Exercise intolerance in Glycogen Storage Disease Type III: weakness or energy deficiency?

Myopathic symptoms in Glycogen Storage Disease Type IIIa (GSD IIIa) are generally ascribed to the muscle wasting that these patients suffer in adult life, but an inability to debranch glycogen likely also has an impact on muscle energy metabolism. We hypothesized that patients with GSD IIIa can experience exercise intolerance due to insufficient carbohydrate oxidation in skeletal muscle. Six patients aged 17-36-years were studied. We determined VO 2peak (peak oxygen consumption), the response to forearm exercise, and the metabolic and cardiovascular responses to cycle exercise at 70% of VO 2peak with either a saline or a glucose infusion. VO 2peak was below normal. Glucose improved the work capacity by lowering the heart rate, and increasing the peak work rate by 30% (108 W with glucose vs. 83 W with placebo, p=0.018). The block in muscle glycogenolytic capacity, combined with the liver involvement caused exercise intolerance with dynamic skeletal muscle symptoms (excessive fatigue and muscle pain), and hypoglycemia in 4 subjects. In this study we combined anaerobic and aerobic exercise to systematically study skeletal muscle metabolism and exercise tolerance in patients with GSD IIIa. Exercise capacity was significantly reduced, and our results indicate that this was due to a block in muscle glycogenolytic capacity. Our findings suggest that the general classification of GSD III as a glycogenosis characterized by fixed symptoms related to muscle wasting should be modified to include dynamic exercise-related symptoms of muscle fatigue. A proportion of the skeletal muscle symptoms in GSD IIIa, i.e. weakness and fatigue, may be related to insufficient energy production in muscle.

Off-pump replacement of the pulmonary valve in large right ventricular outflow tracts: a transcatheter approach using an intravascular infundibulum reducer.

We report our experience of pulmonary valve replacement in animals with large right ventricular outflow tracts (RVOTs) using a percutaneous approach. We intended to implant a device to percutaneously reduce the diameter of the pulmonary artery (PA). Following its insertion, we intended to implant a valved stent inside the restriction. Animals were killed acutely (group 1, n=6) and after a mean follow-up of 1 (group 2, n=3) and 2 mo (group 3, n=9). In group 1, all reducers were successfully deployed and allowed the reduction of the PA to a diameter of 12-mm. In one animal, the proximal part of the reducer did not reach its final configuration. Another reducer embolized when manipulating the stiff wire. The insertion of valves was therefore possible in 17/18 animals. One animal died from an arrhythmia during positioning of the valve. Angiographic evaluations showed no leak between devices and the pulmonary wall. During the follow-up, there was no device migration. At autopsy, reducers were fixed to the pulmonary wall and completely covered by a fibrous tissue. In conclusion, with the use of an intravascular reducer, implantation of a pulmonary valve is possible in sheep through a transcatheter approach when the RVOT exceeds 22-mm in diameter.

Development of a device for transcatheter pulmonary artery banding: evaluation in animals.

AIMS: Pulmonary artery banding (PAB) is the first palliation in infants with complex congenital heart disease and elevated pulmonary blood flow. In older patients with corrected transposition of the great arteries, it may be used to re-train the left ventricle. To date, the only option is surgical. We report the development and the evaluation of a device for transcatheter PAB. METHODS AND RESULTS: We intended to implant a pulmonary artery (PA) reducer percutaneously between the native pulmonic valve and the pulmonary bifurcation. Immediately following its insertion, we planned to implant a balloon expandable stent inside the restriction to calibrate the banding. Sheep were sacrificed acutely (group 1, n=6) and after 1 month of follow-up (group 2, n=6), the reducer was implanted successfully in all animals. It allowed the PA diameter to be reduced from 25 to 10.5 mm. Bare stents were successfully delivered inside the reducer. No paraprosthetic leak was found by injecting contrast dye. After the insertion procedure, signs of intolerance to obstruction were present in all animals and prompted us to dilate the stents from 12 to 16 mm. One animal from group 1 died before a balloon dilatation could be achieved. In the animals from group 2, the mean systolic gradient was 19 and 34.8 mmHg, respectively, at early and late evaluation. CONCLUSION: Implantation of a PA reducer is possible in sheep, through a transcatheter approach allowing intravascular PAB. Miniaturization of the device is necessary to enlarge its use from adulthood to childhood.

Off-label use of an adjustable gastric banding system for pulmonary artery banding.

BACKGROUND: Pulmonary artery banding is proposed as a first palliation in infants with complex congenital heart disease and high pulmonary blood flow. In addition, it may be used to retrain the left ventricle. Optimal tightening may be difficult to obtain, leading to reoperation. An implantable device for pulmonary artery banding with telemetric control was recently developed allowing for repeated adjustments, but it is presently limited to patients weighing less than 20 kg. In large animals, we tested an off-label adjustable gastric banding system for pulmonary artery banding. METHODS AND RESULTS: Fourteen ewes weighing 50 to 75 kg underwent implantation of the Lap-Band device (BioEnterics Corp, Santa Barbara, Calif) around the main pulmonary artery through a left thoracotomy. All had functional evaluation with progressive occlusion and opening of the device at implantation and every 2 weeks until sacrifice immediately after implantation (group 1, n = 8), at 1 month (group 2, n = 3), at 3 months (group 3, n = 3), or death. Invasive pressure measurements in the right ventricle and aorta were carried out each time. Devices were easily implanted in all animals. Progressive occlusion and reopening were possible in all animals during each time point. Two animals died of right heart failure related to excessive tightening of the band. Retrieval of the device without any major damage was possible in 12 of 14 animals. CONCLUSION: With this implantable device, we were able to adjust the pulmonary artery diameter in animals. Patients requiring left ventricle retraining and weighing more than 30 kg would benefit from the device's use in humans.

Expandable right ventricular-to-pulmonary artery conduit: an animal study.

This study was performed to assess a new vascular stent graft as an expandable valved conduit for right ventricular outflow tract (RVOT) reconstruction in sheep. Conduits were constructed by sewing an 18-mm valved conduit inside a stent. Crimped to 16 mm, they were implanted either under or without extracorporeal circulation in seven (group A) and in five (group B) sheep, respectively. Six weeks and 3 mo after their insertion, conduits were dilated intraluminally. A valved stent was implanted percutaneously into conduits before they were killed. Two animals from group A recovered normally, whereas five animals had a complicated postoperative course. In group B, one died acutely due to kinking of the conduit. Balloon dilatations were performed in all surviving animals. First dilatations had a slight impact on valvular function in all animals but one, whereas second dilatations led to significant PR in all. Transcatheter valve implantation was performed successfully. When animals were killed, no bleeding was found around the surgically implanted device. In conclusion, we designed a biologic valved conduit for RVOT reconstruction that can be dilated sequentially to follow animal growth. This new device can have tremendous applications in children with congenital heart diseases involving the RVOT.