ANGINA PECTORIS: PATHOPHYSIOLOGY AND EVOLVING THERAPEUTIC STRATEGIES-A COMPREHENSIVE REVIEW
Keywords:
Angina Pectoris, Coronary Artery Disease, Ischemia, Pathophysiology, PharmacotherapyAbstract
Angina pectoris, a medical disorder characterised by transient chest discomfort or pain due to myocardial ischaemia, remains a prevalent and debilitating condition worldwide. It is primarily caused by an imbalance between oxygen supply and demand in the myocardium resulting in oxygen deficit, often resulting from obstructive or non-obstructive coronary artery disease (CAD). Despite considerable advancement in diagnostic imaging, pharmacological interventions, and revascularization techniques, angina continues to pose an evident burden on patients’ quality of life and healthcare systems globally. Traditional pharmacologic therapies, including β-blockers, calcium channel blockers, nitrates, and antiplatelet agents, have been the cornerstone of treatment. However, a considerable portion of patients persistently exhibit symptoms despite receiving guideline-directed medical therapy and undergoing revascularization procedures. The emergence of newer drugs such as ranolazine, ivabradine, and trimetazidine has provided additional therapeutic options, targeting distinct mechanisms of action to alleviate symptoms. In recent years, research into regenerative therapies has opened new frontiers in angina management. Gene therapy, stem cell interventions, and exosome-based treatments demonstrate potential in targeting the root causes of ischemia and promoting myocardial repair. Furthermore, advancements in drug delivery systems and the potential for personalized therapies are poised to improve clinical outcomes. This review delivers a comprehensive overview of the pathophysiology of angina pectoris, examines current treatment strategies, and explores the future potential of innovative therapeutic approaches. By highlighting the ongoing evolution in angina management, this review aims to contribute to the understanding and management of this chronic condition, thereby contributing to better clinical outcomes and improved quality of life.
References
Abdelmohsen, K., Panda, A. C., Munk, R., Grammatikakis, I., Dudekula, D. B., De, S., Kim, J., Noh, J. H.,
Kim, K. M., Martindale, J. L., & Gorospe, M. (2017). Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biology, 14(3), 361–369. https://doi.org/10.1080/15476286.2017.1279788
Aggarwal, R., Akhthar, T. & Jain, S. K. (2016). Coronary artery disease and its association with vitamin D deficiency. Journal of Mid-life Health, 7(2), 56–60. https://doi.org/10.4103/0976-7800.185334
Arbab-Zadeh, A., Nakano, M., Virmani, R., & Fuster, V. (2012). Acute coronary events. Circulation, 125(9), 1147–1156. https://doi.org/10.1161/CIRCULATIONAHA.111.047431
Arsenault, B. J. (2022). The promise and challenges of RNA-targeted therapeutics in preventive cardiology. European Heart Journal, 43(7), 550–552. https://doi.org/10.1093/eurheartj/ehab462
Balla, C., Pavasini, R., & Ferrari, R. (2018). Treatment of angina: Where are we? Cardiology, 140(1), 52–67. https://doi.org/10.1159/000487936
Batkai, S., Genschel, C., Viereck, J., Rump, S., Bär, C., Borchert, T., Traxler, D., Riesenhuber, M., Spannbauer, A., Lukovic, D., & Zlabinger, K. (2021). CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure. European Heart Journal, 42(2), 192–201. https://doi.org/10.1093/eurheartj/ehaa791
