Effect of chronic angiotensin system inhibitor treatment on cardiovascular adaptations to exercise training in adults with metabolic syndrome

Effect of chronic angiotensin system inhibitor treatment on cardiovascular adaptations to exercise training in adults with metabolic syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Effect of chronic angiotensin system inhibitor treatment on cardiovascular adaptations to exercise training in adults with metabolic syndrome Felix Morales-Palomo, Irene Labrador-Sanchez, Alfonso Moreno-Cabañas, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9530735/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are commonly prescribed alongside exercise to manage hypertension in individuals with metabolic syndrome (MetS). However, whether chronic renin–angiotensin system (RAAS) inhibition modifies exercise-induced physiological adaptations remains unclear. In this prospective parallel-group study, 62 sedentary adults with MetS completed a 16-week supervised high-intensity interval training (HIIT) program. Participants were either chronically treated with ACEi or ARBs (antihypertensive medication group, AHM, n = 27) or not receiving pharmacological treatment (CONTROL, n = 35). Primary outcomes included changes in resting and exercise blood pressure (BP), MetS components, and cardiorespiratory fitness (CRF). Both groups showed significant improvements over time in cardiometabolic health (MetS Z-score: AHM − 0.22 ± 0.42; CONTROL − 0.30 ± 0.33; p 0.05). Resting blood pressure decreased similarly in both groups (mean arterial pressure [MAP]: AHM − 4.2 ± 8.7; CONTROL − 6.5 ± 6.3 mmHg; p = 0.005; interaction p > 0.05). Exercise blood pressure responses also improved, with significant time effects for maximal MAP ( p = 0.008) and submaximal diastolic BP ( p = 0.047), without between-group differences (interaction p > 0.05). Chronic treatment with ACEi or ARBs does not appear to attenuate improvements in cardiometabolic health, BP, or CRF by 16 weeks of supervised HIIT in adults with MetS. These findings suggest that RAAS inhibition is compatible with structured exercise training, supporting HIIT as an effective adjunct therapy in individuals receiving antihypertensive medication. However, the absence of significant interactions should be interpreted in the context of limited power to detect small-to-moderate differences. Health sciences/Diseases/Cardiovascular diseases/Hypertension Biological sciences/Physiology/Cardiovascular biology Exercise hypertension metabolic syndrome antihypertensive medication angiotensin-converting enzyme inhibitors angiotensin receptor blockers Figures Figure 1 Figure 2 Figure 3 Figure 4 What is known about the topic Hypertension and metabolic syndrome (MetS) are major cardiovascular risk factors commonly managed with antihypertensive drugs and exercise. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) target the renin–angiotensin system and are first-line therapies in hypertension. High-intensity interval training (HIIT) improves blood pressure (BP), cardiorespiratory fitness (CRF), and metabolic health in MetS. What this study adds Chronic ACEi/ARB therapy does not attenuate adaptations to 16 weeks of supervised HIIT in adults with MetS. HIIT produced similar reductions in BP and improvements in CRF (~18–22% VO 2MAX increase) in medicated and non-medicated participants. Exercise-induced cardiometabolic benefits are preserved despite long-term RAAS inhibition, supporting combined therapy in clinical practice. INTRODUCTION Hypertension remains one of the most prevalent modifiable risk factors for cardiovascular disease (CVD) 1 . Despite the widespread use of antihypertensive medications (AHM), their global burden continues to rise, affecting nearly one-third of adults 2 . Current guidelines recommend lifestyle interventions as first-line therapy; however, long-term adherence is often suboptimal, and pharmacological treatment is frequently initiated early in high-risk individuals owing to concerns about target organ damage 3 . Consequently, clinical management commonly combines pharmacotherapy with structured exercise interventions. Global use of AHM has increased substantially over the past decade, and angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers, and thiazide/thiazide-like diuretics are widely recommended as first-line therapies 4 . ACEi and ARBs act by inhibiting the renin–angiotensin–aldosterone system (RAAS), a key regulator of vascular tone, blood volume, and systemic vascular resistance 5 , and provide additional cardiovascular benefits, including improved endothelial function and reduced myocardial remodeling 6 . In parallel, exercise training is a cornerstone of hypertension management 7 , with robust evidence supporting its blood pressure (BP)-lowering effects 8 , mediated in part by reductions in sympathetic activity and modulation of RAAS signaling 9 . Emerging evidence suggests that combining AHM with high-intensity interval training (HIIT) may produce additive or synergistic effects on BP reduction. HIIT can further reduce ambulatory BP beyond pharmacotherapy in hypertensive individuals with metabolic syndrome (MetS) 10 , and exercise-induced reductions in systolic BP may approach those achieved with pharmacological interventions under certain conditions although comparisons remain limited by the heterogeneity across studies 11 . Higher cardiorespiratory fitness (CRF) is also consistently associated with lower BP and reduced cardiovascular risk 12 , and improvements in CRF appear to be preserved during ACEi therapy 13 . However, whether chronic RAAS inhibition modifies the magnitude of exercise-induced cardiometabolic and hemodynamic adaptations remains unclear. Therefore, this study examined the effects of chronic ACEi or ARBs therapy on cardiometabolic and hemodynamic adaptations to a 16-week supervised HIIT program in adults with MetS. We hypothesized that RAAS inhibition would not attenuate training-induced improvements in blood pressure, cardiorespiratory fitness, or metabolic health. METHODS Subjects. Sixty-two middle-aged volunteers (51 ± 12 years; 29 women and 33 men) with overweight and obesity (i.e., body mass index [BMI], 32.2 ± 4.3 kg·m − 2 ) with MetS criteria 14 completed the study. Participants were previously sedentary as assessed by the 7-day IPAQ (International Physical Activity Questionnaire) with less than 150 min·wk − 1 of moderate-intensity activity. Exclusion criteria included untreated cardiovascular or renal disease, any condition associated with exercise intolerance, and the use of any pharmacological therapy targeting MetS components other than ACEi or ARBs. Upon questioning at the onset of the intervention, subjects reported a stable body weight (± 1%) over the 4 months preceding the survey. All subjects provided written, witnessed, and informed consent under a protocol approved by the local Virgen de la Salud Hospital Ethics Committee of Toledo (reference #170) and in accordance with the Declaration of Helsinki. This is a substudy of a larger clinical trial assessing the effects of medication and exercise interactions in individuals with MetS (ClinicalTrials.gov Identifier: NCT03019796). Experimental design. This prospective parallel-group intervention study examined the effects of exercise training in participants either treated or untreated with RAAS inhibitors (ACEi or ARBs). Participants were allocated using a non-randomized block design based on medication treatment. Recruitment, screening, intervention, and all assessments were conducted in the sequence outlined in Fig. 1 . Twenty-seven individuals with MetS receiving chronic antihypertensive therapy with ACEi or ARBs for more than six months constituted the antihypertensive medication group (AHM). Thirty-five individuals with MetS who had never received chronic pharmacologic treatment served as the control group (CONTROL; Table 1 ). Table 1 Medication use. Medication AHM (n = 27) CONTROL (n = 35) Antihypertensive medication 27 (100%) - ACEi 12 (44%) - Enalapril 11 (41%) - Imidapril 1 (4%) - ARBs 15 (56%) - Candesartan 1 (4%) - Irbesartan 6 (22%) - Losartan 4 (15%) - Telmisartan 1 (4%) - Valsartan 3 (11%) - Cholesterol lowering - - Triglyceride lowering - - Glucose lowering - - Data are presented as the number of subjects taking each medication, expressed as absolute frequency (n) and proportion (%). Abbreviations: ACEi , angiotensin-converting enzyme inhibitors; and ARBs , angiotensin receptor blockers. Intervention. All participants completed a 16-week supervised aerobic training program, performed three times per week (Monday, Wednesday, and Friday), consisting of high-intensity interval training (HIIT) on stationary cycle ergometers (Tomahawk S-Series, Nürnberg, Germany). Participants were required to attend at least 90% of sessions to be included in the analysis. Each session began with a 10-minute warm-up at 70% of maximum heart rate (HR MAX ), followed by four 4-minute intervals at 90% HR MAX , interspersed with 3-minute active recovery periods at 70% HR MAX , and concluded with a 5-minute cool-down. Exercise intensity was prescribed as a percentage of HR MAX determined during the pre-intervention maximal exercise test. Heart rate was continuously monitored using a telemetry system (Seego, RealTrack Systems, Spain) and displayed on a large screen. Participants adjusted the cycling workload to remain within their individualized target HR zones under the direct supervision of a research team member. Training progression was implemented over the first three weeks (nine sessions), gradually increasing the number and duration of high-intensity intervals. HRMAX was reassessed monthly, and workloads were adjusted accordingly to maintain the prescribed training intensity. Participants were instructed to maintain their usual dietary and physical activity habits throughout the intervention. Monthly, they completed a 3-day dietary record (CESNID v1.0, Barcelona, Spain) and wore a wrist-based activity monitor (Polar Loop Electro, Polar, Kempele, Finland) for 48 hours. Personalized feedback was provided each month to minimize fluctuations in caloric intake and non-training physical activity. Outcomes measures Clinical investigation. Before and after the intervention, participants reported to the laboratory in the morning following an overnight fast (8–12 h). Body weight (Hawk, Mettler; Toledo, USA), height (Stadiometer, SECA 217; Hamburg, Germany), and waist circumference were measured by the same investigator according to the protocol proposed by Alberti et al. 14 , using a non-elastic measuring tape. BMI was calculated, and fat mass (FM) and fat-free mass (FFM) were assessed using dual-energy X-ray absorptiometry (DXA; Hologic Discovery Wi QDR Series, Bedford, USA). Resting blood pressure was measured in triplicate using a calibrated ECG-gated automated sphygmomanometer (Tango, SunTech Medical; Morrisville, USA) after 10 minutes of supine rest. Exercise testing was performed at least 48 hours apart from fasting venous blood collection, which was used to determine serum glucose, insulin, and lipid profile (triglycerides, total cholesterol, HDL-c, and LDL-c). Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Sex-specific Z scores were calculated for each MetS criterion using the group SD, and the sum of the Z scores for each MetS component was divided by 6 to obtain the MetS risk score. The equations used were as follows: Men’s MetS Z Score= [(40 – HDL-cholesterol)/SD] + [(triglycerides – 150)/SD] + [(glucose – 100)/SD] + [(waist circumference – 94)/SD] + [(systolic blood pressure – 130)/SD] + [(diastolic blood pressure – 85)/SD] Women’s MetS Z Score= [(50 – HDL-cholesterol)/SD] + [(triglycerides – 150)/SD] + [(glucose – 100)/SD] + [(waist circumference – 80)/SD] + [(systolic blood pressure – 130)/SD] + [(diastolic blood pressure – 85)/SD] Cardiorespiratory fitness and maximal power output. Maximal oxygen uptake (VO 2MAX ), maximal cycling power (W MAX ), and maximal heart rate (HR MAX ) were determined during a graded exercise test (GXT) performed on an electronically braked cycle ergometer (Ergoselect 200, Ergoline; Bitz, Germany). Gas exchange was continuously measured using indirect calorimetry (Quark RMR, Cosmed; Rome, Italy), and cardiac electrical activity was monitored via a standard 12-lead ECG (Quark T12, Cosmed; Rome, Italy). Following a 3-minute warm-up at 30 W for women and 50 W for men, the workload was increased by 15 W for women and 20 W for men every minute until volitional exhaustion. Immediately afterward, a verification test was conducted at 110% of the maximal workload achieved during the GXT to confirm attainment of VO 2MAX . Blood pressure monitoring during exercise. During the GXT, BP was manually measured by a trained practitioner using a calibrated sphygmomanometer (Gamma G7, Heine; Gilching, Germany), following established methodological standards 15 . Measurements were obtained from the left arm, with an appropriately sized cuff positioned at heart level and the arm supported throughout the test to minimize motion artifacts and ensure accuracy. BP was recorded with participants seated on the cycle ergometer at the onset of the exercise protocol (15 W for women, 50 W for men at minute 3), and every 2 minutes at the end of each odd-numbered stage. Peak BP was determined immediately upon cessation of exercise at maximal exertion. Exercise was terminated either upon volitional exhaustion or if any predefined safety criteria for test termination were met, including chest pain with ischemic ECG changes, complex ectopy or high-grade atrioventricular block, symptomatic SBP drop > 20 mmHg, severe exercise hypertension (SBP > 240 mmHg or DBP > 120 mmHg), oxygen desaturation, neurological symptoms, or at the discretion of the supervising physician. Statistical analysis. A per-protocol analysis was conducted, including only participants who completed the intervention. Sample size calculations were based on expected changes in CRF, using data from our previous study in which individuals with MetS who completed a 16-week exercise program similar to the present protocol 16 . In this study, participants increased 0.24 ± 0.27 L·min − 1 following HIIT, translating to an effect size of d = 1.11. Therefore, 23 participants