The Never-Ending Challenge of Anti-Inflammatory Therapy after Acute Myocardial Infarction

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, with acute myocardial infarction (AMI) among the primary culprits [1, 2]. While early percutaneous coronary intervention (PCI) remains the cornerstone of AMI management, ischemia-induced damage extends far beyond macroscopic coronary lesions, triggering a cascade of cellular and molecular responses. If left unchecked, these processes can drive adverse myocardial remodeling, exacerbating long-term cardiac dysfunction [3].Current optimal medical therapy primarily aims to prevent recurrent thrombosis and slow the progression of atherosclerosis through the use of antithrombotic agents, lipid-lowering drugs, beta-blockers, and renin-angiotensin-aldosterone system inhibitors [1, 4]. However, despite mounting evidence highlighting the role of post-AMI inflammation in myocardial injury and atherosclerosis progression, no treatments specifically target this inflammatory response [3, 5].Inflammation plays a paradoxical role in the pathogenesis and recovery of myocardial infarction (MI). In the immediate aftermath of an infarction, a finely tuned immune response is essential for clearing necrotic tissue and initiating healing [3, 6]. Yet, when inflammation becomes chronic – identified as residual inflammatory risk – it can have deleterious consequences. Persistent low-grade inflammation can exacerbate myocardial damage, contribute to adverse remodeling, and heighten the risk of major cardiovascular events, including reinfarction and heart failure, while also accelerating atherosclerosis progression [3]. Notably, many AMI patients exhibit sustained inflammation rather than elevated low-density lipoprotein cholesterol levels, and in those undergoing intensive lipid-lowering therapy, inflammation – measured by high-sensitivity C-reactive protein – emerges as a stronger predictor of future cardiovascular events than low-density lipoprotein cholesterol itself.Various strategies to mitigate post-infarction inflammation have been explored, albeit with mixed results. Methotrexate, a well-established immunosuppressant widely used in rheumatological diseases, was hypothesized to offer cardiovascular benefits by dampening inflammation. Epidemiological studies in patients with rheumatoid arthritis suggested its potential to reduce atherosclerotic burden and vascular inflammation [3]. However, clinical trials have largely failed to translate these theoretical benefits into tangible outcomes. The Cardiovascular Inflammation Reduction Trial (CIRT) found no significant improvement in cardiovascular events when methotrexate was administered to patients with stable coronary artery disease [7]. Similarly, the TETHYS trial, which investigated the early administration of methotrexate in ST-segment elevation myocardial infarction (STEMI) patients – administered prior to PCI with a 6-hour infusion – did not demonstrate a reduction in infarct size [6]. Moreover, at the 3-month follow-up, left ventricular ejection fraction (LVEF) was found to be lower in patients who had received methotrexate. However, long-term outcome data from this study remained unavailable.In this context, the 5-year follow-up of the TETHYS trial, as reported in the present paper by Raimundo et al. [8], provides crucial insights into the prolonged effects of methotrexate in patients with STEMI. This observational analysis included 81 patients previously randomized to receive either methotrexate or placebo in the original trial. The primary endpoint was a composite measure of cardiovascular events, assessed through the win ratio (WR), which integrated mortality, reinfarction, stroke, rehospitalization, and changes in LVEF. The study revealed that patients treated with methotrexate had significantly fewer wins in the WR analysis compared to those in the placebo group (WR 0.56, 95% CI: 0.34–0.93; p = 0.026).One of the most striking findings was the absence of significant differences in LVEF trajectory over time between the two groups (p = 0.308). Although a transient improvement in LVEF was observed at 180 days in the methotrexate group, this benefit did not persist in the long term. Instead, the study highlighted an increased incidence of adverse cardiovascular events in patients treated with methotrexate over 5 years, suggesting that any early anti-inflammatory benefits were ultimately outweighed by long-term risks. Nevertheless, these findings should be interpreted with caution and remain open to debate.First, the inflammatory response following AMI encompasses a complex spectrum of molecular, cellular, and histological processes. While excessive inflammation can contribute