2024 Volume 88 Issue 4 Pages 606-611
Background: Patients with severe aortic stenosis (AS) frequently have concomitant aortic regurgitation (AR), but the association between aortic valvular calcification (AVC) and the severity of AR remains unclear.
Methods and Results: We retrospectively reviewed patients with severe AS who underwent transthoracic echocardiography and multidetector computed tomography (MDCT) within 1 month. The patients were divided into 3 groups according to the degree of concomitant AR. The association between AVC and the severity of concomitant AR was assessed in patients with severe AS. The study population consisted of 95 patients: 43 men and 52 women with a mean age of 82±7 years. Of the 95 patients with severe AS, 27 had no or trivial AR, 53 had mild AR, and 15 had moderate AR. The AVC score (AVCS) and AVC volume (AVCV) significantly increased as the severity of concomitant AR increased (P=0.014 for both), and similar findings were obtained for the AVCS and AVCV indexes (P=0.004 for both).
Conclusions: The severity of AR correlated with AVCS and AVCV measured by MDCT in patients with severe AS. AVC may cause concomitant AR, leading to worsening of disease condition.
Patients with severe aortic stenosis (AS) frequently have concomitant aortic regurgitation (AR). Previous studies have shown that 19–39% of patients with severe AS have concomitant moderate or greater AR.1–3 AS causes concentric left ventricular (LV) hypertrophy, leading to a decrease in LV diastolic function. Concomitant AR increases LV end-diastolic pressure because of volume overload. Thus, patients with AS combined with AR are more likely to develop heart failure, resulting in poor outcomes.2–5
AS is characterized by progressive thickening of the aortic valve (AV) and stiffening mainly due to the accumulation of valvular calcification, leading to orifice obstruction.6 Pathological changes secondary to valvular calcification can result in the development of AR. However, because few reports have focused on the association between aortic valvular calcification (AVC) and the severity of AR, we evaluated the association between AVC and the severity of concomitant AR in patients with severe AS.
We retrospectively reviewed patients with severe AS diagnosed in Okayama University Hospital between January 2011 and December 2021, and we included 95 patients who underwent transthoracic echocardiography (TTE) and multidetector computed tomography (MDCT) within 1 month. We excluded patients <18 years of age and those with endocarditis, rheumatic aortic stenosis, and bicuspid AV or other congenital heart disease. The patients were divided into 3 groups according to the degree of concomitant AR: isolated AS group (patients with severe AS and no or trivial AR), AS with mild AR group (patients with severe AS and mild AR), and AS with moderate AR group (patients with severe AS and moderate AR). This study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee at Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences (2212-029).
Clinical DataThe following clinical data were obtained from medical records: age, sex, body mass index, body surface area, medical history (e.g., hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, chronic kidney disease, and coronary artery disease), systolic and diastolic blood pressures, heart rate, and clinical outcomes (admission for heart failure and cardiovascular death) after interventions. Atrial fibrillation included paroxysmal and persistent atrial fibrillation. Chronic kidney disease was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Coronary artery disease was defined as a history of myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention.
Echocardiographic MeasurementsAll patients underwent TTE performed by experienced echocardiographers using a high-quality commercially available ultrasound system. The conventional clinical parameters were measured based on the current guideline.7 The LV ejection fraction (LVEF) and left atrial volume were measured by the biplane disc summation method. LV mass was measured by the linear dimension method. Relative wall thickness was calculated according to the formula: 2×LV posterior wall thickness/LV internal diameter at end-diastole. The maximal aortic jet velocity was obtained, and the mean aortic pressure gradient (MPG) was calculated according to the Bernoulli equation. An MPG ≥40 mmHg was defined as a high-gradient state, and an MPG <40 mmHg was defined as a low-gradient state according to the current guideline. The AV area (AVA) was measured using the standard continuity equation according to the current recommendation.8 Stroke volume (SV) was measured by pulsed-wave Doppler. The AVA, SV, left atrial volume, and LV mass were indexed to the body surface area to account for interindividual variability in body size. An SV index ≤35 mL/m2 was defined as a low-flow state, >58 mL/m2 was defined as a high-flow state, and 36–58 mL/m2 was defined as a normal-flow state. The presence/absence of AR was qualitatively assessed by color Doppler. The severity of AR was quantitively estimated using the vena contracta, jet width/LV outflow tract width ratio, regurgitant volume, and effective regurgitant orifice area derived from the proximal isovelocity surface area method.
