Predictors of Rapid Progression and Clinical Outcome of Asymptomatic Severe Aortic Stenosis

Abstract

Background: The optimal timing of aortic valve replacement (AVR) is controversial in patients with asymptomatic severe aortic stenosis (AS) except when very severe. Prediction of progression of severe AS is helpful in deciding on the timing of AVR. The purpose of this study was to clarify the predictors of progression rate and clinical outcomes of severe AS.

Methods and Results: We retrospectively investigated 140 consecutive patients with asymptomatic severe AS (aortic valve area [AVA], 0.75–1.0 cm²). First-year progression rate and annual progression rate of AVA and of aortic jet velocity (AV-Vel) were calculated. Cardiac events were examined and the predictors of rapid progression and cardiac events were analyzed. The median follow-up period was 36 months. The median annual progression rate was −0.05 cm²/year for AVA and 0.22 m/s/year for AV-Vel. Dyslipidemia, moderate-severe calcification, and first-year AV-Vel progression ≥0.22 m/s/year were independent predictors of cardiac events. Cardiac event-free rate was lower in patients with AV-Vel first-year progression rate ≥0.22 m/s/year than in those with a lower rate. Diabetes and moderate-severe calcification were related to first-year rapid progression.

Conclusions: The annual progression rate of severe AS was −0.05 cm²/year for AVA and 0.22 m/s/year for AV-Vel. Patients with first-year rapid progression or severely calcified aortic valve should be carefully observed while considering an early operation. (Circ J 2016; 80: 1863–1869)

The number of patients with aortic stenosis (AS) has been increasing along with the increasing longevity of the population, especially in developed countries.^1,2 AS is a chronic and progressive disease;³ once an AS-related symptom develops, the prognosis on conventional treatment is poor.^4–7 Therefore aortic valve replacement (AVR), which results in good long-term survival, is recommended for patients with symptomatic severe AS.^3,8

Editorial p 1712

In contrast, the management of asymptomatic severe AS remains controversial. It has recently been reported that patients with asymptomatic very severe AS with aortic valve area (AVA) <0.75 cm² have poor clinical outcomes with conventional treatment, so that early surgery is considered as a therapeutic option in very severe AS.^3,9–11 There are no established principles, however, regarding the timing of AVR for patients with asymptomatic severe AS with AVA between 0.75 and 1.0 cm².

Several reports have investigated the progression rate of AS, but the AS severity ranged widely from mild to severe.^12–14 There are few reports on severe AS within this limited range (AVA 0.75–1.0 cm²), especially in Japanese patients, and it is possible that the progression rate of AS may vary according to severity and ethnicity.⁸

Furthermore, annual follow-up echocardiography is thought to play an important role in the management of asymptomatic severe AS,^3,8 but long-term waiting may increase the risk of cardiac events. If progression rate during the first year after diagnosis can predict long-term clinical outcome, it may provide valuable information to facilitate management of asymptomatic severe AS.

The purpose of this study was therefore to clarify the predictors of clinical outcome and evaluate the clinical importance of first-year follow-up on long-term clinical outcome in Japanese patients with severe AS.

Methods

Subjects

Among 702 consecutive patients who were initially diagnosed with severe AS with AVA ≤1.0 cm²,¹⁵ and followed up at Tenri Hospital between January 1994 and December 2013, 375 patients had very severe AS with AVA <0.75 cm², and 327 patients had severe AS with AVA between 0.75 and 1.0 cm². Among these 327 patients, 118 (36%) had low ejection fraction (EF) <50% and 70 (21%) were symptomatic.

After excluding these patients, the remaining 155 patients were potential candidates for the present study. Among the 155 patients, 15 patients did not receive first-year follow-up transthoracic echocardiography (TTE), although they had later follow-up TTE. (The first year was defined as 6–18 months after diagnosis.) Therefore, the present subjects consisted of 140 asymptomatic patients who had severe AS with AVA 0.75–1.0 cm² and EF ≥50% (Figure 1). All of these 140 patients were not primarily referred for AVR and received follow-up TTE at both the first year and at later time points after diagnosis. The progression rate of AS and clinical outcomes were evaluated, and the predictors were investigated. The study protocol was approved by the institutional ethics committee at Tenri Hospital.

