Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1) The rationale for including PNI and GNRI needs further clarification. PNI was originally used in gastro surgery of malnourished cancer pts and GNRI was used in at risk elderly medical people. How do the authors justify the applicability and clinical relevance of these scores in this specific population who were neither malnourished nor very old?

2) The discussion of the discriminatory performance of GNRI appears insufficient compared with that of PNI. AUC for PNI showed highest although moderate/acceptable discirminative ability with a score of 0.72 , but for GNRI AUC 0.677 would be considered as fair. Could the authors discuss the implications of the observed differences?

Overall, I congratulate the authors for their work and writing this manuscript.

Author Response

Response to Reviewer 1

Manuscript: Prognostic Value of Inflammatory and Nutritional Indices in Patients Undergoing Permanent Pacemaker Implantation for Degenerative Complete Atrioventricular Block

General Response

We sincerely thank the reviewer for the careful evaluation, constructive comments, and encouraging assessment of our work. The comments helped us clarify the clinical rationale for using PNI and GNRI in this pacemaker population and improve the interpretation of their discriminatory performance. We revised the Abstract, Introduction, Methods, Results, Discussion, Conclusion, references, tables, and figures. The changes are described point by point below.

Comment 1

The rationale for including PNI and GNRI needs further clarification. PNI was originally used in gastrointestinal surgery among malnourished cancer patients and GNRI was used in at-risk elderly medical patients. How do the authors justify the applicability and clinical relevance of these scores in this specific population, who were neither malnourished nor very old?

Response

We thank the reviewer for this important observation. We agree that the original settings in which PNI and GNRI were developed should be distinguished from their application in the present study. We have therefore expanded both the Introduction and Discussion to explain the biological and clinical rationale more clearly.

Although our patients were not selected on the basis of overt malnutrition, the absence of a documented diagnosis of malnutrition does not exclude subclinical impairment in nutritional reserve, immune competence, or systemic inflammatory status. PNI combines serum albumin and lymphocyte count and may therefore capture immune-nutritional vulnerability that is not apparent from body weight or a clinical diagnosis of malnutrition alone. Similarly, GNRI can reflect nutrition-related physiological reserve in older cardiovascular patients, even when overt malnutrition is not an inclusion criterion.

Our cohort was also predominantly older rather than a young pacemaker population. Median age was 72.0 years among survivors and 83.5 years among non-survivors. Degenerative complete atrioventricular block generally occurs in older adults with varying degrees of comorbidity, frailty, and reduced physiological reserve. Accordingly, assessment of subclinical nutritional and immune-inflammatory vulnerability is clinically relevant in this population.

We further supported this rationale with contemporary cardiovascular evidence. A recent study including 927 patients with cardiac pacemakers demonstrated that both low baseline PNI and deterioration in PNI during follow-up were associated with heart failure hospitalization and all-cause mortality. In addition, a meta-analysis has demonstrated the prognostic value of GNRI in older patients with heart failure. These studies support the use of these indices beyond their original oncological and general geriatric settings.

Changes made in the revised manuscript

Introduction

In this context, composite inflammatory and nutritional indices derived from routinely available laboratory parameters have attracted increasing interest as prognostic markers across clinical settings [7–20]. The prognostic nutritional index combines serum albumin and lymphocyte count and therefore reflects both nutritional status and immune-inflammatory balance [7]. Similarly, the geriatric nutritional risk index was developed as a practical tool for assessing nutrition-related risk in older medical patients [8]. Although PNI and GNRI were originally developed in surgical oncology and geriatric medicine, respectively, subsequent evidence has supported their prognostic application in cardiovascular populations [9,10,16,17,19,20] and, for PNI, specifically in patients with cardiac pacemakers [9]. These indices do not require clinically overt malnutrition to provide prognostic information; instead, they may capture subclinical depletion of nutritional reserves, systemic inflammation, and reduced physiological resilience. This may be particularly relevant to degenerative complete atrioventricular block, which predominantly affects older adults with comorbidities and potential frailty. Other hematologic indices, including the neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, systemic inflammation response index, and pan-immune-inflammation value, may reflect different aspects of systemic inflammation and immune dysregulation [11–15,18]. These indices can be calculated from routinely obtained laboratory parameters, require no additional testing costs, and are readily available in routine clinical practice.

Discussion – applicability of PNI

PNI was originally developed as a nutritional and immunological index using serum albumin and lymphocyte count [7]. Serum albumin reflects protein-calorie reserve, hepatic synthetic function, inflammation-related capillary leakage, and overall disease burden, whereas lymphocyte count reflects immune competence and may decrease in chronic inflammation, malnutrition, and physiological stress. Therefore, PNI may capture the interaction between nutritional depletion and immune-inflammatory dysfunction more comprehensively than albumin or lymphocyte count alone. Importantly, the absence of a documented diagnosis of malnutrition does not exclude subclinical immune-nutritional impairment. Our cohort was predominantly older, with median ages of 72.0 years among survivors and 83.5 years among non-survivors, making assessment of physiological and nutritional reserve clinically relevant. Furthermore, a recent study of 927 patients with cardiac pacemakers showed that both low baseline PNI and a deterioration in PNI during follow-up were associated with heart failure hospitalization and all-cause mortality [9], supporting the applicability of PNI beyond its original surgical oncology setting. In our ROC analysis, PNI had a numerically higher AUC than albumin and lymphocyte count. Moreover, although albumin, lymphocyte count, GNRI, LMR, and several inflammatory markers differed between survivors and non-survivors, only PNI remained independently associated with mortality in the multivariable model.

Discussion – applicability of GNRI

GNRI was originally developed to assess nutrition-related risk in older medical patients [8] and has subsequently demonstrated prognostic value in older cardiovascular populations [10]. This supports its relevance to our predominantly older pacemaker cohort even though patients were not selected on the basis of overt malnutrition.

New references added

9. Zhang J, Yao H, Lu Y, Lian L, Zheng R, Chen C. Baseline and changes in prognostic nutritional index associate with heart failure hospitalization and all-cause death in patients with cardiac pacemaker. BMC Cardiovasc Disord. 2025;25(1):239. doi:10.1186/s12872-025-04688-7
10. Li H, Cen K, Sun W, Feng B. Prognostic value of geriatric nutritional risk index in elderly patients with heart failure: a meta-analysis. Aging Clin Exp Res. 2021;33(6):1477-1486. doi:10.1007/s40520-020-01656-3

Comment 2

The discussion of the discriminatory performance of GNRI appears insufficient compared with that of PNI. The AUC for PNI was the highest and showed moderate/acceptable discriminatory ability, with a value of 0.720, whereas an AUC of 0.677 for GNRI would be considered fair. Could the authors discuss the implications of the observed differences?

Response

We thank the reviewer for this valuable suggestion. We have revised the Abstract, Results, Discussion, and Conclusion to distinguish more clearly between the discriminatory performances of PNI and GNRI. PNI showed moderate discriminatory performance (AUC 0.720), whereas GNRI showed fair discrimination (AUC 0.677).

The two indices also demonstrated different operating characteristics. PNI had higher sensitivity than GNRI (82.8% vs. 57.6%) but lower specificity (53.4% vs. 78.1%). Thus, at the ROC-derived cut-offs, PNI identified a larger proportion of patients who died during follow-up, whereas GNRI provided more selective classification. This distinction is now explicitly discussed as a clinically relevant difference rather than treating the two indices as equivalent.

The numerically higher AUC of PNI may partly relate to its inclusion of lymphocyte count, which captures immune-inflammatory dysfunction in addition to serum albumin. In contrast, GNRI incorporates actual body weight relative to ideal body weight. BMI did not differ significantly between survivors and non-survivors in our cohort (p=0.125), which may have limited the additional discriminatory contribution of the weight-based component of GNRI. We therefore interpret PNI and GNRI as complementary adjunctive markers rather than standalone prognostic tools.

