Widespread Down-Regulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients With Sepsis

Abstract

Objectives: The mechanism(s) for septic cardiomyopathy in humans is not known. To address this, we measured messenger RNA alterations in hearts from patients who died from systemic sepsis, in comparison to changed messenger RNA expression in nonfailing and failing human hearts.

Design: Identification of genes with altered abundance in septic cardiomyopathy, ischemic heart disease, or dilated cardiomyopathy, in comparison to nonfailing hearts.

Setting: ICUs at Barnes-Jewish Hospital, St. Louis, MO.

Patients: Twenty sepsis patients, 11 ischemic heart disease, nine dilated cardiomyopathy, and 11 nonfailing donors.

Interventions: None other than those performed as part of patient care.

Measurements and main results: Messenger RNA expression levels for 198 mitochondrially localized energy production components, including Krebs cycle and electron transport genes, decreased by 43% ± 5% (mean ± SD). Messenger RNAs for nine genes responsible for sarcomere contraction and excitation-contraction coupling decreased by 43% ± 4% in septic hearts. Surprisingly, the alterations in messenger RNA levels in septic cardiomyopathy were both distinct from and more profound than changes in messenger RNA levels in the hearts of patients with end-stage heart failure.

Conclusions: The expression profile of messenger RNAs in the heart of septic patients reveals striking decreases in expression levels of messenger RNAs that encode proteins involved in cardiac energy production and cardiac contractility and is distinct from that observed in patients with heart failure. Although speculative, the global nature of the decreases in messenger RNA expression for genes involved in cardiac energy production and contractility suggests that these changes may represent a short-term adaptive response of the heart in response to acute change in cardiovascular homeostasis.

Figure 1. Distinct transcriptional profile of septic cardiomyopathy

A, Box and whisker plots for cardiac structure and function for patients with sepsis. Left, LV end-systolic dimension; middle, LV end-diastolic dimension; right, LV ejection fraction (%). All of the patients whose data contributed to this figure (n=12) were supported by inotropes and/or vasopressors. B, Principal component analysis plot using all 6,719 mRNAs above a minimum detection limit as defined in Methods. The x-axis represents the first principal component, or PC (encompassing the most variance) while the y-axis represents the second principal component (PC). C, Venn analysis of mRNA transcripts altered in human heart failure. mRNAs from hearts failing secondary to ischemic heart disease (IHD) or to dilated cardiomyopathy (DCM), vs nonfailing hearts (NF), were selected at false discovery rate (FDR) <0.05; mRNAs from septic hearts vs NF were selected at FDR < 0.01 (see main text). D, Standardized heatmap (mean 0, standard deviation 1) of differentially expressed mRNAs from C, using unsupervised hierarchical clustering with Euclidean distance and average linkage on both hearts and mRNAs.

Figure 2. Shared mRNA dysregulation between cardiomyopathies

A, Plot of the degree of fold-change vs NF hearts (x-axis) against p-value for each comparison (y-axis), for the 169 mRNAs altered in IHD and/or DCM hearts together with septic hearts. A thumbnail of the Venn diagram from Figure 1C is shown at right denoting the mRNAs under consideration. B, Gene Ontology category over-representation for genes that were dysregulated in septic hearts and/or IHD and DCM; FDR < 0.05 using BiNGO (6). C, Column graphs of selected heart failure marker mRNAs (ANP / NPPA, BNP / NPPB, SERCA2a / ATP2A2); mean ± standard error of Affymetrix microarray abundance measurements are shown. * denotes FDR<0.01 (for septic vs NF) or <0.05 (for IHD/DCM vs NF).

Figure 3. Dysregulation of mRNAs encoding mitochondrial components in septic hearts

A, Gene Ontology category over-representation for genes that were uniquely dysregulated in septic hearts; FDR < 0.05 using BiNGO (6). A thumbnail of the Venn diagram from Figure 1C is shown at right denoting the mRNAs under consideration. B, Schematic representation of the mitochondrial oxidative phosphorylation / electron transport chain. C, percentage of mRNAs for each of the mitochondrial electron transport chain complexes I-V with observed dysregulation in septic hearts (FDR < 0.01 vs nonfailing).

Figure 4. Dysregulation of mRNAs encoding nonmitochondrial proteins in septic hearts

A, Plot of the degree of fold-change vs NF hearts (x-axis) against p-value for each comparison (y-axis), for the remaining 991 mRNAs altered in septic hearts. B, KEGG pathway enrichment and FDR for uniquely dysregulated mRNAs in septic hearts using DAVID (24). A thumbnail of the Venn diagram from Figure 1C is shown at right denoting the mRNAs under consideration. C, percentages of mRNAs belonging to previously described matrix-collagen, EC coupling, integrin-cytoskeleton and sarcomere gene modules (25) (derived from KEGG pathway gene lists for hypertrophic and dilated cardiomyopathy) ; lists of individual mRNAs are in Supplemental Digital Content - Table 6.