Expert Review: Lipid / Metabolic, Pharmacotherapy

Trimetazidine and Other Metabolic Modifiers

Although cardiovascular mortality has declined progressively in developed countries, ischaemic heart disease (IHD) and chronic stable angina cause a worse prognosis and poor quality of life and can dramatically increase healthcare costs.1–4 Traditionally, chronic stable angina has been interpreted as reversible episodes of myocardial ischaemia due to the presence of coronary artery disease. Coronary artery disease hampers coronary blood flow augmentation in response to an increase in myocardial oxygen consumption, thus causing myocardial ischaemia. Based on this assumption, myocardial ischaemia is the direct consequence of an imbalance between the demand and supply of oxygen and metabolites. Current guidelines recommend pharmacological agents that can modulate cardiac work, such as beta-blockers and calcium channel blockers (or modulate coronary blood flow (nitroglycerin), alone or in combination, in addition to percutaneous coronary intervention.1 These strategies were expected to prevent episodes of myocardial ischaemia, improving symptoms and prolonging survival but available data indicates that this approach is not effective and about one-third of patients experience angina despite successful coronary revascularisation, or medical therapy and percutaneous coronary interventions.5–7 The failure of these interventions to improve the prognosis of patients with IHD shows an oversimplified approach to mycoardial ischaemia and its multifactorial aetiology.

Recent research has shown that myocardial ischaemia may be precipitated by several different mechanisms, including coronary stenosis, coronary vasospasm, microvascular dysfunction and mitochondrial dysfunction.8,9 Therefore, a combined approach to IHD that targets multiple mechanisms may be a more successful treatment strategy.1,10 Targeting cardiac myocytes, protecting them from ischaemic damage and modulating myocardial metabolism could improve cardiac efficiency and long-term outcomes.11–13 Indeed, studies have shown that metabolic modulation therapy plays a critical role in the acute phase of ischaemic events, affecting the results of acute interventions and the subsequent development of heart failure (HF), stunned and hybernated myocardium, as well as chronic stable angina.14

Heart Metabolism in Health and During Ischaemia

The healthy heart derives most of its energy from the free fatty acid pathway that accounts for about two thirds of energy production in the form of adenosine triphosphate (ATP), and the rest is derived from glucose oxidation and lactate. The healthy heart is able to modulate the use of substrates according to availability, general nutritional status and exercise levels. During mild to moderate cardiac ischaemia, myocardial cells respond by accelerating glucose uptake to generate enough ATP to maintain ionic gradients and calcium homeostasis. Paradoxically, during prolonged and severe ischaemia, the myocardium continues to derive most of its energy from beta-oxidation despite a high rate of lactate production. In this condition, high rates of fatty acid oxidation further inhibit glucose oxidation due to competitive interaction, known as the Randle mechanism.15 Although the complete oxidation of fatty acid produces more ATP than complete oxidation of glucose, a greater amount of oxygen is required. Therefore, for a given amount of oxygen consumed, glucose metabolism is ‘oxygen sparing’ compared with fatty acid metabolism, producing about 15 % more ATP. Therefore, when there is a low availability of oxygen, fatty acid oxidation has an unfavourable effect on cells requiring more oxygen, producing less ATP and more reactive oxygen species (ROS), further depressing mitochondrial respiratory efficiency. These metabolic changes are responsible for metabolic, morphological and functional alteration of the myocardium leading to arrhythmias and contractive failure.16–18 Figure 1 depicts energy generation in the healthy heart, while Figure 2 shows metabolic derangements occurring during ischaemia.

Cardiac Metabolism in Normal Conditions

Metabolic Alterations During Sustained Period of Ischaemia

Coupling glycolysis to glucose oxidation is of pivotal importance due to the link between these enzymes and the activity of two survival-promoting membrane-bound pumps, namely the sodium-potassium ATPase, and the calcium uptake pump of the sarcoendoplasmic reticulum (SERCA).19 This interplay explains the efficacy of anti-ischaemic fatty acid inhibitors such as trimetazidine and ranolazine. In line with this, the greatest progress for patients with stable angina came with the use of metabolic therapy, particularly with the advent of direct inhibitors of myocardial fatty acid oxidation, trimetazidine and ranolazine.17

Cardiac Metabolic Modulators

Significant progress has been made since it was acknowledged in 1999 that it was necessary to treat ischaemia, a metabolic disorder, with metabolic therapy.20

Given the interdependence between fatty acid and glucose oxidation, metabolic modulation therapy with optimisation of the use of energy substrate can be achieved by either inhibiting fatty acid oxidation or stimulating glucose oxidation. This can be achieved through three major strategies:

  • directly enhancing glucose oxidation;
  • decreasing the circulating levels of fatty acids and/or their uptake by cardiac myocytes or mitochondrion; and
  • directly inhibiting the enzymes that participate in fatty acid oxidation.

Figure 3 shows the specific mechanism of cardio-metabolic drugs.

