Skip to main content

Advertisement

SpringerLink
Log in

Effects of short-term manipulation of serum FFA concentrations on left ventricular energy metabolism and function in patients with heart failure: no association with circulating bio-markers of inflammation

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Background and aims

We wanted to assess the effects of short-term changes in serum free fatty acids (FFAs) on left ventricular (LV) energy metabolism and function in patients with heart failure and whether they correlated with circulating markers of inflammation.

Methods and results

LV function and phosphocreatine (PCr)/ATP ratio were assessed using MR imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) in 11 men with chronic heart failure in two experimental conditions 7 days apart. Study 1: MRI and 31P-MRS were performed before and 3–4 h after i.v. bolus + continuous heparin infusion titrated to achieve a serum FFA concentration of 1.20 mM. Study 2: The same protocol was performed before and after the oral administration of acipimox titrated to achieve a serum FFA concentration of 0.20 mM. Serum concentrations of IL6, TNF-α, PAI-1, resistin, visfatin and leptin were simultaneously assessed. Serum glucose and insulin concentrations were not different between studies. The PCr/ATP ratio (percent change from baseline: +6.0 ± 16.9 and −16.6 ± 16.1 % in Study 1 and Study 2, respectively; p = 0.005) and the LV ejection fraction (−1.5 ± 4.0 and −6.9 ± 6.3 % in Study 1 and Study 2, respectively; p = 0.044) were reduced during low FFA when compared to high FFA. Serum resistin was higher during Study 1 than in Study 2 (p < 0.05 repeated measures ANOVA); meanwhile, the other adipocytokines were not different.

Conclusion

FFA deprivation, but not excess, impaired LV energy metabolism and function within hours. Cautions should be used when sudden iatrogenic modulation of energy substrates may take place in vulnerable patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258

    Article  CAS  PubMed  Google Scholar 

  2. Ingwall JS (2007) On substrate selection for ATP synthesis in the failing human myocardium. Am J Physiol Heart Circ Physiol 293:H3225–H3226

    Article  CAS  PubMed  Google Scholar 

  3. Taegtmeyer H, McNulty P, Young ME (2002) Adaptation and maladaptation of the heart in diabetes: part I: general concepts. Circulation 105:1727–1733

    Article  CAS  PubMed  Google Scholar 

  4. Korvald CEO, Myrmel T (2000) Myocardial substrate metabolism influences left ventricular energetics in vivo. Am J Physiol Heart Circ Physiol 278:H1345–H1351

    CAS  PubMed  Google Scholar 

  5. Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, Ashrafian H, Horowitz J, Fraser AG, Clarke K, Frenneaux M (2005) Metabolic modulation with perhexiline in chronic heart failure. A randomized, controlled trial of short-term use of a novel treatment. Circulation 112:3280–3288

    Article  CAS  PubMed  Google Scholar 

  6. Kantor PF, Lucien A, Kozak R, Lopaschuk GD (2000) The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 86:580–588

    Article  CAS  PubMed  Google Scholar 

  7. Neubauer S (2007) The failing heart. An engine out of fuel. N Engl J Med 356:1140–1151

    Article  PubMed  Google Scholar 

  8. Fragasso G, Perseghin G, De Cobelli F, Esposito A, Palloshi A, Lattuada G, Scifo P, Calori G, Del Maschio A, Margonato A (2006) Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J 27:942–948

    Article  CAS  PubMed  Google Scholar 

  9. Tuunanen H, Engblom E, Naum A, Någren K, Hesse B, Airaksinen KEJ, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J (2006) Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 114:2130–2137

    Article  CAS  PubMed  Google Scholar 

  10. Fragasso G, Montano C, Lattuada G, Salerno A, Palloshi A, Calori G, Luzi L, Perseghin G, Margonato A (2011) A high carbohydrate meal yields a lower ischemic threshold than a high fat meal in patients with stable coronary disease. Int J Cardiol 147:209–213

    Article  PubMed  Google Scholar 

  11. Fragasso G, Piatti PM, Monti L, Palloshi A, Lu C, Valsecchi G, Setola E, Calori G, Pozza G, Margonato A, Chierchia S (2002) Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease. Evaluation of the protective role of the metabolic modulator trimetazidine. J Am Coll Cardiol 39:413–419

    Article  CAS  PubMed  Google Scholar 

  12. Perseghin G, Fiorina P, De Cobelli F, Scifo P, Esposito A, Danna M, Canu T, Gremizzi C, Secchi A, Luzi L, Del Maschio A (2005) Cross-sectional assessment of the effect of kidney and kidney-pancreas transplantation on resting left ventricular energy metabolism in type 1 diabetic-uremic patients: a 31P-MRS study. J Am Coll Cardiol 46:1085–1092

