Adverse impact of heart failure on the electrophysiological response to ischaemia-reperfusion in human myocardium

BackgroundAcute ischaemia and reperfusion (I-R) are associated with pro-arrhythmic electrophysiological changes such as action potential duration (APD) shortening and conduction velocity (CV) slowing, though data from human myocardium are sparse. We studied electrophysiological changes during I-R in intact human myocardium, comparing differences between failing and non-failing hearts.MethodsWe optically mapped coronary-perfused left ventricular wedge preparations from six human hearts with end-stage heart failure (HF) and six non-failing hearts from donors rejected for transplant (NF). At baseline, the preparations were subjected to steady-state pacing across a range of cycle lengths, and then subjected to 30 min of global ischaemia, followed by 30 min of reperfusion. Restitution pacing protocols were repeated after reperfusion.FindingsAt baseline, HF hearts had longer APD80 and slower transmural CV compared with NF hearts across a range of cycle lengths (both ANOVA p<0·001). APD80 and CV were reduced with ischaemia (at cycle lengths of 1000 ms, baseline vs 10 min ischaemia: mean HF APD 375 ms [SE 23] vs 324 [5], p<0·01; NF APD 308 [14] vs 271 [28], p<0·05; HF CV 29 cm/s [4] vs 16 [6], p<0·05; NF CV 40 [2] vs 23 [2], p<0·001), and were restored with reperfusion. APD shortening was greater in HF hearts during ischaemia (ΔAPD80 at 8 min ischaemia: mean HF 75 ms [SE 11], NF 25 [5]; p<0·01). Recovery of electrical excitability after reperfusion was delayed in HF (4·8 min [1·8] vs NF 1·0 [0], p<0.05). APD was restored to pre-ischaemic levels within the first minute of reperfusion in NF hearts, but restoration of APD was incomplete in HF early after reperfusion.InterpretationIn human myocardium, acute ischaemia was associated with APD shortening and CV slowing, which were reversed with reperfusion. In end-stage HF, these changes were accelerated during ischaemia, and recovery was slower following reperfusion. This may enhance the spatial gradients of repolarisation during acute I-R in failing hearts, and thus increase arrhythmia susceptibility. Further work is needed to elucidate the metabolic mechanisms underlying the adverse electrophysiological response to I-R in human heart failure.FundingNational Institute for Health Research, US National Institutes of Health, and British Heart Foundation.     

Amyloid precursor-like protein 2 suppresses irradiation-induced apoptosis in Ewing sarcoma cells and is elevated in immune-evasive Ewing sarcoma cells

Despite surgery, chemotherapy, and radiotherapy treatments, the children, adolescents, and young adults who are diagnosed with metastasized Ewing sarcoma face a dismal prognosis. Amyloid precursor-like protein 2 (APLP2) has recently been implicated in the survival of cancer cells and in our current study, APLP2’s contribution to the survival of Ewing sarcoma cells was examined. APLP2 was readily detected in all Ewing sarcoma cell lines analyzed by western blotting, with the TC71 Ewing sarcoma cells expressing the lowest level of APLP2 among the lines. While irradiation induces apoptosis in TC71 Ewing sarcoma cells (as we determined by quantifying the proportion of cells in the sub-G₁ population), transfection of additional APLP2 into TC71 decreased irradiation-induced apoptosis. Consistent with these findings, in parallel studies, we noted that isolates of the TC71 cell line that survived co-culture with lymphokine-activated killer (LAK) cells (which kill by inducing apoptosis in target cells) displayed increased expression of APLP2, in addition to smaller sub-G₁ cell populations after irradiation. Together, these findings suggest that APLP2 lowers the sensitivity of Ewing sarcoma cells to radiotherapy-induced apoptosis and that APLP2 expression is increased in Ewing sarcoma cells able to survive exposure to cytotoxic immune cells.     

Special Schooling in Children with Congenital Heart Disease: A Risk Factor for Being Disadvantaged in the World of Employment

The objective of this study was to evaluate type of schooling in children with congenital heart disease (CHD) who were inpatients at a tertiary pediatric cardiology center. This retrospective cohort study included 227 consecutive children with CHD (male, 125; female, 102) who had been inpatients from 1996 to 2005. Data on type of schooling had been documented by the in-hospital teacher at the time of admission. Medical data were obtained by reviewing medical charts. The primary endpoint was the percentage of children requiring special schooling, which was related to the respective percentage in the Austrian pediatric background population. Furthermore, the influence of clinical and demographic covariables was assessed. Fifteen percent (vs. 3.6% in the background population) of the study cohort required special schooling; 86% of them had a history of cardiac surgery. Cardiopulmonary bypass surgery in the first year of life showed a trend for an association with an increased frequency of special schooling. There were no significant associations with the Aristotle Basic Score (a measure for procedure complexity in CHD), gender, or first language. In conclusion, the need for special schooling is increased in children with CHD.