High-intensity interval training is effective and superior to moderate continuous training in patients with heart failure with preserved ejection fraction: A randomized clinical trial

Background

Heart failure with preserved ejection fraction (HFpEF) is a prevalent syndrome, with exercise intolerance being one of its hallmarks, contributing to worse quality of life and mortality. High-intensity interval training is an emerging training option, but its efficacy in HFpEF patients is still unknown.

Design

Single-blinded randomized clinical trial.

Methods

Single-blinded randomized clinical trial with exercise training 3 days per week for 12 weeks. HFpEF patients were randomly assigned to high-intensity interval training or moderate continuous training. At baseline and after 12 week follow-up, patients underwent clinical assessment, echocardiography and cardiopulmonary exercise testing (CPET).

Results

Mean age was 60 ± 9 years and 63% were women. Both groups (N = 19) showed improved peak oxygen consumption (VO₂), but high-intensity interval training patients (n = 10) had a significantly higher increase, of 22%, compared with 11% in the moderate continuous training (n = 9) individuals (3.5 (3.1 to 4.0) vs. 1.9 (1.2 to 2.5) mL·kg⁻¹·min⁻¹, p < 0.001). Ventilatory efficiency and other CPET measures, as well as quality of life score, increased equally in the two groups. Left ventricular diastolic function also improved with training, reflected by a significant reduction in E/e′ ratio by echocardiography (−2.6 (−4.3 to −1.0) vs. −2.2 (−3.6 to −0.9) for high-intensity interval training and moderate continuous training, respectively; p < 0.01). There were no exercise-related adverse events.

Conclusions

This randomized clinical trial provided evidence that high-intensity interval training is a potential exercise modality for HFpEF patients, being more effective than moderate continuous training in improving peak VO₂. However, the two strategies were equally effective in improving ventilatory efficiency and other CPET parameters, quality of life score and diastolic function after 3 months of training.

Exercise training, heart failure, peak oxygen uptake

Introduction

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome accounting for 40–55% of all heart failure cases, being more frequent among women and hypertensive, obese and elderly individuals.¹ Prognosis is almost comparable to heart failure with reduced ejection fraction (HFrEF) in accordance with observational data^1,2 and slightly better in retrospective analysis of randomized clinical trials (RCTs).³ Despite its increasing incidence, mortality rate has remained relatively high, without any proven therapy to reduce major outcomes.⁴ Most patients exhibit several pathophysiological abnormalities, including cardiac (diastolic dysfunction, reduced cardiac output reserve, atrial fibrillation and coronary artery disease) and non-cardiac aspects (reduced vasodilation, arterial stiffness, ventilatory dysfunction, skeletal myopathy and renal dysfunction).⁵

HFpEF patients are characterized by marked exercise intolerance, dyspnea and reduced quality of life (QoL), which are comparable to the findings for HFrEF patients, when taking into account variables measured by cardiopulmonary exercise testing (CPET).⁶ To date, standard pharmacological therapy has failed to show a substantial benefit in HFpEF treatment.^4,5,7 Among other potential therapies, aerobic exercise has demonstrated a consistent benefit in RCTs.⁸⁻¹¹ Published meta-analyses point towards the significant benefit of exercise training in improving peak oxygen consumption (peak VO₂) and QoL, although rates are modest.^12,13 Even if it was not consistent through major RCTs, improvement in diastolic function, reflected by a reduction in E/e′ was achieved with training, being one of the mechanisms involved in exercise capacity enhancement.^11,14,15 Most of these studies consisted of aerobic training interventions, with moderate continuous training (MCT) as the standard exercise modality.¹²

High-intensity interval training (HIIT) is a modality where intervals of 1−4 min of greater intensity, at a high submaximal load, are performed alternately with low- to moderate-intensity intervals. Data from RCTs and meta-analyses are conflicting, with smaller studies showing benefit of HIIT to peak VO₂ improvement and a possible superior effect in HFrEF patients.^16,,–19 However, two large multicenter studies found that both modalities equally improved aerobic exercise capacity.^20,21 A cornerstone trial including patients with prior myocardial infarction and left ventricle (LV) systolic dysfunction showed markedly superior effects on peak VO₂ and LV remodeling with HIIT compared with MCT.¹⁷ Current evidence also suggests that HIIT may increase peak VO₂ and reduce cardiometabolic risk factors, including blood pressure and lipid levels.

