Ulf Thilén

Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology

AIMS To describe the outcome of pregnancy in patients with structural or ischaemic heart disease. METHODS AND RESULTS In 2007, the European Registry on Pregnancy and Heart disease was initiated by the European Society of Cardiology. Consecutive patients with valvular heart disease, congenital heart disease, ischaemic heart disease (IHD), or cardiomyopathy (CMP) presenting with pregnancy were enrolled. Data for the normal population were derived from the literature. Sixty hospitals in 28 countries enrolled 1321 pregnant women between 2007 and 2011. Median maternal age was 30 years (range 16-53). Most patients were in NYHA class I (72%). Congenital heart disease (66%) was most prevalent, followed by valvular heart disease 25%, CMP 7%, and IHD in 2%. Maternal death occurred in 1%, compared with 0.007% in the normal population. Highest maternal mortality was found in patients with CMP. During pregnancy, 338 patients (26%) were hospitalized, 133 for heart failure. Caesarean section was performed in 41%. Foetal mortality occurred in 1.7% and neonatal mortality in 0.6%, both higher than in the normal population. Median duration of pregnancy was 38 weeks (range 24-42) and median birth weight 3010 g (range 300-4850). In centres of developing countries, maternal and foetal mortality was higher than in centres of developed countries (3.9 vs. 0.6%, P < 0.001 and 6.5 vs. 0.9% P < 0.001) CONCLUSION The vast majority of patients can go safely through pregnancy and delivery as long as adequate pre-pregnancy evaluation and specialized high-quality care during pregnancy and delivery are available. Pregnancy outcomes were markedly worse in patients with CMP and in developing countries.

Bosentan Improves Exercise Capacity in Adolescents and Adults After Fontan Operation The TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) Study

Background —The Fontan procedure has improved survival in children with functionally univentricular hearts. With time however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial but pulmonary vascular resistance (PVR) probably plays a crucial role. Elevated PVR has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardio-pulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. Methods and Results —Seventy-five adolescents and adults were randomized 1:1 to 14 weeks treatment with bosentan or placebo. Cardio-pulmonary exercise-test (CPET), functional class, blood samples and quality-of-life questionnaire were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 (from 28.7 to 30.7) ml/kg/min in the bosentan group compared to 0.6 (from 28.4 to 29.0) ml/kg/min in the placebo group, p=0.02. CPET time increased 0.48 (from 6.79 to 7.27) vs. 0.08 (from 6.94 to 7.02) minutes, p=0.04. Nine bosentan treated patients improved one functional class, whereas none improved in the placebo group, p=0.0085. Side effects were mild and occurred equally in both groups. No serious adverse effects were seen and no patients had liver enzyme levels above three-fold upper limit. Conclusions —Bosentan improves exercise capacity, exercise time and functional class in Fontan patients without serious adverse events or hepatotoxicity. Clinical Trial Registration Information —www.clinicaltrials.gov. Identifier [NCT01292551][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01292551&atom=%2Fcirculationaha%2Fearly%2F2014%2F10%2F20%2FCIRCULATIONAHA.113.008441.atomBackground— The Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. Methods and Results— Seventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL·kg−1·min−1 (from 28.7 to 30.7 mL·kg−1·min−1) in the bosentan group compared with 0.6 mL·kg−1·min−1 (from 28.4 to 29.0 mL·kg−1·min−1) in the placebo group (P=0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; P=0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group (P=0.0085). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit. Conclusions— Bosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292551.

Bosentan Improves Exercise Capacity in Adolescents and Adults After Fontan Operation: The TEMPO Study

