Nazarian, Saman

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Is Ventricular Arrhythmia a Possible Mediator of the Association Between Aortic Stenosis-Related Midwall Fibrosis and Mortality?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the author and do not necessarily reflect the views of JACC or the American College of Cardiology. 

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Journal of the American College of Cardiology Vol. 58, No. 12, 2011
© 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2011.04.045EDITORIAL COMMENT
Is Ventricular Arrhythmia a
Possible Mediator of the
Association Between Aortic
Stenosis-Related Midwall
Fibrosis and Mortality?*
Saman Nazarian, MD
Baltimore, Maryland
In 1954, Mitchell et al. (1) reported on 40 years of
experience with clinical features of 533 cases of aortic
stenosis managed at the Peter Bent Brigham Hospital of
Boston, Massachusetts. This patient series spanned the
development of mercurial diuretics, surgical cure for aortic
stenosis, and penicillin, advances that have transformed the
epidemiology and prognosis of aortic stenosis. Several re-
markable observations of this study remain central to the
findings reported in this issue of the Journal. Mitchell et al.
(1) noted significantly shorter expected survival after the
onset of symptoms. The average lifespan was 4 years after
the onset of angina, 3.5 years after the onset of congestive
heart failure, and 3 years after syncope. Among patients
with witnessed deaths, 35% died of congestive failure,
20.1% of subacute bacterial endocarditis, 2.3% of myocar-
dial infarction, and 18.7% of sudden death; the remaining
causes of death were noncardiac. Sudden death tended to
occur in the later stages of disease and was associated with
history of angina. However, autopsy examinations revealed
that sudden death frequently occurred in the absence of
See page 1271
significant coronary disease. Examination of the coronary
arteries in patients with aortic stenosis and angina revealed
coronary atherosclerosis in some cases. However, in patients
younger than 50 years, 28% had normal coronary arteries
and 56% had only up to moderate atherosclerosis. Even
among those older than 50 years, 22% had normal coronary
arteries and 32% had only up to moderate atherosclerosis.
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the author and do not necessarily reflect the views of JACC or the American
ollege of Cardiology.m
From The Johns Hopkins Hospital, Baltimore, Maryland. Dr. Nazarian is funded
y grant K23-HL089333 from the National Institutes of Health.Examination of the myocardium of patients with angina
revealed that no one younger than 50 years, and only 19% of
those older than 50 years, had prior myocardial infarction.
When comparing aortic stenosis patients with and without
angina, there was no significant difference in the degree of
aortic stenosis, but the average cardiac weight was signifi-
cantly higher in those with angina. The observations of
Mitchell et al. (1) thus suggested that in aortic stenosis: 1)
sudden death was associated with history of angina; and 2)
angina was associated with left ventricular hypertrophy.
Since the publication of the observations by Mitchell et
al. (1), significant advances have been made in medical
therapy for congestive heart failure, prophylaxis of bacterial
endocarditis, and treatment of associated coronary occlu-
sions. Despite these medical advances, for a patient with
aortic stenosis, the advent of symptoms today heralds as
adverse a prognosis as that in 1954, unless the patient
undergoes surgery (2). Sudden death remains a major
contributor to mortality and occurs in up to 5% of patients
with asymptomatic, and 35% of patients with symptomatic
aortic stenosis (3–8). Multiple mechanisms have been
implicated to explain sudden death in the setting of aortic
stenosis. These mechanisms include myocardial ischemia
and elevated levels of catecholamines leading to ventricular
tachyarrhythmia, and/or an abnormal Bezold-Jarisch reflex
resulting in hypotension or bradyarrhythmias (8–10). The
risk of cardiac death is mitigated with valve replacement,
consistent with the idea that bradyarrhythmias or tachyar-
rhythmias, without a fixed substrate and secondary to
primary valvular pathology, are responsible for a significant
proportion of sudden deaths in the setting of aortic stenosis.
However, even after corrective surgery, patients exhibit an
elevated risk of sudden death (11). In fact, sudden death is
reportedly the most frequent mode of death after aortic
valve surgery and seems to be associated with greater left
ventricular hypertrophy (12). Some of these sudden deaths
are likely due to causes other than arrhythmia, such as
embolism or valvular dehiscence. However, Blackstone and
Kirklin (13) found normal prosthetic valve and peripros-
thetic myocardium in 8 of 15 autopsies conducted in
subjects with sudden death after valve replacement. It
seems, therefore, that even after corrective surgery for aortic
stenosis, some patients remain predisposed to sudden death.
