ST elevation myocardial infarction pathophysiology of reperfusion

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The Importance of Restoring and Sustaining Complete Epicardial and Myocardial Perfusion
Recently, it has become recognized that it is necessary but not sufficient to restore epicardial flow in ST elevation MI. Not all TIMI grade 3 flow is created equally. In addition to epicardial flow, myocardial perfusion must be restored as well. This has been demonstrated in both myocardial contrast echo studies as well as angiographic studies            As a result of this new understanding, the goal of reperfusion therapies has shifted to include reperfusion downstream at the level of capillary bed, and it might be more appropriate that the current reperfusion hypothesis now be termed "the time dependent open muscle hypothesis."

TIMI Flow Grades (TFGs)
The Thrombolysis In Myocardial Infarction (TIMI) flow grade classification scheme has been widely used to assess coronary blood flow in acute coronary syndromes. TFG 0 means the artery is closed; TFG 1 means that dye penetrates the stenosis but does not reach the downstream bed; TFG 2 means that flow is slow down the artery and TFG 3 means that normal flow has been restored. The association of the TFGs with clinical outcomes (including mortality) has been well documented

The association of the TFGs with mortality must be interpreted with caution as there are several confounders:

1. The majority of TIMI grade 2 flow is observed in the left anterior descending artery (LAD) territory, whereas the majority of TIMI grade 3 flow is observed in the right coronary artery (RCA). Thus, the improved mortality observed among patients with TIMI grade 3 flow may be explained at least in part by the fact that inferior myocardial infarction (MI) location is associated with a lower mortality rate

2. The clinical improvement associated with TIMI grade 3 flow may have be nonlinear. For example, greater clinical benefits may be observed if a closed artery (TFG 0/1) is opened (TFG 2) compared with the improvement that might occur if an artery with TFG 2 is converted to TFG 3 flow.

3. As more arteries with TFG 2 flow are treated with adjunctive percutaneous coronary intervention (PCI), the prognosis associated with this flow grade may improve. The fact that patients who were treated with an inferior fibrinolytic monotherapy strategy faired so well in GUSTO V may be explained in part by the fact that these patients underwent PCI more often. Two-year follow-up in more recent studies indicates that the survival advantage of TFG 3 flow over TFG 2 flow at 2 years may not be as great as it once was in the era before aggressive utilization of rescue and adjunctive PCI

Reocclusion
While PCI may obviously improve epicardial flow, another often unrecognized benefit is the fact that rescue PCI (dilating a closed artery) and adjunctive PCI (dilating an open artery) following fibrinolytic administration may reduce the risk of reocclusion. Reinfarction doubles early mortality by 30 days. Controversy has surrounded the use of PCI immediately following PCI, and for many years, immediate PCI was classified as a class III contraindication. These early trials preceded the use of stents, thienopyridines, platelet GP IIb/IIIa inhibitors, and the monitoring of activated clotting times. Among 20 101 patients enrolled in recent TIMI trials, Gibson et al have reported that the performance of PCI during the index hospitalization was associated with a lower rate of in-hospital recurrent MI (1.6% versus 4.5%, P<0.001) and a lower 2-year mortality (5.6% versus 11.6%, P<0.001). In addition to flow other nonangiographic findings and processes may also underlie the pathophysiology of reocclusion as well as other clinical outcomes.

The TIMI Frame Count: A More Precise Angiographic Index of Coronary Blood Flow
There are several limitations to the TFG classification scheme. To overcome these limitations, Gibson developed a more objective and precise index of coronary blood flow called the corrected TIMI frame count (CTFC). In this method, the number of cineframes required for dye to reach standardized distal landmarks are counted. Each frame is 1/30th of a second, and the angiogram is therefore essentially a measure of the time for dye to go down the artery. In the first frame used for TIMI frame counting, a column of dye touches both borders of the coronary artery and moves forward. In the last frame, dye begins to enter (but does not necessarily fill) a standard distal landmark in the artery. These standard distal landmarks are as follows: in the RCA, the first branch of the posterolateral artery; in the circumflex system, the most distal branch of the obtuse marginal branch, which includes the culprit lesion in the dye path; and in the LAD, the distal bifurcation, which is also known as the "moustache," "pitchfork" or "whale’s tail". These frame counts are corrected for the longer length of the LAD by dividing by 1.7 to arrive at the CTFC. Knowing the time for dye to go down the artery from the CTFC (CTFC/30=seconds), and length of the artery (either from an angioplasty guide wire or by planimetry), dye velocity (cm/s) can also be calculated in a more refined fashion. . This refined measure allows calculation of the velocity proximal and distal to the lesion.

