Vascular-endothelial adaptations following low and high volumes of high-intensity interval training in patients after myocardial infarction

Abstract

Background:

Determinants of coronary artery disease, such as endothelial dysfunction and oxidative stress, could be attenuated by high-intensity aerobic interval exercise training (HIIT). However, the volume of this type of training is not well established.

Objective:

To assess the impact of two volumes of HIIT, low (LV-HIIT, <10 min at high intensity) and high (HV-HIIT, >10 min at high intensity), on vascular-endothelial function in individuals after an acute myocardial infarction (AMI).

Materials and methods:

Clinical trial in 80 AMI patients (58.4 ± 8.3 years, 82.5% men) with three study groups: LV-HIIT (n = 28) and HV-HIIT (n = 28) with two sessions per week for 16 weeks and control group (CG, n = 24) with unsupervised physical activity recommendations. Endothelial function (brachial flow-mediated dilation, FMD), atherosclerosis (carotid intima-media thickness ultrasound, cIMT), and levels of oxidized low-density lipoprotein (ox-LDL) as a marker of oxidative stress were determined before and after the intervention period.

Results:

After the intervention, in the exercise groups, there was an increase in FMD (LV-HIIT, ↑58.8%; HV-HIIT, ↑94.1%; p < 0.001) concurrently with a decrease in cIMT (LV-HIIT, ↓3.0%; HV-HIIT, ↓3.2%; p = 0.019) and LDLox (LV-HIIT, ↓5.2%; HV-HIIT, ↓8.9%; p < 0.001), with no significant changes in the CG. Furthermore, a significant inverse correlation was observed between ox-LDL and endothelial function related to the volume of HIIT training performed (LV-HIIT: r = −0.376, p = 0.031; HV-HIIT: r = −0.490, p < 0.004), with no significance in the CG (r = 0.021, p = 0.924).

Conclusion:

In post-AMI patients, HIIT may lead to a volume-dependent enhancement in endothelial function, attributed to a decrease in oxidative stress, with added beneficial effects in reducing vascular wall thickness. An LV-HIIT program, with less than 10 min at high intensity per session, has proven enough efficiency to initiate favorable vascular-endothelial adaptations, potentially reducing cardiovascular risk among patients with coronary artery disease.

Trial registration:

INTERFARCT, ClinicalTrials.gov: NCT02876952.

Graphical abstract

Main adaptations to supervised high-intensity interval training (HIIT) programs for 16 weeks on vascular-endothelial function in patients with symptomatic atherosclerosis manifested by acute myocardial infarction compared to traditional training recommendations.

Keywords

carotid intima-media thickness endothelium dependent flow-mediated dilation high-intensity interval training oxidized low-density lipoprotein vasodilators

Introduction

Acute myocardial infarction (AMI) is a significant contributor to global morbidity and mortality.¹ It stems from the dysfunction of vascular-endothelial homeostasis.^2,3 Nitric oxide (NO) is crucial for vascular function, preventing smooth muscle proliferation and inhibiting pro-inflammatory factors.⁴ Endothelial dysfunction, marked by reduced vasodilation capacity, contributes to atherosclerotic disease via inflammation, thrombosis, and arterial stiffness.^5,6 Traditional cardiovascular risk factors exacerbate endothelial dysfunction, impacting NO bioavailability.^7,8

Vascular function is commonly assessed by measuring vessel dilation in response to stimuli such as acetylcholine or shear stress, which induces NO release.⁹ Evaluating coronary artery function can be complex, but brachial artery endothelial function is a noninvasive alternative.¹⁰ Flow-mediated dilation (FMD), assessed through ultrasound images, offers a standardized evaluation. Thus, FMD relies on increased blood flow, triggering endothelial NO production and promoting vasodilation.¹¹ In addition, analyzing carotid arteries, determining carotid intima-media thickness (cIMT), and detecting plaques are markers for generalized atherosclerosis and its severity.¹² In this sense, cIMT is recognized as a cardiovascular risk factor due to its association with an elevated risk of cardiovascular events.¹³ Numerous studies have underscored the correlation between cIMT and the extent of atherosclerosis in coronary arteries, suggesting that the progression of cIMT in individuals with established coronary artery disease predicts new coronary events.^14,15

High oxidative stress causes the progressive oxidation of lipoprotein phospholipids by reactive oxygen species. This process transforms low-density lipoproteins (LDL) into structures known as “oxidized LDL” (ox-LDL) as they modify apolipoprotein B molecules.¹⁶ The elevation of ox-LDL levels prompts macrophages in vessel walls to initiate a process leading to foam cell formation. This process triggers the production of pro-inflammatory cytokines, contributing to endothelial cell dysfunction, immune cell activation, smooth muscle cell proliferation, matrix metalloproteinase expression, and the subsequent development of atherosclerosis and plaques.¹⁷ Intervening in the pathways of oxidative stress development in patients who have experienced an AMI appears to hold promising pathophysiological relevance.

