Inflammation in Cardiovascular Disease: Current Status and Future Perspectives

Abstract

Atherosclerosis has been defined as an inflammatory disease. Three decades of research have pointed to a pivotal role of interleukin 6 for many aspects of cardiovascular disease, not the least of which is atherosclerosis. In this review, experimental and clinical studies are reported on a timeline, exploring mechanisms and possible explanations that form the basis of current knowledge. Some successful clinical trials were proof of concept studies, showing that not only inflammatory biomarkers are related to cardiovascular outcomes, but also that decreasing inflammation can reduce cardiovascular events. Great advances have been made in the management of residual cardiovascular risk due to cholesterol, thrombosis, and metabolic diseases, but the next frontier now seems to be targeting inflammation. In the upcoming years, the importance of inflammation will be evaluated in high-risk patients with chronic kidney disease, after acute coronary heart disease or heart failure with preserved ejection fraction. Inflammation seems to precede the development of cardiovascular risk factors. Moreover, counseling for a heathy lifestyle and, when necessary, the use of cardiometabolic therapies capable of decreasing inflammation, might be important.

Keywords
Interleukin-6; C-Reactive Protein; Lymphocytes; Cytokines; Inflammasomes

Pivotal contributions to the inflammatory theory of atherosclerosis

In the late 90s, Ross defined atherosclerosis as an inflammatory disease.¹ Shortly before his study, Ridker described that among apparently healthy men participating in the Physicians’ Health Study, those in the upper quartile of high-sensitivity C-reactive protein (hsCRP) at baseline had three times the risk of myocardial infarction and two times the risk of ischemic stroke during a follow-up of eight years.² Details of the atherogenesis process, as well as the complex interaction of inflammatory cells, cytokines, and lipids, were better understood from the fascinating publications made by Libby.³–⁵ The next step was the description of the major characteristics of the vulnerable atherosclerotic plaque for thrombotic outcomes.⁶,⁷ Meta-analysis of observational studies confirmed the association between hsCRP, coronary heart disease, ischemic stroke, and mortality.⁸ However, a causal role of CRP in coronary heart disease was considered unlikely, based mainly on a large Mendelian randomization study.⁹ Thus, hsCRP, even without a causal role in cardiovascular disease, has become a useful and affordable marker for risk stratification or follow-up in clinical practice.¹⁰,¹¹ In the CARE study, a significant decrease in hsCRP levels was reported among those individuals treated with pravastatin.¹² In the AFCAPS/TexCAPS trial, statin therapy reduced coronary outcomes even in subjects with lower levels of LDL-C, but it did present higher CRP levels at baseline.¹³ The proof that patients with relatively normal cholesterol levels, but at increased cardiovascular risk due to elevated CRP levels, could benefit from statin therapy, was demonstrated in the JUPITER trial.¹⁴ However, the real proof of concept that treating inflammation per se, without changes in lipids, glucose, or blood pressure, came with the CANTOS trial.¹⁵ In addition to the reduction of CRP caused by the monoclonal antibody anti-interleukin 1-beta (IL-1b), this therapy also decreased interleukin-6 (IL-6), a cytokine with a causal role in cardiovascular disease.¹⁶ Interestingly, based on genetic studies, any benefit of a decrease in IL-6 seems proportional to the absolute reduction in hsCRP levels.¹⁷ Intravascular ultrasound (IVUS) performed in patients with ST-elevation myocardial infarction (STEMI) revealed that significant improvement in the atherosclerotic plaque composition was reported among those patients receiving high-intensity statin therapy, showing the largest decrease in hsCRP levels.¹⁸,¹⁹ More recently, low-cost anti-inflammatory therapy with colchicine successfully reduced cardiovascular outcomes in patients with acute or chronic coronary artery disease.²⁰,²¹

Inflammatory and cholesterol residual risk

Recently, a collaborative analysis of three randomized trials (n = 31,245 patients) was performed to evaluate the importance of inflammation and cholesterol as determinants of future cardiovascular outcomes.²² The study examined increasing quartiles of baseline hsCRP and of increasing baseline LDL-C as a predictors of cardiovascular deaths and all-cause deaths. The authors found that hsCRP was a stronger predictor of future cardiovascular events than was LDL-C. These findings suggested the need for combined therapies, including effective lipid-lowering and inflammatory-inhibition drugs to reduce residual cardiovascular risk.

