Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): The Multifaceted Biology, Diseases, and Pharmaceutical Interventions

Jia Kuang , Lei Hao , Meibiao Zhang , Zhao Yang

MedComm ›› 2025, Vol. 6 ›› Issue (11) : e70451

PDF
MedComm ›› 2025, Vol. 6 ›› Issue (11) : e70451 DOI: 10.1002/mco2.70451
REVIEW

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): The Multifaceted Biology, Diseases, and Pharmaceutical Interventions

Author information +
History +
PDF

Abstract

Ischemic stroke remains a leading cause of global disability and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as potent lipid-lowering agents with expanding therapeutic potential. Beyond robust low-density lipoprotein cholesterol reduction, accumulating evidence suggests these drugs may confer benefits in ischemic stroke prevention and management. However, challenges regarding accessibility, real-world efficacy, and integration into combination therapies persist, necessitating a comprehensive evidence synthesis. This review systematically consolidates the molecular mechanisms of PCSK9 inhibition and classifies current inhibitors. We delineate recent preclinical advances underscoring their neuroprotective and vasculoprotective effects, alongside critical findings from major clinical trials. These developments highlight promising avenues for both secondary prevention and acute-phase treatment strategies. Collectively, this synthesis establishes a foundational framework for positioning PCSK9 inhibitors as transformative agents in stroke therapeutics and paves the way for precision neurovascular medicine.

Keywords

PCSK9 / LDL-C / ischemic stroke / intervention strategies / precision therapy

Cite this article

Download citation ▾
Jia Kuang, Lei Hao, Meibiao Zhang, Zhao Yang. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): The Multifaceted Biology, Diseases, and Pharmaceutical Interventions. MedComm, 2025, 6(11): e70451 DOI:10.1002/mco2.70451

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

D. Sims, “Ask the Consultant: Stroke, ” Bmj 389 (2025): r436.

[2]

V. L. Feigin, M. Brainin, B. Norrving, et al., “World stroke organization (WSO): Global stroke Fact Sheet 2022, ” International Journal of Stroke 17 (2022): 18-29.

[3]

F. Mach, C. Baigent, A. L. Catapano, et al., “2019 ESC/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk, ” European Heart Journal 41 (2020): 111-188.

[4]

P. Gargiulo, C. Basile, A. Cesaro, et al., “Efficacy, Safety, Adherence and Persistence of PCSK9 Inhibitors in Clinical Practice: A Single Country, Multicenter, Observational Study (AT-TARGET-IT), ” Atherosclerosis 366 (2023): 32-39.

[5]

V. L. Feigin, B. A. Stark, C. O. Johnson, et al., “Global, Regional, and National Burden of Stroke and Its Risk Factors, 1990-2019: A Systematic Analysis for the Global Burden of Disease Study 2019, ” Lancet Neurology 20 (2021): 795-820.

[6]

J. Vicente-Valor, X. García-González, S. Ibáñez-García, et al., “PCSK9 inhibitors Revisited: Effectiveness and Safety of PCSK9 inhibitors in a Real-life spanish Cohort, ” Biomedicine and Pharmacotherapy 146 (2022): 112519.

[7]

X. Bao, Y. Liang, H. Chang, et al., “Targeting Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): From Bench to Bedside, ” Signal Transduction and Targeted Therapy 9 (2024): 13.

[8]

H. H. Hobbs, J. C. Cohen, and J. D. Horton, “PCSK9: From Nature's Loss to Patient's Gain, ” Circulation 149 (2024): 171-173.

[9]

R. D. Santos, K. Nasir, and M. D. Shapiro, “A Step Forward for Long-acting PCSK9 Inhibition: Improvements Without a Breakthrough, ” Journal of the American College of Cardiology 84 (2024): 2048-2050.

[10]

T. E. Strandberg, P. T. Kovanen, D. M. Lloyd-Jones, F. J. Raal, R. D. Santos, and G. F. Watts, “Drugs for Dyslipidaemia: The Legacy Effect of the scandinavian Simvastatin Survival Study, ” Lancet 404, no. 4S (2024): 2462-2475.

[11]

S. Hummelgaard, J. P. Vilstrup, C. Gustafsen, S. Glerup, and K. Weyer, “Targeting PCSK9 to Tackle Cardiovascular Disease, ” Pharmacology and Therapeutics 249 (2023): 108480.

[12]

N. G. Seidah and A. Prat, “The Biology and Therapeutic Targeting of the Proprotein Convertases, ” Nature Reviews Drug Discovery 11 (2012): 367-383.

[13]

S. Poirier, G. Mayer, S. Benjannet, et al., “The Proprotein Convertase PCSK9 Induces the Degradation of Low Density Lipoprotein Receptor (LDLR) and Its Closest family Members VLDLR and ApoER2, ” Journal of Biological Chemistry 283 (2008): 2363-2372.

[14]

A. Grefhorst, M. C. McNutt, T. A. Lagace, and J. D. Horton, “Plasma PCSK9 Preferentially Reduces Liver LDL Receptors in Mice, ” Journal of Lipid Research 49 (2008): 1303-1311.

[15]

Y. Wang, Y. Huang, H. H. Hobbs, and J. C. Cohen, “Molecular Characterization of Proprotein Convertase Subtilisin/Kexin Type 9-mediated Degradation of the LDLR, ” Journal of Lipid Research 53 (2012): 1932-1943.

[16]

E. Gallego-Colon, A. Daum, and C. Yosefy, “Statins and PCSK9 Inhibitors: A New Lipid-lowering Therapy, ” European Journal of Pharmacology 878 (2020): 173114.

[17]

J. Cohen, A. Pertsemlidis, I. K. Kotowski, R. Graham, C. K. Garcia, and H. H. Hobbs, “Low LDL Cholesterol in Individuals of african Descent Resulting From Frequent Nonsense Mutations in PCSK9, ” Nature Genetics 37 (2005): 161-165.

[18]

I. K. Kotowski, A. Pertsemlidis, A. Luke, et al., “A Spectrum of PCSK9 Alleles Contributes to Plasma Levels of Low-density Lipoprotein Cholesterol, ” American Journal of Human Genetics 78 (2006): 410-422.

[19]

M. Abifadel, M. Varret, J. Rabès, et al., “Mutations in PCSK9 Cause Autosomal Dominant Hypercholesterolemia, ” Nature Genetics 34 (2003): 154-156.

[20]

M. S. Sabatine, J. A. Underberg, M. Koren, and S. J. Baum, “Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice, ” Postgraduate Medicine 128, no. Suppl 1 (2016): 31-39.

[21]

F. J. Raal, V. Mehta, M. Kayikcioglu, et al., “Lerodalcibep and evolocumab for the Treatment of Homozygous Familial Hypercholesterolaemia With PCSK9 Inhibition (LIBerate-HoFH): A Phase 3, Randomised, Open-label, Crossover, Non-inferiority Trial, ” The Lancet Diabetes and Endocrinology 13 (2025): 178-187.

[22]

N. A. Marston, F. K. Kamanu, G. E. M. Melloni, et al., “Endothelial Cell-related Genetic Variants Identify LDL Cholesterol-sensitive Individuals Who Derive Greater Benefit From Aggressive Lipid Lowering, ” Nature Medicine 31 (2025): 963-969.

[23]

U. Laufs, R. De Caterina, F. Schiele, et al., “The ACS EuroPath Survey Series: Time Trends in Lipid Management After an Acute Coronary Syndrome, ” European Journal of Preventive Cardiology (2025): zwaf399, https://doi.org/10.1093/eurjpc/zwaf399.

[24]

P. Gaba, M. L. O'Donoghue, J. Park, et al., “Association Between Achieved Low-density Lipoprotein Cholesterol Levels and Long-term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE, ” Circulation 147 (2023): 1192-1203.

