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Imaging of the Aortic Valve Using Fluorodeoxyglucose Positron Emission Tomography
Journal of the American College of Cardiology © 2011 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 57, No. 25, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2010.12.046
Cardiac Imaging
Imaging of the Aortic Valve Using Fluorodeoxyglucose Positron Emission Tomography
CME
Increased Valvular Fluorodeoxyglucose Uptake in Aortic Stenosis Gergana Marincheva-Savcheva, MD,*† Sharath Subramanian, MD,†‡ Sadia Qadir, MD, MPH,†‡ Amparo Figueroa, MD,†‡ Quynh Truong, MD, MPH,*†‡ Jayanthi Vijayakumar, MD,†‡ Thomas J. Brady, MD,†‡ Udo Hoffmann, MD, MPH,†‡ Ahmed Tawakol, MD*†‡ Boston, Massachusetts
JACC JOURNAL CME This article has been selected as the month’s JACC Journal CME activity. Accreditation and Designation Statement The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The American College of Cardiology designates the educational activities in JACC for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Method of Participation and Receipt of CME Certificate To obtain credit for JACC CME, you must: 1. Be an ACC member or JACC subscriber. 2. Carefully read and reflect upon the CME-designated article available online and in this issue of JACC. 3. Answer the post-test questions and complete the brief evaluation available at http://cme.jaccjournals.org.
From the *Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts; †Cardiac MR PET CT Program, Massachusetts General Hospital, Boston, Massachusetts; and the ‡Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. Supported by National Institutes of Health Grant No. R01
4. Claim your CME credit and receive your certificate electronically by following the instructions given at the conclusion of the online activity. CME Objective for This Article: At the end of this activity, the learner should be able to assess whether FDG uptake in the aortic valve (AV) is increased in AS. CME Editor Disclosure: JACC CME Editor Ajit Raisinghani, MD, FACC, reports that he has no financial relationships or interests to disclose. Author Disclosures: Supported by National Institutes of Health Grant No. R01 HL095123-01 and Center for the Integration of Medicine and Innovative Technologies. The authors have reported that they have no relationships to disclose. Medium of Participation: Print (article only); online (article and quiz) CME Term of Approval: Issue date: June 21, 2011 Expiration date: June 20, 2012
HL095123-01 and Center for the Integration of Medicine and Innovative Technologies. The authors have reported that they have no relationships to disclose. Manuscript received May 24, 2010; revised manuscript received December 10, 2010, accepted December 21, 2010.
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Marincheva-Savcheva et al. Imaging Aortic Valve Inflammation With FDG-PET
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Imaging of the Aortic Valve Using Fluorodeoxyglucose Positron Emission Tomography Increased Valvular Fluorodeoxyglucose Uptake in Aortic Stenosis Objectives
Because fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provides a noninvasive index of inflammation, we sought to assess whether FDG uptake in the aortic valve (AV) is increased in aortic stenosis (AS).
Background
AS is associated with valvular inflammation.
Methods
FDG-PET/computed tomography data were retrospectively evaluated in 84 patients (age 73 ⫾ 9 years, 45% female), 42 patients with AS, and 42 age-matched controls. FDG uptake was determined within the AV while blinded to AS severity. Target-to-background ratio (TBR) was calculated as valvular/blood activity. Stenosis severity was established on echocardiography, and presence of AV calcification was independently assessed on computed tomography.
Results
The aortic valve PET signal (TBR) was increased in AS compared with controls (median 1.53 [interquartile range (IQR): 1.42 to 1.76] vs. 1.34 [IQR: 1.20 to 1.55]; p ⬍ 0.001). Further, compared with controls, TBR was increased in mild (median 1.50 [IQR: 1.36 to 1.75]; p ⫽ 0.01) and moderate (median 1.70 [IQR: 1.52 to 1.94]; p ⬍ 0.001), but not in severe AS (median 1.49 [IQR: 1.40 to 1.54]; p ⫽ 0.08). When subjects were categorized according to AV calcification, valvular FDG uptake was increased in mildly (median 1.50 [IQR: 1.36 to 1.79]; p ⬍ 0.01) and moderately (median 1.67 [IQR: 1.50 to 1.85]; p ⬍ 0.001), but not severely calcified valves (median 1.51 [IQR: 1.38 to 1.54]; p ⫽ 0.15), compared with noncalcified valves (median 1.35 [IQR: 1.20 to 1.52]).
Conclusions
This study supports the hypothesis that AS is an inflammatory condition and suggests that inflammation may be reduced in late-stage disease. This may have important implications in the design of studies assessing the effect of therapeutic agents in modifying progression of AS. (J Am Coll Cardiol 2011;57:2507–15) © 2011 by the American College of Cardiology Foundation
Once considered to represent the result of years of mechanical stress on an otherwise normal valve, the evolving concept is that calcific aortic stenosis (AS) results from active proliferative and inflammatory changes, with lipid accumulation, upregulation of angiotensin-converting enzyme activity, and infiltration of macrophages and T-lymphocytes ultimately leading to calcium deposition in a manner analogous to vascular calcification (1– 4). Progressive calcification further leads to immobilization of the cusps. However, there are no direct clinical data to either support or refute a link between local inflammation within aortic valves (AVs) and progression of AS. A primary reason for the absence of such studies is that there has not been a reliable method to noninvasively measure AV inflammation. Numerous positron emission tomography (PET) studies demonstrate that fluorodeoxyglucose (FDG) uptake is increased in inflamed tissues such as tumors and infectious foci (5–7). Several groups have demonstrated that FDGPET imaging provides a measure of inflammation, both in animal models (8,9) and humans (10 –13). Furthermore, measurement of metabolic activity within the aortic root (including the AV annulus) and coronary tree is feasible (14). Accordingly, we sought to test the hypothesis that the AV PET signal is increased in stenotic AVs compared with matched controls. Second, we sought to test the hypothesis that the inflammatory signal varies across groups of patients according to severity of AS and severity of valve calcification.
