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Background: This study investigated the prognostic value of cardiovascular magnetic resonance (CMR)-derived global coronary flow reserve (G-CFR) in addition to cardiopulmonary exercise testing (CPET) variables in patients with acute myocardial infarction (AMI). Methods and Results: We investigated 127 patients with AMI who underwent primary or urgent percutaneous coronary intervention (PCI) and post-intervention CMR and CPET. The incidence of major cardiac and cerebrovascular events (MACCE), defined as all-cause death, recurrent non-fatal myocardial infarction, re-hospitalization due to congestive heart failure, and stroke, was evaluated (median follow-up, 2.8 years). Patients with MACCE (n=14) had lower ejection fraction (EF) (50 [43-59] vs. 58 [51-63]%; P=0.014), lower G-CFR (1.74 [1.19-2.20] vs. 2.40 [1.61-3.66]; P=0.008), and lower peak oxygen consumption (V̇O2) (15.16±2.64 vs. 17.19±3.70 mL/kg/min; P=0.049) than patients without MACCE. G-CFR<2.33 and peak V̇O2 <15.65 mL/kg/min (cut-off values derived from receiver operating characteristic curve analyses) were significantly associated with the incidence of MACCE (log-rank test, P=0.01). The combination of low G-CFR and low peak V̇O2 improved risk discrimination for MACCE when added to the reference clinical model including age, male sex, post-PCI peak creatine kinase, EF, and left anterior descending artery culprit lesion. Conclusions: G-CFR and peak V̇O2 showed incremental prognostic information compared with the reference model using historically important clinical risk factors, indicating that this approach may help identify high-risk patients who suffer subsequent adverse events.

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AIMS: Emerging evidence suggests that smaller left ventricular volumes may identify subjects with lower cardiorespiratory fitness. Whether left ventricular size predicts functional capacity in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. This study aimed to explore the association between indexed left ventricular end-diastolic volume (iLVEDV) and maximal functional capacity, assessed by peak oxygen consumption (peakVO2), in stable outpatients with HFpEF. METHODS AND RESULTS: We prospectively analysed data from 133 consecutive stable outpatients who underwent cardiopulmonary exercise testing and echocardiography on the same day. Data were validated in a cohort of HFpEF patients from San Paolo Hospital, Milan, Italy. A multivariable linear regression assessed the association between iLVEDV and peakVO2. The mean age was 73.2 ± 10.5 years, and 75 (56.4%) were women. The median iLVEDV, indexed left ventricular end-systolic volume, and left ventricular ejection fraction were 46 ml/m2 (30-56), 15 ml/m2 (11-19), and 66% (60-74%), respectively. The median peakVO2 and percentage of predicted peakVO2 were 11 ml/kg/min (9-13) and 64.1% (53-74.4), respectively. Adjusted linear regression analysis showed that smaller iLVEDV was associated with lower peakVO2 (p = 0.0001). In the validation cohort, adjusted linear regression analysis showed a consistent pattern: a smaller iLVEDV was associated with a higher likelihood of reduced peakVO2 (p = 0.004). CONCLUSIONS: In stable outpatients with HFpEF, a smaller iLVEDV was associated with a lower maximal functional capacity. These findings suggest a need for further studies to understand the pathophysiological mechanisms underlying these observations and to explore targeted treatment strategies for this patient subgroup.

