Exercise, cancer, and the cardiovascular system: clinical effects and mechanistic insights.

Cardiovascular diseases and cancer are the leading causes of death in the Western world and share common risk factors. Reduced cardiorespiratory fitness (CRF) is a major determinant of cardiovascular morbidity and cancer survival. In this review we discuss cancer- induced disturbances of parenchymal, cellular, and mitochondrial function, which limit CRF and may be antagonized and attenuated through exercise training. We show the impact of CRF on cancer survival and its attenuating effects on cardiotoxicity of cancer-related treatment. Tailored exercise programs are not yet available for each tumor entity as several trials were performed in heterogeneous populations without adequate cardiopulmonary exercise testing (CPET) prior to exercise prescription and with a wide variation of exercise modalities. There is emerging evidence that exercise may be a crucial pillar in cancer treatment and a tool to mitigate cardiotoxic treatment effects. We discuss modalities of aerobic exercise and resistance training and their potential to improve CRF in cancer patients and provide an example of a periodization model for exercise training in cancer.

Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations.

BACKGROUND: Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking. METHODS: Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case-control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed. RESULTS: Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V ˙ e, V ˙ O2, V ˙ CO2, V ˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V ˙ e/ V ˙ CO2, PetCO2, O2pulse, work, V ˙ O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1. CONCLUSIONS: Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.

Cardiopulmonary exercise test to detect cardiac dysfunction from pulmonary vascular disease.

BACKGROUND: Cardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease. METHODS: We reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O2·pulseAT/O2·pulserest with RHC-determined SVAT/SVrest. We evaluated the sensitivity and specificity of O2·pulseAT/O2·pulserest to detect SVAT/SVrest below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRVpeak) with SVAT/SVrest. RESULTS: From July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O2·pulse and SV at rest and at AT. O2·pulseAT/O2·pulserest correlated highly with SVAT/SVrest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001), whereas TRVpeak did not (r = -0.09, 95% CI -0.47, 0.33; p = 0.69). The AUROC to detect SVAT/SVrest below the LLN was significantly higher for O2·pulseAT/O2·pulserest (0.92, SE 0.04; p = 0.0002) than for TRVpeak (0.69, SE 0.10; p = 0.12). O2·pulseAT/O2·pulserest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SVAT/SVrest. CONCLUSIONS: CPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O2·pulseAT/O2·pulserest may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism.

Monomeric Fe(III)-Hydroxo and Fe(III)-Aqua Complexes Display Oxidative Asynchronous Hydrogen Atom Abstraction Reactivity.

This paper presents the synthesis and characterization of a series of novel monomeric aqua-ligated iron(III) complexes, [FeIII(L5R)(OH2)]2+ (R=OMe, H, Cl, NO2), supported by an amide-containing pentadentate N5 donor ligand, L5R [HL5R=2-(((1-methyl-1H-imidazol-2-yl)methyl)(pyridin-2-yl-methyl)amino)-N-(5-R-quinolin-8-yl)acetamide]. The complexes were characterized by various spectroscopic and analytical techniques, including electrochemistry and magnetic measurements. The Fe(III)-hydroxo complexes, [FeIII(L5R)(OH)]1+, were generated in situ by deprotonating the corresponding aqua complexes in a pH ~7 aqueous medium. In another way, adding one equivalent of a base to a methanolic solution of the Fe(III)-aqua complexes also produced the Fe(III)-hydroxo complexes. The study uses linoleic fatty acid as a substrate to explore the hydrogen atom abstraction (HAA) reactivity of both hydroxo and aqua complexes. The investigation highlights the substitution effect of the L5R ligand on reactivity, revealing a higher rate when an electron-withdrawing group is present. Hammett analyses and(or) determination of the asynchronicity factor (η) suggest an oxidative asynchronous concerted proton-electron transfer (CPET) pathway for the HAA reactions. Aqua complexes exhibited a higher asynchronicity in CPET, resulting in higher reaction rates than their hydroxo analogs. Overall, the work provides insights into the beneficial role of a higher imbalance in electron-transfer-proton-transfer (ET-PT) contributions in HAA reactivity.