Regarding the effect of HIIT on HFpEF, there are scarce data on the benefit and safety of this training modality in exercise limitation. Therefore, the purpose of this trial was to test the hypothesis that HIIT is effective and possibly superior to MCT in improving functional capacity in HFpEF patients.

Methods

Study design

A single-blinded, parallel RCT was conducted between July 2014 and January 2017 in a tertiary university hospital in southern Brazil. The study was approved by the local ethics committee, and all participants signed an informed consent form prior to participation. Patients were randomly assigned to HIIT or MCT training three times per week for 3 months. At baseline and after 12 weeks of follow-up, patients underwent a physical examination, Doppler echocardiography, CPET and blood sampling and responded to a QoL questionnaire. Primary outcome was peak VO₂ measured by CPET, and secondary endpoints were QoL score, echocardiographic data and natriuretic peptide level. Baseline and outcome measurements and all training sessions as well were performed at Hospital de Clínicas de Porto Alegre, Brazil. Patients’ flow diagram describing inclusion, allocation, and follow-up was in accordance with CONSORT (Consolidated Standards for Reporting of Trials)²² and is provided in Figure 1.

Figure 1.

Flow diagram of the study.

MCT: moderate continuous training; HIIT: high-intensity interval training

Patients

Subjects were recruited from a review of hospital and outpatient clinic records for potential patients. First, a telephone interview was conducted to check availability and interest in participating. Later, a personal evaluation and echocardiogram were performed to verify fulfillment of inclusion and absence of exclusion criteria. All patients with signs and symptoms of heart failure, functional class II or III of the New York Heart Association (NYHA), LV ejection fraction >50% and evidence of diastolic dysfunction with E/e′ above 15 were considered eligible. For those with E/e′ between 8 and 15 and elevation of type B natriuretic peptide (BNP or NT-proBNP) or other diastolic criteria as proposed previously by Heart Failure and Echocardiography Associations of the European Society of Cardiology were considered.²³ All subjects needed to be clinically stable for at least 3 months under optimal pharmacological therapy and capable of walking without limitations.

Exclusion criteria were the presence of unstable ventricular arrhythmias, unstable or severe angina, moderate to severe valvular heart disease, anemia and cognitive limitations in understanding the study’s protocol. Presence of pacemaker, autonomic neuropathy, cardiomyopathy, moderate to severe pulmonary disease, recent acute cardiovascular event (less than 3 months), congenital heart disease, symptomatic peripheral arterial disease or severe musculoskeletal diseases limiting exercise were also considered exclusion criteria.

Exercise training

Exercise training was performed on a treadmill (Inbramed KT 10200, Inbramed, Porto Alegre, Brazil), supervised by a physical education professional, three times per week for 12 consecutive weeks. Borg rating of perceived exertion (RPE) was assessed periodically and heart rate (HR) was continuously monitored by a portable monitor (Polar Fitness FS1, Kempele, Finland). Both were recorded on a form for each training session, every 5 min for MCT and every interval for the HIIT group. Intensity was regulated during sessions to maintain HR under a prescribed percentage, with an exception for patients with atrial fibrillation, in whom RPE was used for this purpose. Treadmill speeds and incline were adjusted every two week or prior if RPE and HR were consistently below the prescribed threshold. HIIT sessions consisted of a warm-up of 10 min at moderate intensity, four intervals of 4 min at high intensity, alternating with three intervals, and a 3-min cool down phase at moderate intensity, totaling 38 min. Moderate intensity was considered 50–60% of peak VO₂ and 60–70% of peak HR, corresponding to 11–13 on the Borg RPE scale. High intensity intervals were performed at 80–90% of peak VO₂ and 85–95% of peak HR, aiming at a RPE of 15–17. The MCT group trained for 47 min at moderate intensity to match the total relative work of both protocols. All patients trained on an individual time schedule on the same treadmill.

CPET

CPET was performed on a treadmill (General Electric T-2100, GE Healthcare, USA) with breath-by-breath gas analysis (Metalyzer 3B, Cortex, Leipzig, Germany). Tests were always performed by the same cardiologist blinded to allocation and, to assess reliability, another blinded investigator confirmed all main CPET measurements. Symptom-limited maximal exercise testing with an individualized ramp protocol was used to yield fatigue-limited exercise duration of 8 to 12 min. Peak VO₂ was determined by the higher measure of 20-s averaging of breath-by-breath values. Other prognostic variables were also measured, such as first and second ventilatory thresholds, which were defined by V-slope for first ventilatory threshold and ventilatory equivalent method to confirm first and determine second ventilatory threshold, minute ventilation–carbon dioxide output relationship (VE/VCO₂ slope), oxygen uptake efficiency slope (OUES) and resting end-tidal carbon dioxide tension. Maximal effort was considered when respiratory exchange ratio (RER) was equal to or above 1.05.

