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Review
Mechanisms of Arrhythmia and Sudden Cardiac
Death in Patients With HIV Infection
Judith Brouillette, MD, PhD,
a,b
Samuel Cyr, BSc,
a,c
and Celine Fiset, PhD
a,c
a
Research Center, Montreal Heart Institute, Montreal, Quebec, Canada
b
Department of Psychiatry and Addiction, Universite de Montreal, Montreal, Quebec, Canada
c
Faculty of Pharmacy, Universite de Montreal, Montreal, Quebec, Canada
ABSTRACT
Long-term survival of HIV-infected patients has significantly improved
with the use of antiretroviral therapy (ART). As a consequence, car-
diovascular diseases are now emerging as an important clinical
problem in this population. Sudden cardiac death is the third leading
cause of mortality in HIV patients. Twenty percent of patients with HIV
who died of sudden cardiac death had previous cardiac arrhythmias
including ventricular tachycardia, atrial fibrillation, and other unspeci-
fied rhythm disorders. This review presents a summary of HIV-related
arrhythmias, associated risk factors specific to the HIV population,
and underlying mechanisms. Compared with the general population,
patients with HIV have several cardiac conditions and electrophysio-
logical abnormalities. As a result, they have an increased risk of
developing severe arrhythmias, that can lead to sudden cardiac death.
Possible explanations may be related to non-ART polypharmacy,
electrolyte imbalances, and use of substances observed in HIV-infected
R
ESUM
E
La survie à long terme des patients infect
es par le VIH s’est con-
sid
erablement am
elior
ee grâce à la th
erapie antir
etrovirale (TAR). En
cons
equence, les maladies cardiovasculaires sont en voie de devenir un
problème clinique important dans cette population. La mort subite d’or-
igine cardiaque se classe au troisième rang des causes de mortalit
e chez
les patients vivant avec le VIH. Vingt pour cent des patients vivant avec le
VIH qui sont d
ec
ed
es de mort subite d’origine cardiaque pr
esentaient
d
ejà des arythmies cardiaques comme la tachycardie ventriculaire, la
fibrillation auriculaire et d’autres troubles du rythme non pr
ecis
es. Cet
article de synthèse pr
esente un r
esum
e des arythmies li
ees au VIH, des
facteurs de risque associ
es propres à la population vivant avec le VIH et
des m
ecanismes sous-jacents. Par rapport à la population g
en
erale, les
patients infect
es par le VIH ont davantage de conditions cardiaques et
d’anomalies
electrophysiologiques. Par cons
equent, ils pr
esentent un
risque accrude d
evelopper desarythmies s
evères qui peuvent mener à la
With the introduction of more effective treatments for persons
infected with HIV, a larger number of patients survive much
longer and develop new complications.
1-3
As a consequence,
HIV-related heart disease, whichdin the earlier yearsdwas
not a major complication of HIV infection, is now emerging
as an important clinical problem.
4-6
Although we do recognize
that the spectrum of cardiovascular diseases in patients with
HIV is broad and includes coronary heart diseases and heart
failure, this review will focus on sudden cardiac death and
cardiac arrhythmias. Mechanistic insight will also be described
and most likely involve complex interactions between risk
factors, drug treatment, and effects related to immunologic
consequences of HIV infection and associated inflammation
(Figure 1).
Causes of death in patients with HIV-1 treated with an-
tiretroviral therapy (ART) between 1996 and 2006 in Europe
and North America was retrospectively studied in 13 different
cohorts.
7
A specific cause of death was found in 85% of the
1,597 patients studied who died during this period. Of the
patients in whom the cause of death could be determined, half
were due to AIDS and AIDS-related malignancies. Among the
noneAIDS-related causes, cardiovascular disease ranks third
(7.9%) behind noneAIDS-related malignancies (11.8%) and
noneAIDS-related infection (8.2%). Of the 126 deaths from
cardiovascular disease, 51 (40%) were coronary heart disease,
23 (18%) were stroke, and 52 (41%) were classified as other
heart diseases. It is important to note that cause of death was
unknown in 15% of cases and could mask sudden cardiac
death.
