Top

European Radiology

Published in:

16-06-2023 | ST-Segment Elevation Myocardial Infarction | Cardiac

The prognostic value of myocardial salvage index by cardiac magnetic resonance in ST-segment elevation myocardial infarction patients: a systematic review and meta-analysis

Authors: Zhengguang Xiao, Jingyu Zhong, Lingna Zhong, Shun Dai, Wenjie Lu, Lei Song, Huan Zhang, Jun Yang, Weiwu Yao

Published in: European Radiology | Issue 11/2023

Abstract

Objective

To assess the prognostic value of myocardial salvage index (MSI) by cardiac magnetic resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) patients.

Methods

We systematically searched PubMed, Embase, Web of Science, Cochrane Central, China National Knowledge Infrastructure, and Wanfang Data to identify primary studies reporting MSI in STEMI patients with major adverse cardiovascular events (MACE) comprised of death, myocardial reinfarction, and congestive heart failure. The MSI and MACE rates were pooled. The bias of risk was assessed using the Quality In Prognosis Studies tool. The evidence level was rated based on the meta-analysis of hazard ratio (HR) and 95% confidence interval (CI) of MSI for predicting MACE.

Results

Eighteen studies were included covering twelve unique cohorts. Eleven cohorts measured MSI using T2-weighted imaging and T1-weighted late gadolinium enhancement, while one cohort applied T2-mapping and T1-mapping. The pooled MSI (95% CI) was 44% (39 to 49%; 11 studies, 2946 patients), and the pooled MACE rate (95% CI) was 10% (7 to 14%; 12 studies, 311/3011 events/patients). Seven prognostic studies overall showed low risk of bias. The HR (95% CI) per 1% increase of MSI for MACE was 0.95 (0.92 to 0.98; 5 studies, 150/885 events/patients), and HR (95% CI) of MSI < median versus MSI > median for MACE was 5.62 (3.74 to 8.43; 6 studies, 166/1570 events/patients), both rated as weak evidence.

Conclusions

MSI presents potential in predicting MACE in STEMI patients. The prognostic value of MSI using advanced CMR techniques for adverse cardiovascular events needs further investigation.

Clinical relevance statement

Seven studies supported the MSI to serve as a predictor for MACE in STEMI patients, indicating its potential as a risk stratification tool to help manage expectations for these patients in clinical practice.

Key Points

• The pooled infarct size (95% CI) and area at risk (95% CI) were 21% (18 to 23%; 11 studies, 2783 patients) and 38% (34 to 43%; 10 studies, 2022 patients), respectively.

• The pooled rates (95% CI) of cardiac mortality, myocardial reinfarction, and congestive heart failure were 2% (1 to 3%; 11 studies, 86/2907 events/patients), 4% (3 to 6%; 12 studies, 127/3011 events/patients), and 3% (1 to 5%; 12 studies, 94/3011 events/patients), respectively.

• The HRs (95% CI) per 1% increase of MSI for cardiac mortality and congestive heart failure were 0.93 (0.91 to 0.96; 1 study, 14/202 events/patients) and 0.96 (0.93 to 0.99; 1 study, 11/104 events/patients), respectively, but the prognostic value of MSI for myocardial re-infraction has not been measured.

Available only for authorised users

Vogel B, Claessen BE, Arnold SV et al (2019) ST-segment elevation myocardial infarction. Nat Rev Dis Primers 5(1):39. https://doi.org/10.1038/s41572-019-0090-3CrossRefPubMed

GBD (2019) Diseases and Injuries Collaborators (2020) Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 396(10258):1204–1222. https://doi.org/10.1016/S0140-6736(20)30925-9CrossRef

Roth GA, Mensah GA, Johnson CO et al (2020) GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol 76(25):2982–3021. https://doi.org/10.1016/j.jacc.2020.11.010CrossRefPubMedPubMedCentral

Ibanez B, James S, Agewall S et al (2018) 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 39(2):119–177. https://doi.org/10.1093/eurheartj/ehx393CrossRefPubMed

Lawton JS, Tamis-Holland JE, Bangalore S et al (2022) 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation 145(3):e18–e114. https://doi.org/10.1161/CIR.0000000000001038CrossRefPubMed

Reinstadler SJ, Thiele H, Eitel I (2015) Risk stratification by cardiac magnetic resonance imaging after ST-elevation myocardial infarction. Curr Opin Cardiol 30(6):681–689. https://doi.org/10.1097/HCO.0000000000000227CrossRefPubMed

Kendziora B, Stier H, Schlattmann P, Dewey M (2020) MRI for measuring therapy efficiency after revascularisation in ST-segment elevation myocardial infarction: a systematic review and meta-regression analysis. BMJ Open 10(9):e034359. https://doi.org/10.1136/bmjopen-2019-034359CrossRefPubMedPubMedCentral

Bhatt DL, Lopes RD, Harrington RA (2022) Diagnosis and treatment of acute coronary syndromes: a review. JAMA 327(7):662–675. https://doi.org/10.1001/jama.2022.0358CrossRefPubMed

Niccoli G, Montone RA, Ibanez B et al (2019) Optimized treatment of ST-elevation myocardial infarction. Circ Res 125(2):245–258. https://doi.org/10.1161/CIRCRESAHA.119.315344CrossRefPubMed

10.

