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Objectives We compared the effect of two inodilators, levosimendan and milrinone, on the plasma levels of myocardial injury biomarkers, that is, high-sensitivity troponin T and heart-type fatty acid binding protein, and on N-terminal prohormone of brain natriuretic peptide as a biomarker of ventricular function. We hypothesized that levosimendan could attenuate the degree of myocardial injury when compared with milrinone. Design A post hoc, nonprespecified exploratory secondary analysis of the Milrinone versus Levosimendan-1 trial (ClinicalTrials.gov Identifier: NCT02232399). Setting Two pediatric tertiary university hospitals. Patients Infants 1-12 months old, diagnosed with ventricular septal defect, complete atrioventricular septal defect, or Tetralogy of Fallot undergoing corrective surgery with cardiopulmonary bypass. Interventions Seventy patients received a loading dose of either levosimendan or milrinone at the start of cardiopulmonary bypass followed by an infusion of the respective drug, which continued for 26 hours. Measurements and main results Plasma levels of the three cardiac biomarkers were measured prior to the initiation of cardiopulmonary bypass and 2, 6, and 24 hours after weaning from cardiopulmonary bypass. In both groups, the levels of high-sensitivity troponin T and heart-type fatty acid binding protein were highest at 2 hours post cardiopulmonary bypass, whereas the highest level of N-terminal prohormone of brain natriuretic peptide occurred at 24 hours post cardiopulmonary bypass. There was no significant difference in the biomarkers' plasma levels between the study groups over time. Neither was there a significant difference in the postoperative peak plasma levels of the cardiac biomarkers. Conclusions In this post hoc analysis of the MiLe-1 trial, there was no demonstrable difference in the postoperative cardiac biomarker profile of myocardial injury and ventricular function when comparing infants managed in the perioperative period with levosimendan versus milrinone.

Objective:The objectives of the present study were to determine whether there was any association between the grade of heart failure, as expressed by preoperative levels of brain natriuretic peptide and Ross score, and the preoperative coagulation status in patients with non-restrictive ventricular shunts and determine whether there were any postoperative disturbances of the coagulation system in these patients, as measured by thromboelastometry and standard laboratory analyses of coagulation.Design:Perioperative coagulation was analysed with laboratory-based coagulation tests and thromboelastometry before, 8 hours after, and 18 hours after cardiac surgery. In addition, brain natriuretic peptide was analysed before and 18 hours after surgery.Patients:40 children less than 12 months old with non-restrictive congenital ventricular or atrio-ventricular shunts scheduled for elective repair of their heart defects.Results:All coagulation parameters measured were within normal ranges preoperatively. There was a significant correlation between brain natriuretic peptide and plasma fibrinogen concentration preoperatively. There was no statistically significant correlation between brain natriuretic peptide and INTEM-MCF, FIBTEM-MCF, plasma fibrinogen, activated partial thromboplastin time, prothrombin time, or platelet count at any other time point, either preoperatively or postoperatively. Postoperatively, fibrinogen plasma concentration and FIBTEM-MCF decreased significantly at 8 hours, followed by a large increase at 18 hours to higher levels than preoperatively.Conclusions:There was no evidence of children with non-restrictive shunts having coagulation abnormalities before cardiac surgery. Brain natriuretic peptide levels or Ross score did not correlate with coagulation parameters in any clinically significant way.

Objective The present study aimed to determine the differential effects of intraoperative administration of milrinone versus levosimendan on myocardial function after pediatric cardiac surgery. Transthoracic echocardiography was used for myocardial function evaluation using biventricular longitudinal strain with 2-dimensional speckle tracking echocardiography in addition to conventional echocardiographic variables. Design A secondary analysis of a randomized, prospective, double-blinded clinical drug trial. Setting Two pediatric tertiary university hospitals. Participants Infants between 1 and 12 months old diagnosed with ventricular septal defect, complete atrioventricular septal defect, or tetralogy of Fallot who were scheduled for corrective surgery with cardiopulmonary bypass. Interventions The patients were randomly assigned to receive an infusion of milrinone or levosimendan at the start of cardiopulmonary bypass and for 26 consecutive hours. Measurements and Main Results Biventricular longitudinal strain and conventional echocardiographic variables were measured preoperatively, on the first postoperative morning, and before hospital discharge. The association between perioperative parameters and postoperative myocardial function also was investigated. Images were analyzed for left ventricular (n = 67) and right ventricular (n = 44) function. The day after surgery, left ventricular longitudinal strain deteriorated in both the milrinone and levosimendan groups (33% and 39%, respectively). The difference was not significant. The corresponding deterioration in right ventricular longitudinal strain was 42% and 50% (nonsignificant difference). For both groups, biventricular longitudinal strain approached preoperative values at hospital discharge. Preoperative N-terminal pro-brain natriuretic peptide could predict the left ventricular strain on postoperative day 1 (p = 0.014). Conclusions Levosimendan was comparable with milrinone for left and right ventricular inotropic support in pediatric cardiac surgery.

Background:Limited data exist on training of European paediatric and adult congenital cardiologists.Methods:A structured and approved questionnaire was circulated to national delegates of Association for European Paediatric and Congenital Cardiology in 33 European countries.Results:Delegates from 30 countries (91%) responded. Paediatric cardiology was not recognised as a distinct speciality by the respective ministry of Health in seven countries (23%). Twenty countries (67%) have formally accredited paediatric cardiology training programmes, seven (23%) have substantial informal (not accredited or certified) training, and three (10%) have very limited or no programme. Twenty-two countries have a curriculum. Twelve countries have a national training director. There was one paediatric cardiology centre per 2.66 million population (range 0.87–9.64 million), one cardiac surgical centre per 4.73 million population (range 1.63–10.72 million), and one training centre per 4.29 million population (range 1.63–10.72 million population). The median number of paediatric cardiology fellows per training programme was 4 (range 1–17), and duration of training was 3 years (range 2–5 years). An exit examination in paediatric cardiology was conducted in 16 countries (53%) and certification provided by 20 countries (67%). Paediatric cardiologist number is affected by gross domestic product (R2 = 0.41).Conclusion:Training varies markedly across European countries. Although formal fellowship programmes exist in many countries, several countries have informal training or no training. Only a minority of countries provide both exit examination and certification. Harmonisation of training and standardisation of exit examination and certification could reduce variation in training thereby promoting high-quality care by European congenital cardiologists.

