Annette S. Jensen

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.

Central and Peripheral Blood Flow During Exercise With a Continuous-Flow Left Ventricular Assist DeviceClinical Perspective

Background— End-stage heart failure is associated with impaired cardiac output (CO) and organ blood flow. We determined whether CO and peripheral perfusion are maintained during exercise in patients with an axial-flow left ventricular assist device (LVAD) and whether an increase in LVAD pump speed with work rate would increase organ blood flow. Methods and Results— Invasively determined CO and leg blood flow and Doppler-determined cerebral perfusion were measured during 2 incremental cycle exercise tests on the same day in 8 patients provided with a HeartMate II LVAD. In random order, patients exercised both with a constant (≈9775 rpm) and with an increasing pump speed (+400 rpm per exercise stage). At 60 W, the elevation in CO was more pronounced with increased pump speed (8.7±0.6 versus 8.1±1.1 L · min−1; mean±SD; P=0.05), but at maximal exercise increases in CO (from 7.0±0.9 to 13.6±2.5 L · min−1; P<0.01) and leg blood flow [0.7 (0.5 to 0.8) to 4.4 (3.9 to 4.8) L · min−1 per leg; median (range); P<0.001] were similar with both pumping modes. Normally, middle cerebral artery mean flow velocity increases from ≈50 to ≈65 cm · s−1 during exercise, but in LVAD patients with a constant pump speed it was low at rest (39±14 cm · s−1) and remained unchanged during exercise, whereas in patients with increasing pump speed, it increased by 5.2±2.8 cm · s−1 at 60 W (P<0.01). Conclusions— With maximal exercise, the axial-flow LVAD supports near-normal increments in cardiac output and leg perfusion, but cerebral perfusion is poor. Increased pump speed augments cerebral perfusion during exercise.

Central and Peripheral Blood Flow During Exercise With a Continuous-Flow Left Ventricular Assist Device Constant Versus Increasing Pump Speed: A Pilot Study

Background— End-stage heart failure is associated with impaired cardiac output (CO) and organ blood flow. We determined whether CO and peripheral perfusion are maintained during exercise in patients with an axial-flow left ventricular assist device (LVAD) and whether an increase in LVAD pump speed with work rate would increase organ blood flow. Methods and Results— Invasively determined CO and leg blood flow and Doppler-determined cerebral perfusion were measured during 2 incremental cycle exercise tests on the same day in 8 patients provided with a HeartMate II LVAD. In random order, patients exercised both with a constant (≈9775 rpm) and with an increasing pump speed (+400 rpm per exercise stage). At 60 W, the elevation in CO was more pronounced with increased pump speed (8.7±0.6 versus 8.1±1.1 L · min−1; mean±SD; P=0.05), but at maximal exercise increases in CO (from 7.0±0.9 to 13.6±2.5 L · min−1; P<0.01) and leg blood flow [0.7 (0.5 to 0.8) to 4.4 (3.9 to 4.8) L · min−1 per leg; median (range); P<0.001] were similar with both pumping modes. Normally, middle cerebral artery mean flow velocity increases from ≈50 to ≈65 cm · s−1 during exercise, but in LVAD patients with a constant pump speed it was low at rest (39±14 cm · s−1) and remained unchanged during exercise, whereas in patients with increasing pump speed, it increased by 5.2±2.8 cm · s−1 at 60 W (P<0.01). Conclusions— With maximal exercise, the axial-flow LVAD supports near-normal increments in cardiac output and leg perfusion, but cerebral perfusion is poor. Increased pump speed augments cerebral perfusion during exercise.

Quality of life and cognitive function in Fontan patients; a population-based study.

BACKGROUND After the Fontan procedure patients are at risk for reduced quality of life (QoL) and cognitive function. We aimed to assess these important factors in Danish Fontan patients and to compare the results with a group of healthy controls. METHODS All Fontan patients living in Denmark were identified and invited to participate. QoL was evaluated using the Pediatric Quality of Life Inventory (PedsQL) version 4.0 generic core module in patients <16 years and the Short Form 36 questionnaire (SF-36) in patients ≥16 years. Cognitive function was evaluated in all patients ≥6 years using the Quick Test of Cognitive Speed. To evaluate if QoL correlated with exercise capacity, patients performed a symptom-limited bicycle test. RESULTS 158 of 179 eligible patients (88%) consented to participate. Median age was 13.9 years (IQR: 10.2-19.3). PedsQL scores increased with age but were significantly lower among patients than among controls. SF-36 physical scores were significantly lower in patients compared to controls while psychosocial scores were similar. Cognitive speed was significantly reduced in patients at all ages compared to controls. No significant difference in PedsQL-/SF-36 scores or cognitive speed was found between hypoplastic left heart syndrome (HLHS) and non-HLHS Fontan patient. PedsQL-/SF-36 scores in patients ≥10 years correlated significantly to cognitive speed but not to peak exercise capacity. CONCLUSION QoL is reduced in Fontan children compared to their healthy counterparts whereas in patients ≥16 years only physical, but not psychosocial QoL is reduced. Cognitive speed was significantly lower in patients at all ages compared to controls.