Exercise training improves vascular function and reduces overall mortality, yet the protective role against vascular disease progression remains unclear.¹⁸ It has been suggested exercise restores vascular homeostasis by enhancing NO availability through shear stress from muscular effort and pulse pressure.¹⁹ High-intensity interval training (HIIT), which alternates short and intense aerobic periods with recovery periods at lower intensities, significantly benefits endothelial function in patients with vascular disease compared to moderate-intensity continuous training.²⁰ Previous investigations have proved that HIIT consistently improves cardiovascular fitness, muscular strength, and overall physical performance across various populations, including aging men and heart failure patients.^21,22 While it maintains vascular function improvements from prior conditioning exercises, its direct impact on endothelial function remains inconclusive and warrants further investigation. Understanding and applying different HIIT protocols are crucial for maximizing health outcomes and ensuring patient safety.²³ However, there is inconsistency in research regarding the optimal volume of HIIT sessions.²⁴ The comparison between low- (LV-HIIT) and high-volume HIIT (HV-HIIT) helps us understand the progressive vascular adaptations associated with this exercise modality, aiding in determining beneficial training minimums.²⁵

The HIIT program has more than nine variables, including the high-intensity training volume.²⁵ Thus, it seems that 10 min could be the time necessary to activate the stimuli generated by HIIT, including cardiovascular work, anaerobic glycolytic energy contribution, acute neuromuscular load, and musculoskeletal strain.^20,25 All the aforementioned raises the question: Is a low-volume HIIT (LV-HIIT) protocol (i.e., less than 10 min at high intensity per session) sufficient to improve endothelial function in people who have suffered an AMI? We hypothesized that LV-HIIT may be enough to generate significant adaptations in vascular function. To address this, our study aimed to assess the impact of 16-week supervised HIIT programs with low and high volumes on endothelial function, oxidative stress, and cIMT in post-AMI individuals. A third unsupervised group, following standard recommendations, was used as an attention control (AC) group. The most important feature of this study was establishing an optimal training volume for physiological benefits on vascular-endothelial function in post-AMI patients. This program may provide an efficient exercise adjuvant strategy to improve adherence in cardiac rehabilitation programs.²⁶

Materials and methods

Study design

A detailed description of the study design, eligibility, and participants of the study on different aerobic INTERval exercise training volumes, high versus low, in people after a myocardial inFARCTion (INTERFARCT, ClinicalTrials.gov: NCT02876952) has been previously published.²⁷ Briefly, patients after AMI with preserved systolic function referred for cardiac rehabilitation were randomly divided into three groups: assigned either to the AC group or one of the two supervised HIIT groups 2 days/week for 16 weeks: LV-HIIT (8 min at high-intensity range during a total 20 min session) and HV-HIIT (16 min at high-intensity range during a total 40 min session). Allocation consignment was performed by one of the exercise physiologists who was not involved in the recruitment process. The participants were randomized to one of the three intervention groups (AC, HV-HIIT, or LV-HIIT) stratified by sex, body mass index (BMI), and age using a block and stratified randomization method and with a randomization ratio of 1:1:1. The trial was conducted at the Cardiac Rehabilitation Facility in Santiago Apóstol Hospital’s Cardiology Department in Miranda de Ebro, Burgos, Spain. To ensure unbiased results, the medical staff and exercise physiologists conducting assessment tests and investigators performing statistical analyses were blinded to the random assignment of participants. All follow-up examinations were performed in the same laboratory setting and by the same researchers as in the baseline measurements. The researchers who carried out the training sessions differed from those who carried out the measurements. Besides, after baseline testing, they were enrolled in the trial and given a trial-specific identification number not linked with all other data.

A visual representation of the study flow is presented in Figure 1, and the inclusion and exclusion criteria for the INTERFARCT study are detailed in Table 1.

Figure 1.

Flow chart of the INTERFARCT study from enrollment to end of intervention with measurements used to assess the impact on the ventricular remodeling of two volumes (low vs high) of HIIT compared to a control group in individuals with acute myocardial infarction.

Table 1.

Inclusion and exclusion criteria for the INTERFARCT study.

Inclusion criteria	Exclusion criteria
- Spontaneous AMI, with and without ST elevation - Effective revascularization treatment (coronary artery bypass grafting or percutaneous coronary intervention) - Age ⩾18 years, clinically stable, and sinus rhythm - Between 1 and 6 months after AMI - Left ventricular ejection fraction >50% - Time availability (45 min, 2 days a week for 16 weeks) to carry out the exercise program - Could perform a valid baseline exercise test - No plans to be out of the city for >2 weeks	- Unstable coronary artery disease, uncontrolled hypertension, malignant ventricular arrhythmia, atrial fibrillation, exercise-induced ischemia, and ventricular failure during exercise - Other significant medical conditions including, but not limited to chronic or recurrent respiratory, gastrointestinal, neuromuscular, neurological, or psychiatric conditions; obesity (>35 kg/m²); musculoskeletal problems interfering with exercise; severe kidney disease (creatinine clearance <30 mL/min); anemia (hemoglobin <12 g/dL); bleeding disorders; systemic malignancies in the past 5 years; type 1 diabetes mellitus; moderate to severe peripheral artery disease (>IIa in Fontaine’s classification); any other medical condition or disease that is life-threatening or that can interfere with or be aggravated by exercise - Any other comorbidity with life expectancy <1 year - Pregnancy or breastfeeding

Inclusion criteria

Exclusion criteria

- Spontaneous AMI, with and without ST elevation
- Effective revascularization treatment (coronary artery bypass grafting or percutaneous coronary intervention)
- Age ⩾18 years, clinically stable, and sinus rhythm
- Between 1 and 6 months after AMI
- Left ventricular ejection fraction >50%
- Time availability (45 min, 2 days a week for 16 weeks) to carry out the exercise program
- Could perform a valid baseline exercise test
- No plans to be out of the city for >2 weeks

- Unstable coronary artery disease, uncontrolled hypertension, malignant ventricular arrhythmia, atrial fibrillation, exercise-induced ischemia, and ventricular failure during exercise
- Other significant medical conditions including, but not limited to chronic or recurrent respiratory, gastrointestinal, neuromuscular, neurological, or psychiatric conditions; obesity (>35 kg/m²); musculoskeletal problems interfering with exercise; severe kidney disease (creatinine clearance <30 mL/min); anemia (hemoglobin <12 g/dL); bleeding disorders; systemic malignancies in the past 5 years; type 1 diabetes mellitus; moderate to severe peripheral artery disease (>IIa in Fontaine’s classification); any other medical condition or disease that is life-threatening or that can interfere with or be aggravated by exercise
- Any other comorbidity with life expectancy <1 year
- Pregnancy or breastfeeding

AMI, acute myocardial infarction.

