Efficacy and Safety of Hybrid Cardiac Telerehabilitation in Patients with Hypertrophic Cardiomyopathy without Left Ventricular Outflow Tract Obstruction and Preserved Ejection Fraction—A Study Design

Round 1

Reviewer 1 Report

1. The article does not fit the idea of a pilot study according to the standards, definitions and stages to be met. I kindly ask the authors to detail these steps, specifying the feasibility, costs, safety and to present the results of a minimum number of patients, which should show what adjustments have been made to safety, the feasibility of research and research costs in order to identify strengths and weaknesses of the research protocol.
2. What means „Control group patients are treated as usual”?  If the authors mean no cardiac rehabilitation treatment, then the study will reveal the superiority of cardiac rehabilitation (any kind of exercise design: standard cardiac rehabilitation, intensive CR, telerehabilitation in cardiac rehabilitation) versus NO cardiac rehabilitation (the treatment might include education, secondary prevention, but NO physical therapy). IF you chose to compare the Training Group with a control group which do not do any physical exercise, it was done before. I was expecting that the authors will choose to compare TG with CG performing standard cardiac rehabilitation in order to underline the benefit of a new method you propose.
3. I assume that the authors, when deciding to submit the article in the field of Applied Biosciences and Bioengineering, considered it is sufficient to present a correctly constructed methodology based on the innovative application of cardiovascular telerehabilitation (which can be applied to any type of telerehabilitation), without providing us with anything, from the results of the study, which we do not even know if it is ongoing. But from a clinical point of view, from the rehabilitation methodology, the design of the study is not enough, results are needed. The authors specified „they recruited patients between July 2017 and January 2020”, so I presume that all the patients began the training and interventions and the majority of them already fulfil the protocol.
4. A major concern is represented by the fact that a training lot (a special design that is desired to be innovative) is compared with a control lot in which the usual treatment is applied (not explaining exactly what it means).
5. The second major concern is the application of telerehabilitation methods after the first month of rehabilitation in which the patient is supposed to have learned the exercises correctly and is able to perform them at home, unattended except by video and EKG recording methods, contradicting current protocols that recommend cardiac rehabilitation performed after the first month under medical supervision, the patient is discharged and scheduled for rehabilitation in the outpatient department.
6. Also, is not clearly stated if the 1-month hospital-based rehabilitation followed by 2 months of home-based telemonitored rehabilitation is applied on acute patients immediately after acute cardiac condition.

I would suggest modifying the article title and abstract and underlining that the present article is just the study protocol proposal, and adjusting each aspect accordingly. Also, I repeat that the article does not fit the idea of a pilot study according to the standards, definitions and stages to be met.

The actual abstract stated „The primary endpoint”, ”Secondary endpoints” (complex evaluation) and ”Tertiary analysis includes safety, acceptance of and adherence to the HCR program”.(line 30-37) So, it is suggested that the article includes this data.

Also, I do not understand the reason why Clinical Examination and Diagnostic Tests.(Table 3)

exclude at 9 months follow-up and 12 months follow-up all of the paraclinical tests, but are based only on Clinical examination and questionnaires. Is this methodology internationally accepted with the aim to conduct a solid and reliable evaluation? Especially since the aim of the study is to assess the Efficacy and safety of a specific and hybrid rehabilitation method.

Author Response

Dear Reviewer

Thank you for the discerning comments concerning our manuscript entitled "Efficacy and safety of cardiac hybrid telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved ejection fraction – a study design." which we accept with comprehension and gratitude. We have studied your comments carefully and made corrections which we hope will meet with your approval. Your questions or comments are answered in detail below, with original reviewer comments denoted in boldface, our responses in regular typeface and all changes in the manuscript in red font.

Detailed answers to review comments:

Responses to reviewers:

Reviewer’s Comment #1. The article does not fit the idea of a pilot study according to the standards, definitions and stages to be met. I kindly ask the authors to detail these steps, specifying the feasibility, costs, safety and to present the results of a minimum number of patients, which should show what adjustments have been made to safety, the feasibility of research and research costs in order to identify strengths and weaknesses of the research protocol.

Author's Response #1: We agree with your suggestion about the pilot study definition. This is not a pilot study but a study design. That is why we have to change the title to "Efficacy and safety of cardiac hybrid telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved ejection fraction – a study design." Regarding the feasibility -we have included all the patients in the study, the follow- up is in progress. In terms of costs: it is not summarized yet. Regarding safety: no patient had died so far, there were no life-threatening arrhythmias. The results will be available after all data is collected.

 

Reviewer’s Comment #2.What means "Control group patients are treated as usual"? If the authors mean no cardiac rehabilitation treatment, then the study will reveal the superiority of cardiac rehabilitation (any kind of exercise design: standard cardiac rehabilitation, intensive CR, telerehabilitation in cardiac rehabilitation) versus NO cardiac rehabilitation (the treatment might include education, secondary prevention, but NO physical therapy). IF you chose to compare the Training Group with a control group which do not do any physical exercise, it was done before. I was expecting that the authors will choose to compare TG with CG performing standard cardiac rehabilitation in order to underline the benefit of a new method you propose.

Author's Response #2: According to your suggestion, we have added the following part in the Methods section: "In our study, each patient is encouraged to exercise activity. All patients are given pro-health lifestyle recommendations: with physical activity prescription, healthy diet recommendation, encouragement to alcohol limitation, and smoking cessation [14]. The only difference between the groups is that the training group undergo the supervised hybrid cardiac rehabilitation program (with supervised exercise training) while the control group do not. Some patients in the control group can participate in cardiac rehabilitation at their place of residence. Besides, the control group receives standard medical care in accordance with current cardiological guidelines."