[25]

G. G. Schwartz, M. Szarek, D. L. Bhatt, et al., “Transiently Achieved Very Low LDL-cholesterol Levels by Statin and Alirocumab After Acute Coronary Syndrome Are Associated With Cardiovascular Risk Reduction: The ODYSSEY OUTCOMES Trial, ” European Heart Journal 44 (2023): 1408-1417.

[26]

E. Hagström, P. G. Steg, M. Szarek, et al., “Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of alirocumab, ” Circulation 146 (2022): 657-672.

[27]

D. Gaudet, J. L. López-Sendón, M. Averna, et al., “Safety and Efficacy of alirocumab in a Real-life Setting: The ODYSSEY APPRISE Study, ” European Journal of Preventive Cardiology 28 (2022): 1864-1872.

[28]

M. Szarek, E. Reijnders, J. W. Jukema, et al., “Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests, ” Circulation 149 (2024): 192-203.

[29]

P. M. Ridker, D. L. Bhatt, A. D. Pradhan, R. J. Glynn, J. G. MacFadyen, and S. E. Nissen, “Inflammation and Cholesterol as Predictors of Cardiovascular Events Among Patients Receiving Statin Therapy: A Collaborative Analysis of Three Randomised Trials, ” Lancet London England 401 (2023): 1293-1301.

[30]

N. A. A. Azhar, Y. Chua, H. Nawawi, and S. A. Jusoh, “Structural Dynamics of LDL Receptor Interactions With E498A and R499G Variants of PCSK9, ” Journal of Molecular Modeling 31 (2025): 161.

[31]

Y. Guan, X. Liu, Z. Yang, et al., “PCSK9 promotes LDLR Degradation by Preventing SNX17-mediated LDLR Recycling, ” Circulation 151 (2025): 1512-1526.

[32]

A. Canfrán-Duque, N. Rotllan, X. Zhang, et al., “Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling, ” Circulation 147 (2023): 388-408.

[33]

R. I. Jaén, A. Povo-Retana, C. Rosales-Mendoza, et al., “Functional Crosstalk Between PCSK9 Internalization and Pro-inflammatory Activation in human Macrophages: Role of Reactive Oxygen Species Release, ” International Journal of Molecular Sciences 23 (2022): 9114.

[34]

S. Katsuki, P. K. Jha, A. Lupieri, et al., “Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms, ” Circulation Research 131 (2022): 873-889.

[35]

D. Gomes, S. Wang, L. Goodspeed, et al., “Comparison Between Genetic and Pharmaceutical Disruption of Ldlr Expression for the Development of Atherosclerosis, ” Journal of Lipid Research 63 (2022): 100174.

[36]

Z. Peng, S. Lv, H. Chen, et al., “Disruption of PCSK9 Suppresses Inflammation and Attenuates Abdominal Aortic Aneurysm Formation, ” Arteriosclerosis, Thrombosis, and Vascular Biology 45 (2025): e1-e14.

[37]

P. Xie, H. Luo, W. Pei, et al., “Saponins Derived From Gynostemma Pentaphyllum Regulate Triglyceride and Cholesterol Metabolism and the Mechanisms: A Review, ” Journal of Ethnopharmacology 319 (2024): 117186.

[38]

F. Teng, X.-W. Li, M. Li, et al., “components and Lipid-lowering Effect of Total Saponins From Underground Part of Gynostemma Pentaphyllum], ” Zhongguo Zhong Yao Za Zhi Zhongguo Zhongyao Zazhi China J Chin Mater Medica 47 (2022): 5022-5031.

[39]

Q. Chen, F. Wu, and Y. Zhao, Effects of Gynostemma Pentaphyllum on Hypolipidemic and the Mechanism of Network Pharmacology and Molecular Docking in Treating Hyperlipidaemia. Preprint at, https://doi.org/10.21203/rs.3.rs-1798888/v1 (2022).

[40]

P. Xie, J. Xie, M. Xiao, et al., “Liver Lipidomics Analysis Reveals the Anti-obesity and Lipid-lowering Effects of Gypnosides From Heat-processed Gynostemma Pentaphyllum in High-fat Diet Fed Mice, ” Phytomedicine 115 (2023): 154834.

[41]

Y. Zou, Z. Chen, X. Zhang, et al., “Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells, ” Frontiers in Immunology 13 (2022): 894789.

[42]

Y. Wang, D. Fang, Q. Yang, et al., “Interactions Between PCSK9 and NLRP3 Inflammasome Signaling in Atherosclerosis, ” Frontiers in Immunology 14 (2023): 1126823.

[43]

Y. X. Zhang, W. J. Cliff, G. I. Schoefl, and G. Higgins, “Coronary C-reactive Protein Distribution: Its Relation to Development of Atherosclerosis, ” Atherosclerosis 145 (1999): 375-379.

[44]

A. A. Momtazi-Borojeni, S. Sabouri-Rad, A. M. Gotto, et al., “PCSK9 and Inflammation: A Review of Experimental and Clinical Evidence, ” European Heart Journal - Cardiovascular Pharmacotherapy 5 (2019): 237-245.

[45]

E. Punch, J. Klein, P. Diaba-Nuhoho, H. Morawietz, and M. Garelnabi, “Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis, ” Journal of the American Heart Association 11 (2022): e023328.

[46]

M. K. Jain and P. M. Ridker, “Anti-inflammatory Effects of Statins: Clinical Evidence and Basic Mechanisms, ” Nature Reviews Drug Discovery 4 (2005): 977-987.

[47]

Z. Tang, L. Jiang, J. Peng, et al., “PCSK9 siRNA Suppresses the Inflammatory Response Induced by oxLDL Through Inhibition of NF-κB Activation in THP-1-derived Macrophages, ” International Journal of Molecular Medicine 30 (2012): 931-938.

[48]

S. Shin, H. Park, H. Chang, et al., “Impact of Intensive LDL Cholesterol Lowering on Coronary Artery Atherosclerosis Progression: A Serial CT Angiography Study, ” JACC Cardiovasc Imaging 10 (2017): 437-446.

[49]

S. Lee, H. Chang, J. M. Sung, et al., “Effects of Statins on Coronary Atherosclerotic Plaques: The PARADIGM Study, ” JACC Cardiovasc Imaging 11 (2018): 1475-1484.

[50]

J. M. Smit, A. R. van Rosendael, M. El Mahdiui, et al., “Impact of Clinical Characteristics and Statins on Coronary Plaque Progression by Serial Computed Tomography Angiography, ” Circulation: Cardiovascular Imaging 13 (2020): e009750.

[51]

C. M. Gibson, D. Duffy, M. C. Bahit, et al., “Apolipoprotein a-I Infusions and Cardiovascular Outcomes in Acute Myocardial Infarction According to Baseline LDL-cholesterol Levels: The AEGIS-II Trial, ” European Heart Journal 45 (2024): 5023-5038.

[52]

L. Barbieri, G. Tumminello, I. Fichtner, et al., “PCSK9 and Coronary Artery Plaque-new Opportunity or Red Herring?, ” Current Atherosclerosis Reports 26 (2024): 589-602.

[53]

C. Landlinger, M. G. Pouwer, C. Juno, et al., “The AT04A Vaccine Against Proprotein Convertase Subtilisin/Kexin Type 9 Reduces Total Cholesterol, Vascular Inflammation, and Atherosclerosis in APOE*3Leiden.CETP Mice, ” European Heart Journal 38 (2017): 2499-2507.

[54]

Q. Zhang, M. Miao, S. Cao, et al., “PCSK9 promotes Vascular Neointimal Hyperplasia Through Non-lipid Regulation of Vascular Smooth Muscle Cell Proliferation, Migration, and Autophagy, ” Biochemical and Biophysical Research Communications 742 (2025): 151081.

