A/Professor David Muller, MD FRACP FACCLaboratory Head, Cardiac Physiology and Transplantation Division
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All endovascular interventions and many vascular surgical reconstruction procedures are limited to some extent by the formation of a neointima at the site of arterial injury. Although variable in its extent, the severity of the intimal hyperplasia may cause recurrent vascular obstruction within months of the interventional procedure.
One focus of the research program has been to develop local pharmacological and molecular therapies designed to limit the extent of neointimal hyperplasia. These include the use of novel local drug delivery catheters, synthetic polymers and therapeutic genes at the site of injury. Similar approaches have been evaluated as approaches to promoting patency of aorto-coronary vein grafts, promoting angiogenesis for end-stage ischaemic cardiomyopathy and for the management of pulmonary vascular disease.
Efforts to better understand the response to arterial injury and the pathological basis for neointimal hyperplasia include the use of intravascular ultrasound imaging. Previous studies have used two-dimensional intravascular ultrasound to characterize the mechanisms of balloon angioplasty according to prescribed lesion characteristics. Longitudinal reconstruction of serial ultrasound images now allows better spatial resolution of the distribution of neointima after coronary interventions.
In particular, this technology allows the volume of neointima that forms after balloon angioplasty or stenting to be quantified using a computerized edge detection algorithm. The precision of this technique allows drug therapies, mechanical therapies and molecular therapies that may potentially inhibit the restenosis process to be compared in relatively small numbers of patients. An ongoing trial is also using this approach to compare drug therapies for the prevention of neointimal hyperplasia after cardiac transplantation.
Another major focus of clinical investigation is the is the optimization of myocardial perfusion after mechanical and pharmacological interventions for acute myocardial infarction and unstable coronary syndromes. Current efforts include the use of platelet glycoprotein Iib/IIIa receptor inhibitors as adjuncts to direct angioplasty and stenting, and the use of catheter-mediated thrombus ablation using high energy ultrasound.
Co-Investigators:
David Baron, MBBS
Paul Roy, MBBS
Collaborators:
Mauro Moscucci, MD; University of Michigan, Michigan, USA
Eric Topol, MD; Cleveland Clinic Foundation, Cleveland, USA
Muller DWM, Topo EJ, Abrams G, Gallagher K, Ellis SG. Intramural methotrexate therapy for the prevention on neointimal thickening after balloon angioplasty. Journal of the American College of Cardiologists 1992; 20:460-466
Chen SJ, Wilson JM, Muller DWM. Adenovirus mediated gene transfer of soluble vascular cell adhesion moleculae to porcine interposition vein grafts. Circulation 1994; 89:1922-1928
Muller DWM, Gordon D, San H, Yang ZY, Pompili VJ, Nabel GJ, Nabel EG. Precutaneous pulmonary vascular gene transfer and in vivo gene expression. Circulation Research 1994; 75:1039-1049
Grossman M, Rader D, Muller DWM, Kolansky D, Kolansky K, Clark BJ, Stein EA, Lupien PJ, Brewer HB, Raper S, Wilson JM. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolemia. Nature Medicine 1995; 1:1148-1154
Muller DWM, Gordon D, Topol EJ, Levey RJ, Golomb G. Sustained release local hirulog therapy decreases early thrombosis but not neointimal thickening after arterial stenting. American Heart Journal 1996; 131:211-218
Muller DWM. Role of oncogenes in restenosis. Progress in Cardiovascular Diseases 1997; 40:117-12
Keogh A, Richardson M, Ruygrok P, Spratt P, Galbraith A, O'Driscoll G, Macdonald P, Esmore D, Muller D, Faddy S. Sirolimus in De Novo Heart Transplant Recipients Reduces Acute Rejection and Prevents Coronary Artery Disease at 2 Years. A Randomized Clinical Trial. Circulation 2004; 110:2694-700
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