Background —The Fontan procedure has improved survival in children with functionally univentricular hearts. With time however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial but pulmonary vascular resistance (PVR) probably plays a crucial role. Elevated PVR has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardio-pulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. Methods and Results —Seventy-five adolescents and adults were randomized 1:1 to 14 weeks treatment with bosentan or placebo. Cardio-pulmonary exercise-test (CPET), functional class, blood samples and quality-of-life questionnaire were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 (from 28.7 to 30.7) ml/kg/min in the bosentan group compared to 0.6 (from 28.4 to 29.0) ml/kg/min in the placebo group, p=0.02. CPET time increased 0.48 (from 6.79 to 7.27) vs. 0.08 (from 6.94 to 7.02) minutes, p=0.04. Nine bosentan treated patients improved one functional class, whereas none improved in the placebo group, p=0.0085. Side effects were mild and occurred equally in both groups. No serious adverse effects were seen and no patients had liver enzyme levels above three-fold upper limit. Conclusions —Bosentan improves exercise capacity, exercise time and functional class in Fontan patients without serious adverse events or hepatotoxicity. Clinical Trial Registration Information —www.clinicaltrials.gov. Identifier [NCT01292551][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01292551&atom=%2Fcirculationaha%2Fearly%2F2014%2F10%2F20%2FCIRCULATIONAHA.113.008441.atomBackground— The Fontan procedure has improved survival in children with functionally univentricular hearts. With time, however, complications such as reduced exercise capacity are seen more frequently. Exercise intolerance is multifactorial, but pulmonary vascular resistance probably plays a crucial role. Elevated pulmonary vascular resistance has been associated with raised levels of endothelin-1, which are common both before and after Fontan operations. Treatment with endothelin-1 receptor antagonists could theoretically improve cardiopulmonary hemodynamics and exercise capacity. The aim of this study was therefore to examine the efficacy and safety of bosentan in Fontan patients. Methods and Results— Seventy-five adolescents and adults were randomized 1:1 to 14 weeks of treatment with bosentan or placebo. Cardiopulmonary exercise test, functional class, blood samples, and quality-of-life questionnaires were evaluated at baseline and at the end of treatment. Sixty-nine patients (92%) completed the study. Peak oxygen consumption increased 2.0 mL·kg−1·min−1 (from 28.7 to 30.7 mL·kg−1·min−1) in the bosentan group compared with 0.6 mL·kg−1·min−1 (from 28.4 to 29.0 mL·kg−1·min−1) in the placebo group (P=0.02). Cardiopulmonary exercise test time increased by 0.48 minute (from 6.79 to 7.27 minutes) versus 0.08 minute (from 6.94 to 7.02 minutes; P=0.04). Nine bosentan-treated patients improved 1 functional class, whereas none improved in the placebo group (P=0.0085). Side effects were mild and occurred equally in both groups. No serious adverse effects were seen, and no patients had liver enzyme levels above the 3-fold upper limit. Conclusions— Bosentan improves exercise capacity, exercise time, and functional class in Fontan patients without serious adverse events or hepatotoxicity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292551.

Cardiovascular Risk, Cardiac Function, Physical Activity, and Quality of Life with and without Long-Term Growth Hormone Therapy in Adult Survivors of Childhood Acute Lymphoblastic Leukemia

CONTEXT Long-term data are missing in GH-treated acute lymphoblastic leukemia (ALL) patients. GH therapy may result in poorer outcome regarding cardiovascular (CV) and particularly cardiac effects than in patients with hypothalamic-pituitary disease. OBJECTIVE Our objective was to evaluate GH therapy on CV risk, cardiac function, physical activity, and quality of life in ALL patients treated with cranial radiotherapy (18-24 Gy) and chemotherapy (anthracycline dose 120 mg/m2). DESIGN AND SETTING We conducted a 5- and 8-yr open nonrandomized prospective study in a university hospital clinic. STUDY PARTICIPANTS Two groups of GH-deficient ALL patients (aged 25 yr; range 19-32 yr) and matched population controls participated. INTERVENTIONS One ALL group (n=16) received GH for 5 yr, and the other ALL group (n=13) did not receive GH therapy. MAIN OUTCOME MEASURES We evaluated the prevalence of CV risk factors and metabolic syndrome (International Diabetes Federation consensus), cardiac function (echocardiography), and quality of life and physical activity questionnaires. RESULTS In comparison with 8 yr without, 5 yr with GH therapy resulted in significant positive changes in plasma glucose (-0.5 vs. 0.6 mmol/liter, P=0.002), apolipoprotein B/apolipoprotein A1 ratio (-0.1 vs. 0.0, P=0.03), and high-density lipoprotein-cholesterol (0.20 vs.-0.01 mmol/liter, P=0.008) and a significant reduction in the prevalence of metabolic syndrome (P=0.008). No significant difference in the left-ventricular systolic function or in physical activity and quality of life was recorded before and after 5 or 8 yr, respectively (all P>0.3). CONCLUSION GH therapy reduced the CV risk in this young ALL population but resulted in no clear benefit or deterioration in cardiac function.

