Abstract
Background
Assessment of patients with aortic stenosis (AS) and impaired left ventricular function remains challenging. Aortic valve calcium (AVC) scoring with computed tomography (CT) and fluoroscopy has been proposed as means of diagnosing and predicting outcomes in patients with severe AS.
Hypothesis
Severity of aortic valve calcification correlates with the diagnosis of true severe AS and outcomes in patients with low‐gradient low‐flow AS.
Methods
Echocardiography and CT database records from January 1, 2000 to September 26, 2009 were reviewed. Patients with aortic valve area (AVA) < 1.0 cm2 who had ejection fraction (EF) ≤ 25% and mean valvular gradient ≤ 25 mmHg with concurrent noncontrast CT scans were included. AVC was evaluated using CT and fluoroscopy. Mortality and aortic valve replacement (AVR) were established using the Social Security Death Index and medical records. The role of surgery in outcomes was evaluated.
Results
Fifty‐one patients who met the above criteria were included. Mean age was 75.1 ± 9.6 years, and 15 patients were female. Mean EF was 21% ± 4.6% with AVA of 0.7 ± 0.1 cm2. The peak and mean gradients were 35.5 ± 10.6 and 19.0 ± 5.1 mmHg, respectively. Median aortic valve calcium score was 2027 Agatston units. Mean follow‐up was 908 days. Patients with calcium scores above the median value were found to have increased mortality (P = 0.02). The benefit of surgery on survival was more pronounced in patients with higher valvular scores (P = 0.001). Fluoroscopy scoring led to similar findings, where increased AVC predicted worse outcomes (P = 0.04).
Conclusions
In patients with low‐gradient low‐flow AS, higher valvular calcium score predicts worse long‐term mortality. AVR is associated with improved survival in patients with higher valve scores.
Introduction
Patients with poor left ventricular ejection fraction, low cardiac output, and aortic stenosis (AS) face an increased risk of morbidity and mortality.1, 2, 3 Although these patients derive survival benefit from aortic valve replacement (AVR) in the long term, the risk associated with surgery is high (8%–22% mortality in selected series), precluding many patients from undergoing this intervention.4, 5, 6, 7, 8, 9, 10, 11, 12 As newer treatment modalities in the form of percutaneous aortic valve replacement (transcatheter aortic valve implantation [TAVI]) emerge, patients previously felt to be high risk for surgery can now be considered for treatment.13 However, given the challenges in prognosticating patients with low‐gradient low‐flow AS, selection of subjects who will benefit from these invasive interventions has proven to be difficult. Although thorough assessment including clinical presentation, resting echocardiogram, and dobutamine challenge provide critical information, the data on how to incorporate morphological characteristics of the valvular apparatus into the clinical decision‐making is limited.1, 5, 6, 14, 15, 16
Several studies have suggested that increased calcification of the aortic valve is associated with worse morbidity and mortality as well as faster progression of AS.17, 18, 19, 20, 21, 22 However, the importance of aortic valve calcification has not been studied in patients with low‐gradient low‐flow AS. In our study, we sought to evaluate the calcification of the aortic valve as measured by computed tomography (CT) and fluoroscopy in patients with low‐gradient low‐flow AS and its implications for outcome.
Methods
Patient Population
The echocardiography database at the Cleveland Clinic was retrospectively screened for patients with severe AS (aortic valve area [AVA] < 1.0 cm2) with ejection fraction (EF) ≤ 25% and mean aortic valve gradient ≤ 25 mmHg. Qualifying patients were included in the study if they had a concurrent chest or cardiac CT without contrast. These included gated cardiac CT scans, acquired for preoperative assessment of aortic calcification and relationship of the cardiovascular structures to the sternum, and chest CT scans, acquired without cardiac gating for assessment of lung disease.
Baseline demographics including age, gender, history of hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, coronary artery disease (CAD), myocardial infarction (MI), stroke, peripheral vascular disease, history of coronary artery bypass grafting (CABG), and atrial fibrillation were obtained from electronic medical records (EMR). Echocardiographic data included baseline EF, aortic valve peak and mean gradients, AVA (measured by continuity equation), presence of aortic insufficiency, mitral regurgitation, tricuspid regurgitation, and right ventricular systolic pressure. Dobutamine echocardiography and left heart catheterization data were also collected. Contractile reserve was defined as an increase of 10 mmHg in the mean gradient across the aortic valve with dobutamine.