per group should be sufficient to achieve a power of 0.95 at an alpha level of 0.05. Due to account for potential dropouts of exercise interventions (i.e., ~ 30% exercise intervention attrition rates) or changing medications (primary care follow-up), the sample size was increased in each group (N = 40). Data are reported as mean ± standard deviation, with 95% confidence intervals (CI) calculated for all outcome measures. Normality was verified using the Shapiro–Wilk test. Baseline comparisons between groups were performed using independent samples t-tests. To assess the effects of training over time and between groups, a mixed-design (split-plot) ANCOVA was used for all variables, with baseline values entered as covariates. This approach allowed evaluation of time × group interactions while accounting for repeated measures (PRE and POST) within participants. Post hoc pairwise comparisons with Bonferroni correction were conducted only when significant interactions were observed. All statistical analyses were performed using SPSS v28 (IBM, Chicago, IL, USA), with significance set at p ≤ 0.05. . RESULTS Baseline subjects’ characteristics. Participants were Caucasians living in southern Europe. Women comprise 48% of the AHM group and 46% of the CONTROL. Data were analyzed without stratification by sex, since all female participants were postmenopausal, not receiving hormone replacement therapy, and showed no significant differences compared to male participants in the main study outcomes (time x sex interaction; MetS Z score, p = 0.31; SBP, p = 0.25; DBP, p = 0.17; body weight, p = 0.31; and VO 2MAX (mL·Kg − 1 ·min − 1 ), p = 0.16). Subjects’ adherence to training sessions was 91% for AHM and 90% for CONTROL ( p > 0.05). There were no differences in calorie intake or physical activity between groups. On average, subjects ingested 2296 ± 93 at baseline and 2322 ± 82 kcal·day − 1 after the intervention (both p > 0.05). Macronutrient distribution remained stable across groups (47 ± 5% carbohydrate, 33 ± 2% fat [40% saturated fat], and 20 ± 1% protein). Baseline physical activity averaged 6025 ± 362 steps·day − 1 , 196 ± 147 min·day − 1 of standing, and 496 ± 165 min·day − 1 supine rest, with similar values after 16 weeks (587 ± 224 steps·day − 1 , 189 ± 77 min·day − 1 standing and 499 ± 201 min·day − 1 supine rest; all p > 0.05). Body weight and composition. At baseline, participants had similar body weight, BMI, fat mass, and fat-free mass (all p > 0.05; Table 2 ). After 16 weeks of HIIT, no significant main effects of time or time × group interaction effects were observed for any anthropometric variable (all p > 0.05). Table 2 Changes in anthropometric, cardiometabolic factors, and maximal exercise variables after 16 weeks of training in both groups. AHM (n = 27) CONTROL (n = 35) P value Baseline 16 weeks Baseline 16 weeks Baseline Time Time x group Age (yr) 55 ± 7 51 ± 9 0.028 % Women 48% 46% Anthropometric Weight (kg) 94.1 ± 18.5 93.1 ± 18.5 89.8 ± 15.4 88.2 ± 14.8 0.338 0.443 0.330 BMI (kg·m − 2 ) 34.2 ± 4.7 33.8 ± 4.8 32.4 ± 3.9 31.8 ± 3.8 0.119 0.695 0.226 Fat mass (kg) 36.3 ± 10.8 35.6 ± 11.0 33.8 ± 11.6 32.6 ± 11.1 0.383 0.771 0.315 Fat-free mass (kg) 57.8 ± 13.8 57.4 ± 13.0 55.2 ± 14.9 54.8 ± 14.7 0.476 0.057 0.747 Metabolic Syndrome factors Waist circumference (cm) 109.9 ± 12.9 108.1 ± 13.1 106.4 ± 10.4 103.6 ± 9.4 0.259 0.110 0.148 Glucose (mg·dL − 1 ) 102.1 ± 12.1 102.5 ± 10.4 105.5 ± 16.5 104.3 ± 18.0 0.366 0.002 0.899 Triglycerides (mg·dL − 1 ) 127.1 ± 48.4 111.2 ± 41.8 149.8 ± 76.6 136.9 ± 72.4 0.165 0.027 0.350 HDL-c (mg·dL − 1 ) 41.7 ± 8.6 43.0 ± 8.4 43.2 ± 10.9 43.7 ± 10.2 0.567 0.001 0.758 MetS Z -score 0.23 ± 0.55 0.01 ± 0.50 0.32 ± 0.61 0.02 ± 0.58 0.554 < 0.001 0.580 Cardiometabolic risk factors Total Cholesterol (mg·dL − 1 ) 192.0 ± 21.3 193.3 ± 28.3 214.4 ± 38.8 215.1 ± 36.9 0.005 0.096 0.687 LDL-c (mg·dL − 1 ) 124.8 ± 21.3 128.1 ± 24.4 141.3 ± 33.4 144.0 ± 30.7 0.023 0.005 0.538 Insulin (µIU·mL − 1 ) 14.4 ± 6.8 13.0 ± 7.2 12.0 ± 6.6 10.3 ± 4.8 0.161 0.009 0.303 HOMA-IR 3.7 ± 1.8 3.3 ± 2.0 3.2 ± 2.0 2.7 ± 1.6 0.360 0.061 0.405 Maximal Exercise parameters Maximal Heart Rate (beats·min − 1 ) 154 ± 15 156 ± 13 155 ± 17 160 ± 14 0.803 < 0.001 0.192 O 2 Pulse at VO 2MAX (mL·beat − 1 ) 12.9 ± 3.5 15.0 ± 4.0 13.3 ± 5.0 15.5 ± 5.2 0.697 0.003 0.750 Heart Rate Reserve (beats·min − 1 ) 86 ± 18 91 ± 17 88 ± 20 93 ± 17 0.635 < 0.001 0.966 Maximal SBP (mmHg) 179.4 ± 22.4 175.5 ± 19.9 170.7 ± 26.4 171.8 ± 18.0 0.432 < 0.001 0.961 Maximal DBP (mmHg) 93.1 ± 13.8 87.5 ± 12.2 93.6 ± 17.0 89.6 ± 19.1 0.933 0.138 0.770 Maximal MAP (mmHg) 121.8 ± 15.9 116.9 ± 13.5 119.3 ± 18.1 117.0 ± 15.6 0.743 0.008 0.806 Data are presented as mean ± SD. Abbreviations: SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure; MAP, Mean Arterial Pressure. MetS components and additional physiological parameters. Changes in MetS components after 16 weeks of training are depicted in Table 2 . Before intervention, MetS components were not different among groups (all p > 0.05). After intervention, we observed a significant time effect in glucose (AHM, 0.4; 95% CI -4.8 to 4.2 mg·dL - 1 and CONTROL, -1.2; 95% CI -4.7 to 3.4 mg·dL - 1 ; p = 0.002), triglycerides (AHM, -15.9; 95% CI -35.5 to -4.0 mg·dL - 1 and CONTROL, -12.8; 95% CI -23.8 to 4.2 mg·dL - 1 ; p = 0.027), and HDL-c (AHM, 1.3; 95% CI -1.1 to 3.3 mg·dL - 1 and CONTROL, 0.5; 95% CI -1.3 to 2.6 mg·dL - 1 ; p = 0.001). Similarly, the MetS Z-score showed a significant time effect ( p < 0.001), with improvements of 96% in the AHM group (− 0.22 SDs; 95% CI − 0.37 to − 0.11) and 93% in the CONTROL group (− 0.30 SDs; 95% CI − 0.41 to − 0.17). However, no significant time × group interaction effects were observed for any MetS components and MetS Z-score (all p > 0.05). At baseline, total cholesterol ( p = 0.005) and LDL-c ( p = 0.023) were higher in the CONTROL than in the AHM group. Following the intervention, a significant time effect was observed for LDL-c (AHM, 3.2; 95% CI -4.8 to 7.8 mg·dL⁻¹ and CONTROL, 2.8; 95% CI -1.4 to 9.7 mg·dL⁻¹; p = 0.005) and insulin (AHM, -1.4; 95% CI -2.6 to 0.7 µIU·mL⁻¹ and CONTROL, -1.7; 95% CI -3.5 to -0.6 µIU·mL⁻¹; p = 0.009). However, no significant time × group interaction was detected for either variable (all p > 0.05). Resting blood pressure. Changes in resting BP over 16 weeks of training are shown in Fig. 2 . At baseline, systolic blood pressure (SBP, p = 0.65), diastolic blood pressure (DBP, p = 0.77), and mean arterial pressure (MAP, p = 0.69) did not differ between groups. After intervention, we observed a significant time effect in rest SBP (AHM, -3.2; 95% CI -7.7 to 0.6 mmHg and CONTROL, -8.0; 95% CI -11.5 to -4.2 mmHg; p = 0.005), DBP (AHM, -4.6; 95% CI -7.0 to -2.5 mmHg and CONTROL, -5.8; 95% CI -7.7 to -3.7 mmHg; p = 0.005), and MAP (AHM, -4.2; 95% CI -7.0 to -1.7 mmHg and CONTROL, -6.5; 95% CI -8.7 to -4.2 mmHg; p = 0.005). However, no significant time × group interaction effects were observed for any component of resting blood pressure (all p > 0.05). Cardiorespiratory fitness and maximal exercise responses. CRF (i.e., VO 2MAX ) and maximal power output (W MAX ) evolution after intervention are shown in Fig. 3 . Before intervention, CRF (expressed as VO 2MAX in L·min - 1 [ p = 0.79] and mL·Kg - 1 ·min - 1 [ p = 0.59] ) and W MAX ( p = 0.41) were similar between AHM and CONTROL groups. After 16 weeks of HIIT, we observed a significant time effect in CRF (AHM, 0.33; 95% CI 0.24 to 0.43 L·min - 1 and CONTROL, 0.42; 95% CI 0.34 to 0.50 L·min - 1 ; p = 0.05) and W MAX (AHM, 33; 95% CI 25 to 41 W and CONTROL, 40; 95% CI 33 to 47 W; p = 0.003). However, no significant time × group interaction effects were observed for any component of exercise performance (all p > 0.05). Since body weight and fat mass decreased similarly in both groups (Table 2 ), changes in CRF per kilogram of body weight responded similarly to the absolute values (AHM, 3.9; 95% CI 2.8 to 4.9 mL·Kg - 1 ·min - 1 and CONTROL, 5.0; 95% CI 4.1 to 5.9 mL·Kg - 1 ·min - 1 ; p = 0.003). The maximal heart rate (HR MAX ), oxygen pulse (O 2 Pulse at VO 2MAX ), and heart rate reserve (HRR) response are shown in Table 2 . At baseline, there were no differences between groups on any of these variables (all p > 0.05). After exercise training, we observed a significant time effect in HR MAX (AHM, 2; 95% CI -1 to 5 beats·min - 1 and CONTROL, 5; 95% CI 2 to 7 beats·min - 1 ; p < 0.001), O 2 Pulse at VO 2MAX (AHM, 2.1; 95% CI 1.4 to 2.7 mL·beat - 1 and CONTROL, 2.2; 95% CI 1.6 to 2.8 mL·beat - 1 ; p = 0.003) and HRR (AHM, 6; 95% CI 1 to 9 beats·min - 1 and CONTROL, 5; 95% CI 1 to 9 beats·min - 1 ; p < 0.001). Blood pressure during graded exercise. BP response during the graded exercise test GXT is shown in Table 2 and Fig. 4 . At baseline, maximal SBP, maximal DBP, and maximal MAP did not differ between groups (all p > 0.05). Following the intervention, a significant main effect of time was observed for maximal SBP ( AHM, -3.9; 95% CI -12.7 to 11.1 mmHg and CONTROL, 1.1; 95% CI -11.9 to 9.6 mmHg; p = 0.001) and maximal MAP (AHM, -5.0; 95% CI -13.4 to 4.9 mmHg and CONTROL, -2.3; 95% CI -11.0 to 5.4 mmHg; p = 0.008). However, no significant time × group interaction was detected for either variable (both p > 0.05; Table 2 ). Blood pressure responses at each stage of the graded exercise test—normalized to the percentage of maximal heart rate achieved (%HR MAX )—showed a significant main effect of time only for DBP ( p = 0.047; Fig. 4 B) with no time × group interaction observed for any variable (all p > 0.05). DISCUSION In this 16-week supervised HIIT intervention, chronic treatment with ACEi or ARBs did not attenuate exercise-induced physiological adaptations in middle-aged adults with MetS. Both pharmacologically treated and untreated participants exhibited clinically meaningful improvements in resting and exercise blood pressure, cardiorespiratory fitness (CRF, as assessed by VO 2MAX ), and metabolic health (assessed by MetS Z-score). Importantly, no significant time × group interactions were detected for any cardiometabolic, hemodynamic, or performance-related outcomes, suggesting that chronic renin–angiotensin system inhibition does not impair the beneficial effects of HIIT. Additionally, body composition, dietary intake, and habitual physical activity remained stable, supporting the interpretation that observed improvements were primarily exercise-induced. Blood pressure reduction and cardiometabolic adaptations. The decrease in resting blood pressure observed in our participants (~ 3–8 mmHg in SBP and ~ 5–6 mmHg in DBP) is consistent with meta-analyses showing average decreases of ~ 3–6 mmHg and ~ 2–3 mmHg, respectively, after aerobic training, including HIIT 8 . Prior evidence also indicates that structured exercise can elicit SBP reductions comparable to first-line antihypertensive therapy 11 . Within this context, our data showed that chronic RAAS inhibition neither attenuated nor enhanced HIIT-induced adaptations, as medicated and non-medicated participants demonstrated comparable metabolic, hemodynamic, and fitness responses. These findings are consistent with placebo-controlled evidence showing that AHM and HIIT exert independent and additive effects on ambulatory BP in hypertensive individuals with MetS 10 . Although RAAS blockade altered biochemical indices (e.g., increased renin activity and a lower aldosterone-to-renin ratio), exercise-induced BP reductions appeared to occur through mechanisms independent of RAAS suppression. In accordance with these findings, our previous work showed that only hypertensive individuals—regardless of treatment status or antihypertensive class—exhibited training-induced BP reductions, and that the magnitude of this response scaled with baseline BP, consistent with Wilder’s principle 17 . Acute and chronic interactions between exercise and RAAS Inhibition. Following these observations, acute studies have shown that combining a single session of aerobic exercise with AHM produces greater immediate BP reductions than either intervention alone 18 , particularly at higher intensities 19 . However, whether such acute synergistic effects persist with long-term training remains unclear. Chronic aerobic or interval training has been shown to reduce arterial stiffness, improve endothelial function 20 , and decrease systemic vascular resistance 21 in individuals with MetS. However, evidence regarding the preservation of these adaptations during chronic ACEi or ARB therapy remains limited, with available data largely derived from animal models suggesting complementary effects of ARBs and exercise on blood pressure and cardiac function 22 . Our findings demonstrate that 16 weeks of HIIT elicited favorable hemodynamic and vascular adaptations in medicated participants, with no evidence that RAAS blockade interfered with these responses. Collectively, these findings support the compatibility of angiotensin antagonist medication with exercise training and reinforce the combined use of pharmacologic and lifestyle interventions in the management of hypertension and MetS. Cardiorespiratory fitness and clinical implications. Evidence on whether RAAS-targeting medications influence exercise-induced improvements in CRF has been controversial. Some studies in older adults have reported that ACEi therapy alone enhances exercise capacity 23 , 24 and may augment functional adaptations in frail populations 25 . However, other trials in functionally impaired older adults 26 , 27 and healthy individuals 13 observed no additive effect of ACEi on training-induced gains. The present findings align with this latter evidence, demonstrating that chronic ACEi or ARBs therapy does not attenuate CRF improvements following HIIT. Absolute VO 2MAX increased by approximately 22% in the AHM group and 18% in the control group, equivalent to gains of ~ 1.4 and ~ 1.1 metabolic equivalents (METs), respectively. Exercise capacity is a strong predictor of cardiovascular and all-cause mortality in patients with hypertension 12 . Our improvements correspond to a ~ 13% reduction in all-cause mortality and a ~ 15% reduction in cardiovascular events 28 . Epidemiological data from an extensive Swedish registry indicate that individuals who increase CRF by > 3% per year have an 