PMID- 35528832 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240313 IS - 2297-055X (Print) IS - 2297-055X (Electronic) IS - 2297-055X (Linking) VI - 9 DP - 2022 TI - Declining Levels and Bioavailability of IGF-I in Cardiovascular Aging Associate With QT Prolongation-Results From the 1946 British Birth Cohort. PG - 863988 LID - 10.3389/fcvm.2022.863988 [doi] LID - 863988 AB - BACKGROUND: As people age, circulating levels of insulin-like growth factors (IGFs) and IGF binding protein 3 (IGFBP-3) decline. In rat cardiomyocytes, IGF-I has been shown to regulate sarcolemmal potassium channel activity and late sodium current thus impacting cardiac repolarization and the heart rate-corrected QT (QTc). However, the relationship between IGFs and IGFBP-3 with the QTc interval in humans, is unknown. OBJECTIVES: To examine the association of IGFs and IGFBP-3 with QTc interval in an older age population-based cohort. METHODS: Participants were from the 1946 Medical Research Council (MRC) National Survey of Health and Development (NSHD) British birth cohort. Biomarkers from blood samples at age 53 and 60-64 years (y, exposures) included IGF-I/II, IGFBP-3, IGF-I/IGFBP-3 ratio and the change (Delta) in marker levels between the 60-64 and 53y sampled timepoints. QTc (outcome) was recorded from electrocardiograms at the 60-64y timepoint. Generalized linear multivariable models with adjustments for relevant demographic and clinical factors, were used for complete-cases and repeated after multiple imputation. RESULTS: One thousand four hundred forty-eight participants were included (48.3% men; QTc mean 414 ms interquartile range 26 ms). Univariate analysis revealed an association between low IGF-I and IGF-I/IGFBP-3 ratio at 60-64y with QTc prolongation [respectively: beta -0.30 ms/nmol/L, (95% confidence intervals -0.44, -0.17), p < 0.001; beta-28.9 ms/unit (-41.93, -15.50), p < 0.001], but not with IGF-II or IGFBP-3. No association with QTc was found for IGF biomarkers sampled at 53y, however both DeltaIGF-I and DeltaIGF-I/IGFBP-3 ratio were negatively associated with QTc [beta -0.04 ms/nmol/L (-0.08, -0.008), p = 0.019; beta -2.44 ms/unit (-4.17, -0.67), p = 0.007] while DeltaIGF-II and DeltaIGFBP-3 showed no association. In fully adjusted complete case and imputed models (reporting latter) low IGF-I and IGF-I/IGFBP-3 ratio at 60-64y [beta -0.21 ms/nmol/L (-0.39, -0.04), p = 0.017; beta -20.14 ms/unit (-36.28, -3.99), p = 0.015], steeper decline in DeltaIGF-I [beta -0.05 ms/nmol/L/10 years (-0.10, -0.002), p = 0.042] and shallower rise in DeltaIGF-I/IGFBP-3 ratio over a decade [beta -2.16 ms/unit/10 years (-4.23, -0.09), p = 0.041], were all independently associated with QTc prolongation. Independent associations with QTc were also confirmed for other previously known covariates: female sex [beta 9.65 ms (6.65, 12.65), p < 0.001], increased left ventricular mass [beta 0.04 ms/g (0.02, 0.06), p < 0.001] and blood potassium levels [beta -5.70 ms/mmol/L (-10.23, -1.18) p = 0.014]. CONCLUSION: Over a decade, in an older age population-based cohort, declining levels and bioavailability of IGF-I associate with prolongation of the QTc interval. As QTc prolongation associates with increased risk for sudden death even in apparently healthy people, further research into the antiarrhythmic effects of IGF-I on cardiomyocytes is warranted. CI - Copyright (c) 2022 Charalambous, Moon, Holly, Chaturvedi, Hughes and Captur. FAU - Charalambous, Christos AU - Charalambous C AD - UCL MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom. FAU - Moon, James C AU - Moon JC AD - UCL Institute of Cardiovascular Science, University College London, London, United Kingdom. AD - Cardiac MRI Unit, Barts Heart Centre, London, United Kingdom. FAU - Holly, Jeff M P AU - Holly JMP AD - National Institute for Health Research (NIHR) Bristol Nutrition Biomedical Research Unit, Level 3, University Hospitals Bristol Education and Research Centre, Bristol, United Kingdom. AD - Faculty of Health Sciences, School of Translational Health Sciences, Bristol Medical School, Southmead Hospital, University of Bristol, Bristol, United Kingdom. FAU - Chaturvedi, Nishi AU - Chaturvedi N AD - UCL MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom. FAU - Hughes, Alun D AU - Hughes AD AD - UCL MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom. AD - UCL Institute of Cardiovascular Science, University College London, London, United Kingdom. FAU - Captur, Gabriella AU - Captur G AD - UCL MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom. AD - UCL Institute of Cardiovascular Science, University College London, London, United Kingdom. AD - Cardiology Department, Centre for Inherited Heart Muscle Conditions, The Royal Free Hospital, London, United Kingdom. LA - eng GR - MC_UU_00019/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20220422 PL - Switzerland TA - Front Cardiovasc Med JT - Frontiers in cardiovascular medicine JID - 101653388 PMC - PMC9072634 OTO - NOTNLM OT - IGF-I (insulin-like growth factor-I) OT - IGF-I/IGFBP-3 molar ratio OT - IGF-II OT - IGFBP-3 OT - QTc interval prolongation OT - cardiac repolarization COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/05/10 06:00 MHDA- 2022/05/10 06:01 PMCR- 2022/01/01 CRDT- 2022/05/09 04:01 PHST- 2022/01/27 00:00 [received] PHST- 2022/03/21 00:00 [accepted] PHST- 2022/05/09 04:01 [entrez] PHST- 2022/05/10 06:00 [pubmed] PHST- 2022/05/10 06:01 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fcvm.2022.863988 [doi] PST - epublish SO - Front Cardiovasc Med. 2022 Apr 22;9:863988. doi: 10.3389/fcvm.2022.863988. eCollection 2022.