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Objectives: The purpose of this multicentre cohort study was to examine the relationship between antiplatelet therapy (APT) at the time of coronary artery bypass grafting (CABG) and postoperative bleeding complications, transfusion requirements and adverse cardiovascular events., Methods: A matched-pair analysis was carried out on 6350 consecutive patients undergoing CABG at the three university hospitals in Western Denmark. Patients exposed to aspirin or clopidogrel within 5 days before surgery were compared with those not exposed to these drugs. The data used in the study were retrieved from the Western Denmark Heart Registry., Results: Of the 6350 patients enrolled, 1846 (29%) had been exposed to aspirin or clopidogrel within 5 days prior to CABG (the APT group). Matching with the remaining 4504 (71%) patients of the control group resulted in 1132 pairs of patients. Patients in the APT group had greater mean chest tube drainage volumes (946 vs 775 ml; P < 0001) and greater transfusion requirements (ranging from 37.4-57.5 vs 29.8%; P < 0.0001) than control group patients. Preoperative aspirin therapy was not associated with greater reoperation rates (4.0 vs 3.9%; P = 0.005); nor was it an independent risk factor for severe postoperative bleeding >1000 ml (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.55-1.34). Preoperative clopidogrel use, on the other hand, was associated with greater reoperation rates (10.2 vs 3.9% in the control group; P = 0.005) and was an independent predictor of severe postoperative bleeding (OR: 2.08, 95% CI: 1.55-2.80). Overall, preoperative APT had no significant effect on postoperative 30-day mortality, incidence of myocardial infarction, stroke or need for dialysis., Conclusions: Preoperative APT is associated with increased bleeding and greater transfusion requirements after CABG. Clopidogrel exposure is associated with greater reoperation rates and is an independent risk factor for severe postoperative bleeding.

Objectives: Treatment of atrial septal defect (ASD) in adults is still controversial, and with older age the likelihood of treatment is decreased. The aim of this study was to investigate the effect of ASD closure in adults and especially in the elderly in our institution in a retrospective review., Methods: Adult patients (n = 220) underwent surgical or catheter closure for an isolated ASD at Aarhus University Hospital from 1990 to 2008. Eleven were lost to follow-up and 13 had cardiac comorbidity, and thus 196 were eligible for analysis in the study. Hospital records were reviewed and symptoms and echocardiographic findings registered preoperatively and at 3-month follow-up. Patients were divided into Group I (n = 117): between 18 and 50 years old and Group II (n = 79): older than 50 years. Symptoms and echocardiographic findings before and 3 months after closure were compared within and between the two groups., Results: One patient (0.5%) died during follow-up. Complications occurred in 16% in Group I and 22% in Group II. There was an absolute risk reduction of -62 and -52%, respectively in right ventricle (RV) dilation after operation. Atrial fibrillation was noticed preoperatively in 6% of the young and 47% of the elderly, with an absolute risk reduction after treatment of -20% in Group II (P < 0.0001). Subjective symptoms occurred in 75% in Group I and 99% in Group II with a postoperative reduction to 43 and 67%, respectively. In Group I, 70% felt an improvement of symptoms while this was true for 89% in Group II., Conclusions: Symptoms and RV dilation are more pronounced in the elderly (>50 years), but reversibility is the same as in the young (<50 years) patients. The elderly benefit substantially from ASD closure. Based on these data, ASD closure is recommendable even after the fifth decade.

Interstitial Cajal-like cells (ICLCs) are speculated to be pacemakers in smooth muscle tissues. While the human thoracic duct (TD) is spontaneously active, the origin of this activity is unknown. We hypothesized that ICLCs could be present in the TD and using histological techniques, immunohistochemistry and immunofluorescence we have investigated the presence of ICLCs, protein markers for ICLCs and the cellular morphology of the human TD. Transmission electron microscopy was employed to investigate ultrastructure. Methylene blue staining, calcium-dependent fluorophores and confocal microscopy were used to identify ICLCs in live tissue. Methylene blue stained cells with morphology suggestive of ICLCs in the TD. Immunoreactivity localized the ICLC protein markers c-kit, CD34 and vimentin to many cells and processes associated with smooth muscle cells (SMCs): coexpression of c-kit with vimentin or CD34 was observed in some cells. Electron microscopy analysis confirmed ICLCs as a major cell type of the human TD. Lymphatic ICLCs possess caveolae, dense bands, a patchy basal lamina, intermediate filaments and specific junctions to SMCs. ICLCs were ultrastructurally differentiable from other interstitial cells observed: fibroblasts, mast cells, macrophages and pericytes. Lymphatic ICLCs were localized to the subendothelial region of the wall as well as in intimate association with smooth muscle bundles throughout the media. ICLCs were morphologically distinct with multiple processes and also spindle shapes. Confocal imaging with calcium-dependent fluorophores corroborated cell morphology and localization observed in fixed tissues. Lymphatic ICLCs thus constitute a significant cell type of the human TD and physically interact with lymphatic SMCs., (Copyright © 2012 S. Karger AG, Basel.)

Recurrent copy number variants (CNVs) are found in a significant proportion of patients with congenital heart disease (CHD) and some of these CNVs are associated with other developmental defects. In some syndromic patients, CHD may be the first presenting symptom, thus screening of patients with CHD for CNVs in specific genomic regions may lead to early diagnosis and awareness of extracardiac symptoms. We designed a multiplex ligation-dependent probe amplification (MLPA) assay specifically for screening of CHD patients. The MLPA assay allows for simultaneous analysis of CNVs in 25 genomic regions previously associated with CHD. We screened blood samples from 402 CHD patients and identified 14 rare CNVs in 13 (3.2%) patients. Five CNVs were de novo and six where inherited from a healthy parent. The MLPA screen led to early syndrome diagnosis in two of these patients. We conclude that the MLPA assay detects clinically relevant CNVs and suggest that it could be used within pediatric cardiology as a first tier screen to detect clinically relevant CNVs and identify syndromic patients at an early stage., (Copyright © 2012 Wiley Periodicals, Inc.)

Background and Aim of the Study: The preservation of aortic root dynamics is considered important for the durability of aortic valve bioprostheses. Stentless heart valves are believed to support physiologic biomechanics. To date, dynamic analysis has been limited to the full root prosthesis, and exclusively in the radial direction. The study aim was to investigate and compare the radial and longitudinal aortic root distensibilities of subcoronary stentless valves, and of stented and native pig valves., Methods: Stented pericardial (Mitroflow) or stentless (Solo, Toronto SPV) valve prostheses, or native porcine valves, were investigated in 32 pigs. Postoperatively, 12 sonomicrometry crystals were placed on the aortic root in order to measure aortic root distensibility, in both radial and longitudinal directions., Results: Sonomicrometry data were obtained from 23 pigs (72%). At the annular level, the native and Solo valves were significantly more distensible in a radial direction than the Mitroflow valve (p = 0.04). However, at the level of the sinotubular junction (STJ), commissures and aorta, the native valve was significantly more distensible than all of the artificial valves (p = 0.006, p = 0.006, and p = 0.02, respectively). The Solo valve exhibited less longitudinal distensibility than the Toronto SPV and Mitroflow valves. The Toronto SPV initiated a radial expansion at the STJ significantly later in the cardiac cycle than did both the Solo and native valves (p = 0.03), but showed no difference compared to the Mitroflow valve. Longitudinal expansion between the annulus and the STJ started significantly earlier for the Solo valve than for both the Toronto SPV (p = 0.03) and Mitroflow (p = 0.02) valves., Conclusion: The Solo valve proved to be superior in maintaining annular distensibility immediately following implantation when compared to the Mitroflow valve. The Solo valve did not, however, preserve longitudinal distensibility as well as the other investigated valves. Finally, the Solo valve appeared to provide a more physiologic aortic root expansion pattern than its prosthetic counterparts.

Estimates of the prevalence of congenital heart defects (CHD) have been published over many years and from many regions. As they are based on different definitions of which cases to include in the CHD prevalence, published prevalence estimates vary substantially. With the increasing use of echocardiography in neonatal intensive care, a patent ductus arteriosus (PDA) or flow over the atrial septum will often be visible. These findings may be coded as CHD at discharge and in this way falsely increase the CHD prevalence in the population. There are several purposes for which population-based data on CHD may be used: etiology, planning of treatment, or obtain information on outcome, including mortality. For etiology studies, it is important to include terminations of pregnancy as well as all births with CHD. For mortality studies in live births, inclusion of preterm born infants with PDA will increase overall mortality of CHD. The Danish Register of Congenital Heart Disease is based on hospital discharge diagnoses and diagnoses from outpatient visits. To increase the validity of these data, extensive data cleaning has been carried out based on record review and knowledge on the discharge coding practice. We include PDA and atrial septal defects as CHD cases if these defects are still open 2 months after birth. International consensus on how to define CHD would improve the validity and comparability of epidemiological studies on CHD., (© 2011 Wiley Periodicals, Inc.)