Secondary endpoints

All echocardiographic examinations were performed using the same equipment (Envisor C HD or HD 11, Philips, USA) by a trained cardiologist blinded to interventions and treatment allocation. Images were acquired following a standardized protocol, according to recommendations present in current guidelines. LV diastolic function was evaluated with transmitral pulsed Doppler (peak E velocity, peak A velocity, E/A ratio and deceleration time) and mitral annulus tissue Doppler velocity (early diastolic velocity – e′, calculated as the average of lateral and septal measurements). To avoid mis-measurement, blood samples were not collected at same day of the CPET. NT-proBNP analyses were performed in a Cobas 8000 modular analyzer series (Roche Diagnostics, USA). The Minnesota Living with Heart Failure questionnaire (MLHF) was used to assess the impact of the interventions on QoL.²⁴

Statistical analysis

Randomization was performed with a computer-generated sequence of random permuted blocks placed in sealed opaque envelopes. All outcome evaluators were blinded to group allocation. This study was powered primarily to demonstrate a significant improvement of peak VO₂ in the HIIT group with type I and II error levels equal to 0.05 and 0.20, respectively. We calculated the sample size for the primary outcome using estimates of effect sizes from Wisløff et al.¹⁷ To detect a difference of 1.5 mL·kg⁻¹·min⁻¹ in peak VO₂ between two group means, considering a dropout rate of 25%, we estimated 18 patients (nine in each group).

Continuous variables with normal distribution are presented as mean ± standard deviation or mean ± standard error of mean (SEM) as mentioned in the figure and table legends. Those without normal distribution were presented as median and interquartile range. As the NT-proBNP values were exponentially distributed, log-transformation was performed for the analysis of within-group changes and the between-group effect of intervention. Fisher’s exact test was utilized to compare categorical variables at baseline, as well as independent samples t-test or Mann–Whitney test for continuous variables. Generalized estimating equations²⁵ were used to compare main outcome measurements, using an exchangeable working correlation matrix and robust covariance matrix estimation. Group and time were considered for main and interaction effects. Adjustment for multiple comparisons with the post-hoc Bonferroni test was also performed. Pearson correlation and multivariate linear regression were used to assess determinants of peak VO₂ improvement. Collected data were analyzed using the Statistical Package for Social Sciences (SPSS version 20.0). p < 0.05 was considered significant in all analyses.

Results

From possible patients screened through medical records reviews, subjects were interviewed and 40 consented to undergo personal evaluation and echocardiogram. Twenty-four individuals were enrolled, equally allocated to MCT or HIIT groups, and 19 patients were fully analyzed. Mean age was 60 ± 9 years in both groups, and the patients included 63% women and 74% obese (body mass index (BMI) > 30). Five losses occurred before follow-up, three patients due to non-cardiovascular problems and two due to withdrawal of consent because of personal reasons (Figure 1). Groups were well matched, without significant differences at baseline (Table 1). Most HFpEF subjects were at NYHA II functional class and every patient was diagnosed with hypertension at baseline. In general, the use of medication was similar, without any significant changes during the trial. All patients in the HFpEF group were using angiotensin-converting enzyme inhibitors/aldosterone receptor antagonists, beta-blockers and diuretics. At follow-up, BMI showed a small but significant decrease in both groups when analyzed together, but not individually (33.9 ± 1.3 to 33.5 ± 1.3, mean ± SEM, p = 0.036).

Table 1.

Subjects characteristics and medication use at baseline.