Measurements by CT
Measurements of aortic valve calcification were performed with commercially available calcium‐scoring software on a clinical workstation (Siemens [Erlangen, Germany] Leonardo with calcium‐scoring module). Using a standard threshold of 130 Hounsfield units, the program identified calcium in the scan volume. A single user identified and marked the calcification corresponding to the aortic valve leaflets with measurements taken in the axial view. Calcification extending into the left ventricular outflow tract, coronary arteries, and aorta were excluded if they were contiguous with the calcification on the valve, and only the calcium on the leaflets and the annulus was included in the analysis. Using the computerized software, Agatston calcium score, volume score, and mass score were calculated. Total calcium score was described in Agatston units (AU), volume in cubic millimeters, and mass in milligrams.
Measurements by Fluoroscopy
The digitally stored angiograms of patients who received a left heart catheterization were reviewed. Calcification of the aortic valve was evaluated with quantification performed in multiple fluoroscopic views. Right anterior oblique fluoroscopic views were used for the evaluation of right and noncoronary leaflets of the aortic valve. Left anterior oblique fluoroscopic views were used for the evaluation of calcifications of right and left coronary leaflets of the aortic valve. The severity of the calcification was assessed at the area with the thickest zone of calcification. Calcification was defined as mild (<2 mm), moderate (2–5 mm), or severe (>5 mm). The angiography catheter size was used for calibration of quantitative measurements. Each leaflet was scored independently, with 0 denoting no, 1 mild (<2 mm), 2 moderate (2–5 mm), and 3 severe (>5 mm) calcification of the leaflet. Scores of all leaflets were then added up to a total calcification score.
Outcomes
Primary outcome was defined as mortality during follow‐up and was established using the Social Security Death Index as well as EMR. AVR in the form of surgical replacement or TAVI was assessed using the EMR and follow‐up notes.
Statistical Analysis
Continuous variables are expressed as mean ± standard deviation and categorical variables as proportions. Patients were divided into 2 groups based on their calcium scores (above or below median value). These 2 groups were then systematically compared. Continuous variables were analyzed with a 2‐sample Student t test, and categorical variables were compared with the χ2 test. Unadjusted survival analysis was first carried out using Kaplan‐Meier analysis. The log‐rank test was utilized for evaluating the differences between groups with high and low calcium scores as well as with AVR vs no AVR. Adjusted survival analysis was carried out using semiparametric Cox proportional hazard modeling. Adjusted survival curves were subsequently constructed to demonstrate meaningful differences between the 2 groups. All statistical tests were 2‐tailed, with a type I error rate of 0.05. All statistical analysis was carried out using the statistical software Stata version 10.0 (StataCorp, College Station, TX).
Results
Baseline Characteristics
A total of 537 patients were identified from the echocardiography database who had EF ≤ 25%, aortic valve area < 1.0 cm2, and mean aortic valve gradient ≤ 25 mmHg between January 1, 2000 and September 26, 2009. Of these patients, 135 had a chest or cardiac CT, and 51 of these were CT studies without contrast. The time difference between the CT scans without contrast and echocardiograms was 110 ± 220 days. The mean age was 75.1 ± 9.6 years, with 71% of the population being male. Hypertension was present in 92% of the cases, hyperlipidemia in 82%, and diabetes mellitus in 59%. CAD with history of MI was seen in 72% of the patients, and 69% had undergone CABG. Baseline characteristics are listed as stratified according to the median calcium score by CT (Table 1).
Table 1.
