Rainer G. Leyh

Methylene blue: The drug of choice for catecholamine- refractory vasoplegia after cardiopulmonary bypass?

OBJECTIVESnVasoplegia is a frequent complication after cardiopulmonary bypass that often requires the application of norepinephrine. In a number of cases, however, vasoplegia is refractory to norepinephrine. The guanylate cyclase inhibitor methylene blue could be an attractive treatment alternative in such cases. This study examines the results of methylene blue therapy for norepinephrine-refractory vasoplegia after cardiopulmonary bypass.nnnMETHODSnA total of 54 patients with norepinephrine-refractory vasoplegia after cardiopulmonary bypass were treated with methylene blue (2 mg/kg) administered intravenously through a period of 20 minutes. The effects on hemodynamics, norepinephrine dosage, and clinical outcome were evaluated.nnnRESULTSnThree patients (5.6%) died during the hospital stay. A clinically relevant increase in systemic vascular resistance and a decrease in norepinephrine dosage were observed in 51 patients within 1 hour after methylene blue infusion. Four patients (7.4%) had no response to methylene blue. No adverse effects related to methylene blue were observed.nnnCONCLUSIONSnA single dose of methylene blue seems to be a potent approach to norepinephrine-refractory vasoplegia after cardiopulmonary bypass for most patients, with no obvious side effects. Guanylate cyclase inhibitors could be a novel class of agents for the treatment of norepinephrine-refractory vasoplegia after cardiopulmonary bypass. A controlled clinical trial is now needed to evaluate the role of methylene blue in this situation.

Hypothermic circulatory arrest during ascending and aortic arch surgery: the theoretical impact of different cerebral perfusion techniques and other methods of cerebral protection.

Operations on the thoracic aorta using hypothermic circulatory arrest are still associated with significant morbidity and mortality due to neurological complications. During the last decades, different cerebral protection techniques have been introduced into clinical practice to reduce the incidence of such complications. Furthermore clinical as well as basic researches have been performed to improve the outcome after these operations. Currently different cerebral perfusion methods are in clinical use and the superiority of one or the other method is a matter of controversial discussion. This review has been undertaken to evaluate the theoretical impact of these different methods of cerebral protection. Based on the experience of the authors the pros and cons are discussed with clinical and experimental reports from the literature.

In vivo repopulation of xenogeneic and allogeneic acellular valve matrix conduits in the pulmonary circulation

BACKGROUNDnApproaches to in vivo repopulation of acellularized valve matrix constructs have been described recently. However, early calcification of acellularized matrices repopulated in vivo remains a major obstacle. We hypothesised that the matrix composition has a significant influence on the onset of early calcification. Therefore, we evaluated the calcification of acellularized allogenic ovine (AVMC) and xenogenic porcine (XVMC) valve matrix conduits in the pulmonary circulation in a sheep model.nnnMETHODSnPorcine (n = 3) and sheep (n = 3) pulmonary valve conduits were acellularized by trypsin/EDTA digestion and then implanted into healthy sheep in pulmonary valve position using extracorporeal bypass support. Transthoracic echocardiography (TTE) was performed at 12 and 24 weeks after the implantation. The animals were sacrificed at week 24 or earlier when severe calcification of the valve conduit became evident by TTE. The valves were examined histologically and biochemically.nnnRESULTSnAll AVMC revealed severe calcification after 12 weeks with focal endothelial cell clustering and no interstitial valve tissue reconstitution. In contrast, after 24 weeks XVMC indicated mild calcification on histologic examination (von Kossa staining) with histologic reconstitution of valve tissue and confluent endothelial surface coverage. Furthermore, immunohistologic analysis revealed reconstitution of surface endothelial cell monolayer (von Willebrand factor), and interstitial myofibroblasts (Vimentin/Desmin).nnnCONCLUSIONSnPorcine acellularized XVMC are resistant to early calcification during in vivo reseeding. Furthermore, XVMC are repopulated in vivo with valve-specific cell types within 24 weeks resembling native valve tissue.