[55]

R. Xu, T. Li, J. Luo, et al., “increases Vulnerability of Carotid Plaque by Promoting Mitochondrial Dysfunction and Apoptosis of Vascular Smooth Muscle Cells, ” CNS Neuroscience and Therapeutics 30 (2024): e14640.

[56]

T. A. Lagace, “PCSK9 and LDLR Degradation: Regulatory Mechanisms in Circulation and in Cells, ” Current Opinion in Lipidology 25 (2014): 387-393.

[57]

J. M. Cheng, R. M. Oemrawsingh, H. M. Garcia-Garcia, et al., “PCSK9 in Relation to Coronary Plaque Inflammation: Results of the ATHEROREMO-IVUS Study, ” Atherosclerosis 248 (2016): 117-122.

[58]

J. P. Ferreira, C. Xhaard, Z. Lamiral, et al., “PCSK9 protein and rs562556 Polymorphism Are Associated With Arterial Plaques in Healthy Middle-aged Population: The STANISLAS Cohort, ” Journal of the American Heart Association 9 (2020): e014758.

[59]

L. Saba, T. Saam, H. R. Jäger, et al., “Imaging Biomarkers of Vulnerable Carotid Plaques for Stroke Risk Prediction and Their Potential Clinical Implications, ” Lancet Neurology 18 (2019): 559-572.

[60]

S. Yasmeen, B. H. Akram, A. H. Hainsworth, and C. Kruuse, “Cyclic Nucleotide Phosphodiesterases (PDEs) and Endothelial Function in Ischaemic Stroke. A Review, ” Cell Signalling 61 (2019): 108-119.

[61]

E. Rexhaj, S. Bär, R. Soria, et al., “Effects of alirocumab on Endothelial Function and Coronary Atherosclerosis in Myocardial Infarction: A PACMAN-AMI Randomized Clinical Trial Substudy, ” Atherosclerosis 392 (2024): 117504.

[62]

S. Ac, I. Breder, J. Barreto, et al., “Evolocumab on Top of empagliflozin Improves Endothelial Function of Individuals With Diabetes: Randomized Active-controlled Trial, ” Cardiovascular Diabetology 21 (2022): 147.

[63]

J. Gao, F. Wu, Y. Liu, et al., “Increase of PCSK9 Expression in Diabetes Promotes VEGFR2 Ubiquitination to Inhibit Endothelial Function and Skin Wound Healing, ” Science China Life Sciences 67 (2024): 2635-2649.

[64]

D. J. McClintick, M. L. O'Donoghue, G. M. De Ferrari, et al., “Long-term Efficacy of evolocumab in Patients With or Without Multivessel Coronary Disease, ” Journal of the American College of Cardiology 83 (2024): 652-664.

[65]

G. G. Schwartz and R. P. Giugliano, “Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition After Acute Coronary Syndrome or Prior Myocardial Infarction, ” Current Opinion in Lipidology 33 (2022): 147-159.

[66]

P. Theofilis, A. Papanikolaou, P. K. Vlachakis, et al., “PCSK9 inhibitors and Coronary Atherosclerotic Plaque Modification: A Meta-analysis, ” European Heart Journal 45 (2024): ehae666.1402.

[67]

N. D'Onofrio, F. Prattichizzo, R. Marfella, et al., “SIRT3 mediates the Effects of PCSK9 Inhibitors on Inflammation, Autophagy, and Oxidative Stress in Endothelial Cells, ” Theranostics 13 (2023): 531-542.

[68]

X. Cao, V. W. Y. Wu, Y. Han, et al., “Role of Argininosuccinate Synthase 1 -dependent L-arginine Biosynthesis in the Protective Effect of Endothelial Sirtuin 3 Against Atherosclerosis, ” Advancement of Science 11 (2024): 2307256.

[69]

Y. Wang, S. Cao, Z. Wang, et al., “PCSK9 affects Vascular Senescence Through the SIRT1 Pathway, ” Experimental Gerontology 201 (2025): 112701.

[70]

B. Furie and B. C. Furie, “The Molecular Basis of Blood Coagulation, ” Cell 53 (1988): 505-518.

[71]

Thrombosis: a major contributor to global disease burden ISTH steering committee for world thrombosis day | request PDF. Researchgate (2024), https://doi.org/10.1160/TH14-08-0671.

[72]

M. U. Puteri, N. U. Azmi, M. Kato, and F. C. Saputri, “PCSK9 promotes Cardiovascular Diseases: Recent Evidence About Its Association With Platelet Activation-induced Myocardial Infarction, ” Life Basel Switzerland 12 (2022): 190.

[73]

M. Puccini, U. Landmesser, and U. Rauch, “Pleiotropic Effects of PCSK9: Focus on Thrombosis and Haemostasis, ” Metabolites 12 (2022): 226.

[74]

E. P. Navarese, M. Kolodziejczak, M. Winter, et al., “Association of PCSK9 With Platelet Reactivity in Patients With Acute Coronary Syndrome Treated With Prasugrel or Ticagrelor: The PCSK9-REACT Study, ” International Journal of Cardiology 227 (2017): 644-649.

[75]

D. Pastori, C. Nocella, A. Farcomeni, et al., “Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation,” Journal of the American College of Cardiology 70, 1455-1462 (2017).

[76]

Z. Qi, L. Hu, J. Zhang, et al., “PCSK9 (proprotein convertase subtilisin/kexin 9) enhances Platelet Activation, Thrombosis, and Myocardial Infarct Expansion by Binding to Platelet CD36,” Circulation 143 (2021): 45-61.

[77]

K. Kotani and M. Banach, “Lipoprotein(a) and Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9, ” Journal of Thoracic Disease 9 (2017): E78-E82.

[78]

B. Moustafa, D. Oparowski, S. Testai, I. Guman, and G. Trifan, “Efficacy and Safety of PCSK9 Inhibitors for Stroke Prevention: Systematic Review and Meta-analysis, ” Journal of Stroke and Cerebrovascular Diseases 33 (2024).

[79]

F. Agnello, M. S. Mauro, C. Rochira, et al., “PCSK9 inhibitors: Current Status and Emerging Frontiers in Lipid Control, ” Expert Review of Cardiovascular Therapy 22 (2024): 41-58.

[80]

B. Gencer, N. A. Marston, K. Im, et al., “Efficacy and Safety of Lowering LDL Cholesterol in Older Patients: A Systematic Review and Meta-analysis of Randomised Controlled Trials, ” Lancet 396 (2020): 1637-1643.

[81]

A. Avogaro, R. Buzzetti, R. Candido, et al., “Exploring the Benefits of alirocumab as Lipid-lowering Therapy in People With Diabetes and Very High Cardiovascular Risk, ” Diabetes Research and Clinical Practice 222 (2025): 112055.

[82]

P. Guedeney, G. Giustino, S. Sorrentino, et al., “Efficacy and Safety of Alirocumab and Evolocumab: A Systematic Review and Meta-analysis of Randomized Controlled Trials, ” European Heart Journal 43 (2022): e17-e25.

[83]

M. Xu, Z. Wang, Y. Zhang, et al., “Recaticimab Monotherapy for Nonfamilial Hypercholesterolemia and Mixed Hyperlipemia: The Phase 3 REMAIN-1 Randomized Trial, ” Journal of the American College of Cardiology 84 (2024): 2026-2036.

[84]

V. Bittner, “Pleiotropic Effects of PCSK9 (proprotein convertase subtilisin/kexin type 9) Inhibitors?, ” Circulation 134 (2016): 1695-1696.

[85]

E. P. Navarese, M. Kołodziejczak, V. Schulze, et al., “Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis, ” Annals of Internal Medicine 163 (2015): 40-51.

