Autonomic function in rheumatoid arthritis

324 Pages·2016·5.79 MB·English

by  Ahmed Adlan

AUTONOMIC FUNCTION IN RHEUMATOID ARTHRITIS
by
AHMED ADLAN
A thesis submitted to the University of Birmingham for the degree of
DOCTOR OF PHILOSOPHY
School of Sport, Exercise and Rehabilitation Sciences
College of Life and Environmental Sciences
University of Birmingham
January 2016
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ABSTRACT
Rheumatoid arthritis (RA) is a chronic inflammatory condition with poorly understood
pathophysiology and increased cardiovascular risk. The mechanisms for increased
cardiovascular risk are not fully known, however one novel mechanism explored in this thesis
is autonomic nervous system (ANS) dysfunction. The thesis comprises of: a systematic
literature review; two case-control studies (n=30 RA patients, n=34 controls; a longitudinal
case-study (n=1 RA patient); a cohort study (n=112 RA patients); and a randomised placebo-
controlled crossover study (n=10 healthy controls). The work presented in this thesis
demonstrates that ANS dysfunction is prevalent in ~60 % of RA patients and characterised by
heightened sympathetic outflow to the peripheral vasculature (determined by muscle
sympathetic nerve activity using microneurography), depressed baroreflex control of heart
rate (determined using the modified Oxford technique), depressed heart rate variability and
heightened vascular responses to stressors (cold pressor test and mental stress). Inflammation
was associated with ANS dysfunction, and may well contribute to the increased
cardiovascular risk seen in RA. Further studies are required to: confirm these findings;
determine whether therapeutic strategies to restore ANS function improve prognosis in RA;
and further explore the precise mechanisms by which inflammatory cytokines may influence
ANS function in health and disease.
DEDICATION
In the name of Allah, The Most Merciful, The Most Gracious.
“Read!In the Name of Your Lord Who Created
Created man from a clot
Read!And Your Lord is Most Generous
Who Taught mankind by the pen
He Taught man that which he knew not.”
Holy Quran (Surah 96, verses 1-5)
Indeed, all Praises belong to Allah, to Him we worship, to Him we turn to, to Him we ask for
Forgiveness and to Him we turn to in repentance. And we seek refuge in Allah from our own
selves, from the evil amongst our deeds. He Whom Allah Guides, indeed he is guided. And he
Whom AllahMisguides, indeed you will not find a helper to guide. I bear witness that there is
none worthy of worship, except Allah and that Muhammad, peace and blessings upon him, is
his servant and final Messenger. All Good comes from Allah, and all mistakes are from
myself.
ACKNOWLEDGEMENTS
I would like to take this opportunity to thank my beautiful wife who has helped me
along each step of the way; without her tireless help and support my achievements would not
have been possible. May Allah reward you for your patience and grant you success in all that
you do. I would like to extend a special thanks to my parents for their continuous support and
encouragement, and to my family and friends. Throughout my research experience I have
been very fortunate to have the very best of supervisors (Dr. James Fisher, Prof. Gregory Lip)
and mentors (Prof. George Kitas, Prof. Julian Paton); they have made this experience
thoroughly enjoyable and I hope to continue to work with them in the coming years. I would
like to especially thank Dr. James Fisher whose close supervision has been thoroughly
appreciated. He has been a great personal inspiration, an excellent example to follow and a
close personal friend. I would like to thank work colleagues at Russells Hall Hospital, City
Hospital and the University of Birminghamwho have helped me over the years. In particular I
would like to thank: Jacqueline Smith and Sue Cadman for the blood analyses; Vasileios
Panoulas and colleagues for their contributions to the QTc chapter; Dave McIntyre and
Stephen Allen for their continued technical support; Helen Shantsila, Aamer Sandoo and Jet
Veldhuijzen van Zanten for their support and guidance; Sharon Petford and Carlene Johnson
for their help in recruiting patients; Arthritis Research UK for providing crucial funding (grant
number196633); and the participants for their valuable time.
Finally, all thanks and praises to Allah for His continuous blessings. May Allah’s peace and
blessings be upon the Prophet Muhammad, his family, companions and followers.
