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The number one cause of mortality in the US is cardiovascular related disease. Future predictions do not see a reduction in this rate especially with the continued rise in obesity [P. Poirier, et al., Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss, Arterioscler Thromb Vasc Biol. 26(5), (2006) 968–976.; K. Obunai, S. Jani, G.D. Dangas, Cardiovascular morbidity and mortality of the metabolic syndrome, Med.Clin. North Am., 91(6), (2007) 1169–1184]. Even so, potential molecular therapeutic targets for cardiac gene delivery are in no short supply thanks to continuing advances in molecular cardiology. However, efficient and safe delivery remains a bottleneck in clinical gene therapy [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453–462].Viral vectors are looked upon favorably for their high transduction efficiency, although their ability to elicit toxic immune responses remains [C.F. McTiernan, et al., Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts, Gene Ther, 14(23), (2007) 1613–1622]. However, this high transduction does not necessarily translate into improved efficacy [X. Hao, et al., Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model, Cardiovasc Res., 73(3), (2007) 481–487]. Naked DNA remains the preferred method of DNA delivery to cardiac myocardium and has been explored extensively in clinical trials. The results from these trials have demonstrated efficacy in regard to secondary end-points of reduced symptomatology and perfusion, but have failed to establish significant angiogenesis or an increase in myocardial function [P.B. Shah, D.W. Losordo, Non-viral vectors for gene therapy: clinical trials in cardiovascular disease, Adv Genet, 54, (2005) 339–361]. This may be due in part to reduced transfection efficiency but can also be attributed to use of suboptimal candidate genes.Currently, polymeric non-viral gene delivery to cardiac myocardium remains underrepresented. In the past decade several advances in non-viral vector development has demonstrated increased transfection efficiency [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453–462]. Of these polymers, those that employ lipid modifications to improve transfection or target cardiovascular tissues have proven themselves to be extremely beneficial.Water-soluble lipopolymer (WSLP) consists of a low molecular weight branched PEI (1800) and cholesterol. The cholesterol moiety adds extra condensation by forming stable micellular complexes and was later employed for myocardial gene therapy to exploit the high expression of lipoprotein lipase found within cardiac tissue. Use of WSLP to deliver hypoxia-responsive driven expression of hVEGF to ischemic rabbit myocardium has proven to provide for even better expression in cardiovascular cells than Terplex and has demonstrated a significant reduction in infarct size (13 ± 4%, p < 0.001) over constitutive VEGF expression (32 ± 7%, p = 0.007) and sham-injected controls (48 ± 7%). A significant reduction in apoptotic values and an increase in capillary growth were also seen in surrounding tissue.Recently, investigations have begun using bioreducible polymers made of poly(amido polyethylenimines) (SS-PAEI). SS-PAEIs breakdown within the cytoplasm through inherent redox mechanisms and provide for high transfection efficiencies (upwards to 60% in cardiovascular cell types) with little to no demonstrable toxicity. In vivo transfections in normoxic and hypoxic rabbit myocardium have proven to exceed those results of WSLP transfections by 2–5 fold [L.V. Christensen, et al., Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery, J Control Release, 118(2), (2007) 254–261]. This new breed of polymer(s) may allow for decreased doses and use of new molecular mechanisms not previously available due to low transfection efficiencies.Little development has been seen in the use of new gene agents for treatment of myocardial ischemia and infarction. Current treatment consists of using mitogenic factors, described decades earlier, alone or in combination to spur angiogenesis or modulating intracellular Ca2+ homeostasis through SERCA2a but to date, failed to demonstrate clinical efficacy. Recent data suggests that axonal guidance cues also act on vasculature neo-genesis and provide a new means of investigation for treatment.