Advertisement

Internal and Emergency Medicine

, Volume 13, Issue 5, pp 661–671 | Cite as

Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry

  • E. Bossone
  • M. Arcopinto
  • M. Iacoviello
  • V. Triggiani
  • F. Cacciatore
  • C. Maiello
  • G. Limongelli
  • D. Masarone
  • F. Perticone
  • A. Sciacqua
  • P. Perrone-Filardi
  • A. Mancini
  • M. Volterrani
  • O. Vriz
  • R. Castello
  • A. Passantino
  • M. Campo
  • P. A. Modesti
  • A. De Giorgi
  • I. Monte
  • A. Puzzo
  • A. Ballotta
  • L. Caliendo
  • R. D’Assante
  • A. M. Marra
  • A. Salzano
  • T. Suzuki
  • A. Cittadini
  • On behalf of TOSCA Investigators
IM - ORIGINAL

Abstract

Recent evidence supports the concept that progression of chronic heart failure (CHF) depends upon an imbalance of catabolic forces over the anabolic drive. In this regard, multiple hormonal deficiency syndrome (MHDS) significantly has impacts upon CHF progression, and is associated with a worse clinical status and increased mortality. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Therapy in Heart Failure) Registry (clinicaltrial.gov = NCT02335801) tests the hypothesis that anabolic deficiencies reduce survival in a large population of mild-to-moderate CHF patients. The T.O.S.CA. Registry is a prospective multicenter observational study coordinated by “Federico II” University of Naples, and involves 19 centers situated throughout Italy. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydroepiandrosterone , and insulin are measured at baseline and every year for a patient-average follow-up of 3 years. Subjects with CHF are divided into two groups: patients with one or no anabolic deficiency, and patients with two or more anabolic deficiencies at baseline. The primary endpoint is the composite of all-cause mortality and cardiovascular hospitalization. Secondary endpoints include the composite of all-cause mortality and hospitalization, the composite of cardiovascular mortality and cardiovascular hospitalization, and change of VO2 peak. Patient enrollment started in April 2013, and was completed in July 2017. Demographics and main clinical characteristics of enrolled patients are provided in this article. Detailed cross-sectional results will be available in late 2018. The T.O.S.CA. Registry represents the most robust prospective observational trial on MHDS in the field of CHF. The study findings will advance our knowledge with regard to the intimate mechanisms of CHF progression and hopefully pave the way for future randomized clinical trials of single or multiple hormonal replacement therapies in CHF.

Keywords

Chronic heart failure Anabolic deficiency Multiple hormonal deficiency syndrome Registry Heart failure metabolism 