Transcatheter closure of post-infarction ventricular septal defect with the Amplatzer Septal occluder device

There is an 80-90% mortality rate within the first 2 months of the occurrence of a post-infarction ventricular septal defect (VSD) with medical treatment alone. The muscular VSD presents a technical problem for the surgeon. Surgical treatment was unsuccessful in two patients. They were treated successfully using the Amplatzer Septal Occluder, with improvement in their condition.There is an 80-90% mortality rate within the first 2 months of the occurrence of a post-infarction ventricular septal defect (VSD) with medical treatment alone. The muscular VSD presents a technical problem for the surgeon. Surgical treatment was unsuccessful in two patients. They were treated successfully using the Amplatzer Septal Occluder, with improvement in their condition.

Long-Term Outcome of Mustard/Senning Correction for Transposition of the Great Arteries in Sweden and Denmark

Background— The atrial switch operation, the Mustard or Senning operation, for the transposition of the great arteries (TGA) was introduced in the late 1950s and was the preferred surgery for TGA until the early 1990s. The Mustard and Senning operation involves extensive surgery in the atria and leaves the right ventricle as the systemic ventricle. The Mustard and Senning cohort is now well into adulthood and we begin to see the long-term outcome. Methods and Results— All the 6 surgical centers that performed Mustard and Senning operations in Sweden and Denmark identified all operated TGA patients. Information about death was obtained in late 2007 and early 2008 from the Danish and Swedish Centralised Civil Register by using the patients’ unique national Civil Registration Numbers. Four hundred sixty-eight patients undergoing the atrial switch operation were identified. Perioperative 30-day mortality was 20%, and 60% were alive after 30 years of follow-up. Perioperative mortality was significantly increased by the presence of a ventricular septal defect, left ventricular outflow obstruction, surgery early in the Mustard and Senning era. However, only pacemaker implantation is predictive of long-term outcome (hazard ratio, 1.90; 95% confidence interval, 1.05–3.46, P=0.04), once the TGA patient has survived the perioperative period. The risk of reoperation was correlated to the presence of associated defects and where the first Mustard/Senning operation was performed. Conclusions— The long-term survival of patients with Mustard and Senning correction for TGA appears to be primarily determined by factors in the right ventricle and tricuspid valve and not the timing of or the type of surgery in childhood. Cardiac function necessitating the implantation of a pacemaker is associated with an increase in mortality.

The haematocrit – an important factor causing impaired haemostasis in patients with cyanotic congenital heart disease

BACKGROUND Patients with cyanotic congenital heart disease(CCHD) have haemostatic abnormalities, which result in an increased risk of bleeding. The cause is unknown, but recent studies have indicated that an elevated haematocrit, which is present in cyanotic patients, could be an important factor. The aim of this study was to characterize the haemostatic profile, examine how changes in haematocrit affect the haemostatic profile, and whether a haematocrit reduction could terminate bleeding in CCHD patients. METHODS This was a prospective, multicenter study. The haemostatic profile consisting of haematocrit, platelet count and thrombelastography(TEG) was characterized in ninety-eight CCHD patients. To evaluate the influence of haematocrit on the haemostatic profile, 21 of the patients underwent phlebotomy and 16 patients received treatment with an iron supplement. Furthermore ten patients with haemoptysis underwent phlebotomy. The haemostatic profile was reevaluated after interventions. RESULTS TEG revealed that patients with CCHD and elevated haematocrit were hypocoagulable due to reduced clot formation and strength. Furthermore a positive correlation between elevated haematocrit and hypocoagulability was present. Interventions such as phlebotomy and treatment with supplemental iron causing significant haematocrit changes confirmed the correlation between haematocrit and the haemostatic profile. Finally a haematocrit reduction by phlebotomy successfully terminated haemoptysis in ten CCHD patients. CONCLUSION Patients with CCHD and elevated haematocrit are hypocoagulable. The hypocoagulable haemostatic profile is positively correlated to increasing haematocrit. An intervention, which increases or decreases haematocrit, changes the haemostatic profile. A haematocrit reduction seems to improve the haemostatic profile, and may thereby terminate bleeding. However, these results warrant further studies.

Fibrinogen function is impaired in whole blood from patients with cyanotic congenital heart disease