Bei, Y., Yu, P., Cretoiu, D., Cretoiu, S. M., & Xiao, J. (2017). Exosome-based biomarkers for the rognosis of cardiovascular diseases. In Xiao, J. (Ed.), Exosomes in cardiovascular diseases: Biomarkers, pathological and therapeutic effects, p. 71–88. Springer. https://doi.org/10.1007/978-981-10-4397-0_5
Chen, C., Kaur, G., Mehta, P. K., Morrone, D., Godoy, L. C., Bangalore, S., & Sidhu, M. S. (2021). Ivabradine in cardiovascular disease management revisited: A review. Cardiovascular Drugs and Therapy, 35, 1045–1056. https://doi.org/10.1007/s10557-020-07124-4
Chia, S. P., Pang, J. K., & Soh, B. S. (2024). Current RNA strategies in treating cardiovascular diseases. Molecular Therapy, 32(3), 580–608. https://doi.org/10.1016/j.ymthe.2024.01.028
Crea, F., Bairey Merz, C. N., Beltrame, J. F., Berry, C., Camici, P. G., Kaski, J. C., Ong, P., Pepine, C. J., Sechtem, U., & Shimokawa, H. (2018). Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization. European Heart Journal, 40(29), 2455–2462. https://doi.org/10.1093/eurheartj/ehy857
Dabravolski, S. A., Popov, M. A., Utkina, A. S., Babayeva, G. A., Maksaeva, A. O., Sukhorukov, V. N., & Orekhov, A. N. (2025). Preclinical and mechanistic perspectives on adipose-derived stem cells for atherosclerotic cardiovascular disease treatment. Molecular and Cellular Biochemistry, 480(8), 4647–4670. https://doi.org/10.1007/s11010-025-05285-0
Elgebaly, S. A., Christenson, R. H., Kandil, H., El-Khazragy, N., Rashed, L., Yacoub, B., Eldeeb, H., Ali, M., Sharafieh, R., Klueh, U., & Kreutzer, D. L. (2021). Nourin-dependent miR-137 and miR-106b: Novel early inflammatory diagnostic biomarkers for unstable angina patients. Biomolecules, 11(3), 368. https://doi.org/10.3390/biom11030368
Ferrari, R., Camici, P. G., Crea, F., Danchin, N., Fox, K., Maggioni, A. P., Manolis, A. J., Marzilli, M., Rosano, G. M. C., & Lopez-Sendon, J. L. (2018). A ‘diamond’ approach to personalized treatment of angina. Nature Reviews Cardiology, 15(2), 120-132. https://doi.org/10.1038/nrcardio.2017.131
Fihn, S. D., Gardin, J. M., Abrams, J., Berra, K., Blankenship, J. C., Dallas, A. P., Douglas, P. S., Foody, J. M., Gerber, T. C., Hinderliter, A. L., King, S. B., Kligfield, P. D., Krumholz, H. M., Kwong, R. Y. K., Lim, M. J., Linderbaum, J. A., Mack, M. J., Munger, M. A., Prager, R. L., ... Williams, S. V. (2012). 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with
stable ischemic heart disease. Journal of the American College of Cardiology, 60(24), e44-e164. https://doi.org/10.1016/j.jacc.2012.07.013
Foley, M. J., Rajkumar, C. A., Ahmed-Jushuf, F., Simader, F. A., Chotai, S., Pathimagaraj, R. H., Mohsin, M., Salih, A., Wang, D., Dixit, P., Davies, J. R., Keeble, T. R., Cosgrove, C., Spratt, J. C., O'Kane, P. D., De Silva, R., Hill, J. M., Nijjer, S. S., Sen, S., ... Al-Lamee, R. K. (2024). Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): A randomised, placebo-controlled trial. The Lancet, 403(10436), 1543–1553. https://doi.org/10.1016/S0140-6736(24)00256-3
Fu, D. G. (2015). Cardiac arrhythmias: Diagnosis, symptoms, and treatments. Cell Biochemistry and Biophysics, 73(2), 291-296. https://doi.org/10.1007/s12013-015-0626-4
Gallone, G., Baldetti, L., Tzanis, G., Gramegna, M., Latib, A., Colombo, A., Henry, T. D., & Giannini, F.
(2020). Refractory angina: From pathophysiology to new therapeutic nonpharmacological technologies. JACC: Cardiovascular Interventions, 13(1), 1–19. https://doi.org/10.1016/j.jcin.2019.08.055
Hassan, M. A. (2023). Angina pectoris. Eurasian Journal of Chemical, Medicinal and Petroleum Research, 2(5), 212–220.
