F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.19907.1 Systematic Review Articles Prognosis associated with geometric patterns of left ventricular remodeling: systematic review and network meta-analysis

[version 1; peer review: 1 approved with reservations, 1 not approved]

 Zheng Qishi Data Curation Formal Analysis Methodology Writing – Original Draft Preparation Writing – Review & Editing 1 2 Loo Germaine Data Curation Formal Analysis Methodology Writing – Original Draft Preparation 3 Le Thu-Thao Data Curation Writing – Review & Editing 4 5 Shi Luming Formal Analysis Methodology Writing – Review & Editing 1 2 6 Chan Edwin Shih-Yen Formal Analysis Methodology Writing – Review & Editing 1 2 6 Chin Calvin W. L. Conceptualization Project Administration Supervision Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0002-9867-4390 a 4 5 Department of Epidemiology, Singapore Clinical Research Institute, Singapore, Singapore Cochrane Singapore, Singapore, Singapore Department of Internal Medicine, Singapore General Hospital, Singapore, Singapore Department of Cardiology, National Heart Center Singapore, Singapore, Singapore Cardiovascular Sciences ACP, Duke NUS Graduate Medical School, Singapore, Singapore Centre for Quantitative Medicine, Duke NUS Graduate Medical School, Singapore, Singapore cchin03m@gmail.com

No competing interests were disclosed.

 19 7 2019 2019 8 1130 10 7 2019 Copyright: © 2019 Zheng Q et al. 2019 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: There are four geometric patterns (normal geometry, concentric remodeling, concentric and eccentric hypertrophy) used to describe cardiac remodeling. Although left ventricular hypertrophy (LVH) is associated with adverse prognosis, the incremental prognostic value of geometric patterns is less certain. We examined characteristics and prognosis associated with the four conventional patterns of left ventricle (LV) remodeling.

Methods: A comprehensive literature search was performed on MEDLINE/PubMed, Embase and the Cochrane Library until January 2019. Network meta-analysis was used to pool data from direct and indirect prognostic comparisons of the four geometric patterns. All-cause mortality was defined as the study outcome.

Results: A total of 22 echocardiographic studies (76, 142 individuals; 50.1% males; 64.4±7.9 years) of diverse cardiovascular diseases were included. Concentric LVH was associated with the highest prevalence of cardiovascular risk factors and diseases; and eccentric hypertrophy was associated with a high prevalence of atrial fibrillation and low LV ejection fraction. Compared to normal geometry, the risk of all-cause mortality was increased in concentric hypertrophy (risk ratio 1.97 [95% confidence interval 1.63-2.39]) but similar to eccentric hypertrophy (risk ratio 1.15 [95% confidence interval 0.97-1.36]).

Conclusions: The study populations examined in the meta-analysis were heterogeneous. Concentric LVH conferred the highest risk of all-cause mortality that overlapped with eccentric hypertrophy. Strategies to improve LVH risk stratification should be examined in future research.

 Left ventricular hypertrophy geometric patterns of left ventricular remodeling concentric remodeling concentric hypertrophy eccentric hypertrophy The author(s) declared that no grants were involved in supporting this work. Introduction

The left ventricle (LV) remodels as a response to cardiovascular disease and myocardial injury. Characterized by an increase in LV myocardial mass, left ventricular hypertrophy (LVH) is an established predictor of poorer cardiovascular outcomes 1 .

Four classical geometric patterns of LV remodeling have been defined based on LV mass and relative wall thickness: normal, concentric remodeling, concentric and eccentric hypertrophy 2 . This convenient approach of characterizing LV remodeling has been studied across various patient populations, including patients with coronary artery disease, aortic stenosis, hypertensive heart disease and community-based general populations 3– 6 . Whilst some studies demonstrated prognostic associations with these patterns of LV remodeling, others have not. Knowledge of remodeling patterns (concentric and eccentric hypertrophy) provided particularly limited incremental prognostic information beyond LVH 1, 7– 10 .

In this study, we aim to conduct a comprehensive systematic review and network meta-analysis to examine the characteristics and prognosis associated with the four conventional geometric patterns of LV remodeling.

 Methods Literature search and eligibility criteria

A comprehensive literature search was performed on MEDLINE/PubMed (1946 onwards), Embase (1974 onwards) and the Cochrane Library (1996 onwards) until January 2019. Full text publications evaluating the four conventional LV geometry patterns (normal geometry, concentric remodeling, concentric and eccentric hypertrophy) and prognosis were included. The basic search protocol and specific terms used in the search strategy are available as Extended data 11 . We conducted the literature search using Medical Subject Headings or Emtree, and free text terms. There were no restrictions on language.

