Impact of aortic valve calcification, as measured by MDCT, on survival in patients with aortic stenosis: results of an international registry study

Abstract

Background: Aortic valve calcification (AVC) load measures lesion severity in aortic stenosis (AS) and is useful for diagnostic purposes. Whether AVC predicts survival after diagnosis, independent of clinical and Doppler echocardiographic AS characteristics, has not been studied.

Objectives: This study evaluated the impact of AVC load, absolute and relative to aortic annulus size (AVCdensity), on overall mortality in patients with AS under conservative treatment and without regard to treatment.

Methods: In 3 academic centers, we enrolled 794 patients (mean age, 73 ± 12 years; 274 women) diagnosed with AS by Doppler echocardiography who underwent multidetector computed tomography (MDCT) within the same episode of care. Absolute AVC load and AVCdensity (ratio of absolute AVC to cross-sectional area of aortic annulus) were measured, and severe AVC was separately defined in men and women.

Results: During follow-up, there were 440 aortic valve implantations (AVIs) and 194 deaths (115 under medical treatment). Univariate analysis showed strong association of absolute AVC and AVCdensity with survival (both, p < 0.0001) with a spline curve analysis pattern of threshold and plateau of risk. After adjustment for age, sex, coronary artery disease, diabetes, symptoms, AS severity on hemodynamic assessment, and LV ejection fraction, severe absolute AVC (adjusted hazard ratio [HR]: 1.75; 95% confidence interval [CI]: 1.04 to 2.92; p = 0.03) or severe AVCdensity (adjusted HR: 2.44; 95% CI: 1.37 to 4.37; p = 0.002) independently predicted mortality under medical treatment, with additive model predictive value (all, p ≤ 0.04) and a net reclassification index of 12.5% (p = 0.04). Severe absolute AVC (adjusted HR: 1.71; 95% CI: 1.12 to 2.62; p = 0.01) and severe AVCdensity (adjusted HR: 2.22; 95% CI: 1.40 to 3.52; p = 0.001) also independently predicted overall mortality, even with adjustment for time-dependent AVI.

Conclusions: This large-scale, multicenter outcomes study of quantitative Doppler echocardiographic and MDCT assessment of AS shows that measuring AVC load provides incremental prognostic value for survival beyond clinical and Doppler echocardiographic assessment. Severe AVC independently predicts excess mortality after AS diagnosis, which is greatly alleviated by AVI. Thus, measurement of AVC by MDCT should be considered for not only diagnostic but also risk-stratification purposes in patients with AS.

Keywords: Doppler echocardiography; aortic valve calcification; aortic valve stenosis; multidetector computed tomography; survival.

FIGURE 1. Impact of AVC Burden on Mortality in Patients With AS, by Sex

Spline curve analysis of absolute aortic valve calcification (AVC) (A and B) and AVC_density (ratio of absolute AVC index to cross-sectional area of aortic annulus) (C and D), in women (A and C) and in men (B and D) with aortic stenosis (AS). The spline curve (solid lines) is presented with 95% confidence interval (dotted lines). The x-axis represents the AVC load; the y-axis, the relative risk (RR) for mortality. The horizontal line at RR = 1 represents the mean risk in the cohort. The grey zone represents the range of AVC loads corresponding to the 95% bracket of the spline curve when it crosses the line at RR = 1. AU = arbitrary unit(s).

FIGURE 2. Effects of AVC Burden on Survival in Patients With AS Under Medical Treatment

Kaplan-Meier curves of survival, according to the presence (solid red line) or absence (dashed blue line) of severe absolute AVC (≥1,274 AU in women and ≥2065 AU in men) (A), and the presence (dashed blue line) or absence (solid red line) of severe AVC_density (≥292 AU/cm² in women and ≥476 AU/cm² in men) (B). Note the considerable excess mortality associated with severe calcification load. Adjusted for age, sex, New York Heart Association functional class ≥III, diabetes, coronary artery disease, aortic valve area indexed to body surface area (AVAi), mean gradient (MG), and left ventricular (LV) ejection fraction. Abbreviations as in Figure 1.

FIGURE 3. Overall Survival, by AVC Burden, in Patients With AS

Kaplan-Meier curves of overall survival according to the presence (dashed blue line) or absence (solid red line) of severe absolute AVC (≥1,274 AU in women and ≥2,065 AU in men) (A), and the presence (dashed blue line) or absence (solid red line) of severe AVC_density (≥292 AU/cm² in women and ≥476 AU/cm² in men) (B). Curves include post-operative survival. Note the considerable excess mortality associated with severe calcification load, supporting the analysis in patients under medical management. Adjusted for age, sex, New York Heart Association functional class ≥III, diabetes, coronary artery disease, AVAi, MG, LV ejection fraction, and aortic valve implantation as a time-dependent variable. Abbreviations as in Figures 1 and 2.

FIGURE 4. Effects of AVC Burden on Survival in Patients With AS Under Medical Treatment, Stratified by Severity of AS on Hemodynamic Assessment

Kaplan-Meier curves of survival, according to AVC burden, in patients with nonsevere (A) and severe (B) aortic stenosis (AS), as evaluated by guideline criteria (1). Severe AS is define by an MG ≥40 mm Hg, V_max ≥4 m/s, or AVA ≤1 cm². In both strata of severity of AS on hemodynamic assessment, severe AVC_density (≥292 AU/cm² in women and ≥476 AU/cm² in men) is associated with lower survival. Both unadjusted and adjusted p values for the comparison of the presence (dashed blue lines) versus the absence (solid red lines) of severe AVC_density are presented for each stratum. Adjusted using stepwise backward Cox analysis. Abbreviations as in Figures 1 and 2.

FIGURE 5. Comprehensive Subgroup Analysis of Mortality in Patients With AS Under Medical Treatment

Mortality in patients with AS under medical treatment, according to the presence of severe AVC_density (≥292 AU/cm² in women and ≥476 AU/cm² in men). In each subgroup, the adjusted hazard ratio and 95% confidence intervals (CIs) are presented, using stepwise backward Cox analysis. LV = left ventricular; NYHA = New York Heart Association functional class; other abbreviations as in Figure 1.

FIGURE 6. CENTRAL ILLUSTRATION AVC: Measurement, Thresholds, and Impact on Survival

(Top left images) AVC on a thoracic slice on computed tomography (CT). The tables (top right panels) and spline curve analysis (middle panel) demonstrate that the thresholds used to define severe AS and its impact on survival are different in women and men. The spline curve (solid line) is presented with 95% confidence interval (dotted lines). The red zone represents the range of AVC_density corresponding to the 95% bracket of the spline curve when it crosses the line at relative risk (RR) = 1. (Lower panel) Kaplan-Meier curves show the impact of AVC burden on survival in patients with AS. HR = hazard ratio (95% confidence interval). *Adjusted for age, sex, New York Heart Association functional class ≥III, diabetes, coronary artery disease, AVAi, MG, LV ejection fraction, and aortic valve implantation as a time-dependent variable.