Background: Extracellular matrix alterations are important elements in the arterial changes seen in diabetes, being associated with increased vascular stiffness and the development of cardiovascular diseases. However, no biomarkers for diabetes-related arterial changes have been defined., Methods: Mammary artery specimens from 17 men with type 2 diabetes and 18 nondiabetic individuals were used for microarray expression profiling, quantitative real-time PCR, immunoassay, and immunohistochemical analyses. A derived candidate marker, fibulin-1, which is an elastin-associated matrix molecule, was measured immunochemically in plasma from (a) 70 patients scheduled for vascular surgery, (b) 305 patients with type 2 diabetes examined with carotid ultrasonography and echocardiography, and (c) 308 patients with type 2 diabetes, followed for 15 years., Results: The most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes encoded the extracellular matrix protein, fibulin-1. Higher concentrations of fibulin-1-protein were present in artery extracts from patients with diabetes than extracts from individuals without diabetes, and increased fibulin-1 immunostaining was apparent around the external elastic lamina of diabetic arteries. Patients with diabetes displayed increased plasma concentrations of fibulin-1 (P = 0.006). Plasma fibulin-1 concentrations correlated with hemoglobin A(1c) (P < 0.001), arterial stiffness indices including pulse pressure (P < 0.001), and carotid compliance (P = 0.004), as well as plasma N-terminal pro-B-type natriuretic peptide concentrations (P < 0.001) and were predictive of 15-year mortality (P = 0.013)., Conclusions: Fibulin-1 accumulates in the arterial wall and in plasma of patients with type 2 diabetes, and appears to be a factor associated with arterial extracellular matrix changes in type 2 diabetes.

Background: Aminoglycoside treatment has been associated with nephrotoxic effects. However, the effect of perioperative aminoglycoside treatment on the risk of acute kidney injury requiring dialysis among patients undergoing cardiac surgery remains uncertain., Methods: We performed a register study based on prospectively collected data from population-based health care databases of 3625 consecutive patients undergoing cardiac surgery at the Aarhus University Hospital, Skejby, Denmark. Patients requiring preoperative dialysis were excluded, leaving a total of 3587 patients (99% of original patient cohort), of whom 89 received perioperative aminoglycosides., Results: The cumulative risk of in-hospital dialysis-dependent acute kidney injury was 3.2% (n = 115). Perioperative use of aminoglycosides was associated with an increased risk of postoperative dialysis (adjusted odds ratio [OR], 4.41; 95% confidence interval [CI], 1.83-10.59). Other predictors included reoperation because of bleeding (adjusted OR, 2.80; 95% CI, 1.63-4.80), use of inotropic support during anesthesia (adjusted OR, 2.10; 95% confidence interval, 1.49-2.95), and cardiopulmonary bypass lasting longer than 120 minutes (adjusted OR, 1.95; 95% CI, 1.19-3.20) along with EuroSCORE variables. Postoperative dialysis was associated with higher 30-day mortality (10.9% vs 2.5%, P < .0001, χ(2) test), but use of aminoglycosides was not independently associated with mortality., Conclusions: Perioperative use of aminoglycosides in adults undergoing cardiac surgery was associated with increased risk of postoperative dialysis., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Regions of turbulence downstream of bioprosthetic heart valves may cause damage to blood components, vessel wall as well as to aortic valve leaflets. Stentless aortic heart valves are known to posses several hemodynamic benefits such as larger effective orifice areas, lower aortic transvalvular pressure difference and faster left ventricular mass regression compared with their stented counterpart. Whether this is reflected by diminished turbulence formation, remains to be shown. We implanted either stented pericardial valve prostheses (Mitroflow), stentless valve prostheses (Solo or Toronto SPV) in pigs or they preserved their native valves. Following surgery, blood velocity was measured in the cross sectional area downstream of the valves using 10MHz ultrasonic probes connected to a dedicated pulsed Doppler equipment. As a measure of turbulence, Reynolds normal stress (RNS) was calculated at two different blood pressures (baseline and 50% increase). We found no difference in maximum RNS measurements between any of the investigated valve groups. The native valve had significantly lower mean RNS values than the Mitroflow (p=0.004), Toronto SPV (p=0.008) and Solo valve (p=0.02). There were no statistically significant differences between the artificial valve groups (p=0.3). The mean RNS was significantly larger when increasing blood pressure (p=0.0006). We, thus, found no advantages for the stentless aortic valves compared with stented prosthesis in terms of lower maximum or mean RNS values. Native valves have a significantly lower mean RNS value than all investigated bioprostheses., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Pregnancy in women with prosthetic heart valves remains a risk factor for both mother and fetus, but unselected and unbiased outcome and complication data remain scarce. We analyzed nationwide outcome data from 1977 to 2007 for all pregnancies in women with prosthetic valves., Methods: Cardiac, obstetric, and neonatal data were obtained from obligatory databases and compared with general female population data. Questionnaires were used to corroborate important information. Outcome data were analyzed according to type of anticoagulation used. The data were compared between the two first and the last decades of the study period. In the last decade, patients were compared to an age-adjusted selected population of healthy, pregnant women., Results: Of 356 women between 15 and 40 years of age, 79 women had 155 pregnancies after valve replacement. Two women died during pregnancy, one from heart failure and one from post-partum bleeding. There were four thrombo-embolic episodes in the early study period in women with mitral prosthesis on unfractionated heparin. Important cardiac complications were otherwise almost absent. There were significantly more early miscarriages and terminations in patients compared with controls (last decade 34%, vs 20% (p=0.0036) and 26% vs 13% (p=0.000019)). Post-partum bleeding was more common in the patient group (p=0.0021). Two late fetal losses (one from intracerebral bleeding) were seen. The remaining pregnancies resulted in 60 live births. Cesarean section was the predominant method of delivery in patients as opposed to controls (55% vs 16%, p=0.000000000097). Premature births were more frequent in patients (49% vs 5.5%, p=0.00000000039) as were congenital malformations (14% vs 5.7%, p=0.044). Two of the six malformations were warfarin embryopathy (8% of all first-trimester warfarin exposures), both seen in high-risk patients on high warfarin dosing. Small for gestational age did not differ significantly from the general population (9.3% vs 6.0%, p=0.39)., Conclusion: Data acquired over 30 years confirm that women with prosthetic heart valves, especially aortic prostheses for congenital lesions, generally tolerate pregnancy well, although cardiac mortality, mortality related to anticoagulation and thrombo-embolic risks are raised. Our data provide further documentation on the significance and importance of the risks associated with predominantly warfarin-based treatment regimens, which still remains optional for a number of patients. Finally, the data also serve as a comparison for recently published series based on low-molecular-weight heparin (LMWH) regimens., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

The force-frequency relationship (FFR) reflects alterations in intracellular calcium cycling during changing heart rate (HR). Tachycardia-induced heart failure is associated with depletion of intracellular calcium. We hypothesized (1) that the relative resistance to tachycardia-induced heart failure seen in neonatal pigs is related to differences in calcium cycling, resulting in different FFR responses and (2) that pretreatment with digoxin to increase intracellular calcium would modifies these changes. LV +dP/dt was measured during incremental right atrial pacing in 16 neonatal and 14 adult pigs. FFR was measured as the change in +dP/dt as HR was increased. Animals were randomized to control or intravenous bolus digoxin (n = 8 neonate pigs in the 0.05 mg/kg group and n = 7 adult pigs in the 0.025 mg/kg group) and paced for 90 min at 25 bpm greater than the rate of peak +dP/dt. Repeat FFR was then obtained. The postpacing FFR in neonatal control pigs shifted rightward, with peak force occurring 30 bpm greater than baseline (P < 0.03). There was no vertical shift; thus, force at 150 bpm decreased (P < 0.03) and force at 300 beats/min increased (P < 0.08). In adult control pigs, FFR shifted downward (P < 0.01), with decreased force generation at all HRs. In both neonates and adult pigs, digoxin increased +dP/dt at all HRs; however, in neonate pigs digoxin decreased the contractile reserve by abrogation of the rightward shift of FFR. An adaptive response to tachycardia in the neonate pig leads to improved force generation at greater HRs. Conversely, the response of the mature pig heart is maladaptive with decreased force generation. Pretreatment with digoxin modifies these responses.

