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MY APPROACH
My approach to the patient with arrhythmogenic
right ventricular cardiomyopathy
By Angeliki Asimaki,
MD
C
linical diagnosis of arrhythmogenic right
ventricular cardiomyopathy (ARVC) is
challenging owing to the broad range of
phenotypic manifestations, reduced genetic
penetrance, and age-related progression char-
acterising the disease.
There is no single “gold-standard” test for
ARVC, and diagnosis relies on a scoring sys-
tem of “major” and “minor” criteria based on
the demonstration of a combination of defects
in ventricular morphology and function, de-
polarisation/repolarisation ECG abnormali-
ties, myocardial tissue histological changes,
arrhythmias, and family history. Definitive
diagnosis, based on the Revised 2010 Task
Force Criteria (TFC), requires two major, one
major and two minor, or four minor criteria
from different categories. Therefore, the initial
evaluation of all patients suspected of having
ARVC should include physical examination,
clinical history, family history of arrhythmias
or sudden cardiac death (SCD), ECG, sig-
nal-averaged ECG, Holter monitoring, and
noninvasive imaging tests, typically echocar-
diography. Following the recent identification
of left-dominant and biventricular forms of
ARVC, comprehensive imaging of the LV is
also indicated.
More recently, cardiac magnetic resonance
(CMR) has been introduced in the clinical
practice when evaluating a patient with pos-
sible ARVC as it can quantitatively assess ven-
tricular volumes and ejection fractions, wall
motion abnormalities, and give information on
tissue characterisation (fatty infiltration and
myocardial fibrosis through late gadolinium
enhancement). If a noninvasive workup is
suggestive but not diagnostic, further testing
should be considered including angiography,
electroanatomic mapping, and, rarely, endo-
myocardial biopsy.
The most important task when managing
a patient with ARVC is prevention of SCD.
Patients with a history of aborted SCD or
sustained VT are considered high-risk and
should get an ICD. Syncope, non-sustained
VT, family history of SCD, severe RV dysfunc-
tion, LV involvement, and QRS dispersion are
considered intermediate risk factors, but their
individual or combined prognostic value has
not been prospectively assessed. Accordingly,
ICD implantation should be decided on a
case-by-case basis. Radiofrequency ablation
should be considered in those patients who are
not candidates for an ICD or who have an ICD
but get multiple shocks despite pharmacologi-
cal treatment.
Anti-arrhythmic medications may be used to
control symptoms in ARVC. The combination
of beta blockers (sotalol) and amiodarone has
proven beneficial in reducing sustained VT
and preventing syncope. Beta blockers and
ACE inhibitors can also be used in ARVC
patients, particularly those with biventricular
dysfunction or heart failure. Cardiac trans-
plantation is indicated in patients with severe
heart failure (typically characterising endstage
disease) and in selected cases with intractable,
incessant ventricular arrhythmias.
Particular caution should be addressed to
avoid competitive sport activities, which in-
crease disease progression and arrhythmic risk.
ARVC is familial in over 50% of cases. Screen-
ing of family members is therefore of pivotal
importance. Clinical evaluation of relatives
should be guided by the observation that SCD
inARVC is extremely rare in children under 10
years of age. Family members who meet TFC
should be closely monitored. However, since
electrical abnormalities precede structural
changes in ARVC, evaluation in family mem-
bers not meeting TFC should initially focus on
the electrical aspects of the disease by ECG
and Holter monitoring. Alternatively, genetic
testing can be performed, and, if a pathogenic
mutation is identified in the proband, family
members can be tested as well to determine
whether they are at risk of disease manifesta-
tion in the future.
Dr Asimaki is Research
Associate, Beth Israel
Deaconess Medical Center,
Faculty member (Instructor),
Harvard Medical School,
Boston, Massachusetts.
EXPERT OPINION
The pivotal position of IL-6 in the pathogenesis of
ischaemic heart disease, and a lot of new questions
By Petter Libby,
MD
The cytokine interleukin (IL)-6 occupies a pivotal position in the innate immune inflammatory cascade. The better-known proinflammatory cytokines
IL-1 and tumour necrosis factor (TNF) strongly induce IL-6. IL-6 in turn regulates the acute-phase response in the hepatocyte, boosting the production
of fibrinogen and the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), proteins implicated in the formation and stability of thrombi. Thus,
IL-6, sandwiched between “primary” proinflammatory cytokines and the acute-phase response, occupies a central pivot point putatively involved in the
pathogenesis of ischaemic heart disease.
R
ecent large, well-conducted,
and concordant studies using
Mendelian randomisation
provide strong evidence for a causal
role for IL-6 in coronary events.
1,2
Thus, IL-6 could represent an at-
tractive target for reducing inflam-
mation in cardiovascular conditions.
Kleveland et al conducted a
two-centre, double-blind placebo-
controlled trial that enrolled 117
patients with non-ST-segment
elevation myocardial infarction
(NSTEMI) 2 days after onset of
symptoms.