Strategies to Enhance Glucose Oxidation

Dicholoroacetate

The rate-limiting step for glucose oxidation is catalysed by the pyruvate dehydrogenase (PDH) complex, which consists of PDH, PDH kinase (PDK), and PDH phosphatase (PDHP) enzymes.21 PDH flux is increased in response to increases in glycolysis and an increased generation of pyruvate, while PDH flux is decreased by increased ratios of mitochondrial nicotinamide adenine dinucleotide (NADH/NAD+) and acetyl-coenzyme A (acetyl CoA/CoA).22 PDHP dephosphorylates activate PDH, whereas PDK phosphorylates inhibit it.21 Dichloroacetate improves glycolysis and glucose oxidation coupling and decreases proton production by inhibiting PDK activity and stimulating mitochondrial PDH.23

There are no data available on the use of this approach on patients with heart disease. Despite the promising experimental evidence when used in other pathological conditions, dichloroacetate treatment has been associated with neurotoxicity which has prevented its use in clinical applications.24

Strategies to Reduce Cellular/Mitochondrial Fatty Acid Uptake

Carnitine Palmitoyl Transferase Inhibitors: Perhexiline

A strategy to inhibit mitochondrial uptake of fatty acids is to suppress the rate-limiting enzyme for the mitochondrial uptake of fatty acids, such as carnitine palmitoyl transferase (CPT) 1 or 2. Perhexiline is a reversible CPT-1 and, to a lesser extent, a CPT-2 inhibitor, and has been shown to relieve angina (Figure 3); it attenuates the increase in diastolic tension associated with myocardial ischaemia, thereby improving myocardial efficiency.25,26 Inhibition of CPT-1/CPT-2 by perhexiline improves the efficiency of myocardial oxygen use by at least 13 %. However, after perhexiline administration, cardiac efficiency increases by about 30 %, suggesting additional mechanisms at work.27 However, perhexiline has been associated with infrequent but serious hepatotoxicity and neuropathy that necessitates regular monitoring of plasma levels and makes perhexiline unsuitable for use in patients with hepatic or renal dysfunction.28

The Mechanism of Action of Drugs Able to Modulate Cardiac Metabolism

Malonyl CoA Decarboxylase Inhibitors

Malonyl CoA is another potent, endogenous inhibitor of CPT-1 which decreases the uptake of fatty acids into the mitochondria, thereby reducing mitochondrial fatty acid beta-oxidation. Malonyl CoA decarboxylase (MCD) degrades malonyl CoA and this leads to an increase in fatty acid oxidation. Inhibition of MCD significantly increases malonyl CoA levels, therefore causing a significant decrease in fatty acid oxidation rates and a subsequent increase in glucose oxidation rates (Figure 3). Inhibition of MCD in animal models has led to a significant improvement in cardiac functional recovery of aerobically reperfused ischaemic hearts.29 Inhibition of MCD in the heart appears to be a safe and promising therapeutic target for IHD but it is not yet ready for clinical testing.

Strategies to Reduce Fatty Acid Oxidation

The concept of metabolic protection of the ischaemic myocardium is gaining more attention and is supported by clinical studies that have confirmed the beneficial effect of fatty acid oxidation inhibitors such as trimetazidine (TMZ) and ranolazine (RNZ), able to couple glycolysis to glucose oxidation.17

Trimetazidine

Trimetazidine (TMZ) has been the first and, for many years, the only registered drug in this class of anti-anginal agents. The beneficial effect of TMZ as an anti-anginal drug was established before it was discovered that the drug acts via partial inhibition of myocardial fatty acid oxidation.17,30,31 Initial preclinical studies demonstrated that it was cytoprotective in several models of myocardial ischaemia and reperfusion.32 Kantor et al. have shown that TMZ specifically inhibits the long-chain activity of the enzyme acetyl CoA C-acyltransferase; an enzyme that is commonly referred to as 3-KAT. The 3-KAT enzyme catalyses the terminal reaction of fatty acid beta-oxidation, using long-chain 3-ketoacyl CoA as a substrate, to generate acetyl CoA.33 These results suggest that TMZ removes the inhibition on PDH by inhibiting 3-KAT in the mitochondrial matrix, and increases the rate of glucose oxidation (Figure 3). TMZ has been shown to significantly increase the rate of glucose oxidation in rats’ hearts despite only modestly reducing the rate of fatty acid oxidation.33,34 In one study, a single dose of TMZ was shown to increase plasma levels of adenosine, suggesting a preconditioning role for this drug.35–37 Several studies have shown that TMZ alone or in addition to calcium channel blockers can effectively improve symptoms, quality of life and markers of ischaemia on stress tests in patients with chronic stable angina and ischaemic cardiomyopathy when used on top of conventional treatment.38–44 Moreover, clinical trials have proved the efficacy of this metabolic agent in refractory angina, and have supported the superior benefit associated to the addition of this metabolic agent to classic haemodynamic agents, such as beta-blockers or nitroglycerin.45–47

In the TRIMetazidine in POLand (TRIMPOL) II trial, a randomised, double-blind, placebo-controlled, multicentre study that recruited patients with stable angina, the addition of TMZ (20 mg three times a day) or placebo on top of metoprolol, resulted in an improvement in time to ST segment depression on exercise tolerance testing, total exercise workload, mean nitrate consumption and angina frequency when compared with patients receiving placebo.45 Similar efficacy was observed in the subgroup of patients revascularised with recurrent angina. The time to 1 mm ST-segment depression (STD) was increased with TMZ by 80 seconds and was significantly greater than that recorded in the placebo group (p<0.01). The time to onset of angina was significantly greater for the group treated with TMZ in comparison with placebo (p=0.031). The total duration of exercise was significantly greater than that recorded for patients with placebo plus metoprolol (p=0.048). A similarly significant observation was made regarding workload (p=0.035). The maximum ST-segment depression at peak exercise was significantly smaller in the TMZ group than the placebo group (p<0.01). The mean number of angina attacks per week was also reduced in patients receiving TMZ compared with those treated with placebo (p<0.01).45

