Combining hemodynamic and metabolic agents in ischemic heart disease



by G. Fragasso, Italy

Gabriele FRAGASSO, MD Heart Failure Unit Istituto Scientifico San Raffaele Milano, ITALY

Myocardial ischemia can be looked at as a metabolic problem, as it leads to an imbalance in the pathways the normal heart relies on for energy production. Use of pharmacological agents to optimize cardiac energy metabolism by stimulating myocardial glucose oxidation can be an effective therapeutic option. The metabolic agent trimetazidine does this indirectly by inhibiting fatty acid b-oxidation, in effect changing the energy substrate preference, promoting a shift from fatty acid metabolism toward glucose metabolism, which is more efficient for ATP production. The efficacy of trimetazidine in the treatment of angina pectoris has been evaluated under various conditions: trimetazidine administered as a monotherapy or in combination, acutely or over a longer-term period, as initial treatment, and in patients resistant to b-blockers or calcium-channel antagonists. All published studies employing trimetazidine in patients with chronic ischemic heart disease have invariably reported beneficial clinical effects without adverse hemodynamic events. In fact, in chronic ischemic heart disease patients with left ventricular dysfunction, trimetazidine has been shown to be a particularly effective adjunctive treatment in terms of improvement in left ventricular metabolism and function. An ongoing randomized clinical study in patients with revascularized coronary artery disease should clarify whether the reported experimental and clinical benefits of trimetazidine also translate into improved prognosis.

Ischemic heart disease is a major cause of morbidity and mortality worldwide. In patients with acute coronary syndromes, revascularization interventions have been shown to reduce myocardial infarction and death1,2; however, this is not the case in patients with chronic stable angina. In fact, according to the European Society of Cardiology (ESC) and the European Association for Cardio Thoracic Surgery (EACTS) 2014 guidelines,3 percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) should be reserved for patients with refractory angina and for patients in whom such procedures would be expected to provide a survival benefit; this would be influenced by a number of factors, such as the number of diseased vessels, lesion location and severity, and the presence of left ventricular dysfunction. Thus, all patients with stable ischemic heart disease, whether they are asymptomatic or experiencing severe symptoms, should first receive optimal medical therapy, which would usually be maintained even after revascularization.

Current anti-ischemic/antianginal therapy focuses on two major actions. The first pertains to vascular protection, in this case aiming to delay progression of atherosclerosis (by use of statins, antithrombotic drugs), which would reduce future cardiovascular events and death and improve quantity of life. The second pertains to improvement in the imbalance between myocardial oxygen supply and demand (ischemic imbalance), which would reduce the severity and frequency of angina symptoms and also contribute to improvement in quality of life. However, this therapeutic view does not consider the cardiac metabolic consequences of myocardial ischemia. In fact, ischemia can be thought of as a metabolic problem (previously discussed in Salerno et al4), because it leads to an imbalance in the pathways the normal heart relies on for energy production. Under normoxic conditions, the healthy heart generates approximately two-thirds of its energy (in the form of adenosine triphosphate, ATP) from the free fatty acid (FFA) pathway; the remaining energy production is derived from glucose oxidation and lactate.5-7 Under hypoxic conditions, such as mild-to-moderate ischemia, myocardial cells turn to another more oxygen-efficient pathway to generate sufficient ATP to support calcium homeostasis and maintenance of ionic gradients: their response is to increase glucose uptake, as glycolysis requires less oxygen per mole of ATP generated than FFA oxidation. Severe ischemia, however, rapidly induces an imbalance between cardiac tissue oxygen demand and the available coronary blood supply. Changes in myocardial function, metabolism, and morphology ensue, leading to arrhythmias, contractile failure, and electrophysiological abnormalities. Myocardial cell uptake of glucose decreases and conversion to lactate increases; there is a switch from lactate uptake to lactate production, and most pyruvate is transformed into lactate, increasing cell acidosis. Concurrently, use of the FFA pathway slows, and overall ATP production decreases. The results of such metabolic changes include the disruption of cell homeostasis, alterations in membrane structure, and ultimately cell death.

