Abstract | BACKGROUND: METHODS AND RESULTS: Comprehensive miRNA polymerase chain reaction arrays were used to assess baseline levels of 766 plasma miRNAs 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 an increase in left ventricular ejection fraction ≥10%). MiR-30d was enriched in coronary sinus 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 and determined that miR-30d is expressed in cardiomyocytes and released in vesicles in response to mechanical stress. Overexpression of miR-30d in cultured cardiomyocytes led to cardiomyocyte growth and protected against apoptosis by targeting the mitogen-associated kinase 4, a downstream effector of tumor necrosis factor. 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 cardiomyocytes correlates with areas of increased wall stress in HFDYS and is protective against deleterious tumor necrosis factor signaling.
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Authors | Yonathan F Melman, Ravi Shah, Kirsty Danielson, Junjie Xiao, Bridget Simonson, Andreas Barth, Khalid Chakir, Gregory D Lewis, Zachary Lavender, Quynh A Truong, Andre Kleber, Ranendra Das, Anthony Rosenzweig, Yaoyu Wang, David Kass, Jagmeet P Singh, Saumya Das |
Journal | Circulation
(Circulation)
Vol. 131
Issue 25
Pg. 2202-2216
(Jun 23 2015)
ISSN: 1524-4539 [Electronic] United States |
PMID | 25995320
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2015 American Heart Association, Inc. |
Chemical References |
- Biomarkers
- MIRN30b microRNA, human
- MicroRNAs
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Topics |
- Aged
- Aged, 80 and over
- Animals
- Apoptosis
(physiology)
- Biomarkers
(blood)
- Cardiac Resynchronization Therapy
(trends)
- Dogs
- Female
- Heart Failure
(blood, diagnosis, therapy)
- Humans
- Male
- MicroRNAs
(blood)
- Middle Aged
- Myocytes, Cardiac
(physiology)
- Pilot Projects
- Rats
- Rats, Sprague-Dawley
- Translational Research, Biomedical
(trends)
- Treatment Outcome
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