The efficacy and acceptability of TMZ in combination with haemodynamic agents (beta-blockers or long-acting nitrates) was tested in the Trimetazidine in Angina Combination Therapy (TACT) study.48 After 12 weeks of therapy, exercise test duration significantly increased in the TMZ group, as well as time to 1 mm STD and time to onset of anginal pain. The mean number of angina attacks per week decreased in the TMZ group, along with mean consumption of short-acting nitrates per week. The addition of TMZ on beta-blockers or long-acting nitrates therapy, significantly improved exercise stress test parameters and angina symptoms compared with placebo. In another randomised, double-blind, controlled trial in people with angina who were symptomatic despite taking propranolol, Michaelides et al. demonstrated that the addition of TMZ significantly decreased the mean number of angina attacks twice as much as isosorbide dinitrate alone.49 Similar results were also observed in the Efficacy of Trimetazidine on Functional Capacity in Symptomatic Patients with Stable Exertional Angina (VASCO-angina) study. This was a randomised, double-blind, placebo-controlled trial, which assessed the anti-anginal efficacy and safety of standard and high-dose modified-release TMZ (70 mg per day and 140 mg per day) in symptomatic and asymptomatic patients with chronic IHD receiving 50 mg per day of atenolol, on exercise test parameters.50 The VASCO-angina study confirmed the efficacy and tolerability of standard and high-dose TMZ in improving effort-induced myocardial ischaemia and functional capacity in patients with chronic stable angina receiving background beta-blockers.50 Furthermore, other studies and meta-analysis have supported the use of TMZ to improve clinical manifestation (i.e. total exercise duration, time to 1-mm ST-segment depression, weekly number of angina attacks, weekly nitroglycerin use, quality of life improvement) in patients with stable IHD.51

TMZ has also been proven to be effective in patients with microvascular angina.52 In a recent study, TMZ was given for 3 months (35 mg twice a day) to patients with microvascular angina and it was associated with better control of angina symptoms and stress testing results compared with conventional therapy (beta-blockers/calcium channel blockers, statins, antiplatelets, long-acting nitrates). Moreover, there was an improvement in myocardial perfusion and endothelial function probably due to a reduction in serum endothelin-1 (ET-1) levels and an increase in total antioxidant status.53 There was a collective decrease of average number of attacks per week and silent myocardial ischaemia, a reduction of mean weekly consumption of short-acting nitrates, an improvement in quality of life, reduced severity of main clinical manifestations of chronic heart failure (CHF) and lowering of its functional class.50,54–58 Moreover, similar efficacy of TMZ has been demonstrated in both men and women and it is also suitable for people with diabetes.59–62 A single dose of 60 mg TMZ (the normal cumulative daily dose) has shown to improve exercise capacity in people with angina pectoris, as reflected by an increase in the duration of exercise, total work performed, and an improvement in ECG signs of ischaemia. All these effects occur without any detectable chronotropic or vasomotor effect.63 One ongoing large, international, randomised study – the efficAcy and safety of Trimetazidine in Patients with angina pectoris having been treated by percutaneous Coronary Intervention (ATPCI) trial – could provide definitive evidence into the clinical benefits of metabolic cardioprotection for patients who have been revascularised, whether for chronic stable angina or acute coronary syndrome.

Short and long-term administration of TMZ has proven to be beneficial in improving clinical parameters and survival in patients with CHF of different aetiology and even in older people.64–70 Indeed, TMZ can improve left ventricular function, exercise capacity and New York Heart Association functional classification, and endothelium-dependent dilation in patients with CHF.50 In addition to these results, in a meta-analysis conducted by Gao et al. TMZ had a significant protective effect for all-cause mortality, cardiovascular events and hospitalisation.71 Further confirming the role metabolic disturbances plays in myocardial ischaemia, TMZ use was associated with improved myocardial perfusion and contractile response in patients with chronically dysfunctional myocardium and ischaemic cardiomyopathy.72

In addition, it has been reported that TMZ has some anti-inflammatory properties because it can attenuate neutrophil activation, thereby protecting post-ischaemic hearts from neutrophil-mediated injury, suggesting a role for this drug in pre- and post-conditioning. TMZ has shown to be cardioprotective when administered before reperfusion. This protection appears to be mediated by activation of p38-mitogen-activated protein kinase and Akt signalling.73

In summary, in patients with IHD, the addition of TMZ has been shown to decrease the amount of angina attacks per week, as well as silent myocardial ischemia episodes; it has reduced the needs for short-acting nitrates and has been shown to improve quality of life. All these results have been accompanied by enhanced exercise tolerance. TMZ has been demonstrated to be effective both in men and women, and in patients with or without diabetes. In patients with CHF, TMZ ameliorates negative left ventricular remodelling, enhances functional capacity, reduces mortality and improves event-free survival. For these reasons as well as its anti-anginal efficacy, TMZ can be used in patients with heart failure and reduced ejection fraction and refractory angina, in addition or as an alternative to conventional medication and is safe for patients with heart failure class IIb, level A.74 Moreover, TMZ has been shown to confer cardioprotection in animal models of ischaemia-reperfusion injury, particularly relevant in patients with stable angina who experience multiple episodes of ischaemia. Generally, TMZ is well-tolerated with minor side effects, mostly comprising gastrointestinal disturbances and headache. However, some patients experience extrapyramidal complications making this drug unsuitable for patients with Parkinson’s disease and similar disorders.75 Precautions should be taken when prescribing to the elderly and those with moderate renal impairment who will need a reduced dose. Although its clinical benefits have been documented since the early 1980s, TMZ still lacks widespread clinical use. It has been classified in European guidelines as a second choice agent for the treatment of chronic ischaemic heart disease, receiving a non-justified class IIb level of recommendation, especially when compared with traditional agents which have been less extensively studied and more largely used.76,77

Ranolazine

Ranolazine (RNZ) is structurally related to piperazine and is similar to TMZ. It has proved to be effective in patients with chronic stable angina on top of or in combination with traditional antianginal drugs.78 RNZ was shown to display anti-ischaemic properties by promoting glucose oxidation at the expense of fatty acid oxidation (Figure 3).79–81 In addition to this, RNZ induces a reduction in intracellular calcium overload through inhibition of the late sodium channels, with consequent attenuation of oxidative stress (Figure 4).82,83