Results of valve-sparing aortic root reconstruction in 158 consecutive patients

BACKGROUNDnThis study assesses the durability and clinical outcome of valve-sparing aortic root reconstruction using the reimplantation technique in a single center cohort.nnnMETHODSnFrom July 1993 to July 2001, 158 patients underwent replacement of the ascending aorta with native valve reimplantation. Mean age of patients was 52 +/- 17 years (9 to 84 years), 103 were men (65%). Thirty-four patients (22%) suffered from Marfans syndrome. Aortic dissection Stanford type A was present in 29 patients (19%) (22 acute, 7 chronic), and concomitant partial or total arch replacement was necessary in 57 patients (36%). One or more additional procedures were performed in 28 patients (18%). Mean follow-up was 36 +/- 25 months (0.4 to 96 months).nnnRESULTSnThirty-day mortality was 3.8% (6 patients), but only 2.2% in elective patients. Mean bypass time was 169 +/- 50 minutes (99 to 440 minutes), aortic cross-clamp time was 129 +/- 31 minutes (79 to 205 minutes). In patients undergoing arch replacement, circulatory arrest was 26 +/- 18 minutes (7 to 99 minutes). During follow-up, there were 5 (3.3%) cardiac-related late deaths. Grade of aortic insufficiency (AI) decreased from 2.3 +/- 1.1 (0 to 4) preoperatively to 0.23 +/- 0.44 (0 to 2) postoperatively (p < 0.0001). Six patients required aortic valve replacement, 4 of those due to progressive AI. Average grade of AI increased significantly to 0.42 +/- 0.61 (0 to 3) at latest evaluation (p = 0.002). Two patients experienced a transient ischemic attack within the first postoperative week. No further thromboembolic complications were noticed. All patients presented with a favorable exercise tolerance.nnnCONCLUSIONSnThe aortic valve reimplantation technique achieves excellent clinical outcome with few complications even in complex pathologies. Lack of anticoagulation and favorable durability encourage wider and earlier use of this technique.

A novel bioartificial myocardial tissue and its prospective use in cardiac surgery

BACKGROUNDnCongenital heart defects such as atrial septal defect, ventricular septal defect, double outlet ventricles and the hypoplastic left heart syndrome as well as ischemic heart disease are associated with aplastic, defective or necrotic myocardial structures. In many of these instances patch closure, reconstruction of the defect or revascularization is required. We have developed a contractile bioartificial myocardial tissue, which offers new perspectives for various reconstructive surgical interventions, including congenital heart surgery.nnnMETHODSnNeonatal rat cardiomyocytes were seeded in vitro in a commercially available collagen scaffold. Histological examination and ultrastructural evaluation were performed. Protein and mRNA analysis were carried out by two-dimensional electrophoresis and reverse transcription-polymerase chain reaction (RT-PCR). Force measurements of contractions from the spontaneously beating or the pharmacologically stimulated bioartificial myocardial patch were obtained.nnnRESULTSnA solid matrix of 20 x 15 x 2 mm with spontaneous contractions resulted 36 h after cardiomyocyte seeding. Histology showed a tight mesh of collagen fibrils. Two-dimensional electrophoresis and RT-PCR revealed cardiotypical proteins (actin, tropomyosin, creatine kinase, ventricular light chain) and mRNA (myosin heavy chain, Connexin 43). The elasticity curve during passive stretch was similar to that of myocardium. Contractile force increased after topical administration of Ca(2+) and adrenaline. However, stretch led to the highest levels of contractile force.nnnCONCLUSIONSnOur novel contractile bioartificial tissue can be engineered in vitro and may open novel avenues for myocardial tissue replacement in congenital and reconstructive heart surgery. From the current standpoint autologous or allogeneic cells would be preferred over xenogeneic sources.

