The Impact of Trimetazidine on Cardiac Fibrosis, Inflammation, and Function in Ischemic Cardiomyopathy Patients

Coronary artery disease (CAD) is one of the most common cardiovascular disorders affecting people worldwide. In both developed and developing countries, this disease has been proven to be the leading cause of death [1]. Ischemic cardiomyopathy (ICM), a term that refers to heart muscle weakness resulting from ischemia or heart attack, which leads to decreased ability of the heart to pump blood [2], has been considered the most severe complication of coronary heart disease [3]. ICM can be characterized as a left ventricular (LV) function deficiency caused by CAD, which results in increased mortality rates and poor quality of life. LV dysfunction in ICM patients may be caused by necrosis or myocardial fibrosis [4]. The most common non-modifiable risk factors for ICM include old age, male sex, and family history. On the other hand, hypertension, diabetes, hyperlipidemia, obesity, smoking, and sedentary lifestyle are the most important modifiable risk factors for ICM [2]. While receiving conventional medication, a large number of ICM patients tend to experience symptoms. Therefore, there is a need to include other ICM drugs with different mechanisms of action [4].

Reports have shown that Trimetazidine (TMZ), a dihydrochloride of 2,3,4-trimethoxybenzyl-piperazine, exerts anti-ischemic properties without any effect on myocardial oxygen intake or blood supply [5]. Some trials have demonstrated that TMZ is beneficial for patients who suffer from heart failure [5]. TMZ is a cardioprotective agent given that it alters energy substrate metabolism. By inhibiting the 3-ketoacyl-coenzyme A thiolase enzyme, TMZ reduces long-chain fatty acid oxidation. This reduction in fatty acid oxidation contributes to a decrease in oxygen intake, which is very beneficial in ischemic conditions, and increases the activity of the pyruvate dehydrogenase enzyme, which contributes to increased glucose oxidation. The homeostasis between glycolysis and glucose oxidation improved following changes in the energy substrate, leading to a reduction in proton and Na+ accumulation. The net result is the more efficient generation of adenosine triphosphate (ATP) in a low-oxygen environment [6, 7]. TMZ is believed to directly suppress cardiac fibrosis. In fact, evidence has shown that TMZ decreases collagen aggregation, connective tissue growth factor (CTGF) expression in cardiac fibroblasts, nicotinamide adenine dinucleotide phosphate-oxidase levels, and production of reactive oxygen species, with the positive impact of this drug on the treatment of congestive heart failure having been attributed to the mentioned mechanisms [6, 8]. Owing to decreased serum endothelin-1 (ET-1) levels, TMZ enhances myocardial endothelial function, thereby alleviating myocardial damage and chronic myocardial ischemia [9]. TMZ reduces the level of oxidative stress markers, including malondialdehyde (MDA), the end product of lipid peroxidation, by reducing membrane injury triggered by reactive oxygen species [10]. TMZ reduces the release of proinflammatory mediators from macrophages induced by reactive oxygen species, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin 1 (IL-1), and interleukin 8 (IL-8) during both inflammation and ischemia [10].

CTGF is a member of the CCN family of multifunctional matricellular proteins that contribute to the initiation of fibrosis in a variety of organs and tissues, including the heart. CTGF is also a key mediator of the profibrotic cytokine transforming growth factor- (TGF-) signaling pathway. Several molecules, such as TGF-, Smads, CTGF, corin, mesenchymal cell products, and inflammatory agents, influence the fibrosis process and collagen metabolism. CTGF stimulates the proliferation of fibroblast and increases the content of the extracellular matrix. CTGF is a “bystander” marker that has the potential to indirectly influence the fibrosis process [11]. However, only a few studies have assessed CTGF, all of which have been in animals [12, 13]. Hence, no clinical trial has yet investigated CTGF inhibition for the treatment of heart diseases [14].

Previous studies have documented the benefits of TMZ in ICM in terms of vascular endothelial function, inflammatory process, and myocardial functions. Thus, the current research aimed to investigate whether TMZ, as an adjuvant drug to conventional ICM therapies, affects cardiac fibrosis assessed using CTGF expression and determine the clinical benefits of adding TMZ on vascular endothelial function, inflammatory process, and myocardial function. The current study has been the first to evaluate CTGF in clinical settings. The assessment of CTGF as an initiator biomarker of cardiac fibrosis [11] will be beneficial for NYHA II patients who are at the early stage of disease progression.