Methods Subjects. In a retrospective observational study, 84 patients (age 73 ⫾ 9 years, 47% female; 42 with AS and 42 age-matched control patients without AS) were identified from a database of subjects who underwent PET/computed tomography (CT) imaging between 2005 and 2010, primarily for evaluation of neoplastic process. The patients with AS were identified by cross-referencing our institution’s clinical PET and echocardiography (echo) patient databases, thereby identifying all patients with: 1) echoconfirmed diagnosis of AS; and 2) PET scanning within 6 months of the echo examination (Fig. 1). To ensure that the AVs were representative of degenerative AS, exclusion criteria included the following: evidence of rheumatic disease, endocarditis, Marfan’s syndrome, known significant aortic regurgitation, or presence of other significant valvular disease. The control group of 42 subjects without AS was constructed by 1:1 age matching to subjects in the AS group. Accordingly, we ultimately analyzed the image datasets for analysis of the first 42 control subjects from the original PET database who met the following criteria: 1) age within 6 years of a subject with AS; 2) no known AS by echo or clinical exam findings concerning for AS; 3) no other exclusion criteria. Determination of AS severity. Severity of AV stenosis was established on echo, using standard American College of Cardiology/American Heart Association criteria (15). AS patients were accordingly classified in 3 groups: those with
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mild, moderate, and severe degree of AS. Determination of stenosis severity was done while investigators were blinded to the PET and CT data. FDG-PET/CT imaging and measurement of AV activity. FDG-PET imaging was performed on a PET-CT scanner (Biograph 16, Siemens, Forcheim, Germany, or similar system). Briefly, FDG was administered (10 to 20 mCi) intravenously after an overnight fast, and PET images were acquired 1 to 3 h later in 3-dimensional mode. Patients were imaged in the supine position, and images were obtained over 15 to 20 min. A low-dose, nongated, noncontrast-enhanced CT (120 keV, 50 mAs) preceded the PET scan. Attenuation correction was done for all PET datasets. FDG uptake was measured within the central portion of the AV apparatus. To accomplish this, the acquired PET and CT datasets were manually coregistered using a multimodality fusion workstation (Leonardo TrueD, Siemens) by an investigator who was blinded to the patients’ status and to the CT and echo evaluations. To register the images, we prioritized the registration of the ascending aorta given that it was discernible on both PET and CT image sets. Once co-registered, maximum standardized uptake value (SUV) of FDG was measured within the central portion of the AV. The CT images were used to guide placement of 5-mm3 volume of interest (VOI) within the center of the AV apparatus, with the goal of minimizing the inclusion of signal (spillover) derived from the left ventricular myocardium, as well as possible atherosclerotic uptake in the arterial wall (Fig. 2). To obtain a background value for FDG uptake, blood SUV was determined by placement of 3 1-cm3 VOIs
Figure 1
Marincheva-Savcheva et al. Imaging Aortic Valve Inflammation With FDG-PET
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within the right atrial activity, in Abbreviations locations devoid of significant and Acronyms spillover activity. The AV comAS ⴝ aortic stenosis missural target-to-background AV ⴝ aortic valve ratio (TBR) was calculated by CRP ⴝ C-reactive protein dividing the AV SUV by atrial CT ⴝ computed blood SUV. tomography Reproducibility of measurement echo ⴝ echocardiography of AV FDG uptake. The interFDG-PET ⴝ reader and intrareader variability fluorodeoxyglucose positron was evaluated in repeated meaemission tomography sures of 66 patients. Inter-reader MSCT ⴝ multislice variability was assessed by comcomputer tomography paring the AV measurements deROI ⴝ region of interest rived by 2 independent readers. SUV ⴝ standardized uptake The intra-reader variability was value assessed by repeat measurement TBR ⴝ target-to-background of the primary reader (A.T.) apratio proximately 6 months after the VOI ⴝ volume of interest initial reads were performed. The blinded interobserver and intraobserver reliability analysis for the FDG uptake reading (TBR) in 66 cases revealed intraclass correlation coefficients of 0.97 (95% confidence interval [CI]: 0.96 to 0.98) and 0.55 (95% CI: 0.27 to 0.73), respectively. Bland-Altman curves are provided as supplemental data. FDG-PET/CT imaging and measurement of aorta activity. We also measured FDG signal in the aortic wall in order to enable a comparison between vascular and valvular FDG uptake in the same patients. This was done by placing
Study Flow Chart
AS ⫽ aortic stenosis; CT ⫽ computed tomography; echo ⫽ echocardiography; MGH ⫽ Massachusetts General Hospital; PET ⫽ positron emission tomography.
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Figure 2
Marincheva-Savcheva et al. Imaging Aortic Valve Inflammation With FDG-PET
Placement of Region of Interest Within the Aortic Valve Apparatus
Coregistered fluorodeoxyglucose positron emission tomography/computed tomography image demonstrate 5-mm3 volume of interest (VOI) focused on the center of the aortic valve apparatus (arrow).
region of interest (ROI) around the aorta within axial images at 5-mm intervals, starting 2.5 cm above the AV (to avoid spillover from the valve) and extending to the aortic arch. The TBR of the aorta was calculated by dividing the aorta SUV by atrial blood SUV. All aorta FDG uptake measurements were done by an investigator who was blinded to the AV FDG uptake data. Assessment of AV calcification. The extent and severity of calcium deposition within the AV was assessed on transverse reconstructions of the chest CT as reported by Willmann et al. (16). Briefly, the AV calcifications were graded qualitatively as grade 1 (no calcification), grade 2 (mildly calcified; small isolated spots), grade 3 (moderately calcified; multiple larger spots); or grade 4 (heavily calcified; extensive calcification of all cusps) (Fig. 3). In a subset of 14 patients, low-dose CT images were unavailable and were replaced with chest CT imaging data obtained on a dedicated CT scanner using clinical protocols. Evaluation of AV disease progression. We sought to test the hypothesis that an increased initial AV PET signal is associated with subsequent progression of AV stenosis. This analysis was done in the subset of patients who had a repeat echo examination between 1 and 2 years after the initial echo and who did not undergo AV replacement during the observation period. Serial echo data meeting these criteria were available for 19 subjects. Thereafter, progression of AS was adjudicated by an investigator (Q.T.) who was blinded to all other clinical and PET data. Progression was defined as any increase in severity class based on any 1 of the 3 components (valve area, peak velocity, and mean gradient) using standard American College of Cardiology/American
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Heart Association criteria (15). Patients with critical AS on the initial echo were excluded because they could not experience an increase in disease progression based on this classification scheme. Accordingly, 15 patients with AS were ultimately included in this analysis. A high baseline AV TBR was defined as a TBR value that is above the median value for all patients with AS. Subsequently, we compared progression (vs. no progression) of AV disease in patients with high (vs. low) AV TBR. Statistical methods. Descriptive analysis was reported as mean ⫾ SD or median (interquartile range [IQR]) for continuous variables and frequency with percentages for nominal variables, as appropriate. For analysis of the baseline characteristics of the age-matched AS and control groups, we used paired t tests for normal continuous variables, related samples Wilcoxon rank sum tests for non-normal continuous variables, and related samples McNemar test for binary variables. To evaluate differences between subgroups in FDG uptake (a non-normally distributed continuous variable), the Mann-Whitney U (Wilcoxon) rank sum test was used. A linear regression analysis was used to assess the strength of the association between the FDG signal and the presence of AS while controlling for potential confounding variables. Intraclass correlation coefficient was calculated to determine interobserver reliability using the TBR max obtained by the readers during the reliability analysis. Additionally, a Fisher exact test was used in the subset of AS patients to test the relationship between 2 unrelated binary variables: AV signal (low vs. high) versus progression of AS (present or absent). All
Figure 3
Grading of Aortic Valve Calcification
Diagrams of different grades of aortic valve calcification: grade 1, no calcification; grade 2, mildly calcified (small isolated spots); grade 3, moderately calcified (multiple larger spots); grade 4, heavily calcified (extensive calcification of all cusps). Modified with permission from Willmann et al. (16).
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Baseline of Patients of Patients Table 1 Characteristics Baseline Characteristics AS Group (n ⴝ 42)
No AS Group (n ⴝ 42)
p Value*
Female
18 (43%)
20 (48%)
0.73
Age, yrs
73.6 ⫾ 9.0
73.3 ⫾ 9.0
0.46
Coronary artery disease
20 (48%)
12 (29%)
0.1
Hypertension
26 (62%)
20 (48%)
0.33
Hypercholesterolemia
25 (60%)
21 (50%)
0.54
Diabetes mellitus
10 (24%)
5 (12%)
0.06
Statin use
23 (52%)
24 (57%)
0.85
Tracer circulation time, min
70 ⫾ 20
62 ⫾ 14
0.06
Characteristic
Values are n (%) or mean ⫾ SD. *p values for statistical difference between groups were calculated by related sample Wilcoxon signed rank test (continuous values) and related samples McNemar test (binary values). AS ⫽ aortic stenosis.
analysis was performed with SPSS version 18.0 (SPSS Inc., Chicago, Illinois). A value of p ⬍ 0.05 was considered significant. A Bonferroni correction was used as appropriate for multiple comparisons.
Figure 4
FDG Uptake Versus Aortic Stenosis
(A) Aortic FDG-PET signal in AS group versus no-AS group. (B) Aortic FDG-PET signal across subgroups according AS severity. Although target-to-background ratio (TBR) was increased in mild and moderate AS, it was not increased in severe AS compared with controls. *p ⬍ 0.01, mild AS versus control; **p ⬍ 0.001, moderate AS versus controls; #p ⬍ 0.01, moderate AS versus severe AS (p ⫽ NS for severe AS vs. controls). FDG ⫽ fluorodeoxyglucose; other abbreviations as in Figure 1.
