Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis

Abstract

Objectives: Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality.

Background: Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis.

Methods: In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m²) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up.

Results: iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/m² vs. 16.1 ± 3.2 ml/m² in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m²; 51% of patients), extracellular expansion (iECV ≥22.5 ml/m²; 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009).

Conclusions: CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936).

Keywords: T1 mapping; aortic stenosis; fibrosis; hypertrophy; magnetic resonance imaging; myocardium.

Graphical abstract

Figure 1

Factors Governing the Magnitude of the Hypertrophic Response in Aortic Stenosis Only a modest correlation between the severity of valve narrowing and the magnitude of the hypertrophic response was observed. The other predictor of left ventricular (LV) mass index on multivariate analysis was sex, with men having more hypertrophy than women.

Figure 2

iECV as a Marker of Extracellular Expansion in the Myocardium (A) Regions of interest manually drawn onto native and post-contrast T1 maps are used to calculate indexed extracellular volume (iECV). (B) Histology from a patient with aortic stenosis (AS) with areas of diffuse fibrosis stained with picrosirus red. (C) Excellent correlation between iECV and diffuse myocardial fibrosis on histology. (D) iECV provided good discrimination between disease states. (E) iECV values were higher in patients with replacement fibrosis than patients with normal myocardium or extracellular expansion.

Figure 3

CMR Categorization of Myocardial Fibrosis in Aortic Stenosis Patients with aortic stenosis were categorized into 3 groups based upon cardiac magnetic resonance (CMR) assessments of fibrosis. iECV = indexed extracellular volume; LGE = late gadolinium enhancement.

Figure 4

Progressive LV Decompensation on Moving From Normal Myocardium to Extracellular Expansion to Replacement Fibrosis On moving from normal myocardium to extracellular expansion and then replacement fibrosis, there was a stepwise increase in the following measures: (A) the severity of valve narrowing; (B) the degree of hypertrophy; (C) myocardial injury; (D) left ventricular (LV) performance; and (E) all-cause-mortality. hsTni = high-sensitivity troponin I concentration.