	MCT N = 9	HIIT N = 10	p value
Female	5 (56)	7 (70)	0.65
Age, years	60 ± 9	60 ± 10	0.59
Weight, kg	87 ± 19	86 ± 17	0.63
Height, cm	165 ± 8	162 ± 7	0.38
Body mass index, kg/m2	34 ± 6	33 ± 5	0.46
NYHA functional class			0.78
II	8 (89)	8 (80)
III	1 (11)	2 (20)
EF, %	65 ± 5	65 ± 5	0.62
VO2, mL·kg−1·min−1	17.6 ± 3.5	16.1 ± 3.3	0.37
NT-proBNP	178 (77−399)	403 (53−929)	0.37
Comorbidities
Hypertension	9 (100)	10 (100)	–a
Diabetes	5 (55)	6 (60)	1.0
Dyslipidemia	6 (66)	5 (50)	0.65
CKD	1 (10)	2 (20)	1.0
Atrial fibrillation	1 (11)	1 (10)	0.74
CAD	3 (33)	2 (20)	0.63
PCI	1 (11)	2 (20)	1.0
CABG	2 (22)	0 (0)	0.21
History of smoking	3 (33)	6 (60)	0.37
Medications
ACEIs/ARAs	9 (100)	10 (100)	–a
Beta blockers	7 (78)	10 (100)	0.21
Diuretics	8 (89)	10 (100)	1.0
Thiazide	6 (67)	5 (50)	0.65
Loop	5 (55)	7 (70)	0.65
Aldosterone blockers	3 (33)	3 (30)	1.0
Ca++ channel blockers	7 (78)	6 (60)	0.63
Statins	7 (78)	8 (80)	1.0
Antiplatelets	6 (67)	7 (70)	1.0

Data are expressed by mean ± SD, median (interquartile range) or number (%) of patients.

a

Not calculated because is present in all patients.

ACEI: angiotensin-converting enzyme inhibitor; ARA: aldosterone receptor antagonist; CABG: coronary artery bypass graft surgery; CAD: coronary artery disease; CKD: chronic kidney disease; EF: ejection fraction; HIIT: high-intensity interval training; MCT: moderate continuous training; NT-proBNP: amino-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; PCI: percutaneous coronary intervention; VO₂: oxygen consumption.

Exercise capacity

Peak VO₂ increased significantly in both groups over time, being higher in HIIT compared with MCT (22.7 vs. 11.3%, respectively, p < 0.001). Peak oxygen pulse, an estimate of stroke volume, also showed a between-group difference favoring HIIT. Peak RER was not different between groups, showing comparable effort. Ventilatory efficiency has increased after exercise training, as seen by a significant decrease in VE/VCO₂ slope and an improvement in OUES and maximal ventilation (VE) with both training modalities. Other CPET results are displayed in Table 2. First ventilatory threshold (anaerobic threshold) increased similarly in both groups (12.1 ± 0.6 to 13.4 ± 0.7 and 11.5 ± 0.8 to 12.6 ± 0.8 mL·kg⁻¹·min⁻¹, for MCT and HIIT, respectively, p < 0.001 for time comparison), whereas second ventilatory threshold (respiratory compensation point) had a greater improvement with HIIT, depicting an extension of the isocapnic buffering period (16.6 ± 1 to 17.8 ± 0.9 and 15.3 ± 1 to 18.0 ± 1 mL·kg⁻¹·min⁻¹, for MCT and HIIT, respectively, p < 0.001 for group–time interaction).

Table 2.

Cardiopulmonary exercise testing data at baseline and post training compared by group.

	MCT			HIIT
	Baseline	Follow-up	Δ	Baseline	12 weeks	Δ
Peak exercise
VO2, mL·kg−1·min−1	17.6 ± 3.5	19.5 ± 3.7	1.9 (1.2 to 2.5)*	16.1 ± 3.3	19.6 ± 3.5	3.5 (3.1 to 4.0)*†
VO2, L·min−1	1.69 ± 0.6	1.83 ± 0.5	0.14 (0.1 to 0.2)*	1.37 ± 0.3	1.66 ± 0.4	0.29 (0.2 to 0.3)*†
O2 pulse, mL/beat	12.4 ± 3.1	13.2 ± 3.0	0.8 (−0.1 to 1.6)	11.6 ± 3.5	13.6 ± 3.8	2.0 (1.2 to 2.8)‡
HR, beats/min	136 ± 24	140 ± 28	5 (−4 to 12)	122 ± 20	127 ± 23	5 (−3 to 12)
BP, mmHg	169 ± 34	172 ± 28	4 (−2 to 10)	173 ± 30	170 ± 41	3 (−21 to 16)
VE, L·min–1	66.3 ± 22	69.6 ± 18	3.3 (−3 to 9)§	60.1 ± 21	65.1 ± 23	5 (0.2 to 10)§
RER	1.17 ± 0.12	1.15 ± 0.07	−0.2 (−0.1 to 0.1)	1.15 ± 0.08	1.12 ± 0.07	−0.3 (−0.1 to 0.3)
Rest
PetCO2, mmHg	34.6 ± 2.8	34.4 ± 3.6	−0.2 (−1.5 to 1.8)	31.3 ± 4.8	32.6 ± 4.1	1.3 (−0.4 to 2.9)
Recovery
HRR 1 min, beats/min	20 ± 9	18 ± 7	−2 (−5 to 4)	16 ± 9	15 ± 11	−1 (−7 to 3)
T½, s	123 ± 17	111 ± 27	−12 (−5 to 30)	119 ± 28	112 ± 28	−7 (−6 to 18)
Slopes
VE/VCO2 slope	36.8 ± 5.4	34.6 ± 5.1	−2.2 (−3.8 to 0.6)*	39.4 ± 6.1	35.7 ± 4.7	−3.7 (−6 to −1.4)*
OUES	1.52 ± 0.8	1.82 ± 0.7	0.3 (0.1 to 0.4)*	1.34 ± 0.4	1.48 ± 0.3	0.14 (−1 to 0.3)*