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Aging is associated with a significant decline in aerobic capacity assessed by maximal exercise oxygen consumption (V̇o2max). The relative contributions of the specific V̇o2 components driving this decline, namely cardiac output (CO) and arteriovenous oxygen difference (A - V)O2, remain unclear. We examined this issue by analyzing data from 99 community-dwelling participants (baseline age: 21-96 yr old; average follow-up: 12.6 yr old) from the Baltimore Longitudinal Study of Aging, free of clinical cardiovascular disease. V̇o2peak, a surrogate of V̇o2max, was used to assess aerobic capacity during upright cycle ergometry. Peak exercise left ventricular volumes, heart rate, and CO were estimated using repeated gated cardiac blood pool scans. The Fick equation was used to calculate (A - V)O2diff,peak from COpeak and V̇o2peak. In unadjusted models, V̇o2peak, (A - V)O2diff,peak, and COpeak declined longitudinally over time at steady rates with advancing age. In multiple linear regression models adjusting for baseline values and peak workload, however, steeper declines in V̇o2peak and (A - V)O2diff,peak were observed with advanced entry age but not in COpeak. The association between the declines in V̇o2peak and (A - V)O2diff,peak was stronger among those ≥50 yr old compared with their younger counterparts, but the difference between the two age groups did not reach statistical significance. These findings suggest that age-associated impairment of peripheral oxygen utilization during maximal exercise poses a stronger limitation on peak V̇o2 than that of CO. Future studies examining interventions targeting the structure and function of peripheral muscles and their vasculature to mitigate age-associated declines in (A - V)O2diff are warranted.NEW & NOTEWORTHY The age-associated decline in aerobic exercise performance over an average of 13 yr in community-dwelling healthy individuals is more closely associated with decreased peripheral oxygen utilization rather than decreased cardiac output. This association was more evident in older than younger individuals. These findings suggest that future studies with larger samples examine whether these associations vary across the age range and whether the decline in cardiac output plays a greater role earlier in life. In addition, studies focused on determinants of peripheral oxygen uptake by exercising muscle may guide the selection of preventive strategies designed to maintain physical fitness with advancing age.

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Background: Poor cardiorespiratory fitness poses the highest risk of mortality. Long-COVID-19 survivors exhibit a reduced cardiorespiratory fitness (CRF). While exercise rehabilitation, such as cardiopulmonary exercise, is used for long-COVID-19 survivors, the effects of exercise on CRF in this population remain inconclusive. In this study, we aim to systematically summarise and synthesise whether exercise rehabilitation improves CRF among long-COVID-19 survivors. Methods: A comprehensive search was performed through PubMed, CINAHL, Embase, Scopus, and the Cochrane Library (since their inception to November 2023) and study reference lists. Studies presenting the effects of exercise rehabilitation on CRF (peak oxygen consumption (VO2peak) and six-minute walk distance (6MWD)) in long-COVID-19 survivors were identified. The standardised mean difference (SMD), mean difference (MD), and 95% confidence interval (CI) were used for analyses. The certainty of evidence was measured using a Grading of Recommendation Assessment, Development and Evaluation approach. Results: Twelve eligible studies (five RCTs and seven non-RCTs) with 682 participants were analysed. The meta-analysis showed significantly improved 6MWDs (MD 76.47, 95% CI 59.19-93.71, low certainty) and significantly greater 6MWDs (SMD 0.85, 95% CI 0.11-1.59, very low certainty) in the exercise rehabilitation group compared to the control group. A significantly improved 6MWD was found in subgroups of young to middle-aged adults and subgroups of patients who undertook aerobic exercise combined with resistance and respiratory exercise and centre-based training programs. Conclusions: Exercise rehabilitation is effective for improving CRF, as measured by the 6MWD in long-COVID-19 survivors. Improvements are likely to be more pronounced in specific subgroups of young to middle-aged adults and patients undertaking aerobic exercise combined with resistance and respiratory exercise and centre-based training programs. However, recommendations for clinical practice are limited due to the very low evidence certainty.

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BACKGROUND: This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson's or Spearman's coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. RESULTS: Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. CONCLUSIONS: This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.

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This study investigated the impact of long-term heat acclimation (HA) training on mouse thermoregulation, metabolism, and running performance in temperate (T) and hot (H) environments. Male Swiss mice were divided into 1) Sedentary (SED) mice kept in T (22 °C; SED/T), 2) Endurance Trained mice (ET, 1 h/day, 5 days/week, 8 weeks, 60 % of maximum speed) in T (ET/T), 3) SED kept in H (32 °C; SED/H), and 4) ET in H (ET/H). All groups performed incremental load tests (ILT) in both environments before (pre-ET) and after four and eight weeks of ET. In the pre-ET period, H impaired (∼30 %) performance variables (maximum speed and external work) and increased (1.3 °C) maximum abdominal body temperature compared with T. In T, after four weeks, although ET/H exercised at a lower (∼30 %) absolute intensity than ET/T, performance variables and aerobic power (peak oxygen uptake, VO2peak) were similarly increased in both ET groups compared with SED/T. After eight weeks, the external work was higher in both ET groups compared with SED/T. Only ET/T significantly increased VO2peak (∼11 %) relative to its pre-ET period. In H, only after eight weeks, both ET groups improved (∼19 %) maximum speed and reduced (∼46 %) post-ILT blood lactate concentrations compared with their respective pre-ET values. Liver glycogen content increased (34 %) in both ET groups and SED/H compared with SED/T. Thus, ET/H was performed at a lower absolute intensity but promoted similar effects to ET/T on metabolism, aerobic power, and running performance. Our findings open perspectives for applying HA training as part of a training program or orthopedic and metabolic rehabilitation programs in injured or even obese animals, reducing mechanical load with equivalent or higher physiological demand.

