Biointerventional Cardiovascular Therapy

European Heart Journal (2002) 23, 1753–1756 doi:10.1053/euhj.2002.3321, available online at http://www.idealibrary.com on

Review Article

Biointerventional cardiovascular therapy

I. D. Cox, C. A. Thompson and S. N. Oesterle

Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, U.S.A.

Introduction However, viral vectors (such as adeno- and retroviruses) are generally considered to provide superior gene trans- Recent advances in gene and cell based therapies have fer efficiency in terms of both magnitude and duration of created exciting possibilities for therapeutic modification gene expression[4]. Non-selective delivery of adenoviral of local vascular and myocardial biology. The parallel vectors, either by intracoronary injection[5] or pressure- evolution of increasingly sophisticated catheter-based regulated retroinfusion via the coronary veins[6], can systems is currently expanding the frontiers of percu- result in diffuse distribution throughout the myocar- taneous intervention in cardiovascular disease[1,2] and dium. More selective gene transfer can be achieved by offers the possibility of delivering gene and cell based direct injection of genetic material into myocardium[7]. therapies by minimally invasive means. This conver- The latter approach achieves higher local tissue con- gence of biotechnology and advanced catheter based centration of therapeutic substrate and thereby seems systems can sensibly be referred to as bio-interventional likely to prove more efficient and less liable to produce cardiovascular therapy and rapid progress is currently undesirable effects in other vascular beds. In most cases, being made in a number of areas within this field. selective local injection of genetic substrate has been achieved through open surgical access to the myocardium. However, recent advances in catheter based tech- Gene therapy nology now offer the possibility to achieve the same objective by minimally invasive, percutaneous means. A It is obvious from first principles that polygenic dis- specialized steerable needle-tipped delivery catheter eases, such as coronary artery disease, are less readily guided by an electromechanical left ventricular mapping amenable to gene therapeutic approaches than other system has already been successfully applied in por- conditions where a single culprit gene has been iden- cine models[8]. Other investigators using a pre-formed, tified. However, a variety of gene therapeutic studies coaxial catheter delivery system have also successfully directed at upregulation of angiogenic growth factors transferred and expressed vascular endothelial growth in the setting of ischaemic heart disease have yielded factor (VEGF) in porcine myocardium[9]. Recently, the encouraging results. The majority of these preliminary same catheter system was evaluated in a single-blind, trials of therapeutic angiogenesis have, necessarily, been crossover, phase I clinical trial[10]. Myocardial transfer small, uncontrolled Phase 1 studies and the limitations of naked plasmid DNA encoding for VEGF-2 was of such findings have been highlighted in a consensus performed in six patients whilst the same number of statement from a panel of experts[3]. The results of three controls underwent a sham procedure. Patients initially larger, randomized controlled angiogenic trials pub- randomised to the control arm crossed over to active lished to date have also proved disappointing (Table therapy at 90 days. The investigators reported reduced 1). Nevertheless, substantial optimism for the future angina and nitroglycerin usage in the treatment arm of potential of cardiovascular gene therapy persists[4]. the study and concluded that such gene delivery is safe The efficiency of genetic transfer by injection of naked and feasible in humans. DNA is generally low but may be augmented by the use A variety of other gene therapeutic strategies for of gene vectors. Plasmid and liposome complexes are cardiovascular disease may also be amenable to catheter safe and reliable non-viral vectors which have been based delivery. Transfection of cDNA encoding for used in a significant proportion of cardiovascular trials. endothelial nitric oxide synthase has been shown to reduce neotintimal hyperplasia in injured carotid Revision submitted 28 May 2002, and accepted 29 May 2002. arteries[11] and a similar approach is now being investigated in a phase I clinical investigation (the Correspondence: Dr I. D. Cox, Cardiology Division, Bulfinch 105, Massachusetts General Hospital, 55 Fruit Street, Boston, MA REGENT I trial) evaluating local, intracoronary admin- 02114, U.S.A. istration of an inducible nitric oxide synthetase (iNOS)

