DOI: 10.1161/CIRCULATIONAHA.115.018951
Moving Beyond Cardio-Centricity in Heart Failure Risk Stratification
Running title: Borlaug; Depression, HIV and Heart Failure
Barry A. Borlaug, MD
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, R
Rochester,
oche
oc
hest
he
ster
st
er,, MN
er
Add
dress for Correspondence:
Corrres
Co
rr spond
pond
nden
nce
ce::
Address
Barr
rry A. Borla
l ugg, MD
D
Barry
Borlaug,
yo C
lini
li
nicc an
ni
nd Fo
Foun
unda
un
dati
da
t on
Mayo
Clinic
and
Foundation
200 First Street SW
Rochester, MN 55905
Tel: 507-284-4442
Fax: 507-266-0228
E-mail: [email protected]
Journal Subject Terms: Risk Factors; Primary Prevention; Epidemiology; Heart Failure
Key words: Editorial; heart failure; infectious disease; risk stratification; depression
1
Heart failure (HF) remains the leading cause of hospitalization among older Americans.1
Survival is improving, and as such, the prevalence of HF is expected to increase 25% by the year
2030, leading to an annual healthcare cost of $70 billion. A number of cardiovascular problems
have been identified that increase the risk for developing HF, including hypertension, coronary
disease, obesity and diabetes.1 HF incidence can be reduced through lifestyle interventions that
target these risk factors, with examples including maintenance of normal BMI, regular exercise,
modest alcohol consumption, avoidance of smoking and consuming a healthy diet.2, 3
More recently, important non-cardiovascular risk factors for HF have been identified,
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
including depression and HIV infection.4-7 With the advent of effective anti-retroviral therapies,
HIV has shifted from being a disease of recurring opportunistic infections to a chr
chronic
hron
hr
onic
on
ic ddisorder
isor
is
orde
or
der
de
complicated by multiple non-infectious comorbidities, not the least of which is cardiovascular
dise
disease.
eas
ase.
e.8 To improve
imp
pro
ove outcomes among the largee cohort
co
of people infected
infeccte
tedd with HIV, it is
important
mportant to identify
ideentiifyy potentially
pote
po
tent
te
ntia
nt
iaall
llyy modifiable
modi
mo
difi
di
f able
le cardiovascular
caardio
ovasccul
ular
ar and
n nnon-cardiovascular
nd
onn-car
car
arddiovas
di as
ascu
cula
cu
larr ri
la
rrisk
skk fac
factors
acto
ac
tors
to
rs
for
HF
and
life.
fo
or di
diseasess such
suchh as
as H
F that aaffect
ffec
ff
fe t qu
qquality
alitty an
al
nd qu
qquantity
an
ntity
y ooff li
ifee.
In this
thi
hiss issue
issu
is
suee of Circulation,
Circul
Ci
ulat
latio
tion, White
Whit
Wh
itee and
it
and colleagues
coll
co
llea
ll
eagu
ea
gues
es pr
pres
present
esen
es
entt in
en
intr
intriguing
trig
tr
igui
ig
uing
ing ddata
ataa th
at
that
at ssheds
heds
he
ds nnew
ew
ew
light on the potential interaction between depression and HIV as risk factors for developing HF.9
The authors evaluated 81,427 patients (33% of whom were HIV+) participating in the Veterans
Aging Cohort Study with follow-up to 5.8 years. Diagnoses of major depressive disorder
(MDD) and HF were identified through ICD-9 codes. As in prior studies, cardiovascular and
non-cardiovascular risk factors were independently associated with incident HF, including older
age, hypertension, diabetes, anemia, renal dysfunction, atrial fibrillation, current smoking, and
cocaine use. The rate of incident HF was higher in HIV+ participants than HIV- patients, but the
highest rate was observed in HIV+ participants with coexisting MDD. Importantly, this
2
difference persisted after adjusting for each of these confounding risk factors. The combination
of HIV and MDD was found to be associated with a 68% higher risk for developing HF as
compared to HIV- participants without MDD. Of particular interest, use of antidepressant
medications in participants with MDD was associated with a 24% lower risk of developing HF,
raising the possibility that depression may be a modifiable risk factor in people predisposed to
developing HF. The authors appropriately conclude that identification and management of MDD
is critical in HIV+ patients and that further study to elucidate the mechanisms linking HIV
infection with depression are needed.9
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
The authors are to be commended for this important contribution that vertically advances
our understanding of the risk factors for HF in people with HIV infection.9 The pr
pros
prospective,
ospe
os
pect
pe
ctiv
ct
ive,
iv
e,
detailed longitudinal assessment is a real strength, enabling adjustment for the potential
confounding
conf
fou
ound
ndin
nd
ingg variables
in
vari
riab
ri
ables that also contribute to thee greater
ab
greeater risk of HF in HIV+
HIV patients,
independent
ndeependent off MDD.
