The current study included patients from 2 high-volume centers in Germany (German Heart Centre Munich and Kerckhoff Klinik, Bad Nauheim) undergoing TAVI after heart team evaluation between January 2014 and December 2022. All patients with native calcified AVS and available high-quality angio-CT for TAVI who received the latest-generation transcatheter heart valves (THV) via femoral access were included in the present study. Patients were treated according to local standards, and the selection of THV type was at the operator's discretion.

The study was performed in accordance with the principles of the Declaration of Helsinki and all patients provided written informed consent for the procedure. Ethics approval was obtained from the ethics committee of the Technical University Munich under the registry OBSERVTAVI (525/17) and from the ethics committee of Landesärztekammer Hessen (FF 155/2014). Angio-CT measurements were performed and recorded in a specific database before THV implantation. Baseline clinical characteristics, procedural characteristics, and laboratory values were entered into a customized database. For Valve Academic Research Consortium 3 (VARC-3)16 defined clinical outcomes, in-hospital and discharge follow-up was monitored and registered. Follow-up was performed via telephone contact, hospital visit, or follow-up letter.

For the purpose of the study, all noncontrast-enhanced angio-CTs were evaluated using the Syngo.via workstation (Siemens Healthineers, Germany), and contrast-enhanced angio-CT studies were evaluated using 3Mensio software (Pie Medical, The Netherlands) to assess the level and distribution of valvular calcification load in Hounsfield units and cubic millimeters (mm3), respectively.

Angio-CT examinations were acquired using a dual-energy scanner (Somatom Force, Siemens Healthineers, Germany) with a collimation of 2 x 192 x 0.6mm and a gantry rotation time of 250ms. Nonenhanced prospective electrocardiogram-gated aortic valve calcium scans were obtained in end-diastole for calcium score analysis and axial thin slice images were reconstructed with a 3-mm slice thickness and an increment of 1.5mm. Tube voltage was selected between 70-120kV associated with 40-80 mAs, and tube current was adapted automatically based on body size (CARE Dose). Contrast circulation time was determined using a test-bolus with 10mL of contrast media (Imeron 350, Bracco Imaging GmbH, Germany), followed by a 50mL 0.9% saline chaser. Axial thin slice images were reconstructed with a 0.6mm slice width (increment of 0.4) for aortic valve angio-CT.

The primary endpoint was all-cause mortality at 1 year. VARC-3 definitions were applied to describe procedural and follow-up outcomes.

Categorical variables were summarized using frequencies and proportions and compared using the chi-square test. Continuous data were tested for normality with the Shapiro-Wilk test and summarized using mean+standard deviation or median [interquartile range (IQR)] depending on data distribution. Correlation analysis of continuous data were applied to compare Hounsfield units and calcium volume from noncontrast-enhanced angio-CT against calcium volume from contrast-enhanced angio-CT. To derive methodological agreement, Bland-Altman analysis was used and validated by the intraclass correlation coefficient (with absolute agreement). Calcium volume was subsequently dichotomized using the median and sex-specific cutoffs established. The Kaplan-Meier method was used to plot the mortality curves and Cox proportional hazard regression analysis was used to calculate the risk associated with increased calcium volume (hazard ratio [HR] 95% confidence interval [95%CI]). Selection of covariates for adjusted Cox proportional hazard regression analysis was performed using the least absolute shrinkage and selection operator regression method after entering all baseline characteristics as potential confounders.

The P value for the interaction effect between covariates and (log)time was derived. In addition, excess hazard models with multidimensional penalized splines were fitted to allow for time-dependent effects. HRs were plotted for patients above the sex-specific calcium volume cutoff relative to the reference HR for patients below the specific cutoff, and P values were generated for each time-period-specific hazard ratio.17,18

To account for disparities in baseline and procedural factors among dichotomized patient strata (high and low calcium volume) and to control for potential confounding factors, we conducted a multivariable regression model based on generalized estimation equations and adjusted for a weighted estimation using a propensity score to be assigned to patients with high or low calcium volume (inverse probability of treatment weighting [IPTW]-analysis). Multiple imputation by chained equations was used for missing data. All tests were 2-sided at the .05 significance level.

The statistical analysis was performed using IBM SPSS Statistics (version 29, IBM Corporation, United States), JMP Pro (version 16.0, Cary, United States), and R Studio (Posit PBC, United States) with R software version 4.1 (R Foundation, Austria).

