High-intensity interval training versus moderate-intensity continuous training on patient quality of life in cardiovascular disease: a systematic review and meta-analysis

This systematic review and meta-analysis aimed to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the quality of life (QOL) and mental health (MH) of patients with cardiovascular disease (CVDs). Web of Science, Medline, Embase, Cochrane (CENTRAL), CINAHL, China National Knowledge Infrastructure, Wanfang, and China Science and Technology Journal databases were searched from their date of establishment to July, 2023. A total of 5798 articles were screened, of which 25 were included according to the eligibility criteria. The weighted mean difference (WMD) and standardized mean difference (SMD) were used to analyze data from the same and different indicator categories, respectively. The fixed-effects model (FE) or random-effects model (RE) combined data based on the between-study heterogeneity. There were no statistically significant differences regarding QOL, physical component summary (PCS), mental component summary (MCS), and MH, including depression and anxiety levels, between the HIIT and MICT groups [SMD = 0.21, 95% confidence interval (CI)  − 0.18–0.61, Z = 1.06, P = 0.290; SMD = 0.10, 95% CI  − 0.03–0.23, Z = 1.52, P = 0.128; SMD = 0.07, 95% CI  − 0.05–0.20, Z = 1.13, P = 0.25; SMD = − 0.08, 95% CI  − 0.40–0.25, Z = − 0.46, P = 0.646; WMD = 0.14. 95% CI  − 0.56–0.84, Z = 0.39, P = 0.694, respectively]. HIIT significantly improved PCS in the coronary artery disease (CAD) population subgroup relative to MICT. HIIT was also significantly superior to MICT for physical role, vitality, and social function. We conclude that HIIT and MICT have similar effects on QOL and MH in patients with CVD, while HIIT is favorable for improving patients’ self-perceived physiological functioning based on their status and social adjustment, and this effect is more significant in patients with CAD.


GRADE of evidence. According to the Grading of Recommendations and Assessment Development and
Evaluation (GRADE) evidence summary, the certainty of QOL, physical component summary (PCS), mental component summary (MCS), and anxiety was moderate, but the certainty of depression was low.Detailed results are shown in Supplement 2.
Depression.Depression levels were reported in 5 of the 23 studies 27,29,30,36,38 .The SMD was used in the metaanalysis for effect size synthesis, and significant heterogeneity was detected between the studies (I 2 = 53.5%,P = 0.072).The FE analysis showed that the difference in depression levels between the HIIT and MICT groups was not statistically significant (SMD = − 0.08, 95% CI − 0.40 ~ 0.25, Z = − 0.46, P = 0.646), as shown in Fig. 6.Anxiety.Anxiety levels were reported in 4 of the 23 studies 27,30,36,38 .The WMD was used in the meta-analysis for effect size synthesis, and no between-study heterogeneity was observed (I 2 = 0.0%, P = 0.832).The FE analysis showed that the difference in anxiety levels between the HIIT and MICT groups was not statistically significant (WMD = 0.14, 95% CI − 0.56 ~ 0.84, Z = 0.39, P = 0.694), as shown in Fig. 7.
Additional analyses.In addition to PCS and MCS, this study conducted additional analyses of sub-indicators for eight dimensions of quality of life: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional (RE), MH, and reported health transition (HT).Ten of the 23 studies reported, in detail, on the eight sub-dimensions of SF-36 and SF-12 25,28,29,32,33,35,36,41,47 .Therefore, additional analyses were performed on these dimensions.Surprisingly, the HIIT group was superior to the MICT group for three dimensions, namely RP, VT, and SF, and the differences were statistically significant.
The results of the meta-analysis for RP (SMD = 0.23, 95% CI 0.04 ~ 0.41, Z = 2.36, P = 0.018) and the FE analysis   Publication bias.Publication bias was assessed regarding QOL, PCS, and MCS.In the funnel plot of QOL, results were distributed on both sides of the symmetry axis.The funnel plots appeared to be asymmetric, suggesting that publication bias may exist in the data regarding QOL; however, the results of the egger test showed no publication bias (t = 1.21,P = 0.260).In the results both of PCS and MCS, the funnel plots were symmetric, suggesting that the data for PCS and MCS were not influenced by publication bias, as supported by the results of the egger test (t = − 1.89, P = 0.087 and t = 0.76, P = 0.466, respectively).According to the principle of inclusion and testing of publication bias, the analysis did not include depression and anxiety due to the limited availability of literature, with less than 10 studies available 48,49 , as shown in Fig. 10.Table 3.The results of meta-analyses of the effect of eight dimensions of quality of life.