    Article  PubMed  Google Scholar 

  13. De Cobelli F, Pieroni M, Esposito A, Belloni E, Chimenti C, Mellone R, Canu T, Perseghin G, Gaudio C, Maseri A, Frustaci A, Del Maschio A (2006) Delayed gadolinium-enhanced cardiac magnetic resonance in patients with chronic myocarditis presenting with heart failure or recurrent arrhythmias. J Am Coll Cardiol 47:1649–1654

    Article  PubMed  Google Scholar 

  14. Lamb HJ, Doornbos J, den Hollander JA, Luyten PR, Beyerbacht HP, van der Wall EE, de Roos A (1996) Reproducibility of human cardiac 31P-NMR spectroscopy. NMR Biomed 9:217–227

    Article  CAS  PubMed  Google Scholar 

  15. Perseghin G, Lattuada G, De Cobelli F, Esposito A, Belloni E, Canu T, Ragogna F, Scifo P, Del Maschio A, Luzi L (2007) Plasma retinol binding protein-4 (RBP-4), leptin and adiponectin concentrations are related to ectopic fat accumulation. J Clin Endocrinol Metab 92:4883–4888

    Article  CAS  PubMed  Google Scholar 

  16. Swan JW, Walton C, Godsland IF, Clark AL, Coats AJ, Oliver MF (1994) Insulin resistance in chronic heart failure. Eur Heart J 15:1528–1532

    CAS  PubMed  Google Scholar 

  17. Opie LH, Knuuti J (2009) The adrenergic-fatty acid load in heart failure. J Am Coll Cardiol 54:1637–1646

    Article  CAS  PubMed  Google Scholar 

  18. Roden M, Price TB, Perseghin G, Petersen KF, Cline GW, Shulman GI (1996) Mechanism of free fatty acid induced insulin resistance in humans. J Clin Invest 97:2859–2865

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Boden G, Chen X, Capulong E, Mozzoli M (2001) Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes. Diabetes 50:810–816

    Article  CAS  PubMed  Google Scholar 

  20. van der Meer RW, Hammer S, Smit JW, Frölich M, Bax JJ, Diamant M, Rijzewijk LJ, de Roos A, Romijn JA, Lamb HJ (2007) Short-term caloric restriction induces accumulation of myocardial triglycerides and decreases left ventricular diastolic function in healthy subjects. Diabetes 56:2849–2853

    Article  PubMed  Google Scholar 

  21. Hammer S, van der Meer RW, Lamb HJ, Schar M, de Roos A, Smit JWA, Romijn JA (2008) Progressive caloric restriction induces dose-dependent changes in myocardial triglyceride content and diastolic function in healthy men. J Clin Endocrinol Metab 93:497–503

    Article  CAS  PubMed  Google Scholar 

  22. Perseghin G, Ntali G, De Cobelli F, Lattuada G, Esposito A, Costantino F, Ragogna F, Canu T, Belloni E, Scifo P, Del Maschio A, Luzi L (2007) Abnormal left ventricular energy metabolism in obese men with preserved systolic and diastolic functions is associated with insulin resistance. Diabetes Care 30:1520–1527

    Article  PubMed  Google Scholar 

  23. Rider OJ, Francis JM, Ali MK, Holloway C, Pegg T, Robson MD, Tyler D, Byrne J, Clarke K, Neubauer S (2012) Effects of catecholamine stress on diastolic function and myocardial energetics in obesity. Circulation 125:1511–1519

    Article  CAS  PubMed  Google Scholar 

  24. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, Dence C, Klein S, Marsala J, Meyer T, Gropler RJ (2004) Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109:2191–2196

    Article  PubMed  Google Scholar 

  25. Tuunanen H, Engblom E, Naum A, Någren K, Scheinin M, Hesse B, Airaksinen KEJ, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J (2008) Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation 118:1250–1258

    Article  CAS  PubMed  Google Scholar 

  26. Fragasso G, Salerno A, Lattuada G, Cuko A, Calori G, Scollo A, Arioli F, Bassanelli G, Spoladore R, Luzi L, Margonato A, Perseghin G (2011) Effect of partial inhibition of fatty-acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure. Heart 97:1495–1500

