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Nanomedicine-based strategies for the treatment of vein graft disease

Nature Reviews Cardiology (2024)Cite this article

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Abstract

Autologous saphenous veins are the most frequently used conduits for coronary and peripheral artery bypass grafting. However, vein graft failure rates of 40–50% within 10 years of the implantation lead to poor long-term outcomes after bypass surgery. Currently, only a few therapeutic approaches for vein graft disease have been successfully translated into clinical practice. Building on the past two decades of advanced understanding of vein graft biology and the pathophysiological mechanisms underlying vein graft disease, nanomedicine-based strategies offer promising opportunities to address this important unmet clinical need. In this Review, we provide deep insight into the latest developments in the rational design and applications of nanoparticles that have the potential to target specific cells during various pathophysiological stages of vein graft disease, including early endothelial dysfunction, intermediate intimal hyperplasia and late-stage accelerated atherosclerosis. Additionally, we underscore the convergence of nanofabricated biomaterials, with a particular focus on hydrogels, external graft support devices and cell-based therapies, alongside bypass surgery to improve local delivery efficiency and therapeutic efficacy. Finally, we provide a specific discussion on the considerations, challenges and novel perspectives for the future clinical translation of nanomedicine for the treatment of vein graft disease.

Key points

  • Saphenous veins are widely used as autologous grafts in coronary and peripheral artery bypass graft surgery but as many as 40–50% of vein grafts occlude within a decade of the procedure.

  • Vein graft disease results from a complex interplay of mechanisms, including early acute thrombosis formation, intermediate vein graft neointimal hyperplasia and the subsequent development of late-stage accelerated atherosclerosis.

  • Advances in our understanding of vein graft biology and disease mechanisms provide opportunities for the rational design and implementation of nanoparticle-based targeting strategies for the treatment of vein graft disease.

  • The combination of nanofabricated biomaterials with bypass surgery facilitates the perivascular delivery of therapeutics to saphenous veins, offering several advantages over systemic administration.

  • Targeting nanotherapies tailored to specific disease stages and nanoparticle-mediated mRNA delivery technology hold substantial promise for the future treatment of vein graft disease.

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Fig. 1: Pathophysiology of vein graft disease.
Fig. 2: Nanoparticle-based strategies targeting pathophysiological processes of VGD.
Fig. 3: Application of nanofabricated biomaterials for vein graft disease treatment.

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References

  1. Byrne, R. A. et al. 2022 Joint ESC/EACTS review of the 2018 guideline recommendations on the revascularization of left main coronary artery disease in patients at low surgical risk and anatomy suitable for PCI or CABG. Eur. Heart J. 44, 4310–4320 (2023).

    Article  PubMed  Google Scholar 

  2. Lawton, J. S. et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145, e18–e114 (2022).

    PubMed  Google Scholar 

  3. Neumann, F. J. et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur. Heart J. 40, 87–165 (2019).

    Article  PubMed  Google Scholar 

  4. Kithcart, A. P. & Beckman, J. A. ACC/AHA versus ESC guidelines for diagnosis and management of peripheral artery disease: JACC guideline comparison. J. Am. Coll. Cardiol. 72, 2789–2801 (2018).

    Article  PubMed  Google Scholar 

  5. Aboyans, V. et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Eur. Heart J. 39, 763–816 (2018).

    Article  PubMed  Google Scholar 

  6. Gerhard-Herman, M. D. et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 69, 1465–1508 (2017).

    Article  PubMed  Google Scholar 

  7. Thuijs, D. et al. Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial. Lancet 394, 1325–1334 (2019).

    Article  PubMed  CAS  Google Scholar 

  8. Fearon, W. F. et al. Fractional flow reserve-guided PCI as compared with coronary bypass surgery. N. Engl. J. Med. 386, 128–137 (2022).

    Article  PubMed  Google Scholar 

  9. Farber, A. et al. Surgery or endovascular therapy for chronic limb-threatening ischemia. N. Engl. J. Med. 387, 2305–2316 (2022).

    Article  PubMed  Google Scholar 

  10. Caliskan, E. et al. Saphenous vein grafts in contemporary coronary artery bypass graft surgery. Nat. Rev. Cardiol. 17, 155–169 (2020).

    Article  PubMed  CAS  Google Scholar 

  11. Hess, C. N. et al. Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV. Circulation 130, 1445–1451 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Conte, M. S. et al. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery. J. Vasc. Surg. 43, 742–751 (2006).

    Article  PubMed  Google Scholar 

  13. Goldman, S. et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J. Am. Coll. Cardiol. 44, 2149–2156 (2004).

    Article  PubMed  Google Scholar 

  14. Gaudino, M. et al. Graft failure after coronary artery bypass grafting and its association with patient characteristics and clinical events: a pooled individual patient data analysis of clinical trials with imaging follow-up. Circulation 148, 1305–1315 (2023).

    Article  PubMed  Google Scholar 

  15. Sandner, S. et al. Association of dual antiplatelet therapy with ticagrelor with vein graft failure after coronary artery bypass graft surgery: a systematic review and meta-analysis. JAMA 328, 554–562 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Valgimigli, M. et al. P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials. BMJ 373, n1332 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhao, Q. et al. Effect of ticagrelor plus aspirin, ticagrelor alone, or aspirin alone on saphenous vein graft patency 1 year after coronary artery bypass grafting: a randomized clinical trial. JAMA 319, 1677–1686 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Kulik, A., Abreu, A. M., Boronat, V. & Ruel, M. Intensive versus moderate statin therapy and early graft occlusion after coronary bypass surgery: the aggressive cholesterol therapy to inhibit vein graft events randomized clinical trial. J. Thorac. Cardiovasc. Surg. 157, 151–161.e1 (2019).

    Article  PubMed  CAS  Google Scholar 

  19. Goodman, S. G. et al. Effects of alirocumab on cardiovascular events after coronary bypass surgery. J. Am. Coll. Cardiol. 74, 1177–1186 (2019).

    Article  PubMed  Google Scholar 

  20. Eisen, A. et al. The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial. Eur. Heart J. 37, 3576–3584 (2016).

    Article  PubMed  CAS  Google Scholar 

  21. Alexander, J. H. et al. Efficacy and safety of edifoligide, an E2F transcription factor decoy, for prevention of vein graft failure following coronary artery bypass graft surgery: PREVENT IV: a randomized controlled trial. JAMA 294, 2446–2454 (2005).

