We test the hypothesis that moderate calorie restriction (CR) reverses negative influences of age on molecular determinants of myocardial stress resistance. Postischemic contractile dysfunction, ...cellular damage, and expression of regulators of autophagy/apoptosis and of prosurvival and prodeath kinases were assessed in myocardium from young adult (YA; 2- to 4-month-old) and middle-aged (MA; 12-month-old) mice, and MA mice subjected to 14 weeks of 40% CR (MA-CR). Ventricular dysfunction after 25%±2%), as was cell death indicated by troponin I (TnI) efflux (1,701±214 ng vs. 785±102 ng in YA). MA hearts exhibited 30% and 65% reductions in postischemic Beclin1 and Parkin, respectively, yet 50% lower proapoptotic Bax and 85% higher antiapoptotic Bcl2, increasing the Bcl2/Bax ratio. Age did not influence Akt or p38-mitogen-activated protein kinase (MAPK) expression; reduced expression of increasingly phosphorylated ribosomal protein S6 kinase (p70S6K), increased expression of dephosphorylated glycogen synthase kinase 3β (GSK3β) and enhanced postischemic p38-MAPK phosphorylation. CR countered the age-related decline in ischemic tolerance, improving contractile recovery (60%±4%) and reducing cell death (123±22 ng of TnI). Protection was not associated with changes in Parkin or Bax, whereas CR partially limited the age-related decline in Beclin1 and further increased Bcl2. CR counteracted age-related changes in p70S6K, increased Akt levels, and reduced p38-MAPK (albeit increasing preischemic phosphorylation), and paradoxically reduced postischemic GSK3β phosphorylation. In summary, moderate age worsens cardiac ischemic tolerance; this is associated with reduced expression of autophagy regulators, dysregulation of p70S6K and GSK3β, and postischemic p38-MAPK activation. CR counters age effects on postischemic dysfunction/cell death; this is associated with reversal of age effects on p70S6K, augmentation of Akt and Bcl2 levels, and preischemic p38-MAPK activation. Age and CR thus impact on distinct determinants of ischemic tolerance, although p70S6K signaling presents a point of convergence.
A potential advantage of the right ventricle to pulmonary artery versus modified Blalock–Taussig shunt in patients undergoing the Norwood procedure is limitation of diastolic runoff from the systemic ...to pulmonary circulation. We evaluated mesenteric flow patterns and gastrointestinal outcomes following the Norwood procedure associated with either shunt type. Patients randomized to a right ventricle to pulmonary artery versus modified Blalock–Taussig shunt in the Pediatric Heart Network Single Ventricle Reconstruction Trial at centers participating in this ancillary study were eligible for inclusion; those with active necrotizing enterocolitis, sepsis, or end-organ dysfunction were excluded. Celiac artery flow characteristics and gastrointestinal outcomes were collected at discharge. Forty-four patients (five centers) were included. Median age at surgery was 5 days interquartile range (IQR) = 4–8 days. Median celiac artery resistive index (an indicator of resistance to perfusion) was higher in the modified Blalock–Taussig shunt group (
n
= 19) versus the right ventricle to pulmonary artery shunt group (
n
= 25) 1.00 (IQR = 0.84–1.14) vs. 0.82 (IQR = 0.74–1.00),
p
= 0.02. There was no difference in interstage weight gain, necrotizing enterocolitis, or feeding intolerance episodes between the groups. The celiac artery resistive index was higher in patients with the modified Blalock–Taussig shunt versus the right ventricle to pulmonary artery shunt but was not associated with measured gastrointestinal outcomes.
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