Table 1 Results of trials

Trials Study design; subjects; active treatment Results

VIVA Trial of rhVEGF for Human Multicentre, double-blind, placebo-controlled Active therapy was safe and well-tolerated. Therapeutic Angiogenesis trial. There was no significant difference in angina Henry et al. J Am Coll Cardiol 1999; 178 patients with stable angina, viable class or treadmill time between the groups 33 (Suppl A): 384A. underperfused myocardium by SPECT and at day 60. However, there was a slight trend not eligible for PCI/CBG. favouring active therapy based on mean Intracoronary VEGF infusion followed by angina class at day 120. No significant three 4-h intravenous infusions at 3, 6, and 9 difference were observed in the angiographic days. A high (17 ng . kg1 min1) and low or nuclear imaging parameters. dose (50 ng . kg1 min1) schedule were tested. The FGF Initiating Revascularization Phase II randomized, double-blind, Active therapy was not associated with any Support Trial (FIRST) placebo-controlled study. significant improvement in exercise treadmill Highlights from the American 337 CAD patients ineligible for conventional time at 90 days. However, quality of life College of Cardiology 49th Annual revascularization. assessment by the Seattle Angina Scientific Sessions: March 2000 A single intracoronary infusion of either 0·3, Questionnaire indicated a strong trend McGuire et al. Am Heart J 2000; 3·0, or 30 g.kg1 of recombinant FGF-2. towards subjective improvement in anginal 140: 181–8. status with active therapy. Older patients and those with the greatest symptom impairment at baseline appeared to derive the greatest benefit. No overall improvement in nuclear perfusion parameters was demonstrated. Angiogenic Gene Therapy (AGENT) Double-blind, randomized, placebo controlled Active therapy seemed to be safe and well trial in patients with stable angina trial (1:3 ratio of placebo to active therapy). tolerated. Safety evaluations were performed pectoris. 79 patients chronic stable angina (CCS class 2 at each visit and exercise treadmill testing Grines CL et al. Circulation 2002; or 3). (ETT) at baseline and at 4 and 12 weeks. 105: 1291–7. Single intracoronary administration of five There was no significant improvement in ascending doses of a replication defective exercise time with active therapy compared adenovirus (Ad) containing a human FGF to placebo. However, a protocol-specified, gene (Ad5-FGF4). subgroup analysis showed a significant improvement in patients with baseline ETT c10 min.

VEGF=recombinant human vascular endothelial growth factor; SPECT=single photon emission computed tomography; PCI=percutaneous coronary intervention; CBG=coronary bypass grafting; CAD=coronary artery disease; CCS=Canadian Cardiovascular Society.

lipocomplex for patients with de novo or restenotic myocardial genetic modification could be used to induce lesions. The iNOS-lipocomplex will be delivered to the overexpression of 2 adrenergic receptors and enhance arterial media using a specifically designed triple lumen myocardial contractility. They performed subselective, catheter that provides local vascular delivery through intracoronary injection of adenovirus with 2 adrenergic side infusion ports with the objective of increasing local receptors in a rabbit model and observed a ten-fold nitric oxide production and thereby reducing hyper- increase in 2 adrenergic expression and improved con- proliferative response associated with vascular injury. tractility in treated animals compared with controls. Antisense oligonucleotide therapy has also been pro- Wieg et al.[15] also detected improved cardiac perform- posed as an alternative genetic strategy for prevention of ance after trans-coronary delivery of recombinant restenosis. This method is based on the inhibition gene adenovirus for the human vasopressin 2 receptor, effec- expression by site specific binding of DNA to comp- tively bypassing the desensitized beta-adrenergic recep- lementary RNA. Although the first human study with tor signalling cascade. Miyamoto et al.[16] examined the intracoronary delivery of c-myc antisense oligonucle- possibility of increasing the expression of sarco(endo) otide after stent implantation showed no significant plasmic reticulin calcium ATPase (SERCA) expression reduction in restenosis[12], further clinical studies are to positively modify the abnormal calcium handling underway to investigate safety and efficacy of similar seen in congestive heart failure. These investigators therapy augmented by phosphorothioate morpho- demonstrated that SERCA-2 (the gene respon- lino oligomers (PMO) which enhance the efficacy and sible for the generation of the SERCA 2a isoform specificity of antisense therapy[13]. expressed in cardiac muscle) expression can be restored Catheter based myocardial gene therapy may also to non-failing levels, and systolic performance improved provide new opportunities for treatment of congestive after coronary delivery of adenovirus encoding for heart failure (CHF). Shah et al.[14] hypothesized that SERCA-2 in a rat heart failure model.

