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REPORTS OF ORIGINAL INVESTIGATIONS
Muscular body build and male sex are independently associated
with malignant hyperthermia susceptibility
Un corps muscle
´et le sexe masculin sont associe
´s de fac¸on
inde
´pendante a
`une susceptibilite
´a
`l’hyperthermie maligne
Brian Butala, DO .Barbara Brandom, MD
Received: 25 May 2016 / Revised: 5 November 2016 / Accepted: 1 January 2017
ÓCanadian Anesthesiologists’ Society 2017
Abstract
Purpose Malignant hyperthermia susceptibility (MHS) is
a disorder of the regulation of calcium in skeletal muscle.
Muscular individuals have been shown to have a 13.6-fold
increased risk of death during malignant hyperthermia
(MH) episodes and are more likely to experience a
recurrence after initial treatment. Twenty-five percent of
severe MH episodes have occurred in elite athletes. This
study investigated the association between MHS and
muscular body build.
Methods Data were obtained from existing reports in the
North American Malignant Hyperthermia Registry,
including the Report of Muscle Biopsy and Contracture
Testing (caffeine-halothane contracture test [CHCT]) as
well as Adverse Metabolic or Muscular Reaction to
Anesthesia (AMRA) reports. Malignant hyperthermia
susceptible individuals were compared with MH negative
individuals with regard to body build and reason for
testing. Males were also compared with females. Both the
CHCT and the AMRA forms were reviewed for comments.
Results Of the 1,292 individuals diagnosed with MHS by
CHCT, males were more likely to be diagnosed with the
disorder than females (odds ratio [OR], 2.33; 95%
confidence interval [CI], 1.99 to 2.7; P \0.001).
Muscular individuals were more likely to be diagnosed
with MHS than non-muscular individuals (OR, 1.94; 95%
CI, 1.51 to 2.49; P \0.001). Males were more likely to be
tested after having a possible MH episode (OR, 2.33; 95%
CI, 1.45 to 2.1; P\0.001). Logistic regression showed that
male sex (OR, 2.28; 95% CI, 1.93 to 2.7; P \0.001) and
muscular body build (OR, 2.17; 95% CI, 1.21 to 3.9; P =
0.01) were independently predictive of MHS. The
interaction between muscular body build and male sex
was not significant (P = 0.13). Indications for testing, MH
episode vs family history of MH, did not differ between
muscular and non-muscular individuals (P = 0.44). Eight
of 839 AMRAs and two reports of CHCT had comments
describing athletic abilities. Ryanodine receptor type 1
(RYR1) gene mutations were found in five of these athletes.
Conclusion Muscular body build and male sex are
strongly associated with MHS.
Re
´sume
´
Objectif La susceptibilite´a` l’hyperthermie maligne
(SHM) est un trouble de la re´gulation du calcium dans
les muscles squelettiques. Il a e´te´de´montre´ que les
personnes muscle´es couraient un risque 13,6 fois plus
e´leve´dede´ce`s pendant des e´pisodes d’hyperthermie
maligne (HM) ainsi qu’un risque plus e´leve´de
re´currence apre`s un premier traitement de la maladie.
Vingt-cinq pour cent des e´pisodes graves d’HM sont
survenus chez des athle`tes de pointe. Cette e´tude a examine´
l’association entre la SHM et la constitution musculaire.
Me
´thode Des donne´es ont e´te´ obtenues a` partir de
rapports existants dans le Registre nord-ame´ricain de
l’hyperthermie maligne (North American Malignant
Hyperthermia Registry), y compris le Rapport de biopsie
musculaire et de test de contracture (Report of Muscle
B. Butala, DO (&)
Allegheny Health Network, Department of Anesthesiology,
Allegheny General Hospital, 302 E North Ave, Pittsburgh,
PA 15212, USA
e-mail: brian.butala@ahn.org; brian.butala@gmail.com
B. Brandom, MD
North American Malignant Hyperthermia Registry of MHAUS,
UPMC Mercy Hospital, University of Pittsburgh, Pittsburgh, PA,
USA
123
Can J Anesth/J Can Anesth
DOI 10.1007/s12630-017-0815-2
Biopsy and Contracture Testing) (test de contracture a`la
cafe´ine et a` l’halothane [CHCT]) ainsi que les rapports de
re´actions me´taboliques ou musculaires ne´gatives a`
l’anesthe´sie (Adverse Metabolic or Muscular Reaction to
Anesthesia - AMRA). Les personnes susceptibles a`
l’hyperthermie maligne ont e´te´ compare´es aux personnes
ne´gatives a` l’HM quant a` leur constitution physique et a`la
raison de leur test. On a e´galement fait une comparaison
hommes-femmes. Les formulaires de CHCT et d’AMRA ont
e´te´ passe´s en revue afin d’en extraire tout commentaire ou
remarque.
