Renal connection to microvascular disease and heart failure with preserved ejection fraction: the next phase

Project summary

Heart failure (HF) is a major health care problem with high mortality. Although significant advances have been made in the treatment of HF patients with reduced ejection fraction (EF), this is not true for HF patients with preserved EF (HFpEF). In 2015 we initiated a consortium focusing on the renal connection to microvascular disease and HFpEF (RECONNECT). In the past 5 years, RECONNECT has demonstrated that impaired kidney function is a strong risk factor for mortality in HFpEF, and has generated two HFpEF diagnostic prediction rules for use in general practice. Moreover, RECONNECT has yielded novel insights into the mechanisms by which chronic kidney disease (CKD) and its systemic consequences, through an effect on the microcirculation, contribute to HFpEF. Our dedicated in-vitro and animal models and patient-cohorts yielded convincing data supporting our hypothesis that inflammation and the consequent coronary microvascular dysfunction play a central role in the pathogenesis of CKD-associated HFpEF. Thus, our consortium identified several potential targets for therapy, including markers of inflammation (TNFα, IL6), reactive oxygen species (OPLAH), microvascular dysfunction (reduced NO-bioavailability, SGLT2, H2S/STS), fibrosis (TGF-β signaling: GDF-15, Activin A), mitochondrial dysfunction (trimetazidine, iron) and cardiomyocyte myofilament dysfunction (heat shock protein activation: GGA). In addition, we established a strong translational pipeline to discover novel targets and bring these to clinical testing via preclinical models.

In RECONNEXT we will use and expand this pipeline to (pre)clinically investigate targets identified during RECONNECT as well as novel targets. In addition, we continue to explore in-depth the molecular mechanisms linking CKD to HFpEF. By combining epidemiology with mechanistic ex- and in-vivo studies, we will evaluate renal drivers of HFpEF and elucidate the mechanisms that contribute to microvascular dysfunction and inflammatory-microvascular-cardiomyocyte crosstalk. We use stateof-the-art techniques, including functionomics, metabolomics, proteomics, single nucleus sequencing, and epigenetics. Following a stratified approach, RECONNEXT will investigate novel drug targets of HFpEF in our unique CKD-HFpEF models. We will perform targeted clinical interventions in focused, well-phenotyped patient-groups. RECONNEXT will enhance our mechanistic insight in the renal drivers of HFpEF and provide a basis for future large-scale intervention trials, ultimately allowing new prognostic and therapeutic solutions for HFpEF patients.