MDCT MeasurementsMDCT was performed using a Somatom Definition Flash scanner (Siemens Medical Solutions, Erlangen, Germany). Calcifications were automatically detected by the software with a detection cutoff of 130 Hounsfield units. The AVC volume (AVCV) was measured using non-contrast axial 3-mm slice images triggered at 60–80% of the RR interval.9 The AVC score (AVCS) was calculated using the Agatston method10 with an automated computerized system (Virtual Place, Raijin; AZE Inc., Tokyo, Japan). AVC was defined as calcification within the valve leaflets, aortic annulus, and aortic wall immediately connected to calcification of the valve leaflet, excluding nonvalvular calcification in the LV outflow tract, aortic sinus, coronary arteries, and mitral annulus. To account for interindividual variability in body size, the AVCS and AVCV were indexed to the body surface area.
Diagnosis of AS and ARThe severities of AS and concomitant AR were diagnosed according to the current guideline.11 Severe AS included high-gradient AS with a maximal aortic jet velocity ≥4.0 m/s, MPG ≥40 mmHg, and AVA ≤1.0 cm2 or AVA index ≤0.6 cm2/m2, as well as low-flow low-gradient AS with an MPG <40 mmHg and AVA ≤1.0 cm2 or AVA index ≤0.6 cm2/m2. For classical low-flow low-gradient AS (LVEF <50%), severe AS was identified using the dobutamine stress test. For paradoxical low-flow low-gradient AS (LVEF ≥50%), severe AS was identified using the AVCS measured by MDCT, applying thresholds of 2,000 and 1,200 Agatston units (AU) for men and women, respectively. We also defined normal-flow low-gradient AS with symptoms and severe AVC as severe AS, because several studies have shown that this subset of patients is highly heterogeneous and that a substantial proportion have severe stenosis.12,13
Mild AR was defined as a combination of ≥2 of the following: vena contracta <0.3 cm, jet width/LV outflow tract width ratio <0.25, regurgitant volume <30 mL/beat, and effective regurgitant area <0.1 cm2. Moderate AR was defined as a combination of ≥2 of the following: vena contracta 0.3–0.6 cm, jet width/LV outflow tract width ratio 0.25–0.65, regurgitant volume 30–59 mL/beat, and effective regurgitant orifice area 0.10–0.29 cm2. Severe AR was defined as a combination of ≥2 of the following: vena contracta >0.6 cm, jet width/LV outflow tract width ratio >0.65, regurgitant volume >60 mL/beat, effective regurgitant orifice area >0.3 cm2, and the presence of holodiastolic flow reversal in the abdominal aorta.14 Trivial AR was defined as clinically insignificant AR with trivial color flow.
Statistical AnalysisThe data were analyzed using IBM SPSS Statistics version 24.0 (IBM Inc., Armonk, NY, USA). For all analyses, P<0.05 was considered statistically significant. Continuous variables are reported as mean±standard deviation or median and interquartile range (IQR) and were examined using one-way analysis of variance or the Kruskal-Wallis test. Categorical variables are reported as number and percentage and were examined using the chi-square test. Receiver-operating characteristics curve analysis was used to assess the association between AVC and concomitant moderate AR. The relationship between the severity of concomitant AR with severe AS and clinical outcomes after interventions was examined using the log-rank test.
The study population consisted of 95 patients: 43 men and 52 women with a mean age of 82±7 years. Of them, 77 were diagnosed with high-gradient AS, 2 with classical low-flow low-gradient AS, 4 with paradoxical low-flow low-gradient AS, and 12 with normal-flow low-gradient AS. In total, 84 patients (88%) were symptomatic; 78 patients (82%) underwent surgical AV replacement (SAVR) or transcatheter AV implantation (TAVI) within 3 months after the diagnosis.
Of the 95 patients, 27 (28%) had severe AS and no or trivial AR (isolated AS group), 53 (56%) had severe AS and mild AR (AS with mild AR group), and 15 (16%) had severe AS and moderate AR (AS with moderate AR group). No patients had severe AS and severe AR. Comparisons of clinical characteristics between the groups are shown in Table 1. There were no significant differences in age, sex, body mass index, body surface area, medical history, systolic and diastolic blood pressures, or heart rate between the groups.
