The disease mutation A77V in Ryanodine receptor RyR2 induces changes in energy conduction pathways in the protein

Energetically responsive residues of the 217 amino acid N-terminal domain of the cardiac Ryanodine receptor RyR2 are identified by a simple elastic net model. These residues lie along a hydrogen bonded path through the protein. The evolutionarily conserved residues of the protein are all located on this path or in its close proximity. All of the residues of the path are either located on the two Mir domains of the protein or are hydrogen bonded to them. Two calcium binding residues, E171 and E173, are proposed as potential binding residues, based on insights gained from the elastic net analysis of another calcium channel receptor, the inositol 1,4,5-triphosphate receptor, IP3R. Analysis of the disease causing A77V mutated RyR2 showed that the path is disrupted by the loss of energy responsiveness of certain residues

Assessment of cardiac rejection by MR-imaging and MR-spectroscopy

Background: Detection of cardiac rejection is a major problem in cardiac transplantation. The gold standard is, and remains, endomyocardial biopsy. Purpose: Evaluation of MR-imaging and MR-spectroscopy for detection of cardiac rejection. Methods: Orthotopic cardiac transplantation (HTX) was performed in 13 pigs (body weight 30 kg). All animals obtained immunosuppressive (triple) therapy for 1 week after the operation. Thereafter immunosuppression was stopped to induce cardiac rejection. MRI and MRS (1.5 Tesla General Electrics Signa) were performed pre- and post-operatively on days 10, 17, 24 and 31. The degree of rejection was determined post-operatively using endomyocardial biopsy (Texas grading score). Results: (1) MR-imaging: LV function remained unchanged after HTX. LV mass increased (+42%; P<0.05) with cardiac rejection. (2) MR-spectroscopy: a marked reduction in the ratio of phosphocreatine and adenosine triphosphate, respectively, to inorganic phosphate was observed in the rejecting hearts. (3) Histologic grading confirmed cardiac rejection after stopping immunosuppression. The Texas score was 5.7±0.8 at autopsy. Conclusions: MR-imaging and MR-spectroscopy allow the detection of changes associated with cardiac rejection. Both techniques are correlated with histologic rejection. However, endomyocardial biopsy remains the gold standard for reliable detection of cardiac rejectio

Assessment of cardiac rejection by MR-imaging and MR-spectroscopy

Background: Detection of cardiac rejection is a major problem in cardiac transplantation. The gold standard is, and remains, endomyocardial biopsy. Purpose: Evaluation of MR-imaging and MR-spectroscopy for detection of cardiac rejection. Methods: Orthotopic cardiac transplantation (HTX) was performed in 13 pigs (body weight 30 kg). All animals obtained immunosuppressive (triple) therapy for 1 week after the operation. Thereafter immunosuppression was stopped to induce cardiac rejection. MRI and MRS (1.5 Tesla General Electrics Signa) were performed pre- and post-operatively on days 10, 17, 24 and 31. The degree of rejection was determined post-operatively using endomyocardial biopsy (Texas grading score). Results: (1) MR-imaging: LV function remained unchanged after HTX. LV mass increased (+42%; P<0.05) with cardiac rejection. (2) MR-spectroscopy: a marked reduction in the ratio of phosphocreatine and adenosine triphosphate, respectively, to inorganic phosphate was observed in the rejecting hearts. (3) Histologic grading confirmed cardiac rejection after stopping immunosuppression. The Texas score was 5.7±0.8 at autopsy. Conclusions: MR-imaging and MR-spectroscopy allow the detection of changes associated with cardiac rejection. Both techniques are correlated with histologic rejection. However, endomyocardial biopsy remains the gold standard for reliable detection of cardiac rejection

Successful Pre-Rewarming Resuscitation after Cardiac Arrest in Severe Hypothermia: A Retrospective Cohort Study from the International Hypothermia Registry.

The aim of our study is to investigate successful pre-rewarming resuscitation after hypothermic cardiac arrest (HCA). The hypothermic heart may be insensitive to defibrillation when core temperature is below 30 °C and after successful defibrillation, sinus rhythm often returns into ventricular fibrillation. Recurrent defibrillation attempts may induce myocardial injury. Discrepancy exists concerning pre-rewarming defibrillation between the guidelines of the European Resuscitation Council and American Heart Association. The International Hypothermia Registry (IHR) gathers hypothermia cases. The primary outcome was survival. Secondary outcomes were the characteristics of defibrillation, the effect of Adrenaline administration under 30 °C, and the duration of CPR. Of the 239 patients, eighty-eight were in cardiac arrest at arrival of the rescue team. Successful pre-rewarming resuscitation was obtained in 14 patients. The outcome showed: seven deaths, one vegetative state, two patients with reversible damage, and four patients with full recovery. A total of five patients had a shockable rhythm, and defibrillation was successful in four patients. The response rate to Adrenaline was reported as normal in six patients. There were no statistically significant differences in the presence of a shockable rhythm, the success of defibrillation, and the effect on Adrenaline administration between the survivors and non-survivors. Successful resuscitation in severe hypothermia is possible before active rewarming and arrival in the hospital, thus improving the chance of survival