Outcome and sample calculation

This study is a subanalysis of the INTERFARCT protocol²⁷ and focused on vascular function, considering %FMD as the main outcome. For this, it was estimated (G*Power 3.1 statistical software) that the total sample size of 78 patients (26 per group allocated 1:1:1) could be sufficient to identify a difference of 2% in mean and 2% in the standard deviation of %FMD,²⁸ with a power of 0.95 for α = 0.05 and extra 15% for loss.

Measurements

The determinations used in the protocol were taken before and after the 16-week intervention period (Figure 1). All tests were conducted following a fasting period of 8 h and abstaining from alcohol, caffeine, and vitamins for at least 12 h. Post-intervention determinations were carried out in the week immediately following the conclusion of the intervention period. The primary outcome variable for this study was the vascular-endothelial function, assessed through FMD. Secondary variables included the evaluation of arteriosclerosis and oxidative stress, determined by evaluating carotid wall thickness and ox-LDL levels, respectively. A detailed description of the measurements conducted in this study is provided below.

Anthropometry and cardiovascular physical examination

The anthropometric measurements taken include height (meters, SECA 213), total body mass (kg, SECA 869), BMI (kg/m²) calculated as (total body mass (kg)/height (m²)), waist and hip circumferences (SECA 200) to calculate the waist-to-hip ratio. All measurements were taken according to international standards. The following determinations were performed on each participant at rest and in a standardized manner: blood pressure (mmHg, OMRON M3), resting heart rate (beats per minute, 12-lead electrocardiogram, ECG), pulse pressure (mmHg) calculated as (systolic blood pressure (SBP) − diastolic blood pressure (DBP)), mean arterial pressure (MAP, mmHg) calculated as (DBP + ((SBP − DBP)/3)), double product calculated as (heart rate (HR) × SBP).

FMD of the brachial artery

Endothelial function was measured using FMD of the brachial artery while participants were in a resting supine position.²⁹ Before FMD evaluation, participants underwent a minimum 15-min rest period, during which SBP and DBP were measured to ensure stability. A rapid inflation and deflation blood pressure cuff was placed on the left arm, 1–2 cm distal to the antecubital fossa, to provide a transient forearm ischemic stimulus. A multifrequency linear matrix probe of 7 MHz connected to a high-resolution ultrasound machine (Vivid 7, General Electric Bucarest, Rumania) was utilized to capture images of the brachial artery. Simultaneously, a single-lead ECG recording was obtained. B-mode and Doppler flow images of the brachial artery were recorded three times at the beginning, each lasting approximately 15 s. The average of these recordings defined the baseline diameter (D0). Following baseline image acquisition, the cuff was inflated to 250 mmHg for 5 min and immediately deflated, inducing forearm ischemia and subsequent reactive hyperemia. During this hyperemic period, the brachial artery exhibited maximum dilation (D1), with individual participants reaching this point between 40 and 90 s after cuff deflation. An automated edge-detection software system (EchoPAC^®, General Electric) identified the maximum diameter, capturing digitized images 30 s before cuff inflation and for 5 min post-release. A probe holder was used to minimize measurement error, and a technician with adequate training performed all pre- and post-tests. Due to the potential aggressiveness of the technique, it was decided not to perform repeated measurements. FMD was calculated as the percentage change in brachial artery diameter relative to baseline (FMD = 100 × (D1 − D0)/D0), with endothelial dysfunction defined as FMD < 8%.¹¹

After a 10-min rest, endothelium-independent dilation was assessed. The baseline brachial artery diameter was measured again, followed by administering 0.4 mg sublingual nitroglycerin (NTG) spray (Trinispray, Sanofi-Aventis). The artery diameter was re-measured 4 min post-NTG application. Endothelium-independent dilation, associated with smooth muscle function, was calculated as %NTG = 100 × (D1NTG − D0NTG)/D0NTG, with smooth muscle vascular dysfunction defined as %NTG < 8%.^9,29

cIMT by ultrasound

The assessment of vascular wall atherosclerosis involved the measurement of cIMT.¹² Participants were positioned supine with their heads slightly turned to both sides, corresponding to the artery under examination (left and right). B-mode ultrasound was employed to capture longitudinal images of the lumen-wall interface of the common carotid artery, with particular attention to the bulb. The measurements were conducted on the posterior wall of both common carotid arteries, positioned between 1 and 2 cm from the carotid bifurcation, utilizing a 7 MHz vascular probe (Vivid 7). All images were consistently acquired at an anterior oblique angle (30° from the midline) and, when necessary, a lateral angle (100° from the midline). To maintain consistency, parameters such as depth of field, gain, input power, dynamic range, monitor intensity, and other instrumentation settings were documented for replication in subsequent visits. Following image acquisition, built-in edge detection software (EchoPAC) was employed to perform three cIMT measurements on each side (a total of 6), and the average of these measurements was computed.

