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. 2021 Jul 13;16(7):e0254641. doi: 10.1371/journal.pone.0254641

Delayed repolarization and ventricular tachycardia in patients with heart failure and preserved ejection fraction

Jae Hyung Cho 1, Derek Leong 1, Natasha Cuk 1, Joseph E Ebinger 1, Catherine Bresee 2, Sung-Han Yoon 1, Ashkan Ehdaie 1, Michael Shehata 1, Xunzhang Wang 1, Sumeet S Chugh 1, Eduardo Marbán 1, Eugenio Cingolani 1,*
Editor: Elena G Tolkacheva3
PMCID: PMC8277017  PMID: 34255806

Abstract

Sudden death is the most common mode of mortality in patients with heart failure and preserved ejection fraction (HFpEF). Ventricular arrhythmias (VA) have been suspected as the etiology but the supporting evidence in patients with HFpEF is scarce. We sought to investigate VA prevalence, and to determine if VA are associated with prolonged repolarization, in patients with HFpEF. In a retrospective case-control study design, Cedars-Sinai patients who underwent prolonged ambulatory electrocardiographic monitoring (Zio Patch) between 2016 and 2018 were screened for a clinical diagnosis of HFpEF. Patients with normal diastolic and systolic function who underwent Zio Patch monitoring were also reviewed as controls. Multivariable logistic regression was used to compare the prevalence of rhythm disturbances in patients with and without HFpEF. Ventricular tachycardia (VT) was more prevalent in patients with HFpEF (37% vs. 16% in controls, p = 0.001). Most episodes were non-sustained except for one case of sustained VT in a patient with HFpEF. Covariate-adjusted logistic regression including HFpEF diagnosis, age, sex, body mass index, and the presence of comorbidities revealed that only HFpEF was associated with increased risk of VT (relative risk 2.86, p = 0.023). Subgroup-analyses revealed an association between increased QTc interval and risk of VT (460 ± 38 ms in HFpEF patients with VT vs. 445 ± 28 ms in HFpEF patients without VT, p = 0.03). Non-sustained VT was more prevalent in patients with HFpEF compared to patients without HFpEF, and QTc interval prolongation was associated with VT in HFpEF.

Introduction

Heart failure and preserved ejection fraction (HFpEF) is increasing in incidence, rivaling heart failure and reduced ejection fraction (HFrEF) [1, 2]. Patients with HF have a poor prognosis, with a 75% mortality rate at 5 years, regardless of EF [3]. Unlike HFrEF, for which numerous medical and device therapies have been proven to reduce mortality, no treatment has been proven to prolong survival of patients with HFpEF. Specifically, traditional HF medications such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor II blockers and aldosterone antagonists, have failed to decrease mortality of patients with HFpEF, although there were regional variations with aldosterone antagonist [4–7]. Although sudden death is the most common mode of mortality in patients with HFpEF, the underlying mechanisms remain unclear [8]. Ventricular arrhythmias (VA) may play a role [9]; however, this remains untested in patients. Preclinical studies have revealed that VA are common and associated with sudden death in a rat HFpEF model [10, 11], with underlying repolarization delays revealed by electrocardiogram (ECG), optical mapping and patch clamp [12]. The present study sought to investigate VA prevalence, and to determine if VA are associated with prolonged repolarization, in patients with HFpEF.

Materials and methods

Study approval

This study was presented to the Institutional Review Board of Cedars-Sinai Medical Center and approval was obtained before the initiation of data collection. The nature of this study is medical record review of patients with HFpEF compared to patients without HFpEF.

Patch ambulatory monitoring of ECG (Zio Patch)

We identified all patients (inpatients and outpatients) who underwent ambulatory monitoring of ECG by Zio Patch (iRhythm, San Francisco, CA) for any reason from January 2016 to December 2018 (3 years, N = 2,913, Fig 1). Our institution currently uses Zio Patch for ambulatory ECG monitoring up to 14 days.

Fig 1. Patient identification algorithm.