Discussion
The current systematic review aimed to investigate the effects of HIIT and MICT on the QOL and MH of patients with CVDs by searching 8 electronic databases and evaluating 25 relevant articles.The study conducted a further analysis on the effects of HIIT and MICT on eight sub-dimensional indicators, including PF, RP, BP, GH, VT, SF, RE, and MH in QOL, with subgroup analyses based on population differences.The results showed that HIIT and MICT have similar effects on improving QOL and MH in patients with CVDs.However, HIIT is more www.nature.com/scientificreports/conducive to the restoration of physiological functions and self-perceived energy, as well as to the alleviation of functional limitations associated with the condition, thus promoting the healthy development of the patient's social adjustment.Notably, this effect was particularly pronounced in patients with CAD.
As the concept of health changes under the model of bio-psycho-social medicine, the measurement of health is gradually changing from a single physical health measurement to a multidimensional measurement of physical, psychological, social, and subjective well-being.The WHO define health as a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity 3 .QOL, as an important health assessment indicator, is defined as an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns.These include individual physiology, psychology, social function, and material state 50 .For patients with CVDs, QOL is a comprehensive concept centered on patients' subjective feelings and encompassing multidimensional assessment indicators.Similar to cardiac function, blood markers, cardiovascular events, or other types of clinical indicators, QOL during a patient's return visit is an important metric for evaluating the effectiveness of the health care services the patient received 6 .In contrast to traditional methods of survival analysis, the QOL evaluation system also includes an investigation of the patient's physiological status.However, the difference is that the process is conducted from the patient's subjective point of view, and therefore, the measurements can be more sensitive to the changes in physiological feedback, proprioception, and attitudes toward treatment during CR 35 .Therefore, health-related QOL is often measured using subjective questionnaires, including general health-related QOL (general tool) and health-related QOL in specific disease-related areas (specific tool) 51,52 .Currently, the majority of clinical trials involving CVDs include QOL as an essential indicator.Through the observation of QOL, physicians and caregivers can have a clearer understanding of the patient's treatment progress from a multidimensional perspective and make timely adjustments to optimize CR.  www.nature.com/scientificreports/ Previous meta-analyses have demonstrated that HIIT is superior to MICT in improving physiological markers, such as flow mediated dilation, mitochondrial function in skeletal muscle, maximal oxygen consumption (VO 2max ), blood pressure, and lipid control in patients with CVDs 31,45,53 .However, the number of reports on subjective markers, such as QOL, is more limited.Both QOL and MH were included in this study as primary outcome indicators, and there were no strict inclusion criteria for participant eligibility, except for the type of disease.Therefore, general health-related QOL was used in the analysis of QOL, which has good reliability and validity 54 .Although there was little difference between HIIT and MICT regarding the improvement of PCS and MCS in the majority of patients, the effect of HIIT in improving PCS in patients with CAD was significant.This outcome, in part, supports the first hypothesis of the current study, which suggests that HIIT enhances the rehabilitative efficiency of physiological functions during CR in patients with CAD, which is consistent with the outcomes of two previous meta-analyses 13,55 .However, the difference to the present study is that other studies only included objective indexes, including VO 2max , anaerobic threshold, and peak power output (PPO), whereas in the present study, PCS was evaluated on the basis of the patient's proprioception.Therefore, it can be concluded that HIIT has a combined benefit for patients with CAD, which may be related to the physiological mechanisms by which HIIT positively affects several aspects of health.Regular HIIT promotes the onset of mitochondrial adaptations within skeletal muscle; an effect that not only enhances the efficiency of adenosine triphosphate supply 56 , but also contributes to the improvement of lipid oxidation and glucose metabolism, which leads to the regulation of blood pressure and blood lipids 57 .Concurrently, repetitive high-and low-intensity stimulation mediates myocardial remodeling, including an increase in ventricular wall thickness and ventricular volume.Myocardial adaptation improves the heart's pumping capacity, thereby increasing cardiorespiratory fitness and aerobic endurance in exercisers 16,58 .Furthermore, the physiological adaptations induced by HIIT were also reflected in improvements to lactate threshold and exercise tolerance 59 .These factors may explain why HIIT induced superior improvements in RP, VT, and other sub-indices than those of MICT in the present study.
In addition, differences in PCS were related to different disease types, and the present study suggests the following explanations.This finding may be due to differences in pathological characteristics of patients with different types of CVDs, which leads to heterogeneity in the effectiveness of the training and feedback at the return visit.For example, in patients with tetralogy of Fallot, congenital ventricular septal defects lead to conditions such as pulmonary stenosis, overriding aorta, and right ventricular hypertrophy; thus, limiting the promotion of CRF by HIIT 60 .Tolerance and adaptation to exercise are also important factors, and heart transplant recipients may require longer cycles of CR to gradually adapt to high intensity training 61 .In contrast, the longest exercise cycle for the group of patients in the present study was only 36 weeks, and thus, good temporal efficacy may not have been achieved.In patients with ischemic heart disease, insufficient blood supply to the coronary arteries is prevalent 62 , which may affect the degree of saturation of the exercise, resulting in failure to meet the established intensity requirements and exercise goals.In addition, HIIT may cause arrhythmias in patients with atrial fibrillation (AF) 63 .In such cases, for safety reasons, physicians and caregivers may adjust the intensity of the exercise program.The experiments involving patients with AF in the present study used PPO as an index of intensity 47 .Unlike absolute indexes, such as maximum heart rate or VO 2max , PPO is a relative index based on the patient's own maximal power output as a baseline, and hence, may contribute to the differences in exercise intensity and intervention effects.Finally, in terms of the results reported for exercise intervention characteristics, despite the high intensity and difficulty of HIIT, adherence to both types of exercise exceeded 70%, with a difference of no more than 5% 64 .Concurrently, the duration of HIIT was generally shorter than that of MICT; therefore, HIIT improves the efficiency of CR.
