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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 2  |  Issue : 3  |  Page : 157-162

Metabolic management of heart disease


Department of Cardiology, King George Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication2-Mar-2017

Correspondence Address:
Akshyaya K Pradhan
Department of Cardiology, King George Medical University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_92_15

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  Abstract 

Alterations of cardiac metabolism occur with ischemia and heart failure (HF). This results in increased utilization of noncarbohydrate substrates for energy production and depletion of myocardial adenosine triphosphate, phosphocreatine, and creatine kinase with decreased efficiency of mechanical work. A direct approach to manipulate cardiac energy metabolism consists in modifying substrate utilization by the failing heart. The results of research suggest that shifting the energy substrate preference away from fatty acid metabolism and toward glucose metabolism could be an effective adjunctive treatment in patients with HF, in terms of left ventricular function and glucose metabolism improvement. In this paper, some of these concepts will be discussed, and the role of drugs such as trimetazidine will be discussed.

Keywords: Cardiac energy metabolism, metabolic agents in heart failure, metabolic changes in heart failure


How to cite this article:
Pradhan AK. Metabolic management of heart disease. J Pract Cardiovasc Sci 2016;2:157-62

How to cite this URL:
Pradhan AK. Metabolic management of heart disease. J Pract Cardiovasc Sci [serial online] 2016 [cited 2020 Oct 26];2:157-62. Available from: https://www.j-pcs.org/text.asp?2016/2/3/157/201388


  Introduction Top


The prevalence of coronary artery disease (CAD) is estimated to be 2.5%–12.6% of the urban Indian population, compared to 1.4%–4.6% in rural India,[1] and the 6-month mortality postdischarge from the hospital is about 26% in patients with heart failure (HF).[2] The recurrence of angina postcoronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) is 24%–43%, which explains the limitation of targeting obstructive coronary pathology.[3],[4] Recurrent angina significantly affects the patient's quality of life and number of working days lost. Hemodynamic drugs are often not sufficient in the management of HF or ischemia and metabolic modulations that correct the energy imbalance introduced in both these conditions, is sometimes useful. There is, therefore, a role for metabolic modulators such as trimetazidine and ranolazine.

The heart has a high energy demand but little energy reserves [5] and therefore continually produces a large amount of adenosine triphosphate (ATP). It uses free fatty acids (FFAs) mainly and carbohydrates to some extent as energy sources. Alterations in cardiac metabolism are a major contributor to a number of heart diseases, and optimizing energy metabolism in the heart is an important approach to treatment.


  Why Should Metabolic Management Be Considered in the Management of Coronary Artery Disease and Heart Failure? Top


Even after the patients undergo successful revascularization (CABG or PCI), over the years, coronary arteries develop restenosis or obstruction of the coronary grafts. This is where the hemodynamic approach manifests its limitation, in preventing the recurrence of ischemia and angina attacks.[3],[4]

When we talk about the management of heart disease, we need to remember the heart is a pump which continuously needs energy derived only through metabolism. Studies have shown that metabolic dysfunction starts early in the development of ischemic heart disease and HF. Hence, targeting the early shift in metabolism with metabolic agents makes the heart work more efficiently and protects it against future crisis such as myocardial infarction (MI).[5]


  What Metabolism Takes Place in the Heart during Normal and Ischemic Conditions? Top


The heart uses fatty acids and glucose oxidation for its energy requirements [Figure 1], 70% fatty acid oxidation and 30% glucose oxidation in normal conditions.[5] However, during ischemia and HF, the FFA oxidation is not as energy efficient as compared to glucose oxidation. This is because FFA oxidation uses more oxygen and yields 5.6 ATPs/oxygen molecule consumed as compared to 6.3 ATPs generated through glucose oxidation. In ischemia, metabolic adaptation occurs which shifts substrate use from FFA to glucose (which also operates in the fetal heart which works in a relatively hypoxic condition). In spite of this, FFA oxidation continues to be the predominant substrate in the ischemic heart. This is detrimental to the heart because a higher amount of oxygen is required for generating energy than glucose metabolism, FFA oxidation also reduces glucose oxidation by directly inhibiting pyruvate dehydrogenase which causes lactate and H + accumulation in cardiac cells which are already ischemic. The rise in lactate concentration and H + leads to a reduction in the cardiac contractility. The cardiac function is also decreased as some amount of ATP is spent to correct cellular ionic homeostasis in addition to support contractile function. Accumulation of FFA metabolites due to β-oxidation causes ventricular arrhythmia and diastolic dysfunction during ischemia.
Figure 1: Metabolic modulators and their mechanism of action. PDH: Pyruvate dehydrogenase, CPT 1 and 2: Carnitine palmitoyltransferase 1 and 2, ATP: Adenosine triphosphate, ADP: Adenosine diphosphate.