Fig 1

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Identification of patients with diastolic dysfunction

The Cedars-Sinai Echocardiography Database was queried for all transthoracic echocardiograms completed on patients between January 2016 to December 2018 (N = 44,875, Fig 1). Patients with normal systolic function (EF > 55%) who underwent Zio Patch monitoring were identified (N = 1,558, Fig 1). Echocardiograms were grouped as demonstrating either normal or abnormal diastolic function based on guideline criteria from the American Society of Echocardiography (average E/e’ > 14, septal e’ velocity < 7 cm/s or lateral e’ velocity < 10 cm/s, tricuspid regurgitation velocity > 2.8 m/s and left atrial volume index > 34 ml/m2) [13]. The severity of diastolic dysfunction (grade I, II, and III) was also determined based on guidelines [13].

Identification of patients with HFpEF vs. without HFpEF

Medical records of patients with diastolic dysfunction of any severity (N = 1,194) were reviewed to identify those with a clinical diagnosis of HFpEF (HF with symptoms, normal EF and diastolic dysfunction on transthoracic echocardiogram). Patients with diastolic dysfunction (due to old age) without documented HF symptoms were excluded. Patients with the following conditions were also excluded: uncorrected primary left sided valvular heart disease (aortic stenosis/regurgitation or mitral stenosis/regurgitation), isolated right ventricular failure (pulmonary hypertension, pulmonary or tricuspid valvular disease, arrhythmogenic right ventricular cardiomyopathy and congenital heart disease), pericardial disease (cardiac tamponade and constrictive pericarditis) and specific cardiomyopathies (amyloidosis, sarcoidosis, hypertrophic cardiomyopathy and restrictive cardiomyopathy) [1]. Patients who had normal diastolic and systolic function (N = 364) were also reviewed and only those without HF symptoms were selected to serve as controls for comparison.

Data collection

Chart reviews were performed (authors J.C. and D.L.) to collect relevant data. Baseline characteristics included age, sex, body mass index, hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, chronic kidney disease, atrial fibrillation, EF and diastolic function from the echocardiogram, medications (beta-blocker, calcium channel blocker, amiodarone and QT prolonging medications), ECG parameters (heart rate [HR], PR interval, QRS width, QT interval and QTc interval) and indications for Zio Patch monitoring (syncope, stroke, atrial fibrillation, palpitations, bradycardia, dizziness, etc.). Zio Patch results were reviewed to identify the prevalence of rhythm disturbances such as ventricular tachycardia (VT), supraventricular tachycardia, atrial fibrillation, atrial flutter, sinus pause and atrioventricular block.

Statistical analyses

SPSS was used to perform the statistical analysis. Baseline patient characteristics are presented as numbers and percentages for categorical variables and mean ± standard deviation for continuous variables. Comparisons of categorical variables were performed using Pearson’s chi-square and comparisons of continuous variables were performed using independent t-test. Both simple and covariate-adjusted multiple logistic regression modeling was used to compare the likelihood of VT between patients with and without HFpEF. Results were considered significant at p < 0.05.

Results

Patients with HFpEF vs. without HFpEF

A total of 110 patients with HFpEF underwent Zio Patch monitoring during the study period (Fig 1). As controls, 97 patients with normal diastolic and systolic function and Zio Patch monitoring were identified during the same time period. Most of the patients underwent Zio Patch within a week from echocardiogram (only 2 patients in each group underwent Zio Patch after 30 days of echocardiogram).

Baseline characteristics

Baseline characteristics of the HFpEF and control groups are shown in Table 1. Patients with HFpEF were older and had increased prevalence of hypertension, hyperlipidemia, coronary artery disease, chronic kidney disease and atrial fibrillation than patients without HFpEF. Male to female ratio of patients were not significantly different between the two groups, nor was the prevalence of diabetes mellitus or difference in body mass index. The severity of diastolic dysfunction in the HFpEF group was grade I in 64%, and grade II in 36%, of cases. None of the HFpEF patients met criteria for grade III diastolic dysfunction. Patients with HFpEF were taking more beta-blockers, calcium channel blockers and amiodarone. Approximately a quarter of patients in each group were taking QT prolonging medications (including amiodarone) at the time of Zio Patch monitoring. Baseline heart rates were not significantly different between the two groups. PR interval and QTc interval were more prolonged in patients with HFpEF compared to controls. QRS width was not different between control and HFpEF patients. Indications for Zio Patch monitoring were similar between the two groups.

Table 1. Baseline characteristics.