The current study characterizes the mechanical properties of the human thoracic duct and demonstrates a role for adrenoceptors, thromboxane, and endothelin receptors in human lymph vessel function. With ethical permission and informed consent, portions of the thoracic duct (2-5 cm) were resected and retrieved at T(7)-T(9) during esophageal and cardia cancer surgery. Ring segments (2 mm long) were mounted in a myograph for isometric tension (N/m) measurement. The diameter-tension relationship was established using ducts from 10 individuals. Peak active tension of 6.24 +/- 0.75 N/m was observed with a corresponding passive tension of 3.11 +/- 0.67 N/m and average internal diameter of 2.21 mm. The equivalent active and passive transmural pressures by LaPlace's law were 47.3 +/- 4.7 and 20.6 +/- 3.2 mmHg, respectively. Subsequently, pharmacology was performed on rings from 15 ducts that were normalized by stretching them until an equivalent pressure of 21 mmHg was calculable from the wall tension. At low concentrations, norepinephrine, endothelin-1, and the thromboxane-A(2) analog U-46619 evoked phasic contractions (analogous to lymphatic pumping), whereas at higher contractions they induced tonic activity (maximum tension values of 4.46 +/- 0.63, 5.90 +/- 1.4, and 6.78 +/- 1.4 N/m, respectively). Spontaneous activity was observed in 44% of ducts while 51% of all the segments produced phasic contractions after agonist application. Acetylcholine and bradykinin relaxed norepinephrine preconstrictions by approximately 20% and approximately 40%, respectively. These results demonstrate that the human thoracic duct can develop wall tensions that permit contractility to be maintained across a wide range of transmural pressures and that isolated ducts contract in response to important vasoactive agents.

A flexible aortic root is essential for natural leaflet stress distribution. It is suggested that stentless bioprosthetic valves retain the flexibility of native valves. We investigated aortic root distensibility and cross-sectional area (CSA) in stentless (Solo, n=4; Toronto SPV, n=7), stented (Mitroflow, n=8) and in native valves (n=8) in pigs. Magnetic resonance imaging was performed to assess aortic root areas. At the annular level the Solo valve had a larger CSA (2.83+/-0.26 cm(2)) than both the Mitroflow (2.24+/-0.23 cm(2)) and Toronto SPV (1.87+/-0.59 cm(2)) (P=0.003; P=0.01). At the sino-tubular junction the Mitroflow valve had a significantly larger CSA (2.96+/-0.80 cm(2)) than the Toronto SPV (2.05+/-0.47 cm(2); P=0.02). At the annular level the percentage change in area between end-diastole and end-systole was lower for the Mitroflow than for all the other valves (P=0.006). No difference was found between native and stentless valves. In conclusion, the Solo valve had a larger CSA at the annulus than both the Mitroflow and the Toronto SPV. However, the stentless valves had a smaller CSA at the sino-tubular junction than the Mitroflow. We, furthermore, found that implantation of stentless heart valves preserves aortic root distensibility at the annular level in pigs.

The right ventricle (RV) tolerates acute pulmonary valvular regurgitation fairly well, however, in the long-term dilatation and failure often ensues. There is little known of the structural and functional myocardial alterations following this pathophysiology, and therefore animal models are sought. We aimed to develop an animal experimental model for RV dilatation emphasizing feasibility, reproducibility and human compatibility. Free pulmonary valve insufficiency and RV dilatation were created with a novel external suture plication technique in nine 5 kg piglets. Six matched animals served as controls. After 10 weeks cardiac dimensions and physiology were assessed with in vivo cardiovascular MRI and conductance technique. RV end-diastolic volume increased 31% in the intervention group (P=0.03). The regurgitation fraction was 37% in the intervention group compared to -2% in controls (P<0.001). Conductance measurements showed preserved RV contractile function, but significant left ventricular diastolic impairment. This study is the first to show that pulmonary valve regurgitation, RV dilatation and functional impairment can be achieved by external leaflet plication. Compared to known methods, the advantages of this model are: 1) no induction of stenosis over time, 2) no risk of stent migration, and 3) very simple and reproducible.

Background and Aim of the Study: Abnormal flow conditions across aortic bioprosthetic valves may result in degenerative processes. Thus, it is important to implant biological valve prostheses with velocity profiles similar to those of native valves. The study aim was to compare blood velocity and velocity gradient profiles downstream of stented and stentless aortic valves implanted in pigs, and in native porcine valves., Methods: Stented valve prostheses (Mitroflow, n = 7) or stentless valve prostheses (Solo, n = 5 or Toronto SPV, n = 7) were implanted into pigs; the native valve was retained in eight animals. After weaning the animals from cardiopulmonary bypass, cardiac magnetic resonance imaging was performed to determine the blood velocities and velocity gradient profiles., Results: The native valves had a significantly lower peak velocity (92 +/- 26 cm/s) than the artificial valves (Solo: 247 +/- 107 cm/s; Toronto: 252 +/- 41 cm/s; Mitroflow: 229 +/- 18 cm/s). The native valves exhibited a flat velocity profile during systole, whereas the Solo valve, and especially the Toronto SPV valve, displayed more parabola-shaped velocity profiles; velocity profiles downstream of the Mitroflow valve exhibited a flat shape. The native valves had a lower mean velocity gradient at peak systole (p < 0.0001). The velocity gradient percentage above mean was lowest for the native valve (0.14 +/- 0.11; p < 0.0001), while the Mitroflow valve had a percentage of 0.57 +/- 0.09, which was lower than the Solo valve (0.69 +/- 0.12; p = 0.074), and significantly lower than the Toronto valve (0.70 +/- 0.08; p = 0.015). All valves displayed high velocity gradients adjacent to the aortic wall; in particular, the Toronto SPV which also had high velocity gradients at the center of the vessel., Conclusion: All of the artificial valves tested had a significantly higher mean velocity gradient and peak velocity than the native valves. However, the Mitroflow had a mean velocity and a velocity gradient percentage lower than the two stentless valves. The Solo and Mitroflow valves displayed velocity profiles most like native valves, while the Toronto valve had a more irregular asymmetric velocity profile.

Background: Chronic pain is common after thoracotomy with reported prevalence rates of 20-60%. The pain may be caused by damage to the intercostal nerves during surgery. Some studies have suggested that young age at the time of surgery reduces the risk of developing chronic pain. So far, no studies have examined if children and adolescents develop chronic pain after thoracotomy., Methods: Eighty-eight patients, mean (sd) age 39.3 (7.7) yr, who underwent thoracotomy between the age of 0 and 25 yr were asked to recall the duration of postoperative pain and-if pain was still present-to describe intensity and character of pain. In addition, all patients underwent quantitative sensory testing., Results: Fourteen patients (16%) recalled that their postoperative pain had lasted for more than 3 months: one (3.2%) patient in the youngest group (0-6 yr), seven (19.4%) patients in the age group 7-12 yr, and six (28.5%) patients in the age group 13-25 yr (P=0.03). Three out of the 14 patients, who were 11, 11, and 18 yr of age at the time of surgery, still had pain at present. Quantitative sensory testing revealed hypo- and hyperphenomena in most patients, including those with persistent pain. Tactile detection thresholds and pressure detection thresholds were significantly higher on the operated side when compared with the contralateral side (n=88; P<0.001)., Conclusions: The risk of developing chronic pain after thoracotomy seems to be lower if surgery is performed at a young age. Pain after thoracotomy is likely to be of neuropathic origin.

The three-dimensional architecture of the right ventricular myocardium is a major determinant of function, but as yet no investigator-independent methods have been used to characterize either the normal or hypertrophied state. We aimed to assess and compare, using diffusion tensor magnetic resonance imaging, the normal architecture with the arrangement induced by chronic hypertrophy. We randomized 20 female 5 kg piglets into pulmonary trunk banding (N = 16) and sham operation (N = 4). Right ventricular hypertrophy was assessed after 8 weeks. The excised and fixed hearts were subject to diffusion tensor imaging to determine myocyte helical angles, and the presence of any reproducible tracks formed by the aggregated myocytes. All banding animals developed significant right ventricular hypertrophy, albeit that no difference was observed in terms of helical angles or myocardial pathways between the banded animals and sham group animals. Helical angles varied from approximately 70 degrees endocardially to -50 degrees epicardially. Very few tracks were circular, with helical angles approximating zero. Reproducible patterns of chains of aggregated myocytes were observed in all hearts, regardless of group. The architecture of the myocytes aggregated in the walls of the right ventricle is comparable to that found in the left ventricle in terms of endocardial and epicardial helical angles, however the right ventricle both in the normal and the hypertrophied state lacks the extensive zone of circular myocytes seen in the mid-portion of the left ventricular walls. Without such beneficial architectural remodelling, the porcine right ventricle seems unsuited structurally to sustain a permanent increase in afterload.

