Circulating MicroRNA-30d is Associated with Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study
Background—Biomarkers that predict response to cardiac resynchronization therapy (CRT) in heart failure patients with dyssynchrony (HFDYS) would be clinically important. Circulating extracellular microRNAs (miRNAs) have emerged as novel biomarkers that may also play important functional roles, but their relevance as markers for CRT response has not been examined.
Methods and Results—Comprehensive miRNA PCR arrays were used to assess baseline levels of 766 plasma miRNA in patients undergoing clinically indicated CRT in an initial discovery set (n=12) with and without subsequent echocardiographic improvement at 6 months after CRT. Validation of candidate miRNAs in 61 additional patients confirmed that baseline plasma miR-30d was associated with CRT response (defined as increase in LVEF≥10%). MiR-30d was enriched in coronary sinus (CS) blood and increased in late-contracting myocardium in a canine model of HFDYS, indicating cardiac origin with maximal expression in areas of high mechanical stress. We examined the functional effects of miR-30d in cultured cardiomyocytes (CMs), and determined that miR-30d is expressed in CMs and released in vesicles in response to mechanical stress. Overexpression of miR-30d in cultured CMs led to CM growth and protected against apoptosis by targeting the mitogen-associated kinase 4 (MAP4K4), a downstream effector of tumor necrosis factor (TNF). In HFDYS patients, miR-30d plasma levels inversely correlated with high sensitivity Troponin T, a marker of myocardial necrosis.
Conclusions—Baseline plasma miR-30d level is associated with response to CRT in HFDYS in this translational pilot study. MiR-30d increase in CMs correlates with areas of increased wall stress in HFDYS, and is protective against deleterious TNF signaling.
- Received September 9, 2014.
- Revision received April 1, 2015.
- Accepted April 22, 2015.