Control (N = 97) HFpEF (N = 110) P value
Age (mean ± SD) 67 ± 9 80 ± 12 < 0.001
Sex (male) 37 (38%) 52 (47%) 0.247
Body mass index (mean ± SD) 27 ± 6 27 ± 6 0.982
Hypertension 60 (62%) 96 (87%) < 0.001
Diabetes mellitus 15 (15%) 23 (21%) 0.313
Hyperlipidemia 56 (58%) 93 (85%) < 0.001
Coronary artery disease 15 (15%) 60 (55%) < 0.001
Chronic kidney disease 4 (4%) 28 (25%) < 0.001
Atrial fibrillation 21 (22%) 44 (40%) 0.005
Ejection fraction (mean ± SD) 64 ± 6 65 ± 8 0.251
Diastolic function (mean ± SD)
Normal 97 (100%) 0 (0%) < 0.001
Grade I diastolic dysfunction 0 (0%) 70 (64%)
Grade II diastolic dysfunction 0 (0%) 40 (36%)
Grade III diastolic dysfunction 0 (0%) 0 (0%)
MV inflow E wave (cm/s) 79.8 ± 15.9 85.6 ± 28.6 0.077
MV inflow A wave (cm/s) 64.4 ± 14.8 93.3 ±30.0 < 0.001
E/A ratio 1.3 ± 0.2 1.0 ± 0.6 < 0.001
Lateral e’ wave 10.2 ± 2.5 7.3 ± 2.2 < 0.001
Lateral E/e’ 8.5 ± 2.5 12.9 ± 6.5 < 0.001
TR velocity (m/s) 2.2 ± 0.4 2.6 ± 0.5 < 0.001
LA volume index (ml/m2) 26.4 ± 13.0 32.8 ± 13.6 0.004
Heart failure symptoms 0 (0%) 110 (100%) < 0.001
Laboratory data (mean ± SD)
BNP (pg/ml) 93.6 ± 110.0 351.4 ± 464.9 0.008
Na (mmol/L) 140.2 ± 4.0 139.7 ± 3.5 0.427
K (mmol/L) 4.1 ± 0.4 4.2 ± 0.6 0.082
Ca (mg/dL) 9.0 ± 0.6 9.1 ± 0.5 0.285
Creatinine (mg/dL) 0.9 ± 0.5 1.4 ± 1.6 0.009
Medications
Beta-blocker 27 (28%) 55 (50%) 0.001
Calcium channel blocker 16 (16%) 39 (35%) 0.002
Amiodarone 2 (2%) 16 (15%) 0.001
QT prolonging medication 27 (28%) 27 (25%) 0.591
ECG parameters
HR (bpm, mean ± SD) 68 ± 13 69 ± 15 0.412
PR interval (ms, mean ± SD) 165 ± 37 192 ± 50 < 0.001
QRS width (ms, mean ± SD) 93 ± 17 100 ± 33 0.051
QT interval (ms, mean ± SD) 414 ± 39 426 ± 48 0.043
QTc interval (ms, mean ± SD) 432 ± 29 451 ± 33 < 0.001
Indications for ECG monitoring
Syncope 23 (24%) 28 (25%) 0.771
Stroke 24 (25%) 19 (17%) 0.186
Atrial fibrillation 15 (15%) 21 (19%) 0.492
Palpitation 20 (21%) 10 (9%) 0.018
Bradycardia 6 (6%) 14 (13%) 0.112
Dizziness 5 (5%) 1 (1%) 0.069
Others 4 (4%) 17 (15%) 0.010
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Prevalence of rhythmic disturbances

VT was more prevalent in patients with HFpEF compared to controls (41/110 = 37% in HFpEF vs. 16/97 = 16% in controls, p = 0.001) (Table 2). Most of the VT episodes were non-sustained (less than 30 seconds by definition) except for one episode of sustained VT in a HFpEF patient. The average number of VT beats and durations were higher in patients with HFpEF than controls, but did not reach statistical significance (average number of beats 12.1 ± 16.1 vs. 8.3 ± 7.8 in controls, p = 0.237 and average duration 5.8 ± 7.5 seconds vs. 3.9 ± 2.5 seconds in controls, p = 0.182). Supraventricular tachycardia was slightly more prevalent in patients with HFpEF. Prevalence of atrial fibrillation and flutter, and atrioventricular block, were not statistically different. Sinus pause was slightly more prevalent in HFpEF patients.

