Salutary reperfusion is the ultimate target of ST- Segment ...sciencetxt.org/pdf/CRM-1-104.pdf · revascularization of the culprit lesion is the premise tissue reperfusion represents

20Card Res Med, 2017; Volume 1, Issue 1

Review Article

Cardiovascular Research and Medicine

Salutary reperfusion is the ultimate target of ST-Segment Elevation Myocardial Infarction (STEMI) and Acute Ischemic Stroke (AIS) interventions and should be routinely assessed in standard clinical and research protocolsPeter Lanzer1*, Richard Leigh2, Colin Berry3, Tim van de Hoef4, Wolf-Dieter Heiss5, Roxy Senior6, Andreas Schwartz7, Christoph Rischpler8 and David Liebeskind9

1Mittteldeutsches Herzzentrum, Klinikum Bitterfeld-Wolfen gGmbH, Germany2Neuro Vascular Brain Imaging Unit, Stroke Center, National Institutes of Health, Bethesda, Maryland, USA3British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom 4AMC Heartcenter, Academic Medical Center, Amsterdam, The Netherlands5Max Planck Institut für Stoffwechselforschung, Köln, Germany6Royal Brompton Hospital, London and National Heart & Lung Institute, Imperial College London, United Kingdom7Klinikum Region Hannover, Hannover, Germany8Nuklearmedizin, Klinikum rechts der Isar, Technische Universität München, München, Germany9Department of Neurology, University of California Los Angeles, Los Angeles, USA

Keywords: ST-Segment Elevation Myocardial Infarction (STEMI), Acute Ischemic Stroke (AIS), Catheter- based interventions, Ischemia, Reperfusion

IntroductionCBI in patients with STEMI and AIS aim to prevent ischemic

injury [1,2]. Critical factors that determine the success of reperfusion include duration, extent, and severity of the ongoing or intermittent ischemic insult potentially mitigated by the presence of collaterals and modified by tissue’s ischemic tolerance [3-8]. While early reperfusion may fully restore functional and structural integrity in both organs reperfusion may also fail; in some cases it may be even detrimental [9-13]. In clinical settings of CBI for STEMI and AIS reperfusion failure ≤ 50 % and ≤ 60% assessed, respectively, has been reported [14,15]. In addition, following reperfusion the ischemic tissue injury may be even aggravated [16,17]. Although numerous differences between the heart and brain exist, in both organs ischaemia-reperfusion injury (IRI) represents a dynamic process governed by similar biological principles [18-20] heralded by microvascular obstructions, intracellular and extracellular oedema, and in

some cases haemorrhagic transformations [21-27]. To date the attempts to prevent IRI produced rather disappointing results in both heart [28-30] and brain [31-33] calling for further improvements in current CBI strategies [34,35].

To improve the true efficacy of CBI strategies direct comparisons based on salutary tissue reperfusion rather than clinical endpoints are required. Using this approach multiple biases related to uncontrolled patients-, procedures and protocols- related variables, and not the least, increasingly prohibitive costs of mega-trials can be avoided [36-38]. Here, we review the current techniques to assess reperfusion following CBI in patients with STEMI and AIS and provide recommendations for their standardization and implementation in research and clinical protocols.

AbstractCatheter-based interventions (CBI) represent the first-line treatment in vast majority of patients with STEMI and in selected patients with AIS. While revascularization of the culprit lesion is the premise tissue reperfusion represents the ultimate target of the CBI. At present the revascularization can be achieved in >90% and 60-70%, and reperfusion in 50-70% and in about 50% in STEMI and AIS, respectively. Improvements of reperfusion rates are required to exploit the full potential of the CBI. To achieve this aim the assessments of reperfusion must be standardized and integrated into clinical and research protocols. Here, the current reperfusion targeting technology in heart and brain is reviewed and recommendations for their use in clinical and research settings are provided.

*Corresponding author: Peter Lanzer, Mitteldeutsches Herzzentrum, Klinikum Bitterfeld-Wolfen, gGmbH Friedrich-Ludwig-Jahn-Straße 2, D-06749 Bitterfeld-Wolfen, Germany, Tel: 49(0) 3493 31 2301; Fax: 49(0) 3493 31 2304; Email: [email protected]

Received: December 06, 2017; Accepted: December 27, 2017; Published: December 29, 2017

Citation: Lanzer P (2017) Salutary reperfusion is the ultimate target of ST-Segment Elevation Myocardial Infarction (STEMI) and Acute Ischemic Stroke (AIS) interventions and should be routinely assessed in standard clinical and research protocols


experimental setting using the gold standard radiolabeled microsphere perfusion imaging and in clinical settings using positron-emission-tomography (PET) [40,41].

In a number of clinical studies MCE performed within 24h of primary PCI in patients with STEMI demarcated the region of myocardial reperfusion and it was predictive of microvascular reflow. Furthermore, the correlation between successful myocardial reperfusion as assessed by MCE and recovery of myocardial function and correlation between reperfusion failure as assessed by MCE and LV remodeling, cardiac death and heart failure have been demonstrated [42,43]. However, poor echocardiographic windows may prevent reliable measurements in up to 8% of patients [44]. Figure 1 shows a representative example of successful and failed reperfusion in a STEMI patient following primary PCI.