In the same visit, a comprehensive analysis of the entire carotid system was conducted to identify the presence of atherosclerotic plaques. As per established recommendations, cIMT values exceeding 0.8 mm and/or the detection of plaques indicated manifest atherosclerosis, equating to target organ damage.³⁰

Oxidative stress marker analysis

A blood sample was obtained from each participant at the established protocol times, before and after the intervention. Samples were obtained after fasting for 12 h in the morning by experienced nursing staff using plastic tubes anticoagulated with ethylenediaminetetraacetic acid (EDTA). As a marker of oxidative stress, ox-LDL (U/L) was determined in EDTA plasma by enzyme-linked immunosorbent assay (murine monoclonal antibody mAB-4E6 and peroxidase antibody conjugated against oxidized apolipoprotein B in the solid phase; Mercodia, Uppsala, Sweden).

Intervention

Participants were randomly assigned to one of three intervention groups; two groups performed a supervised HIIT training program, and one group followed unsupervised physical activity recommendations within the AC (Figure 1). The intensity of the exercise for each participant in the three groups was individually scheduled based on cardiorespiratory fitness and ventilatory thresholds (VT1 and VT2), which were determined from the peak oxygen consumption (VO_2peak) obtained by an ergospirometry (Lode Excalibur Sport Cycle, Part number: 925909, 2007, Groningen, The Netherlands) and expired gas analysis (Ergometrix. Ergocard Medisoft SS, Belgium Ref. USM001 V1.0). Based on the identification of the two VT, the three intensity ranges of exercise were determined: (R1) light to moderate intensity with HR values below VT1; (R2) moderate to high intensity with HR values between VT1 and VT2; and (R3) high to severe intensity with HR values from VT2 to the maximum HR achieved in the cardiopulmonary stress test. More specific information regarding the exercise cardiopulmonary test and VT assessment have been previously published.²⁷

The supervised HIIT groups exercised two non-consecutive days per week in one of two randomly assigned interval training programs (alternating R2 with R3): (1) LV-HIIT group, with 8 min at R3 each session, with a total volume of 20 min and (2) HV-HIIT group with more than 10 min (16 min) at R3 each session and gradually increased from 20 to 40 min for the total volume. Supervised groups performed exercise sessions on the treadmill on 1 day and the cycle ergometer on the second day for 16 weeks (32 sessions). Training intensity was controlled by monitoring beat-to-beat HR (Polar Electro, Kempele, Finland) and through the rate of perceived exertion using the original Börg scale (6–20 points). The justification for a mixed training model alternating a treadmill and a cycle ergometer was to avoid the greater osteoarticular impact that 2 days on a treadmill would generate, considering the high intensity of the program and the high prevalence of overweight among the participants. To achieve the “target” HR goals in each range (R2 and R3), the intensity was individually adapted through speed and incline on the treadmill and watts on the cycle ergometer. The specific protocols of the HIIT programs have been previously published.²⁷ Briefly, on the treadmill, there were intervals of 4 min at R3 followed by 3 min at R2, and on the exercise bike, intervals of 30 s at R3 followed by 60 s at R2. The basic recommendations that patients with coronary heart disease must follow were verbally and written indicated to try to control physical activity outside the HIIT programs.³¹

The AC received individualized recommendations to perform physical activity without supervision for 16 weeks. They were advised to engage in at least 30 min of moderate-intensity aerobic physical activity (i.e., walking, jogging, cycling, swimming) 5–7 days per week.³² Each participant received training information with their HR intensity domains calculated by ergospirometry for self-control. In addition, a written record of 7-day baseline physical activity was made in all participants at the beginning and end of the intervention to detect bias in daily caloric intake that could influence the results.

All participants had individual nutritional counseling every 2 weeks to help them increase their adherence to a cardio-healthy diet (Mediterranean diet).³³ This nutritional counseling was performed by a nurse specializing in family and community medicine, who had specific training in nutrition for high-risk cardiovascular populations blinded to the randomized intervention groups. Patients had an individual interview 2 weeks before and every 2 weeks during the intervention to program their diet according to the calories required individually to avoid uncontrolled changes.

Statistical analysis

Statistical analyses were conducted using IBM SPSS Statistics 22.0 (IBM Corp., Armonk, NY, USA). Baseline and pre–post mean comparisons between groups employed either a one-way analysis of variance (ANOVA) or the nonparametric Kruskal–Wallis method, accompanied by the Chi-square test. A linear regression model with ANOVA was utilized to assess the impact of interventions on primary (FMD) and secondary variables. Pre–post differences (delta, Δ) and their relative values (%Δ) for each variable within each group were calculated. The normal distribution of variables was assessed using the Shapiro–Wilk test to confirm the normality assumption.

In addition, a paired analysis of means for each pre- and post-intervention variable was conducted, and a Pearson correlation analysis explored relationships between continuous variables of physiological interest. Data were analyzed based on the intention-to-treat principle and presented as mean ± standard deviation (SD) or absolute numbers and percentages, depending on the variable type. The analysis adhered to the intention-to-treat principle, and statistical significance was set at 5% (α = 0.05).

Results

Study population

A total of 225 consecutive patients who had AMI were referred from the Cardiology Department. After applying the inclusion and exclusion criteria for this study, 115 patients were excluded. After this, 109 patients were enrolled, but 29 refused to participate and did not consent. Finally, 80 patients were included and randomized to the study, and all completed the 16-week training protocol (Figure 1). Six patients, three from each exercise group, missed two training sessions for reasons unrelated to the study but did not discontinue the program. They carried out 93.7% of the 32 program sessions, so it was decided to keep them in the final analysis under the premise of “intention-to-treat.”