Cardiopulmonary exercise testing prior to radical cystectomy: a systematic review and meta-analysis.

OBJECTIVE: To identify the association between cardiopulmonary exercise testing (CPET) and outcomes of radical cystectomy (RC), as RC is historically associated with high rates of short- and long-term morbidity and mortality. METHODS: This quantitative systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. An electronic literature search was conducted to identify all relevant studies evaluating the relationship between CPET parameters and RC outcomes. The primary outcome was short-term mortality. Secondary outcomes included hospital length of stay (LOS) and rate of serious adverse events as defined by the Clavien-Dindo classification. RESULTS: The search identified six studies for inclusion. A total of 546 patients underwent CPET prior to RC. There were significantly more deaths following RC observed in patients with poorer cardiopulmonary function (risk ratio RR 5.80, 95% confidence interval 4.96-6.78). There was no significant association between CPET parameters and adverse events or hospital LOS. CONCLUSIONS: The present systematic review and meta-analysis identified a greater risk of 90-day mortality in patients with poorer cardiorespiratory function, as measured by CPET. However, there remains a paucity of robust clinical data and further high-quality studies are required to verify these results.

Epimeric vitamin D and cardiovascular structure and function in advanced CKD and after kidney transplantation.

BACKGROUND: 25-hydroxyvitamin D can undergo C-3 epimerization to produce 3-epi-25(OH)D3. 3-epi-25(OH)D3 levels decline in chronic kidney disease (CKD), but its role in regulating the cardiovascular system is unknown. Herein, we examined the relationship between 3-epi-25(OH)D3, and cardiovascular functional and structural endpoints in patients with CKD. METHODS: We examined n = 165 patients with advanced CKD from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) study cohort, including those who underwent kidney transplant (KTR, n = 76) and waitlisted patients who did not (NTWC, n = 89). All patients underwent cardiopulmonary exercise testing and echocardiography at baseline, 2 months and 12 months. Serum 3-epi-25(OH)D3 was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: Patients were stratified into quartiles of baseline 3-epi-25(OH)D3 (Q1: <0.4 ng/mL, n = 51; Q2: 0.4 ng/mL, n = 26; Q3: 0.5-0.7 ng/mL, n = 47; Q4: ≥0.8 ng/mL, n = 41). Patients in Q1 exhibited lower peak oxygen uptake [VO2Peak = 18.4 (16.2-20.8) mL/min/kg] compared with Q4 [20.8 (18.6-23.2) mL/min/kg; P = .009]. Linear mixed regression model showed that 3-epi-25(OH)D3 levels increased in KTR [from 0.47 (0.30) ng/mL to 0.90 (0.45) ng/mL] and declined in NTWC [from 0.61 (0.32) ng/mL to 0.45 (0.29) ng/mL; P < .001]. Serum 3-epi-25(OH)D3 was associated with VO2Peak longitudinally in both groups [KTR: ß (standard error) = 2.53 (0.56), P < .001; NTWC: 2.73 (0.70), P < .001], but was not with left ventricular mass or arterial stiffness. Non-epimeric 25(OH)D3, 24,25(OH)2D3 and the 25(OH)D3:24,25(OH)2D3 ratio were not associated with any cardiovascular outcome (all P > .05). CONCLUSIONS: Changes in 3-epi-25(OH)D3 levels may regulate cardiovascular functional capacity in patients with advanced CKD.

Maximal cardiopulmonary exercise testing in glioblastoma patients undergoing chemotherapy: assessment of feasibility, safety, and physical fitness status.