Nuclear imaging techniquesA number of nuclear imaging techniques may be employed

to assess myocardial reperfusion in the clinic. IIn Single Photon Emissions Tomography (SPECT) using 99mTc-labeled sestamibi or tetrofosmin [45,46] the perfusion tracer is injected intravenously before the occluded coronary has been revascularized; immediately following percutaneous coronary intervention (PCI) the first set of images can be generated. Because 99mTc-labeled perfusion radiotracers do not redistribute the images reflect the area at risk (AAR). To determine the amount of the infarcted myocardium and resulting net myocardial salvage a second perfusion SPECT study is performed following PCI. This approach has become the reference technique for cross-validation of other

Myocardial reperfusion imaging and invasive studies

Myocardial contrast echocardiography (MCE), cardiac magnetic resonance imaging (CMRI), nuclear techniques of single photon emission tomography (SPECT) and positron emission tomography (PET) as well as invasive functional studies allow assessments of myocardial tissue reperfusion.

Myocardial contrast echocardiography (MCE)MCE utilizes microbubbles to assess myocardial perfusion.

The microbubbles have the size and rheological properties comparable to red blood cells (RBC); because they remain entirely within the intravascular space they are considered an ideal perfusion tracer. Approximately 90% of the total myocardial blood volume resides within the microcirculation. Thus, following injection of microbubbles myocardial contrast intensity reflects their concentration within the microcirculatory compartment of the myocardium. In steady state, during continuous infusion of microbubbles, the observed signal intensity reflects the blood volume contained within the microcirculatory compartment (BVMC) [39]. Consequently, alterations in signal intensity mirror the changes in BVMC. Furthermore, microbubbles myocardial capillary blood velocity (MCBV) can be measured based on the myocardial contrast replenishment following destruction of microbubbles within the myocardium by using high-energy ultrasound impulses. Thus, the product of BVMC and MCBV closely approximates myocardial blood flow at the tissue level i.e. myocardial perfusion. MCE has been validated as a robust methodology to assess myocardial perfusion in both

Figure 1. Apical four-chamber view in systole showing akinetic septum and apex (arrows) 12 h after successful PTCA. (Ab) Homogeneous contrast opacification of the akinetic segments. (Ac) Follow-up echocardiography at 1 month, showing recovery of function of these segments (arrows) with reduction of left ventricular end-systolic volume. (Ba) Apical four-chamber view in systole showing akinetic mid septum and apex (arrows) 12 h after successful PTCA. (Bb) No contrast opacification seen in mid-septum and apex. (Bc) Follow-up echocardiography at 1 month, showing lack of recovery of function of these segments (arrows) with no change in left ventricular end-systolic volume.



imaging modalities [47]. Besides the conventional perfusion tracers a number of other agents including 99mTc-labeled Annexin V, 99mTc-pyrophosphate and radiolabeled Fab fragments [48] as well as the SPECT employing Metaiodbenzylguanidine (MIBG) tracer specific for the sympathetic nerve fibers that appear to be more sensitive to ischaemia compared to cardiomyocytes [49] have been proposed but not widely used clinically.

Positron emission tomography (PET) tracers such as 11C-labeled meta-hydroxyephedrine, epinephrine or phenylephrine may also provide excellent definition of reperfusion states using the glucose or fatty acid based tracers [50,51]. Due to ischaemia cardiomyocytes temporarily switch their metabolism from fatty acid to glucose utilization via anaerobic glycolysis to generate ATP; consequently, the defect in tracer accumulation using radiolabeled fatty acids such as 123I-BMIPP appears to reflect the AAR [52]. Conversely, the 18F-FDG Fluordesoxyglucose uptake of the ischemic myocardium of fasted patients is increased following reperfusion [53]. At least part of the increased cardiac 18F-FDG accumulation occurring after reperfusion is caused by post-ischemic myocardial inflammation associated with infiltrating leukocytes [54] The cardiac 18F-FDG accumulation following STEMI reperfusion in fasting patients exceeds the infarct area assessed by MRI and likely corresponds to the AAR [55]. If confirmed, post-ischemic inflammatory response may also become a target for post-reperfusion assessments. Figure 2 provides an example of a multiparametric approach to post-reperfusion states using PET/MRI and SPECT.

Cardiac Magnetic Resonance (CMR)CMR typically depicts reperfusion states in STEMI patients

using specific imaging sequences combined with the contrast agent gadolinium. Microvascular obstruction is depicted as a central dark core within the hyperintense infarct zone [56-59] reflecting a failure of gadolinium to penetrate within the obstructed infarct core microvessels. Haemorrhagic transformation within the infarct core, or extravasation of red cells and capillary degradation that may subsequently supervene [60,61], causes local dephasing of spins, i.e. hydrogen atoms of the myocardium, due to the paramagnetic effects of deoxyhaemoglobin associated with a shortening of tissue magnetic relaxation times. Using T2* CMR, myocardial haemorrhage can be visually defined as a hypointense area in the centre (i.e. core) of the ooedematous zone with a mean T2* value <20 ms, and a minimum area of 1% left ventricular mass [62-64]. Myocardial haemorrhage can be described as a percentage of the left ventricular mass. Microvascular obstruction [56-59] and myocardial haemorrhage [65-68] are commonly observed affecting about one third to one half of all-comers with acute STEMI undergoing PCI. Pre-clinical studies have described a bimodal time-course of ooedema in a pig model of ischemia-reperfusion [69,70]. Carrick, et al. [71] studied the temporal evolution of myocardial haemorrhage in a longitudinal clinical study involving serial contrast-enhanced CMR on four occasions in 30 patients following acute STEMI. The investigators found that myocardial haemorrhage increases

