https://doi.org/10.1007/s00392-025-02625-4
1University Medical Center Göttingen Department of Cardiology and Pneumology Göttingen, Deutschland; 2University Medical Center Göttingen Department of Clinical Chemistry Göttingen, Deutschland
Background: In severe aortic stenosis (AS), left-ventricular cardiomyocytes hypertrophy to compensate for increased left-ventricular (LV) pressure overload and to reduce wall stress. Hypertrophic remodeling impairs the diastolic capacity of the left-ventricle. Reverse remodeling after transcatheter aortic valve implantation (TAVI) may restore the integrity of the LV but fails to occur in a subgroup of normal ejection-fraction high-gradient (NEF-HG) AS patients. This is associated with worsening post-interventional outcome.
In chronic pressure overload, compensated LV hypertrophy may degrade into LV dysfunction and dilation, accompanied by interstitial fibrosis. In patients with reduced ejection-fraction low-gradient (LEF-LG) AS, recovery of LV-EF after TAVI can be seen in parts of patients only. Often, this is due to pre-existing ischemic heart disease, but not limited to it.
Objectives: To identify the molecular mechanisms of reversible vs. fixed myocardial hypertrophy and recovery vs. consistently poor LV-EF after TAVI to optimize and individualize treatment strategies in AS.
Methods: Out of 90 NEF-HG AS and 32 LEF-LG AS patients from the Collaborative Research Center 1002 database, 20 LV biopsies from NEF-HG AS and 19 biopsies from LEF-LG AS patients, harvested during transcatheter aortic valve replacement, were chosen. Samples from non-failing (NF) donor hearts served as control. Based on clinical follow-up (FU), patients with left-ventricular mass index (LVMI) regression six-month post TAVI were grouped above and below the median of -20.45 g/m2 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). Consequently, LEF-LG AS patients were grouped above and below the median LV-EF recovery of 10.3 % and n = 10 vs. 9 samples were analyzed as described above.
Results: DIA-MS reliably detected 3.726 proteins in human left-ventricular tissue across all samples. Moreover, 827 proteins were significantly up-/ down-regulated compared to non-failing samples. 24 proteins showed significant abundance changes between reversible versus fixed myocardial hypertrophy. Unsupervised hierarchical clustering of the significant proteins revealed proteomic signatures and gene ontology identified cellular mechanisms concerning actin filament organization, muscle tissue development and microtubule polymerization (NRAP, STMN1, XIRP1/2, MAPRE2). Clinical data of the NEF-HG cohort confirmed worse outcomes in fixed hypertrophy shown via Minnesota Living with Heart-Failure Questionnaire (MLHFQ): 6 months FU: fixed hypertrophy: 22.39 points; hypertrophy regression: 16.26 points (t-test, p = 0.04).
Of the LEF-LG AS cohort 1437 proteins were detected and showed significant abundance changes compared to NF samples. Calcineurin B homologous protein 1 (CHP-1), important for heart development and homeostasis, was significantly up-regulated between recovered vs. impaired LV-EF. Survival analysis show 77% lower CV mortality of patients with recovered LV-EF in comparison to the impaired cohort (HR 0.23, 95% CI: 0.08 to 0.70, p = 0.02).
Conclusion: Our data identify the proteomic nature of left-ventricular hypertrophy regression and LV-EF recovery in severe AS post-TAVI, 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.