Abstract
Introduction
Data from the “Trattamento Ormonale nello Scompenso CArdiaco” (T.O.S.CA) registry showed that heart failure (HF) represents a complex clinical syndrome with different hormonal alterations. Renal failure represents a frequent complication in HF. We evaluated the relationship between renal function and insuline-like growth factor-1 (IGF-1) deficiency and its impact on cardiovascular mortality (CVM) in patients enrolled in the T.O.S.CA. registry.
Methods
At the enrolment, all subjects underwent chemistry examinations, including circulating hormones and cardiovascular functional tests. COX regression analysis was used to evaluate factors related to CVM during the follow-up period in all populations, in high-risk patients and in the young-adult population. Also, we evaluate the effects of renal function on the CVM.
Results
337 patients (41 deceased) were analyzed. CVM was related to severe renal dysfunction (HR stages IV–V = 4.86), high-risk conditions (HR 2.25), serum IGF-1 (HR 0.42), and HF etiology (HR 5.85 and HR 1.63 for valvular and ischemic etiology, respectively). In high-risk patients, CVM was related to IGF-1 levels, severe renal dysfunction and valvular etiology, whereas in young patients CMV was related to the high-risk pattern and serum IGF-1 levels.
Conclusions
Our study showed the clinical and prognostic utility of the IGF-1 assay in patients with HF.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Heart failure (HF) represents an important public health problem, affecting around 23 million patients worldwide [1]. The HF burden has a huge impact in economic terms, resulting in about 2% of the total health-care budget in many European countries; the overall economic cost of HF in 2012 was estimated at $ 108 billion per annum. These costs, linked to the high morbidity and health needs of an aging, rapidly expanding and industrializing population, are expected to grow progressively over time—all costs linked to the elevated morbidity, healthcare needs and mortality [2].
The HF is a complex clinical syndrome affecting different functional systems of the body. Although the causes leading to HF are mainly related to cardiac alterations, HF is undoubtedly associated with multi-organ dysfunctions affecting lungs, kidneys, brain and endocrine glands. Notably, a multihormonal deficit syndrome (i.e. alterations of thyroid, pituitary, adrenal and pancreatic hormones), characterized by changes in the catabolism/anabolism balance, has been reported in patients with HF [3, 4]. Hormonal deficiency is associated with the progressive reduction of cardiac functional capacity until cardiac cachexia occurs, thus resulting in a powerful and independent predictor of prognosis in patients with chronic HF [5]. Recently, data from the “Trattamento Ormonale nello Scompenso CArdiaco” (T.O.S.CA) registry showed that patients with HF and pre-served ejection fraction (HFpEF) had at least one endocrine dysfunction in 54% of cases, while this percentage reached 96% in the case of patients with HF and reduced ejection fraction (HFrEF) [6]. Similar results were detected in a study performed by Favuzzi et al. in 40 patients with HFpEF showing that only 2.5% of patients had no hormonal deficiencies [7]. The alteration in the synthesis of the Growth Hormone (GH) and its peripheral effector insuline-like Growth Factor-1 (IGF-1) was documented in approximately 40–60% of HF patients [8]; on the other hand, the presence of a peripheral resistance to GH appears to be associated with the development of heart failure and cardiac cachexia [9]. The GH/IGF-1 axis acts during the post-infarct ventricular remodeling that results from myocyte apoptosis; it favors vasodilation through action on nitric oxide and it improves muscle performances [10]. For these reasons, IGF-1 deficiency would seem to have important effects in terms of both HF development and worse prognosis [11]. Furthermore, among HF patients, low serum IGF-1 was associated with worse outcomes [11–13] including cardiovascular and all cause of mortality [14]. Nevertheless, other clinical studies exploring the relationships between serum IGF-1 and the prognosis of HF patients were contradictory [15, 16].
Renal failure is a well-known risk factor for further cardiovascular diseases in patients with HF [17] and, at the same time, the relationship between HF and renal function is a condition belonging to the family of the cardiorenal syndromes. Relationship between IGF-1 and renal function is still a matter of debate. In addition to heart failure, IGF-1 values seem to be associated with the risk of developing CKD, as demonstrated by Teppala et al. [18] in a population of 5388 patients. The elevated serum levels of IGF-1 were associated with the development of CKD after adjustment for different confounding factors such as age, sex, race/ethnicity, education levels, smoking, alcohol intake, body mass index, diabetes, hypertensionand serum cholesterol. On the other hand, in patients with CKD the effect of IGF-1 serum levels on mortality is opposite. In incident dialysis patients, lower serum levels of IGF-1 seem to be associated with metabolic alterations and predict the risk of mortality [19]. In arthritic rats, GH treatment decreased serum creatinine levels and IGF-1 concentrations [20].