Figure 1.

Patient selection process. AS, aortic stenosis; AVA, aortic valve area; LVEF, left ventricular ejection fraction; TTE, transthoracic echocardiography.

Echocardiography and Progression of AS

Comprehensive echocardiography was conducted by experienced sonographers using commercially available ultrasound systems. Left ventricular EF (LVEF) was measured using the modified Simpson’s method. Maximum aortic jet velocity (AV-Vel) was measured and AVA obtained using the standard continuity equation. The annual progression rate of AVA (cm²/year) and AV-Vel (m/s/year) were calculated as follows:

AVA annual progression rate=(AVA at final measurement−AVA at initial diagnosis)/time interval between the 2 measurements;

AV-Vel annual progression rate=(AV-Vel at final measurement−AV-Vel at initial diagnosis)/time interval between the 2 measurements.

First-year progression rate of AVA (cm²/year) and AV-Vel (m/s/year) were calculated respectively as follows:

(AVA at first-year measurement−AVA at initial diagnosis)/time interval between the 2 measurements; and

(AV-Vel at first-year measurement–AV-Vel at initial diagnosis)/time interval between the 2 measurements.

As in a previous study, the degree of calcification of aortic valve was scored as follows: 1, no calcification; 2, mildly calcified (small isolated spots); 3, moderately calcified (multiple larger spots); and 4, heavily calcified (extensive thickening and calcification of all cusps).⁸

Clinical Outcome and Predictors

The clinical follow-up data were obtained from medical records. Cardiac events were defined as cardiac death or adverse valve-related events. Cardiac death was defined as sudden death or death from congestive heart failure related to AS. Adverse valve-related events were defined as eventual AVR or balloon aortic valvuloplasty. To evaluate the predictors of clinical outcomes we examined clinical factors, medications and echocardiographic parameters at diagnosis. Clinical factors included age, gender, smoking habit, and underlying disease. Underlying disease included hypertension, diabetes mellitus, dyslipidemia, coronary artery disease (CAD), connective tissue disease, and hemodialysis. Hypertension was defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, or use of anti-hypertensive medications. Dyslipidemia was defined as serum cholesterol ≥220 mg/dl or the use of cholesterol-lowering medications. Diabetes mellitus was defined as hyperglycemia requiring medications. CAD was defined as a previous history of angina, myocardial infarction or percutaneous coronary intervention, or significant coronary artery stenosis on coronary angiography. Connective tissue disease included rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, anti-neutrophil cytoplasmic antibody-associated vasculitis, remitting seronegative symmetrical synovitis with pitting edema, Sjögren’s syndrome, and Behcet’s disease. Medications included β-blockers, calcium-channel antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, warfarin, antiplatelet drugs, and corticosteroids. Echocardiographic parameters included AVA at diagnosis (> or < 0.875 cm²), AV-Vel at diagnosis (> or < 4.0 m/s), calcification score (> or < grade 3), and first-year progression rate of AV-Vel. The continuous variables were dichotomized by center values or clinically meaningful reference values. The first-year progression rate cut-off was determined by the median of the AV-Vel annual progression rate.

Predictors of Rapid Progression During First-Year Follow-up

We divided the study patients into 2 groups according to first-year progression rate (> or < cut-off). To assess the determinants of first-year progression rate, we compared the clinical factors, laboratory data, echocardiographic parameters, and medication at diagnosis between these 2 groups. Clinical factors and medications were the same as aforementioned. Laboratory data included hemoglobin, white blood cell count, total cholesterol, lactate dehydrogenase, and C-reactive protein (CRP). Echocardiographic parameters included LVEF, AVA, AV-Vel, mean aortic pressure gradient, and calcification score at diagnosis.

