The endothelium: a therapeutic target in post-PCI patients and the role of trimetazidine in endothelial function



by S. Lim, South Korea

Soo LIM, MD, PHD Department of Internal Medicine Seoul National University College of Medicine, Seoul National University Bundang Hospital Seongnam, SOUTH KOREA

The vascular endothelium, the surface monolayer of the vascular wall, plays an important role in the maintenance of vascular health. It releases various mediators—such as angiotensin II, endothelin-1, endothelium- derived hyperpolarizing factor, nitric oxide, prostacyclin, prostaglandin H2, and thromboxane A2—that are involved in vasodilation or vasoconstriction under specific conditions. Dysfunction of the endothelium has been implicated in various vascular pathophysiological processes, including abnormal vascular proliferation, excessive thrombus formation, vasoconstriction, and vasospasm. It is also associated with restenosis after percutaneous coronary intervention (PCI). However, there are few clinical studies on the use of pharmacological agents to improve endothelial function and decrease the rate of restenosis after PCI. Trimetazidine—an agent possessing a broad spectrum of pharmacological activities, including protection against damage to the cardiovascular system—has recently been shown to improve vascular endothelial cell function and may reduce the risk of restenosis after PCI. These actions occur through antioxidative and anti-inflammatory activities, increased adiponectin levels, and decreased insulin resistance. Although there is no direct evidence that trimetazidine can reduce cardiovascular morbidity and mortality, reductions in these may result indirectly from its effects on endothelial function. Prospective studies with a cardiovascular end point as a primary objective are warranted to confirm the cardioprotective effects of trimetazidine.

Worldwide, cardiovascular disease (CVD) and stroke impose huge health and economic burdens, with CVD being the number one cause of death globally.1 Roughly 17.5 million people died from CVD in 2012, representing 31% of all global deaths. An estimated 7.4 million of these CVD deaths were due to coronary heart disease and 6.7 million, stroke. In the United States, in 2011, CVD accounted for 31.3% (786 641) of the 2 515 458 deaths overall, with a CVD death rate of 229.6 per 100 000 Americans2 (275.7 in men, 192.3 in women), this after a 30.8% decline in CVD death rate and 15.5% decline in actual number of CVD deaths from 2001 to 2011.2

The prevalence of diabetes mellitus is increasing rapidly worldwide, and this increase implies an increase in vascular complications. Vascular complications in the heart, brain, and peripheral arteries are more than twice as prevalent in people with diabetes compared with those without diabetes. Nearly 80% of people with diabetes die from CVDs, such as coronary heart disease, cerebrovascular disease, and peripheral artery occlusive disease. Therefore, the vascular complications of diabetes are now an important public health priority worldwide.

A 2015 statistical report on heart disease and stroke in the United States demonstrated that the number of percutaneous coronary intervention (PCI) procedures is increasing. 2 In patients undergoing PCI, the use of drug-eluting stents (DESs) has greatly reduced the need for reintervention compared with the use of bare metal stents (BMSs).3,4 However, the incidence of in-stent restenosis in patients after PCI, using either DESs or BMSs, remains high.5 Thus, instent restenosis continues to be a major problem after coronary stenting.6

Endothelial dysfunction, a key step in the development of restenosis after PCI

Restenosis is the recurrence of narrowing of the coronary artery in a maladaptive response to damage caused by angioplasty. Chronic exposure to cardiovascular risk factors, such as high blood pressure, high blood glucose concentration, dyslipidemia, smoking, and low physical activity level impair the defense mechanisms in the vascular endothelium (Figure 1). Chronic inflammation and oxidative stress are wellknown causes of endothelial dysfunction, which along with proliferation of vascular cells, production of extracellular matrix, platelet activation, and increased thrombotic activity, processes in which endothelial dysfunction has been implicated, contribute to restenosis.7 Many people with diabetes have increasingly complex lesion characteristics and disease comorbidities,6 and the risk for restenosis is high among diabetics. 8


Figure 1. Role of endothelial dysfunction
in the development of restenosis after percutaneous coronary intervention. Abbreviations: eNOS, endothelial nitric oxide synthase; PCI, percutaneous coronary intervention; ROS, reactive oxygen species.