Results Demographic information is summarized in Table 1. The disease severity distribution across the AS group was as follows: mild AS (n ⫽ 18), moderate AS (n ⫽ 16), and severe AS (n ⫽ 8) (Table 2). The AV PET signal (TBR) was increased in patients with AS compared with matched controls: median 1.53 (IQR: 1.42 to 1.76) versus 1.34 (IQR: 1.20 to 1.55); p ⬍ 0.001 (Fig. 4A). The difference in TBR between patients with and without AS remained significant after correcting for age, sex, presence of hyperlipidemia, clinical coronary artery disease, and previous statin treatment, resulting in a mean increase in TBR of 0.27 [IQR: 0.14 to 0.40] in AS versus controls (mean, 95% CI, p ⬍ 0.001). Likewise, the difference in TBR between patients with and without AS remained significant after correcting for tracer circulation time, resulting in a mean increase in TBR of 0.20 (IQR: 0.04 to 0.36) in AS versus controls (p ⫽ 0.01). The uncorrected measure of valvular FDG uptake (SUV) was not different between the AS and control groups
(median 1.93 [IQR: 1.66 to 2.5] vs. 1.88 [IQR: 1.55 to 2.22]; p ⫽ 0.24). Similarly, the venous blood (background) SUV was not different between the 2 groups (median 1.24 [IQR: 1.04 to 1.70] vs. 1.39 [IQR: 1.10 to 2.04]; p ⫽ 0.44). However, the difference in valvular SUV between patients with and without AS was significant after correcting for background SUV, resulting in a mean increase in SUV of 0.29 [IQR: 0.15 to 0.43] in AS versus controls (p ⬍ 0.001). Moreover, the ratio of SUV in the AV to that within the wall of the ascending aorta within the same patients (valve-to-wall uptake ratio) was significantly higher in AS compared with controls (median 0.99 [IQR: 0.91 to 1.14] vs. 0.90 [IQR: 0.81 to 0.98]; p ⬍ 0.001). There was a significant difference in TBR across subgroups stratified according to AS severity (p ⬍ 0.0001). Compared with FDG uptake in patients without AS
Aortic Group Characteristics TableStenosis 2 Aortic Stenosis Group Characteristics AS Severity Subgroups Characteristic Aortic-jet velocity, m/s AV pressure gradient, mm Hg Aortic-valve area, cm2
Mild (n ⴝ 18)
Moderate (n ⴝ16)
2.9 ⫾ 0.3
3.5 ⫾ 0.5
Severe (n ⴝ 8) 4.0 ⫾ 0.6
18.0 ⫾ 2.8
27.7 ⫾ 9.5
55.8 ⫾ 19.7
⬎1.5
1.01 ⫾ 0.28
0.68 ⫾ 0.22 0
Degree of calcification 1, none
2 (11%)
1 (6%)
2, mild (isolated small spots)
13 (72%)
3 (19%)
0
3, moderate (multiple larger spots)
3 (17%)
9 (56%)
3 (38%)
0
3 (19%)
5 (62%)
4, severe (heavy calcification of all cusps) Values are mean ⫾ SD or n (%). AS ⫽ aortic stenosis; AV ⫽ aortic valve.
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(median 1.33 [IQR: 1.31 to 1.49]), TBR was increased in mild (median 1.57 [IQR: 1.44 to 1.75]; p ⬍ 0.01) and moderate (median 1.76 [IQR: 1.52 to 1.95]; p ⬍ 0.001), but not in severe AS (median 1.49 [IQR: 1.38 to 1.54]; p ⫽ 0.08) (Fig. 4B). Representative images are shown in Figure 5. Similar trends were observed when subjects were grouped according to AV calcification (independent of AS severity). The PET signal was increased in calcified AVs compared with noncalcified controls: (median 1.54 [IQR: 1.44 to 1.77] vs. 1.35 [IQR: 1.20 to 1.52]; p ⬍ 0.001) (Fig. 6A). Moreover, compared with the FDG uptake in noncalcified AVs (median 1.35 [IQR: 1.20 to 1.52]), TBR was increased in mildly (median 1.51 [IQR: 1.36 to 1.80]; p ⬍ 0.01) and moderately (median 1.67 [IQR: 1.50 to 1.85]; p ⬍ 0.001), but not severely calcified valves (median 1.51 [IQR: 1.38 to 1.54]; p ⫽ 0.13) (Fig. 6B). As anticipated, there was a significant correlation between valvular calcification grade and AS severity (r ⫽ 0.90, p ⬍ 0.001). Furthermore, we analyzed the relationship between the initial FDG uptake in the AV and the subsequent progression of AV stenosis. Patients with high AV TBR (⬎ median TBR value of 1.54) had a higher likelihood of stenosis progression on repeat echo, obtained 1 to 2 years after the index echo. Specifically, 5 of 6 patients (83%) with high initial AV TBR experienced subsequent progression of AS, compared with 2 of 9 patients (22%) with low TBR (p ⫽ 0.04 by Fisher exact test). Discussion This study demonstrates for the first time that FDG uptake is increased within AVs of patients with AS. We found that FDG uptake is increased in mild and moderate AS, but not
Figure 5
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Figure 6
FDG Uptake Versus Aortic Calcification
(A) Aortic FDG-PET signal in calcified versus noncalcified AV. (B) Aortic FDG-PET signal across subgroups according degree of calcification. Although target-tobackground ratio (TBR) was increased in mildly and moderately calcified AV, it was not increased in severely calcified valves. *p ⬍ 0.01, mild calcification versus no calcification; **p ⬍ 0.001, moderate calcification versus no calcification; #p ⬍ 0.01, moderate calcification versus severe calcification (p ⫽ NS for severe calcification vs. no calcification); #p ⬍ 0.01, moderate calcification versus severe calcification (p ⫽ NS for severe calcification vs. no calcification). Abbreviations as in Figure 5.
in the more severe stage of the disease. In parallel with these observations, we found a similar association between the FDG signal and the degree of AV calcification. Furthermore, in a subset of patients, we found that the valvular TBR is increased in patients who subsequently experience progression of AS. These observations support the hypoth-
Example PET and CT Images
(A) CT images of AV with different degree of AS and valve calcification. (B) Coregistered FDG-PET/CT images demonstrate increased FDG uptake in AV of mild and moderate AS (arrows) compared with lower uptake in severe AS and normal AV. AV ⫽ aortic valve; FDG ⫽ fluorodeoxyglucose; other abbreviations as in Figure 1.