Clarification regarding statistical comparison of the AUCs

A formal pairwise AUC comparison, such as the DeLong test, was not performed. The reviewer requested a clearer discussion of the observed difference rather than a formal test of statistical superiority. We have therefore removed wording that could imply proven superiority and now consistently use expressions such as “numerically highest AUC” and “numerically higher AUC.” We also explicitly state in the Results and Discussion that the confidence intervals overlapped, that no formal pairwise AUC comparison was performed, and that the observed differences should be interpreted descriptively. Consequently, the revised manuscript does not claim that PNI is statistically superior to GNRI.

Changes made in the revised manuscript

Abstract – Results

PNI had the numerically highest AUC for mortality prediction (AUC: 0.720, 95% CI: 0.648–0.793; p < 0.001), corresponding to moderate discriminatory performance, whereas GNRI showed fair discrimination (AUC: 0.677, 95% CI: 0.589–0.766; p < 0.001).

Results – ROC analysis

Receiver operating characteristic analysis was performed to evaluate the discriminatory performance of inflammatory, nutritional, and conventional laboratory parameters for all-cause mortality. The AUC estimates were derived from the common complete-case ROC sample (n = 222; 55 deaths), whereas cohort-specific cut-offs and operating characteristics were calculated using all available observations for each marker. PNI yielded the numerically highest AUC (0.720, 95% CI: 0.648–0.793; p < 0.001), corresponding to moderate discriminatory performance. At the exploratory, cohort-specific ROC-derived cut-off of ≤48.90, PNI yielded a sensitivity of 82.8% and specificity of 53.4%. GNRI showed fair discrimination (AUC: 0.677, 95% CI: 0.589–0.766; p < 0.001), with lower sensitivity (57.6%) but higher specificity (78.1%) than PNI. Because formal pairwise comparisons of AUCs were not performed, the observed differences should be interpreted descriptively.

Discussion – comparison of PNI and GNRI

Other inflammatory and nutritional indices also provided relevant information. GNRI, LMR, NLR, and SIRI differed significantly between survivors and non-survivors, whereas SII and PIV were numerically higher among non-survivors but were not statistically significant. GNRI was originally developed to assess nutrition-related risk in older medical patients [8] and has subsequently demonstrated prognostic value in older cardiovascular populations [10,16]. Contemporary data also support the association of NLR with all-cause and cardiovascular mortality in cardiovascular populations [18]. These observations support the relevance of such indices to our predominantly older pacemaker cohort, even though patients were not selected on the basis of overt malnutrition. PNI yielded a numerically higher AUC than GNRI (0.720 vs. 0.677), corresponding to moderate and fair discrimination, respectively. However, the confidence intervals overlapped, and no formal pairwise AUC comparison was performed; therefore, these findings do not establish statistically superior discrimination by PNI. The performance profiles of the two indices were complementary: PNI had higher sensitivity than GNRI (82.8% vs. 57.6%) but lower specificity (53.4% vs. 78.1%). Thus, PNI identified a larger proportion of patients who died during follow-up, whereas GNRI provided more specific classification. The numerically higher discrimination of PNI may partly reflect the inclusion of lymphocyte count, which captures immune-inflammatory dysfunction in addition to serum albumin. By contrast, GNRI incorporates body weight relative to ideal weight. BMI did not differ significantly between survivors and non-survivors in our cohort (p = 0.125), which may have limited the incremental contribution of the weight-based component. Accordingly, both indices should be regarded as complementary adjunctive risk markers rather than standalone prognostic tools.

Conclusion

Among the evaluated inflammatory and nutritional indices, PNI demonstrated the numerically highest discriminatory performance and remained independently associated with long-term all-cause mortality in patients undergoing permanent pacemaker implantation for degenerative complete atrioventricular block. These findings support PNI as a readily available adjunct to clinical risk stratification, although its incremental clinical value and cohort-specific cut-off require external validation. Prospective multicenter studies should validate the prognostic role of PNI, and pilot randomized feasibility trials should determine whether early post-implantation nutritional optimization or frailty-directed rehabilitation improves outcomes in this population.

Closing Statement

We again thank the reviewer for these constructive comments. We believe that the revisions have clarified the clinical applicability of PNI and GNRI, provided a more balanced interpretation of their discriminatory performance, and strengthened the overall presentation of the manuscript.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to Authors:
This manuscript was interesting and clinically relevant. The authors assessed readily available inflammatory and nutritional indices in a relatively homogeneous population of patients undergoing permanent pacemaker implantation for degenerative complete atrioventricular block. The finding that the prognostic nutritional index (PNI) had the best discriminative performance and was independently associated with long-term mortality may have practical clinical importance in particular. The manuscript is overall well written. The study question is clearly presented and the conclusions are appropriately cautious. I only have some minor comments that may further improve the clarity, transparency and reproducibility of the study.
1. Please indicate the precise time of the baseline laboratory measurements relative to pacemaker implantation. The manuscript says that the laboratory parameters used to calculate the inflammatory and nutritional indices were obtained before implantation. A more reproducible approach would be to clarify whether these measurements were obtained, for example, within 24 or 48 hours before the procedure.
2. Please give us a brief clarification on the adjudication of ‘degenerative’ complete atrioventricular block. The exclusion criteria are described well. It would be helpful to specify if the final classification of degenerative conduction system disease was based on the treating physician's diagnosis, retrospective chart review or a predefined diagnostic assessment.
3. Briefly report what authors did with missing data for continuous variables. The available-case approach for categorical variables is well explained in the manuscript. Providing the number of available observations for continuous laboratory parameters, especially in presence of missing values, would be more transparent.
4. Report whether the proportional hazards assumption was tested for the Cox regression model and if so, briefly describe the method used. This would increase the statistical reporting. Not major changes to the analysis.
5. The interpretation of the ROC-derived PNI cut-off might be a little loose. The cut-off of ≤48.90 showed good sensitivity but modest specificity. Hence, terms such as “optimal threshold” or “screening marker” should be presented as exploratory and cohort-specific. This would also be consistent with the limitation already acknowledged by the authors for conventional ROC analysis in time-to-event data.
Overall evaluation
The study is addressing a clinically relevant question with routinely available and inexpensive parameters. The main findings may be useful to risk stratify this specific pacemaker population. The above points are minor and mostly related to methodological clarity and interpretation. I would recommend publication with the caveat that the minor revisions are adequately addressed.

Author Response

Response to Reviewer 2

Prognostic Value of Inflammatory and Nutritional Indices in Patients Undergoing Permanent Pacemaker Implantation for Degenerative Complete Atrioventricular Block

Dear Editor and Reviewer,

We sincerely thank Reviewer 2 for the careful, constructive, and clinically focused review of our manuscript. We appreciate the positive assessment of the study's relevance, methodological approach, and cautious interpretation. The comments have helped us improve the reproducibility, transparency, and precision of the manuscript.

We have addressed each point in detail below. The reviewer comments are reproduced verbatim, followed by our response and the corresponding text added to or revised in the manuscript and supplementary material.

Comment 1

Reviewer comment: Please indicate the precise time of the baseline laboratory measurements relative to pacemaker implantation. The manuscript says that the laboratory parameters used to calculate the inflammatory and nutritional indices were obtained before implantation. A more reproducible approach would be to clarify whether these measurements were obtained, for example, within 24 or 48 hours before the procedure.

Response:

We agree that a clearly defined preprocedural sampling window is important for reproducibility. All baseline laboratory parameters used in the study were obtained from blood samples collected within 24 hours before permanent pacemaker implantation. We have now stated this explicitly in the Laboratory Measurements and Calculation of Inflammatory and Nutritional Indices subsection of the Methods.

Revised manuscript text: Baseline laboratory parameters were obtained from blood samples collected within 24 hours before pacemaker implantation.

