Heart Rate Reduction Is Associated With Reverse Left Ventricular Remodeling and Mechanism-Specific Molecular Phenotypes in Dilated Cardiomyopathy

Figures

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  Figure 1.. PROBE-IT study (Pulse Reduction on β-Blocker and Ivabradine Therapy), CONSORT diagram. Details of patient dropouts are in section II.A in Supplemental Results. ∆LVEF indicates change in LVEF; bpm, beats per minute; CONSORT, Consolidated Standards of Reporting Trials; Covid+, positive diagnosis for COVID-19; CU, University of Colorado; d/c, discontinued; d.o., dropped out; f/u, follow-up; HR ∆, change in heart rate; ICD, implanted cardioverter defibrillator; LVEF, left ventricular ejection fraction; OSU, Ohio State University; Pbo, placebo; Pt, patient; Rx, treatment; SCD, sudden cardiac death; VT, ventricular tachycardia; and w/d, withdrawn.

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  Figure 2.. Heart rate (HR; beats per minute [bpm]) changes (∆) in the HR change and Ivabradine vs Placebo groups. A, Distribution of HR changes in the HR change and Ivabradine vs Placebo groups; dotted line=median change. B, Scatterplot of changes in averaged HR (Avg HR) and left ventricular ejection fraction (LVEF) changes in the 17 patients completing the PROBE-IT study (Pulse Reduction on β-Blocker and Ivabradine Therapy); closed circles are 12 ivabradine-treated subjects, and closed squares are 5 placebo-treated patients. Rs values are Spearman correlation coefficient. Dotted line denotes 0 change in LVEF.

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  Figure 3.. Number of upregulated and downregulated mRNA transcripts at 24-week follow-up study, by significance level, Decreased vs Unchanged Heart Rate (HR) group.

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  Figure 4.. Heat map and cluster analysis of the 151 genes with changed impression in Figure 3, heart rate (HR) change groups. Group 1 (Grp1) is the 8 Unchanged HR subjects, and group 2 (Grp2) is the Decreased HR patients. Treatment assignments to ivabradine (Ivb) or placebo (Pbo) are designated for each subject. Values plotted are 24-week−baseline log2 fragments per kilobase per million map reads (FPKMs). Ordering across the axes is governed by hierarchical clustering, representing similarities in closeness of the gene expression relationships between subjects (top dendrogram) and between genes (right dendrogram).

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  Figure 5.. Gene expression (mRNA transcripts) changes in 21 ventricular myocardial ontology9,10 categories from nonischemic dilated cardiomyopathy Decreased HR subjects with left ventricular (LV) reverse remodeling compared with the Unchanged HR group with no change in LV ejection fraction (LVEF). A, Upregulated genes with reverse remodeling. B, Downregulated genes. The significance level is α 0.0025, and differences in upregulated vs downregulated transcripts within the same category are designated by an asterisk (*); there are no statistically significant differences in the proportion (percentage of total upregulated or downregulated) transcripts. Pie slice sizes indicate percentage of the total upregulated or downregulated transcripts. β-AR indicates β-adrenergic receptor; AKAP, A-kinase anchoring protein; ECM, extracellular matrix; HTY, hypertrophy; IP3, inositol triphosphate; LPA, lysophosphaditic acid; PROBE-IT, Pulse Reduction on β-Blocker and Ivabradine Therapy; and TGFB, transforming growth factor beta.

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  Figure 6.. Ion channel mRNA expression (fragments per kilobase per million map reads; FPKM) in heart rate (HR) change groups. A, Ion channel FPKM expression in the Decreased HR group (N=9), at baseline (BsL) and 24 weeks. B, Ion channel FPKM expression, 24-week changes from baseline in the Decreased HR minus the Unchanged HR group (N=8). ADRB1 indicates adrenoceptor beta 1; ADRB2, adrenoceptor beta 2; HCN1-4, hyperpolarization activated cyclic nucleotide gated potasium channel (1-4); KCNA5, potassium voltage-gated channel subfamily A member 5; KCNJ11, potassium inwardly rectifying channel subfamily J member 11; and sCN3A, sodium voltage-gated channel alpha subunit 3.