The aim of this study was to evaluate whether a relationship between renal function and IGF-1 deficiency exist and its impact on cardiovascular mortality in patients with moderately or severely HFrEF, enrolled in the T.O.S.CA. registry.
Methods
Patient selection and eligibility
Data for the present analysis come from the T.O.S.CA. Registry, an out-come-oriented, multicenter, prospective observational study, designed to evaluate the prevalence of multiple hormone deficiency syndromes in patients with CHF and its impact on clinical outcomes. The study design has been already published [21]. Briefly, all patients had CHF with reduced EF (≤ 45%) and stable home therapy for at least 3 months. At the time of enrolment, all subjects underwent routine clinical chemistry examinations, such as B-type natriuretic peptides (BNP) and renal function with evaluation of serum creatinine and estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [22], and cardiovascular functional assessments, such as echocardiography and evaluations the New York Heart Association (NYHA) classification, in the peripheral centers, while the evaluation of circulating hormones (thyroid hormones, GH/IGF-1 axis, total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and insulin) were analyzed in a dedicated core-lab (IRCSS-SDN, Naples, Italy) collaborating with the Clinical Coordinating Center.
After enrolment, all subjects were followed as outpatients with each procedure and blood sample collection that were repeated annually during the study period. Intermediate visits were scheduled for clinical follow-up, therapy monitoring, and to collect relevant clinical event information (for mortality and hospitalization).
Clinical data and index events from enrolled patients identified by a unique identifier number were updated on a Web-based platform (URL: http://www.registrotosca.com).
Based on the analyses performed on the entire population, we searched for factors independently associated with mortality from cardiovascular events. Such analyses were performed for both the general population and two sub-classes of patients derived from it. Renal Failure was classified according to KDIGO classification [23]. We analyzed the subclass of young-adult patients (aged < 65 years) and the subclass of patients at high risk of mortality and unexpected death. The latter subgroup was defined according to the most recent guidelines about HF and is referred to patients with EF ≤ 35% and NYHA stage 2–3, who are theoretically eligible for implantable cardioverter-defibrillator placement [1]. We focused our study on the relationship between GH/IGF-1 axis, renal function, and cardiovascular mortality. The study has been conducted in accordance with Good Clinical Practice, Declaration of Helsinki 2002. The trial has been registered on Clinicaltrials.gov (NCT02335801). The study has been approved by ethical committee of “Federico II” University Hospital (n. 34/13) and all patients agreed in signing informed consent.
Statistical analysis
Data are shown as absolute numbers, percentages, and means ± standard deviation (SD). A descriptive analysis of the whole population was performed, followed by a comparison of survivors and deceased during the follow-up period. The analysis of variables was performed by using the Chi-Squared test, the Student t test or the Mann–Whitney U test as appropriate. Moreover, in order to assess the independent factors associated with cardiovascular (CV) mortality, a COX regression analysis was performed including age, sex, chronic kidney disease stage calculated using the CKD-EPI formula [22], logarithm of BNP and IGF-1 (parameters were not normally distributed in the population), high-risk conditions. Also, we performed a Cox regression analysis to evaluate the effects of CKD-EPI stage and the estimated cardiovascular risk of patients at the time of enrollment on the mortality risk. Using Receiver operating characteristic (ROC) curve the area under the curve (AUC) was calculated for diagnostic value and accuracy of LnIGF-1 levels with the best sensitivity and specificity for given cut-off values. Hazard ratios (HRs) and their 95% Confidence Intervals (CI) were reported. SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, 2004) was used for statistical analyzes.
Results
A total of 337 patients (80.7% male sex) with a mean age of 63 ± 12 years were analyzed.
The analysis of renal function showed an average eGFR of 72.9 ± 25.4 ml/min/1.73 m2. Most patients (66.5%) had normal or mildly decreased renal function (KDIGO stage I and II, eGFR ≥ 60 ml/min/1.73 m2) [22].
