Cardiovascular Journal of Africa: Vol 27 No 5 (September/October 2016)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 5, September/October 2016 304 AFRICA
mechanical stretch, angiotensin-II and pro-inflammatory
cytokines synthesised in the infarcted area may also stimulate
adrenomedullin production.12
Activation of the renin–angiotensin–aldosterone system
commonly accompanies MI.18 Angiotensin-II, a potent
vasoconstrictor, is involved with vascular tone and endothelial
function, cardiac contractility, impulse propagation, and it
stimulates the formation and secretion of aldosterone from the
adrenal gland.19 We found increased levels of angiotensin-II in
both the plasma and pericardial fluid in the anterior MI group.
Schunkert et al.20 reported that plasma angiotensin-II levels
were increased six weeks after experimental MI in rats with
congestive heart failure. Both our finding and the results reported
by Schunkert et al.20 suggest activation of the renin–angiotensin
system and a subsequent increase in circulating angiotensin-II.
On the other hand, Huang et al.21 found that in rats three
months after subjection to MI, the plasma renin level was
increased but plasma angiotensin-II levels were not different
from those in the control group. The authors concluded that
decreased lung angiotensin converting enzyme activity could
possibly have contributed to keeping plasma angiotensin-II levels
in the normal range. Another explanation may be the clearance
of angiotensin-II from the circulation in the three-month period
after MI.
Serneri et al.4 found that the clinical course of heart failure
is associated with a progressive increase in cardiac angiotensin-
II formation, as expressed by the mean aorta–coronary sinus
concentration gradient. In agreement with this study, we found
the highest pericardial fluid angiotensin-II level was in the
anterior MI group, the group which had the worst LV function.
IL-6 is a classic multifunctional cytokine, with several
activities that could explain its potential importance in acute
coronary syndromes.22 In addition, IL-6 has been suggested as
a marker of severity of coronary artery disease, since increased
plasma concentrations and activated myocardial gene expression
have been demonstrated after MI.
IL-1 is a prototypic pro-inflammatory cytokine with a wide
range of actions systemically and at the cardiovascular level.23
The IL-1 family encompasses IL-1 α, IL-1 β and IL-1Ra and is
mainly produced by monocytes and macrophages, and to a lesser
degree by endothelial cells.23
Birner et al. 24 performed a human study in which plasma
N-terminal proBNP (NT-proBNP) and IL-6 levels weremeasured
in a large group of patients in the chronic phase after MI and
found that both NT-proBNP and IL-6 levels were significantly
elevated in subjects with MI compared to the control group.
When they analysed NT-proBNP and IL-6 levels with regard to
EF, they observed a significant increase in NT-proBNP levels in
the presence of LV dysfunction. By contrast, IL-6 level did not
increase further in MI subjects with LV dysfunction, compared
to MI subjects with preserved LV function. These findings
may suggest that plasma levels of IL-6 are not as sensitive as
NT-proBNP as a biomarker of LV dysfunction in the presence
of MI.
We also found that the levels of IL-6 and IL-1β in plasma
did not differ significantly between the groups. The lack of
significant elevation of plasma levels of IL-6 in patients with
MI in our study could have been due to insufficient numbers of
patients. These findings could also be interpreted that levels of
IL-6 and IL-1β in plasma were not influenced by the site of MI.
On the other hand, the elapsed time from MI seems to be an
important factor in the marker role of IL-6 and IL-1β on MI.
In addition, IL-1α and IL-1β lack a signal peptide and they are
not readily secreted into the systemic circulation and therefore
determination of plasma level is unreliable. 25
Plasma levels of IL-1Ra, a sensitive marker of biologically
active IL-1β, and IL-6 were measured at the time of admission
to the coronary care unit and 48 hours later in patients who were
hospitalised due to unstable angina.25 The authors found that a
fall in IL-1Ra and IL-6 48 hours after admission was associated
with an uneventful course.
In our study, complicated medical conditions such as
development of new cardiac events, emergent operation,
cardiogenic shock or complications of acute MI were all
exclusion criteria. Therefore the lack of difference in plasma
levels of IL-6 and IL-1β in our study could also be partly due
to their relatively stable medical status and the absence of major
new-onset cardiac events.
We also found that pericardial fluid levels of IL-1β and IL-6
were markedly increased in the anterior MI group. This indicates
that pericardial fluid levels of these two cytokines may be superior
to plasma levels as a marker of LV dysfunction in the setting of
MI. It has also been reported that pericardial concentrations
of IL-1β may reflect the extent of ischaemic heart disease and
that elevated IL-1 β concentrations in pericardial fluid may also
directly promote the process of coronary atherosclerosis. 7
TNF-α is a multifunctional circulating cytokine derived from
endothelial and smooth muscle cells as well as macrophages
associatedwith coronary atheroma.26,27 TNF-α possesses cytotoxic
and negative inotropic actions, aggravates the inflammatory
process, and plays a role in neutrophil pre-activation and
ischaemic injury. 28,29 Brunetti et al.30 reported that levels of
TNF-α in patients with acute coronary syndrome were
associated with a worse prognosis at follow up. Prior data have
demonstrated that those individuals with evidence of severely
reduced ejection fraction and clinical heart failure had markedly
elevated levels of TNF-α .31,32 Torre-Amione et al.33 also reported
that concentrations of TNF- α were high in patients with heart
failure, in association with noticeable activation of the renin–
angiotensin system. There was, however, a wide variation in
TNF-α levels between patients and in many it was not detected.
Dutka et al .34 examined the concentrations of circulating
TNF-α in patients with congestive heart failure and found that
the mean concentration of TNF-α was greater than the upper
95% confidence interval for healthy controls, but there was
considerable between- and within-patient variation. Therefore
the authors concluded that the stimulus resulting in enhanced
plasma concentrations of TNF-α in congestive heart failure
remains unclear and concentrations at any particular time were
not prognostic.
In our study, although both plasma and pericardial fluid
TNF-α levels in the anterior MI group were slightly higher than
those in the other groups, the differences were not statistically
significant. We believe that the lack of statistically significant
elevation in the levels of TNF-α in the anterior MI group, the
group which had the poorest LV function, may have been due to
the absence of severe clinical heart failure. Another explanation
could be that the wide variation in TNF-α levels between
patients resulted in relatively high standard deviations and
precluded finding significant differences with statistical analysis.