It has been shown that, in contrast to other inotropic agents, levosimendan improves glomerular filtration rate after adult cardiac surgery. The aim of this study was to investigate the efficacy of levosimendan, compared with milrinone, in preventing acute kidney dysfunction in infants after open-heart surgery with cardiopulmonary bypass.Two-center, double-blinded, prospective, randomized clinical trial.The study was performed in two tertiary pediatric centers, one in Sweden (Gothenburg) and one in Finland (Helsinki).Infants between 1 and 12 months old, diagnosed with Tetralogy of Fallot, complete atrioventricular septal defect or nonrestrictive ventricular septal defect, undergoing total corrective cardiac surgery with cardiopulmonary bypass.Seventy-two infants were randomized to receive a perioperative infusion of levosimendan (0.1 µg/kg/min) or milrinone (0.4 µg/kg/min). The infusion was initiated at the start of cardiopulmonary bypass and continued for 26 hours.The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. Secondary outcomes included the following: 1) acute kidney injury according to the serum creatinine criteria of the Kidney Diseases: Improving Global Outcomes; 2) acute kidney injury with serum creatinine corrected for fluid balance; 3) plasma neutrophil gelatinase-associated lipocalin; 4) cystatin C; 5) urea; 6) lactate; 7) hemodynamic variables; 8) use of diuretics in the PICU; 9) need of dialysis; 10) length of ventilator therapy; and 11) length of PICU stays. There was no significant difference in postoperative serum creatinine between the treatment groups over time (p = 0.65). The occurrence rate of acute kidney injury within 48 hours was 46.9% in the levosimendan group and 39.5% in the milrinone group (p = 0.70). There were no significant differences in other secondary outcome variables between the groups.Levosimendan compared with milrinone did not reduce the occurrence rate of acute kidney injury in infants after total corrective heart surgery for atrioventricular septal defect, ventricular septal defect, or Tetralogy of Fallot.

Background Despite advances in pediatric health care over recent decades, it is not clear whether survival in children with congenital heart disease (CHD) is still increasing. Methods and Results We identified all patients with CHD using nationwide Swedish health registries for 1980 to 2017. We examined the survival trends in children with CHD; we investigated the mortality risk in patients with CHD compared with matched controls without CHD from the general population using Cox proportional regression models and Kaplan–Meier survival analysis. Among 64 396 patients with CHD and 639 012 matched controls without CHD, 3845 (6.0%) and 2235 (0.3%) died, respectively. The mean study follow‐up (SD) was 11.4 (6.3) years in patients with CHD. The mortality risk was 17.7 (95% CI, 16.8–18.6) times higher in children with CHD compared with controls. The highest mortality risk was found during the first 4 years of life in patients with CHD (hazard ratio [HR], 19.6; 95% CI, 18.5–20.7). When stratified by lesion group, patients with non‐conotruncal defects had the highest risk (HR, 97.2; 95% CI, 80.4–117.4). Survival increased substantially according to birth decades, but with no improvement after the turn of the century where survivorship reached 97% in children with CHD born in 2010 to 2017. Conclusions Survival in children with CHD has increased substantially since the 1980s; however, no significant improvement has been observed this century. Currently, >97% of children with CHD can be expected to reach adulthood highlighting the need of life‐time management.

Background CoA is associated with hypertension caused by reduced wind kessel function in the aortic arch, general hypoplasia of the arch and/or essential hypertension. In patients with a native or recurrent/rest CoA, a gradient >20 mmHg by non-invasive meassurement if associated with hypertension is an ESCguideline indication for intervention. We studied the persistence and presence of hypertension after transcatheter intervention of a CoA Methods All consecutive patients undergoing catheter interventions for CoA from 1st of January 2000 to 31st of December 2016 were identified by each of the particpating nine centers. The nine centers perform all catheter interventions for CoA for a complete population coverage of 25 millions inhabitants. A common protocoll was filled out from medical records. Hypertension was defined as a pre-intervention blood pressure above 140/80 or pharmacological treatment of hypertension. Exclusion criteria were weight less than 20 kg at the time of intervention or Norwood surgery Results 590 interventions were performed on 520 patients: two interventions n=76, three: n=11, four n=2 and one patient underwent five interventions. Before intervention, 437 (74%) of the patients were hypertensive and 285 were on pharmacologocal treatment; 134 (48%) were treated with one drug, 79 patients (28%) with two drugs, 41 patients (15%) with three drugs and 14 (5%) with four drugs. After the intervention during follow up hypertension was present in 294 patients (50%, p Conclusions Catheter intervention of CoA reduced the presence of hypertension significantly from 74% down to 50% but many patients will remain hypertensive and in need for treatment. Life time follow up also after transcatheter CoA intervention seems warranted. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): ALF-LUA, Heart and Lung Foundation

Background Patients with a native or re CoA with an invasively meassured peak to peak gardient >20 mmHg have a guideline indication for intervention. The decision regarding transcatheter versus surgical intervention depends on a variety of factors including location and complexity of CoA, patient/parent preference and availability of a team capable to perform the intevention with a low rate of complications. The aim of the present analysis was to describe factors associated with risk for procedural complications during transcatheter interventions in CoA. Separate anlysis was done for complications at intervention site and at access site. Methods All consecutive patients undergoing catheter interventions for CoA from 1st of January 2000 to 31st of December 2016 were identified by each of the particpating nine centers. The nine centers perform all catheter interventions for CoA for a complete population coverage of 25 millions inhabitants. A common protocol was filled out from medical records. Exclusion criteria were weight less than 20 kg at the time of intervention or Norwood surgery for hypoplastic left heart surgery. Complications at the intervention site included aneurysm formation, dissection of the aorta, extravasation of the aorta or neurological impairment. Complications at the access site was defined as any complication that prolonged the hospital stay. Results 590 interventions were performed on 520 patients: two interventions n=76, three: n=11, four n=2 and one patient underwent five interventions. There was no mortality in relation to the procedure or during the hospitalisation. The age span of the patients was wide; 4–79 years old (median= 23). 51% had a native CoA, 42% post surgery re-CoA, 22% had had a previous catheter intervention. In 160 (27%) of the interventions balloon dilatation only was performed. Overall, procedural succes was 87%, n=513, 44 procedures (8%) were partially successful and 9 procedures (2%) were not successful. 512 (87%) had one day in hospital stay and 17 patients (6%) had a hospital stay longer than 3 days. In 11 procedures (1.9%) at least one complication occurred at the intervention site; (6 aneurysm formation, 3 neurological impairment, 3 dissection of aorta, 2 extra vasation of aorta), nine of them without prolonged hospital stay. In 25 procedures (4.2%) at least one complications at the access site was observed. Access site complications were associated with older age (mean 38 years (10–79)) Conclusions In a large, multicenter registry with complete follow-up, complications at the intervention site occurred in 1.9% and at the access site in 4.2% of interventions. Transcatheter intervention of CoA can be performed with low risk of complications. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): ALF-LUA, Gothenburg Heart and Lung Foundation

