Chemokine receptor patterns and right heart failure in mechanical circulatory support

Abstract

Background Right Ventricular failure (RVF) complicates 9–44% of LVAD implants postoperatively. Current prediction scores perform only modestly in validation studies, and do not include immune markers. Chemokines are inflammatory signaling molecules with a fundamental role in cardiac physiology and stress adaptation. We aimed to study chemokine receptor regulation in LVAD recipients who develop RVF. Methods Expression of chemokine receptor genes 3–8 was examined in the peripheral blood of 111 LVAD patients, collected 24 hours prior to implant. RNA was isolated using a PAXgene protocol. Gene expression was assessed using a targeted microarray (RT2 Profiler PCR array, Qiagen). Results were expressed as PCR cycles to threshold and normalized to the average of 3 control genes- GAPDH, HPRT1 and B2M. Secondary outcomes studied were 1 year mortality and long-term RV failure (RVF-LT). Results Chemokine receptors CCR3, CCR4, CCR6, CCR7 and CCR8 were down regulated in LVAD recipients who had RVF. Within this cohort of patients, CCR4, CCR7 and CCR8 were further down regulated in those that required mechanical support of their RV. Additionally, under-expression of CCR3–8 was independently associated with an increased risk of mortality at 1 year, even after adjusting for RVF. Chemokine receptor expression did not predict RVF-LT in our patient cohort. Conclusions Pre-LVAD chemokine receptor down regulation is associated with RVF and increased mortality after implant. Inflammatory signatures may play an important role in prognostication in this patient population.

Left ventricular assist device bioinformatics identify possible hubgenes and regulatory networks involved in the myocardium of patients with left ventricular assist device

“…Overall, the role of cytokine-signaling in the post-LVAD pathophysiology is evidently associated with the events that determine adverse ventricular remodeling, as seen by Grosman-Rimon et al’s report ( 29 ), who demonstrate recipients with continuous-flow LVADs as demonstrating a higher level of inflammatory biomarkers and specific expression changes in the chemokine signaling pathway. Contrastingly, Nayak et al ( 30 ) found increased mortality was associated with the downregulation of chemokine signaling, and these effects were translated by the progression toward right heart failure—one of the fatal complications of LVAD assistance. Disparities maybe due to the different types of devices, or the lengths of time the LVAD assistance remained in place, but the validation of this requires further study and investigation.…”

“…CX3CR is involved in chemokine binding. Nayak et al found that when chemokine signaling was downregulated, it increased mortality and facilitated the fatal adverse effects after LVAD implantation, particularly, the process of right heart failure ( 30 ).…”

Effects of left ventricular assist device on heart failure patients: A bioinformatics analysis

“…It has been proved that chemokine dysregulation potentiates the progression of end‐stage HF . Nayak et al found that downregulation of chemokine signaling increased mortality and facilitated the process of right heart failure, which is one of the fatal adverse effects after LVAD implantation. However, in Grosman et al’s report, a higher level of inflammatory biomarkers and specific expression changes in the chemokine signaling pathway were observed in the recipients with continuous‐flow LVADs.…”

Prediction, prevention, and management of right ventricular failure after left ventricular assist device implantation: A comprehensive review

“…Readily available inflammatory markers such as white cell count, neutrophil to lymphocyte ratio, or C reactive protein correlate with rates of RVF ( 62 ). A more in-depth analysis showed that patients with RVF displayed a pre-operative downregulation of chemokine receptors CCR3, 4, 6, 7, and 8 that was even more profound in patients who required RVAD, which suggests a dose-response relationship that supports a causative role ( 63 ). Other inflammatory biomarkers such as procalcitonin, neopterin, or endothelin 1 have also been linked to RVF ( 64 ).…”