Arterial Stiffness Is an Important Predictor of Heart Failure with Preserved Ejection Fraction (HFpEF)—The Effects of Phosphate Retention
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
This manuscript presents the results of original research that provides a new perspective on the development of heart failure and atherosclerosis. The shift from the widely held view of the predominant role of calcium metabolism to that of phosphate metabolism has allowed the identification of new factors, the control of which is capable of qualitatively changing existing methods of predicting the development of complications and mortality in cardiac patients. The introduction adequately describes the problem to be solved and the methods used have allowed us to obtain and analyse a wide range of clinically important data. The results are discussed in accessible and understandable language, and reasonable conclusions are drawn about the need to control arterial wall stiffness as a prognostic factor in heart failure patients with preserved cardiac ejection fraction. As a limitation of the study, the choice of the patient cohort studied is justified.
I believe that the manuscript can be accepted for printing without additional corrections.
Author Response
We appreciate Reviewer #1 for sparing his precious time for giving us valuable comments on our paper. Your comments have encouraged us very much.　 Thank you very much.
Reviewer 2 Report
Comments and Suggestions for Authors
The authors present a study associating phosphate retention (using serum levels of FGF23 as a surrogate), arterial stiffness and HFPEF.
They show that age, renal function, systolic BP, markers of LV dysfunction by echocardiography are associated with HFPEF, but also correlate in a linear fashion with arterial stiffness measured by PWV. Are these relationships independent or other confounders?
The serum FGF23 levels are significantly higher in the HFPEF group.
In this study, it is not clear how FGF23 levels are directly connected to arterial stiffness and HFPEF, mechanistically. The conclusion that can be made that there is an association, but not causal given higher serum levels in the HFPEF group. There is a comment made on Line 213 about this relationship and despite significant the R=0.3.
Why are serum phosphate levels no different in the HFpEF and non-HFpEF groups?
There is an analysis of TAC, but it is not put in the linear aggression analysis and should be included.
The inclusion of Table 2 with gender comparison is not supportive of the primary intent of the study and does not add to the analysis/discussion. Why is this included?
Comments on the Quality of English Language
Minor editing of grammar needed.
Author Response
We appreciate Reviewer #2 for sparing his precious time for giving us valuable comments on our paper. His comments have improved our manuscript much.　Following are our responses to the reviewer ‘s comments:
The authors present a study associating phosphate retention (using serum levels of FGF23 as a surrogate), arterial stiffness and HFPEF.
- reviewer ‘s comments
They show that age, renal function, systolic BP, markers of LV dysfunction by echocardiography are associated with HFPEF, but also correlate in a linear fashion with arterial stiffness measured by PWV. Are these relationships independent or other confounders?
(Response) Thank you for your important question. We think arterial stiffness (PWV) is a significant independent factor for HFpEF from our logistic regression analysis. Arterial stiffness produces reflection wave (augmentation pressure), and the more arterial stiffness produce the more afterload leading to LV thickness and or HFpEF. Furthermore, you know that arterial stiffness is affected by many factors: aging, renal dysfunction and blood pressure etc. Phosphate retention (aging promoting factor) is an important cause of arterial calcification. (J Atheroscler Thromb 2021, 28, 203-213.ect.) Now calciprotein particles (CCPs) due to phosphate retention is thought to be an important effector for arterial calcification (and /or arterial stiffness) from the recent aging research results as we explained in this paper. (Kidney Int 2020, 97, 702-712. Sci Rep 2020, 10, 20125.)
- reviewer ‘s comments
The serum FGF23 levels are significantly higher in the HFPEF group. In this study, it is not clear how FGF23 levels are directly connected to arterial stiffness and HFPEF, mechanistically. The conclusion that can be made that there is an association, but not causal given higher serum levels in the HFPEF group. There is a comment made on Line 213 about this relationship and despite significant the R=0.3.
(Response) Thanks for his questions. As he say, the serum FGF23 levels are significantly higher in the HFPEF group. There is a significant relationship apparently between FGF23 and HFpEF (R=0.3). (as indicating Table 3) FGF23 is a good marker of phosphate deterioration of phosphate homeostasis and/or phosphate retention. FGF23 may has no promoting effects for arterial stiffness and HFpEF, however it decreases the serum phosphate level via phosphate excretion from nephron.
- reviewer ‘s comments
Why are serum phosphate levels no different in the HFpEF and non-HFpEF groups?
