Unveiling Human Proteome Signatures of Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent but still poorly understood clinical entity. Its current pathophysiological understanding supports a critical role of comorbidities and their chronic effect on cardiac function and structure. Importantly, despite the replication of some HFpEF phenotypic features, to this day, experimental models have failed to bring new effective therapies to the clinical setting. Thus, the direct investigation of HFpEF human myocardial samples may unveil key, and possibly human-specific, pathophysiological mechanisms. This study employed quantitative proteomic analysis by advanced mass spectrometry (SWATH–MS) to investigate signaling pathways and pathophysiological mechanisms in HFpEF. Protein-expression profiles were analyzed in human left ventricular myocardial samples of HFpEF patients and compared with a mixed control group. Functional analysis revealed several proteins that correlate with HFpEF, including those associated with mitochondrial dysfunction, oxidative stress, and inflammation. Despite the known disease heterogeneity, proteomic profiles could indicate a reduced mitochondrial oxidative phosphorylation and fatty-acid oxidation capacity in HFpEF patients with diabetes. The proteomic characterization described in this work provides new insights. Furthermore, it fosters further questions related to HFpEF cellular pathophysiology, paving the way for additional studies focused on developing novel therapies and diagnosis strategies for HFpEF patients.

Myocardial RNA Sequencing Reveals New Potential Therapeutic Targets in Heart Failure with Preserved Ejection Fraction

“…Cardiac biopsies were obtained from patients recruited to undergo cardiac surgery at Centro Hospitalar São João, as described previously [ 11 ]. All procedures were realized according to the Declaration of Helsinki and were approved by the local ethics committee and data protection authority (CES2006, 35/2017, and 1774/2017).…”

“…All procedures were realized according to the Declaration of Helsinki and were approved by the local ethics committee and data protection authority (CES2006, 35/2017, and 1774/2017). All patients were assessed in terms of clinical characteristics, echocardiography, and blood sampling [ 11 ], and they were categorized into two groups: HFpEF according to ESC guidelines [ 2 ] and a non-HFpEF control group composed of aortic stenosis patients, from now on designated as “Control”.…”

“…Left ventricle tissue samples (~5 mg) were collected as described previously [ 11 ]. Total RNA was isolated from liquid nitrogen frozen samples using the Norgen Biotek kit (Norgen Biotek, Thorold, Canada), including a DNase treatment step.…”

Multi‐omic analyses and network biology in cardiovascular disease

“…In addition to HFrEF etiologies, left ventricular proteomic profiling has recently been performed in patient samples with heart failure with preserved ejection fraction (HFpEF) [69], using sequential window acquisition of all theoretical mass spectra (SWATH-MS) [70] for label free quantification. Interestingly, as human HFpEF is a heterogeneous disease with multiple related co-morbidities, these analyses were able to stratify proteomic signatures in HFpEF patients with or without diabetes to identify reduced mitochondrial oxidative phosphorylation and fatty-acid oxidation capacity in HFpEF + diabetes patients [69].…”

“…In addition to HFrEF etiologies, left ventricular proteomic profiling has recently been performed in patient samples with heart failure with preserved ejection fraction (HFpEF) [69], using sequential window acquisition of all theoretical mass spectra (SWATH-MS) [70] for label free quantification. Interestingly, as human HFpEF is a heterogeneous disease with multiple related co-morbidities, these analyses were able to stratify proteomic signatures in HFpEF patients with or without diabetes to identify reduced mitochondrial oxidative phosphorylation and fatty-acid oxidation capacity in HFpEF + diabetes patients [69]. Moreover, work from our group utilized a comparative, integrative analysis of global and phosphoproteomic profiling of human HCM, as compared to murine cardiac hypertrophy by transverse aortic constriction and the Biowire II [71] heart-on-a-chip platform, to identify common pathological pathways governing cardiac fibrosis with putative therapeutic potential [72].…”