Pulsatility index: Insights into post-stroke haemodynamics

Abstract

Acute ischaemic stroke is a leading cause of acquired disability globally, with millions of patients afflicted each year. Fast and efficient recanalization therapies have revolutionized long-term patient outcomes. However, a substantial fraction of patients does not regain complete functional independence, despite undergoing timely and successful recanalization. Although various alterations in cerebral haemodynamics have been reported in both animal and clinical studies, the underlying mechanisms are complex and remain to be fully elucidated. In this mini-review, we summarize the current understanding of pulsatile haemodynamics in occlusion-reperfusion and emphasize the potential value of pulsatility assessment as a biomarker with prognostic and diagnostic value in the clinic.

Introduction

Acute ischaemic stroke (AIS) is caused by an acute thromboembolic occlusion of a cerebral artery,^1,2 resulting in reduced cerebral blood flow and changes in cerebral haemodynamics that are associated with deleterious long-term outcomes.^1,2 The implementation of thrombectomy that mechanically removes the offending blood clot has revolutionized treatment efficiency, survival rates and quality of life for stroke survivors. ³ However, 25% to 50% of stroke patients treated with thrombectomy do not improve clinically and experience poor functional outcome with reduced motoric and cognitive skills.^{4 -6} This phenomenon has been termed ‘futile reperfusion’, ⁷ and is attributed to haemodynamic abnormalities in the cerebral circulation, in which patients experience abnormal changes in cerebral blood flow velocity and infarct growth following emergency recanalization treatment.^8,9 Whilst a decrease in cerebral blood flow in the stroke-affected hemisphere is inherent in the pathophysiology of AIS, ² the cellular and molecular mechanisms underlying persisting cerebrovascular disturbances after reperfusion remain unknown. ¹⁰ The large fraction of AIS patients who do not achieve favourable outcome despite undergoing recanalization therapy, ³ has motivated the continued search for pathophysiological mechanisms, which underpin these cerebrovascular disturbances. ¹⁰ Whilst the underlying causes remain unknown, multiple detrimental ischaemia-induced alterations in the cerebral macro- and microcirculation, for example, increased middle cerebral artery (MCA) blood flow velocity and pulsatility index, an ultrasonographic parameter, ¹¹ capillary stalling ¹² and hypoperfusion, ¹³ have been observed in preclinical and clinical studies.

Multiple cardiovascular risk factors are associated with AIS, for example, atherosclerosis, ¹⁴ hyperlipidaemia, atrial fibrillation, arterial hypertension, diabetes mellitus and smoking,^15,16 which greatly increase the lifetime risk of fatal and nonfatal stroke. ¹⁵ Furthermore, AIS patients are often afflicted with cardiovascular comorbidities, that is, ischaemic heart disease, peripheral artery disease and diabetes mellitus. ¹⁶ The aetiology and vascular risk factors of AIS appear somewhat age-dependent.^{16 -18} The proportion of atherosclerosis is high especially among elderly AIS patients aged ⩾ 75 to 85 years,^16,18,19 whereas the proportions of small-vessel occlusion, diabetes mellitus, smoking, arterial hypertension and hyperlipidaemia are higher among middle-aged patients aged 50 to 84 years.^{16 -18} Nevertheless, the proportion of cardioembolic disease and large artery atherosclerosis remain high across all age groups.^16,20 Accordingly, clinical predictors of unfavourable post-stroke outcome appear to depend on age, ²¹ stroke severity,^{20 -22} post-treatment complications^20,22 and pre-existing comorbidities and impairments.^{19 -22} In advanced age, that is, age ⩾ 85 years, atrial fibrillation, ²¹ severe stroke,^19,21 severe frailty prior to stroke, ¹⁹ post-stroke dysphagia ¹⁹ and total anterior circulation infarction ¹⁹ appear to be predictors of poor outcome at 3 months post-stroke. In middle-aged patients, diabetes mellitus,^{20 -22} atrial fibrillation,^20,22 heart failure, ²² previous myocardial infarction, ²¹ smoking ²¹ and severe stroke^20,22 are recognized as clinical predictors for poor outcome at 3 to 12 months post-stroke. Additionally, post-thrombolysis intracranial haemorrhage, a high risk of haemorrhage (ie, high HAS-BLED scores), recurrent thromboembolic stroke and high risk of thromboembolism (ie, high CHA₂DS₂-VASc scores) have also previously been shown to correlate with poor long-term post-stroke outcome.^20,22 This contrasts with predictors of death within 3 months after discharge that appear to correlate mainly with the index stroke.^19,21

In this mini-review, we aim to summarize current knowledge regarding pulsatile haemodynamics after AIS and highlight future questions to be resolved in elucidating the haemodynamic mechanisms underlying futile reperfusion.

