The study, led by Jingyi Xie and Zhide Liang with corresponding author Bin Wang, pooled data from 7,760 participants with coronary heart disease across 129 randomised controlled trials. That scale matters. Individual trials of exercise in cardiac patients are often small, brief, and heterogeneous, making it difficult to compare one training modality against another with any statistical confidence. By using a network meta-analysis — a technique that simultaneously compares multiple interventions, both through direct head-to-head trials and indirect comparisons across the network of studies — the team could rank exercise modalities that had rarely, if ever, been tested against each other in the same experiment.

The outcome the researchers focused on was peak oxygen uptake, or VO₂peak, the maximum rate at which the body can consume oxygen during incremental exercise. Cardiologists prize this measurement because it integrates the performance of the entire oxygen transport chain: the lungs, the heart’s pumping capacity, the vasculature, and the oxidative machinery of skeletal muscle. In patients with coronary heart disease, higher VO₂peak consistently tracks with lower mortality, fewer hospitalisations, and better quality of life, which is why guidelines from bodies such as the American College of Sports Medicine place cardiorespiratory fitness at the centre of exercise prescription.

The headline finding is that most exercise modalities outperformed control conditions, but two stood out. Interval aerobic exercise training — sessions built around alternating periods of higher and lower intensity — produced a mean improvement of 3.43 millilitres per kilogram per minute in VO₂peak compared with control, with a 95 percent credible interval of 2.87 to 3.99. Combined aerobic and resistance exercise training came next, with a mean difference of 2.49 (95 percent credible interval: 1.81 to 3.17). For context, even modest gains in peak oxygen uptake on the order of one metabolic equivalent are associated with clinically meaningful reductions in cardiovascular risk, so differences of this magnitude across an entire rehabilitation population are far from trivial.

Why might interval training hold an edge? The physiological rationale is that repeated bouts near a patient’s tolerance impose a potent stimulus on both central cardiovascular function and peripheral muscle oxidative capacity, while the recovery intervals allow total work to accumulate without excessive fatigue. The combined-training result is similarly intuitive: resistance work complements aerobic conditioning by improving skeletal muscle strength and mass, which can raise the ceiling on whole-body oxygen consumption. But the authors are careful to temper these rankings. They report substantial heterogeneity across trials and describe the certainty of the modality-specific comparisons as low, meaning the ordering of interventions should be read as exploratory rather than definitive.

What sets this analysis apart from earlier meta-analyses is its second analytical engine. The team deployed a meta-analytic random forest, or MARF, a machine learning model trained on study-level characteristics to predict how large an exercise effect would be, and then interpreted the model using Shapley Additive Explanations, or SHAP. SHAP values, a technique rooted in cooperative game theory, quantify how much each feature — such as participant age, intervention length, or training intensity — contributes to each prediction. This approach lets researchers probe heterogeneity in a way traditional subgroup analyses cannot, revealing which variables genuinely drive differences between trials rather than merely appearing to.

The machine learning exploration converged on a clear signal: intervention length emerged as an influential study-level moderator of effect. In plain terms, longer programmes were associated with bigger improvements in fitness. This aligns with the biology of training adaptation, where structural and enzymatic remodelling of heart and muscle tissue accrues over weeks and months, not days. It also carries a practical warning for health systems that fund short courses of cardiac rehabilitation and then discharge patients, potentially cutting the adaptation curve short at its steepest point.

The dose-response analyses added further nuance. Using meta-regression models, the researchers found that greater weekly exercise dose was generally associated with larger improvements in VO₂peak — more volume, more benefit, at least across the range studied. Per-session dose, however, told a different story: the relationship was inverted-U-shaped, rising to a peak and then declining. That shape suggests there is an optimal amount of work per session beyond which additional load yields diminishing, or even counterproductive, returns — a pattern consistent with the idea that overly demanding single sessions may compromise quality, adherence, or safety in a cardiac population.

The authors frame their conclusions with deliberate caution. Exercise-based cardiac rehabilitation does improve VO₂peak in adults with coronary heart disease, they conclude, but the substantial heterogeneity and low-certainty evidence limit confidence in the precise ranking of modalities. They recommend that exercise dose and programme duration be considered alongside patient characteristics, comorbidity burden, and safety when designing rehabilitation programmes, and they stress that these exploratory, aggregate-level findings require prospective validation before they can guide individualised exercise prescriptions. Notably, the research received no specific external funding, and the authors declare no competing interests.