Comment 2

Reviewer comment: Please give us a brief clarification on the adjudication of 'degenerative' complete atrioventricular block. The exclusion criteria are described well. It would be helpful to specify if the final classification of degenerative conduction system disease was based on the treating physician's diagnosis, retrospective chart review or a predefined diagnostic assessment.

Response:

Thank you for highlighting the need to clarify the adjudication process. Because the study was retrospective, the final classification was made by the study investigators through review of the institutional medical records. Degenerative conduction system disease was assigned when the patient had isolated complete atrioventricular block requiring permanent pacing and the predefined exclusion review did not identify a potentially reversible, secondary, iatrogenic, congenital, inflammatory, infectious, malignant, or hematologic cause. We have clarified both the review method and the diagnostic framework in the Study Population and Design subsection.

Revised manuscript text: The classification of degenerative conduction system disease was adjudicated retrospectively by the study investigators through review of the institutional medical records. Degenerative disease was defined as isolated complete atrioventricular block requiring permanent pacemaker implantation after exclusion of potentially reversible, secondary, iatrogenic, congenital, inflammatory, infectious, malignant, or hematologic causes.

Comment 3

Reviewer comment: Briefly report what authors did with missing data for continuous variables. The available-case approach for categorical variables is well explained in the manuscript. Providing the number of available observations for continuous laboratory parameters, especially in presence of missing values, would be more transparent.

Response:

We agree and have expanded the reporting of missing continuous data. No imputation was performed. Descriptive and between-group analyses used the available observations for each variable. To provide variable-level transparency without overloading the main manuscript tables, Supplementary Table S1 reports the available number, missing number, and percentage completeness for each continuous baseline clinical or laboratory variable with missing observations. For the ROC analysis, AUCs were estimated in a common complete-case sample with data for all 12 markers (n = 222; 55 deaths) to permit direct descriptive comparison, whereas cohort-specific cut-offs and operating characteristics were calculated using all available observations for each individual marker. The multivariable Cox model used complete cases for all included covariates (n = 237; 61 deaths).

Supplementary Table S1 title: Availability of continuous baseline clinical and laboratory variables.

Revised Methods text: No imputation was performed. Descriptive and between-group analyses used available observations on a variable-by-variable basis, whereas the multivariable Cox model was based on complete cases for all included covariates (n = 237; 61 deaths). To permit direct descriptive comparison across markers, ROC curves and AUCs were estimated in a common complete-case ROC sample (n = 222; 55 deaths); cohort-specific cut-offs and operating characteristics were calculated using all available observations for each individual marker.

Comment 4

Reviewer comment: Report whether the proportional hazards assumption was tested for the Cox regression model and if so, briefly describe the method used. This would increase the statistical reporting. Not major changes to the analysis.

Response:

We agree and performed a formal assessment of the proportional hazards assumption for the final multivariable Cox model. Time-dependent interaction terms were created between every covariate in the final model and the natural logarithm of analysis time. The seven interaction terms were then entered as an additional block in the Cox model.

The global interaction block was not statistically significant (χ² = 6.034, df = 7, p = 0.536). Furthermore, none of the individual covariate-by-time interaction terms reached statistical significance (individual p values ranged from 0.057 to 0.932). These findings provide no evidence of a violation of the proportional hazards assumption. We have added the testing method and result to the Statistical Analysis subsection.

Revised manuscript text: The proportional hazards assumption was assessed by adding time-dependent interaction terms between each covariate and the natural logarithm of analysis time to the final Cox model. The global interaction test was not statistically significant (χ² = 6.034, df = 7, p = 0.536), and none of the individual covariate-by-time interactions reached statistical significance, supporting the proportional hazards assumption.

Comment 5

Reviewer comment: The interpretation of the ROC-derived PNI cut-off might be a little loose. The cut-off of ≤48.90 showed good sensitivity but modest specificity. Hence, terms such as 'optimal threshold' or 'screening marker' should be presented as exploratory and cohort-specific. This would also be consistent with the limitation already acknowledged by the authors for conventional ROC analysis in time-to-event data.

Response:

We agree that the original wording could imply a degree of clinical certainty not supported by a single-cohort conventional ROC analysis. We therefore removed the terms 'optimal threshold' and 'screening marker' from the interpretation. The value of ≤48.90 is now consistently described as a cohort-specific, ROC-derived exploratory cut-off.

We also now explicitly acknowledge that the cut-off combines good sensitivity (82.8%) with modest specificity (53.4%) and should not be regarded as a definitive clinical decision threshold. The text states that the value may support adjunctive risk stratification but requires external validation before clinical application. Corresponding revisions were made in the Statistical Analysis section, the ROC Results/Figure 1 discussion, and the Limitations section.

Statistical Analysis: For exploratory purposes, a cohort-specific ROC-derived cut-off value for each evaluated parameter was identified using the Youden index.

ROC Results and Figure 1 interpretation: The cohort-specific ROC-derived PNI cut-off selected using the Youden index was ≤48.90, yielding a sensitivity of 82.8% and a specificity of 53.4%. Given its modest specificity and the use of conventional ROC analysis in a time-to-event dataset, this value should be interpreted as an exploratory cut-off in the present cohort rather than a definitive clinical threshold. It may support adjunctive risk stratification but requires external validation before clinical application.

Limitations: Conventional ROC analysis does not fully account for time-to-event information; therefore, the ROC-derived cut-off value and discriminatory findings should be interpreted as cohort-specific and exploratory.

Additional editorial comment — Figures and tables can be improved

Editorial comment: Figures and tables can be improved.

Response:

We agree and have comprehensively revised the visual presentation. All four main-text tables were reformatted with consistent typography, alignment, spacing, borders, units, footnotes, and multi-line headers where needed. Supplementary Table S1 was condensed to a clear one-page layout. Figure 1 was regenerated at 600 dpi using the same common complete-case sample as the reported AUCs (n = 222; 55 deaths), with a color-blind-friendly palette, distinct line styles, and a clear AUC legend. Figure 2 was standardized at 600 dpi and includes censoring marks, group sizes, the log-rank result, and numbers at risk. Both figures are supplied separately as high-resolution PNG files.

Location of revision: Tables 1–4; Figures 1–2; Supplementary Table S1; separate high-resolution figure files.

We again thank Reviewer 2 for these constructive suggestions, which have improved the methodological clarity, transparency, and interpretive precision of the manuscript.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript entitled “Prognostic Value of Inflammatory and Nutritional Indices in Patients Undergoing Permanent Pacemaker Implantation for Degenerative Complete Atrioventricular Block” investigates a highly clinically relevant gap in cardiac pacing literature: the prognostic utility of composite inflammatory and nutritional indices (specifically PNI and GNRI) in a homogeneous patient cohort with degenerative complete atrioventricular block. The study design is solid, and the statistical framework is appropriate. However, critical metadata inconsistencies, temporary template placeholders, defensive reasoning, and specific wording choices require direct refinement before submission to peer-reviewed journals. Here are several issues must be addressed:

• Defensive Tone in Abstract (Lines 29-31): The phrase 'although this should be interpreted in the context of baseline vulnerability and device-selection patterns' weakens your endpoint findings. Instead of using defensive framing, explicitly state that single-chamber pacing correlates with higher mortality due to its selection for older, frailer patients with extensive baseline comorbidities.
• CODE Study Reference (Line 42): The introduction mentions 'the CODE study' without defining the acronym or providing an immediate in-text citation number at the exact point of mention. Always introduce acronyms upon first use.
• Academic Vocabulary Enhancements: Terms like 'inexpensive' can sound informal or low-quality. Replace with 'cost-effective'. Similarly, change 'daily clinical practice' to 'routine clinical practice' to better match high-impact peer-reviewed cardiac journals.
• Lines 29-31: "...although this should be interpreted in the context of baseline vulnerability and device-selection patterns." To "...reflecting residual confounding from a higher baseline frailty and comorbidity burden in patients selected for single-chamber devices."
• Line 42: "In the literature, the CODE study demonstrated..." to "The Clinical Outcomes Driving Evidence (CODE) registry demonstrated... [3]"
• Lines 71-72: "These indices are inexpensive, easily calculated, and widely available in daily clinical practice." To "The Clinical Outcomes Driving Evidence (CODE) registry demonstrated... [3]"
• Lines 28-30: "(HR 2.137, 95% CI 1.202-3.802; p=0.010), although this..." to "(HR: 2.137, 95% CI: 1.202–3.802, p = 0.010). However, this finding..."
• Many grammatical errors in manuscript text must be corrected.
• Conclusions must me revised according to the aims.