Hassanzadeh, A., Shomali, N., Kamrani, A., Nasiri, H., Ahmadian Heris, J., Pashaiasl, M., Sadeghi, M., Sadeghvand, S., Valedkarimi, Z., & Akbari, M. (2024). Detailed role of mesenchymal stem cell (MSC)-derived exosome therapy in cardiac diseases. EXCLI Journal, 23, 401–420. https://doi.org/10.17179/excli2023-6538
He, A. T., Liu, J., Li, F., & Yang, B. B. (2021). Targeting circular RNAs as a therapeutic approach: Current strategies and challenges. Signal Transduction and Targeted Therapy, 6(1), 185. https://doi.org/10.1038/s41392-021-00569-5
Henry, T. D., Bairey Merz, C. N., Wei, J., Corban, M. T., Quesada, O., Joung, S., Kotynski, C. L., Wang, J., Lewis, M., Schumacher, A. M., Bartel, R. L., Takagi, H., Shah, V., Lee, A., Sietsema, W. K., Losordo, D. W., & Lerman, A. (2022). Autologous CD34+ stem cell therapy increases coronary flow reserve and reduces angina in patients with coronary microvascular dysfunction. Circulation: Cardiovascular Interventions, 15(2), e010802. https://doi.org/10.1161/CIRCINTERVENTIONS.121.010802
Hoenig, M. R., Doust, J., Aroney, C. N., & Scott, I. A. (2006). Early invasive versus conservative strategies for unstable angina and non-ST-elevation myocardial infarction in the stent era. Cochrane Database of Systematic Reviews, (3), CD004815. https://doi.org/10.1002/14651858.CD004815.pub2
Hu, X., Ning, X., Zhao, Q., Zhang, Z., Zhang, C., Xie, M., Huang, W., Cai, Y., Xiang, Q., & Ou, C. (2022).
Islet-1 mesenchymal stem cells-derived exosome-incorporated angiogenin-1 hydrogel for enhanced
acute myocardial infarction therapy. ACS Applied Materials & Interfaces, 14(32), 36289–36303. https://doi.org/10.1021/acsami.2c04686
Jain, A., Elgendy, I. Y., Al-Ani, M., Agarwal, N., & Pepine, C. J. (2017). Advancements in pharmacotherapy for angina. Expert Opinion on Pharmacotherapy, 18(5), 457–469. https://doi.org/10.1080/14656566.2017.1303483
Jansen, T. P., Konst, R. E., De Vos, A., Paradies, V., Teerenstra, S., Van den Oord, S. C., Dimitriu-Leen, A., Maas, A. H., Smits, P. C., Damman, P., & Van Royen, N. (2022). Efficacy of diltiazem to improve coronary vasomotor dysfunction in ANOCA: The EDIT-CMD randomized clinical trial. JACC: Cardiovascular Imaging, 15(8), 1473–1484. https://doi.org/10.1016/j.jcmg.2022.03.012
Jones, D. A., Weeraman, D., Colicchia, M., Hussain, M. A., Veerapen, D., Andiapen, M., Rathod, K. S., Baumbach, A., & Mathur, A. (2019). The impact of cell therapy on cardiovascular outcomes in patients with refractory angina. Circulation Research, 124(12), 1786–1795. https://doi.org/10.1161/CIRCRESAHA.118.314118
Kaski, J. C., Arrebola-Moreno, A., & Dungu, J. (2011). Treatment strategies for chronic stable angina. Expert Opinion on Pharmacotherapy, 12(18), 2833–2844. https://doi.org/10.1517/14656566.2011.634799
Kaski, J. C., Crea, F., Gersh, B. J., & Camici, P. G. (2018). Reappraisal of ischemic heart disease: Fundamental role of coronary microvascular dysfunction in the pathogenesis of angina pectoris. Circulation, 138(14), 1463–1480. https://doi.org/10.1161/CIRCULATIONAHA.118.031373
Knuuti, J., Wijns, W., Saraste, A., Capodanno, D., Barbato, E., Funck-Brentano, C., Prescott, E., Storey, R. F., Deaton, C., Cuisset, T., & Agewall, S. (2020). 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). European Heart Journal, 41(3), 407–477. https://doi.org/10.1093/eurheartj/ehz425