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BACKGROUND: Endothelial dysfunction and peak oxygen uptake (VO2peak) are also predictors of increased risk of cardiovascular events in heart transplantation (HTx) recipients. The preservation of endothelial function may contribute to exercise tolerance. OBJECTIVE: To investigate the correlation between peripheral endothelial function and exercise tolerance through VO2peak and ventilation to carbon dioxide production slope (VE / VCO2 slope) in HTx recipients. METHODS: A pilot cross-sectional study was conducted with adult individuals aged 18-65 years, HTx ≥ six months after surgery, who had a stable medical condition and no changes over the last three months of immunosuppressive treatment. The patients underwent an assessment of endothelial function through PAT (EndoPAT-2000®) and performed a cardiopulmonary exercise test (CPET). RESULTS: A total of 41% of the studied population presented endothelial dysfunction. The individuals were divided into two groups: the endothelial dysfunction (GED; n=9) group and the normal endothelial function (GNEF; n=13) group according to the logarithm of the reactive hyperemia index (LnRHI). There was a positive and moderate correlation between the LnRHI and VO2 peak (r=0.659, p=0.013) and a negative and moderate correlation between the LnRHI and VE/VCO2 slope (r= -0.686, p= 0.009) in the GNEF. However, no significant correlations were found in the GED. CONCLUSION: The results showed that the preservation of peripheral endothelial function is significantly correlated with an increase in exercise tolerance in individuals after HTx. These findings bring important considerations for cardiovascular risk prevention and emphasize that therapeutic strategies with physical training programs must be implemented early.

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AIMS: In patients with peripheral arterial disease (PAD), exercise therapy is recommended to relieve leg symptoms, as noted in the 2016 AHA/ACC and 2017 ESC/ESVS guidelines. We assessed the trainability for cardiopulmonary fitness (CPF) and quality of life (QOL); three distinct patient types, namely, PAD, heart failure (HF), and stroke, were compared. METHODS AND RESULTS: This is a multicentre, retrospective analysis of prospectively collected data from three clinical studies. Data collected from 123 patients who completed 36 sessions of supervised aerobic training of moderate intensity were analysed, with 28 PAD, 55 HF, and 40 stroke patients totalling 123. Before and after training, cardiopulmonary exercise testing with non-invasive cardiac output monitoring and QOL evaluation using a 36-Item Short Form Survey (SF-36) were performed. Non-response was defined as a negative change in the post-training value compared with that in the pre-training value. The result showed an improvement in CPF in all three groups. However, cardiorespiratory fitness (CRF) increased by a lesser extent in the PAD group than in the HF and stroke groups; the physical and mental component scores (MCS) of SF-36 exhibited a similar pattern. Non-response rates of peak V˙O2, oxygen uptake efficiency slope, and MCS were higher in the PAD group. In the PAD group, non-responders regarding peak V˙O2 had a higher pulse wave velocity than responders. CONCLUSION: In patients with PAD following exercise therapy, CRF and QOL improved to a lesser extent on average; their non-response rate was also higher compared with that of HF or stroke patients. Therefore, a higher dose of exercise might be needed to elicit adaptation in PAD patients, especially those with high pulse wave velocity.

