Abstract
Background
According to WHO 2020, CAD is the second leading cause of death in Indonesia with death cases reaching 259,297 or 15.33% of total deaths. Unfortunately, most of the patients of CAD in Indonesia did not match the golden period or decline to be treated with Percutaneous Coronary Intervention (PCI). Based on the recent study, there were increases in MMP-9, NOX2, and TGF-β1 in STEMI patients which contribute to cardiac remodeling. Moreover, there is controversy regarding the benefit of late PCI (12-48 hours after onset of STEMI) in stable patients. Lately, colchicine is widely used in cardiovascular disease. This study was conducted to explore the effect of colchicine to reduce MMP- 9, NOX2, and TGF-β1 levels after myocardial infarction in stable patients.
Method
In this clinical trial study, we assessed 129 STEMI patients, about 102 patients who met inclusion criteria were randomized into four groups. Around 25 patients received late PCI (12–48 h after the onset of chest pain), optimal medical treatment (OMT) for STEMI, and colchicine; 24 patients received late PCI and OMT; 22 patients didn’t get the revascularization (No Revas), OMT, and colchicine; and 31 patients received No Revas and OMT only. The laboratory test for MMP-9, NOX2, and TGF-β1 were tested in Day-1 and Day-5. The data were analyzed using Mann-Whitney.
Results
A total of 102 patients with mean age of 56 ± 9.9, were assigned into four groups. The data analysis showed significant results within No Revas + OMT + Colchicine group versus No Revas + OMT + Placebo in MMP-9 (Day-1: p = 0.001; Day-5: p = 0.022), NOX2 (Day-1: p = 0.02; Day-5: p = 0.026), and TGF-β1 (Day-1: p = 0.00; Day-5: p = 0.00) with the less three markers in OMT + Colchicine group than OMT + Placebo group. There were no significant differences within the late PCI + OMT + colchicine group and PCI + OMT + Placebo group.
Conclusions
Colchicine could significantly reduce MMP-9, NOX2, and TGF-β1 levels in stable STEMI patients. So that, colchicine could be a potential agent in STEMI patients and prevent cardiac remodeling events.
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Introduction
Coronary artery disease (CAD) is a disease caused by an inadequate supply of blood and oxygen to the myocardium. This condition made the oxygen demand higher than the oxygen supply to the myocardium, which occurred from the complete or partial occlusion of the coronary arteries lumen due to atherosclerotic plaque [1]. There are some conditions due to CAD, such as myocardial infarction (MI), stable angina, unstable angina, and also sudden death [2]. CAD is very common in both developed and develo** countries. Brown et al. estimated that CAD represented 2.2% of the overall global burden of disease and 32.7% of cardiovascular diseases [3]. According to the latest WHO data published in 2020, CAD is the second leading cause of death in Indonesia with death cases reaching 259,297 or 15.33% of total deaths. The age-adjusted death rate is 125.99 per 100,000 of the population in Indonesia is ranked 70 in the world [4]. If the coronary arteries are seriously blocked, blood flow may not be adequate for any increased demand, such as that of exercise or an emotional upset.
When there is complete occlusion which makes myocardial cells necrosis, it will become myocardial infarction (MI) and might show the ST-elevation myocardial infarction (STEMI) pattern in ECG [5]. Percutaneous coronary intervention (PCI) still becomes an important treatment for STEMI. PCI could open up the infarct-related artery and prevent re-occlusion. However, in the real world, after being transferred to the PCI center, many patients have missed the optimal PCI time or even refused the PCI, especially in develo** countries including Indonesia [6, 7]. This condition is caused by many reasons such as chest pain denial, poor access to the PCI center, poor economic condition, and refusal to be done by PCI procedure. However, there are controversies regarding the benefit of late PCI (12-48 hours after onset of STEMI) in stable patients, since the current publications showed different results [7]. That is why this study included patients with the onset of STEMI between 12 and 48 h.
Besides the results in the No Revas group already suggest the benefit of colchicine in reducing MMP-9, NOX2, and TGF-β1, the analysis in both late PCI groups is still not significant. If we compare the level of biomarkers in Fig. 2, the trends showed that the PCI + Colchicine group had lower MMP-9, NOX2, and TGF-β1 levels than the PCI + Placebo group. These results may happen because of the PCI intervention, since it may develop Ischemia/Reperfusion Injury (IRI) in the acute phase. IRI is a term used to describe the functional and structural abnormalities that occur when blood flow is restored after a period of ischemia. In addition to reversing ischemia, the restoration of blood flow can result in potentially highly damaging side effects, such as necrosis of irreversibly injured cells, significant cell swelling, and nonuniform flow restoration to all tissue regions [34].
IRI initially mobilizes neutrophils via chemotaxis and endothelial adhesion, CD4 + T cells, and circulating platelets in the vascular space. Neutrophils induce the generation of tissue-damaging reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), and local inflammatory mediators [35]. CD4 + T lymphocytes produce macrophage-stimulating factors, interferon-gamma, and TNF- α, which augment macrophage activation and cytokine release [35]. Furthermore, re-oxygenation increases the number of oxygen free radicals in the parenchymal, endothelial, and lymphocytic cells that infiltrate the lesion. The production of superoxide anions is due to the inadequate reduction of oxygen by damaged mitochondria and the action of neutrophils, endothelial cells, or parenchymal cells.
These processes lead to the formation of free radicals, which are unstable molecules that destabilize inorganic and organic substances and cause cell damage [36]. The activation of ROS and inflammation process in IRI increases the level of MMP-9, NOX2, and TGF-β1. The results may not be significant because the data extraction happens in Day-1 and Day-5 (acute phase). Therefore, further research is needed to confirm whether higher doses of colchicine may reduce MMP-9, NOX2, and TGF-β1 or not, since the results in the No Revas group (without IRI).
Conclusion
Colchicine could significantly reduce MMP-9, NOX2, and TGF-β1 levels in stable STEMI patients. So that, colchicine could be a potential agent in STEMI patients and prevent cardiac remodeling events.
Data Availability
The corresponding author will provide the dataset upon reasonable request, which was used to conduct the current work.
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We want to express our gratitude to all the patients who took part in the trial.
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SS performing the PCI, drafting the manuscript, and article guarantor. MSR evaluated the latest draft of the manuscript. EW performing data analysis. SP giving expert opinion. TAW drafting the manuscript. YHO giving expert opinions.
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This research was approved by the Health Research Ethical Committee of Saiful Anwar General Hospital with the following registered number: 400/235/K.3/302/2020. This research was conducted in conformity with the provisions of the Helsinki Declaration. Written informed consent was obtained from all included patients in this research. An independent quality control board of Saiful Anwar General Hospital maintained attention to the efficacy, safety, and security of the data.
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Suryono, S., Rohman, M.S., Widjajanto, E. et al. Effect of Colchicine in reducing MMP-9, NOX2, and TGF- β1 after myocardial infarction. BMC Cardiovasc Disord 23, 449 (2023). https://doi.org/10.1186/s12872-023-03464-9
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DOI: https://doi.org/10.1186/s12872-023-03464-9