Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis

Abstract

Aims: Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes.

Methods and results: One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson's trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01].

Conclusion: Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

Keywords: Aortic stenosis; Endomyocardial biopsy; Myocardial fibrosis; Transcatheter aortic valve implantation.

Figure 1

Burden of myocardial fibrosis in different haemodynamic subtypes of severe aortic stenosis (box plots indicating minimum, maximum, median, and 25th + 75th percentile). Fibrosis was assessed in Masson’s trichrome stained biopsy sections as blue area in relation to total tissue area. NEF-HG, normal EF, high gradient; LEF-HG, reduced EF, high gradient; LEF-LG, reduced EF, low gradient (classic low-flow, low-gradient); PLF-LG, paradoxical low-flow, low-gradient.

Figure 2

Masson's trichrome stained endomyocardial biopsies of four patients with different AS subtypes. (A) A 73-year-old man with normal EF, high-gradient AS, coronary artery disease (CAD) excluded, no diabetes, baseline EF 60%, LVEDV 91 mL, and LVMI 124 g/m²; low MF burden (5%), predominantly interstitial (including perivascular) localization; uneventful follow-up with favourable outcome. (B) A 67-year-old man with reduced EF, high-gradient AS, CAD excluded, no diabetes, baseline EF18%, LVEDV 175 mL, and LVMI 224 g/m²; high MF burden (42%) with subendocardial and interstitial localization; uneventful follow-up with very good clinical and echocardiographic recovery (EF at 6 months 52%). (C) An 89-year-old woman with reduced EF, low-gradient AS, CAD with CTO LAD, no diabetes, baseline EF 17%, LVEDV 222 mL, and LVMI 235 mL/m²; high MF burden (40%), predominantly subendocardial localization with massive fibroblast infiltration of the endocardium, and the subendocardial layer; focal replacement fibrosis; direct post-interventional course uneventful, but patient died 5 days after TAVI due to incessant VT and unsuccessful CPR. (D) A 76-year-old man with paradoxical low-flow, low-gradient aortic stenosis, CAD without prior infarction, diabetes, baseline EF 54%, LVEDV 82 mL, LVMI 96 g/m²; high MF burden (45%) with predominantly subendocardial and to a lesser extent interstitial localization; focal replacement fibrosis; patient did not benefit clinically and died 125 days after TAVI (after subsequent cardiac surgery for severe tricuspid regurgitation).

Figure 3

Reverse left ventricular remodelling at 6-month follow-up in patients with reduced baseline ejection fraction (reduced ejection fraction, high-gradient and reduced ejection fraction, low-gradient aortic stenosis) in dependence on myocardial fibrosis burden (box plots indicating minimum, maximum, median, and 25th + 75th percentile); only matched observations included. Development of (A) ejection fraction, (B) left ventricular end-diastolic volume, and (C) left ventricular mass index. BL, baseline; EF, ejection fraction; LVEDV, left ventricular end-diastolic volume; LVMI, left ventricular mass index; MF+, myocardial fibrosis ≥11% (=median total cohort); MF−, myocardial fibrosis <11%.

Figure 4

Cardiovascular and all-cause mortality in dependence of fibrotic burden. Kaplan–Meier curves displaying cardiovascular (A) and all-cause (B) mortality in patients with myocardial fibrosis below (black) and above (red) the median.

Figure 5

Multivariate Cox regression analysis for prediction of cardiovascular mortality during follow-up after transcatheter aortic valve implantation (hazard ratios with 95% confidence intervals, displayed as forest plot).

Take home figure

This figure summarizes flow and main findings of the study which was designed to link myocardial fibrosis to LV remodelling, recovery and clinical outcome after TAVI.