Multi-Modality Cardiovascular Imaging Assessment in Fabry Disease

Round 1

Reviewer 1 Report

This is a study aimed to review the multi-modality imaging approach in the assessment of Fabry disease.  The authors analyze in a very good way the myocardial thickness imaging approach but this have little to do with the certain diagnosis of Fabry disease. Myocardial hypertrophy is found in a variety of myocardial diseases and the imaging approach simply identify the phonotype rather a specific disease per se. Sphingolipid accumulation in the heart can not be a direct imaging finding.   

Author Response

Many thanks for your comments which indeed are correct. This review article outlines the various imaging modalities and techniques that enable clinicians to stage and prognosticate rather than diagnose. When patients have an enzymatic or genotypic diagnosis of Fabry Disease confirmed on biochemical testing, they then proceed with cardiac imaging to investigate cardiac involvement to stage and prognosticate. We have therefore removed the word “diagnosis” from the abstract. Please see amended sentence below:

This review outlines the advances in multimodality imaging in staging and prognosticating FCM as well the applications of cardiac imaging in assessing symptoms and complications of FCM.

 

Reviewer 2 Report

Yhe manuscript brilliantly revises the state of the art in the difficult multimodal diagnosis of Fabry disease. The work is well structured and organized, it appears very clear and pleasant to read. The authors focus on the implications of current advances in imaging technology in the diagnosis and management of Fabry Disease.  The subsections of the paper are very clear and useful to the reader.

In the section "Diagnosis: Tissue carachterization" I would suggest to the authors to spend a few words on the possible and theoretical use of new echocardiographic technologies in identifying myocardial fibrosis. A recent review on dilated cardiomyopathies (https://doi.org/10.3390/jcm10235518) dedicated a sub-chapter (number 8) precisely to echocardiographic advances in the detection of fibrosis and scars. While MRI remains the gold standard in identifying fibrosis, new ultrasound technologies could find a niche in this area as well.

Author Response

Yhe manuscript brilliantly revises the state of the art in the difficult multimodal diagnosis of Fabry disease. The work is well structured and organized, it appears very clear and pleasant to read. The authors focus on the implications of current advances in imaging technology in the diagnosis and management of Fabry Disease.  The subsections of the paper are very clear and useful to the reader.

In the section "Diagnosis: Tissue carachterization" I would suggest to the authors to spend a few words on the possible and theoretical use of new echocardiographic technologies in identifying myocardial fibrosis. A recent review on dilated cardiomyopathies (https://doi.org/10.3390/jcm10235518) dedicated a sub-chapter (number 8) precisely to echocardiographic advances in the detection of fibrosis and scars. While MRI remains the gold standard in identifying fibrosis, new ultrasound technologies could find a niche in this area as well.

Many thanks for your comments. Please find our added paragraph below:

Novel technologies are emerging in identifying myocardial fibrosis in both ischaemic and non-ischaemic cardiomyopathies [Faggiano et al] including the use of contrast-enhanced 3D TTE, speckle tracking 3D TTE, pulse cancellation ultrasound techniques and radiomic-based analysis. Their application has not been tested in FD specifically but provides an area of future work to identify fibrosis and scar associated with FCM which enables clinicians to stage and prognosticate with both TTE and CMR.

Reviewer 3 Report

In the present work authors aimed to review the current state-of-the-art in the multimodality imaging for the diagnosis and management of the cardiomyopathy that often occurs in patients with Fabry disease. Authors extensively described the different types of imaging tools in relation to several cardiac complications of this rare disease.

Although the work is overall well organized, here a few consideration and suggestions:

- the sentence “FD patients were frequently started on therapy prematurely” in line 92-93 might be quite misleading since, as authored stated properly in their work, early initiation of ERT therapy is crucial in FD patients. Probably authors referred to the adjunctive treatment for the cardiac outcomes, but this should be better stated. Please rephrase

- the images should be better adapted in the layout of the manuscript and with the same high within the same figure (e.g. figure 4 the images have different dimensions). Moreover, a distinction in panel A-B-C rather than in left, middle and right could be more helpful for the reader.