Univentricular hearts in Denmark 1977 to 2009: incidence and survival.

BACKGROUND The incidence of children born with functional univentricular heart (UVH) and their prognosis presumably changed substantially in recent years. This is due to introduction of fetal echocardiography and potential termination of pregnancy (TOP) when UVH is diagnosed (UVH TOP), and to improvements in treatment. We aimed to explore changes in incidence, to estimate changes in survival, and to describe predictors of mortality in UVH patients. METHODS Using a population-based design we identified all UVH cases in Denmark from 1977 to 2009. RESULTS 703 UVH live births and 106 UVH TOP were identified. A dramatic decrease in birth incidence of UVH patients and a corresponding increase in UVH TOP was observed in recent years. Mean incidence rate of UVH (live births and UVH TOP) was 0.39 per 1000 births. In adjusted analysis survival improved significantly from birth era 1977-1989 to 1990-1999 (HR 2.65, 95% confidence interval (CI), 2.06-3.42) but not significantly from 1990-1999 to 2000-2009 (HR 0.77, 95% CI, 0.57-1.05). In the birth era 2000-2009, the lowest five-year survival was seen with hypoplastic left heart syndrome (HLHS) (18.8%), whereas the best survival was seen with tricuspid atresia (79.8%). Adjusted risk of death was 7.3 times higher in the HLHS group compared to the tricuspid atresia group (95% CI, 3.94-13.47). CONCLUSIONS This study demonstrates a dramatic decrease in birth incidence of UVH patients most probably due to a corresponding increase in UVH TOP. Despite survival improved after introduction of Fontan surgery, survival has not improved significantly during the last 20years.

Arrhythmia and exercise intolerance in Fontan patients: current status and future burden.

BACKGROUND Long-term survival after the Fontan procedure shows excellent results but is associated with a persistent risk of arrhythmias and exercise intolerance. We aimed to analyze the current burden of clinically relevant arrhythmia and severe exercise intolerance in Danish Fontan patients and furthermore, to estimate the future burden from analysis of mortality and the current burden related to age. METHODS All Danish citizens with Fontan completion from 1981 to 2009 were identified (n=235). Surviving patients performed exercise test, Holter monitoring, echocardiography, pulmonary function test, and blood sampling and medical history was retrieved from medical records. RESULTS Twenty-six (11%) patients died or had heart transplantation (HTx) after a mean (± SD) post-Fontan follow-up of 8.3 ± 5.7 years. Excluding perioperative deaths (n=8), a linear probability of HTx-free survival was observed and estimated to 99.1% per year. Prevalence of clinically relevant arrhythmia and severe exercise intolerance increased significantly with age and was found in 32% and 85% of patients ≥ 20 years, respectively. Thus, from survival data and logistic regression models the future prevalence of patients, clinically relevant arrhythmia and severe exercise intolerance were estimated, revealing a considerable augmentation. Furthermore, resting and maximum cardiac index, resting stroke volume index and pulmonary diffusing capacity decreased significantly with age while diastolic and systolic ventricular function was unchanged. CONCLUSIONS The prevalence of clinically relevant arrhythmia and severe exercise intolerance increased significantly with age in Danish Fontan patients. The future Fontan burden was estimated showing an increase in the prevalence of older patients, clinically relevant arrhythmia, and severe exercise intolerance.

Impaired Right, Left, or Biventricular Function and Resting Oxygen Saturation Are Associated With Mortality in Eisenmenger Syndrome A Clinical and Cardiovascular Magnetic Resonance Study

Background—Patients with Eisenmenger syndrome (ES) have better survival, despite similar pulmonary vascular pathology, compared with other patients with pulmonary arterial hypertension. Cardiovascular magnetic resonance (CMR) is useful for risk stratification in idiopathic pulmonary arterial hypertension, whereas it has not been evaluated in ES. We studied CMR together with other noninvasive measurements in ES to evaluate its potential role as a noninvasive risk stratification test. Methods and Results—Between 2003 and 2005, 48 patients with ES, all with a post-tricuspid shunt, were enrolled in a prospective, longitudinal, single-center study. All patients underwent a standardized baseline assessment with CMR, blood test, echocardiography, and 6-minute walk test and were followed up for mortality until the end of December 2013. Twelve patients (25%) died during follow-up, mostly from heart failure (50%). Impaired ventricular function (right or left ventricular ejection fraction) was associated with increased risk of mortality (lowest quartile: right ventricular ejection fraction, <40%; hazard ratio, 4.4 [95% confidence interval, 1.4–13.5]; P=0.01 and left ventricular ejection fraction, <50%; hazard ratio, 6.6 [95% confidence interval, 2.1–20.8]; P=0.001). Biventricular impairment (lowest quartile left ventricular ejection fraction, <50% and right ventricular ejection fraction, <40%) conveyed an even higher risk of mortality (hazard ratio, 8.0 [95% confidence interval, 2.5–25.1]; P=0.0004). No other CMR or noninvasive measurement besides resting oxygen saturation (hazard ratio, 0.90 [0.83–0.97]/%; P=0.007) was associated with mortality. Conclusions—Impaired right, left, or biventricular systolic function derived from baseline CMR and resting oxygen saturation are associated with mortality in adult patients with ES. CMR is a useful noninvasive tool, which may be incorporated in the risk stratification assessment of ES during lifelong follow-up.