Cardiac Rhythm Disturbances
Sudden cardiac death
From 2000 to 2009, Tseng et al conducted a retrospective
study of 2860 outpatients with HIV, treated or not with
Canadian Journal of Cardiology 35 (2019) 310e319
Received for publication October 1, 2018. Accepted December 9, 2018.
Corresponding author: Dr Celine Fiset, Montreal Heart Institute, 5000
Belanger, Montreal, Quebec H1T 1C8, Canada. Tel.: þ1-514-376-3330
ext. 3025.
E-mail: celine.fiset@umontreal.ca
See page 316 for disclosure information.
https://doi.org/10.1016/j.cjca.2018.12.015
0828-282X/Ó2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
ART, to examine all causes of death in this population.
8
They
reported that sudden cardiac death was the third leading cause
of death (13%) after AIDS (57%) and overdoses/suicides/
unknown causes (19%). Remarkably, sudden cardiac death
accounted for 86% of all cardiac deaths and was 4.5 times
higher than in the general population. HIV-positive patients
who died from sudden cardiac death had more previous
hypertension, heart failure/cardiomyopathies, myocardial
infarction and arrhythmias (including atrial fibrillation,
ventricular tachycardia, and other unspecified rhythm disor-
ders) than persons with HIV who died of AIDS and natural
causes.
8
In the general population, prevalence of sudden cardiac
death increases with age and is more common in men than
women. This parallels the risk factor for coronary heart dis-
ease, which is thought to be the most common cause un-
derlying sudden cardiac death, followed by other structural
heart disease such as heart failure and cardiomyopathy. In
young adults (<40 years), 10% of sudden cardiac death is
thought to occur in the absence of structural heart disease and
is associated with conduction system abnormalities.
9
Non-structural heart diseases associated with sudden cardiac
death may include Brugada syndrome, Wolff-Parkinson-
White syndrome, idiopathic ventricular fibrillation, as well
as congenital or drug-induced long QT syndrome.
10-12
Both
forms (congenital and acquired) of long QT syndrome are
associated with the development of torsades de pointes, a well-
recognized cause of sudden cardiac death.
13,14
QTc prolongation and torsades de pointes
Acquired long QT syndrome. Torsades de pointes is a life-
threatening polymorphic ventricular tachycardia associated
with delayed ventricular repolarization reflected on the elec-
trocardiogram (ECG) as a prolonged QTc interval.
14
In the
last decade, several groups have reported higher prevalence of
prolonged QTc interval in patients with HIV.
15-18
Several
studies showed that hospitalized patients with HIV had
prolonged QTc intervals: 1.6 to 4 times more than unin-
fected hospitalized controls.
5,19,20
Table 1 summarizes results
of 8 prevalence studies conducted between 1997 and 2017.
The reported prevalence of prolonged QTc in HIV pop-
ulations varied between 7.4% and 37.6%, with a weighted
average (by number of patients) of 18.9%. Four of these
studies included HIV-negative controls. The prevalence of
prolonged QTc in these control populations varied between
7.0% and 16.6%, with a weighted average (by number of
patients) of 7.2%.
Compared with the congenital long QT syndrome, the
acquired form is a more common cause of QTc prolongation.
It refers to the impact of some conditions (hypokalemia or
drugs, for example) on ventricular repolarization, mainly via
the blockade of the rapidly activating delayed rectifier potas-
sium current (I
Kr
), encoded by the human ether-a-go-goe
related gene (hERG).