PURPOSE: Maximal cardiopulmonary exercise testing (max. CPET) provides the most accurate measurement of cardiorespiratory fitness. However, glioblastoma (GBM) patients often undergo less intensive tests, e.g., 6-min walk test or self-rating scales. This study aims to demonstrate feasibility and safety of max. CPET in GBM patients, concurrently evaluating their physical fitness status. METHODS: Newly diagnosed GBM patients undergoing adjuvant chemotherapy were offered participation in an exercise program. At baseline, max. CPET assessed cardiorespiratory fitness including peak oxygen consumption (VO2peak), peak workload, and physical work capacity (PWC) at 75% of age-adjusted maximal heart rate (HR). Criteria for peak workload were predefined based on threshold values in HR, respiratory quotient, respiratory equivalent, lactate, and rate of perceived effort. Data were compared to normative values. Adverse events were categorized according to standardized international criteria. Further, self-reported exercise data pre- and post-diagnosis were gathered. RESULTS: All 36 patients (median-aged 60; 21 men) met the predefined criteria for peak workload. Mean absolute VO2peak was 1750 ± 529 ml/min, peak workload averaged 130 ± 43 W, and mean PWC was 0.99 ± 0.38 W/kg BW, all clinically meaningful lower than age- and sex-predicted normative values (87%, 79%, 90%, resp.). Only once (3%) a minor, transient side effect occurred (post-test dizziness, no intervention needed). Self-reported exercise decreased from 15.8 MET-h/week pre-diagnosis to 7.2 MET-h/week post-diagnosis. CONCLUSION: Max. CPET in this well-defined population proved feasible and safe. GBM patients exhibit reduced cardiorespiratory fitness, indicating the need for tailored exercise to enhance health and quality of life. CPET could be essential in establishing precise exercise guidelines.

Distinct effects of type 2 diabetes and obesity on cardiopulmonary performance.

AIM: Effort intolerance is frequent in patients with overweight/obesity and/or type 2 diabetes (T2D) free from cardiac and respiratory disease. We sought to quantify the independent effects of T2D and body mass index (BMI) on cardiopulmonary capacity and gain insights on the possible pathophysiology by case-control and regression analyses. METHODS: Patients at high/moderate cardiovascular risk, with or without T2D, underwent spirometry and combined echocardiography-cardiopulmonary exercise test as part of their clinical workup. Subjects with evidence of cardiopulmonary disease were excluded. The effects of T2D and obesity were estimated by multivariable models accounting for known/potential confounders and the major pathophysiological determinants of oxygen uptake at peak exercise (VO2peak ) normalized for fat-free mass (FFM). RESULTS: In total, 109 patients with T2D and 97 controls were included in the analysis. The two groups had similar demographic and anthropometric characteristics except for higher BMI in T2D (28.6 ± 4.6 vs. 26.3 ± 4.4 kg/m2 , p = .0003) but comparable FFM. Patients with T2D achieved lower VO2peak than controls (18.5 ± 4.4 vs. 21.7 ± 8.3 ml/min/kg, p = .0006). Subclinical cardiovascular dysfunctions were observed in T2D: concentric left ventricular remodelling, autonomic dysfunction, systolic dysfunction and reduced systolic reserve. After accounting for confounders and major determinants of VO2peakFFM , T2D still displayed reduced VO2peak by 1.0 (-1.7/-0.3) ml/min/kgFFM , p = .0089, while the effect of BMI [-0.2 (-0.3/0.1) ml/min/kgFFM , p = .06 per unit increase], was largely explained by a combination of chronotropic incompetence, reduced peripheral oxygen extraction, impaired systolic reserve and ventilatory (in)efficiency. CONCLUSIONS: T2D is an independent negative determinant of VO2peak whose effect is additive to other pathophysiological determinants of oxygen uptake, including BMI.

(Non)-Exertional Variables of Cardiopulmonary Exercise Testing in Heart Failure with and Without Cardiac Amyloidosis.