Radiation doses from paediatric cardiac catheterizations were analysed based on procedure type and patient weight, and local diagnostic reference levels (LDRLs) were proposed. The procedures were performed on a Siemens Artis Q.zen biplane system with high-sensitivity detectors allowing low-dose imaging. Good radiological practice, e.g. adapting dose level and frame rate continuously and minimizing the x-ray field with collimators, was routine during procedures. The median total dose-area-product (DAP) value was 58 μGym2 for diagnostic catheterizations, 48 μGym2 for interventional catheterizations and 33 μGym2 for myocardial biopsies. The median DAP per body weight was 4.0 μGym2 kg−1. The median total fluoroscopy time varied from 6.0 min for myocardial biopsies, to 9.7 and 10.5 min, respectively, for diagnostic and interventional catheterizations. The third quartile of the DAP values in each weight group was proposed as LDRL. LDRLs for fluoroscopy time were determined solely based on procedure type, due to the absence of weight dependence.

Aim The aim of the study was to assess the incidence, mortality and morbidity of dilated cardiomyopathy (DCM) and noncompaction of the left ventricle (LVNC) in Swedish children. Methods We reviewed hospital records of all children with dilated cardiomyopathy (DCM) or left ventricular noncompaction cardiomyopathy (LVNC) up to the age of 18 in the healthcare region of western Sweden from 1991 to 2015. Results In total, 69 cases (61% males) were identified. The combined incidence of DCM and LVNC was 0.77 (95% CI 0.59‐0.96) per 100 000 person years. Children were divided into six groups, and their outcomes were analysed depending on their aetiology. Idiopathic DCM was reported in 43%, and familial dilated and left ventricular noncompaction aetiology was present in 32%. DCM due to various diseases occurred in 8%. DCM associated with neuromuscular diseases was present in 16%. The overall risk of death or receiving transplants in children with idiopathic and familial DCM was 30% over the study period, and 21% died in the first year after diagnosis. Conclusion The combined incidence of DCM and LVNC was similar to previous reports. Most children with idiopathic DCM presented during infancy, and mortality was highest during the first year after diagnosis.

BackgroundHeart transplantation has been an option for children in Sweden since 1989. As our unit faced an increased rate of post-transplant lymphoproliferative disorder, the objective of the study was to identify possible risk factors.MethodsThis is a retrospective study of all children aged 0–18 years who underwent heart transplantation in Gothenburg from 1989 to 2014.ResultsA total of 71 children underwent heart transplantation. The overall incidence of post-transplant lymphoproliferative disorder was 14% (10/71); however, 17% (6/36) of those undergoing transplantation after 2007 developed lymphoma, compared with only 10% (4/35) of transplantation cases before 2007 (p=0.85). The mean age at transplantation was 9 years (0–17). The mean post-transplant follow-up time was 5.5 years (0.5–21.9) in the group that developed post-transplant lymphoproliferative disorder, compared with 10.2 years (0.02–25.2) in those who did not. In our study group, risk factors for post-transplant lymphoproliferative disorder were surgically palliated CHD (p=0.0005), sternotomy during infancy (p⩽0.0001), hypoplastic left ventricle (p=0.0001), number of surgical events (p=0.0022), mismatch concerning Epstein–Barr virus infection – that is, a positive donor–negative recipient (p⩽0.0001) – and immunosuppressive treatment with tacrolimus compared with ciclosporine (p=0.028).DiscussionThis study has three major findings. First, post-transplant lymphoproliferative disorder only developed in subjects born with CHD. Second, the vast majority (9/10) of the subjects developing the disorder had undergone sternotomy as infants. Third, the number of surgical events correlated with a higher risk for developing post-transplant lymphoproliferative disorder.

The European Pediatric Pulmonary Vascular Disease Network (EPPVDN) investigated the safety and efficacy of add-on selexipag, an oral prostacyclin receptor agonist approved for pulmonary arterial hypertension (PAH) in adults, in the largest, exploratory pediatric cohort to date.This is a prospective observational study of 15 consecutive children with PAH, treated with oral add-on selexipag at 3 centers. Most patients underwent cardiac catheterizations at baseline and median of 8 months follow-up. All patients had clinical, echocardiographic, and N-terminal pro b-type natriuretic peptide studies, including the EPPVDN pediatric pulmonary hypertension (PH) risk score.There was no death during the use of selexipag. Two of 15 patients ultimately underwent lung transplantation. One patient with heritable PAH died on intravenous treprostinil (off selexipag). The mean right atrial pressure, the ratio of pulmonary arterial pressure (PAP) to systemic arterial pressure (SAP) (mean PAP/mean SAP, diastolic PAP/diastolic SAP: -17%), and transpulmonary pressure gradients (TPG) (mean TPG: -17%; p0.01; diastolic TPG: -6 mm Hg; p0.05) were improved after the therapy (n = 10). Selexipag therapy was associated with a better right ventricular systolic function (tricuspid annular plane systolic excursion: +14.5%; p0.01) and functional class. Improvement was seen in non-invasive and combined invasive/non-invasive PH risk scores (lower risk: +18%-22%, higher risk: -35%-37%; p0.05). Overall, the efficacy of selexipag was variable, often with a better response in less sick patients.Oral selexipag use in children with PAH is well tolerated and safe when closely monitored. Add-on selexipag therapy improved several outcome-relevant variables in about 50% of patients and prevented disease progression in additional 27% of patients. The novel EPPVDN pediatric PH risk score indicated these drug effects properly, can be useful in clinical follow-up, and should be validated in larger prospective studies.

The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term "pulmonary hypertension" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.

Objectives Not all patients in need of durable mechanical circulatory support are suitable for a continuous-flow left ventricular assist device. We describe patient populations who were treated with the paracorporeal EXCOR, including children with small body sizes, adolescents with complex congenital heart diseases, and adults with biventricular failure. Methods Information on clinical data, echocardiography, invasive hemodynamic measurements, and surgical procedures were collected retrospectively. Differences between various groups were compared. Results Between 2008 and 2018, a total of 50 patients (21 children and 29 adults) received an EXCOR as bridge to heart transplantation or myocardial recovery. The majority of patients had heart failure compatible with Interagency Registry for Mechanically Assisted Circulatory Support profile 1. At year 5, the overall survival probability for children was 90%, and for adults 75% (P = .3). After we pooled data from children and adults, the survival probability between patients supported by a biventricular assist device was similar to those treated with a left ventricular assist device/ right ventricular assist device (94% vs 75%, respectively, P = .2). Patients with dilated cardiomyopathy had a trend toward better survival than those with other heart failure etiologies (92% vs 70%, P = .05) and a greater survival free from stroke (92% vs 64%, P = .01). Pump house exchange was performed in nine patients due to chamber thrombosis (n = 7) and partial membrane rupture (n = 2). There were 14 cases of stroke in eleven patients. Conclusions Despite severe illness, patient survival on EXCOR was high, and the long-term overall survival probability following heart transplantation and recovery was advantageous. Treatment safety was satisfactory, although still hampered by thromboembolism, mechanical problems, and infections.

