Declining Levels and Bioavailability of IGF-I in Cardiovascular Aging Associate With QT Prolongation-Results From the 1946 British Birth Cohort.

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 (Δ) 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: β -0.30 ms/nmol/L, (95% confidence intervals -0.44, -0.17), < 0.001; β-28.9 ms/unit (-41.93, -15.50), < 0.001], but not with IGF-II or IGFBP-3. No association with QTc was found for IGF biomarkers sampled at 53y, however both ΔIGF-I and ΔIGF-I/IGFBP-3 ratio were negatively associated with QTc [β -0.04 ms/nmol/L (-0.08, -0.008), = 0.019; β -2.44 ms/unit (-4.17, -0.67), = 0.007] while ΔIGF-II and ΔIGFBP-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 [β -0.21 ms/nmol/L (-0.39, -0.04), = 0.017; β -20.14 ms/unit (-36.28, -3.99), = 0.015], steeper decline in ΔIGF-I [β -0.05 ms/nmol/L/10 years (-0.10, -0.002), = 0.042] and shallower rise in ΔIGF-I/IGFBP-3 ratio over a decade [β -2.16 ms/unit/10 years (-4.23, -0.09), = 0.041], were all independently associated with QTc prolongation. Independent associations with QTc were also confirmed for other previously known covariates: female sex [β 9.65 ms (6.65, 12.65), < 0.001], increased left ventricular mass [β 0.04 ms/g (0.02, 0.06), < 0.001] and blood potassium levels [β -5.70 ms/mmol/L (-10.23, -1.18) = 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.