CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 1, January/February 2013
AFRICA
285
the -174 IL6 G allele and CAD in SAI was found (84 vs 71% – SAI
controls;
p
=
0.0431, OR
=
0.468, 95% CI: 0.23–0.953). Circulating
levels of IL6 were elevated in total (6.58
±
0.56 pg/ml) and healthy
(6.62
±
0.63 pg/ml) SABs compared to total (1.80
±
0.22pg/ml) and
healthy (2.51
±
0.57pg/ml) SAI groups, as well as CAD patients
(1.46
±
0.36pg/ml,
p
<
0.0001). Levels of IL6 were elevated in all
groups with homozygous -174 IL6 C alleles but only significant in
the healthy SAI group (GG: 3.73
±
0.94 pg/ml vs GC/CC: 0.89
±
0.5
pg/ml,
p
=
0.0001).
Conclusion:
The presence of the IL-6 -174 G allele influences levels
of IL-6 and increases the risk of CAD in South African Indians.
922: AUTOPHAGY UPREGULATION IN CARDIOTOXICITY:
PHARMACOLOGICAL VS GENETIC MANIPULATION
Balindiwe Sishi
1
, Benjamin Loos
1
, Jacques van Rooyen
2
, Anna-Mart
Engelbrecht
1
1
Stellenbosch University, South Africa
2
Cape Peninsula University of Technology, Cape Town, South Africa
Background
: Cardiotoxicity is a well-known side effect of anthracy-
clines such as doxorubicin (DXR), resulting in substantial morbidity.
The most widely accepted hypothesis for their mechanism of action
is oxidative stress, which leads to the induction of cell death as a
direct consequence of DNA damage and/or interference with DNA
repair. Autophagy, a major catabolic process, has been shown to play
a vital role in cardiac homeostasis. This process is often elevated
following various forms of cardiovascular stress. However, whether
autophagy participates as a pro-survival or pro-death pathway
remains to be determined. This study therefore aimed to determine
whether pharmacological or genetic manipulation of autophagy alle-
viates DXR-induced toxicity.
Methods
: H9C2 rat cardiac myoblasts were treated with rapamycin
(50 nM - CR) or siRNA (mTOR - CM) for 24 hours to up-regulate
autophagy. This was followed by treatment with DXR alone (3
μ
M
- CD) or in combination with rapamcin (RD) or siRNA (MD) for a
further 24 hours, where after cell viability, apoptosis, mitochondrial
morphology and DXR localisation was assessed.
Results:
Assessment of cell viability indicated that groups CM and
CD significantly reduced viability [75.48
±
1.81% (
p
<
0.001) and
65.58
±
2.25% (
p
<
0.01)] versus the control. Group RD signifi-
cantly improved viability [78.93
±
10.85% (
p
<
0.05)] versus CD.
Caspase activity was also significantly elevated in group CD [444.60
±
29.33% (
p
<
0.001)] versus the control, whereas group RD signifi-
cantly reduced (78.86
±
7.14%) caspase activity. Normal mitochon-
drial morphology was not adversely affected in groups CM, CR and
RD. However groups CD and MD displayed abnormal mitochondria
that were shorter, fragmented and discontinuous.
Conclusions
: These results indicate a prospective role for rapamycin
against DXR-induced cardiotoxicity and highlight rapamycin as a
plausible adjuvant therapy to counteract and improve the life-threat-
ening impediment of DXR’s actions in clinical practice.
928: GRAPE SEED PROANTHOCYANIDIN EXTRACT
LIMITS CARDIAC DAMAGE
Maritza Kruger, Neil Davies, Sandrine Lecour
Hatter Cardiovascular Research Institute, Cape Town, South Africa
Background
: Heart failure is a leading cause of mortality world-
wide. To date, many pharmaceutical agents have been used to treat
cardiac hypertrophy and early stages of heart failure. These therapies
have proven reasonably effective; however, there is a need for alter-
native therapeutic strategies, more specifically, natural therapies that
are cost effective and safe, to prevent or reverse hypertrophy before
it develops into heart failure. Proanthocyanidolic oligomer supple-
mentation (PCO), a grape seed extract, was shown to quicken muscle
recovery and reduce inflammation in a skeletal muscle model of
injury. Considering the positive effects on muscle recovery, as well as
results suggesting that resveratrol, another member of the polyphenol
family, could limit the occurrence of cardiac hypertrophy, the possi-
bility exists that PCO might also be beneficial.