The high degree of decline in LDL-C, with major benefits for cardiovascular outcomes, has been well established from robust meta-analysis.²³,²⁴ However, the same applies to the degree of reduction in inflammatory markers, hsCRP²⁵ and IL-6²⁶ based on a large prospective trial. In the CANTOS trial, those patients receiving canakinumab (monoclonal antibody anti-interleukin 1-beta) who achieved IL-6 levels below the median, showed a 32% reduction in major cardiovascular events, a 52% decrease in cardiovascular mortality, and 48% lower rates of all-cause mortality.²⁶

Fascinating findings were recently reported on the importance of inflammation to predict outcomes in patients with chronic kidney disease.²⁷ Among 9,151 stable patients with previous myocardial infarction, the contribution of residual cholesterol and inflammatory risk were evaluated. Among patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m², as well as increasing quartiles of both inflammatory markers (hsCRP and IL-6) and lipid markers (LDL-C and non-HDL-C), were positively related to the risk of recurrent cardiovascular events. Conversely, among those patients with eGFR < 60 mL/min/1.73m², only the inflammatory markers (hsCRP and IL-6) were associated with cardiovascular outcomes. Furthermore, both inflammatory markers were predictors of total mortality, whereas LDL-C and non-HDL-C were not. Similar results were observed in an analysis stratified by albumin to creatinine ratio.

In addition to renal glomerular hemodynamics, inflammation appears to be related to the stage of chronic kidney disease. In this scenario, the amount of monocyte-derived microparticles were progressively greater according to the stage of chronic kidney disease.²⁸

In the STABILITY trial,²⁹ 14,611 patients with chronic coronary heart disease had baseline levels of IL-6 and were followed up for a median of 3.7 years. Patients were categorized into those with normal eGFR (≥ 90 mL/min/1.73m²), mildly decreased eGFR (60-90 mL/min/1.73m²), and moderately to severely decreased eGFR level (<60 mL/min/1.73 m²). High levels of IL-6 (≥ 2 ng/L) were associated with cardiovascular outcomes in all stages of chronic kidney disease.

Role of inflammation after acute myocardial infarction

The relevance of lymphocyte subtypes and circulating cytokines was examined in the BATTLE-AMI trial.³⁰ Circulating levels of IL-1beta, IL-4, IL-6, IL-10, and IL-18 were collected during the first day of an ST-segment elevation myocardial infarction (STEMI) in patients undergoing a pharmacoinvasive strategy. In this study, the amount of infarcted mass and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging (cMRI). After 30 days of STEMI, marked improvement in the balance of pro- and anti-inflammatory cytokines was observed, except for IL-6.³¹ Titers of IL-6 at baseline were associated with infarcted mass (rho = 0.41, P < 0.001) and inversely related to LVEF (rho = -0.38, P<0.001)³². In addition, hsCRP collected on the first day of STEMI, as well as B2 classic lymphocytes at day 30, were related to the LVEF.³² All of these findings reinforce the core role of IL-6 in cardiovascular disease.

Ongoing clinical trials and perspectives

It has been progressively established that the cell signaling pathway involving the NOD-, LRR-, and pyrin domain-containing protein (NLRP3) inflammasome to IL-1beta to IL-6 to hsCRP is clearly implicated in cardiovascular disease.³³ Thus, inhibition of this pathway is of great interest for cardioprotection, and therapies targeting IL-6 can be considered a research priority among therapies aiming to reduce residual risk.

The phase 2 trial RESCUE³⁴ with ziltivekimab (a fully human monoclonal antibody directed against the IL-6 ligand), showed a marked decrease in inflammatory biomarkers, no change in lipids [(except for a favorable reduction in Lp(a)], in addition to very good tolerability. In addition, in RESCUE, ziltivekimab reduced thrombotic markers (e.g. fibrinogen). Thus, a large clinical trial was the next step.

