Modern day cardiac surgery evolved upon the advent of cardiopulmonary bypass machines (CPB) in the 1950s. Following this development, cardiac surgery in recent years has improved significantly. Despite such advances and the introduction of new technologies, neurological sequelae after cardiac surgery still exist. Ischaemic stroke, delirium, and cognitive impairment cause significant morbidity and mortality and unfortunately remain common complications. Postoperative cognitive decline (POCD) is believed to be associated with the presence of new ischaemic lesions originating from emboli entering the cerebral circulation during surgery. Cardiopulmonary bypass was thought to be the reason of POCD, but randomised controlled trials comparing with off-pump surgery show contradictory results. Attention has now turned to the growing evidence that perioperative risk factors, as well as patient-related risk factors, play an important role in early and late POCD. Clearly, identifying the mechanism of POCD is challenging. The purpose of this systematic review is to discuss the literature that has investigated patient and perioperative risk factors to better understand the magnitude of the risk factors associated with POCD after cardiac surgery.
Neurological complication after cardiac surgery is of a considerable concern and debate exists as to which perioperative factors may be responsible for this adverse injury. Significant advances in all aspects of intraoperative and postoperative care mean cardiac surgery is now safer than ever before [
Over time, the demographic characteristics of patients undergoing cardiac surgery have shifted to include a higher proportion of elderly patients, undergoing increasingly complex procedures. The average age of cardiac surgery patients has increased from ~64 years in 2001 to ~67 years in 2010. The number of patients with neurological disease prior to surgery has nearly doubled from 1.4% in 2001 to ~2.8% in 2010. Cardiac surgery procedures have also become more complex, with the number of patients undergoing isolated coronary artery bypass graft (CABG) decreasing by almost 20% from 2001 to 2010. Despite higher patient risk profiles, the mortality rate has fallen slightly from 4.0% in 2001/2002 to 3.1% in 2010/2011 (National Cardiac Surgery Audit, UCL, 2012).
Routine clinical examination covers crucial neurological abnormalities such as ataxia, visual defects, paresis, and hypaesthesia [
A systematic literature search was conducted from searching articles from PubMed and EMBASE. Search terms were created by combining the following medical subject headings (MeSH terms): “Coronary Artery Bypass” OR “Coronary Artery Bypass, Off-Pump” OR “Valve Surgery” OR “Thoracic Surgery” OR “Cardiac Surgical Procedures” AND “Cognitive Therapy” OR “Cognition Disorders” OR “Cognition” OR “Neuropsychology” OR “Neuropsychological Tests” OR “Mild Cognitive Impairment.”
All studies published in English between June 1967 and August 2014 and featuring adult human subjects were eligible for review. Abstracts were excluded if they involved paediatric surgery, operations other than cardiac surgery, or no measurement of cognitive function. Case reports and studies of cardiac procedures such as angioplasty, angiography, valvuloplasty, and Transcatheter Aortic Valve Implantation (TAVI) were also excluded. Studies generating multiple publications from the same cohort were reported only once.
Abstracts involving both cardiac surgery and cognitive function were independently reviewed by two investigators (Nikil Patel and Emma M. L. Chung) and studies of adult cardiac surgery patients that assessed both before and after operative cognitive function were identified for full paper review. Where there was disagreement among investigators the full text was reviewed. Additionally, the reference lists of selected articles were evaluated for any additional articles of interest.
Articles short-listed for full manuscript review were summarised in an Excel spreadsheet listing the study design (observational, RCT, etc.), number of patients, type(s) of surgery, outcome measures, and time point of neurocognitive assessment. Studies that included assessment of anxiety and depression were also recorded, as these conditions can impact the outcome of cognitive assessments. There was insufficient homogeneity between studies to allow a quantitative, meta-analytic approach of region of interest studies. Therefore, a critical, systematic review was undertaken.
A total of 638 abstracts were systematically identified using our search criteria of which 426 papers were suitable for full review. Of these, 296 were observational studies and 130 were RCTs. Although over 420 original research articles were identified as having investigated cognitive decline following cardiac surgery, we found little consensus on the incidence, severity, and time course of symptoms. Differing methodologies used between studies made it difficult to directly compare study findings through systematic meta-analysis.
