CORONARY VENOUS SYSTEM DISEASES

Coronary_Venous_System_Diseases

CORONARY VENOUS DISEASES TREATMENT AND PHARMACOLOGICAL INNOVATIONS

Ender Tekeş

Çanakkale Onsekiz Mart University, Faculty of Medicine, Department of Pharmacology, Çanakkale, Türkiye

Tekeş E. Coronary Venous Diseases Treatment and Pharmacological Innovations. In: Altay S, Akşit E, Kemaloğlu Öz T editor. Coronary Venous System Diseases. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.119-129.

ABSTRACT

Coronary venous system diseases represent an under-recognized yet clinically meaningful domain in cardiovascular medicine. While treatment efforts in cardiovascular medicine have traditionally cen- tered on the arterial system, there is increasing recognition of the coronary venous circulation as a distinct and clinically important domain. This chapter explores new directions in therapy—including pharmacological, gene-based, and pharmacogenetic approaches—designed to improve outcomes in conditions affecting the coronary venous system, such as coronary sinus dysfunction and complications involving saphenous vein grafts (SVGs). Pharmacological innovations targeting thrombosis, inflam- mation, fibrosis, and microcirculatory dysfunction are reviewed. Among these, colchicine, anti-fibrotic agents such as pirfenidone, and neurohormonal inhibitors offer promising indirect benefits in venous pathology. The section on SVG disease addresses the role of dual antiplatelet therapy, high-intensity statins, RAAS blockade, and newer adjunctive approaches to improve graft patency and remodeling. Gene therapy has gained momentum in recent years, with clinical trials such as CUPID, ReGenHeart, and EXACT exploring intracoronary, epicardial, and venous delivery routes for angiogenic or remod- eling-targeted genes. The coronary venous system’s anatomical accessibility enables it to serve as a delivery platform for vectors and biologics, particularly in no-option patients. Emerging modali- ties such as modified mRNA, CRISPR/Cas9, and miRNA-based interventions hold further promise. Pharmacogenetics remains an evolving field. While CYP2C19-guided antiplatelet therapy has entered clinical practice, other applications, such as warfarin dosing or b-adrenergic receptor polymorphism profiling, remain investigational. Implementation challenges include cost, clinician awareness, and limited outcome data beyond antithrombotics. However, polygenic risk scores and genotype-driven therapy optimization are being evaluated in cardiovascular trials. Finally, this chapter outlines barriers to clinical translation—such as immune responses to vectors, regulatory hurdles, and delivery limita- tions—and highlights the need for interdisciplinary collaboration. Retrograde coronary sinus infusion, in particular, may offer a viable route for targeted delivery of advanced therapeutics. Future progress depends on translational studies, personalized medicine integration, and ethical frameworks that ensure safety and equity in gene-based cardiovascular therapy.

Keywords: Coronary vessels; Drug therapy; Genetic therapy; Vascular grafting; Pharmacogenetics; Heart failure