Randomised clinical trials have demonstrated an improvement in exercise capacity and reduction in angina episodes with ranolazine in patients with chronic stable angina. In patients undergoing elective coronary angioplasty, ranolazine demonstrated a reduction in peri-procedural MI.84 Moreover, in women with evidence of MI, angina and no obstructive coronary stenosis, ranolazine improved quality of life, angina stability and myocardial perfusion reserve index.85 This therapeutic benefit occurs without the haemodynamic effects seen with conventional anti-anginal agents.86 Despite QTc-prolonging action, clinical data have not shown a predisposition to torsades de pointes, and the medication has shown a reasonable safety profile even in those with structural heart disease. RNZ may play a role in the treatment of patients with CHF as its mode of action involves the inhibition of late sodium current and it is able to modulate myocardial metabolism. In an animal model of CHF, RNZ significantly increased left ventricular ejection fraction, peak LV+dP/dt and stroke volume, primarily by optimising cardiac metabolism in the setting of CHF.17 At the cellular level, RNZ influenced hypertrophy, fibrosis and capillary density, as well as the expression for pathological hypertrophy and Ca2+ cycling genes.87

In 2006, RNZ was approved for the relief of angina in patients who remained symptomatic despite taking beta-blockers, calcium channel blockers, or nitrates.88,89 RNZ, even at dosages lower than that currently prescribed, has been shown to confer significant clinical benefit in controlling angina as a monotherapy or an add-on therapy.79–81,90 Short-term use of RNZ therapy has been showed to improve myocardial perfusion and decrease the ischaemic burden, evaluated by single photon emission CT (SPECT).91 The anti-anginal activity of RNZ was tested as a monotherapy in the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial. Compared with placebo, RNZ taken twice daily significantly increased exercise duration, time to onset of angina and time to diagnostic ST-segment depression in 175 patients who were not receiving other anti-anginal medications.81 RNZ was evaluated as combination therapy in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial. It was assessed in patients with anginal symptoms and reduced exercise capacity despite taking standard doses of atenolol, amlodipine or diltiazem. Exercise duration, time to angina and time to ischaemic ECG changes increased in both RNZ groups versus placebo group (p< 0.01).79 In a post hoc analysis, RNZ 750 and 1,000 mg reduced HbA1c versus placebo; the HbA1c levels appeared to remain unchanged over time during long-term therapy.92,93

Main Mechanism of Action of Ranolazine

In the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial, RNZ reduced the weekly frequency of angina and sublingual nitroglycerin use in subjects with type 2 diabetes, coronary artery disease and chronic stable angina who remained symptomatic despite treatment with up to two anti-anginal agents.94 The therapeutic benefits of RNZ were shown to be greater in those with higher HbA1c values.95

RNZ has proven to be effective not only in patients with coronary artery disease, but also in those with microvascular dysfunction.96 Compared with placebo, patients on RNZ had significantly better Seattle angina questionnaire scores, including physical functioning, angina stability and quality of life. There was a trend towards better mid-ventricular perfusion when using RNZ. Among women with coronary reactivity testing, those with coronary flow reserve (CFR) ≤3.0 had a significantly improved perfusion on RNZ versus placebo compared with women with CFR >3.0.95 This phase 2 study provided the basis to conduct a definitive large clinical trial to evaluate the role of RNZ in microvascular coronary dysfunction.85

Despite original observations, RNZ has been shown to improve non-invasive CFR in women with MI and no obstructive coronary atherosclerosis.97

When evaluated for chronic stable angina, as in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes (MERLIN-TIMI 36) trial, the addition of RNZ to standard treatment was not effective in reducing major cardiovascular events.98 However, RNZ proved to be more effective in reducing recurrent ischaemia in this high-risk population, having particular efficacy in reducing recurrence of ischaemic events in women without increasing the risk of fatal arrhythmias, despite QT prolongation.99–101 In a post hoc analysis, in patients with BNP >80pg/ml, RNZ reduced the primary end point (a composite of cardiovascular death, myocardial infarction and recurrent ischemia).102 As with the CARISA trial, RNZ treatment improved glycaemic control, reducing fasting plasma glucose and HbA1c levels.93 Despite such promising results, in the subset of patients with stable angina that had been incompletely revascularised the Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention [RIVER-PCI] study), RNZ at the doses of 1,000 mg twice a day failed to ameliorate angina and quality of life and to reduce the composite rate of ischaemia-driven revascularisation or hospitalisation without revascularisation.103,104 In a second analysis of the RIVER-PCI trial, specifically evaluating the role of RNZ on angina frequency and quality of life in relation to diabetes, RNZ ameliorated glycaemic control (HbA1c) at 6 and 12 months compared with placebo. In line with this result, in people with diabetes, angina frequency and quality of life was better at 6 months, but remained unchanged at 1-year follow-up. Better results were observed in patients with poor glycaemic control at enrolment (HbA1c≥58 mmol/mol).105

Larger trials are warranted to find out whether RNZ is capable of improving morbidity and mortality. In summary, RNZ appears to be an effective anti-anginal drug with great potential to fill an unmet need in the management of patients with IHD. The availability of an effective, well-tolerated, and apparently safe, anti-anginal medication such as RNZ is particularly important for patients with angina who are not candidates for revascularisation and for patients with persistent angina. This population appear to have an increased risk of developing cardiac arrhythmias and may benefit from the adjunct of RNZ on top of other medication.83,106–108 In addition to these data, new evidence suggest a possible benefit of using RNZ for CHF due to its ability to modulate myocardial metabolism and its action on late sodium current, which may suggest that this drug may offer additional benefits in patients with ischaemic and non-ischaemic cardiomyopathy due to different aetiology.87,109–115 RNZ has a good safety profile with mild gastrointestinal side-effects (constipation and nausea) and dizziness. Caution should be applied when RNZ is used in patients who already take medication to prolong QT and have liver cirrhosis. However, RNZ-induced QT prolongation has not been associated with torsades de pointes. RNZ may be used as an alternative when beta-blockers are not tolerated in patients with heart failure with reduced ejection fraction and ischaemic heart disease. RNZ can also inhibit late Na(+) current, suggesting a clinical role for this drug in patients with long QT syndrome type 3.116–118