Most studies evaluating cognitive decline focus on changes in executive function, learning language, visual spatial skills, attention, and memory [
Studies attempting to quantify neuropsychological decline at various time points. The weighted mean and standard deviation (number of patients and % decline) are plotted by combining data from a total of 15649 patients and 94 studies; discharge (17 studies), 1-2 weeks (16 studies), 1 month (4 studies), 6 weeks (15 studies), 2-3 months (18 studies), 6 months (11 studies), 1 year (8 studies), and 3–5 years (5 studies).
Large variations in the estimated incidence of postoperative cognitive decline are observed, even after grouping studies where tests were performed at similar time points, Figure
Further, we investigated perioperative risk factors associated with cognitive decline. Potential mechanisms implicated in the pathogenesis of cognitive decline investigated in previous research resulted in a total of 92 articles (see PRISMA chart in Supplementary Material available online at
Sedative and anaesthetic agents with
Studies comparing cognition after cardiac surgery following administration of different types of anaesthetic.
Study | Study design | Number of |
Type of anaesthesia/drug | Time of assessment | Outcome |
---|---|---|---|---|---|
Dumas et al., 1999 [ |
RCT | 48 | Fentanyl and early extubation | 8 weeks | Improved cognition |
Dowd et al., 2001 [ |
RCT | 78 | Propofol and lorazepam | 6–12 months | Improved cognition |
Bottio et al., 2007 [ |
Obsv. | 50 | Epidural anaes. | 6 months | Improved cognition |
Delphin et al., 2007 [ |
Obsv. | 91 | Sevoflurane and isoflurane | 2 hours and 1 day | Improved cognition |
Kanbak et al., 2007 [ |
RCT | 40 | Isoflurane, sevoflurane, and desflurane | 3 and 6 days | Improved cognition |
Hudetz et al., 2009 [ |
Obsv. | 78 | Ketamine | 1 week | Improved cognition |
Schoen et al., 2011 [ |
RCT | 117 | Sevoflurane and propofol | 2, 4, and 6 days | Improved cognition |
Kanbak et al., 2007 [ |
RCT | 40 | Sevoflurane and desflurane | 3 and 6 days | Decline |
Kadoi et al., 2003 [ |
RCT | 180 | Propofol and fentanyl | 6 months | No difference |
Silbert et al., 2006 [ |
Obsv. | 300 | Fentanyl | 1 week, 3 months, 1 year | No difference |
Kadoi and Goto, 2007 [ |
Obsv. | 109 | Sevoflurane | 6 months | No difference |
Lehmann et al., 2007 [ |
RCT | 66 | Sufentanil and midazolam | Discharge | No difference |
Evered et al., 2011 [ |
Obsv. | 281 | General anaesthetics | 1 week and 3 months | No difference |
Parra et al., 2011 [ |
Obsv. | 48 | Sevoflurane | 3 months | No difference |
Royse et al., 2011 [ |
RCT | 180 | Desflurane andpropofol | Discharge and 3 months | No difference |
Obsv.: observational.
This research suggests that choice of anaesthetic has potential to affect cognition, particularly when tests are performed soon after surgery. However, in the majority of larger studies, the choice of anaesthetic had no impact on cognitive outcome.
A number of studies have investigated the association between low blood pressure during cardiac surgery and cognitive decline. Although normal blood pressure in conscious patients is approximately 120/80
Studies investigating POCD associated with intraoperative blood pressure variation.
Study | Study |
Number of |
Type of intervention | Time of assessment | Outcome |
---|---|---|---|---|---|
Gold et al., 1995 [ |
RCT | 248 | High (80–100 mmHg) versus low (50–60 mmHg) BP | 6 months | Decline with lower BP |
Siepe et al., 2011 [ |
RCT | 92 | High (80–90 mmHg) versus low (60–70 mmHg) BP | 2 days | Decline with lower BP |
Gottesman et al., 2007 [ |
Obsv. | 15 | Low MAP (50–70 mmHg) | 3–5 days and 1 month | Decline with lower BP |
Newman et al., 1995 [ |
Obsv. | 237 | Low MAP (50–60 mmHg) | Discharge | Decline with lower BP |
Charlson et al., 2007 [ |
RCT | 412 | High MAP (57–90 mmHg) versus custom (capped at 90 mmHg) | 6 months | No difference in outcome |
Obsv.: observational.
In the study by Gold et al., a higher mean arterial pressure (80–110
Some researchers have proposed that it is not mean arterial pressure (MAP)
Studies investigating cerebral autoregulation during cardiac surgery in conjunction with neurocognitive tests.
