Multimodality Imaging to Detect Rejection, and Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients—An Illustrative Review

Round 1

Reviewer 1 Report

The authors provide a comprehensive review of the different non-invasive imaging techniques that are either currently being used or could be considered for clinical use in detecting heart transplant rejection and or the presence of coronary artery vasculopathy. The abstract and introduction however are a bit cumbersome and would be improved by more clearly stating the goal, ie to identify those methods that could be used to assess for rejection and CAV. 

In the first section on echocardiography, there is a discussion about increasing LV mass and thickening due to graft edema and infiltration etc. that is associated with Figure 1. While I believe all this to be true, I am not sure why this is relevant to the stated purpose above as these changes are not thought to signal rejection or CAV in a post transplant patient. 

In this same section, coronary flow reserve as well as contractile reserve are introduced without any explicit definition of what these techniques are or what they entail which would be important for the reader who is not of a sophisticated imaging background, even just a brief explanation would be useful. 

The future directions are useful, but overall this feels like a large amount of information about all the techniques without any discussion of which one in particular or which ones in combination might be of the highest yield to the clinician. 

Author Response

Response to Reviewer 1

The authors provide a comprehensive review of the different non-invasive imaging techniques that are either currently being used or could be considered for clinical use in detecting heart transplant rejection and or the presence of coronary artery vasculopathy. The abstract and introduction however are a bit cumbersome and would be improved by more clearly stating the goal, ie to identify those methods that could be used to assess for rejection and CAV.

• Thank you. We have edited the abstract and introduction to state the purpose of this review paper.

In the first section on echocardiography, there is a discussion about increasing LV mass and thickening due to graft edema and infiltration etc. that is associated with Figure 1. While I believe all this to be true, I am not sure why this is relevant to the stated purpose above as these changes are not thought to signal rejection or CAV in a post transplant patient.

• I agree with the reviewer that a 2-D echo showing myocardial thickening is to differentiate usual cardiac translation immediately after transplant from graft dysfunction. As it takes about 3-6 months of RV dysfunction to improve and LV diastolic function to become normal, we feel it is essential to show the echocardiography finding of a normal expected thickened appearance of LV immediately after a heart transplant. We clarified the message in this section.

In this same section, coronary flow reserve as well as contractile reserve are introduced without any explicit definition of what these techniques are or what they entail which would be important for the reader who is not of a sophisticated imaging background, even just a brief explanation would be useful.

• We have elaborated on CFR and described its physiology and usefulness.

The future directions are useful, but overall this feels like a large amount of information about all the techniques without any discussion of which one in particular or which ones in combination might be of the highest yield to the clinician.

• We changed the section “Future direction” and described the current status of each imaging method and used AI as the future to analyze the information obtained from multimodality imaging.

Reviewer 2 Report

This is a well written manuscript entitled:  Multimodality Imaging to Detect Rejection and Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients-An Illustrative Review.

General Comments

Noninvasive imaging plays a key role in screening for rejection and allograft vasculopathy.  However, there are limitations to echocardiogram as the authors have discussed.  The modalities discussed in the manuscript all play a role in surveillance of rejection and coronary disease.  This will be an important review for all who take care of patients following heart transplant.   

The review is well structured. I do suggest organizing the review with Tissue Doppler Imaging, Speckle Tracking, and Stress Echocardiography as subcategories under Echocardiography. Likewise place adenosine stress under MRI

Specific Recommendations

1.     Z-scores and LV mass/thickness may also reflect increased thickness when the heart is from an oversized donor.

2.     The legend for Figure 1 should state “increased wall thickness.”

3.     For Figure 2, I recommends including a normal Tissue Doppler image.

4.     I do not believe Figure 3 adds utility to the manuscript. I would exclude the images. I recommend including normal strain data in the body of the manuscript.

Author Response

Response to Reviewer 2

This is a well written manuscript entitled:  Multimodality Imaging to Detect Rejection and Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients-An Illustrative Review.

- Thank you

General Comments

Noninvasive imaging plays a key role in screening for rejection and allograft vasculopathy. However, there are limitations to echocardiogram as the authors have discussed. The modalities discussed in the manuscript all play a role in surveillance of rejection and coronary disease. This will be an important review for all who take care of patients following heart transplant.  

