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Microvascular obstruction: time to bust the clot hypothesis?
  1. Sean Coffey1,
  2. Philip D Adamson2,3
  1. 1 Department of Medicine - HeartOtago, University of Otago, Dunedin, New Zealand
  2. 2 Christchurch Heart Institute, University of Otago, Christchurch, New Zealand
  3. 3 British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
  1. Correspondence to Dr Sean Coffey, Department of Medicine, Otago Medical School - Dunedin Campus, University of Otago, PO Box 56, Dunedin 9054, New Zealand; sean.coffey{at}otago.ac.nz

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Primary percutaneous coronary intervention (PPCI) is a cornerstone of treatment for acute myocardial infarction (AMI). Despite major achievements in the procedure itself and in the infrastructure allowing timely delivery of PPCI, a substantial proportion of patients will suffer significant myocardial injury despite successful treatment of the epicardial coronary artery. Microvascular obstruction (MVO), due to a combination of distal thrombotic embolisation, ischaemia reperfusion injury and related endothelial dysfunction, myocardial oedema and intramyocardial haemorrhage (IMH), is postulated as a mechanism for this residual myocardial injury. When measured by cardiac magnetic resonance (CMR) early after AMI, MVO is predictive of subsequent longer-term outcomes. At the time of PPCI, potential predictors of MVO include AMI characteristics, such as anterior territory AMI, and procedurally assessed characteristics, the most common being reduced or slow intracoronary flow.

T-TIME trial

Many approaches have been proposed to minimise the extent of MVO—thrombus aspiration prior to PCI, glycoprotein IIb/IIIa inhibitors and conventional dose fibrinolysis, with no therapy showing significant clinical efficacy once assessed in randomised trials. On the basis that MVO might be reduced by reducing the overall thrombus burden, low-dose fibrinolytic therapy has been proposed as a potential treatment in this setting. The T-TIME trial examined whether low-dose (one-fifth or one-tenth full dose) intracoronary alteplase would reduce MVO and IMH when administered during PPCI, after reperfusion of the infarct related artery, but before stent implantation.1 The trial was stopped after an interim analysis showed likely futility, with no improvement in the primary outcome—MVO measured by cardiac MRI 2–7 days after enrolment. In this issue of Heart, Maznyczka et al present a prespecified subanalysis, examining the effect of alteplase in those with normal (Thrombolysis in myocardial infarction (TIMI) 3) flow compared with those with reduced (TIMI≤2) flow immediately before study drug infusion.2 The authors hypothesised that reduced coronary flow, shown by TIMI flow of ≤2, would reduce the effective delivery of alteplase to the microcirculation and therefore lead to less reduction of MVO. However, more than this, they found that MVO and IMH were actually more frequent in those with TIMI flow of ≤2 who underwent alteplase therapy, and the MVO that was present involved a greater proportion of left ventricular (LV) mass. In those with TIMI 3 flow, there was no difference in the presence or the extent of MVO or IMH between those receiving placebo and those receiving alteplase.

Intraprocedural prediction of MVO

There are a number of possibilities that may explain this result, alongside those of the earlier T-TIME analyses and the neutral outcomes from other trials aiming to reduce MVO. The first is that our methods of detecting MVO at the time of the PPCI procedure are not accurate enough for the purpose. For example, in those with TIMI 3 flow, there may be so little MVO in those with TIMI 3 flow that alteplase could make little difference to the outcome. However, this analysis of the T-TIME trial shows this not to be the case, as 48.2% of those receiving placebo with TIMI 3 flow had MVO, and 47.6% had IMH. Similarly, at 3 months of follow-up, in the TIMI 3 flow group treated with placebo, infarct size was substantial at 17.5% of total LV mass. In a separate analysis of T-TIME, in those with two measures of invasive measures of microvascular injury (resistive reserve ratio and coronary flow reserve) within the ‘low-risk’ range, more than a quarter (27%) had MVO, compared with 41% in the subgroup tested as a whole.3 Moreover, even in those with less than 2 hours from symptom onset to reperfusion, more than 30% had MVO.4 As such, more accurate measures of subsequent MVO that can currently be performed intraprocedurally are still needed to identify those who would most benefit from treatment.

Pathophysiology of MVO

Second, we need to ask the question: are we aiming to treat the right mechanism of MVO? To date, adjunctive fibrinolytic therapy at any time point or dose alongside PPCI has not been shown to confer clinical improvement.5 6 In the present study, the authors suggest that this finding may be related to undesired procoagulant effects of fibrinolytic therapy in slow microvascular flow conditions. In contrast, myocardial haemorrhage appeared to be increased in those with TIMI flow of ≤2. An alternative possibility is that microvascular thrombosis and distal embolisation are not a major direct cause of MVO. Consistent with this, no other therapy targeting this potential mechanism has shown any benefit, with, for example, delayed stent implantation, thrombectomy and distal protection devices all largely failing to show clinical utility.

A number of potentially modifiable pathophysiological processes remain suitable targets for reducing MVO (figure 1). Some, for example, the use of vasoactive agents to improve endothelial function,7 or the use of preischaemic or postischaemic conditioning to reduce ischaemia/reperfusion injury,8 have yet to bear fruit, while others remain underexplored. For example, a hallmark of AMI imaging on CMR is the intense T2 signal reflecting predominantly extracellular oedema. Preclinical studies have shown that the end-diastolic pressure in the LV myocardium can more than double (from 15 mm Hg above the left ventricular end-diastolic pressure (LVEDP) to 38 mm Hg above the LVEDP) with experimentally induced increases in myocardial extravascular fluid,9 levels which are highly likely to affect coronary perfusion pressure. In addition, myocardial water content can be reduced in the ischaemic zone using steroid therapy.10 Whether such a treatment can demonstrate clinical efficacy remains to be determined, but in light of the work by Maznyczka et al, we would suggest that investigators look beyond microvascular thrombosis in the worthwhile search for future treatment gains.

Figure 1

Mechanisms of MVO. After primary percutaneous coronary intervention re-establishes perfusion following acute myocardial ischaemia, an ischaemia/reperfusion injury occurs in the distal microcirculation. The mechanisms of MVO include myocardial inflammation with migration of neutrophils and other inflammatory cells (A); myocardial oedema, increased intramyocardial pressure and subsequent extravascular compression (B); endothelial dysfunction with vasoconstriction, endothelial gaps, extravasation of red blood cells and intramyocardial haemorrhage (C); microvascular thrombosis with a platelet/neutrophil aggregate (D); and distal embolisation of both thrombotic and atherosclerotic material (E). MVO, microvascular obstruction.

References

Footnotes

  • Contributors Both authors were responsible for manuscript planning. SC wrote the first draft. Both authors made critical revisions and provided intellectual content to the manuscript, approved the final version to be published and agreed to be accountable for all aspects of the work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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