Δ 

= difference between follow-up and baseline. Data are mean ± SD or mean (95% confidence interval).

*

p < 0.001 for time comparisons

§

p < 0.05 for time comparisons

†

p < 0.001 for group–time interaction

‡

p < 0.05 for group–time interaction

BP: blood pressure; HIIT: high-intensity interval training; HR: heart rate; HRR: heart rate recovery; MCT: moderate continuous training; O₂ pulse: oxygen pulse; OUES: oxygen uptake efficiency slope; PetCO₂: expiratory end-tidal pressure of CO₂; RER: respiratory exchange rate; T½: time to VO₂ 50% reduction; VE: expiratory volume; VE/VCO₂ slope: carbon dioxide equivalent slope; VO₂: oxygen consumption.

Exercise training

There were no serious adverse events related to training. All patients performed at least 85% of total training sessions. From a total of 36 possible sessions, mean attendance was 34.9 ± 1 (97%) and 34.1 ± 1 (95%) sessions for HIIT and MCT, respectively. Mean prescribed treadmill velocities increased significantly in both groups during the three training months (4.5 ± 1 to 5.2 ± 1 km/h for HIIT intervals and 3.5 ± 0.4 to 4.2 ± 0.5 km/h for MCT, p < 0.01 for both within-group comparisons). Incline was also adjusted in both groups, being significantly higher only in the HIIT group (4.4% to 5.3%, p < 0.01), without difference in MCT (1.8% to 2.0%, p = NS).

To ascertain execution under prescribed training intensities, HR was continuously measured and Borg’s RPE was periodically assessed for each training session. Relative training intensity was analyzed using peak HR percentage (Figure 2), and the data are displayed in a similar fashion as in a recent RCT by Ellingsen et al.²⁰ Relative training intensity was under the prescribed thresholds for both groups during the whole training program, as seen in Figure 2, and was 21% higher in the HIIT group (88% ± 4% vs. 67% ± 4%, p < 0.001). Regarding estimated training intensity distribution, 87% of HIIT sessions and 83% of MCT sessions were performed under the prescribed area (Figure 2(c)). Only 2% of total exercise training sessions in MCT and 8% in HIIT were below prescribed target, whereas 15% and 5% were above threshold for MCT and HIIT, respectively.

Figure 2.

Training intensity during the 12-week intervention.

(a) Heart rate during training. Average heart rate during the 12-week intervention, estimated as weekly mean (SD) during continuous training (MCT) and during the last 2 min of intervals (HIIT). (b) Training intensity. Average relative training intensity (percentage of maximal heart rate). (c) Training intensity on target. Distribution of average training intensity during the 12-week intervention; MCT (left histogram), HIIT (right histogram).

MCT: moderate continuous training; HIIT: high-intensity interval training

Secondary outcomes

Echocardiographic resting diameters, ejection fraction, indexed volumes and LV mass were not significantly different pre- and post-exercise training and between groups (Table 3). E/e′ ratio decreased significantly at follow-up in both groups (Table 3). NT-proBNP baseline values were above 125 pg/mL in 17 patients (89%) and were exponentially distributed. Log-transformed values decreased over time in both groups (5.1 ± 1.1 to 4.8 ± 1.1 for MCT and 5.7 ± 1.7 to 5.5 ± 1.7 for HIIT, p = 0.046 for time comparison). QoL improved after training in both groups, without difference regarding training modality, as seen by total MLHF score (38 ± 16 to 24 ± 13 for MCT, 32 ± 15 to 18 ± 12 for HIIT, p < 0.001 for time comparison).