(Response) Thank you important questions. The retention of phosphate in the blood produce the unfavorite aging process in the body, so the blood level is controlled within normal range by FGF23 releasing from the bones etc. mainly.
We thought that there was no difference in the serum phosphate levels between the HFpEF and Non-HFpEF groups, but the deterioration of phosphate homeostasis (phosphate retention) has appeared in HFpEF from the differences of serum FGF23 levels.
- reviewer ‘s comments
There is an analysis of TAC, but it is not put in the linear aggression analysis and should be included.
(Response) Thank you for question. TAC is a representative feature of aging. It is an important factor leading to arterial stiffness as shown in our previous study. We excluded TAC in multi logistic regression analysis, because there was significant collinearity between TAC and PWV (r=0.669, p<0.0001).
- reviewer ‘s comments
The inclusion of Table 2 with gender comparison is not supportive of the primary intent of the study and does not add to the analysis/discussion. Why is this included?
(Response) Thank you for your question. The serum phosphate level is significantly higher in female than male. This means that elderly females have disadvantage in phosphate control. There is a possibility that elderly females frequently have osteoporosis leading to increasing serum levels of phosphate. The elderly female, therefore, indicates higher rates of HFpEF than male practically. There are some reports that osteoporosis treatments have advantage in protection of cardiovascular diseases. Phosphate control treatment is now focused on protection for cardiovascular disease. Therefore, we showed sex differences including phosphate. We think this Table 2 will be focused in feature in sex difference.
Please confirm line from343 to 349 in revised manuscript.
Thank you very much for your advice and cooperation.
Reviewer 3 Report
Comments and Suggestions for Authors
Mizuno et al demonstrate correlation between various parameters, e.g.: age and PWV, PWV and LV mass index, PWV and LV wall thickness…
While the data presented is somewhat interesting, it is out of focus and the authors do not precisely separate between state of knowledge and the novel data. The authors should present/state clearly, what is new here.
The data in some instances is over interpreted, e.g.: The authors conclude that the phosphate retention is an important predictor of the HFpEF, I am assuming via increase in arterial stiffness and PWV. How do authors conclude this? How was phosphate retention measured, via eGFR? If yes, correlation of eGFR with PWV (Figure 1) could be merely age dependent changes in both parameters. Other example could be eGFR and vital capacity of the lung. Both decline by aging and also well correlate with each other, although completely independently. PWV increases with age, whereas eGFR declines, resulting in correlation, not necessarily dependent one.
First conclusion of the abstract is also overstated. Here one can only talk about associations and not causal effects.
Were other cardiac parameters assessed, e.g. EDV, ESV…
Introduction is somewhat confusing and out of focus. Please limit and/or omit the information, which is not necessarily related to the current data.
Discussion seems more like a second description of the results and literature rather interpretation of the data in conjunction with a state of knowledge. This must be improved.
Comments on the Quality of English Language
Well written.
Author Response
We appreciate Reviewer #3 for sparing his precious time for giving us valuable comments on our paper. His comments have improved our manuscript much.　Following are our responses to the reviewer ‘s comments:
Mizuno et al demonstrate correlation between various parameters, e.g.: age and PWV, PWV and LV mass index, PWV and LV wall thickness…
- While the data presented is somewhat interesting, it is out of focus and the authors do not precisely separate between state of knowledge and the novel data. The authors should present/state clearly, what is new here.
(Response) Thank you for your suggestions.
It is known that the cause and treatment of HFpEF have not yet been resolved in the cardiovascular field, and many researchers are currently competing with their own theories. On the other hand, HFpEF is frequently observed in patients with CKD and especially in elderly female patients with osteoporosis. Recently there is a growing recognition of the causal interplay between arterial stiffness and HFpEF. This research was conducted with the purpose of reconsidering the line of this thinking. This is a cross-sectional study, not to identify the cause of HFpEF, but rather to statistically examine the pathology and predictors of HFpEF from the perspective of arterial stiffness caused by phosphate retention, which has recently focused in aging research area. Therefore, we explained the background and the objectives logically in introduction. We changed explanation in revised text as your suggestion.
Thank you.
Please confirm line 66-79 with highlighted in revised manuscript.
- The data in some instances is over interpreted, e.g.: The authors conclude that the phosphate retention is an important predictor of the HFpEF, I am assuming via increase in arterial stiffness and PWV. How do authors conclude this? How was phosphate retention measured, via eGFR? If yes, correlation of eGFR with PWV (Figure 1) could be merely age dependent changes in both parameters. Other example could be eGFR and vital capacity of the lung. Both decline by aging and also well correlate with each other, although completely independently. PWV increases with age, whereas eGFR declines, resulting in correlation, not necessarily dependent one.