This review discusses the rationale behind a pharmacological approach to stop this vicious circle in patients with chronic ischemic heart disease.

Medical treatment of chronic ischemic heart disease

In addition to lifestyle and hygienic dietary measures, guideline- recommended first-line treatment for patients with stable angina includes aspirin, statins, and b-blockers. This recommendation is consistent across all guidelines for the diagnosis and management of this condition. The main probable mechanism by which b-blockers relieve anginal symptoms is a reduction in both heart rate and contractility. However, their indication as a first-line treatment is still under debate. They are given a class I indication for the treatment of chronic angina, mainly on the basis of a general agreement on the issue, whereas they are attributed a level of evidence A on the basis of studies that were carried out in patients after a myocardial infarction or heart failure, in which they consistently decreased morbidity and mortality. However, several reports have discussed potential pitfalls in their use in patients with stable coronary artery disease (CAD). In the REACH registry (REduction of Atherothrombosis for Continued Health), b-blockers were not associated with a lower risk of composite cardiovascular events, and they were associated with higher rates for the secondary outcome (comprising primary outcome and hospitalization for atherothrombotic events or a revascularization procedure) in chronic CAD patients.8 A recent post-hoc analysis of the CHARISMA study (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance) indicated that use of b-blockers in patients that had a previous myocardial infarction but no heart failure was associated with a better cardiovascular prognosis—determined by reduced reinfarction rate—but did not reduce overall mortality. Additionally, in patients without previous myocardial infarction, b-blockers did not reduce cardiovascular events but were rather associated with a higher incidence of stroke, confirming previous meta-analyses of studies performed in hypertensive patients.9 The hypothesized mechanism to explain these potential deleterious effects of b-blockers is related to an insufficient reduction in central aortic pressure, potentially related to heart rate reduction, which in certain contexts would not play a positive role. Therefore, there is still no clear evidence from randomized clinical trials for the efficacy of b-blockers used in first-line treatment in patients with chronic stable angina. Yet, we enthusiastically continue to use them.

If a patient continues to complain of symptoms after the firstline treatment scheme has been implemented, other drugs, such as calcium-channel blockers or long-acting nitrates, could be prescribed. Calcium-channel blockers (mostly dihydropyridine derivatives) cause coronary and peripheral vasodilation (but increase heart rate and partially reduce the beneficial heart rate–lowering effect of b-blockers); the phenylalkylamine derivative verapamil and, to a lesser extent, diltiazem (benzothiazepine calcium-channel blocker) reduce heart rate and contractility and are used when b-blockers are contraindicated. Combining verapamil or diltiazem with b-blockers yields additive effects in terms of bradycardia, heart block, and negative inotropic effects. When added to b-blockers or calciumchannel blockers, long-acting nitrates improve exercise tolerance, increase time toonsetof angina, and reduce ST-segment depression during exercise testing; however, their use is limited by the development of tolerance on long-term administration. In summary and similarly to b-blockers, there is no clear-cut evidence of the prognostic utility of these additional antianginal drugs in chronic CAD. Furthermore, conflicting evidence exists about combining antianginal hemodynamic drugs.

Having said this, pharmacological treatment of chronic ischemic heart disease continues to be based mostly on bblockers, calcium-channel blockers, and nitrates. In most cases, if symptoms are not brought under control by treatment with a single traditional antianginal drug, a drug combination would be used, with the addition of a second or third agent. However, there are no clinical studies demonstrating a real additive efficacy of a combination of classic hemodynamically active drugs as compared with monotherapy. Furthermore, significant side effects may limit the maximal doses that can be used for such drugs, especially in an aged population. In such a context, the use of alternative therapeutic approaches would be warmly welcomed and, with this in mind, pharmacologically addressing the underlying derangements in cardiac metabolism, discussed next in further detail, could be a rational solution to this problem.

