Chronic ischemic heart disease: an energy imbalance

by G. Guarini and M. Marzilli, Italy

Mario MARZILLI, MD Giacinta GUARINI, MD, PhD Cardiovascular Medicine Division Cardio Thoracic and Vascular Department, University of Pisa ITALY

Alterations in cardiac metabolism have recently been implicated in the pathophysiology of ischemic heart disease. In normal conditions, the heart derives most of its energy from b-oxidation of free fatty acids. However, the healthy heart can easily switch from one substrate to another according to substrate availability, nutritional status, and exercise level. Paradoxically, during prolonged and severe ischemia, the myocardium continues to derive most of its energy (up to 90%) from b-oxidation. A greater amount of oxygen is required to completely oxidize a fatty acid with a carbon-chain length equivalent to that of glucose. Fatty acid oxidation is thought to be detrimental in that, while requiring more oxygen, it produces less adenosine triphosphate (ATP) and more reactive oxygen species, thus further reducing mitochondrial respiratory efficiency. Aside from metabolic alterations, the process of producing and utilizing energy is very complex and includes multiple steps from uptake of metabolites by cardiac myocytes, oxidative phosphorylation in the mitochondria, and transport of ATP to intracellular components. Therefore, impairment in any one of these steps can have a tremendous impact on cell homeostasis. In addition to acute and chronic changes in cardiac metabolism, mitochondrial dysfunction has been implicated in promoting myocardial ischemia and myocardial damage during the reperfusion phase of an ischemic event, thereby further reducing the heart’s ability to synthesize and utilize ATP.

Despite a global reduction in cardiovascular mortality owing to improved therapy and well-designed educational programs, ischemic heart disease (IHD) remains the most important cause of death in Western countries. In the United States, in the 10-year period from 2003 to 2013, death rates attributable to cardiovascular disease (CVD) declined by 28.8%, while the actual number of CVD deaths per year declined by 11.7%. Even so, CVD still accounted for 30.8% of all deaths (ie, 1 out of every 3 deaths) in the United States in 2013. That same time period witnessed a decline in the prevalence of angina pectoris: between 2009 and 2012, there was an average of 3.4 million people aged 40 years or over in the United States with angina each year compared with 4 million between 1988 and 1994.1 In Europe, as in the United States, the prevalence of angina increases with age, with prevalence ranging from 2%-5% in men aged 45-54 years to 11%-20% in men aged over 60; in women, from 0.5%-1% to 10%-14%, respectively.2

Myocardial ischemia is often due to coronary atherosclerotic disease, which limits coronary blood flow, causing an imbalance between available blood supply and the heart’s metabolic demands. Anti-ischemic therapy is based on this concept and focuses on alleviating the problem by removal of the coronary obstructions by mechanical means, and/or modulating cardiac work and coronary blood flow through pharmacological agents. Although such therapeutic strategies aim to restore an adequate supply/demand balance, to improve symptoms, and to prolong survival, available evidence indicates that this goal is not always reached. Indeed, a number of trials report persistent angina in over 30% of patients despite optimal medical therapy and despite “successful” coronary revascularization, both in patients treated by percutaneous coronary intervention and those treated by coronary artery bypass graft (CABG) surgery.3-5