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esis that AS is an active inflammatory condition and provide a novel method to evaluate the pathobiological processes involved in AS. FDG-PET imaging as a measure of inflammation. We observed increased glycolytic metabolic activity within the AV in AS and postulate that this in turn represents AV inflammatory cell (specifically macrophage) activity. Indeed, other cells within the valve, including fibroblasts, would not be expected to generate the increased signal (13). Further, the median signal measured in the mild to moderate AS group in this study is consistent with the signal that would be found within large atherosclerotic plaques with at least moderate macrophage staining (13). Although these points suggest that valvular FDG uptake is a function of valvular inflammation, this observation will need more direct validation. Inflammation and calcification in AS. Our observation, that inflammation is increased in mild to moderate AS but reduced in late-stage disease, is reminiscent of what has been observed in atherosclerotic disease. In an animal model of atherosclerosis, Aikawa et al. (17) recently reported a negative interrelationship between inflammation and calcification. Likewise, several studies in humans have noted that macrophage density is higher in early plaques with high content of lipid and hemorrhage and reduced in advanced plaques dominated by calcification and fibrous tissue (18 –20). Rudd et al. (21) recently reported that the FDG-PET signal is reduced in atherosclerotic lesions that are calcified, observing that plaque inflammation and calcification rarely overlap. Similar trends have been noted for inflammation in AS. Animal models of AS demonstrate that macrophages accumulate in the early AV lesions (22). In humans, Otto et al. (1) observed that the early lesion of “degenerative” AS is an active inflammatory process. Others have shown that although earlier AV lesions are characterized by infiltration of inflammatory cells, late lesions were characterized by formation of calcific plaque and a relative reduction in inflammation (23,24). Similarly, in mild AS, microscopic “spotty” calcifications are seen co-localizing to areas of lipoprotein accumulation and inflammatory cell infiltration, whereas in later stage disease, active bone formation is seen (4,25). Consistent with previously described histological observations, our study suggests that inflammation may be reduced in late-stage disease. Inflammatory biomarkers in AS. If inflammation is the fundamental process of early AV disease, with calcification predominating in the later stages, one might anticipate that systemic biomarkers of inflammation, such as C-reactive protein (CRP), might prove useful for predicting disease progression. However, Novaro et al. (26) showed that progression of AS is not well predicted by CRP values. A concern that has been since raised about that observation is that the inflammatory focus within the AV might not be large enough to affect a systemic biomarker such as CRP
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(27). Thus it may be useful to identify a local biomarker of AV inflammation, rather than a systemic one, to predict patients likely to develop aortic sclerosis and those likely to progress to AS (27). Accordingly, the PET imaging method used in the current study has potential to serve as a local biomarker to study changes in inflammation and metabolism relative to the valvular disease process. Targeting inflammation in AS. Given the broad overlap in the pathophysiologies of atherosclerosis and AS, statin therapy has been proposed as a way to slow the rate of progression of AS. Indeed, several small retrospective studies have suggested a benefit (28 –31). However, more recently published larger prospective studies of statin use in AS failed to demonstrate a beneficial effect on stenosis progression (32–34). It is not clear why statins failed to modify progression of this inflammatory disease. It is conceivable that inflammation in AS is less responsive to statins compared with atherosclerotic inflammation and that compounds acting as direct anti-inflammatory agents may be more effective. Future studies evaluating the effect of anti-inflammatory therapies on AS progression might benefit from measurement of aortic valvular inflammation, possibly using the methods described in this paper, to determine eligibility and, perhaps, as an additional measurement of efficacy. Further, the negative statin trials do not refute the potential importance of inflammation to the underlying AS pathobiology. Our study supports the theory that AS is an active inflammatory condition with high metabolic activity and further confirms that the early and mid stages of the disease are the metabolically active stages, which might represent optimal targets for future treatment trials. Furthermore, we observed that patients with high aortic valvular FDG uptake are more likely to experience progression of AV stenosis than patients with a low AV signal. Although these findings are highly preliminary and are derived from a limited dataset, they do provide initial insight into the potential role for biological imaging to provide prognostic information regarding patients with valvular disease. This encouraging observation will require confirmation in a larger prospective trial. Study limitations. Several methodological limitations should be noted. First, the PET-CT methodology used in this study was not optimized for measurement of inflammation. Several studies (10,13) suggest that an optimal time for inflammation imaging is 180 min after FDG injection (whereas in clinical practice, 45 to 75 min after injection is the norm). Additionally, it would have been preferable to use electrocardiography gating of the PET imaging. However, despite these technical limitations, we observed a substantial difference across the AS groups. It is possible that the between-group differences would have been greater had the imaging parameters been optimized. Second, the measurement of valvular FDG uptake is a novel methodology and requires substantial expertise to
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co-register the PET images with the contrast-enhanced CT images and to identify the center of the AV apparatus. Although such image registration and evaluation currently requires manual input and judgment, it is expected that automatic registration methods could be optimized for co-registration of the aortic root should PET imaging of the AV become more commonplace. Although we observed that the co-registration and measurement process was reproducible within ROI focused in 5-mm3 sample volume of the AV commissure, we acknowledge that the data sampled for PET measurements extend beyond the drawn VOI (owing to the resolution of PET). However, we had chosen the small VOI to constrain localization of the ROI to the center of the AV. This rather small, centrally placed VOI thereby served to limit inclusion of spillover activity from the myocardium and aortic wall (whose inflammatory signal may reflect atherosclerosis rather than valvular inflammation). The measurement of FDG uptake in the small ROI within the AV is limited by the small size of the ROI as well as by motion of the cardiac valve. This likely leads to underestimation of the true valve activity. Furthermore, prospective trials are needed to evaluate the true reproducibility of the AV signal using this technique, because only reproducibility of the image analysis is provided here. Once such reproducibility data are available, interventional studies can be designed to evaluate the effect of treatment on AV disease progression. It should also be noted that there is substantial overlap in values for valvular TBR between patients with and without AS. Much of the overlapping values between patients with AS (vs. controls) are derived from patients with mild and severe AS (less overlap is seen in the patients with moderate AS). It is possible that the overlap is caused by inherent limitations in the accuracy of the measurement. It is also plausible that the control patients without AS who have higher valvular TBR values will eventually develop AS, a hypothesis that should be explored prospectively. Future directions. The pursuit of therapies aimed at modifying the progression of AV stenosis is a challenging but potentially worthwhile endeavor. Thus far, the approach of using statins to modify disease progression using echocardiographic endpoints has been disappointing. The further development of molecular imaging tools to assess therapeutic efficacy at the tissue level of the AV may provide important new opportunities to develop new treatment strategies. An important next step in evaluating PET-CT imaging of the AV is to prospectively test whether the FDG-PET signal is associated with progression of AS. If such a study demonstrates that the PET signal predicts progression, then the imaging tool might be used to identify anti-inflammatory agents that modify valvular inflammation. Indeed, the ability to noninvasively assess AV inflammation at molecular level would likely serve as a powerful stimulus for intensification of efforts to develop such therapies aimed at AV stenosis.
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Conclusions This preliminary study demonstrates that FDG uptake is increased in AS, thereby supporting the hypothesis that inflammation is present in AS. Further, the FDG signal is increased in mild and moderate AS, but not in severe AS, a finding that suggests that inflammation may play an important role in early but not late disease. Accordingly, FDGPET/CT imaging potentially represents a novel molecular imaging method for characterizing the biological activity within the AV. This technique, once further validated, may provide new opportunities for risk stratification of patients and for identification of treatments to modify the progression of AS. Reprint requests and correspondence: Dr. Ahmed Tawakol, Massachusetts General Hospital, Division of Cardiology, Cardiac MR PET CT Program, 165 Cambridge Street, Suite 400, Boston, Massachusetts 02114. E-mail: [email protected].
REFERENCES
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JACC Vol. 57, No. 25, 2011 June 21, 2011:2507–15 14. Rogers IS, Nasir K, Figueroa AL, et al. Feasibility of FDG imaging of the coronary arteries: comparison between patients with acute coronary syndromes and stable angina. J Am Coll Cardiol Img 2010;3:388 –97. 15. Bonow RO, Carabello BA, Chatterjee K, 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. J Am Coll Cardiol 2006;48:e1–148. 16. Willmann JK, Weishaupt D, Lachat M, et al. Electrocardiographically gated multi-detector row CT for assessment of valvular morphology and calcification in aortic stenosis. Radiology 2002;225:120 – 8. 17. Aikawa E, Nahrendorf M, Figueiredo JL, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 2007;116:2841–50. 18. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–26. 19. Gronholdt ML, Nordestgaard BG, Bentzon J, et al. Macrophages are associated with lipid-rich carotid artery plaques, echolucency on B-mode imaging, and elevated plasma lipid levels. J Vasc Surg 2002;35:137– 45. 20. Wahlgren CM, Zheng W, Shaalan W, Tang J, Bassiouny HS. Human carotid plaque calcification and vulnerability. Relationship between degree of plaque calcification, fibrous cap inflammatory gene expression and symptomatology. Cerebrovasc Dis 2009;27:193–200. 21. Rudd JH, Myers KS, Bansilal S, et al. Relationships among regional arterial inflammation, calcification, risk factors, and biomarkers: a prospective fluorodeoxyglucose positron-emission tomography/ computed tomography imaging study. Circ Cardiovasc Imaging 2009; 2:107–15. 22. Aikawa E, Nahrendorf M, Sosnovik D, et al. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation 2007;115:377– 86. 23. Sui SJ, Ren MY, Xu FY, Zhang Y. A high association of aortic valve sclerosis detected by transthoracic echocardiography with coronary arteriosclerosis. Cardiology 2007;108:322–30.
