Targeting Reperfusion Injury in the Era of Primary PCI
Several factors influence the effect of cardioprotection: (1) in experimental studies, ischaemia is induced by ligation of a vessel and not by plaque rupture and thrombus formation; (2) comorbidities; (3) thrombectomy and more effective antiplatelet drugs; (4) general improvement for patients with STEMI; and (5) preinfarction angina, pre-PCI thrombolysis in myocardial infarction (TIMI) flow, collateral flow, duration of ischaemia and hyperglycaemia are suggested to be determinants of reperfusion injury. The impact of this last set of factors on reperfusion injury and cardioprotection is discussed in the following paragraphs, and recommendations for future clinical studies are shown in Table 4.
Angina preceding an acute myocardial infarction may resemble the mechanism of ischaemic preconditioning and lead to cardioprotection. Observational clinical studies support this notion since preinfarction angina improved clinical outcomes, probably through increasing myocardial salvage index and reducing infarct size. The cardioprotective mechanism of preinfarction angina may involve ischaemic preconditioning, recruitment of existing collaterals, increasing use of medication and accelerated thrombolysis. Ischaemic preconditioning includes an early protective window (1–2 h before infarction) and a late window (24–48 h before infarction). Conversely, existing data suggest that preinfarction angina at any time (<90 days) is associated with cardioprotection, maybe because these patients experience symptomatic and silent ischaemic episodes on a regular basis. Whether preinfarction angina interferes with protective treatments is uncertain.
Poor preprocedural flow regarded as TIMI flow 0/1 vs 2 or vs 3 in the infarct-related artery is present in approximately 60% of patients with STEMI treated with primary PCI and is independently associated with adverse outcomes, smaller myocardial salvage and larger myocardial infarct size in a stepwise manner. The time window for cardioprotection is restricted to the very first minutes of reperfusion, and conditioning only supposed to work in TIMI 0/1, because it will be applied at the time of reperfusion. This is confirmed in clinical studies since the effects of several cardioprotective strategies are lost in patients with pre-TIMI flow 2/3.
Experimental data show that collateral flow to the ischaemic myocardium is a major determinant of myocardial infarct size and salvage. Approximately one-fifth of patients without coronary artery disease and one-third of patients with coronary artery disease have well-developed collateral flow sufficient to prevent ischaemia. It is therefore believed that collateral flow to the infarct-related artery during a STEMI prevents reperfusion injury. This effect may be more pronounced in humans since the collateral flow constitutes a larger proportion of the antegrade flow in comparison to most other species. Collateral flow in patients with STEMI is traditionally assessed using the angiographic Rentrop score. However, the cardioprotective consequence of angiographic visible collateral in patients with STEMI seems to be smaller than expected since it is not related to either myocardial salvage or mortality. The discrepancy between experimental and clinical studies may be explained by the following: (1) collateral flow during coronary occlusion is recruited by angiographic invisible small vascular overlay or angiographic visible larger arteries. Thus, angiography does not quantitate the collateral flow or take invisible collaterals into account. (2) The importance of collaterals may be blunted by differences in baseline characteristics. (3) Patients with collateral flow sufficient to prevent ischaemia may not present with a STEMI, but with a non-STEMI or chronic total occlusion. Altogether, the presence of angiographic visible collaterals in patients with STEMI should not influence the revascularisation and cardioprotective strategy.
It seems that longer time of ischaemia results in loss of cardioprotection, and therefore, focus on the early presenters in clinical trials is important. This may be because interventions generally are most effective in the first two to three hours after onset of ischaemia, patients with long duration of ischaemia demonstrate large areas of irreversible myocardial damage and subsequently fewer cardiomyocytes are exposed to reperfusion injury with a potential of reversibility, and longer duration of ischaemia leads to changes in the mitochondria, rendering them more resistant to cardioprotection.
Duration of ischaemia in patients with STEMI is traditionally assessed as time from symptom onset until wire/balloon (treatment delay). However, observational clinical studies demonstrate a weak nearly horizontal correlation between treatment delay and mortality. Also, the influence of treatment delay on infarct size and myocardial salvage is controversial. There are several explanations for this discrepancy. First, in observational studies late presenters typically are characterised as low-risk patients that have survived the initial critical phase and benefit less from reperfusion and early presenters as high-risk patients. Second, treatment delay is hampered by patient memory bias. Third, symptom onset may represent preinfarction angina. Fourth, the proportion of the infarct size caused by reperfusion injury is relatively smaller in patients with longer time of ischaemia due to less viable myocardium. Alternatively duration of ischaemia can be assessed as time from first medical contact to balloon (system delay), which is associated with mortality, infarct size and myocardial salvage.
Hyperglycaemia upon admission is observed frequently in patients with STEMI and may be unfavourable during reperfusion and linked to the subsequent injury. Previous studies have demonstrated larger infarct size and poorer prognosis in patients with hyperglycaemia upon admission compared with patients without hyperglyacemia. However, hyperglycaemia is also related to larger area at risk, and hence not to a smaller myocardial salvage index or infarct size adjusted for area at risk or other predictors. Similarly, hyperglycaemia upon admission fails to predict prognosis adjusted for other important predictors. These findings imply that the larger myocardial damage and adverse prognosis reported in patients with hyperglycaemia are the result of larger area at risk and not smaller salvage. Thus, it seems plausible that hyperglycaemia is a high-risk indicator and an innocent bystander rather than being a detrimental factor per se.