MDD
D. HIV
HIV and
and the
the antiretroviral
an
ntirrettro
oviral therapies
th
herap
apie
ap
iess us
ie
used
ed
d too trea
ttreat
rea
eat iitt are
re kknown
no
own tto
o in
increase
ncr
crea
easse
ea
the
which
most
common
he ri
risk
s for ccoronary
oronnary aartery
rttery ddisease,
issea
e see, wh
whic
ch iss the
th mo
ost co
ommo
ommo
monn cause
cauuse
use of HF
HF inn the United
Uniteed States.
Staatees.1,
10
0
While
Whil
Wh
ilee coronary
il
coro
co
rona
ro
nary
na
ry disease
dis
isea
ease
ea
se was
as not
not adjusted
adj
djus
uste
ste
tedd for
for in m
multivariable
ullti
ulti
tiva
vari
ari
riab
able
ab
le aanalysis,
naly
na
lysi
siss, tthe
si
he rrisk
iskk fa
is
fact
factors
ctor
ct
orss
or
associated with it including hypertension, diabetes, lipids, smoking status and cocaine use were
included in the model. This is important, because HIV+ patients were more likely to display
dyslipidemia, renal disease, anemia and cocaine abuse as compared to HIV- patients.9 Similarly,
participants with MDD displayed greater HF risk factors independent of HIV status, including
more diabetes, hypertriglyceridemia, smoking and cocaine abuse.
The mechanisms by which MDD and HIV interact to increase HF risk remain unclear.9
The authors point out that both disorders are associated with inflammation and vascular
dysfunction, which may contribute to the association. Both MDD and HIV also increase the risk
3
of coronary heart disease.4-6 The rate of incident myocardial infarction during the follow up
period was not reported, but it is known that patients with HF often develop worsening LV
dysfunction even in the absence of a clinically-overt infarct.11 It is also possible that physical
inactivity might be the critical mediator coupling MDD together with adverse cardiovascular
outcomes.5
The observation of decreased HF incidence among participants treated with
antidepressants, while hypothesis-generating, is very exciting, because it points to a potentially
novel role for MDD intervention above and beyond the indication for the mood disorder per se.9
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
The authors appropriately point out that a beneficial effect of antidepressant therapy cannot be
proven from these data, because this was not a randomized trial. However, there is already
alr
lrea
eady
ea
dy
sound
ound rationale to treat MDD in people at risk for heart disease, such as those with HIV,6 and
give
en the
the very
very
r large
laarg
arge sample size that would be required
reequ
quir
i ed to show a reduct
ctio
ct
i n in newly incident HF
given
reduction
ccases,
asees, it would
woulld seem
seem
em
m unlikely
unl
nlik
ikeely
ik
ely that
that any
any such
suuch
h trial
triial would
would
d be
be performed
perf
pe
r or
rf
orme
medd specifically
me
speecific
sp
iccal
ally
ly for
for th
thi
this
is ppurpose.
urpo
ur
pose
po
The weaknesses
w ak
we
knesses
es of the
th
he study
s uddy relate
st
reelaate
t to
to the
the observational
obbserrva
vatioonal
onal nature
natturre of
of thee data,
dat
a a, along
alo
ong
g with
with th
the
he
fact
fa
ct tthat
hatt th
ha
this
is vet
veteran
eter
et
eran
er
an ccohort
ohor
oh
ortt was
or
waas by
by aand
nd llarge
arge
ar
ge ma
male
male,
le, an
le
andd th
thee re
resu
results
sult
ltss ma
lt
may no
nott ap
appl
apply
ply in tthe
pl
he ssame
amee
am
way to women.9 Ascertainment of MDD and HF was based upon ICD-9 code, and it is likely
that both disorders were present but undiagnosed in a sizeable number of patients, though this
would not appear to jeopardize the findings, since the presence of occult MDD in the apparently
MDD-free population would only bias the results toward the null. Echocardiographic data was
not presented, and it would have been interesting to see how many of the participants developed
HF with preserved ejection fraction as opposed to HF with reduced ejection fraction. People
with HF and preserved ejection fraction often present with exertional dyspnea in the absence of
overt volume overload or increases in natriuretic peptide levels, and it may be that participants
4
suffering from this form of HF were relatively under-detected given the difficulties in making
this diagnosis.12
People with several chronic illnesses like HIV and MDD are likely to seek medical
attention more often, which could lead to greater recognition of other problems like HF.