Statistical Analysis

Statistical analysis was performed using JMP version 8 (SAS Institute Inc, Cary, NC, USA). Continuous variables are presented as mean±SD or median (IQR). The difference between 2 groups was determined using unpaired t-test for continuous variables and Fisher’s exact test for non-continuous variables. Logistic regression modeling was used to assess the contribution of clinical and echocardiographic features to the rapid progression of AS during first-year follow-up. Landmark analysis was used to assess the importance of first-year follow-up after diagnosis. The landmark point was the time when first-year follow-up TTE was performed. Event-free survival rates are presented as Kaplan-Meier curves, and comparison between 2 groups was performed using log-rank test. Relative risk and 95% CI were calculated using Cox proportional hazard analysis. Variables with P<0.05 in the univariate model were included in the multivariate model. P<0.05 was considered statistically significant.

Results

Baseline Patient Characteristics and Echocardiography

Baseline patient characteristics and echocardiographic data of the 140 patients are listed in Table 1. The mean follow-up period was 47±36 months (median, 36 months; IQR, 23–63 months). Median and mean annual progression rate of AVA were −0.05 cm²/year and –0.07 cm²/year, respectively. Median and mean annual progression rate of AV-Vel were 0.22 m/s/year and 0.27 m/s/year, respectively.

Table 1. Subject Characteristics at Initial Diagnosis

Characteristics	All patients (n=140)	First-year progression		P-value
		Rapid (n=59)	Slow (n=81)
Age (years)	73±8.6	74±7.6	72±9.5	0.37
Female	86 (61)	38 (64)	48 (59)	0.54
Comorbidities
Hypertension	108 (77)	45 (76)	63 (78)	0.83
Dyslipidemia	70 (50)	27 (46)	43 (53)	0.39
Diabetes	29 (21)	19 (32)	10 (12)	0.004
Smoking	41 (29)	19 (32)	22 (27)	0.52
Coronary artery disease	35 (25)	19 (32)	16 (20)	0.093
Atrial fibrillation	19 (14)	8 (14)	11 (14)	1.0
Connective tissue disease	12 (8.6)	3 (5.0)	9 (11)	0.21
Hemodialysis	12 (8.6)	8 (14)	4 (4.9)	0.072
Medication
ACEI	12 (8.6)	4 (6.8)	8 (9.9)	0.52
ARB	48 (34)	22 (37)	26 (32)	0.52
β-blocker	36 (26)	11 (19)	25 (31)	0.10
Calcium channel blocker	64 (46)	25 (42)	39 (48)	0.50
Warfarin	23 (16)	10 (17)	13 (16)	0.89
Statin	60 (43)	24 (41)	36 (44)	0.77
Antiplatelet drugs	57 (41)	26 (44)	31 (38)	0.49
Corticosteroid	20 (14)	6 (10)	14 (17)	0.24
Laboratory data
Hemoglobin (g/dl)	12.6±1.7	12.7±1.6	12.5±1.8	0.53
WBC count (/μl)	6,200±1,900	6,300±2,000	6,000±1,800	0.36
Total cholesterol (mg/dl)	193±35	197±36	191±34	0.39
Lactate dehydrogenase (IU/L)	241±87	233±81	247±90	0.35
Creatinine (mg/dl)	1.4±2.1	1.8±2.6	1.1±1.5	0.085
CRP (mg/dl)	0.53±1.6	0.55±1.2	0.51±1.9	0.88
Echocardiographic parameters
LVEF (%)	70.2±10.0	69.7±10.3	70.7±9.2	0.57
AVA at diagnosis (cm2)	0.90±0.08	0.89±0.08	0.92±0.07	0.052
AV-Vel at diagnosis (m/s)	3.68±0.56	3.67±0.55	3.70±0.57	0.77
Mean aortic PG at diagnosis (mmHg)	33.1±11.3	32.9±10.6	33.3±11.7	0.85
Calcification score at diagnosis (≥3) (%)	68 (49)	36 (61)	32 (40)	0.012
Mean annual progression rate
AV-Vel (m/s/year)	0.27±0.35	0.51±0.40	0.10±0.17	<0.001
AVA (cm2/year)	−0.07±0.10	−0.11±0.12	−0.05±0.07	<0.001