MH is an important clinical assessment and includes the evaluation of many psychological factors.Among them, depression and anxiety are important indicators that often appear in self-assessment entries during the return visit of patients with clinical diseases 65,66 .Both diseases are closely related to patients' QOL and social adjustment 67 .The presence of anxiety and depression can lead to psychological distress, dysfunction, and social problems, and in severe cases, can lead to heart disease, immune deficiency, and other physical health problems 68 .For patients with CVDs, a study conducted over a 10-year period found that the development of CVDs is strongly associated with poor mood.The prevalence of depression was 9.2% and 4.9% in patients with CAD and hypertension, respectively, while the prevalence of anxiety was 45.8% and 47.2% for patients with CAD and hypertension, respectively.Before percutaneous coronary intervention, anxiety was present in 70% of patients and definite depression in 38% 69 .Therefore, MH is particularly important in CR, and a favorable psychological state will have a positive effect on the individual's efficiency in recovering from the disease, social adaptability, and psychological resilience.In recent years, MH disorders, including depression and anxiety, have been increasingly used as assessment indicators in the return visit of patients during rehabilitation.MH can be assessed primarily on the basis of scales such as the Beck Depression Inventory and Hospital Anxiety and Depression Scale 30,37 .Through the observation of the two, physicians and nursing staff can more intuitively understand the changes in the patients' psychological state and negative emotions during CR, which is of certain significance for the development and adjustment of nursing care.
Currently, medication is the main method of intervention for depression and anxiety; however, adverse effects and addiction may lead to poor efficacy and affect the QOL of patients 70 .In recent years, with the increasing integration of physical medicine, exercise has been used as an MH intervention in selected clinical trials.There is evidence that elevated exercise intensity induces higher levels of MH improvement, e.g.HIIT may be superior to MICT in reducing depression and anxiety levels 27,71,72 .However, in this review, no significant differences were observed between the effects of HIIT and MICT on anxiety and depression among patients with CVDs.Therefore, the second hypothesis of this study cannot be accepted based on the current results.Notably, the sensitivity analyses of depression outcomes showed that depression data were unstable, which may be explained by the large heterogeneity between studies 27 .Nonetheless, the present study speculates that this result may still be due to differences in the duration and intensity of the intervention period.
In addition, the results of the QOL sub-indicator showed that HIIT improved SF better than did MICT.The present study suggests that this may be due to the different psychological mechanisms of the two exercise types in affecting SF.Some studies have found that high-intensity exercise is superior to other exercises in improving physical form, self-esteem, self-confidence, and positive mood 73 and that acute HIIT may lead to greater exercise achievement and self-satisfaction 74 .Therefore, the present study suggests that appropriate exercise can improve MH, and HIIT may be more beneficial for enhancing social well-being, such as restoring confidence and returning to work, in patients with late CR.
Due to the unique physical condition of patients with CVDs, it is particularly important to prescribe the correct intensity and monitor the load of their physical exercise, considering the risk factors of inappropriate activity.By this means, a positive effect of recovery can be achieved only through reasonable exercise on the basis of avoiding the exacerbation of the patients' condition 32 .Among the studies included in this paper, in addition to QOL as an outcome index, body mass index, heart rate, VO 2max , 6 min walking performance, and exercise tolerance were among the additional variables measured to examine the effect of difference exercise regimens on patients.
In recent years, studies have confirmed that moderate HIIT can improve cardiopulmonary function and QOL in patients with CAD or HF.However, due to the alternating high-and low-intensity nature of the program, it is risky as a primary rehabilitation program for patients with myocardial infarction, tetralogy of Fallot, AF, and heart transplant recipients 28,30 .Therefore, this paper suggests that MICT performed with a constant load as the dominant training program, interspersed with HIIT, may have a positive impact on patients' alleviation of negative emotions, restoration of exercise capacity, and promotion of overload recovery.Real-time monitoring of patients' physiological load throughout training, for instance using cardio-pulmonary exercise testing, is beneficial for not only assessing the patient's risk of cardiac emergencies, but also allowing the development of an individualized cardiac rehabilitation treatment strategy 29 .In addition, it is possible to record real-time heart rate, target heart rate, heart rate variability (HRV), blood glucose and lactate concentrations, VO 2max , rating of perceived exertion, basal metabolic rate, and metabolic index, among other parameters, during exercise to give patients the best exercise experience with minimal invasiveness.This not only ensures activity and training quality, but also reduces cardiac burden and injury risk and prevents exacerbation and recurrence of the disease.
Limitations and suggestions for future research.This study was conducted in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement, but there are still some limitations: (i) there are some differences in intensity, duration, and frequency of intervention among studies, which produced large heterogeneity.Moreover, after sensitivity analysis and subgroup analysis, heterogeneity of some outcomes was not eliminated; (ii) some studies included small sample sizes, which may have influenced the results.
We recommend that future research should focus on expanding the following areas.First, questions regarding the extent to which internal control, exercise format, and sex differences influence the effects of HIIT need to be further explored.Nevertheless, due to a paucity of relevant literature and limited number of studies included in the present analysis, more high-quality studies need to be conducted to subsequently validate them.Second, the results of this study show that HIIT and MICT have similar effects on the improvement of QOL and MCS total scores in patients with CVDs, but HIIT has a significant advantage on the improvement of PCS total scores in patients with CAD.HIIT has a low time burden and high enjoyment levels.These factors improve compliance with HIIT, making it an effective alternative to MICT.It is recommended that HIIT be promoted as a form of exercise in the rehabilitation of patients with CAD.In this way, more rehabilitation options are available to patients with CVDs.Third, studies have shown that exercise preference and level of enjoyment affect exercise adherence 75 .Exercisers can choose exercise based on their personal preferences to improve exercise adherence.HIIT has similar beneficial effects on QOL and MH compared to MICT, which helps exercisers choose exercise patterns based on their preferences.HIIT has similar or higher levels of enjoyment and adherence than MICT 76 .Also, HIIT has a shorter workout duration than MICT 28 .Lack of time is one of the most common reasons for not exercising.Therefore, exercise forms with the least time investment and the same exercise effect may be an effective way to improve exercise adherence in the population 77,78 .Studies have shown that reducing the time needed to achieve health improvements can help increase adherence rates 79,80 .In this review, the efficacy of HIIT was superior to MICT.In addition, the vast majority of the 25 papers included in this study were found to include warm-up and cool-down periods in their exercise programs, indicating the importance of pre-exercise and post-exercise preparation.Fourth, the results of this study differ from the findings of Gomes et al. and Xiong et al. 81,82 , which may be due to differences in the pathological characteristics of patients with CVDs included in the present study.Future research should be targeted to a particular patient population, and the best exercise modality should be selected based on the pathological characteristics of the patient.Thus, it is recommended that future studies should refine the study population to obtain more precise outcomes.

