Editorial
Sex Differences in Congenital Heart Disease
Should a Woman Be More Like a Man?
Carole A. Warnes, MD, FRCP
S ex differences in the clinical presentation, diagnosis, and
treatment outcomes of cardiac disease have long been
recognized. Since the mid-1980s, the total number of deaths
from cardiovascular disease has been higher for women than
for men. A greater proportion of women (52%) than men
(42%) with myocardial infarction die of sudden cardiac death
before reaching the hospital, perhaps in part because women
tend to have nonspecific prodromal symptoms rather than
chest pain and these symptoms are not recognized as being
cardiac in origin.1 Even after acute myocardial infarction,
Downloaded from http://circ.ahajournals.org/ by guest on June 21, 2017
women are 46% less likely to undergo coronary angiography
than men, despite accounting for confounders.2 Two-thirds of
women who suffer a myocardial infarction never completely
recover,3,4 and those who do survive have a 2-fold recurrence
of myocardial infarction and mortality during the first year
compared with their male counterparts.5
Article p 26
Women with stable angina have higher in-hospital mortal-
ity rates6 and worse outcomes after coronary interventions,
both percutaneous and surgical. Following percutaneous cor-
onary interventions women have higher rates of short- and
long-term mortality, cardiac events, and the need for emer-
gency coronary artery bypass grafting. This may relate to the
comparatively smaller coronary artery size of women,7 al-
though this is unproven.8 Higher mortality and complication
rates of coronary artery bypass grafting also occur, with
women obtaining less functional relief, more frequent hospi-
tal readmissions, and lower functional gains than their male
counterparts.9 Whether some of these sex disparities relate to
an autoimmune precursor for atherosclerotic disease remains
speculative. Sex-specific differences in C-reactive protein, as
an inflammatory marker, are consistent with the 10-fold
increased frequency of inflammatory-mediated autoimmune
diseases, such as rheumatoid arthritis, systemic lupus erythe-
matosus, and thyroiditis in women compared with men.4,10
Recent studies report atherosclerotic plaque in both the
carotid and coronary arteries to be significantly increased in
women with systemic lupus erythematosus.
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Divisions of Cardiovascular Diseases and Pediatric Cardiol-
ogy, Mayo Clinic, Rochester, Minn.
Correspondence to Carole A. Warnes, MD, Division of Cardiovascular
Diseases, 200 1st St SW, Gonda 5368, Rochester, MN 55905. E-mail
warnes.carole@mayo.edu
(Circulation. 2008;118:3-5.)
2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.785899
3
Sex differences may also extend to cardiac electrophysiol-
ogy. Women have higher resting heart rates and longer
corrected QT intervals compared with men.11 Variations in
arrhythmia frequency in relation to the menstrual cycle have
also been observed. Sudden cardiac death with coronary
artery disease has a male-to-female ratio of 1.4:1.12
Now, in the current issue of Circulation, the article by
Verheugt et al13 from the CONgenital CORvitia (CONCOR)
Dutch national registry reports sex differences in outcomes of
congenital heart disease. This database comprises over 7000
adult patients with congenital heart disease with a median age
of 35 years; half of them are women. No sex differences in
mortality were found but 4 specific cardiac outcomes ap-
peared to be different in men and women.
Pulmonary Hypertension
Pulmonary arterial hypertension was defined as a systolic
pulmonary pressure above 40 mm Hg. Women had a 35%-
higher risk of pulmonary hypertension with an odds ratio of
1.33, an observation which has been noted previously. Atrial
and ventricular septal defects were the 2 most frequent
defects in this whole series and these defects were associated
with pulmonary hypertension more commonly than any other
lesion.
The association of pulmonary hypertension with female
sex is intriguing. Idiopathic pulmonary arterial hypertension
is also much more common in women with a ratio of
approximately 2.5:1, and although various genetic mutations
and polymorphisms have been found to be associated with
idiopathic pulmonary arterial hypertension, none appear to be
sex-linked. In the study by Verheugt et al,13 no sex difference
was found in patients with irreversible pulmonary vascular
disease but perhaps secundum atrial septal defect (ASD)
deserves special examination. In our adult congenital heart
disease clinic at Mayo Clinic, comprising over 4000 patients,
the frequency of isolated secundum ASD with Eisenmenger
syndrome in women exceeds that in males by 28:1. Some
authors have even speculated that the ASD in this situation is
really an innocent bystander and that the underlying pa-
thology is really that of idiopathic pulmonary arterial hyper-
tension. Nonetheless the female vulnerability to the develop-
ment of pulmonary hypertension in this setting is striking,
perhaps suggesting that a two-hit hypothesis is necessary
(ie, a genetic susceptibility exists) and then the trigger of a
secundum ASD initiates the vascular injury in the lungs
which, in turn, leads to endothelial and vascular smooth
muscle dysfunction and subsequent pulmonary vascular re-
modeling. The explanation that hormonal differences and
pregnancy account for these sex disparities appears somewhat
simplistic.