RNZ has been a major success and has gained a class IIa level B recommendation for angina relief in both European and American guidelines on management of stable IHD.1,10

Conclusions

Metabolic agents can be recommended in conjunction with or as an alternative when classic anti-anginal agents are not tolerated or they are contraindicated. Their efficacy has been proven in clinical trials in patients with refractory angina, chronic IHD and in patients exposed to ischaemia-reperfusion injury. Moreover, in patients with heart failure, metabolic agents slow the progression of the disease and improve prognosis. The failing and the ischaemic heart are energy-starved organs dependent on inefficient fatty acid oxidation. Metabolic agents induce a switch in substrate use, rendering the heart more oxygen efficient. Through this and other mechanisms, modulation of cellular energetics has the potential to improve cardiac performance and reduce symptoms in patients with chronic stable angina without relying on alteration of haemodynamics or further neuro-hormonal modulation. As such, agents acting with this approach are likely to complement or substitute, rather than mimic, established therapy and hold a possibility for clinical benefit in a wide range of cardiovascular disorders.

Cardiac metabolic modulators open the way to a better understanding of ischaemic heart disease and its common clinical manifestations, where myocardial ischaemia is no longer considered as a mere imbalance in oxygen and metabolites demand/supply but as an energetic disorder. A better understanding of the mechanisms underlying IHD and chronic stable angina helps in the selection of the most appropriate agents, to properly design clinical trials, to improve symptoms and to improve patient prognosis.