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Background: Heart failure (HF) is a debilitating and often fatal disease that affects millions of people worldwide. Diminished nitric oxide synthesis, signaling, and bioavailability are believed to contribute to poor skeletal muscle function and aerobic capacity. The aim of this clinical trial (iNIX-HF) is to determine the acute and longer-term effectiveness of inorganic nitrate supplementation on exercise performance in patients with HF with reduced ejection fraction (HFrEF). Methods: This clinical trial is a double-blind, placebo-controlled, randomized, parallel-arm design study in which patients with HFrEF (n = 75) are randomized to receive 10 mmol potassium nitrate (KNO3) or a placebo capsule daily for 6 wk. Primary outcome measures are muscle power determined by isokinetic dynamometry and peak aerobic capacity (VO2peak) determined during an incremental treadmill exercise test. Endpoints include the acute effects of a single dose of KNO3 and longer-term effects of 6 wk of KNO3. The study is adequately powered to detect expected increases in these outcomes at P < 0.05 with 1-ß>0.80. Discussion: The iNIX-HF phase II clinical trial will evaluate the effectiveness of inorganic nitrate supplements as a new treatment to ameliorate poor exercise capacity in HFrEF. This study also will provide critical preliminary data for a future 'pivotal', phase III, multi-center trial of the effectiveness of nitrate supplements not only for improving exercise performance, but also for improving symptoms and decreasing other major cardiovascular endpoints. The potential public health impact of identifying a new, relatively inexpensive, safe, and effective treatment that improves overall exercise performance in patients with HFrEF is significant.

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Background and Objectives: Cardiopulmonary exercise testing (CPET) is a cornerstone of risk stratification in heart failure with reduced ejection fraction (HFrEF). However, there is a paucity of evidence on its predictive power in older patients. The aim of this study was to evaluate the prognostic power of current heart transplantation (HTx) listing criteria in HFrEF stratified according to age groups. Materials and Methods: Consecutive patients with HFrEF undergoing CPET between 2009 and 2018 were followed-up for cardiac death and urgent HTx. Results: CPET was performed in 458 patients with HFrEF. The composite endpoint occurred in 16.8% of patients ≤50 years vs. 14.1% of patients ≥50 years in a 36-month follow-up. Peak VO2 (pVO2), VE/VCO2 slope and percentage of predicted pVO2 were strong independent predictors of outcomes. The International Society for Heart and Lung Transplantation thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to ß-blockers), VE/VCO2 slope > 35 and percentage of predicted pVO2 ≤ 50% presented a higher overall diagnostic effectiveness in younger patients (≤50 years). Specific thresholds for each age subgroup outperformed the traditional cut-offs. Conclusions: Personalized age-specific thresholds may contribute to an accurate risk stratification in HFrEF. Further studies are needed to address the gap in evidence between younger and older patients.

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BACKGROUND: Coronary artery (CA) Z-score system is widely used to define CA aneurysm (CAA). Children and adolescents after acute stage of Kawasaki disease (KD-CA) have a higher risk of developing CAAs if their CA Z-score ≥ 2.5. Z-score system of peak oxygen consumption (Peak VO2 Z-score) allows comparisons across ages and sex, regardless of body size and puberty. We aimed to compare the exercise capacity (EC) indicated by peak VO2 Z-score during cardiopulmonary exercise testing (CPET) directly between KD-CA with different CA Z-score. METHODS: KD-CA after acute stage who received CPET in the last 5 years were retrospectively recruited. CA Z-score was based on Lambda-Mu-Sigma method. Max-Z was the maximum CA Z-score of different CAs. KD children with Max-Z < 2.5 and ≥ 2.5 were defined as KD-1 and KD-2 groups, respectively. Peak VO2 Z-score was calculated using the equation established based on Hong Kong Chinese children and adolescent database. RESULTS: One hundred two KD-CA were recruited (mean age: 11.71 ± 2.57 years). The mean percent of measured peak VO2 to predicted value (peak PD%) was 90.11 ± 13.33. All basic characteristics and baseline pulmonary function indices were comparable between KD-1 (n = 87) and KD-2 (n = 15). KD-1 had significantly higher peak VO2 Z-score (p = .025), peak PD% (p = .008), peak metabolic equivalent (p = .027), and peak rate pressure product (p = .036) than KD-2. CONCLUSIONS: KD-CA had slightly reduced EC than healthy peers. KD-CA with Max-Z ≥ 2.5 had significantly lower peak EC than those < 2.5. Max-Z is potentially useful follow-up indicator after acute stage of KD.