Method
s: An osmotic mini-pump containing isoproterenol (2 mg/
kg/day), a dual
β
1
–
β
2
-adrenergic receptor agonist, was used to induce
hypertrophy. Male Wistar rats (280–320 g) were orally gavaged with
either PCO (20 mg/kg/day) or distilled water for two weeks prior to
the subscapular implantation of the pump containing isoproterenol
or ascorbate (vehicle). After seven days, the rats were killed and the
heart isolated. Paraffin wax-embedded hearts were sectioned (2
μ
m)
and stained with Picro Sirius for fibrosis. A macrophage marker,
ED1, was used to determine the infiltration of immune cells.
Results
: Results indicated that the isoproterenol groups lost signifi-
cant amounts of weight one day (
p
<
0.05) after implantation. PCO
treatment reduced hypertrophy, as measured by a lower heart weight
to tibia length and heart weight to body weight ratio. Histological
analysis showed more damage, inflammation and fibrosis in the
isoproterenol group receiving placebo treatment (I-PLA) compared
to the group receiving PCO supplementation (I-PCO). Both groups
displayed significantly more fibrosis than their respective controls.
Conclusion
: The cost-effective, over-the-counter PCO supplement
resulted in better recovery after isoproterenol infusion.
932: GLUCOSE AND INSULIN IMPROVE FUNCTIONAL
RECOVERY AFTER
DE NOVO
ACUTE HEART FAILURE BY
STIMULATING THE SINUS NODE
Gaurang Deshpande, Sandrine Lecour, Lionel Opie
Hatter Institute for Cardiovascular Research in Africa, Department of
Medicine, UCT, Cape Town, South Africa
Background:
Glucose–insulin–potassium infusions improved recov-
ery from sinus node dysfunction in patients. GIK infusions given in
the ambulance to patients with acute coronary syndrome reduced
hard end-points in the IMMEDIATE study, but effects on acute heart
failure (AHF) are still unknown.
Methods:
We therefore tested GI therapy on isolated rat hearts
perfused retrogradely by a modified Krebs-Henseleit solution in
the Langendorff system subject to
de novo
AHF. In this model the
initial stabilisation phase hearts were perfused at 100 cm H
2
O with
glucose (11.1 mM) as sole substrate Thereafter AHF was induced by
under-perfusion at 20 cm H
2
O. We added adrenaline 10
-8
M to induce
a hyperadrenergic stimulus while reducing perfusate glucose to 2.5
mM and adding high free fatty acids (FFA) to the buffer (1.3 mM, 0.1
mM BSA). In the recovery phase the hearts recovered incompletely
although the perfusion pressure was restored to 100 cm H
2
O with the
continued presence of high FFA, and with increased glucose (11.1
mM). Only half of the hearts in this phase received insulin (0.3 mU).
Results:
Glucose coupled with insulin in the recovery phase
increased the heart rate (168.5
±
34.5 vs 36.7
±
25.0 beats/min,
p
<
0.01). LV developed pressure was unchanged in both groups (31.9
±
7.2 vs 38.9
±
16.9 mmHg). We attribute this cardioprotective increase
of heart rate to the electrophysiological effects of glucose and insulin
on sinus node function.
Conclusions:
Our data suggest that glucose and insulin improve the
heart rate of the acutely failing isolated heart by improving sinus
node recovery after
de novo
AHF.
960: ANTI-SENESCENT EFFECT OF STATIN THERAPY IN
CORONARY ARTERY DISEASE
Sajidah Khan
1
, Alisa Phulukdaree
2
, Devapregasan Moodley
2
, Anil
Chuturgoon
2
1
Department of Cardiology, Nelson R Mandela School of Medicine,
University of KwaZulu-Natal, Durban, South Africa
2
Discipline of Medical Biochemistry, University of KwaZulu-Natal,
Durban, South Africa
Introduction:
Atherosclerosis is a premature-ageing syndrome asso-
ciated with senescence of vascular endothelial and smooth muscle
cells. Premature cellular senescence is induced by extrinsic risk