Clinical Baseline Characteristics of Patients Included in the Retrospective Analysis (Total N = 51) as Well as Those With Valvular Calcium Score Above or Below the Median
| Characteristic | Total Cohort | Calcium Score < 2027 AU | Calcium Score > 2027 AU | P, High vs Low Calcium Scores |
|---|---|---|---|---|
| Age, ya | 75.1 ± 9.6 | 72 ± 10.1 | 78 ± 8.3 | 0.04 |
| Male, No. (%) | 36 (71) | 21 (84) | 15 (58) | 0.03 |
| Hypertension, No. (%) | 47 (92) | 21 (84) | 26 (100) | 0.03 |
| Hyperlipidemia, No. (%) | 43 (84) | 20 (80) | 23 (88) | 0.40 |
| Diabetes mellitus, No. (%) | 30 (59) | 15 (60) | 15 (58) | 0.87 |
| History of myocardial infarction, No. (%) | 42 (73) | 21 (84) | 21 (81) | 0.72 |
| History of coronary artery bypass grafting, No. (%) | 35 (69) | 17 (68) | 18 (69) | 0.92 |
| History of atrial fibrillation, No. (%) | 22 (43) | 12 (48) | 10 (38) | 0.49 |
| History of stroke, No. (%) | 10 (20) | 6 (23) | 4 (15) | 0.48 |
| History of COPD, No. (%) | 11 (22) | 2 (8) | 9 (34) | 0.02 |
| Baseline creatininea | 1.6 ± 0.7 | 1.6 ± 0.8 | 1.6 ± 0.7 | 0.84 |
| Ejection fraction (%)a | 21 ± 4.6 | 20.4 ± 4.9 | 21.1 ± 5.2 | 0.62 |
| Aortic valve area, cm2a | 0.7 ± 0.1 | 0.7 ± 0.1 | 0.7 ± 0.1 | 0.48 |
| Aortic valve pressure gradient, mmHga | ||||
| Peak | 35.5 ± 10.6 | 31.7 ± 10.4 | 39.2 ± 9.2 | 0.01 |
| Mean | 19.0 ± 5.1 | 16.6 ± 4.8 | 21.3 ± 4.4 | 0.0005 |
| Aortic insufficiency ≥ 3, No. (%)b | 2 (4) | 1 (4) | 1 (4) | 1.00 |
| Mitral regurgitation ≥ 3, No. (%)b | 11 (22) | 5 (20) | 6 (23) | 0.78 |
| Right ventricular systolic pressure, mmHg | 48.0 ± 14.1 | 46.3 ± 15.4 | 49.5 ± 13.2 | 0.56 |
Abbreviations: AU, Agatston units; COPD, chronic obstructive pulmonary disease.
Plus–minus values represent mean ± standard deviation.
Regurgitation was scored by color Doppler. Score ≥ 3 signifies at least moderately severe regurgitation.
Baseline echocardiographic evaluation showed a mean EF of 21% ± 4.6% (range, 10%–25%), with an AVA of 0.7 ± 0.1 cm2. The peak and mean aortic valve gradients were 35.5 ± 10.6 and 19.0 ± 5.1 mmHg, respectively (Table 1). Of the 51 patients included, 12 had dobutamine echocardiogram (3 in the low‐calcium‐score and 9 in the high‐calcium‐score groups). Of these, 2 of the 3 patients in the low‐calcium group and 5 of the 9 in the high‐calcium group had a >10 mmHg increase in their mean gradients with dobutamine.
Follow‐up and Outcome
Mean follow‐up was 908 days (range, 12–3286 days). Of the 51 patients in the study, 21 underwent surgical AVR during follow‐up, and 1 patient underwent TAVI. In addition, 1 patient underwent total artificial heart placement (TAH) followed by heart transplantation, and 6 patients underwent aortic balloon valvuloplasty. Thirty of the 51 patients died during follow‐up.
Calcium Scoring
Calcium score analysis using CT scans of the valve (mean slice thickness, 3.06 ± 1.16 mm) in the overall population of 51 patients yielded a median score of 2027 AU (range, 140–9210 AU), with a mean calcium volume of 1972 ± 1118 mm3 and mass of 530 ± 381 mg. The distribution of the calcium scores over the measured range was close to Gaussian distribution.
Calcium scoring with fluoroscopy in 42 patients yielded a mean score of 3.7 ± 2.9, with a median of 4. A total score of ≥4 was present in 22 cases, and a total score of <4 was present in 20 cases. The CT and fluoroscopy scores of the valve showed a modest correlation with respect to absolute values (r = 0.48).
Outcomes Stratified by CT Calcium Scoring
Kaplan‐Meier survival analyses were performed after stratifying patients in high‐ or low‐calcium groups with regard to the median calcium score as determined by CT (2027 AU). The unadjusted analysis showed that 13 of the 25 patients (52%) with low calcium scores and 17 of the 26 patients (65%) with high calcium scores died during follow‐up. Survival curves with adjustment for baseline comorbid conditions as well as echocardiographic parameters (EF, peak and mean gradients) showed significantly better survival in patients with low calcium scores (P = 0.02; Figure 1a).
Figure 1.