[86]

K. Oyama, R. P. Giugliano, M. Tang, et al., “Effect of evolocumab on Acute Arterial Events Across all Vascular territories : Results From the FOURIER Trial, ” European Heart Journal 42 (2021): 4821-4829.

[87]

M. L. O'Donoghue, R. P. Giugliano, S. D. Wiviott, et al., “Long-term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease, ” Circulation 146 (2022): 1109-1119.

[88]

S. Al Said, M. L. O'Donoghue, X. Ran, et al., “Long-term Lipid Lowering With Evolocumab in Older Individuals, ” Journal of the American College of Cardiology 85 (2025): 504-512.

[89]

S. J. Nicholls, Y. Kataoka, S. E. Nissen, et al., “Effect of evolocumab on Coronary Plaque Phenotype and Burden in Statin-treated Patients Following Myocardial Infarction, ” JACC Cardiovascular Imaging 15 (2022): 1308-1321.

[90]

H. Yano, S. Horinaka, and T. Ishimitsu, “Effect of Evolocumab Therapy on Coronary Fibrous Cap Thickness Assessed by Optical Coherence Tomography in Patients With Acute Coronary Syndrome, ” Journal of Cardiology 75 (2020): 289-295.

[91]

J. Rakocevic, M. Dobric, R. Vucic, et al., “Small Interfering Ribonucleic Acid as Lipid-Lowering Therapy: Inclisiran in Focus, ” International Journal of Molecular Sciences 24 (2023): 6012.

[92]

Z. Luo, Z. Huang, F. Sun, et al., “The Clinical Effects of inclisiran, a First-in-class LDL-C Lowering siRNA Therapy, on the LDL-C Levels in Chinese Patients With Hypercholesterolemia, ” Journal of Clinical Lipidology 17 (2023): 392-400.

[93]

F. Gomez-Delgado, M. Raya-Cruz, N. Katsiki, J. Delgado-Lista, and P. Perez-Martinez, “Residual Cardiovascular Risk: When Should We Treat It?, ” European Journal of Internal Medicine 120 (2024): 17-24.

[94]

D. M. Lloyd-Jones, P. B. Morris, C. M. Ballantyne, et al., “2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the american college of cardiology solution set oversight committee, ” Journal of the American College of Cardiology 80 (2022): 1366-1418.

[95]

C. Gao, B. Zhu, F. Ouyang, et al., “Stepwise Dual Antiplatelet Therapy De-escalation in Patients After Drug Coated Balloon Angioplasty (REC-CAGEFREE II): Multicentre, Randomised, Open Label, Assessor Blind, Non-inferiority Trial, ” Bmj 388 (2025): e082945.

[96]

A. Dec, A. Niemiec, E. Wojciechowska, et al., “Inclisiran-a Revolutionary Addition to a Cholesterol-lowering Therapy, ” International Journal of Molecular Sciences 24 (2023): 6858.

[97]

L. Räber, Y. Ueki, T. Otsuka, et al., “Effect of alirocumab Added to High-intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial, ” Jama 327 (2022): 1771-1781.

[98]

P. M. Ridker, J. G. MacFadyen, B. M. Everett, et al., “Relationship of C-reactive Protein Reduction to Cardiovascular Event Reduction Following Treatment With canakinumab: A Secondary Analysis From the CANTOS Randomised Controlled Trial, ” Lancet London England 391 (2018): 319-328.

[99]

E. Q. Klug, S. Llerena, L. J. Burgess, et al., “Efficacy and Safety of lerodalcibep in Patients With or at High Risk of Cardiovascular Disease: A Randomized Clinical Trial, ” JAMA Cardiology 9 (2024): 800-807.

[100]

M. G. Silverman, B. A. Ference, K. Im, et al., “Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis, ” Jama 316 (2016): 1289-1297.

[101]

I. T. Farmakis, K. C. Christodoulou, L. Hobohm, S. V. Konstantinides, and L. Valerio, “Lipid Lowering for Prevention of Venous Thromboembolism: A Network Meta-analysis, ” European Heart Journal 45 (2024): 3219-3227.

[102]

D. Zahger, G. G. Schwartz, W. Du, et al., “Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome, ” Journal of the American College of Cardiology 84 (2024): 994-1006.

[103]

Epigenetic Editing of PCSK9 for a Durable Reduction in Cholesterol. Nature Medicine 31 (2025): 1083-1084.

[104]

E. Samuel, M. Watford, U. O. Egolum, D. N. Ombengi, H. Ling, and D. W. Cates, “Inclisiran: A First-in-class siRNA Therapy for Lowering Low-density Lipoprotein Cholesterol, ” Annals of Pharmacotherapy 57 (2023): 317-324.

[105]

I. Gouni-Berthold, J. Schwarz, and H. K. Berthold, “PCSK9 monoclonal Antibodies: New Developments and Their Relevance in a Nucleic Acid-based Therapy Era, ” Current Atherosclerosis Reports 24 (2022): 779-790.

[106]

T. Kosenko, M. Golder, G. Leblond, W. Weng, and T. A. Lagace, “Low Density Lipoprotein Binds to Proprotein Convertase Subtilisin/Kexin Type-9 (PCSK9) in human Plasma and Inhibits PCSK9-mediated Low Density Lipoprotein Receptor Degradation*, ” Journal of Biological Chemistry 288 (2013): 8279-8288.

[107]

G. Lambert, F. Charlton, K. Rye, and D. E. Piper, “Molecular Basis of PCSK9 Function, ” Atherosclerosis 203 (2009): 1-7.

[108]

L. Da Dalt, A. Baragetti, and G. D. Norata, “Targeting PCSK9 Beyond the Liver: Evidence From Experimental and Clinical Studies, ” Expert Opinion on Therapeutic Targets 29 (2025): 137-157.

[109]

S. A. Burnap, K. Sattler, R. Pechlaner, et al., “PCSK9 activity Is Potentiated Through HDL Binding, ” Circulation Research 129 (2021): 1039-1053.

[110]

G. G. Schwartz, M. Szarek, V. A. Bittner, et al., “Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol, ” Journal of the American College of Cardiology 78 (2021): 421-433.

[111]

Y. Sun, Q. Lv, Y. Guo, et al., “Recaticimab as Add-on Therapy to Statins for Nonfamilial Hypercholesterolemia: The Randomized, Phase 3 REMAIN-2 Trial, ” Journal of the American College of Cardiology 84 (2024): 2037-2047.

[112]

S. U. Khan, S. H. Yedlapati, A. N. Lone, et al., “PCSK9 inhibitors and Ezetimibe With or Without Statin Therapy for Cardiovascular Risk Reduction: A Systematic Review and Network Meta-analysis, ” Bmj 377 (2022): e069116.

[113]

J. I. Morton, D. Liew, G. F. Watts, et al., “Rethinking Cardiovascular Prevention: Cost-effective Cholesterol Lowering for Statin-intolerant Patients in Australia and the UK, ” European Journal of Preventive Cardiology 32, no. 13 (2025): 1259-1270.

[114]

Q. Hao, B. Aertgeerts, G. Guyatt, et al., “PCSK9 inhibitors and Ezetimibe for the Reduction of Cardiovascular Events: A Clinical Practice Guideline With Risk-stratified Recommendations, ” Bmj 377 (2022): e069066.

[115]

J. W. Mulder, A. M. Galema-Boers, and J. E. Roeters van Lennep, “First Clinical Experiences With inclisiran in a Real-world Setting, ” Journal of Clinical Lipidology 17 (2023): 818-827.

[116]

Y. Tang, S. Li, J. Hu, K. Sun, L. Liu, and D. Xu, “Research Progress on Alternative Non-classical Mechanisms of PCSK9 in Atherosclerosis in Patients With and Without Diabetes, ” Cardiovascular Diabetology 19 (2020): 33.