Determinants of Reperfusion Injury in Patients With STEMI
Several factors influence the effect of cardioprotection: (1) in experimental studies, ischaemia is induced by ligation of a vessel and not by plaque rupture and thrombus formation; (2) comorbidities; (3) thrombectomy and more effective antiplatelet drugs; (4) general improvement for patients with STEMI; and (5) preinfarction angina, pre-PCI thrombolysis in myocardial infarction (TIMI) flow, collateral flow, duration of ischaemia and hyperglycaemia are suggested to be determinants of reperfusion injury. The impact of this last set of factors on reperfusion injury and cardioprotection is discussed in the following paragraphs, and recommendations for future clinical studies are shown in Table 4.
Preinfarction Angina
Angina preceding an acute myocardial infarction may resemble the mechanism of ischaemic preconditioning and lead to cardioprotection. Observational clinical studies support this notion since preinfarction angina improved clinical outcomes, probably through increasing myocardial salvage index and reducing infarct size. The cardioprotective mechanism of preinfarction angina may involve ischaemic preconditioning, recruitment of existing collaterals, increasing use of medication and accelerated thrombolysis. Ischaemic preconditioning includes an early protective window (1–2 h before infarction) and a late window (24–48 h before infarction). Conversely, existing data suggest that preinfarction angina at any time (<90 days) is associated with cardioprotection, maybe because these patients experience symptomatic and silent ischaemic episodes on a regular basis. Whether preinfarction angina interferes with protective treatments is uncertain.
Pre-PCI TIMI Flow
Poor preprocedural flow regarded as TIMI flow 0/1 vs 2 or vs 3 in the infarct-related artery is present in approximately 60% of patients with STEMI treated with primary PCI and is independently associated with adverse outcomes, smaller myocardial salvage and larger myocardial infarct size in a stepwise manner. The time window for cardioprotection is restricted to the very first minutes of reperfusion, and conditioning only supposed to work in TIMI 0/1, because it will be applied at the time of reperfusion. This is confirmed in clinical studies since the effects of several cardioprotective strategies are lost in patients with pre-TIMI flow 2/3.
Collateral Flow
Experimental data show that collateral flow to the ischaemic myocardium is a major determinant of myocardial infarct size and salvage. Approximately one-fifth of patients without coronary artery disease and one-third of patients with coronary artery disease have well-developed collateral flow sufficient to prevent ischaemia. It is therefore believed that collateral flow to the infarct-related artery during a STEMI prevents reperfusion injury. This effect may be more pronounced in humans since the collateral flow constitutes a larger proportion of the antegrade flow in comparison to most other species. Collateral flow in patients with STEMI is traditionally assessed using the angiographic Rentrop score. However, the cardioprotective consequence of angiographic visible collateral in patients with STEMI seems to be smaller than expected since it is not related to either myocardial salvage or mortality. The discrepancy between experimental and clinical studies may be explained by the following: (1) collateral flow during coronary occlusion is recruited by angiographic invisible small vascular overlay or angiographic visible larger arteries. Thus, angiography does not quantitate the collateral flow or take invisible collaterals into account. (2) The importance of collaterals may be blunted by differences in baseline characteristics. (3) Patients with collateral flow sufficient to prevent ischaemia may not present with a STEMI, but with a non-STEMI or chronic total occlusion. Altogether, the presence of angiographic visible collaterals in patients with STEMI should not influence the revascularisation and cardioprotective strategy.
Duration of Ischaemia
It seems that longer time of ischaemia results in loss of cardioprotection, and therefore, focus on the early presenters in clinical trials is important. This may be because interventions generally are most effective in the first two to three hours after onset of ischaemia, patients with long duration of ischaemia demonstrate large areas of irreversible myocardial damage and subsequently fewer cardiomyocytes are exposed to reperfusion injury with a potential of reversibility, and longer duration of ischaemia leads to changes in the mitochondria, rendering them more resistant to cardioprotection.
Duration of ischaemia in patients with STEMI is traditionally assessed as time from symptom onset until wire/balloon (treatment delay). However, observational clinical studies demonstrate a weak nearly horizontal correlation between treatment delay and mortality. Also, the influence of treatment delay on infarct size and myocardial salvage is controversial. There are several explanations for this discrepancy. First, in observational studies late presenters typically are characterised as low-risk patients that have survived the initial critical phase and benefit less from reperfusion and early presenters as high-risk patients. Second, treatment delay is hampered by patient memory bias. Third, symptom onset may represent preinfarction angina. Fourth, the proportion of the infarct size caused by reperfusion injury is relatively smaller in patients with longer time of ischaemia due to less viable myocardium. Alternatively duration of ischaemia can be assessed as time from first medical contact to balloon (system delay), which is associated with mortality, infarct size and myocardial salvage.
Hyperglycaemia Upon Admission
Hyperglycaemia upon admission is observed frequently in patients with STEMI and may be unfavourable during reperfusion and linked to the subsequent injury. Previous studies have demonstrated larger infarct size and poorer prognosis in patients with hyperglycaemia upon admission compared with patients without hyperglyacemia. However, hyperglycaemia is also related to larger area at risk, and hence not to a smaller myocardial salvage index or infarct size adjusted for area at risk or other predictors. Similarly, hyperglycaemia upon admission fails to predict prognosis adjusted for other important predictors. These findings imply that the larger myocardial damage and adverse prognosis reported in patients with hyperglycaemia are the result of larger area at risk and not smaller salvage. Thus, it seems plausible that hyperglycaemia is a high-risk indicator and an innocent bystander rather than being a detrimental factor per se.