11% lower risk of incident hypertension. In contrast, individuals who experience CRF declines have a 25% increased risk, independent of lifestyle factors 29 . Collectively, these results suggest that HIIT-induced improvements in CRF may contribute to both short-term BP control and long-term decreases in cardiovascular risk, and that these benefits are preserved despite chronic RAAS inhibition. Blood pressure responses during exercise. During dynamic exercise, SBP rises in proportion to intensity due to increased cardiac output driven by sympathetic activation, whereas DBP typically remains stable or slightly decreases owing to peripheral vasodilation. Exaggerated SBP responses reflect impaired vascular regulation and are associated with arterial stiffness, endothelial dysfunction, and increased long-term cardiovascular risk 30 . Chant et al. 31 showed that individuals with treated and apparently controlled hypertension exhibit elevated SBP responses during both submaximal and maximal exercise, comparable to those observed in untreated or uncontrolled hypertension. This phenomenon has been attributed, at least in part, to heightened metaboreflex sensitivity that appears relatively resistant to conventional antihypertensive pharmacotherapy. In contrast, in the present study, baseline SBP responses across exercise intensities did not differ between groups, suggesting that chronic angiotensin receptor blockade did not materially alter the acute exercise pressor response. Differences in baseline hypertension severity and treatment burden may explain the discrepancies between our findings and those of Chant et al. Notably, their participants' cohort entered the study with resting SBP values near the hypertensive threshold (~ 138 mmHg). It was predominantly managed with multidrug regimens, a clinical phenotype more likely to exhibit persistently exaggerated pressor responses during physical stress. After 16 weeks of HIIT, both groups exhibited a significant time effect in maximal MAP (Table 2 ) and submaximal DBP (Fig. 4 B), accompanied by improvements in workload capacity, CRF, heart rate reserve, and maximal oxygen pulse (Fig. 3 , Table 2 ). Consistent with previous findings, oxygen pulse kinetics during exercise are closely associated with both systolic and diastolic left ventricular performance in older adults with mild hypertension 32 , supporting its use as an indirect marker of improved central hemodynamic responses to exercise. Importantly, indexing SBP to external workload has been shown to predict all-cause mortality more accurately than peak SBP, underscoring the clinical relevance of improved hemodynamic efficiency during exercise 33 . These results align with prior studies reporting modest reductions in exercise BP following training 34 , and with a pooled analysis of 10 RCTs showing a ~ 7 mmHg decrease in exercise SBP after aerobic training despite heterogeneity in age, BP status, and intervention protocols 35 . Collectively, the data suggest that HIIT improves vascular dynamics and exercise tolerance, moderating MAP and DBP responses through enhanced vascular compliance, improved endothelial function, and attenuated sympathetic activation, even in the context of chronic inhibition of the RAAS Strengths and Limitations. The primary strength of this study is its prospective, supervised intervention design, which enabled a direct comparison of exercise-induced adaptations between two clinically relevant populations: adults with MetS under chronic ACEi or ARBs therapy and those not receiving pharmacological treatment. This pragmatic approach enhances clinical applicability and provides insights into real-world interactions between pharmacologic RAAS inhibition and exercise-induced cardiovascular adaptations. However, several limitations should be acknowledged. First, although baseline adjustment was performed, the absence of randomization warrants caution when inferring causality. Second, pharmacologic heterogeneity—specifically the use of multiple ACEi and ARBs agents at varying doses—may have influenced vascular and hemodynamic outcomes. Future randomized controlled trials with standardized pharmacotherapy protocols are needed to delineate the specific contributions of individual RAAS inhibitors to exercise-induced adaptations. Conclusions In summary, chronic ACEi or ARBs therapy did not attenuate the cardiometabolic, hemodynamic, or functional adaptations elicited by 16 weeks of supervised HIIT in adults with MetS. Medicated and non-medicated participants exhibited comparable improvements in resting and exercise blood pressure, CRF, and metabolic health, with no evidence of impaired responsiveness associated with chronic RAAS inhibition. These findings support the physiological compatibility of RAAS blockade with structured exercise training and reinforce the role of HIIT as an effective therapeutic strategy in the management of MetS among individuals receiving long-term antihypertensive treatment. Declarations DATA AVAILABILITY STATEMENT The datasets generated and/or analyzed during the current study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author on reasonable request. AUTHOR CONTRIBUTIONS ILS and FMP conceived and designed the study. ILS, AMC, LGG, RMR and FMP conducted the investigation and data collection. ILS., AMC., DMG, and FMP performed data curation and formal statistical analysis. ILS, AMC and FMP. drafted the original manuscript. AMC, LGG, DMG, and RMR critically reviewed and revised the manuscript for important intellectual content. RMR and FMP supervised the project. RMR acquired funding. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work. FUNDING Spanish Ministry of Economy, Industry and Competivity (DEP-2017-83244-R) and Spanish Ministry of Science and Innovation (PID2020-116159RB- IOO MCIN/AEI/10.13039/501100011033). The granting agencies have no role in the design, execution, or reporting of the results of this study. COMPETING INTERESTS The authors declare that they have no competing interests. ETHICAL APPROVAL The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Virgen de la Salud Hospital of Toledo (reference #170). All participants provided written informed consent. The work is a substudy of a registered clinical trial (ClinicalTrials.gov: NCT03019796). References Yusuf S, Joseph P, Rangarajan S, Islam S, Mente A, Hystad P et al. Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study. The Lancet 2020; 395(10226): 795–808. Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nature Reviews Nephrology 2020; 16(4): 223–237. Mancia G, Kreutz R, Brunström M, Burnier M, Grassi G, Januszewicz A et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). Journal of hypertension 2023; 41(12): 1874–2071. Jayawardana S, Campbell A, Aitken M, Andersson CE, Mehra MR, Mossialos E. Global consumption patterns of combination hypertension medication: An analysis of pharmaceutical sales data from 2010–2021. PLOS global public health 2024; 4(9): e0003698. Caulfield L, Heslop P, Walesby KE, Sumukadas D, Sayer AA, Witham MD. Effect of Angiotensin System Inhibitors on Physical Performance in Older People – A Systematic Review and Meta-Analysis. Journal of the American Medical Directors Association 2021; 22(6): 1215–1221.e2. Wei J, Galaviz KI, Kowalski AJ, Magee MJ, Haw JS, Narayan KMV et al. Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications: A Systematic Review and Network Meta-analysis. JAMA Network Open 2020; 3(2): e1921618-e1921618. Cornelissen VA, Fagard RH. Effects of Endurance Training on Blood Pressure, Blood Pressure–Regulating Mechanisms, and Cardiovascular Risk Factors. Hypertension 2005; 46(4): 667–675. Edwards JJ, Deenmamode AHP, Griffiths M, Arnold O, Cooper NJ, Wiles JD et al. Exercise training and resting blood pressure: a large-scale pairwise and network meta-analysis of randomised controlled trials. British journal of sports medicine 2023; 57(20): 1317–1326. Baffour-Awuah B, Man M, Goessler KF, Cornelissen VA, Dieberg G, Smart NA et al. Effect of exercise training on the renin-angiotensin-aldosterone system: a meta-analysis. Journal of human hypertension 2024; 38(2): 89–101. Ramirez-Jimenez M, Morales-Palomo F, Moreno-Cabañas A, Alvarez-Jimenez L, Ortega JF, Mora-Rodriguez R. Effects of antihypertensive medication and high-intensity interval training in hypertensive metabolic syndrome individuals. Scandinavian journal of medicine & science in sports 2021; 31(7): 1411–1419. Naci H, Salcher-Konrad M, Dias S, Blum MR, Sahoo SA, Nunan D et al. How does exercise treatment compare with antihypertensive medications? A network meta-analysis of 391 randomised controlled trials assessing exercise and medication effects on systolic blood pressure. British journal of sports medicine 2019; 53(14): 859–869. Kokkinos P. Cardiorespiratory Fitness, Exercise, and Blood Pressure. Hypertension 2014; 64(6): 1160–1164. Sjúrðarson T, Bejder J, Breenfeldt Andersen A, Bonne T, Kyhl K, Róin T et al. Effect of angiotensin-converting enzyme inhibition on cardiovascular adaptation to exercise training. Physiological reports 2022; 10(13): e15382. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120(16): 1640–5. Nayor M, Gajjar P, Murthy VL, Miller PE, Velagaleti RS, Larson MG et al. Blood Pressure Responses During Exercise: Physiological Correlates and Clinical Implications. Arteriosclerosis, thrombosis, and vascular biology 2023; 43(1): 163–173. Morales-Palomo F, Ramirez-Jimenez M, Ortega JF, Mora-Rodriguez R. Effectiveness of Aerobic Exercise Programs for Health Promotion in Metabolic Syndrome. Medicine and science in sports and exercise 2019; 51(9): 1876–1883. Mora-Rodriguez R, Ortega JF, Morales-Palomo F, Ramirez-Jimenez M, Moreno-Cabañas A, Alvarez-Jimenez L. Endurance Exercise Training reduces Blood Pressure according to the Wilder's Principle. International journal of sports medicine 2022; 43(4): 336–343. Ramirez-Jimenez M, Morales-Palomo F, Ortega JF, Mora-Rodriguez R. Post-exercise Hypotension Produced by Supramaximal Interval Exercise is Potentiated by Angiotensin Receptor Blockers. International journal of sports medicine 2019; 40(12): 756–761. Morales-Palomo F, Ramirez-Jimenez M, Ortega JF, Pallarés JG, Mora-Rodriguez R. Acute Hypotension after High-Intensity Interval Exercise in Metabolic Syndrome Patients. International journal of sports medicine 2017; 38(7): 560–567. Mora-Rodriguez R, Ramirez-Jimenez M, Fernandez-Elias VE, Guio de Prada MV, Morales-Palomo F, Pallares JG et al. Effects of aerobic interval training on arterial stiffness and microvascular function in patients with metabolic syndrome. Journal of clinical hypertension (Greenwich, Conn.) 2018; 20(1): 11–18. Mora-Rodriguez R, Fernandez-Elias VE, Morales-Palomo F, Pallares JG, Ramirez-Jimenez M, Ortega JF. Aerobic interval training reduces vascular resistances during submaximal exercise in obese metabolic syndrome individuals. Eur J Appl Physiol 2017; 117(10): 2065–2073. Aguilar BA, Vieira S, Veiga AC, da Silva JVMB, Paixao TV, Rodrigues KP et al. Physical exercise is essential for increasing ventricular contractility in hypertensive rats treated with losartan. Hypertension Research 2024; 47(5): 1350–1361. Hutcheon SD, Gillespie ND, Crombie IK, Struthers AD, McMurdo ME. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised double blind placebo controlled trial. Heart (British Cardiac Society) 2002; 88(4): 373–7. Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. CMAJ: Canadian Medical Association journal = journal de l'Association medicale canadienne 2007; 177(8): 867–74. Buford TW, Manini TM, Hsu FC, Cesari M, Anton SD, Nayfield S et al. Angiotensin-converting enzyme inhibitor use by older adults is associated with greater functional responses to exercise. Journal of the American Geriatrics Society 2012; 60(7): 1244–52. Sumukadas D, Band M, Miller S, Cvoro V, Witham M, Struthers A et al. Do ACE inhibitors improve the response to exercise training in functionally impaired older adults? A randomized controlled trial. The journals of gerontology. Series A, Biological sciences and medical sciences 2014; 69(6): 736–43. Baptista LC, Machado-Rodrigues AM, Veríssimo MT, Martins RA. Exercise training improves functional status in hypertensive older adults under angiotensin converting enzymes inhibitors medication. Experimental gerontology 2018; 109: 82–89. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M et al. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. Jama 2009; 301(19): 2024–35. Holmlund T, Ekblom B, Börjesson M, Andersson G, Wallin P, Ekblom-Bak E. Association between change in cardiorespiratory fitness and incident hypertension in Swedish adults. European journal of preventive cardiology 2021; 28(13): 1515–1522. Carlén A, Lindow T, Cauwenberghs N, Elmberg V, Brudin L, Ekström M et al. Exercise systolic blood pressure response during cycle ergometry is associated with future hypertension in normotensive individuals. European journal of preventive cardiology 2024; 31(9): 1072–1079. Chant B, Bakali M, Hinton T, Burchell AE, Nightingale AK, Paton JFR et al. Antihypertensive Treatment Fails to Control Blood Pressure During Exercise. Hypertension 2018; 72(1): 102–109. Lim JG, McAveney TJ, Fleg JL, Shapiro EP, Turner KL, Bacher AC et al. Oxygen pulse during exercise is related to resting systolic and diastolic left ventricular function in older persons with mild hypertension. American heart journal 2005; 150(5): 941–6. Hedman K, Cauwenberghs N, Christle JW, Kuznetsova T, Haddad F, Myers J. Workload-indexed blood pressure response is superior to peak systolic blood pressure in predicting all-cause mortality. European journal of preventive cardiology 2020; 27(9): 978–987. Barone BB, Wang NY, Bacher AC, Stewart KJ. Decreased exercise blood pressure in older adults after exercise training: contributions of increased fitness and decreased fatness. British journal of sports medicine 2009; 43(1): 52–6. Pescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA, Ray CA. American College of Sports Medicine position stand. Exercise and hypertension. Medicine and science in sports and exercise 2004; 36(3): 533–53. Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Under Review Version 1 posted Review # 1 received at journal 11 May, 2026 Reviewer # 1 agreed at journal 11 May, 2026 Reviewers invited by journal 10 May, 2026 Submission checks completed at journal 01 May, 2026 First submitted to journal 01 May, 2026 Unknown event 28 Apr, 2026 Editor assigned by journal 26 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9530735","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":629690638,"identity":"f5a5355b-f276-47f1-98a0-d23dae491f93","order_by":0,"name":"Felix Morales-Palomo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIie2RMQrCMBSGXyi0S7SbBCLtFZQODg5epcHBK3RwSCm0V3AQj9E5JeDkDTrlBoqL3UxbLbjE4uSQjwx/ho/3fh6AxfKHeNzhoo8OB0gApt8ULNBbQVq5ALhjFBgUlI9RvDSVGMpgVVSpak4ydGcCqYdJwRWvDlBH8wvLokkplzmNnQgblA1hXFyhZgdgOUWljF2qn3GxUHERt4qviqY5dorXGBcj6DWFsBwmvJ8CpsUwZrrLoo4IURnF553uwnQwKZ6Ud5zUAfG31e2xX4c+bYOpTMfi4zdcymKxWCy/8gShPUwmmFSjdgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8881-8592","institution":"University of Castilla-La Mancha","correspondingAuthor":true,"prefix":"","firstName":"Felix","middleName":"","lastName":"Morales-Palomo","suffix":""},{"id":629690639,"identity":"72d19161-7fa7-4080-922f-4ed8fcb6b9af","order_by":1,"name":"Irene Labrador-Sanchez","email":"","orcid":"","institution":"University of Castilla-La Mancha","correspondingAuthor":false,"prefix":"","firstName":"Irene","middleName":"","lastName":"Labrador-Sanchez","suffix":""},{"id":629690640,"identity":"ae03f234-2ca5-45d1-a1c5-738093a67d51","order_by":2,"name":"Alfonso Moreno-Cabañas","email":"","orcid":"","institution":"University of Castilla-La Mancha","correspondingAuthor":false,"prefix":"","firstName":"Alfonso","middleName":"","lastName":"Moreno-Cabañas","suffix":""},{"id":629690641,"identity":"3174eeeb-2d83-49f2-8fea-dda59cb5cee1","order_by":3,"name":"Lucia Gonzalez-Garcia","email":"","orcid":"","institution":"University of Castilla-La Mancha","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Gonzalez-Garcia","suffix":""},{"id":629690642,"identity":"512808d6-23a2-48e0-a2b2-bab3269f7a05","order_by":4,"name":"Diego Mora-Gonzalez","email":"","orcid":"","institution":"University of Castilla-La Mancha","correspondingAuthor":false,"prefix":"","firstName":"Diego","middleName":"","lastName":"Mora-Gonzalez","suffix":""},{"id":629690643,"identity":"5bb82c32-f565-49fa-bfe3-f8ca7a745760","order_by":5,"name":"Ricardo Mora-Rodriguez","email":"","orcid":"https://orcid.org/0000-0001-9252-4933","institution":"University of Castilla-La Mancha","correspondingAuthor":false,"prefix":"","firstName":"Ricardo","middleName":"","lastName":"Mora-Rodriguez","suffix":""}],"badges":[],"createdAt":"2026-04-26 09:20:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9530735/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9530735/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108012751,"identity":"cd3a6f70-3926-449b-abe5-869c0a26c911","added_by":"auto","created_at":"2026-04-28 13:16:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":471834,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of participant recruitment, group allocation based on medication status, intervention, and follow-up.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-9530735/v1/5d5e11fae4b491b342b1030d.png"},{"id":109067640,"identity":"e9d92904-11d4-40bb-a711-ca5ef75a8da6","added_by":"auto","created_at":"2026-05-12 09:58:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10157063,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in resting systolic blood pressure (A), diastolic blood pressure (B), and mean arterial pressure (C) after 16 weeks of high-intensity interval training in the AHM and CONTROL groups. Values are presented as bars and dot plots with mean ± SD.\u003c/p\u003e","description":"","filename":"FIG2.png","url":"https://assets-eu.researchsquare.com/files/rs-9530735/v1/bb8860e61770f4322caebc6d.png"},{"id":108012534,"identity":"35601ee7-03e8-4f14-b4fe-d9340ac2d6cb","added_by":"auto","created_at":"2026-04-28 13:15:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":9676685,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in absolute VO\u003csub\u003e2MAX\u003c/sub\u003e (A), relative VO\u003csub\u003e2MAX\u003c/sub\u003e (B), and maximal power output (C) after 16 weeks of high-intensity interval training in the AHM and CONTROL groups. Values are presented as bars and dot plots with mean ± SD.\u003c/p\u003e","description":"","filename":"FIG3.png","url":"https://assets-eu.researchsquare.com/files/rs-9530735/v1/c9047cfd509ca84d90fa0279.png"},{"id":108012492,"identity":"b3b8a95a-024a-4f4a-a803-a96611f25e16","added_by":"auto","created_at":"2026-04-28 13:15:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":5659888,"visible":true,"origin":"","legend":"\u003cp\u003eSystolic blood pressure (A), diastolic blood pressure (B), and mean arterial pressure (C) responses during graded exercise before and after 16 weeks of high-intensity interval training in the AHM and CONTROL groups. Blood pressure values are normalized to the percentage of HR\u003csub\u003eMAX\u003c/sub\u003e to allow direct comparisons between groups and over time and are presented as mean ± SD with individual data points.\u003c/p\u003e","description":"","filename":"FIG4.png","url":"https://assets-eu.researchsquare.com/files/rs-9530735/v1/4a04b949275fb49db70abd04.png"},{"id":109069234,"identity":"be0b85c7-4f9c-4985-8d20-598fa4afe112","added_by":"auto","created_at":"2026-05-12 10:21:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":19183644,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9530735/v1/b3e651f0-0dfb-4bc5-b96f-78b44dfc6b1c.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Effect of chronic angiotensin system inhibitor treatment on cardiovascular adaptations to exercise training in adults with metabolic syndrome","fulltext":[{"header":"What is known about the topic","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003eHypertension and metabolic syndrome (MetS) are major cardiovascular risk factors commonly managed with antihypertensive drugs and exercise.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) target the renin\u0026ndash;angiotensin system and are first-line therapies in hypertension.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHigh-intensity interval training (HIIT) improves blood pressure (BP), cardiorespiratory fitness (CRF), and metabolic health in MetS.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat this study adds\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eChronic ACEi/ARB therapy does not attenuate adaptations to 16 weeks of supervised HIIT in adults with MetS.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHIIT produced similar reductions in BP and improvements in CRF (~18\u0026ndash;22% VO\u003csub\u003e2MAX\u003c/sub\u003e increase) in medicated and non-medicated participants.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eExercise-induced cardiometabolic benefits are preserved despite long-term RAAS inhibition, supporting combined therapy in clinical practice.\u003c/li\u003e\n\u003c/ul\u003e\n"},{"header":"INTRODUCTION","content":"\u003cp\u003eHypertension remains one of the most prevalent modifiable risk factors for cardiovascular disease (CVD) \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Despite the widespread use of antihypertensive medications (AHM), their global burden continues to rise, affecting nearly one-third of adults \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Current guidelines recommend lifestyle interventions as first-line therapy; however, long-term adherence is often suboptimal, and pharmacological treatment is frequently initiated early in high-risk individuals owing to concerns about target organ damage \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Consequently, clinical management commonly combines pharmacotherapy with structured exercise interventions.\u003c/p\u003e \u003cp\u003eGlobal use of AHM has increased substantially over the past decade, and angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers, and thiazide/thiazide-like diuretics are widely recommended as first-line therapies \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. ACEi and ARBs act by inhibiting the renin\u0026ndash;angiotensin\u0026ndash;aldosterone system (RAAS), a key regulator of vascular tone, blood volume, and systemic vascular resistance \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, and provide additional cardiovascular benefits, including improved endothelial function and reduced myocardial remodeling \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In parallel, exercise training is a cornerstone of hypertension management \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, with robust evidence supporting its blood pressure (BP)-lowering effects \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, mediated in part by reductions in sympathetic activity and modulation of RAAS signaling \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEmerging evidence suggests that combining AHM with high-intensity interval training (HIIT) may produce additive or synergistic effects on BP reduction. HIIT can further reduce ambulatory BP beyond pharmacotherapy in hypertensive individuals with metabolic syndrome (MetS) \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, and exercise-induced reductions in systolic BP may approach those achieved with pharmacological interventions under certain conditions although comparisons remain limited by the heterogeneity across studies \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Higher cardiorespiratory fitness (CRF) is also consistently associated with lower BP and reduced cardiovascular risk \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, and improvements in CRF appear to be preserved during ACEi therapy \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. However, whether chronic RAAS inhibition modifies the magnitude of exercise-induced cardiometabolic and hemodynamic adaptations remains unclear.\u003c/p\u003e \u003cp\u003eTherefore, this study examined the effects of chronic ACEi or ARBs therapy on cardiometabolic and hemodynamic adaptations to a 16-week supervised HIIT program in adults with MetS. We hypothesized that RAAS inhibition would not attenuate training-induced improvements in blood pressure, cardiorespiratory fitness, or metabolic health.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cb\u003eSubjects.\u003c/b\u003e Sixty-two middle-aged volunteers (51\u0026thinsp;\u0026plusmn;\u0026thinsp;12 years; 29 women and 33 men) with overweight and obesity (i.e., body mass index [BMI], 32.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 kg\u0026middot;m\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e) with MetS criteria \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e completed the study. Participants were previously sedentary as assessed by the 7-day IPAQ (International Physical Activity Questionnaire) with less than 150 min\u0026middot;wk\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e of moderate-intensity activity. Exclusion criteria included untreated cardiovascular or renal disease, any condition associated with exercise intolerance, and the use of any pharmacological therapy targeting MetS components other than ACEi or ARBs. Upon questioning at the onset of the intervention, subjects reported a stable body weight (\u0026plusmn;\u0026thinsp;1%) over the 4 months preceding the survey. All subjects provided written, witnessed, and informed consent under a protocol approved by the local Virgen de la Salud Hospital Ethics Committee of Toledo (reference #170) and in accordance with the Declaration of Helsinki. This is a substudy of a larger clinical trial assessing the effects of medication and exercise interactions in individuals with MetS (ClinicalTrials.gov Identifier: NCT03019796).\u003c/p\u003e \u003cp\u003e \u003cb\u003eExperimental design.\u003c/b\u003e This prospective parallel-group intervention study examined the effects of exercise training in participants either treated or untreated with RAAS inhibitors (ACEi or ARBs). Participants were allocated using a non-randomized block design based on medication treatment. Recruitment, screening, intervention, and all assessments were conducted in the sequence outlined in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Twenty-seven individuals with MetS receiving chronic antihypertensive therapy with ACEi or ARBs for more than six months constituted the antihypertensive medication group (AHM). Thirty-five individuals with MetS who had never received chronic pharmacologic treatment served as the control group (CONTROL; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMedication use.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAHM (n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCONTROL (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntihypertensive medication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eACEi\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e12 (44%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnalapril\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (41%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImidapril\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eARBs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e15 (56%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCandesartan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIrbesartan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLosartan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTelmisartan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValsartan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCholesterol lowering\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglyceride lowering\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose lowering\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eData are presented as the number of subjects taking each medication, expressed as absolute frequency (n) and proportion (%). Abbreviations: \u003cb\u003eACEi\u003c/b\u003e, angiotensin-converting enzyme inhibitors; and \u003cb\u003eARBs\u003c/b\u003e, angiotensin receptor blockers.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u003cb\u003eIntervention.