    Article  PubMed  Google Scholar 

  22. Goldstein, D. J. et al. External support for saphenous vein grafts in coronary artery bypass surgery: a randomized clinical trial. JAMA Cardiol. 7, 808–816 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hajipour, M. J. et al. Nanoscale technologies for prevention and treatment of heart failure: challenges and opportunities. Chem. Rev. 119, 11352–11390 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Mahmoudi, M. et al. Multiscale technologies for treatment of ischemic cardiomyopathy. Nat. Nanotechnol. 12, 845–855 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Chen, W. et al. Macrophage-targeted nanomedicine for the diagnosis and treatment of atherosclerosis. Nat. Rev. Cardiol. 19, 228–249 (2022).

    Article  PubMed  Google Scholar 

  26. Lobatto, M. E., Fuster, V., Fayad, Z. A. & Mulder, W. J. Perspectives and opportunities for nanomedicine in the management of atherosclerosis. Nat. Rev. Drug Discov. 10, 835–852 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Smith, B. R. & Edelman, E. R. Nanomedicines for cardiovascular disease. Nat. Cardiovasc. Res. 2, 351–367 (2023).

    Article  PubMed  Google Scholar 

  28. Huang, X. et al. Synthesis of siRNA nanoparticles to silence plaque-destabilizing gene in atherosclerotic lesional macrophages. Nat. Protoc. 17, 748–780 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. He, Z. et al. Resolvin D1 delivery to lesional macrophages using antioxidative black phosphorus nanosheets for atherosclerosis treatment. Nat. Nanotechnol. 19, 1386–1398 (2024).

    Article  PubMed  CAS  Google Scholar 

  30. Tierney, J. W. et al. Therapeutic MK2 inhibition blocks pathological vascular smooth muscle cell phenotype switch. JCI Insight 6, e142339 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Evans, B. C. et al. MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia. Sci. Transl. Med. 7, 291ra295 (2015).

    Article  Google Scholar 

  32. Decano, J. L. et al. Systems approach to discovery of therapeutic targets for vein graft disease: PPARα pivotally regulates metabolism, activation, and heterogeneity of macrophages and lesion development. Circulation 143, 2454–2470 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Nishio, H. et al. MicroRNA-145-loaded poly(lactic-co-glycolic acid) nanoparticles attenuate venous intimal hyperplasia in a rabbit model. J. Thorac. Cardiovasc. Surg. 157, 2242–2251 (2019).

    Article  PubMed  CAS  Google Scholar 

  34. Rajathurai, T. et al. Periadventitial rapamycin-eluting microbeads promote vein graft disease in long-term pig vein-into-artery interposition grafts. Circ. Cardiovasc. Interv. 3, 157–165 (2010).

    Article  PubMed  CAS  Google Scholar 

  35. Xu, H., Li, S. & Liu, Y. S. Nanoparticles in the diagnosis and treatment of vascular aging and related diseases. Signal. Transduct. Target. Ther. 7, 231 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Shi, Y. et al. Chemically modified platforms for better RNA therapeutics. Chem. Rev. 124, 929–1033 (2024).

    Article  PubMed  CAS  Google Scholar 

  37. Chen, S. et al. Nanotechnology-based mRNA vaccines. Nat. Rev. Methods Primers 3, 63 (2023).

    Article  CAS  Google Scholar 

  38. Huang, X. et al. The landscape of mRNA nanomedicine. Nat. Med. 28, 2273–2287 (2022).

    Article  PubMed  CAS  Google Scholar 

  39. Flores, A. M. et al. Nanoparticle therapy for vascular diseases. Arterioscler. Thromb. Vasc. Biol. 39, 635–646 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Cicha, I. et al. From design to the clinic: practical guidelines for translating cardiovascular nanomedicine. Cardiovasc. Res. 114, 1714–1727 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Mylonaki, I. et al. Perivascular medical devices and drug delivery systems: making the right choices. Biomaterials 128, 56–68 (2017).

    Article  PubMed  CAS  Google Scholar 

  42. Chaudhary, M. A. et al. Periadventitial drug delivery for the prevention of intimal hyperplasia following open surgery. J. Control. Release 233, 174–180 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Somarathna, M. et al. Nitric oxide releasing nanomatrix gel treatment inhibits venous intimal hyperplasia and improves vascular remodeling in a rodent arteriovenous fistula. Biomaterials 280, 121254 (2022).

    Article  PubMed  CAS  Google Scholar 

  44. Chu, T. et al. A novel nanocellulose-gelatin-AS-IV external stent resists EndMT by activating autophagy to prevent restenosis of grafts. Bioact. Mater. 22, 466–481 (2023).

    PubMed  CAS  Google Scholar 

  45. Deng, Y., Li, Y., Chu, Z., Dai, C. & Ge, J. Exosomes from umbilical cord-derived mesenchymal stem cells combined with gelatin methacryloyl inhibit vein graft restenosis by enhancing endothelial functions. J. Nanobiotechnol. 21, 380 (2023).

    Article  CAS  Google Scholar 

  46. de Vries, M. R., Simons, K. H., Jukema, J. W., Braun, J. & Quax, P. H. Vein graft failure: from pathophysiology to clinical outcomes. Nat. Rev. Cardiol. 13, 451–470 (2016).

    Article  PubMed  Google Scholar 

  47. Osgood, M. J. et al. Surgical vein graft preparation promotes cellular dysfunction, oxidative stress, and intimal hyperplasia in human saphenous vein. J. Vasc. Surg. 60, 202–211 (2014).

    Article  PubMed  Google Scholar 

  48. Stigler, R. et al. The impact of distension pressure on acute endothelial cell loss and neointimal proliferation in saphenous vein grafts. Eur. J. Cardiothorac. Surg. 42, e74–79 (2012).

    Article  PubMed  Google Scholar 

  49. Weaver, H., Shukla, N., Ellinsworth, D. & Jeremy, J. Y. Oxidative stress and vein graft failure: a focus on NADH oxidase, nitric oxide and eicosanoids. Curr. Opin. Pharmacol. 12, 160–165 (2012).

    Article  PubMed  CAS  Google Scholar 

  50. Dashwood, M. R., Anand, R., Loesch, A. & Souza, D. S. Hypothesis: a potential role for the vasa vasorum in the maintenance of vein graft patency. Angiology 55, 385–395 (2004).

    Article  PubMed  Google Scholar 

  51. Shi, Y. et al. Oxidative stress and lipid retention in vascular grafts: comparison between venous and arterial conduits. Circulation 103, 2408–2413 (2001).