BACKGROUND Patients with cyanotic congenital heart disease (CCHD) have haemostatic abnormities associated with bleeding and thrombo-embolic events. The haemostatic abnormalities are not fully understood, but recent studies indicate that elevated haematocrit and fibrinogen function may be of importance. The aim of this study was to characterise the haemostatic profile and examine the potential role of haematocrit on clot formation and strength in CCHD patients. Furthermore to examine whether CCHD patients with history of haemoptysis have diminished fibrinogen function compared to those without haemoptysis. METHODS In a prospective study 75 adult CCHD patients had haematocrit, platelet count, and plasma fibrinogen concentration examined. Furthermore thrombelastography(TEG) as well as TEG Functional Fibrinogen(TEG FF) assay evaluating fibrinogen function(FLEV) was performed. Data were compared with historical data regarding previous haemoptysis in CCHD patients. RESULTS Haematocrit was 57 ± 8% and platelet counts in the lower normal range. TEG revealed a hypocoagulable condition with impaired clot formation. TEG values were correlated to haematocrit, indicating that elevated haematocrit causes impaired clot formation and strength. Despite high levels of plasma fibrinogen, TEG FF demonstrated that FLEV was diminished and negatively correlated to haematocrit. Furthermore CCHD patients with previous history of haemoptysis had significantly lower FLEV compared to CCHD patients without haemoptysis. CONCLUSION Patients with CCHD are hypocoagulable mainly due to impaired fibrinogen function. Despite a low platelet count, platelet function does not seem to be severely affected in CCHD patients. Haemostasis, and especially fibrinogen function, is negatively affected by elevated haematocrit, and fibrinogen function is diminished in CCHD patients with haemoptysis.

Functional evaluation of extracardiac ventriculopulmonary conduits and of the right ventricle with magnetic resonance imaging and velocity mapping

Extracardiac ventriculopulmonary conduits tend to deteriorate over time, developing both obstruction and regurgitation. In this prospective study, magnetic resonance imaging (MRI) was compared with Doppler echocardiography to determine whether MRI improves the noninvasive evaluation of conduit patients. Twenty-five patients (median age 10 years, range 2.5 to 32) were investigated 27 times with Doppler echocardiography and an MRI protocol with spin echo sequences for morphology, velocity mapping, and multislice gradient echo technique for right ventricular volume measuring. Cardiac catheterization data were available in 6 patients. Echocardiography could assess the morphology of the conduits in 6 patients, whereas MRI demonstrated all conduits efficiently. Doppler echocardiography could evaluate the occurrence of regurgitation in 18 patients and could quantify peak velocity in 20 of the patients. A technically adequate MRI velocity mapping was obtained in 25 patients. There was good agreement between MRI and Doppler echocardiography in establishing or not establishing regurgitation, but Doppler echocardiography was less reliable in evaluating the degree of regurgitation. The correlation between peak velocity determined with Doppler and magnetic resonance imaging was r = 0.63 [corrected]. Correlations between catheterization pressure gradients and noninvasive techniques were r = 0.97 for magnetic resonance imaging [corrected] versus catheterization, and r = 0.86 [corrected] for Doppler versus catheterization. MRI can provide complete information on the morphology and function of extracardiac ventriculopulmonary conduits, as well as of the right ventricle. If the results of MRI and echocardiography with Doppler are in agreement, heart catheterization and angiography can be avoided, even in patients considered for conduit replacement.

Prevalence of cerebral and pulmonary thrombosis in patients with cyanotic congenital heart disease

Background Patients with cyanotic congenital heart disease (CCHD) have a high prevalence of thrombosis, the most frequently described locations being the cerebral and pulmonary vessels. The reported prevalence of both cerebral infarction and pulmonary thrombosis has been highly variable. The aim of this study was to examine the prevalence of both cerebral and pulmonary thrombosis in CCHD according to medical history and imaging. In addition, the role of known erythrocytosis and haemostatic abnormalities as risk factors was evaluated. Methods and results A cross-sectional descriptive study examining 98 stable adult patients with CCHD with a medical questionnaire, blood samples, MRI of the cerebrum (n=72), multidetector CT imaging (MDCT) of the thorax (n=76) and pulmonary scintigraphy (ventilation/perfusion/single-photon emission computerised tomography/CT) (n=66). The prevalence of cerebral infarction and pulmonary thrombosis according to imaging were 47% and 31%, respectively. Comparing the findings with previous medical history revealed a large under-reporting of thrombosis with only 22% of the patients having a clinical history of stroke and 25% of pulmonary thrombosis. There was no association between the degree of erythrocytosis or haemostatic abnormalities and the prevalence of thrombosis. Conclusions Patients with CCHD have a prevalence of both cerebral and pulmonary thrombosis of around 30%–40%, which is much higher than that reported previously. Furthermore, there is a large discrepancy between clinical history and imaging findings, suggesting a high prevalence of silent thrombotic events. Neither erythrocytosis nor haemostatic abnormalities were associated with the prevalence of thrombosis in patients with CCHD. Trial registration number http://www.cvk.sum.dk/CVK/Home/English.aspx (H-KF-2006-4068).