Takashi Tsuda, MD, and Shaukat Khan, PhD, Investigators
Tom Force, MD, and Ulhas Naik, PhD, Mentors
Extracellular Matrix Remodeling and Human Heart Failure
Congestive heart failure (CHF) is a chronic, progressive disease with significant morbidity and mortality. The central element of the disease process is characterized as progressive geometric changes of ventricular myocardium in conjunction with functional deterioration, which is induced by dysregulation of normal compensatory mechanism against overwhelming injury and/or biomechanical stress.
Insight is lacking regarding the cellular and molecular regulatory mechanisms that protect the heart from rapid disease progression. It is crucial to understand the underlying mechanism of dysregulation that induces affected heart from physiological compensatory adaptation to progressive pathological maladaptation.
We have recently demonstrated that fibulin-2, an extracellular matrix (ECM) protein, modulates transformation growth factor (TGF)-b signaling that promotes ventricular remodeling after myocardial infarction (MI). ECM serves as an essential tissue reservoir in regulating biological activation of multiple growth factors, proteinases, and enzymes in addition to providing structural integrity as a connective tissue scaffold.
We hypothesize that fibulin-2 enhances TGF-b activation by releasing active TGF-b from inactive latent complex that is stored in ECM. The current project is to test whether this hypothesis is also true in advanced human heart failure. We will examine the degree of fibulin-2 expression, TGF-b activation level, and ECM remodeling (ECM synthesis and degradation) in the myocardial tissues from the patients with end-stage heart failure.
Also we will test prospectively whether the degree of ECM remodeling determines the prognosis after volume unloading interventions in advanced heart failure; (a) mitral valve replacement for mitral insufficiency and (b) left ventricular assist device (LVAD). Clinical data, serum markers, and patients’ activity levels will be assessed before and after interventions to correlate molecular, biochemical, and histological findings of myocardium.
The aims of this proposal are to determine whether up-regulation of fibulin-2 is associated with enhanced TGF-b activation and advanced ECM remodeling in the myocardium of end-stage human heart failure, and whether the degree of ECM remodeling rules the prognosis after ventricular unloading surgical interventions. This translational approach will generate clinical data whether inhibition of fibulin-2 will attenuate the progression of human heart failure after ventricular unloading.
Collaboration:
Mitchell T. Saltzberg, M.D., FACC (Christiana Care)
Michael K. Banbury, M.D., FACS, (Christiana Care)
Kenneth B. Margulies, M.D. (U Penn)
Staff and Student Participants:
Jennifer Joyce - Sr. Research Assistant (Nemours)