Transcriptomic Analysis Identifies the Effect of Beta-Blocking Agents on a Molecular Pathway of Contraction in the Heart and Predicts Response to Therapy

Abstract

Over the last decades, beta-blockers have been a key component of heart failure therapy. However, currently there is no method to identify patients who will benefit from beta-blocking therapy versus those who will be unresponsive or worsen. Furthermore, there is an unmet need to better understand molecular mechanisms through which heart failure therapies, such as beta-blockers, improve cardiac function, in order to design novel targeted therapies. Solving these issues is an important step towards personalized medicine. Here, we present a comprehensive transcriptomic analysis of molecular pathways that are affected by beta-blocking agents and a transcriptomic biomarker to predict therapy response.

Keywords: AR, adrenergic receptor; EF, ejection fraction; EMB, endomyocardial biopsy; GO, gene ontology; HF, heart failure; MYH, myosin heavy chain; MiPP, Misclassified Penalized Posteriors; SAM, significance analysis of microarrays; SERCA, sarcoplasmic reticulum calcium-dependent ATPase; TBB, transcriptomic-based biomarker; beta-blocking agents; biomarker; gene expression; heart failure; transcriptomics.

Graphical abstract

Figure 1

Study Design We analyzed a cohort of 43 patients with idiopathic dilated cardiomyopathy for molecular changes that are induced by beta-blocking agents. Among the patients on beta-blocking agents, we selected patients with poor (n = 13) versus good prognosis (n = 17) to identify gene expression changes in patients who improved during therapy with beta-blockers. Two-thirds of the data were used as a train set to develop the biomarker (poor prognosis n = 8; good prognosis: n = 11) and one-third of the data was used as an independent test set for validation of the molecular signature (poor prognosis: n = 5; good prognosis: n = 6).

Figure 2

Significance Analysis of Microarrays Plot of Differentially Expressed Genes in Patients on Beta-Blocking Agents Versus Alternative Therapy in IDCM There were 94 genes differentially expressed in patients treated with beta-blocking agents versus alternative therapy (q value <5%, fold change >1.2). No downregulated genes were detected in patients treated with beta-blocking agents. The 94 overexpressed genes are depicted in red. IDCM = idiopathic dilated cardiomyopathy.

Figure 3

Heat Map of Samples From All Patients With IDCM When we applied this unsupervised clustering algorithm, samples from patients on beta-blocking agents were grouped in a classification tree (highlighted in a dotted square) that was very distinct from patients who received alternative therapy. Each column represents a patient sample, and each row corresponds to a gene. Down-regulated genes are depicted in red, whereas up-regulated genes are labeled in blue.

Figure 4

Signaling Pathway of Rho Guanine Nucleotide Exchange Factor Important functions of this pathway involve antiapoptotic actions and regulation of actin-myosin interaction.