Lipid analysis at the molecular species level represents a valuable opportunity for clinical applications due to the essential roles that lipids play in metabolic health. However, a comprehensive and high-throughput lipid profiling remains challenging given the lipid structural complexity and exceptional diversity. Herein, we present an ‘omic-scale targeted LC-MS/MS approach for the straightforward and high-throughput quantification of a broad panel of complex lipid species across 21 lipid (sub)classes. The workflow involves an automated single-step extraction with 2-propanol, followed by lipid analysis using Hydrophilic Interaction Liquid Chromatography (HILIC) in a dual-column setup coupled to tandem mass spectrometry with data acquisition in timed-selective reaction monitoring (t-SRM) mode (12 min total run time). The analysis pipeline consists of an initial screen of 1922 lipid species, followed by high-throughput quantification of robustly detected species. Lipid quantification is achieved by a single-point calibration with 75 isotopically labeled standards representative of different lipid classes, covering lipid species with diverse acyl/alkyl chain lengths and unsaturation degrees. When applied to human plasma, 807 lipid species were measured with median intra- and inter-day precision of 9.5 % and 13.6 %, respectively, evaluated within a single and across multiple batches. The concentration ranges measured in NIST plasma were in accordance with the consensus intervals determined in previous ring-trials. Finally, to benchmark our workflow, we characterized NIST plasma materials with different clinical and ethnic backgrounds and analyzed a sub-set of sera (n=81) from a clinically healthy elderly population. Our quantitative lipidomic platform allowed for a clear distinction between different NIST materials and revealed the sex-specificity of the serum lipidome, highlighting numerous statistically significant sex differences.

Fabry’s Disease (FD) is one of many disorders that result in altered vascular function. With the Dynamic Vessel Analyzer (DVA, IMEDOS Systems), retinal vessels can be recorded non-invasively in real time and dynamic responses to stimuli that affect vessel diameter can be directly visualized. The data obtained can be further mathematically evaluated in terms of dynamic time- and location-dependent vessel behavior. This principle of multimodal analysis of dynamic retinal vascular behavior has been applied to demonstrate specific structural and functional retinal microvascular changes in Fabry’s disease. The retinal vascular response was examined with DVA in 10 patients with FD, 4 women, 6 men including 1 child aged 42.5 (34.3–57.3) years (median (1st quartile–3rd quartile)) and in 10 age- and sex-matched healthy participants. The vessel width of an arterial and a venous retinal vessel segment of ~ 1 mm in length was examined in all participants. After 50 s of baseline observation, a monochromatic rectangular luminance flicker (530–600 nm; of 12.5 Hz frequency) was applied three times for 20 s. The vascular response to flicker light was analyzed. Using mathematical signal analysis, the longitudinal microstructure of retinal vessels was assessed and unstimulated vessel wall oscillations were characterized. Group comparisons were performed exploratively using Mann–Whitney-U test. The entire patient group showed no significant difference in response to the flicker light compared to the control group. After dividing the patient group by sex, male patients with FD showed significantly larger arterial dilatation of 6.3 (5.6–7.9)% compared to age-matched controls: 3.3 (2.5–4.1)%, p < 0.01. In contrast, female patients showed a reduced arterial response of 3.4 (3.1–3.7)% compared to age-matched controls: 5.4 (4.0–6.7)%, p = 0.1. When analyzing the periodicity of the spontaneous unstimulated vessel wall modulation, female Fabry patients had a higher and less scattered periodicity of vasomotions in arteries and veins, while male patients showed lower periodicity of vasomotions in arteries with more scattered periods and longer more scattered periods in veins, compared to age-matched controls. The cardiac rhythm was more aperiodic and less pronounced in male patients. In addition, the longitudinal microstructure of retinal arteries and veins in FD was structurally and functionally altered. This was particularly notable in veins at all stages of the vascular reaction and in arteries at all stages except the baseline by more pronounced waves with periods of ~ 50–100 µm. Multimodal dynamic retinal vessel analysis conveys information about different aspects of vascular regulatory potential. The flicker provoked retinal arterial response is more pronounced in male patients with FD. This reaction is nitric oxide (NO) mediated and conveyed by the vascular endothelial cells. With an altered baseline smooth muscle activity in vessel walls subsequent reactions to vascular stimuli such as flicker light for the retina may be more pronounced in the imbalanced system of male Fabry patients. Spontaneous retinal vessel oscillations are altered in Fabry’s disease. These alterations are more dramatic in male patients, and are especially characterized with less periodic vessel behavior over the large frequency range. This is a result of altered smooth muscle reaction potentially due to disease mediated altered potassium channel activity. Both arterial and venous retinal vessel walls in FD show peculiar microstructural changes. The characteristic microirregularities of retinal vessels are of functional nature in arteries and rather of structural nature in veins. The DVA examination with multimodal retinal vessel analysis represents a practical possibility to investigate central microvascular status of Fabry’s disease in more detail and might elucidate the effect of potential therapeutic interventions.