    Article  PubMed  CAS  Google Scholar 

  52. Garoffolo, G. et al. Coronary artery mechanics induces human saphenous vein remodelling via recruitment of adventitial myofibroblast-like cells mediated by thrombospondin-1. Theranostics 10, 2597–2611 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Ruiter, M. S. & Pesce, M. Mechanotransduction in coronary vein graft disease. Front. Cardiovasc. Med. 5, 20 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Coon, B. G. et al. A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells. J. Cell Biol. 221, e202109144 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Chatterjee, S. & Fisher, A. B. Mechanotransduction in the endothelium: role of membrane proteins and reactive oxygen species in sensing, transduction, and transmission of the signal with altered blood flow. Antioxid. Redox Signal. 20, 899–913 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Khaleel, M. S. et al. High-pressure distention of the saphenous vein during preparation results in increased markers of inflammation: a potential mechanism for graft failure. Ann. Thorac. Surg. 93, 552–558 (2012).

    Article  PubMed  Google Scholar 

  57. Chello, M. et al. Pressure distension stimulates the expression of endothelial adhesion molecules in the human saphenous vein graft. Ann. Thorac. Surg. 76, 453–458 (2003).

    Article  PubMed  Google Scholar 

  58. Gluckman, T. J. et al. Effects of aspirin responsiveness and platelet reactivity on early vein graft thrombosis after coronary artery bypass graft surgery. J. Am. Coll. Cardiol. 57, 1069–1077 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Davì, G. & Patrono, C. Platelet activation and atherothrombosis. N. Engl. J. Med. 357, 2482–2494 (2007).

    Article  PubMed  Google Scholar 

  60. Kapur, N. K. et al. Inhibition of transforming growth factor-β restores endothelial thromboresistance in vein grafts. J. Vasc. Surg. 54, 1117–1123.e1 (2011).

    Article  PubMed  Google Scholar 

  61. Zhang, L. et al. Tumor necrosis factor receptor-2 signaling attenuates vein graft neointima formation by promoting endothelial recovery. Arterioscler. Thromb. Vasc. Biol. 28, 284–289 (2008).

    Article  PubMed  Google Scholar 

  62. Moreno, K. et al. Circulating inflammatory cells are associated with vein graft stenosis. J. Vasc. Surg. 54, 1124–1130 (2011).

    Article  PubMed  Google Scholar 

  63. Schlitt, A. et al. Neutrophil adherence to activated saphenous vein and mammary endothelium after graft preparation. Ann. Thorac. Surg. 81, 1262–1268 (2006).

    Article  PubMed  Google Scholar 

  64. Schober, A. Chemokines in vascular dysfunction and remodeling. Arterioscler. Thromb. Vasc. Biol. 28, 1950–1959 (2008).

    Article  PubMed  CAS  Google Scholar 

  65. Mitra, A. K., Gangahar, D. M. & Agrawal, D. K. Cellular, molecular and immunological mechanisms in the pathophysiology of vein graft intimal hyperplasia. Immunol. Cell Biol. 84, 115–124 (2006).

    Article  PubMed  CAS  Google Scholar 

  66. Liang, M., Liang, A., Wang, Y., Jiang, J. & Cheng, J. Smooth muscle cells from the anastomosed artery are the major precursors for neointima formation in both artery and vein grafts. Basic Res. Cardiol. 109, 431 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Simons, K. H. et al. CD8+ T cells protect during vein graft disease development. Front. Cardiovasc. Med. 6, 77 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Ozmen, J., Bobryshev, Y. V. & Lord, R. S. CD40 co-stimulatory molecule expression by dendritic cells in primary atherosclerotic lesions in carotid arteries and in stenotic saphenous vein coronary artery grafts. Cardiovasc. Surg. 9, 329–333 (2001).

    Article  PubMed  CAS  Google Scholar 

  69. Cherian, S. M. et al. Immunohistochemical and ultrastructural evidence that dendritic cells infiltrate stenotic aortocoronary saphenous vein bypass grafts. Cardiovasc. Surg. 9, 194–200 (2001).

    Article  PubMed  CAS  Google Scholar 

  70. de Vries, M. R. et al. C57BL/6 NK cell gene complex is crucially involved in vascular remodeling. J. Mol. Cell. Cardiol. 64, 51–58 (2013).

    Article  PubMed  Google Scholar 

  71. Wu, J. et al. Perivascular mast cells regulate vein graft neointimal formation and remodeling. PeerJ 3, e1192 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  72. de Vries, M. R. et al. Complement factor C5a as mast cell activator mediates vascular remodelling in vein graft disease. Cardiovasc. Res. 97, 311–320 (2013).

    Article  PubMed  Google Scholar 

  73. Zhang, D., Cao, Y., Liu, D., Zhang, J. & Guo, Y. The etiology and molecular mechanism underlying smooth muscle phenotype switching in intimal hyperplasia of vein graft and the regulatory role of microRNAs. Front. Cardiovasc. Med. 9, 935054 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Liu, H. et al. HnRNPA1 prevents endothelial-to-mesenchymal transition-induced VSMC activation and neointimal hyperplasia in vein grafts. J. Cardiovasc. Transl. Res. https://doi.org/10.1007/s12265-024-10545-3 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Cooley, B. C. et al. TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci. Transl. Med. 6, 227ra234 (2014).

    Article  Google Scholar 

  76. Kenagy, R. D. et al. Proliferative capacity of vein graft smooth muscle cells and fibroblasts in vitro correlates with graft stenosis. J. Vasc. Surg. 49, 1282–1288 (2009).

    Article  PubMed  Google Scholar 

  77. Turner, N. A., Hall, K. T., Ball, S. G. & Porter, K. E. Selective gene silencing of either MMP-2 or MMP-9 inhibits invasion of human saphenous vein smooth muscle cells. Atherosclerosis 193, 36–43 (2007).

    Article  PubMed  CAS  Google Scholar 

  78. Sharony, R. et al. Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2. Am. J. Physiol. Heart Circ. Physiol. 290, H1651–1659 (2006).

    Article  PubMed  CAS  Google Scholar 

  79. Simons, K. H. et al. The protective role of Toll-like receptor 3 and type-I interferons in the pathophysiology of vein graft disease. J. Mol. Cell. Cardiol. 121, 16–24 (2018).

    Article  PubMed  CAS  Google Scholar 

  80. Karper, J. C. et al. Toll-like receptor 4 is involved in human and mouse vein graft remodeling, and local gene silencing reduces vein graft disease in hypercholesterolemic APOE*3Leiden mice. Arterioscler. Thromb. Vasc. Biol. 31, 1033–1040 (2011).