Re
´sultats Parmi les 1292 personnes ayant rec¸u un
diagnostic de SHM apre`s avoir passe´ un test de CHCT, les
hommes e´taient plus enclins a`eˆtre diagnostique´s avec ce
trouble que les femmes (rapport de cotes [RC], 2,33;
intervalle de confiance [IC] 95 %, 1,99 a` 2,7; P \0,001).
Les personnes muscle´es couraient un risque plus e´leve´de
diagnostic de SHM que les personnes non muscle´ es (RC,
1,94; IC 95 %, 1,51 a` 2,49; P \0,001). Les hommes
couraient un risque plus e´leve´ de passer un test apre`s avoir
subi un possible e´pisode d’HM (RC, 2,33; IC 95 %, 1,45 a`
2,1; P\0,001). L’analyse de re´gression logistique a montre´
que le sexe masculin (RC, 2,28; IC 95 %, 1,93 a` 2,7; P \
0,001) et un corps muscle´ (RC, 2,17; IC 95 %, 1,21 a` 3,9;
P = 0,01) e´taient des pre´dicteurs inde´ pendants de SHM.
L’interaction entre avoir un corps muscle´ et le sexe masculin
n’e´tait pas significative (P = 0,13). Les indications pour
envisager un test, pre´voir un e´pisode d’HM vs les
ante´ce´ dents familiaux d’HM ne diffe´raient pas entre les
personnes muscle´es et non muscle´es (P = 0,44). Huit des 839
AMRA et deux rapports de CHCT comportaient des
commentaires de´crivant des capacite´s athle´tiques. Des
mutations du ge`ne RYR1 (re
´cepteur de ryanodine de type
1) ont e´te´ observe´es chez cinq de ces athle`tes.
Conclusion Un corps muscle´ et le sexe masculin sont
associe´s de fac¸on significative a` une susceptibilite´a`
l’hyperthermie maligne.
Malignant hyperthermia (MH) is a disorder of the
regulation of calcium in skeletal muscle. In response to
certain anesthetic
1,2
agents or other stressors, such as
exercise,
3-5
excessive calcium in the muscle cell increases
metabolism to the point of producing lethal temperatures.
Mutations in the ryanodine receptor type 1 (RYR1)
6
gene
are the most frequent genetic changes found in individuals
with malignant hyperthermia susceptibility (MHS).
Mutations in the alpha one subunit of the voltage-gated
calcium channel (the dihydropyridine receptor)
7
are less
common than RYR1 mutations.
6,8
The STAC 3 protein has
also been found to be associated with MHS in some
myopathic patients.
9
There are 35 mutations in the RYR1
gene and two in the CACNA1S gene, encoding the alpha
one subunit of the dihydropyridine receptor, that have been
shown to be MH causative.
10
Even with an emerging
genetic understanding of MHS, the gold standard for a
diagnosis of MH risk in North America remains the
caffeine-halothane contracture test (CHCT), which is
reported to be 97% sensitive and 78% specific.
11
Muscular individuals have been shown to have a
13.6-fold increased risk of death from MH episodes
12
and are more likely to experience recurrence of MH
episodes after initial treatment.
13
Twenty-five percent of
severe MH episodes have occurred in elite athletes.
12
There have also been other reports of athletes suffering
MH episodes both with
14,15
and without exposure to
anesthesia.
16-18
It was previously noted that three of 25
Danish individuals who experienced MH episodes were
elite athletes competing at the international and Olympic
levels.