Pulsatile Haemodynamics After AIS in Patients

Post-stroke changes in macrovascular haemodynamics have been reported in multiple clinical studies, in which asymmetrical cerebral blood flow velocities in the MCA and intracranial part of the internal carotid arteries of the occluded and non-occluded hemispheres may occur after recanalization therapy.^8,23,24 Indeed, increased peak-systolic and mean blood flow velocity in the internal carotid artery and MCA, measured by transcranial Doppler ultrasonography (TCD), are associated with the development of secondary cerebral haemorrhage (ie, haemorrhagic transformation).^8,24 TCD evaluates real-time cerebral blood flow velocity and flow direction in the cerebral arteries.^25,26 Pulsatility index (PI), a Doppler ultrasonography parameter, ²⁷ describes the pulsatile variation in the blood flow velocity waveform during a cardiac cycle ²⁸ and is used clinically as a proxy for downstream vascular resistance.^{29 -31} PI is calculated as (peak-systolic flow velocity − end-diastolic flow velocity)/mean flow velocity^8,9 (Figure 1), and is influenced by haemodynamic factors such as the cross-sectional area of the arterial bed, vascular resistance, vessel wall compliance and intravascular pressure. ²⁸

Figure 1.

Transcranial Doppler ultrasonography (TCD) measurements of the human middle cerebral artery: (A) measurement of blood flow velocity in proximal segments of middle cerebral arteries using TCD and (B) measurements of cerebral blood flow velocity at the circle of Willis. The green lines demarcate the outlines of the middle cerebral artery. The red and blue colour denote flow going towards and away from the transducer, respectively. Unpublished observations. BioRender.com was used to create this figure.

Common PI findings in AIS patients are asymmetrical inter-hemispheric cerebral blood flow velocities that are associated with poor long-term outcome,^8,13,24 and abnormally elevated PI values.^11,13,32 Elevation and reduction in post-stroke PI have been reported in the ischaemic, ipsilateral hemisphere,^11,13,33 which may provide pathological insight into futile reperfusion. Indeed, decreased PI in the MCA has been associated with internal carotid artery stenosis > 70% in the affected hemisphere and impaired neurological function and infarction upon admission, ³³ whereas increased PI in the affected hemisphere correlates positively with impaired neurological function 24 hours after recanalization therapy and impaired long-term functional outcome 90-days after recanalization.^11,13,34 These findings contradict a previous study that reported no difference in PI between 2 groups that either proceeded to develop intracranial haemorrhage or did not, ⁸ despite the observation that peak-systolic blood flow velocity in the MCA increased by 2.6-fold, compared to the contralateral side, immediately after recanalization therapy. ⁸ This aligns with the findings by Kneihsl et al, ²⁴ who observed that mean blood flow velocity in the ipsilateral MCA increased by 32% compared to the contralateral MCA 24 hours after thrombectomy, but did not report any differences in PI.

Increased PI is associated with increased infarct volume. ¹¹ However, changes in intracranial pressure caused by large infarct volumes also affect PI and blood flow velocity. ³⁵ Direct invasive measurement of intracranial pressure requires surgical implantation of monitors, which carries inherent risks of infection and haemorrhage. ³⁶ However, midline shift and compression of basal cisterns assessed non-invasively with MRI or CT scans can serve as proxies for increased intracranial pressure. ³⁶ Assessment of PI and blood flow velocity should therefore optimally encompass estimation of infarct volume to control for the confounding effect of mass effect exerted by infarct size, as large infarct volumes increase intracranial pressure, which may lead to changes in cerebral blood flow. ³⁷