\u003c/b\u003e All participants completed a 16-week supervised aerobic training program, performed three times per week (Monday, Wednesday, and Friday), consisting of high-intensity interval training (HIIT) on stationary cycle ergometers (Tomahawk S-Series, N\u0026uuml;rnberg, Germany). Participants were required to attend at least 90% of sessions to be included in the analysis. Each session began with a 10-minute warm-up at 70% of maximum heart rate (HR\u003csub\u003eMAX\u003c/sub\u003e), followed by four 4-minute intervals at 90% HR\u003csub\u003eMAX\u003c/sub\u003e, interspersed with 3-minute active recovery periods at 70% HR\u003csub\u003eMAX\u003c/sub\u003e, and concluded with a 5-minute cool-down. Exercise intensity was prescribed as a percentage of HR\u003csub\u003eMAX\u003c/sub\u003e determined during the pre-intervention maximal exercise test. Heart rate was continuously monitored using a telemetry system (Seego, RealTrack Systems, Spain) and displayed on a large screen. Participants adjusted the cycling workload to remain within their individualized target HR zones under the direct supervision of a research team member. Training progression was implemented over the first three weeks (nine sessions), gradually increasing the number and duration of high-intensity intervals. HRMAX was reassessed monthly, and workloads were adjusted accordingly to maintain the prescribed training intensity. Participants were instructed to maintain their usual dietary and physical activity habits throughout the intervention. Monthly, they completed a 3-day dietary record (CESNID v1.0, Barcelona, Spain) and wore a wrist-based activity monitor (Polar Loop Electro, Polar, Kempele, Finland) for 48 hours. Personalized feedback was provided each month to minimize fluctuations in caloric intake and non-training physical activity.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes measures\u003c/h2\u003e \u003cp\u003e \u003cb\u003eClinical investigation.\u003c/b\u003e Before and after the intervention, participants reported to the laboratory in the morning following an overnight fast (8\u0026ndash;12 h). Body weight (Hawk, Mettler; Toledo, USA), height (Stadiometer, SECA 217; Hamburg, Germany), and waist circumference were measured by the same investigator according to the protocol proposed by Alberti et al. \u003csup\u003e14\u003c/sup\u003e, using a non-elastic measuring tape. BMI was calculated, and fat mass (FM) and fat-free mass (FFM) were assessed using dual-energy X-ray absorptiometry (DXA; Hologic Discovery Wi QDR Series, Bedford, USA). Resting blood pressure was measured in triplicate using a calibrated ECG-gated automated sphygmomanometer (Tango, SunTech Medical; Morrisville, USA) after 10 minutes of supine rest. Exercise testing was performed at least 48 hours apart from fasting venous blood collection, which was used to determine serum glucose, insulin, and lipid profile (triglycerides, total cholesterol, HDL-c, and LDL-c). Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Sex-specific Z scores were calculated for each MetS criterion using the group SD, and the sum of the Z scores for each MetS component was divided by 6 to obtain the MetS risk score. The equations used were as follows:\u003c/p\u003e \u003cp\u003eMen\u0026rsquo;s MetS \u003cem\u003eZ\u003c/em\u003e Score= [(40 \u0026ndash; HDL-cholesterol)/SD] + [(triglycerides \u0026ndash; 150)/SD] + [(glucose \u0026ndash; 100)/SD] + [(waist circumference \u0026ndash; 94)/SD] + [(systolic blood pressure \u0026ndash; 130)/SD] + [(diastolic blood pressure \u0026ndash; 85)/SD]\u003c/p\u003e \u003cp\u003eWomen\u0026rsquo;s MetS \u003cem\u003eZ\u003c/em\u003e Score= [(50 \u0026ndash; HDL-cholesterol)/SD] + [(triglycerides \u0026ndash; 150)/SD] + [(glucose \u0026ndash; 100)/SD] + [(waist circumference \u0026ndash; 80)/SD] + [(systolic blood pressure \u0026ndash; 130)/SD] + [(diastolic blood pressure \u0026ndash; 85)/SD]\u003c/p\u003e \u003cp\u003e \u003cb\u003eCardiorespiratory fitness and maximal power output.\u003c/b\u003e Maximal oxygen uptake (VO\u003csub\u003e2MAX\u003c/sub\u003e), maximal cycling power (W\u003csub\u003eMAX\u003c/sub\u003e), and maximal heart rate (HR\u003csub\u003eMAX\u003c/sub\u003e) were determined during a graded exercise test (GXT) performed on an electronically braked cycle ergometer (Ergoselect 200, Ergoline; Bitz, Germany). Gas exchange was continuously measured using indirect calorimetry (Quark RMR, Cosmed; Rome, Italy), and cardiac electrical activity was monitored via a standard 12-lead ECG (Quark T12, Cosmed; Rome, Italy). Following a 3-minute warm-up at 30 W for women and 50 W for men, the workload was increased by 15 W for women and 20 W for men every minute until volitional exhaustion. Immediately afterward, a verification test was conducted at 110% of the maximal workload achieved during the GXT to confirm attainment of VO\u003csub\u003e2MAX\u003c/sub\u003e.\u003c/p\u003e \u003cp\u003e\u003cb\u003eBlood pressure monitoring during exercise.\u003c/b\u003e During the GXT, BP was manually measured by a trained practitioner using a calibrated sphygmomanometer (Gamma G7, Heine; Gilching, Germany), following established methodological standards \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Measurements were obtained from the left arm, with an appropriately sized cuff positioned at heart level and the arm supported throughout the test to minimize motion artifacts and ensure accuracy. BP was recorded with participants seated on the cycle ergometer at the onset of the exercise protocol (15 W for women, 50 W for men at minute 3), and every 2 minutes at the end of each odd-numbered stage. Peak BP was determined immediately upon cessation of exercise at maximal exertion. Exercise was terminated either upon volitional exhaustion or if any predefined safety criteria for test termination were met, including chest pain with ischemic ECG changes, complex ectopy or high-grade atrioventricular block, symptomatic SBP drop\u0026thinsp;\u0026gt;\u0026thinsp;20 mmHg, severe exercise hypertension (SBP\u0026thinsp;\u0026gt;\u0026thinsp;240 mmHg or DBP\u0026thinsp;\u0026gt;\u0026thinsp;120 mmHg), oxygen desaturation, neurological symptoms, or at the discretion of the supervising physician.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical analysis.\u003c/b\u003e A per-protocol analysis was conducted, including only participants who completed the intervention. Sample size calculations were based on expected changes in CRF, using data from our previous study in which individuals with MetS who completed a 16-week exercise program similar to the present protocol \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In this study, participants increased 0.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27 L\u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e following HIIT, translating to an effect size of d\u0026thinsp;=\u0026thinsp;1.11. Therefore, 23 participants per group should be sufficient to achieve a power of 0.95 at an alpha level of 0.05. Due to account for potential dropouts of exercise interventions (i.e., ~\u0026thinsp;30% exercise intervention attrition rates) or changing medications (primary care follow-up), the sample size was increased in each group (N\u0026thinsp;=\u0026thinsp;40). Data are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, with 95% confidence intervals (CI) calculated for all outcome measures. Normality was verified using the Shapiro\u0026ndash;Wilk test. Baseline comparisons between groups were performed using independent samples t-tests. To assess the effects of training over time and between groups, a mixed-design (split-plot) ANCOVA was used for all variables, with baseline values entered as covariates. This approach allowed evaluation of time \u0026times; group interactions while accounting for repeated measures (PRE and POST) within participants. Post hoc pairwise comparisons with Bonferroni correction were conducted only when significant interactions were observed. All statistical analyses were performed using SPSS v28 (IBM, Chicago, IL, USA), with significance set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e \u003cb\u003eBaseline subjects\u0026rsquo; characteristics.\u003c/b\u003e Participants were Caucasians living in southern Europe. Women comprise 48% of the AHM group and 46% of the CONTROL. Data were analyzed without stratification by sex, since all female participants were postmenopausal, not receiving hormone replacement therapy, and showed no significant differences compared to male participants in the main study outcomes (time x sex interaction; MetS Z score, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.31; SBP, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.25; DBP, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.17; body weight, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.31; and VO\u003csub\u003e2MAX\u003c/sub\u003e (mL\u0026middot;Kg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.16). Subjects\u0026rsquo; adherence to training sessions was 91% for AHM and 90% for CONTROL (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). There were no differences in calorie intake or physical activity between groups. On average, subjects ingested 2296\u0026thinsp;\u0026plusmn;\u0026thinsp;93 at baseline and 2322\u0026thinsp;\u0026plusmn;\u0026thinsp;82 kcal\u0026middot;day\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e after the intervention (both \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Macronutrient distribution remained stable across groups (47\u0026thinsp;\u0026plusmn;\u0026thinsp;5% carbohydrate, 33\u0026thinsp;\u0026plusmn;\u0026thinsp;2% fat [40% saturated fat], and 20\u0026thinsp;\u0026plusmn;\u0026thinsp;1% protein). Baseline physical activity averaged 6025\u0026thinsp;\u0026plusmn;\u0026thinsp;362 steps\u0026middot;day\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, 196\u0026thinsp;\u0026plusmn;\u0026thinsp;147 min\u0026middot;day\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e of standing, and 496\u0026thinsp;\u0026plusmn;\u0026thinsp;165 min\u0026middot;day\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e supine rest, with similar values after 16 weeks (587\u0026thinsp;\u0026plusmn;\u0026thinsp;224 steps\u0026middot;day\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, 189\u0026thinsp;\u0026plusmn;\u0026thinsp;77 min\u0026middot;day\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e standing and 499\u0026thinsp;\u0026plusmn;\u0026thinsp;201 min\u0026middot;day\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e supine rest; all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cb\u003eBody weight and composition.\u003c/b\u003e At baseline, participants had similar body weight, BMI, fat mass, and fat-free mass (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). After 16 weeks of HIIT, no significant main effects of \u003cem\u003etime\u003c/em\u003e or \u003cem\u003etime \u0026times; group\u003c/em\u003e interaction effects were observed for any anthropometric variable (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges in anthropometric, cardiometabolic factors, and maximal exercise variables after 16 weeks of training in both groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eAHM (n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eCONTROL (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c11\" namest=\"c9\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 weeks\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16 weeks\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTime x group\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (yr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e51\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.028\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% Women\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnthropometric\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94.1\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93.1\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e89.8\u0026thinsp;\u0026plusmn;\u0026thinsp;15.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e88.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.338\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.443\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.330\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg\u0026middot;m\u003csup\u003e\u0026minus;\u0026thinsp;2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.695\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.226\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFat mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.3\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33.8\u0026thinsp;\u0026plusmn;\u0026thinsp;11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e32.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.383\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.771\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.315\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFat-free mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.8\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e54.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.476\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.747\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetabolic Syndrome factors\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWaist circumference (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e109.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108.1\u0026thinsp;\u0026plusmn;\u0026thinsp;13.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e106.4\u0026thinsp;\u0026plusmn;\u0026thinsp;10.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e103.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.259\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.148\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose (mg\u0026middot;dL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e105.5\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e104.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.366\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.899\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides (mg\u0026middot;dL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e127.1\u0026thinsp;\u0026plusmn;\u0026thinsp;48.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e111.2\u0026thinsp;\u0026plusmn;\u0026thinsp;41.