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Original Research |
1 Department of Radiology, Columbia University Medical Center, 630 W 168th St.,
New York, NY 10032.
2 Department of Medicine, Columbia University Medical Center, New York, NY
10032.
Received August 31, 2004;
accepted after revision January 31, 2005.
Address correspondence to J. H. M. Austin.
Abstract
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MATERIALS AND METHODS. One hundred fifteen subjects who were 60 years old or older and who showed aortic valve calcification on chest CT (5-mm reconstructed section width, no IV contrast material) and who had also undergone transthoracic echocardiography within 3 months of the CT examination were identified retrospectively. Aortic valve calcification scores (Agatston and volumetric) and subjective calcification pattern scores (based on a 9-point scale) were calculated and correlated with echocardiographic gradients.
RESULTS. Thirty patients (26%) (median age, 81 years) were identified who showed an increased pressure gradient across the aortic valve at echocardiography. Eighty-five subjects (74%), including 30 age-matched but otherwise randomly selected control subjects, showed no increase in pressure gradient. The severity of aortic valve calcification was greater for the 30 subjects with an increased gradient than for the control subjects (p < 0.0001). Increased mean and peak gradients across the aortic valve correlated with the subjective scores for aortic valve calcification (r = 0.69 and 0.65, respectively; p < 0.0001), with Agatston scores (r = 0.76 and 0.70, respectively; p < 0.0001), and with volumetric scores (r = 0.78 and 0.73, respectively; p < 0.0001). In terms of specific commissures, the greatest correlation with mean and peak gradients was for peripheral left-posterior commissural calcification (r = 0.71 and 0.65, respectively; p < 0.0001) and central right-left commissural calcification (r = 0.69 and 0.66, respectively; p < 0.0001).
CONCLUSION. The severity of aortic valve calcifications on chest CT, as assessed either subjectively or objectively, correlated with increased pressure gradients across the aortic valve, particularly for calcification of the peripheral left-posterior commissure and the central right-left commissure. These results indicate that the severity and location of aortic valve calcifications on chest CT are associated with an increased pressure gradient across the aortic valve.
Keywords: aortic valve • calcification • cardiovascular disease • CT • heart • stenosis
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Patients suspected of having aortic stenosis usually undergo Doppler echocardiography as part of the evaluation [3, 4]. Doppler quantification of the systolic pressure gradient and of the aortic valve area is useful for management decisions because aortic valve area and systolic pressure gradients (mean and peak) across the aortic valve are recognized predictors of outcome [4].
Aortic valve calcification can sometimes be seen on chest radiography, and the presence of such calcifications—usually best seen on the lateral radiograph—is a sensitive marker for clinically significant aortic stenosis [5]. CT is a sensitive imaging tool for detecting focal calcifications, and we have noted subjectively that aortic valve calcifications are often seen as incidental findings on CT of elderly persons and that, moreover, these aortic valve calcifications appear to show some characteristic patterns. Recent studies have shown correlations between CT measurements of the severity of aortic valve calcification and the severity of increased pressure gradients across the valve [6-9]. Because the severity and patterns of aortic valve calcification offer the potential of aiding in presymptomatic detection of aortic valve stenosis, we undertook this study.
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Chest CT scans (0.75-sec scanning time per section, 120-140 kVp, 200-240 mA), each with the patient in the supine position, were obtained on four single-detector CT scanners (Somatom Plus-4, Siemens Medical Solutions) using collimation of 5 mm, and on one 4-MDCT scanner (Siemens Volume Zoom) from August 1999 through December 2002. Images were reconstructed using a high-spatial-frequency algorithm and reconstructed section width of 5 mm. Each CT study was evaluated quantitatively for aortic valve calcification using Agatston and volumetric calcification scores [10, 11] (Vitrea 2 software, Vital Images) on a PACS (Kodak) workstation. Pixels having a CT attenuation of 130 H or greater were considered to be showing calcification [10]. The calcifications assessed were limited to the region of the aortic valve and specifically excluded any arcuate or other focal calcifications of atherosclerosis of the aortic root, calcifications of atherosclerosis of the proximal right and left coronary arteries, and calcification of the superomedial aspect of the mitral annulus.