- in line 99 there are two consecutive apostrophes, please correct

- in line 303 please check the typos of the letter n before the word “Holter”

- in line 304 there is maybe double space between arrhythmia and in those, please check this a n throughout the manuscript

- in line 307 please ad the full stop at the end of the sentence.

- in line 334 please check the comma in the spelling of the molecule

- in line 335 please add the hyphen in “lyso Gb3

- in line 367 please correct the bracket

- in line 462 please ad the full stop at the end of the sentence

- please check reference n. 5, is this a peer reviewed article?

- please add in reference n.8 and 68 the missing information (number, issue, year)

- please check and correct reference n. 55

Author Response

In the present work authors aimed to review the current state-of-the-art in the multimodality imaging for the diagnosis and management of the cardiomyopathy that often occurs in patients with Fabry disease. Authors extensively described the different types of imaging tools in relation to several cardiac complications of this rare disease.

Although the work is overall well organized, here a few consideration and suggestions:

- the sentence “FD patients were frequently started on therapy prematurely” in line 92-93 might be quite misleading since, as authored stated properly in their work, early initiation of ERT therapy is crucial in FD patients. Probably authors referred to the adjunctive treatment for the cardiac outcomes, but this should be better stated. Please rephrase

Many thanks for this comment. We have made the following change in the manuscript:

“TTE consistently over-estimated both MWT and LV mass, suggesting that FD patients  frequently are liable to  over-estimated MWT and LV mass.”

 

- the images should be better adapted in the layout of the manuscript and with the same high within the same figure (e.g. figure 4 the images have different dimensions). Moreover, a distinction in panel A-B-C rather than in left, middle and right could be more helpful for the reader.

Many thanks for this comment. We have amended the figure accordingly

- in line 99 there are two consecutive apostrophes, please correct

We have corrected

- in line 303 please check the typos of the letter n before the word “Holter”

We have corrected this and added the word “on”

- in line 304 there is maybe double space between arrhythmia and in those, please check this a n throughout the manuscript

We have removed the double space

- in line 307 please ad the full stop at the end of the sentence.

We have added the full stop

- in line 334 please check the comma in the spelling of the molecule

We have removed this comma

- in line 335 please add the hyphen in “lyso Gb3

We have added the hyphen

- in line 367 please correct the bracket

We have corrected the bracket

- in line 462 please ad the full stop at the end of the sentence

We have added the full stop here

- please check reference n. 5, is this a peer reviewed article?

Many thanks. This is not a peer reviewed article but a consensus expert statement

- please add in reference n.8 and 68 the missing information (number, issue, year)

Many thanks We have added this

- please check and correct reference n. 55

Many thanks. We have corrected this

Reviewer 4 Report

The authors provide a review of the role of multi-modality cardiovascular imaging in the management of patients with Fabry disease.

The main limitation of the paper is the lack of novelty as there are a number of prior original studies and review papers on the topic. The section on "Staging Disease" and the relatively non-specific figures with minimal figure legend details could also be improved.

Nevertheless, the strengths of the paper are that it is well-written, provides clear clinically relevant points, and includes some important updates from recent studies.

Overall, the paper accomplishes its aim of providing an overview of the current state of multi-modality imaging in the assessment of cardiac involvement in Fabry disease.

This reviewer would support publication with minor revisions (see suggestions in the attached PDF).

