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Biomarkers Cardiovascular

Cardiovascular CT

Biomarker Acquisition Modality Acquisition requirements Extracting biomarker (Reading/Algorithm) Target Level of evidence References Evidence Issues
Calcium score (Agatston Score, calcium volume) CT ECG triggered non enhanced CT scan Semiautomatic quantification stratification of global cardiovascular risk for asymptomatic patients 1 [1-5!] Substantial Standardization of Agatston score obtained from contrast-enhanced scans missing. Not capable to distinguish from localized amount or dispersed 
Coronary stenoses (luminal narrowing, segment involved score) CT ECG triggered contrast enhanced CT coronary angiography Visual assessment, Semiautomatic quantification Assessment of coronary artery disease severity 1 [3!, 6-11!] Substantial Observer variability of visual assessment, particularly in the 50-70% range; Blooming effect (overestimation of high calcified plaques)
Suboptimal correlation with subtending haemodynamic significance
Visual assessment of coronary plaque density (calcified, noncalcified, mixed) CT ECG triggered contrast enhanced CT coronary angiography Visual assessment Assessment of coronary artery disease severity and risk of future myocardial infarction 2 - 3 [12-15!] Poor Observer variability. Variability of research study findings. Potential HU variability across centers due to difference in kV values
Visual assessment of high risk plaque features (positive remodelling, low attenuation plaque, spotty calcification, napkin ring sign) CT ECG triggered contrast enhanced CT coronary angiography Visual assessment Assessment of coronary artery disease severity and risk of future myocardial infarction 2 [12-15!] Moderate Observer variability. Commonly identified but only some lead to myocardial infarction. Potential HU variability across centers due to difference in kV values
Quantitative assessment of coronary plaque burden (total, non calcified, calcified, low attenuation, and other plaque volume and burden) (segment involved score, Leaman score) CT ECG triggered contrast enhanced CT coronary angiography Semi-quantitative assessment Assessment of coronary artery disease severity and risk of future myocardial infarction (likelihood of being revascularized on invasive coronary angiography, risk of future myocardial infarction or other major adverse cardiac events) 2 [16-22!] Moderate Variability between softwares. Blooming effect (overestimation of high calcified plaques)
Suboptimal correlation with subtending haemodynamic significance
CT-FFR CT ECG triggered contrast enhanced CT coronary angiography quantitative quantification of coronary artery disease severity. (hemodynamic significance of stenosis) 2 [23-30!] substantial Limited availability due to pay-per-service model; avilable at the moment only from one provider for clinical use
CT-ECV CT non-contrast and late contrast-enhanced ECG triggered CT  semiquantitative quantification of myocardial fibrosis 3 [31-34!] low latest CT scanner generation required; increased radiation dose of the exam for the additional late phase; dedicated software analysis required
LV/RV ventricular function (ESV, EDV, EF) CT ECG triggered contrast enhanced CT coronary angiography quantitative fundamental information about ventricular function and disease severity in all cardiac disorders 2 [35-41!] moderate increased radiation dose since images have to be obtained during the entire cardiac cycle
Myocardial wall, thickness and mass CT ECG gated CT scan including images from the enddiastole quantitive diagnosis of ventricular hypertrophy 1 [42-43!] substantial measurement has to be obtained from real end- diastole
Trabeculation index CT ECG gated CT scan including images from the enddiastole semi-quantitative indicator for non-compaction cardiomyopathy and predictor for cardiac events 3 [44-46!] poor Suboptimal inter-technique agreement
Aortic valve calcification CT ECG triggered non enhanced CT scan quantitive risk estimation and outcome prediction in aortic vavluar disease 2 [47-54!] moedrate exact discrimination from coronary and aortic calcifications required; calculation is technically challenging if concomitant high-grade coronary sclerosis is present
Aortic valve orifice area CT ECG triggered Contrast enhanced CT aortic angiography quantitive quantification of aortic valve disease (severity of stenosis and regurgitation) 2-3 [55-57!] moderate  systolic (aortic stenosis) and daistolc (aortic regurgitation) pahse images required; Blooming effect of cusps calcification (difficult to depict valve orifice when calcifications are severe)
Aortic annulus (maximum, minimum and average diameter, perimeter, area) CT ECG triggered Contrast enhanced CT aortic angiography quantitive planing of transarterial aortic valve repair (TAVR) 1-2 [47!; 58!] substantial exact double angulation required
Aorta diameter CT Contrast enhanced CT aortic angiography, for the ascending aorta: ECG triggered Contrast enhanced CT aortic angiography quantitative diagnosis and quantification of aortic dilatation / aneurysm 1 [59-61!] Substantial accurate measurements required plane perpendicular to the vessel axis
Pericardial thickness and calcification CT measured on noncontrast cardiac CT quantitative localization and characterization of various pericardial lesions, including effusion, constrictive pericarditis and pericardial thickening, pericardial masses, and congenital anomalies such as partial or complete absence of the pericardium. 2-3 [63!] low Observer variability. Variability of research study findings.