Referanslar

  1. De Maria GL, Kassimis G, Raina T, Banning AP. Reconsidering the back door approach by targeting the coronary sinus in ischaemic heart disease. Heart. 2016;102(16):1263-1269. [Crossref]  [PubMed]
  2. Chen JJ, Lee WJ, Wang YC, Tsai CT, Lai LP, Hwang JJ, et al. Morphologic and Topologic Characteristics of Coronary Venous System Delineated by Noninvasive Multidetector Computed Tomography in Chronic Systolic Heart Failure Patients. J Card Fail. 2007;13(6):482-488. [Crossref]  [PubMed]
  3. Damman K, Navis G, Voors AA, Asselbergs FW, Smilde TDJ, Cleland JGF, et al. Worsening Renal Function and Prognosis in Heart Failure: Systematic Review and Meta-Analysis. J Card Fail. 2007;13(8):599-608. [Crossref]  [PubMed]
  4. Molina CE, Heijman J, Dobrev D. Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis. Arrhythm Electro physiol Rev. 2016;5(1):14. [Crossref]  [PubMed]  [PMC]
  5. Gu-Cheng X, Yu Y, Wang C. Surgical Treatment for Diffuse Coronary Artery Diseases. In: Artery Bypass. InTech; 2013. [Crossref]
  6. Abdelnaby M, Almaghraby A, Abdelkarim O, Saleh Y, Hammad B, Badran H. The role of rivaroxaban in left ventricular thrombi. The Anatolian Journal of Cardiology. 2019;21(1):47-50. [Crossref]
  7. Esenboga K, Sahin E, Ozyuncu N, Tan TS, Atmaca Y. Apixaban for massive intracoronary thrombosis: A case series. The Anatolian Journal of Cardiology. 2021;25(9):661-664. [Crossref]  [PubMed]  [PMC]
  8. Frisoli JK, Sze D. Mechanical thrombectomy for the treatment of lower extremity deep vein thrombosis. Tech Vasc Interv Radiol. 2003;6(1):49-52. [Crossref]  [PubMed]
  9. Kaemmel J, Heck R, Lanmüller P, Falk V, Starck C. Remov Tekeş Coronary Venous Diseases Treatment and Pharmacological Innovations al of Wall-Adherent Inferior Vena Cava Thrombus with a Combined Approach Using Vacuum-Assisted Thrombectomy and a Rotational Thrombectomy Device. Case Rep Vasc Med. 2023;2023:5178998. [Crossref]  [PubMed]  [PMC]
  10. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. New England Journal of Medicine. 2019;381(26):2497-2505. [Crossref]  [PubMed]
  11. Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, et al. Colchicine in Patients with Chronic Coronary Disease. New England Journal of Medicine. 2020;383(19):1838-1847. [Crossref]  [PubMed]
  12. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. New England Journal of Medicine. 2017;377(12):1119-1131. [Crossref]  [PubMed]
  13. Miguel CB, Andrade R de S, Mazurek L, Martins-de-Abreu MC, Miguel-Neto J, Barbosa AM et al. Emerging Pharmacological Interventions for Chronic Venous Insufficiency: A Comprehensive Systematic Review and Meta-Analysis of Efficacy, Safety, and Therapeutic Advances. Pharmaceutics. 2025;17(1):59. [Crossref]  [PubMed]  [PMC]
  14. Floris E, Cozzolino C, Marconi S, Tonicello F, Picchio V, Pagano F, et al. A Review of Therapeutic Strategies against Cardiac Fibrosis: From Classical Pharmacology to Novel Molecular, Epigenetic, and Biotechnological Approaches. Rev Cardiovasc Med. 2023;24(8):226. [Crossref]  [PubMed]  [PMC]
  15. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. Corrigendum to: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2021;42(48):4901-4901. [Crossref]  [PubMed]
  16. Li N, Hang W, Shu H, Zhou N. Pirfenidone alleviates cardiac fibrosis induced by pressure overload via inhibiting TGF-1/Smad3 signalling pathway. J Cell Mol Med. 2022;26(16):4548-4555. [Crossref]  [PubMed]  [PMC]
  17. Lewis GA, Dodd S, Clayton D, Bedson E, Eccleson H, Schelbert EB, et al. Pirfenidone in heart failure with preserved ejection fraction: a randomized phase 2 trial. Nat Med. 2021;27(8):1477-1482. [Crossref]  [PubMed]
  18. Yue Y, Meng K, Pu Y, Zhang X. Transforming growth factor beta (TGF-) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res Clin Pract. 2017;133:124-130. [Crossref]  [PubMed]
  19. Yu L, Ruifrok WPT, Meissner M, Bos EM, Goor HV, Sanjabi B, et al. Genetic and Pharmacological Inhibition of Galectin-3 Prevents Cardiac Remodeling by Interfering With Myocardial Fibrogenesis. Circ Heart Fail. 2013;6(1):107-117. [Crossref]  [PubMed]
  20. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR et al. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. New England Journal of Medicine. 2014;371(11):993-1004. [Crossref]  [PubMed]
  21. Paulus WJ, Tschöpe C. A Novel Paradigm for Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2013;62(4):263-271. [Crossref]  [PubMed]
  22. Camici PG, Crea F. Coronary Microvascular Dysfunction. New England Journal of Medicine. 2007;356(8):830-840. [Crossref]  [PubMed]
  23. Cattaneo M, Porretta AP, Gallino A. Ranolazine: Drug overview and possible role in primary microvascular angina management. Int J Cardiol. 2015;181:376-381. [Crossref]  [PubMed]