Acellularized porcine heart valve scaffolds for heart valve tissue engineering and the risk of cross-species transmission of porcine endogenous retrovirus

OBJECTIVEnAcellularized porcine heart valve scaffolds have been successfully used for heart valve tissue engineering, creating living functioning heart valve tissue. However, there is concern about the possibility of porcine endogenous retrovirus transmission. In this study we investigated whether acellularized porcine heart valve scaffold causes cross-species transmission of porcine endogenous retrovirus in a sheep model.nnnMETHODSnAcellularized porcine pulmonary valve conduits (n = 3) and in vitro autologous repopulated porcine pulmonary valve conduits (n = 5) were implanted into sheep in the pulmonary valve position. Surgery was carried out with cardiopulmonary bypass support. The animals were killed 6 months after the operation. Blood samples were collected regularly up to 6 months after the operation and tested for porcine endogenous retrovirus by means of polymerase chain reaction and reverse transcriptase-polymerase chain reaction. In addition, explanted tissue-engineered heart valves were tested for porcine endogenous retrovirus after 6 month in vivo.nnnRESULTSnPorcine endogenous retrovirus DNA was detectable in acellularized porcine heart valve tissue. However, 6 months after implantation of in vitro and in vivo repopulated acellularized porcine heart valve scaffolds, no porcine endogenous retrovirus sequences were detectable in heart valve tissue and peripheral blood.nnnCONCLUSIONnAcellularized porcine matrix scaffolds used for creation of tissue-engineered heart valves do not transmit porcine endogenous retrovirus.

Valve-sparing aortic root reconstruction in patients with significant aortic insufficiency

BACKGROUNDnTo assess the feasibility and outcome of the valve-sparing aortic root reimplantation technique in patients with severe preoperative aortic insufficiency (AI).nnnMETHODSnWithin 8 years we have operated on 158 patients with aneurysms of the ascending aorta using the reimplantation technique. We identified 83 patients with AI grade 3 or 4 (mean 3.1 +/- 0.4) preoperatively (study group). This cohort was compared with 71 patients with AI grade 2 or less (mean 1.3 +/- 0.9; control group) with regard to mortality, operative variables, complications, need for reoperation, postoperative AI, and clinical presentation during follow-up.nnnRESULTSnPatient demographics were comparable in both groups. However, Marfans syndrome (32% versus 13%, p = 0.006) and acute type A aortic dissection (20% versus 8.4%, p = 0.059) were more frequent in the control group. In addition, bypass (177 +/- 60 minutes versus 160 +/- 36 minutes, p = 0.022) and cross clamp times (133 +/- 34 minutes versus 124 +/- 27 minutes, p = 0.049) were significantly longer in controls. Mortality was low in the study group and comparable with controls (30-day, 3.6% versus 4.2%; during follow-up, 3.8% versus 5.9%; p = not significant [NS]). Reoperation rate was almost identical in both groups (3.8% versus 4.4%, p = NS). Mean grade of AI was significantly higher in the study group early postoperatively (0.31 +/- 0.46 versus 0.18 +/- 0.42, p = 0.049) but comparable at the last visit (0.43 +/- 0.58 versus 0.42 +/- 0.62, p = NS). During follow-up neither thromboembolic complications nor bleeding events were noted in either group. Clinical performance at the last visit revealed no significant difference between the groups.nnnCONCLUSIONSnPreoperative severe aortic insufficiency does not impair the excellent outcome seen after a mean of 3 years of follow-up in patients undergoing the reimplantation technique for valve-sparing aortic root reconstruction.

Bioartificial grafts for transmural myocardial restoration: a new cardiovascular tissue culture concept.

OBJECTIVEnSurvival of bioartificial grafts that are destined to restore cardiac function stands and falls with their nutrient supply. Engineering of myocardial tissue is limited because of lack of vascularization. We introduce a new concept to obtain bioartificial myocardial grafts in which perfusion by a macroscopic core vessel is simulated.nnnMETHODSnWe have designed an experimental reactor with multiple chambers for the production of bioartificial tissue or tissue precursors. By introduction of in- and output lines of distinct diameter and insertion of a core vessel into each chamber, we established pulsatile, continuous flow through the embodied three-dimensional tissue culture. In the present study, collagen components served as the ground matrix wherein neonatal rat cardiomyocytes were inoculated. For the assessment of cellular viability and distribution in comparison to static, non-perfused culture, fluor-desoxy-glucose-positron-emission-tomography and life/dead assays were employed.nnnRESULTSnWe obtained 3D constructs of 8-mm thickness, which display high viability and metabolism (6.0+/-1.3(e-03) in the perfused vs. 4.0+/-0.3(e-03) in the unperfused chambers). The core vessel has the size of a human coronary and remained patent during the entire culture process. We observed centripetal migration of the embedded cardiomyocytes to the site of the core vessel. Cardiomyocytes partially resumed a spindle like form without additional stretch.nnnCONCLUSIONSnThe present dynamic tissue culture concept is highly effective in manufacturing thick, viable grafts for cardiac muscle restoration, which could be surgically anastomosable. The bioreactor may accommodate multiple types of cells and tissues for innumerable in vitro and in vivo applications.