Purpose There is an increasing interest in the use of donor-derived cfDNA (dd-cfDNA) in transplantation for non-invasive diagnosis of allograft injury. We hereby describe a non-commercial routine procedure for dd-cfDNA detection and quantification using digital droplet PCR and target-specific preamplification of a SNP-panel of 35 SNP-assays. The method is based on the difference in genotype between recipients and donors. After establishing our protocol, it has been used in a prospective study following recipients for 12 months after heart transplantation (HTx), and we here briefly describe our protocol. Methods A total of 728 samples from 67 HTx patients have been retrieved and analyzed. The recipients were genotyped preoperatively with respect to the SNP-panel. Upon transplantation, the donor genotype was interrogated with respect to the homozygous alleles found in the recipient. After HTx, blood samples were collected in cell free DNA collection tubes and delivered within the same day to the hospital laboratory. Plasma was separated by centrifugation at 2000g and 16000g, respectively. Isolated plasma was stored at -80C or used immediately for cfDNA extraction. Quality controls were performed by the 4200 Tape Station. The same primers were used for preamplification and downstream PCR. Non-template controls were included in all preamplification steps. The amount of dd-cfDNA was calculated as a fraction of the total cfDNA. Results The variation of extracted cfDNA yield was 10-130 ng/ml plasma. The 50-800 bp sized cfDNA constitutes 90% of the extracted samples, indicating a low background. An average of 2-5 informative SNPS assays for each transplant recipient were used for dd-cfDNA quantification with a detection rate down to 0.01% dd-cfDNA. Elevation of dd-cfDNA was seen not only in conjunction with cellular rejection but also during infection and in episodes of heart failure Conclusion Samples from HTx recipients demonstrated low levels of dd-cfDNA in consecutive samples during optimal treatment in non-eventful cases. Elevation of dd-cfDNA was seen not only during rejection but also in other conditions. This non-invasive method is relatively cheap, enables large sample yields by preamplification, has a fast turn-around time (48 hours) and is thus useful for clinical monitoring of HTx patients. However, it needs to be carefully related to clinical events.

Purpose Donor-derived cell-free DNA (dd-cfDNA) as a highly sensitive marker of rejection after heart transplantation (HTx) has gained emerging interest. Recent studies are based on sequencing techniques and use fractional abundance (dd-cfDNA as a fraction of total cfDNA) as their outcome. Here we present patient examples of the BIODRAFT-study (NCT03477383) based on PCR-techniques. Methods Blood samples are taken prospectively in parallel with endomyocardial biopsies (EMB) during the first year after HTx. dd-cfDNA is analyzed using targeted preamplification of 35 single nucleotide polymorphisms followed by digital droplet-PCR. Outcome is fractional abundance as well as total number of DNA copies, both from the donor and the recipient. Results 71 patients (57 adults, 14 children) are so far included and more than 500 blood samples analyzed. In otherwise stable patients, both fractional abundance and total DNA copies seem to follow biopsy patterns with respect to rejection. However, we could also identify different scenarios in which the distribution of cfDNA seems more complicated than hitherto described: Patients with primary graft failure, clinically silent CMV-infection or mild right heart failure show elevated levels of dd-cfDNA, thus complicating the interpretation of results. Some patients present with markedly elevated levels of their own cfDNA without obvious clinical reasons. Conclusion Besides the well-known concept of fractional abundance, our approach gives results that allow following absolute DNA copy numbers of both donor and recipient. This widens the horizon of cfDNA as a marker of graft injury after HTx, and gives an outlook to clinical scenarios with possible false positive (mimicking rejection) and, even worse, false negative results: high levels of recipient-cfDNA could mask ongoing rejection if only fractional abundance can be reported. The biology of cell-free DNA is complex and seems not yet fully understood.

Background Platelet deficiency, impaired platelet function, or both increase the risk of bleeding complications. We assessed platelet count and function during and after paediatric cardiac surgery. Secondary aims included the effect of modified ultrafiltration, identification of factors associated with platelet dysfunction, and to assess associations between platelet function and transfusion requirements. Methods Fifty-seven patients were included in a prospective observational study. Platelet count and platelet function (multiple-electrode impedance aggregometry) were analysed before and during cardiopulmonary bypass (CPB), after modified ultrafiltration, on arrival at the intensive care unit, and on the first postoperative day. Intraoperative transfusions of blood products were registered. Results Both platelet count and platelet aggregation were markedly reduced during surgery with the greatest reduction at the end of CPB. On postoperative day 1, platelet count was still reduced by 50%, while platelet aggregation had returned to—or above—preoperative levels. There were only moderate correlations between platelet count and platelet aggregation. Modified ultrafiltration had no significant influence on platelet count or aggregation. Young age, low weight, and long operation time were associated with poor platelet aggregation during surgery, while young age, low weight, high preoperative haemoglobin levels, and low preoperative platelet count were associated with poor aggregation after operation. Patients with impaired platelet function during CPB had markedly increased intraoperative transfusion requirements. Conclusions Platelet count and platelet aggregation are markedly reduced during and immediately after paediatric cardiac surgery, especially in neonates. The recovery in aggregation is faster than that in platelet count. Intraoperative platelet dysfunction is associated with increased transfusion requirements.

