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Commentary

Targeting Inflammation After Myocardial Infarction—Another Piece of the Puzzle

Bromage, Daniel I. MD, PhD*,†; Pareek, Nilesh MD, PhD*,†; Cannata, Antonio MD*,†; Ameri, Pietro MD, PhD,‡,§

Author Information
Journal of Cardiovascular Pharmacology: June 2022 - Volume 79 - Issue 6 - p 769-771
doi: 10.1097/FJC.0000000000001261

Coronary artery disease (CAD) is one of the major causes of morbidity and mortality in the western world. Despite major improvements in treatment in the acute phase, myocardial infarction (MI), especially ST-elevation MI (STEMI), remains a major cause of heart failure (HF) and death.1 Along with prompt revascularization and antithrombotic drugs, statin therapy and pharmacological inhibition of the sympathetic nervous and renin–angiotensin–aldosterone systems are known to improve outcomes after MI. Nonetheless, patients who suffer from MI are at high risk of future atherosclerotic and HF-related events.

The recent Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction (PARADISE-MI) tested the hypothesis that further neurohormonal modulation by blockade of neprilysin with sacubitril/valsartan would reduce the rate of cardiovascular (CV) death or incident HF in patients with MI, reduced LV ejection fraction, pulmonary congestion, or both and additional high-risk features.2 Unfortunately, sacubitril/valsartan was not superior to long-established therapy—the angiotensin-converting enzyme inhibitor (ACEi), ramipril. Noteworthy, most patients were already on medical therapy at randomization, ie, 85% on beta-blockers, 78% on ACEi or an angiotensin receptor antagonist, and 40% on mineralocorticoid receptor antagonist. Despite this background therapy, CV death or HF occurred in 11.9% of the participants assigned to sacubitril/valsartan and 13.2% of those allocated to ramipril. The results of the PARADISE-MI shed light on the important unmet need of identifying new strategies to tackle the residual risk of mortality and HF after MI.

The detrimental role of inflammation in post-MI remodeling and the development of HF is increasingly apparent. It is well established that, after STEMI, cardiac cell necrosis triggers a cascade of proinflammatory chemokine and cytokine release, resulting in the rapid expansion of cells of the innate immune system.3 This so-called inflammatory phase contributes to extracellular matrix degradation and phagocytosis of necrotic cells. This gives way to the proliferative phase, characterized by a switch to reparative cell phenotypes, fibroblast proliferation, and deposition of collagen, which can contribute to LV remodeling, LV systolic dysfunction, and, ultimately, HF.

On this background, there is also emerging evidence for the pharmacologically targeted inhibition of inflammation to reduce both vascular and HF events, although distinct and separate pathways may mediate this. Indeed, the benefit of aggressive statin therapy is the result of a combination of reduction of ldl-cholesterol and inflammation. Several studies have confirmed that this leads to stabilization of the so-called “vulnerable plaque”, which is significantly associated with a higher event rate. On the other hand, neurohormonal inhibition counteracts left ventricular (LV) remodeling, which underlies HF after MI and is highest for anterior STEMI.4

Inflammation has long been considered an attractive therapeutic target for preventing progression to LV systolic dysfunction and HF after STEMI, although with mixed results. Recently, multiomics approaches have revealed the complexity, plasticity, and heterogeneity of inflammatory cells after MI, and it is therefore unsurprising that nonspecific, one-size-fits-all immunosuppression has failed to mitigate HF after MI.3 Contemporary anti-inflammatory approaches broadly relate to impeding inflammatory or metabolic risk factors upstream of MI, including with canakinumab in the CANTOS trial,5 limiting stimulation of the inflammatory cascade by restricting the production of reactive oxygen species or damage-associated molecular patterns, targeting excessive recruitment and expansion of innate immune cells, or focusing on adaptive immunity. On this line, the IL-1β inhibitor canakinumab and the anti-inflammatory agent colchicine have both been shown to reduce a range of atherosclerotic events after MI. This effect is related to a reduction in markers of inflammation but with a lesser-known effect on HF events.5

In the present issue, Del Buono et al report the effects of anakinra, a selective IL-1 receptor antagonist, on HF outcomes from 3 early phase randomized clinical trials, the Virginia Commonwealth University Anakinra Response Trial (VCUART)-1, -2, and -3.11 In this pooled analysis, anakinra reduced the combined end point of death or new-onset HF in all patients, regardless the territory of MI and, importantly, regardless of changes in myocardial function. These important results contribute to our understanding of the basic mechanism of the inflammatory response after MI. Interfering with the inflammatory cascade during and after MI has been long debated. In the immediate acute phase, inflammation and fibrotic response has been considered as part of a positive healing process. However, the potential benefit of modulating the inflammatory response is promising and not yet completely understood. On the one side, inflammation is required to activate the healing process and potentially myocardial regeneration, but from the other side, prolonged inflammation might be detrimental and lead to fibrotic replacement.6,7

Anakinra attenuates the proinflammatory milieu of the myocardium after MI, blocking inflammatory cytokines such as IL-1 and leading to better long-term outcomes. The results of this study support the targeting of inflammation in patients with CAD. Indeed, in this setting, the VCUART trials found that a reduced systemic inflammatory response was associated with reduced death or new‐onset HF or death and hospitalization for HF in the anakinra arm compared with placebo.8–10 This evidence supports the potential modulation of the inflammatory response in virtually all patients with CAD in the acute phase. This analysis supports the notion that IL-1 blockade with anakinra appears to have less effect on vascular but more effect on HF-related events, although the ultimate reasons for this are not clear yet.

Studies like the present one on the role of inflammation in CAD are necessary to allow us to exploit the positive effects of inflammation in activating the healing process while limiting the detrimental effects of scar formation, ventricular remodeling, and HF. Future studies are now also required to fully delineate therapeutic targets and to better classify patients who will benefit from anti-inflammatory strategies (Fig. 1).

F1
FIGURE 1.:
Benefit of a personalized approach targeting inflammation after MI.

Inflammation is clearly a promising target in patients with CAD, but so far, the lack of strong evidence for immune-suppressive strategies suggests that more work is needed to identify both the targets and the patients who will benefit from this strategy. An enhanced combined understanding of these concepts has the potential to lead to a personalized medicine approach of targeting specific manifestations of the post-MI proinflammatory state based on a patient's individualized risk and a tangible improvement in outcomes.

Novel studies filling the gap from bench to bedside are needed in this setting. Furthermore, the use of tailored diagnostic tests and therapeutic strategies may ameliorate long-term outcomes in patients with cardiovascular disease. Targeting inflammation adds another piece to the puzzle of pharmacological treatment for patients after MI. However, only a complete and holistic management of patients using the whole range of available therapies at hand, from timely invasive approaches to long-standing pharmacological therapies, will allow patients to enjoy the full picture of a lifelong benefit free from any further cardiovascular event after an MI.

REFERENCES

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