Comments on the Quality of English Language

The manuscript entitled “Prognostic Value of Inflammatory and Nutritional Indices in Patients Undergoing Permanent Pacemaker Implantation for Degenerative Complete Atrioventricular Block” investigates a highly clinically relevant gap in cardiac pacing literature: the prognostic utility of composite inflammatory and nutritional indices (specifically PNI and GNRI) in a homogeneous patient cohort with degenerative complete atrioventricular block. The study design is solid, and the statistical framework is appropriate. However, critical metadata inconsistencies, temporary template placeholders, defensive reasoning, and specific wording choices require direct refinement before submission to peer-reviewed journals. Here are several issues must be addressed:

• Defensive Tone in Abstract (Lines 29-31): The phrase 'although this should be interpreted in the context of baseline vulnerability and device-selection patterns' weakens your endpoint findings. Instead of using defensive framing, explicitly state that single-chamber pacing correlates with higher mortality due to its selection for older, frailer patients with extensive baseline comorbidities.
• CODE Study Reference (Line 42): The introduction mentions 'the CODE study' without defining the acronym or providing an immediate in-text citation number at the exact point of mention. Always introduce acronyms upon first use.
• Academic Vocabulary Enhancements: Terms like 'inexpensive' can sound informal or low-quality. Replace with 'cost-effective'. Similarly, change 'daily clinical practice' to 'routine clinical practice' to better match high-impact peer-reviewed cardiac journals.
• Lines 29-31: "...although this should be interpreted in the context of baseline vulnerability and device-selection patterns." To "...reflecting residual confounding from a higher baseline frailty and comorbidity burden in patients selected for single-chamber devices."
• Line 42: "In the literature, the CODE study demonstrated..." to "The Clinical Outcomes Driving Evidence (CODE) registry demonstrated... [3]"
• Lines 71-72: "These indices are inexpensive, easily calculated, and widely available in daily clinical practice." To "The Clinical Outcomes Driving Evidence (CODE) registry demonstrated... [3]"
• Lines 28-30: "(HR 2.137, 95% CI 1.202-3.802; p=0.010), although this..." to "(HR: 2.137, 95% CI: 1.202–3.802, p = 0.010). However, this finding..."
• Many grammatical errors in manuscript text must be corrected.
• Conclusions must me revised according to the aims.

Author Response

Response to Reviewer 3

Prognostic Value of Inflammatory and Nutritional Indices in Patients Undergoing Permanent Pacemaker Implantation for Degenerative Complete Atrioventricular Block

Dear Reviewer,

We sincerely thank you for your careful and constructive evaluation of our manuscript. Your comments prompted us to refine the presentation of the principal findings, verify citation metadata, standardize statistical notation and terminology, revise the Conclusion to align more directly with the study aim, and perform a comprehensive line-by-line English-language edit. We have addressed each point below. The comments repeated under ‘Comments on the Quality of English Language’ are identical to those in the main review and are therefore answered once in the corresponding sections.

Comment 1. Tone and interpretation of the single-chamber pacemaker finding

Defensive Tone in Abstract (Lines 29-31): The phrase ‘although this should be interpreted in the context of baseline vulnerability and device-selection patterns’ weakens your endpoint findings. Instead of using defensive framing, explicitly state that single-chamber pacing correlates with higher mortality due to its selection for older, frailer patients with extensive baseline comorbidities.

Response:

We agree that the original wording was indirect. To keep the Abstract focused on the primary study aim and to avoid overinterpreting a secondary device-selection association, the pacemaker-type finding was removed from the Abstract. The association remains reported in the multivariable Cox model and is interpreted in the Discussion as secondary and hypothesis-generating. Because pacemaker type was not randomly assigned and frailty was not measured using a validated instrument, we retained non-causal wording and did not attribute the observed mortality difference directly to pacing mode or measured frailty.

Revised text in the manuscript:

Pacemaker type was retained only as an adjustment covariate. Because device selection is closely related to rhythm status, frailty, comorbidity burden, and physician judgment, the observed association with mortality should be considered secondary and hypothesis-generating rather than evidence of a causal effect of pacing mode [24].

Comment 2. Definition and citation of the CODE study

CODE Study Reference (Line 42): The introduction mentions ‘the CODE study’ without defining the acronym or providing an immediate in-text citation number at the exact point of mention. Always introduce acronyms upon first use.

Response:

We agree. To avoid unnecessary acronym use and improve readability, the abbreviated reference to the CODE study was removed from the revised Introduction. The relevant finding is now described directly, with the corresponding source cited immediately in the sentence. The Paixão et al. publication is Reference 2 in the final manuscript.

Revised text in the manuscript:

Contemporary primary-care data have shown that atrioventricular block is associated with reduced survival and that third-degree atrioventricular block carries the poorest prognosis among atrioventricular block subtypes [2].

Comment 3. Academic vocabulary and routine availability

Academic Vocabulary Enhancements: Terms like ‘inexpensive’ can sound informal or low-quality. Replace with ‘cost-effective’. Similarly, change ‘daily clinical practice’ to ‘routine clinical practice’ to better match high-impact peer-reviewed cardiac journals.

Response:

We agree that the terminology should be more formal. The phrase ‘daily clinical practice’ has been replaced with ‘routine clinical practice.’ We also removed ‘inexpensive’ throughout. To convey the intended practical advantage without implying that a formal health-economic analysis was performed, we used the more precise wording ‘require no additional testing costs’ and ‘readily available.’

Revised text in the manuscript:

These indices can be calculated from routinely obtained laboratory parameters, require no additional testing costs, and are readily available in routine clinical practice.

Comment 4. Requested revision of Lines 29–31

Lines 29-31: ‘...although this should be interpreted in the context of baseline vulnerability and device-selection patterns.’ To ‘...reflecting residual confounding from a higher baseline frailty and comorbidity burden in patients selected for single-chamber devices.’

Response:

This point has been addressed together with Comment 1. Rather than attributing the mortality association to frailty or pacing mode, which cannot be established in this retrospective study, the final manuscript interprets pacemaker type as an adjustment covariate and the observed association as secondary and hypothesis-generating. This approach acknowledges the role of rhythm status, frailty, comorbidity burden, and physician judgment in device selection without presenting unmeasured frailty as an observed baseline characteristic.

Revised text in the manuscript:

Pacemaker type was retained only as an adjustment covariate. Because device selection is closely related to rhythm status, frailty, comorbidity burden, and physician judgment, the observed association with mortality should be considered secondary and hypothesis-generating rather than evidence of a causal effect of pacing mode [24].

Comment 5. Requested revision of the CODE sentence

Line 42: ‘In the literature, the CODE study demonstrated...’ to ‘The Clinical Outcomes Driving Evidence (CODE) registry demonstrated... [3]’

Response:

We agree that the citation should be clear at the point of use. In the final manuscript, we removed the CODE acronym rather than introducing an additional abbreviation and now state the finding directly, followed immediately by Reference 2. This resolves the acronym issue while preserving the source-supported statement.

Revised text in the manuscript:

Contemporary primary-care data have shown that atrioventricular block is associated with reduced survival and that third-degree atrioventricular block carries the poorest prognosis among atrioventricular block subtypes [2].

