Incremental Value of Aortomitral Continuity Calcification for Risk Assessment after Transcatheter Aortic Valve Replacement
To investigate the association of aortomitral continuity calcification (AMCC) with all-cause mortality, postprocedural paravalvular leak (PVL), and prolonged hospital stay in patients undergoing transcatheter aortic valve replacement (TAVR).
Materials and Methods
The authors retrospectively evaluated 329 patients who underwent TAVR between March 2013 and March 2016. AMCC, aortic valve calcification (AVC), and coronary artery calcification (CAC) were quantified by using preprocedural CT. Pre-procedural Society of Thoracic Surgeons (STS) score was recorded. Associations between baseline AMCC, AVC, and CAC and 1-year mortality, PVL, and hospital stay longer than 7 days were analyzed.
The median follow-up was 415 days (interquartiles, 344–727 days). After 1 year, 46 of the 329 patients (14%) died and 52 (16%) were hospitalized for more than 7 days. Of the 326 patients who underwent postprocedural echocardiography, 147 (45%) had postprocedural PVL. The CAC score (hazard ratio: 1.11 per 500 points) and AMCC mass (hazard ratio: 1.13 per 500 mg) were associated with 1-year mortality. AVC mass (odds ratio: 1.93 per 100 mg) was associated with postprocedural PVL. Only the STS score was associated with prolonged hospital stay (odds ratio: 1.19 per point).
AMCC is associated with mortality within 1 year after TAVR and substantially improves individual risk classification when added to a model consisting of STS score and AVC mass only.
Keywords: Adults, Aortic Valve, CT, Calcifications/Calculi, Cardiac, Coronary Arteries, Heart, Outcomes Analysis, Transcatheter Aortic Valve Implantation/Replacement (TAVI / TAVR), Valves, Vascular
© RSNA, 2019
See also the commentary by Brown and Leipsic in this issue.
Aortomitral continuity calcification was a predictor of mortality within 1 year after transcatheter aortic valve replacement and, together with coronary calcium, substantially improved individual risk classification when added to the clinically used Society of Thoracic Surgeons score.
■ Aortomitral continuity calcification (AMCC) is easily measurable at preprocedural CT in patients undergoing transcatheter aortic valve replacement (TAVR).
■ AMCC is associated with mortality within 1 year after TAVR.
■ AMCC substantially improves individual risk classification when added to the Society of Thoracic Surgeons score and AVC mass only.
Transcatheter aortic valve replacement (TAVR) has evolved into a safe and effective treatment option for patients with severe aortic stenosis and intermediate-to-high surgical risk (1,2). Not all patients benefit from the procedure, however, and despite the use of the Society of Thoracic Surgeons (STS) risk score and frailty index as risk stratification tools, TAVR is still associated with poor survival in some patients. Identification of patients in whom the procedure will not improve cardiac function or survival remains an important challenge (3), particularly in high-risk patients, who are more likely to experience poor outcomes.
Cardiovascular calcifications are increasingly recognized as the product of a highly regularized process of mineral deposition involving a wide range of cell types and signaling pathway components (4). Macroscopic calcifications are easily detected and quantified at CT, and aortic valve calcification (AVC) and mitral annulus calcification are highly prevalent in patients referred for TAVR, spurring interest in calcification as a TAVR outcome marker (5–7).
The extensiveness of cardiac calcifications in patients undergoing TAVR often impedes the differentiation of valve calcifications from adjacent calcified fibrous tissue involving the annulus and aortomitral curtain within the left ventricular outflow tract. The evaluation of aortomitral continuity calcification (AMCC) as a whole, including the aortic valve, left ventricular outflow tract, and mitral annulus and/or valve, would therefore be more clinically feasible in this population.
We sought to determine whether AMCC as a whole, isolated AVC, and coronary artery calcification (CAC), quantified at CT, are associated with 1-year all-cause mortality, prolonged hospital stay, and postprocedural paravalvular leak (PVL) in patients with severe aortic stenosis undergoing TAVR.