The ongoing Ziltivekimab Cardiovascular Outcomes Study (ZEUS) was designed to address the benefit of this medication in a large and high-risk population of patients with established atherosclerotic cardiovascular disease, chronic kidney disease, and elevated inflammatory biomarkers. Thus, ZEUS will answer if the high residual risk of this population can be safely reduced by the monthly injection of ziltivekimab.

Two additional clinical trials are on our horizon based on the potential benefits of IL-6 inhibition.³⁵ The first study will examine the benefit of IL-6 inhibition in patients with heart failure and preserved ejection fraction (HERMES), while the second will test if IL-6 inhibition improves outcomes in patients with acute coronary syndromes (ARTEMIS).

What are the triggers for inflammation?

Advanced atherosclerotic lesions contain cholesterol crystals in the necrotic core, a highly disregarded fact in atherosclerosis. However, a well-conducted experiment using new microscopic techniques showed that cholesterol crystals can be viewed early on in diet-induced atherosclerosis.³⁶ The presence of cholesterol crystals coincides with the appearance of inflammatory cells. This novel aspect in atherogenesis revealed the potential link between cholesterol and inflammation due to the activation of NLRP3-inflammasome and the cascade of IL-1b to IL-6.³⁶ Soon afterward, new mechanisms were reported for inflammasome activation, such as neutrophil extracellular traps, atheroprone flow, and local tissue hypoxia.³⁷

Recurrent cardiovascular events are common after an acute myocardial infarction.³⁸,³⁹ Inflammation can contribute to these repeated events, and one fascinating study showed a marked increase in monocyte recruitment in chronic atherosclerosis.⁴⁰ Thus, a systemic inflammatory state for many weeks after acute myocardial infarction may well contribute to recurring cardiovascular events.

Conclusions

After three decades of clinical and experimental research involving inflammation and cardiovascular disease, the cell signaling pathway involving NLRP3 inflammasome, subsequently triggering the IL-6 expression, was progressively established as a main therapeutic target. Ongoing clinical trials will establish the safety and benefits of IL-6 inhibition. The availability of hsCRP in clinical practice constitutes a very useful inflammatory marker, which points out the IL-6 pathway. Formerly used for risk stratification for lipid-lowering therapy, hsCRP can now be used to estimate residual cardiovascular risk and identify those individuals most likely to benefit from an anti-inflammatory therapy, and was progressively established as a main therapeutic target (Graphic 1).

Graphic 1
A. Residual cardiovascular risk has been lowered by therapies that have improved thrombotic, metabolic, and lipid risks. Promising therapies are now proposed to reduce residual inflammatory risk. B. Many stimuli can activate the NLRP3 inflammasome. Once activated by caspase 1, IL-1b is released into the blood stream and increases the expression of IL-6. Furthermore, expression of CRP, fibrinogen are also observed. C. Studies have suggested a pivotal role of IL-6 in outcomes related to cardiovascular and renal diseases. D. Decrease in inflammation targeting IL-6 has been proposed as the next frontier to reduce cardiovascular risk.

Finally, uncontrolled cardiovascular risk factors, such as hypertension, obesity, diabetes, smoking, and sedentary lifestyle, are all common conditions related to inflammation.⁴¹ Thus, changes in lifestyle and the choice of therapies (statins, RAS blockers, some glucose lowering agents) can result in a marked decrease in inflammatory biomarkers. Therefore, the use of anti-inflammatory agents is not the only way to decrease inflammation. This approach seems particularly important for primordial prevention, avoiding the development of risk factors for cardiovascular diseases.

• Disclosures
  Dr. Fonseca has served as steering committee member of the JUPITER trial and CANTOS trial.
• Sources of Funding
  There were no external funding sources for this study.
• Study Association
  This study is not associated with any thesis or dissertation work.
• Ethics Approval and Consent to Participate
  This article does not contain any studies with human participants or animals performed by any of the authors.