Physical activity is a cornerstone of health for older adults. Recent evidence underscores that even regular light activity, such as routine walking, offers substantial health benefits. Traditional approaches to promoting walking often overlook the importance of the local neighbourhood environment and the wide range of abilities and preferences of older adults. A personalised walking intervention – emphasizing personal preferences and local facilitators by employing Geographic information System (GIS)-based methods for communication and goal setting – might help to overcome problems of low long-term adherence to walking interventions. The MOBITEC-Routes trial aims to assess the effects of personalised, GIS-based walking promotion – versus general information on determinants of health – for mobility-limited and chronically ill older adults on walking (primary outcome) immediately after the 15-week intervention period (primary endpoint) and after another 8 months of follow-up (secondary endpoint). This prospective, two-arm, single centre randomised controlled trial targets sedentary, mobility-limited, chronically ill, and community-living older adults aged 65 + (target N = 130). Outcomes are assessed after 15 weeks of intervention and after an additional 8 months of follow-up. The experimental intervention offers personalised promotion of habitual walking, delivered by an exercise professional in face-to-face and telephone sessions. Opportunities to increase leisure as well as utilitarian walking are identified by using interactive digital maps, personalised walking routes are co-created by the exercise professional and the participant, and a personalised activity plan is developed. Behaviour change strategies are employed. The control group receives general information on determinants of health. Outcomes include walking (average steps per day; primary outcome), time spent lying, sitting, standing and stepping, physical function, life-space mobility, health-related quality of life, fall-related self-efficacy, active aging, as well as constructs of the Health Action Process Approach (HAPA) model (secondary outcomes). Effects will be analysed by analysis of covariance (ANCOVA; primary analysis intention-to-treat, complemented by per-protocol). By incorporating personal preferences and the neighbourhood environment, this intervention aims to promote walking as a sustainable and meaningful part of everyday life for mobility-limited and chronically ill older adults. If the personalised GIS-based approach is successful, it could be seamlessly integrated into preventive healthcare strategies. ISRCTN17473086 (Registration date 22/11/2024).

To define training zones, ventilatory thresholds (VTs) are commonly established by cardiopulmonary gas-exchange analysis during incremental exercise tests. Portable near-infrared spectroscopy (NIRS) devices have emerged as a potential tool for detecting these thresholds by monitoring muscle oxygenation. This study evaluated the accuracy of NIRS measurements to determine VTs or critical power (CP) based on muscle oxygen saturation and assesses the device’s consistency across 2 constant-load tests. Data from 2 cross-sectional studies involving trained recreational endurance athletes (26 from study 1) and CrossFit athletes (59 from study 2) were examined. Incremental ramp tests on a cycle ergometer were performed and followed by either a constant-load test (study 1) or a CP test (study 2). When comparing power output or heart rate between NIRS-derived breakpoints and VTs, weak to moderate agreement was found. Mean differences in power output and heart rate ranged from 16.8 to 22.4 W and 3.8 to 6.0 beats·min−1 at the first threshold and 27.4 to 31.2 W and 7.1 to 7.8 beats·min−1 at the second threshold. Comparing with CP, mean differences ranged from −0.4 to 0.4 W and −0.6 to 0.9 beats·min−1. Test–retest reliability showed moderate agreement, with a mean bias of 1.2 percentage points between constant-load tests. Thus, NIRS may not be accurate for determining VTs or CP during exercise due to limited agreement in power output or hear rate, notable variability on individual level, and moderate reproducibility.

