Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by progressive accumulation of glycosaminoglicans (GAGs) in various tissues. Enzyme replacement therapy (ERT) for several MPS is available to date. However, ERT efficacy is limited, in particular on compartments like the bone, the cartilage, the brain and the eye. We selected a rodent model of an MPS, with no central nervous system storage, to study the impact on the disease systemic features of different stable levels of exogenous enzymes produced by adeno-associated viral vector-mediated liver gene transfer. Low levels (6% of normal) of circulating enzyme were enough to reduce storage and inflammation in the visceral organs and to ameliorate skull abnormalities; intermediate levels (11% of normal) were, instead, required to reduce urinary GAG excretion whereas high levels (>/= 50% of normal) bought to the rescue of the abnormalities of the long bones and of motor activity. These data will be instrumental to design appropriate clinical protocols either based on enzyme or gene replacement therapy for MPS and to predict their impact on MPS pathological features.

The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases.

The role of invasive mapping in the context of cardiac resynchronization has been essentially confined to improving knowledge of the depolarization processes and spread of ventricular activation. Experimental and limited clinical data obtained from high resolution three-dimensional contact and non-contact mapping have consistently pointed to the heterogeneity and the complexity of ventricular sequential activation in heart failure with conduction disturbance. The present article reviews current knowledge about activation mapping in patients with different types of ventricular conduction disturbance (right and left bundle branch block) putting this in the perspective of selection of most appropriate pacing site in cardiac resynchronization therapy (CRT) patients. Furthermore, recent comparative data of epicardial and endocardial pacing have been discussed. There is little doubt that invasive mapping will continue to contribute in a substantial manner to progresses in CRT especially in the new era of endocardial pacing. Therefore, it is possible to envision that endocardial mapping may serve to selectively target the most adequate positions for the left ventricular lead in order to optimize CRT.

BACKGROUND: Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. METHODS: We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5x10(10) vector genomes), medium (4.8x10(10) vector genomes), or high dose (1.5x10(11) vector genomes) for up to 2 years. FINDINGS: AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. INTERPRETATION: The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. FUNDING: Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.

OBJECTIVES: The purpose of this study was to assess the effect of remote patient monitoring (RPM) on the outcome of chronic heart failure (HF) patients. BACKGROUND: RPM via regularly scheduled structured telephone contact between patients and health care providers or electronic transfer of physiological data using remote access technology via remote external, wearable, or implantable electronic devices is a growing modality to manage patients with chronic HF. METHODS: After a review of the literature published between January 2000 and October 2008 on a multidisciplinary heart failure approach by either usual care (in-person visit) or RPM, 96 full-text articles were retrieved: 20 articles reporting randomized controlled trials (RCTs) and 12 reporting cohort studies qualified for a meta-analysis. RESULTS: Respectively, 6,258 patients and 2,354 patients were included in RCTs and cohort studies. Median follow-up duration was 6 months for RCTs and 12 months for cohort studies. Both RCTs and cohort studies showed that RPM was associated with a significantly lower number of deaths (RCTs: relative risk [RR]: 0.83, 95% confidence interval [CI]: 0.73 to 0.95, p = 0.006; cohort studies: RR: 0.53, 95% CI: 0.29 to 0.96, p < 0.001) and hospitalizations (RCTs: RR: 0.93, 95% CI: 0.87 to 0.99, p = 0.030; cohort studies: RR: 0.52, 95% CI: 0.28 to 0.96, p < 0.001). The decrease in events was greater in cohort studies than in RCTs. CONCLUSIONS: RPM confers a significant protective clinical effect in patients with chronic HF compared with usual care.

BACKGROUND: We investigated the benefits of the more physiological activation achieved by left ventricular (LV) endocardial pacing (ENDO) as compared with conventional epicardial (EPI) LV pacing in cardiac resynchronization therapy. METHODS AND RESULTS: In 8 anesthetized dogs with experimental left bundle-branch block, pacing leads were positioned in the right atrium, right ventricle, and at 8 paired (EPI and ENDO) LV sites. Systolic LV pump function was assessed as LVdP/dtmax and stroke work and diastolic function as LVdP/dtmin. Electrical activation and dispersion of repolarization were determined from 122 epicardial and endocardial electrodes and from analysis of the surface ECG. Overall, ENDO-biventricular (BiV) pacing more than doubled the degree of electrical resynchronization and increased the benefit on LVdP/dtmax and stroke work by 90% and 50%, respectively, as compared with EPI-BiV pacing. During single-site LV pacing, the range of AV intervals with a >10% increase in LV resynchronization (79+/-31 versus 32+/-24 ms, P<0.05) and LVdP/dtmax (92+/-29 versus 63+/-39 ms) was significantly longer for ENDO than for EPI pacing. EPI-BiV but not ENDO-BiV pacing created a significant (40+/-21 ms) transmural dispersion of repolarization. CONCLUSIONS: Data from this acute animal study indicate that the use of an endocardial LV pacing electrode may increase the efficacy of resynchronization therapy as compared with conventional epicardial resynchronization therapy.

BACKGROUND: The sequence of left ventricular (LV) systolic emptying is not completely understood. Using real-time 3-dimensional echocardiography, we investigated this sequence and LV synchronicity in physiological and pathological conditions. METHODS AND RESULTS: The study population consisted of 116 healthy volunteers, 20 top-level athletes, 35 patients with LV dysfunction, and 84 patients with LV dysfunction and left bundle-branch block (LBBB). We subdivided the LV into 16 volumetric segments for regional analysis and into apical, middle, and basal regions to calculate the mean of end-systolic times and the time to minimum systolic volume of each region. In healthy volunteers and in top-level athletes, the emptying systolic times increased smoothly from apex to base. These differences determined an apex-to-base time gradient in the LV emptying sequence. In patients with LV dysfunction and without LBBB, this gradient was maintained with a relatively higher LV dyssynchrony. However, in patients with LV dysfunction and LBBB, there was no clear sequence in LV emptying volumes, and this group had the highest LV dyssynchrony. CONCLUSIONS: Real-time 3-dimensional echocardiography tomographic slicing of the LV enables accurate analysis of LV emptying in physiological conditions and in conditions of LV dysfunction with and without electrical dyssynchrony. Progressive dilation of LV produces deterioration in LV synchronicity. However, it is the presence of LV dysfunction in combination with LBBB that determines the loss of the apex-to-base time gradient in LV emptying.