Figure 2. Multiparametric assessment of area at risk, perfusion defect after revascularization, scarring and inflammation using a combined fasted 18F-FDG PET/MRI and 99mTc-sestamibi SPECT approach. On late gadolinium enhancement (LGE) MR images (A) there is scarring and subendocardial microvascular obstruction of the anterior wall and the septum. Fasted 18F-FDG PET images indicating active inflammation with suppressed glucose utilization of remote myocardium demonstrate intense 18F-FDG uptake approximately corresponding to LGE. Area at risk assessed by 99mTc-sestamibi SPECT with tracer injection prior to revascularization demonstrates a perfusion defect roughly corresponding to the 18F-FDG accumulation. Perfusion defect after revascularization (D) assessed by 99mTc-sestamibi SPECT a few days after revascularization is clearly smaller than the area at risk and inflamed myocardial area.



occurs immediately after reperfusion and expands over time [78]. Per-procedural identification could therefore provide an optimal window for treatment. While coronary angiography readily gives access to contrast- based assessment of coronary perfusion, measures as thrombolysis in myocardial infarction (TIMI) flow grade and myocardial blush grade have been documented to provide only limited identification of perfusion at the microvascular level [79]. Several invasive coronary physiological tools are available that may allow more accurate identification of the presence and extent of MVI after reperfusion.

Coronary blood flow velocity patternsMVI leads to characteristic alterations in the coronary blood

flow velocity pattern due to the disruption of microvascular integrity resulting in an increase of microvascular impedance [80]. MVI is characterized by the appearance of abnormal systolic retrograde flow (SRF: peak velocity ≥ 10 cm/s, duration ≥ 60 ms) and a rapid deceleration time of diastolic flow velocity (DDT, <600 m/s) (Figure 4, Panel A). The occurrence of SRF carries an odds ratio of 1.19 (95% CI 1.05-1.35) for the occurrence of as documented on magnetic resonance imaging (MRI) and with high sensitivity (91%) and specificity (97%) (80). The decrease in DDT is linearly related to the extent of MVI (r=0.75) (81).

Coronary flow reserveThe vasodilatory capacity of the coronary microcirculation,

expressed by the coronary flow reserve (CFR), depends on the

progressively after reperfusion with a primary hyperacute phase <12 hours post-MI that culminates in a peak 3 days later. The temporal changes in myocardial ooedema, reflected by T2 relaxation times (ms), are inversely associated with myocardial haemorrhage. Myocardial ooedema (T2 values, ms) evolves with a bimodal time-course in patients with myocardial haemorrhage but a unimodal time-course in patients without myocardial haemorrhage [71].

Myocardial haemorrhage is a prognostically important complication of reperfused STEMI [65-72], and in particular, it is independently associated with adverse remodeling [73,74] and heart failure in the longer term [74]. Paradoxically, the improvements in survival after acute STEMI in recent decades translate to more surviving patients with injured hearts who are at risk of developing adverse left ventricular remodeling and heart failure in the longer term [73,74]. Myocardial haemorrhage is a consequence of severe microvascular injury, and loss of endothelial integrity [75]. Haemoglobin degradation products are toxic [76,77] and pro-inflammatory [76]. Persistence of iron within the infarct zone is evidenced by immune-histochemical localization within macrophages and sustained inflammation within the infarct zone may have pro-fibrotic effects. Since there are no evidence-based treatments for microvascular obstruction and myocardial haemorrhage to date, we submit that more research is needed to better understand the pathophysiology and natural history of these reperfusion disorders.

Persistence of infarct core haemorrhage- work in progress

The clinical significance of persistent iron within the infarct core after (STEMI) complicated by acute myocardial haemorrhage is poorly understood. Carberry, et al. (submitted) aimed to determine the incidence and prognostic significance of persistent infarct core iron in the long term in patients after an acute STEMI in a cohort study (BHF MR-MI:NCT02072850). The authors found that persistent iron detection within the infarct core at 6 months post-STEMI occurs in approximately three fifths of patients with documented myocardial haemorrhage at baseline. It appears to be associated with persistent infarct zone ooedema, worsening left ventricular volumes and function and adverse health events, including all-cause death and heart failure on follow-up. Further studies are warranted to investigate whether the occurrence of myocardial haemorrhage is a primary driver of inflammation leading to accumulation of iron-laden tissue macrophages, or alternatively, whether persistent iron may reflect a defect in macrophage-mediated clearance of haemoglobin degradation products.

Myocardial haemorrhage is a progressive phenomenon occurring acutely post-reperfusion in some patients and occurring subsequently in other patients during a secondary phase between the first and third day post-reperfusion. This time-course gives rise to the possibility of a therapeutic window to prevent and reduce myocardial haemorrhage with targeted therapy [77]. Figure 3 demonstrates the typical findings following reperfusion in STEMI patients.

