Modulation of cardiac metabolism in heart failure

Published: November 5, 2024
Abstract Views: 69
PDF: 24
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Heart failure is associated with altered cardiac metabolism, in part, due to maladaptive mechanisms, in part secondary to comorbidities such as diabetes and ischemic heart disease. The metabolic derangements taking place in heart failure are not limited to the cardiac myocytes but extend to skeletal muscles and the vasculature causing changes that contribute to the worsening of exercise capacity. Modulation of cardiac metabolism with partial inhibition of free fatty acid oxidation has been shown to be beneficial in patients with heart failure. At the present, the bulk of evidence for this class of drugs comes from trimetazidine. Newer compounds partially inhibiting free fatty acid oxidation or facilitating the electron transport on the mitochondrial cristae are in early phase of their clinical development.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

1. Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll
Cardiol 2014;64:1388400.
2. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med 2007;356:114051. DOI: https://doi.org/10.1056/NEJMra063052
3. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic
cardiomyopathy. Br J Pharmacol 2014; 171:208090.
4. Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbonlabeled
carbohydrate isotope experiments. J Clin Invest 1988;82:201725.
5. Abozguia K, Shivu GN, Ahmed I, Phan TT, Frenneaux MP. The heart metabolism: pathophysiological aspects in ischaemia and heart failure. Curr Pharm Des 2009;15:82735. DOI: https://doi.org/10.2174/138161209787582101
6. Weber KT, Janicki JS. The metabolic demand and oxygen supply of the heart: physiologic and clinical considerations. Am J Cardiol
1979;44:7229.
7. Lommi J, Koskinen P, Naveri H, Harkonen M, Kupari M. Heart failure ketosis. J Intern Med 1997;242:2318. DOI: https://doi.org/10.1046/j.1365-2796.1997.00187.x
8. Lommi J, Kupari M, Koskinen P, Naveri H, Leinonen H, Pulkki K, Harkonen M. Blood ketone bodies in congestive heart failure. J Am
Coll Cardiol 1996;28:66572.
9. Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 2013;113:70924. DOI: https://doi.org/10.1161/CIRCRESAHA.113.300376
10. Heusch G, Libby P, Gersh B, Yellon D, Bohm M, Lopaschuk G, Opie L. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet 2014;383:193343. DOI: https://doi.org/10.1016/S0140-6736(14)60107-0
11. Fragasso G. Deranged cardiac metabolism and the pathogenesis of heart failure. Card Fail Rev 2016;2:813. DOI: https://doi.org/10.15420/cfr.2016:5:2
12. Lionetti V, Stanley WC, Recchia FA. Modulating fatty acid oxidation in heart failure. Cardiovasc Res 2011;90:2029. DOI: https://doi.org/10.1093/cvr/cvr038
13. Beadle RM, Williams LK, Kuehl M, Bowater S, Abozguia K, Leyva F, et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail 2015;3:20211.
14. Lee L, Campbell R, ScheuermannFreestone M, Taylor R, Gunaruwan P, Williams L, et al. Metabolic modulation with perhexiline
in chronic heart failure: a randomized, controlled trial of shortterm use of a novel treatment. Circulation 2005;112:32808.
15. Fragasso G, Rosano G, Baek SH, Sisakian H, Di Napoli P, Alberti L, et al. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int J Cardiol 2013;163:3205. DOI: https://doi.org/10.1016/j.ijcard.2012.09.123
16. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial longchain 3ketoacyl coenzyme A thiolase. Circ Res 2000;86:5808. DOI: https://doi.org/10.1161/01.RES.86.5.580
17. Vitale C, Wajngaten M, Sposato B, Gebara O, Rossini P, Fini M, et al. Trimetazidine improves left ventricular function and quality of
life in elderly patients with coronary artery disease. Eur Heart J 2004;25:181421. DOI: https://doi.org/10.1016/j.ehj.2003.09.009
18. Khan M, Meduru S, Mostafa M, Khan S, Hideg K, Kuppusamy P. Trimetazidine, administered at the onset of reperfusion, ameliorates
myocardial dysfunction and injury by activation of p38 mitogenactivated protein kinase and Akt signaling. J Pharmacol Exp Ther 2010;333:4219. DOI: https://doi.org/10.1124/jpet.109.165175
19. Brottier L, Barat JL, Combe C, Boussens B, Bonnet J, Bricaud H. Therapeutic value of a cardioprotective agent in patients with severe
ischaemic cardiomyopathy. Eur Heart J 1990;11:20712.