Due to the fact that the diagnosis of hypertrophic cardiomyopathy (HCM) for many years was associated with limiting physical activity, the aim of the study was to demonstrate that cardiac rehabilitation in a selected subgroup of HCM patients is effective and safe. Therefore, it was not our goal to prove that telerehabilitation is better than standard cardiac rehabilitation. Even now, in most cardiac rehabilitation centers, HCM patients constitute a small percentage of rehabilitated patients. The use of inpatient rehabilitation before telerehabilitation in our study allowed for a better assessment of the patient and, secondarily, provided him with greater safety.

[14] Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, Benetos A, Biffi A, Boavida JM, Capodanno D, Cosyns B, Crawford C, Davos CH, Desormais I, Di Angelantonio E, Franco OH, Halvorsen S, Hobbs FDR, Hollander M, Jankowska EA, Michal M, Sacco S, Sattar N, Tokgozoglu L, Tonstad S, Tsioufis KP, van Dis I, van Gelder IC, Wanner C, Williams B; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur J Prev Cardiol. 2021 Sep 24:zwab154. DOI: 10.1093/Europe/zwab154. Epub ahead of print. PMID: 34558602.

Reviewer’s Comment #3.I assume that the authors, when deciding to submit the article in the field of Applied Biosciences and Bioengineering, considered it is sufficient to present a correctly constructed methodology based on the innovative application of cardiovascular telerehabilitation (which can be applied to any type of telerehabilitation), without providing us with anything, from the results of the study, which we do not even know if it is ongoing. But from a clinical point of view, from the rehabilitation methodology, the design of the study is not enough, results are needed. The authors specified "they recruited patients between July 2017 and January 2020", so I presume that all the patients began the training and interventions and the majority of them already fulfil the protocol.

Author's Response #3: We understand your point of view. On the other hand, this manuscript is a research study design. Therefore our article is a framework of methods and procedures used to collect and analyze variables specified in a particular research problem. The results will be presented in the following article after the follow-up is done.

Reviewer’s Comment #4 A major concern is represented by the fact that a training lot (a special design that is desired to be innovative) is compared with a control lot in which the usual treatment is applied (not explaining exactly what it means).

Author's Response #4: According to your suggestion, we have explained this issue in the Methods section:"In our study, each patient is encouraged to exercise activity. All patients are given pro-health lifestyle recommendations: physical activity prescription, healthy diet recommendation, encouragement to alcohol limitation, and smoking cessation [14]. The only difference between the groups is that the training group undergo the supervised hybrid cardiac rehabilitation program (with supervised exercise training) while the control group do not. Some patients in the control group can participate in cardiac rehabilitation at their place of residence. Besides, the control group receives standard medical care in accordance with current cardiological guidelines."

[14] Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, Benetos A, Biffi A, Boavida JM, Capodanno D, Cosyns B, Crawford C, Davos CH, Desormais I, Di Angelantonio E, Franco OH, Halvorsen S, Hobbs FDR, Hollander M, Jankowska EA, Michal M, Sacco S, Sattar N, Tokgozoglu L, Tonstad S, Tsioufis KP, van Dis I, van Gelder IC, Wanner C, Williams B; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur J Prev Cardiol. 2021 Sep 24:zwab154. DOI: 10.1093/Europe/zwab154. Epub ahead of print. PMID: 34558602.

Reviewer’s Comment #5.The second major concern is the application of telerehabilitation methods after the first month of rehabilitation in which the patient is supposed to have learned the exercises correctly and is able to perform them at home, unattended except by video and EKG recording methods, contradicting current protocols that recommend cardiac rehabilitation performed after the first month under medical supervision, the patient is discharged and scheduled for rehabilitation in the outpatient department.

Author's Response #5: According to your suggestion, we would like to clarify the issue.

As in the case of stationary rehabilitation of patients with other cardiovascular diseases, also in the case of patients with HCM, we assumed one month of hospital-based rehabilitation. The critical problem is patients’ motivation to continue the exercise training. The way to help the patient continue the rehabilitation is the home-based telemonitored rehabilitation. During this type of rehabilitation, the patient is still telesupervised. It leads to better long-term adherence to exercise training and healthy behaviors.

Reviewer’s Comment #6. Also, is not clearly stated if the 1-month hospital-based rehabilitation followed by 2 months of home-based telemonitored rehabilitation is applied on acute patients immediately after acute cardiac condition.

Author's Response #6: According to your suggestion, we would like to underline that the 1-month hospital-based rehabilitation followed by two months of home-based telemonitored rehabilitation is applied only for the patient in stable condition for one month and no acute conditions were present. According to recent guidelines, participation in a medically supervised, structured, comprehensive, multidisciplinary exercise-based cardiac rehabilitation (EBCR) and prevention program for patients after atherosclerotic cardiovascular disease events and/or revascularization, and for patients with HF (mainly HFrEF), is recommended to improve patient outcomes. Home-based cardiac rehabilitation, telehealth, and mHealth interventions may be considered to increase patient participation and long-term adherence to healthy behaviors [14].