Introduction: Previously, the Mustard operation was the preferred surgical technique in patients with transposition of the great arteries. After this procedure the anatomical right ventricle remains the systemic ventricle, which entails long-term complications, especially heart failure. The Mustard-operated patients are now adults, and pregnancy has become an important issue. We assessed pregnancy and delivery data in a complete cohort of female patients who had previously undergone a Mustard procedure at Aarhus Hospital in the 1971-1991 period. The women giving birth were compared with those who did not., Material and Methods: Information on diagnosis, procedure, functional status, pregnancy, delivery and congenital heart disease in the off-spring were found in registers (The National Register of Health, The National Birth Register) and in medical records. Questionnaires were mailed to the 16 surviving women over 15 years of age., Results: Four women gave birth to nine children. Two women temporally had heart symptoms during pregnancy and delivery, but this caused no objective changes. The women who had children were older than those who did not. None of the children had congenital heart disease nor were they small for their gestational age., Conclusion: Pregnancy and delivery are well-tolerated in the vast majority of Mustard-operated women with no deterioration in functional class during or after pregnancy and delivery.

Although myocardial architecture has been investigated extensively, as yet no evidence exists for the anatomic segregation of discrete myocardial pathways. We performed post-mortem diffusion tensor imaging on 14 pig hearts. Pathway tracking was done from 22 standardized voxel groups from within the left ventricle, the left ventricular papillary muscles, and the right ventricular outflow tract. We generated pathways with comparable patterns in the different hearts when tracking from all chosen voxels. We were unable to demonstrate discrete circular or longitudinal pathways, nor to trace any solitary tract of myocardial cells extending throughout the ventricular mass. Instead, each pathway possessed endocardial, midwall, and epicardial components, merging one into another in consistent fashion. Endocardial tracks, when followed towards the basal or apical parts of the left ventricle, changed smoothly their helical and transmural angulations, becoming continuous with circular pathways in the midwall, these circular tracks further transforming into epicardial tracks, again by smooth change of the helical and transmural angles. Tracks originating from voxels in the papillary muscles behaved similarly to endocardial tracks. This is the first study to show myocardial pathways that run through the mammalian left and right ventricles in a highly reproducible manner according to varying local helical and transmural intrusion angles. The patterns generated are an inherent feature of the three-dimensional arrangement of the individual myocytes aggregated within the walls, differing according to the regional orientation and branching of individual myocytes. We found no evidence to support the existence of individual muscles or bands. Anat Rec, 2009. (c) 2008 Wiley-Liss, Inc.

Background: Limited data exist on the risk factors for acute renal failure (ARF) following cardiac surgery in children with congenital heart disease. This cohort study was conducted to examine this subject, as well as changes in the incidence of ARF from 1993 to 2002, the in-hospital mortality and the time spent in the intensive care unit (ICU)., Methods: One thousand, one hundred and twenty-eight children, operated on for congenital heart disease between 1993 and 2002, were identified from our prospectively collected ICU database to obtain data on potential risk factors., Results: A total of 130 children (11.5%) developed ARF after surgery. A young age [> or =1.0 vs. <0.1 year; odds ratio (OR), 0.23; 95% confidence interval (CI), 0.12-0.46], high Risk Adjusted Classification of Congenital Heart Surgery (RACHS-1) score (OR, 2.72; 95% CI, 1.66-4.45) and cardiopulmonary bypass (CPB) (<90 min vs. none; OR, 2.68; 95% CI, 1.03-6.96; > or =90 min vs. none; OR, 12.94; 95% CI, 5.46-30.67) were independent risk factors for ARF. The risk of ARF decreased during the study period. Children with ARF spent a significantly longer time in the ICU (2-7 days vs. <2 days, P = 0.002; > or =7 days vs. <2 days, P < 0.001) compared with non-ARF patients, and showed increased in-hospital mortality (20% vs. 5%, P < 0.001)., Conclusion: A young age, high RACHS-1 score and CPB were independent risk factors for ARF after surgical procedures for congenital heart disease in children. The risk of ARF decreased during the study period. Children with severe ARF spent a longer time in the ICU, and the mortality in ARF patients was higher than that in non-ARF patients.

The surgical reconstruction of the aortic arch is necessary in pediatric patients suffering from different types of congenital heart malformations, in particular, coarctation of the aorta. Among the reconstruction techniques used in surgical practice end-to-end anastomosis (E/E), Gore-tex graft interposition (GGI) and Gore-tex patch graft aortoplasty (GPGA) are compared in this study with a control model, employing a computational fluid-structure-interaction scheme. This study analyzes the impact of introducing synthetic materials on aortic hemodynamics and wall mechanics. Three-dimensional (3D) geometries of a porcine aortic arch were derived from magnetic resonance imaging (MRI) images. Inlet conditions were derived from MRI velocimetry. A multiscale approach was used for the imposition of outlet conditions, wherein a lumped parameter net provided an active afterload. Evidence was found that ring-like repairs increased blood velocity, whereas GPGA limited it. Vortex presence was greater and longer lasting in GGI. The highest power losses corresponded to GPGA. GGI had an intermediate effect, while E/E dissipated only slightly more than the control case. Wall stresses peak in a longitudinal strip on the subject's left side of the vessel, particularly in the frontal area. There was a concentration of stress at the suture lines. All surgical techniques performed equally well in restoring physiological pressures.

Objective: We reviewed our experience with mechanical valves inserted between 1988 and 2002 in children aged 15 years or younger., Methods: Hospital files were extracted retrospectively. Follow-up was completed by March 2005., Results: Of 41 patients, we inserted a valve in atrioventricular position in 27 children, having a median age of 3.1 years, ranging from 0.4 to 14.5 years, and in aortic position in the remaining 14, having a median age of 13.5 years, and a range from 7.0 to 14.9 years. For the valves inserted in atrioventricular position, the underlying disease was congenital in 23, rheumatic in two, post-endocarditic in one, and Marfan's syndrome in one. Mean follow-up was 7.7 years, with standard deviation of 5.3, giving a total follow-up of 209 patient years. Mortality at 30 days was 7%, and survival was 73% at up to 16 years follow-up. Events related to anticoagulation were seen in 3 patients, corresponding to 1.4% per patient year. In 6 patients (22%), heart block ensued which required implantation of a pacemaker treatment, and 5 patients (19%) had reoperations. For the implantations in aortic position, the underlying disease was congenital in 13, stenosis in 10 and insufficiency in three, and post-endocarditis in one. Mean follow-up was 6.8 years, with standard deviation of 4.6, giving a total of 95 patient years. We lost one patient within 30 days (7.7% mortality), and survival was 77% at up to 13 years follow-up. There were no incidents of thrombosis, nor events related to anticoagulation, but one patient (7%) needed insertion of a pacemaker due to a perioperative heart block, and one (7%) required new valvar replacement., Conclusions: Although preferably avoided, mechanical valves can be implanted in children with an acceptable mortality and morbidity, and good long-term results.

Background: Atrial tachycardia is very frequent after mitral valve surgery using the superior transseptal approach., Methods: Sixteen patients operated on for mitral valve disease (superior transseptal approach = Group A, n = 9, and left atrial approach = Group B, n = 7) underwent radiofrequency catheter ablation of atrial tachycardia guided by electroanatomic mapping. Twenty-six consecutive patients without previous cardiac surgery with typical atrial flutter served as controls (Group C)., Results: Atrial tachycardia occurred earlier after the operation in Group A than in Group B (median 97 vs 2,159 days, P = 0.003). Typical atrial flutter was the most frequent circuit in all groups (Group A-7 patients, Group B-5 patients, Group C-26 patients). Three patients in Group A developed right atrial incisional tachycardia. Ten of 14 tachycardia circuits (typical atrial flutter, n = 7, incisional tachycardia, n = 3) in Group A depended on the corridor between the right atrial part of the atriotomy and the tricuspid annulus. Slow conduction during typical atrial flutter was detected in this corridor in Group A, but not in the corresponding region in Groups B and C (P < 0.001). The cycle length of typical atrial flutter was longer in Groups A and B than in Group C (mean 283 ms and 282 ms vs 233 ms, P = 0.003). Patients in Group B with typical atrial flutter had larger right atria than patients in Group A or Group C (mean 156 mL vs 96 mL and 113 mL, P = 0.033)., Conclusions: The superior transseptal incision may predispose to atrial tachycardia by creating slow conduction between the atriotomy and the tricuspid annulus.