• Thank you.

The review is well structured. I do suggest organizing the review with Tissue Doppler Imaging, Speckle Tracking, and Stress Echocardiography as subcategories under Echocardiography. Likewise place adenosine stress under MRI

• Thank you. We subgrouped the TDI, STE, and stress echo under echocardiography heading, IVUS, and OCT under heading intracoronary imaging, and a separate category for CTA, CMR, SPECT, and PET

Specific Recommendations

1. Z-scores and LV mass/thickness may also reflect increased thickness when the heart is from an oversized donor.

• Thank you, we added the sentence.

2. The legend for Figure 1 should state “increased wall thickness.”

• Thank you, we changed the legend in Figure 1.

3. For Figure 2, I recommends including a normal Tissue Doppler image.

• Thank you, we added a normal TDI

4. I do not believe Figure 3 adds utility to the manuscript. I would exclude the images. I recommend including normal strain data in the body of the manuscript.

• The goal of the paper is the illustrative review, we believe a picture is worth of thousand words. We hope the reviewer will not oppose keeping this figure.

Reviewer 3 Report

I appreciate the opportunity to review this article by Das et al. The authors are commended for a comprehensive review on imaging in heart transplant pediatric patients. The review is well written. It certainly warrants publication. I have some minor comments listed below. I also would ask the authors to consider including CTA as an important imaging modality for CAV, or at least comment on why it was not included.

1. I would rewrite the final sentence of the 2nd paragraph (lines 80-81). The second half of this sentence doesn't fit well. It's just not a good or clear sentence. Should be stronger.

2. By convention, the E' is written e' for TDI (lines 122).

3. Line 129, fix this: "(18)(18)(18)"

4. Line 320. Should be "removed"

5. Consider moving sentence in lines 68-71 up to the end of the prior paragraph.

6. In the last paragraph of the introduction, please add the time frame of the literature search (i.e. through 12/31/2021, or whenever).

Author Response

Response to Reviewer 3

I appreciate the opportunity to review this article by Das et al. The authors are commended for a comprehensive review on imaging in heart transplant pediatric patients. The review is well written. It certainly warrants publication. I have some minor comments listed below. I also would ask the authors to consider including CTA as an important imaging modality for CAV, or at least comment on why it was not included.

• Thank you. We added a new paragraph on CTA for surveillance of CAV. “CT coronary angiography (CTA) has higher sensitivity and specificity for diagnosing CAV compared to stress echocardiography. It has been used in adults for routine detection of CVA with good image quality and low radiation dose. (42) With photon-counting CT, we are entering a new era that decreases radiation dose and less need for contrast agent CTA to detect CAV early in the disease process. (43) The advantage of CTA is that it is accessible in most centers, has a relatively low cost compared to MRI, and has high-resolution images. Also, based on CTA, 2010 ISHLT has decreased the stenosis of coronary to 50% rather previous 70% for early diagnosis of CAV. (3) The disadvantages are radiation exposure; contrast cannot be used with renal dysfunction and does not give any information on coronary microvasculature. CTA is considered a gatekeeper for coronary angiography. An example of early detection of CAV in a 16-year-old HT recipient is shown in Figure 4. However, it has been challenging to use CTA in younger HT recipients because of their high heart rate, small vessel size, and inability to lie still or breath hold.”

1. I would rewrite the final sentence of the 2nd paragraph (lines 80-81). The second half of this sentence doesn't fit well. It's just not a good or clear sentence. Should be stronger.

• Thank you. We modified the sentence and added a new line to describe the role of OCT.

2. By convention, the E' is written e' for TDI (lines 122).

         - Thank you. We changed E’ to e”.

3. Line 129, fix this: "(18)(18)(18)"

        - Thank you. We corrected the error and removed duplicate numbers.

4. Line 320. Should be "removed"

        - Thank you, we deleted line 320.

5. Consider moving sentence in lines 68-71 up to the end of the prior paragraph.

• Thank you. We moved the sentences from 68-71 to the end of the first paragraph.

6. In the last paragraph of the introduction, please add the time frame of the literature search (i.e. through 12/31/2021, or whenever).

• Thank you, we added the timeframe up to 4/30/2022.