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24. Mazzone A, Epistolato MC, Gianetti J, et al. Biologic features (inflammation and neoangiogenesis) and atherosclerotic risk factors in carotid plaques and calcified aortic valve stenosis: two different sites of the same disease? Am J Clin Pathol 2006;126:494 –502. 25. Mohler ER, 3rd.Mechanisms of aortic valve calcification. Am J Cardiol 2004;94:1396 – 402, A6. 26. Novaro GM, Katz R, Aviles RJ, 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– 8. 27. Stone PH. C-reactive protein to identify early risk for development of calcific aortic stenosis: right marker? Wrong time? J Am Coll Cardiol 2007;50:1999 –2001. 28. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis. Circulation 2001;104: 2205–9. 29. Shavelle DM, Takasu J, Budoff MJ, Mao S, Zhao XQ, O’Brien KD. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002;359:1125– 6. 30. Aronow WS, Ahn C, Kronzon I, Goldman ME. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol 2001;88:693–5. 31. Rosenhek R, Rader F, Loho N, et al. Statins but not angiotensinconverting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110:1291–5. 32. Cowell SJ, Newby DE, Prescott RJ, et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389 –97. 33. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–56. 34. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:306 –14. Key Words: aortic stenosis y cardiac imaging y FDG-PET y inflammation.
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Vol. 57, No. 25, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2010.12.046
Cardiac Imaging
Imaging of the Aortic Valve Using Fluorodeoxyglucose Positron Emission Tomography
CME
Increased Valvular Fluorodeoxyglucose Uptake in Aortic Stenosis Gergana Marincheva-Savcheva, MD,*† Sharath Subramanian, MD,†‡ Sadia Qadir, MD, MPH,†‡ Amparo Figueroa, MD,†‡ Quynh Truong, MD, MPH,*†‡ Jayanthi Vijayakumar, MD,†‡ Thomas J. Brady, MD,†‡ Udo Hoffmann, MD, MPH,†‡ Ahmed Tawakol, MD*†‡ Boston, Massachusetts
JACC JOURNAL CME This article has been selected as the month’s JACC Journal CME activity. Accreditation and Designation Statement The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The American College of Cardiology designates the educational activities in JACC for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Method of Participation and Receipt of CME Certificate To obtain credit for JACC CME, you must: 1. Be an ACC member or JACC subscriber. 2. Carefully read and reflect upon the CME-designated article available online and in this issue of JACC. 3. Answer the post-test questions and complete the brief evaluation available at http://cme.jaccjournals.org.
From the *Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts; †Cardiac MR PET CT Program, Massachusetts General Hospital, Boston, Massachusetts; and the ‡Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. Supported by National Institutes of Health Grant No. R01
4. Claim your CME credit and receive your certificate electronically by following the instructions given at the conclusion of the online activity. CME Objective for This Article: At the end of this activity, the learner should be able to assess whether FDG uptake in the aortic valve (AV) is increased in AS. CME Editor Disclosure: JACC CME Editor Ajit Raisinghani, MD, FACC, reports that he has no financial relationships or interests to disclose. Author Disclosures: Supported by National Institutes of Health Grant No. R01 HL095123-01 and Center for the Integration of Medicine and Innovative Technologies. The authors have reported that they have no relationships to disclose. Medium of Participation: Print (article only); online (article and quiz) CME Term of Approval: Issue date: June 21, 2011 Expiration date: June 20, 2012
HL095123-01 and Center for the Integration of Medicine and Innovative Technologies. The authors have reported that they have no relationships to disclose. Manuscript received May 24, 2010; revised manuscript received December 10, 2010, accepted December 21, 2010.
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Marincheva-Savcheva et al. Imaging Aortic Valve Inflammation With FDG-PET
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Imaging of the Aortic Valve Using Fluorodeoxyglucose Positron Emission Tomography Increased Valvular Fluorodeoxyglucose Uptake in Aortic Stenosis Objectives
Because fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provides a noninvasive index of inflammation, we sought to assess whether FDG uptake in the aortic valve (AV) is increased in aortic stenosis (AS).
Background
AS is associated with valvular inflammation.
Methods
FDG-PET/computed tomography data were retrospectively evaluated in 84 patients (age 73 ⫾ 9 years, 45% female), 42 patients with AS, and 42 age-matched controls. FDG uptake was determined within the AV while blinded to AS severity. Target-to-background ratio (TBR) was calculated as valvular/blood activity. Stenosis severity was established on echocardiography, and presence of AV calcification was independently assessed on computed tomography.
Results
The aortic valve PET signal (TBR) was increased in AS compared with controls (median 1.53 [interquartile range (IQR): 1.42 to 1.76] vs. 1.34 [IQR: 1.20 to 1.55]; p ⬍ 0.001). Further, compared with controls, TBR was increased in mild (median 1.50 [IQR: 1.36 to 1.75]; p ⫽ 0.01) and moderate (median 1.70 [IQR: 1.52 to 1.94]; p ⬍ 0.001), but not in severe AS (median 1.49 [IQR: 1.40 to 1.54]; p ⫽ 0.08). When subjects were categorized according to AV calcification, valvular FDG uptake was increased in mildly (median 1.50 [IQR: 1.36 to 1.79]; p ⬍ 0.01) and moderately (median 1.67 [IQR: 1.50 to 1.85]; p ⬍ 0.001), but not severely calcified valves (median 1.51 [IQR: 1.38 to 1.54]; p ⫽ 0.15), compared with noncalcified valves (median 1.35 [IQR: 1.20 to 1.52]).
Conclusions
This study supports the hypothesis that AS is an inflammatory condition and suggests that inflammation may be reduced in late-stage disease. This may have important implications in the design of studies assessing the effect of therapeutic agents in modifying progression of AS. (J Am Coll Cardiol 2011;57:2507–15) © 2011 by the American College of Cardiology Foundation
Once considered to represent the result of years of mechanical stress on an otherwise normal valve, the evolving concept is that calcific aortic stenosis (AS) results from active proliferative and inflammatory changes, with lipid accumulation, upregulation of angiotensin-converting enzyme activity, and infiltration of macrophages and T-lymphocytes ultimately leading to calcium deposition in a manner analogous to vascular calcification (1– 4). Progressive calcification further leads to immobilization of the cusps. However, there are no direct clinical data to either support or refute a link between local inflammation within aortic valves (AVs) and progression of AS. A primary reason for the absence of such studies is that there has not been a reliable method to noninvasively measure AV inflammation. Numerous positron emission tomography (PET) studies demonstrate that fluorodeoxyglucose (FDG) uptake is increased in inflamed tissues such as tumors and infectious foci (5–7). Several groups have demonstrated that FDGPET imaging provides a measure of inflammation, both in animal models (8,9) and humans (10 –13). Furthermore, measurement of metabolic activity within the aortic root (including the AV annulus) and coronary tree is feasible (14). Accordingly, we sought to test the hypothesis that the AV PET signal is increased in stenotic AVs compared with matched controls. Second, we sought to test the hypothesis that the inflammatory signal varies across groups of patients according to severity of AS and severity of valve calcification.