[14] Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, Benetos A, Biffi A, Boavida JM, Capodanno D, Cosyns B, Crawford C, Davos CH, Desormais I, Di Angelantonio E, Franco OH, Halvorsen S, Hobbs FDR, Hollander M, Jankowska EA, Michal M, Sacco S, Sattar N, Tokgozoglu L, Tonstad S, Tsioufis KP, van Dis I, van Gelder IC, Wanner C, Williams B; ESC National Cardiac Societies; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021 Sep 7;42(34):3227-3337. DOI: 10.1093/eurheartj/ehab484. PMID: 34458905.

Reviewer’s Comment #7 I would suggest modifying the article title and abstract and underlining that the present article is just the study protocol proposal, and adjusting each aspect accordingly. Also, I repeat that the article does not fit the idea of a pilot study according to the standards, definitions and stages to be met.

Author's Response #7: According to your suggestion, we have modified the article title and abstract to show that it is a study design.

The title "Efficacy and safety of cardiac hybrid telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved ejection fraction – a study design."

Abstract: Hypertrophic cardiomyopathy (HCM) is the most common hereditary disease and the most common cause of sudden cardiac death due to cardiovascular disease in young athletes, accounting for one-third of deaths. For many years HCM patients were excluded from exercise training. However, data are showing that patients with HCM undergoing supervised exercise training could improve physical performance without significant adverse events to be recorded. A study was designed as a randomized clinical trial to evaluate the effectiveness and safety of hybrid cardiac rehabilitation (HCR) – a combination of hospital-based cardiac rehabilitation (1 month) with a new form of home-based telemonitored cardiac rehabilitation (2 months) in patients with HCM without left ventricular (LV) outflow tract obstruction and preserved systolic function. Sixty patients who fulfill the inclusion criteria have been randomly assigned (in ratio 1:1) to either HCR plus usual care (training group) or usual care only (control group). The primary endpoint is a functional capacity assessed by peak oxygen uptake (pVO₂). Secondary endpoints include workload duration during the cardiopulmonary exercise testing, a six-minute walk test distance, NT-pro BNP level, echocardiographic parameters of the left ventricular diastolic function (E/A, E/e', myocardial strain rate), right ventricular systolic pressure, a gradient in the LV outflow tract and quality of life. The tertiary analysis includes safety, acceptance of, and adherence to the HCR program. Our study will provide novel data on the effectiveness and safety of hybrid cardiac rehabilitation in HCM patients without LV outflow tract obstruction and preserved systolic function.

Reviewer’s Comment #8.The actual abstract stated "The primary endpoint"," Secondary endpoints" (complex evaluation) and" Tertiary analysis includes safety, acceptance of and adherence to the HCR program".(line 30-37) So, it is suggested that the article includes this data.

Author's Response #8: According to your suggestion we would like to explain, that because it is a study design article, we describe the methodology of this trial.

Reviewer’s Comment #9 Also, I do not understand the reason why Clinical Examination and Diagnostic Tests.(Table 3) exclude at 9 months follow-up and 12 months follow-up all of the paraclinical tests, but are based only on Clinical examination and questionnaires. Is this methodology internationally accepted with the aim to conduct a solid and reliable evaluation? Especially since the aim of the study is to assess the Efficacy and safety of a specific and hybrid rehabilitation method.

Author's Response #9: We agree with you that not all the tests were conducted during the follow-up. The effectiveness of hybrid cardiac rehabilitation (HCR) are assessed by changes - delta (Δ) in peak oxygen consumption (pVO₂) and duration (t) of the workload in cardiopulmonary exercise test, 6-minute walking test distance (6-MWT) as a result of comparing t (s), pVO₂ (ml/kg/min), 6-MWT (m) from the beginning and the end of the HCR program. All the remaining tests were performed to find the answer if patients are able to maintain the hypothetical improvement achieved after the HCR program. The authors decided to abandon tests that were not crucial during the follow-up period for logistic reasons.

 

On behalf of all co-authors

  Krzysztof Sadowski MD

Reviewer 2 Report

This protocol for a randomized controlled trial will be performed to evaluate the effects of cardiac hybrid telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved systolic function. The study designs and methods used are appropriate. There are some areas where the protocol needs to be strengthened.

 

Abstract: 

• unify the terms „physical training“ and „exercise training“ for better clarity (then check this throughout the manuscript as well)

Background:

• This section should be more robust.
• Please edit the reference numbers because they do not match the bibliography; it is confusing
• pg2 line 57-58 Statement: "The limitations of the study were: the number of patients included (twenty), no control group and 58 no cardiopulmonary exercise testing." Consider deleting; this sentence is redundant

• Furthermore, "The first randomized trial" does not follow on from the fourth paragraph ("There are no published papers"). Rework, or supplement with appropriate content

• Consider better introducing the "new model of home-based telemonitored rehabilitation"

What are the potential benefits and effects of HCR in cardiac patients?

Can it be applied to different types of CVD?

• Also, consider brief comments regarding safety and telerehabilitation interventions for cardiac patients. This is an essential point for supporting telerehab HCR interventions
• Finally, consider including the hypothesis statement (if any)

 

Methods:

• Table 2 footnote: „Target heart rate during an endurance training was calculated according to Karvonen formula (heart rate at rest plus a result of a subtraction of a maximum heart rate and heart rate at rest multiplied by 40-80%“

Didn't the authors mean 60-80%? (as above text?)

• pg 4, automatic ECG recording 

Do patients have to wear a sensor before each exercise? Specify where it is placed?

