GDF-15 levels but not NTproBNP levels predict diastolic heart failure in morbid obesity M. Fischer, C. Strack, J. Bruxmeier, F. Wagner, E. Rousseva, G. Schmitz, G. Riegger, A. Baessler Clinic for Internal Medicine II, University of Regensburg, Germany
Disclosure Statement of Financial Interest I DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.
Background Obese persons are at increased risk for diastolic heart failure Natriuretic peptides have been shown to provide diagnostic and prognostic utility in patients with diastolic heart failure However, in the obese the usefulness of the natriuretic peptides has been questioned because of the inverse relationship of BNP with BMI
Background The rapid and accurate differentiation of heart failure from other causes of dyspnea remains a clinical challenge in the emergency, particularly in the obese Growth-differentiation factor 15 (GDF-15), a stress-responsive member of the transforming growth factor beta cytokine superfamily, has emerged as a biomarker of heart failure and increased mortality in cardiovascular disease
Objectives This study aimed to examine the predictive value of NTproBNP and GDF-15 levels alone or in combination in morbidly obese patients with and without diastolic heart failure.
Methods Study Population Obesity Weight Reduction and Remodeling Study (ongoing recruitment, currently n=258, DRKS0003087) Participants of a standardized weight reduction program (OPTIFAST 52, n=207) inclusion criteria: BMI >30kg/m 2, age<60 yrs., no liver, kidney, endocrine disease, no cancer, no pregnancy Obese control subjects, no intervention Same inclusion criteria, matched by age and gender Healthy lean control subjects, no intervention (n=51) BMI 18-25 kg/m 2, healthy, matched by age and gender
Obesity Weight Reduction and Remodeling Study Questionnaires Physical Examination 6-Minute-Walk Blood Tests Urine sample Bioelectrical Impedance Analysis Indirect Calorimetry ECG/ECHO Family history Risk factors Lifestyle Anthropometry Blood pressure ABI- index Fitness Adhesion molecules Medication Quality of life State of health Heart failure symptoms Standard parameters (liver, ) Glucose/Insulin-metabolism Lipid species, apolipoproteins Hormones of energy homoeostasis Adipocytokines, markers of inflammation Markers of early atherogenesis Oxidative stress markers 48h Activity and Sleep Monitoring Carotid Ultrasound Imaging (Micro)albuminuria Body composition Basal metabolic rate, energy expenditure Insulin resistance Dyslipidemia Cardiac function & structure Hypertension Obesity Endothelial dysfunction/ atherosclerosis Intima media thickness Arterial elasticity Diabetes mellitus Cardiometabolic Syndrome, adiposopathy? Cardiovascular disease
Study protocol weight reduction program baseline examination 3-month follow-up 1-year follow-up weeks 1 2-13 14-19 20-52 Preparation Phase Intensive Phase Transition Phase Maintenance and Stabilization Phase Psychological and medical examination Weight reduction phase VLCD (800 kcal/day) + exercise training Meals are step-by-step introduced Exercise training and training in healthy nutrition
Methods GDF-15 measurements: Human GDF-15 Quantikine ELISA (R&D Systems) Definition Diastolic Heart Failure: - symptoms consistent with heart failure - preserved systolic LV-function (EF>50%) - exclusion criteria: E 10 and normal LA-size (ASE 2009) - at least 2 criteria compatible with LV diastolic dysfunction: - E/E > 8 - E/A < 0.8 and DT > 200 ms - E/A > 2 und DT<160 ms - E /A < 0.9 - S<D in pulmonary venous flow - Ard-Ad > 0 - LV-mass > 149 g/m 2 (m), >122 g/m 2 (w)
Frequency of LVDD criteria 100% 90% 80% 70% 60% 50% 40% controls (n=51) 41% obese (n=207) 30% 20% 10% 0% <= 1 2-3 >= 4
Baseline clinical characteristics obese lean * LVDD vs. no LVDD
Baseline echo characteristics obese lean * LVDD vs. no LVDD
NTproBNP in severe obesity by LVDD by the number of LVDD criteria n.s. n.s. median Box and whisper quantiles
GDF-15 in severe obesity by LVDD by the number of LVDD criteria P<0.0001 P<0.0001 P<0.0001 P=0.002
LVDD parameters by quartiles of NTproBNP and GDF-15 NTproBNP n.s. GDF-15 P for trend <0.0001 n.s. P for trend <0.0001
LVDD parameters by quartiles of NTproBNP and GDF-15 NTproBNP n.s. GDF-15 P for trend <0.0001 P for trend <0.05 P for trend <0.0001
LVDD parameters by quartiles of NTproBNP and GDF-15 NTproBNP P for trend <0.0001 GDF-15 P for trend <0.0001 n.s. P for trend <0.0001
ROC analysis: NTproBNP vs. GDF-15 (univariate) P=0.027
ROC analysis: NTproBNP vs. GDF-15 (multivariate) P=0.54 xb1: age, sex, syst.bp, Dm, BMI, NTproBNP xb2: age, sex, syst.bp, Dm, BMI, GDF-15 xb3: age, sex, syst.rr, Dm, BMI, NTproBNP, GDF-15
Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI)
Conclusions - In morbidly obese individuals, GDF-15 levels seem to better correlate with diastolic dysfunction than NTproBNP levels. - GDF-15 significantly improves reclassification for the diagnosis of diastolic heart failure and, thus, add incremental value to NTproBNP. - In summary, GDF-15 levels may better reflect inadequate myocardial adaptation to chronic overload in very obese subjects with diastolic heart failure.
Achnowledgement Andrea Baessler, MD Christina Strack, MD Florian Wagner Janine Bruxmeier Martin Schmiedel Daniela Biermeier Guenter Riegger, MD