21,22
A review of monographs and
postmarketing studies was conducted to determine whether
ART drugs currently prescribed in Canada for HIV-infected
patients could prolong the QTc interval. The most
preferred initial ART regimen in Canadian HIV-positive pa-
tients comprise a combination of nucleotide reverse tran-
scriptase inhibitors (NtRTI: eg, tenofovir), nucleoside reverse
transcriptase inhibitors (NRTI: eg, emtricitabine, lamivudine,
abacavir), non-nucleoside reverse transcriptase inhibitors
(NNRTI: eg, efavirenz) and protease inhibitors (eg, ritonavir,
atazanavir).
23
The majority of these drugs do not present
clinically significant risks of QTc interval prolongation based
on a threshold of 500 ms
24
(or even a lower threshold of 440
ms for some studies or a change of more than 10 ms).
25-31
There is 1 case report of QT prolongation with efavirenz
32
as well as QT prolongation with this same drug in
CYP2B6*6*6 allele carriers.
33
On the other hand, a case-
control study showed no association between QTc prolon-
gation and this drug.
25
Protease inhibitors (atazanavir,
lopinavir and saquinavir)
34-36
have also been pointed out as
QTc interval-prolonging drugs (CredibleMeds.org), and
in vitro studies showed that HIV protease inhibitors block
hERG channels.
37
However, this does not seem to translate
into a clinical risk for users of protease inhibitors. Indeed,
Soliman et al showed a similar and minimal effect on the QTc
interval of different protease inhibitor-based regimens
(including atazanavir, lopinavir, and saquinavir) compared
with NNRTI regimens.
38
In fact, the QTc interval was 1.5 ms
lower in patients taking protease inhibitors than in the
NNRTI group.
38
The unadjusted mean QTc intervals for
users of atazanavir/ritonavir, lopinavir/ritonavir, and saquina-
vir/ritonavir were 414 ms, 413 ms, and 422 ms, respectively.
patients; many of these conditions are associated with alterations in
cardiac electrical activity, increasing the risk of arrhythmia and sudden
cardiac death. However, clinical and experimental evidence has also
revealed that cardiac arrhythmias occur in HIV-infected patients, even
in the absence of drugs. This indicates that HIV itself can change the
electrophysiological properties of the heart profoundly and cause car-
diac arrhythmias and related sudden cardiac death. The current
knowledge of the underlying mechanisms, as well as the emerging
role of inflammation in these arrhythmias, are discussed here.
mort subite d’origine cardiaque. Ce ph
enomène pourrait s’expliquer
par la polypharmacie s’ajoutant à la TAR, les d
es
equilibres
electrolytiques et l’utilisation de substances que l’on observe chez les
patients infect
es par le VIH; bon nombre de ces facteurs sont associ
es
à une alt
eration de l’activit
e
electrique cardiaque, augmentant ainsi le
risque d’arythmie et de mort subite d’origine cardiaque. Toutefois, les
donn
ees probantes tant cliniques qu’exp
erimentales ont
egalement
r
ev
el
e que même en l’absence de m
edicaments, des arythmies sont
pr
esentes chez les patients infect
es par le VIH. Autrement dit, le VIH
lui-même est capable de causer de profondes modifications des
propri
et
es
electrophysiologiques du cœur et d’entraîner des arythmies
cardiaques et la mort subite d’origine cardiaque. Les connaissances
actuelles au sujet des m
ecanismes sous-jacents et le rôle
emergent de
l’inflammation dans ces arythmies sont analys
es dans le pr
esent
article.
Brouillette et al. 311
HIV and Arrhythmias
Of note, the QTc interval difference between saquinavir/
ritonavir users and non-protease inhibitor users has dis-
appeared after adjusting for race. Indeed, more Asians have
been treated with saquinavir, and the Asian population is
associated with prolonged QTc intervals.
38
None of the 815
patients treated with either atazanavir/ritonavir, lopinavir/
ritonavir or saquinavir/ritonavir had QTc intervals greater
than 500 ms. Overall, the data presented here suggest that
ART regimen in Canadian patients with HIV do not appear
to have a clinical impact on the QTc interval.