Comments for author File: Comments.pdf

Author Response

• Title: Consider modifying to highlight the focus on “cardiovascular” imaging •

 

Many thanks. We had added this to the title

 

• Line 21 consider changing “this potentially providing” to “… process, thus potentially providing” or “This potentially provides…”

 

Many thanks. We have changed this to “This potentially provides”

 

• Line 40 consider changing “it is a paradigm” to “it serves as a paradigm”

 

Many thanks. We have changed this to “it serves as a paradigm”

 

• Lines 46-47 “Echocardiography” should be in lower case 

 

Many thanks. We have changed this to lower case

 

• Line 52 statement that “TTE imaging triggers the initiation of ERT or OCT at the point of diagnosis of the phenotype” should be reviewed. According to the reference provided, “in males with ‘classical variants […] Fabry-specific therapy should be considered at diagnosis” regardless of TTE imaging findings.

 

Many thanks. We have amended the phrase as below:

In those with confirmed ‘classical’ variant FD (in whom leucocyte enzyme activity is less than 5%), Fabry-specific therapy is considered at the point of diagnosis of the phenotype [5]. In those with ‘later onset’ variants, TTE imaging triggers the initiation of ERT or OCT in patients with a maximum wall thickness (MWT) >12mm in males and >11mm in females [6], or an increase in LV mass above normal range for age and sex (see Figure 1). American and European guidelines on chamber quantification specify that measurements of wall thickness and mass should be performed using 2D echocardiography [7].

 

• Figure 3: Would the authors be able to provide a more illustrative figure than the one shown? The current figure seems to simply show a single example of a typical 16-segment map of the LV with wall thickness measurements apparently generated by AI. However, there are no details of what AI model was used and no visual representation of how it compares to expert readers, therefore adding little to what is written in the text.

 

Many thanks for this comment. We have amended this figure. We have included a figure with manual contouring of the MWT in different segments of the mid LV wall, an AI-generated image, a 16 segment map of MWT using AI, and finally a corresponding 4 chamber view depicting the slice through the LV. We have added the following figure legend:

CMR analysis of wall thickness using manual contouring versus AI. A: Manual contouring and corresponding quantification of MWT using a 3D short-axis stack image of the mid-wall of the LV . B: Corresponding 4 chamber view demonstrating the mid-wall slice through the LV where the manual/AI contouring is done. C: Semi-automated AI-generated quantification of wall thickness derived from 3D short axis imaging demonstrating end-diastolic MWT. D: Corresponding map of AI-generated MWT measurements (millimetres) from base-apex of the LV. Images contoured and semi-automated AI conducted using cvi42 version 5.11.2 (Circle Cardiovascular Imaging, Calgary, Alberta, Canada).

 

• Figure 4: PW sample volume is generally placed at the tip of the mitral leaflets not through the mitral valve.

 

Many thanks. We have amended the text to “pulsed-wave doppler through the mitral valve leaflets”

 

• Figure 5: Consider including an apical long-axis view as well since this is usually necessary for an LV GLS measurement. Can the authors also clarify what the two numbers for RV GLS represents? Is one global and the other free wall strain?

 

Many thanks. We have added a separate figure with CMR (Figure 6) long axis assessment of strain. We have added the following figure legend:

Long axis CMR assessment of 2D-strain using feature tracking by manually contouring endocardial and epicardial borders in end-diastole. A: apical 4-chamber view, B: apical 2-chamber view, C: apical 3-chamber view, D: myocardial strain curve with normal peak GLS measured (-26%)

 

 

We have clarified the RV GLS as follows:

GLS assessment of the RV from the Apical 4-chamber view demonstrating reduced GLS ( free wall strain -16.1% and longitudinal strain -12.2%).

 

• Line 199: Could the authors provide a proposed explanation for why T1 relaxation times increase or pseudonormalise?

 

Many thanks We have amended the text as follows:

T1 lowering is progressive up until this ‘pseudonormalisation’. Native non-contrast T1 may lengthen with interstitial expansion due to a number of processes including the development of myocardial fibrosis and inflammation, likely due to increased free fluid associated with this state [Dass S et al 2012). T1 lowering is greater in males than females and, as with LVH-progression, the decline in values continues despite ERT

 

• Staging Disease section: Is this an appropriate heading for this section? There do not seem to be any well-defined stages based on the imaging that have actual treatment implications at this time. Would the authors be able to propose an actual staging system and its clinical significance? Alternatively, should this section be a continuation of “Tissue Characterisation” but perhaps post development of LVH?

