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Kristen Kokkonen

Class 2013
Education BA, University of Colorado Boulder
Email kokkon1@jhmi.edu
Mentor

Dr. David Kass

Research Interests

Heart failure affects almost 6 million people in the United States, and costs $108 billion per year. Up to 50% of these patients will die within five years of diagnosis. The overall economic burden in health care and societal costs is enormous; thus developing new and more effective treatments is crucial. Recently the drug LCZ696, a neprilysin inhibitor, was tested in the PARADIGM clinical trial, and became the first new drug in decades to decrease mortality due to heart failure. LCZ696 prevents natriuretic peptide (NP) degradation, hence increasing the benefits of this signaling pathway. NPs stimulate cGMP production through NP receptors and receptor-coupled guanylate cyclases (rGCs). This cGMP then activates protein kinase G (PKG), which is known to be cardioprotective. Recently, our lab has shown phosphodiesterase 9a (PDE9a) selectively regulates cGMP derived from the NP/rGC pathway in the heart. Mice with genetic deletion of PDE9a, as well as pharmacological inhibition of PDE9a, showed improved cardiac function during pressure overload-induced heart failure, indicating that loss of PDE9a is beneficial. Combined with the outcome of the PARADIGM trial, it is apparent that modulation of the NP pathway is therapeutically beneficial. Hence, further mechanistic exploration of PDE9a as a regulator of the NP pathway is critical.

PDE9a has so far only been investigated in male rodent models of heart failure with reduced ejection fraction (HFrEF), leaving its role in heart disease beyond HFrEF unknown. Data from our lab has shown that PDE9a expression is upregulated in patients with heart failure with preserved ejection fraction (HFpEF), indicating a potential pathophysiological role for PDE9a in forms of HF beyond HFrEF. It is also unknown whether or not treatment with PDE9a inhibitor in HF is sex-dependent, as previous studies were limited to male subjects only. To these ends, my thesis projects aims to investigate the role of PDE9a in diverse forms of heart failure, including ischemic heart failure, heart disease associated with metabolic syndrome, and heart failure in women.