The unexpected prevalence of angina despite optimal medical therapy plus successful revascularization strongly challenges the current approach to treating IHD. Up to this point, cardiologists have focused on the vascular inability to supply myocytes with sufficient oxygen and nutrients. Only recently has the scientific community considered additional mechanisms that may contribute to myocardial ischemia. Just as there may be multiple paths to a dysfunctional car engine, there may be multiple paths to myocardial ischemia. In this analogy, an inadequate blood supply for the heart would be like a shortage of gasoline for a car; an impaired cellular uptake of nutrients would be like an altered transmission of gasoline to the car engine; mitochondrial dysfunction, like an engine’s inability to transform chemical energy into mechanical energy; and an inability to transfer adenosine triphosphate (ATP) to the cellular contractile machinery, like an inability of the engine’s receiving system to generate external work. Indeed, free fatty acids (FFAs) and glucose that are taken up by the cells need to be transformed into intermediary components (acetyl coenzyme A [CoA]) by b-oxidation and glycolysis so that they can enter the Krebs cycle and produce carbon dioxide (CO2) and nicotinamide adenine dinucleotide (NADH), a key substrate of oxidative phosphorylation. Respiratory-chain complexes I through IV transfer electrons from NADH to oxygen, creating a proton electrochemical gradient (Dm H+) across the inner mitochondrial membrane. This gradient is used by ATP synthase to phosphorylate adenosine diphosphate (ADP), thereby producing the high-energy phosphate compound ATP, the direct source of energy for all energy-consuming reactions in the heart. Once generated in the mitochondria, ATP is transferred by the creatine kinase energy shuttle to myofibrils and to sarcolemmal and sarcoplasmic reticulum ion pumps. On the basis of these considerations and an overwhelming body of evidence, factors other than epicardial stenosis, such as mitochondrial dysfunction and metabolic derangement, have been recognized as pathological mechanisms for persistent ischemia.6,7

Due to the complex pathophysiology of IHD, some challenging questions about treatment arise. How should we deal with persistent angina in patients that have already been revascularized? Which drugs can be used to treat IHD in patients free of coronary stenosis? Indeed, most available antianginal drugs were developed to counteract the effects of a flow-limiting stenosis, and their efficacy has been attributed to their ability to either increase coronary blood flow or to decrease myocardial oxygen demand. None of these agents were tested after the removal of the flow-limiting stenosis. The incomplete success with current treatment has fostered a large interest in therapeutic strategies that target the “alternative pathological mechanisms,” ie, metabolic modulation. Indeed, there is evidence that metabolic modulation therapy may play a key role in the acute phase of ischemic events, where it would affect results of acute interventions on the subsequent development of heart failure (HF)—stunned and hibernated myocardium—as well as for those who experience chronic stable angina.8 Our improved understanding of metabolic changes that occur during ischemic events and after reperfusion is now being translated into new therapeutic opportunities.

Ischemic heart disease: an energy crisis

Significant progress has been made in recent years in understanding the role of cardiac energy metabolism in the pathogenesis of myocardial ischemia. As a natural consequence, a better understanding of the metabolic derangements associated with IHD is translating into new therapeutic strategies.

Under normal conditions, the healthy heart derives approximately two-thirds of its energy (in the form of ATP) from the FFA pathway; glucose oxidation and pyruvate are the other source for the remainder of the energy produced. The healthy heart switches easily from one substrate to another as needed, according to substrate availability, nutritional status, and exercise level. The myocardium responds to mild-to-moderate cardiac ischemia by increasing uptake of glucose so that it can produce the ATP necessary to maintain ionic gradients and calcium (Ca2+) homeostasis. Paradoxically and to detrimental effect, the myocardium continues to rely on b-oxidation for production of most of its energy (90%) during prolonged and severe ischemia, despite the elevated lactate production that occurs under these conditions. Furthermore, due to the Randle phenomenon—a competitive interaction between fatty acid (FA) oxidation and glucose oxidation—high rates of FA oxidation inhibit glucose oxidation, already low, even further. Although the complete oxidation of FAs produces more ATP per molecule of CO2 than that produced from the complete oxidation of glucose, more oxygen is used to completely oxidize a FA of equivalent carbon-chain length. Therefore, glucose oxidation, which produces roughly 15% more ATP for a given amount of oxygen used, is considered more “oxygen sparing” than FA oxidation. During ischemia, FA oxidation can become detrimental, because it uses more oxygen and produces less ATP and more reactive oxygen species (ROS), and so further depresses mitochondrial respiratory efficiency. FFAs promote their own uptake and oxidation and they antagonize the uptake of glucose, lactate, and pyruvate, in part through direct inhibition of pyruvate dehydrogenase. The effects of FFAs on the mitochondria include uncoupling of cellular respiration, resulting in decreased ATP production and oxygen wasting. Thus, excessive levels of FFAs in the blood lead to lactate and proton accumulation, lowered cellular pH, and disrupted cellular function, as well as impaired Ca2+ handling, oxidative stress, reduced activity of the glucose transporter GLUT-4, and apoptosis of myocytes.9 Such metabolic changes disrupt cell homeostasis and alter membrane structure, and they ultimately lead to cell death.

