RECONNECT (2015 - 2020)
RECONNECT – Renal connection to microvascular disease and heart failure with preserved ejection fraction (2015-2020). The RECONNECT consortium was established in 2015, supported by CardioVasculair Onderzoek Nederland (CVON) and the Dutch Heart Foundation. RECONNECT has provided fundamental knowledge on the connection between chronic kidney disease and HFpEF and established a translational pipeline for the discovery and evaluation of potential diagnostic, prognostic and therapeutic targets.
Summary
Heart failure (HF) is a major health care problem with high mortality. Although advances have been made in treatment of HF patients with reduced ejection fraction (EF), this is not true for HF patients with preserved EF (HFpEF).
Our consortium demonstrated that impaired kidney function is a strong risk factor for mortality in HFpEF. However, the mechanisms by which chronic kidney disease (CKD) and its systemic consequences aggravate HFpEF were poorly understood. More recent insights indicated a central role for the microvasculature in HFpEF aetiology, and a causal relation between CKD and microvascular dysfunction.
The RECONNECT consortium tested the hypothesis that impaired kidney function and its systemic consequences adversely impact the coronary microvasculature, modifying pathophysiology and course of HFpEF. RECONNECT brought together existing cohorts with >1500 patients in different stages of HFpEF with and without CKD. By combining basic epidemiology with mechanistic ex-vivo studies we evaluated (pre-defined and novel) renal drivers of HFpEF, and made excellent progress in elucidating the mechanisms that contribute to microvascular dysfunction and inflammatory-microvascular-cardiac cell crosstalk, using state-of-the-art functionomics, metabolomics and epigenetics. Additionally, RECONNECT studied the mechanism and evaluated drug targets of HFpEF in unique in-vivo models of CKD-HFpEF, evaluated novel diagnostic and prognostic renal markers for HFpEF and designed a strategy for targeted clinical interventions, prioritizing renal drivers in relation to patient risk profile to provide a basis for future large-scale intervention trials.
The RECONNECT project has thus contributed to enhancing our mechanistic insight in the renal drivers of HFpEF, ultimately allowing new personalized therapeutic solutions for HFpEF patients.
More about RECONNECT
Using an integrated and multidisciplinary research approach, RECONNECT has made excellent progress in unravelling the mechanisms underlying the reno-cardiac interaction, particularly in CKD-associated HFpEF.
We established a translational pipeline through:
- Development of state-of-the-art in vitro assays (e.g. co-culture of cardiomyocytes and vascular cells, vessel-on-a-chip) that allow the study of patient materials.
- Generation and characterization of small (rodent) and large (porcine) animal models of CKD-associated HFpEF that reflect the multimorbid state of HFpEF patients and are associated with inflammation and coronary vascular endothelial dysfunction.
- Strong patient cohorts: we have further strengthened our patient cohorts for target discovery and testing.
- Investing in setting up a clinical trial infrastructure, which allows testing of targeted clinical interventions in well-defined small patient-groups by taking a stratified approach.
Our RECONNECT translational pipeline demonstrated that impaired kidney function is a strong risk factor for onset and progression as well as for mortality in HFpEF and provides novel insights in the mechanisms by which CKD – and its systemic consequences, including inflammation and coronary microvascular dysfunction – plays a central role in the pathogenesis of HFpEF. Based on this, our consortium has identified a number of specific potential targets for therapy.
Through our RECONNECT pipeline we also developed prediction rules for use in general practice where the majority of the HFpEF population resides in society. These constitute the basis for further evaluation of the added value of biomarkers or a biomarker panel in the prediction of HFpEF onset and progression.
In the course of the RECONNECT program these were our top publications (chronological order).
For the full list, please check our Output page.
1: Junaid A, Schoeman J, Yang W, Stam W, Mashaghi A, van Zonneveld AJ,
Hankemeier T. Metabolic response of blood vessels to TNFα. Elife. 2020 Aug
4;9:e54754. doi: 10.7554/eLife.54754. PMID: 32749215; PMCID: PMC7476757.
2: Nguyen ITN, Klooster A, Minnion M, Feelisch M, Verhaar MC, van Goor H, Joles
JA. Sodium thiosulfate improves renal function and oxygenation in L-NNA-induced
hypertension in rats. Kidney Int. 2020 Aug;98(2):366-377. doi:
10.1016/j.kint.2020.02.020. Epub 2020 Mar 23. PMID: 32605800.
3: Juni RP, Kuster DWD, Goebel M, Helmes M, Musters RJP, van der Velden J,
Koolwijk P, Paulus WJ, van Hinsbergh VWM. Cardiac Microvascular Endothelial
Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and
Restored by Empagliflozin. JACC Basic Transl Sci. 2019 Sep 4;4(5):575-591. doi:
10.1016/j.jacbts.2019.04.003. PMID: 31768475; PMCID: PMC6872802.