18
Thus, for this study, we looked for more evidence
in the North American Malignant Hyperthermia Registry
(NAMHR) that muscularity and athleticism were
associated with MHS.
Methods
After institutional review board approval, data were
obtained from reports existing in the NAMHR from
January 1, 1987 to December 31, 2014, including the
Report of Muscle Biopsy and Contracture Testing and the
Adverse Metabolic or Muscular Reaction to Anesthesia
(AMRA) report. The CHCT is completed by physicians in
the MH diagnostic testing centres, and the AMRA is
completed by the anesthesiologist or other healthcare
provider who observed a possible or actual MH event.
The CHCT and AMRA contain a check box for body build
that includes options for normal, lean, muscular, obese,
postpartum, and other. The judgment of body build is
subjective on the part of the physician completing the
report and not based on objective measurement of fat or
muscle. For purposes of analysis, the cases were sorted into
categories of muscular and non-muscular, first on the basis
of responses to this check box. If comments reported
muscular in a text field as well as noting body build other
than muscular in the check box, the case was put into the
muscular group for analysis. All forms contain a section for
comments. Since 2002, forms include a check box for
‘‘regular regimen of physical activity’’. The CHCT form
contains the question ‘‘What was the reason for MH
diagnostic muscle biopsy?’’ with options for fulminant MH
episode, possible MH episode with associated AMRA,
possible MH episode without AMRA, family history,
control, and other. For the purposes of analysis, fulminant
B. Butala, B. Brandom
123
MH episodes and possible MH episodes as the reason for
biopsy are grouped together and referred to as possible MH
episode. These are the probands.
Three thousand twenty-four CHCT reports from
individuals in the USA or Canada were examined. These
CHCTs were performed after 1979 and before 2013 and
include cases in previously published studies from the
NAMHR. We excluded 103 of these reports with equivocal
results. At the time of testing, the director of the MH
diagnostic centre indicated equivocal result to mean that
risk of MHS could not be determined. The magnitude of
the contractures in the presence of halothane or caffeine
were not evaluated in this report. Reports with unknown
sex (12), absent or other body type (335), and 12 reports of
CHCT performed prior to standardization
19
were also
excluded (Figure). Eight hundred thirty-nine AMRAs were
reviewed for comments, and CHCT reports were also
reviewed for comments regarding athletic achievement and
genetic test results.
Analysis was performed using Fisher’s exact test for
categorical variables. The associations between CHCT
result and body build, CHCT result and body build in male
and female sex, body build and indication for testing, as
well as sex and CHCT result were examined with Fisher’s
exact test in SPSSÒ(versions 22, 23, & 24; IBM, NY,
USA). Since muscularity may be associated with being
male, we used logistic regression to determine if
muscularity was independently predictive of MHS (over
and above sex). We used MHS as the dependent variable
and muscularity and sex (as well as their interaction) as the
independent variables. There was no correction of Pvalues
for multiple comparisons.
Results
Results of CHCTs were reported for 1,284 males and 1,278
females. Muscular body build was reported in 194 of 1,292
individuals diagnosed with MHS by CHCT and in 106 of
1,270 individuals diagnosed as not MH susceptible (MHN)
by CHCT (Table 1). Thus, those with muscular body build
were more likely than those with non-muscular body build
to have CHCT results indicate a diagnosis of MHS (odds
ratio [OR], 1.94; 95% confidence interval [CI], 1.5 to 2.5;
P\0.001). Males were more likely to be diagnosed with
MHS by CHCT (OR, 2.33; 95% CI, 1.99 to 2.7) than
females (P\0.001). Logistic regression showed that
muscularity was indeed predictive of MHS independent of
sex. The OR for muscularity (adjusted for sex) was 2.17
(95% CI 1.21 to 3.9; P= 0.01), consistent with the
unadjusted effect of muscularity on MHS. Being male
continued to be predictive of MHS after adjustment for
muscularity (OR, 2.28; 95% CI, 1.93 to 2.7; P\0.001).