Catheter-based studiesIdeally, operators should be able to assess the post- reperfusion

status of the myocardium directly in the catheterization laboratory, because if microvascular injury (MVI) develops, it

Figure 3. Three patients, all with acute inferior ST-segment-elevation myocardial infarction treated successfully with primary percutaneous coronary intervention (PCI). Each patient had thrombolysis in myocardial infarction (TIMI) grade 3 flow at the end of PCI. Cardiac magnetic resonance imaging was performed at between 3 and 5 days post reperfusion. A: Patient with an inferior infarct but no microvascular obstruction or haemorrhage on MRI. Late gadolinium contrast-enhanced MRI revealed an inferior infarct with no evidence of microvascular obstruction (middle image, yellow arrows). B: Patient with an infero-lateral infarct with microvascular obstruction but no evidence of myocardial haemorrhage. Late gadolinium contrast- enhanced imaging revealed an area of microvascular obstruction (middle image, red arrow) within the bright area of iQnfarction superiorly but no evidence of myocardial haemorrhage. C: Patient with haemorrhagic infarction on MRI. T2*-MRI (far right image) revealed myocardial haemorrhage (white arrow) within the infarct core. Contrast-enhanced MRI revealed microvascular obstruction (middle image, red arrow) within the bright area of infarction. The microvascular obstruction within the infarct core spatially corresponded with the myocardial haemorrhage. Figure provided by Dr Peter McCartney, Golden Jubilee National Hospital and University of Glasgow, UK.



Figure 4. Characteristics of microvascular injury (MVI) for invasive coronary physiology indices. The occurrence of MVI is characterized by A) shortening of diastolic deceleration time (DDT) and the presence of systolic retrograde flow (SRF); B) a decrease in coronary flow reserve (CFR) and an increase in hyperemic microvascular resistance index (HMR); C) an increase in the index of microcirculatory resistance (IMR); or D) a decrease in coronary conductance expressed by the instantaneous hyperemic diastolic velocity pressure slope index (IHDVPS), and an increase in zero-flow pressure (Pzf).



functional integrity of the microvasculature. Consequently, CFR is reduced in the presence of MVI, with the extent of CFR reduction directly related to the extent of MVI (Figure 4, Panel B and C) [81-84]. To identify MVI the CFR area under the receiver-operating-characteristics curve (AUC) has been reported between 0.71 and 0.75, with optimal CFR cut-off values ranging from 1.6 to 2.0. At these cut-points, the sensitivity was 65-71% and specificity was 61-71%, respectively [83,85]. Nonetheless, CFR can also be affected by factors not related to MVI, such as heart rate and left ventricular loading conditions [86]. Hence, the diagnostic value of CFR for MVI detection is still a matter of debates [87]. Whether combining CFR with microcirculation-specific indices, such as microvascular resistance or conductance indices may improve diagnostic accuracy [81], appears questionable [87].

Microvascular resistance indexesMicrovascular resistance can be calculated by combining

coronary pressure and flow measurements as the ratio of distal coronary pressure to distal coronary flow, measured using a guide wire equipped with a Doppler flow velocity crystal - termed hyperemic microvascular resistance (HMR; Figure 4, Panel B)- or by employing coronary thermodilution measurements - termed index of microcirculatory resistance (IMR; Figure 4, Panel C). HMR has been directly related to histological changes in microvascular integrity; scarce comparative data has suggested better sensitivity of HMR compared to IMR to assess MVI [88]. Nonetheless, both HMR and IMR increase with increasing extent of MVI, and as such have been documented to be independent predictors of MVI. HMR was documented to provide an AUC for the detection of MVI of 0.68 (95% confidence interval [CI], 0.53–0.83), and an AUC of 0.80 (95% CI, 0.67–0.93; P<0.01) for extensive volumetric MVI. At the best cut-off value of 2.5 mmHg/cm/s, HMR had a sensitivity of 71% (95% CI, 58%–84%) and a specificity of 63% (95% CI, 49%–77%) for MVI in general, and a sensitivity of 93% (95% CI, 87%–99%) and a specificity of 65% (95% CI, 52%–78%) for extensive volumetric MVI [84]. In comparison, in a large study, an IMR cut-off value of >27 Units was documented to provided highest sensitivity and specificity for MVI, with a sensitivity of 66% (95% CI, 55% – 76%), and a specificity of 67% (95% CI, 60%-77%) for myocardial haemorrhage, and a sensitivity of 58% (95% CI, 49% – 66%) and specificity of 72% (95% CI, 63%-79%) for microvascular obstruction, both considered part of MVI [89].

Coronary conductance and zero-flow pressureThe phasic pressure and flow velocity waveforms derived from

combined pressure and Doppler flow velocity measurements allow to calculate measures of microvascular conductance such as instantaneous hyperemic diastolic pressure velocity slope index (IHDVPS) and extravascular compression (zero-flow pressure (Pzf)) (Figure 4, Panel D). IHDVPS was documented to best identify structural changes in the coronary microvasculature, and proved to be superior to both resistance indices and CFR [90]. Nevertheless, it has been scarcely studied in the setting of MVI and may be of limited diagnostic value for this purpose [84]. Pzf was shown to provide superior diagnostic efficiency for biochemical and imaging parameters of myocardial infarction when compared with IMR and HMR [88]. The AUC for Pzf to predict MVI was 0.75 (95% CI, 0.55–0.89) for MVI in general, and 0.77 (95% CI, 0.58–0.91; P<0.01) for extensive volumetric MVI [82]. IMR>40 has been confirmed an independent predictor of death and hospitalization for heart failure [87,91].