References

  1. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J 2013;34:2949–3003.
    Crossref PubMed
  2. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2014;131:e29–322.
    Crossref PubMed
  3. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics – 2013 update: a report from the American Heart Association. Circulation 2013;127:e6–245.
    Crossref PubMed
  4. Henderson RA, Pocock SJ, Clayton TC, et al. Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy. J Am Coll Cardiol 2003;42:1161–70.
    Crossref PubMed
  5. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16.
    Crossref PubMed
  6. Five-year clinical and functional outcome comparing bypass surgery and angioplasty in patients with multivessel coronary disease. A multicenter randomized trial. JAMA 1997;277:715–21.
    Crossref PubMed
  7. Marzilli M, Huqi A, Morrone D. Persistent angina: the Araba Phoenix of cardiology. Am J Cardiovasc Drugs 2010;1:27–32.
    Crossref PubMed
  8. Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link! J Am Coll Cardiol 2012; 60:951–6.
    Crossref PubMed
  9. Pepine CJ, Douglas PS. Rethinking stable ischemic heart disease: is this the beginning of a new era? J Am Coll Cardiol 60:957–9.
    Crossref PubMed
  10. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation 2014;130:1749–67.
    Crossref PubMed
  11. Marzilli M, Affinito S. Meeting the challenge of chronic ischaemic heart disease with trimetazidine. Coron Artery Dis 2005;16:S23–7.
    Crossref PubMed
  12. Guarini G, Huqi A, Morrone D, et al. Pharmacological approaches to coronary microvascular dysfunction. Pharmacol Ther 2014;144:283–302.
    Crossref PubMed
  13. Guarini G, Huqi A, Capozza P, et al. Therapy against ischemic injury. Curr Pharm Des 19:4597–621.
    Crossref PubMed
  14. Wolff AA, Rotmensch HH, Stanley WC, et al. Metabolic approaches to the treatment of ischemic heart disease: the clinicians’ perspective. Heart Fail Rev 2002;7:187–203.
    Crossref PubMed
  15. Randle PJ. Regulation of glycolysis and pyruvate oxidation in cardiac muscle. Circ Res 1976;38:8–15.
    PubMed
  16. Wang W, Lopaschuk GD. Metabolic therapy for the treatment of ischemic heart disease: reality and expectations. Expert Rev Cardiovasc Ther 2007;5:1123–34.
    Crossref PubMed
  17. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 2005;85:1093–129.
    Crossref PubMed
  18. Jaswal JS, Keung W, Wang W, et al. Targeting fatty acid and carbohydrate oxidation – a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta 2011;1813:1333–50.
    Crossref PubMed
  19. Rupp H, Zarain-Herzberg A, Maisch B. The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure. Herz 2002;27:621–36.
    Crossref PubMed
  20. Opie LH. Proof that glucose-insulin-potassium provides metabolic protection of ischaemic myocardium? Lancet 1999;353:768–9.
    Crossref PubMed
  21. Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab 2003;284:E855–62.
    Crossref PubMed
  22. Spriet LL, Heigenhauser GJ. Regulation of pyruvate dehydrogenase (PDH) activity in human skeletal muscle during exercise. Exerc Sport Sci Rev 2002;30:91–5.
    Crossref PubMed
  23. McVeigh JJ, Lopaschuk GD. Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. Am J Physiol 1990;259:H1079–85.
    Crossref PubMed
  24. Felitsyn N, Stacpoole PW, Notterpek L. Dichloroacetate causes reversible demyelination in vitro: potential mechanism for its neuropathic effect. J Neurochem 2007;100:429–36.
    Crossref PubMed
  25. Cole PL, Beamer AD, McGowan N, et al. Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation 1990;81:1260–70.
    Crossref PubMed
  26. Klassen GA, Zborowska-Sluis DT, Wright GJ. Effects of oral perhexiline on canine myocardial flow distribution. Can J Physiol Pharmacol 1980;58:543–9.
    Crossref PubMed
  27. Unger SA, Kennedy JA, McFadden-Lewis K, et al. Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium. J Cardiovasc Pharmacol 2005;46:849–55.
    Crossref PubMed
  28. Barclay ML, Sawyers SM, Begg EJ, et al. Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status. Pharmacogenetics 2003;13:627–32.
    Crossref PubMed
  29. Dyck JR, Cheng JF, Stanley WC, et al. Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation. Circ Res 2004;94;e78–84.
    Crossref PubMed
  30. McClellan KJ, Plosker GL. Trimetazidine. A review of its use in stable angina pectoris and other coronary conditions. Drugs 1999;58:143–57.
    Crossref PubMed
  31. Bucci M, Borra R, Nagren K, et al. Trimetazidine reduces endogenous free fatty acid oxidation and improves myocardial efficiency in obese humans. Cardiovasc Ther 2012;30:333–41.
    Crossref PubMed
  32. Vaillant F, Tsibiribi P, Bricca G, et al. Trimetazidine protective effect against ischemia-induced susceptibility to ventricular fibrillation in pigs. Cardiovasc Drugs Ther 2008;22;29–36.
    Crossref PubMed
  33. Kantor PF, Lucien A, Kozak R, et al. 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 2000;86:580–8.
    Crossref PubMed
  34. Lopaschuk GD. Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated? Coron Artery Dis 2001;12:S8–11.
    PubMed
  35. Blardi P, de Lalla A, Volpi L, et al. Increase of adenosine plasma levels after oral trimetazidine: a pharmacological preconditioning? Pharmacol Res 2002;45:69–72.
    Crossref PubMed
  36. Polonski L, Dec I, Wojnar R, et al. Trimetazidine limits the effects of myocardial ischaemia during percutaneous coronary angioplasty. Curr Med Res Opin 2002;18:389–96.
    Crossref PubMed
  37. Rebrova TY, Lasukova TV, Afanas’ev SA, et al. Cardioprotective effect of trimetazidine during thrombolytic therapy in patients with acute myocardial infarction. Bull Exp Biol Med 2002;134:559–61.
    Crossref PubMed
  38. Lévy S. Value of the combination of trimetazidine (Vastarel 20 mg) with diltiazem (Tildiem 60 mg) in stable effort angina. A double-blind versus placebo multicenter study. Ann Cardiol Angeiol (Paris). 1995;44:203–12 [in French].
    PubMed
  39. Monpère C, Brochier M, Demange J, et al. Combination of trimetazidine with nifedipine in effort angina. Cardiovasc Drugs Ther 1990;4:824–5.
    Crossref PubMed
  40. Deroux A, Brochier M, Demange J, et al. Therapeutic value of a combination of trimetazidine with a calcium inhibitor in the treatment of chronic coronary insufficiency. Presse Med 1986;15:1783–7 [in French].
    PubMed
  41. Gallet M. Clinical effectiveness of trimetazidine in stable effort angina. A double-blind versus placebo controlled study. Presse Med 1986;15:1779–82 [in French].
    PubMed
  42. Manchanda SC, Krishnaswami S. Combination treatment with trimetazidine and diltiazem in stable angina pectoris. Heart 1997;78:353–7.
    Crossref PubMed