QR in V1 - an ECG sign associated with right ventricular strain and adverse clinical outcome in pulmonary embolism

Aims To test the hypothesis that Qr in V1is a predictor of pulmonary embolism, right ventricular strain, and adverse clinical outcome. Methods and Results ECG's from 151 patients with suspected pulmonary embolism were blindly interpreted by two observers. Echocardiography, troponin I, and pro-brain natriuretic peptide levels were obtained in 75 patients with pulmonary embolism. Qr in V1(14 vs 0 in controls; p<0.0001) and ST elevation in V1≥1mV (15 vs 1 in controls; p=0.0002) were more frequently present in patients with pulmonary embolism. Sensitivity and specificity of Qr in V1and T wave inversion in V2for predicting right ventricular dysfunction were 31/97% and 45/94%, respectively. Three of five patients who died in-hospital and 11 of 20 patients with a complicated course, presented with Qr in V1. After adjustment for right ventricular strain including ECG, echocardiography, pro-brain natriuretic peptide and troponin I levels, Qr in V1(OR 8.7, 95%CI 1.4-56.7; p=0.02) remained an independent predictor of adverse outcome. Conclusions Among the ECG signs seen in patients with acute pulmonary embolism, Qr in V1is closely related to the presence of right ventricular dysfunction, and is an independent predictor of adverse clinical outcom

Failed coronary artery bypass anastomosis detected by intraoperative coronary flow measurement

Objectives: To assess intraoperative flow of arterial and venous coronary grafts after myocardial revascularization which may allow early detection of low flow situations, especially during minimally invasive coronary bypass surgery (MIDCAB), and lead to immediate correction of technical problems. Methods: In two patients with severe and diffuse multi-vessel disease the left internal mammary artery (IMA) was connected to the left anterior descending artery (LAD). During reperfusion, the flow was measured in the IMA and vein grafts using a transit time flow meter. Results: In both cases the IMA showed only a systolic pendulating flow curve with a mean flow of 0-1 ml/min and a high resistance. Manual IMA assessment revealed an adequate pulsation. Both distal IMA anastomoses were re-explored on cardiopulmonary bypass yielding an initial flow of 7 and 14 ml/min, respectively. After treatment with papaverine/adenosine the IMA flow increased from 7 to 26 ml/min (coronary flow reserve (CFR)=3.7) and from 14 to 46 ml/min (CFR=3.3), respectively. Conclusion: Intraoperative flow assessment of IMA and venous bypass grafts can be recommended to monitor flow; especially during MIDCAB procedure

Different techniques of distal aortic repair in acute type A dissection: impact on late aortic morphology and reoperation

Objective: To compare three different techniques of distal aortic repair in acute type A (de Bakey type I) aortic dissection and to evaluate their impact on the late morphology of the aortic arch and descending aorta and on the incidence of reoperation. Methods: From 65 patients operated on due to an acute type A aortic dissection between 1989 and 1993, 54 long-term survivors underwent clinical and radiologic follow-up examination after a mean postoperative interval of 62±16 months. The surgical techniques of distal aortic reconstruction included closed repair using Teflon felt reinforcement under moderate hypothermic cardiopulmonary bypass (n=20) and open repair in deep hypothermic circulatory arrest using either Teflon felt reinforcement (n=16) or gelatin-resorcin-formaldehyde (GRF) glue (n=18) to readapt the dissected aortic layers. In all patients, MR imaging was performed on a 1.5-T whole body imaging system for the evaluation of the morphology and function of the heart, aorta and supraaortic branches. Results: Overall hospital mortality following surgical repair of type A aortic dissection was 15.4% during this time period. The highest rate of persistent false lumen perfusion (17/20, 85%) and presence of an intimal flap in the aortic arch (13/20, 65%) was observed in patients following closed repair of acute ascending aortic dissection, whereas the lowest rate of such findings was demonstrated in patients who had undergone open distal aortic repair using biological glue (false lumen perfusion 10/18, 55% and intimal flap in the arch 2/18, 11%). Redo-surgery was significantly reduced in the open repair group using GRF glue (1/18, 5.5%) as compared with the Teflon felt repair group (3/16, 18%) and the closed repair group (6/20, 30%). Conclusions: In patients with acute type A dissection, open distal aortic repair using GRF-glue favourably influences both (1) the severity of late morphologic alterations in the downstream aorta and (2) the incidence of reoperatio

