We really appreciated your valuable comments and addressed each of the raised points. The manuscript has beenaccordingly revised and we hope that the following amendments will satisfy your suggestions. Please find below our answers.
Firstly, we would like to underline that we do not report an apparent excess of CAC but a higher prevalence of coronary plaques associated with severe stenoses(>50% lumen reduction)assessed by MDCT-CAin Charcot group.
The first problem relates to population selection. It is implied, but not stated,that all subjects were free from symptoms of cardiac disease and the studies were undertaken simply for the purposes of research. I presume also that all had normal ECGs. If they didn't, then these details (symptoms, ECG abnormalities) need to be included in Table 1.
We agree with you and as you requested, additional information about population selection have been included in the revised manuscript. All subjects included were free from symptoms of cardiac disease and they had normal ecg at rest. These details have been added in the text.
The study was undertaken in order to better define the coronary plaque burden in these populations above all from a structural and morphological point of view. Furthermore in the choose of the test that we wanted to perform we have considered also that Charcot subjects could not perform a stress ecg.
The second problem is that they speculate from their results that people with an acute Charcot foot (or a history of one - it isn't clear) have an increased risk of cardiovascular death. But there is no evidence that this is the case. Indeed the very large matched case-control series of van Baal et al reported that mortality in people with a history of Charcot foot was exactly the same as in a population with a history of neuropathic foot ulcer
We thank you for your comments that allow us to explain the meaning of our paper deeply. We speculate that subjects with Charcot have an higher risk of cardiovascular disease,as we have modified in the text and not an higher risk of mortality.
The study from Van Baal et al. showed that there were no differences regarding the mortality between Charcot acute foot group and uninfected neuropathic foot ulcers group, but in both groupsmortality was very high if compared to healthy group.
Furthermore, van Baal et al. did not investigate any cause of mortality in such populations; in particular, the study they did not assess the differences about the coronary plaque burden between the two populations, as we did in our paper. So, we think that our (preliminary) results may have an important role in the risk-stratification of such subjects with important prognostic consequences.
The literature therefore suggests that it is the neuropathy which increases CVS risk, and not the Charcot, and I fear that the information in the present report isn't strong enough to refute it
We completely agree with you that diabetic neuropathy is linked to cardiovascular risk, indeed our aim is not to contest that neuropathy increases cardiovascular risk, but to show that in the setting of neuropathy as essentialcardiovascular risk factor, theneuropathic subjects with Charcot-foot have a coronary atherosclerotic plaque burden more expressedand, in our opinion, this is a completely original result.
This result could be a further confirm of the data showed in the paper “Proinflammatory modulation of the surface and cytokine phenotype of monocytes in patients with acute Charcot foot”Uccioli L. et al Diabetes Care. 2010 Feb;33(2):350, in which Charcot subjects showed an increased inflammatory status compared to only neuropathic subjects, considering the pivotal role played by inflammation in the pathogenesis of coronary artery disease
We do not know, for instance, if the neuropathy group in the present study had a history of ulceration, with or without infection, (with its possible effect on pro-inflammatorycytokines) and we do not know if the duration of known neuropathy (as opposed to diabetes) was the same in the two groups. We also do not know if any of either group had had a major amputation - with its known association early mortality.
The neuropathy group in the present study didn’t show a history of ulceration,and it was chosen in order to rule out the effect of acute inflammation, for the same reasons Charcot group included subjects not in acute phase. At the same time were ruled out subjects with major amputation, for its relationship with mortality.
I think that define the real duration of diabetic neuropathy is very difficult, considering thatsome studies have showed an increased prevalence of neuropathy in IFG and IGT status (Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3 Diabetes Care. 2008 Mar;31(3):464-9 Ziegler D et al.)
The authors also make no attempt to distinguish between calcification of atheromatous plaques and calcification of the media of the arterial wall. The evidence suggests that the cause of the two is different but similar, and that it is on medial calcification that neuropathy probably has its dominant effect. Can the technique they used to identify arterial calcification reliably discriminate between the two ?
The Multidetector-CT Coronary Angiography (MDCT-CA) is the only non-invasive diagnostic technique able to show the atherosclerosis (ATS) of coronary arteries. In particularMDCT-CA allows to differentiate normal coronary arteries without any findings of ATS from coronary arteries with non-obstructive ATS (stenosis <50% of the lumen) , and coronary arteries with obstructive ATS (stenosis >50%).
The sub-millimetric spatial resolution of MDCT-CA allows to differentiate the components (non-calcified, mixed or calcified) which could be present in the context of coronary plaques, but to date it is not able to distinguish between calcification of ATS plaque and calcification of the media of the arterial wall.
Moreover all subjects had hypertension, with a similar duration and treatment (no difference between the two groups about the use of the classes of medications for hypertension)
Therefore, in our conclusions we state that our results are the first (in-vivo) demonstration that subjects with Charcot foot have an highercoronary atherosclerotic plaque burden, considering that at our knowledge there are not similar data in the recent literature.