• 2.4. Control group „Control group patients are treated as usual.“

Consider to specifying in more detail:

Will they have Hospital-based rehabilitation?

Any exercise advice at discharge?

• Include a sample size estimation based on the power analysis, which will address how you obtained the target sample of sixty patients
• In Table 3. you have included long-term follow-up. A short statement supporting the long-term effects of HCR should be included in the protocol (if any)

Discussion

• Is there any other version or content? because the reference list is up to number 36, please edit this. It is confusing

• consider adding a short discussion in the context of telerehabilitation and the COVID-19 pandemic, as well as a discussion of the latest ESC statement supporting the telerehabilitation content "the future is now“
• also, a brief discussion of the latest content regarding the comparison of adherence with training prescription in cardiovascular telehealth interventions is highly recommended

• Ultimately, I would like to congratulate the authors for the enthusiasm invested in this trial. However, the protocol does not reach the level of quality required without revisions in Applied Sciences.

Author Response

Warsaw 6^th January 2022

Dear Reviewer

Thank you for the discerning comments concerning our manuscript entitled "Efficacy and safety of cardiac hybrid telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved ejection fraction – a study design."which we accept with comprehension and gratitude. We have studied your comments carefully and made corrections which we hope will meet with your approval. Your questions or comments are answered in detail below, with original reviewer comments denoted in boldface, our responses in regular typeface and all changes in the manuscript in red font.

Detailed answers to review comments:

Responses to reviewers:

Reviewer's Comment #1.This protocol for a randomized controlled trial will be performed to evaluate the effects of cardiac hybrid telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved systolic function. The study designs and methods used are appropriate. There are some areas where the protocol needs to be strengthened. 

  

Abstract:  

• unify the terms "physical training "and "exercise training "for better clarity (then check this throughout the manuscript as well)  

Author's Response #1: According to your suggestion, we have unified the term by choosing "exercise training"- lines 69, 71, 84, 89, 299. 

 

Reviewer's Comment #2.Background: 

• This section should be more robust.  

Author's Response #2: According to your suggestion, we have added an additional part in the Background part: 

  “Numerous papers have shown that HCM is the most common cause of sudden cardiac death due to cardiovascular disease in young athletes, responsible for about 1/3 of deaths (data from The US National Registry of Sudden Death in Athletes) [2]. In addition, vigorous physical activity is considered an essential factor in sudden cardiac arrest in HCM patients. The risk of sudden cardiac death in all HCM patients is estimated at less than 1% per year, but in the athletes' group, it is much lower - in the range of 0.03-0.1% per year. For many years, the diagnosis of HCM has been tantamount to a reduction in exercise training. However, the association between HCM and cardiac arrest or exercise-induced sudden cardiac death was hypothesized mainly due to the lack of systematic national registries”. 

The results of the first study of HCM patients undergoing exercise training were published in 2015. Klempfner and colleagues demonstrated that the majority of HCM patients with moderate risk benefit from supervised exercise training  - in some patients seen in the evident improvement of achieved workloads (expressed in metabolic equivalents - METs) and NYHA class [3]. Suggested beneficial training mechanisms in patients with HCM were: improvement of chronotropic response and vascular endothelial function, increase in vagal nerve tension, improvement of LV diastolic function, reduction of neurohormonal activation and cytokine expression [3]. No adverse events were observed, neither in the group of patients with constriction of LV outflow nor in the group of patients in the NYHA III class. In addition, there were no significant arrhythmias in patients undergoing exercise training, even among those who had an implantable cardioverter-defibrillator (ICD) as part of the primary prevention of sudden cardiac death [3] .

The first randomized trial for patients with HCM undergoing exercise training was conducted by the Universities of Michigan and Stanford during the period April 2010 - October 2015 [4] . One hundred thirty-six patients with HCM were randomized to two groups (subjected to aerobic training of moderate intensity for 16 weeks or subjected to ordinary activity). Saberi et al. have assessed that patients in the group subjected to exercise training  had a significant increase in pVO₂ compared to the control group. None of the patients had life-threatening ventricular arrhythmias, sudden cardiac death, ICD intervention, or died [4]. 

Comprehensive cardiac rehabilitation contributes to improving the quality of life and its extension, and the omission of rehabilitation in cardiological patients should be considered malpractice. 

  The home-based telemonitored cardiac rehabilitation was introduced to clinical practice as a new, promising model of cardiac rehabilitation few years ago. It consists of telecare with psychological telesupport, telesupervised exercise training and remote monitoring of cardiovascular implantable electronic devices [5-12]. Admittedly some studies compare hospital-based rehabilitation with this model of home-based telemonitored rehabilitation [5-6], but there are missing data that evaluate the combination of these two methods in patients with HCM. A typical period of a hospital-based cardiac rehabilitation is one month. The key problem is the patients’ motivation to continue the exercise training after the inpatient cardiac rehabilitation program. The way to help the patients to continue the rehabilitation is exactly the home-based telemonitored rehabilitation - it is an effective and safe alternative to outpatient rehabilitation and hospital-based rehabilitation for patients with different heart diseases. Besides, previous studies have shown that shortly after the telerehabilitation, patients present an increase in pVO₂, and then this positive effect of telerehabilitation decreases.

LV outflow tract obstruction has been associated with an increased risk of sudden cardiac death. The same is for patients with a reduced LV ejection fraction (compared to patients with preserved ejection fraction). Therefore, the study authors arbitrarily decided to evaluate the group of HCM patients less at risk of SCD - patients with HCM without the LV outflow tract obstruction and preserved LV ejection fraction.