Pharmacological manipulation of cardiac energy metabolism

Given the above-described pathophysiology of ischemic heart disease and the difficulties encountered with many patients when trying to control the total ischemic burden with classic hemodynamically active drugs, an adjunctive therapeutic option that pharmacologically manipulates cardiac energy metabolism seems reasonable (previously discussed in Salerno et al4). This approach is based on stimulating myocardial glucose oxidation to optimize cardiac energy metabolism, and is proven to improve cardiac function and protect myocardial tissue against ischemia-reperfusion injury.10 Myocardial glucose oxidation can be promoted either directly by stimulating glucose metabolism or indirectly by inhibiting fatty acid b-oxidation, producing a shift of energy substrate utilization away from fatty acid metabolism and toward glucose metabolism, a more oxygen-efficient path to ATP production (more ATP produced per mole of oxygen used). Indeed, oxygen consumption efficiency in the heart can be improved within the range of 16% to 26% by the increased use of glucose and lactate—more efficient fuels for aerobic respiration.10

Additionally, the uptake of glucose in the heart and arm skeletal muscle has been shown to be inversely related to serum FFA levels,11 and an increased flux of FFA from adipose tissue to nonadipose tissue exacerbates metabolic abnormalities characteristic of the insulin resistance syndrome,12 a common pattern in patients with ischemic heart disease. Furthermore, there is new evidence that elevated levels of FFA may not only impair glucose uptake in heart and skeletal muscle but also alter metabolism in the vascular endothelium, which leads to premature cardiovascular disease.13 These findings suggest that metabolic therapy could have a beneficial role in glucose metabolism homeostasis.

Manipulation of cardiac energy metabolism through a number of approaches has been investigated. Trimetazidine is the most extensively studied cardiac metabolic drug and has been shown to increase glucose oxidation and reduce FFA utilization, restoring cardiac coupling between glycolysis and glucose oxidation. The next section will look more closely at the beneficial effects of cardiac metabolic manipulation by trimetazidine in ischemic heart disease.

Complementary role of trimetazidine in ischemic heart disease

Trimetazidine’s use in patients with ischemic heart disease has consistently provided clinical benefits (previously discussed in Salerno et al4). Although its mechanism of action is still under debate,14,15 experimental evidence indicates that trimetazidine exerts its effects predominantly through partial inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase, the last enzyme involved in b-oxidation,16 in effect causing a switch in energy substrate use away from FFA to glucose and lactate. As mentioned briefly in the previous section, the resulting reduction in FFA oxidation and increase in glucose oxidation restores the myocardial coupling between glycolysis and carbohydrate oxidation, allowing ATP production with less consumption of oxygen.17 Trimetazidine also promotes membrane phospholipid turnover during ischemia and reperfusion, redirecting FFA toward phospholipids and thus increases the cell’s tolerance to ischemia-reperfusion damage.17-19 Trimetazidine’s anti-ischemic actions are independent of hemodynamic changes and are associated with a greater recovery of mechanical function after ischemia.17

Trimetazidine’s efficacy in the treatment of angina pectoris has been investigated under various conditions: trimetazidine administered as a monotherapy or in combination, acutely or over a longer-term period, as initial treatment, and in patients resistant to b-blockers or calcium-channel antagonists.20-30

Initially studied in patients with chronic stable effort angina during exercise testing, acute administration of trimetazidine increased effort tolerance and delayed the appearance of ischemic symptoms and electrocardiogram changes.20

With long-term treatment, the benefits seen with acute administration were confirmed. Such treatment was well-tolerated, with no appreciable side effects, including no significant changes in heart rate and/or aortic pressure.21 In comparison studies, improvement in ischemic threshold and exercise tolerance on trimetazidine treatment is similar to that reported for propranolol and nifedipine, and there was even a lower incidence of side effects.22,23

Figure 1. Bar charts showing mean values (+ 1 standard deviation) from dobutamine stress echocardiography in chronic ischemic heart disease patients taking placebo (grey bars) or trimetazidine (red bars) on top of optimal hemodynamic therapy. Trimetazidine significantly induced an increase in the administered dobutamine dose (panel A) versus placebo. Despite a higher administered stress, left ventricular function (assessed by wall motion score index) was significantly less impaired when patients were on trimetazidine (panel B). These findings indicate that metabolic therapy added to treatment schemes yields a better response to stress. Based on data from reference 32: Lu et al. Am J Cardiol. 1998;82:898-901.