After screening the patients according to the inclusion and exclusion criteria, as previously described, 52 patients were initially included in this study. However, during the 3-month treatment period, four patients were excluded for the following reasons: irregular use of TMZ or for less than 3 months (one patient) and non-adherence to their medications (three patients). Finally, 48 patients completed the study as shown in Fig. 1.

The average age of the study participants was 59.4 ± 9 years, and 60.4% of the participants were males. As shown in Table 1, the two groups had almost similar baseline demographics, with no statistically significant differences. Moreover, 18.75% of the participants were smokers, 62.5% had diabetes, 47.9% had a previous history of percutaneous intervention, and 20.8% had undergone post-coronary artery bypass grafting (CABG). Baseline medications were comparable in the two groups.

ICM, which remains a considerable burden in developing countries [5], has been the leading cause of heart failure (HF), accounting for approximately 60% of cases globally [18, 19]. HF has been associated with substantially higher rates of mortality and morbidity in humans [18, 20].

Evidence has shown that enhancement in HF functional class [5, 21], systolic function and functional capacity without changes in cardiac perfusion [22], wall motion score index at rest [5, 23], LV end-diastolic volume [5, 24], and the inflammatory process measured using CRP levels in the blood was the major benefit of TMZ [5, 21, 25]. A long-term study (24 months of follow-up) investigating the impact of TMZ on 200 ICM patients similar to those included herein revealed a significant decrease in the frequency of angina episodes per week (P < 0.01) and correspondingly a decrease in sublingual nitroglycerin (glyceryl trinitrate) tablet intake per week [5, 26].

Novel knowledge regarding myocardial ischemia, a multifactorial disease, has been discovered in recent years [27, 28]. In addition to the vascular mechanisms of atherosclerotic CAD, non-vascular causes, such as cardiac energy metabolism disorders and variations in blood rheology due to platelet activation and/or inflammation, would likely be included among the mechanisms responsible for myocardial ischemic syndromes in the near future [27, 29, 30].

HF can further influence metabolic changes. Therefore, targeting cardiac metabolism in patients with ischemic heart disease can prevent the poor prognosis of LV function and prevent progression to HF. For these purposes, several trials have indicated the benefits of TMZ, a free fatty acid oxidation inhibitor that converts cardiac and muscle metabolism to glucose utilization. A retrospective cohort study examining the data from 669 participants with congestive HF (CHF) showed that 362 patients were on TMZ due to recurrent symptoms after taking all traditional CHF medications, whereas the remaining patients were treated with traditional CHF medications. As an additional therapy to other conventional CHF drugs, TMZ has improved mortality and event-free survival in CHF patients [31]. Given its mechanism of action, TMZ has been shown to have cardioprotective effects in angina patients and LV dysfunction, as well as those undergoing revascularization procedures, without any relevant side effects. TMZ, including other antianginal medications, have successfully improved exercise tolerance, delayed angina symptoms initiation, and extended the time to 1-mm ST-segment depression through exercise relative to placebo in a randomized placebo-controlled study involving 166 participants who were reluctant to use nitrates or beta-blockers. The aforementioned study also confirmed that TMZ could be used in conjunction with hemodynamic agents given that the rate pressure product was unchanged [32, 33].

A prospective double-blind, controlled trial that sought to investigate the impact of the preoperative use of TMZ on the biochemical parameters of myocardial injury, including myoglobin, troponin T, creatine kinase (CK), and creatine kinase muscle and brain (CK-MB) during CABG, found that the TMZ group had significantly lower levels of biochemical markers after surgery compared to the placebo group, which suggested that TMZ offered more protection of the myocardium [33, 34].

The ESC recommendations for the diagnosis and treatment of chronic coronary syndromes suggested that TMZ can be used as first-line therapy to minimize angina incidence and increase exercise tolerance in subjects with low baseline heart rate and low blood pressure [15]. Considering its lack of impact on heart rate or arterial blood pressure, the neutral hemodynamic profile of TMZ makes it an appealing choice for patients as well as clinicians [32]. Conversely, several studies have shown that TMZ (applied chronically in vivo or acutely in vitro) had no impact on cardiac fatty acid and carbohydrate oxidation, implying that therapeutic effects of TMZ were more likely due to an intracardiac mechanism that has yet to be identified [35].

The therapeutic effects of TMZ on cardiac fibrosis in ICM patients must be verified conclusively. Our study indicated that the addition of MR TMZ to traditional ICM therapies improved the patients’ vascular endothelial function, reduced the inflammatory process, and reduced the risk of cardiac fibrosis—an added clinical effect. Our research also reported that TMZ improved certain echocardiographic parameters.