Two investigators (Q.Z. and G.L.) independently searched for eligible studies based on the pre-defined eligibility criteria. Full-text studies that compared the prognosis of the four conventional LV geometry patterns (i.e. normal geometry, concentric remodeling, concentric and eccentric hypertrophy) were included. We excluded publications in non-adult populations, case reports, commentaries, abstracts, letters-to-editors and review articles. The bibliography in the identified publications and review articles were also reviewed.

 Data extraction and quality assessment

The following data were extracted in duplicates by the two investigators (Q.Z. and G.L.) from the included studies: (1) study characteristics (publication year and patient population); (2) baseline characteristics (mean age, sex distribution, and proportion of patients with hypertension, coronary artery disease, diabetes and other significant risk factors); (3) the four LV remodeling patterns; and (4) adverse prognosis defined as all-cause mortality. Eligible studies that did not report all-cause mortality as an end-point were still included to examine clinical characteristics associated with geometric patterns of LV remodeling. Any disagreements were resolved by discussion with a third investigator (C.W.L.C.). In publications with survival curves, the cumulative survival rates were estimated by digitizing the plots (WebPlotDigitizer version 3.9, Austin, Texas, USA).

Two investigators (C.W.L.C. and Z.Q.) independently appraised the quality of each study using the Quality In Prognosis Studies tool 12 . Six domains (study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding; and statistical analysis and reporting) were evaluated to assess the risk of bias in the prognostic studies. In each of the six domains, the risk of bias was classified as “low”, “moderate” or “high”.

 Statistical analysis

A network geometry of the four LV remodeling patterns was constructed. Each node represented a remodeling pattern and its size was weighted by the number of individuals in that group. The connecting line between two nodes denoted direct comparison and its thickness reflected the number of studies included.

The random-effects meta-regression models were used to measure the impact of baseline characteristics on the effect size of the outcome. The risk ratio (RR) of each LV remodeling group was estimated and reported in the study. To rank the prognosis of all the geometric patterns, we used surface under the cumulative ranking (SUCRA) values 13 . Rank probabilities of all the groups were first estimated, then followed by a step function to summarize the cumulative ranking for estimating the SUCRA values of each group, ranging from 0 to 100%. Larger SUCRA values indicated better prognosis.

Both node-splitting and inconsistency modeling were used to test the consistency assumption. The former method involved fitting a series of node-splitting models, one model for each group pair in which there was direct and indirect comparisons. In the latter method, an inconsistency model was fitted and the global Wald test would determine if significant inconsistency was present 14 . Statistical analyses were performed using Stata/MP Version 13 (StataCorp., College Station, Texas, USA), with the network and network graphs package.

 Results Studies and participants

From an initial 257 publications, 22 echocardiographic studies of diverse cardiovascular diseases satisfied inclusion/exclusion criteria and were included in this study ( Figure 1) 6– 10, 15– 31 . The thresholds used to define LVH and increased concentricity were heterogeneous across the studies ( Table 1).

PRISMA flow chart.

The systematic review and network meta-analysis was conducted according to the guidelines recommended by PRISMA.

