|Year : 2016 | Volume
| Issue : 3 | Page : 157-162
Metabolic management of heart disease
Akshyaya K Pradhan
Department of Cardiology, King George Medical University, Lucknow, Uttar Pradesh, India
|Date of Web Publication||2-Mar-2017|
Akshyaya K Pradhan
Department of Cardiology, King George Medical University, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
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, and the 6-month mortality postdischarge from the hospital is about 26% in patients with heart failure (HF). 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., 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  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?|| |
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.,
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).
| What Metabolism Takes Place in the Heart during Normal and Ischemic Conditions?|| |
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. 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).,,,
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].
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?|| |
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. The clinical data in HF have shown that continuing trimetazidine over 5 years improves survival  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?|| |
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.,
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?|| |
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).
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|| |
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. 
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]