Background Impaired platelet function increases the risk of bleeding complications in cardiac surgery. Reliable assessment of platelet function can improve treatment. We investigated whether thromboelastometry detects clinically significant preoperative, perioperative, and postoperative adenosine diphosphate (ADP)-dependent platelet dysfunction in paediatric cardiac surgery patients. Methods Fifty-seven children were included in a single-centre prospective observational study. Clot formation (modified rotational thromboelastometry with heparinase, HEPTEM) and platelet aggregation (multiple electrode aggregometry) were analysed at five time points before, during, and after surgery. The accuracy of thromboelastometric indices of platelet function [maximal clot firmness (MCF) and clot formation time (CFT)] to detect ADP-dependent platelet dysfunction (defined as ADP-induced aggregation ≤30 units) was calculated with receiver operating characteristics analysis, which also identified optimal cut-off levels. Positive and negative predictive values for the identified cut-off levels (CFT≥166 s; MCF≤43 mm) to detect platelet function were determined. Results The MCF and CFT were highly accurate in predicting platelet dysfunction during cardiopulmonary bypass [CPB; area under the aggregation curve 0.89 (95% confidence interval 0.80–0.97) and 0.86 (0.77–0.96), respectively] but not immediately after CPB [0.64 (0.48–0.79) and 0.67 (0.52–0.82), respectively] or on arrival at the intensive care unit [0.53 (0.37–0.69) and 0.60 (0.44–0.77), respectively]. The positive and negative predictive values were acceptable during CPB (87 and 67%, respectively, for MCF≤43 mm; 80 and 100% for CFT≥166 s) but markedly lower after surgery. Conclusion In paediatric cardiac surgery, thromboelastometry has acceptable ability to detect ADP-dependent platelet dysfunction during, but not after, CPB.

BackgroundPatients with bidirectional cavopulmonary anastomosis have unphysiologically high superior caval vein pressure as it equals pulmonary artery pressure. Elevated superior caval vein pressure may cause communicating hydrocephalus and macrocephaly. This study analysed whether there exists an association between head circumference and superior caval vein pressure in patients with single ventricle physiology.MethodsWe carried out a retrospective analysis of infants undergoing Fontan completion at our institution from 2007 to 2013. Superior caval vein pressures were measured during routine catheterisation before bidirectional cavopulmonary anastomosis and Fontan completion as well as head circumference, adjusted to longitudinal age-dependent percentiles.ResultsWe included 74 infants in our study. Median ages at bidirectional cavopulmonary anastomosis and Fontan were 4.8 (1.6–12) and 27.9 (7–40.6) months, respectively. Head circumference showed significant growth from bidirectional cavopulmonary anastomosis until Fontan completion (7th (0–100th) versus 20th (0–100th) percentile). There was no correlation between superior caval vein pressure and head circumference before Fontan (R2=0.001). Children with lower differences in superior caval vein pressures between pre-bidirectional cavopulmonary anastomosis and pre-Fontan catheterisations showed increased growth of head circumference (R2=0.19).ConclusionsPatients with moderately elevated superior caval vein pressure associated with single ventricle physiology did not have a tendency to develop macrocephaly. There is no correlation between superior caval vein pressure before Fontan and head circumference, but between bidirectional cavopulmonary anastomosis and Fontan head circumference increases significantly. This may be explained by catch-up growth of head circumference in patients with more favourable haemodynamics and concomitant venous pressures in the lower range. Further studies with focus on high superior caval vein pressures are needed to exclude or prove a correlation.

BackgroundShunt thrombosis after implantation of systemic-to-pulmonary shunts in paediatric patients is common. Acetyl salicylic acid is used for anti-thrombotic treatment; however, the effect is rarely monitored, although it is known that the response varies. The aim was to determine the effects of acetyl salicylic acid medication on platelet aggregation in children with systemic-to-pulmonary shunts.MethodsA total of 14 children – median age 12 days; ranging from 3 to 100 days – were included in a prospective observational longitudinal study. All children were treated with oral acetyl salicylic acid (3–5 milligrams per kilogram once daily) after shunt implantation. Acetyl salicylic acid-dependent platelet aggregation in whole blood was analysed with impedance aggregometry (Multiplate®) after addition of arachidonic acid. Analyses were carried out before the primary operation, before and 5 and 24 hours after the first acetyl salicylic acid dose, and after 3–6 months of treatment. The therapeutic range for acetyl salicylic acid was defined as a test result less than 60 units.ResultsAcetyl salicylic acid reduced the arachidonic acid-induced platelet aggregation in all but one patient. Of the patients, 93% were in the therapeutic range 5 hours after acetyl salicylic acid intake, 86% were in the range after 24 hours, and 64% after 3–6 months.ConclusionsAcetyl salicylic acid reduces platelet aggregation after shunt implantation in paediatric patients, but a considerable percentage of the children are outside the therapeutic range. Monitoring of platelet aggregation has the potential to improve anti-platelet treatment after shunt implantation by identifying children with impaired acetyl salicylic acid response.

Aims: To evaluate outcome in the first generation of children with end-stage heart disease to whom heart transplantation was available. Methods: Retrospective review of all 135 Swedish children

We analyzed the natriuretic peptide type B (BNP) and A (ANP) levels in the plasma of 38 children with stable functionally univentricular heart defects, 10 of whom had undergone the first palliative step (Shunt), 13 of whom had undergone the second palliative step (Glenn), and 15 of whom had completed total cavopulmonary connection (TCPC). The levels of BNP and ANP were significantly higher after the first palliative step, 31.6 ng/l (8.3-122) (median and range) and 101.2 ng/l (17.1-203), respectively, than after the Glenn procedure, 6.7 ng/l (0.0-16.0) and 23.6 ng/l (15.7-54.4), respectively, as well as after completed TCPC, 9.0 ng/l (0.0-39.1) and 20.9 ng/l (11.2-28.3), respectively, and, in a control group of children without heart defects, 5.8 ng/l (0.0-38.7) and 32.9 ng/l (11.7-212.1), respectively (p = 0.0003 and p = 0.0003, respectively). After the first palliative step, the BNP and ANP levels were the same in children with right and left ventricular morphology (p = 0.67 and p = 0.52, respectively). After unloading the ventricle (Glenn and TCPC together), BNP levels were higher in children with right ventricular morphology compared with those with left ventricular morphology and controls (p = 0.02). Children with functionally univentricular hearts in stable condition have increased BNP and ANP levels after the first palliative procedure. After the second and third palliative steps, the BNP and ANP levels were low and similar to those of children without heart defects. However, BNP levels in children with a systemic ventricle of right ventricular morphology were higher than those in children with left ventricular morphology.

