Heart failure (HF) with preserved (HFpEF) and reduced (HFrEF) ejection fraction may be driven by different pathophysiologies. We explored novel biomarkers, associations with clinical characteristics, Show more
Heart failure (HF) with preserved (HFpEF) and reduced (HFrEF) ejection fraction may be driven by different pathophysiologies. We explored novel biomarkers, associations with clinical characteristics, discrimination between LVEF categories and associations with outcomes. In HFpEF(n=76) and HFrEF(n=36), 19 plasma biomarkers were measured including seven novel research assays for ANGPT2, BMP10, DKK3, FABP3, FGF23, IGFBP7 and MYBPC3. HFpEF patients were older (73 vs 63 years), more often female (50% vs 14%). All seven novel biomarkers except FABP3 tended to be higher in HFrEF vs HFpEF and associated with worse NYHA class and lower eGFR in both LVEF categories. MYBPC3 and FGF23 (higher in HFrEF) discriminated best between LVEF categories (AUC 85.8 and 80.0 respectively). In HFpEF, higher ANGPT2 was associated with worse right (TAPSE:β=-1.03;p=0.04) and left ventricular function (LV-GLS; β=1.29;p=0.03) and left atrial strain (LA-GLS:β=5.03;p<0.001) whereas higher IGFBP7 and MYBPC3 with diastolic dysfunction (E/e´:β=4.09;p=0.02 and β=1.36;p=0.01 respectively). All biomarkers except DKK3 were positively associated with the outcome (HFpEF:all-cause death, HF-hospitalization;HFrEF: all-cause death, LVAD or heart transplantation). Specifically (ANGPT2 (HR 1.45[95% CI 1.00-2.13]) more strongly in HFpEF and IGFBP7 (2.51[0.95-6.64]) more strongly in HFrEF (MYBPC3 (1.62[0.99-2.64]). Among seven novel biomarker assays, higher MYBPC3 (reflecting muscle injury and myopathy) and FGF23 (endothelial dysfunction, oxidative stress) distinguished HFrEF from HFpEF. Higher MYBPC3 was most prognostic in HFrEF while higher ANGPT2 and IGFBP7 (endothelial dysfunction and oxidative stress) in HFpEF. These hypothesis-generating findings support primary cardiomyocyte injury as a driver of HFrEF and systemic inflammation and oxidative stress as a driver of HFpEF. ClinicalTrials.gov NCT00774709. Show less
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide associatio Show more
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Show less