Objective: The Risk Adjusted classification for Congenital Heart Surgery (RACHS-1) was created in order to compare in-hospital mortality for groups of children undergoing surgery for congenital heart disease. The method was evaluated with two large multi-institutional data sets-the Paediatric Cardiac Care Consortium (PCCC) and Hospital Discharge (HD) data from three states in the USA. The RACHS-1 classification was later applied to a large German paediatric cardiac surgery population in Bad Oeynhausen (BO), where it was found that the RACHS-1 categories were also associated with length of stay. We applied the RACHS-1 classification to the 957 operations performed during January 1996 to December 2002 at Skejby Sygehus, Denmark and we examined the association between the RACHS-1 categories, in-hospital mortality and length of stay in the Intensive Care Unit., Methods: The operations were classified according to the six RACHS-1 categories by matching the procedure of each patient with a risk category. The ability of the RACHS-1 classification to predict mortality in our population was examined by estimating the area under the receiver operator characteristic (ROC) curve. Likelihood ratio chi(2) tests were used to compare the distribution of RACHS-1 categories and the distribution of mortality with PCCC, HD and BO. Linear regression was used to examine the correlation between the RACHS-1 categories and length of stay in the Intensive Care Unit., Results: The RACHS-1 category frequencies in our population were: category 1: 18.4%, category 2: 37.4%, category 3: 34.6%, category 4: 8.2%, category 5: 0% and category 6: 1.5%. The overall ability of the RACHS-1 classification to predict in-hospital mortality (area under the ROC curve 0.741; 95% confidence interval=0.690; 0.791) was equal to the findings from larger populations. We found no differences in the category specific mortality when comparing with the larger reported series. There was a positive association between RACHS-1 category and length of stay in the Intensive Care Unit., Conclusions: The RACHS-1 classification can also be used to predict in-hospital mortality and length of stay in the Intensive Care Unit in a small volume centre.

Objective: Although earlier a feared complication of congenital cardiac surgery, the incidence of heart-block and sinus node dysfunction has been lowered to 1-4% due to improved surgical techniques and better anatomical understanding of the cardiac conduction system. Development of feasible pacemaker technologies has further lowered mortality and morbidity. However, pacemaker implantation in paediatric patients is in itself associated with significant morbidity due to pacemaker system failure and replacement. The aim of the present study was to examine prognostic factors of mortality, failure of systems and timing of implantation after surgery in post-surgical pacemaker patients., Methods: We carried out a historical prospective follow-up analysis of all patients (age less than 18 years) who underwent pacemaker implantation due to post-surgical heart-block or sinus node dysfunction in the period 1981-2002 at our institution. Data was extracted from the Danish Pacemaker Register and hospital records. Kaplan-Meier survival time estimates and Cox proportional hazards analysis (Relative Risk, RR) were used to identify prognostic factors., Results: High RACHS score (RR, 16.57), low age at implantation (RR, 0.22), low age at operation (RR, 0.06) and epicardial lead (RR, 0.18) were significant predictors for early mortality. Similarly, high RACHS score (RR, 4.84), low age at implantation (RR, 0.32), low age operation (RR, 0.38) and epicardial lead (RR, 0.40) were significant predictors failure of 1st pacemaker system., Conclusions: We identified a number of prognostic factors of patient mortality and failure of systems. One factor, high RACHS score, was previously shown to predict mortality and length of ICU stay in paediatric cardiac surgery; however, this study is the first to show a correlation between RACHS score and mortality as well as failure of pacemaker systems. This may have future implications for preoperative risk stratification of patients and counselling of parents to patients with congenital heart disease.

Objectives: The purpose of this study was to compare atrial tachycardia circuits after a range of cardiac operations., Background: Knowledge of circuits occurring in a given postsurgical substrate should help to ablate these challenging tachycardias and develop potential preventive strategies., Methods: We analyzed tachycardia circuits in 83 consecutive patients (60 males; median age 47 years, range 9-73) after atrial incisions undergoing ablation of atrial tachycardias. A combined strategy of electroanatomic (CARTO) and entrainment mapping was used. Fifty-two patients (63%) underwent operation for congenital and 31 (37%) for acquired heart disease. Patients were divided into subgroups based on the intervention performed in the atria: right lateral atriotomy (39 patients), left atrial (11) and superior transseptal (10) approach to the mitral valve, biatrial heart transplantation (8), Mustard (8) and Fontan (4) procedure, and other interventions (3)., Results: Most of the 119 tachycardias mapped were isthmus-dependent atrial flutter (66) and incisional tachycardia (30). Isthmus-dependent atrial flutter was the most frequent arrhythmia in all subgroups except for Fontan patients, in whom incisional tachycardia was most frequent. The distribution of tachycardia circuits did not differ significantly among groups., Conclusions: The observed circuits did not differ among the postsurgical substrates. Isthmus-dependent atrial flutter should be the first circuit considered in patients after atrial incisions.

Background: Fetal tachycardia often leads to cardiac failure, which in experimental settings can be prevented by direct fetal glucose-insulin administration. In this study, we hypothesize that similar effects can be obtained indirectly by inducing maternal hyperglycemia., Methods and Results: Systolic and diastolic indices (dP/dt(max) and tau) of left ventricular function were measured by use of high-fidelity catheters during 180 minutes of aggressive atrial pacing ( approximately 300 bpm) in 12 preterm porcine fetuses. In 6 fetuses, maternal hyperglycemia (15 mmol/L) was induced for the last 120 minutes of pacing. The remaining fetuses served as controls. Glucose, insulin, and free fatty acid levels were determined, as was fetal myocardial glycogen content. Maternal glucose infusion led to significant fetal hyperglycemia and hyperinsulinemia but did not change the inherently low fetal levels of free fatty acids. There were no differences between groups with regard to dP/dt(max) (1025+/-226 and 1037+/-207 mm Hg, P=NS) and tau (20.6+/-2.0 and 21.4+/-1.6 ms, P=NS) at baseline (100%). During the 180 minutes of pacing, systolic function (dP/dt(max)) and diastolic function (tau) deteriorated more in the control group than in the hyperglycemic group (P<0.001 for both). At 180 minutes, dP/dt(max) was 62+/-18% of baseline in controls and 85+/-11% in hyperglycemic fetuses (P=0.03), and tau was 117+/-12% and 98+/-4%, respectively (P=0.004)., Conclusions: Induced maternal hyperglycemia improves fetal cardiac function during fetal tachycardia and suggests a possible additional therapeutic option to improve the function of the failing fetal heart before or during antiarrhythmic therapy. The findings may be relevant in fetal heart failure in general.

Background: Animal experimental testing is imperative for preclinical evaluation of prosthetic heart valves and implantation techniques. Because human and pig cardiovascular structures including mitral valves show remarkable anatomical similarity, these animals are good candidates for preclinical testing. Previous attempts to establish such long-term models were hampered by both intra- and postoperative difficulties. Our aim was to overcome these difficulties to develop a porcine model for mitral valve replacement (MVR) and furthermore to investigate the practical feasibility of 3 chordal reconstruction procedures., Methods: Sixteen 60-kg pigs were allocated to undergo 1 of 3 surgical procedures, (1) preservation of the entire subvalvular apparatus (n = 8), (2) preservation of the secondary chordae only (n = 4), or (3) excision of the native valve and papillary resuspension with sutures (n = 4). St. Jude Medical valves (29 mm) were implanted during extracorporeal circulation and cold cardioplegic arrest. Postoperative anticoagulation was administered by subcutaneous heparin injections., Results: Fourteen animals survived 1 month, thriving and without signs of heart failure. One animal was euthanized due to irreversible bleeding in the tracheal tube, and another animal died on the third postoperative day owing to valve thrombosis., Conclusion: A practically feasible long-term porcine model of MVR has been established. Because the pig is superior to other species with respect to anatomical and physiological similarity to humans, we consider this model as an optimal platform for experimental preclinical testing of heart valve prostheses.

Bilateral empyema is a rare condition in children. In the current era of minimally invasive surgical treatment, our experience with two cases suggests that video thoracoscopic drainage and decortication for children with bilateral empyema is safe, effective, and potentially less expensive.