Even with those caveats, the study marks a methodological milestone. Pairing network meta-analysis with interpretable machine learning offers a template for how exercise science — a field drowning in small, heterogeneous trials — might extract more reliable guidance from the evidence it already has. For clinicians, the actionable takeaways are refreshingly concrete: favour interval-based aerobic work or combined aerobic-resistance programmes where feasible, extend programme duration where possible, and think in terms of weekly dose rather than pushing any single session to its limit. For patients, the message is simpler and older than any algorithm: the exercise you do consistently, at an appropriate dose, over a long enough period, is what reshapes the heart’s capacity — and with it, the odds of a longer life.

Subject of Research: Comparative effects of exercise modalities on peak oxygen uptake in coronary heart disease rehabilitation

Article Title: Exercise-based management of patients with coronary heart disease: an integrated network meta-analysis and machine learning exploration

Article References: Xie, J., Liang, Z., Wang, B., Cai, X., & Gan, Z. (2026). Exercise-based management of patients with coronary heart disease: an integrated network meta-analysis and machine learning exploration. BMC Medicine. https://doi.org/10.1186/s12916-026-05229-5

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05229-5

Keywords: coronary heart disease, cardiac rehabilitation, peak oxygen uptake, interval training, network meta-analysis, machine learning, random forest, SHAP, exercise dose-response, aerobic exercise, resistance training, VO2peak

The research team recruited 21 adults aged 35 to 68, dividing them into 11 controls and 10 individuals with long COVID. Every participant had a documented history of SARS-CoV-2 infection, but the two groups differed sharply in the severity of the acute illness and in their recovery. The controls had all experienced asymptomatic or mild infections and reported no lingering symptoms. The long COVID group, by contrast, had suffered moderate-to-critical disease: 60 percent required hospitalization, 60 percent needed oxygen therapy, and one person required mechanical ventilation. At the time of testing, roughly three years after infection, they continued to report fatigue, exercise intolerance, breathlessness, and headaches, and their scores on the Post-COVID-19 Functional Status Scale indicated substantially greater functional limitation than the controls.

To disentangle the possible mechanisms behind this persistent limitation, the investigators designed a three-visit protocol that separated each measurement from the others. On the first visit, participants completed a symptom-limited cardiopulmonary exercise test on a cycle ergometer, with breath-by-breath gas exchange analysis, continuous electrocardiography, and blood pressure monitoring. The second visit was devoted to transthoracic echocardiography, including advanced speckle-tracking analyses of myocardial work. The third visit assessed endothelial function using brachial artery flow-mediated dilation, a noninvasive ultrasound technique in which a blood pressure cuff is inflated for five minutes to induce ischemia and the subsequent surge of blood upon release is used to probe how well the artery dilates. Participants abstained from caffeine, alcohol, and strenuous activity before each session to prevent interference between measurements.

The exercise testing revealed clear and quantifiable deficits. Compared with controls, the long COVID group achieved a lower peak oxygen uptake, a lower predicted peak oxygen uptake relative to reference values, and a lower oxygen uptake at the first ventilatory threshold, the point during incremental exercise where metabolism begins to shift toward anaerobic contribution. These differences carried large effect sizes, indicating that the impairment was not marginal. Because both maximal and submaximal aerobic capacity were reduced, the results suggest that everyday activities, not just athletic performance, demand more physiological effort from these individuals than from their fully recovered counterparts.

The vascular findings were even more striking. Flow-mediated dilation was dramatically lower in the long COVID group, with a Cohen’s d of 2.30, an effect size that is exceptionally large for a between-group comparison in human vascular physiology. Crucially, the team also measured the shear-rate stimulus, the frictional force that flowing blood exerts on the vessel wall and that normally triggers the endothelium to release nitric oxide and other vasodilators. Peak shear rate, the area under the shear-rate curve during the hyperemic period, and the area under the curve up to maximal vasodilation were all significantly reduced in the long COVID participants. This means the problem involves not only a blunted vasodilatory response but also a diminished hyperemic signal, a double hit to the mechanisms that normally match blood flow to metabolic demand.

The researchers took care to ensure that the difference in flow-mediated dilation was not an artifact of differing artery sizes. Allometric scaling of log-transformed baseline and peak diameters showed no significant group-by-diameter interaction, and the between-group difference remained significant after adjustment for baseline diameter. The difference also persisted after statistical adjustment for age, sex, body composition, and comorbidities, strengthening the conclusion that the vascular impairment is a genuine feature of the long COVID phenotype rather than a byproduct of the higher body mass index and obesity prevalence observed in this group.

