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Susceptibility to Cerebral Infarction in the Stroke-Prone
Spontaneously Hypertensive Rat Is Inherited as
a Dominant Trait
Julie A. Gratton, PhD; Andre Sauter, PhD; Markus Rudin, PhD; Kennedy R. Lees, MD, FRCP;
John McColl, MSc; John L. Reid, MD, FRCP; Anna F. Dominiczak, MD; I. Mhairi Macrae, PhD
Background and Purpose—Susceptibility to cerebral infarction was compared in stroke-prone spontaneously hypertensive
(SHRSP), normotensive Wistar-Kyoto (WKY) rats, and F1hybrids derived from a SHRSP/WKY cross.
Methods—The proximal left middle cerebral artery (MCA) was occluded under anesthesia and infarct volume assessed 24
hours later by magnetic resonance imaging and confirmed 5 days later by quantitative histopathology. Total hemispheric
infarct volume was expressed as a percentage of the total brain volume.
Results—Infarct volumes measured by MRI in adult SHRSP (19.562.0%) and F1hybrid rats (19.461.9%) were significantly
greater than in WKY (11.162.4; CI [6.07, 10.76]) and (5.93, 10.52), respectively, P,.001). Sensitivity to an ischemic
insult was unrelated to blood pressure: although systolic blood pressures differed between young versus adult male SHRSP
and between female versus male SHRSP and F1hybrids, infarct volumes were equal. A close correlation was found
between infarct volumes measured by MRI and histology (r5.92, P,.0001).
Conclusions—Outcome to MCA occlusion (MCAO) measured with MRI provides a reproducible and nonterminal
quantitative phenotypic marker of stroke susceptibility in the SHRSP. This is the first study to employ MCAO with MRI
to quantify stroke susceptibility in F1hybrid rats and indicates a dominant mode of inheritance for this phenotype. (Stroke.
1998;29:690-694.)
Key Words: cerebral infarction ngenetics nhypertension nmagnetic resonance imaging
Permanent MCAO is the definitive model of focal cerebral
ischemia.1,2 SHR and SHRSP have much larger and less
variable infarcts after MCA occlusion than all other rat
strains.3–5 Furthermore, this increased sensitivity to cerebral
ischemia, which we believe is genetically determined, may be
unrelated to hypertension because SHR and SHRSP suffer
large infarcts at 5 weeks of age before hypertension and
vascular hypertrophy are fully established.6,7 Studies by Coyle
and coworkers suggested that in the SHRSP susceptibility to
infarction was inherited as an autosomal recessive trait and that
decreased luminal diameters in vascular anastomoses between
the MCA and anterior cerebral artery were responsible for the
pathophysiology.8,9 The importance of vascular anastomoses
and genetic predisposition rather than blood pressure alone was
stressed further by evidence that rats made hypertensive by
deoxycorticosterone acetate and salt administration failed to
develop large infarcts after MCA occlusion,3whereas adult
SHR and SHRSP, in which hypertension had been treated
early, still developed large infarcts.10,11
The analysis of previous data therefore suggests that the
large infarcts induced by MCAO were due to inadequate
collateral blood flow and that this phenotype is genetically
See Editorial Comment, page 694
associated with but not directly linked to hypertension.12 This
implies that a gene marker or markers for infarct susceptibility
may exist both in animal models and perhaps also in humans.
Rubattu and coworkers13 recently performed a genome-wide
screening approach to an SHRSP/SHR cross using an alter-
native phenotype, latency to stroke after salt loading, as a
marker of stroke proneness. They identified three major loci
that contributed significantly to the variance of this stroke
phenotype in F2hybrids. Thus, in SHRSP, primary blood
pressure–independent genetic factors may play a critical role in
both stroke onset and increased susceptibility to infarction.
Previous studies in SHR and SHRSP used histological
methods to assess infarct size. These methods are very time-
consuming, difficult to perform in the large number of animals
required for genetic cosegregation analysis, and involve a
terminal end point. In the current study, MRI was used to
measure infarct volume after MCAO both in adult (24-week-
old) and young (9-week-old) SHRSP, in their normotensive
reference strain—the WKY rat, and in adult F1hybrids
obtained by crossing SHRSP and WKY rats. Quantitative
Received October 3, 1997; revision received December 5, 1997; accepted January 5, 1998.