Interestingly, derangements in myocardial energy metabolism are associated with heart failure (HF) as well10; such altered metabolism is the final common pathway of several cardiac disorders, such as IHD, cardiomyopathies, hypertension, and diabetes-induced HF. Recent data suggest that HF may itself promote metabolic changes, such as insulin resistance, in part through neurohumoral activation, generating a vicious cycle in which metabolic abnormalities further aggravate and precipitate HF. The associations between altered energy metabolism, insulin resistance, and HF may be explained by the following compatible processes: (i) activation of the neurohumoral system, including the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS); (ii) inflammation, indicated by increased levels of tumor necrosis factor a (TNF-a) and its soluble receptors; (iii) alterations in skeletal muscle function and mass as a result of reduced physical activity; (iv) endothelial dysfunction; (v) increased adipocytokines, such as adiponectin and leptin; and (vi) pharmacological exacerbation of insulin resistance (eg, by diuretics). Of these, neurohumoral activation has been the most studied and is probably the strongest contributor to altered metabolism in HF. Neurohumoral homeostasis is activated in response to a long-term depression in cardiac output—characterized by persistent activation of the SNS and the interlinked RAAS— resulting in increased catecholamine secretion. At the same time, catecholamine reuptake in the heart is decreased. Increased levels of catecholamines are directly detrimental to the heart, causing substantial enzyme loss as an index of diffuse myocardial damage, and much oxygen wastage even in the absence of FFAs in the perfusate. Furthermore, the catecholamine norepinephrine promotes both coronary vasoconstriction and increased plasma FFA levels, further exacerbating oxygen wastage. Therefore, addressing the abnormal cardiac metabolism in IHD patients may also improve patient prognosis by halting the progression to HF.

Ischemic heart disease: a mitochondrial issue

Aside from their key role in energy production and metabolic modulation, mitochondria are essential to cardiomyocyte survival during ischemia and reperfusion. They are implicated in ATP synthesis, maintenance of Ca2+ homeostasis, cell survival, and cardioprotection, all of which are regulated by the proton gradient across the mitochondrial membrane. Under aerobic physiologic conditions, mitochondria are not involved in the beat-to-beat regulation of cytosolic Ca2+ levels, though a small flux of Ca2+ into the mitochondrial matrix has been observed. Small increases in mitochondrial Ca2+ concentration stimulate the Krebs cycle and the NADH redox potential. This fine regulation of mitochondrial Ca2+ is important to enhance oxidative phosphorylation and ATP synthesis. However, under pathological conditions, the mitochondria can take up too much Ca2+, activating a series of steps that trigger a vicious cycle that ultimately leads to irreversible cell damage. During ischemia, intracellular Ca2+ homeostasis is deranged; however, mitochondria can still buffer cytosolic Ca2+, suggesting that they do not lose their ability to pump Ca2+. Mitochondria isolated after prolonged periods of ischemia are still able to use oxygen for ATP phosphorylation. Conversely, mitochondria isolated after reperfusion are structurally altered; their membrane pores are open; they contain large amounts of Ca2+; they produce large amounts of oxygen free radicals, and the oxidative phosphorylation system is irreversibly damaged. In addition, ischemia followed by reperfusion induces irreversible deletions in several parts of the mitochondrial genome, impairing ATP production, which is ultimately responsible for cardiomyocyte death (ischemia-reperfusion injury).

