Summary Background Metachromatic leukodystrophy (a deficiency of arylsulfatase A ARSA) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes ...in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT). Methods This is an ad-hoc analysis of data from an ongoing, non-randomised, open-label, single-arm phase 1/2 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy (presymptomatic late-infantile or early-juvenile disease or early-symptomatic early-juvenile disease) at the Paediatric Clinical Research Unit, Ospedale San Raffaele, in Milan. Trial participants received HSC-GT, which consisted of the infusion of autologous HSCs transduced with a lentiviral vector encoding ARSA cDNA, after exposure-targeted busulfan conditioning. The primary endpoints of the trial are safety (toxicity, absence of engraftment failure or delayed haematological reconstitution, and safety of lentiviral vector-tranduced cell infusion) and efficacy (improvement in Gross Motor Function Measure GMFM score relative to untreated historical controls, and ARSA activity, 24 months post-treatment) of HSC-GT. For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015. This trial is registered with ClinicalTrials.gov , number NCT01560182. Findings Between April, 2010, and February, 2013, we had enrolled nine children with a diagnosis of early-onset disease (six had late-infantile disease, two had early-juvenile disease, and one had early-onset disease that could not be definitively classified). At the time of analysis all children had survived, with a median follow-up of 36 months (range 18–54). The most commonly reported adverse events were cytopenia (reported in all patients) and mucositis of different grades of severity (in five of nine patients grade 3 in four of five patients). No serious adverse events related to the medicinal product were reported. Stable, sustained engraftment of gene-corrected HSCs was observed (a median of 60·4% range 14·0–95·6 lentiviral vector-positive colony-forming cells across follow-up) and the engraftment level was stable during follow-up; engraftment determinants included the duration of absolute neutropenia and the vector copy number of the medicinal product. A progressive reconstitution of ARSA activity in circulating haemopoietic cells and in the cerebrospinal fluid was documented in all patients in association with a reduction of the storage material in peripheral nerve samples in six of seven patients. Eight patients, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression as per clinical and instrumental assessment, compared with historical untreated control patients with early-onset disease. GMFM scores for six patients up to the last follow-up showed that gross motor performance was similar to that of normally developing children. The extent of benefit appeared to be influenced by the interval between HSC-GT and the expected time of disease onset. Treatment resulted in protection from CNS demyelination in eight patients and, in at least three patients, amelioration of peripheral nervous system abnormalities, with signs of remyelination at both sites. Interpretation Our ad-hoc findings provide preliminary evidence of safety and therapeutic benefit of HSC-GT in patients with early-onset metachromatic leukodystrophy who received treatment in the presymptomatic or very early-symptomatic stage. The results of this trial will be reported when all 20 patients have achieved 3 years of follow-up. Funding Italian Telethon Foundation and GlaxoSmithKline.
Objectives The aim of this study was to assess the long-term prognostic role of multidetector computed tomography coronary angiography (CTA) in patients with suspected coronary artery disease (CAD). ...Background Use of CTA is increasing in patients with suspected CAD. Although there is a large body of data supporting the prognostic role of CTA for major adverse cardiac events in the intermediate term, its long-term prognostic role in patients with suspected CAD is not well studied. Methods Between February 2005 and March 2008, 1,304 consecutive patients were prospectively studied with CTA for detecting the presence and assessing extent of CAD (disease extension and coronary plaque scores). Patients were classified according to the presence of normal coronaries and nonobstructive (<50%) and obstructive (>50%) coronary lesions. The composite rates of hard cardiac events (cardiac deaths and nonfatal myocardial infarctions) and all cardiac events (including late revascularization) were the endpoints of the study. Results Seventy patients were excluded because their CTA data were uninterpretable. Of the remaining 1,234 patients, clinical follow-up (mean 52 ± 22 months) was obtained for 1,196 (97%). A total of 475 events were recorded, with 136 hard events (18 cardiac deaths and 118 nonfatal myocardial infarctions) and 123 late revascularizations. A total of 216 patients with early elective revascularizations were excluded from the survival analysis. Significant independent predictors of events in multivariate analysis were multivessel disease and left main CAD. Cumulative event-free survival was 100% for hard and all events in patients with normal coronary arteries, 88% for hard events and 72% for all events in patients with nonobstructive CAD, and 54% for hard events and 31% for all events in patients with obstructive CAD. Multivessel CAD was associated with a higher rate of hard cardiac events. Conclusions CTA provides prognostic information in patients with suspected CAD and unknown cardiac disease, showing excellent long-term prognosis when there is no evidence of atherosclerosis and allowing risk stratification when CAD is present.
