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Rationale: Premature birth is an independent predictor of long-term cardiovascular risk. Individuals affected are reported to have a lower rate of oxygen consumption at peak exercise intensity and at ventilatory anaerobic threshold, but little is known about their response to exercise training.Objectives: To explore if peak exercise oxygen consumption and ventilatory anaerobic threshold responses to exercise training differ between preterm-born and term-born individuals.Methods: Fifty-two preterm-born and 151 term-born participants were randomly assigned (1:1) to 16-weeks of aerobic exercise training (n=102) or a control group (n=101). Cardiopulmonary exercise tests were conducted before and after the intervention to measure oxygen consumption at peak exercise intensity and the ventilatory anaerobic threshold. A prespecified subgroup analysis was conducted by fitting an interaction term for preterm and term birth history and exercise group allocation.Measurements and Main Results: Within term-born participants, peak exercise oxygen consumption increased by 3.1 (95% confidence interval: 1.7 to 4.4)ml/kg/min and ventilatory anaerobic threshold increased by 2.3 (95% confidence interval: 0.7 to 3.8)ml/kg/min in the intervention group versus controls. Within preterm-born participants, peak exercise oxygen consumption increased by 1.8 (95% confidence interval: -0.4 to 3.9)ml/kg/min and ventilatory anaerobic threshold increased by 4.6 (95% confidence interval: 2.1 to 7.0)ml/kg/min in the intervention group versus controls. No significant interaction was observed for peak exercise oxygen consumption (p=0.32) or ventilatory anaerobic threshold (p=0.12).Conclusion: The training intervention led to significant improvements in peak exercise oxygen consumption and ventilatory anaerobic threshold, with no evidence of a statistically different response based on birth history. Clinical trial registration available at www.Clinicaltrials: gov, ID: NCT02723552. [ABSTRACT FROM AUTHOR]

The Br/+ mutant mouse displays decreased embryological expression of the homeobox transcription factor Six2, resulting in hertitable renal hypoplasia. The purpose of this study was to characterize the renal physiological consequences of embryonic haploinsuffiency of Six2 by analyzing renal morphology and function in the adult Br heterozygous mutant. Adult Br/+ kidneys weighed 50% less than those from wild-type mice and displayed glomerulopathy. Stereological analysis of renal glomeruli showed that Br/+ kidneys had an average of 88% fewer glomeruli than +/+ kidneys, whereas individual glomeruli in Br/+ mice maintained an average volume increase of 180% compared with normal nephrons. Immunostaining revealed increased levels of endothelin-1 (ET-1), endothelin receptors A ([ET.sub.A]) and B ([ET.sub.B]), and Na-K-ATPase were present in the dilated renal tubules of mutant mice. Physiological features of chronic renal failure (CRF) including elevated mean arterial pressure, increased plasma creatinine, and dilute urine excretion were measured in Br/+ mutant mice. Electron microscopy of the Br/+ glomeruli revealed pathological alterations such as hypercellularity, extracellular matrix accumulation, and a thick irregular glomerular basement membrane. These results indicate that adult Br/+ mice suffer from CRF associated with reduced nephron number and renal hypoplasia, as well as glomerulopathy. Defects are associated with embryological deficiencies of Six2, suggesting that proper levels of this protein during nephrogenesis are critical for normal glomerular development and adult renal function. Br mutant mouse; glomerulus

Aims  We tested the hypothesis that the known reduction in myocardial functional reserve in preterm-born young adults is an independent predictor of exercise capacity (peak VO2) and heart rate recovery (HRR). Methods and results  We recruited 101 normotensive young adults (n = 47 born preterm; 32.8 ± 3.2 weeks' gestation and n = 54 term-born controls). Peak VO2 was determined by cardiopulmonary exercise testing (CPET), and lung function assessed using spirometry. Percentage predicted values were then calculated. HRR was defined as the decrease from peak HR to 1 min (HRR1) and 2 min of recovery (HRR2). Four-chamber echocardiography views were acquired at rest and exercise at 40% and 60% of CPET peak power. Change in left ventricular ejection fraction from rest to each work intensity was calculated (EFΔ40% and EFΔ60%) to estimate myocardial functional reserve. Peak VO2 and per cent of predicted peak VO2 were lower in preterm-born young adults compared with controls (33.6 ± 8.6 vs. 40.1 ± 9.0 mL/kg/min, P = 0.003 and 94% ± 20% vs. 108% ± 25%, P = 0.001). HRR1 was similar between groups. HRR2 decreased less in preterm-born young adults compared with controls (−36 ± 13 vs. −43 ± 11 b.p.m. P = 0.039). In young adults born preterm, but not in controls, EFΔ40% and EFΔ60% correlated with per cent of predicted peak VO2 (r 2 = 0.430, P = 0.015 and r 2 = 0.345, P = 0.021). Similarly, EFΔ60% correlated with HRR1 and HRR2 only in those born preterm (r 2 = 0.611, P = 0.002 and r 2 = 0.663, P = 0.001). Conclusions  Impaired myocardial functional reserve underlies reductions in peak VO2 and HRR in young adults born moderately preterm. Peak VO2 and HRR may aid risk stratification and treatment monitoring in this population. [ABSTRACT FROM AUTHOR]