Materials and Methods
The Stanford Cardiovascular Institute institutional review board approved this Health Insurance Portability and Accountability Act–compliant retrospective study. The requirement to obtain written informed consent was waived. All patients who underwent TAVR between March 2013 and March 2016 were eligible. Only patients without prior valve replacement who underwent preprocedural unenhanced and contrast material–enhanced CT of the aorta were included. Preprocedural demographic and clinical information, including cardiac risk factors, STS score, and frailty index (based on gait speed, Katz activities of daily living score, serum albumin level, and grip strength), as well as procedural details and clinical follow-up data were collected from electronic medical records.
All patients underwent electrocardiography-synchronized unenhanced and contrast-enhanced aortic CT. Tube voltage and current varied according to patient size. Thin-section images were selected for evaluation. The calcification burden of the aortomitral continuity as a whole (AMCC mass, including the aortic valve, left ventricular outflow tract, and mitral annulus and/or valve), isolated aortic valve (AVC mass), and coronary arteries (Agatston score and CAC score) were quantified from unenhanced CT scans by using commercially available software (Aquarius iNtuition; TeraRecon, Foster City, Calif) (Fig 1, Fig E1 [supplement]). Because calcium attenuation is influenced by tube voltage, we used a calcium threshold of 130 HU for tube voltages of at least 120 kVp. For tube voltages less than 120 kVp, we used a calcium threshold of 147 HU (8). Previous studies have shown that the quantification of aortic and mitral valve calcification with three-dimensional workstations is fast and highly reproducible (6,9). To correct valve calcifications for aortic annulus size, we normalized AMCC and AVC for the aortic annulus area, measured on the contrast-enhanced CT scans. CT measurements were performed separately by two observers with more than 7 years of experience in cardiovascular imaging (M.J.W. and E.M., 8 and 20 years of experience, respectively). Observers were blinded to clinical, echocardiographic, and outcome data.
Patients underwent transthoracic echocardiography before and after the procedure before hospital discharge. Echocardiographic evaluation was performed according to the European Association of Echocardiography guidelines (10). Mean aortic valve gradient, aortic valve area, peak aortic jet velocity, left ventricular ejection fraction, and right ventricular systolic pressure were assessed. Postprocedural echocardiograms were reviewed by an independent experienced observer for the presence and severity of PVL and were classified as none, mild, moderate, or severe (11).
The primary end point was defined as all-cause mortality 1 year after TAVR. Secondary end points were prolonged hospital stay (hospitalization >7 days) and postprocedural paravalvular aortic regurgitation (mild-to-severe PVL as determined with postprocedural echocardiography) (11).
Data are presented as medians (first quartile to third quartile) for continuous variables and as numbers of patients and percentages for categorical variables. We compared baseline data between survivors and nonsurvivors by using the Mann-Whitney U test for continuous data and the Pearson χ2 test for categorical data when no cell counts less than five present, the Fisher exact test for categorical data when cell counts less than five were present, or the Kendall tau-c for ordinal data.
We tested associations between baseline variables and 1-year all-cause mortality with univariable Cox regression analyses. For multivariable analyses, we evaluated the added prognostic value of the CAC score, AVC mass, and AMCC mass beyond traditional clinical factors. In the multivariable models, we only used the STS risk score (continuous variable) and not dichotomous STS score of at least 8, owing to potential multicollinearity considerations. The multivariable model was corrected for overoptimism by using internal validation with bootstrap analysis at 1000 iterations adjusting for age, sex, cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, and smoking status), frailty index, New York Heart Association classification, and valve type. On the basis of the prediction models, the hazard ratios of the predictors were calculated with 95% confidence intervals. We used the Youden index to determine the optimal thresholds for Kaplan-Meier survival analyses. Survival curves were compared by using the log-rank test. To evaluate the discriminative capacity of the models to predict mortality, we calculated concordance statistics and net reclassification improvement indexes for four risk categories: less than 6%, 6%–10%, 10%–20%, and greater than 20% (12,13). Area under receiver operating characteristic curve values were compared by using the method described by DeLong et al (14).
To evaluate the secondary end points, we used univariable logistic regression analyses, with postprocedural aortic PVL and prolonged hospital stay as outcome variables. For multivariable analyses, we evaluated the added prognostic value of the CAC score, AVC mass, and AMCC mass beyond traditional clinical factors. The multivariable models were adjusted for age, sex, cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, and smoking status), frailty index, the New York Heart Association classification, and valve type. Odds ratios of the predictors were calculated with 95% confidence intervals.