From the Wellcome Surgical Institute (J.A.G., I.M.M.), the Department of Medicine and Therapeutics (K.R.L., J.L.R., A.F.D.), and the Department of
Statistics (J.M.) of the University of Glasgow (Scotland) and Novartis Pharma Ltd. (A.S., M.R.), Basel, Switzerland.
Correspondence to I. Mhairi Macrae, PhD, Wellcome Surgical Institute & Hugh Fraser Neuroscience Laboratories, University of Glasgow, Garscube
Estate, Glasgow G 61, 1QH, Scotland, UK.
E-mail m.macrae@udcf.gla.ac.uk
© 1998 American Heart Association, Inc.
690
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histology at 5 days postischemia was carried out to confirm the
sensitivity and accuracy of the MRI measurements.
A preliminary report of these results has been published in
abstract form.14
Materials and Methods
Experimental Animals
Inbred colonies of SHRSP and WKY rats have been maintained in the
Department of Medicine and Therapeutics at the University of
Glasgow since 1991.15 The breeding animals were a gift from Dr D.F.
Bohr at the University of Michigan where they have been maintained
as inbred colonies for more than 15 years. F1hybrids were produced
by mating two SHRSP females with one WKY male. SHRSP, WKY,
and F1hybrids were weaned at 4 weeks, divided by sex, and
maintained in family groups (3 to 4 per cage) in constant temperature
at 21°C and 12-hour light/dark cycle (7 AM to 7 PM). SBP and heart
rate were measured in all animals by plethysmography as previously
described.16 To verify these physiological measurements, littermates of
SHRSP, WKY, and F1hybrids underwent direct blood pressure and
heart rate recordings using a telemetry system.16 MCAO was per-
formed on SHRSP and WKY at 9 weeks (SHRSP, n515; WKY,
n510) and 24 weeks (SHRSP, n510, WKY, n59) of age. F1hybrids
underwent MCAO at 24 weeks of age (n511). All experiments were
carried out in accordance with institutional and Home Office
guidelines.
Surgical Intervention to Produce
MCA Occlusion
Rats were anesthetized with isoflurane (1% to 2%) in oxygen–nitrous
oxide (1:2) via a face mask. The left MCA was permanently occluded
by electrocoagulation using the technique of Tamura et al1with minor
modifications.17 Anesthesia was given for no longer than 15 minutes.
MRI
A Biospec 47/15 spectrometer (Bruker) with imaging facility was
used. The radiofrequency probe was a home-built Alderman-Grant
type resonator18 with a 40-mm inner diameter and a length of 50 mm.
Twelve coronal sections, 1 mm thick, that covered the whole
forebrain were taken 24 hours after MCAO using a spin echo (SE)
sequence with an echo delay of 60 ms and a repetition delay of 2000
ms (SE 2000/60). The spatial resolution in the imaging plane (pixel
dimension) was 0.1630.16 mm2(field of view540 mm). Further
experimental details are described elsewhere.17,19 Infarct area in each
section was determined using a semiautomated segmentation proce-
dure based on intensity thresholding. Regional resolution into cortical
and striatal infarction involved interactive drawing of a borderline
between the respective structures prior to intensity thresholding. The
infarct size determined either by thresholding alone or by adding up
cortical and striatal values yielded identical numbers within error
limits. The total infarct volume was calculated by summation of the
number of pixels in each slice and multiplication by the pixel size and
slice thickness. Infarct volumes generated by MRI and histology were
expressed as a percentage of total brain volume to account for brain
swelling and differences in brain size between sexes and strains. Image
analysis was carried out by a person unaware of strain, age, or sex of
the animal.
Histology
Five days after MCAO, the rats were decapitated, and their brains
removed and immediately frozen on a block of dry ice. Coronal
cryostatic sections 20
m
m thick were cut at 12 equidistant levels (1 mm
apart, covering the entire forebrain), mounted on glass slides, and
stained with cresyl violet. The area of infarct in each section was
determined using a calibrated digitizing tablet from a video-image
analyzer. The sum of the infarct areas in the twelve sections, multiplied
by the slice thickness, was taken as total infarct volume. All infarct
volumes have been expressed as a percentage of the total
brain volume.