In preclinical AIS animal models using MCA occlusion, cessation of vessel occlusion only partially resolves the decrease in blood flow (up to ~70% of baseline),^38,39 causing prolonged hypoperfusion of cerebral tissue.^40,41 To address the existence, significance and role of this phenomenon in AIS patients, several studies have assessed brain perfusion in AIS patients with successful recanalization.^8,13,24,42 The assessments were based on the modified treatment in cerebral infarction (mTICI) score of the angiographic appearance of vessel patency following recanalization, in which mTICI 2b–3 score indicate that recanalization leads to complete reperfusion or reperfusion in more than 50% of the vascular territory affected by the occlusion. ⁴³ Twenty-four hours following thrombectomy, hypoperfusion (defined as an asymmetry between hemispheres above 15% in median cerebral blood volume or cerebral blood flow) was found in 25% of AIS patients, encompassing 60% of infarct volume.^13,44 This was frequently accompanied by reduced mean capillary transit time in the regions of hypoperfusion, indicating increased blood flow velocity through the microcirculation, ⁴ which probably reduces the time of oxygen release from erythrocytes to the brain tissue. ⁴⁰ This hypoperfusion has been associated with impaired 90-day outcome, either death or functional dependency, and greater infarct growth. ⁴ In addition, tissue areas with prolonged mean capillary transit time of erythrocytes also show greater susceptibility to infarction, which may represent salvageable tissue in the penumbra, ⁴⁵ where impeded microcirculatory blood flow after focal cerebral ischaemia, despite complete upstream macrovascular recanalization, may lead to neuronal cell death and infarction. ⁴⁶ In fact, 31% of tissue regions with prolonged mean capillary transit time progressed to infarction 24 hours following recanalization in AIS patients. ⁴⁵

Evidently, the capillary flow pattern undergoes profound changes following cerebral ischaemia, ⁴⁴ which may affect the time available for oxygen extraction and hinder the metabolic efficacy of the brain. ⁴⁰ Previous observations of post-stroke cerebral hypoperfusion and increased arterial PI in the ipsilateral hemisphere in clinical studies may represent an increase in downstream capillary resistance that is not always in line with changes in upstream vascular resistance. Indeed, mechanisms of capillary arterio-venous shunting caused by ischaemia-induced increases in capillary resistance have been proposed. ⁴⁴ This mismatch between upstream macrovascular patency and downstream microvascular tissue hypoperfusion, the so-called ‘no-reflow’ phenomenon, may underlie futile reperfusion, ⁴⁴ possibly through various mechanisms that have previously been observed in animal studies.^12,39,47,48

Microvascular Failure After Cerebral Ischaemia

The existence of brain tissue hypoperfusion caused by microvascular failure following reperfusion after cerebral ischaemia was first proposed in 1968, when it was shown that transient cerebral ischaemia led to significant alterations to the microcirculation that impeded reperfusion in an experimental rabbit model of AIS. ⁴⁹ This is consistent with more recent preclinical findings that have observed segmental capillary obstruction and impeded capillary flow following localized cerebral ischaemia in mouse models of AIS.^12,50 It has been proposed that these changes may decrease the total effective capillary area and impede oxygen extraction by increasing blood flow velocity through patent capillaries.^44,51 Pericytes located downstream to the occluded cerebral arteries have been found to constrict irreversibly around the capillaries upon exposure to focal cerebral ischaemia both in brain slices and in vivo.^50,52 The contractile state of the pericytes possibly persists because the cells undergo apoptosis before upstream reperfusion is established. ⁵⁰ An accumulation of intracellular [Ca²⁺]^53,54 due to continuous Ca²⁺ influx through voltage-gated Ca²⁺ channels with limited Ca²⁺ extrusion because of ATP absence has been proposed as a mechanism behind sustained pericyte constriction following cerebral ischaemia. ⁴⁴ These capillary constrictions have been shown to cause entrapment of leucocytes, platelets and erythrocytes, leading to segmental capillary obstruction and capillary stalling, which impede capillary blood flow, in the cerebral vasculature both in the ischaemic core and in the penumbra^39,47,52 (Figure 2).

Figure 2.

Proposed microcirculatory haemodynamic alterations underlying no-reflow and futile reperfusion in acute ischaemic stroke (AIS) patients, including but not limited to neutrophil plugging, pericyte constriction and distal embolization. BioRender.com was used to create this figure.