Methods Subjects. In a retrospective observational study, 84 patients (age 73 ⫾ 9 years, 47% female; 42 with AS and 42 age-matched control patients without AS) were identified from a database of subjects who underwent PET/computed tomography (CT) imaging between 2005 and 2010, primarily for evaluation of neoplastic process. The patients with AS were identified by cross-referencing our institution’s clinical PET and echocardiography (echo) patient databases, thereby identifying all patients with: 1) echoconfirmed diagnosis of AS; and 2) PET scanning within 6 months of the echo examination (Fig. 1). To ensure that the AVs were representative of degenerative AS, exclusion criteria included the following: evidence of rheumatic disease, endocarditis, Marfan’s syndrome, known significant aortic regurgitation, or presence of other significant valvular disease. The control group of 42 subjects without AS was constructed by 1:1 age matching to subjects in the AS group. Accordingly, we ultimately analyzed the image datasets for analysis of the first 42 control subjects from the original PET database who met the following criteria: 1) age within 6 years of a subject with AS; 2) no known AS by echo or clinical exam findings concerning for AS; 3) no other exclusion criteria. Determination of AS severity. Severity of AV stenosis was established on echo, using standard American College of Cardiology/American Heart Association criteria (15). AS patients were accordingly classified in 3 groups: those with
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mild, moderate, and severe degree of AS. Determination of stenosis severity was done while investigators were blinded to the PET and CT data. FDG-PET/CT imaging and measurement of AV activity. FDG-PET imaging was performed on a PET-CT scanner (Biograph 16, Siemens, Forcheim, Germany, or similar system). Briefly, FDG was administered (10 to 20 mCi) intravenously after an overnight fast, and PET images were acquired 1 to 3 h later in 3-dimensional mode. Patients were imaged in the supine position, and images were obtained over 15 to 20 min. A low-dose, nongated, noncontrast-enhanced CT (120 keV, 50 mAs) preceded the PET scan. Attenuation correction was done for all PET datasets. FDG uptake was measured within the central portion of the AV apparatus. To accomplish this, the acquired PET and CT datasets were manually coregistered using a multimodality fusion workstation (Leonardo TrueD, Siemens) by an investigator who was blinded to the patients’ status and to the CT and echo evaluations. To register the images, we prioritized the registration of the ascending aorta given that it was discernible on both PET and CT image sets. Once co-registered, maximum standardized uptake value (SUV) of FDG was measured within the central portion of the AV. The CT images were used to guide placement of 5-mm3 volume of interest (VOI) within the center of the AV apparatus, with the goal of minimizing the inclusion of signal (spillover) derived from the left ventricular myocardium, as well as possible atherosclerotic uptake in the arterial wall (Fig. 2). To obtain a background value for FDG uptake, blood SUV was determined by placement of 3 1-cm3 VOIs
Figure 1
Marincheva-Savcheva et al. Imaging Aortic Valve Inflammation With FDG-PET
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within the right atrial activity, in Abbreviations locations devoid of significant and Acronyms spillover activity. The AV comAS ⴝ aortic stenosis missural target-to-background AV ⴝ aortic valve ratio (TBR) was calculated by CRP ⴝ C-reactive protein dividing the AV SUV by atrial CT ⴝ computed blood SUV. tomography Reproducibility of measurement echo ⴝ echocardiography of AV FDG uptake. The interFDG-PET ⴝ reader and intrareader variability fluorodeoxyglucose positron was evaluated in repeated meaemission tomography sures of 66 patients. Inter-reader MSCT ⴝ multislice variability was assessed by comcomputer tomography paring the AV measurements deROI ⴝ region of interest rived by 2 independent readers. SUV ⴝ standardized uptake The intra-reader variability was value assessed by repeat measurement TBR ⴝ target-to-background of the primary reader (A.T.) apratio proximately 6 months after the VOI ⴝ volume of interest initial reads were performed. The blinded interobserver and intraobserver reliability analysis for the FDG uptake reading (TBR) in 66 cases revealed intraclass correlation coefficients of 0.97 (95% confidence interval [CI]: 0.96 to 0.98) and 0.55 (95% CI: 0.27 to 0.73), respectively. Bland-Altman curves are provided as supplemental data. FDG-PET/CT imaging and measurement of aorta activity. We also measured FDG signal in the aortic wall in order to enable a comparison between vascular and valvular FDG uptake in the same patients. This was done by placing
Study Flow Chart
AS ⫽ aortic stenosis; CT ⫽ computed tomography; echo ⫽ echocardiography; MGH ⫽ Massachusetts General Hospital; PET ⫽ positron emission tomography.
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Figure 2
Marincheva-Savcheva et al. Imaging Aortic Valve Inflammation With FDG-PET
Placement of Region of Interest Within the Aortic Valve Apparatus
Coregistered fluorodeoxyglucose positron emission tomography/computed tomography image demonstrate 5-mm3 volume of interest (VOI) focused on the center of the aortic valve apparatus (arrow).
region of interest (ROI) around the aorta within axial images at 5-mm intervals, starting 2.5 cm above the AV (to avoid spillover from the valve) and extending to the aortic arch. The TBR of the aorta was calculated by dividing the aorta SUV by atrial blood SUV. All aorta FDG uptake measurements were done by an investigator who was blinded to the AV FDG uptake data. Assessment of AV calcification. The extent and severity of calcium deposition within the AV was assessed on transverse reconstructions of the chest CT as reported by Willmann et al. (16). Briefly, the AV calcifications were graded qualitatively as grade 1 (no calcification), grade 2 (mildly calcified; small isolated spots), grade 3 (moderately calcified; multiple larger spots); or grade 4 (heavily calcified; extensive calcification of all cusps) (Fig. 3). In a subset of 14 patients, low-dose CT images were unavailable and were replaced with chest CT imaging data obtained on a dedicated CT scanner using clinical protocols. Evaluation of AV disease progression. We sought to test the hypothesis that an increased initial AV PET signal is associated with subsequent progression of AV stenosis. This analysis was done in the subset of patients who had a repeat echo examination between 1 and 2 years after the initial echo and who did not undergo AV replacement during the observation period. Serial echo data meeting these criteria were available for 19 subjects. Thereafter, progression of AS was adjudicated by an investigator (Q.T.) who was blinded to all other clinical and PET data. Progression was defined as any increase in severity class based on any 1 of the 3 components (valve area, peak velocity, and mean gradient) using standard American College of Cardiology/American
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Heart Association criteria (15). Patients with critical AS on the initial echo were excluded because they could not experience an increase in disease progression based on this classification scheme. Accordingly, 15 patients with AS were ultimately included in this analysis. A high baseline AV TBR was defined as a TBR value that is above the median value for all patients with AS. Subsequently, we compared progression (vs. no progression) of AV disease in patients with high (vs. low) AV TBR. Statistical methods. Descriptive analysis was reported as mean ⫾ SD or median (interquartile range [IQR]) for continuous variables and frequency with percentages for nominal variables, as appropriate. For analysis of the baseline characteristics of the age-matched AS and control groups, we used paired t tests for normal continuous variables, related samples Wilcoxon rank sum tests for non-normal continuous variables, and related samples McNemar test for binary variables. To evaluate differences between subgroups in FDG uptake (a non-normally distributed continuous variable), the Mann-Whitney U (Wilcoxon) rank sum test was used. A linear regression analysis was used to assess the strength of the association between the FDG signal and the presence of AS while controlling for potential confounding variables. Intraclass correlation coefficient was calculated to determine interobserver reliability using the TBR max obtained by the readers during the reliability analysis. Additionally, a Fisher exact test was used in the subset of AS patients to test the relationship between 2 unrelated binary variables: AV signal (low vs. high) versus progression of AS (present or absent). All
Figure 3
Grading of Aortic Valve Calcification
Diagrams of different grades of aortic valve calcification: grade 1, no calcification; grade 2, mildly calcified (small isolated spots); grade 3, moderately calcified (multiple larger spots); grade 4, heavily calcified (extensive calcification of all cusps). Modified with permission from Willmann et al. (16).
