyses of time to the three types of outcome after surgical
AVR are summarized in Table 4. With respect to all-cause death, there was no association
between aortic valve etiology and mortality after adjustments. However, compared to thepost-inflammatory group, the calcific/degenerative group was independently associatedwith an increased risk of cardiac events (hazard ratio [HR], 4.45; 95% confidence interval[CI], 1.07–18.4; p = 0.04) and combined adverse events (HR, 3.59; 95% CI, 1.30–9.88;
p = 0.01). After adjustments for several confounders (age, sex, previous HF, and EuroSCORE II), the calcific/degenerative group remained independently associated with the riskof cardiac events (HR, 5.84; 95% CI, 1.39–24.4; p = 0.01). Risks for combined adverse eventswere significantly higher in the calcific/degenerative group (HR, 5.69; 95% CI, 1.87–17.2;
p = 0.002) and congenital group (HR, 4.13; 95% CI, 1.20–14.2; p = 0.02) after adjustments
for age, sex, previous HF, AF, concomitant surgical procedures, estimated GFR, and EuroSCORE II.
The New York Heart Association functional classification of patients with severe AS at thefirst diagnosis, within 30 days prior to surgical AVR, and at the end of the follow-up period issummarized in Fig 4 with a comparison among the three etiologies. Eighty-six patients (43%)
were asymptomatic at the first diagnosis with severe AS, which decreased to 54 (27%) preoperatively. Patients in the post-inflammatory group were more symptomatic than those in thecongenital group during the preoperative period (p = 0.02). At the end of the follow-up period,
44 patients (72%) were free from cardiac symptoms, and the proportion of asymptomaticpatients in the congenital group (94%) was much greater than that in the other two groups(p = 0.04).

Discussion
Patients with severe AS due to calcific/degenerative etiology had significantly worse postoperative clinical outcomes (defined as cardiac and combined adverse events) than those with severe
AS due to post-inflammatory processes who were more symptomatic preoperatively, with themost frequent admission for HF along with the highest operative risk defined by EuroSCORE

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Table 3. Detailed clinical outcomes following surgical AVR according to aortic valve etiology.

All-cause death

Overall(n = 201)

Post-inflammatory(n = 28)

Congenital(n = 35)

Calcific/degenerative(n = 138)p-value30 (15)2 (7.1)2 (5.7)26 (19)0.07

Cardiovascular death

13 (6.5)0 (0)2 (5.7)

11 (7.9)

0.29

Non-cardiovascular death

17 (8.5)

2 (7.1)0 (0)15 (11)

0.12

Perioperative death

7 (3.5)

0 (0)

0 (0)

7 (5.1)

0.19

Hospitalization for heart failure

22 (11)1 (3.6)

4 (11)

17 (12)

0.40

Aortic valve deterioration

1 (0.5)

0 (0)

0 (0)

1 (0.7)0.80

Unplanned coronary revascularization

9 (4.5)

0 (0)

0 (0)

9 (6.5)0.12

Non-fatal stroke

13 (6.5)

3 (11)0 (0)10 (7.3)

0.18

Pacemaker or ICD implantation

11 (5.5)0 (0)3 (8.6)8 (5.8)

0.32

Gastrointestinal bleeding

15 (7.5)0 (0)3 (8.6)

12 (8.7)

0.27

Total follow-up period (years)

4.1 [2.7, 5.1]

4.0 [3.2, 4.5]

4.6 [3.4, 5.3]

4.1 [2.4, 5.2]

0.22

Data are presented as n (%) or median [interquartile range]. AVR indicates aortic valve replacement; ICD, implantable cardioverter defibrillator
https://doi.org/10.1371/journal.pone.0229721.t003