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Cell based therapy most promising cell source for transplantation[24]. Such multipotential stem cells have the advantage of being Cell based therapies may provide other biointerven- easily harvested and expanded from autologous bone tional options for the treatment of cardiovascular marrow, thus avoiding issues such as immune rejection disease including CHF. Although pharmacological and ethical issues regarding the use of foetal or embry- therapies for CHF have improved substantially over onic tissues. They also have potential for trans differen- recent years, such treatments act primarily by mitigating tiation into both vascular and cardiac muscle cells, the effects of ventricular systolic dysfunction rather than a process which has been termed myoangiogenesis. reversing this process. At present, orthotopic cardiac However, only a relatively small proportion of harvested allograft transplantation is the only safe and effec- bone marrow cells possess such potential for phenotypic tive method to restore ventricular systolic function change, and therefore identification and amplification of in advanced cardiomyopathic disorders. However, this optimal cell population remains a significant chal- advances in the field of replacement biology have raised lenge in such studies[25]. Recently, Orlic et al.[26] demon- the possibility that cardiomyocyte cell transfer could strated that highly enriched stem progenitor cell from offer a new treatment modality in advanced CHF with adult bone marrow could repopulate newly infarcted the potential to restore contractile function and favour- myocardium and differentiate to form proliferating ably influence ventricular remodelling — this technique myocytes and vascular structures in a mouse model. has been termed cellular cardiomyoplasty. The adapta- Furthermore, haemodynamic assessment indicated tion of steerable catheter based systems recently devel- superior preservation of left ventricular function in oped and used in applications such as percutaneous treated animals compared to controls. Kocher et al.[27] transmyocardial laser revascularization[1,2] have raised have demonstrated similar findings after intra- the possibility that this technology could also be applied venous injection of human bone marrow stem cells after using minimally invasive, percutaneous techniques. experimental myocardial infarction in a mouse model. Koh et al.[17] were first to report the feasibility of In summary, rapid progress is being made towards surgically transplanting skeletal myoblasts into non- demonstrating the safety and feasibility of cellular car- injured ventricular myocardium. The transplanted diomyoplasty and Menasche et al.[28] have recently myoblasts had ultrastructural characteristics of differen- reported the first successful clinical case which was tiated myotubes and the grafts were present for at least completed an as adjunct to two vessel coronary bypass 3 months suggesting that the myocardium could serve as surgery using autologous skeletal myoblasts. Clearly, the a stable platform for cell transfer. The same investiga- ready availability of donor cells would provide an obvi- tors later provided electron microscopic evidence that ous advantage for cellular cardiomyoplasty over whole engrafted foetal cardiomyocytes and host cells formed organ transplantation but the application of this tech- nascent intercalated disks in a non-injured murine nique in severely ill CHF patients would be limited by model[18]; they concluded that grafted cells could poten- the morbidity and mortality associated with an open tially communicate and contribute to myocardial func- surgical delivery technique. However, the adaptation of tion. Leor et al.[19] further demonstrated that foetal advanced catheter based systems to achieve cellular cardiomyocytes could be implanted and survive in cardiomyoplasty by percutaneous, minimally invasive infarcted rat myocardium. Other investigators have sub- means could substantially broaden the potential clinical sequently demonstrated that transplantation of cultured application of this technique[29]. foetal cardiomyocytes into injured myocardial tissue in a rat model could actually improve myocardial Summary function[20]. [21] Li et al. studied the natural history of allogeneic The application of gene and cell based therapies offers foetal cardiomyocyte transplantation and concluded exciting therapeutic potential in cardiovascular disease. that it may be limited by rejection as evidenced by The parallel evolution of advanced catheter based sys- lymphocyte infiltration, decreased graft size, and tems will provide cardiologists with the opportunity to increase in scar tissue formation at 20 weeks. Therefore, deliver such therapies by minimally invasive, percu- a variety of alternate cell sources less liable to invoke taneous means and thereby substantially broaden the immune recognition are under investigation. Immature therapeutic scope of these techniques in the future. skeletal myoblasts are an attractive cell source because of immunocompatability and relative resistance to No conflict of interests. I.D.C. is supported by an International ischaemia. Taylor et al.[22] demonstrated that autologous Fellowship Grant from the British Heart Foundation. S.N.O. is myoblasts can regenerate viable striated muscle within an Associate Professor of Medicine at Massachussets General Hospital/Harvard Medical School and Senior Vice President for cryo-injured myocardium of rabbits and favourably Medicine and Technology for Medtronic. alter cardiac performance. Skeletal myoblasts have equivalent positive effects on post-infarction remodelling as foetal cardiomyocytes, but as an autologous References transplant, may avoid graft rejection[23]. However, multipotential bone marrow stem cells capable of differ- [1] Oesterle SN, Reifart N, Hauptmann E, Hayase M, Yeung AC. entiating into a cardiomyocyte phenotype may offer the Percutaneous in situ coronary venous arterialization: report

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