Novel Interventions for Heat/Exercise Induced Sudden Death and Fatigue
Abstract
The goals are 1) to indentify RYR1 mutations associated with enhanced susceptibility to EHS/ER/MH by enrolling subjects diagnosed with these conditions and performing genetic screening. 2) to determine the mechanism of action of aminoimidazole carboxamide ribonucleotide (AICAR) and A769662 compound and test their suitability as interventions to prevent heat induced deaths in the porcine MH models. During the project period, 10 individuals were enrolled. RYR1 mutations/variants were identified in 5 of 10 enrolled subjects. Three of these mutations have been described as Malignant Hyperthermia (MH) causative mutations (Arg163Cys, Gly2434Arg and Arg2454Cys); one previously published MHS associated mutation, and one novel variant were identified in the RYR1 gene. Of the common mutations, the Arg2454Cys was identified in African American with positive CHCT results and a history of exertional rhabdomyolysis (ER). Identification of this mutation in a subject with ER further strengthens a link between MHS and ER. A new variant, Gly4820Arg, was found in a family with a history of death due to MHS and heat exertion. In the swine model of MH we compared the effectiveness of AICAR with dantrolene (2.4mgs/kg) in treatment of halothane triggered MH . Dantrolene was consistently effective, but AICAR 300,600 and -1200mgs/Kg was ineffective as a pre or post treatment for anesthetic induced MH. Consistent with this, AICAR prevents the heat induced deaths but not the anesthetic induced deaths in the mouse model of MH, suggesting different mechanisms. We demonstrate that AICAR prevents the heat response by preventing Ca2+ leak from RyR1.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2011
- Accession Number
- ADA599525
Entities
People
- John Capacchione
- Nyamkhishig Sambuughin
- Rolf Bunger
- Sheila M. Muldoon
- Susan L. Hamilton
Organizations
- Baylor College of Medicine