Periodic Reporting for period 1 - uPROPHET (uPROPHET: Urinary PROteomics in Predicting HEart Transplantation outcomes)
Periodo di rendicontazione: 2016-10-01 al 2018-03-31
Sintesi del contesto e degli obiettivi generali del progetto
The problem addressed
----------------------------
The prevalence of heart failure (HF) among adults living in developed countries is ~2%, amounting to 15 million in the European Union [1] with a 5-year mortality rate of 50% [1]. Heart transplantation (HTx) is the treatment of choice for selected terminally ill HF patients not responsive to medical treatment [2]. With >5000 HTx procedures performed annually worldwide, HTx has a 1-year survival rate of 85% and results in substantial symptomatic improvement in 90% of survivors at 3 years after HTx [2]. Despite this undeniable success, HTx keeps meeting major challenges. First, endomyocardial biopsy (EMB), the standard procedure to monitor graft rejection after HTx, is an invasive risk-carrying procedure [3]. Even if EMB is associated with an acute complication rate of <2% [3], the procedure is costly, time consuming and cumbersome for patients. Repeated EMBs entail a complication rate 10–20 times higher if expressed per patient than per procedure. Furthermore, small EMB samples taken from the right ventricular septal wall (the wall between the right and left heart chambers) are not representative for the usually patchy rejection lesions. Inter-observer variability in histologically grading rejection is far from optimal [4]. EMB is also less informative in acute antibody-mediated rejection [5], a condition characterised by myocardial capillary injury occurring in the first year after HTx in up to 15% of patients [6] with a high risk of graft failure [5,6]. Second, mild-to-severe coronary vasculopathy occurs in >15% of HTx patients with an overall likelihood of death or retransplantation of 7% at 5 years post HTx. Its diagnosis requires invasive coronary angiography and exposure to nephrotoxic contrast media [6]. Third, in HTx patients, the cumulative incidence of cancer is ~15%, ~30% and ~60% after 5, 10 and 20 years of follow-up [7], but no predictive test is available. Fourth, there is no easily applicable biomarker test reproducibly predicting decline in renal function on nephrotoxic immunosuppressants [8] or the long-term outcome of HTx. Finally, current state-of-the-art procedures do not provide guidance other than clinical intuition to taper or stop corticosteroids or immunosuppressants in patients who survive the first 12–18 months after HTx without major rejection.
The solution
---------------
The Epidemiological Left Ventricular Outcome Research in Europe project (EPLORE-94713) focused on novel approaches to curb the HF epidemic. In partnership with SME Mosaiques Diagnostics and Therapeutics, Hannover, Germany (MOS [http://mosaiques-diagnostics.de]) EPLORE firmly established in populations [9-13] and patients [14,15] that diastolic left ventricular (LV) dysfunction [10,12], HF [14,16], chronic kidney disease (CKD) [9,13,15] and the incidence of cardiovascular (CV) complications are associated [9,11] with specific multidimensional urinary proteomic (UP) markers [9,10,14] or sequenced UP fragments [12-15] identifying parent proteins mechanistically underlying the culprit pathophysiological processes. Thus, EPLORE made a strong case for porting UP profiling to clinical practice, for instance as a cost-effective method to screen for diastolic LV dysfunction, a condition affecting 25% of Europeans [17,18] and over time progressing to overt HF [14,19,20] and premature morbidity and death [21]. The Urinary Proteomics in Predicting Heart Transplantation Outcomes project (uPROPHET-713601) set up a unique resource to test the concept generated by EPLORE that UP biomarkers might contribute to the management of HTx patients. The published protocol describes the construction, governance and analysis of the database [22]. uPROPHET was approved by Ethics Committee of the University Hospitals Leuven and passed review by the European Research Council Executive Agency. Of ~400 HTx patients enrolled at the University Hospitals