Clinical Characteristics of Study Patients With Severe AS
| Total (n=95) |
Isolated AS (n=27) |
AS with mild AR (n=53) |
AS with moderate AR (n=15) |
P value | |
|---|---|---|---|---|---|
| Age (years) | 82±7 | 81±9 | 82±7 | 84±6 | 0.354 |
| Male | 43 (45%) | 13 (48%) | 21 (56%) | 9 (60%) | 0.352 |
| Body mass index (kg/m2) | 23.9±3.6 | 24.5±3.9 | 23.7±3.5 | 23.4±3.7 | 0.597 |
| Body surface area (m2) | 1.53±0.20 | 1.57±0.20 | 1.50±0.19 | 1.53±0.21 | 0.408 |
| Hypertension | 82 (86%) | 23 (85%) | 46 (87%) | 13 (87%) | 0.98 |
| Diabetes mellitus | 23 (24%) | 8 (30%) | 14 (26%) | 1 (6%) | 0.213 |
| Dyslipidemia | 69 (73%) | 20 (74%) | 38 (40%) | 11 (73%) | 0.973 |
| Atrial fibrillation | 11 (12%) | 3 (11%) | 5 (9%) | 3 (20%) | 0.527 |
| Chronic kidney disease | 55 (58%) | 14 (52%) | 32 (60%) | 9 (60%) | 0.754 |
| Coronary artery disease | 26 (27%) | 7 (26%) | 16 (30%) | 3 (20%) | 0.723 |
| Diastolic blood pressure (mmHg) | 70±12 | 72±12 | 70±13 | 70±9 | 0.633 |
| Heart rate (beats/min) | 66±13 | 67±12 | 66±13 | 63±12 | 0.626 |
Data are presented as number (%) or median (interquartile range). AR, aortic regurgitation; AS, aortic stenosis.
Echocardiographic Parameters
Echocardiographic parameters are shown in Table 2. Among all patients, the mean AVA was 0.8±0.2 cm2, AVA index was 0.5±0.1 cm2/m2, maximal aortic jet velocity was 4.4±0.6 m/s, and MPG was 45±14 mmHg. There were no significant differences in the AVA, AVA index, maximal aortic jet velocity, or MPG between the groups. Although the LVEF was comparable, the LV end-diastolic diameter and LV end-systolic diameter tended to increase as the severity of concomitant AR increased. The relative wall thickness was increased in each group, and the LV mass index significantly increased as the severity of concomitant AR increased. Although the LV outflow tract diameter was significantly greater in the AS with mild AR group than in the other groups, it was within the normal range in all groups.
Echocardiographic Parameters
| Total (n=95) |
Isolated AS (n=27) |
AS with mild AR (n=53) |
AS with moderate AR (n=15) |
P value | |
|---|---|---|---|---|---|
| Maximal aortic jet velocity (m/s) | 4.4±0.6 | 4.2±0.4 | 4.4±0.7 | 4.4±0.6 | 0.171 |
| Mean aortic pressure gradient (mmHg) | 45±14 | 41±8 | 47±15 | 48±16 | 0.126 |
| Aortic valve area (mm2) | 0.8±0.2 | 0.8±0.1 | 0.8±0.2 | 0.8±0.2 | 0.335 |
| Aortic valve area index (mm2/m2) | 0.5±0.1 | 0.5±0.1 | 0.5±0.1 | 0.5±0.1 | 0.567 |
| Stroke volume index (mL/m2) | 54±12 | 53±15 | 54±12 | 54±11 | 0.942 |
| LV outflow tract diameter (mm) | 21±2 | 22±2 | 21±2 | 22±2 | 0.018 |
| Sinus of Valsalva diameter (mm) | 32±3 | 31±3 | 31±3 | 33±3 | 0.143 |
| Sinotubular junction diameter (mm) | 25±3 | 25±3 | 25±3 | 27±3 | 0.133 |
| LV end-diastolic diameter (mm) | 44±5 | 42±5 | 44±6 | 46±4 | 0.061 |
| LV end-systolic diameter (mm) | 28±5 | 26±5 | 28±6 | 29±4 | 0.131 |
| LV ejection fraction (%) | 66±8 | 68±8 | 66±9 | 66±8 | 0.491 |
| LV mass index (g/m2) | 110±30 | 94±21 | 113±33 | 129±21 | <0.001 |
| Relative wall thickness | 0.5±0.1 | 0.5±0.1 | 0.5±0.1 | 0.5±0.1 | 0.981 |
| Early diastolic mitral inflow velocity/early diastolic mitral annular velocity ratio |
20.0±9.6 | 18.3±5.9 | 21.0±11.3 | 19.4±8.4 | 0.48 |
| Left atrial diameter (mm) | 41±7 | 40±6 | 42±9 | 41±5 | 0.693 |
| Left atrial volume index (mL/m2) | 53±19 | 49±17 | 54±20 | 58±18 | 0.303 |
| Mitral regurgitation ≥moderate | 5 (5%) | 0 | 4 (8%) | 1 (7%) | 0.348 |
| Tricuspid regurgitation ≥moderate | 6 (6%) | 1 (4%) | 5 (9%) | 0 | 0.334 |
| Tricuspid regurgitation gradient (mmHg) | 26±8 | 26±8 | 27±9 | 27±7 | 0.828 |
| Inferior vena cava diameter (mm) | 11±4 | 11±3 | 11±4 | 13±4 | 0.039 |
Data are presented as number (%) or median (interquartile range). LV, left ventricular. Other abbreviations as in Table 1.