Study | Study design | Number of patients | Cerebral autoregulation measures | Time of assessment | Outcome |
---|---|---|---|---|---|
Patel et al., 1993 [ |
RCT | 70 | Xenon-133 isotope clearance, CMRO2 (cerebral metabolic rate for oxygen), CERO2 (cerebral extraction ratio for oxygen) | 6 weeks | Decline with impaired CA |
Patel et al., 1996 [ |
RCT | 70 | CBF, CBFv, and O2 saturation were measured during 4 phases of surgery | 6 weeks | Decline with impaired CA |
Govier et al., 1984 [ |
Obsv. | 67 | Partial pressure of arterial carbon dioxide (PaCO2), clearance of xenon-133 | Discharge | No difference |
Newman et al., 1994 [ |
Obsv. | 215 | Xenon-133 clearance, CMRO2, cerebral AV difference (C[AV]O2) | Discharge | No difference |
Obsv.: observational.
All four studies determined pressure-flow and metabolic-flow cerebral autoregulation during cardiopulmonary bypass using the 133Xe clearance cerebral blood flow method. Two studies in Table
All types of surgery have the risk of developing systemic inflammation; however, in cardiac surgery using CPB the blood is exposed to foreign surfaces which have potential to stimulate proinflammatory responses. Inflammation causes endothelial dysfunction, which can lead to leakage between the blood-brain barrier and tissue oedema [
Cardiopulmonary bypass components that come into contact with the blood can be coated with biocompatible materials such as poly-2-methoxyethylacrylate, heparin, trillium, and synthetic proteins. These coatings aim to reduce inflammatory responses triggered during CPB. Heparin-coated circuits, in particular, have undergone considerable investigation in previous research. A total of 26 studies (including 7 RCTs) have used neuropsychological tests to investigate whether there is a strong association between inflammation and cognitive decline, Table
Studies investigating whether biomarkers associated with inflammation and/or interventions aimed at reducing inflammation are associated with changes in cognition after surgery.
Study | Study |
Number of |
Marker for cerebral damage | Time of assessment | Outcome |
---|---|---|---|---|---|
Fitch et al., 1999 [ |
RCT | 35 | Inhibition of complement activation by specific antibody and no antibody | Discharge | Improved cognition |
Heyer et al., 2002 [ |
RCT | 99 | Inhibition of complement activation by heparin-coated CPB | 5 days and 6 weeks | Improved cognition |
Baufreton et al., 2005 [ |
RCT | 30 | Inhibition of complement activation by heparin-coated CPB | Discharge | Improved cognition |
Skrabal et al., 2006 [ |
RCT | 39 | PMEA-coated circuits and noncoated circuits | 7–10 days | Improved cognition |
Wimmer-Greinecker et al., 1998 [ |
Obsv. | 76 | >S-100 and NSE | 5 days and 2 months | Decline |
Jönsson et al., 1999 [ |
Obsv. | 132 | >S-100 | 2 weeks and 2 months | Decline |
Kilminster et al., 1999 [ |
Obsv. | 130 | >S-100 | 6–8 weeks | Decline |
Rasmussen et al., 1999 [ |
Obsv. | 35 | >NSE | Discharge and 3 months | Decline |
Derkach et al., 2000 [ |
RCT | 27 | >S-100 and NSE (deep and mild hypothermic) | 6 months | Decline |
Diegeler et al., 2000 [ |
RCT | 40 | >S-100 (on- and off-pump) | 1 week | Decline |
Georgiadis et al., 2000 [ |
Obsv. | 190 | >S-100 | Discharge | Decline |
Lloyd et al., 2000 [ |
RCT | 125 | >S-100 (on- and off-pump) | 3 months | Decline |
Basile et al., 2001 [ |
Obsv. | 16 | >S-100 and NSE | 6 months | Decline |
Rasmussen et al., 2002 [ |
Obsv. | 15 | >NSE | Discharge and 3 months | Decline |
Farsak et al., 2003 [ |
Obsv. | 50 | >S-100 | Discharge | Decline |
Mathew et al., 2003 [ |
Obsv. | 460 | Reduced preoperative endotoxin immunity | 6 weeks | Decline |
Jönsson et al., 2004 [ |
Obsv. | 56 | >S-100 | 6 months | Decline |
Kofke et al., 2004 [ |
Obsv. | 28 | Apo epsilon 4 allele, >S-100 | 8 and 24 hrs | Decline |
Snyder-Ramos et al., 2004 [ |
Obsv. | 64 | >S-100 and NSE | Throughout 7 days | Decline |
Kálmán et al., 2006 [ |
Obsv. | 14 | >Cytokine interleukin-6 | 1 week and 6 months | Decline |
Ramlawi et al., 2006 [ |
Obsv. | 42 | >C-reactive protein | 6 hours and 4 days | Decline |
Lazibat et al., 2012 [ |
Obsv. | 62 | >S-100 | 2 days | Decline |
Bayram et al., 2013 [ |
Obsv. | 64 | >S-100 | 1 week | Decline |
Westaby et al., 2001 [ |
Obsv. | 1001 | >S-100 and NSE | 5 days and 3 months | No difference |
Mathew et al., 2005 [ |
Obsv. | 440 | Statin treatment | 6 weeks | No difference |
Plaschke et al., 2013 [ |
Obsv. | 151 | Preoperative serum anticholinergic activity | 3 months | No difference |
NSE: neuron-specific enolase, PMEA: poly-2-methoxyethylacrylate, and Obsv.: observational.