The aim of the study is to evaluate the effectiveness and safety of HCR in patients who suffered from HCM without the LV outflow tract obstruction and preserved LV ejection fraction. 

  The hypothesis of the study is that HCR is effective and safe in patients with HCM without the LV outflow tract obstruction and preserved LV ejection fraction.”

 

 

Reviewer's Comment #3. 

• Please edit the reference numbers because they do not match the bibliography; it is confusing  

Author's Response #3: According to your suggestion, we have edited the reference numbers. 

Reviewer's Comment #4. 

• pg2 line 57-58 Statement: "The limitations of the study were: the number of patients included (twenty), no control group and 58 no cardiopulmonary exercise testing." Consider deleting; this sentence is redundant  

Author's Response #4: According to your suggestion, we have deleted the mentioned sentence. 

Reviewer's Comment #5. 

• Furthermore, "The first randomized trial" does not follow on from the fourth paragraph ("There are no published papers"). Rework, or supplement with appropriate content  

Author's Response #5: Thank you for your comment, but in this part, I wanted to highlight that before our research, there was only one randomized study dealing with HCM patients undergoing cardiac rehabilitation.

 

Reviewer's Comment #6. 

• Consider better introducing the "new model of home-based telemonitored rehabilitation."  

Author's Response #6: According to your suggestions, we have added sentences in the Background section:

 “ The home-based telemonitored cardiac rehabilitation was introduced to clinical practice as a new, promising model of cardiac rehabilitation few years ago. It consists of telecare with psychological telesupport, telesupervised exercise training and remote monitoring of cardiovascular implantable electronic devices [5-12]. Admittedly some studies compare hospital-based rehabilitation with this model of home-based telemonitored rehabilitation [5-6], but there are missing data that evaluate the combination of these two methods in patients with HCM. A typical period of a hospital-based cardiac rehabilitation is one month. The key problem is the patients’ motivation to continue the exercise training after the inpatient cardiac rehabilitation program. The way to help the patients to continue the rehabilitation is exactly the home-based telemonitored rehabilitation - it is an effective and safe alternative to outpatient rehabilitation and hospital-based rehabilitation for patients with different heart diseases. Besides, previous studies have shown that shortly after the telerehabilitation, patients present an increase in pVO₂, and then this positive effect of telerehabilitation decreases.”

 

Reviewer's Comment #7. 

What are the potential benefits and effects of HCR in cardiac patients? 

Author's Response #7: According to your suggestions, we have added sentences in the Background section:

 “There are premises that the HCR program contributes to the improvement of physical performance (expressed by an increase in pVO₂) and the improvement in the quality of life.”

 

Reviewer's Comment #8. 

Can it be applied to different types of CVD? 

Author's Response #8: The home-based telemonitored rehabilitation was performed in patients with coronary artery disease as well as heart failure patients, but it was not implemented in HCM patients.[5-12]

Reviewer's Comment #9. 

• Also, consider brief comments regarding safety and telerehabilitation interventions for cardiac patients. This is an essential point for supporting telerehab HCR interventions  

Author's Response #9: According to your suggestion, we have added the following statement to the Background section. 

„Data from published studies including the largest TELEREH-HF randomized clinical trial demonstrated that telerehabilitation is a safe medical procedure [5-12].  Neither death nor other major adverse events occurred during telemonitored exercise training sessions. There were no interventions from CIEDs during the remotely supervised telemonitored exercise training. There were a few minor events, such as minor skin reactions due to the electrodes and paroxysmal atrial fibrillation [5-12].”

 

Reviewer's Comment #10. 

• Finally, consider including the hypothesis statement (if any)  

Author's Response #10: According to your suggestion, we have added the following statement to the Background section. 

“The hypothesis of the study is that HCR is effective and safe in patients with HCM without the LV outflow tract obstruction and preserved LV ejection fraction.”

 Reviewer's Comment #11. 

Methods: 

• Table 2 footnote: "Target heart rate during an endurance training was calculated according to Karvonen formula (heart rate at rest plus a result of a subtraction of a maximum heart rate and heart rate at rest multiplied by 40-80%"  

Didn't the authors mean 60-80%? (as above text?) 

Author's Response #11: According to your suggestion, we have to admit that it should be 60-80%. 

"Target heart rate during an endurance training was calculated according to Karvonen formula (heart rate at rest plus a result of a subtraction of a maximum heart rate and heart rate at rest multiplied by 60-80%)." 

 

Reviewer's Comment #12. 

• pg 4, automatic ECG recording   

Do patients have to wear a sensor before each exercise? Specify where it is placed? 

Author's Response #12:  The telerehabilitation takes place according to the procedure described below: 

An EHO mini device is adjusted to register 16-seconds–5-minutes fragments of ECG recording from three precordial leads and to transmit the data via mobile phone network to the monitoring center. An EHO mini device has training sessions preprogrammed individually for each patient (defined exercise duration, breaks, timing of ECG recording). The moments of automatic ECG registration are preset and coordinated with the exercise training. The planned training sessions are executed with the device indicating what should be done with sound and light signals. There are sound signals in the form of bleeps and light signals from color-emitting diodes. Bleeps and green diode blinking mean the patient should do exercise, another set of bleeps and red diode blinking mean stop exercise. The timing of automatic ECG recordings corresponded to peak exercise. An EHO mini device has a tele-event-Holter ECG feature as well. Tele-event-Holter ECG is a feature that enables a patient, whenever a worrying symptom occurs, to register and immediately send the ECG recording via mobile phone network to the telemonitoring center. The system works in a loop scheme, owing to which it is possible to analyze the part of ECG recording which directly preceded an event that made a patient press the signal button. Patients are also able to make additional registrations and send them at any time, for example, when they felt unwell if they experienced symptoms like palpitations, chest pain, etc.