Trimetazidine’s effects were shown to be additive to those of hemodynamically active drugs, with direct evidence provided by a randomized, double-blind study in patients with chronic effort angina and documented CAD. This study compared the combination of trimetazidine plus the b-blocker propranolol with nitrates plus propranolol, and found that the combination including trimetazidine was not only more effective and better tolerated than the other combination, but also the only one that showed improvement. The other combination had no effect on symptoms and exercise capacity.24 In another randomized, double-blind study in patients with angina uncontrolled by diltiazem, the addition of trimetazidine to a full-dose diltiazem treatment scheme yielded beneficial effects.25 It significantly reduced the number of ischemic attacks, prolonged the time to 1-mm ST-segment depression, increased the time to onset of exercise-induced angina, and increased the maximum work at peak exercise, without adverse hemodynamic events or increased side effects. In yet another study, this time in patients with stable effort angina uncontrolled by metoprolol alone, 12-week treatment with trimetazidine and metoprolol significantly reduced clinical symptoms compared with placebo and metoprolol.26 A previous study, TRIMPOL-I (TRIMetazidine in POLand), had already shown that in diabetic patients, 4 weeks of treatment with trimetazidine was associated with a significantly lower number of anginal episodes and an improvement in myocardial ischemia and exercise capacity.27 In diabetic patients with chronic stable angina, Marazzi et al have shown that trimetazidine added to standard medical therapy reduces the number of episodes of ST-segment depression and silent ischemia and reduces total ischemic burden.28 In patients with stable angina pectoris, the efficacy of trimetazidine was found to be comparable to that of other drugs that have no influence on heart rate (ie, other non–heart-ratelowering antianginal drugs).29

Figure 2. Insulin sensitivity. Bar chart showing mean (+1 standard deviation) glucose infusion rate at the hyperinsulinemic/euglycemic clamp during short-term (15 days) and long-term (6 months) placebo and trimetazidine administration in patients with chronic ischemic heart disease, left ventricular dysfunction, and diabetes. The infusion rate of glucose necessary to maintain euglycemia after an insulin bolus was greater when patients were on trimetazidine, both in the short and long term. This indicates that in these high-risk patients, trimetazidine, compared with placebo, was also able to significantly improve insulin sensitivity. Abbreviations: LT, long term; ST, short term. Based on data from reference 33: Fragasso G et al. Am Heart J. 2003;146: E1-E8 and reference 36: Monti et al. Am J Physiol Endocrinol Metab. 2006; 290:E54-E59.

Figure 3. Baseline and follow-up Tpeak-Tend dispersion (mean + 1 standard deviation) in patients with left ischemic and nonischemic left ventricular dysfunction and treated with trimetazidine (red columns) or conventional therapy alone (controls; greycolumns). Tpeak-Tend dispersion index is a noninvasive marker of dispersion of ventricular repolarization and is positively related to the risk of arrhythmias. The evidence of a significant TMZ-induced Tpeak-Tend dispersion reduction only in patients with post-ischemic left ventricular dysfunction supports the hypothesis that the potential antiarrhythmic properties of TMZ could be directly mediated by the anti-ischemic action of the drug. Abbreviations: TMZ, trimetazidine. Based on data from reference 37: Cera et al. J Cardiovasc Pharmacol Ther. 2010;15: 24-30.