  43. Lu C, Dabrowski P, Fragasso G, et al. Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease. Am J Cardiol 1998;82:898–901.
    Crossref PubMed
  44. Bricaud H, Brottier L, Barat JL, et al. Cardioprotective effect of trimetazidine in severe ischemic cardiomyopathy. Cardiovasc Drugs Ther 1990;4:861–5.
    Crossref PubMed
  45. Szwed H, Sadowski Z, Elikowski W, et al. Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J 2001;22:2267–74.
    Crossref PubMed
  46. Passeron J. Effectiveness of trimetazidine in stable effort angina due to chronic coronary insufficiency. A double-blind versus placebo study. Presse Med 1986;15:1775–8 [in French].
    PubMed
  47. Hanania G, Haïat R, Olive T, et al. Coronary artery disease observed in general hospitals: ETTIC study. Comparison between trimetazidine and mononitrate isosorbide for patients receiving betablockers. Ann Cardiol Angeiol (Paris) 2002;51:268–74 [in French].
    Crossref PubMed
  48. Chazov EI, Lepakchin VK, Zharova EA, et al. Trimetazidine in Angina Combination Therapy – the TACT study: trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. Am J Ther 2005;12:35–42.
    Crossref PubMed
  49. Michaelides A, Spiropoulos K, Dimopoulos K, et al. Antianginal efficacy of the combination of trimetazidine-propranolol compared with isosorbide dinitrate-propranolol in patients with stable angina. Clinical Drug Investigation 1997;13:8–14.
    Crossref
  50. Vitale C, Spoletini I, Malorni W, et al. Efficacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina–the VASCO-angina study. Int J Cardiol 2013;168:1078-1081.
    Crossref PubMed
  51. Danchin N, Marzilli M, Parkhomenko A, et al. Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis. Cardiology 2011;120:59–72.
    Crossref PubMed
  52. Nalbantgil S, Altintig A, Hasan Y, et al. The effect of trimetazidine in the treatment of microvascular angina. Int J Angiol 1999;8:40–3.
    Crossref PubMed
  53. Leonova I A DS, Xakharova O, Gaykovaya L. Trimetazidine improves symptoms and reduces microvascular dysfunction in patients with microvascular angina. Eur Heart J 2017;38:ehx501.P887.
    Crossref
  54. Peng S, Zhao M, Wan J, et al. The efficacy of trimetazidine on stable angina pectoris: a meta-analysis of randomized clinical trials. Int J Cardiol 2014;177:780–5.
    Crossref PubMed
  55. Grabczewska Z, Bialoszynski T, Szymanski P, et al. The effect of trimetazidine added to maximal anti-ischemic therapy in patients with advanced coronary artery disease. Cardiol J 2008;15:344–50.
    PubMed
  56. Marzilli M. Cardioprotective effects of trimetazidine: a review. Curr Med Res Opin 2003;19:661–72.
    Crossref PubMed
  57. Danchin N, Marzilli M, Parkhomenko A, et al. Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis. Cardiology 2011;120:59–72.
    Crossref PubMed
  58. Marzilli M. Does trimetazidine prevent myocardial injury after percutaneous coronary intervention? Nat Clin Pract Cardiovasc Med 2008;5:16–7.
    Crossref PubMed
  59. Danchin N. Clinical benefits of a metabolic approach with trimetazidine in revascularized patients with angina. Am J Cardiol 2006;98:8J–13J.
    Crossref PubMed
  60. Vasiuk IuA, Shal’nova SA, Shkol’nik EL, et al. The (PRIMA) Study. Comparison of clinical effect of trimetazidine MR in men and women. Kardiologiia 2011;51:11–5 [in Russian].
    PubMed
  61. Rodríguez Padial L, Maicas Bellido C, Velázquez Martin M, Gil Polo B. A prospective study on trimetazidine effectiveness and tolerability in diabetic patients in association to the previous treatment of their coronary disease. DIETRIC study. Rev Clin Esp 2005;205:57–62 [in Spanish].
    Crossref PubMed
  62. Ribeiro LW, Ribeiro JP, Stein R, et al. Trimetazidine added to combined hemodynamic antianginal therapy in patients with type 2 diabetes: a randomized crossover trial. Am Heart J 2007;154:78 e71–7.
    Crossref PubMed
  63. Sellier P, Audouin P, Payen B, et al. Acute effects of trimetazidine evaluated by exercise testing. Eur J Clin Pharmacol 1987;33:205–7.
    Crossref PubMed
  64. Fragasso G, Palloshi A, Puccetti P, 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.
    Crossref PubMed
  65. Wimmer NJ, Stone PH. Anti-anginal and anti-ischemic effects of late sodium current inhibition. Cardiovasc Drugs Ther 2013;27:69–77.
    Crossref PubMed
  66. Zhao P, Zhang J, Yin XG, et al. The effect of trimetazidine on cardiac function in diabetic patients with idiopathic dilated cardiomyopathy. Life Sci 2013;92:633–8.
    Crossref PubMed
  67. Hu B, Li W, Xu T, et al. Evaluation of trimetazidine in angina pectoris by echocardiography and radionuclide angiography: a meta-analysis of randomized, controlled trials. Clin Cardiol 2011;34:395–400.
    Crossref PubMed
  68. Fragasso G, Piatti Md PM, Monti L, et al. Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am Heart J 2003;146:E18.
    Crossref PubMed
  69. Fragasso G, Rosano G, Baek SH, 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.
    Crossref PubMed
  70. Rosano GM, Vitale C, Sposato B, et al. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol 2003;2:16.
    Crossref PubMed
  71. Gao D, Ning N, Niu X, et al. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart 2011;97:278–86.
    Crossref PubMed
  72. Belardinelli R, Lacalaprice F, Faccenda E, et al. Trimetazidine potentiates the effects of exercise training in patients with ischemic cardiomyopathy referred for cardiac rehabilitation. Eur J Cardiovasc Prev Rehabil 2008;15:533–40.
    Crossref PubMed
  73. El-Kady T, El-Sabban K, Gabaly M, et al. 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.
    Crossref PubMed
  74. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed) 2016;69:1167.
    Crossref PubMed
  75. Masmoudi K, Masson H, Gras V, et al. Extrapyramidal adverse drug reactions associated with trimetazidine: a series of 21 cases. Fundam Clin Pharmacol 2012;26:198–203.
    Crossref PubMed
  76. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003.
    Crossref PubMed
  77. Ferrari R, Camici PG, Crea F, et al. Expert consensus document: A ‘diamond’ approach to personalized treatment of angina. Nat Rev Cardiol 2017;15:120–32.
    Crossref PubMed
  78. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949–3003.
    Crossref PubMed
  79. Chaitman BR, Pepine CJ, Parker JO, 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.
    Crossref PubMed
  80. Rousseau MF, Pouleur H, Cocco G, et al. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris. Am J Cardiol 2005;95:311–6.
    Crossref PubMed
  81. Chaitman BR, Skettino SL, Parker JO, 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.
    Crossref PubMed
  82. Zhang XQ, Yamada S, Barry WH. Ranolazine inhibits an oxidative stress-induced increase in myocyte sodium and calcium loading during simulated-demand ischemia. J Cardiovasc Pharmacol 2008;51:443–9.