II. Likewise, the former showed poorer prognosis than the latter, although the association was
not statistically significant. Patients in the congenital group had a markedly increased risk ofdeveloping combined adverse events after surgical AVR than those in the post-inflammatorygroup. These results highlighted the immense importance of accurate identification of theFig 3. Kaplan-Meier event curves for mid-term outcomes following surgical AVR among the three types of aortic
valve etiologies with respect to (A) all-cause death, (B) cardiac events, and (C) combined adverse events. Followups were commenced on the day of index surgical AVR. Cardiac events were defined as all-cause death, aortic valve
deterioration requiring repeated AVR, and hospitalization for HF. Combined clinical events included, along withcardiac events, non-fatal stroke, new-onset ischemic heart disease requiring unplanned coronary revascularization,
symptomatic bradycardia/ventricular tachycardia treated with pacemaker/implantable cardioverter defibrillator, andadmission for non-fatal gastrointestinal bleeding. AVR, aortic valve replacement.
https://doi.org/10.1371/journal.pone.0229721.g003

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9 / 15PLOS ONEClinical outcome by aortic stenosis etiology after surgical aortic valve replacement

Table 4. Unadjusted and adjusted outcomes according to valve etiology among patients with severe AS undergoing surgical AVR.
Outcomes
All-cause death

Cardiac events

Combined adverse events

Variables

Univariate analysis

Multivariate analysis

HR (95% CI)

p-valueHR (95% CI)

p-value

Congenital�

0.79 (0.11–5.65)

0.81

0.69 (0.09–5.40)

0.73

Calcific/degenerative�

2.74 (0.65–11.5)

0.16

3.09 (0.73–13.1)

0.12

Age (years)

0.99 (0.95–1.02)

0.63

0.97 (0.93–1.01)

0.27

Male sex

1.60 (0.78–3.29)

0.19

1.73 (0.81–3.72)

0.15

EuroSCORE II

1.18 (1.04–1.35)<0.01

1.16 (1.02–1.33)

0.02

Congenital�

2.03 (0.39–10.4)

0.39

2.44 (0.44–13.5)

0.30

Calcific/degenerative�

4.45 (1.07–18.4)

0.04

5.84 (1.39–24.4)

0.01

Age (years)

0.99 (0.96–1.02)

0.79

0.98 (0.95–1.01)

0.38

Male sex

1.58 (0.89–2.81)

0.11

1.87 (1.01–3.46)

0.04

Previous heart failure

1.76 (0.99–3.12)

0.05

1.92 (1.06–3.48)

0.03
0.02

EuroSCORE II

1.15 (1.03–1.28)<0.01

1.13 (1.01–1.26)

Congenital�

2.39 (0.76–7.52)

0.14

4.13 (1.20–14.2)

0.02

Calcific/degenerative�

3.59 (1.30–9.88)

0.01

5.69 (1.87–17.2)<0.01

Age (years)

0.99 (0.97–1.02)

0.78

0.98 (0.96–1.01)

0.39

Male sex

1.20 (0.76–1.88)

0.41

1.30 (0.79–2.16)

0.29

Previous heart failure

1.27 (0.81–2.00)

0.29

1.19 (0.74–1.92)

0.46

Atrial fibrillation

1.07 (0.61–1.85)

0.80

1.71 (0.90–3.23)

0.09

Concomitant surgical procedures

1.38 (0.88–2.17)

0.15

1.46 (0.90–2.37)

0.12

2

Estimated GFR (mL/min/1.73 m )0.97 (0.96–0.98)<0.0010.98 (0.97–0.99)

0.01

EuroSCORE II

1.08 (0.98–1.18)

0.09

1.00 (0.90–1.11)

0.91

AS indicates aortic stenosis; AVR, aortic valve replacement; HR, hazard ratio; CI, confidence interval; EuroSCORE, European System for Cardiac Operative Risk
Evaluation; GFR, glomerular filtration rate. Cardiac events were defined as all-cause death, aortic valve deterioration requiring repeated AVR, and hospitalization forheart failure. Combined clinical events included, along with cardiac events, non-fatal stroke, new-onset ischemic heart disease requiring unplanned coronary
revascularization, symptomatic bradycardia/ventricular tachycardia treated with pacemaker/implantable cardioverter defibrillator, and admission for non-fatal
gastrointestinal bleeding.
�

The valve etiology “Post-inflammatory” was used as a common reference.

https://doi.org/10.1371/journal.pone.0229721.t004

etiology of diseased aortic valves as well as postoperative management for comorbidities andlate complications.
There are several reports on the pathology of surgically excised stenotic aortic valve; however, these involved a wide range of AS severity from mild to severe and were conducted
between 1960 and 2000 [20]. Temporal changes in the etiology of stenotic aortic valves wereclearly observed, with calcific/degenerative AS being the more dominant etiology in developed
countries [21]. A few reports on the incidence according to aortic valve etiology have been
published. In a large-scale pathology study [22] with 250 excised native stenotic aortic valves,
calcific/degenerative tricuspid aortic, congenital, and rheumatic valves were reported in
66.4%, 18.4%, and 15.2% of cases, respectively, which were comparable to our findings at
68.6%, 17.4%, and 13.9%, respectively.
Echocardiography has become an established tool for the diagnosis and evaluation of aortic
valve disease, and with this primary noninvasive method, aortic valve etiology has been identifiable in most cases [23]. There are, however, a limited number of cases or studies on AS thatwere unidentified or misled using these noninvasive imaging modalities in daily practice [24,25]. A recently published meta-analysis study investigated a pooled sensitivity of 87.7% andpooled specificity of 88.3% for bicuspid aortic valve on preoperative TTE examinations,highlighting that suboptimal diagnosis often occurred under certain conditions, including

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PLOS ONEClinical outcome by aortic stenosis etiology after surgical aortic valve replacement

Fig 4. NYHAfc of patients with severe aortic stenosis at the first diagnosis, within 30 days prior to surgical AVR,
and at 3 years after surgical AVR (A) with a comparison of the three different aortic valve etiologies (B–D).
NYHAfc, New York Heart Association functional classification; AVR, aortic valve replacement.
https://doi.org/10.1371/journal.pone.0229721.g004

non-tertiary care center, the presence of aortic aneurysm, and the presence of severe aortic
valve calcification [5]. Although preoperative cardiac computerized tomography can be moreaccurate in differentiating between tricuspid and bicuspid aortic valves than TTE examinations, sufficient studies have not been implemented in the distinction between calcific/degenerative and post-inflammatory valves within the tricuspid aortic valves [25].
With respect to clinical outcomes, there exist limited data on whether aortic valve etiology postoperatively validated by pathological examination can affect mid-term outcomes
following the surgical procedure. In a relatively large-scale study [18] with a design similar
to ours, tricuspid AS was associated with a higher prevalence of cardiovascular risk factors
and worse survival rates after surgical AVR compared with bicuspid AS. Our findings suggested that calcific/degenerative AS could have an association with an increased risk of cardiac and combined adverse events versus post-inflammatory AS. Based on our findings, we
speculate that the valve etiology profiles might have some effects on the mid-term outcomeseven after removal of the diseased valve. Such differences in late complications among thethree groups may possibly stem from the extent of postoperative regression of diffuse myocardial fibrosis and myocardial cellular hypertrophy based on the aortic valve etiology, as
investigated in a recent study [26]. Recently, calcific/degenerative AS has been understood
to be an active disease process akin to atherosclerosis from the perspectives of compelling
histopathological and clinical data [27]. In contrast, the congenital aortic valve disease often
involves many vascular abnormalities [28], and the post-inflammatory disease can affect the
myocardium and heart valves and the brain, joints, and skin [29]. In our present study, 23%of patients in the congenital group underwent ascending aorta replacement concomitantly,
and 82% and 36% of patients in the post-inflammatory group underwent additional surgical