After a mean follow-up period of 44 ± 11 months, the percentage of deaths was 12.2% (41 patients); the clinical and laboratory characteristics of the cohort stratify by living status are reported in Table 1. Among the 41 recorded deaths 23 (56%) patients experienced a malignant arrythmias with unsuccessful ICD intervention, 12 patients (29%) had an acute coronary syndrome and 6 patients (15%) died because of a bradyarrhythmia.
Compared with alive patients at follow-up, deceased subjects were older (69 ± 11 vs. 63 ± 12 years, p = 0.003), with a more advanced NYHA class and ventricular dysfunction based on EF values (27.4 ± 8.1 vs. 33.3 ± 6.8%, p < 0.001), with a higher serum BNP (219.3 ± 290.2 vs. 108.6 ± 187.2 pg/ml, p = 0.001), with a reduced renal function (eGFR 58.8 ± 28.7 vs. 74.9 ± 24.3 ml/min, p < 0.001) and with lower serum IGF-1 values (103.3 ± 47.0 vs. 128.4 ± 67.8 ng/ml, p = 0.025). No differences were present according to treatment. HF secondary to ischemic heart disease (IHD) and valve diseases were the 2 etiologies more likely associated with cardiovascular mortality (Table 1).
COX regression analysis (Table 2) showed that the factors independently associated with the cardiovascular mortality in patients with HFrEF were as follows: (i) severe renal dysfunction (eGFR ≤ 30 ml/min/1.73 m2), (HR stage III = 1.63, 95% CI 0.73–3.63, p = 0.16; HR stages IV–V = 4.86, 95% CI 1.48–15.95, p = 0.009), respectively; (ii) being classified as high-risk patient of mortality/unexpected death (HR 2.25, 95% CI 1.04–4.86, p = 0.039), and (iii) serum IGF-1 (HR 0.42, 95% CI 0.23–0.77, p = 0.005). The underlying valvular etiology of cardiomyopathy was strongly associated with CV mortality (HR 5.85, 95% CI 2.02–16.94, P = 0.001), while the HR concerning the ischemic form was 1.63 (95% CI 0.73–3.63, p = 0.23).
Figure 1 shows the Kaplan Meier curves in relation to CKD-EPI stage (tab. A) and to the high-risk of death (tab. B). LnIGF-1 showed the best predictive value for incidence of CV death with the cut-off value of 4.07 ng/mL (AUC 0.608, 95% C.I. 0.51–0.70) (see Supplemental material).
In high-risk patients it was possible to highlight how the factors associated with higher mortality were IGF-1 values, the presence of severe renal dysfunction and the valvular etiology (Table 3A). Analyzing the factors associated with higher mortality in patients younger than 65 years (Table 3B), the development of fatal CV events was independently associated with the presence of the high-risk pattern and depended also on serum IGF-1 levels at the time of the enrollment.
Discussion
The main findings of the present analyses are that in a cohort of HFrEF the serum IGF-1 level independently predicted CV mortality, more so in younger patients and regardless of HF severity and renal function.
Prior work showed that the serum IGF-1 was a predictor of mortality from cardiovascular events in patients with HFrEF [24]. Our findings confirmed and extended the prognostic value in both the young-adult and the high-risk population (therefore, candidates for treatment with implantable cardioverter-defibrillator) [1]. The usefulness of measuring the serum levels of IGF-1 in patients with HFrEF appears prognostically crucial especially in younger subjects, regardless of the degree of renal and cardiac impairment. In such patients the presence of reduced eGFR and increased circulating BNP, usually considered as a prognostic factor in patients with HF [25–27], tend to lose their predictive role towards mortality compared with serum IGF-1.
Evaluation of IGF-1 is important because this hormone can be considered as a modifiable factor. Previous studies showed that exogenous administration of GH in patients with HF induces an improvement in functional and instrumental performances. Indeed, the study conducted by Cittadini et al. on a cohort of 17 patients treated with GH (compared with 14 control patients) [28] showed not only improved instrumental performances based on echocardiographic measurements, but also functional improvements in relation to the clinical conditions of patients, after a follow-up of 4 years. Patients were evaluated through the administration of the “Minnesota Living With Heart Failure Questionnaire” [29] (− 9.81 vs. 1.40 points, p = 0.001) and the changes in the NYHA class (− 0.38 ± 0.14 vs. 0.42 ± 0.17, p = 0.001). Beneficial effects of exogenous administration of GH were also highlighted in the case of shorter treatments (up to 6 months) in a cohort of 28 patients enrolled in the T.O.S.CA. registry [8]. In this study, positive effects due to hormonal treatment were both functional (gain in EF values) and clinical (lower duration of physical exercise).