Acute exhaustive exercise acts as a physiological stressor, leading to endothelial activation and the release of circulating progenitor cells (CPC). In heart failure, this CPC response may be blunted. Reactive oxygen species provided by oxidised low density lipoproteins (oxLDL), and nitric oxide metabolites (nitrate, NOm) secreted from activated endothelial cells, could influence endothelial shedding by circulating endothelial cells (CEC) and the mobilisation of CPC - especially in untrained heart failure patients with preserved ejection fraction (HFpEF). MicroRNAs (miRs) such as miR-21-5p, miR-126-3p, miR-138-5p and miR-155-5p regulate CPC and endothelial function influenced by oxidative stress and NOm. This study aimed to investigate the immediate stress, CEC, CPC, and miR-response to an exhaustive incremental exercise test (CPET) in patients with HFpEF (n=43, 14 male; 72.4(9.7) yrs, 26.0(5.2) kg/m2). We assessed the expression of the described miRs by RT-qPCR in peripheral mononuclear cells (MNC), CD34+/CD45dim CPC, CD31+/CD45- CEC by flow cytometry as well as oxLDL and NOm in serum before and directly after the CPET. Data are presented as mean(SE), except patient characteristics as mean(SD). Comparisons pre-to-post exercise were done by Wilcoxon signed-rank test, paired or one-sample t-tests. Parameter associations were evaluated by respective correlation analyses. A two-sided p-value of <0.05 was considered significant. OxLDL did not increase after the exhaustive exercise (63.2(2.7) U/L to 65.3(2.8) U/L, p=0.097, n=37), while NOm decreased (29.8(2.8) µmol/L to 26.0(2.2) µmol/L, p<0.001, n=37). Levels of miR-126 (+2.3(0.5)-fold vs. baseline, p=0.016, n=31), and miR-138 (+2.2(0.4)-fold vs. baseline, p=0.002, n=29) were higher within circulating MNC after the CPET than before. Endothelial shedding by CEC and mobilisation of CPC were enhanced by the CPET (40.0(8.6) CEC/µl to 45.4(10.4) CEC/µl, p=0.021; 0.917(0.178) CPC/µl to 1.252(0.235) CPC/µl, p=0.004, both n=23). Neither miR-155 (+5.7(2.5)-fold vs. baseline, p=0.074, n=31) nor MiR-21 expression were significantly altered (1.8(0.6)-fold vs. baseline, p=0.157, n=30), but miR-21 expression change was linked to the increase in CPC (rho=0.51, p=0.027, n=19 after outlier exclusion, Fig.1), and expression changes in miR-155 (rho=0.52, p=0.007, n=26 after outlier exclusion, Fig.2). Both acute exercise-induced OxLDL and NOm were not related to any cell or miR changes post-CPET (all p>0.05). In HFpEF patients, acute exercise elevates endothelial cell shedding, progenitor cell mobilisation, and MNC miR levels. A non-significant rise in miR-21 correlates with higher CPC, potentially limiting their mobilisation. This effect appears independent of oxidative stress and NOm, but is linked to increased pro-inflammatory miR-155, which negatively affects endothelial cell contacts. This indicates an altered stress response during exhaustive exercise in HFpEF.Fig. 1Correlation miR-21 & CPC changesFig. 2Correlation miR-155 & -21 changes

An association of mental health and in particular depression with cardiovascular disease has been shown in adults and to a lesser extent in the young. Recently improved measurement methods of carotid-intima media thickness (CIMT) and carotid stiffness (CS) allow more differentiated analyses of this link. We examined 4,361 participants of the nationwide KiGGS cohort aged 3–17 years at baseline and 14–28 years at follow-up. Using linear and logistic regressions, we analyzed cross-sectional and longitudinal associations of mental health with systolic blood pressure (SBP), body mass index (BMI) and total cholesterol (TC) as well as CIMT and CS from high-resolution carotid sonography at follow-up. Mental health in children was measured with the Strength and Difficulties Questionnaire (SDQ) and in adults with the Mental Health Inventory (MHI-5) and the Patient Health Questionnaire (PHQ-9). Childhood SDQ scores were associated longitudinally with SBP, BMI and TC (-0.03≤ ß≥ 0.02) but not with CIMT or CS one decade later. Similarly, SDQ at follow-up was associated cross-sectionally with SBP, BMI and TC, but not CIMT or CS. MHI-5 scores were not linked to any outcome. PHQ-9 scores in young adults were associated cross-sectionally with SBP and BMI (-0.26≤ ß≥ 0.01), but not with CIMT or CS. Our study shows that children, adolescents and young adults with impaired mental health also have an increased long-term cardiovascular risk through higher BMI and TC. However, in this sample with predominantly mild mental health impairments carotid remodeling was not evident.

