Cardiac biomarkers in chronic kidney disease are independently associated with myocardial edema and diffuse fibrosis by cardiovascular magnetic resonance

Luca Arcari, Juergen Engel, Tilo Freiwald, Hui Zhou, Hafisyatul Zainal, Monika Gawor, Stefan Buettner, Helmut Geiger, Ingeborg Hauser, Eike Nagel, Valentina O Puntmann, Luca Arcari, Juergen Engel, Tilo Freiwald, Hui Zhou, Hafisyatul Zainal, Monika Gawor, Stefan Buettner, Helmut Geiger, Ingeborg Hauser, Eike Nagel, Valentina O Puntmann

Abstract

Background: High sensitivity cardiac troponin T (hs-cTnT) and NT-pro-brain natriuretic peptide (NT-pro BNP) are often elevated in chronic kidney disease (CKD) and associated with both cardiovascular remodeling and outcome. Relationship between these biomarkers and quantitative imaging measures of myocardial fibrosis and edema by T1 and T2 mapping remains unknown.

Methods: Consecutive patients with established CKD and estimated glomerular filtration rate (eGFR) < 59 ml/min/1.73 m2 (n = 276) were compared to age/sex matched patients with eGFR ≥ 60 ml/min/1.73 m2 (n = 242) and healthy controls (n = 38). Comprehensive cardiovascular magnetic resonance (CMR) with native T1 and T2 mapping, myocardial ischemia and scar imaging was performed with venous sampling immediately prior to CMR.

Results: Patients with CKD showed significant cardiac remodeling in comparison with both healthy individuals and non-CKD patients, including a stepwise increase of native T1 and T2 (p < 0.001 between all CKD stages). Native T1 and T2 were the sole imaging markers independently associated with worsening CKD in patients [B = 0.125 (95% CI 0.022-0.235) and B = 0.272 (95% CI 0.164-0.374) with p = 0.019 and < 0.001 respectively]. At univariable analysis, both hs-cTnT and NT-pro BNP significantly correlated with native T1 and T2 in groups with eGFR 30-59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2 groups, with associations being stronger at lower eGFR (NT-pro BNP (log transformed, lg10): native T1 r = 0.43 and r = 0.57, native T2 r = 0.39 and r = 0.48 respectively; log-transformed hs-cTnT(lg10): native T1 r = 0.23 and r = 0.43, native T2 r = 0.38 and r = 0.58 respectively, p < 0.001 for all, p < 0.05 for interaction). On multivariable analyses, we found independent associations of native T1 with NT-pro BNP [(B = 0.308 (95% CI 0.129-0.407), p < 0.001 and B = 0.334 (95% CI 0.154-0.660), p = 0.002 for eGFR 30-59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2, respectively] and of T2 with hs-cTnT [B = 0.417 (95% CI 0.219-0.650), p < 0.001 for eGFR < 29 ml/min/1.73 m2].

Conclusions: We demonstrate independent associations between cardiac biomarkers with imaging markers of interstitial expansion, which are CKD-group specific. Our findings indicate the role of diffuse non-ischemic tissue processes, including excess of myocardial fluid in addition to diffuse fibrosis in CKD-related adverse remodeling.

Keywords: Cardiovascular magnetic resonance; Chronic kidney disease; Edema; Heart failure; Myocardial remodeling; Troponin.

Conflict of interest statement

There are no conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
Consort diagram. Study details and imaging protocols available at the dedicated webpages: TrueTypeCKD Study and International T1 Outcome study. CKD chronic kidney disease, GBCA gadolinium-based contrast agent, LVH left ventricular hypertrophy, MRI magnetic resonance imaging, SID systemic inflammatory disease, Tx transplantation
Fig. 2
Fig. 2
Representative measurement of native T1 and T2 in a CKD patient (a) and a control (b) Native T1 and T2 measurements (mean midventricular septal ROI measurement, normal values for native T1 using FFM-MOLLI: 3.0-T: mean of the normal range 1052 ± 23 ms; i.e. upper limit of normal range: 1098 ms at 3T), native T2: T2-FLASH sequence 35 ± 2 ms)
Fig. 3
Fig. 3
Native T1 and T2 values across groups of healthy controls and patients with differential degree of CKD
Fig. 4
Fig. 4
Subgroup of participants undergoing a repeat CMR immediately after hemodialysis. a Graph showing significant native T2 reduction after hemodialysis. b Graph showing significant correlation between removed ultrafiltration volume and change in native T2. MD mean difference, SD standard deviation
Fig. 5
Fig. 5
Relationships between high sensitivity cardiac troponin Ths-cTnT (a, b) and N-terminal pro brain natriuretic peptide (NT-pro BNP) (c, d) with native T1 and T2 in patients with differential degrees of CKD. hs-cTnT high-sensitive cardiac troponin T, lg10 log transformed