Objectives: The aim of this work was to study the effects of substrate deficiency and supplementation on cardiac function during fetal tachycardia., Background: Although sustained fetal tachycardia may lead to cardiac failure and intrauterine death, neonatal tachycardia is generally better tolerated. Fetal myocardial energy production relies almost solely on glucose as substrate. We hypothesized that increased substrate availability by glucose-insulin (GI) infusion would improve fetal myocardial responses to tachycardia., Methods: We used three porcine models: 1) an isolated fetal heart model; 2) an in vivo fetal model; and 3) an in vivo closed-chest neonatal model. Each animal was randomized to control or GI treatment during tachycardia. In model 1, the controls were perfused with conventional Krebs-Henseleit solution containing a glucose concentration of 5.5 mmol/l; the GI hearts received double glucose concentration and added insulin. In models 2 and 3, the GI animals received insulin in a 20% glucose solution. All hearts were exposed to 90 min of pacing at 250 to 330 beats/min., Results: The isolated fetal hearts in the GI group showed no decline in dP/dt(max) during pacing, while the controls declined. In the in vivo fetal hearts, dP/dt(max) remained unchanged in the GI group and decreased significantly in the control group. Myocardial glycogen content was higher in the GI group than in controls. Functional indexes remained unchanged among both neonatal groups despite a higher glycogen content in the GI group., Conclusions: Glucose-insulin infusion during fetal tachycardia has a beneficial effect on myocardial metabolism and cardiac function. These observations may have direct clinical relevance to the management of fetal arrhythmia.

The aim was to investigate if organ dysfunction is a consequence of cell accumulation in the tissue and whether this accumulation is caused by the cardiopulmonary bypass (CPB) procedure. Twenty-six piglets were used in the sham group (sternotomy, n=12) or in the CPB group (sternotomy, CPB, n=14). Isotope-labeled autologous (99m)Tc-neutrophils (PMNs) and (111)In-platelets were infused and dynamically followed at organ level with a gamma camera before, during, and 4 h after termination of CPB. The CPB group showed a 49% increase in (99m) Tc-PMNs in the kidneys in the postoperative period compared to a decrease of 2% in the sham group. A less marked decrease was observed in the lungs and peripheral blood between the two groups. The increased radioactivity at organ level post-CPB could be due to changes in flow, extraction in the organ or accumulation of cells, especially in the kidneys and lungs, and might contribute to temporary organ dysfunction postoperatively.

Background: Little is known about blood flow and its relationship to respiration during exercise in patients with total cavopulmonary connection (TCPC)., Methods and Results: We studied 11 patients 12.4+/-4.6 years (mean+/-SD) of age 5.9+/-2.8 years (mean+/-SD) after TCPC operation. Real-time MRI was used to measure blood flow in the superior vena cava (SVC), inferior vena cava (IVC), and ascending aorta under inspiration and expiration during supine lower-limb exercise (rest, 0.5 and 1.0 W/kg) on an ergometer bicycle. IVC and aortic flow increased from 1.60+/-0.52 and 2.99+/-0.83 L/min per m2 at rest to 2.58+/-0.71 and 3.97+/-1.20 L/min per m2 at 0.5 W/kg and to 3.25+/-1.23 and 4.62+/-1.49 L/min per m2 at 1.0 W/kg (P< or =0.05). SVC flow remained unchanged. Resting flow in the IVC was greater during inspiration (2.99+/-1.25 L/min per m2) than during expiration (0.83+/-0.44 L/min per m2) (inspiratory/mean flow ratio, 1.9+/-0.5), and retrograde flow was present during expiration (11+/-12% of mean flow). The predominance of inspiratory flow in IVC diminished with exercise to an inspiratory/mean flow ratio of 1.5+/-0.2 (P< or =0.05) and 1.4+/-0.3 at 0.5 and 1.0 W/kg, respectively., Conclusions: In the TCPC, circulation IVC and aortic but not SVC flows increase with supine leg exercise. Inspiration facilitates IVC flow at rest but less so during exercise, when the peripheral pump seems to be more important.

Background: Plasma concentrations of inflammatory markers are increased in response to the trauma of cardiac surgery and cardiopulmonary bypass (CPB). It is, however, unknown whether the plasma cytokine levels and cytokine mRNA expression at organ level reflect each other., Methods: Twenty-six piglets (17-19 days) were allocated to the sham-group (sternotomy only, n = 13) or to the CPB-group (sternotomy, 120 min CPB procedure with 60-min aortic cross-clamp, n = 13). The pigs were observed for 0.5 h or 4 h post-CPB. Plasma levels of IL-1beta, IL-6, IL-8 and IL-10 and mRNA expression of TNF-alpha, IL-1beta, IL-6, IL-8, IL-10 and iNOS in organs were registered with concomitant changes in oxygenation index (OI) and expiratory nitric oxide (NO)., Results: In pigs killed 0.5 h post-CPB there was a significant increase in IL-10 mRNA in the lungs and kidneys compared with the sham-group. IL-1beta mRNA was detectable in the kidneys and lungs of the CPB-pigs, while IL-6 mRNA was up regulated only in lungs. In pigs killed 4 h post-CPB a significantly higher IL-6 mRNA was found in heart tissue and a lower IL-10 mRNA was found in lungs of CPB pigs compared with the sham-group. There was a concomitant significant increase in OI and increased plasma IL-8 and IL-10 concentrations in the CPB-pigs compared with the sham-pigs., Conclusion: The cytokine mRNA expression pattern was very different for the pigs killed already 0.5 h after the CPB procedure compared with the pigs killed 4 h post-CPB. The plasma cytokine levels poorly reflected mRNA expression of the pro- and anti-inflammatory cytokines.

Objective: The optimal treatment of pediatric empyema remains controversial. The objective of this study is to compare the use of conventional management versus primary thoracoscopic drainage and decortication in children with empyema., Methods: Conventional management has consisted of chest drain insertion under general anesthesia plus intravenous antibiotics. Thoracoscopic drainage and decortication has consisted of primary thoracoscopic drainage and decortication plus antibiotics. The clinical course of 54 patients treated conventionally between 1989 and 1997 was compared with that of 21 patients treated by means of thoracoscopic drainage and decortication between September 2000 and September 2001., Results: Results of the study demonstrated that patients in the drainage-decortication group had fewer invasive interventions per patient than those in the conventional management group (1.0 vs 1.26). Patients undergoing thoracoscopic drainage and decortication also had significantly shorter durations of intravenous antibiotic therapy (7.6 +/- 1.2 vs 18.2 +/- 7.5 days), chest tube drainage (4.0 +/- 0.5 vs 10.2 +/- 6.1 days), and hospital stays (7.4 +/- 0.8 vs 15.4 +/- 7.4). Moreover, there were no open thoracotomies and decortications in the thoracoscopic drainage and decortication group, whereas in the conventional management group 39% (21/54) of patients underwent an open procedure., Conclusion: Although the 2 groups were not prospectively randomized and they were treated in different time periods, the results of this study support the use of thoracoscopic surgery as the primary therapeutic modality in children presenting with pleural empyema. This strategy appears to offer significant benefits over conventional treatment in terms of duration of treatment and the need for more invasive surgery.

Background: In neonatal pigs cardiopulmonary bypass (CPB) is associated with endothelial dysfunction in isolated large pulmonary arteries. It is, however, of great importance if this functional change extends to the small pulmonary resistance arteries, which are the key regulators of pulmonary flow and pressure. The aim of this study was to assess changes in pulmonary microvascular function after CPB using a clinically relevant pediatric procedure., Methods: From three groups of neonatal pigs (CPB-, sham- and control group) pulmonary resistance arteries and systemic resistance arteries (from skeletal muscle) were isolated and mounted as ring preparations in wire myographs. Vessel diameters were less than 500 microm. Concentration-response curves were constructed for norepinephrine (NA), vasopressin (Vp), and the thromboxane A2-analog U46619, while the endothelium-dependent and -independent vasodilator functions were assessed as responses to acetylcholine and nitric oxide (NO)., Results: Maximum pulmonary vasodilator response to acetylcholine was attenuated after CPB compared with sham-operated and control animals (P=0.04). NO-induced relaxation, and contractile responses to NA, Vp, and U46619 were not influenced by CPB. In systemic arteries no changes in contractile or relaxant responses were seen after CPB., Conclusion: CPB seems to induce pulmonary endothelial dysfunction in pulmonary but not peripheral resistance arteries in neonatal piglets.