Comment 6. Wording at Lines 71–72

Lines 71-72: ‘These indices are inexpensive, easily calculated, and widely available in daily clinical practice.’ To ‘The Clinical Outcomes Driving Evidence (CODE) registry demonstrated... [3]’

Response:

We understood this item as referring to the wording describing the practical availability of the indices. The suggested CODE sentence appears to correspond to the preceding citation-related comment rather than to the sentence at Lines 71–72. Accordingly, we revised the relevant sentence to use formal academic language while preserving its intended scientific meaning.

Revised text in the manuscript:

These indices can be calculated from routinely obtained laboratory parameters, require no additional testing costs, and are readily available in routine clinical practice.

Comment 7. Statistical notation in the Abstract and main text

Lines 28-30: ‘(HR 2.137, 95% CI 1.202-3.802; p=0.010), although this...’ to ‘(HR: 2.137, 95% CI: 1.202–3.802, p = 0.010). However, this finding...’

Response:

We agree and standardized the reporting of hazard ratios, confidence intervals, AUCs, and p values throughout the manuscript. Colons are used after statistical labels where appropriate, spaces are used around equality and inequality signs, and en dashes are used for numerical ranges. Because the secondary pacemaker-type finding was removed from the Abstract to keep it focused on the primary study aim, the reviewer-cited Abstract sentence no longer appears; the association remains reported in Table 4 and is interpreted cautiously in the Discussion.

Revised text in the manuscript:

Table 4 reports the single-chamber versus dual-chamber pacemaker association as HR: 2.139, 95% CI: 1.201–3.808; p = 0.010, while the Discussion treats this association as secondary and hypothesis-generating rather than causal.

Comment 8. Comprehensive English-language revision

Many grammatical errors in manuscript text must be corrected.

Response:

The entire manuscript was edited line by line for academic English. The revision addressed subject–verb agreement, article and preposition use, modifier placement, parallel structure, punctuation, hyphenation, terminology, redundancy, and consistency of tense. Statistical language was also refined; for example, ‘risk’ was replaced with ‘hazard’ when interpreting the Cox model, ‘independent predictors’ was replaced with ‘variables independently associated with mortality’ where appropriate, and ‘discriminative ability’ was standardized to ‘discriminatory performance.’ Repetitive constructions were reduced, including ‘showing that PNI ... showed,’ and the incorrect singular construction ‘inflammatory and nutritional status was’ was replaced by a direct statement of the principal finding. Figure legends, table notes, section headings, author-information sections, and references were also checked for linguistic and formatting consistency. No numerical results, study definitions, table data, or reference order were changed as part of the language edit.

Revised text in the manuscript:

In this retrospective study of patients undergoing permanent pacemaker implantation for degenerative complete atrioventricular block, the principal finding was that PNI had the numerically highest discriminatory performance among the evaluated inflammatory and nutritional indices and remained independently associated with long-term all-cause mortality after adjustment for hemoglobin, renal function, age, pacemaker type, heart failure, and atrial fibrillation.

Comment 9. Revision of the Conclusion according to the study aim

Conclusions must be revised according to the aims.

Response:

We agree. The Conclusion has been revised to mirror the stated aim by focusing on the prognostic performance of the evaluated inflammatory and nutritional indices in relation to long-term all-cause mortality. It now foregrounds PNI, characterizes it as an adjunctive rather than standalone marker, notes the cohort-specific nature of the cut-off, and emphasizes the need for external validation. The secondary pacemaker-type association was not included in the final Conclusion so that the conclusion remains aligned with the primary study objective.

Revised text in the manuscript:

Among the evaluated inflammatory and nutritional indices, PNI demonstrated the numerically highest discriminatory performance and remained independently associated with long-term all-cause mortality in patients undergoing permanent pacemaker implantation for degenerative complete atrioventricular block. These findings support PNI as a readily available adjunct to clinical risk stratification, although its incremental clinical value and cohort-specific cut-off require external validation. Prospective multicenter studies should validate the prognostic role of PNI, and pilot randomized feasibility trials should determine whether early post-implantation nutritional optimization or frailty-directed rehabilitation improves outcomes in this population.

Comment 10. Metadata consistency and template-placeholder audit

The reviewer noted critical metadata inconsistencies and temporary template placeholders.

Response:

We conducted an additional audit of the title page, affiliations, section headings, tables, figure captions, supplementary-material statement, document properties, and reference metadata. The corresponding-author affiliation was standardized to match the institutional affiliation on the title page. The Paixão et al. CODE study remains correctly listed as Reference 2. Bibliographic metadata for References 3, 4, 6, and 25 was verified against the publisher or indexed record and corrected, including author sequences, publication details, and the DOI for Reference 4 (10.2217/bmm-2021-0991). The manuscript was also checked for unresolved template or placeholder text; none remain. These corrections did not alter the study data or analyses.

Revised text in the manuscript:

2. Paixão GMM, Lima EM, Quadros AB, Cabral DPR, Coelho RR, Oliveira DM, et al. Association between atrioventricular block and mortality in primary care patients: The CODE study. Arq Bras Cardiol. 2022;119(4):564–571. doi:10.36660/abc.20210763

Closing statement

We again thank the reviewer for these constructive recommendations. We believe that the revised wording, corrected citation metadata, standardized statistical presentation, comprehensive English-language editing, and aim-focused Conclusion have substantially improved the clarity and precision of the manuscript.

Sincerely,
The Authors

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

General Comments

The manuscript addresses the critical issue of predicting adverse outcomes in patients with degenerative complete atrioventricular (AV) block. To achieve this, the authors evaluated several prognostic metrics, including the Prognostic Nutritional Index (PNI), Geriatric Nutritional Risk Index (GNRI), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), Systemic Immune-Inflammation Index (SII), Systemic Inflammation Response Index (SIRI), and the Pan-Immune-Inflammation Value (PIIV). Patient clinical and demographic characteristics were also incorporated into the analysis.

The authors concluded that the PNI is highly informative for mortality risk stratification in patients undergoing permanent pacemaker (PPM) implantation due to degenerative complete AV block. These findings hold clear clinical significance for cardiologists and electrophysiologists managing pacemaker implantations.

The manuscript is well-structured and contains all the necessary sections. The data are presented clearly and concisely. The research methods are described in sufficient detail, and the statistical analysis is both correct and appropriate for the study's scope. The inclusion of 4 tables and 2 figures presents the data in an accessible format, making the results well-substantiated. However, the reference list contains 24 sources, more than half of which were published over 5 years ago (including outdated citations from 1978 and 1984).

Specific Comments and Major Revisions

1. Table 1 Data: In Table 1, the prevalence of heart failure (HF) is reported as 19.5% and 41.8% among survivors and non-survivors, respectively. This seems exceptionally low for the analyzed cohort, considering that the vast majority of patients suffered from hypertension, coronary artery disease, and atrial fibrillation, with a mean age of 72 and 83.5 years. Could the authors clarify the specific diagnostic criteria used for heart failure? It is possible that these data are presented incorrectly and require verification.
2. Pacemaker Type Analysis: The manuscript dedicates substantial attention to analyzing patient survival based on single- vs. dual-chamber pacemakers. The authors themselves acknowledge that these results should be interpreted with caution, as the choice of pacing mode is influenced by numerous confounding factors, making a direct survival comparison potentially flawed. In my opinion, this section could be omitted from the manuscript without loss of core value.
3. Medical Therapy: There is no information regarding the medical therapy prescribed to patients after PPM implantation, which undoubtedly could have influenced survival rates. I strongly recommend including this data and, if feasible, adjusting for it in the statistical analysis.
4. References: The reference list includes a large number of papers published more than 5 years ago. The authors should revise and update the literature, replacing outdated references with recent studies.