    Crossref PubMed
  83. Maier LS. A novel mechanism for the treatment of angina, arrhythmias, and diastolic dysfunction: inhibition of late I(Na) using ranolazine. J Cardiovasc Pharmacol 2009;54:279–86.
    Crossref PubMed
  84. Pelliccia F, Pasceri V, Marazzi G, et al. A pilot randomized study of ranolazine for reduction of myocardial damage during elective percutaneous coronary intervention. Am Heart J 2012;163:1019–23.
    Crossref PubMed
  85. Mehta PK, Goykhman P, Thomson LE, et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging 2011;4:514–22.
    Crossref PubMed
  86. Stone PH, Chaitman BR, Stocke K, et al. The anti-ischemic mechanism of action of ranolazine in stable ischemic heart disease. J Am Coll Cardiol 2010;56:934–42.
    Crossref PubMed
  87. Rastogi S, Sharov VG, Mishra S, et al. Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am J Physiol Heart Circ Physiol 2008;295:H2149–55.
    Crossref PubMed
  88. Koren MJ, Crager MR, Sweeney M. Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J Am Coll Cardiol 2007;49:1027–34.
    Crossref PubMed
  89. Rich MW, Crager M, McKay CR. Safety and efficacy of extended-release ranolazine in patients aged 70 years or older with chronic stable angina pectoris. Am J Geriatr Cardiol 2007;16:216–21.
    Crossref PubMed
  90. Cocco G, Rousseau MF, Bouvy T, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol 1992;20:131–8.
    PubMed
  91. Venkataraman R, Belardinelli L, Blackburn B, et al. A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images. JACC Cardiovasc Imaging 2009;2:1301–9.
    Crossref PubMed
  92. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J 2006;27:42–8.
    Crossref PubMed
  93. Chisholm JW, Goldfine AB, Dhalla AK, et al. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care 2010;33:1163–8.
    Crossref PubMed
  94. Kosiborod M, Arnold SV, Spertus JA, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol 2013;61:2038–45.
    Crossref PubMed
  95. Arnold SV, McGuire DK, Spertus JA, et al. Effectiveness of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina according to baseline hemoglobin A1c. Am Heart J 2014;168:457–65.
    Crossref PubMed
  96. Mehta PK, Goykhman P, Thomson LE, et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging 2011;4:514–22.
    Crossref PubMed
  97. Tagliamonte E, Rigo F, Cirillo T, et al. Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease. Echocardiography 2015;32:516–21.
    Crossref PubMed
  98. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 2007;297:1775–83.
    Crossref PubMed
  99. Melloni C, Newby LK. Metabolic efficiency with ranolazine for less ischemia in non-ST elevation acute coronary syndromes (MERLIN TIMI-36) study. Expert Rev Cardiovasc Ther 2008;6:9–16.
    Crossref PubMed
  100. Mega JL, Hochman JS, Scirica BM, et al. Clinical features and outcomes of women with unstable ischemic heart disease: observations from metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromes-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36). Circulation 2010;121:1809–17.
    Crossref PubMed
  101. Karwatowska-Prokopczuk E, Wang W, Cheng ML, et al. The risk of sudden cardiac death in patients with non-ST elevation acute coronary syndrome and prolonged QTc interval: effect of ranolazine. Europace 2013;15:429–36.
    Crossref PubMed
  102. Morrow DA, Scirica BM, Sabatine MS, et al. B-type natriuretic peptide and the effect of ranolazine in patients with non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial. J Am Coll Cardiol 2010;55:1189–96.
    Crossref PubMed
  103. Alexander KP, Weisz G, Prather K, 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.
    Crossref PubMed
  104. Weisz G, Genereux P, Iniguez A, 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.
    Crossref PubMed
  105. Fanaroff AC, James SK, Weisz G, et al. Ranolazine after incomplete percutaneous coronary revascularization in patients with versus without diabetes mellitus: RIVER-PCI Trial. J Am Coll Cardiol 2017;69:2304–13.
    Crossref PubMed
  106. Antzelevitch C, Burashnikov A, Sicouri S, et al. Electrophysiologic basis for the antiarrhythmic actions of ranolazine. Heart Rhythm 2011;8:1281–90.
    Crossref PubMed
  107. Bunch TJ, Mahapatra S, Murdock D, et al. Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks. Pacing Clin Electrophysiol 34:1600–6.
    Crossref PubMed
  108. Frommeyer G, Rajamani S, Grundmann F, et al. New insights into the beneficial electrophysiologic profile of ranolazine in heart failure: prevention of ventricular fibrillation with increased postrepolarization refractoriness and without drug-induced proarrhythmia. J Card Fail 2012;18:939–49.
    Crossref PubMed
  109. Sabbah HN, Chandler MP, Mishima T, et al. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 2002;8:416–22.
    Crossref PubMed
  110. Chandler MP, Stanley WC, Morita H, et al. Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure. Circ Res 2002;91:278–80.
    Crossref PubMed
  111. Aaker A, McCormack JG, Hirai T, et al. Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J Cardiovasc Pharmacol 1996;28:353–62.
    Crossref PubMed
  112. Randle PJ, Garland PB, Hales CN, et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785–9.
    Crossref PubMed
  113. Sossalla S, Wagner S, Rasenack EC, et al. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts – role of late sodium current and intracellular ion accumulation. J Mol Cell Cardiol 2008;45:32–43.
    Crossref PubMed
  114. Wu Y, Song Y, Belardinelli L, et al. The late Na+ current (INa) inhibitor ranolazine attenuates effects of palmitoyl-L-carnitine to increase late INa and cause ventricular diastolic dysfunction. J Pharmacol Exp Ther 2009;330: 550–7.
    Crossref PubMed
  115. Fragasso G, Spoladore R, Cuko A, et al. Modulation of fatty acids oxidation in heart failure by selective pharmacological inhibition of 3-ketoacyl coenzyme-A thiolase. Curr Clin Pharmacol 2007;2:190–196.
    Crossref PubMed
  116. Singh BN, Wadhani N. Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs. J Cardiovasc Pharmacol Ther 2004;9:S85–97.
    Crossref PubMed
  117. Moss AJ, Zareba W, Schwarz KQ, et al. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol 2008;19:1289–93.
    Crossref PubMed
  118. Kaufman ES. Use of ranolazine in long-QT syndrome type 3. J Cardiovasc Electrophysiol 2008;19:1294–5.
    Crossref PubMed

Citation: Guarini G, Huqi A, Morrone D, Capozza PFG, Marzilli M. Trimetazidine and Other Metabolic Modifiers. Eur Cardiol. 2018;13(2):104-111. doi:10.15420/ecr.2018.15.2

Leave a Reply

Your email address will not be published. Required fields are marked *