All studies that have randomised patients to receive a heparin-coated CPB system found neuropsychological outcome was better in patients receiving the heparin-coated circuit [
A number of neuroprotective agents have been investigated to assess whether these could be administered to help preserve neurocognitive function. The results of 17 studies investigating whether neuroprotective agents reduce the incidence of POCD are summarised in Table
RCTs investigating the efficacy of neuroprotection, or neuroprotective agents, in reducing cognitive decline after cardiac surgery.
Study | Number of patients | Type of neuroprotective drug | Time of assessment | Outcome |
---|---|---|---|---|
Grieco et al., 1996 [ |
29 | GM-100 (ganglioside) or placebo | 1 week and 6 months | Improved cognition |
Arrowsmith et al., 1998 [ |
171 | Remacemide or placebo | 2 months | Improved cognition |
Svensson et al., 2002 [ |
403 | Mannitol, thiopental, MgSO4, lidocaine | 2-3 weeks | Improved cognition |
Wang et al., 2002 [ |
118 | Lidocaine or placebo | 9 days | Improved cognition |
Uebelhack et al., 2003 [ |
64 | Piracetam or placebo | 3 days | Improved cognition |
Szalma et al., 2006 [ |
98 | Piracetam or placebo | 6 weeks | Improved cognition |
Haljan et al., 2009 [ |
32 | Erythropoietin or placebo | Discharge and 2 months | Improved cognition |
Hudetz et al., 2009 [ |
52 | Ketamine or placebo | 1 week | Improved cognition |
Zhang et al., 2011 [ |
200 | Benzyl alcohols or saline (placebo) | Discharge and 3 months | Improved cognition |
Kong et al., 2002 [ |
245 | Chlormethiazole/administration or placebo | 4–7 weeks | No difference |
Taggart et al., 2003 [ |
150 | Imidazoles: low dose (10 mg) or high dose (100 mg) or placebo | 5 days and 3 months | No difference |
Mathew et al., 2004 [ |
914 | Pexelizumab bolus, bolus plus infusion, or placebo | 4 days and 1 month | No difference |
Mathew et al., 2005 [ |
440 | Hydroxymethylglutaryl-CoA reductase inhibitors | 6 weeks | No difference |
Hogue et al., 2007 [ |
174 | 17-beta estradiol or placebo | 4–6 weeks | No difference |
Mathew et al., 2009 [ |
241 | Lidocaine or placebo | 6 weeks and 1 year | No difference |
Mitchell et al., 2009 [ |
158 | Lidocaine or placebo | 10 weeks and 25 weeks | No difference |
Holinski et al., 2011 [ |
88 | Piracetam or placebo | 3 days | No difference |
One of the most commonly used neuroprotective agents is Lidocaine, which featured in 4 of the 17 studies. Lidocaine is thought to inhibit inflammatory responses during cardiac surgery by modulation of inflammatory mediators, reduction in cerebral metabolism, and deceleration of ischaemic ion fluxes [
The patient’s temperature during cardiac surgery has long been thought to play a role in neurological outcome. Several studies have focused their trials on whether reducing the metabolic demand of the brain through hypothermia is neuroprotective. Based on our literature search, 41 studies investigating the effects of temperature were identified. Seventeen studies were excluded from the final result due to lack of clarity in neuropsychological assessments and outcomes. Results from a total of 19 studies investigating the effect of temperature on pre- and postoperative neuropsychological tests are summarised in Table
Studies investigating POCD associated with temperature during cardiac surgery.