Kunadian, V., Chieffo, A., Camici, P. G., Berry, C., Escaned, J., Maas, A. H. E. M., Prescott, E., Karam, N., Appelman, Y., Fraccaro, C., Buchanan, G. L., Manzo-Silberman, S., Al-Lamee, R., Regar, E., Lansky, A., Abbott, J. D., Badimon, L., Duncker, D. J., Mehran, R., ... Baumbach, A. (2020). An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation endorsed by Coronary Vasomotor Disorders International Study Group. European Heart Journal, 41(37), 3504–3520. https://doi.org/10.1093/eurheartj/ehaa503
Lee, D. Y. (2024). Emerging circulating biomarkers for enhanced cardiovascular risk prediction. Journal of Lipid and Atherosclerosis, 13(3), 262–279. https://doi.org/10.12997/jla.2024.13.3.262
Leikas, A. J., Hassinen, I., Hedman, A., Kivelä, A., Ylä-Herttuala, S., & Hartikainen, J. E. K. (2022). Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study. Gene Therapy, 29(5),
–293. https://doi.org/10.1038/s41434-021-00295-1
Lele, J. A. J. M. N., Dewa, V., Sihaloho, K. B., Rampengan, D. D. C. H., Rampengan, S. H., Jagannatha, G. N. P., & Purnomo, A. F. (2025). New insights on efficacy and safety autologous CD34+ stem cells for refractory angina: Systematic review and meta-analysis of comparative long- versus short-term therapy. Journal of Preventive, Diagnostic and Treatment Strategies in Medicine, 4(1),
–17. https://doi.org/10.4103/jpdtsm.jpdtsm_114_24
Li, J., Lin, A., Jiang, R., Chen, P., Xu, C., & Hou, Y. (2024). Exosomes-mediated drug delivery for the treatment of myocardial injury. Annals of Medicine & Surgery, 86(1), 292–299. https://doi.org/10.1097/MS9.0000000000001473
Li, N., Yang, Y.-J., Zhang, Q., Jin, C., Wang, H., & Qian, H.-Y. (2013). Stem cell therapy is a promising tool for refractory angina: A meta-analysis of randomized controlled trials. Canadian Journal of Cardiology, 29(8), 908–914. https://doi.org/10.1016/j.cjca.2012.12.003
Liu, H., Deng, S., Han, L., Ren, Y., Gu, J., He, L., Liu, T., & Yuan, Z.-X. (2022). Mesenchymal stem cells,
exosomes and exosome-mimics as smart drug carriers for targeted cancer therapy. Colloids and
Surfaces B: Biointerfaces, 209, 112163. https://doi.org/10.1016/j.colsurfb.2021.112163
Losordo, D. W., Vale, P. R., & Isner, J. M. (1999). Gene therapy for myocardial angiogenesis. American Heart Journal, 138(2), S132-S141. https://doi.org/10.1016/S0002-8703(99)70333-9
Lucas, T., & Dimmeler, S. (2016). RNA therapeutics for treatment of cardiovascular diseases: Promises and challenges. Circulation Research, 119(7), 794–797. https://doi.org/10.1161/CIRCRESAHA.116.308730
Maideen, N. M. P., Balasubramanian, R., Muthusamy, S. & Nallasamy, V. (2022). An overview of
clinically imperative and pharmacodynamically significant drug interactions of renin-angiotensin-aldosterone system (RAAS) blockers. Current Cardiology Reviews, 18(6), 42–53. https://doi.org/10.2174/1573403X18666220511152330
McCarthy, C. P., Mullins, K. V., & Kerins, D. M. (2016). The role of trimetazidine in cardiovascular disease: Beyond an anti-anginal agent. European Heart Journal – Cardiovascular Pharmacotherapy, 2(4), 266–272. https://doi.org/10.1093/ehjcvp/pvv051
McMullan, E., Joladarashi, D., & Kishore, R. (2025). Unpacking exosomes: a therapeutic frontier for
cardiac repair. Current Cardiology Reports, 27(1), 73. https://doi.org/10.1007/s11886-025-02225-8