PURPOSE OF REVIEW: Cardiac amyloidosis (CA) constitutes an important etiology of heart failure with preserved ejection fraction (HFpEF) or heart failure with mildly reduced ejection fraction (HFmrEF). Since patients with CA show early exhaustion, we aimed to investigate whether non-exertional variables of cardiopulmonary exercise testing (CPET) provide additional information in comparison to traditional peak oxygen consumption (VO2peak). RECENT FINDINGS: We retrospectively investigated CPET variables of patients with HFpEF and HFmrEF with (n = 21) and without (n = 21, HF) CA at comparable age and ejection fraction. Exertional and non-exertional CPET variables as well as laboratory and echocardiographic markers were analyzed. The primary outcome was the difference in CPET variables between groups. The secondary outcome was rehospitalization in patients with CA during a follow-up of 24 months. Correlations between CPET, NTproBNP, and echocardiographic variables were calculated to detect patterns of discrimination between the groups. HF patients with CA were inferior to controls in most exertional and non-exertional CPET variables. Patients with CA were hospitalized more often (p = 0.002), and rehospitalization was associated with VE/VCO2 (p = 0.019), peak oxygen pulse (p = 0.042), the oxygen equivalent at the first ventilatory threshold (p = 0.003), circulatory (p = 0.024), and ventilatory power (p < .001), but not VO2peak (p = 0.127). Higher performance was correlated with lower E/e' and NTproBNP as well as higher resting heart rate and stroke volume in CA. Patients with CA displayed worse non-exertional CPET performance compared to non-CA HF patients, which was associated with rehospitalization. Differences between correlations of resting echocardiography and CPET variables between groups emphasize different properties of exercise physiology despite comparable ejection fraction.

A Pilot Randomized Trial of Combined Cognitive-Behavioral Therapy and Exercise Training Versus Exercise Training Alone for the Management of Chronic Insomnia in Obstructive Sleep Apnea.

Insomnia treatment among individuals with comorbid insomnia and obstructive sleep apnea is suboptimal. In a pilot randomized controlled trial, 19 individuals with comorbid insomnia and obstructive sleep apnea were allocated to one of two arms: EX + EX, consisting of two 8-week phases of exercise training (EX), or RE + CBTiEX, encompassing 8 weeks of relaxation training (RE) followed by 8 weeks of combined cognitive-behavioral therapy and exercise (CBTiEX). Outcomes included Insomnia Severity Index (ISI), polysomnography, and cardiorespiratory fitness measures. A mixed-model analysis of variance revealed a Group × Time interaction on peak oxygen consumption change, F(1, 14) = 10.1, p = .007, and EX increased peak oxygen consumption (p = .03, g' = -0.41) and reduced ISI (p = .001, g' = 0.82) compared with RE (p = .49, g = 0.16) post-8 weeks. Post-16 weeks, there was a significant Group × Time interaction (p = .014) driven by RE + CBTiEX yielding a larger improvement in ISI (p = .023, g' = 1.48) than EX + EX (p = .88, g' < 0.1). Objective sleep was unchanged. This study showed promising effects of regular EX alone and combined with cognitive-behavioral therapy for insomnia on ISI in comorbid insomnia and obstructive sleep apnea.

Electrocatalytic Conversion of Small Molecules Utilizing Concerted Proton-electron Transfer Mediators.

Activation of small molecules such as CO2, N2 or organic substrates and their subsequent transformation into complex value-added chemicals by electrocatalysis, utilizing renewable energy sources under ambient conditions, has gained considerable interest in the last few years. However, activation of these chemically inert molecules is hindered by their intrinsically high activation energy barrier presupposing the development of tailored catalytic systems, often precluding selective transformation to the desired target products. Recent studies have shown that the utilization of concerted proton-electron transfer (CPET) mediators (med-H) may facilitate these challenging electrocatalytic reactions.

Revisiting cardiac output estimated noninvasively from oxygen uptake during exercise: an exploratory hypothesis-generating replication study.

