Intermittent aerobic-resistance interval training versus continues aerobic training: Improvement in cardiac electrophysiologic and anthropometric measures in male patients post myocadiac infarction, a randomized control trial.

PURPOSE: Exercise is a valuable intervention modality for patients post-myocardial infarction (MI). Aerobic and resistance training are both commonly used separately in cardiac rehabilitation. However, the effect of aerobic interval exercise combined with alternating sets of resistance training (super-circuit training, SCT) on cardiac electrophysiologic and anthropometric measures had not been thoroughly investigated. AIM: The primary objective of this study was to compare the effectiveness of moderate-intensity continuous-aerobic training (CAT) vs. SCT on cardiac electrical measures (resting electrocardiographic, ECG; a nd heart rate variability, HRV) in patients' post-MI presenting reduced left ventricular function. Second, to examine its effect on anthropometric measures.
MATERIAL AND METHODS: Twenty-nine men post-MI with reduced left ventricular function were assigned randomly to either 12 weeks of CAT (n = 15) or SCT (n = 14). CAT group performed moderate-intensity activity. SCT group performed high-intensity exercise, alternating between resistance and aerobic training. Differences between CAT and SCT groups were done using independent t-tests, paired t-tests and effect size (ES).
RESULTS: Participants in both groups improved their HRV measures (increase in HFnu; p < 0.05; ES > 0.51) and ECG (reduction in QT-dispersion; p < 0.05; ES > 0.51). Only the SCT group had significant improvements in waist circumference (p < 0.05).
CONCLUSION: Exercise improves cardiac electrical measures post-MI. However, in comparison to CAT, SCT may yield greater anthropometric changes. In order to have improvements in cardiac electrical stability, clinicians working with post-MI patients may use both CAT and SCT. However, SCT might result in greater improvements.

Introduction

Exercise training is considered an essential approach component for rehabilitation and secondary prevention of coronary heart disease [1] and usually consists of moderately intense continuous aerobic training (CAT) [2]. The benefits of CAT in cardiac patients are well established [2-4]. However, CAT leads to only a minor increase in muscle mass or strength and is usually associated with a more pronounced improvement in aerobic exercise capacity [5]. Thus, resistance training is part of every guideline for exercise-based cardiac rehabilitation [1]. There is evidence for the safety and efficacy of resistance training in cardiac patients [6, 7]. For example, studies showed that appropriate resistance training induces metabolic, histochemical, and functional adaptations in skeletal muscles. Resistance training also increases muscle mass and strength effectively [8].

In cardiac patients, high-intensity interval training is safe, feasible, and is more effective than CAT in several outcome measures (e.g., peak oxygen consumption) [9, 10]. Super-circuit training (SCT) is a novel type of training that involves two combined training modalities: resistance-training set simultaneously followed by an aerobic exercise interval. Studies on SCT showed that this type of training in healthy individuals increased strength and aerobic capacity. Compared to CAT, intensive SCT among healthy overweight middle-aged men led to a significant decrease in metabolic indices [8]. These results are of special interest in cardiac rehabilitation as studies have shown that obesity can increase the risk of sudden death due to arrhythmic disorders [11] and changes in the autonomic nervous system [12-14]. In a previous study, we compared the effects of CAT to SCT on men post-myocardial infarction (MI) with reduced left ventricle function. SCT yielded better benefits to the patient’s mechanical cardiac function (left ventricle mechanical function). Moreover, compared to CAT, SCT yielded a better benefit to the patient’s fitness level, namely, aerobic capacity and strength [15]. However, the effects of CAT and SCT on cardiac electrical outcome measures [resting electrocardiograph (ECG) and heart rate variability (HRV)], were not analyzed. These non-invasive measures are of special interest as they correlate with patients’ cardiovascular health and electrophysiological stability in individuals with cardiac conditions (e.g., left ventricle dysfunction) [16, 17]. Since obesity is associated with adverse cardiac events [11], it was also vital to examine the CAT and SCT effects on anthropometric measures.

The primary objective of the study was to compare the effectiveness of SCT vs. CAT on cardiac electrical outcome measures (i.e., resting ECG and HRV) in post-MI patients with reduced left ventricle function. Our second objective was to compare the effects of these two regimes on patient’s anthropometric measures (body mass index, BMI; and waist circumference). We hypothesized that both CAT and SCT would be beneficial to improve electrophysiological measures. However, SCT may be more effective to improve cardiac ECG and anthropometric measures.

Materials and methods

Study participants

Post-MI male patients were referred to the cardiac rehabilitation center at Hadassah Mt. Scopus 6±10 weeks’ post-hospitalization due to acute MI. Inclusion criteria: 1) echo testing exhibited reduced left ventricle function (ejection fraction < 45%). Ejection fraction of < 45% was selected as it is one of the predictors of poor prognosis and increased mortality in hospitalized patients [18]; and 3) New York heart association level 3 or less. New York heart association was used as an inclusion criteria as it commonly used as a fundamental tool for risk stratification of heart failure and determines clinical trial eligibility and candidacy for drugs and devices [19]. and 3) patients were able to attend regularly a supervised exercise program.

Exclusion criteria: 1) chronic atrial fibrillation, 2) severe valvular disease, 3) angina or peripheral arterial occlusive disease, and 4) cerebrovascular or musculoskeletal disease-preventing exercise testing or training. The study was approved by the Helsinki ethics committee, Hadassah medical center (0440-12-HMO, ClinicalTrials.gov Identifier: NCT01912690). All participants gave written informed consent.