Leuven, 39% and 40% had a history of ischaemic or dilated cardiomyopathy (CMP); 37% and 7% experienced mild (grade 1B) or severe (≥2) cellular rejection; and 6% had an episode of anti-body mediated rejection [22]. The mean time interval between HTx and first UP assessment was 8 years (interquartile range, 6–12) with a median of 3 urine samples per patient analysed during further follow-up (~950 in total). The multidimensional UP marker HF2 [9,10] was associated with higher right heart pressures [23], the current state-of-the-art in monitoring the haemodynamic status post HTx. The decline in glomerular filtration rate (GFR) commonly observed in HTx patients, partly due to the nephrotoxicity of immunosuppressants [8], was associated with higher urinary levels of a mucin 1 peptide fragment, which is shed from the tubular epithelium and of the multidimensional classifier CKD273, which outperformed proteinuria as predictor of GFR decline in HTx patients (submitted). The uPROPHET findings on HF2, CKD273 and mucin -1 extend previous EPLORE observations in populations [9,10,13] and patients [15]. The tissue proteomic study embedded in uPROPHET [24] included myocardial biopsies of 15/14 patients with ischaemic/dilated CMP and 12 discarded healthy donor hearts. Diseased vs. healthy hearts showed higher abundance of proteins involved in the organisation of the extracellular matrix or derived from circulating blood and lower abundance of mitochondrial proteins [24] and thereby identified new drug targets (IPR protected). Thus, the large uPROPHET database confirmed the feasibility of developing UP biomarkers in HTx patients and of generating IPR covering diagnostic UP markers in HTx recipients and new drug targets in HF patients.
References
-------------
1. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbély A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL (2007). How to diagnose heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 28: 2539-2550.
2. Haddad H, Isaac D, Legare JF, Pflugfelder P, Hendry P, Chan M, Cantin B, Giannetti N, Zieroth S, White M, Warnica W, Doucette K, Rao V, Dipchand A, Cantarovich M, Kostuk W, Cecere R, Charbonneau E, Ross H, Poirier N (2009). Canadian Cardiovascular Society Consensus Conference update on cardiac transplantation 2008: Executive Summary. Can J Cardiol 25: 197-205.
3. Holzmann M, Nicko A, Kühl U, Noutsias M, Poller W, Hoffmann W, Morguet A, Witzenbichler B, Tschöpe C, Schultheiss HP, Pauschinger M (2008). Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period. Circulation 118: 1722-1728.
4. Angelini A, Andersen CB, Bartoloni G, Black F, Bishop P, Doran H, Fedrigo M, Fries JW, Goddard M, Goebel H, Neil D, Leone O, Marzullo A, Ortmann M, Paraf F, Rotman S, Turhan N, Bruneval P, Frigo AC, Grigoletto F, Gasparetto A, Mencarelli R, Thiene G, Burke M (2011) A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allograft rejection: the European experience. J Heart Lung Transplant 30: 1214-1220.
5. Berry GJ, Burke MM, Andersen C, Bruneval P, Fedrigo M, Fishbein MC, Goddard M, Hammond EH, Leone O, Marboe C, Miller D, Neil D, Rassl D, Revelo MP, Rice A, Rene Rogriguez E, Stewart S, Tan CD, Winters GL, West L, Mehra MR, Angelini A (2013). The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 32: 1147-1162.
6. Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE, Kobashigawa JA, Madsen J, Parameshwar J, Starling RC, Uber PA (2010). International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant 29: 717-727.
7. Van Keer J, Droogné W, Van Cleemput J, Vörös G, Rega F, Meyns B, Janssens S, Vanhaecke J (2016). Cancer after heart transplantation: a 25-year single-center perspective. Transplant Proc 48: 2172-2177.
8. Crespo-Leiro MG, Delgado JF, Paniagua MJ, Vázquez de Prada JA, Fernandez-Yañez J, Almenar L, Diaz-Molina B, Roig E, Arizón JM, Alonso-Pulpón L, Garrido IP, Sanz ML, de la Fuente L, Mirabet S, Manito N, Muñiz J (2010). Prevalence and severity of renal dysfunction among 1062 heart transplant patients according to criteria based on serum creatinine and estimated glomerular filtration rate: results from the CAPRI study. Clin Transplant 24: E88-E93.