    Article  PubMed  CAS  Google Scholar 

  81. de Vries, M. R. et al. Plaque rupture complications in murine atherosclerotic vein grafts can be prevented by TIMP-1 overexpression. PLoS One 7, e47134 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  82. George, S. J. et al. Sustained reduction of vein graft neointima formation by ex vivo TIMP-3 gene therapy. Circulation 124, S135–S142 (2011).

    Article  PubMed  Google Scholar 

  83. Hu, Y., Baker, A. H., Zou, Y., Newby, A. C. & Xu, Q. Local gene transfer of tissue inhibitor of metalloproteinase-2 influences vein graft remodeling in a mouse model. Arterioscler. Thromb. Vasc. Biol. 21, 1275–1280 (2001).

    Article  PubMed  CAS  Google Scholar 

  84. George, S. J., Lloyd, C. T., Angelini, G. D., Newby, A. C. & Baker, A. H. Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3. Circulation 101, 296–304 (2000).

    Article  PubMed  CAS  Google Scholar 

  85. Baganha, F., de Jong, A., Jukema, J. W., Quax, P. H. A. & de Vries, M. R. The role of immunomodulation in vein graft remodeling and failure. J. Cardiovasc. Transl. Res. 14, 100–109 (2021).

    Article  PubMed  Google Scholar 

  86. Bradshaw, A. C. & Baker, A. H. Gene therapy for cardiovascular disease: perspectives and potential. Vasc. Pharmacol. 58, 174–181 (2013).

    Article  CAS  Google Scholar 

  87. Mikami, T., Dashwood, M. R., Kawaharada, N. & Furuhashi, M. An obligatory role of perivascular adipose tissue in improved saphenous vein graft patency in coronary artery bypass grafting. Circ. J. 88, 845–852 (2024).

    Article  PubMed  Google Scholar 

  88. Spadaccio, C. et al. Preventing treatment failures in coronary artery disease: what can we learn from the biology of in-stent restenosis, vein graft failure, and internal thoracic arteries? Cardiovasc. Res. 116, 505–519 (2020).

    Article  PubMed  CAS  Google Scholar 

  89. Gu, W. et al. Single-Cell RNA-sequencing and metabolomics analyses reveal the contribution of perivascular adipose tissue stem cells to vascular remodeling. Arterioscler. Thromb. Vasc. Biol. 39, 2049–2066 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Michaud, M. E. et al. Early injury landscape in vein harvest by single-cell and spatial transcriptomics. Circ. Res. 135, 110–134 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Tian, M. et al. No-touch versus conventional vein harvesting techniques at 12 months after coronary artery bypass grafting surgery: multicenter randomized, controlled trial. Circulation 144, 1120–1129 (2021).

    Article  PubMed  Google Scholar 

  92. Souza, D. S., Christofferson, R. H., Bomfim, V. & Filbey, D. ‘No-touch’ technique using saphenous vein harvested with its surrounding tissue for coronary artery bypass grafting maintains an intact endothelium. Scand. Cardiovasc. J. 33, 323–329 (1999).

    Article  PubMed  CAS  Google Scholar 

  93. Desai, N. D. et al. Impact of patient and target-vessel characteristics on arterial and venous bypass graft patency: insight from a randomized trial. Circulation 115, 684–691 (2007).

    Article  PubMed  Google Scholar 

  94. Yazdani, S. K. et al. Pathology of drug-eluting versus bare-metal stents in saphenous vein bypass graft lesions. JACC Cardiovasc. Interv. 5, 666–674 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Yahagi, K. et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat. Rev. Cardiol. 13, 79–98 (2016).

    Article  PubMed  CAS  Google Scholar 

  96. Kolodgie, F. D. et al. Intraplaque hemorrhage and progression of coronary atheroma. N. Engl. J. Med. 349, 2316–2325 (2003).

    Article  PubMed  CAS  Google Scholar 

  97. Bulcha, J. T., Wang, Y., Ma, H., Tai, P. W. L. & Gao, G. Viral vector platforms within the gene therapy landscape. Signal. Transduct. Target. Ther. 6, 53 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).

    Article  PubMed  CAS  Google Scholar 

  99. Nankivell, V. et al. Targeting macrophages with multifunctional nanoparticles to detect and prevent atherosclerotic cardiovascular disease. Cardiovasc. Res. 120, 819–838 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Kovacic, J. C. et al. Endothelial to mesenchymal transition in cardiovascular disease: JACC state-of-the-art review. J. Am. Coll. Cardiol. 73, 190–209 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Taniguchi, R. et al. Endothelial cell TGF-β (transforming growth factor-beta) signaling regulates venous adaptive remodeling to improve arteriovenous fistula patency. Arterioscler. Thromb. Vasc. Biol. 42, 868–883 (2022).

    Article  PubMed  CAS  Google Scholar 

  102. Atukorale, P. U., Covarrubias, G., Bauer, L. & Karathanasis, E. Vascular targeting of nanoparticles for molecular imaging of diseased endothelium. Adv. Drug Deliv. Rev. 113, 141–156 (2017).

    Article  PubMed  CAS  Google Scholar 

  103. Dahlman, J. E. et al. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nat. Nanotechnol. 9, 648–655 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Khan, O. F. et al. Endothelial siRNA delivery in nonhuman primates using ionizable low-molecular weight polymeric nanoparticles. Sci. Adv. 4, eaar8409 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Koga, J. I. et al. Macrophage notch ligand delta-like 4 promotes vein graft lesion development: implications for the treatment of vein graft failure. Arterioscler. Thromb. Vasc. Biol. 35, 2343–2353 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Lopes, L. B. et al. A novel cell permeant peptide inhibitor of MAPKAP kinase II inhibits intimal hyperplasia in a human saphenous vein organ culture model. J. Vasc. Surg. 52, 1596–1607 (2010).

    Article  PubMed  Google Scholar 

  107. Kilchrist, K. V., Evans, B. C., Brophy, C. M. & Duvall, C. L. Mechanism of enhanced cellular uptake and cytosolic retention of MK2 inhibitory peptide nano-polyplexes. Cell. Mol. Bioeng. 9, 368–381 (2016).