Study procedures

Participants were randomly assigned (sealed envelope method) to either twice a week CAT or SCT by cardiac rehabilitation staff who were not involved in the research study. The technical work and analysis of the results were blinded. The care providers were not blinded. During the trial, drug therapy remained unchanged, and patients with type 2 diabetes, or hypertensive, were not regulated in their drug therapy dosage during the 12-week intervention. A participant was deducted from the study if he developed adverse effects such as chest tightness, ECG changes, or severe arrhythmias.

Patients in both groups started each training session with five minutes warm-up, followed by either CAT or SCT. Throughout the training sessions, exercise intensity was defined using heart rate measurement (Polar Electro, Kempele, Finland; or Nihon Kohden ECG telemetry) and calculation of heart rate reserve (i.e., maximal heart rate—resting heart rate). Participants’ maximal heart rate was established using a baseline Bruce graded exercise tolerance test (GE Marquette CASE 8000 Exercising Testing System). The graded exercise tolerance test was terminated if the patient presented a > 10 mmHg decrease in systolic blood pressure with increasing workload, a moderate-to-severe angina, evidence of significant arrhythmia’s (e.g., > 3 premature ventricular contractions in a row), unusual or severe shortness of breath, evidence of poor perfusion, equipment’s mal function, or if the patient requested to stop the test. At the end of the exercise, both groups conducted five minutes of gradual cool down. For additional information on the test’s protocol, refer to Dor-Haim et al. [15].

CAT group participants exercised continually at 60% to 70% of their heart rate reserve using a treadmill (TechnoGym) and lower and upper extremity cycle ergometer (Star Terk). A modified Borg 1-to-10 scale was used to assess the rate of perceived exertion, during and after each training session. Speed and inclination of the treadmill or resistance and cadence of the cycle ergometer were adjusted continuously, to ensure that every training session was carried out at the assigned heart rate reserve throughout the training period (Fig 1).

Fig 1

Super-circuit training and continuous-aerobic training—Training program (adapted from Dor-Haim et al., 2018) [15].

Continues aerobic training group conducted only continues aerobic training and super-circuit training group conducted both aerobic and strength training.

The SCT group performed high-intensity exercise, alternating between resistance and aerobic training. One resistant training set was followed by three minutes of aerobic exercises and a resting period, repeated eight times. Each exercise consisted of one set of 15 repetitions on a Cybex resistance training machine. In the first two weeks of the program, the training intensity was light, RM 1 was assessed in the second day, according to the method of Kraemer and Fry [20]. Starting from- 30% of 1-repetition maximum, and progressively increased to 50% of 1-repetition maximum. Participants had to maintain appropriate lifting techniques, not hold their breath to avoid the Valsalva maneuver, and carefully alternate positions to adapt to the blood pressure orthostatic changes. The aerobic intensity was determined at 75% to 85% of heart rate reserve. Resting periods between intervals was minimal, and gradually decreased from two minutes in the first two weeks to 1.5 minutes in weeks 3–6 and 1 minute in weeks 7–12 (Fig 1).

For a more detailed description of the study design and exercise protocol, refer to Dor-Haim et al (2018) [15].

Outcome measures

All outcome measures were evaluated at baseline and post-12 weeks of the exercise training.

Resting electrocardiogram (ECG)–Twelve lead resting ECG for a duration of 10 minutes was recorded before the graded exercise tolerance test (Cardio scape PC ECG, version 3.1) using a fixed speed of 25 mm/sec and standardization of 1 mm as 1 millivolt throughout the measurement. QT interval was measured from the QRS complex onset point to the T wave offset point (the return of T wave to baseline). QT-dispersion (QTd) and Corrected QTd (QTcd) was calculated as the difference between the maximum and minimum QT intervals for any of the 12 leads [21].

Heart rate variability (HRV): Measurements of heart rate (Cardio scape PC ECG, version 3.1) were performed at rest. For analysis and calculation of HRV, the Kubios HRV software 2.0 was used [22]. The data were visually examined for quality control. Periods of excessive noise were removed from the analysis. Spectral analysis was used to calculate high-frequency (0.15–0.40 Hz) and low frequency (0.04–0.15 Hz) normalized units (HFnu and LFnu, respectively) using Fast Fourier Transformation. The ratio of low-to-high frequency (LF/HF) band powers was evaluated. A frequency-domain analysis method was selected for comparison to time-domain measures, as frequency-based analyses provide a more accurate interpretation of parasympathetic and sympathetic influences [16, 23].

Anthropometric measures

Two anthropometric parameters were measured: body mass index (BMI; weight in kg/height in m2) and waist circumference (measured 2.5 centimeters above the umbilicus) [24]. All anthropometric measures were conducted by one technician.

Data analysis

Normality assumption was evaluated using the Shapiro-Wilk test [25]. The analysis revealed the all study variables are normally distributed (p > 0.05) with W ranging from 0.90 to 0.94. In addition, in order to test whether or not data are missing completely at random (i.e., p > 0.05), Little’s test of missing completely at random test [26] was conducted. This test is useful for testing the assumption of missing completely at random for multivariate, partially observed quantitative data [27]. The test’s assumption is that the missingness of the data is independent of both the unobserved and the observed data [28]. In the current study, Little’s Missing data analysis showed that data were missing completely at random (Chi-square distance = 89.50, p = 0.32). This information was added to the statistical analysis section.