(Response)
Thanks for his comments. We conclude that arterial stiffness, not phosphate retention, is an important predictor of HFpEF. To protect misunderstanding, we divided the title into new title and subtitle as follows with taking his suggestion into account.
Arterial stiffness is an important predictor of heart failure with preserved ejection fraction (HFpEF) - possible effects of aging promotor: phosphate -
Please confirm new title with highlighted in revised manuscript.
He speculates that this is due to arterial stiffness and increased PWV. We agree with what has been commented. We also believe that there is a strong relationship between HFpEF and arterial stiffness. It is not yet clear, however what mechanism causes the arterial stiffness according to aging and CKD. We will statistically examine the relationship between HFpEF and arterial stiffness not only from viewing of cardiovascular area but also from the perspective of phosphate retention, which has recently attracted attention in aging and endocrinology research area. We measured the serum levels of FGF23 and VD3 as phosphate retention markers, as we presented before. (Circ Rep 2023, 5, 4-12.)
As he pointed out, age is included in the eGFR value calculation. As mentioned in the paper, the number of nephron decreases with aging or decline in renal function, so it decreases. The serum Cr does not include age values. Even when Cr is used instead of eGFR, significant correlations similar to those of eGFR is observed between arterial stiffness and HFpEF as follows.
Association between Cr and PWV. R=0.210, P=0.008
Association between Cr and HFpEF. R=0.196, P=0.013
Thank you.
３）　　　First conclusion of the abstract is also overstated. Here one can only talk about associations and not causal effects.
（Response）
As mentioned earlier, this study is not a paper showing the causes and consequences of HFpEF. This is clearly explained in the limitations section.
This is a study that uses statistics to logically examine the relationship and whether it can become a predictor of HFpEF using logistic regression analysis. Using FGF23, we indicated that phosphate retention, an aging promoting factor, is involved in arterial stiffness, which is thought to be caused by nephron loss caused by aging and renal dysfunction. We believe that this is a paper that shows this. I would like to respectfully inform him that this is not a paper that describes and summarizes the causes and consequences of HFpEF, however we discuss the predictor of HFpEF by using regression analysis.
Please confirm line 23 to 25 in abstract with highlighted in revised manuscript.
４）　　Were other cardiac parameters assessed, e.g. EDV, ESV…
（Response）　
We apologize for the inconvenience, but from the beginning, this study did not focus on HFrEF, and we only considered the relationship with cardiac parameters related to left ventricular diastolic dysfunction and left ventricular hypertrophy, including BNP, in accordance with the ESC2019 HFpEF Guideline in this time.
５）　　Introduction is somewhat confusing and out of focus. Please limit and/or omit the information, which is not necessarily related to the current data.
（Response）
We apologize for the inconvenience, but although we have already mentioned this in 2), we have made some changes to the text in consideration of your advice.
Please confirm line from 66 to 69 in introduction with highlighted in revised manuscript.
６）　　Discussion seems more like a second description of the results and literature rather interpretation of the data in conjunction with a state of knowledge. This must be improved.
（Response）
This is a cross-sectional observation study. We never described arterial stiffness due to phosphate retention is a cause of HFpEF. We can understand the limitations for causes and effects, as described in limitation in this paper. We stated arterial stiffness is a predictor of HFpEF scientifically and logically by using logistic regression analysis. In consideration of your points, however we changed some expression in the text in the discussion. Furthermore, we changed the title to express more scientifically as his suggestions.Please confirm line 383 to 383 in limitation with highlighted in revised manuscript.Please confirm line 390 to 393 in conclusion with highlighted in revised manuscript.
Thank you very much for your advice and cooperation.
Round 2
Reviewer 2 Report
Comments and Suggestions for Authors
Thank you for addressing major concerns.
Recommend changing subtitle from "possible effects of aging promoter: phosphate" to "Association with phosphate retention."
Causal links have been removed and associations described.
Comments on the Quality of English Language
Minor edits to English language.
Author Response
I would like to take this opportunity to thank you for your very valuable guidance and advice. I think the subtitle you suggested is excellent, so I have changed it. Please confirm the subtitle change. Thank you very much for your guidance and cooperation during this time. thank you very much.
