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.

Our findings showed that ET-1, CTGF, and TNF-α were a bit significantly correlated with echocardiographic indices in the TMZ group (P > 0.05). This may be explained by the small non-clinically significant changes in LVEF, LVESD, and LVEDD. However, with longer treatment duration, a better correlation may be expected.

TMZ had been well tolerated throughout the study, with none of the participants needing to cease administration. The established pharmacological actions of TMZ are supported by its neutral hemodynamic impact without significantly modifying systolic or diastolic BP or heart rate [41, 42].

One major limitation of the current study is the limited sample size, with only 48 patients having been included (24 in each group). At the 3-month follow-up examination, the effects of TMZ were detected. To further demonstrate the cardioprotective function of TMZ, more studies with larger sample size and longer follow-ups are required. Furthermore, cardiac fibrosis is best measured with cardiac magnetic resonance (MR) imaging, considering that CTGF is an indirect method. In addition, more than two indicators were needed to jointly corroborate cardiac fibrosis, vascular endothelial function, and the inflammatory process. While there are improvements in markers of fibrosis and potential echocardiographic indices of ventricular function, functional assessments are required. As such, we consider this study an exploratory trial.