Ibanez B, Aletras AH, Arai AE et al (2019) Cardiac MRI endpoints in myocardial infarction experimental and clinical trials: JACC scientific expert panel. J Am Coll Cardiol 74(2):238–256. https://doi.org/10.1016/j.jacc.2019.05.024CrossRefPubMedPubMedCentral

11.

Beijnink CWH, van der Hoeven NW, Konijnenberg LSF et al (2021) Cardiac MRI to visualize myocardial damage after ST-segment elevation myocardial infarction: a review of its histologic validation. Radiology 301(1):4–18. https://doi.org/10.1148/radiol.2021204265CrossRefPubMed

12.

Carlsson M, Ubachs J, Hedström E, Heiberg E, Jovinge S, Arheden H (2009) Myocardium at risk after acute infarction in humans on cardiac magnetic resonance: quantitative assessment during follow-up and validation with single-photon emission computed tomography. JACC Cardiovasc Imaging 2(5):569-576. https://doi.org/10.1016/j.jcmg.2008.11.018

13.

Thiele H, Kappl MJ, Conradi S, Niebauer J, Hambrecht R, Schuler G (2006) Reproducibility of chronic and acute infarct size measurement by delayed enhancement-magnetic resonance imaging. J Am Coll Cardiol 47(8):1641–1645. https://doi.org/10.1016/j.jacc.2005.11.065CrossRefPubMed

14.

Messroghli DR, Walters K, Plein S et al (2007) Myocardial T1 mapping: application to patients with acute and chronic myocardial infarction. Magn Reson Med 58(1):34–40. https://doi.org/10.1002/mrm.21272CrossRefPubMed

15.

Carrick D, Haig C, Rauhalammi S et al (2016) Prognostic significance of infarct core pathology revealed by quantitative non-contrast in comparison with contrast cardiac magnetic resonance imaging in reperfused ST-elevation myocardial infarction survivors. Eur Heart J 37(13):1044–1059. https://doi.org/10.1093/eurheartj/ehv372CrossRefPubMed

16.

Kendziora B, Dewey M (2020) Prognostic value of the myocardial salvage index measured by T2-weighted and T1-weighted late gadolinium enhancement magnetic resonance imaging after ST-segment elevation myocardial infarction: a systematic review and meta-regression analysis. PLoS One 15(2):e0228736. https://doi.org/10.1371/journal.pone.0228736CrossRefPubMedPubMedCentral

17.

Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. https://doi.org/10.1136/bmj.n71CrossRefPubMedPubMedCentral

18.

Rethlefsen ML, Kirtley S, Waffenschmidt S et al (2021) PRISMA-S Group PRISMA-S: an extension to the PRISMA statement for reporting literature searches in systematic reviews. Syst Rev 10(1):39. https://doi.org/10.1186/s13643-020-01542-zCrossRefPubMedPubMedCentral

19.

Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C (2013) Assessing bias in studies of prognostic factors. Ann Intern Med 158(4):280–286. https://doi.org/10.7326/0003-4819-158-4-201302190-00009CrossRefPubMed

20.

Ma LL, Wang YY, Yang ZH, Huang D, Weng H, Zeng XT (2020) Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better? Mil Med Res 7(1):7. https://doi.org/10.1186/s40779-020-00238-8CrossRefPubMedPubMedCentral

21.

Zeng X, Zhang Y, Kwong JS et al (2015) The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med 8(1):2–10. https://doi.org/10.1111/jebm.12141CrossRefPubMed

22.

Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. Accessed via https://www.math.hkbu.edu.hk/~tongt/papers/median2mean.html on Oct 2022

23.

Shi J, Luo D, Wan X et al (2020) Detecting the skewness of data from the sample size and the five-number summary. arXiv preprint. https://arxiv.org/abs/2010.05749

24.

Shi J, Luo D, Wan X et al (2020) Optimally estimating the sample standard deviation from the five-number summary. Res Synth Methods 11(5):641–654. https://doi.org/10.1002/jrsm.1429CrossRefPubMed

25.