In 1309 of the 3318 patients included, noncontrast-enhanced angio-CT was also available. One-year Kaplan-Meier analysis performed in patients with noncontrast-enhanced angio-CT and AVC stratified by Hounsfield units (n=1300) showed lower mortality in patients above the sex-specific median of Hounsfield units compared to those below the sex-specific median (11.1% vs 13.9%) (figure 1 of the supplementary data). Adjusted Cox proportional hazard regression analysis up to 1 year revealed a 14% lower mortality (HR, 0.86; 95%CI, 0.76-0.98; P=.02) (table 1 of the supplementary data) for patients above the sex-specific median of Hounsfield units. Landmark analysis showed no Hounsfield units related difference in mortality up to 30 days [adjusted HR, 1.01; 95%CI, 0.90-1.02; P=.36] (figure 2 of the supplementary data).

Noncontrast-enhanced angio-CT calcium volume showed good correlation to contrast-enhanced angio-CT calcium volume (r=0.823, r2=0.678; P<.001); even better correlation was observed between Hounsfield units and contrast-enhanced calcium volume (r=0.825, r2=0.680; P<.001) (table 2 of the supplementary data and figure 3A,C of the supplementary data). Bland-Altman plots showed good agreement between methods (figure 3B,D of the supplementary data), with an intraclass correlation coefficient for agreement of 0.794 for noncontrast-enhanced and contrast-enhanced angio-CT calcium volume, and 0.865 for contrast-enhanced angio-CT calcium volume and Hounsfield units (table 3 of the supplementary data).

Baseline clinical, echocardiographic and angio-CT characteristics are described in table 1. Obtained median calcium volume values for contrast-enhanced angio-CT calcium volume were 514 mm3 in women and 1025 mm3 in men (table 4 of the supplementary data). Median age was 81 [78; 85] years, and 46.8% were female. The median Society of Thoracic Surgeons (STS) Predicted Risk of Mortality in the entire population was 3.54 [3.42; 5.41] and median EuroSCORE II was 3.57 [2.23; 6.29]. Patients with aortic valve high calcium volume (HCV) had a smaller valve area (all=0.70 [0.58; 0.83] cm2; low calcium volume [LCV]=0.71 [0.60; 0.86] cm2; HCV=0.66 [0.52; 0.80] cm2; P<.001) and a higher transvalvular mean gradient (all=43 [35; 52] mmHg; LCV=39 [29; 45] mmHg; HCV=48 [41; 59] mmHg; P<.001).

Procedural characteristics and complications according to VARC-3 definitions are described in table 2. The Sapien family THV (Edwards Lifesciences, United States) was the most frequently used device (all=62.3%; LCV=52.7%; HCV=71.9%; P<.001) followed by the Acurate family (Boston Scientific, United States) (all=31.9%; LCV=41.7%; HCV=22.1%; P<.001). Overall, the 23mm THV was the most frequently implanted THV size (all=29.9%), followed by 26mm (all=26.6%) and 29mm THVs (all=17.3%). Technical success was similar within groups (all=93.3%; LCV=93.4%; HCV=93.1%; P=.78). Predilation was more common in HCV (75.8%), compared to LCV (61.8%, P<.001). Slightly higher mean gradients were observed in HCV (all 11 [8; 14] mmHg; LCV=10 [7; 13] mmHg; HCV=11 [8; 14] mmHg; P<.001); aortic insufficiency greater than moderate was observed more often in HCV compared to LCV (2.6% vs 1.0%, respectively, P<.001).

Kaplan-Meier analysis up to 1 year demonstrated lower mortality in patients above the sex-specific median of calcium volume compared to those below the sex-specific median (8.8% vs 12.1%, respectively, P=.04) (figure 3). Adjusted (from baseline, tomographic, echocardiographic characteristics and valve type [table 1 and table 2]) Cox proportional hazard regression analysis up to 1 year revealed a 16% lower mortality [HR, 0.84; 95%CI, 0.71-0.98); P=.02] (table 3) for patients above the sex-specific median of calcium volume. Landmark analysis showed no calcium volume related difference in mortality up to 30 days (adjusted HR, 1.09; 95%CI, 0.94-1.26; P=.23) (figure 4); after this time to 1-year, patients with HCV showed a significantly lower mortality adjusted (HR, 0.81; 95%CI, 0.73-0.90); P<.001) (figure 5). When calcium volume was included as a continuous parameter in the Cox proportional hazard analysis, its significant association with lower 1-year mortality was confirmed (HR, 0.92; 95%CI, 0.87-0.98, P=.009 per 1000 mm3) (table 4).

Figure 3.

One-year Kaplan-Meier mortality curve. Comparison between low calcium volume (red line) and high calcium volume (blue line). 95%CI, 95% confidence interval; HR, hazard ratio.

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Figure 4.

30-day Kaplan-Meier analysis. Comparison of patients with low calcium volume (red line) and high calcium volume (blue line) and mortality at 30 days. 95%CI, 95% confidence interval; HR, hazard ratio.

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Figure 5.

