Exploring the Reno-Cardiac Connection Protect your kidneys save your heart
Heart Failure: a major health care problem ~23 million people with heart failure worldwide Heart failure increases progressively with age Heart failure is associated with high morbidity and mortality While treatment options and clinical outcome have improved for HFrEF, this is not true for HFpEF HFrEF Heart Failure with reduced Ejection Fraction HFpEF Heart Failure with preserved Ejection Fraction
HFpEF: A major unmet clinical need Heart Failure with preserved Ejection Fraction Up to 50% of heart failure patients demonstrate HFpEF High mortality: 5 year mortality ~74% Limited therapeutic options for HFpEF patients Pathophysiological mechanisms largely unknown Jessup, Circulation 2014
HFpEF: associated with multiple usually interrelated, co-morbidities Aging Female gender Comorbidities: Obesity Diabetes Hypertension Renal dysfunction Male gender Myocardial infarction Genetic myopathies Chronic low-grade inflammation Neurohormonal activation Oxidative stress Chronic pressure overload
Chronic Kidney Disease predisposes to HFpEF increased urinary albumin excretion and cystatin C were significantly more associated with the risk for HFpEF, but not for HFrEF In established HFpEF albuminuria and impaired kidney function predict mortality The renal connection Mechanisms David H. Smith et underlying al. Circ Cardiovasc CKD Qual Outcomes. HFpEF 2013;6:333-342 relation unknown
Role of the microvasculature Renal drivers: Uremic toxins Endocrine Metabolic Ca/P/Vit D FGF23 Salt Comorbidities: Obesity Diabetes Hypertension Renal dysfunction HFpEF HFrEF Adapted from Paulus & Tschope, JACC 2013
Central Hypothesis Renal impairment and its systemic consequences adversely impact the coronary microvasculature, thereby modifying pathophysiology, course and prognosis of HFpEF Renal Dysfunction Microvascular Dysfunction Heart Failure with preserved EF Systemic Factors Uremic toxins Endocrine Metabolic Ca/P/VitD FGF23 Salt Inflammation Endothelium Pericytes & Perivascular Fibroblasts IL6 TNFα sst2 Pentr. 3 Chemokines Cytokines Adhesion Molecules ROS Permeability Fibrosis Vascular Stability Inflammatory cell recruitment NO Monocyte activation TGFβ-fibrogenesis cgmp PKG Myofibroblast Interstitial fibrosis Resting tension Hypertrophy Cardiomyocyte ter Maaten et al. Eur J Heart Fail 2016
Multicenter Consortium RECONNECT REnal CONNECTion to microvascular disease and heart failure with preserved ejection fraction Amsterdam Groningen Leiden Utrecht Rotterdam www.reconnect-umc.eu
Multidisciplinary Consortium RECONNECT Basic Research Clinical Research Epidemiology www.reconnect-umc.eu
Aims RECONNECT Aims to: Enhance mechanistic insight in the renal drivers of HFpEF Develop new prognostic tools to define a patient's susceptibility to HFpEF onset and progression Develop customized therapeutic solutions for HFpEF patients
Overall Work Plan COHORTS PATIENTS WP1 DISCOVERY WP2 IN-VITRO PATIENTS WP5 PROGNOSIS & THERAPY DESIGN WP4 WP2 MECHANISTIC STUDIES WP3 IN-VIVO ANIMALS
WP5 Clinical risk prediction models for onset & prognosis HFpEF in CKD population WP4.2 Clinical strategy design WP1 Exploration, discovery and validation of CKD- HFpEF associated systemic factors COHORTS PATIENTS COHORTS PATIENTS WP5 WP1 PROGNOSIS & THERAPY DESIGN WP4 WP4.1 Preclinical drug-target Evaluation in vivo WP2.1 Functionomic analysis of plasma samples in vitro DISCOVERY IN-VIVO ANIMALS WP2 IN-VITRO PATIENTS Immune response PATIENTS phenotyping in relation to EndoMT & fibrosis WP2 MECHANISTIC STUDIES WP3 Overall Work Plan IN-VITRO WP2.2 Microfluidic and metabolomic analysis of plasma WP3 WP2.3 WP2.4 Transcriptional and epigenetic phenotyping Mechanistic studies in unique rodent and porcine animal models of CKD & HFpEF
10 RECONNECT cohorts: >2000 HFpEF patients General population PREVEND 125 HFpEF Screen-detected cases from primary care UHFO-DM 133 HFpEF STRETCH 70 HFpEF TREE 91 HFpEF New-onset or established HFpEF in cardiology outpatient clinic CTMM-CC UCORBIO 296 HFpEF BIOSTAT 430 HFpEF MEDIA 612 HFpEF New-onset or established HFpEF in hospitalized patients CTMM- TRIUMPH 65 HFpEF COACH 204 HFpEF PROTECT 130 HFpEF Different co-morbidities Different stages of cardiac & renal dysfunction
Functionomic analysis of plasma samples in vitro (i) Microvasculature in vitro (ii) Microvascular interaction with white blood cells and cardiac fibroblasts (iii) Cardiomyocyte contractility Effect of plasma on: Microfluidic and metabolomic analysis of plasma (i) Endothelial barrier function (ii) White blood cell recruitment (iii) Endothelial mirna profile and Metabolite release Metabolomic analysis of plasma composition Gel channel Perfusion channel
Maarten Brandt Renal Dysfunction Microvascular Dysfunction Heart Failure with preserved EF Systemic Factors Uremic toxins Endocrine Metabolic Ca/P/VitD FGF23 Salt Inflammation Endothelium Pericytes & Perivascular Fibroblasts IL6 TNFα sst2 Pentr. 3 Chemokines Cytokines Adhesion Molecules ROS Permeability Fibrosis Vascular Stability Inflammatory cell recruitment NO Monocyte activation TGFβ-fibrogenesis cgmp PKG Myofibroblast Interstitial fibrosis Resting tension Hypertrophy Cardiomyocyte Oana Sorop
Innovation and Translation Unique patient cohorts and biological samples Focus on the microvasculature State-of-the-art technology and beyond - Organ-on-a-Chip Novel (large) animal models of CKD-HFpEF Strong multidisciplinary consortium Renal Dysfunction Microvascular Dysfunction Heart Failure with preserved EF Systemic Factors Uremic toxins Endocrine Metabolic Ca/P/VitD FGF23 Salt Inflammation Endothelium Pericytes & Perivascular Fibroblasts IL6 TNFα sst2 Pentr. 3 Chemokines Cytokines Adhesion Molecules ROS Permeability Fibrosis Vascular Stability Inflammatory cell recruitment NO Monocyte activation TGFβ-fibrogenesis Myofibroblast Interstitial fibrosis Resting tension Hypertrophy cgmp PKG Cardiomyocyte
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