Some of the advantages of the TIMI frame count method are as follows. In contrast to the TFG classification scheme, the CTFC is quantitative rather than qualitative, it is objective rather than subjective, it is a continuous rather than a categorical variable, and it is reproducible. The CTFC demonstrates that flow is not divided into arbitrary slow and fast categories, but rather coronary blood flow is unimodally distributed as a continuous variable. The CTFC has been shown to be quite reproducible with a 1- to 2-frame difference between observers. The CTFC is also highly correlated with other measures of flow such as Doppler velocity wire measures of coronary flow reserve, distal velocity, average peak velocity, and volumetric flow,  as well as fractional flow reserve (r=0.85)

Several technical and physiological variables may impact the CTFC    :

1. Injection force: A power injector to change the force of injection (cc/sec) from the 10th to the 90th percentile of human injection rates lowers the CTFC by only 2 frames.

2. Nitrate administration significantly increases the CTFC by 6 frames (P<0.001)

3. Dye injection at the beginning of diastole decreases the CTFC by 3 to 6 frames

4. Increasing the heart rate by 20 beats per minute significantly decreases the CTFC by 5 frames (P<0.001)

Association of the CTFC with Clinical Outcomes
Following fibrinolytic administration as well as PCI, the CTFC is related to a variety of clinical outcomes       Flow in the infarct-related artery in survivors is significantly faster than in patients who die (49.5 versus 69.6 frames; P=0.0003). In NSTEMI and STEMI, the post-PCI culprit flow among survivors is significantly faster than among those patients who died (CTFCs 20.4 versus 33.4 frames, P=0.017). Among patients undergoing PCI, the CTFC has demonstrated greater sensitivity in detecting improvements in epicardial flow compared with the use of TIMI grade 3 flow among patients treated with new device interventions and in the detection of transplant rejection.

The Pathophysiology of STEMI and UA/NSTEMI Based on measures of epicardial flow
One of the more interesting observations learned with the use of the CTFC is the fact that flow in nonculprit arteries in the setting of acute coronary syndromes is "abnormal." For instance, the CTFC in uninvolved arteries in acute STEMI (30.5 frames) is in fact 40% slower than normal (21 frames, P<0.001)   Adjunctive and rescue PCI following fibrinolysis restores flow in culprit vessels that is nearly identical to that of nonculprit arteries in the STEMI setting (30.5 versus 30.5 frames, p=NS), but this flow remains slower than normal (21 frames). It is notable that PCI of the culprit lesion is also associated with improvements in the nonculprit artery after the intervention in both the STEMI and UA/NSTEMI settings. Slower flow throughout all 3 arteries in STEMI is associated with a higher risk of adverse outcomes, poorer wall motion in remote territories , poorer tissue perfusion on digital subtraction angiography (DSA) , and a greater magnitude of ST depression in remote territories such as the anterior precordium in inferior MI. The basis of slowed flow in non-culprit arteries is not clear. It has been speculated that the delayed flow in the non-culprit artery may be the result of spasm in shared territories of microvasculature, or a result of global vasoconstriction mediated through either a local neurohumoral or paracrine mechanism. Gregorini et al have highlighted the importance of sympathetic storm. Consistent with this hypothesis, they have demonstrated that the CTFC and fractional wall shortening is improved in both the culprit and nonculprit arteries after administration of alpha-blockers. Willerson and others      have also demonstrated that a wide range of vasoconstrictors including thromboxane A2, serotonin, endothelin, oxygen-derived free radicals, and thrombin are all released in the setting of vessel injury, thrombosis and reperfusion. While a residual stenosis following PCI in the setting of STEMI may be responsible for the delay in flow, it is important to note that despite a minimal 13% residual stenosis and the relief of intraluminal obstruction with stent placement, flow remains persistently abnormal in 34% of stented vessels.

Assessment of Myocardial Perfusion on the Angiogram: The TIMI Myocardial Perfusion Grade (TMPG)
Studies of myocardial constrast echocardiography (MCE) and angiography have demonstrated that restoration of epicardial flow does not necessarily lead to restoration of tissue level or microvascular perfusion. Perfusion of the myocardium can also be assessed using the angiogram. In the TMPG system, TMPG 0 represents minimal or no myocardial blush; in TMPG 1, dye stains the myocardium, and this stain persists on the next injection; in TMPG 2, dye enters the myocardium but washes out slowly so that dye is strongly persistent at the end of the injection; and in TMPG 3, there is normal entrance and exit of dye in the myocardium. Another method of assessing myocardial perfusion on the angiogram is the myocardial blush grade (MBG) developed by van’t Hof et al. A grade of 0 (no blush) and a grade of 3 (normal blush) are the same in the TMPG and MBG systems. An MBG grade 1 or 2 represents diminished intensity in the myocardium and corresponds to a value of 0.5 in the expanded TMPG grading system. A TMPG of 1 or a stain in the TIMI system is subsumed within the value of a 0 in the MBG system. Thus, normal perfusion in the myocardium carries a score of 3 in both the TMPG and MBG systems, and a closed muscle carries a score of 0 in both systems. Lepper et al. have demonstrated that angiographic and echocardiographic myocardial perfusion are closely related, and among patients undergoing primary PCI for acute MI, impaired MBG was the best multivariate predictor of nonreperfusion on myocardial contrast echocardiography.