4: van der Pol A, Gil A, Tromp J, Silljé HHW, van Veldhuisen DJ, Voors AA,
Hoendermis ES, Grote Beverborg N, Schouten EM, de Boer RA, Bischoff R, van der
Meer P. OPLAH ablation leads to accumulation of 5-oxoproline, oxidative stress,
fibrosis, and elevated fillings pressures: a murine model for heart failure with
a preserved ejection fraction. Cardiovasc Res. 2018 Dec 1;114(14):1871-1882.
doi: 10.1093/cvr/cvy187. PMID: 30032247.
5: Tromp J, Westenbrink BD, Ouwerkerk W, van Veldhuisen DJ, Samani NJ,
Ponikowski P, Metra M, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der
Harst P, Lang CC, Ng LL, Zannad F, Zwinderman AH, Hillege HL, van der Meer P,
Voors AA. Identifying Pathophysiological Mechanisms in Heart Failure
With Reduced Versus Preserved Ejection Fraction. J Am Coll Cardiol. 2018 Sep
4;72(10):1081-1090. doi: 10.1016/j.jacc.2018.06.050. PMID: 30165978.
6: Sorop O, Heinonen I, van Kranenburg M, van de Wouw J, de Beer VJ, Nguyen ITN,
Octavia Y, van Duin RWB, Stam K, van Geuns RJ, Wielopolski PA, Krestin GP, van
den Meiracker AH, Verjans R, van Bilsen M, Danser AHJ, Paulus WJ, Cheng C, Linke
WA, Joles JA, Verhaar MC, van der Velden J, Merkus D, Duncker DJ. Multiple
common comorbidities produce left ventricular diastolic dysfunction associated
with coronary microvascular dysfunction, oxidative stress, and myocardial
stiffening. Cardiovasc Res. 2018 Jun 1;114(7):954-964. doi: 10.1093/cvr/cvy038.
PMID: 29432575; PMCID: PMC5967461.
7: Brandt MM, Meddens CA, Louzao-Martinez L, van den Dungen NAM, Lansu NR,
Nieuwenhuis EES, Duncker DJ, Verhaar MC, Joles JA, Mokry M, Cheng C. Chromatin
Conformation Links Distal Target Genes to CKD Loci. J Am Soc Nephrol. 2018
Feb;29(2):462-476. doi: 10.1681/ASN.2016080875. Epub 2017 Nov 1. PMID: 29093029;
PMCID: PMC5791087.
8: Shah SJ, Kitzman DW, Borlaug BA, van Heerebeek L, Zile MR, Kass DA, Paulus
WJ. Phenotype-Specific Treatment of Heart Failure With Preserved Ejection
Fraction: A Multiorgan Roadmap. Circulation. 2016 Jul 5;134(1):73-90. doi:
10.1161/CIRCULATIONAHA.116.021884. PMID: 27358439; PMCID: PMC4930115.
9: van Dijk CG, Oosterhuis NR, Xu YJ, Brandt M, Paulus WJ, van Heerebeek L,
Duncker DJ, Verhaar MC, Fontoura D, Lourenço AP, Leite-Moreira AF, Falcão-Pires
I, Joles JA, Cheng C. Distinct Endothelial Cell Responses in the Heart and
Kidney Microvasculature Characterize the Progression of Heart Failure With
Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic
Syndrome. Circ Heart Fail. 2016 Apr;9(4):e002760. doi:
10.1161/CIRCHEARTFAILURE.115.002760. PMID: 27056881.
10: Ter Maaten JM, Damman K, Verhaar MC, Paulus WJ, Duncker DJ, Cheng C, van
Heerebeek L, Hillege HL, Lam CS, Navis G, Voors AA. Connecting heart failure
with preserved ejection fraction and renal dysfunction: the role of endothelial
dysfunction and inflammation. Eur J Heart Fail. 2016 Jun;18(6):588-98. doi:
10.1002/ejhf.497. Epub 2016 Feb 10. PMID: 26861140.
Within RECONNECT we have developed a strong talent program with regular PhD/postdoc meetings; networking sessions with (inter)national leading scientists, clinicians, patients and patient representatives; successful 2-day summer schools; a mentoring program; fellowships; and several RECONNECT courses/symposia, aimed at supporting, attracting and developing talent.
In three calls for Talent Program fellowships we awarded a total of 11 ‘out of the box grants’ and 2 CVON ‘crazy idea grants’ to talented PhDs and Post-Docs. The talent program has resulted in recruitment of talent and activities not only from within but also from outside the consortium, stimulating collaborations with new national partners as well as international collaborations and strengthening the link with other large research consortia, including CVON-DOSIS, CVON-PHAEDRA and Queen of Hearts. RECONNECT has financially contributed to enable the Annual Translational Cardiovascular Research Meeting facilitating participation and networking for PhD students and post-docs and allowing them to present their work at the national level. In the past years several RECONNECT Talents have been awarded (inter)national grants related to the RECONNECT program.