  24. Marinescu MA, Löffler AI, Ouellette M, Smith L, Kramer CM, Bourque JM. Coronary Microvascular Dysfunction, Microvascular Angina, and Treatment Strategies. JACC Cardiovasc Imaging. 2015;8(2):210-220. [Crossref]  [PubMed]  [PMC]
  25. Taqueti VR, Di Carli MF. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options. J Am Coll Cardiol. 2018;72(21):2625-2641. [Crossref]  [PubMed]  [PMC]
  26. Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and No Obstructive Coronary Artery Disease (INOCA). Circulation. 2017;135(11):1075-1092. [Crossref]  [PubMed]  [PMC]
  27. Lawton JS, Tamis-Holland JE, Bangalore S, Bates ER, Beckie TM, Bischoff JM, 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. 2022;145(3):e18-e114. [Crossref]
  28. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407-477. [Crossref]  [PubMed]
  29. Shibata R, Yamaguchi S, Murohara T. Therapeutic Angiogenesis Using Bone Marrow Mononuclear Cell Transplantation A New Standard Treatment for Thromboangiitis Obliterans?. Circulation Journal. 2020;84(4):549-550. [Crossref]  [PubMed]
  30. Rydén L, Tadokoro H, Sjöquist PO, Regardh C, Kobayashi S, Corday E, et al. Pharmacokinetic analysis of coronary venous retroinfusion: A comparison with anterograde coronary artery drug administration using metoprolol as a tracer. J Am Tekeş Coronary Venous Diseases Treatment and Pharmacological Innovations Coll Cardiol. 1991;18(2):603-612. [Crossref]  [PubMed]
  31. Nakamura K, Henry TD, Traverse JH, Latter DA, Mokadam NA, Answini GA, et al. Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial. Circ Cardiovasc Interv. 2024;17(5):e014054. [Crossref]  [PMC]
  32. Magadum A. Modified mRNA Therapeutics for Heart Diseases. Int J Mol Sci. 2022;23(24):15514. [Crossref]  [PubMed]  [PMC]
  33. Southerland KW, Frazier SB, Bowles DE, Milano CA, Kontos CD. Gene therapy for the prevention of vein graft disease. Translational Research. 2013;161(4):321-338. [Crossref]  [PubMed]  [PMC]
  34. White SJ, Newby AC. Gene Therapy for All Aspects of VeinGraft Disease. J Card Surg. 2002;17(6):549-555. [Crossref]  [PubMed]
  35. Gallone G, Baldetti L, Tzanis G, Gramegna M, Latib A, Colombo A, et al. Refractory Angina. JACC Cardiovasc Interv. 2020;13(1):1-19. [Crossref]  [PubMed]
  36. Zangi L, K. Kaundal R, Kaur K. Gene Therapy for Heart Disease: Modified mRNA Perspectives. In: Cardiomyopathy Disease of the Heart Muscle. IntechOpen; 2021. [Crossref]
  37. Zsebo K, Yaroshinsky A, Rudy JJ, Wagner K, Greenberg B, Jessup M, et al. Long-Term Effects of AAV1/SERCA2a Gene Transfer in Patients With Severe Heart Failure. Circ Res. 2014;114(1):101-108. [Crossref]  [PubMed]
  38. Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Desai AS, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. The Lancet. 2016;387(10024):1178-1186. [Crossref]  [PubMed]
  39. Cao G, Xuan X, Zhang R, Hu J, Dong H. Gene Therapy for Cardiovascular Disease: Basic Research and Clinical Prospects. Front Cardiovasc Med. 2021;8:760140. [Crossref]  [PubMed]  [PMC]
  40. Claassens DMF, Vos GJA, Bergmeijer TO, Hermanides RS, Hof AWJ, Harst PWD, et al. A Genotype-Guided Strategy for Oral P2Y 12 Inhibitors in Primary PCI. New England Journal of Medicine. 2019;381(17):1621-1631. [Crossref]  [PubMed]
  41. Gurbel PA, Rout A, Tantry US. Pharmacogenetic considerations in antiplatelet therapy. Expert Rev Precis Med Drug Dev. 2020;5(4):235-238. [Crossref]
  42. Voora D, Ginsburg GS. Clinical Application of Cardiovascular Pharmacogenetics. J Am Coll Cardiol. 2012;60(1):9-20. [Crossref]  [PubMed]
  43. Rysz J, Franczyk B, Rysz-Górzyńska M, Gluba-Brzózka A. Pharmacogenomics of Hypertension Treatment. Int J Mol Sci. 2020;21(13):4709. [Crossref]  [PubMed]  [PMC]
  44. Pereira NL, Sargent DJ, Farkouh ME, Rihal CS. Genotype-based clinical trials in cardiovascular disease. Nat Rev Cardiol. 2015;12(8):475-487. [Crossref]  [PubMed]  [PMC]
  45. Bonowicz K, Jerka D, Piekarska K, Olagbaju J, Stapleton L, Shobowale M, et al. CRISPR-Cas9 in Cardiovascular Medicine: Unlocking New Potential for Treatment. Cells. 2025;14(2):131. [Crossref]  [PubMed]  [PMC]
  46. Soroudi S, Jaafari MR, Arabi L. Lipid nanoparticle (LNP) mediated mRNA delivery in cardiovascular diseases: Advances in genome editing and CAR T cell therapy. Journal of Controlled Release. 2024;372:113-140. [Crossref]  [PubMed]
  47. Kim Y, Landstrom AP, Shah SH, Wu JC, Seidman CE. Gene Therapy in Cardiovascular Disease: Recent Advances and Future Directions in Science: A Science Advisory From the American Heart Association. Circulation. 2024;150(23):e471-e480. [Crossref]