There was no significant interaction (P= 0.13) between
muscularity and sex, indicating that the effect of
muscularity on MHS did not differ appreciably between
males and females (or, equivalently, the effect of sex on
2,562 CHCT reports included for analysis
2,574 CHCT reports
Excluded for procedures prior to standardization (n=12)
2,921 CHCT reports
Excluded for unknown gender (n=12) Excluded for absent or "other" body type
(n=335)
3,024 CHCT reports in the NAMHR
Excluded for equivocal results as judged by diagnostic center director (n=103)
Figure Exclusion algorithm. CHCT = caffeine-halothane contracture test; NAMHR = North American Malignant Hyperthermia Registry
Table 1 Percent muscular build and malignant hyperthermia
susceptibility
Male Female
MHS 166/781 (21.2%) 28/511 (5.5%)
MHN 86/503 (17.1%) 20/767 (2.6%)
MHS = malignant hyperthermia susceptibility; MHN = not malignant
hyperthermia susceptible.
Muscular build and male sex are associated with MH
123
MHS did not differ appreciably between muscular and non-
muscular individuals) (Table 2).
With regard to the indication for testing, 458 of 1,091
(42%) males were tested after having a possible MH
episode compared with 338 of 1,145 (29.5%) females (P\
0.001). There was no difference in the indication for testing
between those with and without muscular build (P= 0.44).
Furthermore, the percentage of muscular probands (those
who underwent CHCT because of an episode of suspected
MH) was no different from that of muscular individuals
who underwent CHCT due to a family history of MH (P=
0.54).
Eight of 839 AMRAs, one of which was linked to a
CHCT report, and two other CHCT reports included
comments describing athletic abilities (Table 3). Four of
these individuals had known MH causative mutations in
RYR1. Two had variants of unproven significance in RYR1,
one of whom also had an RYR1 mutation known to be
causative of MH.
Discussion
In this report, the CHCT outcome diagnostic of MHS was
more strongly related to sex than to report of muscular
body build. Our observation that the odds of MHS is more
than twice as great in males than in females seems
Table 2 Logistic regression of sex, muscular body build status, and
their interaction
Parameter Odds ratio 95% Confidence
interval
Pvalue
Sex 2.28 1.93 to 2.70 \0.001
Muscular 2.17 1.21 to 3.89 0.01
Muscular by sex interaction 0.6 0.32 to 1.16 0.13
Table 3 Athletic ability and malignant hyperthermia
Evidence of athleticism
In comments
Sex Body type RYR1 finding MH Episode
Chronic issues
Previously
published in
reference #
Professional athlete Male Muscular N/A Fulminant MH 12,23
College football player Male Muscular N/A Fulminant MH 12,15,23
Multiple fractures during sports Male Muscular N/A Suspected MH 12,23
Olympic athlete Female N/A N/A Death,
Fulminant MH
12,23
College cheerleader, athletic Female Non-
muscular
p.Gly2434Arg* Death,
Fulminant MH
Larach, 2014
College level volleyball and track to
State competition; cheerleader; gymnast
reported before MH event at \25 yr of age
Female Muscular p.Arg614Cys*
& p.Thr3711Arg
Fulminant MH 6,
Larach, 2014
Regular regimen of physical activity in mixed
martial arts at \25 yr of age
Male Muscular N/A Fulminant MH Larach, 2014
Regular bicycling [20 minday
-1
3 timeswk
-1
prior to MH event at \30 yr of age
Male Muscular p.Gly2434Arg* Fulminant MH 12,23
Runs [6 milesday
-1
; bench presses 300 lb
when had CHCT at 30 yr of age
Male Muscular p.Leu4824Pro No personal MH;
Reported relative died of MH;
CCD histology;
Intolerant to heat
Sei, 2004
Long distance cyclist; semi-pro hockey
player before MH event at *40 yr of age
Male N/A p.Gly2434Arg* Suspected MH;
Postop Rhabdomyolysis,
max CK 70,000 IU;
Exercise-induced
rhabdomyolysis and weakness.
6
Reports with evidence of athleticism and sex; most include body type and some include type 1 ryanodine receptor mutation findings.