Reperfusion after PCI in STEMI: Flow, resistance, conduction, or compression?

As described above, all available catheter-based tools for assessment of microvascular function show alterations in the presence of MVI. Using CMRI as the reference standard, however, diagnostic efficiency of a single index to predict the occurrence of MVI at the time of the intervention remains moderate at present. Nonetheless, diagnostic efficiency for the identification of more extensive MVI seems to be much higher, which may be enough to identify those cases where MVI becomes clinically meaningful. Furthermore, more complex physiology techniques such as Pzf are becoming more customary, and may allow more accurate identification of MVI. Ultimately, it is more likely that the complex nature of MVI, combining microvascular haemorrhage and obstruction as well as extravascular compression, will be optimally explored using a combination of these techniques to optimize diagnostic efficiency across these pathophysiological mechanisms expressed in MVI. The use of such combinations of techniques remains, however, ill-explored as yet, with emerging evidence in terms of diagnostic efficiency [83]. Based on current evidence, it appears sufficient to use IMR and/or HMR to assess the success of reperfusion in STEMI patients.

Imaging studies of the brainThe most widely used imaging modality for selecting

patients for reperfusion therapies is computed tomography (CT). CT, CT angiography (CTA) and/or CT perfusion imaging (CTPI), can all be rapidly acquired in the emergency settings [92-94]. Magnetic resonance imaging (MRI) offers greater physiologic information than CT, but takes longer. However, at specialized centers, MRI can be used as the primary imaging modality within the recommended time frame [95]. For example, the UCLA and NIH stroke services routinely use MRI as the primary imaging modality for evaluating acute stroke patients.

Computed tomography (CT)Computer Tomography, non-contrast enhanced (NC-

CT): For more than 4 decades non-contrast cranial computer tomography (NC-CT) has been the gold standard for detection of ischemic tissue and stroke patterns in acute ischaemic stroke (AIS) [96]. Nevertheless this widely available method is only of minor importance to detect ischaemia and it serves primarily to exclude haemorrhagic stroke in patients considered for reperfusion. Even with approaches such as Alberta Stroke Program Early CT scores (ASPECTS) acceptable sensitivity could not be achieved [97, 98]. Nevertheless, because of its accessibility, speed, and patient tolerance, NC-CT still represents the standard modality permitting exclusion of haemorrhage for the rapid triage of stroke patients [99].

Contrast enhanced Computer Tomography (CE-CT): Blood-brain barrier (BBB) disruption due to acute ischemic stroke can be demonstrated based on contrast enhancement. Reperfusion causing contrast enhancement in the reperfused area represents the strongest independent predictor of early BBB disruption. In addition contrast enhancement has been also associated with haemorrhagic transformation and worse clinical outcome in affected patients [100].

Computed Tomography-Angiography (CTA): CT angiography represents an important tool in the assessment



of AIS. The sensitivity of CTA to detect vessel occlusion [101] or severe stenosis appears comparable with that of digital subtraction angiography (DSA) and magnetic resonance angiography (MRA) [102]. In addition, CTA allows assessments of collaterals important for tissue survival in AIS patients [103]. CE-CT and CTA represent the currently established imaging- based standard to identity patients likely to benefit from mechanical thrombectomy (MT).

CT-Perfusion Imaging (CTPI): CTPI is the central multimodal CT imaging technique allowing the definition of salvageable ischemic brain tissue based on infarct core/penumbra mismatch as well as the outcome of reperfusion interventions and it has become a part of standard protocols to assess AIS and comprising NC-CT, CTA and CTPI [104]. Based on continuous (cine) mode of acquisition following a bolus of injection the entire passage of a contrast agent through the brain circulation can be tracked allowing automated calculation of perfusion indices including the total cerebral blood volume (CBV; mL/100g tissue), cerebral blood flow (CBF; mL/100g tissue/minutes), mean transit time of contrast to pass through a defined volume of brain tissue – CBV/CBF (MTT; seconds), time to peak contrast enhancement (TTP; seconds), rate of contrast extravasation from the intravascular to the extravascular compartment due to disruption of BBB calculated as permeability surface area product (PS; mL/min/100g tissue) and time to peak of the residual function (Tmax; seconds) calculated by commercially available post-processing software platforms [105]. In combination, CE-CT, CTA and CBV/CBF maps used as multimodal CT have been reported to have high sensitivity for detecting infarction [106]. The occurrence of haemorrhagic transformation does not seem to be associated with reperfusion. BBB disruption can occur due to ischemic conditions of the vessel wall after failure of recanalization as well as after hyperperfusion as a condition for successful reopening of the occlusion [107]. Based on a combination of image- based and clinical data tissue salvage following recanalization can be calculated [108]. CTPI appears to improve selection of patients for MT [109] and has been proposed to be included into the standard pre- interventional imaging protocols [110]. Figure 5 provides an example of the correspondence between multimodal CT and angiographic imaging.