    Article  PubMed  CAS  Google Scholar 

  108. Evans, B. C. et al. Endosomolytic nano-polyplex platform technology for cytosolic peptide delivery to inhibit pathological vasoconstriction. ACS Nano 9, 5893–5907 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Mukalel, A. J. et al. Excipients for the lyoprotection of MAPKAP kinase 2 inhibitory peptide nano-polyplexes. J. Control. Release 282, 110–119 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Kawatsu, S., Oda, K., Saiki, Y., Tabata, Y. & Tabayashi, K. External application of rapamycin-eluting film at anastomotic sites inhibits neointimal hyperplasia in a canine model. Ann. Thorac. Surg. 84, 560–567 (2007).

    Article  PubMed  Google Scholar 

  111. Schachner, T. et al. Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts. Ann. Thorac. Surg. 77, 1580–1585 (2004).

    Article  PubMed  Google Scholar 

  112. Zou, J. et al. Rapamycin-loaded nanoparticles for inhibition of neointimal hyperplasia in experimental vein grafts. Ann. Vasc. Surg. 25, 538–546 (2011).

    Article  PubMed  Google Scholar 

  113. Liu, K. et al. Pretreatment with intraluminal rapamycin nanoparticle perfusion inhibits neointimal hyperplasia in a rabbit vein graft model. Int. J. Nanomed. 5, 853–860 (2010).

    CAS  Google Scholar 

  114. Kimura, S. et al. Local delivery of imatinib mesylate (STI571)-incorporated nanoparticle ex vivo suppresses vein graft neointima formation. Circulation 118, S65–S70 (2008).

    Article  PubMed  CAS  Google Scholar 

  115. Gadde, S. & Rayner, K. J. Nanomedicine meets microRNA: current advances in RNA-based nanotherapies for atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 36, e73-9 (2016).

    Article  PubMed  Google Scholar 

  116. Ohnaka, M. et al. Effect of microRNA-145 to prevent vein graft disease in rabbits by regulation of smooth muscle cell phenotype. J. Thorac. Cardiovasc. Surg. 148, 676–682.e2 (2014).

    Article  PubMed  CAS  Google Scholar 

  117. Sala, F. et al. MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr−/− mice. Thromb. Haemost. 112, 796–802 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Wolff, R. A. et al. Macrophage depletion reduces monocyte chemotactic protein-1 and transforming growth factor-β1 in healing rat vein grafts. J. Vasc. Surg. 39, 878–888 (2004).

    Article  PubMed  Google Scholar 

  119. Leuschner, F. et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat. Biotechnol. 29, 1005–1010 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Nakano, T., Fukuda, D., Koga, J. & Aikawa, M. Delta-like ligand 4-notch signaling in macrophage activation. Arterioscler. Thromb. Vasc. Biol. 36, 2038–2047 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Fung, E. et al. Delta-like 4 induces notch signaling in macrophages: implications for inflammation. Circulation 115, 2948–2956 (2007).

    Article  PubMed  CAS  Google Scholar 

  122. Tahara, N. et al. 2-Deoxy-2-[18F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat. Med. 20, 215–219 (2014).

    Article  PubMed  CAS  Google Scholar 

  123. Tao, W. et al. siRNA nanoparticles targeting CaMKIIγ in lesional macrophages improve atherosclerotic plaque stability in mice. Sci. Transl. Med. 12, eaay1063 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Liu, Y. et al. CARD9 mediates necrotic smooth muscle cell-induced inflammation in macrophages contributing to neointima formation of vein grafts. Cardiovasc. Res. 108, 148–158 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Shi, H. T. et al. Cathepsin S contributes to macrophage migration via degradation of elastic fibre integrity to facilitate vein graft neointimal hyperplasia. Cardiovasc. Res. 101, 454–463 (2014).

    Article  PubMed  CAS  Google Scholar 

  126. de Jong, A. et al. Interfering in the ALK1 pathway results in macrophage-driven outward remodeling of murine vein grafts. Front. Cardiovasc. Med. 8, 784980 (2021).

    Article  PubMed  Google Scholar 

  127. Deo, S. V., Al-Kindi, S., Virani, S. S. & Fremes, S. Novel therapies to achieve the recommended low-density lipoprotein cholesterol concentration (LDL-C) targets for patients after coronary artery bypass grafting. J. Thorac. Cardiovasc. Surg. 167, 723–730.e4 (2024).

    Article  PubMed  Google Scholar 

  128. Knatterud, G. L. et al. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators. Circulation 102, 157–165 (2000).

    Article  PubMed  CAS  Google Scholar 

  129. Jones, P. H., Nair, R. & Thakker, K. M. Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis. J. Am. Heart Assoc. 1, e001800 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Libby, P. & Tokgözoğlu, L. Chasing LDL cholesterol to the bottom — PCSK9 in perspective. Nat. Cardiovasc. Res. 1, 554–561 (2022).

    Article  PubMed  Google Scholar 

  131. Gao, J. et al. Association between proprotein convertase subtilisin/kexin type 9 and late saphenous vein graft disease after coronary artery bypass grafting: a cross-sectional study. BMJ Open 8, e021951 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Katsuki, S. et al. Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes macrophage activation via LDL receptor-independent mechanisms. Circ. Res. 131, 873–889 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. Int. Ed. Engl. 51, 8529–8533 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Frank-Kamenetsky, M. et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl Acad. Sci. USA 105, 11915–11920 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Fitzgerald, K. et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 383, 60–68 (2014).

    Article  PubMed  CAS  Google Scholar 

  136. Fitzgerald, K. et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med. 376, 41–51 (2017).

    Article  PubMed  CAS  Google Scholar 

  137. Ray, K. K. et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 376, 1430–1440 (2017).

    Article  PubMed  CAS  Google Scholar 

  138. Ray, K. K. et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N. Engl. J. Med. 382, 1507–1519 (2020).

    Article  PubMed  CAS  Google Scholar 

  139. Lee, R. G. et al. Efficacy and safety of an investigational single-course CRISPR base-editing therapy targeting PCSK9 in nonhuman primate and mouse models. Circulation 147, 242–253 (2023).

    Article  PubMed  CAS  Google Scholar 

  140. Musunuru, K. et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature 593, 429–434 (2021).

    Article  PubMed  CAS  Google Scholar 

  141. Horie, T. & Ono, K. VERVE-101: a promising CRISPR-based gene editing therapy that reduces LDL-C and PCSK9 levels in HeFH patients. Eur. Heart J. Cardiovasc. Pharmacother. 10, 89–90 (2024).

    Article  PubMed  Google Scholar 

  142. US National Library of Medicine. A study of VERVE-101 in patients with familial hypercholesterolemia and cardiovascular disease. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05398029 (2022).