P < .05 was considered indicative of a statistically significant difference. Statistical analyses were performed with R version 3.3.3 (R Foundation for Statistical Computing, Vienna, Austria) with the survival, rms, and nricens packages, SPSS version 24 (IBM SPSS Statistics, IBM, Armonk, NY), and MedCalc version 17.9.7 (MedCalc, Ostend, Belgium).
A total of 415 patients underwent TAVR between March 2013 and March 2016. Eighty-six patients were excluded owing to previous aortic valve replacement (n = 23), incomplete clinical data to determine the frailty index (n = 32), or missing preprocedural noncontrast CT data (n = 31). The final study population included 329 patients with a median follow-up of 415 days (interquartile range, 344–727 days).
After 1 year, 46 of the 329 patients (14%) died and 283 (86%) survived. Baseline characteristics of the entire cohort, survivors, and nonsurvivors are provided in Table 1. Age and sex distribution of survivors and nonsurvivors did not differ significantly (median age: 86 years [interquartiles, 80–89 years] vs 87 years [80–91 years], respectively, P = .244; sex distribution: 139 men [49%] vs 26 men [57%], P = .352). History, cardiac risk factors, and baseline laboratory data were similar for survivors and nonsurvivors. Pulmonary hypertension (estimated right ventricular systolic pressure >50 mm Hg) was significantly more prevalent in nonsurvivors than in survivors (21 patients [46%] vs 74 patients [26%]; P = .007), and STS scores were significantly higher for nonsurvivors than for survivors (median score: 9 [interquartile range, 7–11] vs 7 [interquartile range, 5–9]; P = .001); other risk assessment variables were similar for survivors and nonsurvivors (P > .05).
Results of pulmonary function tests, echocardiography, and CT are provided in Table 2. Pulmonary function tests were performed in 311 of the 329 patients (95%); the diffusing capacity of the lungs for carbon monoxide was available for 267 patients. Preprocedural echocardiography was performed in all patients, and sufficient tricuspid regurgitation allowed the estimation of right ventricular systolic pressure in 309 (94%).
Clinical outcome variables, including mortality and length of hospitalization, and postprocedural echocardiographic findings are provided in Table 3.
Results of primary outcome analyses are provided in Table 4. STS score, CAC score, and AMCC mass were the strongest predictors for all-cause mortality within 1 year after TAVR at univariable Cox regression analysis. The same variables remained associated with all-cause mortality within 1 year after TAVR in the adjusted multivariable model corrected for overoptimism. AVC mass was not predictive of mortality within the 1st year after TAVR. AMCC mass and CAC score did not add discriminative power over the basic model, despite having slightly higher C statistic values (Table 5). However, adding these variables together did result in improved reclassification of patients, with net reclassification improvement indexes of 14%–25%.
Optimal thresholds for a CAC score of 2001, AVC mass of 300 mg, and AMCC mass of 700 mg derived from receiver operating characteristic curve analysis were used in the Kaplan-Meier survival analyses (Figs 2, 3). One-year survival was significantly worse with AMCC mass greater than 700 mg (P < .001), AVC mass greater than 300 mg (P = .0496), CAC score greater than 2001 (P = .0019), and STS score of at least 8 (P = .0018). After 2 years, the differentiation for AMCC mass became more prominent compared with other variables (Fig E2 [supplement]). One-year mortality in high-risk patients with an STS score of at least 8 was 22% (28 of 130 patients), which increased to 28% (19 of 67 patients) when these patients had an AMCC mass greater than 700 mg. One-year mortality in low-risk patients with an STS score lower than 8 was 9% (18 of 199 patients), which decreased to 6% (seven of 117 patients) with an AMCC mass of 700 mg or less.
Prolonged Hospital Stay and Postprocedural PVL
Results of the secondary outcome analyses are shown in Table 6. Postprocedural echocardiography could not be performed in three patients who died shortly after TAVR. Mild-to-severe aortic PVLs were found in 147 of the 329 patients (45%) and moderate-to-severe PVLs were found in 32 (10%). Age, STS score, baseline mean aortic valve area, and baseline AVC mass were significantly associated with aortic PVLs at univariable logistic regression analysis. AVC mass was associated with postprocedural aortic PVLs (odds ratio: 1.93 [95% confidence interval: 1.39, 2.48] per 100 mg, P = .001). AMCC mass and CAC score were not significantly associated with PVLs; however, AMCC mass and AVC mass were higher at increasing aortic regurgitation (Table E1 [supplement]).
