Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and associated with impaired functional tolerance, quality of life, morbidity and mortality. Although medical advances have led to effective treatments for heart failure with reduced ejection fraction, there are very limited treatment options for treating HFpEF which is now recognized as a heterogeneous syndrome. Therefore, there is a critical need to better understand and identify the underlying pathophysiologic mechanisms associated with HFpEF to identify novel therapeutic targets and for personalizing therapy. Despite having normal ejection fraction, it is increasingly being recognized that the heart is not “normal” in patients with HFpEF. While contemporary clinical assessment provides some information beyond ejection fraction in assessment of cardiac function in patients with HFpEF, there is an unmet need to identify novel biomarkers that associate with known pathophysiologic mechanisms and impaired cardiac function.

Pathophysiological alterations in the heart in HFpEF include cardiac remodeling (hypertrophy and fibrosis) and associated changes in cardiac function (LV diastolic dysfunction, longitudinal LV systolic dysfunction, RV systolic and diastolic dysfunction). Cardiac remodeling includes alterations in myofiber orientation in the ventricles, which in turn impacts both systolic and diastolic function. In parallel, HFpEF is associated with impaired myocardial metabolism and energetics (microvascular dysfunction, ischemia, steatosis, and mitochondrial dysfunction) that have a detrimental impact on cardiac function as well. However, few studies have performed comprehensive non-invasive assessment for these key mechanisms in patients with HFpEF and little is known about how these mechanisms relate to functional capacity and quality of life in HFpEF. Amongst the contemporary imaging techniques, Cardiac Magnetic Resonance Imaging (CMR) stands out as a modality that can perform structural, functional, and metabolic assessment of the myocardium. CMR has emerged as the new gold standard for the assessment of the LV and RV function due to its ability to acquire images in multiple planes and direct measurement of volumes. Additionally, advanced techniques such as magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) can be used to provide information pertaining to myocardial energetics/metabolism and myocardial fiber orientation, respectively. However, no studies have been performed that comprehensively use these advanced sequences in assessment of patients with HFpEF.

In addition to imaging biomarkers, there are emerging circulating biomarkers and assays of HF that relate to underlying pathophysiological mechanisms such as cardiac remodeling (BNP, endothelin-1, Pentraxin-3, and collagen turnover markers) and mitochondrial dysfunction (long-chain acylcarnitines, platelet and PBMC mitochondrial function). However, it is not known whether these biomarkers correlate with the imaging biomarkers of remodeling (DTI) and energetics (MRS) in patients with HFpEF.

Our overall objective in this proposal is to identify imaging and circulating biomarkers with pathophysiological underpinning that are associated with exercise tolerance and quality of life in patients with HFpEF. We hypothesize that novel imaging biomarkers of cardiac remodeling and energetics will relate to functional capacity, quality of life, and circulating biomarkers in patients with HFpEF.

Specific Aim 1: We will examine the association of imaging biomarkers of myocardial fiber orientation with exercise tolerance and quality of life and circulating biomarkers in patients with HFpEF.

Specific Aim 2: We will investigate the relationship of imaging biomarkers of myocardial energetics with exercise tolerance and quality of life and circulating biomarkers in patients with HFpEF.

The expected outcome of this study is that myocardial fiber orientation and myocardial energetics will be associated with circulating biomarkers and exercise tolerance and quality of life in patients with HFpEF. Correlating these key biomarkers with specific underlying mechanisms of ventricular dysfunction will allow for identification of the dominant pathophysiologic mechanism and personalization of therapy for each patient and pave way for future studies to assess the temporal relationship of these mechanisms in HFpEF and changes in these biomarkers in response to therapy.