Similar effects on EF were also shown in an Iranian study for shorter period of GH administration (up to 3 months) in patients with post-myocardial infarction HF and reduced EF (8 treated patients compared with 8 controls). However, the beneficial effect tended to decrease after about 9 months from the interruption of the therapy [30].
This indirectly indicates the clinical and functional importance of IGF-1 in patients with HF and the beneficial and protective effects by this hormone towards physical performances in a highly prevalent disease such as HF itself.
At the same time, it is also important to underline how a meta-analysis conducted in 2007 showed how the beneficial effects of GH administration in amelioration of EF (+ 5.1%), diameter of the left ventricle (− 2.02 mm), NYHA class (− 0.97) and duration of physical exercise (+ 103.7 s) were influenced by sex, being more favorable in males than females [31]. The causes of such sex-dependent differences can be partially explained by the different hormonal asset of males and females, but further studies are still needed for the identification of the leading factors.
Cittadini et al. [8] demonstrated that exogenous administration of GH led to a significant reduction in circulating N-terminal pro-BNP levels. As highlighted by our study, the serum values of IGF-1 seem to correlate only with serum BNP, which represents one of the main prognostic indicators clinically used for the evaluation of patients with HF. The association between serum BNP and worse outcomes was not found when we performed the multivariate analyses, suggesting the greater statistical strength of circulating IGF-1.
Our results did not show any relationship between serum IGF-1 and EF or with the degree of renal impairment, confirming that serum IGF-1 would not seem to be influenced by the presence of such abnormalities. These findings are in agreement with the study of Ravassa et al. on a group of 686 patients with HF. These authors showed no relationship between IGF-1 and renal dysfunction, while a significant difference was found in circulating protein binding insulin-like growth factor 2 (IGFBP-2), whose levels are usually higher in patients with impaired renal function [32]. It is known that IGF-1 functionality is affected by IGFBP-2 levels (98% of IGF-1 is bound to this protein) [33], so that an increase in IGFBP-2 levels in patients with CKD affects the peripheral function of the hormone and seems to be partially responsible for the association with a higher risk of mortality in patients with HF and CKD. Also, IGFBP-2 is an important prognostic factor for cardiovascular mortality in HF and it might be a novel therapeutic target in the treatment of HF [34, 35].
Neprilysin inhibitors have been recently introduced in the management of patients with HF and concomitant renal insufficiency levels [36], with a clinical net benefit for CV and renal outcomes, especially among young adults and in patients with HFrEF [37]. Neprilysin inhibitors seem to act in part on the GH/IGF-1 axis, as they reduce the circulating levels of insulin-like growth factor-binding protein-7 (IGFBP-7), which is a modulator of the biological activities of IGF-1 [38]. In normal conditions, IGFBP-7 binds to IGF-1 and neutralizes its activity, similarly to what happens with IGFBP-2. By acting on the IGFBP-7/IGF-1 ratio, in fact, neprilysin inhibitors can effectively modify the prognosis of patients with HF by modulating the final effector represented by IGF-1 too.
This study has several limitations: first of all its retrospective nature. Moreover, our analyses did not take into account patients’ comorbidities that could increase mortality in subjects with HF. It has to be considered that comorbidities, such as diabetes mellitus and CKD have a negative prognostic effect on patients with HF,
consequent to alterations in the serum levels of IGF-1. Furthermore, none of the patients were under sacubitril/valsartan therapy. This was because this treatment was not recommended by current guidelines at the time of enrollment. Moreover, this drug cost is refundable in Italy only starting from 2018.
Serum levels of IGF-1 may also be affected by pulsatile GH secretion. In healthy patients, GH is secreted according to a complex circadian rhythm and with different secretory peaks between males and females in terms of both the time of onset and the duration of the secretory peaks themselves [39, 40]. For these reasons, the time of execution of sampling would have been inevitably affected by such biological fluctuations in the hormonal secretion.