References

• ¹
  Ross R. Atherosclerosis-an Inflammatory Disease. N Engl J Med. 1999;340(2):115-26. doi: 10.1056/NEJM199901143400207.
  » https://doi.org/10.1056/NEJM199901143400207
• ²
  Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men. N Engl J Med. 1997;336(14):973-9. doi: 10.1056/NEJM199704033361401.
  » https://doi.org/10.1056/NEJM199704033361401
• ³
  Libby P. Inflammation in Atherosclerosis. Nature. 2002;420(6917):868-74. doi: 10.1038/nature01323.
  » https://doi.org/10.1038/nature01323
• ⁴
  Libby P, Ridker PM, Hansson GK. Progress and Challenges in Translating the Biology of Atherosclerosis. Nature. 2011;473(7347):317-25. doi: 10.1038/nature10146.
  » https://doi.org/10.1038/nature10146
• ⁵
  Libby P. The Changing Landscape of Atherosclerosis. Nature. 2021;592(7855):524-533. doi: 10.1038/s41586-021-03392-8.
  » https://doi.org/10.1038/s41586-021-03392-8
• ⁶
  Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From Vulnerable Plaque to Vulnerable Patient: A Call for New Definitions and Risk Assessment Strategies: Part I. Circulation. 2003;108(14):1664-72. doi: 10.1161/01.CIR.0000087480.94275.97.
  » https://doi.org/10.1161/01.CIR.0000087480.94275.97
• ⁷
  Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From Vulnerable Plaque to Vulnerable Patient: A Call for New Definitions and Risk Assessment Strategies: Part II. Circulation. 2003;108(15):1772-8. doi: 10.1161/01.CIR.0000087481.55887.C9.
  » https://doi.org/10.1161/01.CIR.0000087481.55887.C9
• ⁸
  Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive Protein Concentration and Risk of Coronary Heart Disease, Stroke, and Mortality: An Individual Participant Meta-Analysis. Lancet. 2010;375(9709):132-40. doi: 10.1016/S0140-6736(09)61717-7.
  » https://doi.org/10.1016/S0140-6736(09)61717-7
• ⁹
  Wensley F, Gao P, Burgess S, Kaptoge S, Di Angelantonio E, Shah T, et al. Association between C Reactive Protein and Coronary Heart Disease: Mendelian Randomisation Analysis Based on Individual Participant Data. BMJ. 2011;342:d548. doi: 10.1136/bmj.d548.
  » https://doi.org/10.1136/bmj.d548
• ¹⁰
  Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e1143. doi: 10.1161/CIR.0000000000000625.
  » https://doi.org/10.1161/CIR.0000000000000625
• ¹¹
  Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. C-Reactive Protein Levels and Outcomes after Statin Therapy. N Engl J Med. 2005;352(1):20-8. doi: 10.1056/NEJMoa042378.
  » https://doi.org/10.1056/NEJMoa042378
• ¹²
  Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-Term Effects of Pravastatin on Plasma Concentration of C-Reactive Protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999;100(3):230-5. doi: 10.1161/01.cir.100.3.230.
  » https://doi.org/10.1161/01.cir.100.3.230
• ¹³
  Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, et al. Measurement of C-Reactive Protein for the Targeting of Statin Therapy in the Primary Prevention of Acute Coronary Events. N Engl J Med. 2001;344(26):1959-65. doi: 10.1056/NEJM200106283442601.
  » https://doi.org/10.1056/NEJM200106283442601
• ¹⁴
  Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med. 2008;359(21):2195-207. doi: 10.1056/NEJMoa0807646.
  » https://doi.org/10.1056/NEJMoa0807646
• ¹⁵
  Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-31. doi: 10.1056/NEJMoa1707914.
  » https://doi.org/10.1056/NEJMoa1707914
• ¹⁶
  Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium; Swerdlow DI, Holmes MV, Kuchenbaecker KB, Engmann JE, Shah T, et al. The Interleukin-6 Receptor as a Target for Prevention of Coronary Heart Disease: A Mendelian Randomisation Analysis. Lancet. 2012;379(9822):1214-24. doi: 10.1016/S0140-6736(12)60110-X.
