Septic Cardiomyopathy: Getting to the Heart of the Matter*
In this issue of Critical Care Medicine, Matkovich et al (3) report on a genome-wide expression profiling study of myocardium from 20 patients with sepsis immediately postmortem when compared with myocardium from 20 patients with other forms of cardiomyopathy, and with 11 nonfailing donor hearts. This study represents an enormous amount of work by the clinical team, and an invaluable contribution from the patients and families who consented.
The clinical settings require close inspection to understand exactly what comparisons were made. The septic patients were mostly on pressors, indicating overall cardiovascular dysregulation. Transthoracic echocardiography was done in 12 of the 20 septic patients at a mean 5.6 ± 2.5 days prior to death. The patients showed a left ventricular ejection fraction of 53 ± 5.1%, though with a wide range (20–70%). Coupled with the varying degrees of inotropic support, and the generally hyperdynamic state of postresuscitation sepsis, it is hard to know what degree of septic cardiomyopathy existed in the studied population. This can be seen as both a strength of the study, in that a broad section of septic patients is represented (albeit only those that progressed to death), and a relative weakness, in that the findings are difficult to correlate with any particular clinical cardiomyopathic phenotype. We generally feel that the inclusion of a broader phenotype leads to results with more widespread applicability (4, 5).
The heart tissue from nonseptic failing hearts was taken at time of explant, and heart tissue from nonfailing hearts was taken from brain-dead organ donors. Notably, the nonseptic cardiomyopathy group is split into both ischemic (n = 11) and dilated (n = 9) phenotypes, which are analyzed sometimes separately and sometimes jointly in the article, based on the argument that prior studies have shown transcriptional differences between the two classes (6). Overall, the study allows for a reasonably informative comparison of the underlying transcriptomics between septic cardiomyopathy and other forms of cardiomyopathy.
Matkovich et al (3) first limited the genes under study to those which had been shown to be expressed at a reasonable level in a previous RNA-seq study of human hearts (6), reducing the number of included variables and increasing the likelihood of finding a biologically meaningful signal. They then showed using dimensionality-reduction techniques that the profiles of the septic hearts are overall substantially different from the other hearts profiled. A more in-depth analysis found that 169 genes were dysregulated in both septic and nonseptic failing hearts, including standard markers of cardiac stress (atrial natriuretic peptide and B-type natriuretic peptide). However, the authors found far more genes (1,185) dysregulated in only the septic hearts and focused the rest of the study on interpreting these genes.