The present study demonstrates that patients with ACS and the highest risk of myocardial infarction or death within 14 days (TIMI 5-7) have significantly lower UII concentration than patients with low risk (TIMI 1-2), and is the first to prove a negative relationship between UII concentration and troponin C level and TIMI score.
The first authors investigating plasma levels of UII in patients with ACS were Joyal et al
]. They found lower plasma UII concentration in 54 patients with ACS compared with patients with stable angina and healthy controls. Moreover, patients with systolic dysfunction accompanying ACS had decreased mean plasma UII concentration in comparison to patients with preserved left ventricular function. The second study to focus on plasma UII concentration in patients with ACS was performed by Khan et al
]. Contrary to Joyal et al
. and our results, they found raised plasma UII concentration in 129 patients with acute myocardial infarction as compared to healthy controls. In addition, partially in line with our findings, the authors demonstrated that lower than median UII concentration was an independent risk factor of adverse outcomes in patients with myocardial infarction. The authors suggested that elevated plasma UII concentration after myocardial infarction has a cardioprotective effect as a peripheral vasodilator. Somewhat contrary are the results obtained by Rdzanek et al
., who did not observe any significant differences in plasma UII concentration in myocardial infarction survivors with and without hypertension [18
]. These data are inconsistent with findings of Cheung et al
. showing raised plasma UII concentration in patients with arterial hypertension [19
We have demonstrated lower plasma UII concentration in patients with myocardial infarction than in other ACS patients, and the inverse relationship between plasma concentration of troponin C and UII (R
= − 0.229; p =
0.005). Such a correlation was previously not examined either by Khan et al
. or Joyal et al
]. As the correlation is rather weak, we agree with their suggestions that plasma UII concentration is not a good marker of myocardial necrosis. On the other hand, the relationship between myocardial necrosis and plasma UII concentration may be indirect, reflecting worse hemodynamic function of the left ventricle. The rationale for such a hypothesis is the almost significant positive correlation between plasma UII and EF (R
=0.157; p =
0.063) and negative with NT-proBNP (R
= − 0.156; p =
0.058). Also Joyal et al
. observed significantly lower plasma UII concentration in patients with lower EF.
It should be stressed that patients with the highest TIMI score had higher incidence of diabetes mellitus, arterial hypertension, coronary artery disease, higher LVM and lower EF that was associated with markedly elevated NT-proBNP. All these states are associated with chronic endothelial dysfunction, and usually increased plasma UII concentration [7
]. However, it is not proved whether acute damage of endothelium in patients with ACS is the cause of diminished release of UII as proposed by Joyal et al
]. Plasma UII concentration has not yet been assessed in patients with cardiac shock.
Based on our findings we suggest that diminished plasma UII concentration in patients with ACS could be associated with more severe injury of cardiac muscle and perhaps greater endothelial damage. Our hypothesis is backed up by the results described by Khan et al
], who demonstrated that plasma levels of UII below the median were associated with poorer survival and increased likelihood of adverse clinical outcome. Thus elevated levels of U II may have a cardioprotective effect. There are some data supporting that hypothesis. Stimulation of UII receptors localized in endothelial cells in animal models was followed by the release of nitric oxide and prostaglandins [21
], even though the release of these potent vasodilators may be counterbalanced by the direct contractile influence of UII on smooth cells. The unanswered question is whether UII may act as a peripheral vasodilator after acute myocardial infarction unloading the injured myocardium – the more so, that it has been proven that UII has both positive inotropic and peripheral vasodilator effects [22
]. These findings suggest that in some circumstances, UII may be cardioprotective and explain the findings that patients with lower levels of UII were at highest risk (TIMI 5-7). However, further, larger studies are required to validate our hypothesis.
The limitation of our study is the lack of plasma samples extraction prior to ELISA, recommended, but not required by the kit manufacturer. This may have explained the relatively high plasma UII concentrations in our study.
In conclusion, decreased plasma UII concentration in patients with ACS could be associated with more severe injury of the myocardium.