On Tuesday, Nov. 25, 2025 Austin Wellette-Hunsucker successfully defended his dissertation and earned his doctoral degree in physiology. Congratulations, Dr. Wellette-Hunsucker!
BIOCHEMICAL PROPERTIES OF CARDIAC SARCOMERES IN HUMAN HEART FAILURE
Heart failure is highly heterogeneous, making it challenging to investigate in human cohorts. Diastolic dysfunction is a common pathophysiological feature yet poorly understood at the molecular level. Sarcomeric proteins play a critical role in cardiac contraction and relaxation. However, the phosphoproteome and structural remodeling impacts diastolic function in heart failure are not fully characterized.
This study examined modifications in sarcomeric proteins and their contribution to diastolic dysfunction in human heart failure. The research concentrated on dilated cardiomyopathy (DCM) and ischemic heart failure (IHF), utilizing non-failing donor hearts as controls. Myocardial samples, which were flash-frozen, from 146 patients were analyzed (Donors: n=33; DCM: n=67; IHF: n=46) employing various electrophoretic and biochemical techniques methods.
Both DCM and IHF patients exhibited significant remodeling of titin, with an ~15% increase in the N2BA isoform. Although N2BA is characterized by greater compliance, its elevated abundance was associated with impaired diastolic function, implying that isoform shifts alone do not mitigate the effects of myocardial stiffness. Key regulatory proteins—including myosin regulatory light chain (RLC), troponin I (TnI), and myosin-binding protein C (MyBP-C)—demonstrated consistent hypophosphorylation. Proteomic analysis indicated extensive extracellular matrix remodeling and alterations in kinase and phosphatase regulators.
The molecular changes observed were strongly associated with clinical measures of diastolic dysfunction, including e’ velocities, E/A ratios, and E/e’ ratios from clinical echocardiograms. This dissertation highlights coordinated sarcomeric remodeling, combining potentially compensatory titin isoform shifts with maladaptive sarcomeric hypophosphorylation. These modifications may underlie diastolic dysfunction and represent therapeutic avenues that may improve cardiac function in heart failure patients.
KEYWORDS: sarcomere biochemistry, ischemic heart failure, dilated cardiomyopathy, post-translational modifications, titin isoforms, diastolic dysfunction.