Extracellular Myocardial Volume in Patients With Aortic Stenosis

Background Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis. Objectives This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes. Methods Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery–based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters. Results Four-hundred forty patients (age 70 ± 10 years, 59% male) from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence (all p > 0.20). ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction (p < 0.05 for all), the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6, and 52.7 deaths per 1,000 patient-years; log-rank test; p = 0.009). Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement (hazard ratio per percent increase in ECV%: 1.10; 95% confidence interval [1.02 to 1.19]; p = 0.013). Conclusions In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality.

A ortic stenosis is a disease of both the valve and myocardium. Progressive myocardial remodeling and hypertrophy occur over time in response to sustained pressure overload, decreasing wall stress, and maintaining cardiac performance. However, if untreated, this hypertrophic response eventually decompensates, and patients transition to symptomatic heart failure and adverse events (1).
Myocardial fibrosis is a key pathological process driving left ventricular (LV) decompensation (2). Two distinct patterns of fibrosis are observed: focal replacement fibrosis and diffuse interstitial fibrosis (3). Both forms of fibrosis can be detected noninvasively using cardiovascular magnetic resonance (CMR): replacement fibrosis with the late gadolinium enhancement technique and diffuse interstitial fibrosis with newer T1 mapping approaches. Although replacement fibrosis appears irreversible, regression of diffuse fibrosis is observed following relief of pressure overload with aortic valve intervention (4)(5)(6). Robust assessment of diffuse fibrosis is therefore desirable to identify early LV decompensation at a stage when pathological myocardial changes are largely reversible and targeted early valve intervention may improve patient outcomes.
In the present study, we investigated CMR T1 mapping in a large international multicenter study of patients with severe aortic stenosis scheduled for aortic valve intervention. In particular, we investigated the asso-  Table 1).
CARDIOVASCULAR MAGNETIC RESONANCE. CMR was performed on a range of different scanners, T1 mapping pulse sequences, and field strengths (Online Table 1). Standard long-axis cine images were acquired as well as a short-axis cine stack of the left ventricle. Late gadolinium enhancement imaging with both a short-axis LV stack and standard longaxis views was performed 5 to 15 min following gadolinium contrast agent administration. T1 mapping data were acquired in a short-axis midventricular view of the left ventricle both before and 10 to 20 min following gadolinium contrast agent administration.  Primary outcome (median 3.8 [2.8, 4.6]

Native T1, ms
Cardiovascular magnetic resonance (CMR) short-axis cine images were contoured to provide ventricular volumes, mass, and ejection fraction (A). Areas of late gadolinium enhancement (B, red arrows) were quantified using the full-width-at-half-maximum technique. Native (C) and post-contrast (D) T1 maps were analyzed, and the mean value from segment 9 (shaded blue) and blood pool (orange contour) were used to calculate the extracellular volume fraction (ECV%

RESULTS
A total of 440 patients across 10 sites in 5 countries were included in the final analysis (70 AE 10 years, 59% male) (Figure 1) with a large proportion having hypertension (64%), diabetes mellitus (21%), and coronary heart disease (38%) ( Table 1 and Online Table 2 Table 3). Although these adjusted native T1 measurements correlated with markers of LV decompensation, they did not demonstrate an association with clinical outcomes (Online Results, Online Tables 4 to 7).

ECV-BASED ASSESSMENTS (ECV% AND iECV).
ECV% values were consistent across the different centers ( Figure 2), with no differences between ECV% values in patients imaged at 1.5-T and 3.  predictor of all-cause mortality on multivariable analysis (C) (hazard ratio: 1.10; p ¼ 0.013). Abbreviations as in Figure 3.  Table 1). These analysis of variance associations remained present on the univariable analysis (Online Table 8 progressed across the tertiles (Figure 3). Associations with iECV on univariable analysis were similar to the tertiles analysis (Online Table 10). On multivariable analysis, clinical measures independently associated with iECV were age, male sex, coronary heart disease, peak aortic-jet velocity, indexed LA volume, late gadolinium enhancement, and LV ejection fraction    (Figure 4). This association remained when peak aortic-jet velocity was added to model 2 (model 3: p ¼ 0.033). Finally, ECV% was associated with outcome independent of STS-PROM There was no difference between all-cause mortality rates when the cohort was analyzed by iECV tertile (p ¼ 0.72) (Online Table 9) nor was iECV associated with all-cause mortality or cardiovascular death using univariable Cox regression analysis (p ¼ 0.12 and p ¼ 0.32, respectively). In aortic stenosis, prognostic T1 mapping data have been limited to single-center studies (9,30   Twitter: @russeverett3.