Data given as n (%) or mean±SD. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AV-Vel, aortic jet velocity; AVA, aortic valve area; CRP, C-reactive protein; LVEF, left ventricular ejection fraction; PG, pressure gradient; WBC, white blood cell.

Cardiac Events and Predictors

Among the 140 patients, there were 7 cardiac deaths and 58 adverse valve-related events during follow-up. Event-free survival rate was evaluated among all 140 patients. To clarify the feasibility of first-year follow-up for predicting future cardiac events, landmark analysis was conducted as aforedescribed. First-year follow-up TTE was performed at 12±3.2 months after diagnosis (median, 12 months; IQR, 11–14 months). Event-free survival curves were measured from the date when first-year follow-up TTE was performed. Freedom from cardiac events was lower in patients with first-year AV-Vel progression rate ≥0.22 m/s/year (n=59) than in those with first-year AV-Vel progression rate <0.22 m/s/year (n=81; 70% vs. 87% at 1 year; 57% vs. 74% at 2 years; and 52% vs. 70% at 3 years; P=0.0043; Figure 2). This cut-off for first-year progression rate was determined by the median annual progression rate of AV-Vel. In 59 patients with first-year AV-Vel progression rate ≥0.22 m/s/year, 5 patients (8.5%) had cardiac death, and 28 patients (47%) underwent AVR (surgical, 26; transcatheter, 2). Among 28 patients receiving AVR, the indications for AVR were as follows: symptomatic (n=18: congestive heart failure, 9; syncope, 3; chest pain, 6); very severe AS, n=8; LV dysfunction, n=1; and attending physician recommendation, n=1. In 81 patients with first-year AV-Vel progression <0.22 m/s/year there were 2 cardiac deaths (2.5%), 29 patients (36%) underwent AVR (surgical, 27; transcatheter, 2), and 1 patient (1.2%) underwent balloon aortic valvuloplasty. Among 30 patients receiving AVR or balloon aortic valvuloplasty, indications were as follows: symptomatic (n=24: congestive heart failure, 10; syncope, 4; chest pain, 10); very severe AS, n=4; and attending physician recommendation, n=2.

Figure 2.

Event-free survival rate vs. first-year aortic jet velocity (AV-Vel) progression. TTE, transthoracic echocardiography.

On univariate analysis, smoking habit, dyslipidemia, hemodialysis, moderate-severe calcification, AV-Vel ≥4.0 m/s at diagnosis, and first-year AV-Vel progression rate ≥0.22 m/s were predictors of cardiac events (Table 2). Multivariate Cox proportional hazard modeling identified dyslipidemia, moderate-severe calcification, and first-year AV-Vel progression rate ≥0.22 m/s as independent predictors of cardiac events (Table 3).