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Baseline of Patients of Patients Table 1 Characteristics Baseline Characteristics AS Group (n ⴝ 42)
No AS Group (n ⴝ 42)
p Value*
Female
18 (43%)
20 (48%)
0.73
Age, yrs
73.6 ⫾ 9.0
73.3 ⫾ 9.0
0.46
Coronary artery disease
20 (48%)
12 (29%)
0.1
Hypertension
26 (62%)
20 (48%)
0.33
Hypercholesterolemia
25 (60%)
21 (50%)
0.54
Diabetes mellitus
10 (24%)
5 (12%)
0.06
Statin use
23 (52%)
24 (57%)
0.85
Tracer circulation time, min
70 ⫾ 20
62 ⫾ 14
0.06
Characteristic
Values are n (%) or mean ⫾ SD. *p values for statistical difference between groups were calculated by related sample Wilcoxon signed rank test (continuous values) and related samples McNemar test (binary values). AS ⫽ aortic stenosis.
analysis was performed with SPSS version 18.0 (SPSS Inc., Chicago, Illinois). A value of p ⬍ 0.05 was considered significant. A Bonferroni correction was used as appropriate for multiple comparisons.
Figure 4
FDG Uptake Versus Aortic Stenosis
(A) Aortic FDG-PET signal in AS group versus no-AS group. (B) Aortic FDG-PET signal across subgroups according AS severity. Although target-to-background ratio (TBR) was increased in mild and moderate AS, it was not increased in severe AS compared with controls. *p ⬍ 0.01, mild AS versus control; **p ⬍ 0.001, moderate AS versus controls; #p ⬍ 0.01, moderate AS versus severe AS (p ⫽ NS for severe AS vs. controls). FDG ⫽ fluorodeoxyglucose; other abbreviations as in Figure 1.
Results Demographic information is summarized in Table 1. The disease severity distribution across the AS group was as follows: mild AS (n ⫽ 18), moderate AS (n ⫽ 16), and severe AS (n ⫽ 8) (Table 2). The AV PET signal (TBR) was increased in patients with AS compared with matched controls: median 1.53 (IQR: 1.42 to 1.76) versus 1.34 (IQR: 1.20 to 1.55); p ⬍ 0.001 (Fig. 4A). The difference in TBR between patients with and without AS remained significant after correcting for age, sex, presence of hyperlipidemia, clinical coronary artery disease, and previous statin treatment, resulting in a mean increase in TBR of 0.27 [IQR: 0.14 to 0.40] in AS versus controls (mean, 95% CI, p ⬍ 0.001). Likewise, the difference in TBR between patients with and without AS remained significant after correcting for tracer circulation time, resulting in a mean increase in TBR of 0.20 (IQR: 0.04 to 0.36) in AS versus controls (p ⫽ 0.01). The uncorrected measure of valvular FDG uptake (SUV) was not different between the AS and control groups
(median 1.93 [IQR: 1.66 to 2.5] vs. 1.88 [IQR: 1.55 to 2.22]; p ⫽ 0.24). Similarly, the venous blood (background) SUV was not different between the 2 groups (median 1.24 [IQR: 1.04 to 1.70] vs. 1.39 [IQR: 1.10 to 2.04]; p ⫽ 0.44). However, the difference in valvular SUV between patients with and without AS was significant after correcting for background SUV, resulting in a mean increase in SUV of 0.29 [IQR: 0.15 to 0.43] in AS versus controls (p ⬍ 0.001). Moreover, the ratio of SUV in the AV to that within the wall of the ascending aorta within the same patients (valve-to-wall uptake ratio) was significantly higher in AS compared with controls (median 0.99 [IQR: 0.91 to 1.14] vs. 0.90 [IQR: 0.81 to 0.98]; p ⬍ 0.001). There was a significant difference in TBR across subgroups stratified according to AS severity (p ⬍ 0.0001). Compared with FDG uptake in patients without AS
Aortic Group Characteristics TableStenosis 2 Aortic Stenosis Group Characteristics AS Severity Subgroups Characteristic Aortic-jet velocity, m/s AV pressure gradient, mm Hg Aortic-valve area, cm2
Mild (n ⴝ 18)
Moderate (n ⴝ16)
2.9 ⫾ 0.3
3.5 ⫾ 0.5
Severe (n ⴝ 8) 4.0 ⫾ 0.6
18.0 ⫾ 2.8
27.7 ⫾ 9.5
55.8 ⫾ 19.7
⬎1.5
1.01 ⫾ 0.28
0.68 ⫾ 0.22 0
Degree of calcification 1, none
2 (11%)
1 (6%)
2, mild (isolated small spots)
13 (72%)
3 (19%)
0
3, moderate (multiple larger spots)
3 (17%)
9 (56%)
3 (38%)
0
3 (19%)
5 (62%)
4, severe (heavy calcification of all cusps) Values are mean ⫾ SD or n (%). AS ⫽ aortic stenosis; AV ⫽ aortic valve.
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(median 1.33 [IQR: 1.31 to 1.49]), TBR was increased in mild (median 1.57 [IQR: 1.44 to 1.75]; p ⬍ 0.01) and moderate (median 1.76 [IQR: 1.52 to 1.95]; p ⬍ 0.001), but not in severe AS (median 1.49 [IQR: 1.38 to 1.54]; p ⫽ 0.08) (Fig. 4B). Representative images are shown in Figure 5. Similar trends were observed when subjects were grouped according to AV calcification (independent of AS severity). The PET signal was increased in calcified AVs compared with noncalcified controls: (median 1.54 [IQR: 1.44 to 1.77] vs. 1.35 [IQR: 1.20 to 1.52]; p ⬍ 0.001) (Fig. 6A). Moreover, compared with the FDG uptake in noncalcified AVs (median 1.35 [IQR: 1.20 to 1.52]), TBR was increased in mildly (median 1.51 [IQR: 1.36 to 1.80]; p ⬍ 0.01) and moderately (median 1.67 [IQR: 1.50 to 1.85]; p ⬍ 0.001), but not severely calcified valves (median 1.51 [IQR: 1.38 to 1.54]; p ⫽ 0.13) (Fig. 6B). As anticipated, there was a significant correlation between valvular calcification grade and AS severity (r ⫽ 0.90, p ⬍ 0.001). Furthermore, we analyzed the relationship between the initial FDG uptake in the AV and the subsequent progression of AV stenosis. Patients with high AV TBR (⬎ median TBR value of 1.54) had a higher likelihood of stenosis progression on repeat echo, obtained 1 to 2 years after the index echo. Specifically, 5 of 6 patients (83%) with high initial AV TBR experienced subsequent progression of AS, compared with 2 of 9 patients (22%) with low TBR (p ⫽ 0.04 by Fisher exact test). Discussion This study demonstrates for the first time that FDG uptake is increased within AVs of patients with AS. We found that FDG uptake is increased in mild and moderate AS, but not
Figure 5
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Figure 6
FDG Uptake Versus Aortic Calcification
(A) Aortic FDG-PET signal in calcified versus noncalcified AV. (B) Aortic FDG-PET signal across subgroups according degree of calcification. Although target-tobackground ratio (TBR) was increased in mildly and moderately calcified AV, it was not increased in severely calcified valves. *p ⬍ 0.01, mild calcification versus no calcification; **p ⬍ 0.001, moderate calcification versus no calcification; #p ⬍ 0.01, moderate calcification versus severe calcification (p ⫽ NS for severe calcification vs. no calcification); #p ⬍ 0.01, moderate calcification versus severe calcification (p ⫽ NS for severe calcification vs. no calcification). Abbreviations as in Figure 5.
in the more severe stage of the disease. In parallel with these observations, we found a similar association between the FDG signal and the degree of AV calcification. Furthermore, in a subset of patients, we found that the valvular TBR is increased in patients who subsequently experience progression of AS. These observations support the hypoth-
Example PET and CT Images
(A) CT images of AV with different degree of AS and valve calcification. (B) Coregistered FDG-PET/CT images demonstrate increased FDG uptake in AV of mild and moderate AS (arrows) compared with lower uptake in severe AS and normal AV. AV ⫽ aortic valve; FDG ⫽ fluorodeoxyglucose; other abbreviations as in Figure 1.