All chest CT studies were also reviewed independently (at soft-tissue settings of 350-H width and 35-H center, and bone settings of 1,500-H width and 300-H center) by two experienced thoracic radiologists who were blinded to all clinical data except each patient's age and sex, including blinding to each patient's echocardiographic data. Aortic valve calcifications were characterized subjectively by the following criteria: presence and location (central or peripheral half for each commissure [Fig. 1]); subjective grade of severity (scale of 1-9), both overall and in each location (Fig. 1); and number of 5-mm sections with calcification present. The 9-point subjective scale of severity corresponded to the following scores for calcification (see Figs. 2A, 2B, 2C, and 2D for examples): 1 = judged absent, but mild calcification was considered and rejected; 2 = judged mild, but absence of calcification was considered and rejected; 3 = judged unequivocally mild; 4 = judged mild, but moderate calcification was considered and rejected; 5 = judged moderate, but mild calcification was considered and rejected; 6 = judged unequivocally moderate; 7 = judged moderate, but severe calcification was considered and rejected; 8 = judged severe, but moderate calcification was considered and rejected; and 9 = judged unequivocally severe. An average of the subjective scores by the two radiologists for overall calcification of the aortic valve and for each region of the aortic valve was used for statistical analysis. An average of the objective scores (Agatston and volumetric) of the two radiologists for the quantity of aortic valve calcification was also used for statistical analysis.
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The peak instantaneous transvalvular aortic jet velocity was determined using the modified Bernoulli equation. The valve was examined from multiple acoustic windows to obtain the highest peak jet velocity. Mean Doppler velocities were calculated by averaging the instantaneous Doppler gradients throughout the ejection period using an online quantification package. Three cardiac beats were averaged and the spectral display velocity curve was traced by hand. There were no cases of additional subaortic or supraaortic stenosis. No aortic valve gradients were unobtainable for technical reasons (e.g., poor acoustic windows).
A retrospective chart review was conducted for the 30 study and the 30 control subjects, documenting clinical variables that have been shown to be associated with aortic stenosis: history of cigarette smoking [1, 12-14], diabetes mellitus [13, 14], systemic hypertension [1, 13] and coronary artery disease [15]. The presence of coronary artery disease was based on the mention in the patient's record of "coronary artery disease," "angina with positive stress test," or "myocardial infarction," but not "chest pain." Serum chemical tests that have been associated with aortic stenosis were evaluated: serum calcium [13,14], low-density and high-density lipoprotein [13, 14], triglyceride [14], and creatinine [13, 16] levels were also recorded. Each laboratory value recorded was the single data point closest in time to the patient's CT examination.
The relationships between pressure gradients and CT aortic valve calcification data and clinical variables were determined using the Spearman's rank correlation. Differences in the presence and distribution of aortic valve calcification between patients and control subjects were tested using the nonparametric rank-sum test. Differences in the distribution of clinical factors between study and control subjects were tested using the two-sided Fisher's exact test. A p value of less than 0.05 was considered significant for analyses. This study was approved by our institutional review board.
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Agatston scores and volumetric scores for severity of aortic valve calcification both differed significantly between study and control subjects (p < 0.0001) (Table 3). The number of 5-mm-thick sections showing aortic valve calcification differed significantly between study and control subjects (p = 0.0004) (Table 3). In addition, study and control subjects differed significantly in the overall subjective calcification grade (p < 0.0001), including at each of the six designated locations of valve calcification (p < 0.01) (Table 3). Diabetes mellitus was documented in 13 (43%) of the control subjects and in four (13%) of the study subjects, but information concerning diabetes mellitus was not available for 11 (37%) of the 30 control subjects or for three (10%) of the 30 study subjects (Table 4).
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The Agatston and volumetric calcium scores were each found in the 30 study subjects to correlate positively with mean (r = 0.76 and 0.78, respectively; p < 0.0001) and peak (r = 0.70 and 0.73, respectively; p < 0.0001) gradients at echocardiography (Table 3). The number of 5-mm-thick sections showing calcification also correlated positively with mean and peak gradients (r = 0.56 and 0.53, respectively; p < 0.003) (Table 3). The subjective calcification grade in five of the six designated commissural regions of the aortic valve correlated positively with peak and mean gradients (r = 0.48-0.71 and r = 0.47-0.66, respectively; p < 0.01), except for the peripheral right-posterior commissure, which showed no significant correlation (Table 3). The highest CT-echocardiographic correlations were found for peripheral left-posterior commissural calcification (mean, r = 0.71; peak, r = 0.65; each p < 0.0001) and central right-left commissural calcification (mean, r = 0.69; peak, r = 0.66; each p < 0.0001) (Table 3). None of the serum chemical or clinical variables correlated significantly with mean or peak gradients (Table 4).