Study | Study |
Number of |
Mean temperature (Celsius) | Time of assessment | Outcome |
---|---|---|---|---|---|
Grimm et al., 2000 [ |
RCT | 144 | (1) Normothermia: 37°C |
1 week and 4 months | Improved cognition |
|
|||||
Shaaban-Ali et al., 2002 [ |
RCT | 60 | (1) Normothermia: 34°C |
5 days | Improved cognition |
|
|||||
Nathan et al., 1995 [ |
Obsv. | 30 | Maintain ≤ 34°C | 1 week | Improved cognition |
|
|||||
Grocott et al., 2002 [ |
Obsv. | 300 | Post-op hypothermia only | 6 weeks | Improved cognition |
|
|||||
Kadoi et al., 2004 [ |
RCT | 60 | (1) Normothermia: 37°C |
1 month | Improved cognition |
|
|||||
Boodhwani et al., 2006 [ |
RCT | 448 | (1) Normothermia: 37°C |
1 week | Improved cognition |
|
|||||
Hiraoka et al., 2012 [ |
Obsv. | 11 | Hypothermia: 20–22°C | 3 weeks and 6 months | Improved cognition |
|
|||||
McLean et al., 1994 [ |
RCT | 155 | (1) Hyperthermia: >34°C |
5 days and 3 months | No difference |
|
|||||
Regragui et al., 1996 [ |
RCT | 97 | (1) Normothermia: 37°C |
6 weeks | No difference |
|
|||||
Heyer et al., 1997 [ |
RCT | 99 | (1) Normothermia: 34°C |
Discharge and 6 weeks | No difference |
|
|||||
Kneebone et al., 1998 [ |
Obsv. | 50 | (1) Normothermia: 37°C |
1 week | No difference |
|
|||||
Reich et al., 1999 [ |
Obsv. | 149 | (1) Deep hypothermia: 12–15°C (<25 mins) |
1 month | No difference |
|
|||||
Kaukinen et al., 2000 [ |
RCT | 36 | (1) Normothermia: 36-37°C |
5 days and 11–23 months | No difference |
|
|||||
Górna et al., 2001 [ |
Obsv. | 33 | No full text | 3–10 days | No difference |
|
|||||
Grigore et al., 2001 [ |
RCT | 300 | (1) Normothermia: 35.5–36.5°C |
6 weeks | No difference |
|
|||||
Kaukuntla et al., 2004 [ |
Obsv. | 60 | (1) Normothermia: 35°C |
1 and 8 weeks | No difference |
|
|||||
Reich et al., 2004 [ |
Obsv. | 61 | Monitoring during deep hypothermic arrest (28°C) | Discharge | No difference |
|
|||||
Boodhwani et al., 2007 [ |
RCT | 268 | (1) Normothermia: 37°C |
Discharge and 3 months | No difference |
|
|||||
Kunihara et al., 2007 [ |
Obsv. | 26 | (1) Normothermia: 34°C |
1 week | No difference |
Obsv.: observational.
Some studies suggest that hypothermia is more effective than normothermia in protecting the brain during surgery; however, other studies report no obvious difference between “mild hypothermia” and “normothermia” in terms of neuropsychological performance at discharge (49% and 45%, resp.) and at 3 months (4% and 8%, resp.) [
Some researchers have proposed that the brain could be susceptible to insult during rewarming from hypothermia, particularly if cerebral autoregulation mechanisms are unable to compensate for a sudden increase in metabolic activity associated with changes in temperature. Six studies have been conducted to examine the effect of rewarming rate on POCD, and all of these have shown a benefit in postoperative outcome associated with slower rewarming, Table
Studies investigating POCD associated with the rate of rewarming during cardiac surgery.