9. Gu YM, Thijs L, Liu YP, Zhang ZY, Jacobs J, Koeck T, Zürbig P, Lichtinghagen R, Brand K, Kuznetsova T, Olivi L, Verhamme P, Delles C, Mischak H, Staessen JA (2014). The urinary proteome as correlate and predictor of renal function in a population study. Nephrol Dial Transplant 29: 2260-2268.
10. Zhang ZY, Staessen JA, Thijs L, Gu Y, Liu Y, Jacobs L, Koeck T, Zürbig P, Mischak H, Kuznetsova T (2014) Left ventricular diastolic function in relation to the urinary proteome: a proof-of-concept study in a general population. Int J Cardiol 176: 158-165.
11. Zhang ZY, Thijs L, Petit T, Gu YM, Jacobs L, Yang WY, Liu YP, Koeck T, Zürbig P, Verhamme P, Voigt JU, Kuznetsova T, Mischak H, Staessen JA (2015). The urinary proteome and systolic blood pressure as predictors of 5-year cardiovascular and cardiac outcomes in a general population. Hypertension 66: 52-60.
12. Zhang ZY, Ravassa S, Yang WY, Petit T, Pejchinovski M, Zürbig P, López B, Wei FF, Pontillo C, Thijs L, Jacobs L, González A, Koeck T, Delles C, Voigt JU, Verhamme P, Kuznetsova T, Díez J, Mischak H, Staessen JA (2016). Diastolic left ventricular function in relation to urinary and serum collagen biomarkers in a general population. PLoS One 11: e0167582.
13. Zhang ZY, Ravassa S, Pejchinovski M, Yang WY, Zürbig P, Lopez B, Wei FF, Thijs L, Jacobs L, Gonzalez A, Voigt JU, Verhamme P, Kuznetsova T, Diez J, Mischak H, Staessen JA (2017). A urinary fragment of mucin-1 subunit a is a novel biomarker associated with renal dysfunction in the general population. KI Reports 2: 811-820.
14. Zhang ZY, Ravassa S, Nkuipou-Kenfack E, Yang WY, Kerr SM, Koeck T, Campbell A, Kuznetsova T, Mischak H, Padmanabhan S, Dominiczak AF, Delles C, Staessen JA (2017). Novel urinary peptidomic classifier predicts incident heart failure. J Am Heart Assoc 6: e005432.
15. Pontillo C, Zhang ZY, Schanstra JP, Jacobs L, Zürbig P, Thijs L, Ramirez-Torres A, Heerspink HJL, Lindhardt M, Klein R, Orchard T, Porta M, Bilous RW, Charturvedi N, Rossing P, Vlahou A, Schepers E, Glorieux G, Mullen W, Delles C, Verhamme P, Vanholder R, Staessen JA, Mischak H, Jankowski J (2017). Prediction of chronic kidney disease stage 3 by CKD273, a urinary proteomic biomarker. KI Reports 2: 1066-1075.
16. Rossing K, Bosselmann HS, Gustafsson F, Zhang ZY, Gu YM, Kuznetsova T, Nkuipou-Kenfack E, Mischak H, Staessen JA, Koeck T, Schou M (2016). Urinary proteomics pilot study for biomarker discovery and diagnosis in heart failure with reduced ejection fraction. PLoS One 11: e0157167.
17. Kuznetsova T, Herbots L, López B, Jin Y, Richart T, Thijs L, González A, Herregods MC, Fagard RH, Díez J, Staessen JA (2009). Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail 2: 105-112.
18. Kloch-Badelek M, Kuznetsova T, Sakiewicz W, Tikhonoff V, Ryabikov A, González A, Loster M, Thijs L, Jin Y, Malyutina S, Stolarz-Skrzypek K, Casiglia E, Díez J, Narkiewicz K, Kawecka-Jaszcz K, Staessen JA, on behalf of the European Project on Genes in Hypertension (EPOGH) Investigators (2012). Prevalence of diastolic left ventricular dysfunction in European populations based on cross-validated diagnostic thresholds. Cardiovascular Ultrasound 10: 10 (doi: 10.1186/1476-7120-10-10).