[117]

J. Golledge, H. S. Lu, and S. Shah, “Proprotein Convertase Subtilisin/Kexin Type 9 as a Drug Target for Abdominal Aortic Aneurysm, ” Current Opinion in Lipidology 35 (2024): 241-247.

[118]

S. Kühnast, J. W. A. van der Hoorn, E. J. Pieterman, et al., “Alirocumab Inhibits Atherosclerosis, Improves the Plaque Morphology, and Enhances the Effects of a Statin, ” Journal of Lipid Research 55 (2014): 2103-2112.

[119]

S. J. Bernelot Moens, A. E. Neele, J. Kroon, et al., “PCSK9 monoclonal Antibodies Reverse the Pro-inflammatory Profile of Monocytes in Familial Hypercholesterolaemia, ” European Heart Journal 38 (2017): 1584-1593.

[120]

A. D. Mazura, A. Ohler, S. E. Storck, et al., “PCSK9 acts as a Key Regulator of Aβ Clearance Across the Blood-brain Barrier, ” Cellular and Molecular Life Sciences CMLS 79 (2022): 212.

[121]

C. Liu, J. Chen, H. Chen, et al., “PCSK9 inhibition: From Current Advances to Evolving Future, ” Cells 11 (2022): 2972.

[122]

B. Papotti, M. P. Adorni, C. Marchi, et al., “PCSK9 affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying in Vitro: Potential Implications in alzheimer's Disease, ” International Journal of Molecular Sciences 23 (2022): 12192.

[123]

F. Yan, L. P. Phan, N. T. T. Le, and Y. Jin, “Research Progress on the Protective Mechanism of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Vascular Endothelium, ” Journal of Clinical Medicine 28 (2024): 142-148.

[124]

L. Wang, Z. Wang, J. Shi, et al., “Inhibition of Proprotein Convertase Subtilisin/Kexin Type 9 Attenuates Neuronal Apoptosis Following Focal Cerebral Ischemia via Apolipoprotein E Receptor 2 Downregulation in Hyperlipidemic Mice, ” International Journal of Molecular Medicine 42 (2018): 2098-2106.

[125]

Y. Zheng, T. Zhu, G. Li, L. Xu, and Y. Zhang, “PCSK9 inhibitor Protects Against Ischemic Cerebral Injury by Attenuating Inflammation via the GPNMB/CD44 Pathway, ” International Immunopharmacology 126 (2024): 111195.

[126]

H. Wang, Q. Wang, J. Wang, et al., “Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Deficiency Is Protective Against Venous Thrombosis in Mice, ” Scientific Reports 7 (2017): 14360.

[127]

M. Zuin, A. Corsini, C. Dalla Valle, et al., “Role of PCSK9 Inhibitors in Venous Thromboembolism: Current Evidence and Unmet Clinical Needs, ” European Heart Journal - Cardiovascular Pharmacotherapy 10 (2025): 719-724.

[128]

A. Demers, S. Samami, B. Lauzier, et al., “PCSK9 induces CD36 Degradation and Affects Long-chain Fatty Acid Uptake and Triglyceride Metabolism in Adipocytes and in Mouse Liver, ” Arteriosclerosis, Thrombosis, and Vascular Biology 35 (2015): 2517-2525.

[129]

J. Grune, H. Meyborg, T. Bezhaeva, et al., “PCSK9 regulates the Chemokine Receptor CCR2 on Monocytes, ” Biochemical and Biophysical Research Communications 485 (2017): 312-318.

[130]

X. Liu, X. Bao, M. Hu, et al., “Inhibition of PCSK9 Potentiates Immune Checkpoint Therapy for Cancer, ” Nature 588 (2020): 693-698.

[131]

M. Sharma, M. P. Schlegel, M. S. Afonso, et al., “Regulatory T Cells License Macrophage Pro-resolving Functions During Atherosclerosis Regression, ” Circulation Research 127 (2020): 335-353.

[132]

W. Yang, Y. Bai, Y. Xiong, et al., “Potentiating the Antitumour Response of CD8+ T Cells by Modulating Cholesterol Metabolism, ” Nature 531 (2016): 651-655.

[133]

A. Cordero, M. Rodríguez-Mañero, L. Fácila, et al., “Prevention of Myocardial Infarction and Stroke With PCSK9 Inhibitors Treatment: A Metanalysis of Recent Randomized Clinical Trials, ” Journal of Diabetes & Metabolic Disorders 19 (2020): 759-765.

[134]

G. G. Schwartz, P. G. Steg, M. Szarek, et al., “Alirocumab and Cardiovascular Outcomes After Acute Coronary Syndrome, ” New England Journal of Medicine 379 (2018): 2097-2107.

[135]

J. G. Robinson, M. Farnier, M. Krempf, et al., “Efficacy and Safety of alirocumab in Reducing Lipids and Cardiovascular Events, ” New England Journal of Medicine 372 (2015): 1489-1499.

[136]

P. M. Ridker, J. Tardif, P. Amarenco, et al., “Lipid-reduction Variability and Antidrug-antibody Formation With bococizumab, ” New England Journal of Medicine 376 (2017): 1517-1526.

[137]

M. S. Sabatine, R. P. Giugliano, S. D. Wiviott, et al., “Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events,” New England Journal of Medicine 372, no. 16 (2015): 1500-1509, https://www.nejm.org/doi/10.1056/NEJMoa1500858.

[138]

A. Zimerman, A. L. F. Kunzler, B. N. Weber, et al., “Intensive Lowering of LDL Cholesterol Levels With evolocumab in Autoimmune or Inflammatory Diseases: An Analysis of the FOURIER Trial, ” Circulation 151, no. 20 (2025): 1467-1476.

[139]

J. W. Jukema, L. E. Zijlstra, D. L. Bhatt, et al., “Effect of alirocumab on Stroke in ODYSSEY OUTCOMES, ” Circulation 140 (2019): 2054-2062.

[140]

M. J. Koren, M. S. Sabatine, R. P. Giugliano, et al., “Long-term Efficacy and Safety of evolocumab in Patients With Hypercholesterolemia, ” Journal of the American College of Cardiology 74 (2019): 2132-2146.

[141]

V. Bittner, M. Bertolet, R. Barraza Felix, et al., “Comprehensive Cardiovascular Risk Factor Control Improves Survival, ” Journal of the American College of Cardiology 66 (2015): 765-773.

[142]

R. M. Sánchez-Hernández, D. Ibarretxe, F. Fuentes Jiménez, et al., “Homozygous Familial Hypercholesterolemia in Spain. Data From Registry of the spanish atherosclerosis society, ” Journal of Clinical Endocrinology and Metabolism 110, no. 8 (2024): 2280-2287.

[143]

M. J. Wilkinson, P. Bijlani, M. H. Davidson, et al., “Real-World Effectiveness and Safety of Evinacumab in Children and Adults with Homozygous Familial Hypercholesterolemia: A Multisite US Perspective-Brief Report, ” Arteriosclerosis, Thrombosis, and Vascular Biology 45 (2025): 1310-1315.

[144]

N. Bansal, R. Katz, C. Robinson-Cohen, et al., “Absolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-based Cohort Studies, ” JAMA Cardiology 2 (2017): 314-318.

[145]

F. Raal, R. Durst, R. Bi, et al., “Efficacy, Safety, and Tolerability of inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial, ” Circulation 149 (2024): 354-362.

[146]

A. Wiegman, A. L. Peterson, R. A. Hegele, et al., “Efficacy and Safety of inclisiran in Adolescents With Genetically Confirmed Homozygous Familial Hypercholesterolemia: Results From the Double-blind, Placebo-controlled Part of the ORION-13 Randomized Trial, ” Circulation 151 (2025): 1758-1766.