 4 Circulation July 1, 2008
Aortic Outcomes
Aortic outcomes in this study included dissection, aortic
surgery, and aneurysm formation, the latter defined as dila-
tation of the ascending aorta 3.7 cm. Here, women fared
better, with a 33%-lower risk of aortic outcomes (odds ratio
0.67), largely because of lower rates of aortic surgery. This is
not surprising because bicuspid aortic valve, aortic stenosis,
and coarctation of the aorta, conditions all associated with an
aortopathy, are more common in men. In addition, the female
aorta is smaller, so women might not be expected to reach the
critical surgical threshold as early as men.
The preponderance of bicuspid aortic valve disease in men,
however, is also intriguing, and because it often occurs in
multiple members of the same family, a genetic cause is
likely.14 Both coarctation and bicuspid aortic valve occur
more frequently in men, with a prevalence of approximately
4:1. A high prevalence of these same lesions is found in
Turner syndrome,15 a sex aneuploidy syndrome caused by the
complete absence of a sex chromosome or the presence of a
Downloaded from http://circ.ahajournals.org/ by guest on June 21, 2017
structurally abnormal one. Structural cardiac anomalies are
most prevalent in those women with pure 45X monosomy
than in those with an isochromosome Xq karyotype16 and
when Turner patients are compared with the general popula-
tion, aortic valve disease occurs 146 times more commonly.15
Thus, because aortic disease is dominantly a male domain
and the absence of a normal second X chromosome is
associated with aortopathy, one might speculate that a genetic
factor that modulates the development of the aorta and aortic
valve might be located on the X chromosome.17 X-linked
genes that might be implicated in cardiovascular development
include the genes encoding for vascular endothelial growth
factor D and the angiotensin type-2 receptor, both of which
have roles in fetal development.18
Infective Endocarditis
Women were noted to have a 47%-lower risk of endocarditis.
Whether this relates to the sex distribution of vulnerable
lesions (most commonly ventricular septal defect, bicuspid
aortic valve, aortic stenosis and tetralogy of Fallot) is uncer-
tain. Another possible explanation might be better oral
hygiene in women. It is noteworthy, however, that if more
than 1 diagnosis occurred in a patient, a hierarchical scheme
was applied so that the patient was categorized with the
diagnosis expected to have the most serious sequel in the
future. This may explain why 10 patients with secundum
ASD reportedly had endocarditis, presumably affecting a
cardiac valve, because patients with isolated secundum ASD
do not develop endocarditis.
Implantable Cardioverter-Defibrillator Use
Women had a 55%-lower risk of receiving an implantable
cardioverter-defibrillator (ICD) compared with men (odds
ratio 0.45), although they had the same frequency of ventric-
ular arrhythmias. This is a phenomenon well recognized with
acquired cardiac disease, wherein the ratio of ICD use may be
up to 6-times higher in men.19 Medicare data from 1991 to
2005 confirmed that men were 3.2-times more likely to
receive an ICD for primary prevention of sudden cardiac
death than women and 2.4-times more likely for the second-
ary prevention cohort.20 This occurred despite the fact that the
survival benefit for ICD is the same in men and women, and
the sex differences persisted even adjusted for age and
comorbidities.
If these devices are safe and efficacious in women, why
they are implanted at such a comparatively low rate remains
unclear. Does this reflect the overall underutilization of
medication and cardiac procedures in women compared with
men? If so, why is the implantation rate of pacemakers in men
and women the same? Are women erroneously perceived to
be at lower risk of sudden cardiac death, or do they decline
treatment? Is the reason for low ICD implantation in women
that they are older and sicker with more comorbidities? These
speculations, however, would appear not to apply to the
younger population of patients with congenital heart disease.