No significant baseline differences were observed among the three randomized groups regarding demographic data, medical conditions, and medication (p > 0.05; Table 2). The study included 80 participants (AC: n = 24, LV-HIIT: n = 28, HV-HIIT: n = 28), with a mean age of 58.4 ± 8.3 years and 82.5% were male. No relevant adverse events were reported throughout the intervention and supervised training sessions. Changes in the doses of the renin–angiotensin–aldosterone system inhibitors were observed in five participants during the study: three patients in the LV-HIIT group had their doses reduced, and two in the HV-HIIT group had their doses reduced. No participant dropped out during the analysis. However, two participants, one from the LV-HIIT group and one from the HV-HIIT group, were excluded from the ox-LDL level and FMD analysis as the tests could not be completed.

Table 2.

Baseline demographic and clinical characteristics of the participants.

Variables	Total group	AC	HIIT groups		p Value
Variables	Total group	AC	Low volume	High volume	p Value
Sample size, n	80	24	28	28
Male sex	66 (82.5)	19 (79.2)	24 (85.7)	23 (82.1)	0.82
Age, year	58.4 ± 8.3	57.0 ± 7.2	59.0 ± 9.6	58.9 ± 8.0	0.63
Body mass, kg	83.4 ± 17.8	79.2 ± 17.0	85.2 ± 20.5	85.4 ± 16.5	0.39
BMI, kg/m²	29.9 ± 6.6	28.1 ± 5.4	30.5 ± 6.8	30.7 ± 4.9	0.21
Rest SBP, mmHg	128.8 ± 12.0	126.0 ± 12.1	127.0 ± 13.4	133.3 ± 10.4	0.06
Rest DBP, mmHg	78.1 ± 8.2	77.4 ± 8.1	77.6 ± 7.3	79.2 ± 9.1	0.68
Rest HR, beats/min	70.3 ± 8.6	69.6 ± 8.7	65.8 ± 12.2	65.7 ± 9.2	0.31
Peak HR, beats/min	136.2 ± 22.9	141.9 ± 25.9	134.1 ± 20.8	132.7 ± 22.3	0.47
VO_2peak, mL/kg/min	23.5 ± 6.6	27.6 ± 8.6	23.1 ± 8.1	23.2 ± 5.2	0.24
MET	7.0 ± 2.1	7.8 ± 2.4	6.6 ± 2.3	6.7 ± 1.4	0.24
Cardiovascular risk factor, %
Hypertension	64 (80.0)	19 (79.2)	23 (82.1)	22 (78.6)	0.23
Dyslipidemia	70 (87.5)	21 (87.5)	24 (85.7)	25 (89.3)	0.92
Diabetes mellitus	23 (28.8)	6 (25.0)	8 (28.6)	9 (32.1)	0.85
Smoking
Ex-smoker	63 (78.8)	18 (75.0)	22 (78.6)	23 (82.1)	0.82
Smoker	7 (8.7)	2 (8.3)	3 (10.7)	2 (7.1)	0.80
Family predisposition	10 (12.5)	3 (12.5)	4 (14.3)	3 (10.7)	0.92
Sleep apnea syndrome	9 (11.2)	2 (8.3)	3 (10.7)	4 (14.2)	0.91
Medication, %
Aspirin	75 (93.8)	22 (91.7)	27 (96.4)	26 (92.9)	0.77
Antithrombotics	44 (55.0)	13 (54.2)	16 (57.1)	15 (53.6)	0.96
Oral anticoagulants	3 (3.8)	1 (4.2)	1 (3.6)	1 (3.6)	0.99
RAAS inhibitors	70 (87.5)	20 (83.3)	24 (85.7)	26 (92.9)	0.54
Beta-blockers	72 (90.0)	21 (87.5)	25 (89.3)	26 (92.9)	0.80
CCB	16 (20.0)	5 (20.8)	6 (21.4)	5 (17.9)	0.94
Diuretics	18 (22.5)	5 (20.8)	6 (21.4)	7 (25.0)	0.92
Lipid-lowering therapy	78 (97.5)	23 (95.8)	28 (100)	27 (96.4)	0.57
Statins	76 (95.0)	22 (91.7)	28 (100)	26 (92.9)	0.59
Antidiabetic medication	19 (23.8)	5 (20.8)	6 (21.4)	8 (28.6)	0.76
SGLT2 inhibitor	9 (11.2)	2 (8.3)	3 (10.7)	4 (14.3)	0.71

Data are expressed as mean ± SD, dichotomous variables are expressed as numbers and percentages (%).Statistics: One-way analysis of variance (ANOVA) or nonparametric Kruskal–Wallis method and Chi-square test were used to compare groups at baseline (p).

AC, attention control group; BMI, body mass index; CCB, calcium channel blocker; DBP, diastolic blood pressure; HIIT, high-intensity interval training; HR, heart rate; MET, metabolic equivalent of task; RAAS inhibitors, inhibitors of the renin–angiotensin–aldosterone system; SBP, systolic blood pressure; SGLT2 inhibitor, sodium-glucose cotransporter-2 inhibitors; VO_2peak, peak oxygen uptake.