In addition, some drugs normally used in clinical practice, such as ACE inhibitors, could induce a modification in the serum concentrations of IGF-1 and its binding proteins, with a more significant effect in patients with HFrEF [ 15, 41 ]. This may represent a further potential explanation to the beneficial effects of ACE-inhibition in patients with HF. The role of proton pump inhibitors (PPIs) also deserves some attention, as such drugs are being widely used. PPIs seem to have a marginal part in reducing serum IGF-1 [42]. Another limitation on the interpretation of our data is that different level of physical activity might influence IGF-1 serum levels. Unfortunately, the extent of daily physical activity has not been collected in our study.
Among the conditions that could modify the serum concentrations of IGF-1, we could also mention the association between cardiac decompensation and hepatocellular dysfunction, having cirrhosis a negative effect on IGF-1 peripheral secretion [43, 44]. Finally, none of the enrolled patients received sacubitril/valsartan as disease modifying therapy.
Conclusions
Our study demonstrates both the clinical and prognostic utility of the IGF-1 assay in patients with HFrEF. In particular, in patients at higher cardiovascular risk, the evaluation of the GH/IGF-1 axis could be useful in predicting the prognosis and planning the therapeutic strategies. This kind of approach could represent useful clinical stratification of prognosis in patients with HF.
We believe that patients with HFrEF, would benefit from early detection of GH/IGF-1 alterations, in order to adequately predict their prognosis. At the same time, clinicians could eventually plan correction of hormonal alterations, with the aim of improving long-term outcomes.
Data availability
Data supporting reported results could be obtained from authors after reasonable request.
References
McDonagh TA, Metra M, Adamo M et al (2021) 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 42:3599–3726. https://doi.org/10.1093/eurheartj/ehab368
Cook C, Cole G, Asaria P et al (2014) The annual global economic burden of heart failure. Int J Cardiol 171:368–376. https://doi.org/10.1016/j.ijcard.2013.12.028
Arcopinto M, Cittadini A (2014) Hormonal alterations in heart failure: anabolic impairment in chronic heart failure—diagnostic, prognostic and therapeutic issues. Front Horm Res 43:57–69. https://doi.org/10.1159/000360559
Cittadini A, Salzano A, Iacoviello M et al (2021) Multiple hormonal and metabolic deficiency syndrome predicts outcome in heart failure: the T.O.S.C.A. Registry. Eur J Prev Cardiol. https://doi.org/10.1093/eurjpc/zwab020
Saccà L (2019) Heart failure as a multiple hormonal deficiency syndrome. Circ Heart Fail 2:151–156. https://doi.org/10.1161/CIRCHEARTFAILURE.108.821892
Salzano A, Marra AM, Ferrara F et al (2016) Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction. Int J Cardiol 225:1–3. https://doi.org/10.1016/j.ijcard.2016.09.085
Favuzzi AMR, Venuti A, Bruno C et al (2020) Hormonal deficiencies in heart failure with preserved ejection fraction: prevalence and impact on diastolic dysfunction: a pilot study. Eur Rev Med Pharmacol Sci 24:352–361. https://doi.org/10.26355/eurrev_202001_19933
Cittadini A, Saldamarco L, Marra AM et al (2009) Growth hormone deficiency in patients with chronic heart failure and beneficial effects of its correction. J Clin Endocrinol Metab 94:3329–3336. https://doi.org/10.1210/jc.2009-0533
Anker SD, Volterrani M, Pflaum CD et al (2001) Acquired growth hormone resistance in patients with chronic heart failure: implications for therapy with growth hormone. J Am Coll Cardiol 38:443–452. https://doi.org/10.1016/s0735-1097(01)01385-7
Napoli R, Guardasole V, Angelini V et al (2003) Acute effects of growth hormone on vascular function in human subjects. J Clin Endocrinol Metab 88:2817–2820. https://doi.org/10.1210/jc.2003-030144