*Known MH causative mutation
Previously published in this # citation in this report or in Larach et al. Malignant hyperthermia deaths related to inadequate temperature
monitoring, 2007-2012: A report from the North American MH Registry of MHAUS. Anesth Analg 2014; 119: 1359-66 or in Sei et al. Malignant
hyperthermia in North America genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824-30
CCD = central core disease; CHCT = caffeine-halothane contracture test; CK = creatine kinase; MH = malignant hyperthermia; MHAUS =
Malignant Hyperthermia Association of the United States; N/A = not available; RYR1= type 1 ryanodine receptor
B. Butala, B. Brandom
123
contradictory to the understanding of MHS as an autosomal
dominant condition. Nevertheless, observation of more
males than females with a positive CHCT was first reported
in 2007 in 1,407 patients evaluated in Sweden.
20
More
recently, a consistent parent-of-origin effect was reported
for the transmission of MHS in view of the fact that fathers
had more affected sons than daughters.
21
Malignant
hyperthermia episodes have been reported more often in
males than in females in several different types of
studies.
22-24
One might speculate that males experience
MH more often than females because of environmental
factors. In this report, more males than females presented
for a CHCT due to personal experience of an MH event.
Nevertheless, in this cohort, there were similar numbers of
males and females who underwent CHCT. Sex discrepancy
in MH warrants further study.
In the CHCT data in this study, muscular body build was
reported in a minority of individuals diagnosed as MHS by
CHCT; however, there was a significant association
between muscular body build and MHS diagnosed by
CHCT. This observation has not been made previously.
Logistic regression analysis showed that muscular body
build is predictive of MHS independent of sex. There may
be ascertainment bias, as a muscular build may be more
easily recognized in females than in males. Perhaps many
males are subjectively judged to be muscular. Assessment
of a larger population with a more objective quantitative
measurement of muscularity might yield a different result,
as our data may be biased by the subjective nature of the
reporting of body build.
The AMRA data, supplemented by a few CHCT reports,
show that, although MHS individuals may have mutations
in genes encoding proteins involved in the excitation-
contraction coupling mechanism in skeletal muscle, some
of these individuals perform athletically at high levels. The
possibility that an MHS person can be a skilled athlete
widens the phenotypic variability of RYR1 mutations.
Myopathies related to the RYR1 gene, such as King-
Denborough syndrome and central core disease, are not the
only clinical presentations of MHS in daily life.
The nature of the data acquisition in this study may
produce significant bias. Selection bias is present as all
reports were submitted voluntarily, and it may be that only
the most severe or memorable cases were reported. Specific
questions to elicit reporting of athletic accomplishment
were recently added (2015) to reports. Testing for
mutations in RYR1 in MHS individuals was experimental
until 2005. Also, CHCT is expensive and inconvenient to
perform. Patients must travel to only a few available testing
centres for muscle biopsy and contracture testing. As a
result, our data underrepresent those of lower
socioeconomic status. It must be emphasized that all
CHCT investigations are done on individuals with an
indication, which makes it difficult to apply our results to
patients without such medical history.
Conclusion
We report a strong association between muscularity and
MHS. Males were more likely to be diagnosed with MHS
by muscle contracture testing. Optimistically, as the
biology of MH continues to be investigated, the causes of
these findingswill be elucidated.
Acknowledgments We acknowledge the support of the not-for-profit
Malignant Hyperthermia Association of the United States, the
Departments of Anesthesiology and Nurse Anesthesia in the
University of Pittsburgh, and the North American Malignant
Hyperthermia Registry of MHAUS —without the accumulated data,
this report would not have been possible.
Conflicts of interest The authors have no conflict of interest to
report.
Editorial responsibility This submission was handled by Dr. Philip
M. Jones, Associate Editor, Canadian Journal of Anesthesia.
Author contributions Brian Butala and Barbara Brandom
contributed substantially to all aspects of this manuscript, including
conception and design; acquisition, analysis, and interpretation of
data; and drafting the article.
Sources of funding We recognize financial support from the North
American Malignant Hyperthermia Registry and the Malignant
Hyperthermia Association of the United States as well as
administrative support from the Departments of Anesthesiology and
Nurse Anesthesia in the University of Pittsburgh.
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