Anthropometry and cardiovascular assessments

The participant’s body mass remained unaffected by varying volumes of HIIT intervention. However, the LV-HIIT group exhibited a mild reduction in BMI (−1.6 ± 0.9%, p = 0.046) and waist-to-hip ratio (−4.1 ± 3.3%, p = 0.039; Table 3). Regarding cardiovascular assessments, SBP values experienced a reduction (−5.8 ± 4.3%, p = 0.004) following HV-HIIT intervention, contrasting with an increase (6.6 ± 4.5%, p = 0.0047) observed in the AC group. DBP values significantly decreased by −9.1 ± 5.1% (p = 0.0007) and −10.2 ± 6.3% (p = 0.0015) in the LV-HIIT and HV-HIIT groups, respectively, with no significant changes noted in the AC group. Resting HR decreased by −11.1 ± 7.2% (p = 0.012) in the AC group, while it increased by 3.5 ± 2.0% (p = 0.024) in the LV-HIIT group. Regarding blood pressure value alterations, pulse pressure increased by 10.4 ± 5.5% (p = 0.0219) in the AC group, and MAP experienced a significant reduction of −5.9 ± 3.3% (p < 0.005) in the LV-HIIT group and −8.1 ± 4.1% (p < 0.001) in the HV-HIIT group (Table 3).

Table 3.

Impact of different volumes of HIIT on anthropometry and cardiovascular examinations compared to a control group of patients after an acute myocardial infarction.

Study times	AC (n = 24)		LV-HIIT (n = 28)		HV-HIIT (n = 28)
	T1	T2	T1	T2	T1	T2
Anthropometry
Body mass, kg	78.9 ± 14.9	79.3 ± 15.0	85.2 ± 20.5	84.1 ± 19.6	85.4 ± 16.5	84.4 ± 15.6
BMI, kg/m²	29.9 ± 6.6	29.5 ± 4.4	30.5 ± 6.8	30.0 ± 6.6*	30.7 ± 4.9	30.3 ± 4.7
Waist-hip ratio	0.94 ± 0.1	0.94 ± 0.1	0.98 ± 0.1	0.94 ± 0.09*	0.99 ± 0.06	0.98 ± 0.09
Cardiovascular
Rest SBP, mmHg	120.0 ± 10.4	128.1 ± 9.9*	127.0 ± 13.4	124.5 ± 12.8^‡	133.3 ± 10.4	125.6 ± 12.6**,^‡
Rest DBP, mmHg	75.6 ± 9.7	77.5 ± 7.3	77.0 ± 7.0	70.0 ± 7.5**,^‡	79.2 ± 9.0	71.1 ± 8.9**,^‡,#
Rest HR, beats/min	68.3 ± 9.4	60.7 ± 7.1*	65.8 ± 12.2	68.1 ± 12.2*,^‡	65.7 ± 9.2	65.4 ± 12.6
Pulse pressure	44.4 ± 6.2	49.0 ± 8.8*	50.0 ± 9.8	54.5 ± 9.4	54.1 ± 7.2	54.5 ± 8.7
MAP	90.4 ± 11.8	95.2 ± 10.3	93.7 ± 10.3	88.2 ± 10.6*,^‡	97.2 ± 11.4	89.3 ± 11.8**,^‡,#
Endothelial dysfunction, n (%)	22 (91.7)	21 (87.5)	26 (92.9)	17 (60.7)*,^‡	24 (85.7)	16 (57.1)*,^‡
Vascular smooth muscle dysfunction, n (%)	0	0	0	0	0	0
Carotid plaque, n (%)	4 (16.7)	4 (16.7)	4 (14.3)	3 (10.7)	3 (10.7)	3 (10.7)

Data are expressed as mean ± standard deviation or as absolute value (n) and percentage (%).

AC, attention control group; BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; HV-HIIT, high-volume high-intensity interval training; LV-HIIT, low-volume high-intensity interval training; MAP, mean arterial pressure; SBP, systolic blood pressure; T1, pre-intervention baseline measurement; T2, measurement at the end of the intervention (16 weeks).

Pre–post analysis within the group: *p < 0.05, **p < 0.01; comparison of the mean change with the control group: ^‡p < 0.05; or between HIIT groups (low vs high): ^#p < 0.05.

Endothelial function

The assessment of endothelial function via brachial artery FMD revealed a high prevalence of endothelial dysfunction (i.e., FMD < 8%) in the sample, affecting 90.0% of individuals (Table 3). No baseline differences were noted between groups. However, following the intervention, endothelial dysfunction was substantially reduced by −34.7 ± 10.5% in the LV-HIIT group and −33.4 ± 9.8% in the HV-HIIT group, respectively (ANOVA p = 0.0018). Thus, the FMD, whose value is inversely proportional to endothelial dysfunction, increased. Changes in pre–post-FMD values in the three study groups are depicted in Figure 2. Prior to the intervention, no differences were observed among the groups; nevertheless, after 16 weeks, significant increases were evident in the HIIT groups compared to the control participants. The LV-HIIT group exhibited a 1.6-fold increase in FMD (58.8 ± 8.5%, ANOVA p < 0.001), while the HV-HIIT group demonstrated a 1.9-fold increase (94.1 ± 9.7%, ANOVA p < 0.001). Conversely, vascular smooth muscle dysfunction was absent in all patients (Table 3).

Figure 2.

Endothelial function determined by FMD of the brachial artery in patients with acute myocardial infarction before and after different volumes of high-intensity interval training (low volume (LV-HIIT) and high volume (HV-HIIT)) compared with an AC group. Results are expressed as mean ± standard deviation (error bars). Each line represents the individual pre- and post-value of each participant.