TABLE OF CONTENTS
CHAPTER 1 Introduction and Purpose..................................................................................1
CHAPTER 2 Background literature review..........................................................................1
2.1 Rheumatoid arthritis (RA)...........................................................................................................2
2.1.1 Epidemiology.............................................................................................................................................3
2.1.2 Pathophysiology.......................................................................................................................................3
2.1.3 Clinical features and diagnosis...........................................................................................................3
2.1.4 Management and prognosis................................................................................................................8
2.2 Immune system..............................................................................................................................15
2.2.1 Basic overview.......................................................................................................................................15
2.2.2 Cytokines..................................................................................................................................................16
2.2.3 Immunological basis of RA................................................................................................................17
2.3 Autonomic nervous system (ANS)...........................................................................................20
2.3.1 The sympathetic and parasympathetic nervous systems....................................................20
2.3.2 Integrative control of the cardiovascular system....................................................................22
2.3.3 The arterial baroreflex........................................................................................................................26
2.4 ANS dysfunction.............................................................................................................................29
2.4.1 Pathophysiological consequences of sympathetic dysfunction.........................................29
2.4.2 Sympathetic-immune interactions................................................................................................32
2.4.4 Parasympathetic-immune interactions.......................................................................................37
2.4.5 Impaired baroreflex sensitivity (BRS)..........................................................................................40
2.4.6 BRS and inflammation........................................................................................................................42
2.4.7 Cardiovascular reactivity...................................................................................................................43
2.4.8 Cardiovascular reactivity and inflammation.............................................................................44
2.4.9 QTc interval and inflammation.......................................................................................................46
2.4.10 Stress, the HPA axis and autonomic function.........................................................................48
2.4.11 Autonomic dysfunction in RA........................................................................................................50
2.5 Assessment of the ANS.....................................................................................................................51
CHAPTER 3 Systematic literature review..........................................................................66
3.1 Abstract.............................................................................................................................................67
3.2 Introduction....................................................................................................................................68
3.3 Aims and hypothesis.....................................................................................................................70
3.4 Methods.............................................................................................................................................71
3.4.1 Search criteria........................................................................................................................................71
3.4.2 Quality assessment...............................................................................................................................72
3.5 Results...............................................................................................................................................74
3.5.1 Assessment of ANS Function............................................................................................................74
3.5.2 Prevalence of ANS dysfunction.......................................................................................................75
3.5.3 Parasympathetic dysfunction..........................................................................................................76
3.5.4 Sympathetic dysfunction...................................................................................................................82
3.5.5 BRS..............................................................................................................................................................83
3.5.6 Time course of ANS dysfunction.....................................................................................................84
3.5.7 Inflammation and ANS dysfunction..............................................................................................84
3.6 Discussion........................................................................................................................................88
3.6.1 Epidemiology of ANS dysfunction in RA......................................................................................88
3.6.2 Pattern of ANS dysfunction in RA...................................................................................................88
3.6.3 Associations between ANS and inflammation..........................................................................89
3.6.4 Limitations...............................................................................................................................................90
3.6.5 Future directions...................................................................................................................................90
3.7 Conclusion........................................................................................................................................91
CHAPTER 4 Methodology........................................................................................................92
4.1 Subjects.............................................................................................................................................93
4.2 Experimental protocol.................................................................................................................95
4.3 Variables...........................................................................................................................................96
4.3.1 Haemodynamic......................................................................................................................................97
4.3.2 MSNA..........................................................................................................................................................97
4.3.3 Cardiovagal BRS (cBRS)...................................................................................................................102
4.3.4 Sympathetic BRS.................................................................................................................................104
4.3.5 Blood flow and vascular conductance........................................................................................105
4.3.6 HRV...........................................................................................................................................................107
4.3.7 Cardiovascular reactivity.................................................................................................................108
4.3.8 BP variability........................................................................................................................................109
4.3.9 QT interval.............................................................................................................................................109
4.3.10 Blood sampling..................................................................................................................................110
4.3.11 Statistical analyses...........................................................................................................................110
CHAPTER 5 Experiment One. Heightened sympathetic nerve activity and
reduced BRS in RA: a case control study.............................................................................111
5.1 Abstract..........................................................................................................................................112
5.2 Introduction.................................................................................................................................113
5.3 Aims and hypothesis..................................................................................................................114
5.4 Methods..........................................................................................................................................115
5.4.1 Subjects...................................................................................................................................................115
5.4.2 Experimental protocol......................................................................................................................115
5.4.3 Measurements......................................................................................................................................115
5.4.4 Data analysis.........................................................................................................................................116
5.4.5 Blood sampling....................................................................................................................................116
5.4.6 Statistics..................................................................................................................................................116
5.5 Results............................................................................................................................................117
5.5.1 Subject characteristics......................................................................................................................117
5.5.2 Haemodynamic parameters...........................................................................................................122
5.5.3 BRS............................................................................................................................................................122
5.5.4 Inflammation and pain......................................................................................................................124
5.5.5 Associations between inflammation and autonomic function.........................................125
5.5.6 Associations between pain and autonomic function............................................................129
5.6 Discussion.....................................................................................................................................130
5.6.1 Increased MSNA in RA......................................................................................................................130
5.6.2 Reduced cBRS in RA...........................................................................................................................130
5.6.3 Pain and autonomic interactions..................................................................................................131
5.6.4 Elevated HR in RA...............................................................................................................................132
5.6.5 Strengths and limitations................................................................................................................133
5.6.6 Future directions.................................................................................................................................133
5.7 Conclusion.....................................................................................................................................134
CHAPTER 6 Experiment Two. HRV and cardiovascular reactivity in RA: a case
control study135
6.1 Abstract..........................................................................................................................................136
