Protein biomarkers associated with left bundle branch block in patients with heart failure and reduced ejection fraction

Figures

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  Figure 1. A flow chart describing the process of patient selection and on which grounds patients were excluded. Nine hundred and ninety-nine patients were excluded due to missing data, where ejection fraction, QRS duration, and measurements of biomarkers were missing. Six hundred and fifty-four patients were excluded due to pacemaker rhythm on electrocardiogram or an implanted device. Seventy-five patients had inconsistent electrocardiogram, and 714 had QRS between 101 and 129 ms, which lead to exclusion. Seven hundred and nine patients did not fulfill heart failure with reduced ejection fraction criteria due to ejection fraction >39% and were therefore excluded. One hundred and thirty-seven patients were excluded due to right bundle branch block or unspecific QRS appearance. After this selection, 966 patients were used for 1:1 propensity score matching, yielding 268 matched patients in each group. BIOSTAT-CHF, Biology Study to Tailored Treatment in Chronic Heart Failure; PM, pace-maker; ECG, electrocardiogram; EF, ejection fraction; RBBB, right bundle branch block; DHF, dyssynchronous heart failure; SHF, synchronous heart failure; HFrEF, heart failure with reduced ejection fraction

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  Figure 2. The volcano plot shows the differences in protein concentrations between HFrEF + LBBB and HFrEF − LBBB. The concentrations of 41 proteins, out of 364 analysed, differed significantly between the two groups and are indicated in red. The level of statistical significance, −log10P is given on the y-axis, and P = 0.05 (false detection rate 5%) is indicated with a grey vertical line. The normalized protein expression difference is given on the x-axis and was calculated as the normalized protein expression for a certain protein in blood samples from patients with HFrEF − LBBB deducted from the normalized protein expression for the same protein from patients with HFrEF + LBBB. Since the normalized protein expression is given in a log2 scale, a difference of 1 responds to a doubling in protein concentration. HFrEF, heart failure with Reduced ejection fraction; LBBB, left bundle branch block; FDR, false detection rate; NPX, normalized protein expression; SFTPD, surfactant protein D; KLK6, kallikrein 6; TNFRSF10C, decoy receptor 1; FGF2, fibroblast growth factor 2; EGFR, epidermal growth factor receptor; CCL2, C–C motif ligand 2; LTBR, lymphotoxin beta receptor; IL1R1, interleukin 1…

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  Figure 3. (A and B) Predicted protein–protein interactions of upregulated (A) or downregulated (B) proteins in HFrEF + LBBB compared with HFrEF − LBBB. The basis for interactions, e.g text-mining or experimentally determined, are illustrated with colour-coded connections. The explanation is found at the lower left of the figure. C lists the 10 most significantly affected gene ontology pathways found for upregulated proteins in HFrEF + LBBB compared with HFrEF − LBBB. Downregulated proteins did not affect gene ontology pathways. (D) Affected KEGG pathways, whether upregulated or downregulated proteins were included are indicated by arrows. The P-value (x-axis C and D) allows for a false discovery rate of 5%. Data were extracted from the STRING database. HFrEF, heart failure with reduced ejection fraction; LBBB, left bundle branch block; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; FDR, false discovery rate