19. Grauhan O, Patzurek J, Hummel M, Lehmkuhl H, Dandel M, Pasic M, Weng Y, Hetzer R (2003). Donor-transmitted coronary atherosclerosis. J Heart Lung Transplant 22: 568-573.
20. Zhang ZY, Nkuipou-Kenfack E, Yang WY, Wei FF, Cauwenberghs N et al. (2018). Epidemiologic observations guiding clinical application of the HF1 urinary peptidomic marker of diastolic left ventricular dysfunction. J Am Soc Hypertens (in press).
21. Kuznetsova T, Thijs L, Knez J, Herbots L, Zhang Z, Staessen JA (2014). Prognostic value of left ventricular diastolic dysfunction in a general population. J Am Heart Assoc 3: e000789.
22. Huang QF, Trenson S, Zhang ZY, Yang WY, Van Aelst L, Nkuipou-Kenfack E, Wei FF, Mujaj B, Thijs L, Ciarka A, Zoidakis J, Droogné W, Vlahou A, Janssens S, Vanhaecke J, Van Cleemput J, Staessen JA (2017). Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET) - Rationale and database description. PLoS One 12: e0184443.
23. Huang QF, Trenson S, Zhang ZY, Van Keer J, Van Aelst L et al. (2018). Biomarkers to monitor right heart pressures in recipients of a heart transplant: a proof-of-concept study. Transplant Direct (in press).
24. Zhang ZY, Trenson S, Yang WY, Zoidakis J, Nkuipou-Kenfack E, et al. (2017). Myocardial proteomic signatures in end-stage dilated and ischemic cardiomyopathy compared with normal human hearts. In: OMICS as Tool to Address the Burden of Non-Communicable Age-Related Disease in Populations in Epidemiological Transition. Leuven University Press. pp. 315-375.
----------------------------
The prevalence of heart failure (HF) among adults living in developed countries is ~2%, amounting to 15 million in the European Union [1] with a 5-year mortality rate of 50% [1]. Heart transplantation (HTx) is the treatment of choice for selected terminally ill HF patients not responsive to medical treatment [2]. With >5000 HTx procedures performed annually worldwide, HTx has a 1-year survival rate of 85% and results in substantial symptomatic improvement in 90% of survivors at 3 years after HTx [2]. Despite this undeniable success, HTx keeps meeting major challenges. First, endomyocardial biopsy (EMB), the standard procedure to monitor graft rejection after HTx, is an invasive risk-carrying procedure [3]. Even if EMB is associated with an acute complication rate of <2% [3], the procedure is costly, time consuming and cumbersome for patients. Repeated EMBs entail a complication rate 10–20 times higher if expressed per patient than per procedure. Furthermore, small EMB samples taken from the right ventricular septal wall (the wall between the right and left heart chambers) are not representative for the usually patchy rejection lesions. Inter-observer variability in histologically grading rejection is far from optimal [4]. EMB is also less informative in acute antibody-mediated rejection [5], a condition characterised by myocardial capillary injury occurring in the first year after HTx in up to 15% of patients [6] with a high risk of graft failure [5,6]. Second, mild-to-severe coronary vasculopathy occurs in >15% of HTx patients with an overall likelihood of death or retransplantation of 7% at 5 years post HTx. Its diagnosis requires invasive coronary angiography and exposure to nephrotoxic contrast media [6]. Third, in HTx patients, the cumulative incidence of cancer is ~15%, ~30% and ~60% after 5, 10 and 20 years of follow-up [7], but no predictive test is available. Fourth, there is no easily applicable biomarker test reproducibly predicting decline in renal function on nephrotoxic immunosuppressants [8] or the long-term outcome of HTx. Finally, current state-of-the-art procedures do not provide guidance other than clinical intuition to taper or stop corticosteroids or immunosuppressants in patients who survive the first 12–18 months after HTx without major rejection.