Stringer et al. [J Appl Physiol (1985) 82: 908-912, 1997] developed a method from invasive data to estimate cardiac output during incremental exercise testing based on Fick's principle. The authors proposed that the arterio-mixed venous oxygen content difference increases linearly with percentage of maximal O2 consumption. We hypothesized an S-shaped pattern in the published data and calculated the inflection point of this curve and of the standard resting oxygen dissociation curve. Using a partial F test, we compared the linear model with a third-order polynomial model, which showed a better fit to the data [F(2,101) = 9.5, P < 0.001]. This finding was reproduced in a dataset published by Åstrand et al. in 1964 [F(2, 122) = 10.6, P < 0.001]. The inflection point of the curve coincided with the lactate acidosis threshold [first ventilatory threshold (VT1)] as measured by Stringer et al. (VT1 at 50% and inflection point at 56% [95% CI, 52.9 to 60.7] of maximal O2 consumption). The inflection point of the standard resting oxygen dissociation curve was calculated at a partial pressure of 21.5 mmHg and a saturation of 36%, matching the "critical capillary Po2" concept of Stringer et al. (21.2 mmHg). We conclude that the arterio-mixed venous oxygen content difference increases in an S-shaped manner with percentage of maximal oxygen consumption and that the inflection point of this curve may correspond to VT1 and that of the in vivo oxygen dissociation curve. Further research is needed to confirm these findings and improve the method.NEW & NOTEWORTHY In 1997, Stringer, Hansen, and Wasserman developed a method for estimating cardiac output during incremental exercise testing. They observed that the arterio-mixed venous oxygen content difference increases linearly with the percentage of maximal O2 consumption. This increase may be better modelled by an S-shaped function, the inflection point of which may be related to the first ventilatory threshold and the inflection point of the oxygen dissociation curve. This finding may help to improve the method.

Endovascular aneurysm repair offers a survival advantage and is cost-effective compared with conservative management in patients physiologically unfit for open repair.

OBJECTIVE: The endovascular aneurysm repair-2 (EVAR-2) trial suggested that EVAR in patients unfit for open surgical repair (OSR) failed to provide a significant overall survival advantage compared with conservative management. The aim is to compare survival and cost-effectiveness in patients with poor cardiopulmonary exercise test (CPET) metrics who underwent EVAR or were managed conservatively. METHODS: A prospective database of all CPETs (1435 patients) performed to assess preoperative fitness for abdominal aortic aneurysm repair was maintained. A total of 350 patients deemed unfit for OSR underwent EVAR or were managed conservatively. A 1:1 propensity-matched analysis incorporating age, gender, anaerobic threshold, and aneurysm size was used to compare survival. Cost-effectiveness analysis was based on the economic model for the National Institute for Health and Care Excellence clinical guideline on abdominal aortic aneurysm treatment. RESULTS: Propensity matching produced 122 pairs of patients in the EVAR and conservative management groups. The median overall survival for the EVAR group was significantly longer than that for the conservative management group (84 vs 30 months, P < .001). One-, three-, and five-year mortality in the EVAR group was 7%, 40%, and 68%, respectively, compared with 25%, 68%, and 82% in the conservative management group, all P < .001. The increment cost-effectiveness ratio for EVAR was £8023 (US$11,644) per quality-adjusted life year gained compared with £430,602 (US$624,967) in the National Institute for Health and Care Excellence guideline, which is based on EVAR-2 results. CONCLUSIONS: EVAR offers a survival advantage and is cost-effective in selected patients deemed unfit for OSR based on CPET compared with conservative management.

Exercise oscillatory ventilation in patients with advanced heart failure with and without left ventricular assist device.

BACKGROUND: Exercise oscillatory ventilation (EOV), indicating pathological fluctuations on pulmonary arterial pressure, is associated with mortality in patients with heart failure (HF). Whether left ventricular assist device (LVAD)-induced ventricular unloading can reverse EOV and may prevent short-term rehospitalization has not been investigated. METHODS: We performed a retrospective single-center in- and outpatient analysis of patients with (n = 20, LVAD) and without (n = 27, HF) circulatory support and reduced ejection fraction (EF, 22.8 ± 7.9%). The association of cardiopulmonary exercise testing (CPET) variables and 3 months-rehospitalization (3MR) as a primary outcome was analyzed. Furthermore, CPET variables were compared regarding the presence of EOV (+/-). RESULTS: Lower VO2peak (11.6 ± 4.9 ml/kg/min vs. 14.4 ± 4.3 ml/kg/min, p = 0.039), lower increase of PETCO2 (CI = 0.049-1.127; p = 0.068), and higher VE/VCO2 (43.8 ± 9.5 vs. 38.3 ± 10.6; p = 0.069) were associated with 3MR. Flattening of O2 pulse (CI = 0.139-2.379; p = 0.487) had no impact on 3MR. EOV was present in 59.5% (n = 28/47) of patients, without a significant difference between LVAD and HF patients (p = 0.959). Patients with HF/EOV+ demonstrated significantly lower VO2peak compared with HF/EOV- (p = 0.039). LVAD/EOV+ displayed significantly lower EF (p = 0.004) and fewer aortic valve opening than LVAD/EOV- (p = 0.027). CONCLUSIONS: Lower VO2peak , but not EOV, was associated with 3MR. EOV occurred at a similar rate in LVAD and HF patients, which may illustrate insufficient unloading during exercise in chronic LVAD therapy and may contribute to the limited exercise capacity following LVAD implantation. Simultaneous CPET and right heart catheterization studies are needed to elucidate whether EOV may serve as a non-invasive predictor of insufficient LV unloading necessitating LVAD reprograming.