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The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%-p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8-72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5-37.8), 67.4 ml/min/1.73 m2 (50.7-82.8), 1,285 pg/ml (898-2,305), 623.4 pg/ml (533.5-736.6), and 72.6 RU/ml (62.6-96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9-37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ-4.6, (-1.7 to -5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.

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BACKGROUND: New therapies with prognostic benefits have been recently introduced in heart failure with reduced ejection fraction (HFrEF) management. The aim of this study was to evaluate the prognostic power of current listing criteria for heart transplantation (HT) in an HFrEF cohort submitted to cardiopulmonary exercise testing (CPET) between 2009 and 2014 (group A) and between 2015 and 2018 (group B). METHODS: Consecutive patients with HFrEF who underwent CPET were followed-up for cardiac death and urgent HT. RESULTS: CPET was performed in 487 patients. The composite endpoint occurred in 19.4% of group A vs. 7.4% of group B in a 36-month follow-up. Peak VO2 (pVO2) and VE/VCO2 slope were the strongest independent predictors of mortality. International Society for Heart and Lung Transplantation (ISHLT) thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to ß-blockers) and VE/VCO2 slope > 35 presented a similar and lower Youden index, respectively, in group B compared to group A, and a lower positive predictive value. pVO2 ≤ 10 mL/kg/min and VE/VCO2 slope > 40 outperformed the traditional cut-offs. An ischemic etiology subanalysis showed similar results. CONCLUSION: ISHLT thresholds showed a lower overall prognostic effectiveness in a contemporary HFrEF population. Novel parameters may be needed to improve risk stratification.

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Estimate the shape and number of cardiorespiratory fitness (CRF) trajectories from childhood to adolescence; and verify whether CRF trajectory membership can be predicted by sex, biological maturation, body weight, body composition and physical activity (PA) in childhood. Data from QUALITY were used. Participants attended baseline (8-10 y old, n = 630) and follow-ups 2 years (n = 564) and 7 years (n = 359) after baseline. Group-based trajectory analysis for relative peak oxygen consumption (VO2peak, ml·kg-1·min-1) was performed. A multinomial logistic regression model was used to estimate the associations between baseline predictors and trajectory membership. Mean age of the 454 participants was 9.7 ± 0.9 years at baseline. Three distinct VO2peak trajectories were identified and all tended to decrease. They were labelled according to the starting point and slope. High-Decreasers were mostly boys, had lower body weight and fat-free mass index and higher PA levels at baseline (p < 0.05). Female sex and higher weight were associated with higher odds of being classified in the Low-Decreaser trajectory (OR = 74.03, 95%CI = 27.06-202.54; OR = 1.48, 95%CI = 1.36-1.60). Those with higher PA were less likely to be Low-Decreasers (OR = 0.96, 95%CI = 0.94-0.97). Sex, body weight and PA in childhood are important influencing factors of VO2peak (ml·kg-1·min-1) trajectories across adolescence.

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Background: Cancer therapy-related cardiotoxicity is a major cause of cardiovascular morbidity in childhood cancer survivors. The aims of this study were to investigate systolic myocardial function and its association to cardiorespiratory fitness in pediatric childhood cancer survivors. Methods: In this sub-study of the international study "Physical Activity and fitness in Childhood Cancer Survivors" (PACCS), echocardiographic measures of left ventricular global longitudinal strain (LV-GLS) and right ventricular longitudinal strain (RV-LS) were measured in 128 childhood cancer survivors aged 9-18 years and in 23 age- and sex-matched controls. Cardiorespiratory fitness was measured as peak oxygen consumption achieved on treadmill and correlated to myocardial function. Results: Mean LV-GLS was reduced in the childhood cancer survivors compared to the controls, -19.7% [95% confidence interval (CI) -20.1% to -19.3%] vs. -21.3% (95% CI: -22.2% to -20.3%) (p = 0.004), however, mainly within normal range. Only 13% of the childhood cancer survivors had reduced LV longitudinal strain z-score. Mean RV-LS was similar in the childhood cancer survivors and the controls, -23.2% (95% CI: -23.7% to -22.6%) vs. -23.3% (95% CI: -24.6% to -22.0%) (p = 0.8). In the childhood cancer survivors, lower myocardial function was associated with lower peak oxygen consumption [correlation coefficient (r) = -0.3 for LV-GLS]. Higher doses of anthracyclines (r = 0.5 for LV-GLS and 0.2 for RV-LS) and increasing time after treatment (r = 0.3 for LV-GLS and 0.2 for RV-LS) were associated with lower myocardial function. Conclusions: Left ventricular function, but not right ventricular function, was reduced in pediatric childhood cancer survivors compared to controls, and a lower left ventricular myocardial function was associated with lower peak oxygen consumption. Furthermore, higher anthracycline doses and increasing time after treatment were associated with lower myocardial function, implying that long-term follow-up is important in this population at risk.