Perhaps the most informative result came from the correlation analyses. Within the long COVID group, flow-mediated dilation was positively and significantly associated with both peak oxygen uptake and predicted peak oxygen uptake, meaning that individuals with better endothelial function tended to have better aerobic capacity. No such association appeared among the controls, whose vascular function was uniformly good. This pattern supports the idea that, in long COVID, the state of the peripheral vasculature becomes a rate-limiting factor for exercise performance, constraining oxygen delivery to skeletal muscle in a way that does not occur in healthy vasculature with reserve capacity to spare.

The heart, meanwhile, told a different story. Conventional echocardiographic measures, including left ventricular ejection fraction, volumes, and global longitudinal strain, were indistinguishable between groups, as were the myocardial work indices derived from pressure-strain analysis: global work index, global constructive work, global wasted work, and global work efficiency. Myocardial work integrates ventricular deformation with afterload and can detect subtle dysfunction that conventional parameters miss, yet even this sensitive approach found no group differences. Exploratory analyses did reveal intriguing internal patterns: in the long COVID group, lower global work index was associated with greater ventilatory drive and poorer ventilatory efficiency during exercise, and with higher body mass index, hinting at interactions between metabolic status, breathing mechanics, and cardiac mechanics that deserve further study in larger cohorts.

Taken together, the data sketch a coherent physiological account of long COVID exercise intolerance. Persistent endothelial injury after SARS-CoV-2 infection, plausibly driven by chronic inflammation, oxidative stress, and reduced nitric oxide bioavailability, compromises the ability of conduit and resistance vessels to dilate appropriately during exercise. The result is a peripheral limit on oxygen delivery that manifests as reduced aerobic capacity, while the central pump continues to function within normal limits. This peripheral mechanism aligns with earlier studies conducted one and two years after infection, but the present work extends the timeline considerably, showing that these abnormalities persist well into the third year after the acute illness.

The authors are careful to note the limitations of their study. It was observational, cross-sectional, and single-center, with a modest sample size, so the findings are hypothesis-generating rather than definitive. The long COVID cohort consisted predominantly of people with previous moderate-to-critical illness, and the controls all had prior asymptomatic or mild infection, so the results may not generalize to the full spectrum of post-COVID conditions. The cohort was also predominantly composed of individuals with overweight or obesity, and the study was not powered to detect sex or race differences. Even so, the large effect sizes and the a priori power calculation lend credibility to the central conclusion. Clinically, the work argues for evaluating vascular health, not just cardiac function, in patients with persistent post-COVID exercise intolerance, and for cardiometabolic risk management alongside structured rehabilitation. Whether improving endothelial function can restore exercise tolerance remains a critical question for future interventional trials.

Subject of Research: Persistent endothelial dysfunction and exercise intolerance in long COVID three years after SARS-CoV-2 infection

Article Title: Persistent endothelial dysfunction is associated with exercise intolerance in adults despite preserved myocardial work 3 years after SARS‐CoV‐2 infection

Article References: de Araújo Alves, C. C., Goulart, C. D. L., D'Ávila, L., de Souza Silva, B. H. E., Alves, I. M., Aguiar, B. V. S., Conde, C., Stein, R., & Cipriano, G., Jr. (2026). Persistent endothelial dysfunction is associated with exercise intolerance in adults despite preserved myocardial work 3 years after SARS‐CoV‐2 infection. Physiological Reports, 14(19), Article e71103. https://doi.org/10.14814/phy2.71103

Image Credits: AI Generated

DOI: 10.14814/phy2.71103

Keywords: long COVID, endothelial dysfunction, flow-mediated dilation, exercise intolerance, myocardial work, cardiopulmonary exercise testing, SARS-CoV-2, vascular function, peak oxygen uptake, echocardiography, nitric oxide, post-COVID condition

The study drew on data from a six-year, school-based physical activity initiative conducted in south-eastern Norway. Of 351 children whose parents provided consent, 330 completed at least one valid maximal treadmill test, an unusually rigorous approach in pediatric research where field estimates of fitness are far more common than direct measurement. Because valid peak oxygen uptake data from 2016 were available from only three of the nine participating schools following a technical data loss, the researchers based their inferential analyses on measurements collected in 2015, 2017, 2018, 2019 and 2020, providing a longitudinal window that spans most of primary school.

At the heart of the research lies a methodological question that has divided pediatric exercise scientists for decades: how should oxygen uptake be expressed when comparing children of different sizes? Raw absolute values in liters per minute naturally favor older, heavier children. Dividing by total body mass is the most common correction, but it penalizes children with higher body fat, who contribute mass but little metabolic machinery for running. Allometric scaling, which uses exponentials of body mass, and scaling to fat-free mass, which isolates metabolically active tissue, offer alternatives. The HOPP team, led by Asgeir Mamen of Kristiania University College, together with Julianna Buer of the Norwegian School of Sport Sciences and Per Morten Fredriksen of the University of Inland Norway, designated fat-free-mass-scaled peak oxygen uptake as their prespecified primary outcome and tracked all four expressions simultaneously.