Luo D, Wan X, Liu J, Tong T (2018) Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 27(6):1785–1805. https://doi.org/10.1177/0962280216669183CrossRefPubMed

26.

Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135. https://doi.org/10.1186/1471-2288-14-135CrossRefPubMedPubMedCentral

27.

Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16. https://doi.org/10.1186/1745-6215-8-16CrossRefPubMedPubMedCentral

28.

Mitchell M, Muftakhidinov B, Winchen T et al (2020) Engauge Digitizer. Accessed via http://markummitchell.github.io/engauge-digitizer/ on Oct 2022

29.

Gosling CJ, Solanes A, Fusar-Poli P, Radua J. metaumbrella project. Accessed via https://www.metaumbrella.org on Oct 2022

30.

Fusar-Poli P, Radua J (2018) Ten simple rules for conducting umbrella reviews. Evid Based Ment Health 21(3):95–100. https://doi.org/10.1136/ebmental-2018-300014CrossRefPubMedPubMedCentral

31.

Dang Y, Hou Y (2021) The prognostic value of late gadolinium enhancement in heart diseases: an umbrella review of meta-analyses of observational studies. Eur Radiol 31(7):4528–4537. https://doi.org/10.1007/s00330-020-07437-wCrossRefPubMed

32.

Oxman AD, Guyatt GH (1992) A consumer’s guide to subgroup analyses. Ann Intern Med 116(1):78–84. https://doi.org/10.7326/0003-4819-116-1-78CrossRefPubMed

33.

Berlin JA, Antman EM (1994) Advantages and limitations of metaanalytic regressions of clinical trials data. Online J Curr Clin Trials. https://doi.org/10.1016/0197-2456(92)90151-oCrossRefPubMed

34.

Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. https://doi.org/10.1002/sim.1186CrossRefPubMed

35.

Bonanad C, Monmeneu JV, Lopez-Lereu MP et al (2016) Prediction of long-term major events soon after a first ST-segment elevation myocardial infarction by cardiovascular magnetic resonance. Eur J Radiol 85(3):585–592. https://doi.org/10.1016/j.ejrad.2015.12.012CrossRefPubMed

36.

Chung S, Song YB, Hahn JY et al (2014) Impact of white blood cell count on myocardial salvage, infarct size, and clinical outcomes in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a magnetic resonance imaging study. Int J Cardiovasc Imaging 30(1):129–136. https://doi.org/10.1007/s10554-013-0303-xCrossRefPubMed

37.

de Waha S, Eitel I, Desch S et al (2014) Prognosis after ST-elevation myocardial infarction: a study on cardiac magnetic resonance imaging versus clinical routine. Trials 15:249. https://doi.org/10.1186/1745-6215-15-249CrossRefPubMedPubMedCentral

38.

Eitel I, Desch S, Fuernau G et al (2010) Prognostic significance and determinants of myocardial salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction. J Am Coll Cardiol 55(22):2470–2479. https://doi.org/10.1016/j.jacc.2010.01.049CrossRefPubMed

39.

Eitel I, Kubusch K, Strohm O et al (2011) Prognostic value and determinants of a hypointense infarct core in T2-weighted cardiac magnetic resonance in acute reperfused ST-elevation-myocardial infarction. Circ Cardiovasc Imaging 354–362. https://doi.org/10.1161/CIRCIMAGING.110.960500

40.

Eitel I, Desch S, de Waha S et al (2011) Long-term prognostic value of myocardial salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction. Heart 97(24):2038–2045. https://doi.org/10.1136/heartjnl-2011-300098CrossRefPubMed

41.

Eitel I, Wöhrle J, Suenkel H et al (2013) Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the AIDA STEMI trial. J Am Coll Cardiol 61(13):1447–1454. https://doi.org/10.1016/j.jacc.2013.01.048CrossRefPubMed

42.

Eitel I, de Waha S, Wöhrle J et al (2014) Comprehensive prognosis assessment by CMR imaging after ST-segment elevation myocardial infarction. J Am Coll Cardiol 64(12):1217–1226. https://doi.org/10.1016/j.jacc.2014.06.1194CrossRefPubMed

43.

Grothoff M, Elpert C, Hoffmann J et al (2012) Right ventricular injury in ST-elevation myocardial infarction: risk stratification by visualization of wall motion, edema, and delayed-enhancement cardiac magnetic resonance. Circ Cardiovasc Imaging 5(1):60–68. https://doi.org/10.1161/CIRCIMAGING.111.967810CrossRefPubMed

44.