Arcopinto M, Isgaard J, Marra AM et al (2014) IGF-1 predicts survival in chronic heart failure. Insights from the T.O.S.CA. (Trattamento Ormonale Nello Scompenso CArdiaco) registry. Int J Cardiol 176:1006–1008. https://doi.org/10.1016/j.ijcard.2014.07.003
Arcopinto M, Bobbio E, Bossone E et al (2013) The GH/IGF-1 axis in chronic heart failure. Endocr Metab Immune Disord Drug Targets 13:76–91. https://doi.org/10.2174/1871530311313010010
Petretta M, Colao A, Sardu C et al (2007) NT-proBNP, IGF-I and survival in patients with chronic heart failure. Growth Horm IGF Res 17:288–296. https://doi.org/10.1016/j.ghir.2007.01.020
Watanabe S, Tamura T, Ono K et al (2010) Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: association with adiponectin. Eur J Heart Fail 12:1214–1222. https://doi.org/10.1093/eurjhf/hfq166
Chisalita SI, Dahlström U, Arnqvist HJ, Alehagen U (2011) Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors. Eur J Endocrinol 165:891–898. https://doi.org/10.1530/EJE-11-0584
Andreassen M, Raymond I, Kistorp C et al (2009) IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population. Eur J Endocrinol 160:25–31. https://doi.org/10.1530/EJE-08-0452
Chioncel O, Lainscak M, Seferovic PM et al (2017) Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 19:1574–1585. https://doi.org/10.1002/ejhf.813
Teppala S, Shankar A, Sabanayagam C (2010) Association between IGF-1 and chronic kidney disease among US adults. Clin Exp Nephrol 14:440–444. https://doi.org/10.1007/s10157-010-0307-y
Jia T, Gama Axelsson T, Heimbürger O et al (2014) IGF-1 and survival in ESRD. Clin J Am Soc Nephrol 9:120–127. https://doi.org/10.2215/CJN.02470213
Ibáñez de Cáceres I, Priego T, Martín AI et al (2002) GH administration and renal IGF-I system in arthritic rats. Life Sci 71:139–151. https://doi.org/10.1016/s0024-3205(02)01640-5
Bossone E, Arcopinto M, Iacoviello M et al (2018) Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry Intern Emerg Med 13:661–671. https://doi.org/10.1007/s11739-018-1844-8
Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006
Levey AS, Eckardt KU, Tsukamoto Y et al (2005) Definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int 67:2089–2100. https://doi.org/10.1111/j.1523-1755.2005.00365.x
Faxén UL, Hage C, Benson L et al (2017) HFpEF and HFrEF display different phenotypes as assessed by IGF-1 and IGFBP-1. J Card Fail 23:293–303. https://doi.org/10.1016/j.cardfail.2016.06.008
Kang J, Park JJ, Cho YJ et al (2018) Predictors and prognostic value of worsening renal function during admission in HFpEF Versus HFrEF: data from the KorAHF (Korean Acute Heart Failure) Registry. J Am Heart Assoc 7:e007910. https://doi.org/10.1161/JAHA.117.007910
Oremus M, Don-Wauchope A, McKelvie R et al (2014) BNP and NT-proBNP as prognostic markers in persons with chronic stable heart failure. Heart Fail Rev 19:471–505. https://doi.org/10.1007/s10741-014-9439-6
Fabbian F, De Giorgi A, Pala M et al (2013) Predictive value of admission N-terminal pro-B-type natriuretic peptide and renal function in older people hospitalized for dyspnoea. Dis Markers 35:735–740. https://doi.org/10.1155/2013/687467
Cittadini A, Marra AM, Arcopinto M et al (2013) Growth hormone replacement delays the progression of chronic heart failure combined with growth hormone deficiency: an extension of a randomized controlled single-blind study. JACC Heart Fail 1:325–330. https://doi.org/10.1016/j.jchf.2013.04.003
Bilbao A, Escobar A, García-Perez L et al (2016) The Minnesota living with heart failure questionnaire: comparison of different factor structures. Health Qual Life Outcomes 14:23. https://doi.org/10.1186/s12955-016-0425-7
Amirpour A, Vakhshoori M, Zavar R et al (2021) The effect of 3-month growth hormone administration and 12-month follow-up duration among heart failure patients four weeks after myocardial infarction: a randomized double-blinded clinical trial. Cardiovasc Ther 2021:2680107. https://doi.org/10.1155/2021/2680107
Le Corvoisier P, Hittinger L, Chanson P et al (2007) Cardiac effects of growth hormone treatment in chronic heart failure: a meta-analysis. J Clin Endocrinol Metab 92:180–185. https://doi.org/10.1210/jc.2006-1313