Notes

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 Translational 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, Salerno, Italy); Guastalamacchia E, Iacoviello M, Leone M, (University of Bari “Aldo Moro”, Bari, Italy); Triggiani V (Interdisciplinary Department of Medicine-Section of Internal Medicine, Geriatrics, 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, Sciacqua A, Cimellaro A (University Magna Graecia of Catanzaro, Catanzaro, Italy); Perrone Filardi P, Casaretti L, Paolillo S, Gargiulo P (Department of Advanced Biomedical Sciences, Federico 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 Department, 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 (Università 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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B et al (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 37:2893–2962CrossRefPubMedGoogle Scholar
  2. 2.
    Braunwald E (2013) Heart failure. JACC. Heart Fail 1:1–20CrossRefGoogle Scholar
  3. 3.
    Pagan J, Seto T, Pagano M, Cittadini A (2013) Role of the ubiquitin proteasome system in the heart. Circ Res 112:1046–1058CrossRefPubMedGoogle Scholar
  4. 4.
    Sacca L (2009) Heart failure as a multiple hormonal deficiency syndrome. Circ Heart Fail 2:151–156CrossRefPubMedGoogle Scholar
  5. 5.
    Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M et al (2006) Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation 114:1829–1837CrossRefPubMedGoogle Scholar
  6. 6.
    Arcopinto M, Salzano A, Bossone E, Ferrara F, Bobbio E, Sirico D et al (2015) Multiple hormone deficiencies in chronic heart failure. Int J Cardiol 184:421–423CrossRefPubMedGoogle Scholar
  7. 7.
    Salzano A, Marra AM, Ferrara F, Arcopinto M, Bobbio E, Valente P et al (2016) Multiple hormone deficiency syndrome in heart failure with preserved ejection fraction. Int J Cardiol 225:1–3CrossRefPubMedGoogle Scholar
  8. 8.
    Arcopinto M, Salzano A, Ferrara F, Bobbio E, Marra AM, Abete R et al (2016) The Tosca Registry: an ongoing, observational, multicenter registry for chronic heart failure. Transl Med UniSa 14:21–27PubMedPubMedCentralGoogle Scholar
  9. 9.
    Suskin N, McKelvie RS, Burns RJ, Latini R, Pericak D, Probstfield J et al (2000) Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J 21:1368–1375CrossRefPubMedGoogle Scholar
  10. 10.
    Bossone E, Limongelli G, Malizia G, Ferrara F, Vriz O, Citro R et al (2011) The T.O.S.CA. Project: research, education and care. Monaldi Arch Chest Dis 76:198–203PubMedGoogle Scholar
  11. 11.
    Arcopinto M, Isgaard J, Marra AM, Formisano P, Bossone E, Vriz O 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 176:1006–1008CrossRefPubMedGoogle Scholar
  12. 12.
    Arcopinto M, Bobbio E, Bossone E, Perrone-Filardi P, Napoli R, Sacca L et al (2013) The GH/IGF-1 axis in chronic heart failure. Endocr Metab Immune Disord Drug Targets 13:76–91CrossRefPubMedGoogle Scholar
  13. 13.
    Arcopinto M, Salzano A, Giallauria F, Bossone E, Isgaard J, Marra AM et al (2017) Growth hormone deficiency is associated with worse cardiac function, physical performance, and outcome in chronic heart failure: insights from the T.O.S.CA. GHD study. PLoS ONE 12:e0170058CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Marra AM, Bobbio E, D’Assante R, Salzano A, Arcopinto M, Bossone E et al (2018) Growth hormone as biomarker in heart failure. Heart Fail Clin 14:65–74CrossRefPubMedGoogle Scholar
  15. 15.
    Cittadini A, Saldamarco L, Marra AM, Arcopinto M, Carlomagno G, Imbriaco M et al (2009) Growth hormone deficiency in patients with chronic heart failure and beneficial effects of its correction. J Clin Endocrinol Metab 94:3329–3336CrossRefPubMedGoogle Scholar
  16. 16.
    Cittadini A, Marra AM, Arcopinto M, Bobbio E, Salzano A, Sirico D 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 1:325–330CrossRefPubMedGoogle Scholar
  17. 17.
    Petretta M, Colao A, Sardu C, Scopacasa F, Marzullo P, Pivonello R et al (2007) NT-proBNP, IGF-I and survival in patients with chronic heart failure. Growth Horm IGF Res 17:288–296CrossRefPubMedGoogle Scholar
  18. 18.
    Niebauer J, Pflaum CD, Clark AL, Strasburger CJ, Hooper J, Poole-Wilson PA et al (1998) Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation. J Am Coll Cardiol 32:393–397CrossRefPubMedGoogle Scholar
  19. 19.
    Marra AM, Arcopinto M, Salzano A, Bobbio E, Milano S, Misiano G et al (2016) Detectable interleukin-9 plasma levels are associated with impaired cardiopulmonary functional capacity and all-cause mortality in patients with chronic heart failure. Int J Cardiol 209:114–117CrossRefPubMedGoogle Scholar
  20. 20.
    Opasich C, Pacini F, Ambrosino N, Riccardi PG, Febo O, Ferrari R et al (1996) Sick euthyroid syndrome in patients with moderate-to-severe chronic heart failure. Eur Heart J 17:1860–1866CrossRefPubMedGoogle Scholar
  21. 21.
    Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M et al (2003) Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 107:708–713CrossRefPubMedGoogle Scholar
  22. 22.
    Pingitore A, Iervasi G (2005) Thyroid (dys)function in heart failure: is it a potential target for medical treatment? Vasc Health Risk Manag 1:97–100CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M et al (2009) Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 54:919–927CrossRefPubMedGoogle Scholar
  24. 24.
    Iellamo F, Volterrani M, Caminiti G, Karam R, Massaro R, Fini M et al (2010) Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol 56:1310–1316CrossRefPubMedGoogle Scholar
  25. 25.
    Arcopinto M, Salzano A, Isgaard J, Cittadini A (2015) Hormone replacement therapy in heart failure. Curr Opin Cardiol 30:277–284CrossRefPubMedGoogle Scholar
  26. 26.
    Doehner W, Rauchhaus M, Ponikowski P, Godsland IF, von Haehling S, Okonko DO et al (2005) Impaired insulin sensitivity as an independent risk factor for mortality in patients with stable chronic heart failure. J Am Coll Cardiol 46:1019–1026CrossRefPubMedGoogle Scholar
  27. 27.
    Wong AK, Symon R, AlZadjali MA, Ang DS, Ogston S, Choy A et al (2012) The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Heart Fail 14:1303–1310CrossRefPubMedGoogle Scholar
  28. 28.
    Cittadini A, Napoli R, Monti MG, Rea D, Longobardi S, Netti PA et al (2012) Metformin prevents the development of chronic heart failure in the SHHF rat model. Diabetes 61:944–953CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Meta-analysis Global Group in Chronic Heart F (2012) The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J 33:1750–1757CrossRefGoogle Scholar
  30. 30.
    Plesner LL, Dalsgaard M, Schou M, Kober L, Vestbo J, Kjoller E et al (2017) The prognostic significance of lung function in stable heart failure outpatients. Clin Cardiol 40(11):1145–1151.  https://doi.org/10.1002/clc.22802 CrossRefPubMedGoogle Scholar
  31. 31.
    Tang WH, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM et al (2014) Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 64:1908–1914CrossRefPubMedGoogle Scholar
  32. 32.
    Maggioni AP, Anker SD, Dahlstrom U, Filippatos G, Ponikowski P, Zannad F et al (2013) Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 15:1173–1184CrossRefPubMedGoogle Scholar
  33. 33.
    Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der Harst P et al (2016) A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF. Eur J Heart Fail 18:716–726CrossRefPubMedGoogle Scholar