Fifty-two of the 329 patients (16%) were hospitalized for more than 7 days after TAVR. Logistic regression showed that only the STS score was associated with prolonged hospital stay (odds ratio: 1.19 [95% confidence interval: 1.08, 1.32], P < .001).
The main finding of this study is that AMCC is associated with mortality within the 1st year after TAVR and substantially improves individual risk reclassification when added to the clinically used STS score. This is important because traditional STS scores are an imperfect tool with which to identify patients at prohibitive or high surgical risk, who do not benefit from a costly procedure that causes considerable patient distress under the best of circumstances and carries a low but potentially devastating procedural risk such as stroke. The addition of a simple measure—such as AMCC mass greater than 700 mg—to patients with an STS score greater than 8 increased the 1-year mortality from 22% to 28%.
Evaluation of the prognostic value of cardiovascular calcifications, such as AVC and mitral annulus calcification, has recently generated substantial interest in patients with aortic stenosis. AVC has been shown to be associated with postprocedural PVLs, procedural complications, and 30-day, 1-year, and long-term mortality (5,15,16). We also found a significant association of AVC with PVLs, which can be explained by its location in the landing zone of the device with direct consequences on the deployment, expansion, and apposition of a stent-mounted valve. However, we did not find a significant association between AVC and mortality in the 1st year after TAVR. Only our 2-year survival analysis (Fig E2 [supplement]) suggests that AVC mass is a better predictor of long-term mortality than of short-term mortality. Many studies have evaluated the prognostic value of mitral annulus calcification in patients undergoing TAVR and have shown associations with increased all-cause and cardiovascular mortality (6,17).
We used AMCC as an aggregate quantitative measure of cardiac and/or valvular calcifications, including valve leaflets and/or annulus, and interspersed tissue between the aortic and mitral valves. AMCC is easy to measure and does not require time-consuming separation of a calcified valve and/or annulus from adjacent fibrous tissue calcifications—a common occurrence in patients with severe aortic stenosis. Correcting for body size is straightforward. We used the readily available aortic valve area, which is routinely measured in candidates for TAVR. Although leaflet calcifications are important in patients with aortic stenosis, we hypothesized that the total burden of calcifications might be a stronger marker of cardiovascular risk and mortality because of a presumed common pathway leading to active cardiovascular mineral deposition. In contradistinction to AVC, AMCC was a strong, significant predictor of mortality 1 year after TAVR in our cohort. The association between AMCC and 2-year mortality may be even stronger (Fig E2 [supplement]).
Another parameter that turned out to be a significant predictor of mortality the 1st year after TAVR was CAC. When adding CAC greater than 2001 and AMCC greater than 700 mg to high-risk patients (STS score >8), the 1-year mortality increased from 22% to 34%. If confirmed in other cohorts, such an estimate may help recalibrate patient and family expectations and guide the difficult process of decision-making in these vulnerable patients.
The different associations of AMCC and/or CAC and AVC indicate that these calcifications may be either driven by disparate pathways or are merely a reflection of their respective anatomic locations.
Our findings are based on a single-center retrospective cohort of patients undergoing TAVR, with 40% of the individuals at high surgical risk (STS score >8). Although the distributions of STS scores will obviously be different in lower-risk populations, the observed associations between CT-detected calcifications and mortality may still be preserved and allow identification of those individuals who benefit least from TAVR. The secondary outcome, prolonged hospital stay, included a heterogeneous group of patients with only a prolonged hospital stay and patients who died within 7 days. The latter only concerned three patients in our study, and repeat analyses after excluding these patients did not substantially change results. Another limitation was that variables such as preprocedural diffusing capacity of the lungs for carbon monoxide and right ventricular systolic pressure were not obtained in all patients. Despite the finding that these differed significantly between survivors and nonsurvivors, the reduced sample size prevented the use of these variables in survival prediction modeling.
AMCC is a predictor of mortality within 1 year after TAVR and, together with CAC, substantially improves individual risk classification when added to the clinically used STS score.