Ravassa S, Beaumont J, Cediel G et al (2020) Cardiorenal interaction and heart failure outcomes. a role for insulin-like growth factor binding protein 2? Rev Esp Cardiol (Engl Ed) 73:835–843. https://doi.org/10.1016/j.rec.2019.10.012
Ferry RJ Jr, Cerri RW, Cohen P (1999) Insulin-like growth factor binding proteins: new proteins, new functions. Horm Res 51:53–67. https://doi.org/10.1159/000023315
Barutaut M, Fournier P, Peacock WF et al (2020) Insulin-like growth factor binding protein 2 predicts mortality risk in heart failure. Int J Cardiol 300:245–251. https://doi.org/10.1016/j.ijcard.2019.09.032
Li Y, Li L, Wang C (2021) Insulin-like growth factor binding protein 2 might be a novel therapeutic target in the treatment of heart failure. Int J Cardiol 332:163. https://doi.org/10.1016/j.ijcard.2021.03.045
Kang H, Zhang J, Zhang X et al (2020) Effects of sacubitril/valsartan in patients with heart failure and chronic kidney disease: a meta-analysis. Eur J Pharmacol 884:173444. https://doi.org/10.1016/j.ejphar.2020.173444
Spannella F, Marini M, Giulietti F et al (2019) Renal effects of Sacubitril/Valsartan in heart failure with reduced ejection fraction: a real life 1-year follow-up study. Intern Emerg Med 14:1287–1297. https://doi.org/10.1007/s11739-019-02111-6
Januzzi JL Jr, Packer M, Claggett B et al (2018) IGFBP7 (insulin-like growth factor-binding protein-7) and neprilysin inhibition in patients with heart failure. Circ Heart Fail 11:e005133. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005133
Surya S, Symons K, Rothman E, Barkan AL (2006) Complex rhythmicity of growth hormone secretion in humans. Pituitary 9:121–125. https://doi.org/10.1007/s11102-006-9079-5
Ribeiro-Oliveira A Jr, Abrantes MM, Barkan AL (2013) Complex rhythmicity and age dependence of growth hormone secretion are preserved in patients with acromegaly: further evidence for a present hypothalamic control of pituitary somatotropinomas. J Clin Endocrinol Metab 98:2959–2966. https://doi.org/10.1210/jc.2013-1581
Giovannini S, Cesari M, Marzetti E et al (2010) Effects of ACE-inhibition on IGF-1 and IGFBP-3 concentrations in older adults with high cardiovascular risk profile. J Nutr Health Aging 14:457–460. https://doi.org/10.1007/s12603-010-0036-7
Maggio M, Lauretani F, De Vita F et al (2014) Relationship between use of proton pump inhibitors and IGF system in older subjects. J Nutr Health Aging 18:420–423. https://doi.org/10.1007/s12603-013-0430-z
Mangieri E, Tosti-Croce C, Tanzilli G et al (1996) Changes in growth hormone/insulin-like growth factor-1 axis in patients with normal pituitary function and biventricular cardiac failure and hepatic stasis. Cardiologia 41:449–453
Assy N, Pruzansky Y, Gaitini D et al (2008) Growth hormone-stimulated IGF-1 generation in cirrhosis reflects hepatocellular dysfunction. J Hepatol 49:34–42. https://doi.org/10.1016/j.jhep.2008.02.013
Acknowledgements
We are especially grateful to the patients and nurses who have participated in this study. The TOSCA investigators also include: Cittadini A, Arcopinto M, Salzano A, Saccà L, Monti MG, Napoli R, Matarazzo M, Stagnaro FM, Schiavo A, Valente P (Department of Trans-lational Medical Sciences, Federico II University, Naples, Italy); D’Assante R, Marra AM (IRCCS S.D.N., Naples, Italy); Bossone E, Ferrara F, Russo V, Malinconico M, Citro R (Heart Department, Cardiology Division, “Cava de’ Tirreni and Amalfi Coast” Hospital, University of Salerno, Sa-lerno, Italy); Guastalamacchia E, Iacoviello M, Leone M, (University of Bari “Aldo Moro”, Bari, Italy); Triggiani V (Interdisciplinary Department of Medicine-Section of Internal Medicine, Geri-atrics, Endocrinology and Rare Diseases. University of Bari “A. Moro”, Bari, Italy) Cacciatore F, Maiello C, Amarelli C, Mattucci I (Heart Transplantation Unit, Monaldi Hospital, Azienda Ospedaliera dei Colli, Naples, Italy); Limongelli G, Masarone D, Calabrò P, Calabrò R, D’Andrea A, Maddaloni