Polypharmacy. Non-ART medications commonly prescribed
to HIV-infected patientsdsuch as macrolides, pentamidine,
antifungals, fluoroquinolones, or methadonedmay cause
greater QTc prolongation concerns than ART. Cases of QTc
prolongation and torsades de pointes in patients with HIV
receiving high doses of methadone have been reported.
39,40
We recognize that methadone maintenance therapy is rec-
ommended as a safe and effective treatment to reduce illicit
consumption of opioids and has undoubtedly great benefits in
reducing overall morbidity. However, it would be advisable to
Access to ART &
overall health care
↑ survival
Coronary
artery diseases
Sudden Cardiac Death
Poly-
pharmacy
↑QTc /
Torsades de pointes
Inflammatory
state
↑ Duraon of
HIV infecon
Ion channel
remodeling
Diseases
associated with ageing
Other
infecons
Electrolyte
deficiencies
Hepac dysfuncon
Renal insufficiency
↑ Viral load
↓ CD4 count
Heart
failure
Atrial
fibrillaon
Substances use
(ex. cigaree, alcohol, cocaine)
↓ HR
variability
Ventricular
arrhythmias
Structural
abnormalies
Figure 1. Representation of the complex links between non-exhaustive risk factors, underlying physiopathological mechanisms (red boxes), cardiac
arrhythmias and sudden cardiac death in HIV population. ART, antiretroviral therapy; HR, heart rate.
Table 1. Summary of prolonged QTc prevalence studies in HIV-infected populations
Reference
Prevalence of QTc prolongation QTc prolongation threshold
HIVþn HIVen Men Women
Kocheril et al
19
28.6% 42 7.0% 34,181 >440 ms
Sani and Okeahialam
5
37.6% 178 10.0% 80 >440 ms
Nordin et al
106
20.5% 816 16.6% 832 >470 ms
Njoku et al
20
17.4% 166 10.5% 38 >440 ms >460 ms
Reinsch et al
17
19.8% 776 >440 ms >460 ms
Qaqa et al
18
17.0% 135 >440 ms >460 ms
Moreno et al
15
12.4% 194 >440 ms >450 ms
Gili et al
16
7.4% 351 >450 ms >470 ms
Bazett’s formula was used in all studies for heart rate QT correction.
n, total number of patients included in the study; QTc, corrected QT.
312 Canadian Journal of Cardiology
Volume 35 2019
limit the number of drugs with known effects on the QTc
interval in HIV-infected patients (for example, choose another
equivalent antibiotic if available). Moreover, as patients with
HIV are often treated with polypharmacy,
41
they have a
higher risk of pharmacodynamics and pharmacokinetics
interactions.
42-44
Finally, comorbidities such as renal and
hepatic insufficiency may be associated with increased plasma
concentration of liable drugs.
45-49
Electrolyte imbalances. Electrolyte disturbance is another
factor that can contribute to the increased risk of QTc pro-
longation in HIV-infected patients. In fact, more than half of
the patients infected with HIV complain of gastrointestinal
symptoms, especially diarrhea.
50
Acute diarrhea is estimated
to be 4 times more prevalent in patients with HIV infection
than in seronegative controls, even after adjusting for multiple
factors (age, sex, and race).
51
This may be due to the virus
itself, opportunistic infections in response to the weak im-
mune system of these patients, ART, or other drug treatments
used in HIV-infected patients.
52
As a consequence, electrolyte
deficienciesdsuch as hypokalemia, hypocalcaemia, and
hypomagnesaemiadare often reported in this population.
Electrolyte imbalances due to diarrhea, vomiting, use of
diuretics, hospitalizations, or nutritional deficiencies also re-
ported in HIV patients become particularly problematic when
they cause hypokalemia, a known risk factor for QTc pro-
longation. Because external potassium ions interact with the
pore and influence the rapid inactivation of the channel,
53
low
extracellular potassium concentration reduces the outward
current generated by hERG channel, even if an increased
gradient could theoretically do the opposite.