[147]

C. Borràs, M. Canyelles, J. Girona, et al., “PCSK9 antibodies Treatment Specifically Enhances the Macrophage-specific Reverse Cholesterol Transport Pathway in Heterozygous Familial Hypercholesterolemia, ” JACC: Basic to Translational Science 9 (2024): 1195-1210.

[148]

Y. Lee, B. Hong, K. H. Yun, et al., “Alternative LDL Cholesterol-lowering Strategy vs High-intensity Statins in Atherosclerotic Cardiovascular Disease: A Systematic Review and Individual Patient Data Meta-analysis, ” JAMA Cardiology 10 (2025): 137-144.

[149]

K. A. Krychtiuk, M. Claeys, B. Gencer, and F. Mach, “In-hospital Initiation of PCSK9 Inhibitors in ACS: Pros and Cons, ” EuroIntervention 19, no. 4 (2023): e283-e285, https://eurointervention.pcronline.com/article/in-hospital-initiation-of-pcsk9-inhibitors-in-acs-pros-and-cons.

[150]

Correction to: 2023 ESC Guidelines for the Management of Cardiovascular Disease in Patients With Diabetes: Developed by the Task Force on the Management of Cardiovascular Disease in Patients With Diabetes of the european society of cardiology (ESC). European Heart Journal 45 (2024): 518.

[151]

J. Los, F. B. Mensink, T. P. J. Jansen, et al., “Functional Improvement of Non-infarct Related Coronary Artery Stenosis by Extensive LDL-C Reduction With a PCSK9 Antibody: The FITTER Trial, Microvascular Function Analysis, ” European Heart Journal 45 (2024): ehae666.1288.

[152]

E. M. Balke, E. V. Balti, B. Van der Auwera, et al., “Accelerated Progression to Type 1 Diabetes in the Presence of HLA-A*24 and -B*18 Is Restricted to Multiple Islet Autoantibody-Positive Individuals with Distinct HLA-DQ and Autoantibody Risk Profiles, ” Diabetes Care 41 (2018): 1076-1083.

[153]

K. K. Ray, E. Bruckert, P. Peronne-Filardi, et al., “Long-term Persistence With Evolocumab Treatment and Sustained Reductions in LDL-cholesterol Levels Over 30 Months: Final Results From the european Observational HEYMANS Study, ” Atherosclerosis 366 (2023): 14-21.

[154]

K. K. Ray, N. Dhalwani, M. Sibartie, et al., “Low-density Lipoprotein Cholesterol Levels Exceed the Recommended european Threshold for PCSK9i Initiation: Lessons From the HEYMANS Study, ” European Heart Journal - Quality of Care and Clinical Outcomes 8 (2022): 447-460.

[155]

I. Fernández-Ruiz, “Alirocumab Induces Plaque Regression, ” Nature Reviews Cardiology 19 (2022): 350.

[156]

Y. Ueki, J. D. Häner, S. Losdat, et al., “Effect of Alirocumab Added to High-Intensity Statin on Platelet Reactivity and Noncoding RNAs in Patients With AMI: A Substudy of the PACMAN-AMI Trial, ” Thrombosis and Haemostasis 124 (2024): 517-527.

[157]

S. Bär, R. Kavaliauskaite, T. Otsuka, et al., “Impact of alirocumab on Plaque Regression and Haemodynamics of Non-culprit Arteries in Patients With Acute Myocardial Infarction: A Prespecified Substudy of the PACMAN-AMI Trial, ” EuroIntervention: Journal of EuroPCR in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 19 (2023): e286-e296.

[158]

X. Sun, S. Bai, H. Wu, T. Wang, and R. Du, “Administration of Evolocumab in Patients With STEMI After Emergency PCI: A Real-world Cohort Study, ” American Journal of Cardiovascular Drugs 25, no. 4 (2025): 533-545.

[159]

F. G. Biccirè, R. Kakizaki, K. C. Koskinas, et al., “Lesion-level Effects of LDL-C-lowering Therapy in Patients With Acute Myocardial Infarction: A Post Hoc Analysis of the PACMAN-AMI Trial, ” JAMA Cardiology 9 (2024): 1082-1092.

[160]

P. M. Ridker, J. Revkin, P. Amarenco, et al., “Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients, ” New England Journal of Medicine 376 (2017): 1527-1539.

[161]

K. K. Ray, F. J. Raal, D. G. Kallend, et al., “Inclisiran and Cardiovascular Events: A Patient-level Analysis of Phase III Trials, ” European Heart Journal 44 (2023): 129-138.

[162]

W. Zhu, Y. Wu, X. Li, et al., “A Stroke Organoids-multiomics Platform to Study Injury Mechanism and Drug Response, ” Bioactive Materials 44 (2025): 68-81.

[163]

C. Staehr, V. Hinkley, V. V. Matchkov, et al., “Hypoxia and Ischemic Stroke Modify Cerebrovascular Tone by Upregulating Endothelial BK(Ca) Channels-lessons From Rat, Pig, Mouse, and human, ” Acta Physiologica (Oxford, England) 241 (2025): e70030.

[164]

T. Yoshikawa, Y. Akiyoshi, K. Motokawa, K. Nojiri, and H. Kawaguchi, “Cerebral Angiography and Neurobehavioral Patterns in a Non-human Primate Middle Cerebral Artery Occlusion Model, ” Vivo Athens Greece 38 (2024): 2245-2253.

[165]

G. Li, L. Lan, T. He, et al., “Comprehensive Assessment of Ischemic Stroke in Nonhuman Primates: Neuroimaging, Behavioral, and Serum Proteomic Analysis, ” Acs Chemical Neuroscience 15 (2024): 1548-1559.

[166]

M. Salman, S. Ismael, and T. Ishrat, “A Modified Murine Photothrombotic Stroke Model: A Minimally Invasive and Reproducible Cortical and Sub-cortical Infarct Volume and Long-term Deficits, ” Experimental Brain Research 241 (2023): 2487-2497.

[167]

F. Tremblay, Q. Xiong, S. S. Shah, et al., “A Potent Epigenetic Editor Targeting human PCSK9 for Durable Reduction of Low-density Lipoprotein Cholesterol Levels, ” Nature Medicine 31, no. 4 (2025): 1329-1338.

[168]

G. Li, C. Zhang, Y. Li, et al., “Optogenetic Vagal Nerve Stimulation Attenuates Heart Failure by Limiting the Generation of Monocyte-derived Inflammatory CCRL2+ Macrophages, ” Immunity 58, no. 7 (2025): 1847-1861.

[169]

Y. Zhang, H. Zhang, M. Jiang, et al., “Neuroprotection on Ischemic Brain Injury by Mg2+/H2 Released From Endovascular Mg Implant, ” Bioactive Materials 42 (2024): 124-139.

[170]

K. K. Ray, E. Oru, R. S. Rosenson, et al., “Durability and Efficacy of solbinsiran, a GalNAc-conjugated siRNA Targeting ANGPTL3, in Adults With Mixed Dyslipidaemia (PROLONG-ANG3): a Double-blind, Randomised, Placebo-controlled, Phase 2 Trial, ” Lancet London England 405 (2025): 1594-1607.

[171]

K. K. Ray, H. Linnebjerg, L. F. Michael, et al., “Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early human Studies, ” Journal of the American College of Cardiology 85 (2025): 1803-1818.

[172]

M. Kerneis, F. Cosentino, R. Ferrari, et al., “Impact of Chronic Coronary Syndromes on Cardiovascular Hospitalization and Mortality: The ESC-EORP CICD-LT Registry, ” European Journal of Preventive Cardiology 29, no. 15 (2022): 1945-1954.