AVC Parameters: AVCS and AVCV
The AVC parameters are shown in Table 3. Among all patients, the median AVCS was 2,093 AU (IQR, 1,513–2,781 AU), and the median AVCV was 1,570 mm3 (IQR, 1,168–2,086 mm3). The AVCS and AVCV significantly increased as the severity of concomitant AR increased (AVCS: 1,776 AU [IQR, 1,394–2,266 AU] in the isolated AS group, 2,009 AU [IQR, 1,610–2,800 AU] in the AS with mild AR group, 2,781 AU [IQR, 2,341–3,447 AU] in the AS with moderate AR group, P=0.014; AVCV: 1,338 mm3 [IQR, 1,065–1,704 mm3] in the isolated AS group, 1,508 mm3 [IQR, 1,222–2,102 mm3] in the AS with mild AR group, 2,086 mm3 [IQR, 1,756–2,590 mm3] in the AS with moderate AR group; P=0.014). Similar findings were obtained for the AVCS index (P=0.004) and AVCV index (P=0.004). Compared with the isolated AS group, the AVCS and AVCV were slightly higher in the AS with mild AR group and remarkably higher in the AS with moderate AR group (Figure 1). Receiver-operating characteristics curve analysis was performed to determine the association between AVC and concomitant moderate AR. The areas under the curve of AVCS and AVCV were both 0.70 (P=0.014 for both). The areas under the curve of the AVCS index and AVCV index were also both 0.70 (P=0.014 for AVCS index and P=0.013 for AVCV index) (Figure 2).
Aortic Valve Calcification Parameters
| Total (n=95) |
Isolated AS (n=27) |
AS with mild AR (n=53) |
AS with moderate AR (n=15) |
P value | |
|---|---|---|---|---|---|
| AVCS (AU) | 2,093 (1,513–2,781) | 1,776 (1,394–2,266) | 2,009 (1,610–2,800) | 2,781 (2,341–3,447) | 0.014 |
| AVCS index (AU/m2) | 1,372 (1,057–1,806) | 1,138 (976–1,424) | 1,423 (1,068–1,775) | 1,857 (1,377–2,220) | 0.004 |
| AVCV (mm3) | 1,570 (1,168–2,086) | 1,338 (1,065–1,704) | 1,508 (1,222–2,102) | 2,086 (1,756–2,590) | 0.014 |
| AVCV index (mm3/m2) | 1,033 (795–1,375) | 853 (749–1,068) | 1,072 (808–1,333) | 1,393 (1,033–1,670) | 0.004 |
Data are presented as median (interquartile range). AU, Agatston units; AVCS, aortic valve calcium score; AVCV, aortic valve calcium volume. Other abbreviations as in Table 1.
Association between aortic valve calcification and severity of concomitant AR in patients with severe AS. AR, aortic regurgitation; AS, aortic stenosis; AU, Agatston units; AVCS, aortic valve calcium score; AVCV, aortic valve calcium volume.
Receiver-operating characteristics curve analysis to assess the association between aortic valve calcification and concomitant moderate AR. (A) AVCS (AU), (B) AVCV (mm3), (C) AVCS index (AU/m2), (D) AVCV index (mm3/m2). AR, aortic regurgitation; AS, aortic stenosis; AU, Agatston units; AVCS, aortic valve calcium score; AVCV, aortic valve calcium volume.