to myocardial damage and adverse remodeling, it also plays a crucial role in tissue repair and healing. Broad immunosuppression with agents like methotrexate may inadvertently disrupt these essential reparative mechanisms, leading to poorer outcomes [3]. Conversely, targeted anti-inflammatory therapies have the potential to selectively suppress pathological immune activation while preserving the physiological healing response. For instance, the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) demonstrated that inhibiting interleukin-1 beta (IL-1β) could effectively reduce cardiovascular events as this cytokine is a key modulator of atherothrombosis-related inflammation [9].Second, the timing of anti-inflammatory therapy is critical. In animal models, excessive suppression of post-MI inflammation during the acute phase has been associated with impaired clearance of necrotic debris, ultimately leading to defective healing and increased myocardial vulnerability [3]. This phenomenon may explain why methotrexate, despite its initial positive impact on LVEF, was ultimately linked to worse long-term cardiovascular outcomes.Furthermore, in the aftermath of AMI – particularly in STEMI – the inflammatory response follows a bimodal pattern. The first phase is triggered by plaque rupture and coronary occlusion, resulting in the release of cytokines and the recruitment of inflammatory cells. This response is further amplified following vessel recanalization due to reperfusion injury [3, 9]. Subsequently, a state of chronic low-grade inflammation emerges, driven by both traditional and non-traditional risk factors, such as air pollution and chronic inflammatory diseases, contributing to long-term cardiovascular complications.Targeting the initial surge of inflammation following AMI may help mitigate subsequent myocardial damage. The Virginia Commonwealth University Anakinra Remodeling Trial (VCU-ART) [10] and the Assessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction (ASSAIL-MI) [11] trials focused on the early inflammatory phase (within 12 and ≤6 h after symptom onset, respectively) and demonstrated beneficial effects. In contrast, the CLEVER-ACS [12] trial found no additional advantages of anti-inflammatory therapy when administered up to 5 days post-PCI, as assessed by cardiac magnetic resonance endpoints. These findings suggest that beyond a critical early window, it may be too late to counteract the initial inflammatory cascade triggered by AMI effectively [13].In the TETHYS trial [6, 8], methotrexate was administered prior to PCI, with a single 6-hour infusion (mean door-to-balloon time: 111.7 ± 47.1 min in the methotrexate group). In this setting, early reperfusion may have already significantly reduced myocardial damage and the subsequent inflammatory spikes, potentially overshadowing any additional benefits of anti-inflammatory therapy. Furthermore, early administration of such therapy may fail to address the chronic phase of residual inflammatory risk, which is a well-established driver of long-term cardiovascular events.Personalizing anti-inflammatory therapy is another crucial consideration. In the TETHYS trial [8], patients exhibited only mild elevations in inflammatory biomarkers. It is likely that those with a greater inflammatory burden – such as individuals with larger infarct sizes – would derive more substantial benefits from targeted anti-inflammatory intervention. Higher levels of troponins, C-reactive protein, or interleukin-6 (IL-6) may serve as useful indicators to identify patients who are more likely to benefit from such therapies [3].The long-term findings of the TETHYS trial underscore the need for caution in implementing anti-inflammatory strategies for STEMI patients. However, the exploratory nature of the study also highlights the inherent limitations of small-scale clinical trials in detecting nuanced treatment effects, as well as the complexity of inflammation-targeting strategies in cardiovascular disease. These results reinforce the importance of evidence-based decision-making in cardiology and emphasize the need for continued research into safer and more effective ways to mitigate post-MI inflammation. As the field progresses, precision medicine is poised to play an increasingly pivotal role in determining which patients stand to benefit from targeted immunomodulation – and, just as importantly, the optimal timing to intervene in the inflammatory cascade, as shown in Figure 1.The authors have no conflicts of interest to declare.This study was not supported by any sponsor or funder.C.P.: supervision, validation, and writing – review and editing. F.A., L.B., and M.A.: conceptualization and writing – original draft.