Table 2. Univariate Indicators of Cardiac Death and Adverse Valve-Related Events

Characteristics	HR (95% CI)	P-value
Age (≥75 years)	0.76 (0.46–1.25)	0.29
Sex (female)	0.87 (0.53–1.44)	0.60
Comorbidities
Hypertension	1.07 (0.63–1.90)	0.81
Dyslipidemia	1.71 (1.04–2.85)	0.034
Diabetes	1.39 (0.74–2.47)	0.29
Smoking	1.74 (1.04–2.86)	0.034
Coronary artery disease	1.41 (0.81–2.38)	0.22
Atrial fibrillation	0.75 (0.31–1.54)	0.46
Connective tissue disease	0.52 (0.16–1.26)	0.16
Hemodialysis	3.21 (1.30–6.79)	0.014
Medications
ACEI	0.81 (0.28–1.83)	0.64
ARB	1.02 (0.60–1.68)	0.95
β-blocker	1.05 (0.59–1.78)	0.86
Warfarin	1.13 (0.56–2.09)	0.72
Statin	1.19 (0.71–1.95)	0.51
Echocardiographic parameters
AVA at diagnosis (≤0.875 cm2)	0.83 (0.46–1.41)	0.49
AV-Vel at diagnosis (≥4.0 m/s)	1.97 (1.17–3.26)	0.011
Calcification score at diagnosis (≥3)	3.33 (1.94–5.91)	<0.001
AVA first-year progression rate ≤−0.05 cm2/year	2.76 (1.68–4.56)	<0.001
AV-Vel first-year progression rate ≥0.22 m/s/year	2.02 (1.23–3.34)	0.006

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AVA, aortic valve area; AV-Vel, aortic jet velocity.

Table 3. Multivariate Indicators of Cardiac Death and Adverse Valve-Related Events

Characteristics	HR (95% CI)	P-value
Smoking	1.67 (0.98–2.80)	0.060
Dyslipidemia	1.81 (1.08–3.06)	0.024
Hemodialysis	2.28 (0.90–5.10)	0.080
AV-Vel at diagnosis (≥4.0 m/s)	1.65 (0.94–2.86)	0.083
Calcification score at diagnosis (≥3)	2.23 (1.22–4.17)	0.009
AV-Vel first-year progression rate ≥0.22 m/s/year	1.85 (1.07–3.21)	0.027

AV-Vel, aortic jet velocity.

Predictors of Rapid Progression During First-Year Follow-up

Clinical and echocardiographic characteristics were compared between patients with first-year progression rate ≥0.22 m/s/year (n=59) and those with first-year AV-Vel progression <0.22 m/s/year (n=81). Diabetes mellitus and moderate-severe calcification were predictors of first-year rapid progression. Prevalence of CAD and hemodialysis tended to be higher but these were not statistically significant. There were no significant differences in other clinical characteristics or medications (Table 1). On multivariate logistic regression modeling, diabetes mellitus and moderate-severe calcification were also independent predictors of first-year rapid progression (Table 4).

Table 4. Multivariate Indicators of First-Year Rapid Progression of Severe AS

Characteristics	OR	95% CI	P-value
Diabetes	2.78	1.15–6.98	0.023
Calcification score at diagnosis (≥3)	2.37	1.15–4.95	0.019

AS, aortic stenosis.

Discussion

According to the guidelines for severe AS, AVR is recommended for symptomatic AS (class I), impaired LV function (class I), and very severe AS (class IIa).³ In contrast, medical follow-up is recommended for asymptomatic severe AS with normal LV function. Improved surgical techniques for patients with severe AS, however, have led to lower operative mortality and morbidity rates.^16,17 Therefore, the optimal timing of therapeutic intervention for severe AS warrants discussion.^18,19

Given the progressive nature of AS, clarification of progression rate and relationship to clinical outcome will be helpful in determining the optimal timing of AVR.

There are several reports on the progression rate of AS, but they involved a wide range of AS severity from mild to severe.^12,13,20 Few data have been published on progression rate and clinical outcomes in asymptomatic severe AS, especially in Japanese patients.⁸ It is possible that the progression rate of AS may vary according to severity and ethnicity. The optimal timing of AVR for asymptomatic patients with AVA 0.75–1.0 cm² is the most controversial clinical issue encountered in daily practice. Therefore, the aim of the present study was to clarify this by assessing progression rate and clinical outcomes in asymptomatic patients with severe AS defined as AVA 0.75–1.0 cm².