  143. US National Library of Medicine. Effect of evolocumab on saphenous vein graft patency following coronary artery bypass surgery (NEWTON-CABG). ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03900026 (2019).

  144. de Vries, M. R. & Quax, P. H. A. Inflammation in vein graft disease. Front. Cardiovasc. Med. 5, 3 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Ward, A. O., Caputo, M., Angelini, G. D., George, S. J. & Zakkar, M. Activation and inflammation of the venous endothelium in vein graft disease. Atherosclerosis 265, 266–274 (2017).

    Article  PubMed  CAS  Google Scholar 

  146. Smith, P. K. et al. Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: combined results from the PRIMO-CABG I and II trials. J. Thorac. Cardiovasc. Surg. 142, 89–98 (2011).

    Article  PubMed  CAS  Google Scholar 

  147. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  PubMed  CAS  Google Scholar 

  148. Tardif, J. C. et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N. Engl. J. Med. 381, 2497–2505 (2019).

    Article  PubMed  CAS  Google Scholar 

  149. Nidorf, S. M. et al. Colchicine in patients with chronic coronary disease. N. Engl. J. Med. 383, 1838–1847 (2020).

    Article  PubMed  CAS  Google Scholar 

  150. Luo, Y. et al. Phospholipid nanoparticles: therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation. EBioMedicine 74, 103725 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Gao, C. et al. Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines. Nat. Commun. 11, 2622 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Boada, C. et al. Rapamycin-loaded biomimetic nanoparticles reverse vascular inflammation. Circ. Res. 126, 25–37 (2020).

    Article  PubMed  CAS  Google Scholar 

  153. Fredman, G. et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci. Transl. Med. 7, 275ra220 (2015).

    Article  Google Scholar 

  154. Oliva, N., Conde, J., Wang, K. & Artzi, N. Designing hydrogels for on-demand therapy. Acc. Chem. Res. 50, 669–679 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Zhong, R. et al. Hydrogels for RNA delivery. Nat. Mater. 22, 818–831 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Escobar-Chávez, J. J. et al. Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations. J. Pharm. Pharm. Sci. 9, 339–358 (2006).

    PubMed  Google Scholar 

  157. Eefting, D. et al. Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice. J. Vasc. Surg. 50, 152–160 (2009).

    Article  PubMed  Google Scholar 

  158. Cao, B. J., Wang, X. W., Zhu, L., Zou, R. J. & Lu, Z. Q. Dedicator of cytokinesis 2 silencing therapy inhibits neointima formation and improves blood flow in rat vein grafts. J. Mol. Cell. Cardiol. 128, 134–144 (2019).

    Article  PubMed  CAS  Google Scholar 

  159. Wang, X. W. et al. Adenovirus-mediated gene transfer of microRNA-21 sponge inhibits neointimal hyperplasia in rat vein grafts. Int. J. Biol. Sci. 13, 1309–1319 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Kip, P. et al. Periprocedural hydrogen sulfide therapy improves vascular remodeling and attenuates vein graft disease. J. Am. Heart Assoc. 9, e016391 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Mylonaki, I. et al. Perivascular sustained release of atorvastatin from a hydrogel-microparticle delivery system decreases intimal hyperplasia. J. Control. Release 232, 93–102 (2016).

    Article  PubMed  CAS  Google Scholar 

  162. Parsonnet, V., Lari, A. A. & Shah, I. H. New stent for support of veins in arterial grafts. Arch. Surg. 87, 696–702 (1963).

    Article  PubMed  CAS  Google Scholar 

  163. Taggart, D. P. et al. Long-term performance of an external stent for saphenous vein grafts: the VEST IV trial. J. Cardiothorac. Surg. 13, 117 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Taggart, D. P. et al. A prospective study of external stenting of saphenous vein grafts to the right coronary artery: the VEST II study. Eur. J. Cardiothorac. Surg. 51, 952–958 (2017).

    Article  PubMed  Google Scholar 

  165. Taggart, D. P. et al. A randomized trial of external stenting for saphenous vein grafts in coronary artery bypass grafting. Ann. Thorac. Surg. 99, 2039–2045 (2015).

    Article  PubMed  Google Scholar 

  166. Gemelli, M. et al. Venous external support in coronary artery bypass surgery: a systematic review and meta-analysis. Curr. Probl. Cardiol. 48, 101687 (2023).

    Article  PubMed  Google Scholar 

  167. Taggart, D. P. et al. External stenting and disease progression in saphenous vein grafts two years after coronary artery bypass grafting: a multicenter randomized trial. J. Thorac. Cardiovasc. Surg. 164, 1532–1541.e2 (2022).

    Article  PubMed  Google Scholar 

  168. Ding, L. et al. A soft, conductive external stent inhibits intimal hyperplasia in vein grafts by electroporation and mechanical restriction. ACS Nano 14, 16770–16780 (2020).

    Article  PubMed  CAS  Google Scholar 

  169. Yang, Q. et al. A novel biodegradable external stent regulates vein graft remodeling via the Hippo-YAP and mTOR signaling pathways. Biomaterials 258, 120254 (2020).

    Article  PubMed  CAS  Google Scholar 

  170. Ranganath, S. H., Levy, O., Inamdar, M. S. & Karp, J. M. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10, 244–258 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Tu, C., Das, S., Baker, A. B., Zoldan, J. & Suggs, L. J. Nanoscale strategies: treatment for peripheral vascular disease and critical limb ischemia. ACS Nano 9, 3436–3452 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Tan, F. et al. Clinical applications of stem cell-derived exosomes. Signal. Transduct. Target. Ther. 9, 17 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Qu, Q. et al. miRNA-126-3p carried by human umbilical cord mesenchymal stem cell enhances endothelial function through exosome-mediated mechanisms in vitro and attenuates vein graft neointimal formation in vivo. Stem Cell Res. Ther. 11, 464 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Bai, X. et al. The effect of lncRNA MIR155HG-modified MSCs and exosome delivery to synergistically attenuate vein graft intimal hyperplasia. Stem Cell Res. Ther. 13, 512 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Nguyen, P. K., Neofytou, E., Rhee, J. W. & Wu, J. C. Potential strategies to address the major clinical barriers facing stem cell regenerative therapy for cardiovascular disease: a review. JAMA Cardiol. 1, 953–962 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Zhou, Z. et al. Long-term outcomes after on-pump vs off-pump coronary artery bypass grafting for ischemic cardiomyopathy. Ann. Thorac. Surg. 115, 1421–1428 (2023).

