A CONTEMPORARY REVIEW OF ST-ELEVATION MYOCARDIAL INFARCTION: Pathophysiology, treatment options and hot topics

The immediate and long-term prognosis of patients experiencing an ST segment elevation myocardial infarction (STEMI) has changed dramatically since the introduction of coronary reperfusion therapies during primary percutaneous coronary intervention (pPCI). The evolution of these therapies accelerated with the understanding that STEMI is caused by occlusive thrombus compromising flow in an epicardial coronary artery^1,2. Initially, drug-based dissolution of the occlusive thrombus was the only therapeutic modality, but this has been superseded by mechanical recanalization and breakdown with wires and balloons with improved outcomes^3,4. The intervention in STEMI is completed with stent implantation and dual antiplatelet therapy that secures the patency of the relevant culprit epicardial coronary artery. A significant body of evidence demonstrates that this reperfusion strategy has dramatically changed the outcome of STEMI and reduced in-hospital mortality to a single digit percentage rate^5-7. Generally, the earlier a patient with STEMI arrives in the catheterization laboratory, the better the outcome^8,9. Out-of-hospital emergency services and hospitals have been reorganized to shorten the time from first contact with a patient with STEMI to the time that the coronary artery is opened, and myocardial reperfusion is secured^8-10. However, while in-hospital mortality following STEMI has been reduced by the advances in pPCI, the number of hospitalizations for heart failure following acute myocardial infarction is still high over the past decades and is associated with poor prognosis^11-12.

The area at risk (AAR) is the region of the myocardial bed supplied by the infarct related artery (IRA). In the era of reperfusion, not all the AAR will become infarcted. Depending on time to reperfusion from onset of symptoms and the exact location of occlusion, there will be a proportion of the AAR (jeopardized but not infarcted) that can be salvaged by reperfusion therapy. This can be calculated as AAR−infarct size^13(figure2).

The fundamental basis of treatment of STEMI is driven by the paradigm that myocardial necrosis is irreversible. Accordingly, the higher the loss of functional myocardium, the larger the infarct size and the higher the chances for poor patient outcomes. A second important concept is that during STEMI, several degrees of myocardial damage occur, ranging from necrosis, which is irreversible, to injury, which may be reversible. Thus, reperfusion therapy is directed to minimize necrosis and reverse myocardial injury. Significant necrosis and loss of myocardial infarction is associated with high rates of in-hospital morbidity and mortality, and poor long-term prognosis^13-16.

The most worrisome syndrome that develops in patients with STEMI and large myocardial loss is heart failure: Necrotic myocardium is replaced by fibrotic tissue, and remodeling of the left ventricle is the mechanism that compensates for myocardial loss¹⁷. Strength and mass of the fibrotic tissue are extremely critical in the remodeling process. Regeneration of the necrotic myocardium after myocardial infarction is probably minimal, if occurring at all. Replacement of the fibrotic scar with viable myocardium is the holy grail of regenerative medicine, but as of 2021 has not reached clinical medicine. It can be estimated that up to 30% of patients presenting with acute myocardial infarction (AMI) develop heart failure within 1 year following PCI with even more patients among those presenting with STEMI^11,12.

As “time is muscle” for re-establishing coronary flow in patients with STEMI, two measurements of standard-of-care were developed: (a) time to first medical care, and (b) door-to-balloon time. The shorter the time from onset of symptoms to intervention and re-establishment of coronary flow, the better the outcome for the patient⁸. Multiple studies have shown that patients with extensive myocardial loss are at higher risk to develop short- and long-term complications of acute myocardial infarction. The in-hospital course of patients with significant myocardial loss is characterized by mechanical and electrical complications such as heart failure, atrial fibrillation, ventricular arrhythmias, pericarditis and left ventricular thrombus. Long-term outcomes are typically dominated by heart failure, and ventricular and atrial arrhythmias, both of which result in poor quality of health and high use of long-term medical resources^8-10.

The current standards of care that are recommended by professional guidelines are implemented and regulated in many countries. These include 90-minutes from entry to the hospital to culprit lesion crossing. However, most recent guidelines recommend reducing this time to 45 minutes which requires an operative catheterization laboratory 24 hours every day all year round¹⁸. Out-of-hospital emergency services are required to perform electrocardiograms as early as possible, to inform the hospital immediately when STEMI is diagnosed, and to transfer patients directly to the catheterization laboratory after loading anti-platelet aggregation drugs and heparin^19-21.

Risk factors for extensive myocardial loss include late arrival for therapy (>6 hours from onset of pain); complete occlusion (TIMI flow 0-1) on arrival of an artery that supplies a large myocardial territory; and no-reflow after opening of the epicardial myocardial artery. The two common denominators of these characteristics are significant microcirculation occlusion and extensive myocardial necrosis^22-23.