54
This is of
clinical significance because hypokalemia caused by diarrhea
or other mechanisms increases the QTc interval and may
exacerbate the effects of hERG-blocking drugs. Therefore,
electrolyte imbalancesdspecifically, hypokalemiadrepresent
an important risk factor for torsades de pointes and sudden
cardiac death in patients with HIV.
Primary association with HIV infection. Although poly-
pharmacy or electrolyte imbalances, such as hypokalemia, are
likely contributors of QTc prolongation in HIV-infected pa-
tients, clinical and experimental evidence also indicate a pri-
mary association with HIV infection itself.
5,16,20,55,56
Indeed,
QTc prolongation and torsades de pointes have been
described in HIV-infected patients, even in the absence of
drugs. Sani and Okeahialam studied 255 hospitalized patients
who were not taking medications known to cause QTc pro-
longation.
5
Among seropositive but asymptomatic patients,
the prevalence of QTc prolongation (greater than 440 ms) was
22 of 78 (28%) and, as they developed AIDS, it reached 45 of
100 (45%). In contrast, prolonged QTc interval was present
only in 8 of 80 (10%) of HIV-negative persons. Their study
shows that HIV patients had a prolonged QTc interval that
was not due to drug treatment, demonstrating that HIV
infection itself is associated with prolongation of the QTc
interval. In a recent study, Njoku et al showed that the
prevalence of QTc prolongation, defined as QTc interval
greater than 440 ms in men and 460 ms in women, was
18.2% in HIV-infected patients on ART, 16.4% in HIV-
positive ART-naive patients, both greater than the 10.5%
reported in controls (P<0.01).
20
These findings support the
view that the effects of ART on QTc interval are negligible, as
mentioned above. In a retrospective study, Gili et al found
that 26 of 351 (7.4%) HIV patients had prolonged QTc
interval (defined as >450 ms in men and >470 ms in
women) regardless of ART.
16
A more advanced state of the
HIV infection, defined by a nadir of the CD4
þ
cell count
below 200 cells/mm
3
, was the only independent predictor of
QTc prolongation in this population (odds ratio [OR] 5.8,
95% confidence interval [CI], 1.3-26.4). Overall, these
studies strongly suggest that an underlying feature of HIV
affects the electrical properties of the heart.
Atrial fibrillation
Atrial fibrillation (AF) is the most common sustained
cardiac arrhythmia in clinical practice and is associated with an
increased risk of stroke, heart failure, and overall mortality.
The prevalence of AF is approximately 1% to 2% in the
general population and increases to nearly 10% in the
elderly.
57
Perhaps because of the younger age of those infected
with HIV, AF seems to be relatively rare in HIV-positive
patients. Accordingly, AF remains largely unexplored in
HIV-infected patients with only 2 studies, to our knowledge,
that have examined potential association between HIV and
development of AF.
58,59
Using a large cohort of American
HIV-infected veterans, Hsu et al was the first group to report
a significant association between markers of HIV severity and
AF.
58
Of the 30,533 HIV-infected patients who participated
in the study, 780 (2.6%) developed AF over a median dura-
tion of HIV infection of 6.8 years. A low number of CD4þT
cells (<200 cells/mm
3
) and a high HIV viral load
(>100,000 copies/mL) were both independently associated
with the development of AF, even after adjusting for tradi-
tional AF risk factors. As the HIV registry used by Hsu et al
included HIV-infected patients only, this study did not have a
comparison group. Recently, Sanders et al compared occur-
rence of AF and atrial flutter (AFL) between HIV positive and
uninfected matched patients.
59
Patients with HIV were
frequency-matched 1:2 on age, sex, race, ZIP code, and clinic
location with uninfected persons. They reported that AF/AFL
were more common in HIV-infected people, with 101
confirmed AF/AFL cases (2.0%) among 5,052 HIV-positive
patients and 159 confirmed AF/AFL cases (1.6%) among
10,121 uninfected controls. However, this difference was
attenuated by adjustment for AF risk factors.