New insights into the aspects of pulmonary diffusing capacity in Fontan patients.

BACKGROUND Patients with a functionally univentricular heart, palliated a.m. Fontan, consequently have non-pulsatile pulmonary blood flow and are known to have a reduced pulmonary diffusing capacity. However, the cause of this reduction remains unclear. We aimed to assess the possible determinants in the aetiology of a reduced diffusing capacity and also to assess whether it could be increased. Furthermore, we aimed to search for predictors of a reduced diffusing capacity. MATERIAL AND METHODS A total of 87 Fontan patients (mean age 16.3 ± 7.6 years) performed advanced pulmonary function tests and maximal cycle ergometer tests. A total of 10 Fontan patients and nine matched controls performed a supine pulmonary function test after a supine rest. RESULTS In the sitting pulmonary function test, the mean z-scores were: diffusing capacity, 2.38 ± 1.20; pulmonary capillary blood volume, 2.04 ± 0.80; and alveolar capillary membrane diffusing capacity, 0.14 ± 0.84. In the supine compared with the sitting pulmonary function test, the diffusing capacity increased by 51.7 ± 11.9% in the Fontan group and by 23.3 ± 17.7% in the control group (p < 0.001); moreover, the pulmonary capillary blood volume increased by 48.3 ± 17.4% in the Fontan group and by 20.2 ± 13.9% in the control group (p = 0.001). In a multiple linear regression analysis including the explanatory variables of surgical data and exercise data at rest and peak exercise, the resting cardiac index was an independent predictor of the diffusing capacity (regression coefficient: 0.18, p < 0.001). CONCLUSIONS The pulmonary diffusing capacity was reduced in Fontan patients because of a reduced pulmonary capillary blood volume, whereas the alveolar capillary membrane diffusing capacity was preserved. The diffusing capacity was highly increasable in Fontan patients compared with controls, and the resting cardiac index was an independent predictor of the diffusing capacity.

Pulmonary Artery Thrombosis and Hemoptysis in Eisenmenger Syndrome

A 37-year-old man with Eisenmenger syndrome caused by a large ventricular septum defect was admitted to the hospital with small-volume hemoptysis, cough, and left-sided chest pain for several weeks. For several years he had been classified as functional-class II, his oxygen saturation was in the ≈85%, hemoglobin was 11.0 mmol/L, and echocardiography visualized a mild tricuspid regurgitation with a gradient of 103 mm Hg (maximum). He had experienced several episodes of minor hemoptysis in the past. There was no previous history …

Subclinical atherosclerosis in patients with cyanotic congenital heart disease

INTRODUCTION Survival in patients with cyanotic congenital heart disease (CCHD) has improved dramatically. The result is an ageing population with risk of acquired heart disease. Previous small uncontrolled studies suggested that these patients are protected against the development of atherosclerosis. To test this hypothesis, we sought to determine the prevalence of subclinical atherosclerosis in a larger population of patients with CCHD. METHOD We compared the prevalence of subclinical atherosclerosis in adult CCHD patients from Denmark, Sweden, Norway and Australia, with that in age-, sex-, smoking status-, and body mass index matched controls. Coronary artery atherosclerosis was assessed on computed tomography with coronary artery calcification (CAC) score. Subclinical atherosclerosis was defined by CAC-score > 0. Carotid artery atherosclerosis was evaluated using ultrasound by measuring carotid plaque thickness (cPT-max) and carotid intima media thickness (CIMT). Lipid status was evaluated as an important atherosclerotic risk factor. RESULTS Seventy-four patients with CCHD (57% women, median age 49.5 years) and 74 matched controls (57% women, median age 50.0 years) were included. There were no differences between the groups in: CAC-score > 0 (21% vs. 19%, respectively; p = 0.8), carotid plaques (19% vs. 9%, respectively; p = 0.1), cPT-max (2.3 mm vs. 2.8 mm, respectively; p = 0.1) or CIMT (0.61 mm vs. 0.61 mm, respectively; p = 0.98). And further no significant differences in lipoprotein concentrations measured by ultracentrifugation. CONCLUSION Young adults with CCHD have similar cardiovascular risk factor profiles and measures of subclinical atherosclerosis, compared with controls. Given their increasing life expectancies, athero-preventive strategies should be an important part of their clinical management.