Statistical Analyses
The effects of systolic blood pressure, sex, strain, and age on infarct
volume established by MRI were examined using ANOVA and
ANCOVA. The Table displays the sample mean6SEM of SBP and
infarct volume for all groups of rats. Since no data were available from
young F1rats, two main analyses were required. In the first, the
(population) mean infarct volumes for adult and young SHRSP and
WKY rats were compared. In the second, (population) mean infarct
volumes of adult SHRSP, WKY, and F1rats were compared.
Both sets of analyses began by fitting a model containing all main
effects and interactions. Nonsignificant effects were then eliminated
beginning with the highest-order interaction or interactions. The final
model included all statistically significant interactions along with
lower-order terms in the same variables. Multiple comparisons were
investigated using Tukey’s method with an overall 95% confidence
level.
A paired ttest was used to compare infarct volumes obtained by
MRI with infarct volumes obtained by quantitative histology.
Results
Lack of Influence of BP on Infarct Volume in
Adult and Young Parental Strains
The relationship between infarct volume and blood pressure
can be judged from the Table. This shows that infarct volumes
are much smaller for the WKY rats (of both sexes and all ages)
than for the SHRSP and F1rats, which also generally have
higher blood pressures. There is, however, no evidence of a
correlation between infarct volume and blood pressure within
any group of rats: (adult SHRSP r5.360, P5.307; adult WKY
r52.245, P5.526; young SHRSP r5.262, P5.346; young
WKY r5.039, P5.921; F1hybrids r52.275, P5.414).
When the full ANCOVA model was fitted to the data for
young and adult SHRSP and WKY rats, no single term
involving blood pressure was statistically significant. Subse-
quent removal of these terms, beginning with the highest-
order interaction, did not result in lower-order terms involving
blood pressure becoming significant.
Consequently, a model was fitted that did not include the
main effect of blood pressure, or any interaction involving
blood pressure. This reduced model was tested within the full
model previously fitted, and was not rejected (F50.425, df58,
28, P5.90). It was concluded that blood pressure did not
influence infarct volume, on average, in any group of rats.
The reduced model was an ANOVA model in three
explanatory variables, namely strain, age (adult or young), and
sex. No individual term involving sex was statistically signifi-
cant and, after checking intermediate models, all of these terms
were removed. Again, this reduced model was tested within
the previous model and was not rejected (F50.627, df54, 36,
P5.63). It was concluded that there was no difference, on
average, between infarct volumes for male and female rats in
Selected Abbreviations and Acronyms
MCA 5middle cerebral artery
MCAO 5MCA occlusion
SBP 5systolic blood pressure
SHR 5spontaneously hypertensive rat
SHRSP 5stroke prone SHR substrain
WKY 5Wistar-Kyoto
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either age group of either strain. Consequently, data for both
sexes were combined for further comparisons of age groups
and strains.
Sensitivity to Ischemic Insult in Adult and
Young Parental Strains
In the reduced ANOVA model, which included only strain
and age group, the interaction term was not statistically
significant (P5.214), but the main effects of both strain and age
were statistically significant. Mean infarct volumes were sig-
nificantly greater in SHRSP than in WKY rats in the same age
group (95% confidence interval [7.96 to 10.96], P,.001).
Also, overall mean infarct volumes were significantly greater in
adult rats than in young rats (95% confidence interval [0.25 to
3.25], P5.023).
Lack of Influence of Blood Pressure on Infarct
Volume in Adult Parental and F1Hybrids
Again, when a full ANCOVA model was fitted to the data
from adult rats of all three strains, no term involving blood
pressure was statistically significant. Proceeding as before, a
reduced model that omitted all the terms involving blood
pressure was tested within the full model, and was not rejected
(F50.811, df56, 18, P5.58). We concluded that blood
pressure did not influence infarct volume, on average, in any
group of adult rats.
In the reduced ANOVA model, which included sex and
strain only, neither the interaction term nor the main effect of
gender was statistically significant. A reduced (one-way)
ANOVA model in strain alone was tested within the previous
model and was not rejected (F50.441, df55, 24, P5.82). We
concluded that there was no difference, on average, between
infarct volumes for male and female rats in any strain of adult
rat. Consequently, data for both sexes were combined for a
further analysis of the three strains.