Differences between CAT and SCT groups in the various outcome measures at both pre and post-tests were examined using independent t-tests. To evaluate within-group changes from pre-to-post-test in the various outcome measures, paired t-tests were conducted (alpha level p<0.05, adjusted to 0.025 using the Bonferroni procedure). For HRV measurements, alpha level was adjusted to 0.016 (0.05/3 = 0.016). Effect sizes (ES) using Cohen’s d [29] were also calculated in order to quantify the degree of change in each study group. A correction for the dependence among means was done using the correlations between the two means following Morris and DeShon’s equation [30]. In general, values smaller and equal to 0.20 were considered trivial ES, values between 0.21 and 0.50 as small ES, values 0.51–0.80 as moderate ES, and values greater than 0.80 as large ES [29].

A posthoc power analysis was conducted using the main outcome measures, mainly, ECG and HRV. The average ES of these variables in the CAT and SCT groups were 1.78 and 0.78, respectively. Using posthoc power analysis for the ESs, α = 0.05, and the study’s sample size, the power to detect differences between two dependent variables (matched pairs) was 0.90 and 0.80, respectively. The mean ES difference between the groups was 0.78. Given this ES, α = 0.05, and the study’s sample size, the study’s power to detect between-group differences (independent t-test) was 0.78. Power analysis calculations were done using G*Power (version 3.0.10).

Results

Fifty-eight patients were referred to the cardiac rehabilitation center. Ten participants declined to participate or did not meet the inclusion criteria. Forty-eight participants (mean age = 59.14 years old + 8.92; range: 42.00–75.00) were assigned randomly to the CAT (n = 26) or SCT (n = 22). No statistically significant differences between CAT and SCT groups in age were observed (mean age = 61.21 ± 8.03 vs. 57.07 ± 9.57, respectively; t statistic = -1.24; p = 0.22; Table 1).

Table 1

Participant’s demographic and clinical background.

Demographic/ clinical measures		Continues aerobic training	Super-circuit training	Between-group differences: t-score OR Chi-squre (p value)
group		Mean (SD) OR n (%)	Mean (SD) OR n (%)
Age, tears: mean (SD)		61.21 (8.03)	57.07 (9.57)	-1.24 (0.22)
Pharmacological treatment: n (%)	Beta-blockers	17 (65.3)	12 (57.1)	0.33 (0.56)
	An angiotensin-converting-enzyme inhibitor	21 (80.7)	15 (68.1)	0.98 (0.32)
	Diuretics	6 (23.0)	6 (27.2)	0.11 (0.74)
	Statins	19 (73.0)	18 (81.8)	0.41 (0.51)
	Anti-coagulations	8 (30.7)	7 (31.8)	0.00 (0.94)
Co-morbidities	Diabetes mellitus	8 (30.7)	4 (18.1)	0.90 (0.34)
	Hypertension	13 (50.0)	12 (54.5)	0.07 (0.78)
	Obesity	6 (23.0)	4 (18.1)	0.17 (0.67)

Notes: SD, standard deviation

In the CAT group, post-test data were available for 15 participants. In the SCT group, post-test data were available for 14 participants. In both CAT and SCT groups most participants were treated with beta-blockers (65.3 and 54.5%, respectively), an angiotensin converting enzyme inhibitor (80.7 and 68.1%, respectively), and statins (73.0 and 81.8%, respectively). In addition, in both CAT and SCT, most participants’ had hypertension (50.0 and 54.5%, respectively; Table 1). For study participants flow-chart, refer to Fig 2.

Fig 2

Study participants’ flow chart (adapted from Dor-Haim et al., 2018) [15].

Forty-eight participants were assigned randomly to the continues aerobic training (n = 26) or super circuit training (n = 22). In the continues aerobic training group, 19 participants completed the program. Post-test data were available for 15 participants. In the super circuit training group, 16 participants completed the program, post-test data were available for 14 participants.

Cardiac electrical measures

The CAT group showed significant differences from pre to post-test in two HRV measures (increased HFnu and decreased LFnu; p < 0.016, Fig 3a) and in QT ECG measures (i.e., decreased QTd and QTcd; p < 0.025, Fig 3b). The SCT group yielded a significant increase in HFnu (p < 0.016, Fig 3a). The SCT group did not demonstrate significant changes in LFnu (Fig 3a). The SCT group showed significant changes in the two ECG measures (p < 0.025, Fig 3b). Regarding ES, the changes observed in both study groups were moderate-to-large (Cohen’s d > 0.51, Table 2). No significant between-group changes were found in the cardiac electrical measures, except for LFnu that in comparison to the SCT group, was significantly lower in the CAT group at pre-test (p = 0.006, Fig 3a and 3b).

Fig 3

Within and between-group differences cardiac electrical measures.

3a—heart rate variability. 3b—electrocardiograph—The central box represents the values from the lower to upper quartile (25 to 75 percentile). The vertical line extends from minimum to maximum values, excluding the outside values displayed as separate points. An outside value is defined as a value that is smaller than the lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range; the middle line represents the median; *significant within-group changes from pre to post-test; abetween-group differences—significantly different than CAT group; bbetween-group differences—significantly different than SCT group.

Table 2

Continuous aerobic training and super-circuit training effect sizes.

Primary and secondary outcome measures		Cohen’s d effect size
Training group		Continues aerobic training	Super-circuit training
Resting electrocardiograph	QT dispersion	-1.24	0.91
	Corrected QT dispersion	-1.22	-0.83
Heart rate variability	HFnu	1.839	1.07
	LFnu	-3.73	-0.51
	LF/HF	-0.90	-0.55
Anthropometric measures	Body mass index	-0.08	-0.34
	Waist circumference (cm)	-0.06	-0.55

Note: Cohen’s d calculation: mean Δ/standard deviation average from two means. Dark gray cells -moderate and large differences (Cohen’s d ≥ 0.51). Light gray cells—small differences (Cohen’s d = 0.21–0.50). White cells—trivial differences (Cohen’s d ≤ 0.20).