The statistical architecture reflected the complexity of the design. Linear mixed models included test year, school allocation group, sex, and the interaction between test year and group as fixed effects, with participant identity as a random intercept and test year as the repeated factor. The primary model incorporated 904 observations from 314 children, a sample that gives the analysis substantial power to detect developmental trends. School-level models were run as sensitivity analyses to probe whether results were being driven by the clustering of children within individual schools, a known hazard of school-based interventions.

The headline result was unambiguous in direction, if nuanced in interpretation. Fat-free-mass-scaled peak oxygen uptake was significantly associated with test year, allocation group, sex, and the test year by group interaction, with all p-values at or below 0.030. From fifth to sixth grade, the adjusted mean fell by 5.73 milliliters per kilogram of fat-free mass per minute in the intervention group and by 5.11 in the control group. Critically, the difference between those group-specific changes was just 0.62 milliliters, with a 95 percent confidence interval spanning from minus 4.25 to 3.00 and a p-value of 0.736. In other words, the school-based physical activity program appeared to make no measurable difference to the final-year decline.

That equivalence between intervention and control schools is perhaps the study’s most sobering finding. The HOPP project was designed as a pedagogical experiment in which schools adopted enhanced physical activity programming, and the reasonable hope was that extra activity would buffer children against fitness losses as they approach adolescence. Instead, the data suggest the late-primary-school decline was resistant to the intervention as delivered. Body-mass-relative and allometrically scaled oxygen uptake also fell significantly in both groups during the final year, while absolute peak oxygen uptake, unadjusted for growth, held roughly steady, hinting that increases in raw aerobic capacity were simply failing to keep pace with children’s rapid physical development.

Sex differences emerged across every expression of fitness, with boys showing higher adjusted values than girls. Yet the magnitude of that gap depended heavily on how the data were scaled. When oxygen uptake was normalized to fat-free mass, which strips away the influence of differences in body composition between the sexes, the sex difference was substantially attenuated. This observation reinforces a growing consensus in pediatric physiology: apparent fitness gaps between boys and girls are partly artifacts of scaling choices and body composition rather than true differences in the oxidative capacity of muscle tissue.

The school-level sensitivity analyses added another layer of nuance. Changes in the three body-size-adjusted expressions of fitness were negative at all nine schools, suggesting the final-year decline was a pervasive phenomenon rather than a quirk of any particular classroom, neighborhood or teaching staff. Such consistency strengthens the biological plausibility of the trend, while also underscoring that whatever combination of growth, maturation and behavior drives the decline, it operates broadly across the study population and overwhelms school-level variation in programming.

The authors are candid about the limitations that temper firm causal conclusions. The study design could not separate growth-related developmental changes from shifts in behavior associated with the COVID-19 pandemic, which overlapped with the later measurement years and is known to have disrupted children’s physical activity worldwide, nor from the possibility that the composition of participants changed over time. A retrospective trial registration, dated 20 June 2015 on ClinicalTrials.gov as NCT02495714, and the 2016 data gap further complicate the inferential picture. Still, the convergence of negative findings across multiple scaling methods and all nine schools makes the late-primary decline difficult to dismiss as statistical noise.

For researchers, the message is methodological: conclusions about childhood aerobic fitness hinge materially on scaling method, body composition and school-level heterogeneity, and studies that report only a single expression of peak oxygen uptake may tell an incomplete or even misleading story. For parents, educators and policymakers, the findings add to mounting evidence that the transition out of primary school is a vulnerable window for children’s cardiovascular health, one that conventional school-based activity interventions, at least as implemented in HOPP, did not shield against. Identifying what does work during those years, and distinguishing genuine developmental biology from modifiable behavior, now stands as an urgent task for pediatric exercise science.

Subject of Research: Longitudinal development of peak oxygen uptake in 6- to 12-year-old children

Article Title: Longitudinal development of oxygen uptake in 6- to 12-year-old children: the Health Oriented Pedagogical Project (HOPP)

Article References: Mamen, A., Buer, J., & Fredriksen, P. M. (2026). Longitudinal development of oxygen uptake in 6- to 12-year-old children: the Health Oriented Pedagogical Project (HOPP). BMC Pediatrics. https://doi.org/10.1186/s12887-026-07631-7

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07631-7

Keywords: peak oxygen uptake, aerobic fitness, children, fat-free mass, allometric scaling, treadmill running, primary school, physical activity, longitudinal study, pediatric health, HOPP, Norway