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esis that AS is an active inflammatory condition and provide a novel method to evaluate the pathobiological processes involved in AS. FDG-PET imaging as a measure of inflammation. We observed increased glycolytic metabolic activity within the AV in AS and postulate that this in turn represents AV inflammatory cell (specifically macrophage) activity. Indeed, other cells within the valve, including fibroblasts, would not be expected to generate the increased signal (13). Further, the median signal measured in the mild to moderate AS group in this study is consistent with the signal that would be found within large atherosclerotic plaques with at least moderate macrophage staining (13). Although these points suggest that valvular FDG uptake is a function of valvular inflammation, this observation will need more direct validation. Inflammation and calcification in AS. Our observation, that inflammation is increased in mild to moderate AS but reduced in late-stage disease, is reminiscent of what has been observed in atherosclerotic disease. In an animal model of atherosclerosis, Aikawa et al. (17) recently reported a negative interrelationship between inflammation and calcification. Likewise, several studies in humans have noted that macrophage density is higher in early plaques with high content of lipid and hemorrhage and reduced in advanced plaques dominated by calcification and fibrous tissue (18 –20). Rudd et al. (21) recently reported that the FDG-PET signal is reduced in atherosclerotic lesions that are calcified, observing that plaque inflammation and calcification rarely overlap. Similar trends have been noted for inflammation in AS. Animal models of AS demonstrate that macrophages accumulate in the early AV lesions (22). In humans, Otto et al. (1) observed that the early lesion of “degenerative” AS is an active inflammatory process. Others have shown that although earlier AV lesions are characterized by infiltration of inflammatory cells, late lesions were characterized by formation of calcific plaque and a relative reduction in inflammation (23,24). Similarly, in mild AS, microscopic “spotty” calcifications are seen co-localizing to areas of lipoprotein accumulation and inflammatory cell infiltration, whereas in later stage disease, active bone formation is seen (4,25). Consistent with previously described histological observations, our study suggests that inflammation may be reduced in late-stage disease. Inflammatory biomarkers in AS. If inflammation is the fundamental process of early AV disease, with calcification predominating in the later stages, one might anticipate that systemic biomarkers of inflammation, such as C-reactive protein (CRP), might prove useful for predicting disease progression. However, Novaro et al. (26) showed that progression of AS is not well predicted by CRP values. A concern that has been since raised about that observation is that the inflammatory focus within the AV might not be large enough to affect a systemic biomarker such as CRP
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(27). Thus it may be useful to identify a local biomarker of AV inflammation, rather than a systemic one, to predict patients likely to develop aortic sclerosis and those likely to progress to AS (27). Accordingly, the PET imaging method used in the current study has potential to serve as a local biomarker to study changes in inflammation and metabolism relative to the valvular disease process. Targeting inflammation in AS. Given the broad overlap in the pathophysiologies of atherosclerosis and AS, statin therapy has been proposed as a way to slow the rate of progression of AS. Indeed, several small retrospective studies have suggested a benefit (28 –31). However, more recently published larger prospective studies of statin use in AS failed to demonstrate a beneficial effect on stenosis progression (32–34). It is not clear why statins failed to modify progression of this inflammatory disease. It is conceivable that inflammation in AS is less responsive to statins compared with atherosclerotic inflammation and that compounds acting as direct anti-inflammatory agents may be more effective. Future studies evaluating the effect of anti-inflammatory therapies on AS progression might benefit from measurement of aortic valvular inflammation, possibly using the methods described in this paper, to determine eligibility and, perhaps, as an additional measurement of efficacy. Further, the negative statin trials do not refute the potential importance of inflammation to the underlying AS pathobiology. Our study supports the theory that AS is an active inflammatory condition with high metabolic activity and further confirms that the early and mid stages of the disease are the metabolically active stages, which might represent optimal targets for future treatment trials. Furthermore, we observed that patients with high aortic valvular FDG uptake are more likely to experience progression of AV stenosis than patients with a low AV signal. Although these findings are highly preliminary and are derived from a limited dataset, they do provide initial insight into the potential role for biological imaging to provide prognostic information regarding patients with valvular disease. This encouraging observation will require confirmation in a larger prospective trial. Study limitations. Several methodological limitations should be noted. First, the PET-CT methodology used in this study was not optimized for measurement of inflammation. Several studies (10,13) suggest that an optimal time for inflammation imaging is 180 min after FDG injection (whereas in clinical practice, 45 to 75 min after injection is the norm). Additionally, it would have been preferable to use electrocardiography gating of the PET imaging. However, despite these technical limitations, we observed a substantial difference across the AS groups. It is possible that the between-group differences would have been greater had the imaging parameters been optimized. Second, the measurement of valvular FDG uptake is a novel methodology and requires substantial expertise to
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co-register the PET images with the contrast-enhanced CT images and to identify the center of the AV apparatus. Although such image registration and evaluation currently requires manual input and judgment, it is expected that automatic registration methods could be optimized for co-registration of the aortic root should PET imaging of the AV become more commonplace. Although we observed that the co-registration and measurement process was reproducible within ROI focused in 5-mm3 sample volume of the AV commissure, we acknowledge that the data sampled for PET measurements extend beyond the drawn VOI (owing to the resolution of PET). However, we had chosen the small VOI to constrain localization of the ROI to the center of the AV. This rather small, centrally placed VOI thereby served to limit inclusion of spillover activity from the myocardium and aortic wall (whose inflammatory signal may reflect atherosclerosis rather than valvular inflammation). The measurement of FDG uptake in the small ROI within the AV is limited by the small size of the ROI as well as by motion of the cardiac valve. This likely leads to underestimation of the true valve activity. Furthermore, prospective trials are needed to evaluate the true reproducibility of the AV signal using this technique, because only reproducibility of the image analysis is provided here. Once such reproducibility data are available, interventional studies can be designed to evaluate the effect of treatment on AV disease progression. It should also be noted that there is substantial overlap in values for valvular TBR between patients with and without AS. Much of the overlapping values between patients with AS (vs. controls) are derived from patients with mild and severe AS (less overlap is seen in the patients with moderate AS). It is possible that the overlap is caused by inherent limitations in the accuracy of the measurement. It is also plausible that the control patients without AS who have higher valvular TBR values will eventually develop AS, a hypothesis that should be explored prospectively. Future directions. The pursuit of therapies aimed at modifying the progression of AV stenosis is a challenging but potentially worthwhile endeavor. Thus far, the approach of using statins to modify disease progression using echocardiographic endpoints has been disappointing. The further development of molecular imaging tools to assess therapeutic efficacy at the tissue level of the AV may provide important new opportunities to develop new treatment strategies. An important next step in evaluating PET-CT imaging of the AV is to prospectively test whether the FDG-PET signal is associated with progression of AS. If such a study demonstrates that the PET signal predicts progression, then the imaging tool might be used to identify anti-inflammatory agents that modify valvular inflammation. Indeed, the ability to noninvasively assess AV inflammation at molecular level would likely serve as a powerful stimulus for intensification of efforts to develop such therapies aimed at AV stenosis.
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Conclusions This preliminary study demonstrates that FDG uptake is increased in AS, thereby supporting the hypothesis that inflammation is present in AS. Further, the FDG signal is increased in mild and moderate AS, but not in severe AS, a finding that suggests that inflammation may play an important role in early but not late disease. Accordingly, FDGPET/CT imaging potentially represents a novel molecular imaging method for characterizing the biological activity within the AV. This technique, once further validated, may provide new opportunities for risk stratification of patients and for identification of treatments to modify the progression of AS. Reprint requests and correspondence: Dr. Ahmed Tawakol, Massachusetts General Hospital, Division of Cardiology, Cardiac MR PET CT Program, 165 Cambridge Street, Suite 400, Boston, Massachusetts 02114. E-mail: [email protected].
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