Recommendation

Major revision 

Author Response

Response to Reviewer 4

Prognostic Value of Inflammatory and Nutritional Indices in Patients Undergoing Permanent Pacemaker Implantation for Degenerative Complete Atrioventricular Block

Dear Editor and Reviewer,

We sincerely thank the reviewer for the careful evaluation and constructive recommendations. We have revised the manuscript to clarify the heart failure definition and verify the reported prevalence, reduce the emphasis placed on pacemaker type, explicitly acknowledge the absence of post-implantation medication data, and update the clinical literature while retaining the original sources required to define the investigated indices and analytical methods. The reviewer’s comments are reproduced below, followed by our point-by-point responses and the revised wording.

Summary of revisions

No.	Reviewer request	Action taken
1	Clarify and verify HF prevalence	HF definition added; Table 1 counts rechecked and confirmed; prevalence stated with valid denominators.
2	Reduce pacemaker-type emphasis	Removed from Abstract and Conclusion; deleted dedicated supplementary analysis and lengthy discussion; retained only as baseline information and a Cox adjustment covariate.
3	Address medical therapy	Explained that medication class, dose, adherence, and longitudinal changes were unavailable; added this explicitly to Limitations.
4	Update references	Expanded the bibliography to 25 references, including 17 sources from 2021–2025; retained older references only when foundational or methodological.

Point-by-point response

Comment 1 — Heart failure definition and Table 1

Reviewer comment: In Table 1, heart failure was reported in 19.5% of survivors and 41.8% of non-survivors. The reviewer asked whether these values were correct and requested the diagnostic criteria used for heart failure.

Response: We agree that the diagnostic definition required clarification. We rechecked the Table 1 data and valid denominators. The reported values are correct: heart failure was present in 39 of 200 survivors (19.5%) and 28 of 67 non-survivors (41.8%), corresponding to 67 of 267 patients with available heart failure data (25.1%). Thus, no numerical correction to Table 1 was required. Hypertension, coronary artery disease, and atrial fibrillation were treated as comorbidities and risk factors; their presence alone was not considered sufficient to diagnose clinical heart failure. Heart failure was not inferred solely from age, cardiovascular comorbidities, or reduced left ventricular ejection fraction. We have now added a reproducible definition based on the 2021 Universal Definition of Heart Failure and specified how heart failure status was retrospectively adjudicated from the available records.

Location of revision: Materials and Methods—Study population and design; Results; Table 1.

Revised text in Methods:

“Heart failure was defined in accordance with the universal definition as a clinical syndrome with current or previous symptoms and/or signs attributable to a structural or functional cardiac abnormality, corroborated by elevated natriuretic peptide concentrations and/or objective evidence of pulmonary or systemic congestion [21]. For this retrospective study, heart failure status was adjudicated from the treating physician’s documented diagnosis and the available clinical, laboratory, and echocardiographic records. Reduced left ventricular ejection fraction alone, in the absence of a documented clinical heart failure syndrome, was not considered sufficient.”

Revised text in Results:

“Heart failure was documented in 67 of 267 patients with available data (25.1%). Its prevalence was 19.5% among survivors and 41.8% among non-survivors (p < 0.001).”

Comment 2 — Pacemaker-type analysis

Reviewer comment: The reviewer noted that direct survival comparisons between single- and dual-chamber pacemakers are vulnerable to confounding by indication and suggested omitting this section because it is not central to the study.

Response: We agree that pacing-mode selection was not randomized and that the observed association cannot be interpreted causally. We therefore substantially reduced the prominence of this secondary result. Specifically, we removed the single-chamber finding from the Abstract and Conclusion, deleted the dedicated Results paragraph and the extended Discussion paragraph, and removed the separate supplementary pacemaker-type comparison. Pacemaker type remains in Table 1 as a baseline cohort characteristic and in Table 4 because it was prespecified as a clinically relevant adjustment covariate. Removing it from the Cox model could leave device-selection differences unaccounted for and potentially alter the estimated association between PNI and mortality. We now state explicitly that the model was not intended to estimate a causal effect of pacing mode.

Location of revision: Abstract; Materials and Methods—Statistical analysis; Results; Discussion; Limitations; Conclusion; Supplementary Materials statement.

Revised text in Methods:

“Pacemaker type was retained as an adjustment covariate because device selection is influenced by rhythm status, comorbidity burden, frailty, and clinical judgment; the model was not designed to estimate a causal effect of pacing mode.”

Revised text in Discussion:

“Pacemaker type was retained only as an adjustment covariate. Because device selection is closely related to rhythm status, frailty, comorbidity burden, and physician judgment, the observed association with mortality should be considered secondary and hypothesis-generating rather than evidence of a causal effect of pacing mode.”

Comment 3 — Post-implantation medical therapy

Reviewer comment: The reviewer recommended reporting post-implantation medical therapy and, if feasible, adjusting for it because treatment could have influenced survival.

Response: We agree that post-implantation therapy is a potentially important prognostic factor. However, medication class, dose, adherence, and longitudinal treatment changes were not systematically captured in the retrospective dataset. A reliable treatment-adjusted analysis could therefore not be performed. We considered it preferable to acknowledge this limitation explicitly rather than introduce bias through incomplete or nonuniformly recorded medication data. This point has been added to the Limitations section, and future prospective studies are now implicitly framed as needing systematic treatment ascertainment.

Location of revision: Limitations.

Revised text:

“Post-implantation pharmacotherapy—including guideline-directed heart failure therapy, anticoagulant, antiplatelet, and lipid-lowering treatment—together with medication dose, adherence, and longitudinal treatment changes, was not systematically available. The potential influence of medical therapy on mortality could therefore not be evaluated, and residual confounding cannot be excluded.”

Comment 4 — Reference currency

Reviewer comment: The reviewer requested an updated literature review because many references were more than five years old, including citations from 1978 and 1984.

Response: We revised and expanded the clinical literature throughout the Introduction and Discussion rather than merely shortening the reference list. Older clinical pacing citations that were no longer essential were replaced with directly relevant contemporary evidence on pacemaker outcomes, frailty among pacemaker recipients, pacing mode in atrioventricular block, PNI and GNRI in cardiovascular populations, inflammatory risk markers, and nutrition-related arrhythmic risk. The revised bibliography now contains 25 references, of which 17 were published between 2021 and 2025. Eight older references were intentionally retained because they are the original development or methodological sources for PNI, GNRI, NLR, LMR, SII, SIRI, PIV, and the CKD-EPI equation. In particular, the 1984 Onodera article was retained because it is the foundational PNI source and directly documents the index’s original clinical setting. We also retained the 2021 Universal Definition of Heart Failure to support the clarified heart failure criteria. All new references were cited in the relevant sections of the manuscript. In the final quality-control step, bibliographic metadata for the recently added pacemaker references was reverified against publisher and indexed records and corrected where necessary.

Location of revision: Introduction; Materials and Methods; Discussion; References.

Examples of recent clinical sources now emphasized:

• 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy.
• 2022 CODE study on atrioventricular block and mortality and a 2024 nationwide study of pacing mode in atrioventricular block.
• 2025 study of mortality risk factors after pacemaker implantation and a 2024 nationwide analysis of frailty among pacemaker recipients.
• 2022 serum-albumin study and 2025 longitudinal PNI study in pacemaker recipients.
• 2025 nationwide PNI mortality study and 2022 long-term cardiovascular PNI study.
• 2023 GNRI cardiovascular mortality study and 2024 NLR cardiovascular mortality study.
• 2022 nutrition-related arrhythmic-risk study and 2023 REPACE registry follow-up report.

Closing statement

We thank the reviewer again for these constructive recommendations. The revisions improve the methodological clarity of the heart failure variable, keep the manuscript aligned with its primary immune-nutritional aim, make the limitations of the retrospective dataset more transparent, and bring the clinical literature up to date without removing the foundational sources needed for reproducibility.