Magnetic Resonance ImagingMRI Biomarkers of Ischaemia: The most sensitive biomarker

for acute cerebral ischaemia is diffusion weighted imaging (DWI) which detects decreased ion-pump activity within minutes [111]. DWI is used to generate apparent diffusion coefficient (ADC) maps that are thresholded to identify core infarct [112]. DWI lesions, however, can be reversible [113], although reversal is typically not sustained [114]. Thus DWI changes can reflect both ischaemia and infarct, temporally transitioning from the former to the latter (Figure 6) [115].

Perfusion weighted imaging (PWI): Uses bolus tracking of a gadolinium injection to generate maps that can be used to identify ischaemia. Delay in contrast arrival or transit is measured [116,117]. The difference between the DWI lesion and the PWI lesion is a commonly used MRI biomarker of the ischemic penumbra [118] identifying the target profile most amenable to revascularization) [119]. In the absence of recanalization the DWI/PWI mismatch progresses to infarction (Figure 6). PWI can also

assess cerebral blood volume (CBV), which initially increases with ischaemia due to vasodilatation but is low in areas of infarction.

Emerging MRI methods can measure more direct physiologic properties of the ischemic brain. The transition to anaerobic metabolism results in a pH drop that can be detected using chemical exchange saturation transfer MRI (Figure 7, panel B) [120-122]. It also seems possible to measure oxygen extraction fraction (OEF) with MRI, although obstacles remain [123].

MRI biomarkers associated with reperfusion injury: Reperfusion injury is tissue damage cause by restoration of blood flow after temporary deprivation. Separating injury caused by the ischaemia from injury caused by reperfusion is generally not achieved in clinical practice. Both types of injury are associated with increased risk of complications and are thus avoided.

The blood brain barrier (BBB) describes complex cellular machinery that isolates the brain from the contents of the blood circulating through it. Normally highly regulated, in the setting of ischaemia, it becomes dysfunctional or damaged. MRI is able to detect BBB disruption as gadolinium leakage into the cerebral

Figure 5. 70 Y old female patients with a hyperacute cardio-embolic MCA occlusion. Above: NC-CT: Hyperdense middle cerebral artery sign (left); DSA: Occlusion of the ri. MCA (right). Middle: NC-CT: Distrupted blood brain barrier with contrast enhancement and bleeding in the MCA territory (reperfusion injury) after mechanical thrombectomy (left); DSA: Revascularization of the ri. MCA after mechanical thrombectomy (right). Below: CBV imaging: Disturbed autoregulation with inlarged local blood volume after thrombectomy in the ri. MCA (left); CBF: reduced perfusion in the central core of the ri. MCA territory even after mechanical thrombectomy.



spinal fluid (CSF) [124] or brain parenchyma (Figure 8, panel C) [125,126]. BBB disruption detected with MRI prior to reperfusion has been associated with an increased risk of haemorrhagic transformation of the infarct [127-129]. Mild diffuse BBB disruption, which is reversible with early reperfusion, must be distinguished from the severe focal pattern of BBB disruption that heralds complications [130]. Reperfusion itself, particularly

in the setting of thrombolysis, may cause BBB disruption that is detected in the CSF on MRI [131].

The strongest predictor of clinical outcome with reperfusion therapy is status of the collateral circulation. Collateral circulation, defined by a variety of imaging and angiographic techniques, has proven to be a potent determinant of patient outcomes after reperfusion. Collateral status varies across any given stroke cohort and MRI may reveal distinct patterns and topography associated with collaterals [132]. Vascular remodeling associated with arteriogenesis may also cause BBB leakage, although the location of such BBB disruption is situated more peripherally at the borderzones where anastomoses exist and not in the region of most severe ischaemia. Impaired collateral perfusion may predispose to reperfusion injury and rapid reperfusion in the setting of poor collaterals may predispose to haemorrhage and other forms of reperfusion injury. MRI can measure injury to the infarct core and thus predict the safety of reperfusion therapy [133]. Predictive properties of the ischemic core include the size of the infarct on DWI [134], the presence of very low CBV [135], and the amount of T2 signal change on fluid attenuated inversion recovery (FLAIR) imaging [136,137]. These measures, similar to BBB imaging, can be used to identify patients in whom reperfusion therapy should be avoided.

MRI biomarkers of reperfusion complications: The most limiting complication of acute stroke therapy is symptomatic intracranial haemorrhage (sICH). Several definitions of sICH [138-141] all combine radiographic evidence of bleeding with clinical evidence of neurologic deterioration. MRI is more sensitive to haemorrhage than CT [142], but interpretation of the clinical significance of haemorrhage on MRI is more challenging [143]. This has resulted in the use of CT as the radiologic end point in many clinical trials (Figure 8, panels D and E).

Figure 6. Lesion reversal is shown on diffusion weighted imaging (DWI) of a single patient at three different time points. Panel A shows the acute stroke (bright white) on presentation prior to treatment. Panel B shows the DWI 3 hours later after successful revascularization with thrombolysis. Notice that the bright area has begun to revert back to normal. Panel C shows that the final infarct at 24hours (bright white) is substantially smaller than the lesion prior to revascularization (panel A). An example of MRI imaging of the ischemic penumbra is shown. Panel D shows the diffusion weighted imaging (DWI) of an acute patient without evidence of infarcted tissue. Panel E shows the perfusion weighted image (PWI) of the same patient at the same time point. Notice the large area of delayed contrast delivery (bright white) representing the tissue at risk of infarction. Panel F shows the DWI 24 hours later after a failed attempt at revascularization. Notice the large infarct that is now evident (bright white) in the area predicted by the PWI..