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PLOS ONEClinical outcome by aortic stenosis etiology after surgical aortic valve replacement

procedures on the mitral and tricuspid valves, respectively. Taking this into consideration,
AS should be deemed as a systemic disease with different potential mechanisms by its valve
etiology, although the definite pathophysiology behind AS remains incompletely investigated [30].
As a clinical implication, our data suggest that the etiology and pathobiology of the valvulardisease should be examined through pathological investigation of the excised valve, which canprovide essential information on its natural history, surgical risk, postoperative outcome, association with systemic disease, and potential vascular complications, irrespective of preoperative imaging assessments. Therefore, the future possibility of establishing accurate diagnosis
of diseased valves using less invasive imaging modalities with pathological examination should
be further explored, which can lead to other novel researches, such as valve progression by aortic valve etiology or associations with non-aortic valves. Moreover, our data on the detailed
clinical outcomes highlight distinct trends in the incidences of harmful events following surgical AVR among the three etiologies. For instance, admission for HF, device implantation, andgastrointestinal bleeding were more prominent in both the congenital and calcific/degenerative groups than in the post-inflammatory group, whereas non-fatal stroke was more common
in both the calcific/degenerative and post-inflammatory groups. In managing these patients,
such novel information could aid in detecting and treating potential late complications uniqueto each valve etiology.

Study limitations and strengths
The strength of our study lies in the larger number of enrolled patients in the cohort. We collected detailed data on patient demographics, physical and medical conditions, and surgicalinterventions during follow-up via medical chart review and achieved a 97% follow-up ratewith a median follow-up period of 4.1 years. Nonetheless, our study also has some limitations.
First, it was conducted at a single medical institute in Japan and may not represent the overall
population or be applicable to other populations. Our institution is the only large cardiovascular center located in the Kitakyushu area, and almost all cardiovascular patients within theregion are referred to our institution because of the lack of viable alternatives. Second, thestudy was mainly a descriptive one with a retrospective design. There was an imbalance inpreoperative characteristics among the three etiology groups, suggesting that confounding factors might have remained even when performing a multivariate regression analysis. Moreover,owing to the limited number of outcomes, we were unable to make full adjustments even for
the variables that we measured. Therefore, our results should not be considered an estimate of
the causal relationship between valve etiology and outcome; rather, our results indicate thatthe pathologically assessed etiology of diseased valves was a strong predictor of patients’ midterm outcomes even after adjustments for patients’ demographic characteristics and cardiac
operative risks, which could certainly guide clinicians and patients in decision-making regarding postoperative follow-ups and support the importance of the accuracy of pathological valve
diagnosis. Lastly, although the mortality rate was not statistically significant among the threegroups, the present study might be underpowered to detect such survival differences, mainly
because the mortality rates were relatively low. However, to the best of our knowledge, ourstudy population is one of the largest ever reported in the surgical AVR literature focusing on
the comparison of major valve etiologies.

Conclusions
This study demonstrates that the pathology-validated etiology of stenotic aortic valves could
be significantly correlated with mid-term outcomes even after surgical AVR and suggested

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PLOS ONEClinical outcome by aortic stenosis etiology after surgical aortic valve replacement

that, compared to post-inflammatory AS, calcific/degenerative AS was associated withincreased postoperative cardiac events. Likewise, compared to post-inflammatory AS, congenital AS could be associated with higher adverse clinical event rates. Our findings reinforce theclinical significance of identifying the accurate etiology with postoperative pathological examination in risk stratification, postoperative management, and prediction of potential late complications peculiar to various etiologies.

Supporting information
S1 File. Dataset for all individuals.
(XLSX)

Author Contributions
Conceptualization: Shiro Miura, Katsumi Inoue, Hiraku Kumamaru.
Data curation: Shiro Miura.
Formal analysis: Shiro Miura, Hiraku Kumamaru.
Investigation: Shiro Miura.
Methodology: Shiro Miura, Hiraku Kumamaru.
Project administration: Takehiro Yamashita.
Resources: Shiro Miura, Katsumi Inoue, Michiya Hanyu.
Supervision: Katsumi Inoue, Hiraku Kumamaru, Takehiro Yamashita, Michiya Hanyu, Shinichi Shirai, Kenji Ando.
Validation: Katsumi Inoue, Takehiro Yamashita, Shinichi Shirai, Kenji Ando.
Writing – original draft: Shiro Miura.
Writing – review & editing: Hiraku Kumamaru, Takehiro Yamashita.

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