Alternatively, recognition of MDD might be a proxy for better care and thus greater recognition
of HF. While the multivariable adjustment performed in the analysis of White and colleagues
increases confidence in the true independence of MDD as a risk factor in HIV+ patients,9 one
cannot discount the possibility of greater detection as a function of greater health care utilization
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
or quality of care in this cohort.
inteere
rest
stin
st
ingg to
in
These data raise additional questions for future research. It would be interesting
examine ventricular structure and function as it relates to HIV and MDD status to determine
whet
etthe
herr there
ther
th
eree is subtle
er
sub
u tle myocardial remodeling or ddysfunction
ysfunction that prece
ceede
d s the development of
whether
precedes
oveert
er HF. The
h same
sam
a e question
ques
qu
esti
es
tion
ti
on could
cou
uld
d be
be asked
aske
k d in
ke
i a complementary
co
omp
ple
lem
menntar
aryy way
way by
by looking
loooki
king
g for
for
o evidence
evide
denc
de
ncee of
nc
o
overt
ow grade
gr
myocaardial damage,
my
damag
ge, for
for example
exaamp
mplee with
wit
i h highly-sensitive
higghly
ly--sen
ly
nsiitiivee troponin
tro
opo
p nin assays.
ass
ssay
a s. If the
ay
ere we
eree
low
myocardial
there
were
earl
ea
rly-st
rl
stag
st
agee bi
ag
biom
omar
om
arke
ar
kerr or eechocardiographic
ke
choc
ch
ocar
oc
ardi
ar
diog
di
ogra
og
raph
ra
phic
ph
ic cchanges,
hang
ha
nges
ng
es, on
es
onee co
coul
uld
ld cconsider
onsi
on
side
si
derr pu
de
ppursuing
urs
rsui
rs
uing
ing ph
phas
asee II ttrials
as
rial
ri
alss
al
early-stage
biomarker
could
phase
where these intermediate endpoints that precede HF development could be targeted. How much
of the excess HF risk conferred by MDD is mediated by coronary disease or vascular
dysfunction? Future studies evaluating endothelium-dependent vasodilation before and after
treatment might be informative in this regard.13 Lower hemoglobin was an independent risk
factor for HF in this study.9 While part of this might have been dilutional (perhaps excess
plasma volume even prior to clinically recognized HF), it is also possible that other contributors
such as occult iron deficiency might have been present, which can impair ventricular function.14
5
As cardiologists, we are inherently ‘cardio-centric’ in our perception of what causes
HF—focussing on modifiable risk factors such as blood pressure and atherosclerosis. However,
as White and colleagues have shown us, non-cardiovascular risk factors such as depression also
substantially increase the risk of HF, especially in people infected with HIV, and that treatment
of MDD may mitigate this risk.9 Now the burden falls on us to do a better job of identifying
people with MDD as well as other risk factors in order to help reduce the risk of HF and improve
quality of life.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Conflict of Interest Disclosures: None.
References:
1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS
CS,
Fran
nco S,
S, Fullerton
Full
Fu
l erto
tonn HJ, Gillespie C, Hailpern SM
to
M, Heit
H it JA, Howard VJ,
He
VJJ, Huffman
H ffman MD, Judd SE,
Hu
Franco
SM,
Kiss
Ki
sseela BM,
ss
BM
M, Kittner
Kittner SJ, Lackland DT, Lichtman JH
JH, Lisabeth LD,
D, Mackey RH, Magid DJ,
Kissela
Marcus
M
arrcus GM, M
Marelli
arellii A
A,, Ma
Matc
Matchar
cha
harr DB
DB, M
McGuire
cGu
Guirre DK
DK,
K, Mo
Mohl
Mohler
hler
hl
er E
ER,
R 33rd,
R,
rd,
rd
d Mo
M
Moy
oy CS
CS, Mu
Muss
Mussolino
ssol
ss
ollin
inoo ME
ME,,
Neumar
N
Ne
umar RW, Nichol
Nic
icchol G,
G, Pandey
Pan
nde
dey DK, Paynter
Payynteer NP,
NP, Reeves
Reevees MJ,
MJ Sorlie
Soorllie PD,
PD
D, Stein
Ste
teein
n J, Towfighi
Tow
wfig
ghi A,,
Turan
Tu
uraan TN, Vi
Viran
Virani
ni S
SS,
S, W
Wong
ongg ND
ND, Wo
W
Woo
oD
D,, T
Turner
urne
ur
n rM
MB.
