CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 2, March 2012
102
AFRICA
36. Turner GD, Ly VC, Nguyen TH, Tran TH, Nguyen HP, Bethell D,
et al
.
Systemic endothelial activation occurs in both mild and severe malaria.
Correlating dermal microvascular endothelial cell phenotype and solu-
ble cell adhesion molecules with disease severity.
Am J Pathol
1998;
152
: 1477–1487. PMID: 9626052.
37. Pongponratn E, Turner GD, Day NP, Phu NH, Simpson JA, Stepniewska
K,
et al
. An ultrastructural study of the brain in fatal
Plasmodium
falciparum
malaria.
Am J Trop Med Hyg
2003;
69
: 345–359. PMID:
14640492.
38. Nwokocha CR, Ebeigbe AB, Ajayi IO. Altered vascular smooth muscle
reactivity induced by malaria parasite.
West Indian Med J
2011;
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β
2
-agonist therapy was found to be associated with an increased
risk of cardiac events among these patients.
4
However, the genetic basis of drug-induced SCD may not be
solely attributable to overt or obscure ion channelopathy eliciting
severe QT prolongation and TdP in response to certain agents.
Impaired repolarisation heterogeneity manifesting as robust
increases in a variety of indices, including T-wave alternance
(TWA) and QT dispersion,
5
and reduction in effective refractory
period (ERP) in myocardial tissue in response to certain agents
may also be associated with drug-induced pro-arrhythmias,
suggesting another potential mechanism of
β
2
-agonist-related
SCD. In a previous study, inhaled fenoterol (a
β
2
-agonist) was
found to induce significant increases in QTc interval and QTc
dispersion in a group of healthy volunteers.
6
Interestingly, in this
study, a proportion of subjects had much higher values of QTc
dispersion after inhaled fenoterol administration, suggesting an
individual oversensitivity to the effects of beta-agonists, includ-
ing fenoterol, in certain subjects.
6
Repolarisation heterogeneity
in response to certain agents was previously suggested to demon-
strate inter-individual variety,
5
and hence may potentially harbour
a genetic basis.
Besides excluding structural heart diseases in candidates of
β
2
-agonist therapy, clinicians should also investigate a variety
of risk factors, including specific symptomatology (palpitation,
syncope), subtle or overt ECG findings (QTc-interval prolonga-
tion,
7
etc) and history or family history of SCD (particularly in
subjects with normal hearts) that are suggestive of an existing
electrophysiological genetic basis for drug-induced SCD. On the
other hand, it is well known that expertise in cardiology is not
a primary skill of most chest physicians.
7
However, in clinical
practice,
β
2
-agonists are usually prescribed by clinicians, includ-
ing chest physicians, who are not familiar with the concept of
drug-induced pro-arrhythmia. Thereby, clinical clues to an elec-
trophysiological genetic basis for
β
2
-agonist-induced SCD may
easily be overlooked in the clinical setting, indicating the neces-
sity of multi-disciplinary evaluation of certain patients before
prescribing these agents.
Pharmacological challenge with inhaled
β
-agonists has been
suggested to identify high-risk candidates of
β
-agonist therapy
by monitoring potential dynamic alterations in the duration of
QTc interval.
7
Partially consistent with this recommendation, in
the event of a strong suggestion of genetic basis (not all candi-
dates),
4
pharmacological challenge with
β
2
-agonists should be
performed in the hospital setting to demonstrate possible life-
threatening increases in the QTc interval or indices of repolarisa-
tion heterogeneity in the candidates of
β
2
-agonist therapy. Hence
the potential risk of
β
2
-agonist-induced pro-arrhythmia may be
predicted, to some degree.
In conclusion, it may be suggested that even though
β
2
-agonist-induced SCD is more likely to occur in the setting of
structural heart diseases, a proportion of patients suffering SCD
due to
β
2
-agonist therapy may have apparently normal hearts (in
post-mortem examination), indicating an electrophysiological
genetic basis for
β
2
-agonist-induced pro-arrhythmia in these
patients. However, clinical clues to a genetic basis associated
with
β
2
-agonist-induced SCD may easily be overlooked in the
clinical setting.
Therefore, besides excluding structural heart diseases before
prescribing these agents, it is of utmost clinical importance to
investigate the risk factors associated with a potential electro-
physiological genetic basis, including specific symptomatology,
subtle ECG findings, family history of SCD in candidates of
β
2
-agonist therapy, through a multi-disciplinary approach in
certain conditions. In selected cases, challenge with
β
2
-agonists
in the hospital setting may uncover a variety of genetically
determined, obscure ECG findings (robust increases in QT
dispersion), and hence may help identify patients at high risk for
β
2
-agonist-related SCD, indicating avoidance of these agents in
certain patients, even with apparently normal hearts.
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