[173]

A. M. Cao Zhang, E. Ziogos, T. Harb, G. Gerstenblith, and T. M. Leucker, “Emerging Clinical Role of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition-part Two: Current and Emerging Concepts in the Clinical Use of PCSK9 Inhibition, ” European Journal of Clinical Investigation 54 (2024): e14272.

[174]

H. D. White, G. G. Schwartz, M. Szarek, et al., “Alirocumab After Acute Coronary Syndrome in Patients With a History of Heart Failure, ” European Heart Journal 43 (2022): 1554-1565.

[175]

S. Giordano, J. Ielapi, N. Salerno, et al., “Rationale for Early Administration of PCSK9 Inhibitors in Acute Coronary Syndrome, ” Reviews in Cardiovascular Medicine 25 (2024): 374.

[176]

J. M. Kraaijenhof, N. S. Nurmohamed, A. T. Nordestgaard, et al., “Low-density Lipoprotein Cholesterol, C-reactive Protein, and Lipoprotein(a) Universal One-time Screening in Primary Prevention: The EPIC-norfolk Study, ” European Heart Journal (2025): ehaf209, https://doi.org/10.1093/eurheartj/ehaf209.

[177]

A. M. Small, A. Pournamdari, G. E. Melloni, et al., “Lipoprotein(a), C-reactive Protein, and Cardiovascular Risk in Primary and Secondary Prevention Populations, ” JAMA Cardiology 9 (2024): 385-391.

[178]

R. C. Hoogeveen, M. R. Diffenderfer, E. Lim, et al., “Lipoprotein(a) and Risk of Incident Atherosclerotic Cardiovascular Disease: Impact of High-sensitivity C-reactive Protein and Risk Variability Among human Clinical Subgroups, ” Nutrients 17 (2025): 1324.

[179]

J. Liao, M. Qiu, X. Su, et al., “The Residual Risk of Inflammation and Remnant Cholesterol in Acute Coronary Syndrome Patients on statin Treatment Undergoing Percutaneous Coronary Intervention, ” Lipids in Health and Disease 23 (2024): 172.

[180]

H. Zhang, C. Zhang, Y. Zhang, et al., “The Role of Residual Inflammatory Risk and LDL Cholesterol in Patients With in-stent Restenosis Undergoing Percutaneous Coronary Intervention, ” Journal of Clinical Lipidology 18 (2024): e746-e755.

[181]

J. Li, K. Yan, P. Zhu, et al., “LDL-C and hs-CRP Jointly Modify the Effect of lp(a) on 5-year Death in Patients With Percutaneous Coronary Intervention, ” Clinical Cardiology 47 (2024): e70025.

[182]

G. Zeng, C. Zhang, Y. Song, et al., “The Potential Impact of Inflammation on the Lipid Paradox in Patients With Acute Myocardial Infarction: A Multicenter Study, ” BMC Medicine [Electronic Resource] 22 (2024): 599.

[183]

P. M. Ridker, L. Lei, M. J. Louie, et al., “Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-risk Patients With Statin Intolerance, ” Circulation 149 (2024): 28-35.

[184]

J. Kim, J. S. Lee, H. Kim, et al., “Differential Impacts of Admission LDL-cholesterol on Early Vascular Outcomes by Ischemic Stroke Subtypes, ” Journal of Clinical Lipidology 18 (2024): e207-e217.

[185]

Writing Committee, K. K. Birtcher, L. A. Allen, et al., “2022 ACC Expert Consensus Decision Pathway for Integrating Atherosclerotic Cardiovascular Disease and Multimorbidity Treatment: A Framework for Pragmatic, Patient-centered Care, ” Journal of the American College of Cardiology 81 (2023): 292-317.

[186]

R. Vergallo and C. Patrono, “The PACMAN-AMI Trial: Game Over for the “Vulnerable Plaque”, ” European Heart Journal 43 (2022): 2179-2180.

[187]

R. Marfella, F. Prattichizzo, C. Sardu, et al., “Evidence of an Anti-inflammatory Effect of PCSK9 Inhibitors Within the human Atherosclerotic Plaque, ” Atherosclerosis 378 (2023): 117180.

[188]

H. Uehara, T. Kajiya, M. Abe, M. Nakata, S. Hosogi, and S. Ueda, “Early and Short-term Use of Proprotein Convertase Anti-subtilisin-kexin Type 9 Inhibitors on Coronary Plaque Stability in Acute Coronary Syndrome, ” European Heart Journal - Open 4 (2024): oeae055.

[189]

G. Di Giovanni, Y. Kataoka, K. Bubb, A. J. Nelson, and S. J. Nicholls, “Impact of Lipid Lowering on Coronary Atherosclerosis Moving From the Lumen to the Artery Wall, ” Atherosclerosis 367 (2023): 8-14.

[190]

F. G. Biccirè, J. Häner, S. Losdat, et al., “Concomitant Coronary Atheroma Regression and Stabilization in Response to Lipid-lowering Therapy, ” Journal of the American College of Cardiology 82 (2023): 1737-1747.

[191]

L. Pérez de Isla, J. L. Díaz-Díaz, M. J. Romero, et al., “Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients With Familial Hypercholesterolemia: The ARCHITECT Study, ” Circulation 147 (2023): 1436-1443.

[192]

L. Pérez de Isla, J. L. Díaz-Díaz, M. J. Romero, et al., “Characteristics of Coronary Atherosclerosis Related to Plaque Burden Regression During Treatment With alirocumab: The ARCHITECT Study, ” Circulation: Cardiovascular Imaging 17 (2024): e016206.

[193]

G. Di Giovanni and S. J. Nicholls, “Intensive Lipid Lowering Agents and Coronary Atherosclerosis: Insights From Intravascular Imaging, ” American Journal of Preventive Cardiology 11 (2022): 100366.

[194]

D. Han, E. Tzolos, R. Park, et al., “Effects of Evolocumab on Coronary Plaque Composition and Microcalcification Activity by Coronary PET and CT Angiography, ” JACC Cardiovasc Imaging 18 (2025): 589-599.

[195]

E. Ziogos, T. Harb, I. Valenta, et al., “Impact of in-hospital PCSK9 Inhibition on Myocardial Inflammation After Myocardial Infarction: A Randomized Clinical Trial, ” JACC: Basic to Translational Science 10 (2025): 709-720.

[196]

A. E. Lima, G. Vilas Boas, A. L. Carvalho Ferreira, M. Benitez Gonzalez, and C. Guida, “PCSK9 inhibitors Modify Plaque and Reduce Plaque Progression: A Systematic Review and Meta-analysis of Randomized Controlled Trials, ” Circulation (2023).

[197]

Z. Li, L. Guo, Y. An, et al., “Evolocumab Attenuates Myocardial Ischemia/Reperfusion Injury by Blocking PCSK9/LIAS-mediated Cuproptosis of Cardiomyocytes, ” Basic Research in Cardiology 120 (2025): 301-320.

[198]

D. Shin, S. Kim, H. Lee, et al., “PCSK9 stimulates Syk, PKCδ, and NF-κB, Leading to Atherosclerosis Progression Independently of LDL Receptor, ” Nature Communications 15 (2024): 2789.

[199]

J. Bi, X. Li, Y. Cheng, et al., “1871-LB: Impact of PCSK9 Inhibitors on Carotid Plaques in Patients With Diabetes Without Diagnosed ASCVD—A Retrospective Cohort Study,” Diabetes 74 (2025): 1871-LB.

[200]

L. Wu, B. Zhang, C. Li, et al., “PCSK9 inhibitors Reduced Early Recurrent Stroke in Patients With Symptomatic Intracranial Atherosclerotic Stenosis, ” Journal of Neurology, Neurosurgery, and Psychiatry 95 (2024): 529-535.