Table 2. Prevalence of rhythm disturbances.

Control (N = 97) HFpEF (N = 110) P value
Ventricular tachycardia 16 (16%) 41 (37%) 0.001
Sustained 0 (0%) 1 (1%) 0.347
Non-sustained 16 (16%) 41 (37%) 0.001
Supraventricular tachycardia 70 (72%) 92 (84%) 0.046
Atrial fibrillation 9 (9%) 12 (11%) 0.699
Atrial flutter 1 (1%) 3 (3%) 0.379
Sinus pause 0 (0%) 5 (5%) 0.034
Atrioventricular block 0 (0%) 1 (1%) 0.235
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Simple logistic regression

Only HFpEF (relative risk [RR] 3.00, 95% confidence interval [CI] 1.55–5.83, p = 0.001) and age (RR 1.05, 95% CI 1.02–1.08, p = 0.001) was found to be associated with increased risk of VT by simple logistic regression (Fig 2). Other risk factors (sex, body mass index, hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, chronic kidney disease and atrial fibrillation) were not found to be independently associated with increased risk of VT.

Fig 2. Simple (A) and multiple (B) logistic regression of the likelihood of ventricular tachycardia.

Fig 2

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Covariate-adjusted logistic regression

After covarying for all factors, only HFpEF was associated with increased risk of VT compared with controls (RR 2.86, 95% CI 1.15–7.08, p = 0.023) (Fig 2). Older age demonstrated a trend towards increased VT risk, but did not reach statistical significance (RR 1.03, 95% CI 0.99–1.07, p = 0.068). Other risk factors (sex, body mass index, hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, chronic kidney disease and atrial fibrillation) were not found to be associated with VT risk.

Electrocardiographic parameter comparison

We investigated whether any of the electrocardiographic parameters are associated with increased risk of VT in patients with HFpEF (Table 3). HR, PR interval, QRS width and QT interval were not different between HFpEF patients with and without VT. Only QTc interval was more prolonged in HFpEF patients with VT compared to HFpEF patients without VT (460 ± 38 ms vs. 445 ± 28 ms, p = 0.032).

Table 3. Subgroup-analyses of HFpEF patients.

VT (N = 41) No VT (N = 69) P value
Age (mean ± SD) 82 ± 8 80 ± 14 0.265
Sex (male) 23 (56%) 29 (42%) 0.260
Body mass index (mean ± SD) 26 ± 5 27 ± 7 0.301
Hypertension 34 (83%) 62 (90%) 0.296
Diabetes 6 (15%) 17 (25%) 0.216
Hyperlipidemia 33 (80%) 60 (87%) 0.390
Coronary artery disease 21 (51%) 39 (57%) 0.595
Chronic kidney disease 7 (17%) 21 (30%) 0.122
Atrial fibrillation 12 (29%) 32 (46%) 0.078
Ejection fraction (mean ± SD) 64 ± 8 66 ± 8 0.113
Diastolic function
Grade I diastolic dysfunction 28 (68%) 42 (61%) 0.612
Grade II diastolic dysfunction 13 (32%) 27 (39%)
Grade III diastolic dysfunction 0 (0%) 0 (0%)
Medications
Beta-blocker 14 (34%) 41 (59%) 0.010
Calcium channel blocker 15 (37%) 24 (35%) 0.851
Amiodarone 3 (7%) 13 (19%) 0.099
QT prolonging medication 8 (20%) 19 (28%) 0.335
ECG parameters
HR (bpm, mean ± SD) 69 ± 13 70 ± 16 0.805
PR interval (ms, mean ± SD) 183 ± 44 198 ± 53 0.122
QRS width (ms, mean ± SD) 99 ± 22 101 ± 38 0.753
QT interval (ms, mean ± SD) 435 ± 49 421 ± 47 0.138
QTc interval (ms, mean ± SD) 460 ± 38 445 ±28 0.032
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Discussion

In this retrospective case control study, non-sustained VT was more prevalent in patients with HFpEF compared to patients without HFpEF. QTc interval was prolonged in patients with HFpEF compared to controls, and the prolongation was more prominent in HFpEF patients with VT compared to HFpEF patients without VT (Fig 3).

