Progression of Hypertrophy and Myocardial Fibrosis in Aortic Stenosis: A Multicenter Cardiac Magnetic Resonance Study

Abstract

Background: Aortic stenosis is accompanied by progressive left ventricular hypertrophy and fibrosis. We investigated the natural history of these processes in asymptomatic patients and their potential reversal post-aortic valve replacement (AVR).

Methods: Asymptomatic and symptomatic patients with aortic stenosis underwent repeat echocardiography and magnetic resonance imaging. Changes in peak aortic-jet velocity, left ventricular mass index, diffuse fibrosis (indexed extracellular volume), and replacement fibrosis (late gadolinium enhancement [LGE]) were quantified.

Results: In 61 asymptomatic patients (43% mild, 34% moderate, and 23% severe aortic stenosis), significant increases in peak aortic-jet velocity, left ventricular mass index, indexed extracellular volume, and LGE mass were observed after 2.1±0.7 years, with the most rapid progression observed in patients with most severe stenosis. Patients with baseline midwall LGE (n=16 [26%]; LGE mass, 2.5 g [0.8-4.8 g]) demonstrated particularly rapid increases in scar burden (78% [50%-158%] increase in LGE mass per year). In 38 symptomatic patients (age, 66±8 years; 76% men) who underwent AVR, there was a 19% (11%-25%) reduction in left ventricular mass index (P<0.0001) and an 11% (4%-16%) reduction in indexed extracellular volume (P=0.003) 0.9±0.3 years after surgery. By contrast midwall LGE (n=10 [26%]; mass, 3.3 g [2.6-8.0 g]) did not change post-AVR (n=10; 3.5 g [2.1-8.0 g]; P=0.23), with no evidence of regression even out to 2 years.

Conclusions: In patients with aortic stenosis, cellular hypertrophy and diffuse fibrosis progress in a rapid and balanced manner but are reversible after AVR. Once established, midwall LGE also accumulates rapidly but is irreversible post valve replacement. Given its adverse long-term prognosis, prompt AVR when midwall LGE is first identified may improve clinical outcomes.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01755936 and NCT01679431.

Keywords: aortic valve stenosis; fibrosis; gadolinium; hypertrophy; magnetic resonance imaging.

Figure 1.

Annualized changes in aortic valve obstruction, left ventricular hypertrophy, and diffuse fibrosis in the natural history and aortic valve replacement (AVR) groups. Annualized progression in peak aortic-jet velocity (A), left ventricular mass (B), and diffuse fibrosis (indexed extracellular volume [iECV], C) increased in a stepwise fashion with severity of aortic stenosis. The slowest progression for each parameter was observed in patients with mild aortic stenosis and the fastest progression in those with severe stenosis. Extracellular volume fraction (ECV%) did not change (D), suggesting balanced progression in cellular hypertrophy and interstitial fibrosis. After AVR, there was significant regression in valve obstruction (A), left ventricular mass index (LVMi; B), and iECV (diffuse fibrosis, C). ECV% increased (D) suggesting more rapid regression in cellular hypertrophy than interstitial diffuse fibrosis (all P<0.005). *Significant (P<0.005) annualized change comparing pre- and post-AVR values for each measure.

Figure 2.

Serial magnetic resonance images in a patient with severe aortic stenosis and progression of replacement fibrosis. Top row, Midwall late gadolinium enhancement (LGE) is present baseline magnetic resonance imaging (MRI; white arrow, baseline image). New areas of LGE can be seen on follow-up MRI after 1 y (red arrows). The patient subsequently developed exertional breathlessness and underwent aortic valve replacement (AVR). Repeat imaging 1 y after AVR demonstrated no change in the pattern or volume of LGE. In patients with established midwall LGE, rapid accumulation of further LGE was observed with the fastest progression in those with the most severe aortic stenosis (A), the highest baseline burden of LGE (B), and the most advanced indexed extracellular volume (iECV; C). After AVR, there was no change in LGE burden (A). NS indicates no significant annualized change in AVR group compared with baseline values.

Figure 3.

Changes in left ventricular mass (LVM), diffuse fibrosis, and replacement fibrosis in aortic stenosis before and after valve replacement. Longitudinal changes in LVM index (LVMi), diffuse fibrosis (indexed extracellular volume [iECV]), and replacement fibrosis (late gadolinium enhancement [LGE]) before and after valve replacement (AVR) are illustrated with 2 example patients (A and B). All 3 measures increase exponentially as stenosis severity increases (patient A, natural history cohort), and new areas of LGE are seen on follow-up imaging (red arrows). However, after AVR, cellular hypertrophy regresses more quickly than diffuse fibrosis, and replacement fibrosis seems unchanged (patient B, white arrows). AVR indicates aortic valve replacement; and V_max, peak aortic-jet velocity.