Importantly, some patients who arrive early, and many who arrive late, develop massive myocardial loss despite revascularization of the epicardial coronary artery. These patients usually present with TIMI flow grade 0 or 1^{24, 25}. Not uncommonly, the flow after stent implantation is TIMI 2 or less in the absence of optimal myocardial blush^24,25. This phenomenon, known as ‘the no-reflow phenomenon’ is related to the pathophysiology of STEMI. An important observation is that embolization to the downstream microcirculation of micro thrombi and microscopic debris from the ruptured plaque and thrombus occurs as part of the STEMI syndrome. This can transpire many hours before the appearance of STEMI symptoms. A second relevant observation is that microcirculation responds to vasospastic materials released by the thrombus, and prolonged spasm results in very high resistance to flow and possible damage to both endothelial and smooth muscle cells. Third, myocardial edema compresses microcirculation, and prevents flow through microcirculation^26-28. The issue of reperfusion injury has been investigated over the course of many years, and its role in irreversible myocardial damage and clinical practice is yet to be determined despite decades long discussions^29-31.

In addition to its relation to the significant myocardial loss that leads to the development of heart failure, left ventricular remodeling is a secondary process that initially compensates for myocardial loss. However, at later stages, left ventricular remodeling is associated with ventricular enlargement and secondary phenomenon such as functional mitral valve regurgitation. The latter contributes to the reduced capacity of the heart to respond to physiological demands, and thus to worsening of heart failure^17,32,33.

Understanding coronary physiology is key for dealing with STEMI patients at risk for extensive myocardial necrosis. Coronary flow is regulated by myocardial oxygen consumption and can be increased by four-fold in healthy individuals. Increased coronary flow is mandatory for increased oxygen supply to the myocardium, as each molecule of hemoglobin that enters the coronary circulation delivers all the oxygen that is carried during its passage through the myocardium. Thus, only increased flow can provide more oxygen. The rate of flow in the coronary circulation is determined by the intramyocardial resistance of coronary arteries. Vasodilation of these arteries increases coronary flow, which leads to some degree of vasodilation of the epicardial coronary arteries in response to the increased flow. In STEMI, all these physiological mechanisms are disrupted, as detailed above^34-38.

Multiple pharmacological agents and devices have been suggested for reducing myocardial necrosis in STEMI, as add-ons to revascularization^39-41.

The pharmacological agents can be classified as vasodilators, anti-inflammatory drugs, and drugs that play a role at the molecular level.

There are three main classes of devices for reducing myocardial infarct size, which are: 1. devices that unload the left ventricle to reduce oxygen consumption and reduce myocyte injury and necrosis. 2. devices that reduce thrombus load to prevent mechanical occlusion and spasm of the microcirculation and 3. devices that affect microcirculation to improve myocardial perfusion.  A new experimental concept was recently introduced, which entails insertion of an epicardial device to deliver drugs directly to the myocardium, thus potentially reducing infarct size and inducing regeneration in the myocardium⁴².

Ejection fraction is frequently used to assess and predict prognosis after an acute STEMI event. However, more sophisticated parameters such as myocardial perfusion and microcirculatory function, as assessed in the catheterization laboratory or by cardiac MRI, provide higher resolution information on treatment effectiveness, and on pathophysiology and prognosis^15,22. Faster recovery of microcirculation predicts better prognosis of STEMI, and thus provides important insights regarding improving STEMI treatments beyond percutaneous coronary intervention^43-45.

Miracor Medical, a company based in Belgium, explored the novel concept proposed by Prof. Mohl from the University of Vienna, Austria. Prof. Mohl placed a balloon catheter in the coronary sinus and showed that by periodic inflation of the balloon and intermittent occlusion of the coronary sinus is safe and that coronary perfusion can be improved^46,47. Pressure-controlled Intermittent Coronary Sinus Occlusion (PiCSO) technology has been explored in multiple animal models and in several human trials and has received a CE-mark for its use in patients with anterior STEMI presenting with TIMI 0 or 1 within 12 hours of symptom onset. Studies in patients with STEMI demonstrated that the procedure is feasible, safe, there is an improvement in microcirculatory function and a significant reduction in infarct size as shown by MRI^48-50.

The basis of the mechanism of action is that: (1) Occlusion of the coronary sinus causes increased venous pressure, leading to redistribution of coronary flow, with recruitment of collaterals, improved myocardial perfusion and vasodilation of the small arteries and capillaries. (2) Re-opening of the coronary sinus causes a sudden pressure drop, which, in combination with vasodilation leads to a washout and clearance of occluding thrombi and micro-debris. For anterior STEMI, the protocol requires a 30- 45 minute session of PiCSO and is initiated once the culprit lesion has been opened to restore flow. Once running, the PiCSO procedure does not interfere with the intervention in the epicardial coronary artery but addresses the additional reperfusion injury that can be caused by the release of debris that occludes microcirculation during the stenting procedure.

A large-scale, multicenter, multination, randomized study of the use of PiCSO in patients with anterior STEMI presenting with TIMI 0-1 flow is currently ongoing. The primary endpoint is infarct size measured at 5 days after reperfusion by MRI⁵¹.