Study | Study |
Number of |
Mean temperature (Celsius) | Time of assessment | Outcome |
---|---|---|---|---|---|
Mora et al., 1996 [ |
RCT | 138 | (1) Rewarm 1-2°C (per increase) |
1–3 days, 7–10 days, and 1 month | Improved cognition with slower rewarm |
|
|||||
Nathan et al., 2001 [ |
Obsv. | 294 | (1) Rewarm to 34°C (1°C per increase) |
1 week and 3 months | Improved cognition with slower rewarm |
|
|||||
Grigore et al., 2002 [ |
Obsv. | 100 | (1) Rewarm to 32°C (max within 3 mins) |
6 weeks | Improved cognition with slower rewarm |
|
|||||
Kawahara et al., 2003 [ |
RCT | 100 | (1) Rewarm 1-2°C (per increase) |
1 month | Improved cognition with slower rewarm |
|
|||||
Nathan et al., 2007 [ |
RCT | 223 | (1) Rewarm to 34°C (1°C per increase) |
1 week | Improved cognition with slower rewarm |
|
|||||
Sahu et al., 2009 [ |
RCT | 80 | (1) Rewarm 1–3°C (per increase) |
5 days | Improved cognition with slower rewarm |
Obsv.: observational.
Neuropsychological function is a soft outcome measure and has proved challenging to quantify postoperatively. Although neuropsychological tests theoretically provide a highly sensitive means of quantifying changes in cognition, differences in test batteries, timing of assessment, and criteria for defining neuropsychological decline generate considerable heterogeneity in the data, which limits our ability to compare the results of different studies. Depending on the timing of the neurocognitive tests and the definition used for determining decline, the reported incidence of neurocognitive decline after cardiac surgery varied extensively. The outcome suggests that 50–70% of patients experience cognitive decline when tested within one week of surgery, falling to 30–50% after 8–10 weeks, recovering to 10–20% at 1 year, and then declines again at 3–5 years. Currently, there is no widely accepted clinical definition of cognitive decline; therefore, it is possible that arbitrary definitions of decline have resulted in an overestimation of the incidence of decline. At present, there is no evidence to suggest that the long-term incidence of cognitive decline differs from that of nonoperative controls. Estimating long-term cognitive decline can be difficult, as normal ageing and dementia interfere with studies with older populations.
Further research is required to develop a more dynamic and nuanced picture of interactions between underlying pre- and perioperative risk factors. It is apparent that studies investigating isolated perioperative factors are insufficient to explain complex interactions between temperature, cerebral autoregulation, oxygen saturation, and brain metabolism. To date, isolated interventions and neuroprotective drugs aimed at improving cognitive outcome have proved to be largely ineffective. Literature examining underlying and perioperative risk factors associated with the pathogenesis of cognitive decline suggests that there is no single causative factor responsible for POCD. It seems likely that the causes are multifactorial, due to emboli, impaired perfusion, chronic cardiovascular disease, and inflammatory responses.
Interpreting the risk factors associated with postoperative cognitive decline, it seems that efforts to protect the brain during surgery are intrinsically linked with the need to control the progression of cardiovascular disease, especially in older patients. It is possible that patients may be exceeding a “threshold” of preexisting vulnerability where the brain’s ability to compensate for injuries or inflammation during surgery is absent. It is also important to address that cardiac surgery equipment advances are a confounder within this review and should be considered. In summary, the literature examining underlying risk factors and perioperative risk factors associated with the pathogenesis of cognitive decline suggests that there is no single factor responsible for postoperative cognitive decline or single intervention capable of protecting the brain during surgery. Overall, the pathogenesis of cognitive decline following surgery still remains unclear.
Several factors have been associated with brain injury including hypoperfusion, arrhythmias, rapid rewarming, and inflammation (local or global) [
Cardiac surgery is a triumph of modern day medicine, and its acceptance as a safe procedure is widespread. Unfortunately, postoperative cognitive issues remain a consideration. As cardiac surgery procedures are now being challenged by less invasive methods, perhaps intraoperative transcranial Doppler monitoring, neuropsychological tests, and neuroimaging will play an increasingly important role in optimising treatment.
The authors declare that they have no conflict of interests.
Nikil Patel and Emma M. L. Chung conducted the literature search and data extraction. Nikil Patel, Emma M. L. Chung, and Jatinder S. Minhas drafted the paper
The authors would like to thank the Department of Cardiovascular Sciences, University of Leicester, and the Department of Medical Physics, University Hospitals of Leicester NHS Trust. Nikil Patel is funded by the National Institute of Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit. Jatinder S. Minhas is an Academic Clinical Fellow in Stroke Medicine funded by the NIHR.