The Br/+ mutant mouse displays decreased embryological expression of the homeobox transcription factor Six2, resulting in hertitable renal hypoplasia. The purpose of this study was to characterize the renal physiological consequences of embryonic haploinsuffiency of Six2 by analyzing renal morphology and function in the adult Br heterozygous mutant. Adult Br/+ kidneys weighed 50% less than those from wild-type mice and displayed glomerulopathy. Stereological analysis of renal glomeruli showed that Br/+ kidneys had an average of 88% fewer glomeruli than +/+ kidneys, whereas individual glomeruli in Br/+ mice maintained an average volume increase of 180% compared with normal nephrons. Immunostaining revealed increased levels of endothelin-1 (ET-1), endothelin receptors A (ETA) and B (ETB), and Na-K-ATPase were present in the dilated renal tubules of mutant mice. Physiological features of chronic renal failure (CRF) including elevated mean arterial pressure, increased plasma creatinine, and dilute urine excretion were measured in Br/+ mutant mice. Electron microscopy of the Br/+ glomeruli revealed pathological alterations such as hypercellularity, extracellular matrix accumulation, and a thick irregular glomerular basement membrane. These results indicate that adult Br/+ mice suffer from CRF associated with reduced nephron number and renal hypoplasia, as well as glomerulopathy. Defects are associated with embryological deficiencies of Six2, suggesting that proper levels of this protein during nephrogenesis are critical for normal glomerular development and adult renal function. [ABSTRACT FROM AUTHOR]

Introduction: Experimental and clinical studies show that prematurity leads to altered right ventricular (RV) performance with potentially clinically significant impairments in RV systolic function in young adulthood. Hypothesis: We hypothesized that reductions in RV function would be out of proportion to changes in pulmonary physiology. Methods: We recruited 101 normotensive young adults born preterm (n=47, mean gestational age 32.8±3.2 weeks) and term (n=54, mean gestational age 39.5±1.4 weeks) for detailed cardiovascular phenotyping. The gestational age range for the preterm cohort was 23 to 36 weeks, with 80.9% (n=38) born 32-36 weeks; 10.6% (n=5) born 28-31 weeks; and 8.5% (n=4) born <28weeks. Resting echocardiograms were performed to characterize RV morphology, RV function, and pulmonary hemodynamics, and spirometry was performed to assess lung function. Results: Preterm-born individuals had smaller RV end-diastolic (p<0.001) and end-systolic areas (p=0.035) and inferior RV lengths (p=0.001) compared to term-born individuals. Measures of RV function, RV fractional area of change (FAC) and tricuspid annular plane systolic excursion (TAPSE) were lower in preterm compared to term-born young adults (FAC: 38.2±9.75 vs 43.8±7.01%, p=0.009 and TAPSE: 1.77±0.26 vs 2.24±0.37 cm, p<0.001). Pulmonary artery acceleration time (PAAT), a reliable estimate of pulmonary hemodynamics, was lower in the preterm-born young adults (PAAT: 123.4±23.8 vs 159.0±23.2 msec, p<0.001), though there were no differences between groups in estimated RV-pulmonary vascular (PV) coupling (TAPSE/PAAT: 0.15±0.02 vs 0.14±0.03 m/sec, p=0.77). Percentage predicted lung function measures were similar between those born preterm and term: forced expiratory volume in 1 second (FEV1, p=0.41); forced vital capacity (FVC, p=0.88); and FEV1/FVC ratio (p=0.84). Lower RV FAC and TAPSE in preterm-born individuals remained significant when adjusting for pulmonary function parameters (p<0.05). Conclusions: Preterm-born young adults have reduced RV function, independent of lung physiology. RV afterload is increased, but the RV remains hemodynamically coupled to its pulmonary circulation despite worse RV function and altered morphology in young adults born preterm. [ABSTRACT FROM AUTHOR]