Fig 3. Prolonged QTc interval in HFpEF patients compared to controls.

Fig 3

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In prospective analyses of rhythm in the Dahl salt-sensitive rat model of HFpEF, VA are more frequent in HFpEF rats than in controls, and these VA are associated with sudden death [11, 12]. The underlying mechanisms include repolarization delays, conduction slowing and inhomogeneities of excitation. Delayed repolarization was manifest in ECG as prolonged QT/QTc interval, and in optical mapping and patch clamp as action potential prolongation [12]. HFpEF rats showed multiple re-entry circuits in optical mapping and increased fibrosis in tissue sections [12]. These anatomical and functional re-entry circuits both contribute to the increased propensity to VA. Ambulatory ECG monitoring revealed that VA were the cause of 75% of documented sudden deaths in HFpEF rats [11]. Here we have described, in human patients, associations among HFpEF, VT prevalence, and QTc interval prolongation. Our clinical data are consistent with the notion that inhomogeneities of excitation and repolarization underlie non-sustained VT in patients with HFpEF, but the insights here fall far short of establishing causality; instead, they should be considered hypothesis-generating.

Sudden death is the leading mode of mortality in patients with HFpEF; however, the mechanisms of sudden death have not been studied in this population. The World Health Organization defines sudden death as death occurring less than 1 hour from acute changes in witnessed cases or found dead within 24 hours in unwitnessed cases [14]. Sudden death can be divided into sudden cardiac death (SCD) and sudden non-cardiac death (SNCD) based on the etiology. In studies to date, most SCD are due to VA, which can be precipitated in coronary artery disease, and cardiomyopathy [15]. SNCD includes causes of death such as pulmonary disease (40%), infectious disease (20%), cerebrovascular disease (18%) and neurologic diseases (8%) [14]. The investigation of sudden death is challenging due to its inherent rapidity, and by its unpredictability [16].

Non-sustained VT (less than 30 seconds) has been recorded in a variety of patients, from healthy individuals to patients with significant heart disease. The actionability of non-sustained VT is highly debatable, but it generally portends enhanced risk. For example, in patients with non-ST elevation acute coronary syndrome, non-sustained VT after 48 hours of admission is associated with more than a 2-fold increase in sudden death [17], but using an automatic external defibrillator does not decrease mortality [18]. In patients with HFrEF (ischemic or nonischemic), non-sustained VT is present in 30–80% and is an independent marker of overall mortality and sudden death [19, 20], but this criterion is not used in the decision to place an implantable cardioverter-defibrillator (ICD). In contrast, in cases of hypertrophic cardiomyopathy, ICD placement is generally indicated for patients with non-sustained VT (more than 3 beats and greater than 120 bpm) [21]. The prevalence and importance of non-sustained VT have not been studied in patients with HFpEF. Our findings suggest that non-sustained VT may be more frequent in patients with HFpEF, but this prediction, and its prognostic implications, should be tested in large-scale prospective studies.

The conclusions must be tempered by several limitations. First, the observational nature of this study introduces selection bias related to indications for both a Zio Patch and an echocardiogram. The indications for Zio Patch monitoring and echocardiography, however, were not different between HFpEF patients and controls, indicating at least similar reasons for referrals. Second, the study design allows us to determine associations between VT and HFpEF; however, mechanistic and causal links remain to be elucidated. Further, the impact of VT on sudden death was not investigated here. Third, although the initial pool of patients is large, the actual dataset used for analysis is small. This is mainly due to the limited use of Zio Patch monitoring. Larger-scale prospective community surveillance is required for more definitive conclusions [15]. Finally, we have not investigated whether prolonged QTc interval is a cause of VT or just an associated phenomenon. Our pre-clinical findings showed that prolongation of QTc interval exacerbated VT, and shortening of QTc interval diminished susceptibility to VT [12, 22]. Once again, large prospective studies are required to test the relationship between QTc interval and VT in HFpEF.

Data Availability

All relevant data are within the paper.

