Pulse Glucocorticoid Therapy in Patients With ST-Segment Elevation Myocardial Infarction

BACKGROUND Myocardial reperfusion with the use of primary percutaneous coronary intervention (PCI) including stent implantation is the most efficacious treatment for patients with (STEMI) and improves prognosis significantly. Due to continuous improvements in the treatment, the mortality for patients with STEMI has decreased dramatically, but despite these improvements, the mortality rate seems to have reached a plateau at around 10% within 1 year. In addition, 10% develop clinical heart failure with a per se 50% mortality rate within 5 years. Moreover, congestive heart failure is associated with a highly impaired quality of life due to fatigue dyspnea and reduced exercise capacity. Thus, there is a need for further improvement in the treatment to drive the event rates further down. One such key target is reducing the damage to the heart muscle (infarct size) to preserve the heart function and prevent mortality and heart failure. One major driver of infarct size is reperfusion injury which may account for up to 50% of the damaged myocardium. Reperfusion injury occurs within the first minutes to hours after the restoration of the blood flow in the occluded artery and reperfusion therapy can therefore be considered a "double-edged sword", since the ischemic injury may additionally be worsened by reperfusion injury. However, the phenomenon of reperfusion injury is not completely understood, and no preventive treatments exist. Multiple pathophysiological factors may contribute to reperfusion injury of which inflammation has been described as a key factor.

Inflammation is induced immediately after the onset of acute myocardial ischemia and is subsequently exacerbated following reperfusion. Hence, inflammation per se may drive excessive cardiomyocyte death resulting in decreased contractility and increased infarct size post-STEMI. Moreover, in the course following STEMI and subsequently reperfusion, the myocardium starts healing and scarring resulting in remodelling of the ventricle potentially causing either compensatory hypertrophy or thinning of the myocardium, which may lead to reduced left ventricle ejection fraction (LVEF) and heart failure. Of note, inflammation plays a critical role in ventricular remodeling post-AMI, thus inflammation in relation to reperfusion injury may extend myocardial damage following STEMI.

Glucocorticoids are crucial in the regulation of the systemic inflammatory response and may therefore be beneficial in limiting myocardial injury following STEMI. Glucocorticoids mediate two different mechanisms: the genomic effect mediated by glucocorticoid receptor occupation, gene transcription, and translation within the cell which is induced within hours, and the non-genomic effect, which is induced rapidly (<15 minutes) after administration via plasma membrane-bound receptors and independent of cytosolic receptor occupation and genomic regulation. Some of the proposed nongenomic effects of glucocorticoids on the cardiovascular system included decreased vascular inflammation and reduced infarct size, cardio protection through membrane stabilisation, and increasing contractility of the vascular smooth muscle cells. Of note, high single-dose glucocorticoid (methylprednisolone) (>250 mg), known as pulse therapy has been proven lifesaving in serval acute conditions including acute rheumatic diseases, exacerbations in lung diseases, imminent cerebral incarceration, and lately COVID-related pulmonary incapacity. The beneficial acute effects of pulse glucocorticoid therapy in these conditions are thought to be mediated by the nongenomic effects of glucocorticoids via plasma membrane-bound receptors, and the estimated complete glucocorticoid receptor occupation is reached at approximately 100 mg methylprednisolone, reaching maximum activation around 250 mg. Moreover, long-term treatment with glucocorticoids is associated with a series of side effects, whereas short-term treatment only has a few side effects. Considering this knowledge of the dual effects of glucocorticoids, safety, and advances in reperfusion strategies, glucocorticoids may now add additional beneficial role in limiting infarct size and improving prognosis in patients with STEMI. Systemic intravenous short-term treatment with glucocorticoids could therefore add an important, beneficial, and safe therapeutic role in limiting the degree of myocardial injury and thereby improving prognosis in patients with STEMI.

In summary, STEMI remains one of the leading causes of mortality globally despite significant advances in reperfusion therapies with timely primary PCI, one in five patients develop heart failure or died within one year following STEMI. The main driver for mortality and heart failure following STEMI is infarct size which is related to ischemia- and reperfusion-induced inflammatory response. Thus, inflammation is an important factor in acute myocardial ischemia and reperfusion injury, which is why inflammation per se is a feasible and desirable target for improving prognosis in these patients. To reduce the degree of inflammation effectively and adequately, intervention is to be made as soon as possible as close to initiation of ischemia, as recognized from patients' symptom debut, and before revascularization with primary PCI in the prehospital setting since the effect is more pronounced if the treatment is initiated early after the onset of STEMI. In addition to reperfusion induced inflammation, ischemia itself, immediately after occlusion of the artery, induces inflammation. Hence, initiation of the intervention in the ambulance is needed to harvest the potentially beneficial and immediate nongenomic effects and subsequent protective genomic actions of pulse glucocorticoid therapy as soon as possible. Thus, by performing intervention in the pre-hospital setting, the investigators expect that participation in the trial will have the potential to produce a direct clinically relevant benefit for the patient resulting in a measurable health-related improvement alleviating the suffering and potentially improving the health of the patient and the prognosis of the medical condition.

HYPOTHESIS In patients with STEMI undergoing primary PCI, 250 mg methylprednisolone administrated in the pre-hospital setting limits reperfusion injury and reduce final infarct size measured by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) 3 months after STEMI.