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Fast Versus Slow Progressors of Infarct Growth in Large Vessel Occlusion Stroke

Clinical and Research Implications
Originally publishedhttps://doi.org/10.1161/STROKEAHA.117.017673Stroke. 2017;48:2621–2627

Approximately 40% of acute ischemic strokes are caused by proximal intracranial large vessel occlusion (LVO) and are associated with the worst clinical outcomes.1 Early reperfusion with IV tPA (tissue-type plasminogen activator) and intra-arterial thrombectomy leads to reduced final infarct volumes, lower disability rates, and improved cognitive function after anterior circulation LVO.26 However, most stroke patients with LVO remain untreated because they present beyond the conventional time windows for acute reperfusion therapies.7,8 Therefore, a growing paradigm has been to transition to a therapeutic window that is tailored to each patient’s individual pathophysiology or brain tissue window rather than a standardized time window.9,10 The principle of pathophysiology-based reperfusion therapy is built on the fundamental concept of a dynamic interrelation between the ischemic core (tissue that is already infarcted) and the ischemic penumbra (physiologically impaired but potentially salvageable tissue).1113 After arterial occlusion, there can be temporal growth of the ischemic core into the penumbral area that is modulated by collateral blood flow, the key element setting the pace of the ischemic process.14 Infarct growth is thought to progress at different speeds across individuals because patients with occlusion of the proximal middle cerebral artery (MCA) or internal carotid artery (ICA) terminus present with widely variable stroke volumes independently of time after symptom onset.1518 We refer to patients with LVO who experience rapid infarct growth as fast progressors. These patients have failing collaterals and a large ischemic core despite presenting early within 6 hours of stroke onset. Conversely, a significant number of patients maintain a small ischemic core and significant salvageable tissue beyond 6 hours and up to several days after persistent LVO.17,19 The latter patients are slow progressors because they maintain good collaterals and experience slow infarct growth over time (Figure 1). Only a small minority of patients who have exceptionally well-preserved collaterals are thought not to experience infarct growth in the absence of recanalization. Although fast and slow progressors of infarction caused by LVO are frequently observed when patients are considered for endovascular therapy,15,20 the incidence and underlying pathophysiology of these clinical phenotypes remain poorly defined in the general population.

Figure 1.

Figure 1. Relative chronology of early infarct growth in 2 scenarios of fast vs slow progression of untreated large vessel occlusion (LVO) stroke. Yellow bar denotes concept of early window for neuroprotective therapies geared toward slowing down infarct growth in fast progressors until reperfusion.

Incidence of Fast and Slow Progressors of Acute LVO and Implications for Reperfusion Therapy

The distribution of fast and slow progressors of LVO likely falls within a spectrum of variable infarct growth rates,18,20 which can be framed in relation to early (≤6 hours) or delayed (>6 hours) time windows after stroke onset. This may reflect a continuum of patients who present with poor to excellent collaterals measured by multimodal computed tomographic imaging or cerebral angiography (Table 1). Good collateral grade on initial presentation has been associated with larger volumes of salvageable ischemic tissue, slow rate of ASPECTS (Alberta Stroke Program Early CT Score) decay between hospital transfers and improved clinical outcomes.2224 In the recent landmark trials of endovascular stroke therapy, which selected for intermediate or good collaterals with emergency CT angiography or CT perfusion, 36% to 47% of patients who achieved substantial reperfusion between 3 and 6 hours still failed to regain functional independence.25 These data suggest that ≤50% of patients with acute MCA or ICA terminus occlusions may be fast progressors whose infarct growth is most sensitive to duration of ischemia because of rapidly failing collaterals and who will benefit from fastest possible reperfusion in the early time window.26 In 1 single-center study of patients with acute M1 MCA segment occlusion who were imaged with xenon-enhanced computed tomographic perfusion within 6 hours of stroke onset, 9 out of 36 patients (25%) had an ischemic core ≥50% of the cortical MCA territory, whereas 10 out of 36 patients (27%) had ≤20% ischemic core before recanalization.18 Another study showed that 20% of patients with M1 occlusion had diffusion-weighted imaging (DWI) volumes >70 mL within 8 hours of witnessed stroke onset,16 perhaps suggestive of ultrafast infarct progression. Thus, 20% to 30% patients with acute LVO likely fall within the spectrum of ultrafast progressors who may be at particular risk to develop accelerated cerebral edema and symptomatic intracranial hemorrhage, which defines a malignant profile.27 Because such patients have lowest rates of favorable outcomes, they are thought to respond poorly to reperfusion.27 However, when compared with standard medical therapy alone, the benefit of mechanical thrombectomy has not been entirely ruled out in ultrafast progressors of LVO stroke who present with large infarcts and are treated early after symptom onset.28 Nonetheless, this subgroup of patients remains largely excluded from acute endovascular treatment because of the previously held belief that reperfusion is detrimental in this circumstance because of increased incidence of symptomatic intracranial hemorrhage and malignant edema.