Annual Progression Rate and Clinical Outcome

Median and mean annual increase in AV-Vel was 0.22 m/s and 0.27 m/s, respectively, and median and mean annual decrease in AVA was 0.05 cm² and 0.07 cm², respectively, in patients with severe AS defined as AVA 0.75–1.0 cm².

In the present study there were no cardiac deaths during the first year of follow-up after diagnosis. This suggests that watchful waiting during 1 year from diagnosis is acceptable in patients with asymptomatic severe AS, defined as AVA 0.75–1.0 cm². The subgroup of patients with AV-Vel first-year progression rate ≥0.22 m/s/year had low event-free rates compared with those with AV-Vel <0.22 m/s/year. On multivariate Cox proportional hazard analysis, first-year progression rate was identified as an independent predictor of cardiac events. This suggests that 1-year follow-up can predict long-term outcome, and contributes more useful information about how to follow up and when to recommend therapeutic intervention for patients with asymptomatic severe AS.

With regard to echocardiographic parameters, moderate-severe calcification of the aortic valve was related to cardiac events, consistent with the previous report.⁸

Regarding clinical factors, dyslipidemia was related to cardiac events. AS and atherosclerosis have a number of risk factors in common, such as hypercholesterolemia, elevated lipoprotein, smoking, and hypertension.²¹ Lipid infiltration and dystrophic calcification have also been observed in AS and atherosclerosis, and these active processes seem to be related to the development and progression of these atherosclerotic diseases.²²

Predictors of Rapid Progression During First-Year Follow-up

The present study has illustrated the clinical importance of first-year follow-up, and shown that diabetes and moderate-severe calcification of the aortic valve are related to first-year rapid progression.

Rosenhek et al also reported that moderate-severe calcification was related to rapid progression.⁸ AS pathogenesis is associated with proliferation of vascular smooth muscle cells and fibroblasts, and calcification of vascular structure.²³ Calcium deposition on the aortic valve is thought to be an important cause of rapid progression.^8,24,25 In addition, diabetes mellitus is related to enhanced inflammation of the aortic valve.²⁶ The present data support these previous findings. In contrast, other previous studies reported that concomitant CAD and hemodialysis were related to rapid progression of AS.^24,27–29 In the present study, prevalence of CAD and hemodialysis also tended to be higher in patients with rapid progression during the first year than those with slow progression, but this was not statistically significant.

With regard to laboratory data and medications, a previous study reported that CRP could predict progression of asymptomatic AS.³⁰ In contrast, another study reported that CRP was not a predictor of progression of calcific aortic disease.³¹ Both of these studies included a wide range of AS severity from mild to severe. The present subjects had severe AS, for whom we could not identify any laboratory data, including CRP, as predictors of rapid progression of AS.

Study Limitations

The present study has several limitations, mainly based on its retrospective nature. The subjects consisted of consecutive patients followed up with multiple echocardiograms at least 6 months from diagnosis, and we excluded some patients with no follow-up echocardiogram. Therefore a selection bias was inevitable. We selected asymptomatic patients at the time of study inclusion based on patient symptom reporting. If patients have severe AS, current guidelines recommend an exercise test, but this was a retrospective cohort study, therefore stress test could not be performed for all patients.³ We cannot exclude decision bias with respect to referral for AVR. All patients were asymptomatic at diagnosis, and most of the patients who received AVR became symptomatic at the time of AVR. Given, however, that this was a retrospective study, the subjects included several patients who developed symptoms but did not undergo AVR, or did not develop symptoms but underwent AVR, which might have affected the results. In addition, the reproducibility of AV-Vel measurement could not be assessed due to the retrospective nature. Finally, the present consecutive patients were selected before 2013, and severe AS was defined as AVA ≤1.0 cm² based on the previous guidelines.^15,32 According to the revised 2014 ACC/AHA guideline, however, the definition of severe AS changed to AV-Vel ≥4.0 m/s or mean aortic pressure gradient ≥40 mmHg.³ Therefore, the present study was different from current status in evaluation of AS severity.

