Hidden Coronary Atherosclerosis Assessment but Not Coronary Flow Reserve Helps to Explain the Slow Coronary Flow Phenomenon in Patients with Angiographically Normal Coronary Arteries

Round 1

Reviewer 1 Report

In the paper "Hidden Coronary Atherosclerosis Assessment but not Coronary Flow Reserve Helps to Explain the Slow Coronary Flow Phenomenon in Patients with Angiographically Normal Coronary Arteries" the authors analyzed the role of coronary flow reserve and hidden epicardial atherosclerosis in explaining the slow coronary flow phenomenon. 

The research is well designed and conducted and the paper well written

- Minor point 

1. Please specify the inclusion criteria of the study

2. How intraobserver ed intraobserver echocardiographic variability were calculated?

3. Add to Table 2 the pharmacologic therapy of the enrolled population.

4. Please revise the manuscript for typos and error

Author Response

Thanks very much for your appreciations and constructive suggestions.

Reviewer1 #1: Please specify the inclusion criteria of the study

Response#1: Thanks for requesting this appropriate specification. In the method we have already specified the selecting criteria of the patients: “A total of 124 consecutive unselected patients scheduled for non-invasive Doppler recording of blood flow in the left main coronary artery (LMCA) and the whole LAD, along with coronary flow velocity reserve in the distal LAD by E-Doppler TTE, then referred for coronary angiography, whose coronary arteries resulted angiographically normal” ; However according with the reviewer comment we have introduced this description by means of a topic sentence: “The inclusion criteria were as it follows:..”

Reviewer1 #2: How intraobserver ed intraobserver echocardiographic variability were calculated?

Response#2: Thanks very much for this important observations. In a landmark study¹ in which we validated the CFR vs intracoronary Doppler flow wire we have also assessed all this intraobserver ed intraobserver variability; CFR variability came out to be minimal confirming how this approach is robust. In any cases I have reported below the table extrapolated from the original paper in which the data of CFR intra and inter-oberserver variability are shown. In addition we have underlined the concept of the low variability by saying in the introduction: “ CFR evaluated by enhanced transthoracic Doppler echocardiography (E-Doppler TTE) in the distal left anterior descending coronary artery (LAD), is a very robust parameter previously largely validated with excellent reproducibility and intra - interobserver variability [6-8]”.

Table 4. Intra-, Inter-Observer Measurement Variability and Reproducibility (from Circulation 1999)

r indicates the correlation coefficient; SEE, standard error of estimates; ULA, upper limit of agreement; LLA, lower limit of agreement; CI, confidence interval; other abbreviations as in Table 2.

1. Caiati C, Montaldo C, Zedda N, Bina A and Iliceto S. New noninvasive method for coronary flow reserve assessment - Contrast-enhanced transthoracic second harmonic echo Doppler. Circulation. 1999;99:771-778.

Reviewer1 #3: Add to Table 2 the pharmacologic therapy of the enrolled population

Response#3: Thanks for this question; we did not include the pharmacologic variables since the risk factors (with the exception of total cholesterol) was uniformly distributed between the two groups so the pharmacologic prescription is expected to mirror this situation and thus should not be significantly different between the two runoff groups. However in order to fulfill the reviewer expectation we have expanded the Table 2 and included the distribution of the drugs that as expected was not significantly different between the 2 groups.

Reviewer1 #4: Please revise the manuscript for typos and error.

Response#4: Thank you very much for this suggestion; in the final rush we made some typos and errors. Now the manuscript has been completely and carefully revised from this point of you and all the variations are evident since in the revision mode.

Reviewer 2 Report

I think that the article is very interesting and could give some new clues about the molecular mechanisms implicated in Slow Coronary Flow Phenomenon. The article is in general well written, but I have some minor comments:

-Line 73: Please rewrite the paragraph as it is too long and difficult to understand.

-Line 83: if you use pts as an abbreviation of patients it should be defined the first time it is used in the text.

-Table 2: It would be desirable to have p-values in the table even when they are not statistically significant.

It seems to be a statistically significant difference between rest SBP between both groups (Table 1). Did the authors checked if this parameter was associated with SCFph as they did for LDL cholesterol?

Author Response

Thanks very much for your appreciations and constructive suggestions.

Reviewer2 #1: Line 73: Please rewrite the paragraph as it is too long and difficult to understand.

Response#1: We agree and accordingly with the suggestions we rewrote it : “…CFR evaluated by enhanced transthoracic Doppler echocardiography (E-Doppler TTE) in the distal left anterior descending coronary artery (LAD), is a very robust parameter previously largely validated with excellent reproducibility and intra - interobserver variability [6-8]. Therefore, this study was aimed at understanding firstly whether CFR as assessed by E-Doppler TTE along with appropriate vasodilation, is lower in SCFph patients compared to subjects with a normal runoff and secondly, whether hidden athero as detected by intra-coronary ultrasound (IVUS) in the epicardial conduit is associated with the SCFph. For this purpose, 124 subjects with angiographically normal coronary arteries (24 showing the SCFph) were enrolled. “

Reviewer2 #2: -Line 83: if you use pts as an abbreviation of patients it should be defined the first time it is used in the text.

Response#2: Thank you very much for this correct observation. In the final rush we forgot to check for the abbreviations legends. All the paper has been reviewed in this sense and all the abbreviations have been defined the first time they have been used. (all this modifications are reported in text in the revision mode).

Reviewer2 #3: -Table 2: It would be desirable to have p-values in the table even when they are not statistically significant.

Response#3: We have added all the p values even if not significant in the table 2 as requested.

Reviewer2 #4: It seems to be a statistically significant difference between rest SBP between both groups (Table 1). Did the authors checked if this parameter was associated with SCFph as they did for LDL cholesterol?

Response#4: Thanks for asking; in Table 1 the hemodynamic values have been already subdivided in the two categories of runoff (normal and slow); so systolic blood pressure statistics indicate that a lower systolic pressure was associated with the slow runoff group; however the effect size was minimal and therefore we did not comment on that.