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Proteomic Signatures of Heart Failure in Relation to LVEF
Quick Takes
- Proteomic profiles differ significantly between HFrEF, HFmrEF, and HFpEF.
- Ejection fraction only captures a small portion of proteomic variability.
- Adequate proteomic phenotyping of HF is limited in small sample sizes and heterogeneous patient groups.
Study Questions:
Do proteomic profiles differ between patients with heart failure and reduced ejection fraction (HFrEF), HF with midrange EF (HFmrEF), and HF with preserved EF (HFpEF)?
Methods:
Age- and sex-matched outpatients with HFrEF (LVEF <40% [n = 47]), HFpEF (LVEF >50% [n = 43]), and HFmrEF (LVEF 40-50% [n = 83]) enrolled in the Washington University Heart Failure registry were randomly selected for plasma proteomic profiling using the aptamer-based SOMAscan. To ensure accuracy and biologic relevance of measurements, the authors showed altered expression of coagulation factors in patients treated with warfarin as well as an association between plasma creatinine and the kidney function marker CST3. They further validated their findings by measuring cystatin C, soluble ST2 and C-reactive protein using enzyme-linked immunosorbent assays (ELISAs), and confirming strong correlations (r > 0.90).
Results:
The cohort consisted of 58% male, 24% African Americans, and 25% with diabetes mellitus, with a mean age of 55 years. The authors identified 280 differentially expressed proteins between HFrEF, HFmrEF and HFpEF. Age, sex, and medications contributed little to the variability in signal between cohorts. EF as a continuous variable contributed to 1% of the overall variability of the proteome. HF etiology (ischemic vs. nonischemic) contributed between 5.8% and 14.1% of the observed variance. The largest component of the variance in the analysis was unassigned. Plasma proteomic profiles were most similar for patients with HFmrEF and HFpEF, and were most dissimilar for patients with HFmrEF and HFrEF. There was greater overlap between proteomic profiles of HFmrEF who had improved EF and HFpEF than HFmrEF and HFrEF. The protein overlap between ischemic and nonischemic etiologies was overall low, regardless of LVEF stratification (1.1%-8.1%), suggesting that differences in proteomic profiles for ischemic versus nonischemic patients did not explain the differences in proteome between the different LVEF classifications. The top five thematic biological clusters that were differentially expressed varied significantly between the different EF classifications; for example, the HFrEF increased-expression categories included growth factor signaling, inflammation, neurotrophic signaling, remodeling/hypertrophy, and angiogenesis (VEGF-A related), whereas decreased-expression themes included those related to coagulation and myeloproliferation.
Conclusions:
Proteomic profiles differ significantly among patients with HF classified by EF.
Perspective:
It is difficult to draw definite conclusions from this study. The sample size was very small, especially for a proteomic analysis, given the large number of comparisons made and the heterogeneity in comorbidities not accounted for such as diabetes mellitus; all bound to affect the proteome significantly. One interesting takeaway is that EF only captured a small portion of the proteome variability, supporting the notion that EF is only a crude measure in differentiating between the various HF phenotypes. The promise of this study is in its feasibility, and the hope that once cost and technical limitations are overcome, proteomic analyses could lead to the next revolution in our understanding of the pathophysiology of HF and its management.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: C-Reactive Protein, Creatinine, Cystatin C, Heart Failure, Hypertrophy, Inflammation, Ischemia, Proteome, Proteomics, Stroke Volume, Vascular Endothelial Growth Factor A, Ventricular Function, Left, Warfarin
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