 Baseline characteristics of included studies.
Reference Population Patients (n) Females (n) Age (years) Definition of left ventricular hypertrophy Definition of increased concentricity Follow-up duration (years)
Males (g/m 2) Females (g/m 2)
Beger 2011 Coronary artery disease 973 251 66.8 102 88 Posterior Wall thickness; 11mm 4.9
Verma 2008 Coronary artery disease 603 192 65.6 115 95 RWT; 0.42 2.1
Ghali 1998 * Coronary artery disease 446 201 56.9 131 100 RWT; 0.45 9.0
Shigematsu 1998 Hypertension 77 25 57.0 125 125 RWT; 0.44 Not stated
Gerdts 2008 Hypertension 937 388 65.5 116 104 RWT; 0.43 4.8
Fabiani 2017 Hypertension 749 325 62.0 115 95 RWT; 0.42 3.7
Verdecchia 1996 Hypertension 274 37 53.0 125 125 RWT; 0.45 3.2
Kohara 1999 Hypertension 150 78 58.3 118 108 RWT; 0.41 Not stated
Krumholz 1995 General Population 3209 1813 57.0 143 102 RWT; 0.45 7.7
Lieb 2014 General Population 4492 216 53.3 207g 170g RWT; Males: 0.419; Females: 0.435 4.0
Gardin 2001 General Population (>65 years old) 2506 1622 - >95th percentile >95th percentile RWT; 0.48 6.0
Milani 2006 Patients EF>50% 35, 602 18, 869 60.0 116 104 RWT; 0.43 3.2
Lavie 2006 Patients EF>50% (>70 years old) 9771 5569 77.5 116 104 RWT; 0.43 3.1
Lavie 2009 Patients EF>50% (>70 years old) 8088 4564 77.0 116 104 RWT; 0.43 3.1
Ghali 1998 * Patients EF>45% 542 347 54.0 131 100 RWT; 0.45 9.0
Katz 2013 HFpEF 402 251 62.8 48g/m 2.7 44g/m 2.7 RWT; 0.42 1.0
Apostolaskis 2014 Atrial fibrillation 2433 1058 69.0 115 95 RWT; 0.42 3.5
Shah 2014 Atrial Fibrillation 1088 496 69.1 115 95 RWT; 0.42 6
Debry 2017 Aortic stenosis 331 150 73.0 115 95 RWT; 0.42 3.1
Capoulade 2017 Aortic stenosis 747 426 69.0 49g/m 2.7 47g/m 2.7 RWT; 0.42 6.4
Rymuza 2017 Aortic stenosis (TAVI) 208 107 79.4 115 95 RWT; 0.42 1.5
Paoletti 2016 Chronic kidney disease 445 222 64.0 131 100 RWT; 0.45 5.9
Park 2018 Ischemic strokes 2069 787 65.5 115 95 RWT; 0.42 3.1

* Two populations were studied in the same publication.

RWT regional wall thickness; HFpEF heart failure preserved ejection fraction; EF ejection fraction; TAVI transcatheter aortic valve implantation

Of the 76,142 individuals pooled from the 22 studies (50.1% males; 64.4±7.9 years), 49.7% had normal geometry; and 31.1%, 10.5% and 8.7% had concentric remodeling, concentric and eccentric hypertrophy, respectively. The proportion of females with concentric and eccentric hypertrophy was high (40–45%). Compared to the other geometric patterns, concentric hypertrophy was associated with the highest prevalence of cardio-metabolic risk factors and cardiovascular diseases. Eccentric hypertrophy was associated with a high prevalence of atrial fibrillation and low LV ejection fraction ( Table 2).

Clinical characteristics associated with geometric patterns of left ventricular remodeling.
Normal Geometry Concentric Remodeling Concentric Hypertrophy Eccentric Hypertrophy
Age, years 61.7 65.3 65.4 64.1
Females, % 15.8 25.1 45.6 42.2
Systolic blood pressure, mmHg 134.6 136.7 147.1 141.5
Diabetes mellitus, % 9.4 16.7 24.4 17.5
Hypertension, % 27.6 44.0 67.1 58.1
Coronary artery disease, % 6.9 12.8 22.1 9.7
Strokes, % 3.5 5.5 7.1 4.4
Atrial fibrillation, % 11.2 21.3 23.9 22.3
Left ventricular mass index, g/m 2 83.9 84.8 133.3 127.2
Regional wall thickness 0.95 1.13 1.29 1.08
Ejection fraction, % 59.2 60.9 58.9 53.3
Adverse prognosis associated with geometric patterns of left ventricular remodeling

Most of the studies demonstrated low risk of bias in the six domains examined ( Table 3). The network geometry of LV remodeling patterns was constructed in Figure 2. Concentric remodeling was associated with higher all-cause mortality compared to normal geometry (RR 1.56 [95% confidence interval (CI): 1.31 to 1.85]), and a lower mortality risk compared to concentric hypertrophy (RR 0.79 [95% CI 0.67 to 0.93]). The mortality risk of concentric remodeling was similar compared to eccentric hypertrophy (RR 0.91 [95% CI 0.76 to 1.09]) ( Table 4).

