Metabolic modulation in heart failure

Metabolic modulation in heart failure

Most of the treatment strategies in heart failure like angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitors (ARNI) and beta blockers utilize hemodynamic modulation. Metabolic modulation on the other hand aims at dealing with myocardial energetic deficiency. Important agents in this group are trimetazidine, ranolazine and perhexiline [1]. Trimetazidine is a 3-ketoacyl coenzyme A thiolase inhibitor, while ranolazine inhibits the late sodium current. Perhexiline inhibits carnitine palmitoyl transferase.

A meta-analysis on trimetazidine published in 2010 found 17 trials including 955 patients. They found that trimetazidine therapy was associated with significant improvement in left ventricular ejection fraction in both ischemic and non-ischemic heart failure. Trimetazidine was shown to have significant protective effects for all-cause mortality, cardiovascular events and hospitalization. They concluded that larger multicentric randomized trials are warranted to clarify the effect of trimetazidine in heart failure [2].

Another meta-analysis published in 2012 had data from 884 patients in 16 randomized controlled trials. They checked the role of additional trimetazidine in patients with chronic heart failure. Hospitalization for cardiac causes, but not all-cause mortality was reduced by trimetazidine treatment. Trimetazidine therapy was associated with increase in left ventricular ejection fraction, total exercise time and a decrease in New York Heart Association (NYHA) functional class [3].

In heart failure there is reduced capacity for fatty acid and carbohydrate oxidation. There is impaired function of the electron transport chain, reduced capacity to transfer ATP and inefficient energy utilization in heart failure. All these contribute to reduced cardiac energetic status in heart failure [4].

Perhexiline which was being used as an anti-anginal agent earlier, is now being evaluated for its role in the treatment of heart failure. A study evaluated 50 patients with systolic heart failure in a randomized double blind placebo controlled trial. Perhexiline therapy was associated with 30% increase in the phosphocreatine/adenosine triphosphate ratio. This was measured using Phosphorus 31 cardiac magnetic resonance spectroscopy. There was also an improvement in the NYHA functional class in this short term study of 1 month [5].

An open label study on ranolazine had 41 patients with systolic heart failure and 13 with diastolic heart failure in the study group. Control group had 43 with systolic heart failure and 13 with diastolic heart failure. In the study group, ranolazine was added to guideline driven therapy. Left ventricular ejection fraction increased in 70% of the study group over a mean follow up period of 23.7 months [6].

In addition to these three well known drugs, others have also been evaluated as metabolic modulators in heart failure. Yet we need data from large randomized controlled trials before we can use them on a regular basis in this context.


  1. Ashrafian H, Neubauer S. Metabolic modulation in heart failure: high time for a definitive clinical trial. Heart. 2011 Feb;97(4):267-8.
  2. Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011 Feb;97(4):278-86.
  3. Zhang L, Lu Y, Jiang H, Zhang L, Sun A, Zou Y, Ge J. Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis. J Am Coll Cardiol. 2012 Mar 6;59(10):913-22.
  4. Noordali H, Loudon BL, Frenneaux MP, Madhani M. Cardiac metabolism – A promising therapeutic target for heart failure. Pharmacol Ther. 2018 Feb;182:95-114.
  5. Beadle RM, Williams LK, Kuehl M, Bowater S, Abozguia K, Leyva F, Yousef Z, Wagenmakers AJ, Thies F, Horowitz J, Frenneaux MP. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail. 2015 Mar;3(3):202-11.