Disease- and sex-specific differences in patients with heart valve disease: a proteome study

Abstract

Pressure overload in patients with aortic valve stenosis and volume overload in mitral valve regurgitation trigger specific forms of cardiac remodeling; however, little is known about similarities and differences in myocardial proteome regulation. We performed proteome profiling of 75 human left ventricular myocardial biopsies (aortic stenosis = 41, mitral regurgitation = 17, and controls = 17) using high-resolution tandem mass spectrometry next to clinical and hemodynamic parameter acquisition. In patients of both disease groups, proteins related to ECM and cytoskeleton were more abundant, whereas those related to energy metabolism and proteostasis were less abundant compared with controls. In addition, disease group–specific and sex-specific differences have been observed. Male patients with aortic stenosis showed more proteins related to fibrosis and less to energy metabolism, whereas female patients showed strong reduction in proteostasis-related proteins. Clinical imaging was in line with proteomic findings, showing elevation of fibrosis in both patient groups and sex differences. Disease- and sex-specific proteomic profiles provide insight into cardiac remodeling in patients with heart valve disease and might help improve the understanding of molecular mechanisms and the development of individualized treatment strategies.

Sex differences and estrogen effects in cardiac mitochondria in human aortic stenosis and in the mouse heart

“…The observed sex differences in mitochondrial function are fully in agreement with sex differences in cardiac energy metabolism that have been described earlier by us and others ( 5 , 26 ). Remarkably, a recent unbiased proteomic profiling analysis compared left ventricular myocardial biopsies from patients with different heart valve diseases: AS and mitral valve regurgitation (MR) and controls.…”

“…Consequently, there is still limited knowledge about the influence of sex and sex hormones on mitochondrial respiration in the cardiovascular system ( 15 ). The sex differences in the rodent hearts are similar to changes observed in human hearts, in exhibiting more concentric hypertrophy, less dilatation, and less downregulation of genes involved in energy metabolism in female hearts compared with males as reviewed recently ( 5 , 16 ). Therefore, the mouse model is suitable to study the mechanistic aspects of sex differences in human mitochondrial function in the heart.…”

“…Remarkably, a recent unbiased proteomic profiling analysis compared left ventricular myocardial biopsies from patients with different heart valve diseases: AS and mitral valve regurgitation (MR) and controls. The authors found that proteins of important metabolic pathways such as in the tricarboxylic acid cycle are downregulated in AS and MR, while other main transporters for long -chain fatty acids or glucose were upregulated in AS and MR ( 5 ). More important sex -stratified analysis among the AS patients revealed that proteins related to mitochondrial function showed a sex-specific pattern: a strong reduction in proteostasis-related proteins and less decrease in proteins involved in energy metabolism in female AS were observed.…”

“…A faster regression after aortic valve replacement (AVR) was observed in women compared with men ( 3 , 4 ), suggesting sex differences in the adaptation to pressure overload and LVH regression ( 2 , 3 ). Sex differences in myocardial gene expression and protein composition in human AS are particularly related to mitochondrial gene expression and protein composition ( 5 ). Sex differences are mostly caused by sex hormones or unequal gene expression from sex chromosomes or autosomes.…”