Conclusions

It is safe to follow up asymptomatic patients with severe AS for at least 1 year. In addition, patients with rapid progression during the first year after diagnosis or severely calcified aortic valve should be carefully observed while considering an early operation.

Name of Grant

None.

References

• 1.    Lung  B,  Baron  G,  Butchart  EG,  Delahaye  F,  Gohlke-Bärwolf  C,  Levang  OW, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003; 24: 1231–1243.
• 2.    Lindroos  M,  Kupari  M,  Heikkila  J,  Tilvis  R. Prevalence of aortic valve abnormalities in the elderly: An echocardiographic study of a random population sample. J Am Coll Cardiol 1993; 21: 1220–1225.
• 3.    Nishimura  RA,  Otto  CM,  Bonow  RO,  Carabello  BA,  Erwin  JP 3rd,  Guyton  RA, 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 2014; 63: 2438–2488.
• 4.    Ross  J Jr,  Braunwald  E. Aortic stenosis. Circulation 1968; 38: 61–67.
• 5.    Horstkotte  D,  Loogen  F. The natural history of aortic valve stenosis. Eur Heart J 1988; 9: 57–64.
• 6.    Frank  S,  Johnson  A,  Ross  J Jr. Natural history of valvular aortic stenosis. Br Heart J 1973; 35: 41–46.
• 7.    Barasch  E,  Petillo  F,  Pollack  S,  Rhee  PD,  Stovold  W,  Reichek  N. Clinical and echocardiographic correlates of mortality in medically treated patients with severe isolated aortic stenosis and normal left ventricular ejection fraction. Circ J 2014; 78: 232–239.
• 8.    Rosenhek  R,  Binder  T,  Porenta  G,  Lang  I,  Christ  G,  Schemper  M, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000; 343: 611–617.
• 9.    Kang  DH,  Park  SJ,  Rim  JH,  Yun  SC,  Kim  DH,  Song  JM, et al. Early surgery versus conventional treatment in asymptomatic very severe aortic stenosis. Circulation 2010; 121: 1502–1509.
• 10.    Rosenhek  R,  Zilberszac  R,  Schemper  M,  Czerny  M,  Mundigler  G,  Graf  S, et al. Natural history of very severe aortic stenosis. Circulation 2010; 121: 151–156.
• 11.    Kitai  T,  Honda  S,  Okada  Y,  Tani  T,  Kim  K,  Kaji  S, et al. Clinical outcomes in non-surgically managed patients with very severe versus severe aortic stenosis. Heart 2011; 97: 2029–2032.
• 12.    Otto  CM,  Burwash  IG,  Legget  ME,  Munt  BI,  Fujioka  M,  Healy  NL, et al. Prospective study of asymptomatic valvular aortic stenosis: Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997; 95: 2262–2270.
• 13.    Nistri  S,  Faggiano  P,  Olivotto  I,  Papesso  B,  Bordonali  T,  Vescovo  G, et al. Hemodynamic progression and outcome of asymptomatic aortic stenosis in primary care. Am J Cardiol 2012; 109: 718–723.
• 14.    Yamamoto  K,  Yamamoto  H,  Takeuchi  M,  Kisanuki  A,  Akasaka  T,  Ohte  N, et al. Risk factors for progression of degenerative aortic valve disease in the Japanese: The Japanese Aortic Stenosis Study (JASS) Prospective Analysis. Circ J 2015; 79: 2050–2057.
• 15.    Bonow  RO,  Carabello  BA,  Kanu  C,  de Leon  AC Jr,  Faxon  DP,  Freed  MD, et al. ACC/AHA 2006 guidelines 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 (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): Developed in collaboration with the Society of Cardiovascular Anesthesiologists: Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006; 114: e84–e231, doi:10.1161/CIRCULATIONAHA.106.176857.
