Elucidating Mechanisms of Cardiac Dysfunction Using Imaging and Proteomics

PROJECT SUMMARY

Heart failure affects 6 million Americans, 1.8% of the US population. Despite substantial progress, heart failure

mortality remains ~50% at 5 years. Mechanisms of cardiac dysfunction in heart failure remain poorly understood.

In this project, we will characterize two cardiac diseases involving mechanisms of infiltration and toxicity: light-

chain amyloid cardiomyopathy (AL-CM), and cancer-therapy-related cardiac dysfunction (CTRCD). AL-CM

results from plasma cell clones producing abnormal immunoglobulin light chains, which aggregate as amyloid

fibrils in the heart. Median untreated survival is 50% in symptomatic patients. There is an unmet need for a

better understanding of mechanisms of cardiac dysfunction, including the reasons that abnormal light chains or

toxic chemotherapy cause cardiac dysfunction in some individuals and not in others.

Our scientific premises are that (1) cardiac dysfunction is accurately detected and quantified by imaging, and (2)

cardiac dysfunction alters circulating levels of proteins involved in pathogenic mechanisms. Therefore, our

overall approach is to join cardiac imaging and plasma proteomics to identify circulating proteins from relevant

mechanistic pathways and to characterize their relationships with imaging metrics of cardiac dysfunction. To

achieve the aims of this research project, my advisory team and training plan will cover cardiac imaging,

proteomics, AL-CM, CTRCD, and data science.

Our first aim is to identify circulating proteins involved in mechanisms of AL-CM by comparison to non-amyloid

participants and by correlation with imaging metrics of cardiac dysfunction. In the K99 phase, we will analyze a

panel of plasma proteins and compare their levels in participants with AL-CM vs. multiple myeloma (abnormal

immunoglobulins without amyloidosis). Then, we will measure correlations between protein levels and cardiac

amyloid burden by 18F-florbetapir PET, extracellular expansion by extracellular volume (ECV) on MRI, and

contractile dysfunction by global longitudinal strain on echocardiography.

Our second aim is to identify novel markers of CTRCD by group comparisons of plasma proteins levels and by

correlations of protein levels with changes in imaging metrics of cardiac dysfunction. In the R00 phase, I will

analyze a panel of plasma proteins and compare their levels in participants undergoing anthracycline

chemotherapy with CTRCD, without CTRCD, and in matched participants with heart failure. Then, I will measure

correlations between changes in protein levels and changes in ejection fraction or in ECV by MRI over 12 months.

Lastly, I will compare baseline protein levels in patients with vs. without subsequent CTRCD.

The successful completion of this project will support my goal of becoming an independent clinician-researcher

on heart failure, deepen our mechanistic understanding of AL-CM and CTR-CM, improve risk stratification and

prevention strategies, and identify novel drug targets to improve the outcomes of patients with heart failure.