59
Similar to the
findings reported by Hsu et al, a lower CD4þcell count
(<200 cells/mm
3
) was associated with approximately a 2-fold
increased risk for AF/AFL, even after adjustment for de-
mographics and cardiovascular risk factors. On the other
hand, in this cohort there was no association between high
HIV viral load and AF/AFL susceptibility.
Adaptive immune system changes and persistent inflam-
mation have been proposed to be associated with increased
risk of AF in HIV-infected individuals. Low CD4þcells
count and high HIV viral load have both been associated with
chronic inflammation with high levels of proinflammatory
cytokines.
60,61
Previous reports have shown that similar in-
flammatory markers are also elevated in AF.
62,63
Of note, in
their study, Sanders et al reported that each additional year on
ART was associated with a reduction of the AF risk.
Brouillette et al. 313
HIV and Arrhythmias
Moreover, many of the inflammatory markers decrease with
ART, suggesting that the increased susceptibility to AF among
HIV-infected patients could be through an inflammatory
mechanism. Future studies will be required to elucidate the
underlying mechanisms by which HIV increases risk of AF.
However, based on findings in the ventricle showing profound
changes in ionic currents induced by HIV and proin-
flammatory cytokines,
55,56,64,65
it is tempting to speculate
that similar electrophysiological remodelling could also occur
in the atrium, which may contribute to the higher incidence
of AF in HIV.
With the benefits of ART, the life expectancy of people
living with HIV will continue to improve, and the incidence
of AF will likely increase, as older age favours AF.
66
In
addition to the risk associated with AF, a higher prevalence of
cerebrovascular events has been reported in HIV-infected
patients.
67
Given that ischemic stroke is one of the main
complications of AF, this represents an additional concern for
this population.
Autonomic Dysfunction (Reduced Heart Rate
Variability)
Compared with the general population, HIV-infected pa-
tients have a higher prevalence of autonomic dysfunction, as
measured by heart rate variability (HRV).
68-71
Indeed, pa-
tients with HIV have decreased HRV, with a shift of cardiac
sympathovagal balance that may contribute to predisposition
to lethal cardiac arrhythmias. Furthermore, as QTc prolon-
gation is associated with parasympathetic and sympathetic
dysfunction,
72
it is not surprising to see that autonomic
dysfunction in HIV-infected patients is often associated with
prolonged QTc interval that can also lead to severe ventricular
arrhythmias.
25
Although sympathovagal balance changes have
been correlated with the severity of HIV disease progression,
73
they are already present in the early stages.
69
The mechanisms underlying autonomic dysregulation in
HIV-infected patients are still poorly understood. Recent
studies reported greater levels of inflammation in HIV pa-
tients with lower HRV.
71,74
Other studies suggest that
neurological complications of HIV may also be implicated.
71
Indeed, it has been suggested that at least the regulatory
protein transactivator of transcription (Tat) could be associ-
ated with changes in cardiac autonomic control as it has been
shown to impair cardiac vagal neurons.
75,76
However, ART
does not seem to be involved.
77
Further studies are still
needed to determine if other mechanisms are implicated.
Mechanisms Underlying HIV-Related Rhythm
Disturbances
Cardiac electrical remodelling
The HIV genome consists of at least 9 genes. Among
them, nef has been shown to be a major determinant for the
pathogenicity of HIV. In support of this notion, it has been
reported that a cohort of patients infected with a strain of
HIV-1 harbouring a nef deletion remained asymptomatic for
several years without ART.
78
Similarly, strains of simian
immunodeficiency virus (SIV) lacking the nef gene have also
been shown to be less pathogenic in macaques.
79
Small-
animal models of HIV infection have been developed to
help study HIV-related pathologies. One model of interest is
the CD4C/HIV transgenic mouse. The gene nef of the HIV-1
genome is expressed in CD4C/HIV transgenic mice under the
control of regulatory sequences (CD4C) comprising the mu-
rine CD4 gene enhancer and the promoter elements of the
human CD4 gene.