Trimetazidine has also been confirmed to be effective in different settings of stable coronary disease,30-32 expanding its use to include patients with heart failure both of ischemic and nonischemic origin.33,34 In such contexts, trimetazidine improves symptoms, cardiac response to ischemia, left ventricular function (Figure 1, page 323),32 and thus quality of life as well. The main mechanism of action is probably through a trimetazidine-induced increase in myocardial cellular energy reserve.35 However, improved endothelial function36 and increased insulin sensitivity33,36 (Figure 2, page 323) may also play a role; it is possible that indirect beneficial electrophysiological effects37 (Figure 3) may also be involved. Long-term administration of trimetazidine has also been shown to improve survival and event-free survival in patients with ischemic and nonischemic left ventricular dysfunction (Figure 4).38

Figure 4. Effects of trimetazidine versus conventional therapy alone (control) on 5-year global and cardiovascular mortality in patients with ischemic and nonischemic left ventricular dysfunction. The histogram on the left shows an 11.3% reduction in 5-year global mortality when trimetazidine (TMZ) is administered in addition to standard medical therapy (P=0.015). The histogram on the right shows an 8.7% reduction in 5-year cardiovascular mortality in the same patients (P=0.05). Abbreviations: CV, cardiovascular; TMZ, trimetazidine. Based on data from reference 38: : Fragasso G et al. Int J Cardiol. 2013;163: 320-325.

Similarly to other established antianginal drugs, the main limitations on the wide use of trimetazidine in chronic ischemic heart disease include the paucity of data on mortality and major cardiovascular events and on direct comparisons between trimetazidine and established antianginal therapies. Nevertheless, in 2005, a Cochrane review including 23 studies (1378 patients) concluded that trimetazidine is a well-tolerated drug that provides benefit in patients with stable angina, in terms of patient-reported intake of glyceryl trinitrate tablets and number of weekly angina episodes when used as monotherapy and in combination with conventional antianginal agents.39 A more recent meta-analysis (13 studies, 1628 patients) that compared trimetazidine with conventional antianginal drugs confirmed the efficacy of trimetazidine treatment for stable angina pectoris, regardless of treatment duration.40

At present, the European Society of Cardiology indicates trimetazidine as an effective adjunctive treatment in patients with angina not completely controlled by standard hemodynamic therapy.41

Combined metabolic action of β-blockers and trimetazidine

Despite their above-described pitfalls, b-blockers continue to be the clinical mainstay of ischemic heart disease treatment. They act principally through reduction in oxygen consumption by reducing heart rate and inotropism. However, they could have a direct complementary metabolic effect themselves, by reducing peripheral lipolysis and reducing FFA availability. Indeed, there is evidence that b-blockade reduces FFA use in favor of greater glucose use in cardiac patients.42 Such a change in cardiac energy metabolism could be a potential mechanism for the decreased cardiac oxygen consumption and improvement in energy efficiency observed with b-blocker treatment of ischemic heart disease and heart failure.43 Whether nonselective b-blockers are more efficient than selective ones in shifting whole-body substrate utilization from FFA to glucose oxidation 44 is still under debate.45 Nonetheless, the better survival rates observed with nonselective b-blockers could be explained by their effect on the metabolism.46 Additionally, inhibition of activity in the sympathetic nervous system with the centralacting antihypertensive drug moxonidine has been associated with increased mortality in patients with chronic heart failure. 47 In fact, despite a significant reduction in catecholamine spillover from the synapses in the sympathethic nervous system— thus reducing catecholamine levels in the blood—and, consequently, heart rate, moxonidine increases both FFA use and myocardial oxygen consumption.48 This could be the reason why central sympathetic inhibition fails to prevent deaths in long-term studies in patients with chronic heart failure; it also indicates that the main mechanism of action of b-blockers in cardiac syndromes probably involves something other than a simple reduction in heart rate. Thus, it is possible that the degree of heart rate reduction is just a marker of the functional response after the administration of b-blockers, ie, a consequent effect rather than a mechanism. On this basis, we can hypothesize that b-blockers and trimetazidine have a complementary, synergistic metabolic action: whereas the former reduces FFA availability, the latter decreases their cardiac utilization. Overall, this drug-induced metabolic shift could reduce FFA oxidation and increase flux through pyruvate dehydrogenase with a consequent energy-sparing effect.35,49