Table 3.

Echocardiography data at baseline and post training compared by group.

	MCT		HIIT
	Baseline	Follow-up	Baseline	Follow-up
LAD, mm	46 ± 5	46 ± 5	46 ± 5	46 ± 2
LAVI, mL/m2	42 ± 8	42 ± 9	47 ± 10	46 ± 12
LVESD, mm	33 ± 5	34 ± 5	32 ± 2	32 ± 1
LVESVI, mL/m2	22 ± 6	24 ± 8	22 ± 4	24 ± 3
LVEDD, mm	52 ± 5	53 ± 5	50 ± 2	50 ± 2
LVEDVI, mL/m2	64 ± 12	64 ± 13	62 ± 5	62 ± 8
LVSVI, mL	42 ± 9	42 ± 14	41 ± 7	41 ± 8
LVMI, g/m2	105 ± 18	106 ± 16	118 ± 24	112 ± 26
IVST, mm	11 ± 2	11 ± 2	12 ± 1	11 ± 1
PWT, mm	11 ± 2	10 ± 2	11 ± 2	11 ± 1
EF, %	65 ± 5	65 ± 5	65 ± 5	66 ± 4
A wave, cm/s	86.1 ± 6	84.8 ± 10	87.9 ± 5	79.5 ± 3
E wave, cm/s	88.0 ± 5	83.8 ± 7	84.8 ± 6	72.5 ± 6
e′ wave, cm/s	7.0 ± 0.8	7.7 ± 0.7	6.2 ± 0.4	6.7 ± 0.7
E/e′	13.3 ± 3	11.1 ± 2*	14.2 ± 4	11.6 ± 3*
E/A ratio	1.05 ± 0.3	1.08 ± 0.3	0.99 ± 0.2	0.91 ± 0.2
DT, ms	214 ± 33	209 ± 37	233 ± 33	222 ± 27

*

p = < 0.001 for time comparison

DT: deceleration time; E/A: early diastolic peak velocity and late diastolic peak velocity ratio; E/e′: early diastolic peak velocity and diastolic peak velocities of the mitral annulus ratio; EF: ejection fraction; HIIT: high-intensity interval training; IVST: interventricular septum thickness; LAD: left atrium diameter; LAVI: left atrium volume index; LVEDD: left ventricle end diastolic diameter; LVEDVI: left ventricle end diastolic volume index; LVESD: left ventricle end systolic diameter; LVESVI: left ventricle end systolic volume index; LVMI: left ventricle mass index; LVSVI: left ventricle stroke volume index; MCT: moderate continuous training; PWT: posterior wall thickness.

Multivariate analysis and determinants of peak VO₂ improvement

A multivariate model was created to adjust main outcome effects for age, BMI and gender. All primary and secondary outcome differences remained statistically significant after adjustment (Table 4). The increase in absolute peak VO₂ was inversely correlated with reduction in E/e′ ratio (r = –0.475, p = 0.04). Multiple linear regression defined training group and E/e′ reduction as major determinants of exercise capacity improvement.

Table 4.

Main exercise testing outcomes and secondary outcomes differences after multivariate analysis.

	MCT	HIIT
	Δ	Δ
Peak exercise
VO2, mL·kg−1·min−1	1.9 (1.1 to 2.6)*	3.5 (3.0 to 4.0)*†
VO2 , L·min−1	0.16 (0.1 to 0.2)*	0.31 (0.2 to 0.4)*†
O2 pulse, mL/beat	0.9 (0.1 to 1.8)*	2.3 (1.2 to 3.4)*†
Secondary outcomes
MLHF score	−13 (−23 to −4)*	−14 (−19 to 19)*
E/e′	−2.2 (−3.6 to −0.9)*	−2.7 (−4.3 to −1.0)*

 

Model adjusted for age, body mass index, sex.Δ= difference between follow-up and baseline. Values are mean (95% confidence interval).