Table 1. Incidence of Collateral Grades and Respective Clinical Outcomes in Anterior Circulation LVO

Scoring SystemImaging ModalityCollateral GradeIncidence, n (%)% mRS 0–2 (90 d)
Miteff et al21*CTA/dynamic CTPPoor17/92 (18)0
Moderate24/92 (26)13
Good51/92 (56)47
Liebeskind et al22Cerebral angiographyPoor (0–1)32/119 (27)4
Intermediate (2)48/119 (40)28
Good (3)35/199 (29)56
Excellent (4)4/199 (3)66
Menon et al23CTAPoor (0–5)38/126 (30)18
Intermediate (6–7)42/126 (33)45
Good (8–10)46/126 (37)57

CTA indicates CT angiography; CTP, CT perfusion; LVO, large vessel occlusion; and mRS, modified Rankin Scale.

*Patients treated with IV tPA (tissue-type plasminogen activator) only.

Patients treated with mechanical thrombectomy.

On the other end, the incidence of slow progressors may be ≤30% of patients with anterior circulation LVO in large referral centers.17 Because slow progressors have been reported to still derive substantial benefit from endovascular reperfusion well after 8 hours after stroke onset with a reasonable safety profile,29 randomized clinical trials to test this hypothesis have become a priority for the field.30 Recently, completed and ongoing trials are testing the benefit of endovascular therapy in patients who may present ≤24 hours after acute MCA/ICA occlusion (NCT01852201, NCT02142283, and NCT02586415). Preliminary results of DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) have shown clinical benefit of delayed reperfusion in patients with small ischemic cores. This reinforces the concept that slow progressors who do not reperfuse will eventually also have poor outcomes as fast progressors. The findings of this study await publication in peer-reviewed journals. However, the underlying pathophysiology of fast and slow progressors of infarction because of acute LVO is not completely understood.

Pathophysiological Basis for Fast and Slow Progressors of Infarct Growth in LVO Stroke

The key notion that the rate of infarct growth during LVO depends on the capacity to sustain collateral blood flow above thresholds of infarction over time rests on the milestone concept of the ischemic penumbra from the 1970s to the 1980s.11 Using a nonhuman primate model of MCA occlusion, Astrup et al31 and Symon et al32 were the first to characterize specific thresholds for reduction of focal cerebral blood flow that caused reversible silencing of electric activity in ischemic but still viable penumbral tissue (20–10 mL/100 g per minute) or irreversible cellular depolarization in infarcted tissue (<10 mL/100 g per minute). Subsequent studies in animals and humans demonstrated that the evolution of penumbra to infarction is a dynamic process that depends on the duration of arterial occlusion counterbalanced by the magnitude of residual collateral blood flow.12,33,34 Human positron emission tomography studies further showed that penumbral tissue has preserved cerebral metabolic rate of oxygen and increased oxygen extraction fraction during acute MCA territory strokes.19,35 The latter occurs in the context of significant interindividual variability of leptomeningeal collateral grade that is directly correlated with final infarct volume and likely also explains fast or slow infarct growth in LVO.3638