The vascular endothelium—the surface monolayer of the vascular wall—plays a critical role in the maintenance of vascular health. In response to physical and chemical stimuli, it releases various vasoactive mediators, such as angiotensin II, endothelin-1, endothelial cell growth factors, endotheliumdependent hyperpolarizing factor, interleukins, plasminogen inhibitors, prostacyclin, prostaglandin H2, nitric oxide, and thromboxane A2.

Although the development of DESs to solve in-stent restenosis has markedly reduced the extent of restenosis after angioplasty, 9 there is concern about delayed reendothelialization and late in-stent thrombosis.10 Various strategies to prevent restenosis by stimulating endothelialization or by inhibiting vascular smooth muscle cell (VSMC) proliferation have thus been tried. However, few reports have identified optimal agents with cell-specific effects on VSMCs and endothelial cells.

Role of trimetazidine in preventing the development of endothelial dysfunction and in reducing the incidence of restenosis after PCI

The piperazine derivative trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride) is an anti-ischemic drug effective in treating patients with angina pectoris (Figure 2).11 Protective effects on cardiomyocytes have been shown in patients treated in primary intervention via coronary artery graft surgery.11 Trimetazidine’s beneficial effects on heart failure and ischemic heart disease are related to cardiac energy metabolism, which shifts from fatty acid oxidation to glucose oxidation through trimetazidine’s inhibition of mitochondrial longchain 3-ketoacyl coenzyme A thiolase; this may contribute to its antianginal effect (Figure 3).12 In addition to trimetazdine’s myocardial anti-ischemic effect, it has a vasodilatory effect on coronary vessels.13

Figure 2. Chemical structure of trimetazidine 1-[2,3,4-
trimethoxybenzyl] piperazine dihydrochloride).

We have recently shown that trimetazidine has beneficial effects on the occurrence of restenosis after vascular balloon injury in diabetes.14 We investigated whether trimetazidine treatment can lower the extent of restenosis occurring in the carotid artery after balloon injury in animal models of diabetes, both type 1 (streptozotocin-injected Sprague Dawley [SD] rats) and type 2 (Otsuka Long-Evans Tokushima Fatty [OLETF] rats). OLETF rats represent an obese model of type 2 diabetes, in which 5-week-old rats are allowed to grow to 24 weeks of age, at which time obesity and insulin resistance develop. 15 Rats from both models were treated with trimetazidine at different concentrations or were sham treated with normal saline, and a well-established balloon injury procedure 16 was carried out in the carotid artery. Two weeks after the procedure, the trimetazidine- treated rats in both models showed significantly less neointimal formation than controls; in the type 1 diabetes model, trimetazidine- treated rats also had lower mean intima-media ratios (this was dose dependent) and markedly lower in vivo cell proliferation (as measured by immunostaining for proliferating cell nuclear antigen) than controls. 14

A series of in vitro experimental studies have shown that reendothelialization after balloon injury is accelerated by trimetazidine treatment.17,18 In one study, trimetazidine had a direct effect on endothelial proliferation in human umbilical vein endothelial cells (HUVECs).14 Proliferation of HUVECs incubated in medium containing 20 mM lysophosphatidylcholine (LysoPC) was about 20% lower than in controls. Trimetazidine treatment restored cell proliferation in a concentration-dependent manner. Similarly, HUVEC proliferation was decreased by tumor necrosis factor a (TNF-a) treatment and recovered with trimetazidine treatment.14 In addition, we found that trimetazidine suppresses caspase-3 activity.14 The effect of trimetazidine on apoptosis in HUVECs was also assessed by measuring mitochondrial membrane function.14 Compared with LysoPC-treated HUVECs, the number of apoptotic cells was markedly lower in the trimetazidinetreated groups. After LysoPC treatment, the ratio of active versus inactive caspase-3 was significantly higher than in controls,14 and trimetazidine lowered the active caspase-3 ratio in a dose-dependent manner.

These findings from in vitro cell studies and in vivo animal studies indicate that trimetazidine helps to prevent damage to the coronary vasculature and to reduce neointimal proliferation after vascular injury by way of targeting both vascular endothelial cells and VSMCs. Recent studies have shown that trimetazidine has a protective effect against restenosis after PCI in humans.17-19 In one study, trimetazidine treatment for 10 weeks lessened endothelial damage in the radial artery after transradial coronary artery angiography or transradial PCI.19 Another study of longer duration showed that trimetazidine treatment reduced the incidence of in-stent restenosis after PCI with DES implantation measured at the 1-year follow-up.20 There were also fewer major adverse cardiac events in the trimetazidine-treated group than in the control group.

