The document discusses research on the therapeutic relevance of elevated blood pressure after ischemic stroke, particularly in hypertensive rats. Key findings indicate that managing blood pressure post-stroke is complex, with the potential for negative consequences if blood pressure is decreased too much below pre-stroke levels. The research suggests that a balanced approach to blood pressure management during the acute phase of stroke could help protect brain perfusion and reduce complications.

1. Pratik Thakkar, Ph.D.
Postdoctoral Research
Fellow
The University of
Auckland
Therapeutic Relevance of
Elevated Blood Pressure After
Ischemic Stroke in the
Hypertensive Rats

2. Small Animal Telemetry Mini Series
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Webinar: Introduction to Measurement of Tissue Oxygen in Rats Via
Telemetry
November 11th, 2020:
Webinar: Tips and Tricks for Successful Rat Telemetry Blood
Pressure Recordings
December 2nd, 2020:

3. Audience Poll

4.  Second largest killer in New Zealand
 9000 adults have stroke/ year
 10%death <65year
 Stroke affects 15 million people each year
 Pre-existing hypertension - single biggest risk factor
causes >50% of strokes
Global and local stroke statistics

5. Stroke and High Blood Pressure
Ischemic Stroke
Blood Pressure
(mmHg)
TIME (DAYS TO WEEKS)
140
Post-stroke hypertension
Stroke
occurrence

6. Post-stroke hypertension - Burning questions
3. Should Post-stroke hypertension be treated?
2. Does post-stroke hypertension a beneficial response which aid blood flow to the brain?
1. Why? How? Triggering mechanisms?
4. If a stroke patient has undiagnosed hypertension, BP may be over-treated; is this dangerous?
Urgent need to improve the understanding of post-stroke
hypertension
5. Whether pre-stroke BP treatment can be re-established?

7. Undiagnosed Hypertensive patients
~15% of population do not know their BP is high and can’t identify baseline BP at hospitalisation
Hypertension and Stroke: Real world clinical scenarios
Treated Hypertensive patients
Still at ↑risk of stroke and controlling BP in acute period of stroke is not clear
Hypertensive patients
Sudden increase in BP can ↑risk of haemorrhage

8. Post-Stroke
Hypertension
Beneficial
No Treatment Treatment necessary
Big hypothesis:
Uncontrolled Controlled
Pathological
Post-stroke hypertension is a beneficial response.

9. Experimental Model of Ischemic Stroke:
Human Cerebral Circulation
Middle Cerebral Artery - 2/3 of all
first-time strokes
Rat Cerebral Circulation
Transient Left Middle Cerebral
Artery Occlusion
(MCAo)
Middle
Cerebral
Artery
Clinical Analogy: Clot
retrieval technique
resembles the reperfusion in
MCAo
Nylon
suture

10. Experimental protocol
28 days for Treated SHRs

11. Acquisition of BP signal using telemetry
BP/ICP dual pressure telemeter
BP catheter implanted to abdominal aorta
Abdominal aorta
BP telemeter

12. Acquisition of Brain tissue oxygen/ICP signal using telemetry
ICP tunnelled towards shoulder blade Tissue oxygen electrode

13. Acquisition of Brain tissue oxygen/ICP signals using telemetry
ICP/pO2 electrodes implanted via stereotaxic frame ICP measured subdurally
CPE
ICPReference
Auxiliary

14. Acquisition of physiological signals using cohousing configuration
Signals recorded - 24 hours a day in freely moving rat in home cage

15. Sticky dot test: (Sensory outcome)
 Performed on pre-stroke, post-stroke – (Days 1, 3, 7 & 10)
Assessment
 Time to remove final dot
 Elimination of dot from each forelimb
Assessment of Functional Recovery

16. Assessment of Functional Recovery
Cylinder test: (Motor functions + Asymmetry)
 Number of rears during exploration
 % of right vs left paw used

17. Audience Poll

18. Recording of live waveform signals

19. Acute response to ischemic stroke
Thakkar et al., stroke (2019)
Anaesthesia Anaesthesia

20. Aim 1: Hypertensive animals
 Is preventing post-stroke hypertension in hypertensive rats detrimental?
 Is "overcontrolling" the post-stroke hypertension down to normotensive levels in hypertensive rats detrimental?
Spontaneously Hypertensive Rat (SHR)
 Uncontrolled
 Sham
 Controlled (Labetalol)
 Over-Controlled (Labetalol) –
(Undiagnosed hypertension)
Normotensive
baseline
Hypertensive
baseline
100
150
Time (days)
200
Uncontrolled
MCAo
Controlled
MAP
(mmHg)
0 1 2 3 4-1
Over-controlled

21. -3
0
3
6
9
12
-3 -2 -1 0 1 2 3 4 5 6 7 8 9
∆ICP(mmHg)
Time (Days)
Results (Aim-1 ):Physiological changes during MCAo (24h average data)
#
*
*
*
-30
-20
-10
0
10
20
∆CPP(mmHg)
#
** *-30
-20
-10
0
10
20
30
∆MAP(mmHg)
#
**
* *
*
*
A. MAP
-70
-30
10
50
90
-3 -2 -1 0 1 2 3 4 5 6 7 8 9
∆btPO2(%)
Time (Days)
* *
B. ICP
C. CPP
D. pO2
*
Data are presented as mean ±sem. # - p<0.05 vs Uncontrolled; * - p<0.05 within-subjects at different time points
StrokeStroke
*
*
*
Thakkar et al., Hypertension (2020)