Funding Statement

National Institutes of Health (RO1 HL135866 to EC and EM) and the Peer-Reviewed Medical Research Program of the US Department of Defense (PR150620 to EM). The sponsors played no role in the the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Elena G Tolkacheva

10 Dec 2020

PONE-D-20-33005

Delayed Repolarization and Ventricular Tachycardia

in Patients with Heart Failure and Preserved Ejection Fraction

PLOS ONE

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1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors of “Delayed repolarization and ventricular tachycardia in patients with Heart Failure Preserve Ejection fraction” attempts to explore the association between HFpEF and ventricular arrhythmias. The hypothesis presented is relevant and statistically methods appear sound. Caution, however, needs to be made in some of the conclusions drawn from this rather small retrospective dataset, among some other minor comments.

1. Caution concluding the enhance propensity of VT contributes to sudden death in these patients as there was no long term follow up or outcome data presented. As mentioned by the authors “non-sustained VT has been recorded in the variety of patients, from healthy individual to patient with significant heart disease. The actionability of non-sustained VT is high debateable …..” I would encourage the authors to focus on the increase prevalence of VT demonstrated by the data presented, underlying mechanisms and be cautious in suggesting a direct association with NSVT and SCD.

2. In the statistical methods the authors have stated that results were considered significant at p < 0.05, please avoid using qualifying words through the manuscript such as “modestly” or “strong trend” to imply statistical significance.

3. In the methods section please clarify if the patients included were inpatients, ambulatory care patients or both.

4. Considering echocardiographic data was used to define HFpEF, these data should be provided.

5. Were laboratory values available around the time of echocardiography, specifically NT-proBNP or metabolic panel?

6. If these data suggest an enhance propensity to VT in HFpEF, why does the frequency of arrhythmias, specifically VT, not increase with severity of diastolic dysfunction.

7. If patients in the HFpEF were taking more rate controlling medication, is there an explanation for why was there no difference in heart rates between to two groups?

8. While the initial pool of patients is large, the actually dataset used for analysis is small and this should be specifically mentioned in the limitations.

Reviewer #2: This study examined Zio Patch data in patients with a clinical diagnosis of HFpEF. Patients with normal diastolic and systolic function served as controls. The results showed that VT was more prevalent in patients with HFpEF (versus those without this diagnosis).

Comments:

-How much time was there between the Zio Patch and TTE?

-The authors used the ASE guidelines to adjudicate evidence of diastolic dysfunction however there is significant controversy on how age influences diastolic parameters – namely septal and lateral e’ velocities. An older patient with lower e’ velocities may also have higher E/e’ ratios. These patients might be categorized with diastolic dysfunction when this may not be the case.

-How were the medical records used to determine the presence of clinical HFpEF? Was BNP used? What criteria were used to classify patients as HFpEF. Relying on the coded medical chart alone leaves a lot of opportunity to introduce errors.

-Rather than say mild, moderate, severe diastolic dysfunction, use grade I, II, or III if this is what the authors are suggesting. I am also surprised that no patients had grade III diastolic dysfunction using criteria E/A>2.

-It’s odd that patients with other risk factors did not have higher chance of VT (namely CAD). This might be due to a sample size issue. Could the authors expand the date range if Zio Patch data was available before 2016.

-I’m sure a number of these patients underwent cardiac MRI…of the ones who underwent CMR, what fraction had myocardial LGE present in this study and how does this impact the data.

-The wording “mode of exodus” in the abstract , introduction, and discusssion is odd…perhaps change to “most common cause of mortality”

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Reviewer #1: No

Reviewer #2: No

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Decision Letter 1

Elena G Tolkacheva

1 Jul 2021

Delayed repolarization and ventricular tachycardia

in patients with heart failure and preserved ejection fraction

PONE-D-20-33005R1

Dear Dr. Cingolani,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Elena G. Tolkacheva, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for addressing concerns raised and adding requested data (echocardiographic data and relevant laboratory studies).

Reviewer #2: This is a revision of the manuscript examining the association of ventricular arrhythmias and HFpEF patients. I have reviewed the responses the authors have submitted. They have addressed them as best as possible. It is surprising that so few patients underwent CMR as often the presence of scar can be linked to ventricular arrhythmias and thus help more on the mechanistic aspect of this study.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Acceptance letter

Elena G Tolkacheva

5 Jul 2021

PONE-D-20-33005R1

  Delayed repolarization and ventricular tachycardia in patients with heart failure and preserved ejection fraction

Dear Dr. Cingolani:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Elena G. Tolkacheva

Academic Editor

PLOS ONE

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