We evaluated the concentrations of brain natriuretic peptide in the plasma as a marker of systolic ventricular function before and after maximal exercise in 15 surgically palliated patients with functionally univentricular hearts, with apparently good ventricular function. Of the patients, 6 with median age of 14.6 years, and a range from 12.5 to 17.9 years, had been palliated by construction of a total cavopulmonary connection, while the other 9 patients, with a median age of 32.1 years, and a range from 15.6 to 54.2 years, had undergone the classical Fontan procedure. We used 8 healthy individuals, with a median age of 13.9 years, and a range from 12.8 to 14.2 years, as a control group for the measurements of brain natriuretic peptide. The values of the peptide were significantly higher in those with the classical Fontan procedure, both before, when the median value was 131.8 nanogram per litre, with a range from 0.5 to 296.4, and after maximal exercise, when the median value was 108.1, with a range from 0.1 to 235.9. The comparable values in those with a total cavopulmonary connection were a median of 12.8, and a range from 0.5 to 39.1 before, and a median of 9.7, with a range from 2.7 to 26.2 after maximal exercise. The median value for the control group was 13.1, with a range from 2.6 to 38.7 before exercise (p = 0.016), and a median of 24.1, with a range from 5.8 to 66.7 after maximal exercise (p = 0.03), respectively. In the control subjects, the level of the peptide increased by a median of 9.7 nanograms per litre, with a range from 1.2 to 28.0 after maximal exercise (p = 0.008). The level was unchanged after maximal exercise in those with classical Fontan procedures and total cavopulmonary connections, with a difference between levels before and after exercise of a median of 5.9 nanogram per litre, and a range from −23.7 to 31.0 (p = 0.96), and a median of −1.0 nanogram per litre, with a range from −12.0 to 3.9 (p > 0.99), respectively. We conclude that maximal exercise did not increase the level of brain natriuretic peptide level in those patients with the classical Fontan procedure, nor those with a total cavopulmonary connection, findings which may indicate that systolic ventricular dysfunction is not the major cause of the decreased working capacity observed in patients with well functioning palliated functionally univentricular hearts.

We evaluated the concentrations of the brain and atrial natriuretic peptides in the plasma as markers of ventricular function and volume load in children with functionally univentricular hearts. We studied 7 children aged from 0.5 to 0.7 years with functionally univentricular hearts who had undergone a first palliative operation, and 10 children aged from 1.8 to 3.7 years who had undergone a bidirectional Glenn anastomosis at ages ranging from 0.4 to 1.0 year. As a control group, we studied 14 children without heart defects aged from 0.1 to 4.5 years. Levels of the brain natriuretic peptide were measured at 8.3 to 122 ng/l, with a mean of 52.8 ng/l, after the first palliative operation, compared to 0 to 16 ng/l, with a mean of 7.3 ng/l, after a bidirectional Glenn anastomosis, and 0 to 13.8 ng/l, with a mean of 5.9 ng/l, in the children serving as controls. Corresponding values for atrial natriuretic peptide were 17 to 203 ng/l, with a mean of 103 ng/l, after the first palliative operation, compared to 16 to 54 ng/l, with a mean of 29 ng/l, after the bidirectional Glenn anastomosis, and 12 to 52 ng/l, with a mean of 32 ng/l in the controls. Echocardiography showed that all the children with functionally univentricular hearts had normal ventricular function. Blood presssure, pulmonary arterial pressure, and arterial saturations of oxygen did not differ between the groups. We conclude, that in children with functionally univentricular hearts, the volume overload imposed on the heart after the first palliative operation is associated with increased production of brain and atrial natriuretic peptides, while after ventricular unloading, levels of the natriuretic peptides return to control values.

We report a case of recurrent syncope in association with moderate ventricular dysfunction and mild AV-valve regurgitation in an 18-year-old girl, 4 years after she underwent total cavopulmonary connection surgery. Cardiac catheterization revealed a transpulmonary gradient of 1-2 mmHg. During exercise, a dramatic fall in blood pressure and blood oxygenation was observed, paralleled by an increase in heart rate and central venous pressure. Although a slight increase in pulmonary vascular resistance could not be excluded, the reaction was interpreted in terms of an extremely low transpulmonary gradient in association with ventricular dysfunction. Five months after heart transplantation, the patient has been completely free from syncope. Fontan circulation usually involves a delicate haemodynamic situation which may necessitate haemodynamic re-evaluations, including dynamic measurements of the central venous pressure during exercise. Also a moderate ventricular dysfunction may result in compromised pulmonary circulation which in turn may lead to syncope during exercise as a result of insufficient systemic circulation.

SummaryObjective Earlier detection of coagulopathy in pediatric cardiac surgery patients. Aim To determine whether thromboelastometry (TEM) analysis before weaning from cardiopulmonary bypass (CPB) and hemoconcentration is predictive of post-CPB results and whether analysis of clot firmness already after 10 min yields reliable results. Background Cardiac surgery with CPB induces a coagulopathy that may contribute to postoperative complications. Earlier detection increases the possibility of initiating countermeasures. Methods/Material Fifty-six pediatric cardiac surgery patients were included in a prospective observational study. HEPTEM and FIBTEM clotting time (CT), clot formation time (CFT), and clot firmness after 10 min (A10) and at maximum (MCF) were analyzed during CPB and after CPB and ultrafiltration with modified rotational thromboelastometry (ROTEM®). The analyses were compared, and correlations and differences were calculated. Results Hemoconcentration with modified ultrafiltration increased hematocrit from 28 ± 3 to 37 ± 4% (P

We report on the reversal of protein-losing enteropathy (PLE) after heart transplantation (HTx) in a 10-yr-old boy with Fontan circulation, previously treated unsuccessfully with heparin for several months. The protein loss continued immediately after the Tx. During the following month, however, a gradual decrease in protein loss was observed, which correlated with a decrease in the inferior vena cava (IVC) pressure. The patient is doing well with a normal serum albumin level and a normal IVC pressure, 2 yr after Tx.

BACKGROUND: The majority of pediatric cardiac surgery patients receive blood transfusions. We hypothesized that the routine use of intraoperative thromboelastometry to guide transfusion decisions would reduce the overall proportion of patients receiving transfusions in pediatric cardiac surgery. METHODS: One hundred pediatric cardiac surgery patients were included in the study. Fifty patients (study group) were prospectively included and compared with 50 procedure- and age-matched control patients (control group). In the study group, thromboelastometry, performed during cardiopulmonary bypass, guided intraoperative transfusions. Intraoperative and postoperative transfusions of packed red blood cells, fresh frozen plasma, platelets, and fibrinogen concentrates, and postoperative blood loss and hemoglobin levels were compared between the 2 groups. RESULTS: The proportion of patients receiving any intraoperative or postoperative transfusion of packed red blood cells, fresh frozen plasma, platelets, or fibrinogen concentrates was significantly lower in the study group than in the control group (32 of 50 [64%] vs 46 of 50 [92%], respectively; P < 0.001). Significantly fewer patients in the study group received transfusions of packed red blood cells (58% vs 78%, P = 0.032) and plasma (14% vs 78%, P < 0.001), whereas more patients in the study group received transfusions of platelets (38% vs 12%, P = 0.002) and fibrinogen concentrates (16% vs 2%, P = 0.015). Neither postoperative blood loss nor postoperative hemoglobin levels differed significantly between the study group and the control group. CONCLUSIONS: The results suggest that routine use of intraoperative thromboelastometry in pediatric cardiac surgery to guide transfusions is associated with a reduced proportion of patients receiving transfusions and an altered transfusion pattern.