Moe, K. T., & Wong, P. (2010). Current trends in diagnostic biomarkers of acute coronary syndrome. Annals Academy of Medicine Singapore, 39(3), 210-215. https://doi.org/10.47102/annals-acadmedsg.V39N3p210
Münzel, T., Steven, S., & Daiber, A. (2014). Organic nitrates: Update on mechanisms underlying
vasodilation, tolerance and endothelial dysfunction. Vascular Pharmacology, 63(3), 105–113. https://doi.org/10.1016/j.vph.2014.09.002
Musolino, P. L., Rosser, S. J., Brittan, M., Newby, D. E., Berry, C., Riley, P. R., Giacca, M., Hajjar, R. J., &
Baker, A. H. (2025). Gene therapy in cardiac and vascular diseases: A review of approaches to treat
genetic and common cardiovascular diseases with novel gene-based therapeutics. Cardiovascular Research, 121(12), 1843–1855. https://doi.org/10.1093/cvr/cvaf109
Nakamura, K., Henry, T. D., Traverse, J. H., Latter, D. A., Mokadam, N. A., Answini, G. A., Williams, A. R., Sun, B. C., Burke, C. R., Bakaeen, F. G., DiCarli, M. F., Chaitman, B. R., Peterson, M. W., Byrnes, D. G., Ohman, E. M., Pepine, C. J., Crystal, R. G., Rosengart, T. K., Kowalewski, E., ... Povsic, T. J. (2024). Angiogenic gene therapy for refractory angina: Results of the EXACT phase 2 trial. Circulation: Cardiovascular Interventions, 17(5), e01405. https://doi.org/10.1161/CIRCINTERVENTIONS.
01405
Nakamura, Y., Kita, S., Tanaka, Y., Fukuda, S., Obata, Y., Okita, T., Nishida, H., Takahashi, Y., Kawachi, Y., Tsugawa-Shimizu, Y., Fujishima, Y., Nishizawa, H., Takakura, Y., Miyagawa, S., Sawa, Y., Maeda, N., & Shimomura, I. (2020). Adiponectin stimulates exosome release to enhance mesenchymal stem-cell-driven therapy of heart failure in mice. Molecular Therapy, 28(10), 2203–2219. https://doi.org/10.1016/j.ymthe.2020.06.026
Nedoshivin, A., Petrova, P. T. S., & Karpov, Y. (2022). Efficacy and safety of ivabradine in combination with beta-blockers in patients with stable angina pectoris: A systematic review and meta-analysis. Advances in Therapy, 39(9), 4189–4204. https://doi.org/10.1007/s12325-022-02222-1
Oliphant, C. S., Owens, R. E., Bolorunduro, O. B., & Jha, S. K. (2016). Ivabradine: A review of labeled and off-label uses. American Journal of Cardiovascular Drugs, 16(4), 337–347. https://doi.org/10.1007/s40256-016-0178-z
Oliva, A., Cao, D., Spirito, A., Nicolas, J., Pileggi, B., Kamaleldin, K., Vogel, B., & Mehran, R. (2023). Personalized approaches to antiplatelet treatment for cardiovascular diseases: An umbrella review. Pharmacogenomics and Personalized Medicine, 16, 973–990. https://doi.org/10.2147/PGPM.S391400
Palatini, P., Faria-Neto, J. R., & Santos, R. D. (2024). The clinical value of β-blockers in patients with stable angina. Current Medical Research and Opinion, 40(sup1), 33–41. https://doi.org/10.1080/03007995.2024.2317443
Parker, J. D., & Parker, J. O. (1998). Nitrate therapy for stable angina pectoris. New England Journal of
Medicine, 338(8), 520–531. https://doi.org/10.1056/NEJM199802193380807
Picard, F., Sayah, N., Spagnoli, V., Adjedj, J., & Varenne, O. (2019). Vasospastic angina: A literature review of current evidence. Archives of Cardiovascular Diseases, 112(1), 44–55. https://doi.org/10.1016/j.acvd.2018.08.002
Radico, F., Cicchitti, V., Zimarino, M., & De Caterina, R. (2014). Angina pectoris and myocardial ischemia in the absence of obstructive coronary artery disease: Practical considerations for diagnostic tests. JACC: Cardiovascular Interventions, 7(5), 453–463. https://doi.org/10.1016/j.jcin.2014.01.157