 

Many thanks. We have changes the headings to “Diagnosis: Tissue characterisation in early disease” and “Diagnosis: Tissue characterisation in later disease”

 

• Line 262: ECG is mentioned as having a role in ‘staging’ but seems out of place in this review about multi-modality imaging and since it was not mentioned at all in the section.

 

Many thanks. We have removed “ECG”

 

• Line 281: Consider adding “… and those… with LVH- and normal renal function”

Many thanks. We have amended the text as follows:

Comparisons were made between patients who were LVH+ and had impaired renal function and those who were LVH- with normal renal function at initiation of ERT.

 

• Lines 288-289: Consider including definitions of GLS, myocardial mechano-energetic efficiency, and strain-based myocardial work efficiency for non-expert readers.

 

Many thanks. We have included the definitions and amended the text as below:

GLS is assessed by 2D speckle tracking echocardiography and has emerged as a technique to assess early impairment in LV function. Myocardial mechano-energetics efficiency by definition is the ratio of work delivered by the myocardium versus the amount of total energy produced per heart beat and is assessed on ultrasound.

 

• Line 305: Consider revising to “this finding is consistent with the established prognostic…”

 

Many thanks. We have revised to phrase to the suggested text.

 

• Line 341-343: The comment about “mandating” investigation of chest pain… with noninvasive CT coronary angiography” seems a bit too strong. Consider revising to: “given the potential presence of perfusion abnormalities even in the absence of significant epicardial stenosis, CT coronary angiography provides an effective non-invasive modality for the identification of atherosclerosis.”

 

Many thanks. We have rephrased the text accordingly

 

• Lines 385-386: Consider adding “as opposed to… or in addition to”

Many thanks. We have rephrased as below:

The exact aetiology of white matter lesions in FD is uncertain but these data raise the possibility that altered atrial size and function may predispose the FD patient to atrial arrhythmia and stroke, in addition to simultaneous sphingolipid accumulation in the heart and brain

 

• Lines 403-404: Minor copy-editing suggestion: “This is compared with the estimated prevalence of moderate or greater VHD in the general population of 5.2-6.0%.”

Many thanks. We have amended as follows:

This compared with the estimated prevalence in of moderate or greater VHD in the general population of 5.2-6%.

 

• Figure 9: Similar to Figure 3, this is a relatively non-specific image showing mitral regurgitation and a few techniques to grade the severity. Consider precisely describing the severity of MR in this example. Also, while the text is trying to make a point about recent data suggesting a higher-than-expected prevalence of VHD, this Figures appears to show mild to moderate MR.

Many thanks. We have amended the text as below to include quantification and grading of MR:

2D TTE MR assessment in an adult with advanced Fabry cardiomyopathy and co-existing end stage renal disease. Left: Parasternal long axis view demonstrating LVH, left atrial dilatation, bilateral annular calcification of the mitral valve (causing basal restriction) with moderate MR evident on colour Doppler and vena contracta of 0.4cm (moderate); Middle: Apical 4 chamber view demonstrating bilateral annular calcification of the mitral valve with MR on colour doppler and proximal isovelocity surface area (PISA) measurement of 0.3cm (moderate); Right: Apical 4 chamber view demonstration  moderate MR on colour Doppler.

 

 

• Consider changing “demonstration” to “demonstrates” on Line 411.

 

Many thanks. We have amended the text as follows:

Apical 4 chamber view demonstrating  moderate MR on colour Doppler.

 

 

Round 2

Reviewer 1 Report

Very nice effort

Author Response

Many thanks for your comment. We have amended the last line of introduction. We have removed "diagnosis" and replaced this with "staging, managing and prognosticating"