(a) Kaplan‐Meier curves adjusted for baseline variables stratified for calcium score without adjustment for aortic valve replacement (AVR). (b) Kaplan‐Meier curves adjusted for baseline variables and for AVR.
Surgical AVR was performed in 11 patients with low calcium and 10 patients with high calcium scores. Additionally, in the high‐calcium‐score group, 1 patient received TAVI and 5 received aortic balloon valvuloplasty, whereas in the low‐calcium‐score group, 1 patient received TAH with transplantation and 1 received aortic balloon valvuloplasty. The patient who received TAH and transplantation was excluded from the survival analysis that evaluated the impact of AVR, and the patient who received TAVI was included in the analysis. Survival curves after adjusting for AVR and baseline comorbidities are shown in Figure 1b and continue to suggest significantly better survival in patients with low calcium scores (P = 0.049).
The impact of calcium scores and AVR on mortality was further studied with the log‐rank test. This analysis showed that in patients not undergoing AVR, patients with high calcium scores had worse outcomes compared to patients with low calcium scores. In patients undergoing AVR, mortality of patients with high calcium scores was no different than that of those with low calcium scores during long‐term follow‐up. Furthermore, the 30‐day mortality in patients who had AVR was also similar with respect to their calcium scores (2 of 11 died in the low calcium and 1 of 10 died in the high‐calcium‐score group; P = 1.0). There was no significant survival difference in patients undergoing AVR if the calcium score was low, whereas patients did significantly worse if they did not undergo AVR with a high calcium score (Table 2). Kaplan‐Meier survival analysis of both cohorts according to their AVR status is shown in Figure 2.
Table 2.
Cross‐Tabulated p Values Comparing High and Low Calcium Scores Based on AVR Status Using the Log‐Rank Test
| High Score, No AVR | High Score, AVR | Low Score, No AVR | Low Score, AVR | |
|---|---|---|---|---|
| High score, no AVR | — | 0.001 | 0.046 | 0.006 |
| High score, AVR | 0.001 | — | 0.025 | 0.39 |
| Low score, no AVR | 0.046 | 0.025 | — | 0.16 |
| Low score, AVR | 0.006 | 0.39 | 0.16 | — |
Abbreviation: AVR, aortic valve replacement.
The outcome measure is mortality.
Figure 2.
Survival analysis with Kaplan‐Meier curves for patients with high and low calcium scores based on their aortic valve replacement (AVR) status.
Outcomes Stratified by Fluoroscopy Scoring
Outcomes were analyzed after patients were stratified based on their median fluoroscopy scores (<4 vs ≥4). There were 16 (72%) deaths in patients with high scores and 9 (45%) in patients with low scores during follow‐up. Unadjusted survival analysis of this cohort showed a significantly better survival among the low‐calcium‐score group (P = 0.04; Figure 3a). Adjusted analysis results were similar (P = 0.02; Figure 3b).
Figure 3.
(a) Unadjusted Kaplan‐Meier survival curves of patients with high and low fluoroscopy score. (b) Analysis after patients who had aortic valve replacement during follow‐up were excluded.
AVR was performed for 7 patients in the low‐calcium‐score group (excluding 1 patient who received TAH and transplantation) and 12 patients in the high‐calcium group (including 1 patient who had TAVI). After excluding these patients who underwent AVR, it was found that all patients with high‐calcium fluoroscopy scores died (10 of 10 patients), whereas 8 of 12 (67%) patients in the low‐calcium‐score group died (P = 0.02; Figure 3b). In patients who underwent AVR during follow‐up, 1 (14%) patient died in the low‐calcium group, whereas 6 (50%) patients died in the high‐calcium group (P = 0.17). There was no 30‐day mortality in patients with low calcium who had AVR, whereas 2 of the 12 patients who had high calcium scores with AVR died at 30 days (P = 0.51).
Discussion
Our data demonstrate that in patients with low‐gradient low‐flow AS, worse calcification of the aortic valve leaflets is associated with poor long‐term survival. Furthermore, AVR provides an incrementally higher survival benefit to patients with worse calcification. These data suggest that quantitative evaluation of aortic valve calcification should be strongly considered in patients with low‐gradient low‐flow AS.