Experimental noninferiority trial of synthetic small-caliber biodegradable versus stable vascular grafts

ObjectiveLong-term evolution of polycaprolactone vascular prostheses has been investigated recently. The goal of this study was to evidence a noninferiority of such grafts compared with expanded polytetrafluoroethylene (ePTFE) implants in an aortic replacement model in the rat.MethodsFourteen anesthetized Sprague-Dawley rats received an infrarenal aortic graft (biodegradable, n = 8; expanded polytetrafluoroethylene, n = 6) replacement (end to end; inner diameter, 2 mm). Biodegradable grafts (polycaprolactone) were produced by random micro-/nanofiber electrospinning. After a median survival of 16.5 months, in vivo ultrasonography and angiography as well as postexplantation microcomputed tomography, histomorphometry, immunohistochemistry, and scanning electron microscopy were performed.ResultsPatency was 100% for polycaprolactone and 67% for ePTFE. No aneurysmal dilatation or stenoses were found in either group. Compliance was significantly higher for polycaprolactone compared with ePTFE (8.2 ± 1.0%/100 mm Hg vs 5.7 ± 0.7%/100 mm Hg; P < .01), but markedly reduced compared with adjacent native aortas and the control group. Histologically, low cellular in-growth was found in ePTFE whereas polycaprolactone showed significantly greater homogenous cellularity, producing an autologous extracellular matrix (10.8% ± 4.0% vs 32.1% ± 9.2%, P < .0001). Morphometry showed 100% neo-endothelialization for both grafts with a totally confluent endothelial coverage for polycaprolactone grafts by scanning electron microscope. More intimal hyperplasia was found in ePTFE compared with polycaprolactone grafts. Calcification was higher in ePTFE than in polycaprolactone grafts (15.8% vs 7.0%, P = .04) and was absent in controls.ConclusionsOutcomes of synthetic biodegradable nanofiber polycaprolactone grafts are not inferior compared with the clinically used expanded polytetrafluoroethylene grafts after long-term implantation in the rat aorta. Moreover, these implants show better patency, compliance, endothelialization, and cell in-growth, and less intimal hyperplasia and calcification than their counterparts

Prevention of neointimal proliferation by immunosuppression in synthetic vascular grafts

Objective: Immunosuppressive agents have been proposed to reduce neointimal hyperplasia in synthetic vascular grafts. Thus, the purpose of the present study was to evaluate the safety and efficacy of rapamycins (systemic vs. local vs. oral administration) and mycophenolate mofetil (MMF) to reduce intimal hyperplasia in infrarenal synthetic vascular grafts of the rat. Methods: Fifty-four Wistar rats (250 g) completed the study after a synthetic vascular graft (ePTFE, Gore-tex, 2 mm diameter, 10 mm length) was implanted end-to-end in the infrarenal aorta. The animals were divided into three groups: group 1 consisted of 12 control animals, group 2 consisted of 37 rats receiving rapamycins, either per os (RAD, 1.5 or 3 mg/kg), intraperitoneally (RPM, 1.5 or 3 mg/kg) or locally (RPM soaking of the graft); and in group 3 (n = 5), MMF (40 mg/kg) was administered orally. The animals were followed weekly with weight controls and signs of toxicity for 30 (n = 37) and 60 (n = 17) days, respectively. All animals were sacrificed and underwent histological examination at completion of the study. Results: All animals survived in groups 1 and 3, but five died in group 2. The weight gain was normal in all groups, except for the subgroup 2a receiving high dose rapamycins orally. All rats in group 3 suffered from diarrhea, whereas animals receiving high dose rapamycins showed toxic signs (hair loss, wound healing problems). Histological examination showed a significant increase in intimal hyperplasia in group 1 (0.03±0.01 and 0.14±0.05 μm after 30 and 60 days, respectively; P < 0.01). Rapamycins in either application or dosage had no significant effect on intimal hyperplasia. Conclusions: Local or systemic administration of rapamycins has no effect on intimal hyperplasia in synthetic vascular grafts. In contrast, toxic signs with weight loss were observed in animals treated with high dose rapamycins, but not in those treated with MMF. Thus, in the rat model, immunosuppresssion with rapamycins or MMF cannot be recommended for the prevention of intimal hyperplasia in the synthetic vascular graft mode