Epicardial fat volume CT measured on noncontrast cardiac CT  quantitative predict the presence and severity of obstructive CAD, ​​ the onset of arrhythmic complications such as AF or Heart Failure with preserved ejection fraction  2  [64!; 65!]  moderate Time consuming post-processing (few dedicated software)
Pericoronary fat volume CT ECG triggered non enhanced CT scan  Visual assessment / semiquantitative  PCAT volume is strongly and independently associated with culprit lesions 2-3 [66!; 67!] Poor Time consuming post-processing (few dedicated software)
Pericoronary adipose tissue attenuation CT ECG triggered non enhanced CT scan quantitative PCAT radiodensity is increased according to underlying inflammation or fat browning 2 -3  [68-71!]  Poor Time consuming post-processing,
myocardial perfusion CT dynamic CT perfusion after pharmacological stress  semiquantitative assessment of lesion dependent ischemia 1-2 [72-75!] substantial increased radiation dose due to dyncamic perfusion as add on to CT angiography
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  2. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary-artery calcium using ultrafast computed-tomography. J Am College Cardiol 1990;15:827–32.
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  12. Low-Attenuation Noncalcified Plaque on Coronary Computed Tomography Angiography Predicts Myocardial Infarction: Results From the Multicenter SCOT-HEART Trial (Scottish Computed Tomography of the HEART). Williams MC, Kwiecinski J, Doris M, McElhinney P, D’Souza MS, Cadet S, Adamson PD, Moss AJ, Alam S, Hunter A, Shah ASV, Mills NL, Pawade T, Wang C, Weir McCall J, Bonnici-Mallia M, Murrills C, Roditi G, van Beek EJR, Shaw LJ, Nicol ED, Berman DS, Slomka PJ, Newby DE, Dweck MR, Dey D.
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  13. Association of plaque calcification pattern and attenuation with instability features and coronary stenosis and calcification grade. Pugliese L, Spiritigliozzi L, Di Tosto F, Ricci F, Cavallo AU, Di Donna C, De Stasio V, Presicce M, Benelli L, D’Errico F, Pasqualetto M, Floris R, Chiocchi M. Atherosclerosis. 2020 Oct;311:150-157.
  14. Association of coronary artery calcium score with qualitatively and quantitatively assessed adverse plaque on coronary CT angiography in the SCOT-HEART trial.
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  15. Coronary Artery Plaque Characteristics Associated With Adverse Outcomes in the SCOT-HEART Study. Williams MC, Moss AJ, Dweck M, Adamson PD, Alam S, Hunter A, Shah ASV, Pawade T, Weir-McCall JR, Roditi G, van Beek EJR, Newby DE, Nicol ED. J Am Coll Cardiol. 2019 Jan 29;73(3):291-301
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  66. Balcer B, Dykun I, Schlosser T, Forsting M, Rassaf T, Mahabadi AA. Pericoronary fat volume but not attenuation differentiates culprit lesions in patients with myocardial infarction. Atherosclerosis. 2018 Sep;276:182-188. doi: 10.1016/j.atherosclerosis.2018.05.035. Epub 2018 May 25. PMID: 29866393.