 

According to your suggestion, we have added the following statement to the Methods section:

“An EHO mini device is adjusted to register 16-seconds–5-minutes fragments of ECG recording from three precordial leads and to transmit the data via mobile phone network to the monitoring center. This device has training sessions preprogrammed individually for each patient (defined exercise duration, breaks, timing of ECG recording). The moments of automatic ECG registration are preset and coordinated with the exercise training [15]..”

 

 

 

[15] Piotrowicz E. How to do: telerehabilitation in heart failure patients. Cardiol J. 2012;19(3):243-8. DOI: 10.5603/cj.2012.0045. PMID: 22641542. 

 

Reviewer's Comment #13. 

• 2.4. Control group "Control group patients are treated as usual. "  

Consider to specifying in more detail: 

Will they have Hospital-based rehabilitation? 

Any exercise advice at discharge? 

Author's Response #13:  According to your comment, we have added additional sentences to the Methods part: 

“ In our study, each patient is encouraged to exercise activity. All patients are given pro-health lifestyle recommendations: with physical activity prescription, healthy diet recommendation, encouragement to alcohol limitation, and smoking cessation [14 ]. The only difference between the groups is that the training group undergo a supervised HCR program (with telesupervised exercise training) while the control group does not. Some patients in the control group can participate in cardiac rehabilitation at their place of residence. Besides, the control group receives standard medical care under current cardiological guidelines [14].”

The use of inpatient rehabilitation before telerehabilitation in our study allowed for a better assessment of the patient and, secondarily, provided him with greater safety. 

Reviewer's Comment #14. 

• Include a sample size estimation based on the power analysis, which will address how you obtained the target sample of sixty patients  

Author's Response #14:  According to your comment, we have added the following sentences to the Statistical analysis section: 

"The sample size calculation was performed with the assumption of a significance level of p = 0.05, two-sided testing and the expected mean increases in peak VO₂ (over 3 months) in the intervention group by 10% (1.9 ml ± 2.6 mL / kg / min) and in the control group by 0.5% (0.10 ± 1.9 mL / kg / min) . Two-sample Satterthwaite t-test for mean differences with the above assumptions and with a sample of 54 people in total (27 patients in the intervention and control groups) gives the power of 81.2% to achieving a statistically significant result. Taking into account the possibility of a 10% loss of patients during the study period, the total number of participants was increased to 60 people." 

 

Reviewer's Comment #15. 

• In Table 3. you have included long-term follow-up. A short statement supporting the long-term effects of HCR should be included in the protocol (if any)  

Author's Response #15:  According to your suggestion, we have added a part to the Background section: 

"There are premises that the HCR program contributes to the improvement of physical performance (expressed by an increase in pVO₂) and the improvement in the quality of life.

 

"Besides, previous studies have shown that shortly after the telerehabilitation, patients present an increase in pVO₂, and then this positive effect of telerehabilitation decreases." 

 

Reviewer's Comment #16. 

Discussion 

• Is there any other version or content? because the reference list is up to number 36, please edit this. It is confusing  

Author's Response #16: Thank you for the important correction. According to your suggestion we  have tidied up the reference list. 

Reviewer's Comment #17. 

• consider adding a short discussion in the context of telerehabilitation and the COVID-19 pandemic, as well as a discussion of the latest ESC statement supporting the telerehabilitation content "the future is now"  

Author's Response #17: According to your suggestion, we have added the following sentence to the Discussion: 

  “Its results, especially during the SARS-CoV 2 pandemic, will contribute to the greater participation of patients in cardiac rehabilitation. Telerehabilitation provides better epidemic conditions: patients remain at their place of residence, with minimal travel or transportation barriers, protected from virus infection [30].”

 

Reviewer's Comment #18. 

• also, a brief discussion of the latest content regarding the comparison of adherence with training prescription in cardiovascular telehealth interventions is highly recommended  

Author's Response #18: According to your suggestion, we have added the following sentence to the Discussion: 

 „The studies describing telerehabilitation have shown that it is a method that increases the patients' participation in exercise training. TELEREH-HF - the most extensive study in telemedicine – has shown that adherence to the telemonitored exercise training was very high (88,4%). Therefore we expect that adherence in HCM patients would also be high [5-12].”

 

 

On behalf of all co-authors

Krzysztof Sadowski MD

 

Reviewer 3 Report

Dear authors,

Thank you for the opportunity to read this interesting manuscript. However, it requires some changes. 

1. The introduction should be expanded. In my opinion, first of all, the introduction should contain information about the general benefits of cardiac rehabilitation, why it should be used. The authors should also explain in the introduction why they decided to conduct research on such a group (without left ventricular outflow tract obstruction and preserved systolic function)
2. The authors of the interventions in the control group described: "Control group patients are treated as usual." - please specify what does it mean.
3. My main concern is the registration of this clinical trial. The authors indicate that the study was registered with the registry clinicaltrials.gov. However, under the indicated number there is a study whose outcome does not correspond to the one indicated in the manuscript by the authors. Similarly, in the case of inclusion and exclusion criteria. Please explain that.