V, Pacileo G, Scarafile R (Cardiology SUN, Monaldi Hospital, Azienda Ospedaliera dei Colli, Second University of Naples, Naples, Italy); Perticone F, Belfiore A, Sci-acqua A, Cimellaro A (University Magna Graecia of Catanzaro, Catanzaro, Italy); Perrone Filardi P, Casaretti L, Paolillo S, Gargiulo P (Department of Advanced Biomedical Sciences, Fed-erico II University of Naples, Naples, Italy); Mancini A, Favuzzi AMR, Di Segni C, Bruno C, Vergani E (Operative Unit of Endocrinology, Catholic University of the Sacred Heart, Rome); Volterrani M, Massaro R (IRCCS S. Raffaele Pisana, Roma, Italy); Vriz O (Heart Center Depart-ment, King Faisal Hospital & Research Center Riyadh, Kingdom of Saudi Arabia), Grimaldi F (Azienda Ospedaliero-Universitaria “Santa Maria della Misericordia” San Daniele del Friuli, Udine, Italy); Castello R, Frigo A (Azienda Ospedaliera Universitaria Integrata di Verona, Italy); Campo M, Sorrentino MR (Ospedali Riuniti di Foggia, Italy); Modesti PA, Malandrino D (Uni-versità di Firenze, Italy); Manfredini R, De Giorgi A, Fabbian F (Azienda Ospedaliera-Universitaria S. Anna, Ferrara, Italy); Puzzo A, Ragusa L (I.R.C.S.S. Oasi Maria SS, Troina, Italy.); Caliendo L, Carbone L (Ospedale Santa Maria della Pietà, Nola, Napoli, Italy); Frigiola A, Generali T, Giacomazzi F, De Vincentiis C, Ballotta A (IRCCS San Donato Milanese, Milano, Italy); Garofalo P, Malizia G (Ospedali Riuniti “Villa Sofia—Cervello”, Palermo, Italy); Milano S, Misiano G (Policlinico P. Giaccone, Palermo, Italy); Suzuki T, Heaney LM (Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Glenfield Hospital, Leicester, UK). Bruzzese D, Statistical Management (Department of Public Health, University Federico II of Naples, Naples, Italy). Dr. Salzano receives research grant support from Cardiopath. The T.O.S.CA. Registry is an Investigator initiated trial with external funding being provided mainly by unrestricted grants from MerckSerono.
Funding
This research received no external funding.
Author information
Authors and Affiliations
Consortia
Contributions
Conceptualization, A.DG, FF, VR; methodology, ADG, FF; software, ADG, FF; validation, ADG, FF, VR; formal analysis, ADG, FF; investigation, ADG, FF; resources, ADG, FF; data curation, ADG, FF; writing—original draft preparation, ADG, FF, VR; writing—review and editing, AMM, MI, VT, GR, FC, CM, GL, DM, FP, PPF, SP, AM, MV, OV, RC, AP, MC, PAM, AS, RDA, MA, AS, AC, TS, EB, AC; visualization, AMM, MI, VT, GR, FC, CM, GL, DM, FP, PPF, SP, AM, MV, OV, RC, AP, MC, PAM, AS, RDA, MA, AS, AC, TS, EB, AC; supervision, AMM, MI, VT, GR, FC, CM, GL, DM, FP, PPF, SP, AM, MV, OV, RC, AP, MC, PAM, AS, RDA, MA, AS, AC, TS, AMM, EB, AC; project ad-ministration, AMM, MI, VT, GR, FC, CM, GL, DM, FP, PPF, SP, AM, MV, OV, RC, AP, MC, PAM, AS, RDA, MA, AS, AC, TS, EB, AC.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Ethical approval
The study is conducted in accordance with Good Clinical Practice, Declaration of Helsinki 2002. The trial has been registered on Clinicaltrials.gov (NCT02335801) and approved by Ethical Committee of Federico II University, Naples, Italy (n° 34/2013).
Informed consent
Informed consent was obtained from all subjects involved in the study.
Human and animal rights statement
The study has been registered on Clinicaltrials.gov (NCT02335801), approved by the Ethical Committee of Federico II University, Naples, Italy (n° 34/2013), and conducted in agreement with declaration of Helsinki of 1975, revised in 2013.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The members of T.O.S.CA. Investigators are listed in acknowledgements.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
De Giorgi, A., Marra, A.M., Iacoviello, M. et al. Insulin-like growth factor-1 (IGF-1) as predictor of cardiovascular mortality in heart failure patients: data from the T.O.S.CA. registry. Intern Emerg Med 17, 1651–1660 (2022). https://doi.org/10.1007/s11739-022-02980-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11739-022-02980-4