Sincerely,
The Authors

Author Response File: Author Response.docx

Reviewer 5 Report

Comments and Suggestions for Authors

Strengths:
1. Compared to other similar studies that group various indications for cardiac pacing, this study is novel because it focuses exclusively on patients with "Isolated Complete Atrioventricular Block of Degenerative Origin." Furthermore, by excluding reversible, infectious, congenital, iatrogenic, or acute systemic causes, they significantly reduce confounding factors and achieve a clear assessment of the intrinsic biological vulnerability of this population.

2. It is important to highlight that the authors of this study do not limit themselves to evaluating a single biomarker, but rather comprehensively compare the performance of multiple routinely available inflammatory and nutritional indices (PNI, GNRI, NLR, LMR, IBS, SIRI, PIV), solidly demonstrating that PNI outperforms the others in predicting all-cause mortality. 3. The authors prudently limited the model to the most clinically relevant variables: PNI, hemoglobin, glomerular filtration rate, age, pacemaker type, heart failure, and atrial fibrillation. This lends high internal validity to the independent association found for PNI.

4. The analyzed indices are calculated from standard, low-cost, and widely available pre-procedural laboratory parameters used in daily practice, such as serum albumin and lymphocyte count. This facilitates their immediate implementation in the real world without added costs.

To improve the quality of the manuscript, the authors should explain and address the following weaknesses of the study in detail:

Weaknesses:
1. This is a retrospective observational study conducted at a single center. Therefore, it is not possible to establish direct causal relationships, and the findings may be affected by localized selection biases, limiting their generalizability.

2. Frailty assessments are necessary: ​​PNI serves as an indirect surrogate for immunonutritional status. There is no evidence of frailty, sarcopenia, or functional capacity measurements in patients using validated clinical scales, such as gait speed, grip strength, or the Mini Nutritional Assessment.

3. It is clear that the immunonutritional and inflammatory indices were calculated solely from preoperative baseline values. HOWEVER, the lack of repeated measurements over time eliminates the opportunity to assess longitudinal or dynamic fluctuations in the PNI (Patient Immune System) and to determine if they have superior prognostic value or if they respond to device implantation.

4. Single-chamber pacemaker implantation was independently associated with mortality, BUT the authors acknowledge that patients who received single-chamber devices were significantly older, frail, and had greater comorbidities. This introduces a strong confounding bias due to indication, which the statistical analysis does not fully correct. The authors should propose ways to mitigate or eliminate this bias.
5. They do not evaluate crucial echocardiographic parameters, such as left ventricular ejection fraction or valvular variables, for inclusion in the multivariable model. Data on cumulative ventricular pacing load and device programming during follow-up were also not included.

6. Oddly, the ROC curve used does not account for time to event or mortality. Therefore, should the established cutoff point for PNI be interpreted strictly as exploratory?

7. The true clinical value of a biomarker lies in its ability to guide therapies. Could pilot studies be conducted to analyze whether intensive nutritional intervention or physical prehabilitation in patients identified with low PNI before or immediately after implantation can mitigate risk and improve post-procedure survival?

Author Response

Response to Reviewer 5

Prognostic Value of Inflammatory and Nutritional Indices in Patients Undergoing Permanent Pacemaker Implantation for Degenerative Complete Atrioventricular Block

Dear Editor and Reviewer,

We sincerely thank the reviewer for the thoughtful, balanced, and constructive assessment of our work. We appreciate the recognition of the study’s homogeneous population, comparative evaluation of multiple inflammatory and nutritional indices, parsimonious multivariable model, and reliance on routinely available laboratory parameters. We agree that the limitations related to the retrospective single-center design, absence of formal frailty and serial biomarker assessments, potential confounding by indication, unavailable echocardiographic and device follow-up variables, conventional ROC methodology, and the need for interventional validation should be stated explicitly. We have therefore strengthened the Discussion, Limitations, and Conclusion while avoiding unsupported analyses with variables that were not available in the retrospective dataset. Our point-by-point responses and the revised wording are provided below.

Summary of revisions

No.	Reviewer concern	Action taken
1	Retrospective single-center design	Retained explicit statements that causal inference is not possible and that generalizability requires external validation.
2	Frailty, sarcopenia, and functional assessment	Clarified that PNI is an indirect marker; named validated frailty and nutritional instruments that were unavailable.
3	Absence of repeated index measurements	Expanded the limitation and recommended serial measurements at discharge and during follow-up.
4	Confounding by indication for pacemaker type	Further de-emphasized causal interpretation and proposed prospective covariate collection plus propensity-score methods for future studies.
5	Unavailable echocardiographic and device variables	Explicitly retained the absence of LVEF, valvular, pacing-burden, and device-programming data as limitations.
6	Conventional ROC and PNI cut-off	Confirmed throughout the manuscript that the cut-off and discrimination findings are exploratory and cohort-specific.
7	Therapy-guiding value of PNI	Added a proposal for pilot randomized feasibility studies, emphasizing early post-implantation interventions when pacing cannot be delayed.
8	Improve figures and tables	Reformatted Tables 1–4 and Supplementary Table S1; regenerated both figures as consistent 600-dpi publication files.

Point-by-point response

Comment 1 — Retrospective single-center design

Reviewer comment: The reviewer noted that the retrospective observational, single-center design precludes direct causal inference and may introduce local selection bias that limits generalizability.

Response: We fully agree. The study was designed to evaluate prognostic associations rather than causal effects. Accordingly, we have maintained cautious language throughout the Abstract, Discussion, and Conclusion and have explicitly stated that the design precludes causal inference and that external validation is required. No causal claim is made for PNI, pacemaker type, or any other covariate.

Location of revision: Limitations; Conclusion.

Revised text in Limitations:

“First, its retrospective, single-center design may limit the generalizability of the findings and precludes causal inference.”

Comment 2 — Frailty, sarcopenia, and functional capacity

Reviewer comment: The reviewer emphasized that PNI is an indirect surrogate of immune-nutritional status and requested acknowledgment of the absence of validated frailty, sarcopenia, nutritional, and functional assessments.

Response: We agree and have strengthened this limitation. PNI should not be interpreted as a direct measurement of frailty or nutritional status. Because gait speed, handgrip strength, the Clinical Frailty Scale, and the Mini Nutritional Assessment were not systematically recorded, we cannot determine whether PNI adds prognostic information beyond formal frailty or nutritional assessment. We now state this explicitly.

Location of revision: Limitations.

Revised text:

“Second, although PNI was independently associated with mortality, it should be regarded as an indirect marker of immune-nutritional vulnerability rather than a direct measure of frailty or nutritional status. Frailty, nutritional status, functional capacity, and sarcopenia were not systematically assessed using validated instruments such as gait speed, handgrip strength, the Clinical Frailty Scale, or the Mini Nutritional Assessment. Consequently, the incremental prognostic value of PNI beyond formal frailty and nutritional assessments could not be determined.”

Comment 3 — Baseline-only inflammatory and nutritional indices

Reviewer comment: The reviewer noted that the indices were calculated only from preprocedural baseline measurements, which prevented assessment of longitudinal changes and their potential relationship with device implantation.

Response: We agree. The available measurements were obtained within 24 hours before implantation, but repeated values at discharge and during follow-up were not systematically available. A dynamic or trajectory-based analysis would therefore not be reliable in this retrospective dataset. We have expanded the limitation and proposed serial measurements in prospective studies to determine whether changes over time add information beyond the baseline value.

Location of revision: Limitations.

Revised text:

“Third, the inflammatory and nutritional indices were calculated only from baseline laboratory values. Serial measurements at discharge and during follow-up were unavailable; therefore, longitudinal changes in PNI, albumin, lymphocyte count, and inflammatory markers, as well as whether these indices change after pacemaker implantation, could not be evaluated. Prospective studies incorporating repeated measurements are needed to determine whether dynamic trajectories provide prognostic information beyond baseline values.”

Comment 4 — Pacemaker type and confounding by indication

Reviewer comment: The reviewer highlighted the strong potential for confounding by indication in the association between single-chamber pacing and mortality and requested strategies that could mitigate this bias.

