Reviewer ’s report  
Title: Flow mediated vasodilation compared with caroti d intima me dia thickness in the 
evaluation of early cardiovascular damage in menopausal women. Influence of biological and 
psychosocial  factors  
 
Version: 1 Date: 12 Jul 2018  
 
Reviewer: HENRIQUE MUELA  
 
Reviewer's report:  
The authors present a very interesting clinical issue, namely Flow mediated vasodilation 
compared with carotid intima media thickness in the evaluation of early cardiovascular damage 
in menopausal women. Influence of biological and psychosocial factors. Th e purpose was to 
study biological and psychosocial factors associated with early cardiovascular damage in pre - 
and postmenopausal women, assessed with carotid intima -media thickness vs flow -mediated 
dilatation. They concluded that Carotid intima -media thic kness had higher predictive value for 
endothelial damage at menopause.  
It is a very interesting issue, in a field were evidence are still lacking.  
The manuscript is well written and the tables and figures are appropriate and of acceptable 
quality.  
I have  some major and minor concerns to the authors:  
 
Major concerns:  
I think that the major problem with this study is the fact that the authors used the Intima -media 
thickness (IMT), as marker of endothelial dysfunction. The IMT, as marker of structural arteri al 
changes, is a good marker of subclinical atherosclerosis (asymptomatic organ structural damage), 
but may not be the appropriate marker for endothelial dysfunction. Endothelial function is better 
measured noninvasively with high -resolution ultrasound by brachial artery flow -mediated 
dilatation (FMD).  
As suggested by Bechlioulis A, et al (J Clin Endocrinol Metab. 2010;95(3):1199 -1206), 
Impairment of endothelial function may be present in the early menopausal years, whereas 
carotid IMT is not affected. This  may be in part corroborated by the data presented in table 1, 
where we see that the means and standard deviation of c -IMT were below the cutoff in all groups 
(<0.9mm), indicating that all women included in the study had in fact normal IMT. The problem 
is that, in the present study, FMD was not predictive marker for endothelial damage at 
menopause and therefore the authors proposed IMT as marker of endothelial dysfunction. 
Although the authors state that are not aware of studies comparing the values of FMD and c -IMT 
in the three stages of menopause and have interpreted that c -IMT is a better predictor of 
endothelial dysfunction, I think that the problem is the use of a structural (anatomical) propriety 
for functional evaluation. I am afraid that this may not  be appropriate and lead to an equivocal 
results. Furthermore, when studying FMD in pre -menopausal women, measurements should be 
performed at the same time of the menstrual cycle (Harris RA et al. Hypertension. 
2010;55(5):1075 -1085). To minimize the impact  of hormonal changes or when the research 
focus is upon sex differences, menses (days 1 -7 of the menstrual cycle) offers the lowest 
attainable levels of both estrogen and progesterone in women and is therefore the optimum time 
for FMD studies. It is not cl ear whether this aspect was taken into account. If not, I think this 
should be included in the limitation section.  
 
Minor concerns:  
 
Material and methods  
Three groups were evaluated: Women at pre -menopause, with regular menstrual periods (n=60); 
at early  postmenopause, women aged 45 to 57 and less than 5 years since the last menstrual 
(n=58). Women older to 57 or with more than 5 years since the last menstrual period were 
classified at late postmenopause (n=59). In the older group (>57 years), were not th e means of c -
IMT and FMD affected by including younger women only by the fact of having more than 5 
years since the last menstrual period?  
I think that early cardiovascular damage was not clearly defined by the authors. For example, 
what was the cutoff po ints for IMT in the present study?  
 
Results  
Page 10, lines 8 -13 
More variables were different among the groups. Why only age, obesity, estrogen deficiency and 
heart rate variability were selected for regression models?  
 
Page 10, lines 19 and 26  
… Non HDL -C was marginally associated (p=0.059) (table 2 and figure 1).  
… In a second model removing age, we found the submission score marginally associated 
(p=0.069).  
I think that in both cases, if significance statistic was set at 0.05, neither non HDL -c nor 
subm ission score were statistically significant.   
 
Page 11, line 43  
Bechlioulis et al., 2010 correct to Bechlioulis et al.  
 
Table 1  
Both Body mass index (p=0,061) and anxiety (p=0.062) were not statistically different among 
the groups;  
I would delete the f column. I think it may not be necessary  
 
Figures  
I felt the lack of the correlation coefficient (r) and p values in the figures. I think they should be 
included.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
No 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
No 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
No 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an a dditional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
I recommend additional statistical review  
Quality of written English  
Please indicate the quality of language in the manuscript:  
Acceptable  
Declaration of competing interes ts 
Please complete a declaration of competing interests, considering the following questions:  
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
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3. Do you hold or are you currently applying for any patents  relating to the content of the 
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holds or has applied for patents relating to the content of the manuscript?  
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6. Do you have any non -financial competing interests in relation to this paper?  
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below. If your reply is yes to any, please give details below.  
 
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