*

p < 0.01 for time comparisons

†

p < 0.001 for time−group interaction

E/e′: early diastolic peak velocity and diastolic peak velocities of the mitral annulus ratio; HIIT: high-intensity interval training; MCT: moderate continuous training; MLHF: Minnesota Living with Heart Failure; O₂ pulse: oxygen pulse; VO₂: oxygen consumption.

The equation ‘Δ peak VO₂ (mL/min) = 99.7 + 138 × (0 for MCT and 1 for HIIT) – 20.7 × Δ E/e′ + error’ had a moderate-to-strong correlation coefficient (R = 0.761, p = 0.002) and explained almost 60% of total improvement in VO₂ (R²= 0.579).

Discussion

According to this efficacy study, HIIT was a potential and safe strategy for patients with HFpEF, where it was able to significantly increase functional capacity. All patients assigned to this form of training showed an increase in baseline peak VO₂ of at least 10%, and the average effect was approximately 1 MET (3.5 mL·kg⁻¹·min⁻¹) after 3 months. Interestingly, in a ‘head-to-head’ comparison, HIIT was clearly superior to MCT, an already studied training intervention^{8,10,11,26,27} for this outcome. On the other hand, the two exercise modalities showed a similar increase in ventilatory efficiency, diastolic function and QoL.

The absence of major benefits in primary outcomes using pharmacological therapy makes exercise a likely intervention for HFpEF patients.^4,5,7 Nevertheless, compared with HFrEF available information, limited RCT data are provided showing exercise training benefits in HFpEF. There is still controversy regarding exercise training and extent of improvement of functional capacity and LV diastolic function.¹⁰⁻¹² It is well accepted that aerobic training can improve functional capacity in most cardiovascular diseases, although the best modality (interval or continuous) and intensity (moderate or high) remains controversial. Although all the main studies on HFpEF have used a non-exercise control group, a comparison of different strategies has not been carried out. Available evidence indicates that HIIT modalities are efficacious and relatively safe, with low risk of injuries even in patients with hypertension or type 2 diabetes. It has been shown that HIIT is a safe exercise modality in patients with stable coronary artery disease,²¹ although it was not superior to MCT in changing LV remodeling or aerobic capacity, and its usefulness remains unresolved in patients with HFrEF.²⁰

Samples of the main exercise training trials on HFpEF are heterogeneous and vary widely in the inclusion criteria. For example, diastolic dysfunction or relevant structural abnormalities were not a prerequisite in several studies.^8,10,27 By using stricter criteria,²¹ we can account to a better external validity, avoiding the inclusion of patients with mild HFpEF. Compared with other studies of exercise training in HFpEF, our patients were five years younger on average, with similar gender distribution, disease severity and prevalence of comorbidities. Atrial fibrillation was an exclusion criterion for some studies^11,27 and showed very low prevalence in the total sample of other trials, as well as in the present study.^8,10

Some previous studies including patients with HFpEF showed that baseline peak VO₂ was slightly lower compared with our patient population.^10,26,27 However, by using a cycle ergometer for peak exercise measurements, we could expect a 10–15% underestimation compared with treadmill testing, suggesting similar peak VO₂ values. In our trial, peak VO₂ improvement in the MCT group was similar to that in a comparison of this training modality with a non-exercise control.¹² For the HIIT group, the increase in peak VO₂ was two times higher than in the MCT group (22.7% vs. 11.3%).The time course of positive adaptations in peak VO₂ can be relatively short after intervention, although the proportion of training-induced determinants (e.g. cardiac output and arteriovenous oxygen difference) of cardiorespiratory fitness (CRF) are likely to be dependent on age and disease status. The only comparison we could make in this regard was with a pilot study that compared the two training strategies, in which endothelial function was the primary outcome.²⁸ During the intervention, peak VO₂ augmentation was 1.8 mL·kg⁻¹·min⁻¹, which was half of the 3.5 mL·kg⁻¹·min⁻¹ increase found in our RCT under HIIT training. Unexpectedly, this cited study showed that MCT training did not improve CRF, perhaps due to the short training period (4 weeks).²⁸ Fu et al., in an RCT of 120 patients, showed that aerobic interval training significantly improved pumping function with enhanced peak cardiac power index in the HFrEF and improved diastolic function with reduction of the E/E′ ratio in the HFpEF group.²⁹

Recently, a European multicenter trial was published, showing no significant advantage of HIIT over MCT in HFrEF patients.²⁰ In this RCT more than half of the HIIT sessions were below prescribed intensity, whereas 80% of MCT sessions were above established limits. In our randomized study, we managed to control HR actively during the whole training period, to ascertain that exercise was at the prescribed intensity and to maximize the reliability of our comparisons. Possibly by setting the lower threshold for submaximal intervals at 85% of peak HR, instead of 90% as in most other trials, we could have made prescribed intensity easier to attain.