Author contributions: Guarantors of integrity of entire study, M.J.W., D.F.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, M.J.W., E.M., K.J.M., J.B.K., F.H., K.H., D.C.M.; clinical studies, E.M., K.J.M., J.B.K., F.H., T.N., A.C.Y., A.M.L., D.C.M., M.F., W.F.F., D.F.; statistical analysis, M.J.W., J.B.K., F.H., Y.K., N.C., T.K., D.C.M.; and manuscript editing, M.J.W., E.M., K.J.M., J.B.K., F.H., Y.K., T.N., K.N., N.C., T.K., K.H., A.M.S., A.M.L., D.C.M., W.F.F., D.F.
M.J.W. is supported by the American Heart Association (grant 18POST34030192) and a Stanford-Philips Trainee Fellowship Award. E.M. is supported by grants from the Swedish Heart-Lung Foundation, the Swedish Heart Association, the Swedish Society of Medicine, and the Erik and Edith Fernström’s Foundation. K.H. is supported by a research grant from the Swiss National Science Foundation.
- 1. . The future of transcatheter aortic valve implantation. Eur Heart J 2016;37(10):803–810. Crossref, Medline, Google Scholar
- 2. . Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med 2017;376(14):1321–1331. Crossref, Medline, Google Scholar
- 3. . How to define a poor outcome after transcatheter aortic valve replacement: conceptual framework and empirical observations from the placement of aortic transcatheter valve (PARTNER) trial. Circ Cardiovasc Qual Outcomes 2013;6(5):591–597. Crossref, Medline, Google Scholar
- 4. . Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res 2006;99(10):1044–1059. Crossref, Medline, Google Scholar
- 5. . Impact of aortic valve calcification, as measured by MDCT, on survival in patients with aortic stenosis: results of an international registry study. J Am Coll Cardiol 2014;64(12):1202–1213. Crossref, Medline, Google Scholar
- 6. . Mitral annular calcium and mitral stenosis determined by multidetector computed tomography in patients referred for aortic stenosis. Am J Cardiol 2016;118(8):1251–1257. Crossref, Medline, Google Scholar
- 7. . Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography. Circulation 2004;110(3):356–362. Crossref, Medline, Google Scholar
- 8. . Coronary artery calcium scoring using a reduced tube voltage and radiation dose protocol with dual-source computed tomography. J Cardiovasc Comput Tomogr 2009;3(6):394–400. Crossref, Medline, Google Scholar
- 9. . Cardiac valve calcifications on low-dose unenhanced ungated chest computed tomography: inter-observer and inter-examination reliability, agreement and variability. Eur Radiol 2014;24(7):1557–1564. Crossref, Medline, Google Scholar
- 10. . Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009;10(1):1–25. Crossref, Medline, Google Scholar
- 11. . Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol 2012;60(15):1438–1454. Crossref, Medline, Google Scholar
- 12. . Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study. Ann Intern Med 2012;156(6):438–444. Crossref, Medline, Google Scholar
- 13. . Prognostic value of heart valve calcifications for cardiovascular events in a lung cancer screening population. Int J Cardiovasc Imaging 2015;31(6):1243–1249. Crossref, Medline, Google Scholar
- 14. . Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44(3):837–845. Crossref, Medline, Google Scholar
- 15. . Device landing zone calcification and its impact on residual regurgitation after transcatheter aortic valve implantation with different devices. Eur Heart J Cardiovasc Imaging 2016;17(5):576–584. Crossref, Medline, Google Scholar
- 16. . Quantity and location of aortic valve complex calcification predicts severity and location of paravalvular regurgitation and frequency of post-dilation after balloon-expandable transcatheter aortic valve replacement. JACC Cardiovasc Interv 2014;7(8):885–894. Crossref, Medline, Google Scholar
- 17. . Concomitant mitral annular calcification and severe aortic stenosis: prevalence, characteristics and outcome following transcatheter aortic valve replacement. Eur Heart J 2017;38(16):1194–1203. Medline, Google Scholar
Article HistoryReceived: Apr 14 2019
Revision requested: May 30 2019
Revision received: Aug 10 2019
Accepted: Sept 5 2019
Published online: Dec 19 2019