CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
AFRICA
129
Editorial
Lessons from the first report of the Arrhythmogenic Right
Ventricular Cardiomyopathy Registry of South Africa
The Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
Registry of South Africa was established in 2004, under the
auspices of the Cardiac Arrhythmia Society of Southern Africa
(CASSA).
1
In the November 2009 supplement of
Heart Rhythm
,
the Registry investigators published the first large, multicentre
series of patients with ARVC in South Africa.
2
The report, which
is based on the first 50 participants with a confirmed diagnosis
of ARVC, has practical implications for the clinical profile, diag-
nosis and management of patients with ARVC in South Africa.
What is the profile of the patient with ARVC in South Africa?
The disease occurs in all racial and ethnic groups. It usually
starts causing symptoms by the third decade of life. Males
manifest with symptoms of the disease more often than females,
with a 2:1 ratio. Most frequently, patients come to their physi-
cian complaining of palpitations, dizziness and syncope. About
a third of South African patients also notice chest pain, which
makes ARVC an important consideration for clinicians evaluat-
ing young people with chest pain.
These young people with ARVC are regularly involved in
sport, and in fact, 28% of patients in the South African cohort
were professional endurance athletes at some point in their lives.
Previous human and animal studies have demonstrated that, if an
individual is genetically prone to ARVC, endurance exercise is
an important environmental factor in determining how quickly
the condition develops.
3,4
The high proportion of sport partici-
pants in this report reiterates the need for physicians to screen
endurance athletes for heart disease, both pre-participation and
throughout their sporting careers.
Diagnosing ARVC can be challenging, though. Standard
cardiology tests can be unremarkable for years during the earlier
phases of ARVC, which means that a high index of suspicion
and repeat evaluations, with close follow up, are needed. Even in
the South African cohort, which typically represented advanced
disease, 6% of subjects had a ‘normal’ resting ECG at their
last follow-up visit. Some 12% of symptomatic patients had
no abnormalities at all on cardiac imaging and were diagnosed
based on family history, electrocardiographic abnormalities and
molecular genetic testing.
Make no mistake, however, this is not a benign cardiomy-
opathy. Several Registry participants had died by the end of the
follow-up period (a median of around eight years). The annual
mortality in this study was 2.8%, and the five-year cumulative
mortality was 10%. Outcomes were worse than in other parts
of the world; on average, patients died two decades earlier than
patients in France.
5
There are several explanations for this, the
most likely of which is that implantable cardioverter-defibrilla-
tors (ICDs), which are life-saving for ARVC patients, are under-
utilised in South Africa. What is more, for the reasons discussed
above, patients do not always find their way to an expert who can
diagnose and manage this complex disease.
As a striking demonstration of the severity ofARVC, outcomes
were compared with control patients who represented the general
South African population. The two groups had the same survival
rates. Bear in mind that South Africa is in the midst of an unprec-
edented increase in mortality, due in large part to the colliding
epidemics of HIV/AIDS and non-communicable diseases.
6
It
is not a surprise that survival from ARVC, a potentially lethal
disease, is similar to survival after the combined effects of HIV/
AIDS and other diseases have taken their toll on the population.
Despite such poor outcomes, however, there is an important
silver lining to this cloud. The survival study identified the
patients who were at high risk of dying suddenly, including those
with a history of syncope and sustained ventricular tachycardia.
Arrhythmias were the cause of death in two out of every three
patients who died, although fortunately, to date not a single
Registry participant who has received an implantable cardio-
verter defibrillator has died. From a practical standpoint, these
data suggest that the early use of ICDs in patients with syncope
and sustained ventricular tachycardia may prevent early mortal-
ity. Any patients with these symptoms and a diagnosis of ARVC
should have top priority to be evaluated by a cardiologist.
It has been known for years thatARVC is an inherited condition
in a significant proportion of cases. The Registry report has made
several key observations about the genetic causes of ARVC. First
of all, 30% of participants in the study had a family member who
was also affected. For the purposes of the
Heart Rhythm
report,
genetic analysis was focused on the most common culprit gene,
known as plakophilin-2 (
PKP2
). Of the blood samples analysed,
25% had a
PKP2
gene defect that caused disease. While this
detection rate is satisfactory in itself, the yield of genetic testing
is likely to be even higher in the future; the laboratory team is
currently incorporating otherARVC-related genes into the screen-
ing technique. All physicians who care for patients with ARVC
are encouraged to send blood samples to the Cardiovascular
Genetics Laboratory in the Hatter Institute for Cardiovascular
Research at the University of Cape Town for genetic screening.
In the process of screening the
PKP2
gene, Registry inves-
tigators made another observation. One of the study subjects
actually had two separate defects in the
PKP2
gene, and when
his sister was screened, she was found to harbour the same two
defects. The other family members had either one or the other
defect – and in none of them was the disease particularly severe.
The two siblings with multiple defects, however, had disease
onset in early childhood, and its course was so severe that both
siblings needed heart transplants by the time they were teenag-
ers. Geneticists refer to this type of phenomenon as an ‘allele
dose effect’, and to date, this is only the second time that such an
effect has been reported in the ARVC research literature.
Perhaps the most important genetic discovery, however, was
that several unrelated study participants actually had the exact