Abstract Background Periodic breathing (PB) during sleep and exercise in heart failure (HF) is related to respiratory acid-base status, CO2 chemosensitivity, and temporal dynamics of CO2 and O2 ...sensing. We studied inhaled CO2 and acetazolamide to alter these factors and reduce PB. Methods and Results We measured expired and arterial gases and PB amplitude and duration in 20 HF patients during exercise before and after acetazolamide given acutely (500 mg intravenously) and prolonged (24 hours, 2 g orally), and we performed overnight polysomnography. We studied CO2 inhalation (1%–2%) during constant workload exercise. PB disappeared in 19/20 and 2/7 patients during 2% and 1% CO2 . No changes in cardiorespiratory parameters were observed after acute acetazolamide. With prolonged acetazolamide at rest: ventilation +2.04 ± 4.0 L/min ( P = .001), tidal volume +0.11 ± 1.13 L ( P = .003), respiratory rate +1.24 ± 4.63 breaths/min (NS), end-tidal PO2 +4.62 ± 2.43 mm Hg ( P = .001), and end-tidal PCO2 −2.59 ± 9.7 mm Hg ( P < .001). At maximum exercise: Watts −10% ( P < .02), VO2 −61 ± 109 mL/min ( P = .04) and VCO2 101 ± 151 mL/min ( P < .02). Among 20 patients, PB disappeared in 1 and 7 subjects after acute and prolonged acetazolamide, respectively. PB was present 80% ± 26, 65% ± 28, and 43% ± 39 of exercise time before and after acute and prolonged acetazolamide, respectively. Overnight apnea/hypopnea index decreased from 30.8 ± 83.8 to 21.1 ± 16.9 ( P = .003). Conclusions In HF, inhaled CO2 and acetazolamide reduce exercise PB with additional benefits of acetazolamide on sleep PB.
Background Hyperventilation and consequent reduction of ventilation (VE) efficiency are frequently observed during exercise in heart failure (HF) patients, resulting in an increased slope of ...VE/carbon dioxide (VE/V co2 ) relationship. The latter is an independent predictor of HF prognosis. β-Blockers improve the prognosis of HF patients. We evaluated the effect on the efficiency of VE of a β1 -β2 unselective (carvedilol) versus a β1 selective (bisoprolol) β-blocker. Methods We analyzed consecutive maximal cardiopulmonary exercise tests performed on 572 clinically stable HF patients (New York Heart Association class I-III, left ventricle ejection fraction ≤50%) categorized in 3 groups: 81 were not treated with β-blocker, 304 were treated with carvedilol, and 187 were treated with bisoprolol. Clinical conditions were similar. Results The VE/V co2 slope was lower in carvedilol- compared with bisoprolol-treated patients (29.7 ± 0.4 vs 31.6 ± 0.5, P = .023, peak oxygen consumption adjusted) and with patients not receiving β-blockers (31.6 ± 0.7, P = .036). Maximum end-tidal CO2 pressure during the isocapnic buffering period was higher in patients treated with carvedilol (39.0 ± 0.3 mm Hg) than with bisoprolol (37.2 ± 0.4 mm Hg, P < .001) and in patients not receiving β-blockers (37.2 ± 0.5 mm Hg, P = .001). Conclusions Reduction of hyperventilation, with improvement of VE efficiency during exercise (reduction of VE/V co2 slope and increase of maximum end-tidal CO2 pressure), is specific to carvedilol (β1 -β2 unselective blocker) and not to bisoprolol (β1 -selective blocker).
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