Ventilatory efficiency, measured by VE/VCO₂ slope during incremental CPET, has been classically described as a prognostic marker in HFrEF and HFpEF.³ Only two previous studies examined the impact of exercise training on ventilatory efficiency, where one found no improvement²⁷ and the other, significant reduction.²⁶ VE/VCO₂ slope levels improved significantly with exercise training, regardless of the modality used. To date, this is the first study to examine and demonstrate an improvement in OUES in patients with HFpEF, an established submaximal marker of cardiorespiratory capacity with a recognized prognostic value in HFrEF.

Changes in diastolic filling pressures are controversial among exercise studies with HFpEF patients.¹⁰⁻¹² Our trial showed similar results to those that observed improved diastolic parameters assessed by echocardiography, but without any significant structural change.^14,17 There was also a significant correlation between peak VO₂ improvement and E/e′ reduction, similar to the findings of Edelmann et al. in a previous multicenter study comparing aerobic exercise with usual care as a control group.¹¹ Hence, improvements in diastolic function may be one of the mechanisms involved in the CRF increase obtained with exercise training. Although this has not been extensively researched in human patients, several studies have examined the effect of HIIT on endothelial function, diaphragm function and skeletal muscle function in animals, suggesting that these may be the underlying mechanisms of improvement in peak oxygen uptake.³⁰ HIIT is known to improve both aerobic and anaerobic contributions to exercise, ultimately resulting in augmented aerobic capacity and tolerance to greater efforts. The isocapnic buffering period, the phase between anaerobic threshold and respiratory compensation point, showed significant increase only with HIIT, this being consonant with previous theoretical assumptions and studies enrolling healthy subjects.

A sample of 19 individuals may appear to be a potential limitation. However, the sample size calculation identified the need for ‘only’ nine subjects per group. In addition, this was an efficacy study, with strict inclusion criteria. Accordingly, this was a not a major limitation, where this study was well in line with previous HFpEF and exercise RCTs, which did not include many patients. Patient selection was very difficult; thus, it is safe to say that this is a highly selected population, limiting the generalizability of the findings. The relatively younger patient sample, compared with other HFpEF trials, could have had some influence on the results. In spite of this, disease severity and symptom burden in our heart failure patient sample was similar to that seen in previous studies. Although we performed blinded analyses of the outcome measures, the nature of intervention did not allow complete blinding. However, the main hypothesis, that HIIT is an effective way to improve CRF and LV diastolic function in HFpEF patients, was confirmed. Also, after 3 months, peak VO₂ increased significantly in the HIIT group compared with those allocated to the MCT. It is unlikely that many structural changes can be observed in cardiac echocardiography after 3 months of HIIT and MCT intervention, but we did show that diastolic function can improve during this period of time in patients with HFrEF. According to these findings, we showed that HIIT training modality should be considered a potential exercise strategy for HFpEF patients, even more widely if not regarded as the standard regimen, at least as an adjunct lifestyle therapy to traditional MCT intervention.

Finally, we believe that the results of our single-center study conducted in southern Brazil serve to increase the body of evidence in this area of knowledge. In this regard, we look forward to the results of the OptimEx-CLIN trial,³¹ the collaborative project from the European Union, which will provide even more robust information about the role of different exercise modalities in the HFpEF scenario.

Author contribution

ADS, RMN, JBL and RS contributed to the conception or design of the work. ADS, JBL, DSP, DLM and MZ contributed to the acquisition, analysis, or interpretation of data for the work. ADS, JBL, DSP, JAL and RS drafted the manuscript. MZ, RS, RMN and JAL critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Acknowledgement

Clinical Trial Registration URL: https://clinicaltrials.gov/, ClinicalTrials.gov identifier: NCT02916225.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by grants from Fundo de Incentivo à Pesquisa e Eventos (FIPE) of Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasília, Brazil, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasília, Brazil. JBL received a grant from CAPES, MZ received a grant from CNPq, and RS is an established CNPq investigator. This study was part of the doctoral thesis of ADS.