    Article  CAS  PubMed  Google Scholar 

  27. Nielsen R, Norrelund H, Kampmann U, Kim WY, Ringgaard S, Schar M, Moller N, Botker HE, Wiggers H (2013) Failing heart of patients with type 2 diabetes mellitus can adapt to extreme short term increases in circulating lipids and does not display features of acute myocardial lipotoxicity. Circ Heart Fail 6:845–852

    Article  CAS  PubMed  Google Scholar 

  28. Lehto H-R, Pärkkä K, Borra R, Tuunanen H, Lepomaki V, Parkkola R, Knuuti J, Nuutila P, Iozzo P (2012) Effects of acute and one-week fatty acid lowering on cardiac function and insulin sensitivity in relation with myocardial and muscle fat and adiponectin levels. J Clin Endocrinol Metab 97:3277–3284

    Article  CAS  PubMed  Google Scholar 

  29. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD, the VADT Investigators (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360:129–139

    Article  CAS  PubMed  Google Scholar 

  30. The Action to Control Cardiovascular Risk in Diabetes Study Group (2008) Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559

    Article  Google Scholar 

  31. Van den Berghe G (2013) What’s new in glucose control in the ICU? Intensive Care Med 39:823–825

    Article  PubMed  Google Scholar 

  32. Bucci M, Borra R, Någren K, Pärkkä JP, Ry S, Del Maggio R, Tuunanen H, Viljanen T, Cabiati M, Rigazio S, Taittonen M, Pagotto U, Parkkola R, Opie LH, Nuutila P, Knuuti J, Iozzo P (2012) Trimetazidine reduces endogenous free fatty acid oxidation and improves myocardial efficiency in obese humans. Cardiovasc Ther 30:333–341

    Article  CAS  PubMed  Google Scholar 

  33. Shah RV, Abbasi SA, Neilan TG, Hulten E, Coelho-Filho O, Hoppin A, Levitsky L, de Ferranti S, Rhodes ET, Traum A, Goodman E, Feng H, Heydari B, Harris WS, Hoefner DM, McConnell JP, Seethamraju R, Rickers C, Kwong RY, Jerosch-Herold M (2013) Myocardial tissue remodeling in adolescent obesity. J Am Heart Assoc 2:e000279

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The current study was supported by a grant by the European Association for the Study of Diabetes (EASD) and by a liberal donation from the family of Angela Musazzi and Mario Stellato.

Conflict of interest

Gianluca Perseghin received lecture fees during the last 3 years from Lilly, Sigma-Tau, AstraZeneca, Takeda, Bristol Myers Squibb, Sanofi-Aventis, Merck and Co/Schering Plough, Novo Nordisk, Novartis. Gabriele Fragasso received lecture fees during the last 3 years from Servier International, Boehringer Ingelheim. Anna Salerno, Antonio Esposito, Tamara Canu, Guido Lattuada, Giuseppina Manzoni, Alessandro Del Maschio, Alberto Margonato, Francesco De Cobelli declare that they have no conflict of interest to disclose.

Ethical standard

The protocol was approved by the Ethical Committee of the Istituto Scientifico H San Raffaele.

Human and animal rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Informed consent

Informed consent was obtained from all subjects after explanation of purposes, nature and potential risks of the study.

Author information

Authors and Affiliations

  1. Clinical Cardiology – Heart Failure Clinic, Ospedale San Raffaele, Milan, Italy

    A. Salerno, G. Fragasso & A. Margonato

  2. Diagnostic Radiology, Ospedale San Raffaele, Milan, Italy

    A. Esposito, T. Canu, A. Del Maschio & F. De Cobelli

  3. Università Vita e Salute San Raffaele, Milan, Italy

    A. Esposito, A. Del Maschio, A. Margonato & F. De Cobelli

  4. Metabolic Medicine, Policlinico di Monza, via Amati 111, 20900, Monza, Italy

    G. Lattuada, G. Manzoni & G. Perseghin

  5. Department of Biomedical Sciences for Health, Università degli Studi di, Milan, Italy

    G. Perseghin

Authors
  1. A. Salerno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Fragasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Canu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Lattuada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Manzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Del Maschio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Margonato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. De Cobelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G. Perseghin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. Perseghin.

Additional information

Managed by Massimo Porta.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 59 kb)

Supplementary material 2 (TIFF 74 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salerno, A., Fragasso, G., Esposito, A. et al. Effects of short-term manipulation of serum FFA concentrations on left ventricular energy metabolism and function in patients with heart failure: no association with circulating bio-markers of inflammation. Acta Diabetol 52, 753–761 (2015). https://doi.org/10.1007/s00592-014-0695-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-014-0695-7

Keywords

Search

Navigation