del Monte Research
Basic Research: Molecular Mechanisms of Dilated Cardiomyopathy Leading to Heart Failure
Dr. del Monte’s basic research program focuses on the molecular mechanisms of dilated cardiomyopathy leading to heart failure. Heart failure is a progressive disease characterized by loss of myocardial function, which results in severe disability and death.
In a significant number of cases, a specific cause for the disease cannot be identified. These cases of unknown etiology are grouped under the descriptive definition of “idiopathic” dilated cardiomyopathy. Understanding the molecular basis for the pathogenesis of idiopathic dilated cardiomyopathy would have important implication in developing novel and effective therapies for this devastating disease.
Previous Experimental Findings
All of our previous experimental findings point to a defect in calcium cycling as key factor in cardiac dysfunction in the late stage heart failure in vivo and in vitro in isolated cardiac myocytes. An unresolved question is what causes this common alteration and the disease.
During heart failure, alterations in the spatial segregation of calcium signals and changes in calcium homeostasis have profound effects on myocyte function, but also on protein processing and may initiate and potentiate the defect in dilated cardiomyopathy and heart failure. Progressive misfolding of proteins into aggregates that can alter function, injure and kill the cells have been identified to be at the origin of many acquired or hereditary diseases such as systemic amyloidosis, cystic fibrosis, emphysema, diabetes, muscular dystrophy and neurodegenerative diseases such as Alzheimer disease.
Current Experimental Investigation
Dr. del Monte's current experimental investigation will test the functional relationship between contractile dysfunction, protein misfolding and calcium regulation in heart failure in vitro and in vivo in animal models of heart failure as well as in human samples and cardiac myocytes isolated from hearts from patients undergoing cardiac transplantation.
Translational Research: Cellular Abnormalities Associated with Left Ventricular Disfunction and Heart Failure
A large area of research and clinical investigation are cellular abnormalities associated with left ventricular disfunction and heart failure. Advances in somatic gene transfer, using viral vectors, has provided investigators with the needed tools to investigate signaling pathways contributing to the pathogenesis of heart failure.
CA++ Cycling Abnormalities
Heart failure is characterized by a number of abnormalities in Ca++ cycling. One of the key abnormalities in both experimental and human heart failure is a defect in the sarcoplasmic reticulum Ca++-ATPase pump (SERCA2a). SERCA2a has been shown to account for a reduced Ca++ uptake during diastole as well as reduced systolic Ca++ levels.
SERCA2a Overexpression
Using a genetic approach through adenoviral gene transfer it is possible to furnish single cardiac myocytes with abundant normal copies of the gene encoding for SERCA2a. Having successfully tested the key hypothesis that SERCA2a overexpression in heart failure would restore myocardial contractility in vitro (in animal and human cardiac myocytes) (Figure 1) and in vivo without adversely affecting cardiac metabolism and cardiac rhythm in a rodent model, we expanded our research to a large animal model.
In a large animal model in swine, overexpression of SERCA2a reduced the incidence of lethal arrhythmias in a model of ischemia-reperfusion (Figure 2). Translational research allows to validate targets in animal models close to humans develop and test new devices and therapeutic strategies that might be applicable to the human condition.
