STROKE AND ATRIAL FIBRILLATION: BETTER DETECTION, EFFECTS ON INFARCT EVOLUTION AND OUTCOME Hans T. H. Tu MBBS FRACP Submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy March 2018 Melbourne Brain Centre at the Royal Melbourne Hospital Department of Medicine (Royal Melbourne Hospital) The University of Melbourne Abstract Ischemic stroke is the commonest stroke and a leading cause of disability and death worldwide. Atrial fibrillation (AF) is the most frequent persistent cardiac arrhythmia and a preventable cause of ischemic strokes. The incidence and prevalence of AF have progressively increased over the last few decades and will likely continue to rise, due to the aging population and ongoing growth in other AF risk factors such as obesity, hypertension, diabetes mellitus, heart failure, coronary artery disease and sleep apnea. The social and economic costs associated with the increasing AF burden represent a mounting public health challenge, leading many to consider AF an evolving epidemic in the twenty-first century. Ischemic strokes related to AF usually result from cardioembolism of a large cerebral artery, therefore tend to be larger, more frequently fatal or associated with greater disability than strokes from other causes. However, the pathophysiological mechanisms underlying this association remain unclear. Analysis of serial multimodal magnetic resonance brain imaging in a cohort of acute hemispheric ischemic stroke patients revealed that patients with AF had greater volumes of more severely hypoperfused brain tissue at 3-6 hours following stroke onset, higher infarct growth and larger final infarcts. These findings were best explained by poorer collateral circulation in patients with AF, supporting further investigation of acute stroke therapy that improve cerebral collateral circulation. Analysis of clinical data in a separate large cohort of acute ischemic stroke patients emphasized that serious cardiac adverse events (SCAE) including acute coronary syndrome, symptomatic heart failure, life threatening cardiac arrhythmias, cardiopulmonary arrest and cardiac death were common and occurred early following stroke. SCAEs were significantly more frequent in patients with AF, contributing to the association between AF and higher mortality following stroke, in addition to greater neurological impairment. Given that most SCAEs are potentially remediable, these results highlight the 1 need for more rigorous surveillance of SCAEs following stroke, particularly in patients with AF. CHADS2 and CHA2DS2-VASc scores are validated and clinically useful tools for assessing stroke risk in patients with AF. Both scores have also been associated with a number of short and long term outcomes following stroke, suggesting potential utility in stroke prognosis. However, both scores had very modest precision in estimating the probability of mortality, functional outcome and SCAEs within 3 months following ischemic stroke in a large cohort of acute ischemic stroke patients with and without AF. Pre-stroke CHA2DS2- VASc score did have high negative predictive value for SCAE and high specificity for poor functional outcome, suggesting that it could be used for identifying patients at lower risk of poor outcomes and SCAEs within 3 months following ischemic stroke in patients with and without AF. AF can be persistent or paroxysmal and is frequently asymptomatic, therefore are hard to detect. However, the stroke risk and benefit from validated prevention therapy do not significantly differ between persistent and paroxysmal AF. There is strong evidence that current standard testing paradigm such as 24-hour Holter monitoring following ischemic stroke misses a large proportion of patients with paroxysmal AF. A pilot study in a prospective cohort of 20 cryptogenic stroke patients confirmed previous findings that a significant proportion has paroxysmal AF undetected by 24- hour Holter monitoring. However, longer monitoring with 28-day Holter monitoring was poorly tolerated and still insufficiently sensitive. Further studies are urgently needed to elucidate the optimal timing, method and duration of cardiac rhythm monitoring following ischemic stroke. 