Oxidative stress

The analysis of ox-LDL levels as an indicator of oxidative stress is depicted in Figure 3. Participants who engaged in the HIIT programs demonstrated a notable reduction in ox-LDL levels (LV-HIIT = 5.2 ± 2.2%, HV-HIIT = −8.9 ± 3.7%; p < 0.0152) compared to the AC group, which exhibited no variations (ANOVA p < 0.001). When examining the correlation between pre–post changes in FMD (ΔFMD) and changes in oxidative stress levels (Δox-LDL), a statistically significant inverse correlation emerged, linked to the volume of HIIT performed, that is, the higher the FMD, the lower the ox-LDL (LV-HIIT: r = −0.376, p = 0.047; HV-HIIT: r = −0.490, p = 0.008; AC: r = 0.021, p = 0.924; see Figure 4(a)).

Figure 3.

Oxidative stress is determined by levels of ox-LDL in patients after acute myocardial infarction before and after different volumes of high-intensity interval training (low volume (LV-HIIT) and high volume (HV-HIIT)) compared with an attention control group (AC). Results are expressed as mean ± standard deviation (error bars).

Figure 4.

Pearson correlation between pre–post changes (∆) in FMD (%) of the brachial artery in relation to (a) levels of ox-LDL (U/L) and (b) carotid intima-media thickness (cIMT, mm⁻³) in patients after acute myocardial infarction before and after different volumes of high-intensity interval training (low volume (LV-HIIT) and high volume (HV-HIIT)) compared with an AC group.

Atherosclerosis

The assessment of cIMT enabled us to gauge the extent of atherosclerosis among the study participants. The average cIMT within the sample stood at 0.675 ± 0.183 mm, and there were no discernible differences at baseline among groups. Following a 16-week HIIT intervention, there were noteworthy yet slight alterations in carotid atherosclerosis means compared to the AC group (ANOVA p = 0.019, Figure 5). Participants in the LV-HIIT program experienced a mean reduction of −3.0 ± 1.1% (p = 0.0389), while those in the HV-HIIT program exhibited a mean reduction of −3.2 ± 1.2% (p = 0.0305). Post-cIMT measurement, ultrasound examination of the carotid arteries uncovered atherosclerotic plaques in 11 participants (13.7%), with no notable differences between groups or within-group variances in baseline and post-intervention assessments (Table 3). Correlations were explored between changes in endothelial function (ΔFMD) and cIMT (ΔcIMT), revealing that there is no significant relationship between these variables (depicted in Figure 4(b)). In addition, correlations were examined between ΔcIMT and Δox-LDL across the three study groups, but no significant associations or trends between variables emerged (results not shown). No differences were found in the change’s pre–post between men and women in the sample. Since the sample of women was small (n = 14), their influence is not significant in the results. Thus, removing the female participants, the results were similar.

Figure 5.

Atherosclerosis was determined by cIMT in patients after acute myocardial infarction before and after different volumes of high-intensity interval training (low volume (LV-HIIT) and high volume (HV-HIIT)) compared to an AC group. Results are expressed as mean ± standard deviation (error bars). B-mode ultrasound images of the carotid artery pre (T1) and post (T2) as an example of three patients belonging to each intervention group where the automated measurement can be seen on the poster wall of the cIMT (green line: middle, red line: intimate). Each image presents the mean value (x-) of the six measurements performed on each patient with their respective ± standard deviation.

Discussion

This study examines the influence of varying volumes of HIIT on the vascular-endothelial function in patients with clinically symptomatic atherosclerosis resulting from AMI. The primary findings highlight the volume-dependent enhancement of FMD through HIIT, coupled with a reduction in levels of ox-LDL and cIMT. These improvements were observed compared to an AC group following recommended and unsupervised physical activity. As we hypothesized, the results suggest that less than 10 min at high intensity in a HIIT program of 20 min total volume may suffice to achieve clinically favorable physiological adaptations for individuals recovering from AMI.

Endothelial dysfunction is a well-established factor contributing to exercise intolerance, myocardial perfusion abnormalities, and left ventricular remodeling in coronary artery disease patients.³⁴ It is also recognized as an independent prognostic marker for future cardiovascular events.³⁵ Evidence supports that aerobic training can enhance endothelium-dependent coronary vasodilation in these patients. Consequently, it is reasonable to suppose that HIIT might induce a similar systemic effect, with the key player being NO.⁴ This study observed a substantial improvement in FMD associated with HIIT (overall mean between the two HIIT groups of 34%, p < 0.001; Figure 2). These results are aligned with recent research in patients with coronary heart disease, although the significant limitation of extrapolation is the heterogeneity of HIIT programs.^20,36 At the same time, the absence of changes in NTG-induced vasodilation (endothelium-independent) pre- and post-intervention implies that the enhanced FMD solely reflects the rehabilitation of vascular function at the endothelial level.⁹ In this context, FMD regulation hinges on the bioavailability of NO, and disruptions in one or more pathways controlling NO availability can result in endothelial dysfunction.³⁷

Extensive documentation establishes that reactive oxygen species and ox-LDL quantity directly impact NO bioavailability. Normal endothelial function relies on maintaining a balance between oxidant and antioxidant mechanisms.³⁸ During periods of elevated oxidative stress, superoxide anions impede endothelial NO synthase function, reducing NO’s half-life and increasing peroxynitrite production from NO and superoxide anions. One mechanism through which HIIT enhances endothelial function is bolstering NO’s bioavailability improving plasma antioxidant status.³⁹ The present study substantiates this issue, revealing a significant decrease in ox-LDL concentration from −4.2% (p < 0.001) at LV-HIIT to −8.9% (p < 0.001) at HV-HIIT.