Rayner-Hartley, E., & Sedlak, T. (2016). Ranolazine: A contemporary review. Journal of the American
Heart Association, 5(3), e003196. https://doi.org/10.1161/JAHA.116.003196
Rinaldi, R., Kunadian, V., Crea, F., & Montone, R. A. (2025). Management of angina pectoris. Trends
in Cardiovascular Medicine, 35, 341–350. https://doi.org/10.1016/j.tcm.2025.03.001
Rousan, T. A., Mathew, S. T., & Thadani, U. (2017). Drug therapy for stable angina pectoris. Drugs, 77(3), 265–284. https://doi.org/10.1007/s40265-017-0691-7
Saglietto, A., Manfredi, R., Elia, E., D'Ascenzo, F., De Ferrari, G. M., Biondi-Zoccai, G., & Münzel, T. (2021). Cardiovascular disease burden: Italian and global perspectives. Minerva Cardiology and Angiology, 69(3), 231–240. https://doi.org/10.23736/S2724-5683.21.05538-9
Schwartze, J. T., Havenga, M., Bakker, W. A. M., Bradshaw, A. C., & Nicklin, S. A. (2022). Adenoviral vectors for cardiovascular gene therapy applications: A clinical and industry perspective. Journal of Molecular Medicine, 100, 875–901. https://doi.org/10.1007/s00109-022-02209-9
Shah, K., Seeley, S., Schulz, C., Fisher, J., & Gururaja Rao, S. (2022). Calcium channels in the heart:
Disease states and drugs. Cells, 11(6), 943. https://doi.org/10.3390/cells11060943
Thadani, U. (2016). Management of stable angina–Current guidelines: A critical appraisal. Cardiovascular Drugs and Therapy, 30(4), 419–426. https://doi.org/10.1007/s10557-016-6681-2
Thupakula, S., Nimmala, S. S., Ravula, H., Chekuri, S., & Padiya, R. (2022). Emerging biomarkers for the detection of cardiovascular diseases. The Egyptian Heart Journal, 74(1), 77. https://doi.org/10.1186/s43044-022-00317-2
Tsaknis, G., Tsangaris, I., Ikonomidis, I., & Tsantes, A. (2014). Clinical usefulness of novel serum and imaging biomarkers in risk stratification of patients with stable angina. Disease Markers, 2014, Article 831364. https://doi.org/10.1155/2014/831364
Tudurachi, A., Anghel, L., Tudurachi, B.-S., Zăvoi, A., Ceasovschih, A., Sascău, R. A., & Stătescu, C. (2024). Beyond the obstructive paradigm: Unveiling the complex landscape of nonobstructive coronary artery disease. Journal of Clinical Medicine, 13(16), 4613. https://doi.org/10.3390/jcm13164613
Varney, J. A., Dong, V. S., Tsao, T., Sabir, M. S., Rivera, A. T., Ghula, S., Moriles, K. E., Cherukuri, M. L.,
Fazal, R., Azevedo, C. B., Mohamed, R. M. K., Jackson, G. R., Fleming, S. E., Rochez, D. E., Abbas, K. S.,
Shah, J. H., Minh, L. H. N., Osman, F., Rafla, S. M., & Huy, N. T. (2022). COVID-19 and arrhythmia:
An overview. Journal of Cardiology, 79(4), 468–475. https://doi.org/10.1016/j.jjcc.2021.11.019
Verheye, S., van de Hoef, T. P., de Silva, R., van Kuijk, J.-P., Byrne, J., Montorfano, M., Buschmann, E.,
Dupont, M., West, N. E. J. & Banai, S. (2024). Coronary sinus narrowing for treating refractory angina: REDUCER-I multicenter “real-world” observational study primary endpoint analysis. JACC: Cardiovascular Interventions, 17(24):2908–2918. https://doi.org/10.1016/j.jcin.2024.08.047
Wei, X., Yang, X., Han, Z.-P., Qu, F.-F., Shao, L., & Shi, Y.-F. (2013). Mesenchymal stem cells: A new trend for cell therapy. Acta Pharmacologica Sinica, 34(6), 747–754. https://doi.org/10.1038/aps.2013.50
