Clinical and Metabolic Signature of Recovered Myocardium in Human Heart Failure Summary: Remarkable improvements in myocardial structure and function have been reported in some advanced heart failure (HF) patients undergoing ?mechanical unloading? induced by left ventricular assist devices (LVAD). Unlike other HF therapies, which have also been associated with significant myocardial improvement, this tractable and specific LVAD population provides us access to pre-treatment myocardial tissue from both responders and non- responders which has enabled us to start probing the ?signature? of myocardium that has the potential to improve. Our central hypothesis is that refining this ?signature? will lead to a rational therapeutic approach in severe HF and will reveal broader recovery principles applicable to all stages and severity of HF. Achieving and defining ?response? in LVAD patients requires a battery of diagnostic and therapeutic protocols and, as shown in the real world of advanced HF multicenter registries, this is challenging. Thus, there is a critical need for a selection process that can reliably predict who will and who will not ?respond? to LVAD therapy. This program will also enable us to develop such a predictive model in addition to our studies of the mechanisms driving myocardial recovery. First we will provide a clinically relevant ?signature? of failing hearts with the potential for recovery. Following a derivation- validation approach we will develop a myocardial recovery score using myocardial structural and/ or functional parameters together with clinical characteristics. This score will create a precise algorithm for selection of patients likely to recover prior to LVAD intervention, enrich the criteria for device explantation and sustained recovery following LVAD intervention and likely increase the real world incidence and sustainability of LVAD enabled recovery. Second, we hypothesized that specific metabolic adaptations drive myocardial recovery. Our preliminary data after examining myocardial tissue from normal donors and LVAD patients suggests a post- LVAD mismatch in glycolytic versus mitochondrial intermediates that might indicate increased flux through the cardioprotective pentose phosphate pathway. We have developed methodology and will employ novel and powerful in vivo metabolic flux studies using stable isotopes, mitochondrial respiratory measurements and additional metabolic assays to test this hypothesis. This project offers a rare opportunity to closely integrate clinical function, structure and in vivo mechanistic studies in human HF and recovery. The physiological insights derived are providing clinical characteristics and biomarkers that will impact our practice in advanced HF patients. They are also revealing novel biological insights that inform both our clinical and basic science understanding of myocardial recovery applicable to all stages and severity of HF.

Public Health Relevance

We propose to study humans with chronic heart failure in an effort to understand and predict how the failing heart can recover. Within a patient population whose disease is so advanced as to require support from cardiac assist devices, we have identified a subpopulation that restores their endogenous heart function to a remarkable level. We are taking advantage of the unique opportunity to study the biology of these humans. With our myocardial tissue and serum experiments we will identify clinical and biological predictors and new therapeutic targets that could inform all stages and severity of human heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135121-02
Application #
9397570
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Sopko, George
Project Start
2016-12-09
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Catino, Anna B; Ferrin, Peter; Wever-Pinzon, James et al. (2018) Clinical and histopathological effects of heart failure drug therapy in advanced heart failure patients on chronic mechanical circulatory support. Eur J Heart Fail 20:164-174
Bonios, Michael J; Koliopoulou, Antigone; Wever-Pinzon, Omar et al. (2018) Cardiac Rotational Mechanics As a Predictor of Myocardial Recovery in Heart Failure Patients Undergoing Chronic Mechanical Circulatory Support: A Pilot Study. Circ Cardiovasc Imaging 11:e007117
Bajpai, Geetika; Schneider, Caralin; Wong, Nicole et al. (2018) The human heart contains distinct macrophage subsets with divergent origins and functions. Nat Med 24:1234-1245
Diakos, Nikolaos A; Passi, Samuel; Taleb, Iosif et al. (2018) Regional myocardial structural characteristics in ischemic and non-ischemic cardiomyopathy: Left ventricle versus right and apex versus base. J Heart Lung Transplant 37:166-169
Pepin, Mark E; Ha, Chae-Myeong; Crossman, David K et al. (2018) Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure. Lab Invest :
Seidel, Thomas; Navankasattusas, Sutip; Ahmad, Azmi et al. (2017) Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional Recovery by Mechanical Unloading. Circulation 135:1632-1645
Drakos, Stavros G; Pagani, Francis D; Lundberg, Martha S et al. (2017) Advancing the Science of Myocardial Recovery with Mechanical Circulatory Support: A Working Group of the National, Heart, Lung, and Blood Institute. ASAIO J 63:445-449
Drakos, Stavros G; Pagani, Francis D; Lundberg, Martha S et al. (2017) Advancing the Science of Myocardial Recovery With Mechanical Circulatory Support: A Working Group of the National, Heart, Lung, and Blood Institute. JACC Basic Transl Sci 2:335-340
Diakos, Nikolaos A; Navankasattusas, Sutip; Abel, E Dale et al. (2016) Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning. JACC Basic Transl Sci 1:432-444