Search

Purpose: To analyze demographic and ophthalmic data in patients with and without chorioretinal atrophy after voretigene neparvovec-rzyl (VN) to identify possible causes for this phenomenon., Design: Retrospective cohort study with longitudinal follow-up., Participants: A total of 71 eyes of 38 patients aged 2 to 44 years with RPE65-mediated retinal dystrophy treated with VN across 2 large gene therapy centers in the United States and Germany., Methods: Patients treated with VN who developed atrophy were compared with those who did not., Main Outcome Measures: Gender, age, surgical center, spherical equivalent refraction, best-corrected visual acuity (BCVA), baseline full-field scotopic threshold testing (FST), and posttreatment change in FST., Results: A total of 20 eyes of 12 patients developed atrophy after treatment with VN (28% of all eyes). There was no significant difference in gender, age, surgical center, or spherical equivalent refraction between the atrophy group and the no atrophy group. However, patients between school age and young adulthood were predominantly affected, whereas the youngest and the oldest patients did not develop atrophy. Baseline BCVA was better in patients who developed atrophy than those who did not (P = 0.006). The postoperative improvement in FST at 1 month was significantly higher in the atrophy group than in the no atrophy group (P = 0.0005), and this difference remained statistically significant at 1 year (P = 0.0001). There was no correlation to baseline FST, to inflammation, or to which eye was treated first., Conclusions: The degree of FST improvement after VN appears to be strongly correlated with the development of VN-related chorioretinal atrophy. This finding raises the possibility that atrophy may develop as a toxic or metabolic sequela of vector-mediated RPE65 expression. In light of the expanding number of retinal gene therapy clinical trials, this complication warrants further study because it may not be limited to VN., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven to prevent PVR. Promising results for 5-fluorouracil (5-FU) and low-molecular weight heparin (LMWH) in high-risk eyes have been reported previously. The objective of this trial was to examine the effect of adjuvant intravitreal therapy with 5-FU and LMWH compared with placebo on incidence of PVR in high-risk patients with primary RRD., Design: Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis., Participants: Patients with RRD who were considered to be at high risk for PVR were included. Risk of PVR was assessed by noninvasive aqueous flare measurement using laser flare photometry., Methods: Patients were randomized 1:1 to verum (200 mg/ml 5-FU and 5 IU/ml dalteparin) and placebo (balanced salt solution) intravitreally applied during routine pars plana vitrectomy., Main Outcome Measures: Primary end point was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) 1 or higher within 12 weeks after surgery. For grading, an end point committee assessed fundus photographs. Secondary end points included best-corrected visual acuity and redetachment rate. A group sequential design with 1 interim analysis was applied using the O'Brien and Fleming boundaries. Proliferative vitreoretinopathy grade CP incidence was compared using a Mantel-Haenszel test stratified by surgeon., Results: A total of 325 patients in 13 German trial sites had been randomized (verum, n = 163; placebo, n = 162). In study eyes, mean laser flare was 31 ± 26 pc/ms. No significant difference was found in PVR rate. Primary analysis in the modified intention-to-treat population results were: verum 28% vs. placebo 23% (including not assessable cases as failures); odds ratio [OR], 1.25; 95% confidence interval [CI], 0.76-2.08; P = 0.77. Those in the per-protocol population were: 12% vs. 12%; OR, 1.05; 95% CI, 0.47-2.34; P = 0.47. None of the secondary end points showed any significant difference between treatment groups. During the study period, no relevant safety risks were identified., Conclusions: Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Introduction: Acute exercise and exercise training may confer epigenetic modifications in healthy subjects. Epigenetic effects after exercise have been showed in patients with cardiovascular disease. The aim of this systematic review was to summarize the evidence from available clinical trials that study epigenetic adaptations after exercise in patients with cardiovascular disease., Methods: The search strategy was performed in PubMed and CENTRAL databases on articles published until September 2020. Studies with titles and abstracts relevant to exercise epigenetic modification applied to cardiovascular patients were fully examined. Inclusion and exclusion criteria were utilized for studies screening. Quality assessment with PEDro scale and evaluation by two independent reviewers was performed., Results: Of the 1714 articles retrieved, 88 articles were assessed for eligibility criteria and 8 articles matched our search criteria and finally included in the systematic analysis. The acute exercise epigenetic (miRNAs) effects were assessed in three studies and the chronic exercise training effects (miRNAs and DNA methylation) in six studies. The results have shown that there is possibly an acute significant exercise effect on epigenetic targets which is more evident after chronic exercise training., Conclusions: By the present systematic review, we provide preliminary evidence of beneficial epigenetic adaptations following acute and chronic exercise in patients with cardiovascular disease. More controlled studies are needed to confirm such evidence., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Skeletal muscle wasting is associated