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Trimetazidine is a partial fatty acid oxidation inhibitor that partially shifts the cardiac metabolism during ischemia and HF from FFA oxidation to more energy efficient glucose oxidation, increases phosphocreatine/ATP level by 33%, thus improving the left ventricular ejection fraction (LVEF) of the heart without causing any hemodynamic change (blood pressure or heart rate).[6],[7],[8],[9]

Ranolazine acts by late sodium current inhibition into cardiac cells and reduces ischemia-induced sodium and calcium overload thus improving myocardial function and does not have any effect on the cardiac energy status (may not be a metabolic drug). Thus, ranolazine can be preferred in angina patients predisposed to electrophysiological disturbances such as arrhythmias as there are small trials suggesting that it may reduce atrial arrhythmias associated with acute coronary syndromes. There is also experimental evidence that ventricular arrhythmias are reduced. There are limited studies with ranolazine in systolic HF patients [Table 1], [Table 2] and [Figure 1].
Table 1: Studies of trimetazidine in different patient profiles

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Table 2: Studies of ranolazine in different patient profiles

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Perhexiline is another metabolic agent which shifts the substrate utilization from FFA to glucose by inhibiting the enzyme carnitine palmitoyltransferase 1 and 2. Currently, perhexiline is not available in India and is used in Australia for the treatment of refractory and unstable angina.

Hence, angina patients with ischemia who already on standard medication like beta-blocker but still symptomatic initiate trimetazidine first, if symptoms persist add ranolazine. In HF patients who are symptomatic despite being on optimal treatment, only trimetazidine has been extensively investigated and shown to improve signs and symptoms among all the other metabolic agents.


  How Long Trimetazidine Should Be Given in Coronary Artery Disease With Heart Failure and What Are Its Potential Benefits? Top


Trimetazidine in patients with CAD and HF has demonstrated to significantly reduce angina symptoms and to improve New York Heart Association (NYHA) functional class, exercise duration, and LVEF. In stable ischemic heart disease, trimetazidine has been demonstrated to reduce mortality after MI.[13] The clinical data in HF have shown that continuing trimetazidine over 5 years improves survival [20] by 11.3%; hence, it is logical to use trimetazidine as long as possible (depending on the patient profile).


  Can Trimetazidine Be Used in Ischemic and Nonischemic Heart Failure Patients and in Which New york Heart Association Class? Top


Studies of trimetazidine have included patients of ischemic and nonischemic HF etiology and from NYHA Class I to Class IV. The benefits that have been discussed above are observed in all functional class patients.[17],[18]

Majority of the times, patients remain asymptomatic, especially diabetics with silent myocardial ischemia. Studies with trimetazidine in these patients demonstrate the beneficial effects in improving exercise duration, NYHA class, and LVEF and in reducing hospitalization.


  Is There Any Ongoing Long-Term Study With Trimetazidine? Top


Presently, trimetazidine is being evaluated in one of the largest trials for secondary prevention of cardiac events, the efficAcy and safety of Trimetazidine in Patients with angina pectoris having been treated by PCI (ATPPCI).[9]

ATPPCI trial is an international multicenter, double-blind, randomized placebo-controlled study that is ongoing in 27 countries and planned to involve nearly 5800 patients having been treated previously by PCI.

The main objective of the trial is to demonstrate the efficacy of trimetazidine in preventing the recurrence or exacerbation of angina pectoris and reducing cardiac events such as cardiac death and hospitalization for a cardiac event over 4-year follow-up.


  Conclusion Top


Ischemic heart disease and HF patients require multifactorial approach to improve their symptoms and quality of life. Metabolic agents such as trimetazidine and/or ranolazine offer an attractive option to improve symptoms and quality of life. Addition of such metabolic drugs needs to be initiated early to provide optimal benefits including quality and quantity of life of patients. [29]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Rao M, Xavier D, Devi P, Sigamani A, Faruqui A, Gupta R, et al. Prevalence, treatments and outcomes of coronary artery disease in Indians: A systematic review. Indian Heart J 2015;67:302-10.  Back to cited text no. 1
    
2.
Seth S, Khanal S, Ramakrishnan S, Gupta N, Bahl VK. Epidemiology of acute decompensated heart failure in India. The AFAR study (Acute Failure Registry Study). J Pract Cardiovasc Sci 2015;1:35-8.  Back to cited text no. 2
  Medknow Journal  
3.
Cameron AA, Davis KB, Rogers WJ. Recurrence of angina after coronary artery bypass surgery: Predictors and prognosis (CASS registry). Coronary artery surgery study. J Am Coll Cardiol 1995;26:895-9.  Back to cited text no. 3
    
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Weintraub WS, Spertus JA, Kolm P, Maron DJ, Zhang Z, Jurkovitz C, et al. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med 2008;359:677-87.  Back to cited text no. 4
    
5.
Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005;85:1093-129.  Back to cited text no. 5
    