Background: Arrested pulmonary development is suspected to lead to reduced exercise capacity in those born preterm. However, severe neonate respiratory distress is uncommon, affecting <10% of preterm infants and premature cohort studies show normal lung capacity is typical by adolescence. Our recent clinical studies in preterm-born individuals have identified altered left ventricular (LV) structure and function including reducing ejection fraction (EF) with increasing exercise intensity. Hypothesis: Preterm-born young adults have reductions in exercise capacity proportional to the degree of systolic impairment in their exercise stress response. Methods: We recruited 101 normotensive young adults born preterm (n=47 mean gestational age 32.8±3.2 weeks) and term (n=54) for cardiovascular phenotyping. Baseline spirometry and echocardiography were performed and subjects completed peak cardiopulmonary exercise testing to measure exercise capacity. Exercise stress echocardiograms were then performed with apical four-chamber views collected while exercising at 40%, 60%, and 80% of peak exercise load. Results: Exercise capacity was lower in preterm participants (94±20% vs 108±25% of predicted peak VO2, P=0.001). Baseline EF was similar between groups. Change in EF from rest to 40% and 60% exercise intensity predicted peak VO2 in the preterm-born group (r2=0.367, P=0.014 and r2=0.373, P=0.007 respectively), but not controls (r2=-0.069, P=0.746 and r2=-0.024, P=0.644 respectively). Resting and dynamic pulmonary measures were similar between groups and did not explain differing exercise capacity. Conclusions: Preterm-born young adults have reduced exercise capacity that relates to their blunted left ventricular systolic response to exercise but not to pulmonary capacity. How prematurity impacts the response to chronic aerobic training and associated alterations in exercise capacity and cardiovascular risk profile requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Individual experience of exercise and willingness to comply with exercise prevention programs varies. We hypothesised early subclinical cardiovascular adaptions in young adults with modest blood pressure (BP) elevation may result in a more adverse response to low intensity exercise. Objectives: To study whether young adults with elevated BP have an altered cardiac stress response and whether this relates to left ventricular structure. Methods: We recruited 146 young adults (age 27±5 years) with a range of blood pressures for resting structural phenotyping with cardiac magnetic resonance. A sub-group (n=71) underwent cardiopulmonary exercise testing and exercise stress echocardiography while exercising at 40%, 60%, and 80% of peak exercise load. Myocardial stress response was assessed by changes in ejection fraction (EF) and post-exercise plasma stress marker (copeptin) release. Results were compared in those with systolic or diastolic BP ≥ 120/80 mm Hg (n=62, mean BP 129/77 mm Hg) vs those with systolic and diastolic BP < 120/80 mm Hg (n=84, mean BP 110/66 mm Hg). Results: Resting EF was similar between groups. However, during physical exercise higher BP was associated with lower EF at 40% and 60% workload (73.9±3.25 vs 80.0±4.54%, p<0.001 and 75.2±6.59 vs 79.4±4.70%, p=0.026 respectively) as well as smaller increases in EF from resting levels (10.4±5.92 vs 19.0±6.90%, p<0.001 and 11.5±8.34 vs 17.5±7.31%, p=0.029 at 40% and 60% respectively). Furthermore, at 40% workload, perceived exertion was greater in those with higher BP (10.7±1.9 vs 9.3±2.4 on Borg scale, p=0.018). Finally, elevated post-exercise plasma copeptin levels were predicted by lower EF at 40% workload (r2=0.188, p=0.043). Higher BP was associated with greater LV mass index (0.68±0.13 vs 0.62±0.12 g/ml, p=0.007) and wall thickness (7.21±1.31 vs 6.62±1.44 mm, p=0.05) but values were within clinically normal ranges and did not predict variation in myocardial stress response. Conclusions: Young adults with modest blood pressure elevation experience greater fatigue and a physiologically significant systolic defect in early response to exercise. Whether intervention can halt functional declines and how perceived exertion may confound exercise prescription needs further study. [ABSTRACT FROM AUTHOR]

Aims: We tested the hypothesis that the known reduction in myocardial functional reserve in preterm-born young adults is an independent predictor of exercise capacity (peak VO2) and heart rate recovery (HRR)., Methods and Results: We recruited 101 normotensive young adults (n = 47 born preterm; 32.8 ± 3.2 weeks' gestation and n = 54 term-born controls). Peak VO2 was determined by cardiopulmonary exercise testing (CPET), and lung function assessed using spirometry. Percentage predicted values were then calculated. HRR was defined as the decrease from peak HR to 1 min (HRR1) and 2 min of recovery (HRR2). Four-chamber echocardiography views were acquired at rest and exercise at 40% and 60% of CPET peak power. Change in left ventricular ejection fraction from rest to each work intensity was calculated (EFΔ40% and EFΔ60%) to estimate myocardial functional reserve. Peak VO2 and per cent of predicted peak VO2 were lower in preterm-born young adults compared with controls (33.6 ± 8.6 vs. 40.1 ± 9.0 mL/kg/min, P = 0.003 and 94% ± 20% vs. 108% ± 25%, P = 0.001). HRR1 was similar between groups. HRR2 decreased less in preterm-born young adults compared with controls (-36 ± 13 vs. -43 ± 11 b.p.m., P = 0.039). In young adults born preterm, but not in controls, EFΔ40% and EFΔ60% correlated with per cent of predicted peak VO2 (r2 = 0.430, P = 0.015 and r2 = 0.345, P = 0.021). Similarly, EFΔ60% correlated with HRR1 and HRR2 only in those born preterm (r2 = 0.611, P = 0.002 and r2 = 0.663, P = 0.001)., Conclusions: Impaired myocardial functional reserve underlies reductions in peak VO2 and HRR in young adults born moderately preterm. Peak VO2 and HRR may aid risk stratification and treatment monitoring in this population., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)