Figure 7. Several methods of imaging injury are shown. Panel A is diffusion weighted image (DWI) showing a large infarct (bright white). Panel B is an MRI method for measuring the pH of the stroke demonstrating low pH in the infarct (dark blue). Panel C is an MRI method for detecting blood-brain barrier (BBB) disruption demonstrating focal regions of severe BBB disruption (colored regions). Panel D is a head CT after spontaneous reperfusion of the infarct from the top row showing hemorrhagic transformation (bright white). Panel E shows a hemosiderin weighted MRI of the patient after undergoing decompressive hemicraniectomy.

Figure 8. Reperfusion after regional cerebral ischemia. Sequential PET images of CBF, CMRO2 and OEF of MCA occlusion in cats compared to images of patients after stroke: Left columns: In the left cat, the progressive decrease of CMRO2 and the reduction of OEF predict infarction and cannot benefit from reperfusion. Only if OEF is increased until start of reperfusion it can be salvaged (right cat). Middle columns: In the patient the areas with preserved OEF are not infarcted and can survive in spontaneous course (posterior part of ischemic cortex in left, anterior part in right patient as indicated on late MRI and CT). Right columns: In patients receiving rTPA treatment measurements of CMRO2 and OEF are not feasible, but flow determinations show the effect. If reperfusion occurs early enough and before tissue damage, tissue can be salvaged (left patient). If reperfusion is achieved too late, tissue cannot be salvaged despite hyperperfusion in some parts (right, patient).



Another major complication after reperfusion therapy is malignant oedema requiring hemicraniectomy [144,145]. Reperfusion can cause faster accumulation of vasogenic oedema detected with FLAIR MRI [133]. Thus, reperfusion of large ischaemic cores is generally avoided [146]. Hyperaemia of the revascularised core can also be detected with MRI [147], although the implications remain unclear. Arterial spin labeling (ASL) is a non-contrast MRI method for measuring cerebral blood flow that is more sensitive to hyperaemia than traditional PWI [148]. After vessel recanalization therapy, post treatment MRI can detect no-reflow by using PWI to assess the capillary level flow in the vascular territory distal to the site of recanalization. However, the no-reflow phenomenon has not been well characterised in stroke patients [149].

MRI offers a wealth of insight into the complex interactions between ischaemia, reperfusion and injury. Although CT is currently the standard imaging tool for assessing AIS patients, MRI provides additional information about the consequences of reperfusion therapy. The role of reperfusion injury has not been well characterized in acute stroke treatment and thus MRI offers an opportunity to study and to better understand its clinical implications.

Positron Emission Tomography (PET)Reperfusion of the ischemic tissue: Therapy for acute

ischemic stroke is only effective if reperfusion (by thrombolysis or mechanical thrombectomy) of the penumbral tissue (Appendix A-D) is established. The percentage of initially critically ischemic voxels as determined by H2

15O-PET within 3 hours of stroke onset that became reperfused to almost normal levels clearly predicts the degree of clinical improvement achieved within 3 weeks [150]. Thus a considerable portion of the critically hypoperfused tissue was probably salvaged by the reperfusion therapy. If the PET study [151] indicated irreversibly damaged tissue, patients do not benefit from reperfusion (Figure 8).

In severe ischaemia a malignant course is indicated by hyperperfusion after reopening of the middle cerebral artery (MCA); this transitions into hypoperfusion and ultimately could lead to severe ischaemia with necrosis of tissue and brain oedema. The severity of ischaemia measurable with residual perfusion is the main factor determining the further course and the extent of tissue damage. Reactive hyperaemia as a functional overshoot reaction [152] has been observed after 30-min episodes of ischaemia in cats. After 60-min of MCA occlusion (MCAO), the grade of postischemic hyperperfusion was related to the severity of ischaemia and a correlation existed between severity of ischaemia during MCAO and extent of hyperperfusion after reopening of the vessel. These results suggest that reperfusion forced through vessels maximally dilated by lactic acidosis affected already damaged tissue. In stroke patients, fatal oedema formation during reperfusion after thrombolysis with rtPA has been attributed to reperfusion injury [153] when perfusion reached some already irreversibly damaged areas bordering large infarcts, where the increased vascular permeability during the revascularization forces oedema formation and parenchymal haemorrhage and enhances ischemic tissue damage by various mechanisms. Reperfusion injury was seen as an important factor of brain damage initiated by ischaemia under certain experimental conditions [154] and may represent a paradoxical

consequence of spontaneous or pharmacologically induced reperfusion [155,156]. Reperfusion injury is indicated when hyperperfusion to a brain area was combined with a more than 40% decrease of cerebral metabolic rate of oxygen (CMRO2) and oxygen extraction fraction (OEF) [157].

