Reappraising myocardial fibrosis in severe aortic stenosis: an invasive and non-invasive study in 133 patients

Abstract

AimsTo investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging.Methods and resultsOne hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone.ConclusionMyocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix.

Imaging of Myocardial Fibrosis and Its Functional Correlates in Aortic Stenosis: A Review and Clinical Potential

“…AS is characterized by a significant increase in DMF, with a large variation in interindividual values [6, 17]. The extent of DMF has been shown to be an independent predictor of adverse clinical outcomes both before and after AVR as well [15, 18, 19]. Notably, patients with paradoxical low-flow low-gradient AS have a higher degree of myocardial fibrosis and LV longitudinal dysfunction than patients with normal-flow high-gradient AS [16, 20].…”

“…However, the invasiveness, susceptibility to sampling errors, and inability to assess the fibrotic burden of the whole LV myocardium hamper its clinical utility in daily practice. CMR has emerged as a reference noninvasive method to assess both FMF and DMF [6, 15, 26]. Late gadolinium enhancement (LGE) at CMR is an established technique for assessing FMR (replacement fibrosis, scar).…”

“…Late gadolinium enhancement (LGE) at CMR is an established technique for assessing FMR (replacement fibrosis, scar). In symptomatic patients with severe AS, FMF occurs mainly in the subendocardial layer of the LV and its degree decreases from the base to the apex [15, 16]. Patients with a larger extent of FMF had a significantly lower freedom from cardiac death at 10 years (42 ± 19% vs. 89 ± 6%, p = 0.002), with congestive heart failure being the most common cause of death [3].…”

“…It is noteworthy that AS-induced DMF starts at the subendocardial level, affecting mainly longitudinal LV function. Since it is predominantly determined by radial function, the LV ejection fraction can be normal for a long time even in the presence of extensive subendocardial fibrosis [6, 15, 19]. Accordingly, the LV ejection fraction, i.e., the class I guideline recommendation for AVR, cannot be used for early risk stratification in asymptomatic AS patients.…”

“…First of all, GLS was found to be related to biomarkers of myocardial fibrosis such as those expressing calcification, collagen formation, or breakdown and inflammation [42, 43]. Several studies have also reported significant associations between LV systolic function and both FMF and DMF at CMR or myocardial histology [3, 14, 15, 18, 19, 24, 29, 44-46] (Table 2). Former studies have investigated the relationship between FMF and LV contractile function [14, 44, 45].…”