Absolute cerebral blood flow thresholds of ischemia and infarct growth rate may also vary depending on baseline tissue oxygen demand. For example, transgenic mice harboring mutations of familial hemiplegic migraine type-1 are more susceptible to peri-infarct depolarizations and display accelerated infarct growth during acute MCA occlusion because of intrinsic neuronal hyperexcitability and greater energetic demand in the penumbral zone.39 The potential benefits of modulating collateral blood supply and parenchymal tissue oxygen demand to slow down early infarct progression during LVO remain largely untested in patients, in part because of our limited understanding of the dynamic pathophysiology of human stroke. Nonetheless, we propose that fast and slow progressors of infarction because of LVO are clinical phenotypes of different tolerance to focal cerebral ischemia. Therefore, future characterization of the determinants of infarct growth rate as a surrogate of cerebral ischemic tolerance during LVO will be central to maximizing patient eligibility for reperfusion therapies and successful translation of neuroprotective therapies in stroke.

Putative Determinants of Infarct Growth Rate, Collateral Grade, and Overall Ischemic Tolerance to LVO

The rate of infarct growth during LVO is likely determined by the interaction of multiple factors including physiological parameters (ie, blood pressure, head position, CO2, temperature, and blood glucose), genetic background, demographics, and acquired comorbidities, which may influence the capacity of leptomeningeal collateral blood flow and ischemic tolerance. Older age and premorbid metabolic syndrome have been found to predict poor collateral grade in a single-center cohort of patients with acute MCA occlusion.40 Although an independent effect of aging on fast collateral failure has not been consistently demonstrated and remains uncertain,22,41 initial hyperglycemia has been associated with increased infarct growth rate and poor collateral grade in separate cohorts.22,42 Nonetheless, the actual mechanisms of collateral blood flow regulation during LVO in patients remain elusive because data from clinical imaging are snapshots in the hyperacute stroke setting, which are often studied retrospectively. Yet mounting evidence from experimental animal models indicates that both the native anatomy of anastomotic leptomeningeal arterioles and their intrinsic physiological properties are key determinants of penumbral reserve during LVO.

With regard to baseline collateral anatomic status, Zhang et al37 and Wang et al43 have comprehensively demonstrated a wide variation in the native number and diameter of leptomeningeal anastomotic arterioles across mice of different genetic backgrounds. Both the extent of collateral number and diameter are strongly inversely correlated with final infarct volume in experimental MCA occlusion across 21 inbred mouse strains.37,43 Approximately 80% of the genetic variation in leptomeningeal collateral number, diameter, and final infarct volume after MCA occlusion has been linked to a single-nucleotide polymorphism of the Rabep2 gene in mice.44 Moreover, mice of identical genetic background except for variation in the same genetic locus display poor and good collaterals with respectively fast versus slow penumbral loss on serial multimodal magnetic resonance imaging within 5 to 24 hours after MCA branch occlusion.45 Therefore, animal data indicate that genetic background may be an important determinant of collateral availability in patients who are slow or fast progressors of acute LVO. Efforts are underway to prospectively determine whether similar genetic polymorphisms account for variation in leptomeningeal collateral grade in a prospective cohort of patients with acute MCA occlusion (GENEDCSS [Genetic Determinants of Collateral Status in Stroke]).46

In addition to the preischemic availability of leptomeningeal collaterals, the stability of collateral blood flow with persistent LVO is likely also dependent on complex physiological determinants.47 We propose a simplified hemodynamic model for the leptomeningeal collateral circulation in analogy to the coronary collateral network, which has been extensively characterized in patients with myocardial infarction.48 During acute MCA occlusion, the leptomeningeal collateral artery network would consist of a supplying artery (ie, anterior cerebral artery or posterior cerebral artery branch, anterograde flow), anastomotic leptomeningeal arteriole, receiving artery (ie, MCA branch, retrograde flow), and penetrating arterioles with respective capillary beds (Figure 2). At a minimum, the capacity for retrograde leptomeningeal blood flow during LVO must be dependent on the perfusion pressure gradient and conductance/resistance through the collateral artery network per se.49,50 Because regional cerebral autoregulation is impaired during LVO,51 collateral blood flow is directly correlated with mean arterial pressure in lower to midranges31,33 and is inversely related to luminal diameter of the leptomeningeal collateral arterioles (ie, resistance).37,50 Future hemodynamic studies to better characterize regulators of arterial conductance within the leptomeningeal collateral network will be of key importance for successful translation of neuroprotectants to slow down infarct growth in acute LVO.