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e149.8\u0026thinsp;\u0026plusmn;\u0026thinsp;76.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e136.9\u0026thinsp;\u0026plusmn;\u0026thinsp;72.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.027\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.350\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL-c (mg\u0026middot;dL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e43.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e43.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.567\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.758\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetS \u003cem\u003eZ\u003c/em\u003e-score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.554\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.580\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCardiometabolic risk factors\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Cholesterol (mg\u0026middot;dL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e192.0\u0026thinsp;\u0026plusmn;\u0026thinsp;21.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e193.3\u0026thinsp;\u0026plusmn;\u0026thinsp;28.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e214.4\u0026thinsp;\u0026plusmn;\u0026thinsp;38.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e215.1\u0026thinsp;\u0026plusmn;\u0026thinsp;36.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.687\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-c (mg\u0026middot;dL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124.8\u0026thinsp;\u0026plusmn;\u0026thinsp;21.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e128.1\u0026thinsp;\u0026plusmn;\u0026thinsp;24.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e141.3\u0026thinsp;\u0026plusmn;\u0026thinsp;33.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e144.0\u0026thinsp;\u0026plusmn;\u0026thinsp;30.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.538\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInsulin (\u0026micro;IU\u0026middot;mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.303\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOMA-IR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.405\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaximal Exercise parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximal Heart Rate (beats\u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e154\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e156\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e155\u0026thinsp;\u0026plusmn;\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e160\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.803\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.192\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eO\u003csub\u003e2\u003c/sub\u003e Pulse at VO\u003csub\u003e2MAX\u003c/sub\u003e (mL\u0026middot;beat\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.750\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart Rate Reserve (beats\u0026middot;min\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91\u0026thinsp;\u0026plusmn;\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e88\u0026thinsp;\u0026plusmn;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e93\u0026thinsp;\u0026plusmn;\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.966\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximal SBP (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e179.4\u0026thinsp;\u0026plusmn;\u0026thinsp;22.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e175.5\u0026thinsp;\u0026plusmn;\u0026thinsp;19.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e170.7\u0026thinsp;\u0026plusmn;\u0026thinsp;26.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e171.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.961\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximal DBP (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93.1\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87.5\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e93.6\u0026thinsp;\u0026plusmn;\u0026thinsp;17.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e89.6\u0026thinsp;\u0026plusmn;\u0026thinsp;19.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.933\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.770\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximal MAP (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e121.8\u0026thinsp;\u0026plusmn;\u0026thinsp;15.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e116.9\u0026thinsp;\u0026plusmn;\u0026thinsp;13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e119.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e117.0\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.743\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.806\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. Abbreviations: SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure; MAP, Mean Arterial Pressure.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eMetS components and additional physiological parameters.\u003c/b\u003e Changes in MetS components after 16 weeks of training are depicted in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Before intervention, MetS components were not different among groups (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). After intervention, we observed a significant \u003cem\u003etime\u003c/em\u003e effect in glucose (AHM, 0.4; 95% CI -4.8 to 4.2 mg\u0026middot;dL\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and CONTROL, -1.2; 95% CI -4.7 to 3.4 mg\u0026middot;dL\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), triglycerides (AHM, -15.9; 95% CI -35.5 to -4.0 mg\u0026middot;dL\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and CONTROL, -12.8; 95% CI -23.8 to 4.2 mg\u0026middot;dL\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027), and HDL-c (AHM, 1.3; 95% CI -1.1 to 3.3 mg\u0026middot;dL\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and CONTROL, 0.5; 95% CI -1.3 to 2.6 mg\u0026middot;dL\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Similarly, the MetS Z-score showed a significant \u003cem\u003etime\u003c/em\u003e effect (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with improvements of 96% in the AHM group (\u0026minus;\u0026thinsp;0.22 SDs; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;0.37 to \u0026minus;\u0026thinsp;0.11) and 93% in the CONTROL group (\u0026minus;\u0026thinsp;0.30 SDs; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;0.41 to \u0026minus;\u0026thinsp;0.17). However, no significant \u003cem\u003etime \u0026times; group\u003c/em\u003e interaction effects were observed for any MetS components and MetS Z-score (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). At baseline, total cholesterol (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005) and LDL-c (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) were higher in the CONTROL than in the AHM group. Following the intervention, a significant \u003cem\u003etime\u003c/em\u003e effect was observed for LDL-c (AHM, 3.2; 95% CI -4.8 to 7.8 mg\u0026middot;dL⁻\u0026sup1; and CONTROL, 2.8; 95% CI -1.4 to 9.7 mg\u0026middot;dL⁻\u0026sup1;; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005) and insulin (AHM, -1.4; 95% CI -2.6 to 0.7 \u0026micro;IU\u0026middot;mL⁻\u0026sup1; and CONTROL, -1.7; 95% CI -3.5 to -0.6 \u0026micro;IU\u0026middot;mL⁻\u0026sup1;; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009). However, no significant \u003cem\u003etime \u0026times; group\u003c/em\u003e interaction was detected for either variable (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cb\u003eResting blood pressure.\u003c/b\u003e Changes in resting BP over 16 weeks of training are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. At baseline, systolic blood pressure (SBP, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.65), diastolic blood pressure (DBP, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.77), and mean arterial pressure (MAP, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.69) did not differ between groups. After intervention, we observed a significant \u003cem\u003etime\u003c/em\u003e effect in rest SBP (AHM, -3.2; 95% CI -7.7 to 0.6 mmHg and CONTROL, -8.0; 95% CI -11.5 to -4.2 mmHg; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), DBP (AHM, -4.6; 95% CI -7.0 to -2.5 mmHg and CONTROL, -5.8; 95% CI -7.7 to -3.7 mmHg; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), and MAP (AHM, -4.2; 95% CI -7.0 to -1.7 mmHg and CONTROL, -6.5; 95% CI -8.7 to -4.2 mmHg; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). However, no \u003cem\u003esignificant time \u0026times; group\u003c/em\u003e interaction effects were observed for any component of resting blood pressure (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eCardiorespiratory fitness and maximal exercise responses.\u003c/b\u003e CRF (i.e., VO\u003csub\u003e2MAX\u003c/sub\u003e) and maximal power output (W\u003csub\u003eMAX\u003c/sub\u003e) evolution after intervention are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Before intervention, CRF (expressed as VO\u003csub\u003e2MAX\u003c/sub\u003e in L\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e [\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.79] and mL\u0026middot;Kg\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e [\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.59] ) and W\u003csub\u003eMAX\u003c/sub\u003e (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.41) were similar between AHM and CONTROL groups. After 16 weeks of HIIT, we observed a significant \u003cem\u003etime\u003c/em\u003e effect in CRF (AHM, 0.33; 95% CI 0.24 to 0.43 L\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and CONTROL, 0.42; 95% CI 0.34 to 0.50 L\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05) and W\u003csub\u003eMAX\u003c/sub\u003e (AHM, 33; 95% CI 25 to 41 W and CONTROL, 40; 95% CI 33 to 47 W; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). However, no significant \u003cem\u003etime \u0026times; group\u003c/em\u003e interaction effects were observed for any component of exercise performance (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Since body weight and fat mass decreased similarly in both groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), changes in CRF per kilogram of body weight responded similarly to the absolute values (AHM, 3.9; 95% CI 2.8 to 4.9 mL\u0026middot;Kg\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and CONTROL, 5.0; 95% CI 4.1 to 5.9 mL\u0026middot;Kg\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). The maximal heart rate (HR\u003csub\u003eMAX\u003c/sub\u003e), oxygen pulse (O\u003csub\u003e2\u003c/sub\u003e Pulse at VO\u003csub\u003e2MAX\u003c/sub\u003e), and heart rate reserve (HRR) response are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. At baseline, there were no differences between groups on any of these variables (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). After exercise training, we observed a significant \u003cem\u003etime\u003c/em\u003e effect in HR\u003csub\u003eMAX\u003c/sub\u003e (AHM, 2; 95% CI -1 to 5 beats\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and CONTROL, 5; 95% CI 2 to 7 beats\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), O\u003csub\u003e2\u003c/sub\u003e Pulse at VO\u003csub\u003e2MAX\u003c/sub\u003e (AHM, 2.1; 95% CI 1.4 to 2.7 mL\u0026middot;beat\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and CONTROL, 2.2; 95% CI 1.6 to 2.8 mL\u0026middot;beat\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) and HRR (AHM, 6; 95% CI 1 to 9 beats\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and CONTROL, 5; 95% CI 1 to 9 beats\u0026middot;min\u003csup\u003e-\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eBlood pressure during graded exercise.\u003c/b\u003e BP response during the graded exercise test GXT is shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. At baseline, maximal SBP, maximal DBP, and maximal MAP did not differ between groups (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Following the intervention, a significant main effect of \u003cem\u003etime\u003c/em\u003e was observed for maximal SBP ( AHM, -3.9; 95% CI -12.7 to 11.1 mmHg and CONTROL, 1.1; 95% CI -11.9 to 9.6 mmHg; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and maximal MAP (AHM, -5.0; 95% CI -13.4 to 4.9 mmHg and CONTROL, -2.3; 95% CI -11.0 to 5.4 mmHg; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008). However, no significant \u003cem\u003etime \u0026times; group\u003c/em\u003e interaction was detected for either variable (both \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Blood pressure responses at each stage of the graded exercise test\u0026mdash;normalized to the percentage of maximal heart rate achieved (%HR\u003csub\u003eMAX\u003c/sub\u003e)\u0026mdash;showed a significant main effect of \u003cem\u003etime\u003c/em\u003e only for DBP (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB) with no \u003cem\u003etime \u0026times; group\u003c/em\u003e interaction observed for any variable (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSION","content":"\u003cp\u003eIn this 16-week supervised HIIT intervention, chronic treatment with ACEi or ARBs did not attenuate exercise-induced physiological adaptations in middle-aged adults with MetS. Both pharmacologically treated and untreated participants exhibited clinically meaningful improvements in resting and exercise blood pressure, cardiorespiratory fitness (CRF, as assessed by VO\u003csub\u003e2MAX\u003c/sub\u003e), and metabolic health (assessed by MetS Z-score). Importantly, no significant \u003cem\u003etime × group\u003c/em\u003e interactions were detected for any cardiometabolic, hemodynamic, or performance-related outcomes, suggesting that chronic renin–angiotensin system inhibition does not impair the beneficial effects of HIIT. Additionally, body composition, dietary intake, and habitual physical activity remained stable, supporting the interpretation that observed improvements were primarily exercise-induced.\u003c/p\u003e \u003cp\u003e \u003cb\u003eBlood pressure reduction and cardiometabolic adaptations.