Objective: To measure caval and pulmonary flows at rest and immediately after exercise in patients with total cavopulmonary connection (TCPC)., Design: An observational study using the patients as their own controls., Setting: Using a combination of magnetic resonance (MR) phase contrast techniques and an MR compatible bicycle ergometer, blood flow was measured in the superior vena cava, the tunnel from the inferior vena cava, and in the left and right pulmonary arteries during rest and on exercise (0.5 W/kg and 1.0 W/kg)., Patients: Eleven patients aged 11.4 (4.6) years (mean (SD)) were studied 6.3 (3.8) years after TCPC operation., Main Outcome Measures: Volume flow measured in all four branches of the TCPC connection during rest and exercise., Results: Systemic venous return (inferior vena cava plus superior vena cava) increased from 2.5 (0.1) l/min/m2 (mean (SEM)) to 4.4 (0.4) l/min/m2 (p < 0.05) during exercise, with even distribution to the two pulmonary arteries. At rest, inferior vena caval flow was higher than superior vena caval flow, at 1.4 (0.1) v 1.1 (0.1) l/min/m2 (p < 0.05). During exercise, inferior vena caval flow doubled (to 3.0 (0.3) l/min/m2) while superior vena caval flow only increased slightly (to 1.4 (0.1) l/min/m2) (p < 0.05). The increased blood flow mainly reflected an increase in heart rate. The inferior vena caval to superior vena caval flow ratio was 1.4 (0.1) at rest and increased to 1.8 (0.1) (p < 0.05) at 0.5 W/kg, and to 2.2 (0.2) at 1.0 W/kg (p < 0.05)., Conclusions: Quantitative flow measurements can be performed immediately after exercise using MR techniques. Supine leg exercise resulted in a more than twofold increase in inferior vena caval flow. This was equally distributed to the two lungs, indicating that pulmonary resistance rather than geometry decides flow distribution in the TCPC circulation.

Objective: The concept of self-management of oral anticoagulation has been shown to entail better quality of treatment than conventional management when assessed in selected adults. We have extended the concept of self-management to include children with congenital cardiac disease, hypothesizing self-management of oral anticoagulation is also possible in this subset of patients. Our aim was to assess the quality of self-management., Methods: We trained 14 children aged from 2.2 to 15.6 years, with a mean age of 9.7 years, and their parents, in domiciliary analysis of the International Normalized Ratio and necessary adjustment of dosage of coumarin. The curriculum for training lasted for 27 weeks, and the patients and their parents were followed for a period of up to 31 months by weekly measurement of the values obtained for the International Normalized Ratio., Results: The patients were observed over a mean of 547 days, with a range from 214 to 953 days. The patients were within the therapeutic targetted range of the International Normalized Ratio for a median of 65.5% of the time, with a range from 17.6% to 90.4%. None of the patients experienced thromboembolic or bleeding complications requiring doctoral intervention. All the patients and their parents expressed full satisfaction with the treatment., Conclusion: Self-management of oral anticoagulation provides a good quality of treatment, which is feasible and safe in selected children with congenital cardiac disease.

Background: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response and organ dysfunction, especially in children. Plasma concentration of inflammatory markers are increased in response to the trauma of cardiac surgery and CPB. The aim of the present study was to investigate whether the CPB procedure in itself elicits increased levels of inflammatory markers in neonatal pigs., Methods: The inflammatory response was measured in piglets undergoing sternotomy alone (sham group, n=13) or sternotomy and CPB (n=14). Inflammatory mediators were measured at baseline and at fixed time-points during and after CPB. IL-8, IL-10 and TNF-alpha levels and C-reactive protein (CRP) concentrations were measured in plasma samples. Polymorphonuclear neutrophils (PMN) chemotaxis was measured ex vivo, and CD-18 expression using an immunofluorescence technique., Results: Immediately after the CPB procedure increased IL-8 levels were found in the CPB group, but not in sham operated animals (P=0.005). Simultaneously, a marked IL-10 response was measured in the CPB group. Concurrently, PMN chemotaxis decreased in CPB animals but not in the sham group (P=0.04). CD-18 expression and CRP levels were not significantly different between groups and TNF-alpha showed no changes in either group. The chemotactic response did not correlate with plasma IL-8 or IL-10, nor with CD-18 expression., Conclusion: The CPB procedure elicited a systemic inflammatory response in terms of significantly elevated plasma levels of IL-8 and IL-10. Furthermore, a temporary and simultaneous decrease in PMN chemotaxis was observed immediately after CPB.

Objective: To evaluate platelet reactivity and coagulation markers after surgical palliation of univentricular hearts., Design and Patients: Cross sectional survey of 24 patients, median age 11 (range 4-22) years, at 2 (range 0.5-6) years after a total cavopulmonary connection (TCPC; n = 14) or a bidirectional Glenn anastomosis (Glenn; n = 10)., Main Outcome Measures: Platelet reactivity and/or coagulation markers were measured in 20 patients (four excluded because of anticoagulant treatment) and compared with 33 healthy controls, median age 12 (range 6-16) years., Results: None of the patients had clinically apparent thromboembolic events. However, increased platelet reactivity was observed ex vivo both after collagen induced platelet aggregation (median 73% (interquartile range 61-84%) in patients, and 61% (47-69%) in controls; p < 0.01), and after ADP induced platelet aggregation (69% (53-77%) in patients, and 56% (40-66%) in controls; p < 0.05). Concentrations of protein S antigen, antithrombin III, and protein C activity were reduced after both TCPC and Glenn. A concomitant decrease was seen in coagulation factor II, VII, X, and factor VII clot activity., Conclusions: Several abnormalities in the coagulation system were observed after bidirectional Glenn anastomosis, similar to alterations previously described in Fontan operated and TCPC patients. Antithrombotic treatment in these patients is still an unresolved issue, but aspirin is often recommended. This study shows that such a strategy is rational and the results suggest that antiplatelet treatment may be advantageous, either alone or in combination with oral anticoagulant treatment.

The parallel conductance volume, created by the conductivity of structures surrounding the ventricular blood pool, can be estimated by using a saline dilution technique. This paper examines the use of a novel volume reduction method, during a standard vena caval preload reduction maneuver, as an alternative to the routinely used saline dilution method to calibrate conductance catheter measurements in the left (LV) and right ventricle (RV) of animals and humans. The serial reproducibility of both methods was examined by measurement of percent difference, and by assessing the coefficient of repeatability 1) between two measurements within the same subject, 2) between the two techniques, and 3) interobserver variability. The effect of ventricular size and contractile state on the volume reduction technique was also observed. It was essential to ensure the technique was not affected by inotropic state. The volume reduction technique and saline dilution method were repeated at three different loading states (baseline, 5, and 10 microg x kg(-1) x min(-1) of dobutamine). The coefficient of repeatability between serial measurements was similar for both the volume reduction and saline dilution methods, and good interobserver variability was demonstrated. The volume reduction technique was compared with the saline dilution technique over a large range of ventricular sizes. No significant difference was observed in the RV or LV of adult humans or in the LV of neonatal pigs and children. There was no significant effect on either the saline dilution or the volume reduction technique as the inotropic state increased. In conclusion, the volume reduction technique is neither affected by ventricular size nor contractile state, is repeatable between different observers, and can be used to substitute the saline dilution method when preload reduction of the ventricle is being employed.

Introduction: The total cavopulmonary connection, and the bidirectional Glenn anastomosis, are widely used for palliation of patients with complex functionally univentricular hearts. Little attention has been paid to the potential for postoperative growth in children after these operations, which are now performed at increasingly younger age., Material and Results: Physical growth, and levels of insulin-like growth factor I in the serum, were measured in 20 patients, aged 11.5 +/- 5.6 years, 2 (0.5-6) years after a total cavopulmonary connection in 12, or a Glenn anastomosis in 8. All patients were in functional class I or II of the categorisation of the New York Heart Association, with excellent haemodynamic and angiographic findings. None of the patients had clinical signs of protein losing enteropathy. Controls included 33 healthy children, aged 11.5 +/- 2.7 years. Preoperatively, the mean Z-scores for weight and height were negative, -1.1 +/- 0.8 and -0.5 +/- 1.5. At follow-up, both parameters had improved significantly by 1.1 +/- 0.9 and 0.8 +/- 1.2 percentiles, and Z-scores were comparable between the two groups (p=0.81 for weight and p=0.88 for height). No correlations were found between haemodynamics and the improvement in growth noted during follow-up. Increases equal to, or greater than 2 standard deviations for weight and height were seen only in children undergoing surgery before the age of 5 years. A significant correlation between age at operation and improvement in growth, however, could not be found. Levels of growth factor measured in the serum were not statistically different from levels in healthy children for either group of patients (p=0.07 for girls and p=0.37 for boys)., Conclusion: Physical growth improved significantly following the surgical procedures. The concentrations of the growth factor measured in the serum were not different from levels in healthy children, suggesting normal nutritional status in both palliative situations.