It is reasonable to posit that HIIT elicits more physiological shear stress during exercise sessions. This assumption is coupled with its capacity to prompt heightened vascular flow and deliver oxygen to the working muscles.³⁸ This combination will likely instigate broader cellular and molecular responses compared to moderate-intensity continuous training exercises.⁴⁰ This proposition gains support from the observation that sedentary individuals, marked by chronic low-shear stress resulting from physical inactivity, are more prone to an elevated presence of biomarkers associated with vascular dysfunction.⁴¹ These biomarkers include oxidative stress, cellular adhesion molecules, and diminished expression of antioxidants.⁴² The shear stress induced by HIIT operates as a mechanical stimulus, activating potassium channels, and facilitating calcium entry into endothelial cells. The heightened intracellular calcium levels then trigger endothelial NO synthase activation and expression, fostering NO production and vasodilation.⁴² Despite the wealth of evidence illustrating how HIIT augments NO synthesis through shear mechanical effects, this phenomenon may exhibit synergy with the potent antioxidant effect intrinsic to HIIT.^43–45 This study underscores the interconnectedness between oxidative stress and endothelial function, with the correlation becoming more pronounced as the volume of HIIT increases.

Identifying atherosclerosis through cIMT and the presence of carotid plaques proves valuable in gauging the extent of coronary artery involvement in patients with AMI.¹⁵ This study’s 16-week intervention involving HIIT yielded a noteworthy reduction in cIMT compared to the AC group (p = 0.019). However, no significant disparity was observed between the two volumes utilized in the protocol (LV-HIIT: −3.0% vs HV-HIIT: −3.2%, p = 0.467). These findings suggest HIIT’s mild, volume-independent impact on cIMT is unrelated to oxidative stress or endothelial function. Unexplored variables in this study might be influencing these outcomes. Similar reductions have been documented in other studies where lifestyle interventions incorporating exercise and diet for atherosclerosis in coronary artery disease patients exhibited limited efficacy.⁴⁶ The gradual regression of atherosclerosis may render it a protracted phenomenon, with 16 weeks potentially insufficient for significant evaluation.⁴⁷ In addition, compelling evidence indicates that lipid-lowering medications initiated in coronary disease patients mitigate the effects of exercise. Statin use in this high-risk cardiovascular cohort necessitates a transient reduction in cIMT, leaving minimal scope for exercise to influence atherosclerosis progression.⁴⁸

Notwithstanding these challenges, various studies indicate that dietary measures and exercise training enhance endothelial function, mitigating atherosclerosis, even in patients undergoing intensive pharmacological therapy.⁴⁹ Furthermore, despite the atherosclerosis improvement facilitated by lipid-lowering treatments, no statin studies demonstrate an enhancement in endothelial function and oxidative stress comparable to or exceeding that achieved by HIIT. Therefore, the outcomes of this study strengthen this assumption, highlighting the anti-atherogenic potential of HIIT. Notably, this effect could complement the pharmacological impact of statins, utilized by 97.5% of the sampled patients. This result bears significance as exercise-induced improvement in endothelial function and measures reducing atherosclerosis progression have been proven to decrease the risk of recurrent cardiovascular events in coronary patients, which is of substantial clinical relevance.⁵⁰

This study provides unprecedented knowledge about HIIT volume of less or more than 10 min at high intensity per session. Both LV-HIIT and HV-HIIT enhance endothelial function through mechanisms involving reduced oxidative stress and shear stress-induced activation of endothelial NO synthase. HV-HIIT may provide a more substantial antioxidant effect and induce more significant shear stress, potentially leading to enhanced endothelial adaptation compared to LV-HIIT. However, the overall impact on endothelial function, as evidenced by improvements in FMD, can be effectively achieved with both low and high volumes of HIIT. In this sense, LV-HIIT is more accessible and efficient for patients, promoting higher compliance and allowing combined training in the same session (aerobic + resistance training).

This study has some limitations that need to be mentioned. The sample size is small and has an uneven gender distribution, with the majority being men. The intervention was 16 weeks, which may represent a relatively short time when studying the development and progression of atherosclerotic disease. In addition, atherosclerosis was only evaluated in the carotid arteries, which limits the interpretation of the results at a systemic level. Only one biomarker (ox-LDL) was used to study oxidative stress without being able to rely on others that could reinforce the study’s findings.

Conclusion

High-intensity aerobic interval training may lead to a volume-dependent enhancement in endothelial function, attributed to decreased oxidative stress, in individuals experiencing symptomatic atherosclerosis, such as those with an AMI, with added beneficial effects in reducing vascular wall thickness. An LV-HIIT program, with less than 10 min at high intensity per session, has proven enough efficiency to initiate favorable vascular-endothelial adaptations, potentially reducing cardiovascular risk among patients with coronary artery disease.

Supplemental Material

sj-docx-1-tak-10.1177_17539447241286036 – Supplemental material for Vascular-endothelial adaptations following low and high volumes of high-intensity interval training in patients after myocardial infarction

Supplemental material, sj-docx-1-tak-10.1177_17539447241286036 for Vascular-endothelial adaptations following low and high volumes of high-intensity interval training in patients after myocardial infarction by Rodrigo Aispuru-Lanche, Jon Ander Jayo-Montoya and Sara Maldonado-Martín in Therapeutic Advances in Cardiovascular Disease

Footnotes

Acknowledgements

We want to thank the Cardiology Department (Dr. Rodrigo Gallardo and Dra. Tatiana Matajira) and the Director of the Santiago Apostol Hospital (Dra. Sonia Blanco) for their assistance in developing the INTERFARCT study. The authors give special thanks to Jessica Werdenberg for proofreading the manuscript and all the study participants. The present study obtained the third prize in the XXIV national awards for research in Sports Medicine Fundación Cajastur year 2022.

Declarations

ORCID iD

Sara Maldonado-Martín

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