20. Fragasso G, Piatti PM, Monti L, Palloshi A, Setola E, Puccetti P, et al. Shortand longterm beneficial effects of trimetazidine in patients
with diabetes and ischemic cardiomyopathy. Am Heart J 2003;146:E18.
21. Rosano GM, Vitale C, Sposato B, Mercuro G, Fini M. Trimetazidine improves left ventricular function in diabetic patients with coronary
artery disease: a doubleblind placebocontrolled study. Cardiovasc Diabetol 2003;2:16.
22. Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol 2006;48:9928. DOI: https://doi.org/10.1016/j.jacc.2006.03.060
23. Di Napoli P, Di Giovanni P, Gaeta MA, D’Apolito G, Barsotti A. Beneficial effects of trimetazidine treatment on exercise tolerance and
Btype natriuretic peptide and troponin T plasma levels in patients with stable ischemic cardiomyopathy. Am Heart J 2007;154:602. DOI: https://doi.org/10.1016/j.ahj.2007.06.033
24. Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory
process in patients with ischaemic dilated cardiomyopathy. Heart 2005;91:1615. DOI: https://doi.org/10.1136/hrt.2003.031310
25. Belardinelli R, Purcaro A. Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to lowdose
dobutamine in ischaemic cardiomyopathy. Eur Heart J 2001;22:216470.
26. Belardinelli R, Lacalaprice F, Faccenda E, Volpe L. Trimetazidine potentiates the effects of exercise training in patients with ischemic
cardiomyopathy referred for cardiac rehabilitation. Eur J Cardiovasc Prev Rehabil 2008;15:53340.
27. Zhang L, Lu Y, Jiang H, Zhang L, Sun A, Zou Y, et al. Additional use of trimetazidine in patients with chronic heart failure: a metaanalysis. J Am Coll Cardiol 2012;59:91322. DOI: https://doi.org/10.1016/j.jacc.2011.11.027
28. Lee L, Campbell R, ScheuermannFreestone M, Taylor R, Gunaruwan P, Williams L, et al. Metabolic modulation with perhexiline
in chronic heart failure a randomized, controlled trial of shortterm use of a novel treatment. Circulation 2005;112:32808.
29. Beadle RM, Williams LK, Kuehl M, Bowater S, Abozguia K, Leyva F, et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail 2015;3:20211. DOI: https://doi.org/10.1016/j.jchf.2014.09.009
30. Abozguia K, Elliott P, McKenna W, Phan TT, NallurShivu G, Ahmed I, et al. Metabolic modulator perhexiline corrects energy deficiency
and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 2010;122:15629. DOI: https://doi.org/10.1161/CIRCULATIONAHA.109.934059
31. Phan TT, Shivu GN, Choudhury A, Khalid A, Davies C, Naidoo U, et al. Multicentre experience on the use of perhexiline in chronic
heart failure and refractory angina: old drug, new hope. Eur J Heart Fail 2009;11:8816.
32. Schmitz FJ, Rosen P, Reinauer H. Improvement of myocardial function and metabolism in diabetic rats by the carnitine palmitoyl
transferase inhibitor Etomoxir. Horm Metab Res 1995;27:51522.
33. Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail 2010;3:42030. DOI: https://doi.org/10.1161/CIRCHEARTFAILURE.109.888479
34. Wilson JR, Mancini DM, Ferraro N, Egler J. Effect of dichloroacetate on the exercise performance of patients with heart failure. J Am Coll Cardiol 1988;12:14649. DOI: https://doi.org/10.1016/S0735-1097(88)80010-X
35. Lewis JF, DaCosta M, Wargowich T, Stacpoole P. Effects of dichloroacetate in patients with congestive heart failure. Clin Cardiol 1998;21:88892. DOI: https://doi.org/10.1002/clc.4960211206
36. Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol 2014;171:201728. DOI: https://doi.org/10.1111/bph.12468
37. Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH. Randomized doseescalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology 2018;90:e121221. DOI: https://doi.org/10.1212/WNL.0000000000005255
38. Sabbah HN, Gupta RC, SinghGupta V, Zhang K, Lanfear DE. Abnormalities of mitochondrial dynamics in the failing heart: normalization following longterm therapy with elamipretide. Cardiovasc Drugs Ther 2018;32:31928. DOI: https://doi.org/10.1007/s10557-018-6805-y
39. Sabbah HN, Gupta RC, SinghGupta V, Zhang K. Effects of elamipretide on skeletal muscle in dogs with experimentally induced heart failure. ESC Heart Fail 2019;6:32835. DOI: https://doi.org/10.1002/ehf2.12408

How to Cite

Rosano, G. M., & Coats, A. J. (2024). Modulation of cardiac metabolism in heart failure. Global Cardiology, 2(3). https://doi.org/10.4081/cardio.2024.30