  » https://doi.org/10.1016/S0140-6736(12)60110-X
• ¹⁷
  Georgakis MK, Malik R, Richardson TG, Howson JMM, Anderson CD, Burgess S, et al. Associations of Genetically Predicted IL-6 Signaling with Cardiovascular Disease Risk Across Population Subgroups. BMC Med. 2022;20(1):245. doi: 10.1186/s12916-022-02446-6.
  » https://doi.org/10.1186/s12916-022-02446-6
• ¹⁸
  Koskinas KC, Zaugg S, Yamaji K, García-García HM, Taniwaki M, Klingenberg R, et al. Changes of Coronary Plaque Composition Correlate with C-Reactive Protein Levels in Patients with ST-Elevation Myocardial Infarction Following High-Intensity Statin Therapy. Atherosclerosis. 2016;247:154-60. doi: 10.1016/j.atherosclerosis.2016.02.015.
  » https://doi.org/10.1016/j.atherosclerosis.2016.02.015
• ¹⁹
  Puri R, Libby P, Nissen SE, Wolski K, Ballantyne CM, Barter PJ, et al. Long-Term Effects of Maximally Intensive Statin Therapy on Changes in Coronary Atheroma Composition: Insights from SATURN. Eur Heart J Cardiovasc Imaging. 2014;15(4):380-8. doi: 10.1093/ehjci/jet251.
  » https://doi.org/10.1093/ehjci/jet251
• ²⁰
  Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383(19):1838-47. doi: 10.1056/NEJMoa2021372.
  » https://doi.org/10.1056/NEJMoa2021372
• ²¹
  Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-505. doi: 10.1056/NEJMoa1912388.
  » https://doi.org/10.1056/NEJMoa1912388
• ²²
  Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE, et al. Inflammation and Cholesterol as Predictors of Cardiovascular Events among Patients Receiving Statin Therapy: A Collaborative Analysis of three Randomised Trials. Lancet. 2023;401(10384):1293-301. doi: 10.1016/S0140-6736(23)00215-5.
  » https://doi.org/10.1016/S0140-6736(23)00215-5
• ²³
  Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and Safety of Cholesterol-Lowering Treatment: Prospective Meta-Analysis of Data from 90,056 Participants in 14 Randomised Trials of Statins. Lancet. 2005;366(9493):1267-78. doi: 10.1016/S0140-6736(05)67394-1.
  » https://doi.org/10.1016/S0140-6736(05)67394-1
• ²⁴
  Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and Safety of More Intensive Lowering of LDL Cholesterol: A Meta-Analysis of Data from 170,000 Participants in 26 Randomised Trials. Lancet. 2010;376(9753):1670-81. doi: 10.1016/S0140-6736(10)61350-5.
  » https://doi.org/10.1016/S0140-6736(10)61350-5
• ²⁵
  Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, 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. 2018;391(10118):319-28. doi: 10.1016/S0140-6736(17)32814-3.
  » https://doi.org/10.1016/S0140-6736(17)32814-3
• ²⁶
  Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, et al. Modulation of the Interleukin-6 Signalling Pathway and Incidence Rates of Atherosclerotic Events and All-Cause Mortality: Analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J. 2018;39(38):3499-507. doi: 10.1093/eurheartj/ehy310.
  » https://doi.org/10.1093/eurheartj/ehy310
• ²⁷
  Ridker PM, Tuttle KR, Perkovic V, Libby P, MacFadyen JG. Inflammation Drives Residual Risk in Chronic Kidney Disease: A CANTOS Substudy. Eur Heart J. 2022;43(46):4832-44. doi: 10.1093/eurheartj/ehac444.
  » https://doi.org/10.1093/eurheartj/ehac444
• ²⁸
  Fonseca F, Ballerini AP, Izar MC, Kato J, Ferreira CE, Fonzar W, et al. Advanced Chronic Kidney Disease is Associated with Higher Serum Concentration of Monocyte Microparticles. Life Sci. 2020;260:118295. doi: 10.1016/j.lfs.2020.118295.
  » https://doi.org/10.1016/j.lfs.2020.118295
• ²⁹
