Importance of Increased Arterial Resistance in Risk Prediction in Patients with Cardiovascular Risk Factors and Degenerative Aortic Stenosis

Round 1

Reviewer 1 Report

In this paper Baran et al. evaluted the prognostic ability of carotid and vertebral resistive index (RI) and pulsatility index (PI) for heart failure and major cardiovascular events among patients with or without degenerative aortic valve stenosis and cardiovascular risk factors. The authors found a positive association of high RI and PI for events in a 2,5 years follow-up.

I feel some terminology rewording may be necessary in the paper. The authors refer to RI and PI as indexes of "arterial stiffness". As the name itself suggests, the "resistive" index is more related to vascular resistance, and not only of vascular impedance and compliance. Thus, we cannot refer to RI and PI as indexes of arterial stiffness alone. This should be mentioned in the paper, and perhaps the title and the discussion should be corrected alongside.

A hemodynamic effect of aortic stenosis on peripheral waveforms is possible and demonstrated in severe cases (see Bardelli et al. "Relationship between aortic valve stenosis and the hemodynamic pattern in the renal circulation, and restoration of the flow wave profile after correction of the valvular defect." Journal of International Medical Research 48.9 (2020): 0300060520956907 as reference). Did the authors consider the downward effect of aortic stenosis? It should be fine if they perform a stratification of severity of aortic valve stenosis in their patient and do a further analysis.

Author Response

Reviewer: In this paper Baran et al. evaluated the prognostic ability of carotid and vertebral resistive index (RI) and pulsatility index (PI) for heart failure and major cardiovascular events among patients with or without degenerative aortic valve stenosis and cardiovascular risk factors. The authors found a positive association of high RI and PI for events in a 2,5 years follow-up.

I feel some terminology rewording may be necessary in the paper. The authors refer to RI and PI as indexes of "arterial stiffness". As the name itself suggests, the "resistive" index is more related to vascular resistance, and not only of vascular impedance and compliance. Thus, we cannot refer to RI and PI as indexes of arterial stiffness alone. This should be mentioned in the paper, and perhaps the title and the discussion should be corrected alongside.

- Thank you for this important remark. RI and PI are calculated ultrasonographic flow parameters derived from Doppler spectrum velocities during cardiac circle. Both are typically used to assess the resistance in a pulsatile vascular system, reflecting microvasculature resistance, and also arterial stiffness. In this study, we used term arterial stiffness, as surrogate of vascular resistance, although RI and PI correspond to wider phenomenon. We corrected this term in the paper, and changed title:

Title: ‘Importance of increased arterial resistance in risk prediction in patients with cardiovascular risk factors and degenerative aortic stenosis’

Reviewer: A hemodynamic effect of aortic stenosis on peripheral waveforms is possible and demonstrated in severe cases (see Bardelli et al. "Relationship between aortic valve stenosis and the hemodynamic pattern in the renal circulation, and restoration of the flow wave profile after correction of the valvular defect." Journal of International Medical Research 48.9 (2020): 0300060520956907 as reference).

- Thank you for paying our attention to this valuable study. We included this statement in Introduction [9]

- Page 1/2: ‘Ultrasonography, can easily and non-invasively provide information on vascular resistance indices (resistive index; RI and pulsatile index; PI), that are surrogate markers of arterial stiffness. Peripheral flow parameters can be particularly important in patients with DAS, in whom severely reduced left-ventricle outflow has an impact on the altered vascular system flow pattern [9].’

Reviewer: Did the authors consider the downward effect of aortic stenosis? It should be fine if they perform a stratification of severity of aortic valve stenosis in their patient and do a further analysis.

- Indeed, there is a downward effect of aortic stenosis on the waveform pattern and vascular resistance, greater DAS degree higher RI and PI, and also longer acceleration time. There is striking gradient for the RI and the PI: from low to high resistance in patients with CRF, then moderate DAS, eventually severe DAS. We added this as paragraph in results:

Page 5, para 2# ‘ In line, in patients with moderate (n=32) vs severe (n=235) DAS, mean values of RI (0.70 ± 0.06 vs. 0.74 ± 0.06; p = 0.001) and PI (1.34 ± 0.21 vs. 1.47 ± 0.23; p = 0.002) differed significantly.’

- However, we did not perform additional sub analyses between moderate and severe DAS due to low number of patients with moderate DAS

Reviewer 2 Report

the authors compared two groups of CRF patients but one group had also moderate to severe aortic stenosis. the research question is therefor not adequate. 

the crf group was significantly younger creating a problem for any conclusion  drawn from this research

in the first part of the results the authors compared a DAS group to a CRF group that didn't had DAS. and reported PI en RI. but due to two imported significant differenced between the group table 1 is comparing oranges to apples.