Assessing quality of prognostic studies in systematic reviews.
Reference Study participation Study attrition Prognostic factor measurement Outcome measurement Study confounding Statistical analysis and reporting
Krumholz 1995 Low Low Low Low Low Low
Verma 2008 Low Low Low Low Low Low
Lieb 2014 Low Low Low Low Low Low
Gardin 2001 Low Low Low Low Low Low
Milani 2006 Low Low Moderate Moderate Low Low
Lavie 2006 Low Low Moderate Moderate Low Low
Beger 2011 Low Low Low Low Low Low
Katz 2013 Low Moderate Low Low Low Low
Verdecchia 1996 Low Low Low Low Low Low
Kohara 1999 Low Low Low Low Low Moderate
Apostolaskis 2014 Low Low Low Low Low Low
Ghali 1998 Low Low Low Low Low Low
Debry 2017 Low Low Low Low Low Low
Paoletti 2016 Low Low Low Low Low Low
Shigematsu 1998 Low Low Low Low Low Low
Gerdts 2008 Low Low Low Low Low Low
Fabiani 2017 Low Low Low Low Low Low
Park 2018 Low Low Low Low Low Low
Lavie 2009 Low Low Moderate Moderate Low Low
Capoulade 2017 Low Low Low Low Low Low
Rymuza 2017 Low Moderate Low Low Low Low
Shah 2014 Low Low Low Low Low Low
Network constructed for the different left ventricular remodeling patterns.

The numbers on the connecting lines denote the studies included for direct comparison.

 Prognosis associated with geometric patterns of left ventricular remodeling.

Results presented in risk ratio and corresponding 95% confidence interval.

Reference group
Normal Geometry Concentric Remodeling Concentric Hypertrophy Eccentric hypertrophy
Normal Geometry 1.00 0.64 [0.54, 0.76] * 0.51 [0.43, 0.60] * 0.59 [0.49, 0.70] *
Concentric Remodeling 1.56 [1.31, 1.85] * 1.00 0.79 [0.67, 0.93] * 0.91 [0.76, 1.09]
Concentric Hypertrophy 1.97 [1.63, 2.39] * 1.27 [1.08, 1.49] * 1.00 1.15 [0.97, 1.36]
Eccentric Hypertrophy 1.71 [1.43, 2.04] * 1.10 [0.92, 1.31] 0.87 [0.73, 1.03] 1.00

*p-value < 0.05

Compared to normal geometry, concentric hypertrophy was associated with highest risk of all-cause mortality (RR 1.97 [95% CI 1.63 to 2.39]; Table 4). The confidence limits overlapped with eccentric hypertrophy (RR 1.71 [95% CI 1.43 to 2.04]). Moreover, the mortality risk of concentric hypertrophy was not significantly increased compared to eccentric LVH (RR 1.15 [95% CI 0.97 to 1.36]). Based on the SUCRA values, the geometric patterns ranked from best to worst prognosis were: normal geometry, concentric remodeling, eccentric hypertrophy and concentric hypertrophy ( Figure 3).

Forest plot of direct comparisons with pooled results from network meta-analysis.

A, normal geometry; B, concentric remodeling; C, concentric hypertrophy; D, eccentric hypertrophy.

Results from both node-splitting method and inconsistency model showed no evidence on the violation of consistency assumption between direct and indirect comparisons. Specifically, the pooled estimates between models of consistency (red diamonds) and inconsistency (green diamonds) were identical because all the studies included the four remodeling patterns ( Figure 4).

( a) Rank probabilities of effectiveness and SUCRA scores; and ( b) prognosis of the four geometric patterns of left ventricular hypertrophy.

 Discussion

In this systematic review and network meta-analysis of 22 echocardiographic publications (n=76,133 individuals), we report the characteristics and prognosis associated with the different patterns of LV remodeling. The study populations were heterogeneous and, importantly, the definitions used to classify the geometric patterns were not uniform. Concentric hypertrophy is associated with the highest prevalence of cardiometabolic risk factors and diseases. Eccentric hypertrophy is associated with a high prevalence of atrial fibrillation and the lowest LV ejection fraction. Although concentric hypertrophy is associated with the highest risk of all-cause mortality, the risks overlapped with eccentric hypertrophy. Eccentric hypertrophy has a similar mortality risk compared to concentric remodeling.