Figure 2.

Figure 2. Hemodynamic model for the leptomeningeal collateral artery network during acute occlusion of the proximal MCA. ACA indicates anterior cerebral artery; and PCA, posterior cerebral artery.

One important regulator of collateral blood flow is thought to be the intrinsic distensibility of the anastomotic leptomeningeal arterioles,52 which allows for rapid reversal of flow into the low-pressure–receiving MCA branches and penetrating parenchymal arterioles that are distal to a proximal MCA occlusion.49,53,54 Even modest increases in leptomeningeal arteriolar diameter of 125% shown in animal models of MCA occlusion53 could explain significant increases in collateral blood flow because vessel resistance is inversely proportional to the fourth power of the vessel radius according to Poiseuille equation (R∝η×L/r4). In that context, Chan et al demonstrated that leptomeningeal collateral arterioles isolated from normotensive rats have intrinsically low myogenic tone and reactivity that allows for passive dilation with increasing intraluminal pressure via NO-dependent mechanisms.52 This property is lost in spontaneously hypertensive rats that have increased collateral myogenic reactivity,52 impaired collateral flow,50,55 and faster infarct growth in experimental MCA occlusion.56,57 At the clinical level, this is consistent with earlier reports that systolic hypertension on hospital presentation is correlated with poor collateral grade in patients with acute MCA occlusion.22,58 Whether severe hypertension contributes to poor baseline collaterals or is a compensatory response to poor collaterals during acute LVO in patients is uncertain. One hypothesis is that premorbid hypertension causes increased baseline collateral tone, triggers severe compensatory hypertension during acute LVO, and establishes a self-perpetuating cycle of worsening collateral capacity (Figure 3). Future prospective studies are needed to elucidate this association. Nonetheless, therapeutic manipulation of myogenic reactivity remains an attractive strategy to maximize the distensibility of available collateral arterioles and slow down infarct progression during acute LVO.52,59

Figure 3.

Figure 3. Hypothetical physiological modulators of leptomeningeal collateral arteriolar resistance during LVO. Cross-sectional diagram of representative arterioles. A, Slow progressors have good collaterals caused by low myogenic reactivity and less early ischemic edema (small black arrows), which would allow for maximal arteriolar distensibility with compensatory MAP elevation during acute stroke. B, Fast progressors have poor collaterals caused by increased myogenic reactivity and predisposition to early edema (large black arrows) causing decreased arteriolar distensibility with a self-perpetuating cycle of severe compensatory MAP elevation and worsening hypoperfusion/edema (semicircular arrow). The green arrow denotes net transmural pressure.

Ischemic cerebral edema likely represents another possible mechanism for early collateral failure during LVO. Numerous experiments across different animal species have consistently demonstrated increases in water content of ischemic tissue measured in the first 1 to 3 hours after proximal MCA occlusion.6063 Symon et al60 elegantly showed that the increase in cerebral water content was strongly correlated with the depth of ischemia below regional cerebral blood flow of 20 mL/100 g per minute in penumbral zones of nonhuman primates. Therefore, one potential mechanism for early collateral failure is that cerebral edema causes elevated interstitial pressure, which increases the resistance of collateral arterioles, downstream perforating arterioles, and capillary beds in the most hypoperfused penumbral zones (Figure 3).62 We hypothesize that slow progressors have little to no early cerebral edema in the penumbra, which may be associated with maintenance of good collaterals over a longer period of time (Figure 3A). Conversely, it is possible that fast progressors are intrinsically more vulnerable to early cerebral edema in the penumbra. The latter would contribute to increased interstitial pressure in regions of faltering collaterals, thereby contributing to more rapid expansion of the ischemic core and worsening edema (Figure 3B). Early cerebral edema is comprised of cytotoxic and ionic edema, which are mediated in part by activation of sulfonylurea receptor 1-transient receptor potential melastatin 4 during focal ischemia.64 Administration of glyburide within 10 hours of onset of LVO stroke causing ultrafast progression with malignant edema has been shown to reduce final infarct size.65 Therefore, targeting early cerebral edema in the prehospital setting represents an attractive neuroprotective strategy to slow down early infarct growth in LVO. Future studies are needed to directly study the relationship of early cerebral edema, collateral blood flow, and infarct growth rate in patients with acute ischemic stroke.