Copyright information

© SIMI 2018

Authors and Affiliations

  • E. Bossone
    • 1
  • M. Arcopinto
    • 2
  • M. Iacoviello
    • 3
  • V. Triggiani
    • 4
  • F. Cacciatore
    • 5
  • C. Maiello
    • 5
  • G. Limongelli
    • 6
  • D. Masarone
    • 6
  • F. Perticone
    • 7
  • A. Sciacqua
    • 7
  • P. Perrone-Filardi
    • 8
  • A. Mancini
    • 9
  • M. Volterrani
    • 10
  • O. Vriz
    • 11
  • R. Castello
    • 12
  • A. Passantino
    • 13
  • M. Campo
    • 14
  • P. A. Modesti
    • 15
  • A. De Giorgi
    • 16
  • I. Monte
    • 17
  • A. Puzzo
    • 18
  • A. Ballotta
    • 19
  • L. Caliendo
    • 20
  • R. D’Assante
    • 21
  • A. M. Marra
    • 21
  • A. Salzano
    • 2
    • 22
  • T. Suzuki
    • 22
  • A. Cittadini
    • 2
  • On behalf of TOSCA Investigators
  1. 1.Heart Department, Cardiology Division, “Cava de’ Tirreni and Amalfi Coast” HospitalUniversity of SalernoSalernoItaly
  2. 2.Department of Translational Medical SciencesFederico II University of NaplesNaplesItaly
  3. 3.Cardiology Unit, Cardiothoracic DepartmentUniversity of Bari “Aldo Moro”BariItaly
  4. 4.Interdisciplinary Department of Medicine-Section of Internal Medicine, Geriatrics, Endocrinology and Rare DiseasesUniversity of Bari “A. Moro”BariItaly
  5. 5.Heart Transplantation Unit, Monaldi HospitalAzienda Ospedaliera dei ColliNaplesItaly
  6. 6.Division of Cardiology SUN, Monaldi HospitalAzienda Ospedaliera dei Colli, Second University of NaplesNaplesItaly
  7. 7.Department of Health SciencesUniversity Magna Graecia of CatanzaroCatanzaroItaly
  8. 8.Department of Advanced Biomedical SciencesFederico II University of NaplesNaplesItaly
  9. 9.Operative Unit of EndocrinologyCatholic University of the Sacred HeartRomeItaly
  10. 10.Department of Medical SciencesIRCCS San Raffaele PisanaRomeItaly
  11. 11.Heart Center DepartmentKing Faisal Hospital & Research CenterRiyadhKingdom of Saudi Arabia
  12. 12.Division of General MedicineAzienda Ospedaliera Universitaria IntegrataVeronaItaly
  13. 13.Division of CardiologySalvatore Maugeri Foundation, IRCCS, Scientific Institute of Cassano MurgeBariItaly
  14. 14.Unit of Endocrinology and Metabolic Diseases, Department of Medical and Surgical SciencesUniversity of FoggiaFoggiaItaly
  15. 15.Dipartimento di Medicina Sperimentale e ClinicaUniversità degli Studi di FirenzeFlorenceItaly
  16. 16.Department of Medical Sciences, School of Medicine, Pharmacy and PreventionUniversity of FerraraFerraraItaly
  17. 17.Department of General Surgery and Medical-Surgery SpecialtiesUniversity of CataniaCataniaItaly
  18. 18.IRCSS. Oasi Maria SSTroinaItaly
  19. 19.IRCCS Policlinico San DonatoMilanItaly
  20. 20.Ospedale Santa Maria della PietàNaplesItaly
  21. 21.IRCCS S.D.NNaplesItaly
  22. 22.Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of LeicesterGlenfield HospitalLeicesterUK

Personalised recommendations