with altered catabolic/anabolic balance and poor prognosis in patients with chronic heart failure (CHF). This study evaluated catabolic and anabolic abnormalities in relation to disease severity in CHF patients., Methods: Forty-two stable CHF patients (34 men; aged 56±12 years, body mass index, 27±5 kg/m2) receiving optimal medical treatment underwent incremental symptom-limited cardiopulmonary exercise testing on a cycle ergometer. Blood samples were drawn within 10 days to determine serum cortisol, plasma adrenocorticotropin (ACTH), and serum dehydroepiandrosterone sulfate, insulin-like growth factor 1, growth hormone, and total testosterone in men., Results: Patients with higher cortisol levels presented with impaired peak oxygen uptake (Vo2 peak: 18.3±3.9 vs. 14.2±3.7 ml/kg/min, p<0.01), ventilatory (Ve) response to exercise (Ve/carbon dioxide output [Vco2] slope: 36±6 vs 30±5, p<0.01), and chronotropic reserve ([peak heart rate [HR]--resting HR/220--age--resting HR]×100%: 40±19 vs. 58±18, p=0.01) compared with those with lower serum cortisol. Cortisol was inversely correlated with Vo2 peak, (r = -0.57; p<0.01) and was correlated with Ve/Vco2 slope (r = 0.47; p<0.01) and chronotropic reserve (r = 0.44; p = 0.017). In multivariate regression analysis, cortisol was an independent predictor of Vo2peak (R2 = 0.365, F = 12.5, SE = 3.4; p≤0.001) and Ve/Vco2 slope (R2 = 0.154; F = 8.5; SE = 5.96; p = 0.006), after accounting for age, body mass index, sex, CHF etiology, creatinine, left ventricular ejection fraction, and ACTH in all patients. In men, cortisol and dehydroepiandrosterone levels were both independent predictors of Vo2peak (R2 = 0.595, F = 24.53, SE = 2.76; p<0.001) after accounting also for all measured hormones, whereas cortisol remained the only independent predictor of Ve/Vco2 slope (R2 = 0.133; F = 6.1; SE = 6.2; p = 0.02)., Conclusions: Enhanced catabolic status is significantly associated with exercise intolerance, ventilatory inefficiency, and chronotropic incompetence in CHF patients, suggesting a significant contributing mechanism to their limited functional status., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Several skeletal muscle abnormalities have been identified in patients with chronic heart failure (CHF), including endothelial dysfunction. We hypothesized that skeletal muscle microcirculation, assessed by near-infrared spectroscopy (NIRS), is impaired in CHF patients and is associated with disease severity., Methods: Eighty-three stable patients with mild-moderate CHF (72 males, mean age 54 ± 14 years, body mass index 26.7 ± 3.4 kg/m(2)) and 8 healthy subjects, matched for age, gender and body mass index, underwent NIRS with the vascular occlusion technique and cardiopulmonary exercise testing (CPET) evaluation on the same day. Tissue oxygen saturation (StO(2), %), defined as the percentage of hemoglobin saturation in the microvasculature compartments, was measured in the thenar muscle by NIRS before, during and after 3-minute occlusion of the brachial artery. Measurements included StO(2), oxygen consumption rate (OCR, %/min) and reperfusion rate (RR, %/min). All subjects underwent a symptom-limited CPET on a cycle ergometer. Measurements included VO(2) at peak exercise (VO(2)peak, ml/kg/min) and anaerobic threshold (VO(2)AT, ml/kg/min), VE/VCO(2) slope, chronotropic reserve (CR, %) and heart rate recovery (HRR(1), bpm)., Results: CHF patients had significantly lower StO(2) (75 ± 8.2 vs 80.3 ± 6, p < 0.05), lower OCR (32.3 ± 10.4 vs 37.7 ± 5.5, p < 0.05) and lower RR (10 ± 2.8 vs 15.7 ± 6.3, p < 0.05) compared with healthy controls. CHF patients with RR ≥9.5 had a significantly greater VO(2)peak (p < 0.001), VO(2)AT (p < 0.01), CR (p = 0.01) and HRR(1) (p = 0.01), and lower VE/VCO(2) slope (p = 0.001), compared to those with RR <9.5. In a multivariate analysis, RR was identified as an independent predictor of VO(2)peak, VE/VCO(2) slope and HRR(1)., Conclusions: Peripheral muscle microcirculation, as assessed by NIRS, is significantly impaired in CHF patients and is associated with disease severity., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with chronic heart failure (CHF) suffer from ventilatory abnormalities. This study examined the effects of interval exercise training on the respiratory drive in CHF patients., Methods: Forty-six clinically stable CHF patients (38 males/8 women, mean age = 53 +/- 11 years) participated in an exercise rehabilitation program (ERP) 3 times/week, for 12 weeks by interval training modality with or without the addition of resistance training. All patients underwent symptom-limited cardiopulmonary exercise testing (CPET), and measurements of mouth occlusion pressure at 100 ms (P(0.1)) and maximum inspiratory muscle strength (P(Imax)) before and after ERP. Respiratory drive was estimated by mouth occlusion pressure P(0.1) and P(0.1)/P(Imax) ratio at rest, and the ventilatory pattern by resting mean inspiratory flow (V(T)/T(I)) and by V(T)/T(I) at identical CPET workloads, before and after ERP. We also studied a control non exercising group of 11 patients (8 men and 3 women)., Results: P(0.1) at rest decreased from 3.04 +/- 1.52 to 2.62 +/- 0.9 cmH(2)O (p = 0.015), P(0.1)/P(Imax) % at rest from 4.56 +/- 3.73 to 3.69 +/- 2.03 (p = 0.006), resting V(T)/T(I) from 0.44 +/- 0.10 to 0.41 +/- 0.10 l/s (p = 0.014), and V(T)/T(I) at identical work rate from 2.13 +/- 0.59 to 1.93 +/- 0.58 l/s (p = 0.001) after ERP. VO(2) at peak exercise increased from 16.3 +/- 4.8 to 18.5 +/- 5.3 ml/kg/min (p < 0.001) in the exercise group. No improvement was noted in the control group., Conclusions: ERP by interval training improves the respiratory drive and ventilatory pattern at rest and during exercise in CHF patients.