Figure 3. Mechanism of action of trimetazidine in energy metabolism in cardiomyocytes. Abbreviations: ATP, adenosine triphosphate; CoA, coenzyme A.

Antioxidant effects of trimetazidine

There is a large amount of evidence that oxidative stress plays a role in the pathogenesis of diabetes, as well as in diabetic complications such as atherosclerosis and restenosis. 21 Indeed, in the vascular wall, oxidative stress may be a key mechanism in processes leading to endothelial dysfunction 22; it promotes VSMC migration and proliferation and is We have shown that trimetazidine treatment lowers, in a dosedependent manner, the cellular production of reactive oxygen species (ROS) in HUVECs treated with LysoPC,14 which is known to generate ROS.8 Repeated administration of trimetazidine reduces production of mitochondrial ROS in rats, and pretreatment with trimetazidine—added to cardioplegic solution—reduces oxidative damage in human patients.9,10 Also, the ischemia-induced increase in free radical production is attenuated by trimetazidine treatment before the onset of ischemia in rat hearts.24 The antioxidant effects of trimetazidine occur in various cells of the cardiovascular system.11

Figure 4. Cardioprotective effects of trimetazidine.

Effect of trimetazidine on the inflammatory process and on adipocytokines

Early after endothelial denudation, an infiltration of inflammatory cells occurs in the vascular wall,25 with the presence of monocytes associated with the neointimal area.26 Neointimal thickening has been shown to be lessened with the use of anti-inflammatory agents that block the early recruitment of monocytes.27 Collectively, these findings suggest a causative role for inflammation and its associated monocyte infiltration in the development of restenosis.

Previous studies have reported that specific markers—including the adipocytokines adiponectin, monocyte chemoattractant protein-1 (MCP-1), and TNF-a, and also the inflammatory marker high-sensitivity C-reactive protein (hsCRP)—can affect the development of restenosis and atherosclerosis.28-30 A low adiponectin concentration is a risk factor for the subsequent development of CVDs.28 MCP-1 is involved in monocyte recruitment, and TNF-a and hsCRP have important roles in the development of atherosclerosis.29,30 Trimetazidine treatment has been shown to increase adiponectin levels and decrease TNF-a and MCP-1 levels.14 These results indicate that the protective effects of trimetazidine against restenosis occur indirectly in part through the increase in adiponectin level and decrease in proinflammatory processes and oxidative stress.

Here, I have described substantial evidence to support the concept that trimetazidine plays a positive role in reducing the extent of restenosis after PCI and have suggested some possible underlying mechanisms. However, there are several issues to note. There are differences between clinical balloon angioplasty procedures carried out on diseased vasculature in human patients and animal balloon injury models, and the carotid arteries in the balloon injury model cannot fully represent the overt atherosclerotic changes found in humans. 31 In addition, in the rat model, it is VSMCs alone that contribute to the response observed after balloon injury; in humans, the injurious response in diseased vasculature arises from the interactions among several cell types, including VSMCs, endothelial cells, macrophages, and T cells.32 Furthermore, although the in vitro studies with HUVECs are performed under high-glucose conditions in an effort to mimic the hyperglycemic state in diabetics, these conditions may not be an accurate reflection of the actual state in such patients.

Conclusion

Trimetazidine has a broad spectrum of pharmacological activities that provide cardiovascular protection through its antioxidative and anti-inflammatory properties, enhancement of mitochondrial function, reduced fatty acid oxidation, and improved endothelial dysfunction (Figure 4). Therefore, using trimetazidine alone or in combination with other antiplatelet agents or statins may ameliorate endothelial dysfunction and improve antiatherosclerotic andantithrombotic efficacy. Though there is no direct evidence of a trimetazidine benefit for cardiovascular morbidity and mortality, we speculate that trimetazidine’s effect on endothelial function could affect this indirectly. Prospective studies with CVD events as a primary objective are needed to confirm these potentially beneficial effects of trimetazidine.

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