*Cohen’s d is based on a single pooled standard deviation. Cohen’s d was corrected for dependence between means, using Morris and DeShon’s equation [30].

Anthropometric measures

No statistical significant between-group differences in BMI were observed in at both pre and post-tests. Similarly, in both groups participants did not present a statistically significant change from pre-to-post-test in BMI. Waist circumference of SCT groups was statistically significantly lower than this of CAT group in both pre-and-posttest. Moreover, only the SCT group presented a significant reeducation in waist circumference from pre-to-posttest (p<0.025; ES = -0.55). For additional information, refer to Tables 2 and 3.

Table 3

Anthropometric measures: Within and between group differences.

Variables		Continues aerobic training			Super-circuit training			Between-groups analysis
		Pre-test: mean (SD)	Post-test: mean (SD)	Statistic t (p value)	Pre-test: mean (SD)	Post-test: mean (SD)	Statistic t (p value)	Pre-test: statistic t (p value)	Post-test: statistic t (p value)
Anthrop-ometric Measures	Body mass index	29.35 (3.81)	29.04 (3.65)	-1.488 (0.164)	28.14 (2.90)	27.14 (2.73)	-2.72 (0.026)	-0.789 (0.439)	-1.305 (0.207)
	Waist circumference (cm)	107.56 (7.36)	107.12 (7.88)	-1.01 (0.302)	98.66 (7.17)	94.66 (6.94)	-6.35 (0.0002) *	-2.59 (0.019)	-3.55 (0.002) *

Notes: SD, standard deviation;

* significant within or between-group differences at the p < 0.05 (alpha level of body composition measurements was adjusted to 0.025 using the Bonferroni procedure.

Discussion

This study’s primary finding was demonstrating that -exercise, primarily SCT post-MI in patients with reduced left ventricular function was valuable to improve electrocardiographic measures (resting ECG and HRV). Secondly, only SCT was effective to reduce waist circumference. The study findings are consistent with the hypothesis that SCT may be more effective for patients post MI with reduced left ventricular function. In our previous study [15], SCT was more efficient than CAT in enhancing cardiac mechanical systolic (ejection fraction) and diastolic function (mitral inflow E velocity to tissue Doppler E/e’ ratio). Resting ECG measure such as QTd and HRV are key electrophysiological markers post-MI in ischemic patients. These measures are related to electrical remodeling of the heart post-MI, arrhythmias such as atrial fibrillation [31], while such modeling in the ventricle may cause potentially lethal ventricular arrhythmias [32]. Therefore, the effects of CAT and SCT on electrocardiograph measures were essential for investigation.

The results presented here indicate an improvement in both QTd and HRV by both CAT and SCT regimes. More specifically, in both groups, QTd and QTdc decreased (p<0.01). Moreover, both groups showed a significant increase in HF spectral component, attributed to an increase in parasympathetic tone and antiarrhythmic protection [33]. Our results are consistent with other studies indicating the benefits of exercise training for the heart’s electrical stability post-MI [17]. The beneficial effects of both CAT and SCT on ECG and HRV measures are encouraging as such improvements are associated with reduced cardiovascular disease burden and mortality. Other clinical and animal studies showed that QTd and HRV are independent non-invasive markers for ventricular arrhythmia and sudden cardiac death following MI [34, 35]. QTd also serves as a marker for electrical inhomogeneity during myocardial repolarization. In addition, HRV is related to autonomic nervous system regulation. In MI survivors, lower HRV was associated with the remodeling of the autonomic nervous system [36] and an increased risk of tachyarrhythmia [37]. Therefore, improved HRV and QTd in the current study by safe exercise protocol may elicit favorable cardiac electrical reversed remodeling among patients’ post-MI with reduced left ventricle function.

Few studies showed a deleterious arrhythmogenic effect of exercise, mostly in vigorous exercise [38, 39]. In the current study, we demonstrated that both exercise regimes resulted in an improvement in electrical markers. However, the SCT method resulted in a better cardiac intrinsic recovery, and thus, may yield a better prognosis post-MI. Animal studies also demonstrated that increased exercise intensity improves cardiovascular electrical stability in a dose-response relationship [40]. In the current study, the only difference between the two training regimes was found in the LF component, which was decreased in the CAT group but not in the SCT group. The LF component represents the interaction of the sympathetic and parasympathetic nervous systems. Exercise training induces adaptations in HRV outcomes with a shift of autonomic balance toward higher parasympathetic activity, consistent with improved cardiac health [16]. The decrease in the LF component is commonly observed in MI survivors and is attributed to increased sympathetic tone and increased risk of sudden death [41]. Hence, from the electrophysiological aspect attenuated LF reduction seen only in the SCT group may represent a relatively improved clinical reaction.

Both training groups did not show significant changes in pre-post BMI, suggesting that participants did not lose or gain weight. However, the SCT group presented significant reductions in waist circumference. These results showed that only the SCT group decreased their abdominal visceral fat [42, 43], which is one component of metabolic syndrome [44]. Reduction of body fat without losing weight may indicate a gain in muscle mass at the expense of fat mass loss [45]. In order to better understand programs’ effect on body composition, additional anthropometric measures should be included in future studies. Compared to subjects with high muscle/low fat, the risk of arrhythmia due to cardiac intrinsic electrical instability is significantly higher in people with a high fat /low muscle ratio [46]. It is also important to note that abnormal autonomic regulation is prevalent in patients with metabolic disorder. For example, several HRV studies showed abnormalities in autonomic nervous control in obese and overweight subjects [47, 48]. In overweight individuals, a sympathovagal imbalance due to increased sympathetic activity and its association with visceral fat was observed [49]. In another 6-month study, aerobics alone was compared to a combined aerobic and resistance training. Both regimes significantly decreased abdominal visceral fat, but combined aerobic and resistance training was more effective [43].

