Background:

Aortic valve stenosis (AS) and mitral valve regurgitation (MR) trigger specific forms of cardiac remodelling, which, if left untreated, can lead to heart failure. Although the cardiac phenotype and global functional parameters in patients with AS and MR are well characterized, little is known about their myocardial proteome profiles and their potential differences.

Methods:

75 patients (AS=41, MR=17) were prospectively studied and characterized by detailed clinical parameters and cardiac magnetic resonance (CMR) imaging. Proteome profiling using high-resolution tandem mass spectrometry was performed from left ventricular (LV) myocardial biopsies of patients with AS and MR and of 17 controls.

Results: 

Proteome profiling showed differentially expressed proteins between patients and controls (AS=1332, MR=400) as well as between AS and MR (903). AS-specific changes (only expressed in AS but not in MR) were identified in 518 proteins, MR-specific changes in 79 proteins.

Proteins found to be differentially expressed mainly belong to four functional categories: extracellular matrix, energy metabolism, cytoskeleton and protein synthesis.

Specifically in AS, for example, a strong increase in fibrillar collagens (collagen type I and type III) and decrease in proteins related to energy metabolism (fatty acid beta oxidation, branched chain amino acid catabolism and mitochondrial proteins) was seen. In MR findings include specific upregulation of enzymatic proteins (carboxypeptidase A3 and chymase 1) and downregulation of mitochondrial cholesterol/porphyrin uptake translocator protein (TSPO).

Distinct differences in protein expression levels were also seen between females and males (462 proteins specifically in female AS, 235 proteins in male AS, 70 proteins in female MR, 82 in male MR). Female AS, for example, showed a strong reduction in protein synthesis capacity (ribosomal subunits and cytosolic eukaryotic initiation factor) and less reduction in proteins related to energy metabolism compared to male AS and this was accompanied by less hypertrophy and fibrosis and better preserved cardiac function.

Conclusions

Our work provides detailed novel insight into heart valve disease driven LV myocardial proteome alterations in patients with AS and MR and expands the understanding of human cardiac remodeling in female and male patients with LV cardiac pressure- and volume overload.