Reverse Myocardial Remodeling Following Valve Replacement in Patients With Aortic Stenosis

Abstract

Background: Left ventricular (LV) hypertrophy, a key process in human cardiac disease, results from cellular (hypertrophy) and extracellular matrix expansion (interstitial fibrosis).

Objectives: This study sought to investigate whether human myocardial interstitial fibrosis in aortic stenosis (AS) is plastic and can regress.

Methods: Patients with symptomatic, severe AS (n = 181; aortic valve area index 0.4 ± 0.1 cm²/m²) were assessed pre-aortic valve replacement (AVR) by echocardiography (AS severity, diastology), cardiovascular magnetic resonance (CMR) (for volumes, function, and focal or diffuse fibrosis), biomarkers (N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T), and the 6-min walk test. CMR was used to measure the extracellular volume fraction (ECV), thereby deriving matrix volume (LV mass × ECV) and cell volume (LV mass × [1 - ECV]). Biopsy excluded occult bystander disease. Assessment was repeated at 1 year post-AVR.

Results: At 1 year post-AVR in 116 pacemaker-free survivors (age 70 ± 10 years; 54% male), mean valve gradient had improved (48 ± 16 mm Hg to 12 ± 6 mm Hg; p < 0.001), and indexed LV mass had regressed by 19% (88 ± 26 g/m² to 71 ± 19 g/m²; p < 0.001). Focal fibrosis by CMR late gadolinium enhancement did not change, but ECV increased (28.2 ± 2.9% to 29.9 ± 4.0%; p < 0.001): this was the result of a 16% reduction in matrix volume (25 ± 9 ml/m² to 21 ± 7 ml/m²; p < 0.001) but a proportionally greater 22% reduction in cell volume (64 ± 18 ml/m² to 50 ± 13 ml/m²; p < 0.001). These changes were accompanied by improvement in diastolic function, N-terminal pro-B-type natriuretic peptide, 6-min walk test results, and New York Heart Association functional class.

Conclusions: Post-AVR, focal fibrosis does not resolve, but diffuse fibrosis and myocardial cellular hypertrophy regress. Regression is accompanied by structural and functional improvements suggesting that human diffuse fibrosis is plastic, measurable by CMR and a potential therapeutic target. (Regression of Myocardial Fibrosis After Aortic Valve Replacement; NCT02174471).

Keywords: aortic stenosis; fibrosis; left ventricular hypertrophy.

Graphical abstract

Central Illustration

Extracellular Volume Fraction Dichotomizes the Myocardium Into Cell and Matrix Compartments (A) The in vivo myocardium consists of cells and the surrounding extracellular matrix. Reactive fibrosis is characterized by expansion of the extracellular matrix, whereas replacement fibrosis follows cell death by focal scar. (B) Cardiovascular magnetic resonance measures both focal fibrosis (scar) by late gadolinium enhancement imaging, where the scar appears bright, and diffuse fibrosis by extracellular volume fraction (ECV) imaging. The ECV divides the myocardium into cell and matrix compartments and allows calculation of cell and matrix volumes. (C) A patient with a left ventricular (LV) volume of 100 ml and an ECV of 25% would have a cell volume of 75 ml and a matrix volume of 25 ml. Regression of left ventricular mass following aortic valve replacement can be driven by matrix regression alone, where the ECV reduces; by cellular regression alone, where the ECV increases; or by a proportional regression in cellular and matrix compartments, where the ECV is unchanged.

Figure 1

Study Flow Chart A total of 181 patients with severe, symptomatic aortic stenosis were recruited (48% of all surgical aortic valve replacements [AVR] at our institution [University College London Hospital NHS Trust, London, United Kingdom]). Before AVR, 10 patients were excluded (claustrophobia [n = 4], cardiac amyloid [n = 2], severe mitral regurgitation [n = 2], pseudosevere aortic stenosis [n = 1], Fabry disease [n = 1]), and 3 patients did not undergo AVR and were treated medically. Following AVR (164 surgical, 4 transcatheter), 4 further patients were excluded because of cardiac amyloid. By 1 year, there were 11 deaths and 16 patients with pacemakers; 21 patients declined follow-up. A total of 116 patients underwent 1-year follow-up assessment. CABG = coronary artery bypass grafting; CMR = cardiac magnetic resonance; eGFR = estimated glomerular filtration rate; mAVR = mechanical aortic valve replacement; pre OP = pre-operative; TAVR = transcatheter aortic valve replacement; tAVR = tissue bioprosthetic aortic valve replacement.

Figure 2

Cell and Matrix Remodeling 1 Year After AVR (A) At 1-year post–aortic valve replacement (AVR), there was a 19% reduction in indexed left ventricular (LV) mass (88 ± 26 g/m² to 71 ± 19 g/m²; p < 0.001) (B) The extracellular volume fraction (ECV) increased unexpectedly from 28.2 ± 2.9% to 29.9 ± 4.0% (p < 0.001). (C) Derived indexed cell volume (left ventricular mass index × [1 − ECV]) reduced by 22% (64 ± 18 ml/m² to 50 ± 13 ml/m²; p < 0.001), and (D) derived indexed matrix volume (left ventricular mass index × ECV) reduced by 16% (25 ± 9 ml/m² to 21 ± 7 ml/m²; p < 0.001).

Figure 3

Reverse Myocardial Remodeling After AVR A 66-year-old man with severe aortic stenosis (peak velocity 4.66 m/s; mean gradient 57 mm Hg; aortic valve area 0.5 cm²). Cardiac magnetic resonance before aortic valve replacement (AVR) showed concentric left ventricular (LV) hypertrophy (133 g/m²). Late gadolinium enhancement (LGE) demonstrated limited nonischemic focal scar (5.3 g/m² [4%]). Extracellular volume fraction (ECV) was 27.5%. At 1 year after AVR (mechanical bileaflet valve), there was a 22% reduction in LV mass (to 104 g/m²). The LV mass regression resulted from a 24% reduction in cell volume and a 17% reduction in matrix volume, so the ECV rose to 29.1%. The focal fibrosis (late gadolinium enhancement [LGE]) was unchanged (5.4 g/m² [5%]), but it slightly increased when it was expressed as a percentage of the LV mass.