References

    1. Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol. 2006;17:2034–2047. doi: 10.1681/ASN.2005101085.
    1. Unger ED, Dubin RF, Deo R, Daruwalla V, Friedman JL, Medina C, et al. Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction. Eur J Heart Fail. 2016;18:103–112. doi: 10.1002/ejhf.445.
    1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37:2129–2200. doi: 10.1093/eurheartj/ehw128.
    1. Arcari L, Ciavarella GM, Altieri S, Limite LR, Russo D, Luciani M, et al. Longitudinal changes of left and right cardiac structure and function in patients with end-stage renal disease on replacement therapy. Eur J Intern Med. 2020 doi: 10.1016/j.ejim.2020.04.051.
    1. Apple FS, Sharkey SW, Hoeft P, Skeate R, Voss E, Dahlmeier BA, et al. Prognostic value of serum cardiac troponin I and T in chronic dialysis patients: a 1-year outcomes analysis. Am J Kidney Dis. 1997;29:399–403. doi: 10.1016/s0272-6386(97)90201-8.
    1. Jacobs LH, Van De Kerkhof J, Mingels AM, Kleijnen VW, Van Der Sande FM, Wodzig WK, et al. Haemodialysis patients longitudinally assessed by highly sensitive cardiac troponin T and commercial cardiac troponin T and cardiac troponin I assays. Ann Clin Biochem. 2009;46:283–290. doi: 10.1258/acb.2009.008197.
    1. Parikh RH, Seliger SL, deFilippi CR. Use and interpretation of high sensitivity cardiac troponins in patients with chronic kidney disease with and without acute myocardial infarction. Clin Biochem. 2015;48:247–253. doi: 10.1016/j.clinbiochem.2015.01.004.
    1. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth universal definition of myocardial infarction (2018) Eur Heart J. 2019;40:237–269. doi: 10.1093/eurheartj/ehy462.
    1. Van Der Linden N, Cornelis T, Kimenai DM, Klinkenberg LJJ, Hilderink JM, Lück S, et al. Origin of cardiac troponin T elevations in chronic kidney disease. Circulation. 2017;136:1073–1075. doi: 10.1161/CIRCULATIONAHA.117.029986.
    1. Puntmann VO, Valbuena S, Hinojar R, Petersen SE, Greenwood JP, Kramer CM, et al. Society for cardiovascular magnetic resonance (SCMR) expert consensus for CMR imaging endpoints in clinical research: part i—analytical validation and clinical qualification. J Cardiovasc Magn Reson. 2018 doi: 10.1186/s12968-018-0484-5.
    1. Mangion K, McDowell K, Mark PB, Rutherford E. Characterizing cardiac involvement in chronic kidney disease using CMR-a systematic review. Curr Cardiovasc Imaging Rep. 2018;11:2. doi: 10.1007/s12410-018-9441-9.
    1. Rutherford E, Talle MA, Mangion K, Bell E, Rauhalammi SM, Roditi G, et al. Defining myocardial tissue abnormalities in end-stage renal failure with cardiac magnetic resonance imaging using native T1 mapping. Kidney Int. 2016;90:845–852. doi: 10.1016/j.kint.2016.06.014.
    1. Kotecha T, Martinez-Naharro A, Yoowannakul S, Lambe T, Rezk T, Knight DS, et al. Acute changes in cardiac structural and tissue characterisation parameters following haemodialysis measured using cardiovascular magnetic resonance. Sci Rep. 2019;9:1388. doi: 10.1038/s41598-018-37845-4.
    1. Puntmann VO, Carr-White G, Jabbour A, Yu C-Y, Gebker R, Kelle S, et al. T1-mapping and outcome in nonischemic cardiomyopathy all-cause mortality and heart failure. JACC Cardiovasc Imaging. 2016 doi: 10.1016/j.jcmg.2015.12.001.
    1. Puntmann VO, Carr-White G, Jabbour A, Yu C-Y, Gebker R, Kelle S, et al. Native T1 and ECV of noninfarcted myocardium and outcome in patients with coronary artery disease. J Am Coll Cardiol. 2018;71:766–778. doi: 10.1016/j.jacc.2017.12.020.
    1. . Last accessed 1st June 2020.
    1. . Last accessed 1st Jun 2020.
    1. Chen M, Arcari L, Engel J, Freiwald T, Platschek S, Zhou H, et al. Aortic stiffness is independently associated with interstitial myocardial fibrosis by native T1 and accelerated in the presence of chronic kidney disease. IJC Heart Vasc. 2019;24:100389. doi: 10.1016/J.IJCHA.2019.100389.
    1. ; ; . Last accessed on 1st June 2020.
    1. . Last accessed on 1st June 2020.
    1. Verhaert D, Thavendiranathan P, Giri S, Mihai G, Rajagopalan S, Simonetti OP, et al. Direct T2 quantification of myocardial edema in acute ischemic injury. JACC Cardiovasc Imaging. 2011;4:269–278. doi: 10.1016/j.jcmg.2010.09.023.