The current study was subject to several limitations. First, the generalizability of the results is in question owing to the single center and the small sample size of male only patients in each study group. The inclusion of only male patients is a common characteristic of numerous studies examining exercise training effects on heart failure patients. For example, in a recent meta-analysis in the subject it was reported that the majority of patients in cardiac rehabilitation and exercise training trials are males (77%) [50]. Second, anthropometric measures were limited in this study and could be expended to measure more variables such as body composition and blood chemistry. Last, the study period of three months is too short to draw conclusions in regarding to prognostic indicators for the two exercise groups, such as re-hospitalizations and mortality.

Conclusions

In conclusion, the current study showed that electrocardiographic measures post-MI stand to benefit from both training regimes, namely, CAT and SCT. Nevertheless, in comparison to aerobic training alone (i.e., CAT), SCT may yield better benefits to autonomic balance and anthropometric measures. Considering the effect of exercise on MI patients, it is vital to introduce novel training modalities that may enhance autonomic balance, intrinsic mycardial recovery and health related anthropometric factors post-MI.

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Reviewer #1: The title should be rewritten to express the real comparative study work.. How would you express that all participants are of same gender ?..The author didn't mention minium ejection fraction for inclusion criteria to provide patients safety

Reviewer #2: Interesting paper, but there are things need to be revised and considered before publication

please see the attached file for recommendations within the manuscript as comments.

A major part is:

- There is no description to the graded exercise test used in the study in the methods section

- There is no demographical data for the participants

- In the results tables, add a table for HRV and QT before and after each training program.

Reviewer #3: PONE-D-22-01160: statistical review

SUMMARY. This study compares the effectiveness of super-circuit training (SCT) versus continuous-aerobic training (CAT) on cardiac outcomes and secondary biometrical outcomes in post-MI males with reduced left ventricle function. It is a follow-up of a previous study, already published in PLOSONE. The statistical analysis correctly relies on ANOVA methods and results seem sound. There are however three points that should be clarified: see the major issues below. I also append some specific points that should be addressed.

MAJOR ISSUES

1. Age ranges from 42 to 75 years and can be a confounder. Please test age differences between the CAT and the SCT group (a standard T-test will do the job). Two are the possible outcomes. Either age means do not significantly differ between groups; in this case the randomization procedure did a good job and the authors just need to display the result of the t-test, to reassure the reader. Or one of the two groups is significantly older (or younger) than the other one; in this case the ANOVA analysis must be extended to a regression analysis, where age is included as a confounder.

2. Page 9, Study participants section: "Fifty-eight patients ... 14 participants". As it often happens, there are missing values and drop-outs in this study. This is not necessarily a problem, provided that the missing values are ignorable. Missing values are ignorable when the probability of a missing value does not depend on the unobserved value. Do we have any information about the missing outcomes? If we can assume that the missing values are missing at random (i.e., neither older nor younger than the included subjects; neither in better nor in worse health status, and so on), then we can safely ignore them, as the authors did in their analysis. Otherwise, the results of the analysis could be possibly questionable.

3. Normality. The whole analysis relies on an assumption of normally-distributed outcomes. Could the authors give some evidence of this assumption? If serious departures from normality are detected, then p-values could be biased.

SPECIFIC POINTS

1. Abstract, first line: "Exercise is a valuable intervention modality post-myocardial infarction (MI)." I think a "in" or a "for" is missing here: please check.

2. An obvious limitation of the study is that women are not considered. This should be remarked in the discussion, perhaps referring to other studies that include women.

3. Figure 3: "The vertical line extends from minimum to maximum values, excluding the outside values displayed as separate points". Please clarify how were outliers defined, as there is not a universal definition of outlying observations.

4. Data availability. Honestly, I don't see specific reasons that would prevent the full availability of the data.

**********

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Submitted filename: PONE-D-22-01160_reviewer.pdf

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24 Mar 2022

Reviewer 1

Thank you very much for the detailed and informative review. We hope we’ve addressed all concerns to your full satisfaction. Below we describe in detail the corrections we’ve made in the manuscript.

1. The title should be rewritten to express the real comparative study work.

Thank you for the comment – the title was changed to represent more precisely the comparative study: Intermittent aerobic-resistance interval training versus continues aerobic training: improvement in cardiac electrophysiologic and cardio-metabolic measures in male patients post myocadiac infarction, a randomize control study

2. How would you express that all participants are of same gender?

Thank you for the comment – the title was changed to represent more precisely the male patients in study.

3. The author didn't mention minium ejection fraction for inclusion criteria to provide patients safety

Patients minimum EF was not an inclusion criterion, however minimum functional capacity was. Meaning NYHA level had to be NYHA 3 or less. Functional capacity is a well-established criterion to classify patient risk level – please note:

Caraballo, C., Desai, N. R., Mulder, H., Alhanti, B., Wilson, F. P., Fiuzat, M., ... & Ahmad, T. (2019). Clinical implications of the New York heart association classification. Journal of the American Heart Association, 8(23), e014240.‏

This information was added to "study participant's section.

Reviewer 2

Thank you very much for the detailed and informative review. We hope we’ve addressed all concerns to your full satisfaction. Below we describe in detail the corrections we’ve made in the manuscript.