To investigate whether quantifying both the absolute and relative intensity of physical activity (PA) improves understanding of age, sex, and occupation-related differences in PA in healthy adults aged 20–89. In the cross-sectional COmPLETE study, participants (N = 460, 48

Background:Bioimpedance cardiography offers a non-invasive and time-efficient method to measure hemodynamic parameters. Previous studies only investigated its reliability under steady-state conditions and at maximum load but not at ventilatory thresholds (VTs). This is the first study that assesses the reliability of measured hemodynamic parameters at different exercise stages during cardiopulmonary exercise testing (CPET) using prespecified strict criteria to assess reliability. Methods:Data from 31 healthy, well-trained adults were analyzed. Each participant completed two CPETs, both following the same ramp protocol, with a 7-day interval between them. Hemodynamic parameters were measured with the PhysioFlow® (Manatec Biomedical, Poissy, France) at characteristic phases and thresholds [VT1, VT2, and peak oxygen uptake (V̇O2peak)]. To ensure comparability, the wattage (power) corresponding to the thresholds in Test 1 (PVT1, PVT2, and PV̇O2peak) was used for Test 2. Results:Heart rate, stroke volume, and cardiac output demonstrated good reliability on a group level (mean intraclass correlation >0.75) at both thresholds (0.91, 0.80, and 0.77 at PVT1; 0.92, 0.80, and 0.77 at PVT2) and at PV̇O2peak (0.93, 0.82, and 0.80). For stroke volume at PV̇O2peak, both individual differences (-39.0 to 36.9 mL for the women and -39.9 to 45.2 mL for the men) and mean detectable change (17.5 mL) were larger than the a priori defined acceptable ranges of agreement (-3.6 to 3.8 mL for the women and -4.5 to 3.3 mL for the men). Conclusion:The PhysioFlow® reliably measures heart rate, stroke volume, and cardiac output during CPET on a group level. However, as shown by the Bland-Altman plots, the reliability is too low to be used for individual comparisons.

Transportation noise is known to increase the risk for multiple cardiometabolic diseases. However, the complex relationship between different noise sources, sleep, metabolic and cardiovascular risk factors is still not well understood. To study how chronic noise exposure contributes to the development of cardiometabolic disease, data from the cross-sectional COmPLETE-Health Study were used, which includes a comprehensive cardiometabolic assessment and accelerometer-based behavioral monitoring from 527 healthy Swiss adults aged 20-89 years. Road traffic, aircraft and railway noise were modelled at the participants' home addresses, followed by a measurement based model validation. For each noise source, the following conceptual model was tested using Structural Equation Modelling (SEM): Noise was assumed to affect the two latent constructs metabolic risk (defined by waist-to-hip ratio and HDL-cholesterol) and cardiovascular risk (defined by systolic blood pressure and pulse wave velocity) directly, as well as indirectly via sleep efficiency. The SEM showed very good fit of the conceptual models. Road traffic noise had a significant, small-medium sized direct link with cardiovascular risk (β = 0.16, 95 %CI: 0.01, 0.31), while negligible associations with sleep efficiency or metabolic risk were observed. Conversely, railway noise was mainly associated with lower sleep efficiency (β = -0.15, 95 %CI: -0.23, -0.06) and increased metabolic risk (β = 0.14, 95 %CI: -0.05, 0.32), with only a negligible association with cardiovascular risk. The inclusion of physical activity did not change results, suggesting that associations of noise with cardiometabolic health are robust to the additional consideration of physical activity. These insights are important to inform effective measures to protect populations from harmful transportation noise exposure.

Introduction:Sphingolipids and ceramides have been identified as critical drivers of cardiometabolic diseases. Ceramide-based scores were developed, predicting cardiometabolic risk independently of and beyond low-density lipoprotein cholesterol. To date, it remains largely unknown whether exercise can modulate sphingolipid levels. Methods:The SphingoHIIT study was the first parallel randomized controlled trial to investigate the impact of a single session of high-intensity interval training (HIIT; 4 ×4 min at 85-95 % of maximal heart rate) on blood sphingolipid levels. Thirty-six healthy young individuals (aged 20-29 years; 50 % female) were randomly assigned to a HIIT (n = 18) or control group (physical rest, n = 18). Sphingolipid levels were measured from dried blood spots collected over three days before and at five time points after the intervention (2, 15, 30, 60 min, and 24 h). Study conditions were tightly controlled: females were tested during the early follicular phase of their menstrual cycle, and standardized meals were provided for four consecutive days before blood sampling. Results:Forty-seven sphingolipid species were acquired, including 25 ceramides, eight glycosphingolipids, eight sphingomyelins, and six sphingoid bases. After adjusting for sex, body fat mass, cardiorespiratory fitness, and daily physical activity, linear mixed models showed no significant differences in sphingolipid levels between the HIIT and control groups at any post-intervention time point. Conclusion:The present findings suggest that circulating sphingolipids are resilient to an acute bout of intensive exercise, an interesting feature for potential biomarkers of cardiometabolic risk. Future studies should investigate whether regular exercise influences sphingolipid levels and improves cardiometabolic health in different clinical populations.

