The proposed study will examine the chronic hypertensive left ventricular hypertrophy subset of heart failure with preserved ejection fraction (HFpEF) to connect skeletal muscle ultrastructure and biochemistry to symptoms, quality of life, and functional capacity. Conditions including hypertension, sedentary lifestyle, muscular deconditioning, and obesity result in a variety of cellular changes, such as cardiac hypertrophy, neurohormonal dysregulation and derangements in protein homeostasis. These processes result in the development of HFpEF with the downstream sequelae of dyspnea and fatigue, decreased functional capacity, and structural muscle damage. Hypertension is one of the greatest contributors to cardiac-related mortality and is a primary cause of HFpEF as a result of left ventricular hypertrophy. This study hypothesizes that that heart failure (HF) symptoms and functional capacity are connected to skeletal muscle ultrastructure and biochemistry in persons with heart failure with preserved ejection fraction (HFpEF). This 2-year cross-sectional study will enroll 40 participants with HFpEF and use stored samples from healthy controls to examine skeletal muscle structure and function. Patient questionnaires will be used to assess fatigue, dyspnea severity and quality of life in persons with HFpEF. In addition, perceived barriers to and benefits of exercise will be assessed via questionnaire. Functional status will be assessed using the six-minute walk test and an exercise treadmill test. Muscle biopsies will be performed to study structural and functional aspects of skeletal muscle that determine functional capacity including the conventional assessment of quantification of fiber types, cross- sectional area, capillary density, and mitochondrial function, and to further explore a novel finding that examines a putative mechanism of myocyte ultrastructural damage, chymase-induced breakdown of desmin and mitochondrial dysfunction, as an important factor of functional capacity in persons with HFpEF. By focusing on a subset of patients with well-defined hypertension and left ventricular hypertrophy, data from this study can be used to create precision medicine in HFpEF prevention and treatment, targeted therapies, and better prediction of outcomes in this high mortality population.

Public Health Relevance

Heart failure is the leading cause of illness and death in the United States, and the discovery of new therapeutic targets that can slow its debilitating progression are urgently needed. This study will examine a subset of heart failure that connects symptoms and skeletal muscle structure and biochemistry with chronic hypertension and left ventricular hypertrophy. By uncovering the mechanisms of physical dysfunction in this phenotype of heart failure, we can create more precise and targeted therapies and better prediction of outcomes in this high mortality population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NR017322-01
Application #
9394639
Study Section
National Institute of Nursing Research Initial Review Group (NRRC)
Program Officer
Banks, David
Project Start
2017-07-17
Project End
2019-07-16
Budget Start
2017-07-17
Budget End
2018-07-16
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Butts, Brittany; Butler, Javed; Dunbar, Sandra B et al. (2018) Effects of Exercise on ASC Methylation and IL-1 Cytokines in Heart Failure. Med Sci Sports Exerc 50:1757-1766
Butts, Brittany; Higgins, Melinda; Dunbar, Sandra et al. (2018) The Third Time's a Charm: Psychometric Testing and Update of the Atlanta Heart Failure Knowledge Test. J Cardiovasc Nurs 33:13-21
Butts, Brittany; Goeddel, Lee A; George, David J et al. (2017) Increased Inflammation in Pericardial Fluid Persists 48 Hours After Cardiac Surgery. Circulation 136:2284-2286