Kamal D, S Ibrahim A, Ahmed Nasr M, S Madkour S (2019) Prognostic value of different cardiac magnetic resonance imaging derived parameters in Egyptian patients with ST-elevation myocardial infarction after successful reperfusion by primary percutaneous intervention. Egypt Heart J 71(1):33. https://doi.org/10.1186/s43044-019-0035-x

45.

Li Y, Wang G, Wang X et al (2022) Prognostic significance of myocardial salvage assessed by cardiac magnetic resonance in reperfused ST-segment elevation myocardial infarction. Front Cardiovasc Med 9:924428. https://doi.org/10.3389/fcvm.2022.924428CrossRefPubMedPubMedCentral

46.

Masci PG, Ganame J, Strata E et al (2010) Myocardial salvage by CMR correlates with LV remodeling and early ST-segment resolution in acute myocardial infarction. JACC Cardiovasc Imaging 3(1):45–51. https://doi.org/10.1016/j.jcmg.2009.06.016CrossRefPubMed

47.

Pontone G, Guaricci AI, Andreini D et al (2017) Prognostic stratification of patients with ST-segment-elevation myocardial infarction (PROSPECT): a cardiac magnetic resonance study. Circ Cardiovasc Imaging 10(11):e006428. https://doi.org/10.1161/CIRCIMAGING.117.006428CrossRefPubMed

48.

Reinstadler SJ, Stiermaier T, Liebetrau J et al (2018) Prognostic significance of remote myocardium alterations assessed by quantitative noncontrast T1 mapping in ST-segment elevation myocardial infarction. JACC Cardiovasc Imaging 11(3):411–419. https://doi.org/10.1016/j.jcmg.2017.03.015CrossRefPubMed

49.

Sohn GH, Kim EK, Hahn JY et al (2014) Impact of overweight on myocardial infarct size in patients undergoing primary percutaneous coronary intervention: a magnetic resonance imaging study. Atherosclerosis 235(2):570–575. https://doi.org/10.1016/j.atherosclerosis.2014.05.961CrossRefPubMed

50.

Song YB, Hahn JY, Gwon HC et al (2012) A high loading dose of clopidogrel reduces myocardial infarct size in patients undergoing primary percutaneous coronary intervention: a magnetic resonance imaging study. Am Heart J 163(3):500–507. https://doi.org/10.1016/j.ahj.2011.12.007CrossRefPubMed

51.

Yoon CH, Chung WY, Suh JW et al (2013) Distal protection device aggravated microvascular obstruction evaluated by cardiac MR after primary percutaneous intervention for ST-elevation myocardial infarction. Int J Cardiol 167(5):2002–2007. https://doi.org/10.1016/j.ijcard.2012.05.029CrossRefPubMed

52.

Zhang S, Ma Q, Jiao Y et al (2022) Prognostic value of myocardial salvage index assessed by cardiovascular magnetic resonance in reperfused ST-segment elevation myocardial infarction. Front Cardiovasc Med 9:933733. https://doi.org/10.3389/fcvm.2022.933733CrossRefPubMedPubMedCentral

53.

Engblom H, Heiberg E, Erlinge D et al (2016) Sample size in clinical cardioprotection trials using myocardial salvage index, infarct size, or biochemical markers as endpoint. J Am Heart Assoc 5(3):e002708. https://doi.org/10.1161/JAHA.115.002708CrossRefPubMedPubMedCentral

54.

Bulluck H, Hammond-Haley M, Weinmann S, Martinez-Macias R, Hausenloy DJ (2017) Myocardial infarct size by CMR in clinical cardioprotection studies: insights from randomized controlled trials. JACC Cardiovasc Imaging 10(3):230–240. https://doi.org/10.1016/j.jcmg.2017.01.008CrossRefPubMedPubMedCentral

55.

Garg P, Broadbent DA, Swoboda PP et al (2017) Extra-cellular expansion in the normal, non-infarcted myocardium is associated with worsening of regional myocardial function after acute myocardial infarction. J Cardiovasc Magn Reson 19(1):73. https://doi.org/10.1186/s12968-017-0384-0CrossRefPubMedPubMedCentral

56.

Bulluck H, White SK, Rosmini S et al (2015) T1 mapping and T2 mapping at 3T for quantifying the area-at-risk in reperfused STEMI patients. J Cardiovasc Magn Reson 17(1):73. https://doi.org/10.1186/s12968-015-0173-6CrossRefPubMedPubMedCentral

57.

Fernández-Jiménez R, Galán-Arriola C, Sánchez-González J et al (2017) Effect of ischemia duration and protective interventions on the temporal dynamics of tissue composition after myocardial infarction. Circ Res 121(4):439–450. https://doi.org/10.1161/CIRCRESAHA.117.310901CrossRefPubMedPubMedCentral

58.