Conclusions
Three conclusions can be derived from this work: (1) The effects of HIIT and MICT on QOL were similar in patients with CVDs, but the physiologic health-promoting effects of HIIT were more pronounced in patients with CAD; (2) HIIT is more conducive to alleviating functional limitations based on physical problems, restoring self-perceived energy, and improving social adaptability; and (3) HIIT and MICT have similar moderating effects on MH, but HIIT increases the efficiency of exercise.Therefore, this study concluded that HIIT is highly valuable and should be promoted in the treatment and rehabilitation phase of patients with CVDs.

Methods
This systematic review was registered at PROSPERO (CRD42022313051), followed the Cochrane guidelines, and complied with the PRISMA checklist 48,49 .
Data sources and search strategy.Study selection.Based on the PICOS, the relevant studies were selected (Table 4).The inclusion criteria were randomized controlled trials (RCTs); literature written in English or Chinese and published in academic journals; studies involving patients with all currently known types of CVDs; comparison between HIIT and MICT exercise interventions; the form of exercise must be consistent with the characteristics of HIIT and MICT; the results were discussed based on QOL and MH, including depression and anxiety, of patients with CVDs.Literature with combined exercise or did not group exercise was excluded.The outcome indicators were QOL and MH, including depression and anxiety, based on subjective scales.