Clinical Outcomes
Of the 78 patients who underwent SAVR or TAVI, 11 underwent SAVR and 55 underwent TAVI at our hospital, and the other 12 patients were treated at other hospitals. Of the 66 patients who were treated at our hospital, 8 patients who underwent SAVR and 53 patients who underwent TAVI were followed up. During the mean follow-up period of 2.0±1.7 years, no patients were admitted for heart failure,1 patient in the AS with mild AR group died of a cardiovascular event after SAVR, 2 patients (1 in the AS with moderate AR group and 1 in the isolated AS group) were admitted for heart failure and no patients died of a cardiovascular event after TAVI. There were no significant differences in the severity of concomitant AR with severe AS or the occurrence of cardiovascular events (admission for heart failure and cardiovascular death) between patients who underwent SAVR and those who underwent TAVI (P=0.647).
The present study showed that the AVCS and AVCV measured by MDCT were significantly associated with the severity of concomitant AR in patients with severe AS, which suggests that AVC may cause concomitant AR in patients with severe AS.
Severity of AR and AVCThe progression of AS is mainly due to accumulated valvular calcification6 and AVCS measured by MDCT is useful for diagnosing the severity of AS.15 The pathological changes secondary to AVC can also lead to the development of AR. El Khoury et al reported that leaflet restriction as a result of calcification, thickening, and fibrosis of the AV leaflets was a factor in AR.16 However, there are few reports about the association between AVC and the severity of AR combined with severe AS. The present study showed that the AVCS and AVCV significantly increased as the severity of concomitant AR increased in patients with severe AS, which suggests that inadequate valve coaptation due to progressive calcification is a risk factor for the development of concomitant AR in patients with severe AS. One previous study showed no correlation between the AVCS and the severity of concomitant AR in patients with AS,17 and we suspect this discrepancy is related to differences in the patient populations. In the previous study, the patients were relatively younger (mean age: early 70s), and patients with a bicuspid valve, which is likely to morphologically cause AR, were included (5% of patients had a bicuspid valve).
AR and LV Mass IndexIn the present study, the LV mass index significantly increased as the severity of concomitant AR increased in patients with severe AS, similar to previous studies,3,17 and indicated that the combination of pressure and volume overload induces myocardial stress, leading to an increase in the LV mass index.
Whether the severity of concomitant AR with severe AS affects postoperative outcomes has been controversial. Recent studies showed that compared with isolated AS, concomitant AR with severe AS had no influence on long-term outcomes after SAVR18,19 or TAVI.1,20 Especially in patients who have undergone TAVI, pre-existing volume overload and LV remodeling due to pre-existing AR are considered to be advantageous in terms of tolerating the influence of postprocedural AR.20 In patients with preoperative significant AR and AS, however, the preoperative LV mass that might indicate pre-existing volume overload and LV remodeling has been reported to be associated with LV dysfunction and all-cause death after SAVR.5 This suggests excessive remodeling has a poor prognosis. Additionally, this discrepancy might be due to the fact that patients who undergo TAVI instead of SAVR are generally in worse clinical condition and that in most cases significant AR is not a complication after SAVR. In the present study, concomitant AR did not affect the patients’ prognoses after SAVR or TAVI. Further studies are required to reveal the association between concomitant AR with severe AS and clinical outcomes after SAVR or TAVI.
Study LimitationsFirst, this study was a retrospective analysis of a single center, and the number of patients was small for the assessment. Larger studies are required to confirm our findings. Second, it is often difficult to evaluate the severity of AR in patients with severe AS because of the severe calcification of leaflets. Third, the AVCS and AVCV measured by MDCT were relatively small compared with those in several Western studies, probably because Japanese people are smaller in stature than Westerners, and the ratio of women was relatively high in this study. Fourth, although it is necessary to evaluate the time trend at ≥2 time points to clarify the relationship between AVC and the severity of AR concomitant with severe AS, this was not possible in the present study because most patients required immediate intervention. Fifth, AR is affected by the calcification of coaptation lesions rather than the entire AVC shown by the AVCS and AVCV. The calcification of coaptation lesions should be analyzed, but was technically difficult in our institution. Further studies, including evaluation of the localization of calcification, are required.
The severity of AR correlated with the AVCS and AVCV measured by MDCT in patients with severe AS. AVC may cause concomitant AR, leading to a worse disease condition.
None.
H.I. is a member of Circulation Journal’s Editorial Team.
This study was approved by the Ethics Committee at Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences (2212-029).
The deidentified participant data will not be shared.
