Characteristics, clinical outcomes and molecular mechanisms associated with severe diastolic dysfunction in aortic stenosis.

OBJECTIVES

We aimed to better understand patient characteristics and pathophysiological mechanisms associated with severe diastolic dysfunction in aortic stenosis patients undergoing transcatheter aortic valve implantation (TAVI).

BACKGROUND

Patients with severe aortic stenosis often have echocardiographic signs of diastolic dysfunction. However, their characteristics and underlying disease mechanisms remain unclear.

METHODS

Untargeted LC-MS lipidomics (1110 lipids) and proteomics (834 proteins) were performed on peri-procedural plasma from 231 TAVI patients. Pre-procedural echocardiography was available in 191 patients. DIABLO (mixOmics, version 6.3.0, R version 4.4.1) was used to integrate lipidomic and proteomic profiles.

RESULTS

Median age was 80 years, and 61% were female. In total, 75 (39%) patients had severe diastolic dysfunction. Patients with severe diastolic dysfunction more often had atrial fibrillation, higher plasma NT-proBNP concentrations, and more heart failure hospitalizations and mortality.Multi-omic network analysis identified two major lipid-protein clusters associated with severe diastolic dysfunction. The first showed dysregulation of membrane phospholipids such as cardiolipins (essential for mitochondrial integrity and energy metabolism), and phosphatidylserines (cytoprotective and anti-inflammatory properties). This cluster was associated with cytoskeletal and extracellular matrix remodeling. The second cluster showed high concentrations of acylcarnitines (indicative of metabolic dysfunction), which were associated with extracellular matrix remodeling and inflammatory responses.

CONCLUSIONS

In patients with aortic stenosis undergoing TAVI, those with severe diastolic dysfunction showed a disrupted balance of membrane phospholipids and acylcarnitines, suggesting that impaired energy metabolism, cellular and extracellular structural remodeling, and inflammatory responses may underlie the development and progression of diastolic dysfunction and heart failure.

CONDENSED ABSTRACT: We investigated clinical features and molecular profiles linked to severe diastolic dysfunction in aortic stenosis patients undergoing TAVI. Untargeted lipidomics (1110 lipids) and proteomics (834 proteins) were performed on peri-procedural plasma from 231 patients. Pre-procedural echocardiography was available in 191 patients. Severe diastolic dysfunction was present in 39% and was associated with atrial fibrillation, higher NT-proBNP, and more heart failure hospitalizations and mortality. Multi-omic integration identified two major lipid-protein clusters. The first was characterized by dysregulated membrane phospholipids, including cardiolipins and phosphatidylserines, linked to cytoskeletal and extracellular matrix remodeling. The other showed elevated acylcarnitines, indicating metabolic dysfunction, and inflammatory activation. These findings suggest that altered energy metabolism, structural remodeling, and inflammation are associated with severe diastolic dysfunction in aortic stenosis.