  67. Mancio J, Azevedo D, Fragao-Marques M, Falcao-Pires I, Leite-Moreira A, Lunet N, Fontes-Carvalho R, Bettencourt N. Am J Cardiol. 2019 Feb 1;123(3):523-531. Meta-Analysis of Relation of Epicardial Adipose Tissue Volume to Left Atrial Dilation and to Left Ventricular Hypertrophy and Functions
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CARDIOVASCULAR MR

Biomarker Acquisition Modality Acquisition requirements Extracting biomarker (Reading/Algorithm) Target Level of evidence references Evidence Issues
T1 mapping (T1 native, post contrast, ECV) MRI hematocrit level (ECV) and T1-mapping prior and after contrast administration quantitative quantification of diffuse myocardial fibrosis; early detection of myocardial disorders 1 [1-3!] substantial ariability among different scanner type and models (poor inter-center reproducibility); standardization for each scanner required
need of dedicated software analysis, motion correction and co-registration algorithms, not feasible in device wearers
Variable inter-observer/software reproducibility 
T2 mapping MRI T2 mapping quantitative quantification of myocardial edema 2 [1!, 4-7!] Moderate
T2* mapping MRI ECG-gated GRE T2* sequence  quantitative quantification of myocardial iron overload  1  [1!, 8-9!]  Substantial variability among different scanner type and models; standardization for each scanner required (possibly using phantom), need of dedicated software analysis,motion correction and co-registration algorithms, not feasible in device wearers, Variable inter-observer/software reproducibility
Late enhancement (LE) (transmurality, voljume, localization, configuration, MVO, haemorrhage) MRI late phase acquisition 10 - 20' after contrast injection semi-quantitative diagnosis and quantification of myocardial necrosis; outcome prediction after myocardial infarction 1 [10-12!] Substantial optimal "nulling" of the myocardium required
LV/RV function (EF, ESV, EDV, co) MRI CINE-sequences obtained in short axis orientatation quantitative fundamental information about ventricular function and disease severity in all cardiac disorders 1 [13-17!]  Substantial manual interaction required for anaysis
LV/RV wall motion (wall motion score index, wall fractional shortening, wall displacement, intra- or interventricular dyssynchrony) MRI CINE-sequences obtained in short axis orientatation quantitative  identification of asymptomatic patients with subclinical LV dysfunction  2-3 [18!] limited dedicated software required
LV/RV myocardial deformation (systolic and diastolic circumferential and longitudinal strain) MRI CINE-sequences obtained in short axis orientatation quantitative  identification of asymptomatic patients with subclinical LV dysfunction  2-3 [19!] limited dedicated software required
Flow quantification (peak and mean velocity, flow, forward or backward volume, maximum pressure gradient) MRI CINE imaging and phase-contrast angiography quantitative  quantification of flow among cardiac valves as well as within the aorta 2-3 [20-21!] moderate difficult after valvular repair with metallic implants
4D flow MRI spoiled gradient echo sequences with short TR  quantitative detailed assessment of fow characteristics in all chambers and great vessels 2-3 [22-23!]  moderate dedicated software for analysis required
MR angiography MRI contrast-enhanced strongly T1-weighted arterial phase sequences semi-quantitative diagnosis and quantification of all kinds of vascular diseases of the large vessles 1 [24-25!]  Substantial calcifications are not visulaized; stent-lumen can not be assessed
Aortic diameter MRI visulaization of aortic lumen and wall; many sequences available (black blood, bright blood) quantitative diagnosis and quantification of aortic dilatation / aneurysm 1 [26-27!] Substantial accurate measurements required plane perpendicular to the vessel axis
 LV wall thickness,  MRI ECG gated MR scan of the entire cardiac cycle in short axis orientation quantitive diagnosis of ventricular hypertrophy 1 [28-30!] substantial measurement of thickness has to be obtained from real end- diastole;
myocardial mass, MRI ECG gated MR scan of the entire cardiac cycle in short axis orientation quantitive diagnosis of ventricular hypertrophy 1 [28-30!] substantial no final consensus if papillary muscles should be included in myocardial mass assessment
 LV trabeculation (trabeculation thickness, ratio of thickness and volume of compacted/ MRI short axis stack cine bSSFP quantitative quantification of trabeculated LV-myocardium, diagnosis of LVNC (left-ventricular non-compaction cardiomyopathy) 2-3 [31-38!] limited no uniform recommendation for measurements (manual versus semiautomatic, trabeculation thickness versus volume versus mass or ratio, blood pool between trabeculae included in or excluded from trabeculation mass or volume)
trabeculation thickness MRI short axis stack cine bSSFP quantitative thickness of trabeculated 3 [31-38!]
NC/C thickness ratio MRI short and long axis cine bSSFP quantitative thickness of trabeculated/compact LV myocardium 3 [31-38!]
Trabeculation mass MRI short axis stack cine bSSFP quantitative mass of trabeculated LV myocardium 3 [31-38!]