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The incidental finding of aortic valve calcifications on routine chest CT examinations has been described previously, yet few studies have examined its clinical relevance. In an early retrospective study of 100 patients (40 years or older) who underwent chest CT examination (1.0-cm collimation), Woodring and West [17] identified five patients with aortic valve calcification, three of whom had echocardiograms showing a significantly increased gradient across the aortic valve. Lippert et al. [18], in a retrospective study of 109 patients (mean age, 60 years) who underwent both chest CT (0.5- to 1.0-cm collimation) and echocardiography over a 2-year period, found aortic valve calcification in 30% of their patients, and five patients showed a hemodynamically significantly increased gradient, defined as a peak gradient of 25 mm Hg or greater. They concluded that aortic valve calcification detected on CT is a common finding that is usually clinically insignificant; however, they noted that calcification was seen in all cases of a hemodynamically significantly increased gradient across the valve.
Our study confirms the results of four recent studies that the echocardiographic assessment of the severity of aortic stenosis correlates well with CT Agatston- and volumetric-based scoring of aortic valve calcification [6-9]. Two of these studies used an MDCT scanner (2.7-mm collimation [6] and 2.5-mm collimation [7], the latter study ECG-gated) and two of the studies used ECG-gated electron beam tomography (EBT) (3-mm collimation) [8, 9]. The validity of EBT in quantifying aortic valve calcification has been confirmed in a recent histomorphometric analysis [19]. However, our study did not use ECG gating or an EBT scanner. Rather, it extends the original results of the four earlier studies [6-9] to the arena of clinical radiology practice using subjective assessment of aortic valve calcification.
Furthermore, MDCT has recently been shown to be comparable to EBT for assessing aortic valve calcification, although low levels of aortic valve calcification tended to show higher levels of interscan variability than moderate to high levels, despite ECG gating [7]. Multidetector, ECG-gated CT has also recently been shown to have good agreement of the assessment of aortic valve calcification with the quantity of calcium in the aortic valve in surgical specimens [20]. The results of our study suggest that ECG gating may not be necessary for clinically useful assessment on CT of aortic valve calcification [6].
The predictive value of commissural patterns of aortic valve calcification has not, to our knowledge, been evaluated previously. In an autopsy study of elderly patients with severe aortic stenosis, nodular calcific deposits were found on the aortic aspects of the valve cusps adjacent to commissures, which were mostly unfused [21]. Two major patterns of aortic valve calcification have been described previously in pathology specimens: first, a coaptation pattern in which calcifications occur as two spokes, parallel and immediately adjacent to each other on each side of the line of cusp coaptation [22]; and second, a radial pattern in which calcifications occur as multiple spokes radiating from the cusp attachment toward the center of the cusp [22]. To our knowledge, the observation that the central right-left commissure and the peripheral left-posterior commissure are the sites of the strongest correlations between the severity of aortic valve calcifications and transvalvular gradients has not previously been reported.
Two mechanisms appear likely to explain these associations. One is that these two specific regions may represent the sites of greatest mechanical stress for the stenotic aortic valve [22], probably in association with decreased compliance of the sinuses of Valsalva [23]. Another possibility is that the left aortic cusp, which forms the posterior aspect of the right-left commissure and the left aspect of the left-posterior commissure, tends to be the largest of the three cusps [24] and perhaps is thus the cusp most associated with the stresses that lead to calcific deposits. However, Cujec and Pollick [25] have reported that the cusp most likely to be involved in isolated aortic valve thickening is most commonly the noncoronary cusp, followed by the right and then the left. A definite mechanism for preferential correlation of calcification of the central right-left commissure and of the peripheral left-posterior commissure and increased pressure gradients across the aortic valve remains to be elucidated. A limitation of the present study is that the aortic valve is slightly oblique to the axial projection of CT, so the three commissures do project slightly obliquely with respect to the plane of a section through the valve.
Although the severity of aortic valve calcification did correlate in our study with gradients across the aortic valve, the association was an imperfect predictor: as false-negatives, two (6.7%) of 30 subjects with an increased gradient had subjective calcification scores of 2 or less on our 9-point subjective scale, and four (13.3%) of these 30 subjects had an Agatston score of 50 or less (Table 1). As false-positives, two (6.7%) of the 30 control subjects had a subjective severity score of 6 or more on the 9-point scale, and four (13.3%) of these 30 control subjects had an Agatston score of 200 or more (Table 2). Nevertheless, these percentages are sufficiently low to support strongly the clinical precept that more than minimal aortic valve calcification of an elderly person on CT is an indication for echocardiographic evaluation.
