Integrated Nanostructured Systems

Translational cardiovascular research, nanoparticle imaging, positron emission tomography and stem cell therapeutics.

Our completed research has demonstrated that the heart subjected to what has traditionally been felt to be reversible ischemia develops programmed cell death of cardiac myocytes. This leads to a progressive loss of myocytes yet there is no fibrosis and regional cardiac mass is maintained normal by compensatory cellular hypertrophy. In the adapted state, hibernating myocardium develops which is characterized by a downregulation in energy utilization and contractile dysfunction. While dysfunctional at rest, this adaptive response prevents the immediate development of metabolic deterioration following stress of the heart. The molecular mechanisms involved include a downregulation in multiple mitochondrial proteins involved in oxidative metabolism and electron transport which prevents further cell death. We have also demonstrated that this substrate leads to abnormalities in sympathetic innervation to the heart which are characterized by reductions in norepinephrine uptake into sympathetic nerves and an attenuation of beta adrenergic receptor signaling. While these adaptive responses occur regionally and are not accompanied by heart failure, they are all similar to that occurring in the advanced failing heart. This raises the possibility that they arise as a common phenotype of myocyte cellular hypertrophy.

While protected from ischemia, the hibernating heart exhibits increased vulnerability to lethal ventricular arrhythmias such as ventricular fibrillation. We are currently trying to understand predictors of sudden death in this disease state so as to better understand how to identify the one out of three patients that present with sudden cardiac death as their first and only manifestation of heart disease. Towards this end, we are developing unique molecular imaging agents that can identify the remodeling associated with sudden death.

Recently, our group has also begun to identify mechanisms of cardiac repair. Our laboratory is actively investigating the role of endogenous adult stem cell regeneration in hibernating myocardium. We have identified that hematopoietic stem cells can be mobilized from bone marrow using drugs such as statins and result in measurable myocyte regeneration in hibernating myocardium. Similar regeneration has been demonstrated with intracoronary administration of mesenchymal stem cells as well as after overexpressing fibroblast growth factor using a replication deficient adenovirus injected into the coronary artery. We are now isolating resident cardiac stem cells for similar in vivo therapeutic use. Collectively, the results to date support the hypothesis that there is considerable cross talk between myocardial and bone marrow derived stem cells that can be recruited to effect cardiac regeneration when residual perfusion is present in chronic ischemic cardiomyopathy.

Page B, R Young, VS Iyer, G Suzuki, M Lis, L Korotchkina, MS Patel, KM Blumenthal, JA Fallavollita, and JM Canty Jr. Persistent regional downregulation in mitochondrial enzymes and upregulation of stress proteins in swine with chronic hibernating myocardium. Circ. Res., 2008. In Press. http://circres.ahajournals.org/cgi/reprint/CIRCRESAHA.107.155895?ijkey=7a9uWAFj793VzM4&keytype=ref

Lynch P, TC Lee, JA Fallavollita, JM Canty Jr, and G Suzuki. Intracoronary administration of AdvFGF-5 (Fibroblast Growth Factor-5) ameliorates left ventricular dysfunction and prevents myocyte loss in swine with developing collaterals and ischemic cardiomyopathy. Circulation 116 (Suppl I):I-71-I-79, 2007. http://circ.ahajournals.org/cgi/reprint/116/11_suppl/I-71

Vacanti V, E Kong, G Suzuki, K Sato, JM Canty Jr, and T-C Lee. Phenotypic changes of adult porcine mesenchymal stem cells induced by prolonged passaging in culture. J. Cell. Physiol., 205:194-201, 2005. http://www3.interscience.wiley.com/cgi-bin/fulltext/110489460/PDFSTART

Suzuki G, T-C Lee, JA Fallavollita and JM Canty Jr. Adenoviral gene transfer of FGF-5 to hibernating myocardium improves function and stimulates myocytes to hypertrophy and reenter the cell cycle. Circ. Res. 96: 767-775, 2005. http://circres.ahajournals.org/cgi/reprint/96/7/767

Thijssen VLJL, M Borgers, M-H Lenders, FC Ramaekers, G Suzuki, B Palka, JA Fallavollita, SA Thomas, JM Canty Jr. Temporal and spatial variations in structural protein expression during the progression from stunned to hibernating myocardium. Circulation 110:3313-3321, 2004. http://circ.ahajournals.org/cgi/reprint/110/21/3313