In addition, individuals likely have different parenchymal and cellular tolerance to similar reductions of regional cerebral blood flow that are likely also determined by genetic background, frequency of peri-infarct depolarizations,39 and cerebral ischemic preconditioning.66 In rodent models of LVO, selective glutamate receptor antagonism reduces peri-infarct depolarizations and final infarct growth.39,67 These factors could translate in differences in penumbral tissue oxygen demand between fast and slow progressors of infarction, but this remains to be better characterized in future experimental and clinical studies. Overall, the putative determinants of early infarct growth rate during LVO are likely inter-related, be it from the perspective of collateral blood supply or parenchymal metabolic demand, and their improved understanding will help identify new targets for neuroprotective therapies in stroke.

Potential Therapeutic Approaches to Slow Down Infarct Progression in Acute LVO

Several interventions such as pharmacologically induced mild hypertension,68 partial aortic balloon occlusion,69 sphenopalatine ganglion stimulation,70 and inhaled NO71 have been shown to enhance leptomeningeal collateral blood flow in experimental animal models. These could be potential adjunctive therapies to slow down infarct growth and extend the window of reperfusion of acute LVO and have been previously reviewed in detail elsewhere.59,72 Other strategies have been geared toward intrinsic neuroprotection of the penumbral tissue as with inhibition of PSD95 (postsynaptic density-95) for selective reduction of excitotoxicity early after stroke onset.73,74 Some of these approaches are summarized in Table 2 as they relate to the putative regulators of infarct progression that have been discussed in this review. A few promising randomized clinical trials are underway to test glyceryl trinitrate (ISRCTN26986053), remote ischemic conditioning (NCT02779712), and PSD95 inhibition (NCT02930018) as bridge therapies to reperfusion in the pre- and early hospital setting. Future studies are needed that will be powered to measure clinical benefit of such therapies in specific subgroups of fast versus slow progressors of anterior circulation LVO.

Table 2. Potential Adjunctive Therapies to Slow Down Early Infarct Growth in Acute LVO

InterventionMechanism of Action
Partial aortic balloon occlusionIncreased perfusion pressure/augmentation of collateral blood flow
Induced moderate hypertension
Sphenopalatine ganglion stimulationDecreased collateral network resistance/augmentation of collateral blood flow
NO donors
GlyburideMinimization of early cerebral edema
KetamineReduction of peri-infarct depolarizations/reduced baseline oxygen tissue demand
NA-1PSD95 inhibition/intrinsic neuroprotection
Cyclic limb ischemia with blood pressure-cuff inflationRemote ischemic conditioning

LVO indicates large vessel occlusion; and NA-1, Tat-NR2B9c peptide.

Conclusions/Summary

Patients with acute ischemic stroke caused by anterior circulation LVO experience a spectrum of fast to slow infarct growth that reflects differences in collateral blood flow capacity and overall cerebral ischemic tolerance. Current clinical trials are underway to individualize patient selection for reperfusion of acute LVO based on salvageable tissue volumes rather than fixed time windows. The underlying determinants of fast and slow progressors are complex, but cumulative evidence indicates that they may be dependent on the genetically predisposed availability of leptomeningeal collateral arterioles and their intrinsic hemodynamic properties. The latter is regulated in part by local perfusion pressure, arteriolar myogenic reactivity, and early cerebral edema, which likely vary in the context of demographics, premorbid vascular risk factors and ischemic conditioning. Future elucidation of the pathophysiology of fast and slow progressors of acute LVO, thus, represents a new opportunity for successful translation of neuroprotective therapies to arrest early penumbral loss and infarct growth on first medical contact for maximization of reperfusion treatments.

Footnotes

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

Correspondence to Tudor G. Jovin, MD, UPMC Stroke Institute, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213. E-mail

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