Research Areas

Over the past two decades, the Goldhaber Laboratory has shown that the fundamental mechanism of heart muscle contraction, known as excitation-contraction coupling, fails as a result of the metabolic and oxidative stress typically seen in heart failure with reduced ejection fraction (HFrEF). Localized calcium release sites responsible for activating contraction, known as couplons, fail to activate normally during metabolic inhibition in a predictable fashion. This is caused by a reduction in the ability of single calcium channels in the cell membrane to open properly because of energy deprivation and abnormal calcium signaling. 

Half of all heart failure is caused by HFpEF. The underlying heart muscle abnormality is also associated with abnormal calcium cycling, but is quite different from what we have found in HFrEF. This likely explains why HFrEF therapies do not work in HFpEF. Understanding the basic mechanisms of HFpEF more thoroughly will allow us to develop specific treatments that actually improve symptoms and survival.

The Goldhaber Laboratory has a particular interest in a cellular transporter known as the sodium-calcium exchange (NCX). The lab uses a suite of mice genetically modified to either overexpress, mutate or ablate NCX to make paradigm-shifting observations. For example, the lab has shown definitively that NCX ablation allows heart cells to resist ischemia and reperfusion injury, and to maintain normal excitation-contraction coupling. NCX is also a critical component of the heart’s pacemaker and conduction system. Mice without NCX have a characteristically abnormal heart rhythm and cellular studies reveal failure of normal pacemaker activity linked to defective cellular calcium handling.