The type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation–contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are “leaky.” RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.

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The benefit of the ␤ 2 -adrenergic agonist, clenbuterol, in left ventricular assist device patients with dilated cardiomyopathy has been reported, but its effect on ischemic heart failure (HF) is unknown. We investigated whether clenbuterol improves left ventricular remodeling, myocardial apoptosis and has synergy with a ␤ 1 antagonist, metoprolol, in a model of ischemic HF. Rats were randomized to: 1) HF only; 2) HF ϩ clenbuterol; 3) HF ϩ metoprolol; 4) HF ϩ clenbuterol ϩ metoprolol; and 5) rats with sham surgery. HF was induced by left anterior descending artery (LAD) artery ligation and confirmed by decreased left ventricular fractional shortening, decreased maximum left ventricular dP/dt (dP/dt max ), and elevated left ventricular end-diastolic pressure (LVEDP) compared with sham rats (p Ͻ 0.01). After 9 weeks of oral therapy, echocardiographic, hemodynamic, and ex vivo end-diastolic pressure-volume relationship (EDPVR) measurements were obtained. Immunohistochemistry was performed for myocardial apoptosis and DNA damage markers. Levels of calcium-handling proteins were assessed by Western blot analysis. Clenbuterol-treated HF rats had increased weight gain and heart weights versus HF rats (p Ͻ 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p Ͻ 0.05). The metoprololtreated group had a lower LVEDP and higher dP/dt max versus the HF group (p Ͻ 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p Ͻ 0.01). Protein levels of the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase were improved in clenbuterol-, metoprolol-, and clenbuterolϩmetoprolol-treated groups versus HF rats. However, as a combination therapy, there were no synergistic effects of clenbuterolϩmetoprolol treatment. We conclude that clenbuterol ameliorates EDPVR, apoptosis, and calcium homeostasis but does not have synergy with metoprolol in our model of ischemic HF.Clenbuterol is a ␤ 2 -adrenergic receptor agonist first used in the mid-1970s to treat asthma and is approved for this indication in Europe (Salorinne et al., 1975). The drug bears structural similarity to albuterol but has enhanced oral absorption and ␤ 2 -selectivity. Clenbuterol also increases muscle bulk (Choo et al., 1992;Maltin et al., 1993;Carter and Lynch, 1994) because of an anabolic effect that may be mediated via long-term ␤ 2 -activation (MacLennan and Edwards, 1989;Choo et al., 1992). Because of this anabolic action, oral clenbuterol has been abused by athletes to enhance size and strength (Beckett, 1992;Perry, 1993). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

Prolonged donor ischemic time is not a risk factor for decreased long-term survival. Procurement of hearts with prolonged donor ischemic time is justified in the setting of an increasing recipient pool with a fixed donor population.

FDG PET scanning can be helpful in managing patients with Stage III melanoma in whom further surgery is contemplated. Although false-positive areas are not uncommon, PET scans did change the management of patients 15% of the time. PET's inability to identify microscopic disease suggests that it is of limited use in evaluating patients with Stage I-II disease.

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Background: While potential benefits of robotic technology include decreased morbidity and improved recovery, some have suggested a prohibitively high cost. This study was undertaken to compare actual hospital costs of robotically assisted cardiac procedures with conventional techniques. Methods: We conducted a retrospective review of clinical and financial data of 20 patients who underwent atrial septal defect (ASD) closure and 20 patients who underwent mitral valve repair (MVr) using either robotic techniques or a conventional approach with a sternotomy. Total hospital cost (actual resource consumption) was subdivided into operative and postoperative costs. Results: Robotic technology did not significantly increase total hospital cost for ASD closure or MVr (p = 0.518 and p = 0.539). However, when including the initial capital investment for the robot through amortization of institutional costs, total hospital cost was increased by $3,773 for robotic ASD closure and $3,444 for robotic MVr (p = 0.021 and p = 0.004). The major driver of cost for robotic cases (operating room time) decreased over time. Conclusions: Robotic technology did not significantly increase hospital cost. While the absolute cost for robotic surgery was higher than conventional techniques after taking into account the institutional cost of the robot, the major driver of cost for robotic procedures will likely continue to decrease, as the surgical team becomes increasingly familiar with robotic technology. Furthermore, other benefits, such as improvement in postoperative quality of life and more expeditious return to work may make a robotic approach cost-effective. Thus, it is possible that the benefits of robotic surgery may justify investment in this technology.