Changes of myocardial gene expression and protein composition in patients with dilated cardiomyopathy after immunoadsorption with subsequent immunoglobulin substitution

Abstract

Immunoadsorption with subsequent immunoglobulin substitution (IA/IgG) represents a therapeutic approach for patients with dilated cardiomyopathy (DCM). Here, we studied which molecular cardiac alterations are initiated after this treatment. Transcription profiling of endomyocardial biopsies with Affymetrix whole genome arrays was performed on 33 paired samples of DCM patients collected before and 6 months after IA/IgG. Therapy-related effects on myocardial protein levels were analysed by label-free proteome profiling for a subset of 23 DCM patients. Data were analysed regarding therapy-associated differences in gene expression and protein levels by comparing responders (defined by improvement of left ventricular ejection fraction ≥20 % relative and ≥5 % absolute) and non-responders. Responders to IA/IgG showed a decrease in serum N-terminal proBNP levels in comparison with baseline which was accompanied by a decreased expression of heart failure markers, such as angiotensin converting enzyme 2 or periostin. However, despite clinical improvement even in responders, IA/IgG did not trigger general inversion of DCM-associated molecular alterations in myocardial tissue. Transcriptome profiling revealed reduced gene expression for connective tissue growth factor, fibronectin, and collagen type I in responders. In contrast, in non-responders after IA/IgG, fibrosis-associated genes and proteins showed elevated levels, whereas values were reduced or maintained in responders. Thus, improvement of LV function after IA/IgG seems to be related to a reduced gene expression of heart failure markers and pro-fibrotic molecules as well as reduced fibrosis progression.

Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans

“…The gene product periostin, is an extracellular matrix protein; the attenuation of which in cardiomyocytes reduces fibrosis and hypertrophy in response to long-term pressure overload, whereas overexpression of periostin resulted in age-dependent hypertrophy. These data strongly suggest that overexpression of periostin significantly contributes to cardiac remodeling following TAC [1, 47]. POSTN expression was also upregulated in LV samples of human failing hearts in our study (by 5.5-fold) and in other studies, and POSTN expression is negatively correlated with LV ejection fraction and positively correlated with end-diastolic diameter following myocardial infarction, suggesting that increased POSTN expression may contribute to cardiac contractile impairment in humans [8, 74].…”

Serum proteome profiling in canine idiopathic dilated cardiomyopathy using TMT-based quantitative proteomics approach

“…While there is widening evidence of role of immune processes in a portion of human DCM cases [30], such findings are poorly documented in canine DCM research. However, in a study of Buse et al [31] there were significantly higher levels of serum auto-antibodies against myosin heavy chain and α-cardiac actin in dogs with DCM than in controls, while Day [32] found anti-mitochondrial antibodies in one third of examined English Cocker Spaniels with DCM.…”

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions

“…However, placebo-controlled clinical trials are needed to validate these observations. Of note, immunoadsorption–IVIG was found to be safe and effective in improving clinical symptoms in patients with virus-positive inflammatory cardiomyopathy, regardless of B19V or HHV6 presence in EMB samples 263 . By contrast, IVIG did not show any beneficial effects in patients with DCM in a study that did not evaluate cardiac viral persistence 264 .…”