Kim HW, van Assche L, Jennings RB et al (2015) Relationship of T2-weighted MRI myocardial hyperintensity and the ischemic area-at-risk. Circ Res 117(3):254–265. https://doi.org/10.1161/CIRCRESAHA.117.305771CrossRefPubMedPubMedCentral

59.

Bulluck H, Chan MHH, Paradies V et al (2018) Impact of cardioprotective therapies on the edema-based area at risk by CMR in reperfused STEMI. J Am Coll Cardiol 71(24):2856–2858. https://doi.org/10.1016/j.jacc.2018.04.016CrossRefPubMed

60.

Göransson C, Ahtarovski KA, Kyhl K et al (2019) Assessment of the myocardial area at risk: comparing T2-weighted cardiovascular magnetic resonance imaging with contrast-enhanced cine (CE-SSFP) imaging-a DANAMI3 substudy. Eur Heart J Cardiovasc Imaging 20(3):361–366. https://doi.org/10.1093/ehjci/jey106CrossRefPubMed

61.

Ubachs JF, Sörensson P, Engblom H et al (2012) Myocardium at risk by magnetic resonance imaging: head-to-head comparison of T2-weighted imaging and contrast-enhanced steady-state free precession. Eur Heart J Cardiovasc Imaging 13(12):1008–1015. https://doi.org/10.1093/ehjci/jes091CrossRefPubMedPubMedCentral

62.

Ortiz-Pérez JT, Meyers SN, Lee DC et al (2007) Angiographic estimates of myocardium at risk during acute myocardial infarction: validation study using cardiac magnetic resonance imaging. Eur Heart J 28(14):1750–1758. https://doi.org/10.1093/eurheartj/ehm212CrossRefPubMed

63.

Fuernau G, Eitel I, Franke V et al (2011) Myocardium at risk in ST-segment elevation myocardial infarction comparison of T2-weighted edema imaging with the MR-assessed endocardial surface area and validation against angiographic scoring. JACC Cardiovasc Imaging 4(9):967–976. https://doi.org/10.1016/j.jcmg.2011.02.023CrossRefPubMed

64.

Lønborg J, Engstrøm T, Mathiasen AB, Vejlstrup N (2011) Myocardial area at risk after ST-elevation myocardial infarction measured with the late gadolinium enhancement after scar remodeling and T2-weighted cardiac magnetic resonance imaging. Int J Cardiovasc Imaging 28(6):1455–1464. https://doi.org/10.1007/s10554-011-9952-9CrossRefPubMed

65.

Stewart LA, Clarke M, Rovers M et al (2015) PRISMA-IPD Development Group Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD statement. JAMA 313(16):1657–1665. https://doi.org/10.1001/jama.2015.3656CrossRefPubMed

Title: The prognostic value of myocardial salvage index by cardiac magnetic resonance in ST-segment elevation myocardial infarction patients: a systematic review and meta-analysis
Authors: Zhengguang Xiao
Jingyu Zhong
Lingna Zhong
Shun Dai
Wenjie Lu
Lei Song
Huan Zhang
Jun Yang
Weiwu Yao
Publication date: 16-06-2023
Publisher: Springer Berlin Heidelberg
Keyword: ST-Segment Elevation Myocardial Infarction
Published in: European Radiology / Issue 11/2023
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI: https://doi.org/10.1007/s00330-023-09739-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The prognostic value of myocardial salvage index by cardiac magnetic resonance in ST-segment elevation myocardial infarction patients: a systematic review and meta-analysis

Abstract

Objective

Methods

Results

Conclusions

Clinical relevance statement

Key Points

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Methods

Results

Conclusions

Clinical relevance statement

Key Points

Please log in to get access to this content

Other articles of this Issue 11/2023

Effectiveness and complication rates of percutaneous transhepatic fluoroscopy-guided management of common bile duct stones: a single-arm meta-analysis

Orbital magnetic resonance imaging of giant cell arteritis with ocular manifestations: a systematic review and individual participant data meta-analysis

Diagnostic performance comparison of conventional radiography to magnetic resonance imaging for suspected osteomyelitis of the extremities: a multi-reader study

Thermal ablation of papillary thyroid microcarcinoma: what radiologists should know

Can we rely on contrast-enhanced CT to identify pancreatic ductal adenocarcinoma? A population-based study in sensitivity and factors associated with false negatives

3-D joint space mapping at the ankle from weight-bearing CT: reproducibility, repeatability, and challenges for standardisation