B.. H
Heart
ear
arrt di
disease
iseease
ase and
an
nd stroke
stro
rooke sta
statistics--2014
atiistics---20114
update:
american
heart
Circulation.
upda
date
te:: A report
te
r port
re
rt from
from
ro
om the
th
he amer
erric
icaan
an hea
art aassociation.
sssocia
ocia
iattion
tion. Ci
Circ
rcul
rc
ulat
ul
ation.
at
n 22014;129:e28-e292.
0144;12
01
4;12
129:e2
e288-e2
e2
8-e2
e2922.
2. Djousse L, Driver JA, Gaziano JM. Relation between modifiable lifestyle factors and lifetime
risk of heart failure. JAMA. 2009;302:394-400.
3. Del Gobbo LC, Kalantarian S, Imamura F, Lemaitre R, Siscovick DS, Psaty BM, Mozaffarian
D. Contribution of major lifestyle risk factors for incident heart failure in older adults: The
cardiovascular health study. JACC Heart Failure. 2015;3:520-528.
4. Abramson J, Berger A, Krumholz HM, Vaccarino V. Depression and risk of heart failure
among older persons with isolated systolic hypertension. Arch Intern Med. 2001;161:1725-1730.
5. Whooley MA, de Jonge P, Vittinghoff E, Otte C, Moos R, Carney RM, Ali S, Dowray S, Na B,
Feldman MD, Schiller NB, Browner WS. Depressive symptoms, health behaviors, and risk of
cardiovascular events in patients with coronary heart disease. JAMA. 2008;300:2379-2388.
6. Whooley MA. Depression and cardiovascular disease: Healing the broken-hearted. JAMA.
2006;295:2874-2881.
6
7. Butt AA, Chang CC, Kuller L, Goetz MB, Leaf D, Rimland D, Gibert CL, Oursler KK,
Rodriguez-Barradas MC, Lim J, Kazis LE, Gottlieb S, Justice AC, Freiberg MS. Risk of heart
failure with human immunodeficiency virus in the absence of prior diagnosis of coronary heart
disease. Arch Intern Med. 2011;171:737-743.
8. Deeks SG, Lewin SR, Havlir DV. The end of aids: Hiv infection as a chronic disease. Lancet.
2013;382:1525-1533.
9. White JR, Chang CC, So-Armah KA, Stewart JC, Gupta SK, Butt AA, Gibert CL, Rimland D,
Rodriguez-Barradas MC, Leaf D, Bedimo RJ, Gottdiener JS, Kop WJ, Gottlieb SS, Budoff MJ,
Khambaty T, Tindle H, Justice AC, Freiberg MS. Depression and hiv infection are risk factors
for incident heart failure among veterans: Veterans aging cohort study. Circulation.
2015;132:XX-XXX.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
10. Boccara F, Lang S, Meuleman C, Ederhy S, Mary-Krause M, Costagliola D, Capeau J,
Cohen A. Hiv and coronary heart disease: Time for a better understanding. J Am Coll Cardiol.
2013;61:511-523.
disease
heart
11. Hwang SJ, Melenovsky V, Borlaug BA. Implications of coronary artery disea
ase iin
n he
hear
artt
ar
failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63:2817-2827.
12. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics
enhance
diagnosis
preserved
fraction.
enha
anc
ncee di
diag
agno
ag
n si
siss of early heart failure
u with pres
eseervved ejection fraction
es
n. Circ Heart Fail.
2010;3:588-595.
20
010
10;3:588
8-5
-595.
13.. Wang D, Me
Melancon
Verbesey
C,, As
Aslam
Young
M,, Wi
113
elaancoon JK, V
erbesey JJ,, Hu H,
H, Liu
uC
Asla
lam
la
m S, Y
oung M
Wilcox CS.
S
Microvascular
endothelial
dysfunction
thromboxane
endothelial
Micr
Mi
rov
o ascu
ula
lar en
ndoth
hel
elial dy
ysffun
u cti
tion
on
n aand
n eenhanced
nd
nh ceed th
nhance
thr
rom
mbox
oxan
ox
an
ne an
and en
ndooth
heliall ccontractility
onttraactiliityy
inn pat
patients
Clin
Res.
atie
at
ient
ie
ntss with
nt
with
h hiv.
hiv
iv. J AIDS
AIID C
linn R
li
es. 22013;4:267.
0133;4:
01
3;4:
4:2267.
267
14. Maeder MT, Khammy O, dos Remedios C, Kaye DM. Myocardial and systemic iron
depletion in heart failure implications for anemia accompanying heart failure. J Am Coll Cardiol.
2011;58:474-480.
7
Moving Beyond Cardio-Centricity in Heart Failure Risk Stratification
Barry A. Borlaug
Circulation. published online September 10, 2015;
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2015 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/early/2015/09/10/CIRCULATIONAHA.115.018951
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/