[201]

M. P. Bonaca, P. Nault, R. P. Giugliano, et al., “Low-density Lipoprotein Cholesterol Lowering With evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (further cardiovascular outcomes research With PCSK9 inhibition in subjects With elevated risk), ” Circulation 137 (2018): 338-350.

[202]

R. P. Giugliano, T. R. Pedersen, J. L. Saver, et al., “Stroke Prevention With the PCSK9 (proprotein convertase subtilisin-kexin type 9) Inhibitor Evolocumab Added to Statin in High-risk Patients With Stable Atherosclerosis, ” Stroke; A Journal of Cerebral Circulation 51 (2020): 1546-1554.

[203]

Q. Xu, Y. Zhao, N. He, et al., “PCSK9: A Emerging Participant in Heart Failure, ” Biomedicine and Pharmacotherapy 158 (2023): 114106.

[204]

W. Zeng, F. Zhou, H. Zhao, et al., “Evaluation of Intensive Statins and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Intracranial Artery Plaque Stability: A Prospective Single-arm Study, ” Journal of the American Heart Association 14 (2025): e035651.

[205]

D. Patriki, S. S. S. Saravi, G. G. Camici, L. Liberale, and J. H. Beer, “PCSK 9: A Link Between Inflammation and Atherosclerosis, ” Current Medicinal Chemistry 29: 251-267.

[206]

S. Pelucchi, L. Da Dalt, G. De Cesare, et al., “Neuronal PCSK9 Regulates Cognitive Performances via the Modulation of ApoER2 Synaptic Localization, ” Pharmacological Research 213 (2025): 107652.

[207]

D. L. Alsbrook, M. Di Napoli, K. Bhatia, et al., “Neuroinflammation in Acute Ischemic and Hemorrhagic Stroke, ” Current Neurology and Neuroscience Reports 23 (2023): 407-431.

[208]

S. J. Nicholls, “PCSK9 inhibitors and Reduction in Cardiovascular Events: Current Evidence and Future Perspectives, ” Kardiologia Polska 81 (2023): 115-122.

[209]

J. A. Howell, J. Larochelle, R. E. Gunraj, et al., “Effects of Global Ripk2 Genetic Deficiency in Aged Mice Following Experimental Ischemic Stroke, ” Aging Brain 7 (2025): 100135.

[210]

W. He, Y. Li, J. Fan, et al., “Gain-of-function PPM1D Mutations Attenuate Ischemic Stroke, ” Cell Death and Differentiation (2025), https://doi.org/10.1038/s41418-025-01523-6.

[211]

Y. Ma, K. Zheng, C. Zhao, et al., “Microglia LILRB4 Upregulation Reduces Brain Damage After Acute Ischemic Stroke by Limiting CD8+ T Cell Recruitment, ” Journal of Neuroinflammation 21 (2024): 214.

[212]

I. Sequí-Domínguez, I. Cavero-Redondo, C. Álvarez-Bueno, D. P. Pozuelo-Carrascosa, S. Nuñez de Arenas-Arroyo, and V. Martínez-Vizcaíno, “Accuracy of Pulse Wave Velocity Predicting Cardiovascular and all-cause Mortality. A Systematic Review and Meta-analysis, ” Journal of Clinical Medicine 9 (2020): 2080.

[213]

G. Chang, Y. Hu, Q. Ge, S. Chu, A. Avolio, and J. Zuo, “Arterial Stiffness as a Predictor of the Index of Atherosclerotic Cardiovascular Disease in Hypertensive Patients, ” International Journal of Environmental Research and Public Health 20 (2023): 2832.

[214]

S. Misra, P. Singh, S. Sengupta, et al., “Subtyping Strokes Using Blood-based Protein Biomarkers: A High-throughput Proteomics and Machine Learning Approach, ” European Journal of Clinical Investigation 55 (2025): e14372.

[215]

G. M. De Marchis, P. Krisai, L. Werlen, et al., “Biomarker, Imaging, and Clinical Factors Associated With Overt and Covert Stroke in Patients With Atrial Fibrillation, ” Stroke; A Journal of Cerebral Circulation 54 (2023): 2542-2551.

[216]

X. Guan, S. Zhu, J. Song, et al., “Microglial CMPK2 Promotes Neuroinflammation and Brain Injury After Ischemic Stroke, ” Cell Reports Medicine 5 (2024): 101522.

[217]

M. J. Koren, R. B. Vega, N. Agrawal, et al., “An Oral PCSK9 Inhibitor for Treatment of Hypercholesterolemia, ” Journal of the American College of Cardiology 85, no. 21 (2025): 1996-2007.

[218]

C. M. Ballantyne, P. Banka, G. Mendez, et al., “Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616, ” Journal of the American College of Cardiology 81 (2023): 1553-1564.

[219]

S. S. Virani, L. K. Newby, S. V. Arnold, et al., “2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the american heart association/american college of cardiology joint committee on Clinical practice Guidelines, ” Circulation 148, no. 9 (2023): e9-e119.

[220]

A. Greco, S. Finocchiaro, M. Spagnolo, et al., “Lipoprotein(a) as a Pharmacological Target: Premises, Promises, and Prospects, ” Circulation 151 (2025): 400-415.

[221]

C. Gregorio, F. Rea, F. Ieva, et al., “Flexible Approaches Based on Multistate Models and Microsimulation to Perform Real-world Cost-effectiveness Analyses: An Application to Proprotein Convertase Subtilisin-kexin Type 9 Inhibitors, ” Value in Health: The Journal of the International Society for Pharmacoeconomics and Outcomes Research 27 (2024): 897-906.

[222]

G. Barbati, C. Gregorio, A. Scagnetto, C. Indennidate, C. Cappelletto, and A. Di Lenarda, “Effectiveness of PCSK9 Inhibitors: A Target Trial Emulation Framework Based on Real-world Electronic Health Records, ” PLoS ONE 19 (2024): e0309470.

[223]

G. Morabito, C. Gregorio, F. Ieva, et al., “Cost-effectiveness of Single-pill and Separate-pill Administration of Antihypertensive Triple Combination Therapy: A Population-based Microsimulation Study, ” BMC Public Health [Electronic Resource] 24 (2024): 1808.

[224]

A. L. Schwartz, S. Kim, A. S. Navathe, and A. Gupta, “Growth of medicare Advantage After Plan Payment Reductions, ” JAMA Health Forum 4 (2023): e231744.

[225]

C. Jiang, K. R. Yabroff, R. D. Nipp, et al., “Costs and Access Barriers to ondansetron in the US, ” JAMA Network Open 7 (2024): e2443978.

[226]

A. P. Chung, J. T. Shafrin, S. Vadgama, et al., “Inequalities in CAR T-cell Therapy Access for US Patients With Relapsed/Refractory DLBCL: A SEER-medicare Data Analysis, ” Blood Advance 9, no. 18 (2025): 4727-4735.

[227]

Y. Tu, B. Chen, C. Liao, et al., “Inequality in Infrastructure Access and Its Association With Health Disparities, ” Nature Human Behaviour 9, no. 8 (2025): 1669-1682.

[228]

L. Vinals, A. Radhakrishnan, and G. Sarri, “Opportunity and Accessibility: An Environmental Scan of Publicly Available Data Repositories to Address Disparities in Healthcare Decision-making, ” Iternational Journal for Equity in Health 23 (2024): 93.

[229]

S. Hayashi, S. Tachibana, T. Maeda, et al., “Real-world Comparative Study of the Efficacy of janus Kinase Inhibitors in Patients With Rheumatoid Arthritis: The ANSWER Cohort Study, ” Rheumatology Oxford England 63 (2024): 3033-3041.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

AI Summary AI Mindmap
PDF

19

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/