The solution
---------------
The Epidemiological Left Ventricular Outcome Research in Europe project (EPLORE-94713) focused on novel approaches to curb the HF epidemic. In partnership with SME Mosaiques Diagnostics and Therapeutics, Hannover, Germany (MOS [http://mosaiques-diagnostics.de]) EPLORE firmly established in populations [9-13] and patients [14,15] that diastolic left ventricular (LV) dysfunction [10,12], HF [14,16], chronic kidney disease (CKD) [9,13,15] and the incidence of cardiovascular (CV) complications are associated [9,11] with specific multidimensional urinary proteomic (UP) markers [9,10,14] or sequenced UP fragments [12-15] identifying parent proteins mechanistically underlying the culprit pathophysiological processes. Thus, EPLORE made a strong case for porting UP profiling to clinical practice, for instance as a cost-effective method to screen for diastolic LV dysfunction, a condition affecting 25% of Europeans [17,18] and over time progressing to overt HF [14,19,20] and premature morbidity and death [21]. The Urinary Proteomics in Predicting Heart Transplantation Outcomes project (uPROPHET-713601) set up a unique resource to test the concept generated by EPLORE that UP biomarkers might contribute to the management of HTx patients. The published protocol describes the construction, governance and analysis of the database [22]. uPROPHET was approved by Ethics Committee of the University Hospitals Leuven and passed review by the European Research Council Executive Agency. Of ~400 HTx patients enrolled at the University Hospitals Leuven, 39% and 40% had a history of ischaemic or dilated cardiomyopathy (CMP); 37% and 7% experienced mild (grade 1B) or severe (≥2) cellular rejection; and 6% had an episode of anti-body mediated rejection [22]. The mean time interval between HTx and first UP assessment was 8 years (interquartile range, 6–12) with a median of 3 urine samples per patient analysed during further follow-up (~950 in total). The multidimensional UP marker HF2 [9,10] was associated with higher right heart pressures [23], the current state-of-the-art in monitoring the haemodynamic status post HTx. The decline in glomerular filtration rate (GFR) commonly observed in HTx patients, partly due to the nephrotoxicity of immunosuppressants [8], was associated with higher urinary levels of a mucin 1 peptide fragment, which is shed from the tubular epithelium and of the multidimensional classifier CKD273, which outperformed proteinuria as predictor of GFR decline in HTx patients (submitted). The uPROPHET findings on HF2, CKD273 and mucin -1 extend previous EPLORE observations in populations [9,10,13] and patients [15]. The tissue proteomic study embedded in uPROPHET [24] included myocardial biopsies of 15/14 patients with ischaemic/dilated CMP and 12 discarded healthy donor hearts. Diseased vs. healthy hearts showed higher abundance of proteins involved in the organisation of the extracellular matrix or derived from circulating blood and lower abundance of mitochondrial proteins [24] and thereby identified new drug targets (IPR protected). Thus, the large uPROPHET database confirmed the feasibility of developing UP biomarkers in HTx patients and of generating IPR covering diagnostic UP markers in HTx recipients and new drug targets in HF patients.
References
-------------
1. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbély A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL (2007). How to diagnose heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 28: 2539-2550.
2. Haddad H, Isaac D, Legare JF, Pflugfelder P, Hendry P, Chan M, Cantin B, Giannetti N, Zieroth S, White M, Warnica W, Doucette K, Rao V, Dipchand A, Cantarovich M, Kostuk W, Cecere R, Charbonneau E, Ross H, Poirier N (2009). Canadian Cardiovascular Society Consensus Conference update on cardiac transplantation 2008: Executive Summary. Can J Cardiol 25: 197-205.
3. Holzmann M, Nicko A, Kühl U, Noutsias M, Poller W, Hoffmann W, Morguet A, Witzenbichler B, Tschöpe C, Schultheiss HP, Pauschinger M (2008). Complication rate of right ventricular endomyocardial biopsy via the femoral approach: a retrospective and prospective study analyzing 3048 diagnostic procedures over an 11-year period. Circulation 118: 1722-1728.