DiscussionIn countries with advanced medical care CBI represent the

first-line therapy in patients with STEMI and AIS [1,2]. However, despite of better outcomes compared to former forms of treatment reperfusion failure characterized by persistent microcirculatory obstruction, development of intracellular and extracellular oedema and cell death [21-23,26,28-30,158,159] occurs in up to 50% and 60% of STEMI and AIS patients treated with CBI, respectively [14,15]. Furthermore, in up to about 10% of treated cases haemorrhagic transformation and tissue haemorrhage occur [24,60,160,161]. To date the attempts to prevent futile and injurious reperfusion in heart and brain have produced rather disappointing results in clinical settings [28-33]. Consequently, with already achieved high revascularization rates in coronary and improving revascularization rates in cerebrovascular interventions successful reperfusion represents the most pressing and immediate target in CBI.

While the use of clinical endpoints provides a reasonable approach in other clinical context it may not be sensitive and/or specific enough to discriminate between different CBI strategies in terms of their efficacy to achieve salutary reperfusion. The main limitations of clinical event based evidence include the enormous heterogeneity of patient cohorts, the variability of outcome-relevant clinical research protocols (both resulting in questionable consistency of data interpretation), the large number of patients and long follow-up required to reach significance, and the increasingly prohibitive costs of mega-trials (often with questionable returns) [36-38,162]. Thus, to address the issues concerning the efficacy of salutary tissue salvage in STEMI and AIS CBI reperfusion must be looked at directly rather than obliquely [11,109].

While experimental data remain critical to determine the key issues such as discovery of the underlined biological processes involved in reperfusion [163,164], there are frequently substantial differences between animal models of STEMI (dogs, pigs) or AIS (rodents, cats, rarely primates) and corresponding human diseases such that experimental data may be less useful and potentially even confusing if transferred to patients [28-33,165,166]. Therefore, to assess the performance of different revascularization-reperfusion strategies in clinical settings the optimum approach is to perform clinical studies in real-life cohorts assessing the results by employing imaging technology allowing direct, potentially quantitative, assessment of salvaged tissue and completeness of reperfusion.

Currently available techniques allow reperfusion assessments in clinical settings in both, heart and brain. However, due to existing limitations of individual techniques regarding availability, sensitivity and costs two- pronged approach appears justified. Thus, in standard clinical protocols reliable, readily available and reasonably priced modalities should be implemented; in clinical research protocols the implementation of the most advanced and most discriminative modalities is justified. Accounting for the need for further standardization and improvements the



development of automated analytical tools and as far as possible establishment of core laboratories allowing inter-laboratory comparisons is eminently required.

Myocardial reperfusion Based on the current experimental and clinical evidence MCE allows rapid assessment of the presence and the extent of reperfusion following percutaneous coronary interventions (PCI) in STEMI patients. Portability, bedside availability and non-invasive character allow integration of MCE into the interventional environment; lack of radiation exposure allows frequent and repeated reassessments in the early post-PCI period employing standardized protocols [42,43]. Currently, the major limitations for broad implementation of MCE in clinical settings represent the lack of availability of robust programs for automated quantification [42]. Nevertheless, MCE provides reliable assessments of reperfusion and should be integrated into standard clinical and research STEMI protocols.

The nuclear imaging techniques employing 99mTc-labeled sestamibi or tetrofosmin SPECT and PET have been firmly established for clinical assessments of reperfusion following PCI. However, due to limitations including the lack of portability, the need for radiation as well as availability and costs (PET) they should be implemented in STEMI related clinical research protocols targeting reperfusion (SPECT) and reperfusion related metabolic changes (PET).

CMRI represents clearly the most versatile tool to assess and to differentiate between the various reperfusion states and should become the primary tool to compare the efficacy of the salutary reperfusion of the available and the emerging CBI- strategies. However, lacking sufficient standardization interfering with inter-laboratory comparisons at present development of standard imaging protocols and establishment of core laboratories is required.

Functional coronary pathophysiology- based measures hold substantial promise to assess reperfusion while interventions are actually performed potentially opening a therapeutic window to improve outcomes. To date a host of indexes is under study and suitable parameters such as IMR have emerged to judge the status of microcirculation, yet still requiring further validation in larger cohort of patients.

Brain perfusion: In the brain imaging the currently available CTP and MRI technology allow excellent definition of reperfusion. However, at present CTP is not routinely used in all patients considered for CBI; if performed, it is employed to improve selection of patients considered for interventional therapy in specialized centers [107,108]. To determine the efficacy of individual protocols and strategies to achieve salutary reperfusion perfusion imaging following the interventions is required. However, to allow broader clinical applications and inter-hospital comparisons further standardization of imaging protocols is required to assure reproducibility and to allow meaningful quality control. Utilization of CT- and MR- perfusion imaging depends largely on emphasis of individual institutions; while CT appears faster and more accessible, MR is far more versatile providing better reperfusion tissue characterization [167]. PET imaging following MT for AIS may provide important insights into the metabolic changes associated with IRI; yet currently it is considered a research modality in this specific application [168,169].

SummaryTo allow consistent and reliable assessments of tissue

reperfusion following CBI for STEMI and AIS standardized and routine clinical use of perfusion imaging modalities is strongly recommended. Development of standardized imaging protocols and sufficient degree of operator independent automation along with the establishment of core- laboratories allowing inter- center comparisons represent the immediate targets.

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Salutary reperfusion is the ultimate target of ST- Segment ...sciencetxt.org/pdf/CRM-1-104.pdf · revascularization of the culprit lesion is the premise tissue reperfusion represents