6.2 Introduction.................................................................................................................................137
6.3 Aims and hypothesis..................................................................................................................138
6.4 Methods..........................................................................................................................................139
6.4.1 Subjects and experimental protocol............................................................................................139
6.4.2 Measurements......................................................................................................................................139
6.4.3 Data analysis.........................................................................................................................................139
6.4.4 Blood sampling....................................................................................................................................140
6.4.5 Statistics..................................................................................................................................................140
6.5 Results............................................................................................................................................141
6.5.1 HRV...........................................................................................................................................................141
6.5.2 Cold pressor test..................................................................................................................................141
6.5.3 PASAT mental stress..........................................................................................................................143
6.5.4 Associations between inflammation and autonomic function.........................................143
6.5.5 Associations between pain and autonomic function............................................................145
6.6 Discussion.....................................................................................................................................152
6.6.1 Reduced HRV in RA............................................................................................................................152
6.6.2 Altered cardiovascular reactivity in RA.....................................................................................153
6.6.3 Inflammation and vascular reactivity.........................................................................................154
6.6.4 Strengths and limitations................................................................................................................154
6.6.5 Future directions.................................................................................................................................155
6.7 Conclusion.....................................................................................................................................155
CHAPTER 7 Experiment Three. Effects of TNF-α inhibitor on autonomic function
inRA: a longitudinal case-study.............................................................................................156
7.1 Abstract..........................................................................................................................................157
7.2 Introduction.................................................................................................................................158
7.3 Aims and hypothesis..................................................................................................................159
7.4 Methods..........................................................................................................................................160
7.4.1 Subjects...................................................................................................................................................160
7.4.2 Measured variables............................................................................................................................160
7.4.3 Blood sampling....................................................................................................................................161
7.5 Results............................................................................................................................................161
7.5.1 Inflammation and pain......................................................................................................................161
7.5.2 MSNA and haemodynamic parameters.....................................................................................162
7.5.3 BRS............................................................................................................................................................162
7.5.4 HRV...........................................................................................................................................................162
7.5.5 PASAT mental stress test.................................................................................................................163
7.6 Discussion.....................................................................................................................................170
7.7 Conclusions...................................................................................................................................174
CHAPTER 8 Experiment Four. Associations between cytokines and QTc interval
in RA: a cohort study..................................................................................................................175
8.1 Abstract..........................................................................................................................................176
8.2 Introduction.................................................................................................................................177
8.3 Aims and hypotheses.................................................................................................................178
8.4 Methods..........................................................................................................................................179
8.4.1 Subjects...................................................................................................................................................179
8.4.2 QT measurements...............................................................................................................................179
8.4.3 Blood sampling....................................................................................................................................179
8.4.4 Statistics..................................................................................................................................................180
8.5 Results............................................................................................................................................181
8.5.1 Subject characteristics......................................................................................................................181
8.5.2 HR correction........................................................................................................................................181
8.5.3 Associations between QTc and demographic variables......................................................181
8.5.4 Associations between QTc and inflammation.........................................................................187
8.5.5 Multivariable linear regression.....................................................................................................188
8.7 Discussion.....................................................................................................................................195
8.7.1 Interleukin-10 and QTc interval...................................................................................................195
8.7.2 CRP and QTc interval.........................................................................................................................196
8.7.3 Immune and autonomic interactions.........................................................................................196
8.7.4 Limitations.............................................................................................................................................197
8.7.5 Future directions.................................................................................................................................198
8.8 Conclusion.....................................................................................................................................198
CHAPTER 9 Experiment Five. Effects of hydrocortisone on BRS, HRV and
cardiovascular reactivity in healthy humans: a randomised placebo-controlled
cross-over study...........................................................................................................................199
9.1 Abstract..........................................................................................................................................200
9.2 Introduction.................................................................................................................................201
9.3 Aims and hypothesis..................................................................................................................202
9.4 Methods..........................................................................................................................................203
9.4.1 Subjects...................................................................................................................................................203
9.4.2 Experimental protocol......................................................................................................................203
9.4.3 Measurements......................................................................................................................................203
9.4.4 Data analysis.........................................................................................................................................204
9.4.5 Blood sampling....................................................................................................................................204
9.4.6 Statistics..................................................................................................................................................205
9.5 Results............................................................................................................................................205
9.5.1 Biochemical and haemodynamic parameters.........................................................................205
9.5.2 cBRS..........................................................................................................................................................206
9.5.3 HRV...........................................................................................................................................................206
9.5.4 BP variability........................................................................................................................................208
9.5.5 Cardiovascular reactivity.................................................................................................................208
9.6 Discussion.....................................................................................................................................217
9.6.1 Central mechanisms for reduced BRS........................................................................................217
9.6.2 Sympathetic activation.....................................................................................................................218
9.6.3 Strengths and limitations................................................................................................................219
9.6.4 Future directions.................................................................................................................................220
9.7 Conclusion.....................................................................................................................................220
CHAPTER 10 Synthesis...........................................................................................................221
10.1 Overall aims of thesis.............................................................................................................222
10.2 General discussion...................................................................................................................224
10.3 Limitations.................................................................................................................................230
10.4 Future directions......................................................................................................................230
10.5 Conclusion..................................................................................................................................231