In the second part of the analysis authors look for association between high pi and ri values and the scored risk factors. In which DAS was handled as a risk factor for higher PI en RI. I presume that all patient were included in the univariate and multivariate analysis but it is not clearly mentioned.

the outcome comparison between DAS vs CRF is apple vs orange.

the second part of the outcomes is interesting because the effect of risk factors individually is analysed. and is the strong part of this study.

conclusion:

I would suggested to skip the comparison between DAS and CRF and focus on DAS as risk factor for higher pi and ri. and look outcome and search for the most important deteminants of outcome and whether predictable with PI and RI.

Author Response

Reviewer: the authors compared two groups of CRF patients but one group had also moderate to severe aortic stenosis. the research question is therefore not adequate. the crf group was significantly younger creating a problem for any conclusion  drawn from this research

in the first part of the results the authors compared a DAS group to a CRF group that didn't had DAS. and reported PI en RI. but due to two imported significant difference between the group table 1 is comparing oranges to apples.

- Indeed, in previously published paper, we have showed that there is huge accumulation of risk factors in patients with DAS, greater than it was seen 10 years ago in DAS patients. Now, we deal with DAS patients in 8^th  and 9^th decade of their life. This causes difficulties with matching groups.

- It is already established that cardiovascular risk factors, and its number, are associated with arterial stiffness and adverse events.

- In this study, CRF group served as a control group to verify hypothesis that DAS leads to greater vascular stiffness, compared to CRF alone, and that it does at greater extend that it would be expected from cardiovascular risk factors presence.

- The Reviewer is right that patients with DAS are older. However, we used in the present study the rule of consecutive patients enrollment, unless ineligible for exclusion criteria. This doesn’t allow random patients selection.

- Statistician performed additional analysis, he used Z‐scores to standardize the raw values of age to a normal distribution (page 4; 2.4. Statistical analysis), in which DAS confirmed its independent association with high RI and high PI in the multivariate analysis. Thus, although patients with aortic stenosis are 4 years older, the relationship between aortic stenosis and arterial resistance parameters is independent from age. We displayed this in Table 2, as additional column with age-adjusted multivariate analysis (page 6, Table 2).  In fact, adjustment did not change anything in p-values, ORs and 95%CI, which demonstrates that both age is associated with arterial resistance and aortic stenosis is associated with arterial resistance independently one from another.

-Page 5, last para: ‘In multivariable logistic regression backward analysis, DAS confirmed its independent association with high RI and high PI in the multivariate analysis, both in unadjusted and Z‐score adjusted analysis to standardize the raw values of age to a normal distribution (Table 2).’

-To overcome this flaw, we also added age-adjusted analysis to Table 2. In multivariate backward logistic regression analysis, after adjustment for age, DAS confirmed its independent association with high RI and high PI. In fact the whole multivariate model did not change after standardization to age, this confirms that our findings are correct.

-We added column to Table 2 with multivariable age-adjusted analysis (page 6, Table 2)

- We also addressed this issue in study limitations: 6. Study limitations

Our study has obvious limitations, as it consisted of a single-center observational design. Secondly, in general, DAS patients are elderly, which caused difficulties when matching with a control group. For this reason, age-adjustment in multivariate analyses were performed.

- We believe that it is important that Readers of this paper would realize that DAS is not only a disease of the valve (or heart), but this is disease of the whole vascular system, and the latter contributes to adverse events.

Reviewer: In the second part of the analysis authors look for association between high pi and ri values and the scored risk factors. In which DAS was handled as a risk factor for higher PI en RI. I presume that all patient were included in the univariate and multivariate analysis but it is not clearly mentioned.

Yes, we included all patients into analysis. Now, we clearly stated this in Statistical analysis (page 4; 2.4. Statistical analysis)

Reviewer: the outcome comparison between DAS vs CRF is apple vs orange.

Here, we completely agree, and we removed Table 3 from the paper

Reviewer: the second part of the outcomes is interesting because the effect of risk factors individually is analysed. and is the strong part of this study.

Thank you, we appreciate your opinion

Reviewer: conclusion: I would suggested to skip the comparison between DAS and CRF and focus on DAS as risk factor for higher pi and ri. and look outcome and search for the most important determinants of outcome and whether predictable with PI and RI.

We corrected the paper according to Your advices as above

Round 2

Reviewer 1 Report

The authors adequately answered to my remarks.

Author Response

We are pleased that the Reviewer is satisfied with revised paper.