2 Declaration This is to certify that: 1. The thesis comprises only my original work towards the PhD except where indicated in the Preface, 2. Due acknowledgement has been made in the text to all other material used, 3. The thesis is fewer than 100 000 words in length, exclusive of tables, maps, bibliographies and appendices. Hans T. H. Tu March 2018 3 Preface The work presented in this thesis was undertaken in the Department of Neurology, The Royal Melbourne Hospital, in association with the Melbourne Brain Centre at the Royal Melbourne Hospital, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne. The work presented in this thesis has all been published in peer-reviewed journals as well as presented at national and international scientific conferences. I am the first author of all presentations and publications derived from this thesis. I wrote all abstracts and manuscripts after considering the suggestions from my co-authors. Peer-Reviewed Journal Articles Tu HT, Campbell BCV, Christensen S, Desmond PM, De Silva DA, Parsons MW, Churilov L, Lansberg MG, Mlynash M, Olivot JM, Straka M, Bammer R, Albers GW, Donnan GA, Davis, SM, for the EPITHET-DEFUSE Investigators. Worse stroke outcome in atrial fibrillation is explained by more severe hypoperfusion, infarct growth and hemorrhagic transformation. Int J Stroke. 2015;10:534-540. Tu HT, Spence S, Kalman JM, Davis SM. Twenty-eight day Holter monitoring is poorly tolerated and insensitive for paroxysmal atrial fibrillation detection in cryptogenic stroke. Int Med J. 2014;44:505-508. Tu HT, Campbell BCV, Meretoja A, Churilov L, Lees KR, Donnan GA, Davis SM, on behalf of the VISTA collaborators. Pre-stroke CHADS2 and CHA2DS2- VASc scores are useful in stratifying three-month outcomes in patients with and without atrial fibrillation. Cerebrovasc Dis. 2013;36:273-280. Tu HT, Campbell BCV, Churilov L, Kalman JM, Lees KR, Lyden PD, Shuaib A, Donnan GA, Davis SM, on behalf of the VISTA collaborators. Frequent early cardiac complications contribute to worse stroke outcome in atrial fibrillation. Cerebrovasc Dis. 2011;32:454-460. 4 Tu HT, Campbell BCV, Christensen S, Collins M, De Silva DA, Butcher KS, Parsons MW, Desmond PM, Barber PA, Levi CR, Bladin CF, Donnan GA, Davis SM, for the EPITHET Investigators. Pathophysiological determinants of worse stroke outcome in atrial fibrillation. Cerebrovasc Dis. 2010;30:389-395. Peer-Reviewed Published Abstracts Tu HT, Campbell BCV, Meretoja A, Churilov L, Lees KR, Donnan GA, Davis SM. The CHADS2 score is independently associated with early serious cardiac adverse events following stroke. Int J Stroke. 2012;7(S1):17. Platform presentation at the Stroke Society of Australasia Annual Scientific Meeting, August 2012, Sydney, Australia. Tu HT, Campbell BCV, Meretoja A, Churilov L, Lees KR, Donnan GA, Davis SM. The impact of CHADS2 score and atrial fibrillation on early stroke morbidity and mortality. Cerebrovasc Dis. 2012;33(S2):789. Poster presentation at the European Stroke Conference, May 2012, Lisbon, Portugal. Tu HT, Campbell BCV, Christensen S, Churilov L, Parsons MW, De Silva DA, Olivot JM, Lansberg MG, Mlynash M, Albers GA, Donnan GA, Davis SM. More severe hypoperfusion leads to greater infarct growth and worse stroke outcome in atrial fibrillation. Int J Stroke. 2011;6(S1):29. Platform presentation at the Stroke Society of Australasia Annual Scientific Meeting, September 2011, Adelaide, Australia. Tu HT, Campbell BCV, Christensen S, De Silva DA, Parsons MW, Churilov L, Olivot JM, Lansberg MG, Mlynash M, Straka M, Bammer R, Albers GA, Desmond PM, Donnan GA, Davis SM. Worse stroke outcome in atrial fibrillation links to more severe hypoperfusion. Stroke. 2011;41:e119. Poster presentation at the International Stroke Conference, February 2011, Los Angeles, California, USA. 5 Tu HT, Collins M, Kalman JM, Lees KR, Lyden PD, Donnan GA, Davis SM. Atrial fibrillation is associated with increased early serious cardiac adverse events following ischemic stroke. Int J Stroke. 2010;5(S1):10. Platform presentation at the Stroke Society of Australasia Annual Scientific Meeting, September 2010, Melbourne, Australia. Tu HT, Collins M, Kalman JM, Lees KR, Lyden PD, Donnan GA, Davis SM. Atrial fibrillation is associated with increased early cardiac morbidity and mortality following ischemic stroke. Cerebrovasc Dis. 2010;30:345. Platform presentation at the European Stroke Conference, May 2010, Barcelona, Spain. Winner of the Young Investigator Award. Tu HT, Campbell BCV, Christensen S, Collins M, De Silva DA, Butcher KS, Parsons MW, Desmond PM, Barber PA, Levi CR, Bladin CF, Donnan GA, Davis SM. The effects of atrial fibrillation on infarct evolution and outcome. Stroke. 2010;41:e337. Poster presentation at the International Stroke Conference, February 2010, San Antonio, Texas, USA. Tu HT, Campbell BCV, Christensen S, Collins M, De Silva DA, Butcher KS, Parsons MW, Desmond PM, Barber PA, Levi CR, Bladin CF, Donnan GA, Davis SM. Atrial fibrillation is associated with increased infarct size, hemorrhagic transformation, and worse outcome in patients with ischemic stroke. Int J Stroke. 2009;4(Supp 1):7. Platform presentation at the Stroke Society of Australasia Annual Scientific Meeting, September 2009, Cairns, Australia. 6 AcKnowledgeMents The studies and analyses presented