Independent of flow in the epicardial artery and other covariates such as age, blood pressure, and pulse, the TMPG has been shown to be multivariate predictors of mortality in acute STEMI at 2 years. The TMPG permits risk stratification even within epicardial TIMI grade 3 flow. Despite achieving epicardial patency with normal TIMI grade 3 flow, those patients whose microvasculature fails to open (TMPG 0/1) have a 7-fold increase in mortality compared with those patients with both TIMI grade 3 flow in the epicardial artery. Achievement of both TIMI grade 3 flow in both the artery and the myocardium is associated with a mortality under 1%10. Likewise, in the setting of primary PCI, both van’t Hof et al. and Haager et al. have demonstrated an association between impaired myocardial perfusion and early and late mortality. These improvements in early and late mortality may be mediated by improvements in myocardial salvage. As Dibra et al. have demonstrated, restoration of TMPG 2/3 is associated with a higher salvage index (0.49±0.42 versus 0.34±0.49, P=0.01) and a smaller final infarct size (15.4±15.5% versus 22.1±16.2% of the left ventricle, P=0.001). Indeed, second only to stent placement, restoration of TMPG 2/3 was the next most powerful independent determinant of the myocardial salvage index, and was more closely associated with higher salvage indexes than the TFGs.

Reperfusion injury refers to damage to tissue caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function.

Mechanisms of reperfusion injury
The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. White blood cells carried to the area by the newly returning blood release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage .The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Damage to the cell's membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis. Leukocytes may also build up in small capillaries, obstructing them and leading to more ischemia.

Reperfusion injury plays a part in the brain's ischemic cascade, which is involved in stroke and brain trauma. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal of chronic wounds such as pressure sores and diabetic foot ulcers. Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion. As this process is repeated, it eventually damages tissue enough to cause a wound.

In prolonged ischemia (60 minutes or more), hypoxanthine is formed as breakdown product of ATP metabolism. The enzyme xanthine dehydrogenase acts in reverse, that is as a xanthine oxidase as a result of the higher availability of oxygen. This oxidation results in molecular oxygen being converted into highly reactive superoxide and hydroxyl radicals. Xanthine oxidase also produces uric acid, which may act as both a prooxidant and as a scavenger of reactive species such as peroxinitrite. Excessive nitric oxide produced during reperfusion reacts with superoxide to produce the potent reactive species peroxynitrite. Such radicals and reactive oxygen species attack cell membrane lipids, proteins, and glycosaminoglycans, causing further damage. They may also initiate specific biological processes by redox signaling.

Treatment
Superoxide dismutase (SOD) as well as a variety of other agents have been studied in an attempt to reduce reperfusion injury. These studies have not been successful in the entire populations studied. However, there are subpopulations in which promising results have been observed. One such subgorup includes patients with anterior myocardial infarction. High dose intravenous adenosine and hypothermia have been associated with improved outcomes in this subgorup of STEMI patients for instance.

Therapeutic Hypothermia
An intriguing area of research demonstrates the ability of a reduction in body temperature to limit reperfusion injuries. This procedure is called therapeutic hypothermia. However, the therapeutic effect of hypothermia does not confine itself to metabolism and membrane stability. Another school of thought focuses on hypothermia’s ability to prevent the injuries that occur after circulation returns to the brain, or what is termed reperfusion injuries. In fact an individual suffering from an ischemic insult continues suffering injuries well after circulation is restored. In rats it has been shown that neurons often die a full 24 hours after blood flow returns. Some theorize that this delayed reaction derives from the various inflammatory immune responses that occur during reperfusion. These inflammatory responses cause intracranial pressure, pressure which leads to cell injury and in some situations cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patient’s inflammatory immune responses during reperfusion. Beyond this, reperfusion also increases free radical production. Hypothermia too has been shown to minimize a patient’s production of deadly free radicals during reperfusion. Many now suspect it is because hypothermia reduces both intracranial pressure and free radical production that hypothermia improves patient outcome following a blockage of blood flow to the brain.