• 16.    Edwards  FH,  Peterson  ED,  Coombs  LP,  DeLong  ER,  Jamieson  WR,  Shroyer  ALW, et al. Prediction of operative mortality after valve replacement surgery. J Am Coll Cardiol 2001; 37: 885–892.
• 17.    Ambler  G,  Omar  RZ,  Royston  P,  Kinsman  R,  Keogh  BE,  Taylor  KM. Generic, simple risk stratification model for heart valve surgery. Circulation 2005; 112: 224–231.
• 18.    Taniguchi  T,  Morimoto  T,  Shiomi  H,  Ando  K,  Kanamori  N,  Murata  K, et al. Initial surgical versus conservative strategies in patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol 2015; 66: 2827–2838.
• 19.    Daimon  M. Can we predict or prevent progression of aortic stenosis? Circ J 2015; 79: 1908–1909.
• 20.    Kume  T,  Kawamoto  T,  Okura  H,  Watanabe  N,  Toyota  E,  Neishi  Y, et al. Rapid progression of mild to moderate aortic stenosis in patients older than 80 years. J Am Soc Echocardiogr 2007; 20: 1243–1246.
• 21.    Stewart  BF,  Siscovick  D,  Lind  BK,  Gardin  JM,  Gottdiener  JS,  Smith  VE, et al. Clinical factors associated with calcific aortic valve disease: Cardiovascular Health Study. J Am Coll Cardiol 1997; 29: 630–634.
• 22.    O’Brien  KD,  Reichenbach  DD,  Marcovina  SM,  Kuusisto  J,  Alpers  CE,  Otto  M. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of “degenerative” valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996; 16: 523–532.
• 23.    Ross  R. The pathogenesis of atherosclerosis: An update. N Engl J Med 1986; 314: 488–500.
• 24.    Perkovic  V,  Hunt  D,  Griffin  SV,  du Plessis  M,  Becker  GJ. Accelerated progression of calcific aortic stenosis in dialysis patients. Nephron Clin Pract 2003; 94: c40–c45.
• 25.    Davies  SW,  Gershick  AH,  Balcon  R. Progression of valvar aortic stenosis: A long-term prospective study. Eur Heart J 1991; 12: 10–14.
• 26.    Natorska  J,  Wypasek  E,  Grudzień  G,  Sobczyk  D,  Marek  G,  Filip  G, et al. Does diabetes accelerate the progression of aortic stenosis through enhanced inflammatory response within aortic valves? Inflammation 2012; 35: 834–840.
• 27.    Ohara  T,  Hashimoto  Y,  Matsumura  A,  Suzuki  M,  Isobe  M. Accelerated progression and morbidity in patients with aortic stenosis on chronic dialysis. Circ J 2005; 69: 1535–1539.
• 28.    Peter  M,  Hoffmann  A,  Parker  C,  Lüscher  T,  Burckhardt  D. Progression of aortic stenosis. Role of age and concomitant coronary artery disease. Chest 1993; 103: 1715–1719.
• 29.    Yilmaz  MB,  Guray  U,  Guray  Y,  Cihan  G,  Caldir  V,  Cay  S, et al. Lipid profile of patients with aortic stenosis might be predictive of rate of progression. Am Heart J 2004; 147: 915–918.
• 30.    Imai  K,  Okura  H,  Kume  T,  Yamada  R,  Miyamoto  Y,  Kawamoto  T, et al. C-reactive protein predicts severity, progression, and prognosis of asymptomatic aortic valve stenosis. Am Heart J 2008; 156: 713–718.
• 31.    Novaro  GM,  Katz  R,  Aviles  RJ,  Gottdiener  JS,  Cushman  M,  Psaty  BM, et al. Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: The Cardiovascular Health Study. J Am Coll Cardiol 2007; 50: 1992–1998.
• 32.    Vahanian  A,  Alfieri  O,  Andreotti  F,  Antunes  MJ,  Baron-Esquivias  G,  Baumgartner  H, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012; 33: 2451–2496.