Acute dissection of the ascending aorta: first results of emergency valve sparing aortic root reconstruction

OBJECTIVEnAcute dissection of the ascending aorta requires immediate surgical intervention. In this study, we report our first results with valve sparing aortic root reconstruction removing all the diseased tissues.nnnMETHODSnFrom August 1995 to December 2000, 22 patients with acute aortic dissection of the ascending aorta (Stanford type A) underwent valve sparing aortic root reconstruction. Their ages ranged from 20 to 76 years (52+/-15, 68% males). Dissection was found in the ascending aorta (3 patients) or both in the ascending aorta and aortic arch (19 patients; 86%). Course and length of hospitalization, echocardiographic and clinical follow-up, complications and mortality were analysed.nnnRESULTSnMean cardiopulmonary bypass time was 212+/-56 min (134-352 min), mean aortic cross clamp time was 157+/-24 min (114-205 min). In patients undergoing additional arch replacement (n=19), circulatory arrest was 35+/-18 min (11-75 min). After reconstruction, intraoperative echocardiography showed aortic insufficiency (AI) grade 0 in 16 patients (84%) and grade 1 in three patients (16%). Stay in intensive care unit was 2.1+/-0.7 days, and postoperative hospitalization was 21+/-14.4 days. There were three perioperative deaths (14%). Mean post-operative follow-up was 18.4+/-18 months (0.4-65.4 month). One patient died 10 months postoperatively. At follow-up, no patient suffered AI grade 2 or higher, and no reoperation for aortic valve failure was necessary. All patients presented with a favorable exercise tolerance being in New York Heart Association functional class I or II.nnnCONCLUSIONnValve sparing aortic root reconstruction in patients with type A dissection can be performed with acceptable intraoperative mortality and morbidity and excellent results during follow-up. The complete resection of the diseased aorta is particularly appealing.

Clinical relevance of intracranial high intensity transient signals in patients following prosthetic aortic valve replacement.

OBJECTIVESnThere has been frequent report on transcranially detected microembolic signals (HITS) following cardiac surgery using extracorporeal bypass support. The clinical relevance of HITS, however, has yet to be clarified. The incidence of thromboembolic events is increased following mechanical heart valve replacement. The purpose of this study was to quantify postoperative HITS after implantation of two types of prosthetic aortic valves and to compare both types of mechanical valves with respect to the generation of HITS. In addition, HITS rates were correlated with clinical, echocardiographical and laboratory findings.nnnMETHODSnForty-two patients following implantation of either a Sorin Biomedica heart valve (n=22, group A) or a Tekna Duromedics mechanical valve (n=20, group B) were examined. A group of ten healthy volunteers served as control. Clinical, echocardiographic, carotid artery duplex and laboratory examinations were performed in all patients. A 60 min bilateral transcranial doppler monitoring of the medial cerebral artery (MCA) was also carried out in order to evaluate cerebral blood flow.nnnRESULTSnIn group A 14 of 22 patients were positive for HITS (53%), with an average of 16.4+/-19 HITS/pt.h. In group B 15 of 20 patients were HITS positive (75%) with an average amount of 14.4+/-24 HITS/pt.h. The incidence of HITS was not significantly different between the two groups. No correlation was seen between the HITS-rate/h and neurological findings, duplex sonographic results, mechanical valve size and anticoagulation regimen (P>0.05). However, a negative correlation was observed between patient age and HITS-rate (P=0.02) as well as between the NYHA degree and HITS-rate (P=0.018). The HITS-rate also correlated with postoperative time (P=0.042). No HITS were detected in the control group.nnnCONCLUSIONSnHITS do not correlate with the individual clinical status and, thus, cannot predict the occurrence of neurological deficits in patients following mechanical aortic valve implantation.