Background: Various respiratory abnormalities are associated with chronic heart failure (CHF). However, changes in inspiratory capacity (IC) and breathing pattern from rest to exercise in patients with CHF have not been thoroughly investigated in these patients., Materials and Methods: Seventy seven (66 male/11 female) patients with clinical stable CHF (age: 52+/-11 years) were studied. All the patients underwent pulmonary function tests, including measurements of IC and maximal inspiratory pressure (Pimax) at rest and then a maximal cardiopulmonary exercise testing (CPET) on a treadmill. During the CPET, IC was measured every 2 min. Pimax was measured again after the end of CPET., Results: Percent predicted forced expiratory volume in 1 s (FEV1) was 91+/-12, %predicted forced vital capacity (FVC) was 92+/-13, %FEV1/FVC was 81+/-4, and %predicted IC was 85+/-18. Peak exercise IC was lower than resting (2.4+/-0.6 vs. 2.6+/-0.6 l, p<0.001). Analysis of variance between Weber's groups revealed statistically significant differences in peak exercise IC (p<0.001), VE/VCO2slope (p<0.001), resting Pimax (p=0.005) and post-exercise Pimax (p<0.001). At rest, there was a statistically significant difference in end-tidal CO2 (P(ETCO2)) (p=0.002), in breathing frequency (p=0.004), in inspiratory time (Ti) (p=0.04) and in total respiratory time (T(Tot)) (p=0.004) among Weber's groups. At peak exercise there was a statistically significant decrease in minute ventilation (VE) (p<0.001), tidal volume (VT) (p<0.001), respiratory cycle (VT/TI) (p<0.001) and P(ETCO2) (p<0.001). Peak IC was correlated with peak VO2 (r=0.72, p<0.001), anaerobic threshold (r=0.71, p<0.001), VO2/t slope (r=0.54, p<0.0001), and post-exercise Pimax (r=0.62, p<0.001)., Conclusions: In patients with CHF, peak exercise IC is reduced in parallel with disease severity, which is probably due to respiratory muscle dysfunction.

Background: Patients with chronic heart failure (CHF) have multiple abnormalities of autonomic regulation that have been associated to their high mortality rate. Heart rate recovery immediately after exercise is an index of parasympathetic activity, but its prognostic role in CHF patients has not been determined yet., Methods: Ninety-two stable CHF patients (83M/9F, mean age: 51+/-12 years) performed an incremental symptom-limited cardiopulmonary exercise testing. Measurements included peak O2 uptake (VO2p), ventilatory response to exercise (VE/VCO2 slope), the first-degree slope of VO2 for the 1st minute of recovery (VO2/t-slope), heart rate recovery [(HRR1, bpm): HR difference from peak to 1 min after exercise] and chronotropic response to exercise [%chronotropic reserve (CR, %)=(peak HR-resting HR/220-age-resting HR)x100]. Left ventricular ejection fraction (LVEF, %) was also measured by radionuclide ventriculography., Results: Fatal events occurred in 24 patients (26%) during 21+/-6 months of follow-up. HRR1 was lower in non-survivors (11.4+/-6.4 vs. 20.4+/-8.1; p<0.001). All cause-mortality rate was 65% in patients with HRR112 bpm (log-rank: 32.6; p<0.001). By multivariate survival analysis, HRR1 resulted as an independent predictor of mortality (chi2=19.2; odds ratio: 0.87; p<0.001) after adjustment for LVEF, VO2p, VE/VCO2 slope, CR and VO2/t-slope. In a subgroup of patients with intermediate exercise capacity (VO2p: 10-18, ml/kg/min), HRR1 was a strong predictor of mortality (chi2: 14.3; odds ratio: 0.8; p<0.001)., Conclusions: Early heart rate recovery is an independent prognostic risk indicator in CHF patients and could be used in CHF risk stratification.