Other mechanisms regarded as contributors to microcirculatory failure upon AIS are microvascular occlusions by clot material formed in situ or triggered by clot fragmentation originating from the original thrombus ¹⁰ (Figure 2). Leucocyte adhesion and extravasation occur in post-capillary venules during cerebral ischaemia and have been observed concurrently with deposition of fibrinogen onto leucocytes. ⁴¹ It has been proposed that the lodging of leucocytes drives the formation of secondary microthrombi, which may subsequently impede blood flow, ⁴¹ and that leucocyte obstruction itself may worsen tissue damage. ¹⁰ This suggestion is supported by pre-clinical findings, where administration of anti-Ly6G antibody, a neutrophil-depleting antibody, before and after middle cerebral artery occlusion-reperfusion partly restores cerebral blood flow to pre-occlusion levels in the ischaemic core and penumbra, reduce infarct volume and improves neurological outcome.^39,47 These findings align with observations from a retrospective clinical AIS study, where poor outcome or death was associated with a higher count of leucocyte in venous blood samples. ⁵⁵ In clinical studies, embolic fragmentation of the primary thrombus during mechanical clot retrieval with thrombectomy may generate clot debris that dislodge and migrate further downstream, causing secondary occlusion. ⁵⁶

Cerebral ischaemia is also associated with increased vasoconstriction and myogenic tone of parenchymal arterioles downstream of occluded cerebral arteries,^48,57 which is independent of intracellular [Ca²⁺] concentration and membrane potential changes in vascular smooth muscle cells ⁴⁸ (Figure 2). This elevation in myogenic tone may be caused by increased Ca²⁺ sensitivity of the contractile apparatus of vascular smooth muscle cells after ischaemia, ⁴⁸ thereby serving as another factor that contributes to incomplete perfusion and infarct expansion. Conversely, penetrating arterioles downstream of middle cerebral artery occlusion have been shown to dilate during occlusion and up to 90 minutes after cessation of occlusion with a concomitant decrease in blood flow velocity. ³⁸ The mechanisms behind this discrepancy are unclear, but differences in arterial diameter, ⁵⁸ as it has been observed in the mesenteric artery or arterial spatial location in the brain in respect to the stroke core may contribute to this discrepancy in results.

The Effect of Systemic Comorbidities on Pulsatile Haemodynamics and Post-Stroke Outcome

AIS patients are commonly affected by comorbid conditions ⁵⁹ that predispose to stroke, for example, atrial fibrillation or that share risk factors and/or pathophysiology with AIS,^59,60 for example, hypertension, peripheral vascular disease, ischaemic heart disease, heart failure and diabetes mellitus. ⁶⁰ The systemic vascular effects imposed by these comorbidities consist of several pathophysiological mechanisms that ultimately lead to increased arterial stiffness.^61,62 In a clinical setting, arterial stiffness can be assessed reliably and reproducibly with carotid-femoral pulse wave velocity (PWV).^{61,63 -66} Increased arterial stiffness is associated with poor post-stroke functional outcome, ischaemic heart disease and heart failure.^61,67 Increased arterial stiffness is characterized by functional and structural changes in the vascular wall that result from endothelial dysfunction, remodelling of the tunica media, loss of elastin content within arteries, leading to fundamental alterations in systemic haemodynamics and ultimately end-organ damage. ⁶² Arterial stiffness may deteriorate the buffer capacity alterations in blood flow and pressure of vessels, that are inherent to pulsatile flow in large arteries. ⁶¹

Stiffening of the arteries increases PWV and leads to elevated pulse pressure and isolated systolic hypertension, which are transmitted to the peripheral vascular beds and generates microvascular damage.^61,62,68 This is also seen in diabetes mellitus,^62,66 cardiac diastolic dysfunction of the left ventricle, ⁶¹ diastolic heart failure^61,62 and increased tunica media-to-lumen ratio in resistance arteries. ⁶⁹ Diabetic patients are also characterized by having extensive atherosclerosis of systemic^70,71 and intracranial vessels, ⁷² a higher prevalence of arterial stenosis of the common carotid artery, ⁷³ and have morphological changes in the cerebral microvasculature. ⁷⁴ Increased mean and systolic blood flow velocities of the internal carotid artery have been observed in diabetic patients, and increased PI in the MCA has been observed to correlate positively with diabetes mellitus duration,^31,75 which may represent increased cerebrovascular resistance.^31,75 In accordance with this, AIS patients with diabetes mellitus have poor post-stroke outcome compared to non-diabetic patients.^20,22 Hypertension may also affect pulsatile flow parameters. The duration of hypertension may correlate negatively with MCA blood flow velocity, that is, the longer the hypertensive state, the lower the flow velocity in MCA, whereas PI in MCA increases with the duration of hypertension. ⁷⁶ Furthermore, hypertension is associated with increased arterial stiffness, ⁶¹ and worsens stroke outcome in AIS patients with pre-existing hypertension.^77,78