80,81
CD4C/HIV transgenic mice develop
a severe AIDS-like disease. Their symptoms are similar to
those observed in human patients with HIV/AIDS. Using the
CD4C/HIV transgenic mouse model, our group has made
significant progress in understanding the mechanisms under-
lying cardiac arrhythmias associated with HIV. We first
showed rhythm disturbances associated with severe ventricular
electrophysiological remodelling that occurred in the absence
of any pharmacological intervention.
55,56,64,65
Notably, the
QTc interval and the ventricular action potential duration
(APD) were significantly prolonged in CD4C/HIV transgenic
mice compared with littermate controls. The 2-fold increase
in APD was attributable to a 50% reduction in the major
repolarizing outward potassium currents present in mouse
ventricular myocytes: the transient outward K
þ
current (I
to
),
the ultrarapid delayed rectifier K
þ
current (I
Kur
) and the
steady-state K
þ
current (I
ss
).
55
In addition, the depolarizing
sodium currents (I
Na
) were also reduced by 30% in these
mice.
64
Thus, the net effect was an alteration in conduction
velocity and repolarization, 2 risk factors for arrhythmias. It is
interesting that all these effects involved no changes in cardiac
function or morphology as assayed by echocardiography.
55
Although we recognize that direct extrapolation of animal
data to humans is difficult and that mice and humans share
some components of ventricular repolarization K
þ
currents
but not all,
82
this study clearly shows that HIV had a similar
physiological effect on the duration of the QTc interval in
both species. These data provided the first experimental evi-
dence that HIV itself might be directly implicated in inducing
cardiac electrical remodelling in HIV.
Subsequently, using pharmacological tools, other groups
examined the impact of another HIV-1 encoded protein, Tat,
on HIV-related QTc prolongation.
83,84
Tat is important for
HIV transcription and pathogenicity.
85
Bai et al first reported
that a 24-hour incubation with 200 ng/mL of Tat protein
significantly reduced hERG current in HEK293 cells through
increasing ROS generation.
83
In addition, they also reported
that in vivo treatment with Tat protein reduced I
Kr
currents
and prolonged the APD of guinea pig ventricular myocytes.
Recently, Tat transfection in COS-7 cells has been reported to
decrease hERG current by 50% and the KCNE1-KCNQ1
current (the slowly activating delayed rectifier K
þ
current, I
Ks
)
by 69% through reduction in availability of phosphatidyli-
nositol-(4,5)-bisphosphate (PIP2).
84
Concurrently, the au-
thors reported that a 24-hour incubation of hiPSC-CM with
Tat protein (200 ng/mL) reduced I
Kr
by 31% and led to a
prolongation of ventricular-like APD at 70% and 90% of
repolarization. Given the importance of nef and tat in the
pathogenicity of HIV, these cellular effects may contribute to
the higher prevalence of QTc prolongation and increased
sudden cardiac death risk in patients with HIV.
314 Canadian Journal of Cardiology
Volume 35 2019
Implication of Cytokines in Electrical
Remodelling
As it is well known that cytokines mediate HIV-related
pathologies, we examined serum levels of proinflammatory
cytokines in CD4C/HIV mice and found a significant in-
crease in the concentrations of tumor necrosis factor
a
(TNF
a
) and interleukin-1
b
(IL1
b
), both at the top of the
inflammatory cascade.
86
To distinguish the specific roles of
each cytokines, we examined the effects of TNF
a
and IL1
b
on ventricular ionic currents.