Trabeculation volume MRI short axis stack cine bSSFP quantitative Volume of trabeculated LV myocardium 3 [31-38!]
NC/C mass ratio MRI short axis stack cine bSSFP quantitative mass of trabeculated/compacted LV myocardium 3 [31-38!]
NC/TM mass ratio MRI short axis stack cine bSSFP quantitative ratio of trabeculated/total LV myocardial mass 3 [31-38!]
Fractal dimension MRI short axis stack cine bSSFP quantitative fractal complexity of LV trabeculation 3 [31-38!]
Myocardial perfusion (myocardial blood flow, perfusion reserve) MRI T1-w first pass perfusion GRE at rest and during vasodilator stress quantitative absolute quantification of myocardial blood flow (MBF) in ml/min/g and calculation of myocardial perfusion reserve (MBF during stress/MBF at rest); assessment of coronary artery disease 1-2 [39-41!] substantial dedicated software required, accurate measurements required, low-dose bolus injection required
Pulmonary artery (diameter) MRI cross sectional 2D or 3D bSSFP quantitative diameter of pulmonary artery; pulmonary hypertension, congenital heart disease 2 [42!] Moderate measurements obtained perpendicular to vessel 
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  2. Seiko Ide, Eugenie Riesenkampff, David A Chiasson, Anne I Dipchand, Paul F Kantor, Rajiv R Chaturvedi, Shi-Joon Yoo, Lars Grosse-Wortmann. Histological validation of cardiovascular magnetic resonance T1 mapping markers of myocardial fibrosis in paediatric heart transplant recipients. J Cardiovasc Magn Reson. 2017 Feb 1;19(1):10. doi: 10.1186/s12968-017-0326-x.
  3. Martin Ugander, Abiola J Oki, Li-Yueh Hsu, Peter Kellman, Andreas Greiser, Anthony H Aletras, Christopher T Sibley, Marcus Y Chen, W Patricia Bandettini, Andrew E Arai. Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology. Eur Heart J. 2012 May;33(10):1268-78. doi: 10.1093/eurheartj/ehr481. Epub 2012 Jan 24
  4. Fernández-Jiménez, R., Sánchez-González, J., Aguero, J. et al. Fast T2 gradient-spin-echo (T2-GraSE) mapping for myocardial edema quantification: first in vivo validation in a porcine model of ischemia/reperfusion. J Cardiovasc Magn Reson 17, 92 (2015). doi: 10.1186/s12968-015-0199-9
  5. Thavendiranathan P, Walls M, Giri S, et al. Improved detection of myocardial involvement in acute inflammatory cardiomyopathies using T2 mapping. Circ Cardiovasc Imaging. 2012 Jan;5(1):102-10. doi: 10.1161/CIRCIMAGING.111.967836. Epub 2011 Oct 28.
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  9. Triadyaksa P, Oudkerk M, Sijens PE. Cardiac T2 * mapping: Techniques and clinical applications. J Magn Reson Imaging. 2020 Nov;52(5):1340-1351. doi: 10.1002/jmri.27023. Epub 2019 Dec 14. PMID: 31837078; PMCID: PMC7687175.
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  13. Kawel-Boehm N, Hetzel SJ, Ambale-Venkatesh B, et al. Reference ranges (“normal values”) for cardiovascular magnetic resonance (CMR) in adults and children: 2020 update. J Cardiovasc Magn Reson. 2020 Dec 14;22(1):87
  14. Tao Q, Yan W, Wang Y, et al. Deep Learning-based Method for Fully Auto‑ matic Quantifcation of Left Ventricle Function from Cine MR Images: A Multivendor Multicenter Study. Radiology. 2019;290:81–8
  15. Schulz-Menger J, Bluemke DA, Bremerich J,, et al. Standardized image interpretation and post-processing in cardiovascular magnetic resonance–2020 update: Society for Cardio‑ vascular Magnetic Resonance (SCMR): Board of Trustees Task Force on Standardized Post-Processing. J Cardiovasc Magn Reson. 2020;22:19
  16. Leiner, T., Bogaert, J., Friedrich, M.G. et al. SCMR Position Paper (2020) on clinical indications for cardiovascular magnetic resonance. J Cardiovasc Magn Reson 22, 76 (2020.