Author Response

                                                                                     Warsaw 6^th January 2022

Dear Reviewer

Thank you for the discerning comments concerning our manuscript entitled "Efficacy and safety of cardiac hybrid telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved ejection fraction – a study design" which we accept with comprehension and gratitude. We have studied your comments carefully and made corrections which we hope will meet with your approval. Your questions or comments are answered in detail below, with original reviewer comments denoted in boldface, our responses in regular typeface and all changes in the manuscript in red font.

Detailed answers to review comments:

Responses to reviewers:

Dear authors,

Thank you for the opportunity to read this interesting manuscript. However, it requires some changes. 

Reviewer’s Comment #1.

1. The introduction should be expanded. In my opinion, first of all, the introduction should contain information about the general benefits of cardiac rehabilitation, why it should be used. The authors should also explain in the introduction why they decided to conduct research on such a group (without left ventricular outflow tract obstruction and preserved systolic function)

Author's response #1: According to your suggestion, we have expanded the Background:

“Hypertrophic cardiomyopathy (HCM) is the most common hereditary heart disease. It is characterized by hypertrophy of the left ventricle (LV) and, in consequence, impaired LV diastolic function. Its prevalence is estimated at 0.2% in the general population [1].

Numerous papers have shown that HCM is the most common cause of sudden cardiac death due to cardiovascular disease in young athletes, responsible for about 1/3 of deaths (data from The US National Registry of Sudden Death in Athletes) [2]. In addition, vigorous physical activity is considered an essential factor in sudden cardiac arrest in HCM patients. The risk of sudden cardiac death in all HCM patients is estimated at less than 1% per year, but in the athletes' group, it is much lower - in the range of 0.03-0.1% per year. For many years, the diagnosis of HCM has been tantamount to a reduction in exercise training. However, the association between HCM and cardiac arrest or exercise-induced sudden cardiac death was hypothesized mainly due to the lack of systematic national registries.

The results of the first study of HCM patients undergoing exercise training were published in 2015. Klempfner and colleagues demonstrated that the majority of HCM patients with moderate risk benefit from supervised exercise training - in some patients seen in the evident improvement of achieved workloads (expressed in metabolic equivalents - METs) and NYHA class [3]. Suggested beneficial training mechanisms in patients with HCM were: improvement of chronotropic response and vascular endothelial function, increase in vagal nerve tension, improvement of LV diastolic function, reduction of neurohormonal activation and cytokine expression [3]. No adverse events were observed, neither in the group of patients with constriction of LV outflow tract, nor in the group of patients in the NYHA III class. In addition, there were no significant arrhythmias in patients undergoing exercise training, even among those who had an implantable cardioverter-defibrillator (ICD) as part of the primary prevention of sudden cardiac death [3].

The first randomized trial for patients with HCM undergoing exercise training was conducted by the Universities of Michigan and Stanford during the period April 2010 - October 2015 [4].One hundred thirty-six patients with HCM were randomized to two groups (subjected to aerobic training of moderate intensity for 16 weeks or subjected to ordinary activity). Saberi et al. have assessed that patients in the group subjected to exercise training had a significant increase in pVO₂ compared to the control group. None of the patients had life-threatening ventricular arrhythmias, sudden cardiac death, ICD intervention, or died [4].

Comprehensive cardiac rehabilitation contributes to improving the quality of life and its extension, and the omission of rehabilitation in cardiological patients should be considered malpractice. 

The home-based telemonitored cardiac rehabilitation was introduced to clinical practice as a new, promising model of cardiac rehabilitation few years ago. It consists of telecare with psychological telesupport, telesupervised exercise training and remote monitoring of cardiovascular implantable electronic devices [5-12]. Admittedly some studies compare hospital-based rehabilitation with this model of home-based telemonitored rehabilitation [5-6], but there are missing data that evaluate the combination of these two methods in patients with HCM. A typical period of a hospital-based cardiac rehabilitation is one month. The key problem is the patients’ motivation to continue the exercise training after the inpatient cardiac rehabilitation program. The way to help the patients to continue the rehabilitation is exactly the home-based telemonitored rehabilitation - it is an effective and safe alternative to outpatient rehabilitation and hospital-based rehabilitation for patients with different heart diseases. Besides, previous studies have shown that shortly after the telerehabilitation, patients present an increase in pVO₂, and then this positive effect of telerehabilitation decreases.

 

LV outflow tract obstruction has been associated with an increased risk of sudden cardiac death. The same is for patients with a reduced LV ejection fraction (compared to patients with preserved ejection fraction). Therefore, the study authors arbitrarily decided to evaluate the group of HCM patients less at risk of SCD - patients with HCM without the LV outflow tract obstruction and preserved LV ejection fraction.

The aim of the study is to evaluate the effectiveness and safety of HCR in patients who suffered from HCM without the LV outflow tract obstruction and preserved LV ejection fraction.

The hypothesis of the study is that HCR is effective and safe in patients with HCM without the LV outflow tract obstruction and preserved LV ejection fraction.

There are premises that the HCR program contributes to the improvement of physical performance (expressed by an increase in pVO₂) and the improvement in the quality of life.