It is fascinating that in both acquired and congenital heart
disease, these sex disparities exist for ICD implantation. This
should form the basis of investigational studies to determine
the cause of this disparity. Are we missing the opportunity to
save lives, or is there something fundamentally different
about women and their risk of preventable arrhythmic cardiac
death? Primary prevention trials show survival benefit of ICD
therapy only in patients with significant left ventricular
dysfunction. Women with heart failure are more likely than
men to have normal systolic function,21 but this alone should
not account for the magnitude of difference. Whether more
men in the study by Verheugt et al exhibited systemic
ventricular dysfunction than women remains unexplored.
Indications for ICD implantation for the adult congenital
heart disease population remain ill defined, and, although it is
tempting to extrapolate indications from acquired heart dis-
ease, no such data currently exist. Risk stratification remains
imprecise, and, in contrast to acquired cardiac disease, which
mainly affects the left ventricle, it is more common to receive
an ICD for ventricular arrhythmias associated with right
ventricular dysfunction, for example after repair of tetralogy
of Fallot with pulmonary regurgitation.
Conclusions
Thus, sex differences in outcomes for patients with adult
congenital heart disease are apparent from this study.
Whether this relates to inherent biological differences, the
smaller size of women, or intrinsic genetic differences re-
mains uncertain. Observational studies such as this one are
vulnerable to recognized and unrecognized biases that may
lead to erroneous conclusions. Nonetheless, it is plausible that
genetic polymorphisms have different expressions in men and
women, just as specific genotypes confer susceptibility to
myocardial infarction in women but not in men.22 This may
relate not simply to the presence or absence of the genetic
variant but to the influence of sex or sex hormones on the
expression of various genes and their potential to modify
cellular function. Understanding the different genetic suscep-
tibility and pathophysiology of these defects in the future
might enable us to prevent the development of such lesions
and complications such as pulmonary hypertension and per-
mit the development of sex-specific treatment modalities to
improve the outcomes for the more than 1 million adults in
the United States with congenital heart disease.
 Warnes
Disclosures
None.
References
1. McSweeney JC, Cody M, OSullivan P, Elberson K, Moser DK, Garvin
BJ. Womens early warning symptoms of acute myocardial infarction.
Circulation. 2003;108:2619 2623.
2. Nguyen JT, Berger AK, Duval S, Luepker RV. Gender disparity in
cardiac procedures and medication use for acute myocardial infarction.
Am Heart J. 2008;155:862 868.
3. Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T,
Zheng ZJ, Flegal K, ODonnell C, Kittner S, Lloyd-Jones D, Goff DC Jr,
Hong J, Adams R, Friday G, Furie K, Gorelick P, Kissela B, Marler J,
Meigs J, Roger V, Sidney S, Sorlie P, Steinberger J, Wassarthiel-Smoller
S, Wilson M, Wolf P. Heart Disease and Stroke Statistics2006 Update:
A Report From the American Heart Association Statistics Committee and
Stroke Statistics Subcommittee. Circulation. 2006;113:e85 e151.
4. Shaw LJ, Bairey Merz N, Pepine CJ, Reis SE, Bittner V, Kelsey SF,
Olson M, Johnson D, Mankad S, Sharaf BL, Rogers WJ, Wessel TR,
Arant CB, Pohost JM, Lerman A, Quyumi AA, Sopko G, for the WISE
Investigators. Insights from the NHLBI-sponsored Womens Ischemia
Syndrome Evaluation (WISE) study: part I: gender differences in tradi-
tional and novel risk factors, symptom evaluation, and gender-optimized
Downloaded from http://circ.ahajournals.org/ by guest on June 21, 2017
diagnostic strategies. J Am Coll Cardiol. 2006;47(suppl):S4 S20.
5. Wenger NK. Coronary heart disease: the female heart is vulnerable. Prog
Cardiovasc Dis. 2003;46:199 229.
6. Shaw LJ, Shaw RE, Bairey Merz N, Brindis RG, Klein LW, Nallamothu
B, Douglas PS, Krone RJ, McKay CR, Block PC, Hewitt K, Weintraub
WS, Peterson ED. Impact of ethnicity and gender differences on angio-
graphic coronary artery disease prevalence and in-hospital mortality in
the American College of Cardiology-National Cardiovascular Data
Registry. Circulation. 2008;117:17871801.