  17. Steen H, Giusca S, Montenbruck M, et al. Left and right ventricular strain using fast strain-encoded cardiovascular magnetic resonance for the diagnostic classification of patients with chronic non-ischemic heart failure due to dilated, hypertrophic cardiomyopathy or cardiac amyloidosis. J Cardiovasc Magn Reson. 2021 Apr 5;23(1):4
  18. Steen H, Giusca S, Montenbruck M, et al. Left and right ventricular strain using fast strain-encoded cardiovascular magnetic resonance for the diagnostic classification of patients with chronic non-ischemic heart failure due to dilated, hypertrophic cardiomyopathy or cardiac amyloidosis. J Cardiovasc Magn Reson. 2021 Apr 5;23(1):4
  19. Korosoglou G, Giusca S, Montenbruck M, et al. Fast Strain-Encoded Cardiac Magnetic Resonance for Diagnostic Classification and Risk Stratification of Heart Failure Patients. JACC Cardiovasc Imaging. 2021 Jun;14(6):1177-1188
  20. Fukui M, Bing R, Dweck M, Cavalcante JL. Assessment of Aortic Stenosis by Cardiac Magnetic Resonance Imaging: Quantification of Flow, Characterization of Myocardial Injury, Transcatheter Aortic Valve Replacement Planning, and More. Magn Reson Imaging Clin N Am. 2019 Aug;27(3):427-437
  21. Rajiah P, Bolen MA. Cardiovascular MR imaging at 3 T: opportunities, challenges, and solutions. Radiographics. 2014 Oct;34(6):1612-35
  22. Elsayed A, Gilbert K, Scadeng M, et al. Four-dimensional flow cardiovascular magnetic resonance in tetralogy of Fallot: a systematic review. J Cardiovasc Magn Reson. 2021 May 20;23(1):59.
  23. Dyverfeldt P, Bissell M, Barker AJ, et al. 4D flow cardiovascular magnetic resonance consensus statement. J Cardiovasc Magn Reson. 2015 Aug 10;17(1):72
  24. Lambert MA, Weir-McCall JR, Salsano M, Gandy SJ, Levin D, Cavin I, Littleford R, MacFarlane JA, Matthew SZ, Nicholas RS, Struthers AD, Sullivan F, Henderson SA, White RD, Belch JJF, Houston JG. Prevalence and Distribution of Atherosclerosis in a Low- to Intermediate-Risk Population: Assessment with Whole-Body MR Angiography. Radiology. 2018 Jun;287(3):795-804. doi: 10.1148/radiol.2018171609. Epub 2018 May 1. PMID: 29714681; PMCID: PMC5979784.
  25. Anzidei M, Napoli A, Zaccagna F, Di Paolo P, Saba L, Cavallo Marincola B, Zini C, Cartocci G, Di Mare L, Catalano C, Passariello R. Diagnostic accuracy of colour Doppler ultrasonography, CT angiography and blood-pool-enhanced MR angiography in assessing carotid stenosis: a comparative study with DSA in 170 patients. Radiol Med. 2012 Feb;117(1):54-71. English, Italian. doi: 10.1007/s11547-011-0651-3. Epub 2011 Mar 7. PMID: 21424318.
  26. Smith LR, Darty SN, Jenista ER, Gamoneda GL, Wendell DC, Azevedo CF, Parker MA, Kim RJ, Kim HW. ECG-gated MR angiography provides better reproducibility for standard aortic measurements. Eur Radiol. 2021 Jul;31(7):5087-5095. doi: 10.1007/s00330-020-07408-1. Epub 2021 Jan 6. PMID: 33409772.
  27. Smith LR, Darty SN, Jenista ER, Gamoneda GL, Wendell DC, Azevedo CF, Parker MA, Kim RJ, Kim HW. ECG-gated MR angiography provides better reproducibility for standard aortic measurements. Eur Radiol. 2021 Jul;31(7):5087-5095. doi: 10.1007/s00330-020-07408-1. Epub 2021 Jan 6. PMID: 33409772.
  28. Kawel N, Turkbey EB, Carr JJ, Eng J, Gomes AS, Hundley WG, Johnson C, Masri SC, Prince MR, van der Geest RJ, et al. Normal left ventricular myocardial thickness for middle-aged and older subjects with steady-state free precession cardiac magnetic resonance: the multi-ethnic study of  atherosclerosis. Circ Cardiovasc Imaging. 2012;5:500–8
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