1. A major part is: There is no description to the graded exercise test used in the study in the methods section

The graded exercise protocol was described in our previous manuscript by Dor-Haim et al., 2018. A reference to the manuscript was added to the methods section. In short, aerobic fitness was assessed by using Bruce graded exercise tolerance treadmill protocol (GE Marquette CASE 8000 Exercise Testing System). The graded exercise tolerance test was terminated if the patient presented a > 10 mmHg decrease in systolic blood pressure with increasing workload, a moderate-to-severe angina, evidence of significant arrhythmia’s (e.g., > 3 premature ventricular contractions in a row), unusual or severe shortness of breath, evidence of poor perfusion, equipment's mal function, or if the patient requested to stop the test. A short description of the protocol was also added to the methods section.

Dor-Haim H, Barak S, Horowitz M, Yaakobi E, Katzburg S, Swissa M, Lotan C. Improvement in cardiac dysfunction with a novel circuit training method combining simultaneous aerobic-resistance exercises. A randomized trial Earnest CP, editor. PLoS ONE. 2018 January 29;13:e0188551.

2. There is no demographical data for the participants

We added the following information to the results study participants section: In both CAT and SCT groups most participants were treated with beta-blockers (66.7 and 57.1%, respectively), an angiotensin converting enzyme inhibitor (81 and 71.4%, respectively), and statins (76.7 and 85.7%, respectively). In addition, in both CAT and SCT, most participant's had hypertension (53.3 and 57.1%, respectively). "

3. In the results tables, add a table for HRV and QT before and after each training program.

We did not add the table as HRV and QT is presented as a figure (figure 3). Our apologies if that was not clear.

3a - heart rate variability. 3b – electrocardiograph

4. Introduction – "These results are of special interest in cardiac rehabilitation as studies have shown that obesity can increase the risk of sudden death due to arrhythmic disorders [11] and changes in the autonomic system [12-14]" change to "autonomic nervous system.

We corrected the sentence.

5. What is the study's hypothesis?

We hypothesized that both CAT and SCT would be beneficial to improve electrophysiological measures. However, SCT may be more effective to improve cardiac ECG and metabolic measures. The hypothesis was added to the end of the introduction.

6. Study participants description: " Inclusion criteria: 1) echo testing exhibited reduced left ventricle function (ejection fraction < 45%)". Based on which guidelines this definition of ejection fraction?

There are some predictors of poor prognosis and increased mortality in hospitalized patients, which include, among others, LVEF under 45%. This information was added to the study participants' section.

Ouwerkerk W, Voors AA, Zwinderman AH. Factors influencing the predictive power of models for predicting mortality and/or heart failure hospitalization in patients with heart failure. JACC Heart Fail. 2014 Oct;2(5):429-36. [PubMed]

7. Study procedures –" Participants' maximal heart rate was established using a baseline graded exercise tolerance test." What was the test?

The graded exercise protocol was described in our previous manuscript by Dor-Haim et al., 2018. A reference to the manuscript was added to the methods section. In short, aerobic fitness was assessed by using Bruce graded exercise tolerance treadmill protocol (GE Marquette CASE 8000 Exercise Testing System). The graded exercise tolerance test was terminated if the patient presented a > 10 mmHg decrease in systolic blood pressure with increasing workload, a moderate-to-severe angina, evidence of significant arrhythmia’s (e.g., > 3 premature ventricular contractions in a row), unusual or severe shortness of breath, evidence of poor perfusion, equipment's mal function, or if the patient requested to stop the test. A short description of the protocol was also added to the methods section.

Dor-Haim H, Barak S, Horowitz M, Yaakobi E, Katzburg S, Swissa M, Lotan C. Improvement in cardiac dysfunction with a novel circuit training method combining simultaneous aerobic-resistance exercises. A randomized trial Earnest CP, editor. PLoS ONE. 2018 January 29;13:e0188551:

8. Study procedures - "Each exercise consisted of one set of 15 repetitions on a Cybex machine." What is this machine?

Cybex machine is a resistance training station, manufactured by Cybex company. The text was changed to clarify the content.

9. Study procedures – "In the first two weeks of the program, the training intensity was light - 30% of 1-repetition maximum" – add information about this measurement. How and when it was made and for which muscles?

Thank you for the comment. RM 1 procedure was performed in the second day, according to the method of Kraemer and Fry, which was proved to be safe in CR. The test started from- 30% of 1-repetition maximum, and progressively increased to 50% of 1-repetition maximum. This information and the reference were added to the manuscript.

Barnard, K. L., Adams, K. J., Swank, A. M., Mann, E., & Denny, D. M. (1999). Injuries and muscle soreness during the one repetition maximum assessment in a cardiac rehabilitation population. Journal of Cardiopulmonary Rehabilitation and Prevention, 19(1), 52-58.‏

10. Metabolic measures – "Two metabolic parameters were measured: body mass index (BMI; weight in kg/height in m2 ) and waist circumference (measured 2.5 centimeters above the umbilicus) [21]. " this was already introduced. Why repeat it?

This information was mentioned earlier only at the end of the introduction where we describe the purpose of the study. In the objective there is no description of measurement method. Therefore, we do think that we need to mention these two measures in the outcome measures section as well. In this section we provide a little information on measurement methods.

11. Data analysis – "Differences between CAT and SCT groups in the various outcome measures at both pre and post-tests were examined using independent t-tests ". Add information about the skeweness of the variables, were all variables normally distributed or not, and in case of not-normal distribution what was the procedure?

Normality assumption was evaluated using the Shapiro-Wilk test. The analysis revealed the all study variables are normally distributed (p > 0.05) with W ranging from 0.90 to 0.94. This information was added to statistical analysis section.