In this issue of the Journal, Dweck et al. (14) report their
findings on cardiac magnetic resonance imaging examina-
tions of 143 patients with moderate (40% of patients, 1.0 to
1.5 cm2) or severe (60% of patients, 1.0 cm2) aortic
tenosis. Before enrollment, all patients underwent evalua-
ion for ischemia, and 57% were found to have concomitant
oronary artery disease. Using the late gadolinium enhance-
ent technique, the investigators found evidence for myo-
ardial fibrosis in 66% of patients with aortic stenosis. It is
ossible that techniques with greater sensitivity for detec-
ion of diffuse myocardial fibrosis, such as T1 mapping (15),
ay modify these results. However, the investigators have
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1281JACC Vol. 58, No. 12, 2011 Nazarian
September 13, 2011:1280–2 Aortic Stenosis-Related Midwall Fibrosis and Mortalityreliably described the extent of macroscopic fibrosis using
validated methods (16–18). Overall, patients with evidence
of macroscopic fibrosis were older and more likely to be
male. A fibrotic pattern consistent with prior myocardial
infarction was seen in 28% of patients, whereas a pattern of
midwall fibrosis was seen in 38% of patients. Those patients
with evidence of myocardial infarction had more severe
coronary artery disease on angiography and lower ejection
fractions than those with midwall fibrosis or no evidence of
fibrosis. Patients with midwall fibrosis had higher left
ventricular mass and lower ejection fraction compared with
those with no fibrosis.
During a mean follow-up of 2 years after imaging, 72
patients underwent aortic valve replacement and 27 died.
On univariate analysis, patients with midwall fibrosis had
8-fold higher risk of all-cause mortality, and those with
myocardial infarction had 6-fold higher risk of all-cause
mortality compared with those without fibrosis. It is worth
noting that midwall fibrosis remained predictive of mortal-
ity even after adjustment for left ventricular function. As
noted by the investigators, this finding suggests that mid-
wall fibrosis is associated with mortality through mecha-
nisms other than pump failure. Only 3 of 27 deaths were
sudden (11%), precluding statistical assessments of any
association with fibrotic patterns. However, all 3 sudden
deaths occurred in patients with midwall fibrosis. Despite
lowering the overall risk for mortality, aortic valve replace-
ment did not completely remove the adverse prognosis
associated with midwall fibrosis. Even after aortic valve
replacement, those with midwall fibrosis had higher mor-
tality than patients without fibrosis (14).
Due to limited information about the immediate cause of
death and paucity of events, the present study cannot assess
the mechanism by which midwall fibrosis is associated with
increased mortality. Ventricular arrhythmia, a possible me-
diator of this association, has been documented as a cause of
sudden death before (9) and after aortic valve surgery (19).
Narasimhan et al. (20) studied 9 patients who presented
with ventricular tachycardia after valve replacement for
aortic stenosis. Of these 9 patients, 2 had bundle branch
re-entry, 5 had myocardial fibrosis–related ventricular
tachycardia, and 2 had both myocardial fibrosis–related and
bundle branch re-entrant ventricular tachycardia. It is no-
table that 3 of those with myocardial fibrosis–related ven-
tricular tachycardia had no associated coronary artery dis-
ease. A more recent report by Eckart et al. (21), which
excluded patients with coronary artery disease, also found
that ventricular tachycardia after valve surgery is most often
due to re-entry around myocardial fibrosis. As noted by
Marchlinski (22) in an editorial that followed the latter
study, the perivalvular distribution of fibrosis in patients
after valve surgery mimics the location of fibrosis in a variety
of other nonischemic cardiomyopathies. The study by
Dweck et al. (14) expands on prior findings and shares this
theme. The midwall fibrosis pattern visualized in 38% of
participants mimics the pattern seen in approximately one-third of patients with nonischemic cardiomyopathy (17).
he “scattered streaky fibrosis” in excess of that expected
rom coronary disease has been previously noted on autopsy
tudies of patients with aortic stenosis (23). In his observa-
ions at autopsy of 7 cases with aortic stenosis in 1957,
igle (24) noted that “the various types of macroscopic
brosis were greatest in the mid-portion of the left ventric-
lar wall,” and predominantly affected the posterobasal
egion of the left ventricle. Midwall fibrosis of the basal left
entricle seems to be a common fibrotic pattern among
atients with aortic stenosis and those with nonischemic
ardiomyopathy. In nonischemic cardiomyopathy, midwall
brosis is associated with ventricular arrhythmia and adverse
utcomes (25,26). The etiology of midwall fibrosis is not yet
nown. As Dweck et al. (14) suggest, the association of
idwall fibrosis with left ventricular hypertrophy points to
schemia and/or mechanical stress, as possible etiologies for
poptosis and scar formation. Conversely, midwall fibrosis
as been observed in nonischemic cardiomyopathies with-
ut prior evidence of left ventricular hypertrophy. Further
nvestigation regarding the etiology and mechanical and
lectrophysiological effects of midwall fibrosis, and the
actors that mediate its association with mortality, may lead
o improved management strategies in aortic stenosis and
ther nonischemic causes of myopathy.
Reprint requests and correspondence to: Dr. Saman Nazarian,
The Johns Hopkins Hospital, Carnegie 592C, 600 North Wolfe
Street, Baltimore, Maryland 21287. E-mail: snazarian@jhmi.edu.
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