Response: We fully agree that pacemaker type cannot be interpreted causally in this cohort. In the preceding revision, we removed the single-chamber finding from the Abstract and Conclusion, deleted the dedicated survival comparison and supplementary pacemaker-type analysis, and retained pacemaker type only as a prespecified adjustment covariate. We have now additionally described how future studies could reduce confounding by prospectively recording the clinical rationale for device selection and detailed rhythm, frailty, functional, and comorbidity variables and by applying propensity-score matching or weighting. We also emphasize that these methods cannot eliminate residual confounding in a non-randomized comparison. We did not add a post hoc propensity analysis to the present study because the granular frailty and device-selection variables required for an adequately specified propensity model were unavailable and pacing mode was not the primary study aim.

Location of revision: Discussion; Limitations.

Revised text in Discussion:

Pacemaker type was retained only as an adjustment covariate. Because device selection is closely related to rhythm status, frailty, comorbidity burden, and physician judgment, the observed association with mortality should be considered secondary and hypothesis-generating rather than evidence of a causal effect of pacing mode [24]. Future studies specifically designed to evaluate pacing mode should prospectively record the clinical rationale for device selection and detailed measures of rhythm status, frailty, functional capacity, and comorbidity burden. Propensity-score matching or weighting and other causal-inference approaches may reduce confounding by indication; nevertheless, residual confounding may persist in non-randomized comparisons.

Revised text in Limitations:

“Fifth, pacemaker type was not randomly assigned; therefore, its association with mortality may have been influenced by confounding by indication, baseline clinical vulnerability, and device-selection patterns. Although pacemaker type was included as an adjustment covariate, conventional multivariable adjustment cannot eliminate unmeasured confounding. More granular covariate collection and propensity-score methods may reduce, but not eliminate, this bias in future observational studies.”

Comment 5 — Echocardiographic and device follow-up variables

Reviewer comment: The reviewer noted that left ventricular ejection fraction, valvular parameters, cumulative ventricular pacing burden, and device programming were not included in the multivariable analysis.

Response: We agree that these variables could influence long-term mortality and would strengthen risk adjustment. However, detailed echocardiographic and longitudinal device-interrogation data were not systematically available for the full retrospective cohort. Including incomplete or nonuniformly recorded values could have introduced additional bias and reduced the effective sample size. We therefore retained the parsimonious model based on consistently available variables and explicitly acknowledged the unavailable parameters as limitations rather than performing an unsupported analysis.

Location of revision: Limitations.

Text in the revised manuscript:

“Sixth, detailed echocardiographic parameters, including left ventricular ejection fraction, chamber dimensions, and valvular variables, were not systematically available and could not be included in the multivariable analysis. Seventh, sufficiently detailed data on pacing burden, device programming, and cause-specific mortality were unavailable.”

Comment 6 — Conventional ROC analysis and the PNI cut-off

Reviewer comment: The reviewer questioned whether the ROC-derived PNI cut-off should be interpreted strictly as exploratory because conventional ROC analysis does not account for time to event.

Response: We agree. The value of ≤48.90 is not presented as a validated clinical threshold. The Methods identify the Youden-derived cut-off as exploratory and cohort-specific; the Results emphasize its modest specificity and the limitations of conventional ROC analysis; and the Limitations and Conclusion require external validation. For additional transparency, the revised Methods now state that AUCs and ROC curves were estimated in a common complete-case sample (n = 222; 55 deaths), whereas the cohort-specific cut-offs and operating characteristics were calculated using all available observations for each marker. The Kaplan–Meier analysis provides a descriptive visualization of risk separation and does not convert the cut-off into a definitive treatment threshold.

Location of revision: Statistical analysis; Results; Limitations; Conclusion.

Text in the revised manuscript:

“Given its modest specificity and the use of conventional ROC analysis in a time-to-event data set, this value should be regarded as exploratory and cohort-specific rather than as a definitive clinical threshold. It may support adjunctive risk stratification but requires external validation before clinical application.”

“Eighth, conventional ROC analysis does not fully account for time-to-event information; therefore, the ROC-derived cut-off and discriminatory findings should be considered cohort-specific and exploratory.”

Comment 7 — Potential nutritional and rehabilitation interventions

Reviewer comment: The reviewer asked whether pilot studies could determine if intensive nutritional intervention or physical prehabilitation in patients with low PNI mitigates risk and improves survival.

Response: We agree that a biomarker’s ultimate value depends on whether it identifies a modifiable risk state and guides an effective intervention. The present observational study cannot establish treatment efficacy. We have therefore added a specific proposal for pilot and randomized feasibility studies of structured nutritional optimization and frailty-directed physical rehabilitation in patients with low PNI. Because complete atrioventricular block frequently requires urgent pacing, delaying implantation for a preprocedural program would often be impractical and potentially unsafe; consequently, an intervention initiated immediately after implantation may be the most feasible initial strategy.

Location of revision: Discussion; Conclusion.

Revised text in Discussion:

The principal clinical implication of this study is that PNI may serve as a readily available adjunctive marker for risk stratification in patients undergoing permanent pacemaker implantation for degenerative complete atrioventricular block. Because PNI is calculated from routine preprocedural laboratory parameters and requires no additional testing, it may help identify patients who warrant closer clinical follow-up, formal assessment of frailty and nutritional status, and optimization of modifiable systemic risk factors. Whether interventions targeting nutritional status or systemic inflammation improve outcomes in this population remains uncertain. Future pilot and randomized feasibility studies could evaluate structured nutritional optimization and frailty-directed physical rehabilitation in patients with low PNI. Because pacemaker implantation for complete atrioventricular block is often urgent and generally cannot be delayed for preprocedural rehabilitation, interventions initiated immediately after implantation may represent the most clinically feasible strategy.

Revised text in Conclusion:

Among the evaluated inflammatory and nutritional indices, PNI demonstrated the numerically highest discriminatory performance and remained independently associated with long-term all-cause mortality in patients undergoing permanent pacemaker implantation for degenerative complete atrioventricular block. These findings support PNI as a readily available adjunct to clinical risk stratification, although its incremental clinical value and cohort-specific cut-off require external validation. Prospective multicenter studies should validate the prognostic role of PNI, and pilot randomized feasibility trials should determine whether early post-implantation nutritional optimization or frailty-directed rehabilitation improves outcomes in this population.

Additional editorial comment — Figures and tables can be improved

Editorial comment: Figures and tables can be improved.

Response:

We agree and have revised all visual materials. Tables 1–4 now use consistent typography, alignment, spacing, borders, unit presentation, and explanatory notes; the dense ROC table uses clear multi-line headings. Supplementary Table S1 was reformatted as a concise one-page table. Figure 1 was regenerated at 600 dpi from the common complete-case ROC sample used for the reported AUCs (n = 222; 55 deaths), with distinct line styles and a color-blind-friendly palette. Figure 2 was standardized at 600 dpi and includes censoring marks, group sizes, the log-rank result, and numbers at risk. Both figures are provided separately as high-resolution PNG files.

Location of revision: Tables 1–4; Figures 1–2; Supplementary Table S1; separate high-resolution figure files.

Closing statement

We thank the reviewer again for these insightful recommendations. The revisions distinguish PNI from direct frailty assessment, make the limitations of baseline-only measurements and unavailable echocardiographic and device data more transparent, further guard against causal interpretation of pacing mode, and define a clinically realistic pathway for prospective validation and intervention studies. We believe these changes have improved the clarity, balance, and clinical relevance of the manuscript.

Sincerely,
The Authors

Author Response File: Author Response.docx

Round 2

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript has been successfully revised in accordance with the previously provided reviewer comments.

Reviewer 5 Report

Comments and Suggestions for Authors The authors have made all the corrections requested by the reviewer.
The reviewer accepts the manuscript for publication in its current state.