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Objective: Diminished physical capacity is common and progressive in patients undergoing dialysis, who are also prone to deficiency in carnitine, which plays a pivotal role in maintaining skeletal muscle and cardiac function. The present study aimed to evaluate the association of carnitine profile with exercise parameters in patients with incident dialysis. Design and Methods: This was a single-center cross-sectional study including 87 consecutive patients aged 20-90 years who were initiated on dialysis in Keio University Hospital between December 2019 and December 2022 and fulfilled the eligibility criteria. Exercise parameters were evaluated via cardiopulmonary testing (CPX) using the electronically braked STRENGTH ERGO 8 ergometer, whereas the carnitine profile was assessed by determining serum free carnitine (FC), acylcarnitine (AC) levels and AC/FC ratio. Results: The mean cohort age was 62.1 ± 15.2 years, with male and hemodialysis predominance (70% and 73%, respectively). AC/FC was 0.46 ± 0.15, and CPX revealed peak oxygen consumption (VO2) of 13.9 ± 3.7 (mL/kg/min) with percent-predicted peak VO2 of 53.6% ± 14.7% and minute ventilation (VE)/carbon dioxide output (VCO2) slope of 35.1 ± 8.0. Fully-adjusted multivariate linear regression analysis showed that AC/FC was significantly associated with decreased peak VO2 (ß, -5.43 [95% confidence interval (CI), -10.15 to -0.70]) and percent-predicted peak VO2 (ß, -19.98 [95% CI, -38.43 to -1.52]) and with increased VE/VCO2 slope (ß, 13.76 [95% CI, 3.78-23.75]); FC and AC did not exhibit similar associations with these parameters. Moreover, only AC/FC was associated with a decreased peak work rate (WR), percent-predicted WR, anaerobic threshold, delta VO2/delta WR, and chronotropic index. Conclusion: In patients on incident dialysis, exercise parameters, including those related to both skeletal muscle and cardiac function, were strongly associated with AC/FC, a marker of carnitine deficiency indicating altered fatty acid metabolism. Further studies are warranted to determine whether carnitine supplementation can improve exercise capacity in patients on incident dialysis.

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BACKGROUND: Exercise training improves physical capacity in patients with heart failure with reduced ejection fraction (HFrEF), but the mechanisms involved in this response is not fully understood. The aim of this study was to determine if physical capacity increase in patients HFrEF is associated with muscle sympathetic nerve activity (MSNA) reduction and muscle blood flow (MBF) increase. METHODS: The study included 124 patients from a 17-year database, divided according to exercise training status: 1) exercise-trained (ET, n = 83) and 2) untrained (UNT, n = 41). MSNA and MBF were obtained using microneurography and venous occlusion plethysmography, respectively. Physical capacity was evaluated by cardiopulmonary exercise test. Moderate aerobic exercise was performed 3 times/wk. for 4 months. RESULTS: Exercise training increased peak oxygen consumption (V̇O2, 16.1 ± 0.4 vs 18.9 ± 0.5 mL·kg-1·min-1, P < 0.001), LVEF (28 ± 1 vs 30 ± 1%, P = 0.027), MBF (1.57 ± 0.06 vs 2.05 ± 0.09 mL.min-1.100 ml-1, P < 0.001) and muscle vascular conductance (MVC, 1.82 ± 0.07 vs 2.45 ± 0.11 units, P < 0.001). Exercise training significantly decreased MSNA (45 ± 1 vs 32 ± 1 bursts/min, P < 0.001). The logistic regression analyses showed that MSNA [(OR) 0.921, 95% CI 0.883-0.962, P < 0.001] was independently associated with peak V̇O2. CONCLUSIONS: The increase in physical capacity provoked by aerobic exercise in patients with HFrEF is associated with the improvement in MSNA.

