Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation

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BACKGROUND

Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx.

METHODS

This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R–3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0RS1 → 2RS2` → 0RS3). Relative expression (2∆Cq) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx.

RESULTS

A total of 21 ACR episodes (0RS1 → 2RS2 → 0RS3) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2−∆Cq) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%.

CONCLUSIONS

miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker (area under the curve = 0.80 and negative predicted value = 98%). Thus, this biomarker could reduce the need for endomyocardial biopsies and the associated risks and costs of this invasive procedure.

Section snippets

Study design

This prospective, observational, single-center study included patients who underwent HTx between April 2013 and August 2018 in the Complexo Hospitalario Universitario A Coruña (A Coruña, Spain). The EMB protocol to monitor rejection was every 10 to 15 days in the first 2 months, every 20 days in Months 3 and 4, and monthly in Months 5 and 6. After the sixth month, in stable patients and without any episode of treated rejection, the next EMB was at 12 months; in those patients who had an episode

Study population

A total of 121 patients were included in the study and their primary heart diseases were dilated cardiomyopathy (n = 45; 37%), ischemic cardiomyopathy (n = 44; 36%), hypertrophic cardiomyopathy (n = 13; 11%), congenital cardiomyopathy (n = 6; 5%), valvular cardiomyopathy (n = 5; 4%), and others (n = 8; 7%). The median age of the recipients was 59 (interquartile range [IQR]: 49-65) years and 82% of them were males. After excluding 4 patients (perioperative death), a total of 1,113 EMBs were

Discussion

MicroRNAs have been postulated as new potential non-invasive biomarker candidates for heart transplant rejection.12, 13, 14, 15, 16, 17, 18 In this study, after evaluating 179 serum microRNAs in the initial discovery phase, the circulating miR-181a-5p showed a rise and fall pattern that make it a potential non-invasive biomarker to detect ACR in HTx. These results were confirmed in the discovery phased using a new cohort of patients with ACR and where miR-181a-5p was found to be overexpressed

Conclusions

miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker with an AUC of 0.80 and an NPV of 98%. Thus, this biomarker could reduce the need for EMBs and the associated risks and costs of this invasive procedure.

Disclosure statement

The authors have no conflicts of interest to disclose.

This study received financial support from Instituto de Salud Carlos III (PI15/02224), is part of the research activities of the Centro de investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), and was cofinanced with FEDER Funds.

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    These authors have contributed equally to this work.

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