Submaximal Exercise Response is Associated with Future Hypertension in Patients with Coarctation of the Aorta.

Hypertension (HTN) is common in patients with a history of coarctation of the aorta (CoA) and remains underrecognized and undertreated. Studies in the non-coarctation otherwise healthy adult population have correlated an exaggerated blood pressure response during mild to moderate exercise with subsequent diagnosis of HTN. The goal of this study was to determine if blood pressure response to submaximal exercise in normotensive CoA patients correlated with development of HTN.Retrospective chart review was performed in individuals ≥ 13 years old with CoA and no diagnosis of HTN at time of cardiopulmonary exercise testing (CPET). Systolic blood pressure (SBP) during CPET at rest, submax 1 (stage 1 Bruce or minute 2 bicycle ramp), submax 2 (stage 2 Bruce or minute 4 bicycle ramp), and peak were recorded. The primary composite outcome was HTN diagnosis or initiation of anti-hypertensive medications at follow up.There were 177 patients (53% female, median age 18.5 years), of whom 38 patients (21%) met composite outcome during a median follow up of 46 months. Men were more likely to develop hypertension. Age at repair and age at CPET were not significant covariates. At each stage of CPET, SBP was significantly higher in those who met the composite outcome. Submax 2 SBP ≥ 145 mmHg was 75% sensitive, 71% specific in males and 67% sensitive, 76% specific in females for development of composite outcome.Our study shows an exaggerated SBP response to submaximal exercise may portend an increased risk of developing hypertension during short- to mid-term follow up.

Open Field Exercise Testing in Pediatric Congenital Heart Disease Patients: A Subsumption of Cardiovascular Parameters.

Heart failure is a common phenomenon in congenital heart disease patients. Cardiopulmonary exercise testing is used for a reliable assessment of heart failure but is still challenging, especially for young children. Implementing mobile cardiopulmonary exercise testing (CPET) can close that diagnostic gap. While average values for healthy children have already been published, this study aims to describe typical ranges of cardiovascular performance parameters of young children with congenital heart disease performing an 8-min running cardiopulmonary exercise test. Children aged 4-8 years with common congenital heart defects after corrective surgery (Tetralogy of Fallot; transposition of the great arteries and univentricular hearts after palliation) were included. The outdoor running protocol consisted of slow walking, slow jogging, fast jogging, and maximum speed running. Each exercise was performed for 2 min, except the last, in which children were instructed to keep up maximal speed as long as possible. A total of 78 children (45 male/33 female, mean age 6,24) with congenital heart disease participated in the study, of which 97% completed the CPET successfully. A detailed description of participating patients, including data on cardiac function and subjective fitness levels, is given to help physicians use this method to classify their patients. This study presents a typical range for cardiovascular performance parameters in a population of 4-8-year-old children with congenital heart disease tested in a newly developed outdoor running protocol for CPET.

Cardiopulmonary Exercise Testing in Pulmonary Arterial Hypertension.