This study investigated the added value of peak oxygen uptake ([Formula: see text]O2peak) measurements during a 4-min time trial (4TT) or a 3-min all-out test (3MT) as compared to a ramp cycling test to enhance sport-specific performance assessment. Data from two cross-sectional studies were analysed. In study 1, 18 male and 13 female recreational cyclists performed two ramp tests and two 4TT on different days. In study 2, 23 male and 17 female CrossFit athletes performed one ramp test followed by a 3MT with an intervening 20-min recovery. The tolerance limits for ∆[Formula: see text]O2peak between the two exercise tests was set to ± 0.13 L·min-1, reflecting common day-to-day variation in [Formula: see text]O2peak. In study 1, comparing the first ramp test with the first 4TT and comparing the second ramp test with the second 4TT showed mean differences of 0.02 L·min-1 (p = 0.930) and 0.03 L·min-1 (p = 0.873), respectively. However, the tolerance limits were - 0.35-0.31 L·min-1 and - 0.36-0.42 L·min-1, respectively. In study 2, the mean difference and tolerance limits were 0.08 L·min-1 (p = 0.637) and - 0.42-0.58 L·min-1. Although the 4TT and 3MT show limited agreement with ramp tests for [Formula: see text]O2peak, the lack of systematic deviations supports their value for sport-specific performance assessment.

Background and aims: Endothelial dysfunction predicts elevated cardiovascular (CV) risk in healthy individuals. Aerobic exercise reduces endothelial dysfunction in part by improving CV risk factors. Yet, this explains less than 50 % of the effect and a direct influence of exercise training on the endothelium is discussed as possible contributor. The VascuFit study applied non-linear periodized aerobic exercise (NLPE) training to assess its multilevel effects on endothelial function including potential epigenetic endothelial modifications by circulating micro-ribonucleic acids (endomiRs). Methods: Sedentary adults with elevated CV risk between 40 and 60 years were randomized 2:1 and engaged in an eight-week ergometer-based NLPE training (n = 30) or received standard exercise recommendations (n = 14). Macro-, microvascular, cellular and molecular adaptations were assessed via brachial-arterial flow-mediated dilation (baFMD), static retinal vessel analysis (SVA), flow cytometry, and endomiRs regulating key pathways of endothelial function. Statistics included ANCOVA, Principal Component Analysis (PCA), and regression analyses. Results: baFMD improved by 2.38 % (CI:0.70-4.06, p = 0.007) independent of CV risk, whereas SVA parameters and circulating endothelial (progenitor) cells did not significantly change in the NLPE group. The mean distance between baseline and follow-up PCA loadings of the endomiR dataset explaining 44.2 % of dataset variability was higher in the NLPE-group compared to the control group (2.71 +/- 2.02 vs. 1.65 +/- 0.93). However, regression analyses showed no evidence of endomiRs explaining the improvement of baFMD. Conclusions: The improvement of macrovascular endothelial function by aerobic exercise training was independent from CV risk factors. Increased heterogeneity among endomiRs did not explain this effect, but suggests an adaptive response to the exercise stimulus on the epigenetic level.