Arterial stiffening is associated with an increased risk of large vessel occlusion and fatal stroke outcome.^61,79 This may be mediated either through an increased risk of atrial fibrillation ⁸⁰ and thus cardioembolic occlusion, or plaque rupture through atherogenesis and turbulent blood flow via increased pulse pressure.^61,81 Thus, it is not unlikely that the aforementioned comorbidities may exacerbate pre-existing pathological pulsatile haemodynamics during AIS, which may have detrimental effects and worsen stroke outcome in AIS patients with comorbidities.

Pulsatility Index: A Biomarker of No-Reflow and Futile Reperfusion?

Research into cerebrovascular alterations in preclinical and clinical studies during and after cerebral ischaemia indicates a significant role of cerebrovascular disturbances in the no-reflow and futile reperfusion phenomena in AIS patients. The lack of prognostic markers and acceptable measurement techniques for no-reflow, where microcirculatory dysfunctions observed in animal studies, as mentioned above, are directly assessed in AIS patients, hinders successful translation of preclinical findings into clinical practice. PI, peak-systolic blood flow velocity and mean blood flow velocity obtained via TCD in clinical studies have previously been proposed as potential biomarkers of no-reflow and disturbances in pulsatile haemodynamics after AIS.^11,13 TCD is a non-invasive, affordable technique that allows for rapid and repeated assessment of pulsatile haemodynamics in a clinical setting. However, PI is influenced by various haemodynamic factors, ²⁸ which complicate the interpretation and utility of this parameter. Furthermore, in clinical cerebrovascular studies, it is used as a proxy for downstream vascular resistance, ²⁸ even though the direct relationship between this parameter and the aforementioned microvascular disturbances leading to altered vascular resistance remains to be investigated in clinical and preclinical studies. Whether the post-stroke alterations in pulsatile haemodynamics reported in clinical studies are caused by microvascular disturbances as observed in preclinical animal studies remain yet to be elucidated. Concurrent examination of macrovascular PI and blood flow velocities in the proximal segments of cerebral arteries with the assessment of downstream microvasculature, for example, vessel diameter and capillary blood flow and velocity, may yield important translational insights into cerebral haemodynamics. Future studies should aim to address the relationship between macro- and microvascular haemodynamics to elucidate how dysfunction in the microcirculation may affect macrocirculation in health and disease. This may lead to new therapeutic approaches for futile reperfusion.

Conclusion

Research into futile reperfusion indicates multiple detrimental ischaemia-induced alterations in cerebral haemodynamics in the micro- and macrocirculation that may underlie poor post-stroke outcomes. However, the relationship between stroke outcomes and dysfunction in cerebral haemodynamics remains unknown. The interpretation of these findings is further complicated by pre-existing cardiovascular comorbidities in AIS patients, for example, hypertension, diabetes mellitus, peripheral vascular disease and ischaemic heart disease, that either predispose to AIS, increase the risk of AIS and worsen post-stroke outcome. TCD measurements of pulsatile parameters, for example, pulsatility index (PI), offer valuable insight into the alterations of pulsatile haemodynamics in occlusion-reperfusion, where PI has potential as a prognostic and diagnostic biomarker of futile reperfusion. However, cardiovascular comorbidities may affect pulsatile flow by contributing to arterial stiffness and atherosclerosis, which are conditions that not only predispose to AIS, but may also exacerbate pre-existing pulsatile haemodynamic abnormalities. Future studies should therefore aim to address how dysfunction in the cerebral microcirculation may affect the macrocirculation, and should also aim to dissect the magnitude of each individual comorbidity’s effect on pulsatile measurements in order to avoid spurious conclusions of causality.