The quantity of aortic valve calcification at the time of diagnosis of aortic stenosis appears to be of prognostic import: the greater the quantity of calcification, the more rapid will be the loss of valve area [4, 16, 26, 27]. Moreover, the smaller the valve area, the greater the rate of progression of aortic stenosis, according to two studies [4, 26], although not according to a third study [28]. The rate of progression is variable [4, 26, 28], but the mean rate of progression of calcific aortic stenosis has been described as in the range of a loss of valve area of approximately 0.1 cm2 per year [4, 26, 28] and as a mean increase of mean gradient of 6-7 mm Hg per year [4, 28], at least as long as cardiac failure does not supervene [4, 29]. None of the patients in our series was in a state of cardiac failure. Five-year event-free survival after the diagnosis of an increased aortic valve gradient in asymptomatic subjects, defining an event as either death or aortic valve replacement, has been reported as only 26% ± 10% [4]. In another series of 128 consecutive asymptomatic persons with severe aortic stenosis, 4-year event-free survival was only 20% ± 5% [27].
Serum chemical values showed no significant differences between study and control subjects in our study (Table 4). Although prior studies have implicated elevated serum cholesterol [1, 12, 13], creatinine [1, 30, 16], and calcium [30] levels as risk factors for progression of aortic stenosis, our results, based on a single serum test, support no such associations. The progression of aortic stenosis does appear to be multifaceted, including current cigarette smoking as a major risk factor for rapid progression [1, 27], and having an association with coronary artery atherosclerotic disease that may respond to serum lipid-lowering therapy [12]. We did not assess therapeutic interventions in this study.
Advanced age is not necessarily a contraindication to aortic valve replacement for aortic stenosis. Long-term postoperative survival and quality of life were termed excellent in a recent series of 105 subjects 75-89 years old (mean, 79 years) [7]. Detecting aortic valve stenosis in this age group, in candidates appropriate for aortic valve replacement, may be clinically beneficial.
A limitation of our study is that the aortic valve was assessed on echocardiography only by Doppler gradients and not by assessment of the continuity equation [31]. Had the continuity equation been used, it would have allowed the aortic valve area to be determined and would thereby have lessened the possibilities of either overcalculation or undercalculation of aortic valve stenosis because of coexisting aortic regurgitation or poor function of the left ventricle, respectively [31]. During the time of our study, our echocardiography laboratory did not routinely use the continuity equation, which involves time-consuming measurement of the outflow tract diameter of the left ventricle.
EBT scans have been shown to yield excellent reliability for Agatston and volumetric assessment of aortic valve calcification in a context of ECG gating [32]. Shavelle et al. [8] have suggested that aortic valve calcification at EBT showing Agatston scores in excess of a certain level (e.g., 150) warrant echocardiographic assessment [8].
Two other limitations of this study are that it excluded subjects with a bicuspid aortic valve [33] and also excluded subjects younger than 60 years. Aortic valve calcification is well recognized as occasionally occurring in subjects younger than 60 years, especially in those with a bicuspid aortic valve or in those who had rheumatic fever in childhood. However, we chose to limit our study to subjects with a tricuspid aortic valve and 60 years old or older because this population is at major risk for the underdiagnosis of senile degeneration of the aortic valve before clinically significant stenosis of the valve develops [2].
Another limitation of our study is that it was retrospective and used a rather small sample (30 subjects with aortic valve stenosis). We suggest that a prospective study of a larger series, including subjects younger than 60 years, would be advisable for further understanding the clinical importance of CT detection of unanticipated aortic valve calcification.
Both a limitation and a strength of our study is that the CT examinations did not use the most sensitive of modern CT technologic approaches (we used mostly single-detector examinations, slice thickness was 0.5 cm, scanning time was 0.75 sec, and ECG gating was not used). In assessing coronary artery calcifications on CT, sections thinner than 0.5 cm and scanning times shorter than 0.75 sec, in a context of ECG gating, produce more accurate calcium scoring than the techniques of our study [10, 34]; presumably, the same observation also holds for the calcified aortic valve [35]. However, aortic valve calcification at MDCT has been shown, using 2.7-mm collimation and no ECG gating, to correlate closely with the severity of aortic stenosis [6]. Correspondingly, the strength of our study is that, because no ECG gating was used, our positive results offer a clinically practical guideline: if the subjective rating of aortic valve calcifications is greater than mild, especially for the central right-left commissure and the peripheral left-posterior commissure, then echocardiographic evaluation may be indicated.
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