Introduction Evidence indicates that sphingolipid accumulation drives complex molecular alterations promoting cardiometabolic diseases. Clinically, it was shown that sphingolipids predict cardiometabolic risk independently of and beyond traditional biomarkers such as low-density lipoprotein cholesterol. To date, little is known about therapeutic modalities to lower sphingolipid levels. Exercise, a powerful means to prevent and treat cardiometabolic diseases, is a promising modality to mitigate sphingolipid levels in a cost-effective, safe, and patient-empowering manner. Methods This randomised controlled trial will explore whether and to what extent an 8-week fitness-enhancing training programme can lower serum sphingolipid levels of middle-aged adults at elevated cardiometabolic risk (n = 98, 50% females). The exercise intervention will consist of supervised high-intensity interval training (three sessions weekly), while the control group will receive physical activity counselling based on current guidelines. Blood will be sampled early in the morning in a fasted state before and after the 8-week programme. Participants will be provided with individualised, pre-packaged meals for the two days preceding blood sampling to minimise potential confounding. An ’omic-scale sphingolipid profiling, using high-coverage reversed-phase liquid chromatography coupled to tandem mass spectrometry, will be applied to capture the circulating sphingolipidome. Maximal cardiopulmonary exercise tests will be performed before and after the 8-week programme to assess patient fitness changes. Cholesterol, triglycerides, glycated haemoglobin, the homeostatic model assessment for insulin resistance, static retinal vessel analysis, flow-mediated dilatation, and strain analysis of the heart cavities will also be assessed pre- and post-intervention. This study shall inform whether and to what extent exercise can be used as an evidence-based treatment to lower circulating sphingolipid levels. Trial registration The trial was registered on www.clinicaltrials.gov (NCT06024291) on August 28, 2023.

Aims The Fick principle states that oxygen uptake (VO2) is cardiac output (Q(c)) (*) arterial-venous O-2 content difference [Delta C(a-v)O-2]. Blood flow distribution is hidden in Fick principle, and its relevance during exercise in heart failure (HF) is undefined. To highlight the role of blood flow distribution, we evaluated peak exercise VO2, Q(c), and Delta C(a-v)O-2, before and after HF therapeutic interventions. Methods and results Symptom-limited cardiopulmonary exercise tests with Q(c) measurement (inert gas rebreathing) was performed in 234 HF patients before and 6 months after successful exercise training, cardiac resynchronization therapy, or percutaneous edge-to-edge mitral valve repair. Considering all tests (n = 468), a direct correlation between peakVO(2) and peakQ(c) (R-2 = 0.47) and workload (R-2 = 0.70) was observed. Patients were grouped according to treatment efficacy in Group 1 (peakVO(2) increase >10%, n = 93), Group 2 (peakVO(2) change between 0 and 10%, n = 60), and Group 3 (reduction in peakVO(2), n = 81). Post-treatment peakVO(2) changes poorly correlated with peakQ(c) and peak Delta C(a-v)O-2 changes. Differently, post-procedure peakQ(c) vs. peak Delta C(a-v)O-2 changes showed a close negative correlation (R-2 = 0.46), becoming stronger grouping patients according to peakVO(2) improvement (R-2 = 0.64, 0.79, and 0.58 in Groups 1, 2, and 3, respectively). In 76% of patients, peakQ(c) and Delta C(a-v)O-2 changes diverged regardless of treatment. Conclusion The bulk of these data suggests that blood flow distribution plays a pivotal role on peakVO(2) determination regardless of HF treatment strategies. Accordingly, for assessing HF treatment efficacy on exercise performance, the sole peakVO(2) may be deceptive and the combination of VO2, Q(c) and Delta C(a-v)O-2, must be considered.

BACKGROUND:Patients with heart failure with preserved ejection fraction (HFpEF) commonly experience exercise intolerance, resulting in reduced cardiorespiratory fitness. This is characterised by a decreased maximal oxygen uptake (V̇O2peak), which is determined by the product of cardiac output (CO) and arteriovenous oxygen difference (a-vDO2). While exercise training has been shown to improve V̇O2peak in HFpEF patients, the effects on CO remain unclear. The aim of this study is to systematically review and analyse the current evidence on the effects of supervised exercise training on CO in patients with HFpEF. METHODS:We will systematically search for literature describing the effects of supervised exercise training on CO in patients with HFpEF. All eligible studies published before 30 June 2023 in the following electronic databases will be included: MEDLINE (Ovid), Embase (Ovid), SPORTDiscus (EBSCOhost), and CENTRAL (Cochrane Library). Effect sizes will be extracted for CO before and after a supervised exercise training intervention at rest and maximal exercise. Mass of heterogeneity (I2) will be calculated, and either fixed-effect models or random-effect models will be used for meta-analysis. To detect a potential publication bias, funnel plot analyses will be performed. DISCUSSION:While several studies have reported a positive effect of supervised exercise training on cardiorespiratory fitness, attempts to assess the underlying determinants of V̇O2peak, CO, and a-vDO2 are much scarcer, especially in patients with HFpEF. From a physiological perspective, measuring CO before and after supervised exercise training seems to be a reasonable way to accurately operationalise a potential improvement in cardiac function. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42022361485.