7. Peterson ED, Lansky AJ, Kramer J, Anstrom K, Lanzilotta MJ. National
Cardiovascular Network Clinical Investigators. Effect of gender on the
outcomes of contemporary percutaneous coronary intervention.
Am J Cardiol. 2001;88:359 364.
8. Argulian E, Patel AD, Abramson JL, Kulkarni A, Champney K, Palmer
S, Weintraub W, Wenger NK, Vaccarino V. Gender differences in
short-term cardiovascular outcomes after percutaneous coronary inter-
ventions. Am J Cardiol. 2006;98:48 53.
9. Vaccarino V, Lin ZQ, Kasl SV, Mattera JA, Roumanis SA, Abramson JL,
Krumholz HM. Sex differences in health status after coronary artery
bypass surgery. Circulation. 2003;108:26422647.
Sex Differences and Congenital Heart Disease 5
10. American Autoimmune Related Disease Association. Autoimmune
disease in women: the facts. Available at: http://www.aarda.org/
women_and_autoimmunity.php. Accessed May 10, 2008.
11. Yarnoz MJ, Curtis AB. More reasons why men and women are not the
same (gender differences in electrophysiology and arrhythmias).
Am J Cardiol. 2008;101:12911296.
12. Abildstrom SZ, Rask-Madsen C, Ottesen MM, Andersen PK, Rosthoj S,
Torp-Pedersen C, Kober L. TRACE Study Group. Trandalopril cardiac
evaluation. Impact of age and sex on sudden cardiovascular death fol-
lowing myocardial infarction. Heart. 2002;88:573578.
13. Verheugt CL, Uiterwaal CSPM, van der Velde ET, Meijboom FJ, Pieper
PG, Vliegen HW, van Dijk APJ, Bouma BJ, Grobbee DE, Mulder BJM.
Gender and outcome in adult congenital heart disease. Circulation 2008;
118:26 32.
14. Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. Bicuspid
aortic valve is heritable. J Am Coll Cardiol. 2004;44:138 143.
15. Prandstraller D, Mazzanti L, Picchio FM, Magnani C, Bergamaschi R,
Perri A, Tsingos E, Cacciari E. Turners syndrome: Cardiologic profile
according to different chromosomal patterns and long-term clinical
follow-up of 136 nonpreselected patients. Pediatr Cardiol. 1999;20:
108 112.
16. Elsheikh M, Dunger DB, Conway GS, Wass JAH. Turners syndrome in
adulthood. Endocrine Reviews. 2002;23:120 140.
17. Warnes CA. Bicuspid aortic valve and coarctation: two villains part of a
diffuse problem. Heart. 2003;89:965966.
18. Sachdev V, Matura LA, Sidenko S, Ho BD, Arai AE, Rosing DR Bond
CA. Aortic valve disease in Turner syndrome. J Am Coll Cardiol. 2008;
51:1904 1909.
19. Staniforth AD, Sporton SC, Robinson NM, Cooper J, Earley MJ, Nathan
AW, Schilling RJ. Is there a sex bias in implantable cardioverter-
defibrillator referral and prescription? Heart. 2004;90:937938.
20. Curtis LH, Al-Khatib SM, Shea AM, Hammill BG, Hernandez AF,
Schulman KA. Sex differences in the use of implantable cardioverter-
defibrillators for primary and secondary prevention of sudden cardiac
death. JAMA. 2007;298:15171524.
21. Masoudi FA, Havranek EP, Smith G, Fish RH, Steiner JF, Ordin DL,
Krumholz HM. Gender, age, and heart failure with preserved left ven-
tricular systolic function. J Am Coll Cardiol. 2003;41:217223.
22. Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H,
Sone T, Tanaka M, Yokota M. Prediction of the risk of myocardial
infarction from polymorphisms in candidate genes. N Engl J Med. 2002;
347:1916 1923.
KEY WORDS: Editorials complications heart defects, congenital
epidemiology
 Sex Differences in Congenital Heart Disease: Should a Woman Be More Like a Man?
Carole A. Warnes

Circulation. 2008;118:3-5
doi: 10.1161/CIRCULATIONAHA.108.785899
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Downloaded from http://circ.ahajournals.org/ by guest on June 21, 2017

Copyright 2008 American Heart Association, Inc. All rights reserved.

Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/118/1/3

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Circulation is online at:

http://circ.ahajournals.org//subscriptions/