Low‐gradient low‐flow AS poses a challenging clinical scenario for clinicians because algorithms for evaluation and management of these patients remain controversial. It is well known that the severity of the AS in these patients can be overestimated by traditional echocardiographic and catheterization studies because gradients and valve area depend on the flow across the valve. Although dobutamine echocardiography provides further validation of stenosis severity, its negative predictive value is limited.5, 6, 14, 23 Furthermore many patients with only moderate AS and poor left ventricular systolic function derive benefit from surgical/transcatheter intervention. With the increasing experience of TAVI, intervening in this patient population is becoming a distinct clinical possibility. However, proper patient selection is important to maximize the effectiveness of TAVI in this patient population. Although several studies have shown that morphological characterization of the valve with severity of calcification is important for TAVI, the role of quantitative calcium scoring in the low‐gradient low‐flow patient population has not been clearly defined.4, 6, 14, 16, 23
Several studies have shown that high calcium scores are independent predictors of death in patients with severe AS. Amount and severity of calcification has been shown to correlate with severity of AS as well as outcomes in these patients.17, 18, 19, 20, 21, 22 These studies have focused on patients who have normal EFs with normal flow conditions and have mostly used qualitative echocardiographic criteria. The single study that has measured the aortic valve calcification in patients with low EF had a wide range of AS and provided no prognostic data.24 Our study is unique in that it evaluates the role of calcium quantification in the prognosis of patients with low‐gradient low‐flow AS with a strict definition of the low‐flow state.
Our study shows that calcium scores as quantified by CT in low‐gradient low‐flow AS patients follow a normal distribution and are associated in linear fashion with fluoroscopic scoring of the valve with a modest degree of correlation. As suggested by the findings in the study, CT evaluation of the valve can be used in identifying and quantifying the calcification of the valve and provides prognostic value. These data suggest that patients with higher calcium scores might have significantly more benefit from AVR as compared to those with lower calcium scores. None of the prior studies has evaluated fluoroscopic calcification in a very rigorous quantitative fashion. We measured calcium by quantitative angiography on each leaflet and created a unique scoring system. This is a very useful and simple method to identify patients at risk of poor outcome. The applicability of this finding is enormous, because almost all of these patients have diagnostic cardiac catheterization for evaluation. Findings from fluoroscopic evaluation of the valve are congruent with those from the CT evaluation in that the higher the calcium, the worse the outcomes. Furthermore, patients who have high calcium on fluoroscopy have worse outcomes in the absence of AVR. Given these findings, we recommend that the valve should be evaluated with fluoroscopy during cardiac catheterization for calcification in patients with low‐gradient low‐flow AS. If this evaluation reveals significant calcification, patient would likely benefit from surgery. If calcification is not demonstrated during fluoroscopy, a noncontrast CT evaluation of the valve to assess for calcification might be of value in predicting outcomes. Our data also suggest that in patients with low‐gradient low‐flow AS, AVR might not be of significant benefit in the absence of calcification.
Given the established histopathology associated with AS, it is biologically plausible that worse calcification is associated with severe AS and worse outcomes. Although our findings echo those that were established in the literature earlier, our study is unique in that we expand on the prior studies and verify the importance of calcification in patients with low‐gradient low‐flow AS. A further benefit of studying the extent of calcification might be the distinction between true AS and pseudostenosis. Our results were limited in this regard (few patients studied with dobutamine echocardiography), and further investigations are necessary comparing dobutamine stress echocardiography with calcification quantification.
Limitations of this study include those associated with its retrospective nature as well as the relatively small number of patients included in the analysis. To account for the retrospective nature of the study, adjustment for baseline variables and AVR was performed. The sample size in this study is the largest published to date in evaluating the prognosis of low‐gradient low‐flow AS patients with respect to calcium content of the valve. Given the paucity of studies that quantify the calcification of the aortic valve in low‐gradient low‐flow AS patients, we believe that this study should lead to further analyses evaluating the importance of calcification of the valve. The study is further limited by the inclusion of CT scans with different indications and protocols. In particular, there may be differences in the accuracy of calcium scores between gated (cardiac) and nongated (chest) CT scans. Subsequent studies with more homogeneous acquisition protocols would be important.
Conclusions
Our data demonstrate that in patients with low‐gradient low‐flow AS, higher valvular calcium score predicts worse long‐term mortality. AVR is associated with improved survival in patients who have higher aortic valve scores. Our study suggests that severity of aortic valve calcification should be evaluated in patients with low‐gradient low‐flow AS, as such an evaluation can be helpful in prognosticating in this patient population.
The authors have no funding, financial relationships, or conflicts of interest to disclose.
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