Notably, strategies that confer cardioprotection from myocardial ischemia-reperfusion injury involve the activation of the reperfusion injury salvage kinase (RISK) and survival activating factor enhancement (SAFE) pathways and the inhibition of mitochondrial permeability transition pore (MPTP) opening. The MPTP is a nonselective channel located on the inner mitochondrial membrane. When this channel is open, the mitochondrial membrane potential collapses, uncoupling oxidative phosphorylation; this results in the depletion of ATP and cell death.11 The MPTP remain closed during myocardial ischemia and they open only during the first few minutes of myocardial reperfusion in response to mitochondrial Ca2+ overload, oxidative stress, and restoration of physiologic pH.12 The RISK pathway13 involves the protein kinases Akt and Erk 1 and 2; the SAFE pathway involves activation of TNF-a and the signal transducer and activator of transcription 3 (STAT3). When specifically activated, these pathways confer powerful cardioprotection against lethal reperfusion injury.14 Thus, from one perspective, the RISK and SAFE pathways could be considered to mediate a form of programmed cell survival. There is extensive evidence that pharmacological or mechanical activation of these two pathways, via ischemic preconditioning or postconditioning for example, may reduce myocardial infarct size by up to 50%.15 The cardioprotective role of these pathways is believed to be due to inhibition of MPTP opening,16 improved mitochondrial Ca2+ handling,17 and recruitment of antiapoptotic pathways. Mitochondria offer several potential targets for cardioprotective therapies. These include the following: (i) prevention of Ca2+ overload; (ii) prevention of ROS generation; and (iii) activation of the ATPdependent potassium channels (KATP channels) that maintain the inner mitochondrial membrane integrity, leading to (iv) prevention of the opening of the nonspecific MPTP complex.18

Innovative approaches to manage myocardial ischemia: mitochondria and cardiac energy metabolism modulators

On the basis of this biochemical background, the pharmacological manipulation of mitochondria to optimize cardiac energy metabolism makes for an attractive therapeutic option. Such an approach is largely based on the promotion of cardiac glucose oxidation along with the suppression of b-oxidation, leading to an improvement in cardiac function and protection against ischemia-reperfusion injury, as well as attenuated progression to congestive HF (CHF). Owing to the Randle phenomenon, carbohydrate metabolism may be indirectly increased by a decreasing rate of FA oxidation. Such a decrease in FA oxidation may be achieved in different ways. One of these involves decreasing the availability of FAs as an energy substrate; this can be achieved through treatment with glucose, insulin, and potassium (GIK therapy), which decreases the circulating levels of FFAs and/or their uptake by cardiac myocytes, or through suppression of carnitine palmitoyl transferase (CPT) I or II to inhibit FA uptake by the mitochondria. Another way to decrease FA oxidation is by direct inhibition of the enzymes involved. Of note, drugs that can manipulate FFA oxidation (eg, trimetazidine) have been shown not only to provide cardioprotection in the acute phase of an ischemic event, but also to ameliorate cardiac metabolism and angina symptoms in patients with IHD with long-term use. These findings are supported by a link between key glycolytic enzymes and the activity of two membrane-bound pumps considered to be survival promoting—the sodium-potassium ATPase and the Ca2+-uptake pump of the sarcoplasmic reticulum. Indeed, ischemia-induced derangement of cardiac metabolism can be minimized through treatment with metabolic modulators that decrease FA oxidation and increase utilization of glucose and lactate as energy substrates. The greatest progress in the use of metabolic therapy occurred with the advent of the direct inhibitors of myocardial FA oxidation, specifically trimetazidine, discussed next in further detail.19