6.
Fragasso G, Perseghin G, De Cobelli F, Esposito A, Palloshi A, Lattuada G, et al. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J 2006;27:942-8.  Back to cited text no. 6
    
7.
Harpey C, Clauser P, Labrid C. Trimetazidine, a cellular anti-ischemic agent. Cardiovasc Drug Rev 1989;6:292-312.  Back to cited text no. 7
    
8.
Marzilli M. Cardioprotective effects of trimetazidine: A review. Curr Med Res Opin 2003;19:661-72.  Back to cited text no. 8
    
9.
Martins GF, Siqueira Filho AG, Santos JB, Assunção CR, Vieira FB, Valência A, et al. Trimetazidine and inflammatory response in coronary artery bypass grafting. Arq Bras Cardiol 2012;99:688-96.  Back to cited text no. 9
    
10.
Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Trimetazidine: A new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group. Br J Clin Pharmacol 1994;37:279-88.  Back to cited text no. 10
    
11.
Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, et al. Combination treatment in stable effort angina using trimetazidine and metoprolol. Eur Heart J 2001;22:2267-74.  Back to cited text no. 11
    
12.
Sellier P, Broustet JP. Assessment of anti-ischemic and antianginal effect at trough plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris: A multicenter, double-blind, placebo-controlled study. Am J Cardiovasc Drugs 2003;3:361-9.  Back to cited text no. 12
    
13.
Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD003614. DOI: 10.1002/14651858.CD003614.pub2.  Back to cited text no. 13
    
14.
Iyengar SS, Rosano GM. Effect of antianginal drugs in stable angina on predicted mortality risk after surviving a myocardial infarction: A preliminary study (METRO). Am J Cardiovasc Drugs 2009;9:293-7.  Back to cited text no. 14
    
15.
Nesukay EG. Treatment of stable angina in Ukraine: Classica study. Ukr J Cardiol 2014;2:43-7.  Back to cited text no. 15
    
16.
El-Kady T, El-Sabban K, Gabaly M, Sabry A, Abdel-Hady S. Effects of trimetazidine on myocardial perfusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyopathy: A 24-month study. Am J Cardiovasc Drugs 2005;5:271-8.  Back to cited text no. 16
    
17.
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;48:992-8.  Back to cited text no. 17
    
18.
Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: A meta-analysis of randomised controlled trials in heart failure. Heart 2011;97:278-86.  Back to cited text no. 18
    
19.
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 meta-analysis. J Am Coll Cardiol 2012;59:913-22.  Back to cited text no. 19
    
20.
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;163:320-5.  Back to cited text no. 20
    
21.
Chen J, Zhou S, Jin J, Tian F, Han Y, Wang J, et al. Chronic treatment with trimetazidine after discharge reduces the incidence of restenosis in patients who received coronary stent implantation: A 1-year prospective follow-up study. Int J Cardiol 2014;174:634-9.  Back to cited text no. 21
    
22.
Xu X, Zhang W, Zhou Y, Zhao Y, Liu Y, Shi D, et al. Effect of trimetazidine on recurrent angina pectoris and left ventricular structure in elderly multivessel coronary heart disease patients with diabetes mellitus after drug-eluting stent implantation: A single-centre, prospective, randomized, double-blind study at 2-year follow-up. Clin Drug Investig 2014;34:251-8.  Back to cited text no. 22
    
23.
Zhang Y, Ma XJ, Shi DZ. Effect of trimetazidine in patients undergoing percutaneous coronary intervention: A meta-analysis. PLoS One 2015;10:e0137775.  Back to cited text no. 23
    
24.
Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial. JAMA 2004;291:309-16.  Back to cited text no. 24
    
25.
Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375-82.  Back to cited text no. 25
    
26.
Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L; ERICA Investigators. Antianginal efficacy of ranolazine when added to treatment with amlodipine: The ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 2006;48:566-75.  Back to cited text no. 26
    
27.
Maier LS, Layug B, Karwatowska-Prokopczuk E, Belardinelli L, Lee S, Sander J, et al. Ranolazine for the treatment of diastolic heart failure in patients with preserved ejection fraction: The RALI-DHF proof-of-concept study. JACC Heart Fail 2013;1:115-22.  Back to cited text no. 27
    
28.
Weisz G, Généreux P, Iñiguez A, Zurakowski A, Shechter M, Alexander KP, et al. Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER-PCI): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2016;387:136-45.  Back to cited text no. 28
    
29.
Alexander KP, Weisz G, Prather K, James S, Mark DB, Anstrom KJ, et al. Effects of ranolazine on angina and quality of life after percutaneous coronary intervention with incomplete revascularization: Results from the ranolazine for incomplete vessel revascularization (RIVER-PCI) trial. Circulation 2016;133:39-47.  Back to cited text no. 29
    


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   Abstract
  Introduction
   Why Should Metab...
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   How Long Trimeta...
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