Sensitivity to Ischemic Insult in Adult Parental
and F1Hybrids
There was a highly significant effect of strain on the average
infarct volume (P,.001). Simultaneous confidence intervals
for all pairwise comparisons showed that adult SHRSP had a
significantly greater mean infarct volume than adult WKY
rats(confidence interval 6.07 to 10.76). Adult F1rats, too, had
a significantly higher mean infarct volume than adult WKY
rats (confidence interval 5.93 to 10.52). There was no signif-
icant difference between the mean infarct volumes of adult
SHRSP and F1rats (confidence interval –2.03 to 2.42); indeed
the sample mean infarct volumes of these two groups were
virtually identical (see Table).
MRI Correlated With Histology
The use of MRI for mapping infarct volume was validated by
comparison with measurements made by quantitative histology
4 days after the animals were initially imaged by MRI. Fig 1
illustrates the strong association between the two measure-
ments in adult and young SHRSP and WKY rats, which
generated a sample correlation coefficient of r5.92 (P,.0001).
Although this indicates that the two measures were strongly
related, it should be noted that the MRI measurement was
greater than the histological measurement in almost every rat
because of acute edema of the infarcted area at 24 hours, which
would have resolved to a certain extent by 5 days postischemia.
A 95% confidence interval for the mean paired difference
between the MRI and histological measurements on the same
rat is 4.35 to 5.72, P,.0001.
Discussion
Infarct volume after MCA occlusion is a highly relevant
phenotype for demonstrating sensitivity to an ischemic insult.
MRI is a precise, nonterminal method for quantitation of
infarct volume. The current study is the first to demonstrate
that combination of this phenotype and technique provides a
very powerful means of investigating the genetics of stroke.
The present results confirm the bimodal distribution of the
MCAO phenotype in parental SHRSP and WKY strains (Fig
2), which has been reported previously.3–8 Two further im-
portant findings are presented. First, a number of results in this
study support the hypothesis that sensitivity to an ischemic
insult in the SHRSP is independent of blood pressure: (1) SBP
Mean Blood Pressure and Infarct Volumes in All Groups
SHRSP WKY F1
Adult Young Adult Young Adult
Male Female Male Female Male Female Male Female Male Female
SBP, mm Hg 22065.0 15963.0 14063.4 15963.0 13563.0 13063.3 12862.0 12163.2 16763.7 13068.1
Infarct volume, % of whole brain 20.561.1 18.960.7 18.560.6 19.360.7 10.561.4 11.660.9 9.461.2 7.961.4 19.360.7 19.561.2
Data are presented as mean6SEM for SBP measured before MCAO and infarct volume measured by MRI. See “Methods” for explanation of groups.
Figure 1. Scattergram illustrating the significant correlation
between infarct volume measured by MRI and histology.
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is significantly lower in young versus adult male SHRSP while
there is no difference in infarct volume; (2) in young animals,
before hypertension is established, there is no significant
difference in SBP in male SHRSP and WKY but infarct
volume is significantly greater in the SHRSP; and (3) in adult
SHRSP and F1hybrids, SBP is significantly higher in males
than females but there is no sex-related difference in infarct
volume.
The second and most interesting finding is that the distri-
bution of infarct volumes in F1rats was virtually identical to the
distribution in the SHRSP, strongly suggesting a dominant
mode of inheritance for this phenotype. The significance of
this finding has prompted a genome-wide screen in F2hybrids
(F13F1cross) to investigate genetic markers for stroke severi-
ty.20 Previous studies that examined the genetics of stroke in
the SHRSP include an earlier cosegregation study by Coyle et
al in which focal ischemia was used to characterize the
stroke-prone phenotype8and two studies13,21 in which an
alternative phenotype was used, latency to stroke on a high salt
diet. Coyle’s studies suggested a single recessive gene was
responsible for the pathogenesis of stroke in the SHRSP.
Possible reasons for the different conclusion from the current
study may include their use of outbred normal Wistar rats
instead of inbred WKY rats and the possibility that there was a
less severe, more distal occlusion in much younger animals (F1
hybrids 8 to 12 weeks old). When they used latency to stroke,
Nagaoka et al21 reported this phenotype to be characterized by
a polygenic inheritance and more recently, Rubattu et al13
performing a genome-wide screen on an F2cross
(SHRSP3SHR) identified three major quantitative trait loci
that together accounted for 28% of the overall phenotypic
variance. However, it should be stated that the genes respon-
sible for the latency to stroke with a high salt diet may be quite
independent of those that determine the size of infarct after
cerebral vessel occlusion (ischemic sensitivity genes).