There is evidence to suggest that trimetazidine’s metabolic effect may occur in other organs and tissues as well.50 In fact, apart from a reduction in whole-body energy demand, a trend for a reduction in whole-body lipid oxidation and in fasting plasma FFA concentration has also been observed (Figure 5).50 This general metabolic shift could in the end reduce the overall metabolic requirements of the body, resulting in a very attractive adaptation strategy in the context of coronary and myocardial insufficiencies. Interestingly, b-blockers have also been shown to directly affect whole-body metabolism. In trained athletes, b-blockade abolishes the increase in plasma glucose levels that occur during intense exercise, owing to an increased peripheral glucose uptake and no significant change in glucose production.51 Such effects from b-blockade on glucose kinetics could be mediated directly; they could also be indirectly mediated through changes in lipid substrates and/or counter-regulatory hormones.

Potential role of metabolic therapy in revascularized chronic ischemic heart disease Despite no clearly demonstrated prognostic gain, nowadays, revascularization procedures are often considered first for the control of angina pectoris. However, recurrent or persistent angina after initially successful revascularization is not infrequent and is frustrating for patients and doctors. In fact, subsequent repeat coronary angiography and revascularization procedures introduce both additional risk for the patient and cost to the health care system.

Figure 5. Bar chart showing mean (+ 1 SD) resting energy expenditure (kcal/day) at baseline and after 3 months of follow-up in patients with ischemic and nonischemic left ventricular dysfunction treated with conventional therapy plus trimetazidine (red columns) or conventional therapy alone (grey columns). Trimetazidine significantly reduces the whole-body energy expenditure, indicating a potential role of this metabolic drug on overall metabolic requirements of the body. Based on data from reference 50: Fragasso et al. Heart. 2011;97:1495-1500.

A more effective medical strategy could certainly improve the management of these patients. In this context, an ongoing international, multicenter, randomized clinical study would provide the cardiological community with new solid data in a few years’ time. The purpose of the ongoing ATPCI study (efficAcy and safety of Trimetazidine in Patients with angina pectoris having been treated by percutaneous Coronary Intervention; EudraCT Number: 2010- 022134-89) is to evaluate the long-term efficacy and safety of trimetazidine, in addition to evidence-based cardiovascular therapy, in patients having had a recent percutaneous coronary intervention. The primary objectives are to demonstrate the superiority of trimetazidine over placebo in preventing recurrence or exacerbation of angina pectoris and in reducing cardiac events, and also to document its safety by analyzing the occurrence of serious adverse events. Apart from the evaluation of the effects of trimetazidine in this widely encountered patient population, this new study will also provide us with much useful information about the current epidemiology, treatment, and outcome in patients with chronic ischemic heart disease. It is expected to provide some of the most solid data about the treatment of chronic ischemic heart disease ever produced.

Conclusions

Optimization of cardiac energy metabolism is attractive as an approach to protect myocardial cells from ischemia and to improve performance of dysfunctioning myocardium. To that effect, trimetazadine, which shifts the energy substrate preference away from FFA metabolism toward increased glucose oxidation, has been shown by a number of studies to be an effective adjunctive treatment in patients with chronic ischemic heart disease and heart failure, reducing ischemic burden and improving left ventricular metabolism and function. Whether the reported experimental and clinical benefits translate into improved prognosis is currently being ascertained by an ongoing international randomized clinical trial. This has potential to be a major therapeutic advance in chronic ischemic heart disease patients, who continue to experience very high morbidity and mortality rates in spite of treatment efforts. Furthermore, most cardiac diseases are associated with derangements in glucose homeostasis, which certainly contribute to primary disease progression. An advantage of trimetazidine treatment is the combined beneficial effects that FFA inhibitors have on left ventricular function and glucose metabolism, which would be especially advantageous in cardiac patients with coexisting myocardial dysfunction and glucose metabolism abnormalities.

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