    1. Dabir D, Child N, Kalra A, Rogers T, Gebker R, Jabbour A, et al. Reference values for healthy human myocardium using a T1 mapping methodology: results from the International T1 Multicenter cardiovascular magnetic resonance study. J Cardiovasc Magn Reson. 2014;16:69. doi: 10.1186/s12968-014-0069-x.
    1. Jahrestagung der Deutsche Gesellschaft für Kardiologie- Herz- und Kreislaufforschung vom 4. bis 7. April 2018 in Mannheim 84th annual meeting of the German Cardiac Society—Cardiac and Circulation Research, April 4–7. 2018, Mannheim. Clin Res Cardiol 2018;107:1–1. 10.1007/s00392-018-1216-4.
    1. Nagel E, Greenwood JP, McCann GP, Bettencourt N, Shah AM, Hussain ST, et al. Magnetic resonance perfusion or fractional flow reserve in coronary disease. N Engl J Med. 2019;380:2418–2428. doi: 10.1056/NEJMoa1716734.
    1. Galderisi M, Cosyns B, Edvardsen T, Cardim N, Delgado V, Di Salvo G, et al. Standardization of adult transthoracic echocardiography reporting in agreement with recent chamber quantification, diastolic function, and heart valve disease recommendations: an expert consensus document of the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2017;18:1301–1310. doi: 10.1093/ehjci/jex244.
    1. Kramer CM, Barkhausen J, Bucciarelli-Ducci C, Flamm SD, Kim RJ, Nagel E. Standardized cardiovascular magnetic resonance imaging (CMR) protocols: 2020 update. J Cardiovasc Magn Reson. 2020 doi: 10.1186/s12968-020-00607-1.
    1. Child N, Suna G, Dabir D, Yap M-L, Rogers T, Kathirgamanathan M, et al. Comparison of MOLLI, shMOLLLI, and SASHA in discrimination between health and disease and relationship with histologically derived collagen volume fraction. Eur Heart J Cardiovasc Imaging. 2018;19:768–776. doi: 10.1093/ehjci/jex309.
    1. Pedrizzetti G, Claus P, Kilner PJ, Nagel E. Principles of cardiovascular magnetic resonance feature tracking and echocardiographic speckle tracking for informed clinical use. J Cardiovasc Magn Reson. 2016;18:51. doi: 10.1186/s12968-016-0269-7.
    1. Edwards NC, Moody WE, Yuan M, Hayer MK, Ferro CJ, Townend JN, et al. Diffuse interstitial fibrosis and myocardial dysfunction in early chronic kidney disease. Am J Cardiol. 2015;115:1311–1317. doi: 10.1016/j.amjcard.2015.02.015.
    1. Arcari L, Hinojar R, Engel J, Freiwald T, Platschek S, Zainal H, et al. Native T1 and T2 provide distinctive signatures in hypertrophic cardiac conditions—comparison of uremic, hypertensive and hypertrophic cardiomyopathy. Int J Cardiol. 2020 doi: 10.1016/j.ijcard.2020.03.002.
    1. Kociol RD, Pang PS, Gheorghiade M, Fonarow GC, O’Connor CM, Felker GM. Troponin elevation in heart failure prevalence, mechanisms, and clinical implications. J Am Coll Cardiol. 2010;56:1071–1078. doi: 10.1016/j.jacc.2010.06.016.
    1. Januzzi JL, Filippatos G, Nieminen M, Gheorghiade M. Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section. Eur Heart J. 2012;33:2265–2271. doi: 10.1093/eurheartj/ehs191.
    1. Franssen CFM, Navis G. Chronic kidney disease: RAAS blockade and diastolic heart failure in chronic kidney disease. Nat Rev Nephrol. 2013;9:190–192. doi: 10.1038/nrneph.2013.39.
    1. Dickhout JG, Carlisle RE, Austin RC. Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease: endoplasmic reticulum stress as a mediator of pathogenesis. Circ Res. 2011;108:629–642. doi: 10.1161/CIRCRESAHA.110.226803.
    1. Winau L, Hinojar Baydes R, Braner A, Drott U, Burkhardt H, Sangle S, et al. High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory cardiovascular involvement in systemic lupus erythematosus. Ann Rheum Dis. 2018;77:1590–1598. doi: 10.1136/annrheumdis-2018-213661.
    1. Verbrugge FH, Bertrand PB, Willems E, Gielen E, Mullens W, Giri S, et al. Global myocardial oedema in advanced decompensated heart failure. Eur Hear J Cardiovasc Imaging. 2017;18:787–794. doi: 10.1093/ehjci/jew131.
    1. Fernández-Jiménez R, Sánchez-González J, Aguero J, Del Trigo M, Galán-Arriola C, Fuster V, 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. 2015;17:92. doi: 10.1186/s12968-015-0199-9.

Source: PubMed

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