Research Highlights

Active Research

Ongoing research address basic mechanisms leading to contractile dysfunction in cardiac hypertrophy, diabetic cardiomyopathy, heart failure, and ischemic heart disease (heart attack). A general focus of investigation is on adaptive and maladaptive changes in cardiac function and metabolism to chronic hypertension, obesity, metabolic syndrome and diabetes. Experimental designs examine the role of metabolic flux regulation, via differential expression of metabolic enzymes and isoforms, in the development of cardiomyopathy. Current protocols focuses on the link between dysregulation of lipid dynamic in heart muscle cells and contractile dysfunction.

Program laboratories are dedicated to developing new methods for detection of metabolic activity in a comprehensive array of experimental models of heart disease and relating metabolic changes to functional changes in heart that are monitored via high field cardiac MRI. Applications of NMR methods and stable isotope kineics for nondestructive measurements of cardiac biochemistry and heart function hold particular programmatic emphasis as do functional measurements of the in vivo heart at high resolution using high field MR microscopy.

Research Highlights

Development and application of stable, NMR detectable isotope kinetics for monitoring metabolic flux regulation via enzyme expression and enzyme activity in the intact, beating heart.

Shifts in metabolic enzyme expression and activity are linked to the pathogenesis of cardiac dysfunction and induce commensurate shifts in metabolic activity that may be maladaptive in the development of heart disease. The resulting changes in metabolic flux can be monitored in the intact heart via carbon-13 (13C) NMR spectroscopy. For example, the hypertrophied heart displays overexpression of the liver isoform of the fatty acid oxidation enzyme, carnitine palmitoyltransferase I (CPT1), and malic enzyme (ME), that have been found through these experimental approaches.

Above. Top panel shows Western blot of the level of expression of the oxoglutarate-malate carrier (OMC) protein in the mitochondrial memberane of adult (low) and neonatal (high) rabbit hearts. Bottom panel presents sequential set of 13C NMR spectra from neonatal rabbit heart that is oxidizing a 13C enriched short-chain fatty acid and displaying accelerated rates of glutamate enrichment in the cytosol due to increased OMC content in the heart. (GLU C-2, 2-carbon position of glutamate; GLU C-4, 4-carbon position of glutamate; GLU C-3, 3-carbon of glutamate).

In vivo, gene therapy studies are ongoing to reverse metabolic defects in both ischemic heart disease and decompensatory cardiac hypertrophy and heart failure.

Above. Gel staining for LacZ expression through several cross sections of a rat heart 72 hours after in vivo delivery of AdV.cmv.LacZ adenovirus using new methods for gene delivery developed in the PICM laboratories. Such methods enable the manipulation of metabolic gene expression in the diseased heart to normalize, and potentially repair, metabolic defects that contribute to impaired heart function.

Ultra-high field, high resolution cardiac (14.1 T) in dilated and hypertrophic cardiac disease.

Transmural, high resolution, tagged cardiac MRI in combination are combined with proton MRS to provide analysis of myocardial lipid content and changes in 2-dimensional strains across the thickness of the heart chamber wall.