4. Angelini A, Andersen CB, Bartoloni G, Black F, Bishop P, Doran H, Fedrigo M, Fries JW, Goddard M, Goebel H, Neil D, Leone O, Marzullo A, Ortmann M, Paraf F, Rotman S, Turhan N, Bruneval P, Frigo AC, Grigoletto F, Gasparetto A, Mencarelli R, Thiene G, Burke M (2011) A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allograft rejection: the European experience. J Heart Lung Transplant 30: 1214-1220.
5. Berry GJ, Burke MM, Andersen C, Bruneval P, Fedrigo M, Fishbein MC, Goddard M, Hammond EH, Leone O, Marboe C, Miller D, Neil D, Rassl D, Revelo MP, Rice A, Rene Rogriguez E, Stewart S, Tan CD, Winters GL, West L, Mehra MR, Angelini A (2013). The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 32: 1147-1162.
6. Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE, Kobashigawa JA, Madsen J, Parameshwar J, Starling RC, Uber PA (2010). International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010. J Heart Lung Transplant 29: 717-727.
7. Van Keer J, Droogné W, Van Cleemput J, Vörös G, Rega F, Meyns B, Janssens S, Vanhaecke J (2016). Cancer after heart transplantation: a 25-year single-center perspective. Transplant Proc 48: 2172-2177.
8. Crespo-Leiro MG, Delgado JF, Paniagua MJ, Vázquez de Prada JA, Fernandez-Yañez J, Almenar L, Diaz-Molina B, Roig E, Arizón JM, Alonso-Pulpón L, Garrido IP, Sanz ML, de la Fuente L, Mirabet S, Manito N, Muñiz J (2010). Prevalence and severity of renal dysfunction among 1062 heart transplant patients according to criteria based on serum creatinine and estimated glomerular filtration rate: results from the CAPRI study. Clin Transplant 24: E88-E93.
9. Gu YM, Thijs L, Liu YP, Zhang ZY, Jacobs J, Koeck T, Zürbig P, Lichtinghagen R, Brand K, Kuznetsova T, Olivi L, Verhamme P, Delles C, Mischak H, Staessen JA (2014). The urinary proteome as correlate and predictor of renal function in a population study. Nephrol Dial Transplant 29: 2260-2268.
10. Zhang ZY, Staessen JA, Thijs L, Gu Y, Liu Y, Jacobs L, Koeck T, Zürbig P, Mischak H, Kuznetsova T (2014) Left ventricular diastolic function in relation to the urinary proteome: a proof-of-concept study in a general population. Int J Cardiol 176: 158-165.
11. Zhang ZY, Thijs L, Petit T, Gu YM, Jacobs L, Yang WY, Liu YP, Koeck T, Zürbig P, Verhamme P, Voigt JU, Kuznetsova T, Mischak H, Staessen JA (2015). The urinary proteome and systolic blood pressure as predictors of 5-year cardiovascular and cardiac outcomes in a general population. Hypertension 66: 52-60.
12. Zhang ZY, Ravassa S, Yang WY, Petit T, Pejchinovski M, Zürbig P, López B, Wei FF, Pontillo C, Thijs L, Jacobs L, González A, Koeck T, Delles C, Voigt JU, Verhamme P, Kuznetsova T, Díez J, Mischak H, Staessen JA (2016). Diastolic left ventricular function in relation to urinary and serum collagen biomarkers in a general population. PLoS One 11: e0167582.
13. Zhang ZY, Ravassa S, Pejchinovski M, Yang WY, Zürbig P, Lopez B, Wei FF, Thijs L, Jacobs L, Gonzalez A, Voigt JU, Verhamme P, Kuznetsova T, Diez J, Mischak H, Staessen JA (2017). A urinary fragment of mucin-1 subunit a is a novel biomarker associated with renal dysfunction in the general population. KI Reports 2: 811-820.
