Proteomic profiling of left ventricular hypertrophy regression in severe aortic valve stenosis after valve replacement

Background: In severe aortic stenosis (AS), left-ventricular cardiomyocytes hypertrophy to compensate for increased left-ventricular pressure overload and to reduce wall stress. Hypertrophic remodeling, however, impairs the diastolic capacity of the left-ventricle. Reverse remodeling after transcatheter aortic valve implantation (TAVI) may restore the integrity of the left-ventricle but fails to occur in a subgroup of normal ejection-fraction high-gradient (NEF-HG) AS patients. Noteworthy, this is associated with worsening post-interventional outcome shown in the PARTNER trials.

Objectives: To identify the molecular mechanisms of reversible versus fixed myocardial hypertrophy after TAVI to optimize and individualize treatment strategies in AS.

Methods: In a new proteomic approach, out of 90 NEF-HG patients from the SFB1002 database, 20 small left-ventricular biopsies harvested from NEF-HG patients during transcatheter aortic valve replacement were chosen. Inclusion criteria were based on echocardiographic diagnosis of severe AS and guideline-defined AS-subtype classification. Samples from non-failing donor hearts served as control. Based on clinical follow-up, patients with left-ventricular mass index regression six-month post TAVI were grouped above and below the median of -22.7 g/m2 (above: mean regression: -34,4 g/m2, below: -1,39 g/m2, p < 0.001) and n= 10 vs. 10 samples were analyzed by small biopsy processing including pressure cycling technology and subsequent data-independent acquisition mass spectrometry (DIA-MS).

Results: DIA-MS reliably detected 3.726 proteins in human left-ventricular tissue across all samples of which 24 proteins showed significant abundance changes between reversible versus fixed myocardial hypertrophy. Moreover, 827 proteins were significantly up-/ down-regulated compared to non-failing samples. Unsupervised hierarchical clustering of the significant proteins revealed proteomic signatures regarding the median regression, and gene ontology identified potential cellular mechanisms concerning cell cycle pathways and cellular component disassembly (NRAP, STMN1, HSPA2). Analysis of the clinical data of the entire NEF-HG cohort confirmed a worse outcome in fixed hypertrophy shown via Minnesota Living with Heart-Failure Questionnaire (MLHFQ): below median, baseline (BL): 30.34 points, 6 months follow-up (FU): 22.39 points; above median, BL: 28.74 points, FU: 16.26 points (t-test, p = 0.04).

Conclusion: Our data identify the proteomic nature of significant left-ventricular hypertrophy regression in severe AS post-TAVI, which is associated with improved clinical outcome. These findings may have implications in terms of timing of valve replacement and the role of adjunctive medical therapy after TAVI.