Central illustration. Sex-specific calcium volume threshold as a predictor for mortality. High calcium volume sex-specific showed lower mortality up to one-year of follow-up in patients undergoing transcatheter aortic valve replacement, with no difference regarding stroke, pacemaker, and paravalvular/valvular insufficiency more than moderate. 95%CI, 95% confidence interval; AI, aortic insufficiency.

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Excess hazard models revealed a time-dependent decrease in HR, with the strongest associations between sex-specific calcium volume cutoff and mortality observed beyond 6 months of follow-up (figure 4 of the supplementary data).

A sensitivity analysis for the sex-specific median of calcium volume and for calcium volume as a continuous parameter was also performed. After excluding EuroSCORE I as an adjustment variable from the multivariable Cox regression model, the association between calcium volume and mortality remained significant (sex-specific median of calcium volume HR, 0.82; 95%CI, 0.71-0.95; P=.006; calcium volume as a continuous parameter HR, 0.90; 95%CI, 0.85-0.96; P<.001); when individual components of EuroSCORE I were excluded from the Cox regression model, the association between calcium volume and mortality also remained significant (sex-specific median of calcium volume HR, 0.79; 95%CI, 0.65-0.96; P=.018); calcium volume as a continuous parameter HR, 0.93; 95%CI, 0.91-0.96; P<.001). Further confirmation of these findings arose from the IPTW-analysis which showed that patients in the HCV stratum had an IPTW-adjusted probability of lower 1-year mortality (odds ratio, 0.77; 95%CI, 0.61-0.99; P=.045). No significant association was observed between HCV and stroke, more than moderate aortic insufficiency or pacemaker implantation (table 5 of the supplementary data).

Contrary to our expectations, our observations showed that higher valvular calcium volume and Hounsfield units were associated with lower mortality at 1 year after TAVI. This could suggest that higher valvular calcification reflects an overall high calcification burden, a biological process that confers long-term stability. Calcification was first studied as a predictor of coronary events19 and as a risk stratification variable in coronary artery disease.20 It was also reported that coronary calcification may indicate stability rather than vulnerability for myocardial infarction based on plaque composition analysis.21 Assessing the correlation between valvular and coronary calcification was beyond the scope of our study due to limitations in evaluating coronary calcium with contrast-enhanced angio-CT. However, in a sensitivity analysis including only patients with known coronary artery status by angiography, the number of affected coronary vessels was not associated with valvular calcification, nor was it an independent predictor of mortality after 12 months. Notably, higher valvular calcification only predicted lower mortality beyond 30 days, suggesting that its protective effect might not apply during the immediate postprocedural phase of TAVI. On the other hand, similar mortality rates in patients above and below the sex-specific median of calcium volume suggest that periprocedural complications secondary to increased calcium volume did not significantly impact patient outcomes. Another important confounding factor in the current analysis may have been a relevant difference in secondary prevention measures such as the intake of statin drugs and others to treat comorbidities. It has been well described that statin drugs cause dose-dependent increases in vascular calcification as assessed by serial angio-CT imaging.22,23 Whether statin drugs also cause increased valvular calcification has not been proven and remains to be determined.

Natural progression studies using noncontrast angio-CT reported higher mortality with higher valvular calcification.24,25 Similar to the validation of the coronary calcium score using the Agatston method, valvular calcification may be a marker of progressive disease including valvular, vascular, and nonvascular comorbidities in patients prospectively observed and receiving medical treatment only. However, the literature on TAVI patients presents conflicting results. Some studies report increased mortality with higher HCV,26 while others could not confirm a positive association.27,28 In a single-center cohort of 68 patients with aortic stenosis treated by self-expandable THVs,26 it was reported that patients with more than 750 mass score had higher mortality, with a HR of 24.73 (2.0- 307.8; P=.01). In addition, Pollari et al.13 observed that higher valvular calcification by contrast-enhanced angio-CT was associated with increased mortality in a sample of 581 patients undergoing TAVI; major limitations of both studies include the single-center design, its relatively small sample size, methodological evaluation of valvular calcification, and the highest tercile in the latter included patients with a calcium volume of 500 mm3; when compared to our population, this value is in the range of patients with overall low calcium volume. On the other hand, 2 additional studies reported no association between valvular calcification severity and mortality27,28; however, major limitations of these studies are the lack of granularity with regards to methodological descriptions used for the evaluation of calcium and their relatively small sample size.

The present study is limited by the observational nature of the investigation, selection bias of patients assigned to procedures and the limited quality of angio-CT. It is also limited by the 1 year of follow-up and the specific THV implanted in this population. The role of statins was not taken into consideration due to the lack of complete information in the patients studied. Furthermore, the lack of CoreLab assessment with regard to angio-CT and echocardiographic data analysis may reduce the reliability of the reported outcomes.