Data from published studies including the largest TELEREH-HF randomized clinical trial demonstrated that telerehabilitation is a safe medical procedure [5-12].  Neither death nor other major adverse events occurred during telemonitored exercise training sessions. There were no interventions from CIEDs during the remotely supervised telemonitored exercise training. There were a few minor events, such as minor skin reactions due to the electrodes and paroxysmal atrial fibrillation [5-12].”

Reviewer’s Comment #2.

 

2. The authors of the interventions in the control group described: "Control group patients are treated as usual." - please specify what does it mean.

 

Author's Response #2 According to your suggestion, we have added additional sentences in the Methods part:

„In our study, each patient is encouraged to exercise activity. All patients are given pro-health lifestyle recommendations: with physical activity prescription, healthy diet recommendation, encouragement to alcohol limitation, and smoking cessation [14 ].

 

The only difference between the groups is that the training group undergo a supervised HCR program (with telesupervised exercise training) while the control group does not. Some patients in the control group can participate in cardiac rehabilitation at their place of residence. Besides, the control group receives standard medical care under current cardiological guidelines [14].”

 

Reviewer’s Comment #3.

3. My main concern is the registration of this clinical trial. The authors indicate that the study was registered with the registry clinicaltrials.gov. However, under the indicated number, there is a study whose outcome does not correspond to the one indicated in the manuscript by the authors. Similarly, in the case of inclusion and exclusion criteria. Please explain that.

 

Author's response #3: According to your suggestion, we have corrected the indicated number in paragraph Methods - NCT03178357 (on line 42, it was written correctly). The inclusion and exclusion criteria are the same at ClinicalTrials.gov and in the manuscript.

                                                               

 

On behalf of all co-authors

                                                                        Krzysztof Sadowski MD

 

 

Round 2

Reviewer 1 Report

The thing that is still unclear to me:

How is the efficiency and effectiveness of the study argued?

Because there are just described things and interventions that the authors will do and they cover themselves with the umbrella of future data that will be presented in another article.

Author Response

                                                                    

                                                                                Warsaw 19^th January 2022

Dear Reviewer                                       

Thank you for the discerning comments concerning our manuscript entitled "Efficacy and safety of hybrid cardiac telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved ejection fraction – a study design" which we accept with comprehension and gratitude. Thank you very much for your question and comments. They are answered in detail below, with original reviewer comments denoted in boldface, our responses in regular typeface.

Detailed answers to review comments:

Comments and Suggestions for Authors

The thing that is still unclear to me:

How is the efficiency and effectiveness of the study argued?

Because there are just described things and interventions that the authors will do and they cover themselves with the umbrella of future data that will be presented in another article.

     A commonly used parameter for assessing the effectiveness of cardiac rehabilitation is the peak oxygen consumption (pVO₂)[46-47]. According to your suggestions, we have added additional parts to the Methods section: “The effectiveness of HCR is assessed by changes - delta (Δ) in pVO2 and workload duration in CPET, 6-MWT distance as a result of comparing pVO₂, workload duration in CPET, 6-MWT distance from the beginning and the end of the HCR program.”

Our manuscript is a study design. Therefore our article is a framework of methods and procedures used to collect and analyze variables specified in a particular research problem [45]. Patient enrollment is completed and the follow-up is ongoing now.

References

[45]. Ranganathan P, Aggarwal R. Study designs: Part 1 - An overview and classification. Perspect Clin Res. 2018 Oct-Dec;9(4):184-186. doi: 10.4103/picr.PICR_124_18. PMID: 30319950; PMCID: PMC6176693.

[46] European Association of Cardiovascular Prevention and Rehabilitation Committee for Science Guidelines; EACPR, Corrà U, Piepoli MF, Carré F, Heuschmann P, Hoffmann U, Verschuren M, Halcox J; Document Reviewers, Giannuzzi P, Saner H, Wood D, Piepoli MF, Corrà U, Benzer W, Bjarnason-Wehrens B, Dendale P, Gaita D, McGee H, Mendes M, Niebauer J, Zwisler AD, Schmid JP. Secondary prevention through cardiac rehabilitation: physical activity counselling and exercise training: key components of the position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation. Eur Heart J. 2010 Aug;31(16):1967-74. doi: 10.1093/eurheartj/ehq236. Epub 2010 Jul 19. PMID: 20643803.

[47] Taylor RS, Dalal HM, McDonagh STJ. The role of cardiac rehabilitation in improving cardiovascular outcomes. Nat Rev Cardiol. 2021 Sep 16:1–15. doi: 10.1038/s41569-021-00611-7. Epub ahead of print. PMID: 34531576; PMCID: PMC8445013.

                                                                                 On behalf of all co-authors

                                                                                   Krzysztof Sadowski MD

 

Reviewer 2 Report

Congratulations to the authors. The manuscript significantly improved its quality.

Author Response

                                                                                      

                                                                                     Warsaw 19^th January 2022

Dear Reviewer

Thank you for the discerning comments concerning our manuscript entitled "Efficacy and safety of hybrid cardiac telerehabilitation in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction and preserved ejection fraction – a study design" which we accept with comprehension and gratitude. Your comments are answered in detail below, with original reviewer comments denoted in boldface, our responses in regular typeface and all changes in the manuscript in red font.

Detailed answer to review comments:

Congratulations to the authors. The manuscript significantly improved its quality.

Thank you very much for your questions and comments. Thanks to them, we were able to clarify our manuscript.

                                                                  On behalf of all co-authors

                                                                  Krzysztof Sadowski MD