HFpEF and HFrEF Display Different Phenotypes as Assessed by IGF-1 and IGFBP-1.

BACKGROUND Anabolic drive is impaired in heart failure with reduced ejection fraction (HFrEF) but insufficiently studied in heart failure with preserved ejection fraction (HFpEF). Insulin-like growth factor 1 (IGF-1) mediates growth hormone effects and IGF binding protein 1 (IGFBP-1) regulates IGF-1 activity. We tested the hypothesis that HFpEF and HFrEF are similar with regard to IGF-1 and IGFBP-1. METHODS AND RESULTS In patients with HFpEF (n = 79), HFrEF (n = 85), and controls (n = 136), we analyzed serum IGF-1 and IGFBP-1 concentrations, correlations, and associations with outcome. Age-standardized scores of IGF-1 were higher in HFpEF, median arbitrary units (interquartile range); 1.21 (0.57-1.96) vs HFrEF, 0.09 (-1.40-1.62), and controls, 0.22 (-0.47-0.96), P overall <.001. IGFBP-1 was increased in HFpEF, 48 (28-79), and HFrEF, 65 (29-101), vs controls, 27(14-35) µg/L, P overall <.001. These patterns persisted after adjusting for metabolic and HF severity confounders. IGF-1 was associated with outcomes in HFrEF, hazard ratio per natural logarithmic increase in IGF-1 SD score 0.51 (95% confidence interval 0.32-0.82, P = .005), but not significantly in HFpEF. IGFBP-1 was not associated with outcomes in either HFpEF nor HFrEF. CONCLUSION HFpEF and HFrEF phenotypes were similar with regard to increased IGFBP-1 concentrations but differed regarding IGF-1 levels and prognostic role. HFrEF and HFpEF may display different impairment in anabolic drive.

[1]  K. Karason,et al.  GH and the cardiovascular system: an update on a topic at heart , 2014, Endocrine.

[2]  M. Kearney,et al.  IGF-dependent and IGF-independent actions of IGF-binding protein-1 and -2: implications for metabolic homeostasis , 2009, Trends in Endocrinology & Metabolism.

[3]  P. Ponikowski,et al.  Anabolic Deficiency in Men With Chronic Heart Failure: Prevalence and Detrimental Impact on Survival , 2006, Circulation.

[4]  P. Douglas,et al.  IGF-1 predicts survival in chronic heart failure. Insights from the T.O.S.CA. (Trattamento Ormonale Nello Scompenso CArdiaco) registry. , 2014, International journal of cardiology.

[5]  L. Bach.  Endothelial cells and the IGF system. , 2014, Journal of molecular endocrinology.

[6]  L. Lund,et al.  Growth hormone resistance in severe heart failure resolves after cardiac transplantation , 2009, European journal of heart failure.

[7]  K. Hall,et al.  Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays: improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand. , 1991, Acta endocrinologica.

[8]  U. de Faire,et al.  Associations between insulin-like growth factor-I (IGF-I), IGF-binding protein-1, insulin and other metabolic measures after controlling for genetic influences: results from middle-aged and elderly monozygotic twins. , 1997, The Journal of endocrinology.

[9]  P. Poole‐Wilson,et al.  Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation. , 1998, Journal of the American College of Cardiology.

[10]  J. Daubert,et al.  Rationale and design of the Karolinska‐Rennes (KaRen) prospective study of dyssynchrony in heart failure with preserved ejection fraction , 2009, European journal of heart failure.

[11]  K. Brismar,et al.  Influence of circulating epinephrine and norepinephrine on insulin-like growth factor binding protein-1 in humans. , 1997, The Journal of clinical endocrinology and metabolism.

[12]  T. Olsson,et al.  Circulating IGF binding protein-1 is inversely associated with leptin in non-obese men and obese postmenopausal women. , 2001, European journal of endocrinology.

[13]  L. Giudice,et al.  Insulin-like Growth Factor Binding Protein-1: Recent Findings and New Directions , 1997, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[14]  K. Brismar,et al.  Gender differences in the relation of insulin‐like growth factor binding protein‐1 to cardiovascular risk factors: a population‐based study , 2005, Clinical endocrinology.

[15]  R. Davies,et al.  Relationship between natriuretic peptides and inflammation: proteomic evidence obtained during acute cellular cardiac allograft rejection in humans. , 2008, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[16]  K. Hall,et al.  Cross-reaction of serum somatomedin-binding protein in a radioimmunoassay developed for somatomedin-binding protein isolated from human amniotic fluid. , 1984, Acta endocrinologica.

[17]  L. Kuller,et al.  High insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly. , 2008, American heart journal.

[18]  S. Catrina,et al.  Desmopressin increases IGF-binding protein-1 in humans. , 2008, European journal of endocrinology.

[19]  W. Paulus,et al.  A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. , 2013, Journal of the American College of Cardiology.

[20]  M. Thorén,et al.  Altered relation between circulating levels of insulin-like growth factor-binding protein-1 and insulin in growth hormone-deficient patients and insulin-dependent diabetic patients compared to that in healthy subjects. , 1995, The Journal of clinical endocrinology and metabolism.

[21]  R. Baxter.  Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. , 2000, American journal of physiology. Endocrinology and metabolism.

[22]  A. Birkenfeld,et al.  INTERACTING DISCIPLINES: Cardiac natriuretic peptides and obesity: perspectives from an endocrinologist and a cardiologist , 2015, Endocrine connections.

[23]  H. Saeki,et al.  Circulating levels of insulin-like growth factor-1 and its binding proteins in patients with hypertrophic cardiomyopathy. , 2002, Circulation journal : official journal of the Japanese Circulation Society.

[24]  R. Napoli,et al.  The GH/IGF-1 axis in chronic heart failure. , 2013, Endocrine, metabolic & immune disorders drug targets.

[25]  Sanjiv J. Shah,et al.  Developing therapies for heart failure with preserved ejection fraction: current state and future directions. , 2014, JACC. Heart failure.

[26]  L. Saccá.  Heart failure as a multiple hormonal deficiency syndrome. , 2009, Circulation. Heart failure.

[27]  J. Laycock,et al.  Plasma insulin-like growth factor-1 elevated in mild-to-moderate but not severe heart failure. , 2001, American heart journal.

[28]  M. Thorén,et al.  Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19-82 years, in relation to those in healthy subjects. , 1999, The Journal of clinical endocrinology and metabolism.

[29]  C. Lang,et al.  Regulation of IGF binding protein-1 in Hep G2 cells by cytokines and reactive oxygen species. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[30]  M. Thorén,et al.  Determinants of circulating insulin-like growth factor-I. , 1999, Journal of endocrinological investigation.