Heart failure (HF) represents a major threat to cardiovascular health in the United States, with nearly 550,000 new cases and over $37 billion in costs annually. Existing metrics of HF severity (e.g., natriuretic peptides, echocardiography, functional class) do not reveal an understanding of cellular disruption in the form of fibrosis/hypertrophy that lead to deleterious whole-organ structural changes termed LV remodeling. In turn, adverse LV remodeling is associated with impaired cardiac performance, poorer cardiorespiratory fitness, and deceased survival in HF, making it an important therapeutic target in HF. Tissue phenotypes (diffuse interstitial fibrosis, myocyte hypertrophy, apoptosis) have been associated with prognosis, HF progression, and reverse LV remodeling in HF. Unfortunately, these myocardial tissue phenotypes are poorly understood in vivo in patients, owing to an inability to non-invasively phenotype the heart.
The aim of this application is to develop novel cardiac magnetic resonance (CMR) markers of myocardial remodeling in HF and to investigate their association with exercise hemodynamics and novel RNA physiologic biomarkers of fibrosis/hypertrophy. In his preliminary work, the PI has developed and validated CMR techniques to quantify cardiomyocyte size (by intracellular lifetime of water, ?ic) and interstitial fibrosis (by extracellular volume fraction, ECV) in patients and animal models of hear disease. He has also demonstrated that CMR fibrosis may be associated with novel RNA biomarkers that are mechanistically involved in fibrosis in LV remodeling. In this application, the PI will identify a tissue signature of LV remodeling in multiple human HF subtypes and its association with circulating extracellular RNAs (Aim 1). He will extend these observations to physiology, investigating the relationship between CMR tissue markers, fitness and exercise hemodynamic indices (Aim 2). Finally, he will investigate the association of CMR tissue signatures with progressive LV remodeling over time in chronic HF using serial CMR (Aim 3). To accomplish these goals, he has assembled a unique mentoring team consisting of senior CMR investigators (Michael Jerosch-Herold, PhD; Warren Manning, MD), basic scientists (Anthony Rosenzweig, MD; Saumya Das, MD, PhD), and a HF physiologist (Gregory Lewis, MD). As part of his training, the PI will enrich his expertise in human CMR imaging, RNA biology, and exercise testing as a platform for future research, and will establish important ongoing collaborations in the field of translational HF research. The PI will obtain further statistical training in clinical research via the Harvard School of Public Health (MPH degree), and will be integral to the HF research mission of his home institution, the Beth Israel Deaconess Medical Center. The long-term goal of the PI is to establish an independent research career in translational imaging-HF research, focusing on early stages of disease for targeted therapy. This project addresses an NHLBI mission by affording an innovative, novel method for assessing HF severity that might improve early identification of advanced HF, for which there remain limited options.

Public Health Relevance

Heart failure is a growing cause of mortality with heart disease in the United States despite optimal therapies. This project will use innovative MRI techniques to examine the tissue of the heart itself to establish a 'tissue signature' of the failing heart. Ultimately, knowing an individal patient's heart tissue signature in heart failure may allow personalization of therapies that might curb the tide of advanced heart failure, for which there remain limited options.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL127099-02
Application #
9267160
Study Section
Special Emphasis Panel (MCBS (JA))
Program Officer
Scott, Jane
Project Start
2016-05-01
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
$167,046
Indirect Cost
$11,596
Name
Massachusetts General Hospital
Department
Type
Independent Hospitals
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
McManus, David D; Rong, Jian; Huan, Tianxiao et al. (2017) Messenger RNA and MicroRNA transcriptomic signatures of cardiometabolic risk factors. BMC Genomics 18:139
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
Spahillari, Aferdita; Talegawkar, Sameera; Correa, Adolfo et al. (2017) Ideal Cardiovascular Health, Cardiovascular Remodeling, and Heart Failure in Blacks: The Jackson Heart Study. Circ Heart Fail 10:
Mick, Eric; Shah, Ravi; Tanriverdi, Kahraman et al. (2017) Stroke and Circulating Extracellular RNAs. Stroke 48:828-834
Shah, Ravi; Murthy, Venkatesh; Pacold, Michael et al. (2017) Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes. Diabetes Care 40:546-553
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
Chatterjee, Neal A; Shah, Ravi V; Murthy, Venkatesh L et al. (2017) Right Ventricular Structure and Function Are Associated With Incident Atrial Fibrillation: MESA-RV Study (Multi-Ethnic Study of Atherosclerosis-Right Ventricle). Circ Arrhythm Electrophysiol 10:
Abbasi, Siddique A; Shah, Ravi V; McNulty, Steven E et al. (2016) Left Atrial Structure and Function in Heart Failure with Preserved Ejection Fraction: A RELAX Substudy. PLoS One 11:e0164914
Murthy, Venkatesh L; Abbasi, Siddique A; Siddique, Juned et al. (2016) Transitions in Metabolic Risk and Long-Term Cardiovascular Health: Coronary Artery Risk Development in Young Adults (CARDIA) Study. J Am Heart Assoc 5:
Shah, Ravi; Pico, Alexander R; Freedman, Jane E (2016) Translational Epidemiology: Entering a Brave New World of Team Science. Circ Res 119:1060-1062

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