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BACKGROUND: Cardiopulmonary exercise testing (CPET) is an important clinical tool that provides a global assessment of the respiratory, circulatory and metabolic responses to exercise which are not adequately reflected through the measurement of individual organ system function at rest. In the context of critical COVID-19, CPET is an ideal approach for assessing long term sequelae. METHODS: In this prospective single-center study, we performed CPET 12 months after symptom onset in 60 patients that had required intensive care unit treatment for a severe COVID-19 infection. Lung function at rest and chest computed tomography (CT) scan were also performed. RESULTS: Twelve months after severe COVID-19 pneumonia, dyspnea was the most frequently reported symptom although only a minority of patients had impaired respiratory function at rest. Mild ground-glass opacities, reticulations and bronchiectasis were the most common CT scan abnormalities. The majority of the patients (80%) had a peak O2 uptake (V'O2) considered within normal limits (median peak predicted O2 uptake (V'O2) of 98% [87.2-106.3]). Length of ICU stay remained an independent predictor of V'O2. More than half of the patients with a normal peak predicted V'O2 showed ventilatory inefficiency during exercise with an abnormal increase of physiological dead space ventilation (VD/Vt) (median VD/VT of 0.27 [0.21-0.32] at anaerobic threshold (AT) and 0.29 [0.25-0.34] at peak) and a widened median peak alveolar-arterial gradient for O2 (35.2 mmHg [31.2-44.8]. Peak PetCO2 was significantly lower in subjects with an abnormal increase of VD/Vt (p = 0.001). Impairments were more pronounced in patients with dyspnea. Peak VD/Vt values were positively correlated with peak D-Dimer plasma concentrations from blood samples collected during ICU stay (r2 = 0.12; p = 0.02) and to predicted diffusion capacity of the lung for carbon monoxide (DLCO) (r2 = - 0.15; p = 0.01). CONCLUSIONS: Twelve months after severe COVID-19 pneumonia, most of the patients had a peak V'O2 considered within normal limits but showed ventilatory inefficiency during exercise with increased dead space ventilation that was more pronounced in patients with persistent dyspnea. TRIAL REGISTRATION: NCT04519320 (19/08/2020).

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This study compared differences in cardiovascular (CV) risk factor responses between males and females following endurance (END) and resistance (RES) training. We present the frequency of responders to each training modality and the magnitude of response. Using a randomized crossover design, 68 healthy adults [age: female (F): 24.5 ± 4.6; male (M): 27.3 ± 6.6] completed 3 mo of RES and END, with 3 mo washout. Peak oxygen consumption (V̇o2peak), strength, body composition, blood pressure, glucose, insulin, and lipids were measured. V̇o2peak (L/min) significantly increased in both sexes following END, but not RES. The magnitude of change was larger in males (F: +0.20 L/min; M: +0.32 L/min), although this did not achieve statistical significance (P = 0.051). Strength significantly increased in both sexes following RES (P < 0.01), with a larger increase in males (Leg press: F: +39 kg; M: +63 kg; P < 0.05). Lean mass significantly increased in both sexes (P < 0.01) following RES and fat mass decreased in females following END (P = 0.019). The change in C-reactive protein following END was significantly different between sexes (F: -0.4 mg/L; M: +0.5 mg/L; P = 0.035). There were no differences between sexes in the proportion of individuals who responded positively to any variable following RES or END; differences between sexes were due to the magnitude of change. Males had a larger increase in V̇o2peak following END and strength following RES. There were no sex differences in other CV risk factors. This suggests differences in physiological responses to strength and V̇o2peak may not translate to changes in CV risk in healthy subjects.NEW & NOTEWORTHY This study investigated sex differences in cardiovascular risk factors in response to different exercise training modalities. Males had a larger improvement in peak oxygen consumption following endurance training and strength following resistance training compared with females. These changes in peak oxygen consumption and strength did not translate to changes in other cardiovascular risk factors. Despite the greater magnitude of change in males, there were no sex differences in the proportion of individuals who responded to training.

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