Shapiro SS, Wilk MB (1965) An analysis of variance test for normality (complete samples). Biometrika 52: 3-4.

12. Data analysis – "In general, values smaller and equal to 0.20 were considered trivial ES, values between 0.21 and 0.50 as small ES, values 0.51-0.80 as moderate ES, and values greater than 0.80 as large ES [22]." Need to write the level of significance accepted at which level.

We calculated ESs to all analyses where t-tests were also conducted. More specifically, the test was conducted in all analyses, regardless of the t test p value (greater or smaller than 0.05). We used the ES in order to understand the magnitude of the changes observed and not their statistical significance. Therefore, we do not think that we need to add significance level to the effect size. We apologize if we missed understand you. If you still think that further changes need to be conducted, we will appreciate receiving more information in the matter.

13. Figure 3 – " Analysis level of significance was set at 0.05 and adjusted to 0.016 in heart rate variability……." This should have been mentioned earlier.

This information also appears in data analysis section. Therefore, we deleted it from Figure 3.

14. Discussion: " This study's primary objective was to evaluate the implications of two-exercise regimes post-MI in patients with RVLF.." introduce this abbreviation.

Because this abbreviation appears only twice, we decided to write the full name instead of using abbreviations.

15. Discussion – normally in the first paragraph of the discussion there should be a summary of the study's findings and whether they are as expected or not.

Thank you for the comment. The text in the first paragraph of the discussion was re-edited to demonstrate the main findings of the study.

16. Discussion – " However, the SCT group presented significant reductions in waist circumference. These results showed that only the SCT group decreased their abdominal visceral fat [35,36], which is one component of metabolic syndrome [37]." This raise a question, abdominal visceral fats are more accurately measured via bioelectrical impedance. However, using waist circumference only to measure or refer to abdominal visceral fats is subject to many confounding factors. Thus, was the measurement performed by 1 person only pre and post or was there many people involved?

This is an important comment: Waist circumference and BMI were only a secondary objective of the study. It was measured by one technician who was very consistent in measurements. This information was added to "outcome measures section".

Body impedance is another way to measure change in body composition, however, it tends to be inaccurate in CHF patients who tend to change their body impedance due to electrolyte, diuretics and water volume level. However, we do agree that it is one of the study limitations, therefore we added this sentence to the study limitations paragraph: Metabolic measures were limited in this study and could be expended to measure more variables such as body composition and blood chemistry.

17. Discussion: " Reduction of body fat without losing weight indicates a gain in muscle mass at the expense of fat mass loss". Unless you precisely measure it, I would advise deleting this statement. Because there are other factors which can contribute to weight other than fat mass and muscle mass.

The text was edited: Reduction of body fat without losing weight may indicate a gain in muscle mass at the expense of fat mass loss. In order to better understand programs' effect on body composition, additional metabolic measures should be included in future studies.

18. Discussion: " It is also important to note that abnormal autonomic regulation is prevalent in metabolic patients". Change to "patients with metabolic disorders".

The sentence was corrected.

19. End discussion: "Prolonged research and follow-up are required to allow firm conclusions regarding re-hospitalizations and mortality." What this statement

The sentence was rephrased: Last, the study period of three months is too short to draw conclusions regarding to the prognostic indicators for the two exercise groups such as regarding re-hospitalizations and mortality.

20. Conclusions: "….. novel training modalities that may enhance the central cardiac recovery….." Do you mean parasympathetic recovery?

Thank you, the sentence was rephrased: ….modalities that may enhance the intrinsic cardiac recovery and peripheral metabolic health-related factors post-MI.

Reviewer 3

Thank you very much for the detailed and informative review. We hope we’ve addressed all concerns to your full satisfaction. Below we describe in detail the corrections we’ve made in the manuscript.

1. Age ranges from 42 to 75 years and can be a confounder. Please test age differences between the CAT and the SCT group (a standard T-test will do the job). Two are the possible outcomes. Either age means do not significantly differ between groups; in this case the randomization procedure did a good job and the authors just need to display the result of the t-test, to reassure the reader. Or one of the two groups is significantly older (or younger) than the other one; in this case the ANOVA analysis must be extended to a regression analysis, where age is included as a confounder.

No statistically significant differences between CAT and SCT groups in age were observed (mean age = 61.21 + 8.03 vs. 57.07 + 9.57, respectively; t statistic = -1.24; p = 0.22). This information was added to the results section.

2. Page 9, Study participants section: "Fifty-eight patients ... 14 participants". As it often happens, there are missing values and drop-outs in this study. This is not necessarily a problem, provided that the missing values are ignorable. Missing values are ignorable when the probability of a missing value does not depend on the unobserved value. Do we have any information about the missing outcomes? If we can assume that the missing values are missing at random (i.e., neither older nor younger than the included subjects; neither in better nor in worse health status, and so on), then we can safely ignore them, as the authors did in their analysis. Otherwise, the results of the analysis could be possibly questionable.

Thank for introducing this very important issue. In order to test whether or not data are missing completely at random (i.e., p > 0.05), Little's test of missing completely at random test (Little, 1988) was conducted. This test is useful for testing the assumption of missing completely at random for multivariate, partially observed quantitative data (Li, 2013). The test's assumption is that the missingness of the data is independent of both the unobserved and the observed data (Graham, 2009). In the current study, Little's Missing data analysis showed that data were missing completely at random (Chi-square distance = 89.50, p = 0.32). This information was added to the statistical analysis section.

Little RJA. A Test of Missing Completely at Random for Multivariate Data with Missing Values. Journal of the American Statistical Association. 1988 December;83:1198–1202.