The pathophysiology of LVH has been well described and studied for the past 50 years 32, 33 . Cardiac hypertrophy is initially an adaptive response to the wall stress according to the Law of LaPlace. Ultimately, cardiac decompensation occurs as a consequence of myocyte death and myocardial fibrosis 34, 35 . Whilst geometric patterns of LV remodeling are clinically meaningful to describe the hypertrophic response due to mechanical stress from either pressure (concentric hypertrophy) or volume overload (eccentric hypertrophy), it may not adequately identify the transition point where adaptive hypertrophy decompensates ( Figure 5). This transition point before cardiac decompensation occurs is an important potential risk marker to target more intensive management and closer surveillance. In this study, we have demonstrated that both concentric and eccentric hypertrophy were associated with similar risks of increased all-cause mortality. These observations may suggest that the risk of adverse prognosis is increased once LVH develops, regardless of geometric patterns. It may also suggest that some patients with concentric or eccentric LVH may be in the compensated phase and begets the question of whether there are other strategies to identify high-risk LVH phenotypes.

Relationship between geometric patterns of cardiac remodeling, mechanical stress and prognosis.

Geometric patterns of left ventricular remodeling are useful to identify the mechanisms of mechanical stress; but may not adequately identify the transition between myocardial adaptation and decompensation.

To address the complex interaction between LV dilatation and myocardial thickening in the pathophysiology of LVH, several studies have recently examined an expanded four-group LVH classification: dilated/non-dilated concentric hypertrophy and dilated/non-dilated eccentric hypertrophy 36– 40 . In this proposed four-group LVH classification, dilated concentric hypertrophy was associated with the worst prognosis and non-dilated eccentric hypertrophy had the most favourable profile 36– 39 . However, more guidance is needed before this complex classification can be integrated into routine clinical practice. Recently, we have developed the remodeling index (RI), based on a biophysical model of Laplace’s Law. The RI integrates LV volume and myocardial thickening into a single measurement 41 . We further demonstrated that hypertensive LVH patients with abnormally low RI (suggestive of excessive myocardial thickening relative to LV dilatation) had increased myocardial fibrosis, elevated circulating markers of myocardial injury and wall stress; and in a small number of patients with dilated cardiomyopathy, an abnormally high RI (suggestive of excessive LV dilatation relative to myocardial thickening) was associated with adverse cardiovascular events 41 . The prognostic value and clinical utility of this index are currently being examined in a large cohort of hypertensive patients (ClinicalTrials.gov identifier: NCT02670031).

These emerging data support the notion that cardiac remodeling in hypertrophy is heterogeneous and complex; and the conventional geometric patterns of LV remodeling is not adequate to risk-stratify patients with LVH.

Study limitations

The study populations included in the meta-analysis were heterogeneous. It is possible that the conventional remodeling patterns has incremental prognostic value in certain cardiac conditions. Unfortunately, the limited number of studies precluded stratified analyses to examine the prognostic value of LV geometric patterns in the different cardiovascular conditions. The definitions used for classifying geometric patterns were not consistent across the different studies. This is concerning and reinforces the necessity to apply consensus definitions in future studies 2 .

 Conclusions

Concentric and eccentric hypertrophy are associated with increased and similar all-cause mortality. Possible explanations for these observations include the heterogeneous populations, inconsistent definitions used in the classification and the inherent limitations of the conventional patterns of LV geometry to adequately risk stratify LVH. Well-validated novel approaches to improve risk stratification of LVH should be explored in future research.

 Data availability Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

 Extended data

Open Science Framework: Prognosis associated with geometric patterns of left ventricular remodeling: systematic review and network meta-analysis. https://doi.org/10.17605/OSF.IO/3CJMW 11 .

This project contains the following extended data:

Data file.xlsx (Sheet 1 contains study questions, search date, search terms and eligibility criteria; Sheet 2 contains a list of the studies identified; Sheet 3 contains the six composites used in this study).

 Reporting guidelines

Open Science Framework: PRISMA checklist for “Prognosis associated with geometric patterns of left ventricular remodeling: systematic review and network meta-analysis”. https://doi.org/10.17605/OSF.IO/3CJMW 11 .

Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

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Circ Cardiovasc Imaging. 2017;10(9): pii: e006840. 28847911 10.1161/CIRCIMAGING.117.006840 5617557 10.5256/f1000research.21845.r55256 Reviewer response for version 1 Yeo Tee Joo 1 Referee https://orcid.org/0000-0002-2462-6257 National University Heart Centre Singapore, National University Health System, Singapore, Singapore

Competing interests: No competing interests were disclosed.

 23 10 2019 Copyright: © 2019 Yeo TJ 2019 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation approve-with-reservations

Zheng et al performed a systematic review and meta-analysis of echocardiographic studies that included prognostic characteristics of 4 geometric patterns of cardiac remodeling.