Data extraction.
According to the screening criteria, two researchers independently read the title and abstract of the retrieved literature.Then, the full texts of studies that met the primary screening criteria were screened and the relevant literature was obtained.Disagreements regarding the literature selection were resolved through discussions among the researchers.Literature screening was performed using Endnote X9 software by two independent investigators; first, with a round of screening based on title and abstract, and second, by downloading the full text of the literature to  Grading of Recommendations and Assessment Development and Evaluation (GRADE) was used to evaluate the quality of evidence with a web-based version (https:// grade pro.org).In this study, based on the GRADE criteria for grading the quality of evidence, the criteria for assessing and downgrading the quality of literature were categorized into five items: risk of bias, inconsistency, indirectness, imprecision, and other considerations, according to which the risk level was evaluated 84 .Any differences in the quality assessment were resolved through discussions among researchers, and if consensus could not be reached, senior researchers were consulted.
Data analysis.Meta-analyses were performed using Stata 17.0 software.All data extracted in this study were continuous variables.If the evaluation measures of outcome indicators were the same, the weighted mean difference (WMD) was used for effect size comparison; if the evaluation measures of outcome indicators were different, the standardized mean difference (SMD) was used for effect size comparison.The calculation of WMD/SMD and the analysis of the results in this study were performed using the methodology described by Khan and Schober 85,86 .If a trial included multiple exercise interventions and a shared control group, we combined the interventions according to the appropriate formula in the Cochrane Systematic Review of Interventions Manual 48 .The I 2 test was used to assess heterogeneity, with an I 2 of 25-50% classified as low heterogeneity, 50-75% as moderate heterogeneity, and > 75% as severe heterogeneity 87 .The FE model was used when I 2 ≤ 50% and the RE model was used when I 2 > 50%.The results of the meta-analysis were presented in the form of forest maps.Literature publication bias was assessed using funnel plots and the Egger's test 88 .A sensitivity analysis was performed by using the one-by-one elimination method.

Figure 1 .
Figure 1.Flow diagram of the evaluation process.

Figure 4 .Figure 5 .
Figure 4.The results of meta-analyses of the effect of physical component summary.The results of HIIT and MICT are shown as: mean, standard deviation (sample size).

Figure 6 .
Figure 6.The results of meta-analyses of the effect of depression.The results of HIIT and MICT are shown as: mean, standard deviation (sample size).

Figure 7 .
Figure 7.The results of meta-analyses of the effect of anxiety.The results of HIIT and MICT are shown as: mean, standard deviation (sample size).

Figure 8 .
Figure 8.The results of meta-analyses of the effect of eight sub-dimensions in QOL.The results of HIIT and MICT are shown as: mean, standard deviation (sample size).

Figure 9 .
Figure 9.The results of sensitivity analyses.

Table 1 .
Characteristics of studies.

Table 2 .
Exercise intervention characteristics.UN unclear, NO no mention, RPE rating of perceived exertion, HRmax maximal heart rate, VO2max maximal oxygen consumption, VT ventilatory threshold, PPO peak power output, MLHF Minnesota living with heart failure questionnaire, SF-36 the MOS 36-item shortform health survey, SF-12 the MOS 12-item short-form health survey, MacNew the MacNew heart disease health related quality of life instrument, KCCQ the Kansas city cardiomyopathy questionnaire, DS14 type D personality scale-14, GMS geriatric mental status scale, QLMI the quality of life after myocardial infarction questionnaire, EQ-5D the EuroQOL instrument, HADS hospital anxiety and depression scale, BDI back depression inventory.
Eight databases were searched including Web of Science (Science and Social Science Citation Index), MEDLINE(R)ALL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, China National Knowledge Infrastructure, Wanfang Database, and China Science and Technology Journal Database.Using PubMed as an example, see Box 1 for details of the search terms.The search was conducted from the database establishment to July 2023.The relevant information was sought through the included references, and unpublished academic literature was not searched.