3
They randomised this
cohort of patients to placebo or
the anti-IL-6 monoclonal antibody
tocilizumab one-to-one. The biologi-
cal agent was given before coronary
arteriography. The study’s primary
endpoint was the area under the
curve (AUC) for high-sensitivity C-
reactive protein (hs-CRP) between
days 1 and 3. They also studied the
AUC for high-sensitivity troponin T
(hsTnT) during this time window.
This study used a daring design, as
acute coronary syndromes (ACS) in-
crease inflammation remarkably, ren-
dering it difficult to show a change.
The standard of care for ACS pa-
tients decreases CRP, and of course
troponin also rises and declines with-
out intervention post-ACS.
In a substudy of the Myocardial
Ischemia Reduction withAcute Cho-
lesterol Lowering (MIRACL) trial,
the CRP fell from 11 to 2.9 mg/L 16
weeks after ACS in a placebo-treated
group and fell from 11.5 to 1.9 in a
group treated with atorvastatin at 80
mg per day.
4
The MIRACL study
was conducted before high-dose
statin therapy became the standard
of care for ACS patients. Thus, there
was 34% statistically significant lower
CRP after 4 months (P < 0.001), but
the magnitude of the absolute change
in hs-CRP was modest compared
with the fall in the placebo group just
with “tincture of time.” As 90+% of
the patients in the Kleveland study
were treated with statins, it raises
the bar even higher for distinguish-
ing a difference in the inflammatory
biomarker due to the tocilizumab
therapy. Yet, this new study handily
met its primary endpoint of theAUC
of hs-CRP from days 1 to 3, which
was 4.2 in the placebo group and
2.0 mg/L/h in the tocilizumab-treat-
ed patients (P < 0.001). The AUC of
hs-TnT follows a similar pattern (234
vs 159 ng/L/h; P = 0.007).
Actually, one could view this study
as an investigation of the effects of
tocilizumab on patients undergoing
PCI in the context of NSTEMI
rather than NSTEMI itself, as the
benefit occurred in the PCI group
and treatment followed the hyper-
acute phase of the ACS – a 2-day
lag. The authors hypothesise that
tocilizumab attenuates secondary
ischaemia reperfusion injury as a
mechanism of its reduction in the
biomarkers studied.
Another plausible interpretation
would be that tocilizumab blunts the
responses to PCI-related myocardial
injury. The patients in the tocilizum-
ab-treated group had an increase in
IL-6. The authors hypothesise that
the monoclonal antibody inhibits
the clearance of this cytokine that
has a short dwell time in the blood
compartment under usual circum-
stances. Nonetheless, one must
always remain vigilant regarding
counter-regulatory responses when
perturbing innate immunity.
Although one proximal inducer
of IL-6, IL-1b, was similar in the
two groups, unmeasured proximal
proinflammatory cytokines such as
TNF or IL-1a might have increased.
In the MRC-ILA-HEART study,
individuals with non-ST-segment el-
evation ACS allocated to treatment
with the IL-1 receptor antagonist
showed a “rebound” in hs-CRP, and
a disquieting excess of recurrent ma-
jor adverse cardiovascular events in
the IL-1Ra group.
5
The tocilizumab
study also documented a decrease in
granulocyte count.
As we have increasing apprecia-
tion of the roles of leukocytes of vari-
ous functional classes in the healing
of myocardial ischaemic injury, this
observation begs the question of the
effects of tocilizumab on monocyte
subpopulations in peripheral blood,
and more importantly the identity
and sequencing of leukocytes in-
volved in myocardial repair following
ACS.
6
While the authors noted no
excess adverse events in 6 months
of follow-up, the study was insuf-
ficiently powered to exclude either
benefit or harm in terms of cardiac
function or outcomes.
This study has great importance
for the inflammation hypothesis of is-
chaemic heart disease. It shows that a
biological approach to interfering with
the action of a proinflammatory cy-
tokine can limit biomarkers associated
with adverse outcomes. Yet, like most
good studies, this one raisesmany new
questions, as touched upon above.
References
1. Hingorani AD and Casas JP.
Lancet
2012;379:1214-1224.
2. Sarwar N, Butterworth AS, Freitag DF, et
al.
Lancet
2012;379:1205-1213.
3. Kleveland O, Kunszt G, Bratlie M, et al.
Eur Heart J
2016;37:2406-2413.
4. Kinlay S, Schwartz GG, Olsson AG, et al.
Circulation
2003;108:1560-1566.
5. Morton AC, Rothman AM, Greenwood
JP, et al.
Eur Heart J
2015;36:377-384.
6. Libby P, Nahrendorf M, Swirski FK.
J Am
Coll Cardiol
2016;67:1091-1103.
Dr Libby is Chief of Cardiovascular
Medicine, Brigham and
Women’s Hospital in Boston,
and Mallinckrodt
Professor of
Medicine,
Harvard Medical
School, Boston,
Massachusetts.
MYOCARDIAL DISEASE
PRACTICEUPDATE CARDIOLOGY
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