Through the combined total of 22 studies comprising diverse populations, including hypertension, aortic stenosis, heart failure with preserved ejection fraction, ischemic strokes, chronic kidney disease etc, the authors conclude that the presence of concentric LVH and eccentric hypertrophy was associated with a higher risk of all-cause mortality.

The overall aim of this study is commendable. Nonetheless, there are a few areas of note:

The study includes populations both with and without pre-existing cardiovascular disease; in such a situation, the baseline risk profiles differ significantly (eg. an apparently healthy individual with newly diagnosed hypertension has a substantially lower risk profile compared to an individual with pre-existing or longstanding aortic stenosis although both may develop LVH eventually).

A suggested approach would be to stratify the risk of LVH based on aetiology (e.g. hypertension-related, aortic stenosis related, multifactorial etc.) which would make the meta-analysis more applicable to the above sub-groups of patients rather than providing a single risk ratio for an entire phenotypic category of cardiac remodeling.

The authors may consider excluding the studies involving the general population to limit the study population to those with pre-existing disease, as the absolute number of Framingham subjects with LVH was actually small.

Importantly, the classification of LVH and RWT differed in certain studies, so applicability is affected. Although the authors listed this as a limitation, studies with substantial differences in quantifying LVH might need to be excluded in order to keep the study population homogenous.

In Table 2, regional (?or relative, as stated by the American Society of Echocardiography and other international echocardiography societies) wall thickness for all 4 categories of cardiac remodeling ranged between 0.95 to 1.29. Do check if this is correct, as that would classify all subjects in the concentric geometry.

For the conclusion, the authors are right to say that the study populations were heterogeneous. As such, it might be more appropriate to generate different risks for the larger subsets of patients (eg. LVH from hypertension vs LVH from aortic stenosis vs LVH from combined causes) rather than to generalise risk for all patients regardless of aetiology.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes

Is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.

Are sufficient details of the methods and analysis provided to allow replication by others?

Yes

Are the conclusions drawn adequately supported by the results presented in the review?

Partly

Reviewer Expertise:

Sports cardiology; Athlete's heart; physiological vs pathological cardiac remodeling in athletes.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

 10.5256/f1000research.21845.r54455 Reviewer response for version 1 Trimarco Bruno 1 Referee Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy

Competing interests: No competing interests were disclosed.

 16 10 2019 Copyright: © 2019 Trimarco B 2019 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation reject

The paper titled “Prognosis associated with geometric patterns of left ventricular remodeling: systematic review and network meta-analysis” by Zheng et al aims to identify different prognostic profile of different left ventricular remodeling patterns. Although the aim is of interest, the method to select data from the international literature is quite messy.

In fact, populations are not homogenous (from population-based studies like the FHS, to patients with stable CAD, to patients with hypertension, aortic stenosis, HFpEF,  etc). In addition, methods reported in studies to categorize left ventricular remodeling are still not homogeneous. Consequently, conclusions of the paper are erroneous.

Authors stated that the new classification of left ventricular remodeling proposed by Khouri is “complex” and  “more guidance is needed before this complex classification can be integrated into routine clinical practice”, so that they propose a more simple index (the remodeling index) which at moment is tested by the authors in a trial of hypertensive patients.

We thank the Author for the suggestion, i.e. to use their index; of course, to demonstrate in the future that their index is superior to that used in the past, they will have to perform a correct statistical analysis, confronting their index with clear-cut values suggested by guidelines and more recently by Khouri, (which, I guess, is very easy to use into clinical practice) for the identification of left ventricular remodeling patterns.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes

Is the statistical analysis and its interpretation appropriate?

No

Are sufficient details of the methods and analysis provided to allow replication by others?

No

Are the conclusions drawn adequately supported by the results presented in the review?

No

Reviewer Expertise:

Hypertension

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Chin Calvin National Heart Center Singapore, Singapore

Competing interests: None

 16 10 2019

We thank the Reviewer for the comments.  We wish to highlight the issues raised by the Reviewer are inherent to the individual studies and not the methodology of the meta analysis.  We agree with the Reviewer that the study populations included in the study are heterogeneous.  Unfortunately, the limited number of studies precluded further analyses to examine prognostic value of LV geometric patterns in different cardiovascular conditions.  The definitions used for classifying geometric patterns were not consistent in the studies as highlighted by the Reviewer, a limitation that reinforces the necessity of applying consensus definitions in future studies.  Both of these points have already been listed as study limitations.