14. Zhang ZY, Ravassa S, Nkuipou-Kenfack E, Yang WY, Kerr SM, Koeck T, Campbell A, Kuznetsova T, Mischak H, Padmanabhan S, Dominiczak AF, Delles C, Staessen JA (2017). Novel urinary peptidomic classifier predicts incident heart failure. J Am Heart Assoc 6: e005432.
15. Pontillo C, Zhang ZY, Schanstra JP, Jacobs L, Zürbig P, Thijs L, Ramirez-Torres A, Heerspink HJL, Lindhardt M, Klein R, Orchard T, Porta M, Bilous RW, Charturvedi N, Rossing P, Vlahou A, Schepers E, Glorieux G, Mullen W, Delles C, Verhamme P, Vanholder R, Staessen JA, Mischak H, Jankowski J (2017). Prediction of chronic kidney disease stage 3 by CKD273, a urinary proteomic biomarker. KI Reports 2: 1066-1075.
16. Rossing K, Bosselmann HS, Gustafsson F, Zhang ZY, Gu YM, Kuznetsova T, Nkuipou-Kenfack E, Mischak H, Staessen JA, Koeck T, Schou M (2016). Urinary proteomics pilot study for biomarker discovery and diagnosis in heart failure with reduced ejection fraction. PLoS One 11: e0157167.
17. Kuznetsova T, Herbots L, López B, Jin Y, Richart T, Thijs L, González A, Herregods MC, Fagard RH, Díez J, Staessen JA (2009). Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail 2: 105-112.
18. Kloch-Badelek M, Kuznetsova T, Sakiewicz W, Tikhonoff V, Ryabikov A, González A, Loster M, Thijs L, Jin Y, Malyutina S, Stolarz-Skrzypek K, Casiglia E, Díez J, Narkiewicz K, Kawecka-Jaszcz K, Staessen JA, on behalf of the European Project on Genes in Hypertension (EPOGH) Investigators (2012). Prevalence of diastolic left ventricular dysfunction in European populations based on cross-validated diagnostic thresholds. Cardiovascular Ultrasound 10: 10 (doi: 10.1186/1476-7120-10-10).
19. Grauhan O, Patzurek J, Hummel M, Lehmkuhl H, Dandel M, Pasic M, Weng Y, Hetzer R (2003). Donor-transmitted coronary atherosclerosis. J Heart Lung Transplant 22: 568-573.
20. Zhang ZY, Nkuipou-Kenfack E, Yang WY, Wei FF, Cauwenberghs N et al. (2018). Epidemiologic observations guiding clinical application of the HF1 urinary peptidomic marker of diastolic left ventricular dysfunction. J Am Soc Hypertens (in press).
21. Kuznetsova T, Thijs L, Knez J, Herbots L, Zhang Z, Staessen JA (2014). Prognostic value of left ventricular diastolic dysfunction in a general population. J Am Heart Assoc 3: e000789.
22. Huang QF, Trenson S, Zhang ZY, Yang WY, Van Aelst L, Nkuipou-Kenfack E, Wei FF, Mujaj B, Thijs L, Ciarka A, Zoidakis J, Droogné W, Vlahou A, Janssens S, Vanhaecke J, Van Cleemput J, Staessen JA (2017). Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET) - Rationale and database description. PLoS One 12: e0184443.
23. Huang QF, Trenson S, Zhang ZY, Van Keer J, Van Aelst L et al. (2018). Biomarkers to monitor right heart pressures in recipients of a heart transplant: a proof-of-concept study. Transplant Direct (in press).
24. Zhang ZY, Trenson S, Yang WY, Zoidakis J, Nkuipou-Kenfack E, et al. (2017). Myocardial proteomic signatures in end-stage dilated and ischemic cardiomyopathy compared with normal human hearts. In: OMICS as Tool to Address the Burden of Non-Communicable Age-Related Disease in Populations in Epidemiological Transition. Leuven University Press. pp. 315-375.