    Article  PubMed  Google Scholar 

  177. Zhou, Z. et al. Randomized evidence on graft patency after off-pump versus on-pump coronary artery bypass grafting: an updated meta-analysis. Int. J. Surg. 98, 106212 (2022).

    Article  PubMed  Google Scholar 

  178. Gaudino, M. et al. Mechanisms, consequences, and prevention of coronary graft failure. Circulation 136, 1749–1764 (2017).

    Article  PubMed  Google Scholar 

  179. Mann, M. J. & Dzau, V. J. Therapeutic applications of transcription factor decoy oligonucleotides. J. Clin. Invest. 106, 1071–1075 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Braun-Dullaeus, R. C., Mann, M. J. & Dzau, V. J. Cell cycle progression: new therapeutic target for vascular proliferative disease. Circulation 98, 82–89 (1998).

    Article  PubMed  CAS  Google Scholar 

  181. Ehsan, A., Mann, M. J., Dell’Acqua, G. & Dzau, V. J. Long-term stabilization of vein graft wall architecture and prolonged resistance to experimental atherosclerosis after E2F decoy oligonucleotide gene therapy. J. Thorac. Cardiovasc. Surg. 121, 714–722 (2001).

    Article  PubMed  CAS  Google Scholar 

  182. Morishita, R. et al. A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc. Natl Acad. Sci. USA 92, 5855–5859 (1995).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Mann, M. J. et al. Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial. Lancet 354, 1493–1498 (1999).

    Article  PubMed  CAS  Google Scholar 

  184. Robertson, K. E., McDonald, R. A., Oldroyd, K. G., Nicklin, S. A. & Baker, A. H. Prevention of coronary in-stent restenosis and vein graft failure: does vascular gene therapy have a role? Pharmacol. Ther. 136, 23–34 (2012).

    Article  PubMed  CAS  Google Scholar 

  185. Wiedemann, D. et al. Perivascular administration of drugs and genes as a means of reducing vein graft failure. Curr. Opin. Pharmacol. 12, 203–216 (2012).

    Article  PubMed  CAS  Google Scholar 

  186. Yu, P., Nguyen, B. T., Tao, M., Campagna, C. & Ozaki, C. K. Rationale and practical techniques for mouse models of early vein graft adaptations. J. Vasc. Surg. 52, 444–452 (2010).

    Article  PubMed  Google Scholar 

  187. Zou, Y. et al. Mouse model of venous bypass graft arteriosclerosis. Am. J. Pathol. 153, 1301–1310 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Maeda, N. Development of apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 31, 1957–1962 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Ishibashi, S. et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J. Clin. Invest. 92, 883–893 (1993).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Schepers, A. et al. Inhibition of complement component C3 reduces vein graft atherosclerosis in apolipoprotein E3-Leiden transgenic mice. Circulation 114, 2831–2838 (2006).

    Article  PubMed  CAS  Google Scholar 

  191. van den Maagdenberg, A. M. et al. Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia. J. Biol. Chem. 268, 10540–10545 (1993).

    Article  PubMed  Google Scholar 

  192. Zadelaar, S. et al. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler. Thromb. Vasc. Biol. 27, 1706–1721 (2007).

    Article  PubMed  CAS  Google Scholar 

  193. Bentzon, J. F. & Falk, E. Atherosclerotic lesions in mouse and man: is it the same disease? Curr. Opin. Lipidol. 21, 434–440 (2010).

    Article  PubMed  CAS  Google Scholar 

  194. Golforoush, P., Yellon, D. M. & Davidson, S. M. Mouse models of atherosclerosis and their suitability for the study of myocardial infarction. Basic Res. Cardiol. 115, 73 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Shay, T. et al. Conservation and divergence in the transcriptional programs of the human and mouse immune systems. Proc. Natl Acad. Sci. USA 110, 2946–2951 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Thomas, A. C. Animal models for studying vein graft failure and therapeutic interventions. Curr. Opin. Pharmacol. 12, 121–126 (2012).

    Article  PubMed  CAS  Google Scholar 

  197. Schachner, T., Laufer, G. & Bonatti, J. In vivo (animal) models of vein graft disease. Eur. J. Cardiothorac. Surg. 30, 451–463 (2006).

    Article  PubMed  Google Scholar 

  198. Chan, C. K. W. et al. Recent advances in managing atherosclerosis via nanomedicine. Small https://doi.org/10.1002/smll.201702793 (2018).

  199. Wu, W. et al. Mature vascular smooth muscle cells, but not endothelial cells, serve as the major cellular source of intimal hyperplasia in vein grafts. Arterioscler. Thromb. Vasc. Biol. 40, 1870–1890 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Hu, Z. et al. Strategies for arterial graft optimization at the single-cell level. Nat. Cardiovasc. Res. 3, 541–557 (2024).

    Article  PubMed  Google Scholar 

  201. Barenholz, Y. Doxil® — the first FDA-approved nano-drug: lessons learned. J. Control. Release 160, 117–134 (2012).

    Article  PubMed  CAS  Google Scholar 

  202. de Lázaro, I. & Mooney, D. J. Obstacles and opportunities in a forward vision for cancer nanomedicine. Nat. Mater. 20, 1469–1479 (2021).

    Article  PubMed  Google Scholar 

  203. Duivenvoorden, R. et al. Nanoimmunotherapy to treat ischaemic heart disease. Nat. Rev. Cardiol. 16, 21–32 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Zhou, Z. et al. Heterogeneous treatment effects of coronary artery bypass grafting in ischemic cardiomyopathy: a machine learning causal forest analysis. J. Thorac. Cardiovasc. Surg. https://doi.org/10.1016/j.jtcvs.2023.09.021 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Aguado, B. A., Grim, J. C., Rosales, A. M., Watson-Capps, J. J. & Anseth, K. S. Engineering precision biomaterials for personalized medicine. Sci. Transl. Med. 10, eaam8645 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Zia, A. et al. The choice of targets and ligands for site-specific delivery of nanomedicine to atherosclerosis. Cardiovasc. Res. 116, 2055–2068 (2020).

    Article  PubMed  CAS  Google Scholar 

  207. Hernandez-Sanchez, D. et al. Manufacturing and validation of small-diameter vascular grafts: a mini review. iScience 27, 109845 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Breuer, T., Jimenez, M., Humphrey, J. D., Shinoka, T. & Breuer, C. K. Tissue engineering of vascular grafts: a case report from bench to bedside and back. Arterioscler. Thromb. Vasc. Biol. 43, 399–409 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. US National Library of Medicine. Xeltis coronary artery bypass graft (XABG) first in human (FIH) (XABG-FIH). ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04545112 (2020).