Background: The purpose of the present study was to describe infarct size and platelet accumulation when reperfusion injury was combined with a thrombogenic lesion in the coronary artery. The left anterior descending artery was damaged in 11 pigs and subsequently occluded proximal to the lesion for 50 min, followed by 4 h of reperfusion., Results: The infarct size/area at risk was 40 (35 63)%. Infarct size correlated with troponin-T-3 h (p=0.85, p<0.002), but not with creatine kinase-3 h. Platelet aggregation decreased by 34% (p<0.01) at 15 min of reperfusion, but returned to baseline. Platelet accumulation in the left ventricle was significantly higher in the area at risk (194 (157-206)%) compared to the right ventricle (137 (120-142)%); p<0.05)., Conclusion: A decreased platelet reactivity and increased accumulation of platelets in the area at risk indicates that activated platelets become entrapped in the myocardium. Troponin-T was a better marker of myocardial damage than creatine kinase in this in vivo model with pigs.

Objective: To determine whether patients with cavopulmonary connection have higher levels of vasoactive/water-salt regulating hormones and if so, whether hormone levels are related to postoperative haemodynamics and postoperative follow up., Design: Cross sectional study., Setting: University hospital., Patients: 20 patients (New York Heart Association functional class I-II), mean age 11 years (range 4 to 22), were studied at a mean of 2 years (0.5 to 6) after a total cavopulmonary connection (TCPC, n = 12) or a bidirectional Glenn anastomosis (BDG, n = 8)., Interventions: Cardiac catheterisation was performed and blood samples were drawn. Control blood samples were drawn from 33 healthy children, mean age 12 years (6 to 16)., Main Outcome Measures: Plasma levels of angiotensin II, renin, aldosterone, arginine, vasopressin, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP)., Results: All neurohormones were significantly increased in both TCPC and BDG patients (p < 0. 05), with a fourfold increase in angiotensin II, renin, and aldosterone, and a twofold increase in vasopressin, ANF, and BNP (compared with healthy controls). There was no correlation between haemodynamic variables and hormone levels. Angiotensin II and renin were inversely correlated with time to follow up. All subjects over 15 years (n = 5) had normal neurohormonal levels., Conclusions: Neurohormones were raised for years after successful cavopulmonary operations but lower levels were observed with time on follow up. This supports the hypothesis that neurohormonal activation is primarily related to altered postoperative physiology and that adaptation takes place over time.

The effect of topical cod liver oil ointment on the rate of wound epithelialisation and neovascularisation was studied using the hairless mouse ear wound model (experiment I). The effect of local application of vitamin A in increasing concentrations was tested in the same model (experiment II). Experiment I: Bilateral standardised full thickness dermal wounds were created on the ears of 42 mice divided into three groups: group I: 25% cod liver oil ointment (n = 10) applied topically to one ear and vehicle (vaseline) to the other; group II: 25% cod liver oil ointment (n = 10) and saline; and group III: vehicle (n = 22) and saline. Experiment II: Using the same model and procedures wounds were made on 12 mice randomised to vitamin A treatment in various doses (250-3000 IU/g) on one ear and vehicle (vaseline) on the other ear. Using in-vivo microscopy and digitised planimetry, wound epithelialisation and neovascularisation were measured at regular intervals until the processes were complete. Wounds treated with 25% cod liver oil ointment epithelialized significantly (p < 0.05) faster (mean (SEM) 8.9 (0.7) days) than control ears treated with vehicle alone (13.9 (1.9) days). Neovascularisation developed significantly faster (p < 0.01) in the ears treated with cod liver oil ointment (22.5 (1.3) days) compared with their vehicle control (29.1 (0.6) days). Neovascularisation was also significantly (p < 0.05) faster in the ears treated with cod liver oil ointment (23.1 (1.4) days) than in those treated with saline (26.8 (1.1) days). There was no significant difference in speed of epithelialisation between cod liver oil ointment and saline. The vitamin A dose study showed that epithelialisation and neovascularisation of the vitamin A treated wounds pass at the same rate as wounds treated with cod liver oil ointment. In conclusion, topical 25% cod liver oil ointment significantly accelerated both the epithelial and the vascular component of healing compared with saline. Vitamin A seems to have an important role in accelerating wound healing and could be the active component in cod liver oil.

Background: Following neonatal open heart surgery a nadir occurs in left ventricular function six to 12 hours after cardiopulmonary bypass. Although initiated by intraoperative events, little is known about the mechanisms involved., Objective: To evaluate the involvement of nitric oxide in this late phase dysfunction in piglets., Design: Piglets aged 2 to 3 weeks (4-5 kg) underwent cardiopulmonary bypass (1 h) and cardioplegic arrest (0.5 h) and then remained ventilated with inotropic support. Twelve hours after bypass, while receiving dobutamine (5 microg/kg/min), the left ventricular response to non-selective nitric oxide synthase inhibition (l-N(G)-monomethylarginine (l-NMMA)) was evaluated using load dependent and load independent indices (E(es), the slope of the end systolic pressure-volume relation; M(w), the slope of the stroke work-end diastolic volume relation; [dP/dt(max)](edv), the slope of the dP/dt(max)-end diastolic volume relation), derived from left ventricular pressure-volume loops generated by conductance and microtip pressure catheters., Results: 10 pigs received 7.5 mg l-NMMA intravenously and six of these received two additional doses (37.5 mg and 75 mg). E(es) (mean (SD)) increased with all three doses, from 54.9 (40.1) mm Hg/ml (control) to 86.3 (69.5) at 7.5 mg, 117.9 (65.1) at 37.5 mg, and 119 (80.4) at 75 mg (p < 0.05). At the two highest doses, [dP/dt(max)](edv) increased from 260.8 (209.3) (control) to 470.5 (22.8) at 37.5 mg and 474.1 (296.6) at 75 mg (p < 0.05); and end diastolic pressure decreased from 16.5 (5.6) mm Hg (control) to 11.3 (5.0) at 37.5 mg and 11.4 (4.9) at 75 mg (p < 0. 05)., Conclusions: In neonatal pigs 12 hours after cardiopulmonary bypass with ischaemic arrest, low dose l-NMMA improved left ventricular function, implying that there is a net deleterious cardiac action of nitric oxide at this time.

This purpose of this study was to evaluate the effect of aprotinin, a serine protease inhibitor, in ischaemia- and reperfusion-injured myocutaneous flaps and skin flaps. Flap survival, microcirculatory platelet accumulation, and regional blood flow were investigated in seventeen pigs which had been subjected to 8 h of ischaemia and 18 h of reperfusion. The pigs were randomly assigned to aprotinin treatment (n = 9) or saline (n = 8). In-vitro studies were performed to investigate the influence of aprotinin on the activated partial thromboplastin time. The survival of skeletal muscle correlated positively with the concentration of aprotinin (P = 0.02) and could not be explained by regional changes in blood flow. Platelet accumulation was decreased in aprotinin-treated muscle (P = 0.04). In-vitro (n = 10), 100 kallikrein inactivator units/ml aprotinin prolonged the activated partial thromboplastin time both in plasma (P = 0.001) and in blood (P = 0.002), suggesting an anticoagulant rather than a procoagulant effect. In conclusion, aprotinin at high concentrations may be beneficial for the survival of skeletal muscle and provides protection from platelet accumulation in the microcirculation of skeletal muscle exposed to ischaemia and reperfusion injury.

Experimental studies have demonstrated that intravenous magnesium (Mg) can protect the ischemic myocardium and has an antithrombotic effect. In patients with myocardial infarction, the reperfusion injury is complicated by the presence of a thrombogenic area in the affected coronary artery that may cause repetitive thrombus formation and embolization. We investigated the effect of Mg on infarct size in a randomized study in pigs. Myocardial infarction was induced by a 50-minute mechanical occlusion of the left anterior descending artery combined with an arterial injury, which stimulated a dynamic thrombus formation with emboli shedding on reperfusion. Magnesium sulfate (6 mmol/20 min plus 3 mmol/h) or saline was started at 30 minutes after coronary occlusion. Real-time ventricular pressure-volume loops were generated from the left ventricle by using a microtip pressure manometer and a conductance catheter. Platelet accumulation in the myocardium was evaluated by using 111In-labeled platelets. After 4 hours of reperfusion, the infarct size/area at risk ratio in the placebo group was 46+/-0.06% (n=8) compared with 22+/-0.07% (n=6) in the Mg-treated animals (P=0. 03). Ejection fraction decreased significantly in the control group but not in the Mg-treated animals (P=0.03). Platelet accumulation in the myocardium did not change significantly between the Mg- and placebo-treated animals (placebo group, 191+/-19%; Mg group, 177+/-29%; NS). The present study demonstrates that intravenous Mg infusion is able to reduce infarct size by >50% and preserve the ejection fraction in this model where ischemia/reperfusion injury was evaluated in the presence of a thrombogenic area in the nutrient artery.