The present study was designed to explore to what extent pressure reduction by antihypertensive therapy and pressure elevation by renal hypertension are able to affect structural vascular and cardiac changes in young spontaneously hypertensive rats (SHR). Pressure elevation in SHR was induced by means of superimposing 2 kidney, 1 clip renal hypertension (2K1C). Pressure reduction was achieved by means of the vasoselective calcium antagonist felodipine from 6 to 13 weeks of age in both clipped and unclipped SHR. Vascular structure of the skeletal muscle was assessed hemodynamically by perfusing a hindlimb preparation and left ventricular dimensions were calculated from pressure-volume relationships of isolated hearts arrested in diastole. Induction of renal hypertension in SHR resulted, besides augmentation of arterial pressure in a marked concentric left ventricular hypertrophy, i.e. elevations of wall thickness to internal radius ratio. Likewise, in renal hypertensive SHR, a structural adaptation of the skeletal muscle vascular bed occurred, reflected as elevations of minimal vascular resistance and maximal generated perfusion pressure. Antihypertensive treatment for 8 weeks with felodipine reduced and also prevented mean arterial pressure from increasing further in SHR, and in SHR with superimposed renal hypertension by approximately 15% (p0.001 for both). In renal hypertensive SHR, felodipine partly prevented the development of exaggerated structural changes, both in the heart and in the skeletal muscle vascular bed, as reflected by reduced wall thickness to internal radius ratio and reduced minimal vascular resistance by 22% and maximal pressure response by 10% respectively (p0.01 for both parameters).(ABSTRACT TRUNCATED AT 250 WORDS)

Summary Natriuretic peptide levels B (BNP) and A (ANP) have been described in children with different diagnose of congenital heart defects (CHD). However, the impact of the type of cardiac load per se on natriuretic peptide levels, irrespective of diagnosis, has not been reported. The aim of the present study was to evaluate the levels of BNP and ANP in children with congenital and acquired heart disease according to different types of cardiac load. Plasma BNP and ANP were analysed in 137 children with CHD/heart disease, median age 2·9 (0·3–16·7) years. Haemodynamic load was classified as: no overload, pressure overload, volume overload of right and/or left ventricle and systolic ventricular dysfunction. Twenty-three children without heart disease served as controls for the natriuretic peptide measurements. The highest BNP and ANP values were observed in the systolic dysfunction, 613 ng l−1 (81·8–3910) and 431 (43·8–1990), and volume groups, 29·8 (5·5–352) and 93·0 (15·9–346), respectively, whereas the values in the pressure, 17·9 (0·7–315) and 51·9 (8·7–210), and no overload groups, 10·3 (0·2–28·1) and 28·6 (8·6–105), respectively, were only slightly higher than those in the controls 4·7 (0·0–17·7) and 32·9 (11·7–212·2), respectively. The highest BNP and ANP values were seen in children with systolic dysfunction, while volume overload in the absence of heart failure resulted in higher levels than pressure overload.

Summary Aim: Natriuretic peptide levels B (BNP) and A (ANP) have been described in children with congenital heart defects (CHD) with pressure and volume overload. However, the impact of ventricular morphology per se on natriuretic peptide levels has not been reported. The aim of the present study was to evaluate plasma BNP and ANP in children with CHD with left or right ventricular volume or pressure overload. Methods and results: Plasma BNP and ANP were analysed in 61 children, median age 3·1 (0·3–16·2) years. Haemodynamic load was evaluated by echo-Doppler and/or catheterization measurements and classified as: pressure overload of the right (RV pressure) or left (LV pressure) ventricle, or volume overload of the right (RV volume) or left (LV volume) ventricle, of a sufficient degree to indicate surgery/catheter intervention. Twenty-three children, with a median age of 1·1 (0·1–8·3) years, without heart disease, served as controls for the natriuretic peptide measurements. Children in the LV volume group had significantly higher BNP and ANP values, 55·4 ng l−1 (10·7–352) and 164 (31·8–346), than children in the RV volume, 15·6 (0·0–105·1) and 57·2 (11·3–234·1), LV pressure, 6·8 (0·7–170) and 40·8 (12·6–210), and RV pressure, 18·0 (5·0–29·1) and 69·3 (8·7–182), groups respectively (P

Aim: To study whether natriuretic peptide types B (BNP) and A (ANP) reflect clinical signs of heart failure (CSHF) in children with congenital heart defects or cardiomyopathy resulting in different types of haemodynamic situations, such as pressure overload in coarctation of the aorta (CoA), volume overload in ventricular septal defect (VSD) or systolic dysfunction in dilated cardiomyopathy (DCM). Methods: Blood samples for plasma P-BNP and P-ANP were taken before procedures during regular investigation from 26 children (9 CoA. 11 VSD and 6 DCM). The ordinary paediatric cardiologist performed the cardiac evaluation and the data were retrieved from medical charts, CSHF was considered positive if two of the following criteria were fulfilled: reduced physical capacity, feeding disorders, dyspnoea, tachypnoea, hepatomegaly and oedema. The statistical methods were non-parametric. Results: 0/9 children with CoA. 5/11 with VSD and 6/6 with DCM had CSHF. In children with CSHF, P-BNP and P-ANP were higher, 263 ng 1 -1 (range 47.5-1300) and 303 ng I -1 (range 168-466), than in those without CSHF, 12.3 ng l -1 ( range 4.8-30.8) and 42.9 ng l -1 (range 13.7-189), respectively (p

We report a case of recurrent syncope in association with moderate ventricular dysfunction and mild AV-valve regurgitation in an 18-year-old girl, 4 years after she underwent total cavopulmonary connection surgery. Cardiac catheterization revealed a transpulmonary gradient of 1-2 mmHg. During exercise, a dramatic fall in blood pressure and blood oxygenation was observed, paralleled by an increase in heart rate and central venous pressure. Although a slight increase in pulmonary vascular resistance could not be excluded, the reaction was interpreted in terms of an extremely low transpulmonary gradient in association with ventricular dysfunction. Five months after heart transplantation, the patient has been completely free from syncope. Fontan circulation usually involves a delicate haemodynamic situation which may necessitate haemodynamic re-evaluations, including dynamic measurements of the central venous pressure during exercise. Also a moderate ventricular dysfunction may result in compromised pulmonary circulation which in turn may lead to syncope during exercise as a result of insufficient systemic circulation.