  210. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).

    Article  PubMed  CAS  Google Scholar 

  211. Polack, F. P. et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    Article  PubMed  CAS  Google Scholar 

  212. Cappelluti, M. A. et al. Durable and efficient gene silencing in vivo by hit-and-run epigenome editing. Nature 627, 416–423 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Kasiewicz, L. N. et al. GalNAc-lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy. Nat. Commun. 14, 2776 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. Anttila, V. et al. Synthetic mRNA encoding VEGF-A in patients undergoing coronary artery bypass grafting: design of a phase 2a clinical trial. Mol. Ther. Methods Clin. Dev. 18, 464–472 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Anttila, V. et al. Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting. Mol. Ther. 31, 866–874 (2023).

    Article  PubMed  CAS  Google Scholar 

  216. Wang, R. F. & Meng, Q. Y. Nanoparticle-mediated arresten gene inhibits neointimal formation of vein grafts: an experimental research. J. Thorac. Dis. 8, 3081–3086 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Ji, J., Yang, J. A., He, X., Ling, W. P. & Chen, X. L. Cardiac-targeting transfection of tissue-type plasminogen activator gene to prevent the graft thrombosis and vascular anastomotic restenosis after coronary bypass. Thromb. Res. 134, 440–448 (2014).

    Article  PubMed  CAS  Google Scholar 

  218. Sun, D. X. et al. Nanoparticle-mediated local delivery of an antisense TGF-β1 construct inhibits intimal hyperplasia in autogenous vein grafts in rats. PLoS One 7, e41857 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Kalra, M., Jost, C. J., Severson, S. R. & Miller, V. M. Adventitial versus intimal liposome-mediated ex vivo transfection of canine saphenous vein grafts with endothelial nitric oxide synthase gene. J. Vasc. Surg. 32, 1190–1200 (2000).

    Article  PubMed  CAS  Google Scholar 

  220. Longchamp, A. et al. Hydrogen sulfide-releasing peptide hydrogel limits the development of intimal hyperplasia in human vein segments. Acta Biomater. 97, 374–384 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Qu, Q., Pang, Y., Zhang, C., Liu, L. & Bi, Y. Exosomes derived from human umbilical cord mesenchymal stem cells inhibit vein graft intimal hyperplasia and accelerate reendothelialization by enhancing endothelial function. Stem Cell Res. Ther. 11, 133 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  222. Sandner, S. et al. Coronary artery bypass graft failure in women: incidence and clinical implications. J. Am. Coll. Cardiol. 84, 182–191 (2024).

    Article  PubMed  Google Scholar 

  223. Gaudino, M. et al. Sex differences in outcomes after coronary artery bypass grafting: a pooled analysis of individual patient data. Eur. Heart J. 43, 18–28 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Peters, S. A. E. & Kluin, J. Why do women do worse after coronary artery bypass grafting? Eur. Heart J. 43, 29–31 (2021).

    Article  PubMed  Google Scholar 

  225. Gaudino, M. et al. Randomized comparison of the outcome of single versus multiple arterial grafts trial (ROMA): women-a trial dedicated to women to improve coronary bypass outcomes. J. Thorac. Cardiovasc. Surg. 167, 1316–1321 (2024).

    Article  PubMed  Google Scholar 

  226. Gaudino, M., Fremes, S. E., Mehran, R. & Bairey Merz, C. N. ROMA:women: innovative approaches for the first cardiac surgery trial in women. Circulation 148, 1289–1291 (2023).

    Article  PubMed  Google Scholar 

  227. Zhou, Z. et al. Bilateral internal thoracic artery coronary grafting: risks and benefits in elderly patients. Eur. Heart J. Qual. Care Clin. Outcomes 8, 861–870 (2022).

    Article  PubMed  Google Scholar 

  228. Schwann, T. A. et al. Bilateral internal thoracic artery versus radial artery multi-arterial bypass grafting: a report from the STS database. Eur. J. Cardiothorac. Surg. 56, 926–934 (2019).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge the funding support from National Institutes of Health (NIH) grants (No. 5R35HL166640-02 to R.A., No. 5P01AI153003-05 to R.A. and No. 1P01AI175397-01A1 to R.A. and W.T.), American Heart Association (AHA) Transformational Project Award (No. 23TPA1072337 to W.T.), AHA’s Second Century Early Faculty Independence Award (No. 23SCEFIA1151841 to W.T.), American Society of Transplantation (AST) Career Transition Grant (No. 1173492 to W.T.), American Lung Association (ALA) Cancer Discovery Award (No. LCD1034625 to W.T.), ALA Courtney Cox Cole Lung Cancer Research Award (No. 2022A017206 to W.T.), Novo Nordisk Validation Award (No. 2023A009607 to W.T.), LEO Foundation Research Grant (No. LF-OC-24-001665 to W.T.), Harvard/Brigham Health & Technology Innovation Fund (No. 2023A004452 to W.T.), Khoury Innovation Award (No. 2020A003219 to W.T.), Center for Nanomedicine Research Fund (No. 2019A014810 to W.T.), Nanotechnology Foundation (No. 2022A002721 to W.T.) and Distinguished Chair Professorship Foundation (No. 018129 to W.T.).

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Authors and Affiliations

  1. Center for Nanomedicine and Department of Anaesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Zhuoming Zhou, Wei Chen & Wei Tao

  2. Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

    Zhuoming Zhou

  3. Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    Yihai Cao

  4. Transplantation Research Center and Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Reza Abdi

Authors
  1. Zhuoming Zhou
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  2. Wei Chen
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  3. Yihai Cao
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  4. Reza Abdi
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  5. Wei Tao
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Contributions

All the authors wrote, reviewed and edited the manuscript before submission. Z.Z. and W.C. designed the figures for initial submission.

Corresponding authors

Correspondence to Wei Chen or Wei Tao.

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Competing interests

W.T. consults for, is on scientific advisory boards for, or has lectured (and received a fee) or conducts sponsored research at Harvard Medical School/Brigham and Women’s Hospital for Novo Nordisk and Henlius USA. The other authors declare no competing interests.

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Nature Reviews Cardiology thanks Maximilan Emmert; Michael J. Mitchell; Margreet de Vries, who co-reviewed with Thijs Sluiter; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Zhou, Z., Chen, W., Cao, Y. et al. Nanomedicine-based strategies for the treatment of vein graft disease. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-024-01094-y

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