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We retrospectively analyzed data from a prospective database of patients with an implanted biventricular pacemaker or defibrillator at the Regional Hospital Liberec, Czech Republic, between June 2005 and © 2015 American Heart Association, Inc. Original ArticleBackground-Electric left ventricular lead position, assessed by the electric delay from the beginning of the QRS complex to the local LV electrogram (QLV), was found in previous studies to be a strong predictor of short-term response to cardiac resynchronization therapy. We hypothesized that suboptimum electric position of the left ventricular lead is associated with an excess of heart failure events and mortality. Methods and Results-We analyzed the clinical outcome of patients with left bundle branch block or intraventricular conduction delay treated with cardiac resynchronization therapy at our institution during 9 years. Baseline clinical characteristics, QLV/ QRS duration (QLV ratio) at cardiac resynchronization therapy implant, and data about heart failure hospitalization and mode of death were collected in 329 patients who were followed for a period of 3.3±1.9 years. Of them, 83 were hospitalized for heart failure and 83 died. Event rates for all-cause mortality, cardiac mortality, noncardiac mortality, heart failure mortality, and sudden death were 25.2%, 14.9%, 10.3%, 12.2%, and 2.1%, respectively. Patients with a QLV ratio ≤0.70 had significantly worse event-free survival for all study end points-hazard ratio, 1.6; 95% confidence interval, 1.0 to 2.4; P=0.05 for heart failure hospitalization; hazard ratio, 2.9; 95% confidence interval, 1.6 to 5.5; P=0.001 for heart failure mortality; hazard ratio, 1.8; 95% confidence interval, 1.1 to 2.7; P=0.01 for cardiac mortality; and hazard ratio, 2.1; 95% confidence interval, 1.2 to 3.7; P=0.01 for all-cause mortality. In multivariable analysis, QLV ratio ≤0.70 remained associated with all study end points. Conclusions-Electric left ventricular lead position in cardiac resynchronization therapy patients was a significant predictor of heart failure hospitalization and mortality.

ProTides comprise an important class of prodrugs currently marketed and developed as antiviral and anticancer therapies. The ProTide technology employs a phosphate masking groups capable of providing more favorable drug-like properties and an intracellular activation mechanism for enzyme-mediated release of a nucleoside monophosphate. Herein we describe the application of phosphoramidate chemistry to 1,3,4-O-acetylated N-acetylmannosamine (Ac3ManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG) caused by mutations in GNE that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac3ManNAc-6phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug 12b showed rapid activation in a carboxylesterase (CPY) enzymatic assay and favorable ADME properties, while also being more effective than ManNAc at increasing sialic acid levels in GNE-deficient cell lines than ManNAc. These 2 results provide a potential platform to address substrate deficiencies in GNE myopathy and other CDGs.

ObjectivesOchronotic spondyloarthropathy represents one of the main clinical manifestations of alkaptonuria (AKU); however, prospective data and description of the effect of nitisinone treatment are lacking.MethodsPatients with AKU aged 25 years or older were randomly assigned to receive either oral nitisinone 10 mg/day (N=69) or no treatment (N=69). Spine radiographs were recorded yearly at baseline, 12, 24, 36 and 48 months, and the images were scored for the presence of intervertebral space narrowing, soft tissue calcifications, vacuum phenomena, osteophytes/hyperostosis and spinal fusion in the cervical, thoracic and lumbosacral segment at each of the time points.ResultsAt baseline, narrowing of the intervertebral spaces, the presence of osteophytes/hyperostosis and calcifications were the three most frequent radiographic features in AKU. The rate of progression of the five main features during the 4 years, ranked from the highest to lowest was as follows: intervertebral spaces narrowing, calcifications, vacuum phenomena, osteophytes/hyperostosis and fusions. The rate of progression did not differ between the treated and untreated groups in any of the five radiographic parameters except for a slower rate of progression (sum of all five features) in the treatment group compared with the control group (0.45 (1.11) nitisinone vs 0.74 (1.11) controls, p=0.049) in the thoracic segment.ConclusionThe present study shows a relatively slow but significant worsening of radiographic features in patients with AKU over 4 years. Our results demonstrate a modest beneficial effect of 10 mg/day of nitisinone on the slowly progressing spondylosis in AKU during the relatively limited follow-up time.Trial registration numberNCT01916382.

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