\u003c/b\u003e The decrease in resting blood pressure observed in our participants (~ 3–8 mmHg in SBP and ~ 5–6 mmHg in DBP) is consistent with meta-analyses showing average decreases of ~ 3–6 mmHg and ~ 2–3 mmHg, respectively, after aerobic training, including HIIT \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Prior evidence also indicates that structured exercise can elicit SBP reductions comparable to first-line antihypertensive therapy \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Within this context, our data showed that chronic RAAS inhibition neither attenuated nor enhanced HIIT-induced adaptations, as medicated and non-medicated participants demonstrated comparable metabolic, hemodynamic, and fitness responses. These findings are consistent with placebo-controlled evidence showing that AHM and HIIT exert independent and additive effects on ambulatory BP in hypertensive individuals with MetS \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Although RAAS blockade altered biochemical indices (e.g., increased renin activity and a lower aldosterone-to-renin ratio), exercise-induced BP reductions appeared to occur through mechanisms independent of RAAS suppression. In accordance with these findings, our previous work showed that only hypertensive individuals—regardless of treatment status or antihypertensive class—exhibited training-induced BP reductions, and that the magnitude of this response scaled with baseline BP, consistent with Wilder’s principle \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAcute and chronic interactions between exercise and RAAS Inhibition.\u003c/b\u003e Following these observations, acute studies have shown that combining a single session of aerobic exercise with AHM produces greater immediate BP reductions than either intervention alone \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, particularly at higher intensities \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. However, whether such acute synergistic effects persist with long-term training remains unclear. Chronic aerobic or interval training has been shown to reduce arterial stiffness, improve endothelial function \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, and decrease systemic vascular resistance \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e in individuals with MetS. However, evidence regarding the preservation of these adaptations during chronic ACEi or ARB therapy remains limited, with available data largely derived from animal models suggesting complementary effects of ARBs and exercise on blood pressure and cardiac function \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Our findings demonstrate that 16 weeks of HIIT elicited favorable hemodynamic and vascular adaptations in medicated participants, with no evidence that RAAS blockade interfered with these responses. Collectively, these findings support the compatibility of angiotensin antagonist medication with exercise training and reinforce the combined use of pharmacologic and lifestyle interventions in the management of hypertension and MetS.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCardiorespiratory fitness and clinical implications.\u003c/b\u003e Evidence on whether RAAS-targeting medications influence exercise-induced improvements in CRF has been controversial. Some studies in older adults have reported that ACEi therapy alone enhances exercise capacity \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e and may augment functional adaptations in frail populations \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. However, other trials in functionally impaired older adults \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and healthy individuals \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e observed no additive effect of ACEi on training-induced gains. The present findings align with this latter evidence, demonstrating that chronic ACEi or ARBs therapy does not attenuate CRF improvements following HIIT. Absolute VO\u003csub\u003e2MAX\u003c/sub\u003e increased by approximately 22% in the AHM group and 18% in the control group, equivalent to gains of ~ 1.4 and ~ 1.1 metabolic equivalents (METs), respectively. Exercise capacity is a strong predictor of cardiovascular and all-cause mortality in patients with hypertension \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Our improvements correspond to a ~ 13% reduction in all-cause mortality and a ~ 15% reduction in cardiovascular events \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Epidemiological data from an extensive Swedish registry indicate that individuals who increase CRF by \u0026gt; 3% per year have an 11% lower risk of incident hypertension. In contrast, individuals who experience CRF declines have a 25% increased risk, independent of lifestyle factors \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Collectively, these results suggest that HIIT-induced improvements in CRF may contribute to both short-term BP control and long-term decreases in cardiovascular risk, and that these benefits are preserved despite chronic RAAS inhibition.\u003c/p\u003e \u003cp\u003e \u003cb\u003eBlood pressure responses during exercise.\u003c/b\u003e During dynamic exercise, SBP rises in proportion to intensity due to increased cardiac output driven by sympathetic activation, whereas DBP typically remains stable or slightly decreases owing to peripheral vasodilation. Exaggerated SBP responses reflect impaired vascular regulation and are associated with arterial stiffness, endothelial dysfunction, and increased long-term cardiovascular risk \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Chant et al. \u003csup\u003e31\u003c/sup\u003e showed that individuals with treated and apparently controlled hypertension exhibit elevated SBP responses during both submaximal and maximal exercise, comparable to those observed in untreated or uncontrolled hypertension. This phenomenon has been attributed, at least in part, to heightened metaboreflex sensitivity that appears relatively resistant to conventional antihypertensive pharmacotherapy. In contrast, in the present study, baseline SBP responses across exercise intensities did not differ between groups, suggesting that chronic angiotensin receptor blockade did not materially alter the acute exercise pressor response. Differences in baseline hypertension severity and treatment burden may explain the discrepancies between our findings and those of Chant et al. Notably, their participants' cohort entered the study with resting SBP values near the hypertensive threshold (~ 138 mmHg). It was predominantly managed with multidrug regimens, a clinical phenotype more likely to exhibit persistently exaggerated pressor responses during physical stress.\u003c/p\u003e \u003cp\u003eAfter 16 weeks of HIIT, both groups exhibited a significant \u003cem\u003etime\u003c/em\u003e effect in maximal MAP (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) and submaximal DBP (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB), accompanied by improvements in workload capacity, CRF, heart rate reserve, and maximal oxygen pulse (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Consistent with previous findings, oxygen pulse kinetics during exercise are closely associated with both systolic and diastolic left ventricular performance in older adults with mild hypertension \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, supporting its use as an indirect marker of improved central hemodynamic responses to exercise. Importantly, indexing SBP to external workload has been shown to predict all-cause mortality more accurately than peak SBP, underscoring the clinical relevance of improved hemodynamic efficiency during exercise \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. These results align with prior studies reporting modest reductions in exercise BP following training \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, and with a pooled analysis of 10 RCTs showing a ~ 7 mmHg decrease in exercise SBP after aerobic training despite heterogeneity in age, BP status, and intervention protocols \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Collectively, the data suggest that HIIT improves vascular dynamics and exercise tolerance, moderating MAP and DBP responses through enhanced vascular compliance, improved endothelial function, and attenuated sympathetic activation, even in the context of chronic inhibition of the RAAS\u003c/p\u003e \u003cp\u003e \u003cb\u003eStrengths and Limitations.\u003c/b\u003e The primary strength of this study is its prospective, supervised intervention design, which enabled a direct comparison of exercise-induced adaptations between two clinically relevant populations: adults with MetS under chronic ACEi or ARBs therapy and those not receiving pharmacological treatment. This pragmatic approach enhances clinical applicability and provides insights into real-world interactions between pharmacologic RAAS inhibition and exercise-induced cardiovascular adaptations. However, several limitations should be acknowledged. First, although baseline adjustment was performed, the absence of randomization warrants caution when inferring causality. Second, pharmacologic heterogeneity—specifically the use of multiple ACEi and ARBs agents at varying doses—may have influenced vascular and hemodynamic outcomes. Future randomized controlled trials with standardized pharmacotherapy protocols are needed to delineate the specific contributions of individual RAAS inhibitors to exercise-induced adaptations.\u003c/p\u003e "},{"header":"Conclusions","content":"\u003cp\u003eIn summary, chronic ACEi or ARBs therapy did not attenuate the cardiometabolic, hemodynamic, or functional adaptations elicited by 16 weeks of supervised HIIT in adults with MetS. Medicated and non-medicated participants exhibited comparable improvements in resting and exercise blood pressure, CRF, and metabolic health, with no evidence of impaired responsiveness associated with chronic RAAS inhibition. These findings support the physiological compatibility of RAAS blockade with structured exercise training and reinforce the role of HIIT as an effective therapeutic strategy in the management of MetS among individuals receiving long-term antihypertensive treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author on reasonable request.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eILS and FMP conceived and designed the study. ILS, AMC, LGG, RMR and FMP conducted the investigation and data collection. ILS., AMC., DMG, and FMP performed data curation and formal statistical analysis. ILS, AMC and FMP. drafted the original manuscript. AMC, LGG, DMG, and RMR critically reviewed and revised the manuscript for important intellectual content. RMR and FMP supervised the project. RMR acquired funding. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpanish Ministry of Economy, Industry and Competivity (DEP-2017-83244-R) and Spanish Ministry of Science and Innovation (PID2020-116159RB- IOO MCIN/AEI/10.13039/501100011033). The granting agencies have no role in the design, execution, or reporting of the results of this study.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eETHICAL APPROVAL\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Virgen de la Salud Hospital of Toledo (reference #170). All participants provided written informed consent. The work is a substudy of a registered clinical trial (ClinicalTrials.gov: NCT03019796).\u003c/p\u003e\n\n\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYusuf S, Joseph P, Rangarajan S, Islam S, Mente A, Hystad P \u003cem\u003eet al.\u003c/em\u003e Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study. \u003cem\u003eThe Lancet\u003c/em\u003e 2020; 395(10226): 795\u0026ndash;808.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMills KT, Stefanescu A, He J. The global epidemiology of hypertension. \u003cem\u003eNature Reviews Nephrology\u003c/em\u003e 2020; 16(4): 223\u0026ndash;237.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMancia G, Kreutz R, Brunstr\u0026ouml;m M, Burnier M, Grassi G, Januszewicz A \u003cem\u003eet al.\u003c/em\u003e 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). \u003cem\u003eJournal of hypertension\u003c/em\u003e 2023; 41(12): 1874\u0026ndash;2071.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJayawardana S, Campbell A, Aitken M, Andersson CE, Mehra MR, Mossialos E. Global consumption patterns of combination hypertension medication: An analysis of pharmaceutical sales data from 2010\u0026ndash;2021. \u003cem\u003ePLOS global public health\u003c/em\u003e 2024; 4(9): e0003698.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaulfield L, Heslop P, Walesby KE, Sumukadas D, Sayer AA, Witham MD. Effect of Angiotensin System Inhibitors on Physical Performance in Older People \u0026ndash; A Systematic Review and Meta-Analysis. \u003cem\u003eJournal of the American Medical Directors Association\u003c/em\u003e 2021; 22(6): 1215\u0026ndash;1221.e2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei J, Galaviz KI, Kowalski AJ, Magee MJ, Haw JS, Narayan KMV \u003cem\u003eet al.\u003c/em\u003e Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications: A Systematic Review and Network Meta-analysis. \u003cem\u003eJAMA Network Open\u003c/em\u003e 2020; 3(2): e1921618-e1921618.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCornelissen VA, Fagard RH. Effects of Endurance Training on Blood Pressure, Blood Pressure\u0026ndash;Regulating Mechanisms, and Cardiovascular Risk Factors. \u003cem\u003eHypertension\u003c/em\u003e 2005; 46(4): 667\u0026ndash;675.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEdwards JJ, Deenmamode AHP, Griffiths M, Arnold O, Cooper NJ, Wiles JD \u003cem\u003eet al.\u003c/em\u003e Exercise training and resting blood pressure: a large-scale pairwise and network meta-analysis of randomised controlled trials. \u003cem\u003eBritish journal of sports medicine\u003c/em\u003e 2023; 57(20): 1317\u0026ndash;1326.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaffour-Awuah B, Man M, Goessler KF, Cornelissen VA, Dieberg G, Smart NA \u003cem\u003eet al.