56,65
Results demonstrated that
long-term exposure to clinically relevant concentrations of
proinflammatory cytokines reduced the current density of
several ionic currents. Specifically, IL1
b
decreases the calcium
currents, whereas TNF
a
reduces potassium and sodium cur-
rents without affecting calcium currents. The net effect of the
decrease in these ionic currents in response to cytokines may
be detrimental. Indeed, by affecting conduction velocity,
prolonging repolarization, and decreasing calcium currents,
the risk of arrhythmia is significantly increased. Together,
these results may contribute to explain the role played by
inflammation and proinflammatory cytokines in the devel-
opment of electrical remodelling and associated cardiac ar-
rhythmias in the setting of HIV infection. Nevertheless, this
question warrants further investigations.
Other Possible Mechanisms Increasing the Risk
of Arrhythmia in HIV Patients
Recreational drugs
People living with HIV have a greater prevalence of
substance use than the general population.
87-94
The negative
effects of tobacco smoking, alcohol,
95
and illicit drugs (eg,
cocaine and heroin) have been documented on outcomes of
HIV such as ART nonadherence.
88-91
Beyond these effects,
tobacco smoking,
96
alcohol,
97
and cocaine
98
are well known
for their cardiac toxicity and put patients at risk for coronary
heart disease, heart failure, and arrhythmias. Moreover,
reports suggest that at least some of these substances can
directly block the hERG channel.
99-104
This may contribute
to increase the risk of QTc prolongation and torsades de
pointes; however, further studies are required to clearly
determine the impact of these substances on the electrical
properties of the heart.
Conclusion
Sudden cardiac death is now the third leading cause of
death in patients with HIV.
8
The complex medical, phar-
macological, and environmental profiles of this population are
Known risk factors for QTc
prolongation/torsades de pointes
General/control
population
HIV+ population
Older age
53.8% < 40 years old*
60.5% < 40 years old †
Female sex
0.99 male : 1 female‡
4.5 male : 1 female107
Congenital long QT syndrome
Equal risk in both populations
Underlying heart disease
1x
1.5x108, §
Electrolyte imbalance (eg, K+)
< 2%108
19%109
Increased inflammatory status¶
-
56% (HIV+ on ART)
26% (HIV+ ART naïve)110
Polypharmacy
11.6%
24.4%41
Lower prevalence in the HIV compared with the general/control population
Equal prevalence in the HIV compared with the general/control population
Increased prevalence in the HIV compared with the general/control population
Figure 2. Comparison of risk factors for QTc prolongation/torsades de pointes between the general/control and HIV-infected populations. ART,
antiretroviral therapy; QTc, corrected QT. *United States Census Bureau: Profile of General Population and Housing Characteristics: 2010: https://
factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?pid¼DEC_10_DP_DPDP1&src¼pt.
y
Center for Disease Control and Pre-
vention: https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2016-vol-28.pdf.
z
United Nations Population Divi-
sion: http://data.un.org/en/iso/ca.html.
x
The incidence in HIV-infected patients is approximately 1.5 times higher than in the general/control
population.
{
Reported as % of patients with level of high-sensitivity C-reactive protein above 3 mg/dL, the cut-off point for increased risk of car-
diovascular complications.
Brouillette et al. 315
HIV and Arrhythmias
associated with several known risk factors of arrhythmias and
sudden cardiac death (Figs. 1 and 2). Although it is generally
recognized that arrhythmias can occur as a result of drug
treatments, substance use, or electrolyte imbalances, accu-
mulating evidence also supports the involvement of HIV in
itself.
5,16,20,55,64
Transgenic mouse models helped to provide
a better understanding of the pathophysiological mechanisms
of HIV-related arrhythmia and strongly support a role for
inflammation and proinflammatory cytokines on cardiac ion
channels and associated pathologic electrical remodel-
ling.
55,56,64,76,85,105
Additional studies are needed to better
understand the complex links between modifiable risk factors
of arrhythmias in patients with HIV and to determine if
pathological electrophysiological processes can be reversed if
they are corrected.
Funding Sources
This work was supported by Canadian Institutes of Health
Research Operating Grant CIHR-MOP-89934 (to C.F.).
Disclosures
The authors have no conflicts of interest to disclose.
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