ET-1 is a vascular contracting substance synthesized by vascular endothelial cells, which is important for the normal function of vascular smooth muscle cells [36]. The increased ET-1 production during cardiac ischemia and reperfusion further exacerbates the problem [37].

In our study, the combined regimen in the TMZ group effectively and significantly improved ET-1 levels (P < 0.05). This may be attributed to the shifting of energy substrates away from fatty acid metabolism and toward glucose metabolism caused by TMZ [17].

The findings of the current study are consistent with those presented in a randomized, double-blind, crossover study where those who received TMZ exhibited lower endothelin-1 release 15 days after treatment relative to those who received placebo [4, 38]. Other studies have demonstrated a reduction in ET-1 serum levels in patients with diabetes undergoing TMZ treatment, both after short-term (2 weeks) and long-term (6 months) therapy; however, no decrease was detected in the placebo group [4, 17].

Inflammation is a key factor in the development of ventricular remodeling. Inflammatory cytokines, such as IL-1, IL-6, and TNF-α, have been shown to increase dramatically after myocardial infarction and are involved in future LV remodeling [39].

The current study found that while both regimens can effectively improve TNF-α levels, the level of improvement was significantly better in the TMZ group than in the placebo group, suggesting that TMZ can effectively reduce inflammatory stress in patients with ICM.

Consistent with our results, the TMZ group exhibited stable CRP plasma concentrations, whereas the placebo group experienced a significant increase in CRP levels throughout the 18-month treatment duration [4, 21].

The interstitial proliferation of fibroblasts induces cardiac fibrosis, whereas prolonged extracellular matrix precipitation causes HF, arrhythmia, sudden cardiac death, and other severe complications. Pressure overload leads to ventricular remodelings, such as myocyte hypertrophy and interstitial fibrosis, when prolonged. Cardiac fibrosis remains a key factor in the progression from compensated ventricular hypertrophy to HF. Notably, CTGF plays a crucial role in the cardiac fibrosis process and has emerged as a novel therapeutic target in the treatment of fibrotic diseases [12]. CTGF is a member of the CCN family of multifunctional matricellular proteins that play a role in initiating fibrosis in a variety of organs and tissues, including the heart. CTGF, which is also a key mediator of the profibrotic cytokine transforming growth factor- (TGF-) signaling pathway, stimulates the proliferation of fibroblasts and increases the contents of the extracellular matrix. CTGF is a “bystander” marker that has the potential to influence the fibrosis process indirectly [11]. Limited data have been available regarding the effects of TMZ on myocardial fibrosis that occurs after ischemia and causes LV dysfunction [14]. Assessment of CTGF as an initiator biomarker of cardiac fibrosis is suitable for NYHA II patients who are in the early stages of disease progression.

Our study revealed that while both groups showed a significant decrease in the CTGF levels, the TMZ group showed better improvement. Our results confirmed that as adjuvant therapy, TMZ can effectively improve the cardiac fibrosis process in patients with ICM. The mechanism by which TMZ exerts its effects may be linked to decreased collagen synthesis, CTGF expression in cardiac fibroblasts, nicotinamide adenine dinucleotide phosphate-oxidase levels, and production of reactive oxygen species [8, 12].

After analyzing the myocardial function of the patients, our results showed that LVEF was increased significantly, whereas both LVESD and LVEDD were significantly decreased in the TMZ group. Notably, new findings observed herein suggested that LV dysfunction in ICM patients is mediated by changes in substrate metabolism. TMZ improves heart metabolism by altering the preferred energy substrate from fatty acid to glucose oxidation, thereby potentially playing an important role in improving myocardial function [23]. The drug’s effects on maintaining the integrity of cell membranes [2], as well as mitochondrial structure and function, may explain the improvement in the LVEF [2, 40]. The increase in glucose oxidation caused by TMZ can improve contractility and microvascular function by promoting glycolytic ATP resynthesis. TMZ treatment may also increase the energy metabolism of chronically hibernated cells, making them more efficient at generating contractile activity, limiting further LV function decline [5]. Although this difference may not be clinically significant, a better effect can be expected with a longer treatment period. However, clinical improvement was detected in the form of a reduction in the number of angina attacks per week and nitrate consumption in the TMZ group when compared with the placebo group.

Adding TMZ to conventional medications for ICM treatment can be of clinical value given its ability to improve vascular endothelial function, hinder inflammatory process progression, and protect myocardial cells by improving some echocardiographic indices, such as LVEF, LVESD, and LVEDD. This study demonstrated that TMZ can effectively inhibit the cardiac fibrosis process in clinical settings by assessing CTGF as an initiator biomarker of cardiac fibrosis.