\u003c/em\u003e Effect of exercise training on the renin-angiotensin-aldosterone system: a meta-analysis. \u003cem\u003eJournal of human hypertension\u003c/em\u003e 2024; 38(2): 89\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamirez-Jimenez M, Morales-Palomo F, Moreno-Caba\u0026ntilde;as A, Alvarez-Jimenez L, Ortega JF, Mora-Rodriguez R. Effects of antihypertensive medication and high-intensity interval training in hypertensive metabolic syndrome individuals. \u003cem\u003eScandinavian journal of medicine \u0026amp; science in sports\u003c/em\u003e 2021; 31(7): 1411\u0026ndash;1419.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaci H, Salcher-Konrad M, Dias S, Blum MR, Sahoo SA, Nunan D \u003cem\u003eet al.\u003c/em\u003e How does exercise treatment compare with antihypertensive medications? A network meta-analysis of 391 randomised controlled trials assessing exercise and medication effects on systolic blood pressure. \u003cem\u003eBritish journal of sports medicine\u003c/em\u003e 2019; 53(14): 859\u0026ndash;869.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKokkinos P. Cardiorespiratory Fitness, Exercise, and Blood Pressure. \u003cem\u003eHypertension\u003c/em\u003e 2014; 64(6): 1160\u0026ndash;1164.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSj\u0026uacute;r\u0026eth;arson T, Bejder J, Breenfeldt Andersen A, Bonne T, Kyhl K, R\u0026oacute;in T \u003cem\u003eet al.\u003c/em\u003e Effect of angiotensin-converting enzyme inhibition on cardiovascular adaptation to exercise training. \u003cem\u003ePhysiological reports\u003c/em\u003e 2022; 10(13): e15382.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA \u003cem\u003eet al.\u003c/em\u003e Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. \u003cem\u003eCirculation\u003c/em\u003e 2009; 120(16): 1640\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNayor M, Gajjar P, Murthy VL, Miller PE, Velagaleti RS, Larson MG \u003cem\u003eet al.\u003c/em\u003e Blood Pressure Responses During Exercise: Physiological Correlates and Clinical Implications. \u003cem\u003eArteriosclerosis, thrombosis, and vascular biology\u003c/em\u003e 2023; 43(1): 163\u0026ndash;173.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorales-Palomo F, Ramirez-Jimenez M, Ortega JF, Mora-Rodriguez R. Effectiveness of Aerobic Exercise Programs for Health Promotion in Metabolic Syndrome. \u003cem\u003eMedicine and science in sports and exercise\u003c/em\u003e 2019; 51(9): 1876\u0026ndash;1883.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMora-Rodriguez R, Ortega JF, Morales-Palomo F, Ramirez-Jimenez M, Moreno-Caba\u0026ntilde;as A, Alvarez-Jimenez L. Endurance Exercise Training reduces Blood Pressure according to the Wilder's Principle. \u003cem\u003eInternational journal of sports medicine\u003c/em\u003e 2022; 43(4): 336\u0026ndash;343.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamirez-Jimenez M, Morales-Palomo F, Ortega JF, Mora-Rodriguez R. Post-exercise Hypotension Produced by Supramaximal Interval Exercise is Potentiated by Angiotensin Receptor Blockers. \u003cem\u003eInternational journal of sports medicine\u003c/em\u003e 2019; 40(12): 756\u0026ndash;761.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorales-Palomo F, Ramirez-Jimenez M, Ortega JF, Pallar\u0026eacute;s JG, Mora-Rodriguez R. Acute Hypotension after High-Intensity Interval Exercise in Metabolic Syndrome Patients. \u003cem\u003eInternational journal of sports medicine\u003c/em\u003e 2017; 38(7): 560\u0026ndash;567.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMora-Rodriguez R, Ramirez-Jimenez M, Fernandez-Elias VE, Guio de Prada MV, Morales-Palomo F, Pallares JG \u003cem\u003eet al.\u003c/em\u003e Effects of aerobic interval training on arterial stiffness and microvascular function in patients with metabolic syndrome. \u003cem\u003eJournal of clinical hypertension (Greenwich, Conn.)\u003c/em\u003e 2018; 20(1): 11\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMora-Rodriguez R, Fernandez-Elias VE, Morales-Palomo F, Pallares JG, Ramirez-Jimenez M, Ortega JF. Aerobic interval training reduces vascular resistances during submaximal exercise in obese metabolic syndrome individuals. \u003cem\u003eEur J Appl Physiol\u003c/em\u003e 2017; 117(10): 2065\u0026ndash;2073.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAguilar BA, Vieira S, Veiga AC, da Silva JVMB, Paixao TV, Rodrigues KP \u003cem\u003eet al.\u003c/em\u003e Physical exercise is essential for increasing ventricular contractility in hypertensive rats treated with losartan. \u003cem\u003eHypertension Research\u003c/em\u003e 2024; 47(5): 1350\u0026ndash;1361.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHutcheon SD, Gillespie ND, Crombie IK, Struthers AD, McMurdo ME. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised double blind placebo controlled trial. \u003cem\u003eHeart (British Cardiac Society)\u003c/em\u003e 2002; 88(4): 373\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. \u003cem\u003eCMAJ: Canadian Medical Association journal\u0026thinsp;=\u0026thinsp;journal de l'Association medicale canadienne\u003c/em\u003e 2007; 177(8): 867\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuford TW, Manini TM, Hsu FC, Cesari M, Anton SD, Nayfield S \u003cem\u003eet al.\u003c/em\u003e Angiotensin-converting enzyme inhibitor use by older adults is associated with greater functional responses to exercise. \u003cem\u003eJournal of the American Geriatrics Society\u003c/em\u003e 2012; 60(7): 1244\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSumukadas D, Band M, Miller S, Cvoro V, Witham M, Struthers A \u003cem\u003eet al.\u003c/em\u003e Do ACE inhibitors improve the response to exercise training in functionally impaired older adults? A randomized controlled trial. \u003cem\u003eThe journals of gerontology. Series A, Biological sciences and medical sciences\u003c/em\u003e 2014; 69(6): 736\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaptista LC, Machado-Rodrigues AM, Ver\u0026iacute;ssimo MT, Martins RA. Exercise training improves functional status in hypertensive older adults under angiotensin converting enzymes inhibitors medication. \u003cem\u003eExperimental gerontology\u003c/em\u003e 2018; 109: 82\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M \u003cem\u003eet al.\u003c/em\u003e Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. \u003cem\u003eJama\u003c/em\u003e 2009; 301(19): 2024\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolmlund T, Ekblom B, B\u0026ouml;rjesson M, Andersson G, Wallin P, Ekblom-Bak E. Association between change in cardiorespiratory fitness and incident hypertension in Swedish adults. \u003cem\u003eEuropean journal of preventive cardiology\u003c/em\u003e 2021; 28(13): 1515\u0026ndash;1522.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarl\u0026eacute;n A, Lindow T, Cauwenberghs N, Elmberg V, Brudin L, Ekstr\u0026ouml;m M \u003cem\u003eet al.\u003c/em\u003e Exercise systolic blood pressure response during cycle ergometry is associated with future hypertension in normotensive individuals. \u003cem\u003eEuropean journal of preventive cardiology\u003c/em\u003e 2024; 31(9): 1072\u0026ndash;1079.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChant B, Bakali M, Hinton T, Burchell AE, Nightingale AK, Paton JFR \u003cem\u003eet al.\u003c/em\u003e Antihypertensive Treatment Fails to Control Blood Pressure During Exercise. \u003cem\u003eHypertension\u003c/em\u003e 2018; 72(1): 102\u0026ndash;109.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLim JG, McAveney TJ, Fleg JL, Shapiro EP, Turner KL, Bacher AC \u003cem\u003eet al.\u003c/em\u003e Oxygen pulse during exercise is related to resting systolic and diastolic left ventricular function in older persons with mild hypertension. \u003cem\u003eAmerican heart journal\u003c/em\u003e 2005; 150(5): 941\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHedman K, Cauwenberghs N, Christle JW, Kuznetsova T, Haddad F, Myers J. Workload-indexed blood pressure response is superior to peak systolic blood pressure in predicting all-cause mortality. \u003cem\u003eEuropean journal of preventive cardiology\u003c/em\u003e 2020; 27(9): 978\u0026ndash;987.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarone BB, Wang NY, Bacher AC, Stewart KJ. Decreased exercise blood pressure in older adults after exercise training: contributions of increased fitness and decreased fatness. \u003cem\u003eBritish journal of sports medicine\u003c/em\u003e 2009; 43(1): 52\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA, Ray CA. American College of Sports Medicine position stand. Exercise and hypertension. \u003cem\u003eMedicine and science in sports and exercise\u003c/em\u003e 2004; 36(3): 533\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-human-hypertension","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jhh","sideBox":"Learn more about [Journal of Human Hypertension](http://www.nature.com/jhh/)","snPcode":"41371","submissionUrl":"https://mts-jhh.nature.com/cgi-bin/main.plex","title":"Journal of Human Hypertension","twitterHandle":"@jhhypertension","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Exercise, hypertension, metabolic syndrome, antihypertensive medication, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers","lastPublishedDoi":"10.21203/rs.3.rs-9530735/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9530735/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAngiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are commonly prescribed alongside exercise to manage hypertension in individuals with metabolic syndrome (MetS). However, whether chronic renin\u0026ndash;angiotensin system (RAAS) inhibition modifies exercise-induced physiological adaptations remains unclear. In this prospective parallel-group study, 62 sedentary adults with MetS completed a 16-week supervised high-intensity interval training (HIIT) program. Participants were either chronically treated with ACEi or ARBs (antihypertensive medication group, AHM, n\u0026thinsp;=\u0026thinsp;27) or not receiving pharmacological treatment (CONTROL, n\u0026thinsp;=\u0026thinsp;35). Primary outcomes included changes in resting and exercise blood pressure (BP), MetS components, and cardiorespiratory fitness (CRF). Both groups showed significant improvements over time in cardiometabolic health (MetS Z-score: AHM\u0026thinsp;\u0026minus;\u0026thinsp;0.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42; CONTROL\u0026thinsp;\u0026minus;\u0026thinsp;0.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and CRF (VO\u003csub\u003e2MAX\u003c/sub\u003e: AHM 3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1; CONTROL 5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 mL\u0026middot;kg⁻\u0026sup1;\u0026middot;min⁻\u0026sup1;; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), with no significant time \u0026times; group interactions (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Resting blood pressure decreased similarly in both groups (mean arterial pressure [MAP]: AHM\u0026thinsp;\u0026minus;\u0026thinsp;4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7; CONTROL\u0026thinsp;\u0026minus;\u0026thinsp;6.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.3 mmHg; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005; interaction p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Exercise blood pressure responses also improved, with significant time effects for maximal MAP (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008) and submaximal diastolic BP (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047), without between-group differences (interaction \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Chronic treatment with ACEi or ARBs does not appear to attenuate improvements in cardiometabolic health, BP, or CRF by 16 weeks of supervised HIIT in adults with MetS. These findings suggest that RAAS inhibition is compatible with structured exercise training, supporting HIIT as an effective adjunct therapy in individuals receiving antihypertensive medication. However, the absence of significant interactions should be interpreted in the context of limited power to detect small-to-moderate differences.\u003c/p\u003e","manuscriptTitle":"Effect of chronic angiotensin system inhibitor treatment on cardiovascular adaptations to exercise training in adults with metabolic syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-28 13:10:13","doi":"10.21203/rs.3.rs-9530735/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-11T10:21:11+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-11T06:38:00+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-05-11T03:36:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-01T12:59:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Human Hypertension","date":"2026-05-01T10:38:52+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2026-04-28T13:34:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-26T09:18:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-human-hypertension","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jhh","sideBox":"Learn more about [Journal of Human Hypertension](http://www.nature.com/jhh/)","snPcode":"41371","submissionUrl":"https://mts-jhh.nature.com/cgi-bin/main.plex","title":"Journal of Human Hypertension","twitterHandle":"@jhhypertension","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4ff518a5-e6b3-4d90-9cb6-748f5653eeb0","owner":[],"postedDate":"April 28th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-11T10:21:11+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-11T06:38:00+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"3","date":"2026-05-11T03:36:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-01T12:59:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Human Hypertension","date":"2026-05-01T10:38:52+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67022900,"name":"Health sciences/Diseases/Cardiovascular diseases/Hypertension"},{"id":67022901,"name":"Biological sciences/Physiology/Cardiovascular biology"}],"tags":[],"updatedAt":"2026-05-11T03:40:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-28 13:10:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9530735","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9530735","identity":"rs-9530735","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}