Aims To determine the frequency of cardiomyopathy in children with mitochondrial disease and describe their clinical course, prognosis and cardiological manifestations. Methods and results Of 301 children with CNS and neuromuscular disease referred to our institution in 1984 to 1999, 101 had mitochondrial disease. Seventeen patients had cardiomyopathy, diagnosed by echo-Doppler investigations, all of the hypertrophic, non-obstructive type. The onset of symptomatic mitochondrial disease ranged from birth to 10 years of age. Eight children had cytochrome- c oxidase deficiency, while the remaining nine had various defects. Cardiomyopathy was diagnosed from birth to 27 years. Left ventricular posterior wall and septal thickness were both increased: z -scores +4.6±2.6 and +4.3±1.6 (mean±SD), respectively. The left ventricular diastolic diameter z -score, +1.3±3.4, and fractional shortening, 24±13%, displayed marked variations. Nine patients developed heart failure. Eleven patients with cardiomyopathy died, including all eight with cytochrome- c oxidase deficiency, and one patient underwent a heart transplantation. Mortality in children with mitochondrial disease was higher in those with cardiomyopathy (71%) than those without (26%) \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((P{

The diagnosis of acute rejection after heart transplantation is made on the basis of endomyocardial biopsy. In children, where the method may be associated with complications, a noninvasive alternative would be desirable. We evaluated the myocardial damage marker cardiac troponin T (cTnT) as a marker of rejection in children who have undergone heart transplantation.Peripheral venous blood was collected in 124 endomyocardial biopsies in 14 children who had undergone heart transplantation (1-20 years of age). Serum levels of cTnT were compared with histologic rejection according to the International Society of Heart and Lung Transplantation (ISHLT) (grades 0-4).Seven children experienced nine episodes of acute rejection. During rejection, cTnT increased from 0.05+/-0.07 (mean+/-SD) microg/L to 0.26+/-0.27 microg/L and remained elevated 7 and 30 days thereafter (0.10+/-0.11 and 0.36+/-0.38 microg/L, respectively) before returning to normal after 50 to 430 days. In surveillance biopsies, cTnT displayed considerable variation at all rejection grades: ISHLT grade 0, median 0.03 microg/L (range 0.01-2.04 microg/L); ISHLT grade 1, median 0.06 microg/L (range 0.01-0.67 microg/L); ISHLT grade 2, median 0.10 microg/L (range 0.01-1.42 microg/L); and ISHLT grade 3, median 0.17 microg/L (range 0.01-0.93 microg/L). A receiver operating characteristics analysis for cTnT versus rejection grade revealed an area under the curve of 0.69, indicating a moderate predictive value for cTnT. However, a cutoff of 0.015 microg/L yielded a specificity of only 36%, with a sensitivity of 89%, whereas a cutoff of 0.1 microg/L resulted in sensitivity and specificity of 53% and 77%, respectively.Cardiac troponin T increased and remained elevated for at least 1 month during acute rejection. The diagnostic power of a single cTnT measurement was not sufficient to replace endomyocardial biopsy.

Therapy with angiotensin II-converting enzyme (ACE) inhibitors has been suggested to prevent cardiovascular hypertrophy in hypertension even in doses that are subantihypertensive. We investigated the effects of two different ACE inhibitors on blood pressure and cardiovascular changes during as well as after discontinuation of treatment in spontaneously hypertensive rats (SHR). SHR were treated with either enalapril (ENA) or ramipril (RAM) from age 12 to age 20 weeks. Each drug was given in either an antihypertensive (ENA 15 mg center dot kg-1, RAM 3 mg center dot kg-1) or a subantihypertensive (ENA 50 mu g center dot kg-1, RAM 10 mu g center dot kg-1) dose. Mean arterial pressure (MAP) was reduced with antihypertensive doses of ENA (26%) as well as RAM (21%). Regression of cardiovascular changes occurred as reduction in left ventricular (LV) weight/body weight ratio (25 and 21% for ENA and RAM, respectively), reduction in perfusion pressure at maximal vasodilation of the perfused hindquarter (PPdil, 17 and 17%), and reduction in maximal developed pressure (PPmax, 13 and 17%). These effects partly persisted 10 weeks after treatment was discontinued. However, treatment with subantihypertensive doses of ENA and RAM had no effect on MAP, LV/body weight ratio, PPdil, or PPmax. Overall, regression of cardiovascular parameters correlated closely to the decrease in MAP. Similarly, no changes in MAP, LV weight/body weight ratio, PPdil, or PPmax were noted when young SHR were treated with subantihypertensive doses of RAM from age 6 to age 12 weeks, during which time hypertension becomes established. At doses having equal effects on blood pressure, plasma concentrations of RAM were considerably lower than those of ENA. Skeletal muscle concentrations were very low or undetectable in comparison to plasma concentrations for both drugs. Therefore, both RAM and ENA caused regression of cardiovascular changes that could be explained by a concomitant reduction in blood pressure. This regression persisted for a considerable time after discontinuation of treatment. On the other hand, no specific antitrophic effects in the absence of blood pressure reduction was evident with either drug. Furthermore, despite substantial differences in plasma concentrations, RAM, and ENA administered chronically appeared to affect cardiovascular parameters equally in the adult SHR.

Left ventricular (LV) function and end-diastolic dimensions were determined during antegrade and retrograde perfusions, respectively. Isolated hearts from spontaneously hypertensive rats (SHRs) and renal hypertensive rats and SHRs to which either feldopine, nifedipine, alpha-methyldopa, or a combination of felodipine and metoprolol was administered were used. Maximal cardiac function [cardiac output x (aortic pressure - left atrial pressure)] was elevated in SHRs, but depressed in those with renal hypertension. The diastolic pressure-volume relationships revealed eccentric rather than concentric LV hypertrophy in the SHRs. Renal hypertension in SHRs caused concentric LV hypertrophy. Antihypertensive therapy with calcium antagonists (but not with alpha-methyldopa) caused reduction of LV wall thickness, but increased LV end-diastolic volume (EDV). In SHRs, coronary flow was reduced at any given level of aortic pressure. At low aortic pressures (and hence, limited coronary perfusion), cardiac function was attenuated in SHRs. This reduction could be reversed by administration of antihypertensive therapy. These results suggest an improvement in maximal stroke work in SHRs as a result of eccentric hypertrophy which allows increased stroke volume for a given degree of myocardial shortening. Structural coronary vascular changes, which can be reversed by antihypertensive therapy, can limit coronary perfusion--and hence, cardiac performance--at low aortic pressures in SHRs. Maintenance of maximal cardiac function in treated SHRs, despite a reduction in LV wall thickness, may be due to an increase in LV end-diastolic volume.