Heart failure (HF) is one of the largest contributors to disease burden in the United States with an annual incidence of 550,000 cases and mortality of 42% within 5 years after diagnosis. An improved understanding of left ventricular (LV) remodeling that comprises the substrate for progression of HF is critical for the delineation of novel pathways and therapeutic targets, and for the identification of biomarkers to predict and track LV remodeling to allow for the initiation of early and effective therapy in patients at risk or worsening HF. This is an area of unmet clinical need because our current understanding of remodeling is incomplete, and risk- stratification strategies lack adequate specificity and sensitivity. MicroRNAs (miRNA) and other non-coding RNAs have been implicated in human heart disease, and their recent discovery in plasma has led to the hypothesis that extracellular RNAs may mediate disease-specific signaling, and spurred their development as biomarkers and disease reporters. Based on the initial findings of our and other laboratories that extracellular RNAs can both predict and play an important role in LV remodeling in HF patients, the objective of this proposal is firstly, to delineate the role of newly discovered as well as previously reported extracellular RNAs (ex-RNAs) in mediating LV remodeling. Secondly, we aim to characterize these ex-RNAs as prognostic biomarkers in HF patients that can be easily imported into the clinic to identify at-risk patients. The group of investigators in this proposal, spanning multiple disciplines within cardiovascular and ex-RNA research will test the central hypothesis that (1) ex-RNAs can predict LV remodeling (a surrogate endpoint) as well as clinical outcomes in patients with HF; (2) ex-RNAs can function not only as disease reporters, but also as mediators of LV remodeling in animal models; and (3) these ex-RNAs can be therapeutic targets in validated animal models of heart disease. The findings resulting from this proposal would identify novel pathways and therapeutic targets in HF, and lay the platform for more effective and targeted HF treatment based on prognostic biomarkers and disease reporters.

Public Health Relevance

Heart failure and its complications are a leading cause of mortality and morbidity in the United States. A better understanding of how the heart structure changes after stress may lead to discovery of new therapies to prevent adverse changes and worsening heart failure, and the development of novel blood markers that can identify at-risk patients who should be targeted early for close monitoring and treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL122547-03
Application #
9318800
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Schwartz, Lisa
Project Start
2015-03-16
Project End
2020-01-31
Budget Start
2016-11-01
Budget End
2017-01-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Shah, Ravi; Ziegler, Olivia; Yeri, Ashish et al. (2018) MicroRNAs Associated With Reverse Left Ventricular Remodeling in Humans Identify Pathways of Heart Failure Progression. Circ Heart Fail 11:e004278
Bei, Yihua; Yang, Tingting; Wang, Lijun et al. (2018) Circular RNAs as Potential Theranostics in the Cardiovascular System. Mol Ther Nucleic Acids 13:407-418
Danielson, Kirsty M; Shah, Ravi; Yeri, Ashish et al. (2018) Plasma Circulating Extracellular RNAs in Left Ventricular Remodeling Post-Myocardial Infarction. EBioMedicine 32:172-181
Shah, Ravi; Yeri, Ashish; Das, Avash et al. (2017) Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report. Am J Physiol Heart Circ Physiol 313:H1162-H1167
Simonson, Bridget; Subramanya, Vinita; Chan, Mun Chun et al. (2017) DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress. Sci Signal 10:
Bei, Yihua; Xu, Tianzhao; Lv, Dongchao et al. (2017) Exercise-induced circulating extracellular vesicles protect against cardiac ischemia-reperfusion injury. Basic Res Cardiol 112:38
Mateescu, Bogdan; Kowal, Emma J K; van Balkom, Bas W M et al. (2017) Obstacles and opportunities in the functional analysis of extracellular vesicle RNA - an ISEV position paper. J Extracell Vesicles 6:1286095
Li, Jin; Chan, Mun Chun; Yu, Yan et al. (2017) miR-29b contributes to multiple types of muscle atrophy. Nat Commun 8:15201
Xiao, Junjie; Gao, Rongrong; Bei, Yihua et al. (2017) Circulating miR-30d Predicts Survival in Patients with Acute Heart Failure. Cell Physiol Biochem 41:865-874
Rowe, Glenn C; Asimaki, Angeliki; Graham, Evan L et al. (2017) Development of dilated cardiomyopathy and impaired calcium homeostasis with cardiac-specific deletion of ESRR?. Am J Physiol Heart Circ Physiol 312:H662-H671

Showing the most recent 10 out of 20 publications