Li C. Little’s Test of Missing Completely at Random. The Stata Journal. 2013 December;13:795–809.

Graham JW. Missing Data Analysis: Making It Work in the Real World. Annu Rev Psychol. 2009 January;60:549–576.

3. Normality. The whole analysis relies on an assumption of normally-distributed outcomes. Could the authors give some evidence of this assumption? If serious departures from normality are detected, then p-values could be biased.

Normality assumption was evaluated using the Shapiro-Wilk test. The analysis revealed the all study variables are normally distributed (p > 0.05) with W ranging from 0.90 to 0.94. This information was added to statistical analysis section.

Shapiro SS, Wilk MB (1965) An analysis of variance test for normality (complete samples). Biometrika 52: 3-4.

4. Abstract, first line: "Exercise is a valuable intervention modality post-myocardial infarction (MI)." I think a "in" or a "for" is missing here: please check.

The sentence was corrected: Exercise is a valuable intervention modality for patients post-myocardial infarction (MI).

5. An obvious limitation of the study is that women are not considered. This should be remarked in the discussion, perhaps referring to other studies that include women.

Thank you for the comment. This study constrained to a small sample of patients, thus authors had to select more homogeneous group of male gender. Title of the manuscript was also rephrased to reflect the above: Intermittent aerobic-resistance interval training versus continues aerobic training: improvement in cardiac electrophysiologic and cardio-metabolic measures in male patients post myocadiac infarction.

In addition, as advised we have also referred to your important comment in the limitation section:

The current study was subject to several limitations. First, the generalizability of the results is in question owing to the single center and the small sample size of male only patients in each study group. The inclusion of only male patients is a common characteristic of numerous studies examining exercise training effects on heart failure patients. For example, in a recent meta-analysis in the subject it was reported that the majority of patients in cardiac rehabilitation and exercise training trials are males (77%) [46].

Tucker WJ, Beaudry RI, Liang Y, Clark AM, Tomczak CR, Nelson MD, Ellingsen O, Haykowsky MJ. Meta-analysis of Exercise Training on Left Ventricular Ejection Fraction in Heart Failure with Reduced Ejection Fraction: A 10-year Update. Progress in Cardiovascular Diseases. 2019 March;62:163–171.

6. Figure 3: "The vertical line extends from minimum to maximum values, excluding the outside values displayed as separate points". Please clarify how were outliers defined, as there is not a universal definition of outlying observations.

An outside value is defined as a value that is smaller than the lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range; the middle line represents the median. This information was added to the figure's notes.

7. Data availability. Honestly, I don't see specific reasons that would prevent the full availability of the data.

Data will now be available.

Submitted filename: Response to reviewers_24_3_2022.docx

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5 Apr 2022

13 Apr 2022

Reviewer 1

Thank you very much for your feedback. We are happy that we were able to appropriately response to all your concerns. Your valuable comments helped improving the manuscript.

Reviewer 2

1. IN HRV, Correct Normalized power to normalized unit (nu)

Corrected.

2. Metabolic measures, I suggest changing it into "anthropometric measures" which is more common and describing the measures used.

Thank you very much for this comment. We changed in the entire manuscript "metabolic" to "anthropometric" except for places that cite from the literature references specifically related to metabolic measures.

3. It caught my attention one of the responses to reviewers that minimum EF was not mentioned, and the authors answered that inclusion criteria is based on NYHA. Does the author suggest that this classification is safer than including EF?

We used the NYHA classification as an inclusion criteria as it commonly used as a fundamental tool for risk stratification of heart failure and determines clinical trial eligibility and candidacy for drugs and devices. We did not try to suggest that this classification is safer than including EF. We rephrased the inclusion criteria to better explain the reason for using the NYHA.

Caraballo C, Desai NR, Mulder H, Alhanti B, Wilson FP, Fiuzat M, Felker GM, Piña IL, O’Connor CM, Lindenfeld J, et al. Clinical Implications of the New York Heart Association Classification. JAHA. 2019 December 3;8:e014240.

4. Thanks for adding information about the medication and co-morbidities, but it would be better to include it in a table with the common demographical data such as age, weight height, BMI

We created a new table, table 1. The table has information regarding the 2 study's groups' demographic and clinical characteristics. We also added between-group analyses for both continues and categorical variables. We did not put in the table BMI as BMI is one of the study's outcome measures and it appears with the other outcome measures in tables 2 and 3.

5. Modalities that may enhance the "intrinsic" cardiac recovery and peripheral metabolic health-related factors post MI - what does the author mean with intrinsic, if the author agree on "parasympathetic recovery" then I would use Extrinsic instead of intrinsic

Thank you for this comment. We reread the sentence and indeed it is not clear and accurate enough. We rephrased the sentence:

"Considering the effect of exercise on MI patients, it is vital to introduce novel training modalities that may enhance autonomic balance, intrinsic myocardial recovery and health related anthropometric factors post-MI."

Reviewer 3

Thank you very much for your time reviewing the manuscript. We are happy that we were able to appropriately response to all your concerns. Your valuable comments helped improving the manuscript.

Submitted filename: Response to reviewers_second.docx

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19 Apr 2022

Intermittent aerobic-resistance interval training versus continues aerobic training: improvement in cardiac electrophysiologic and anthropometric  measures in male patients post myocadiac infarction, a randomized control trial

PONE-D-22-01160R2

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Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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25 Apr 2022

PONE-D-22-01160R2

Intermittent aerobic-resistance interval training versus continues aerobic training: improvement in cardiac electrophysiologic and anthropometric  measures in male patients post myocadiac infarction, a randomized control trial

Dear Dr. Barak:

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