22. 0
60
120
0 1 2 3 4 5 6 7 8 9 10
Removaloffinaldot(Sec)Results (Aim-1): Functional and neurological outcome
A. Sticky dot test
#
*
B. SHIRPA score
*
4
8
12
16
0 1 2 3 4 5 6 7 8 9 10
SHIRPAscore/14
*
#
0
4
8
12
16
0 1 2 3 4 5 6 7 8 9 10
NoofRears
Time (Days)
C. Cylinder test
*
***
*
*
*
Data are presented as mean ±sem. # - p<0.05 vs Sham; * - p<0.05 within-subjects at different time points
Thakkar et al., Hypertension (2020)

23. Results (Aim-1): Infarct volume and survival
A. Histology B. Survival
#
0
100
200
300
400
500
Infarctvolume
(mm3
)
Uncontrolled Controlled Overcontrolled
Time (Days)
0 2 4 6 8 10 12
Survival
0.0
0.2
0.4
0.6
0.8
1.0
Uncontrolled
Sham
Controlled
Overcontrolled
#
Data are presented as mean ±sem. # - p<0.05 between Uncontrolled vs Overcontrolled
Thakkar et al., Hypertension (2020)

24. Summary of Aim 1:
When setting BP targets after stroke :
 No differences in Controlled SH rats vs Uncontrolled SH rats : Treating towards pre-stroke
baseline may not be detrimental
 Higher mortality and infarct volume in Overcontrolled SH rats : Treating below baseline
may have negative consequences due to hypoperfusion
Thakkar et al., Hypertension (2020)

25. Aim 2: Treated hypertensive animals
 Is controlling BP after stroke in Treated SH rats detrimental?
Treated SHRs
 Treated (Enalapril)
 Controlled + Treated
(Enalapril + Labetalol)
Normotensive
baseline
Hypertensive
baseline
100
150
Time (days)
200
Controlled +
Treated
MCAo
MAP
(mmHg)
-30
Treated
28 days
1 2 3 40
Thakkar et al., Hypertension (2020)

26. -25
-15
-5
5
15
25
-3 -2 -1 0 1 2 3 4 5 6 7 8 9
∆MAP(mmHg)
Time (Days)
Results (Aim- 2):Physiological changes during MCAo (24h average data)
A. MAP B. pO2
-30
-15
0
15
30
45
60
-3 -2 -1 0 1 2 3 4 5 6 7 8 9
∆btPO2(%)
Time (Days)
***
*
* * **
#
*
Data are presented as mean ±sem. # - p<0.05 between Treated vs Controlled + Treated; * - p<0.05 within-subjects at different time points
StrokeStroke
Thakkar et al., Hypertension (2020)

27. 4
6
8
10
12
14
16
0 1 2 3 4 5 6 7 8 9 10
SHIRPAscore/14
0
40
80
120
0 1 2 3 4 5 6 7 8 9 10
Removaloffinaldot(Sec)
Results (Aim- 2): Functional and neurological outcome
A. Sticky dot test B. SHIRPA score
#
*
*
*
*
Thakkar et al., Hypertension (2020)
0
5
10
15
20
25
0 1 2 3 4 5 6 7 8 9 10
NoofRears
Time (Days)
C. Cylinder test
*
* **
#
Data are presented as mean ±sem. # - p<0.05 between Treated vs Controlled + Treated; * - p<0.05 within-subjects at different time points
*
*
*

28. Results (Aim-2): Infarct volume and survival
A. Histology
0
100
200
300
400
500
Infarctvolume
(mm3
)
Treated Controlled + Treated
B. Survival
Time (Days)
0 2 4 6 8 10 12
Survival
0.0
0.2
0.4
0.6
0.8
1.0
Treated Controlled + Treated
Data are presented as mean ±sem.
Thakkar et al., Hypertension (2020)

29. Summary of Aim 2:
When setting BP targets after stroke :
 No differences in infarct size and mortality in both chronically treated SH rats
 No consistent evidence to suggest preventing post-stroke hypertension in subjects
already on anti-hypertensive medications is detrimental
Thakkar et al., Hypertension (2020)

30. Key findings:
 Post-stroke hypertension: immediately after the onset of ischemic stroke regardless of BP status before
stroke.
 In acute period of stroke,
Preventing BP to pre-stroke baseline: relatively safe
Preventing BP to below pre-stroke baseline: detrimental
 A middle ground approach for BP level in acute period of stroke may protect the perfusion pressure to the
brain and prevent secondary complications

31. Acknowledgements
Dr Fiona McBryde
Dr Carolyn Barrett
Dr Sarah-Jane Guild
Prof. Simon Malpas
Prof. Julian Paton
Ms. Steph Lindsay

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SESSION:
Pratik Thakkar, Ph.D.
Postdoctoral Research Fellow
The University of Auckland