Cardiopulmonary exercise testing (CPET) is a comprehensive methodology well studied in pulmonary arterial hypertension (PAH) with roles in diagnosis, treatment response, and prognosis. Submaximal and maximal exercise data is a valuable tool in detecting abnormal hemodynamics associated with exercise-induced and resting pulmonary hypertension as well as right ventricular dysfunction. The increased granularity of CPET may help further risk stratify patients to inform prognosis and better individualize treatment decisions. This article reviews the most commonly implicated variables from CPET in PAH literature and summarizes the latest developments in CPET and exercise testing.

Meta-analysis addressing the impact of cardiovascular-acting medication on peak oxygen uptake of patients with HFpEF.

As our therapeutic armamentarium for HFpEF is insufficient, research has been focusing on the potential beneficial effect of existing pharmaceutical regimens on this specific patient population. A series of RCTs have recently examined the impact of various pharmaceutical treatments with proven benefit in HFrEF, on the improvement of symptoms of HFpEF patients. This systematic review and meta-analysis comprised studies of adult patients with HFpEF and evaluated the impact of different cardiovascular acting medication on cardiorespiratory fitness, reflected by peak VO2 values measured during CPET. The primary outcome was difference between groups in the change of peak VO2 (ΔpeakVO2). Literature search involved PubMed/MEDLINE, Scopus and Web of Science databases. Our search identified 3634 records and 19 studies were included in qualitative analysis; 12 studies with 1341 patients were finally included in primary outcome analysis. ΔpeakVO2 between baseline and study-end did not significantly change after treatment with spironolactone, ivabradine, sildenafil, or oral inorganic nitrate and neither did difference in 6MWT distance after treatment with spironolactone. Spironolactone led to statistically significant reduction in E/E' ratio study-end values (WMD - 1.64, 95%CI - 2.42 to - 0.86, I2 = 87%, p < 0.0001), as well as to a significant increase in MLHFQ values (WMD 0.75, 95%CI 0.02 to 1.48, I2 = 0%, p = 0.65), indicating deterioration in HRQoL among HFpEF patients. A series of established cardiovascular acting medication in HFrEF seems not to confer significant benefit in peak VO2 and 6MWT distance in HFpEF. Spironolactone is associated with improvements in diastolic function and with a significant deterioration in HRQoL of this population.

Mixed Valence (µ-Phenoxido) FeII FeIII and FeIII FeIV Compounds: Electron and Proton Transfers.

Mixed-valence non-heme diiron centers are present at the active sites of a few enzymes and confer them interesting reactivities with the two ions acting in concert. Related (µ-phenoxido)diiron complexes have been developed as enzyme mimics. They exhibit very rich spectroscopic properties enabling independent monitoring of each individual ion, which proved useful for mechanistic studies of catalytic hydrolysis and oxidation reactions. In our studies of such complexes, we observed that these compounds give rise to a wide variety of electron transfers (intervalence charge transfer), proton transfers (tautomerism), coupled electron and proton transfers (H. abstraction and PCET). In this minireview, we present and analyze the main results illustrating the latter aspects.

Cardiopulmonary exercise testing in patients with end-stage kidney disease: principles, methodology and clinical applications of the optimal tool for exercise tolerance evaluation.

Chronic kidney disease (CKD), especially end-stage kidney disease (ESKD), is associated with an increased risk for cardiovascular events and all-cause mortality. Exercise intolerance as well as reduced cardiovascular reserve is extremely common in patients with CKD. Cardiopulmonary exercise testing (CPET) is a non-invasive, dynamic technique that provides an integrative evaluation of cardiovascular, pulmonary, neuropsychological and metabolic function during maximal or submaximal exercise, allowing the evaluation of functional reserves of these systems. This assessment is based on the principle that system failure typically occurs when the system is under stress and thus CPET is currently considered to be the gold standard for identifying exercise limitation and differentiating its causes. It has been widely used in several medical fields for risk stratification, clinical evaluation and other applications, but its use in everyday practice for CKD patients is scarce. This article describes the basic principles and methodology of CPET and provides an overview of important studies that utilized CPET in patients with ESKD, in an effort to increase awareness of CPET capabilities among practicing nephrologists.