  Batra G, Lakic TG, Lindbäck J, Held C, White HD, Stewart RAH, et al. Interleukin 6 and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Chronic Coronary Syndrome. JAMA Cardiol. 2021;6(12):1440-5. doi: 10.1001/jamacardio.2021.3079.
  » https://doi.org/10.1001/jamacardio.2021.3079
• ³⁰
  Fonseca FAH, Izar MC, Maugeri IML, Berwanger O, Damiani LP, Pinto IM, et al. Effects of Four Antiplatelet/Statin Combined Strategies on Immune and Inflammatory Responses in Patients with Acute Myocardial Infarction Undergoing Pharmacoinvasive Strategy: Design and Rationale of the B and T Types of Lymphocytes Evaluation in Acute Myocardial Infarction (BATTLE-AMI) Study: Study Protocol for a Randomized Controlled Trial. Trials. 2017;18(1):601. doi: 10.1186/s13063-017-2361-1.
  » https://doi.org/10.1186/s13063-017-2361-1
• ³¹
  Coste MER, França CN, Izar MC, Teixeira D, Ishimura ME, Longo-Maugeri I, et al. Early Changes in Circulating Interleukins and Residual Inflammatory Risk after Acute Myocardial Infarction. Arq Bras Cardiol. 2020;115(6):1104-11. doi: 10.36660/abc.20190567.
  » https://doi.org/10.36660/abc.20190567
• ³²
  Casarotti ACA, Teixeira D, Longo-Maugeri IM, Ishimura ME, Coste MER, Bianco HT, et al. Role of B Lymphocytes in the Infarcted Mass in Patients with Acute Myocardial Infarction. Biosci Rep. 2021;41(2):BSR20203413. doi: 10.1042/BSR20203413.
  » https://doi.org/10.1042/BSR20203413
• ³³
  Ridker PM. From RESCUE to ZEUS: Will Interleukin-6 Inhibition with Ziltivekimab Prove Effective for Cardiovascular Event Reduction? Cardiovasc Res. 2021;117(11):e138-e140. doi: 10.1093/cvr/cvab231.
  » https://doi.org/10.1093/cvr/cvab231
• ³⁴
  Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, et al. IL-6 Inhibition with Ziltivekimab in Patients at High Atherosclerotic Risk (RESCUE): A Double-Blind, Randomised, Placebo-Controlled, Phase 2 Trial. Lancet. 2021;397(10289):2060-9. doi: 10.1016/S0140-6736(21)00520-1.
  » https://doi.org/10.1016/S0140-6736(21)00520-1
• ³⁵
  Ridker PM, Rane M. Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease. Circ Res. 2021;128(11):1728-46. doi: 10.1161/CIRCRESAHA.121.319077.
  » https://doi.org/10.1161/CIRCRESAHA.121.319077
• ³⁶
  Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 Inflammasomes are Required for Atherogenesis and Activated by Cholesterol Crystals. Nature. 2010;464(7293):1357-61. doi: 10.1038/nature08938.
  » https://doi.org/10.1038/nature08938
• ³⁷
  Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circ Res. 2016;118(1):145-56. doi: 10.1161/CIRCRESAHA.115.306656.
  » https://doi.org/10.1161/CIRCRESAHA.115.306656
• ³⁸
  Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular Risk in Post-Myocardial Infarction Patients: Nationwide Real World Data Demonstrate the Importance of a Long-Term Perspective. Eur Heart J. 2015;36(19):1163-70. doi: 10.1093/eurheartj/ehu505.
  » https://doi.org/10.1093/eurheartj/ehu505
• ³⁹
  Krumholz HM, Normand SL, Wang Y. Trends in Hospitalizations and Outcomes for Acute Cardiovascular Disease and Stroke, 1999-2011. Circulation. 2014;130(12):966-75. doi: 10.1161/CIRCULATIONAHA.113.007787.
  » https://doi.org/10.1161/CIRCULATIONAHA.113.007787
• ⁴⁰
  Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, et al. Myocardial Infarction Accelerates Atherosclerosis. Nature. 2012;487(7407):325-9. doi: 10.1038/nature11260.
  » https://doi.org/10.1038/nature11260
• ⁴¹
  Cercato C, Fonseca FA. Cardiovascular Risk and Obesity. Diabetol Metab Syndr. 2019;11:74. doi: 10.1186/s13098-019-0468-0.
  » https://doi.org/10.1186/s13098-019-0468-0

Publication Dates

• Publication in this collection
  28 Aug 2023
• Date of issue
  2023

History

• Received
  21 May 2023
• Reviewed
  14 June 2023
• Accepted
  23 June 2023