Targeting Residual Inflammation in Cardiovascular Disease: Beyond LDL Cholesterol Toward Precision Cardiometabolic Prevention
DOI:
https://doi.org/10.64784/253Palabras clave:
Residual inflammatory risk, LDL cholesterol, Atherosclerosis, Cardiovascular disease, Chronic inflammation, High-sensitivity C-reactive protein, NLRP3 inflammasome, Interleukin-1β, Interleukin-6, Colchicine, Canakinumab, Cardiometabolic prevention, Precision medicine.Resumen
Cardiovascular disease remains the leading cause of mortality worldwide despite substantial advances in lipid-lowering therapies. Although achieving recommended low-density lipoprotein cholesterol (LDL-C) targets significantly reduces cardiovascular risk, many patients continue to experience recurrent cardiovascular events, a phenomenon known as residual cardiovascular risk. Increasing evidence indicates that chronic low-grade inflammation is a major contributor to this persistent risk. This review analyzes current scientific evidence regarding the biological mechanisms, inflammatory biomarkers, and emerging therapeutic strategies associated with residual inflammatory risk beyond LDL cholesterol. The literature demonstrates that activation of the NLRP3 inflammasome and the interleukin-1β/interleukin-6 pathway plays a central role in endothelial dysfunction, plaque progression, and atherosclerotic instability. High-sensitivity C-reactive protein (hs-CRP) remains the most widely validated biomarker for identifying persistent inflammatory activity in clinical practice. Landmark clinical trials, including CANTOS, COLCOT, and LoDoCo2, have demonstrated that selective anti-inflammatory therapies reduce recurrent cardiovascular events independently of additional LDL-C lowering, whereas nonspecific anti-inflammatory approaches have shown limited benefit. Furthermore, obesity, type 2 diabetes mellitus, metabolic syndrome, and chronic kidney disease substantially amplify residual inflammatory risk through shared pathophysiological mechanisms. Current evidence supports a transition toward comprehensive cardiometabolic prevention integrating lipid management, lifestyle modification, metabolic optimization, and targeted anti-inflammatory therapy. Future precision medicine strategies incorporating inflammatory biomarkers and individualized risk assessment may further improve cardiovascular outcomes and reduce the global burden of atherosclerotic disease.
Referencias
• Aday, A. W., & Ridker, P. M. (2019). Targeting residual inflammatory risk: A shifting paradigm for atherosclerotic disease. Frontiers in Cardiovascular Medicine, 6, 16. https://doi.org/10.3389/fcvm.2019.00016
• Arnett, D. K., Blumenthal, R. S., Albert, M. A., et al. (2019). 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation, 140(11), e596–e646.
• Cosentino, F., Grant, P. J., Aboyans, V., et al. (2023). ESC Guidelines on cardiovascular disease in patients with diabetes. European Heart Journal.
• Everett, B. M. (2019). Residual inflammatory risk: A common and important risk factor for recurrent cardiovascular events. Journal of the American College of Cardiology, 73(19), 2405–2408. https://doi.org/10.1016/j.jacc.2019.02.056
• Henein, M. Y., Vancheri, S., Longo, G., et al. (2019). Does low-density lipoprotein cholesterol induce inflammation? Current insights and future perspectives for novel therapies. BMC Medicine, 17, 197.
• Ikonomidis, I., & Lekakis, J. (2025). Association between chronic inflammation and cardiovascular disease: Focus on high-sensitivity C-reactive protein. Journal of Atherosclerosis and Thrombosis.
• Kim, H. L., & Kim, S. H. (2019). Strategies to overcome residual risk during statins era. Journal of Lipid and Atherosclerosis, 8(3), 260–272.
• Libby, P., & Hansson, G. K. (2019). From focal lipid storage to systemic inflammation: JACC review topic of the week. Journal of the American College of Cardiology, 74(12), 1594–1607.
• Libby, P. (2021). The changing landscape of atherosclerosis. Nature, 592(7855), 524–533.
• Lüscher, T. F. (2023). An update on inflammation in atherosclerosis: How to effectively treat residual risk. Clinical Therapeutics, 45(11), 1055–1059. https://doi.org/10.1016/j.clinthera.2023.08.016
• McMurray, J. J. V., Solomon, S. D., Inzucchi, S. E., et al. (2019). Dapagliflozin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine, 381(21), 1995–2008.
• Nidorf, S. M., Fiolet, A. T. L., Mosterd, A., et al. (2020). Colchicine in patients with chronic coronary disease. New England Journal of Medicine, 383(19), 1838–1847.
• Pradhan, A. D., Aday, A. W., Rose, L. M., et al. (2018). Residual inflammatory risk on treatment with PCSK9 inhibition and statin therapy. Circulation, 138(2), 141–149. https://doi.org/10.1161/CIRCULATIONAHA.118.034645
• Ridker, P. M. (2013). Moving beyond JUPITER: Will inhibiting inflammation reduce vascular event rates? Current Atherosclerosis Reports, 15(1), 295. https://doi.org/10.1007/s11883-012-0295-3
• Ridker, P. M., Danielson, E., Fonseca, F. A. H., et al. (2008). Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New England Journal of Medicine, 359(21), 2195–2207.
• Ridker, P. M., Everett, B. M., Thuren, T., et al. (2017). Antiinflammatory therapy with canakinumab for atherosclerotic disease. New England Journal of Medicine, 377(12), 1119–1131.
• Ridker, P. M., MacFadyen, J. G., Glynn, R. J., Bradwin, G., Hasan, A. A., & Rifai, N. (2020). Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: Secondary analyses from the Cardiovascular Inflammation Reduction Trial. European Heart Journal, 41(31), 2952–2961. https://doi.org/10.1093/eurheartj/ehaa160
• Ridker, P. M., & Libby, P. (2023). Inflammation in atherosclerosis: From pathophysiology to practice. European Heart Journal.
• Solomon, S. D., Rizkala, A. R., Lefkowitz, M. P., et al. (2023). Semaglutide and cardiovascular outcomes in overweight or obesity (SELECT Trial). New England Journal of Medicine.
• Tardif, J. C., Kouz, S., Waters, D. D., et al. (2019). Efficacy and safety of low-dose colchicine after myocardial infarction. New England Journal of Medicine, 381(26), 2497–2505.