A number of hypotheses have been put forward to explain
the increased ischemic sensitivity in the SHRSP. The most
commonly cited hypotheses propose that the SHRSP exhibit
arterial hypertrophy in cerebral arteries, resulting in decreased
functional compliance with limited dilatation to ischemia. This
may be particularly important in collateral vessels where a
reduction in anastomotic diameter would result in collateral
flow impairment during ischemia. In support of this, MCAO
in normotensive animals is associated with a marked increase in
nitric oxide release in the ischemic region.22 Since central
nervous system nitric oxide synthase activity is reduced in
SHRSP compared with WKY,23 defective nitric oxide release
may be a contributory factor in the impaired collateral perfu-
sion of the ischemic area in SHRSP. In addition, SHRSP may
also demonstrate an intensified inflammatory response to the
ischemic insult that could further compromise flow.24 Indirect
evidence for an impaired collateral supply comes from neuro-
protection studies in hypertensive strains in which drugs with
flow-enhancing properties (eg, L-type calcium channel block-
ers) are found to be more effective than NMDA glutamate
antagonists with proven efficacy in normotensive strains.25,26
The present findings are consistent with a dominant mode of
inheritance for ischemic sensitivity in the SHRSP. Recent
studies from our laboratory20 and from Rubattu and cowork-
Figure 2. A, Representative T2-weighted MRI images obtained
24 hours after MCA occlusion in adult SHRSP and WKY rats. B,
Comparison of infarct volumes (mean6SEM) measured by MRI
24 hours post-MCAO in adult and young SHRSP and WKY,
*P,.001.
Gratton et al 693
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ers13 provide strong evidence for the existence of primary
blood pressure independent genetic factors which influence
both latency to stroke13 and sensitivity to an ischemic insult20 in
the SHRSP. Whether outcome to stroke has a genetic basis in
man needs to be examined further but such research should be
strongly encouraged in view of these results.
Acknowledgments
This work was funded by the Wellcome Trust (Grant No. 045924/95)
and the Cunningham Trust. Dr Dominiczak is a British Heart
Foundation Senior Research Fellow.
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Editorial Comment
The most widely used experimental model of cerebral infarc-
tion results from MCA occlusion in the rat. The severity of this
infarct is quantified by its volume, and in the current decade
MRI has been established as a precise tool for monitoring this
volume. Using these techniques, the Glasgow investigators
observed much larger infarcts in the hypertensive SHRSP rats
than in the normotensive WKY, yet they firmly established
that infarct size was independent of blood pressure. They do
discuss alternative hypotheses that could explain a decrease in
collateral blood flow and thereby be responsible for the large
infarcts in SHRSP. Most attractive among these hypotheses are
arterial hypertrophy and a deficit in nitric oxide release.
1
Following cross-breeding between SHRSP and WKY rats,
they found that the infarct size in the F1 generation rat was as
large as that in the SHRSP parental strain. This clear evidence
for dominance of the genetic trait of the large infarct size adds
to the spectacular identification by these investigators of the
quantitative trait locus on chromosome 5 as responsible for
stroke size in SHRSP.
2
It is of special interest to see Glasgow University regaining
its leadership role in hypertension-related research.
David F. Bohr, MD, Guest Editor
Department of Physiology
University of Michigan Medical School
Ann Arbor, Michigan
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is deficient in genetic hypertension. Am J Hypertens. 1996;9:237–241.
2. Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gaugier D, Reid
JL, Macrae IM, Dominiczak AF. Sensitivity to cerebral ischemic insult in
a rat model of stroke is determined by a single genetic locus. Nat Genet.
1997;16:364 –367.
694 Cerebral Infarction in the Stroke-Prone Spontaneously Hypertensive Rat
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Anna F. Dominiczak and I. Mhairi Macrae
Julie A. Gratton, Andre Sauter, Markus Rudin, Kennedy R. Lees, John McColl, John L. Reid,
Is Inherited as a Dominant Trait
Susceptibility to Cerebral Infarction in the Stroke-Prone Spontaneously Hypertensive Rat
Print ISSN: 0039-2499. Online ISSN: 1524-4628
Copyright © 1998 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/01.STR.29.3.690
1998;29:690-694Stroke.
http://stroke.ahajournals.org/content/29/3/690
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