Trimetazidine was the first and, for many years, the only registered drug in its class. It is available in over 80 countries worldwide. It has an established antianginal efficacy, known even before the discovery of how the drug acts, which is via partial inhibition of myocardial FA oxidation.19,20 Initial preclinical studies in animal models of myocardial ischemia and reperfusion demonstrated a cytoprotective effect for this drug.21 It has been shown by Kantor et al to specifically inhibit the long-chain activity of the enzyme 3-ketoacyl CoA thiolase (EC (3-KAT),22 the enzyme that catalyzes the last step in FA b-oxidation, using long-chain 3-ketoacyl-CoA as a substrate to generate acetyl-CoA. Trimetazidine’s inhibition of 3-KAT reduces the NADH/NAD+ and acetyl-CoA/free CoA ratios in the mitochondrial matrix, in effect removing the inhibition on pyruvate dehydrogenase and thus increasing the rate of glucose oxidation. Indeed, in the working rat heart, although only modestly reducing the rate of FA oxidation, trimetazidine significantly increases the rate of glucose oxidation.22,23 Trimetazidine’s efficacy in refractory angina has been demonstrated in clinical trials, which also support the superior benefit associated with the addition of this metabolic agent to classic hemodynamic drug therapy, such as b-blockers or nitrates. The efficacy and acceptability of trimetazidine in combination with hemodynamic agents was tested in the TACT study (Trimetazidine in Angina Combination Therapy).24 In that study, exercise stress test parameters and angina symptoms were significantly improved with the addition of trimetazidine to therapy including b-blockers or long-acting nitrates, compared with addition of placebo. Similar results were observed in the VASCO-Angina study. This randomized, double-blind, placebo-controlled trial, assessed antianginal efficacy on exercise test parameters and safety of both a standard dosage (70 mg/day) and a high dosage (140 mg/day) of modified-release trimetazidine in symptomatic and asymptomatic patients with chronic stable angina who were receiving background b-blocker therapy with atenolol (50 mg/day).25 That study confirmed the efficacy and tolerability of both trimetazidine dosages in improving effort-induced myocardial ischemia and functional capacity in such patients.25 Furthermore, evidence from other studies suggest trimetazidine may improve clinical manifestation in patients with stable IHD. Indeed, with longterm administration of trimetazidine, the following have been observed: a lower average number of weekly attacks, a lower mean weekly consumption of short-acting nitrates, improvement in quality of life, lessened severity of main clinical manifestations of chronic HF, and improved (lowered) functional class.26-29 Moreover, as trimetazidine has been demonstrated to have similar efficacy in men and women, this metabolic myocardial cytoprotector can be recommended for patients with IHD irrespective of sex.30,31 Trimetazidine has also been used for cardioprotection in patients undergoing coronary bypass surgery and percutaneous coronary intervention. 28,32 Consistent with IHD and HF being considered energetic disorders, trimetazidine was effective in reducing mortality and event-free survival in patients with chronic HF in an international, multicenter, retrospective cohort study. The addition of trimetazidine to optimal medical therapy improved long-term survival in these patients.33 That retrospective analysis further confirmed the results of previous small studies in patients with chronic HF that had shown that trimetazidine improves left ventricular function, exercise capacity, and New York Heart Association functional class compared with placebo. Furthermore, the addition of trimetazidine to exercise training resulted in greater improvements in functional capacity, left ventricular ejection fraction, and endothelium-dependent dilation in patients with chronic HF.34

Conclusions: ischemic heart disease, an energetic disorder

Historically, IHD has been considered a vasculardisease, where coronary atherosclerosis causes an imbalance between blood supply and demand. However, recent evidence suggests that cardiac metabolic derangement and the inability of mitochondria to efficiently produce energy are able to induce energy starvation similar to that produced by coronary blood flow blockage. In other words, it is conceivable that cardiac metabolic derangements and/or mitochondrial dysfunction can directly put the myocardium under ischemic conditions, independently of oxygen and nutrient availability. Accordingly, in an experimental model (Zucker obese fatty rat), repairing mitochondrial DNA damage improved mitochondrial function, restored vascular and myocyte properties, and reduced the consequences of oxidative stress.35 Similarly, in Zucker lean rats in which mitochondrial dysfunction was selectively induced through mitochondrial DNA damage, areas of myocardial ischemia, endothelial dysfunction, and depressed contractile function under cardiac stress were observed in the absence of coronary atherosclerosis.35 These observations support the hypothesis that myocardial ischemia should be considered an energetic disorder.


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